FORM-1

for

PROPOSED BULK DRUGS, BULK DRUG INTERMEDIATES & SPECIALITY CHEMICALS TO BE MANUFACTURED IN THE PREMISES

of

M/s Mendas Pharmaceuticals

PLOT NO.D-2/CH/ 136, DAHEJ II , DAHEJ INDUSTRIAL ESTATE, TALUKA: VAGRA, DIST: BHARUCH, GUJARAT

Prepared by: APPENDIX I (See paragraph - 6) FORM 1 Sr. Item Details No. 1. Name of the project/s M/s Mendas Pharmaceuticals 2. S. No. in the schedule 5 (f) 3. Proposed capacity/area/length/tonnage Proposed capacity = 350.1 MT /Month to be handled/command area/lease (For detailed product list please refer area/number of wells to be drilled Annexure – I) 4. New/Expansion/Modernization New 5. Existing Capacity/Area etc. Plot Area: 13924.02 sq. mt. 6. Category of Project i.e. ‘A’ or ‘B’ B 7. Does it attract the general condition? If No yes, please specify. 8. Does it attract the specific condition? If No yes, please specify. 9. Location Plot/Survey/Khasra No. Plot No.D-2/CH/136 Village Dahej II Tehsil Vagra District Bharuch State Gujarat 10.) Nearest railway station/airport along Railway Station Bharuch = 38.8 Kms with distance in kms. Airport Vadodara = 91.21 Kms 11. Nearest Town, city, District Headquarters Nearest town: Bharuch: 38 kms, Nearest along with distance in kms. District Head quarter: Bharuch: 38 kms 12. Village Panchayats, Zilla Parishad, Dahej Ind. Estate, Village: Dahej, Tal: Vagra, Municipal Corporation, local body Dist: Bharuch-392130, Gujarat. (complete postal address with telephone nos. to be given) 13. Name of the applicant Mendas Pharmaceuticals 14. Registered Address Plot No. D-2/CH/136, Dahej II, Dahej Industrial Estate, Taluka: Vagra, Dist: Bharuch, Gujarat 15. Address for correspondence: E-3, Garden city, Ankleshwar - 393002

Name Mr. Umesh Mendapara

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Designation (Owner/Partner/CEO) Partner Address E-3, Garden city, Ankleshwar - 393002 Pin Code 393002

E-mail [email protected] Telephone No. --- Fax No. --- Mobile No. 9825711244 16. Details of Alternative Sites examined, if NA any. Location of these sites should be shown on a topo sheet. 17. Interlinked Projects NA 18. Whether separate application of NA interlinked project has been submitted? 19. If yes, date of submission NA 20. If no, reason NA 21. Whether the proposal involves No approval/clearance under: if yes, details of the same and their status to be given. (a) The Forest (Conservation) Act, 1980? (b) The Wildlife (Protection) Act, 1972? (c) The C.R.Z. Notification, 1991? 22. Whether there is any Government No Order/Policy relevant/relating to the site? 23. Forest land involved (hectares) No 24. Whether there is any litigation pending No against the project and/or land in which the project is propose to be set up? (a) Name of the Court (b) Case No. (c) Orders/directions of the Court, if any and its relevance with the proposed project.

• Capacity corresponding to sectoral activity (such as production capacity for manufacturing, mining lease area and production capacity for mineral production, area for mineral exploration, length for linear transport infrastructure, generation capacity for power generation etc.,)

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(II) Activity 1. Construction, operation or decommissioning of the Project involving actions, which will cause physical changes in the locality (topography, land use, changes in water bodies, etc.)

Sr. Information/Checklist confirmation Yes/No Details thereof with approximate No. quantities freights, wherever possible) with source of information data 1.1 Permanent or temporary change in land Yes Propos ed project activity is at GIDC use, land cover or topography including Plot at Dahej II wherein land increase intensity of land use (with clearing and construction of respect to local land use plan) industrial buildings will be involved. 1.2 Clearance of existing land, vegetation Yes Minor clearance activities will be and Buildings? carried out in the form of removal of thorny shrubs. 1.3 Creation of new land uses? No -- 1.4 Pre-construction investigations e.g. bore No -- Houses, soil testing? 1.5 Construction works? Yes Plan for construction work is attached as Annexure:II 1.6 Demolition works? No There will be not any demolition work at the site. 1.7 Temporary sites used for construction No No temporary construction works works or housing of construction are proposed workers? 1.8 Above ground buildings, structures or Yes Plan for construction work is earthworks including linear structures, attached as Annexure:II cut and fill or excavations 1.9 Underground works mining or No --- tunneling? 1.10 Reclamation works? No --- 1.11 Dredging? No --- 1.12 Off shore structures? No --- 1.13 Production and manufacturing Yes Please refer Annexure –III processes? 1.14 Facilities for storage of goods or Yes Dedicated storage area for storage materials? of raw materials, finished products, solvents, etc. will be provided. 1.15 Facilities for treatment or disposal of Yes For Facilities for treatment or solid waste or liquid effluents? disposal of liquid effluents please refer Annexure-V. For Hazardous waste disposal details please refer Annexure –VI.

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1.16 Facilities for long term housing of No --- operational workers? 1.17 New road, rail or sea traffic during No --- Construction or operation? 1.18 New road, rail, air waterborne or other No --- transport infrastructure including new or altered routes and stations, ports, airports etc? 1.19 Closure or diversion of existing transport No --- routes or infrastructure leading to changes in or Traffic movements? 1.20 New or diverted transmission lines or No --- Pipelines? 1.21 Impoundment, damming, culver ting, No --- realignment or other changes to the hydrology of watercourses or aquifers? 1.22 Stream crossings? No --- 1.23 Yes No ground water shall be used. The Abstraction or transfers of water from requirement of raw water shall be ground or surface waters? met through GIDC Water Supply. 1.24 Changes in water bodies or the land No --- surface affecting drainage or run -off? 1.25 Transport of personnel or materials for Yes Transportation of personnel, raw construction, operation or material and products will be by decommissioning? road. 1.26 Long-term dismantling or No --- decommissioning or restoration works? 1.27 Ongoing activity during No --- decommissioning which could have an impact on the environment? 1.28 Influx of people to an area either Yes About 50 people will be employed temporarily or permanently? 1.29 Introduction of alien species? No --- 1.30 Loss of native species or genetic No --- diversity? 1.31 Any other actions? No ---

2. Use of Natural resources for construction or operation of the Project (such as land, water, materials or energy, especially any resources which are non-renewable or in short supply):

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Sr. Information/checklist confirmation Yes/No Details thereof (with approximate No. quantities /rates, wherever possible) with source of information data 2.1 Land especially undeveloped or agricultural No --- land (ha) 2.2 Water (expected source & competing users) Yes Water Source: GIDC Water Supply and unit: KLD competing users ar e other industries of Dahej For details please refer Annexure – IV. 2.3 Minerals (MT) No Not applicable 2.4 Construction material - stone, aggregates, Yes Company will use Sand, stone, Cement and / soil (expected source - MT) and Structural Steel for Construction as per requirement. 2.5 Forests and timber (source - MT) No. --- 2.6 Energy including electricity and fuels Yes FUEL: (source, competing users) Unit: fuel (MT), Proposed: energy (HP) For Steam Boiler, Briquettes = 700 Kg/Hour or Natural Gas = 230 SCM/hour For Thermic fluid heater, Natural gas= 250 SCM/Hour For DG Set, Diesel= 20 Liters/hour ENERGY: Power requirement from DGVCL is 150 KVA. D.G. Set: 1 No.: 150 KVA in emergency case only. Competing users are other industries of Dahej Industrial Area. 2.7 Any other natural resources (use No --- appropriate standard units)

3. Use, storage, transport, handling or production of substances or materials, which could be harmful to human health or the environment or raise concerns about actual or perceived risks to human health.

Sr. Information/Checklist confirmation Yes/No Details there of (with approximate No. quantities/rates, wherever possible) with source of information data 3.1 Use of substances or materials, which are Yes Please refer Annexure –VIII. hazardous (as per MSIHC rules) to human health or the environment (flora, fauna,

6

and water supplies)

3.2 Changes in occurrence of disease or affect No --- disease vectors (e.g. insect or water borne diseases) 3.3 Affect the welfare of people e.g. by No --- changing living conditions? 3.4 Vulnerable groups of people who could be No --- affected by the project e.g. hospital patients, children, the elderly etc. 3.5 Any other causes No ---

4. Production of solid wastes during construction or operation or decommissioning (MT/month)

Sr. Information/Checklist confirmation Yes/No Details there of (with approximate No. quantities/rates, wherever possible) with source of information data

4.1 Spoil, overburden or mine wastes No --- 4.2 Municipal waste (domestic and or No --- commercial wastes) 4.3 Hazardous wastes (as per Hazardous Waste Yes Please refer Annexure – VI. Management Rules) 4.4 Other industrial process wastes No --- 4.5 Surplus product --- No

4.6 Sewage sludge or other sludge from Yes Sewage will be disposed to septic tank effluent treatment or soak pit system. 4.7 Construction or demolition wastes Construction waste shall be utilized for Yes leveling, land filling in the premises. 4.8 Redundant machinery or equipment No --- 4.9 Contaminated soils or other materials No --- 4.10 Agricultural wastes No --- 4.11 Other solid wastes No ---

5. Release of pollutants or any hazardous, toxic or noxious substances to air (Kg/hr)

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Sr. Information/Checklist confirmation Yes/No Details there of (with approximate No. quantities/rates, wherever possible) with source of information data

5.1 Emissions from combustion of fossil fuels Yes Please refer Annexure – VII. from stationary or mobile sources 5.2 Emissions from production processes Yes Please refer Annexure – VII. 5.3 Emissions from materials handling storage Yes All liquid raw materials will beprocured or transport in closed tankers and will be Transferred through closed pipelines.Solid raw materials shall be handled in closed charging rooms with proper Ventilation. 5.4 Emissions from construction activities Yes Emissions from construction activities including plant and equipment will be controlled by water sprinkling, storage of construction materials in covered sheds and utmost care during unloading and storage. 5.5 Dust or odours from handling of No --- materials including construction materials, sewage and waste 5.6 Emissions from incineration of waste No --- 5.7 Emissions from burning of waste in open No --- air e.g. slash materials, construction

debris) 5.8 Emissions from any other sources No ---

6.Generation of Noise and Vibration, and Emissions of Light and Heat:

Sr. Information/Checklist confirmation Yes/No Details there of (with approximate No. quantities/rates, wherever possible) with source of information data with source of information data 6.1 From operation of equipment e.g. Yes The Noise level will be within the prescribed engines, ventilation plant, crushers limits. There will be no significant noise, vibrations or emission of light & heat from the proposed unit. Adequate noise control measures will be taken during construction and operation phase.

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6.2 From industrial or similar processes Yes All machinery / equipment will be well Maintained and will be provided with proper foundations along with anti vibrating pads wherever applicable and noise levels shall be kept well within permissible limits. 6.3 From construction or demolition No --- 6.4 From blasting or piling No --- 6.5 From construction or operational No --- traffic 6.6 From lighting or cooling systems No --- 6.7 From any other sources No ---

7. Risks of contamination of land or water from releases of pollutants into the ground or into sewers, surface waters, groundwater, coastal waters or the sea:

Sr. Information/Checklist confirmation Yes/No Details there of (with approximate No. quantities/rates, wherever possible) with source of information data 7.1 From handling, storage, use or spillage Yes Spillages will be collected and adequately of hazardous materials stored within factory premises for reuse. All the raw material will be stored. separately in designated storage area. Bund walls will be provided around storage tanks for containing any liquid spillage. Raw materials will be stored in bags /drums on pallets with concrete flooring. For details please refer Annexure – VIII. 7.2 From discharge of sewage or other Yes For details please refer Annexure – V. effluents to water or the land (expected mode and pl ace of discharge) 7.3 By deposition of pollutants emitted to No The project is located in Dahej Industrial air into the and or into water area. The emissions shall Confirm to the GPCB / CPCB discharge norms. 7.4 From any other sources No --- 7.5 Is there a risk of long termbuild up of No Complete Environmental management pollutants in the environment from System (EMS) will be installed which these sources? includes ETP, Air Pollution Control measures and proper Hazardous Waste Handling anddisposal as per norms. This will

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eliminate the possibility of long term build up of pollutants.

8. Risk of accidents during construction or operation of the Project, which could affect human health or the environment

S.No. Information/Checklist confirmation Yes/No Details there of (with approximate quantities/rates, wherever possible) with source of information data 8.1 From explosions, spillages, fires etc from Yes The risk assessment will be carried out storage, handling, use or production of and all mitigation measures will be hazardous substances taken to avoid accidents. For details please refer Annexure – VIII. . 8.2 From any other causes No --- 8.3 Could the project be affected by natural No --- disasters causing environmental damage (e.g. floods, earthquakes, landslides, cloudburst etc)?

9. Factors which should be considered (such as consequential development) which could lead to environmental effects or the potential for cumulative impacts with other existing or planned activities in the locality

Sr. Information/Checklist confirmatio n Yes/No Details there of (with approximate No. quantities/rates, wherever possible) with source of information data 9.1 Lead to development of supporting. Yes Site is located in Dahej Industrial utilities, ancillary development or development stimulated by the project area which is already having the which could have impact on the required infrastructure facilities. environment e.g. Local people will be employed and no housing is required. For details • Supporting infrastructure (roads, power please refer Annexure – IX. supply, waste or waste water treatment, etc.)

• housing development • extractive industry • supply industry • other

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9.2 Lead to after-use of the site, which could No --- have an impact on the environment 9.3 Set a precedent for later developments No ---

9.4 Have cumulative effects due to proximity No --- to other existing or planned projects with similar effects

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(II) Environmental Sensitivity

Sr. Areas Name/ Aerial distance (within 15km.) Proposed No. Identity project location boundary

1 Areas protected under international conventions, No Proposed project site is within Dahej national or local legislation for their ecological, Industrial area landscape, cultural or other related value 2 Areas which important for are or sensitive Ecol No Proposed project site is within Dahej logical reasons - Wetlands, watercourses or other Industrial area. water bodies, coastal zone, biospheres, mountains, forests 3 Area used by protected, important or sensitive. No There is no protected area, important or Species of flora or fauna for breeding, nesting, sensitive species within 15 kms from the foraging, resting, over wintering, migration proposed expansion project boundary.

4 Inland, coastal, marine or underground waters Yes Narmada River - 6.0 kms 5 State, National boundaries No --- 6 Routes or facilities used by the public for access No --- to recreation or other tourist, pilgrim areas 7 Defense installations No --- 8 Densely populated or built-up area Yes Bharuch City is about 38 kms away and has a population of about 4.0 lakh. 9 Area occupied by sensitive man-made land uses No --- Hospitals, schools, places of worship, community facilities) 10 Areas containing important, high quality or No --- scarce resources (ground water resources, surface resources, forestry, agriculture, fisheries, tourism, minerals) 11 Areas already subjected to pollution Yes Dahej industrial area. environmental damage. (those where existing legal environmental standards are exceeded)or 12 Areas susceptible to natural hazard which could No --- cause the project to present environmental problems (earthquake ,subsidence ,landslides, flooding erosion, or extreme or adverse climatic conditions)

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IV). Proposed Terms of Reference for EIA studies: Please refer Annexure - X

I hereby given undertaking that, the data and information given in the application and enclosures are true to the best of my knowledge and belief and I am aware that if any part of the data and information submitted is found to be false or misleading at an y stage the project will be rejected and clearance give, if any to the project will be revoked at our risk and cost.

Date: 10/06/2019 Place: Dahej II

For Mendas Pharmaceuticals

Mr Umesh Mendapara (Partner)

NOTE:

1. The projects involving clearance under Coastal Regulation Zone Notification, 1991 shall submit with the application a C.R.Z. map duly demarcated by one of the authorized agencies, showing the project activities, w.r.t. C.R.Z. (at the stage of TOR) and the reco mmendations of the State Coastal Zone Management Authority (at the stage of EC). Simultaneous action shall also be taken to obtain the requisite clearance under the provisions of the C.R.Z. Notification, 1991 for the activities to be located in the CRZ.

2. The projects to be located within 10 km of the National Parks, Sanctuaries, Biosphere Reserves, Migratory Corridors of Wild Animals, the project proponent shall submit the map duly authenticated by Chief Wildlife Warden showing these features vis -à-vis th e project location and the recommendations or comments of the Chief Wildlife Warden thereon (at the stage of EC).

3. All correspondence with the Ministry of Environment & Forests including submission of application for TOR/Environmental Clearance, subsequent clarifications, as may be required from time to time, participation in the EAC Meeting on behalf of the project proponent shall be made by the authorized signatory only. The authorized signatory should also submit a document in support of his cl aim of being an authorized signatory for the specific project.

LIST OF ANNEXURES

SR. NO. NAME OF ANNEXURE I List of Products and Raw materials along with their Production Capacity II Layout Map of the Plant III Brief Manufacturing Process Description IV Details of water consumption & waste water generation V Details of Effluent Treatment Scheme VI Details of Hazardous Waste Generation and Disposal VII Details of Stacks and Vents, Fuel & Energy Requirements VIII Details of Hazardous Chemicals Storage & Handling IX Socio-economic Impacts X Proposed Terms of Reference XI GIDC Plot Allotment Letter XII Toposheet

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ANNEXURE-I ______LIST OF PROPOSED PRODUCTS ALONG WITH THEIR PRODUCTION CAPACITY WITH RAW MATERIALS

SR. PRODUCTS CAS NO. PROPOSED End Use of the product NO QUANTITY (MT/MONTH ) (I) ACTIVE PHARMACEUTICAL INGREDIENT (API) Cyclo-oxygenase inhibitor;

1 Ibuprofen 15687-27-1 analgesic; anti- inflammatory. Cyclo-oxygenase inhibitor;

2 Aspirin 50-78-2 100 analgesic; anti- inflammatory. Cyclo-oxygenase inhibitor;

3 Diclofenac Sodium 15307-86-5 analgesic; anti- inflammatory.

4 Dolutegravir 1051375 -16 -6 to treat HIV/AIDS (Antivirus) Purine nucleoside analogue;

5 Acyclovir 59277-89-3 antiviral (herpesviruses). Purine nucleoside analogue;

6 Valacyclovir 124832-27-5 antiviral (herpesviruses).

7 Tenofovir 147127-20-6 to treat HIV/AIDS (Antivirus)

8 Efavirenz 154598 -52 -4 to treat HIV/AIDS (Antivirus)

9 Levetiracetam 102767 -28 -2 Antiepileptic

10 Lamivudine 134678-17-4 to treat HIV/AIDS (Antivirus)

11 Guifenesin 93 -14 -1 Expectorant

12 Gabapentin 60142-96-3 Antiepileptic Anti histamine (anti allergic)

13 Chlorpheniramine Maleate 113-92-8 50 drug an antibiotic and

14 Metronidazole 443-48-1 antiprotozoal medication Cyclo-oxygenase inhibitor;

15 Naproxen sodium 26159-34-2 analgesic; anti- inflammatory. as antibiotic primarily used

16 4-Aminosalicylic acid 65-49-6 to treat tuberculosis Cyclo-oxygenase inhibitor;

17 Ibuprofen Sodium 31121-93-4 analgesic; anti- inflammatory. Local anaesthetic; Class I

18 Lidocaine hydrochloride 6108-05-0 antiarrhythmic

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19 Tranexamic Acid 1197 -18 -8 Antifibrinolytic agent

20 Phenyramidol hydrochloride 326-43-2 Muscle relaxant 30 Cyclo-oxygenase inhibitor;

21 Ibuprofen Lysinate 57469-77-9 analgesic; anti- inflammatory. to treat inflammatory bowel

22 Mesalmine/Mesalazine 89-57-6 disease, anti -inflammatory. Cyclo-oxygenase inhibitor;

23 Aceclofenac 89796-99-6 analgesic; anti- inflammatory. used for the treatment of

24 Albendazole 54965-21-8 parasitic worm infestations

25 Ambroxol hydrochloride 23828-92-4 Mucolytic expectorant Monoamine reuptake

26 Trazodone 19794-93-5 inhibitor; antidepressant.

27 Pregabalin 148553 -50 -8 Antiepileptic Proton pump inhibitor;

28 Omeprazole 73590-58-6 treatment of peptic ulcer disease. Proton pump inhibitor;

29 Esomeprazole 119141-88-7 treatment of peptic ulcer disease. Proton pump inhibitor;

30 Pantoprazole sodium 138786-67-1 treatment of peptic ulcer disease. Proton pump inhibitor;

31 Rabeprazole 117976-90-6 treatment of peptic ulcer disease. Proton pump inhibitor;

32 Lansoprazole 103577-45-3 treatment of peptic ulcer disease.

33 Fluconazole 86386-73-4 Antifungal 20 Cyclo-oxygenase inhibitor;

34 Dexibuprofen 51146-56-6 analgesic; anti- inflammatory. Angiotensin II (AT1) receptor

35 Telmisartan 144701-48-4 antagonist; treatment of Hypertensio n Angiotensin II (AT1) receptor

36 Losartan 114798-26-4 antagonist; treatment of Hypertension

37 Valsartan 137862 -53 -4 Angiotensin II (AT1) receptor

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antagonist; treatment of Hypertension Angiotensin II (AT1) receptor

38 Olmisartan 144689-63-4 antagonist; treatment of Hypertension Angiotensin II (AT1) receptor

39 Candesartan cilexetil 145040-37-5 antagonist; treatment of Hypertension Angiotensin II (AT1) receptor

40 Irbesartan 138402-11-6 antagonist; treatment of Hypertension Smooth muscle relaxant;

41 Mebeverin hydrochloride 2753-45-9 antispasmodic Calcium channel blocker;

42 Verapamil hydrochloride 152-11-4 treatment of Hypertension Antispasmodic drug; used to

43 Drotaverinhydroch;loride 985-12-6 enhance cervical dilation during birth Angiotensin converting

44 Lisinopril 83915-83-7 enzyme inhibitor; treatment of Hypertension Angiotensin converting

45 Ramipril 87333-19-5 enzyme inhibitor; treatment of Hypertension HMG Co-A reductase

46 Atorvastatin calcium 134523-03-8 inhibitor; lipid-regulating drug HMG Co-A reductase

47 Rosuvastatin calcium 147098-20-2 inhibitor; lipid-regulating drug Inhibition of 5HT and

48 Venlafaxin hydrochloride 99300-78-4 noradrenaline reuptake; antidepressant Alpha-adrenoceptor agonist;

49 Phenylephrin hydrochloride 61-76-7 nasal decongestant

50 Lamotrigine 84057-84-1 Antiepileptic Alpha-and beta-

51 Labetalol hydrochloride 32780-64-6 adrenoceptor antagonist; treatment of Hypertension Histamine H1 receptor

52 Cetrizine hydrochloride 83881-52-1 antagonist; antihistamine.

53 Levocetrizine hydrochloride 130018-77-8 Histamine H1 receptor

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antagonist; antihistamine.

54 Vitamin D3 67-97-0 Vitamin D3 analogue

55 Terbinafine hydrochloride 78628 -80 -5 Antifungal Vasodilator; treatment of

56 Minoxidil 38304-91-5 hypertension; male pattern baldness. Selective serotonin reuptake

57 Sertaline hydrochloride 79559-97-0 inhibitor; antidepressant. Reversal of neuromuscular

58 Sugammadex sodium 343306-79-6 blockade

59 Apixaban 503612 -47 -3 Anticoagulant treatment of rheumatoid

60 Tofacitinib 477600-75-2 arthritis and ulcerative colitis. dipeptidyl peptidase-4

61 Teneligliptin HBr 1572583-29-9 inhibitors; treatment of type 2 diabe tes mellitus Local anaesthetic; Class I

62 Lidocaine base 137-58-6 antiarrhythmic

63 Benzocaine 94 -09 -7 Local anaesthetic

64 Procaine 59 -46 -1 Local anaesthetic

65 Articaine 23964 -57 -0 Local anaesthetic

66 Prilocaine hydrochloride 1786-81-8 Local anaesthetic

67 Prilocaine base 721 -50 -6 Local anaesthetic

68 Bupivacaine hydrochloride 18010-40-7 Local anaesthetic

69 Ropivacaine hydrochloride 132112 -35 -7 Local anaesthetic

70 Tetracaine hydrochloride 136-47-0 Local anaesthetic

71 Cinchocaine hydrochloride 61-12-1 Local anaesthetic Cyclo-oxygenase inhibitor;

72 Meloxicam 71125-38-7 analgesic; anti- inflammatory. Cyclo-oxygenase inhibitor;

73 Piroxicam 36322-90-4 analgesic; anti- inflammatory. Cyclo-oxygenase inhibitor;

74 Lornoxicam 70374-39-9 analgesic; anti- inflammatory. Cyclo-oxygenase inhibitor;

75 Piroxicam Betacyclodextrin 96684-39-8 analgesic; anti- inflammat ory.

76 Sodium Picosulphate 1307301 -38 -7 Stimulant laxative

77 Bisacodyl 603-50-9 Stimulant laxative

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78 Alendronate Sodium 121268 -17 -5 Treatmet of osteoporosis Leukotriene CysLT1 receptor

79 Montelukast Sodium 151767-02-1 antagonist; treatment of asthma. TOTAL OF API 200

(II) ACTIVE PHARMACEUTICAL INGREDIENT (API) INTERMEDIATES

80 Isobutyl acetophenone 38861 -78 -8 Ibuprofen 1-(2,6-Dichlorophenyl)-2- 81 15307-86-05 Diclofenac

indolinone

82 Try amino pyrimidine sulphate 35011 -47 -3 Guanine

83 Guanine 73 -40 -5 Valacyclovir

84 Adenine 73 -24 -5 Tenofovir (2S)-2-aminobutanamide 50 85 7682-20-4 Levetiracetam

Hydrochloride

86 1,1-Cyclohexane diacetic acid 4355-11-7 Gabapentin 3,4-Dimethoxybenzoic 87 93-07-2 Mebeverin

acid(Veratric Acid)

88 Para Amino Benzoic Acid 150 -13 -0 Benzocaine 1-(2,2-Dimethoxyethyl)-1,4- dihydro-3-methoxy-4-oxo-2,5- 89 1335210-23-5 Dolutegravir pyridinedicarboxylic acid 2-methyl

es ter (S)-1-(2-Amino-5-chlorophenyl)-1- 90 (trifluoromethyl)-3-cyclopropyl-2- 209414-27-7 Efavirenz

propyn -1-ol (S)-5-Chloro-alpha- (cyclopropylacetenyl)-2-[((4- 91 173676-60-3 Efavirenz methoxyphenyl)methyl)amino]- alpha - 25 (1R,2S,5R)-Menthyl-(2R,5S)-5-(4- 92 amino-2-oxo-2H-pyrimidin-1-yl)- 147027-10-9 Lamivudine

[1,3]oxathiolane-2-carboxylic acid 2-Amino-3,5- 93 50910-55-9 Ambroxol

dibromobenzaldehyde

94 Trans -4-Aminocyclohexanol 27489 -62 -9 Ambroxol

95 (3,4 -Dimethoxyphenyl)acetonitrile 93 -17 -4 Verapamil

96 Denatonium Benzoate 3734 -33 -6 Bitterant

97 4-(Aminomethyl) Benzoic Acid 56 -91 -7 Tranexamic Acid 1-(3-Chlorophenyl)-4-(3- 98 chloropropyl)piperazine 52605-52-4 10 Trazadone

hydrochloride

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(R)-(-)-3-(2-Amino-2-oxo ethyl)-5- 99 181289-33-8 Pregabaline

methyl hexanoic acid 2-Chloromethyl-4-methoxy-3,5- 100 86604-75-3 Omeprazole

dimethylpyridine hydrochloride 5-Methoxy-2-Mercapto 101 37052-78-1 Omeprazole

Benzimidazole 5-Difluromethoxy-2-Mercapto 102 97963-62-7 Pantoprazole

Benzimidazole 5-Difluoromethoxy-2-{[(3,4- dimethoxy-2- 103 102625-64-9 Pantoprazole pyridinyl)methyl]thio}-1H-

benzimidazole 2-Chloromethyl 3,4-Dimethoxy 104 72830-09-2 Pantoprazole

Pyridine HCl

105 2-Mercapto Benzimidazole 583 -39 -1 Rabeprazole 2-Chloromethoxy-4-(3-Methoxy 106 153259-31-5 Rabeprazole

Propoxy)-3-Methyl Pyridine 2-[[[4-(3-Methoxy Propoxy)-3- 107 Methyl Pyridine-2-yl] Methyl] 117977-21-6 Rabeprazole

Thio] -1H -Benzimidazole [1,1’-Biphenyl]-2-carbonitrile,4’- [(1,4’-dimethyl -2’-propyl [2,6”-bi- 108 144702-27-2 Telmisartan 1H-benzimidazole ] -1’-yl) methyl ]

– (1,1 -biphenyl) -2-carbonitrile Methyl 4'-bromomethyl biphenyl- 109 114772-38-2 Telmisartan

2-carboxylate 2-n-propyl-4-methyl-6-(1- 110 methylbenzimidazole-2- 152628-02-9 Telmisartan

yl)benzimidazole 2n-Butyl-4-chloro-[1-(2'- 111 cyanobiphenyl-4-yl) methyl]-5- 114772-55-3 Losartan

(hydroxymethyl)-imidazole 5-(4'-Bromomethyl-1, 1'-biphenyl- 112 2-yl)-1-triphenylmethyl-1H- 124750-51-2 Losartan

tetrazole (TTBB) 2-Butyl 4-Chloro 5-Formyl 113 83857-96-9 Losartan

Imidazole(BCFI)

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4-(1-Hydroxy-1-methylethyl)-2- propyl-1-[[2'-[(triphenylmethyl)- 114 1H-tetrazol-5-yl][1,1'-biphenyl]-4- 144690-33-5 Olmesartan yl]methyl]-1H-imidazole-5-

carboxylic acid ethyl ester) 5-Methoxy – 2-oxo-1,3-dioxol - 4 - yl ) methyl - 4 - (1-hydroxy -1 - methylethyl -2 propyl-1- (2 –(2- 115 144690-92-6 Olmesartan triphenylmethyl ) -2H – tetrazole - 5 – yl ) biphenyl -4-yl ) methyl ) -

1H-imidazole – 5 – carboxylate Methyl 1-[(2'-cyanobiphenyl-4- 116 yl)methyl]-2-ethoxy-1H- 139481-44-0 Candesartan

benzimidazole -7-carboxylate Ethyl 2-ethoxy-1-[(2'- 117 cyanobiphenyl-4-yl)methyl]-1H- 139481-41-7 Candesartan

benzimidazole -7-carboxylate N-[(2'-Cyanobiphenyl-4-methyl)- 118 (L)-Valine methyl ester 482577-59-3 Valsartan

Hydrochloride

4'-[(2-Butyl-4-oxo-1,3-

119 138401-24-8 Irbesartan diazaspiro[4.4]non-1-en-3-

yl)methyl]biphenyl-2-carbonitrile tert-Butyl (4R,6R)-2-[[[6-(2-4- fluorophenyl)-5-isopropyl-3- 120 125971-95-1 Atorvastatin phenyl-4- (phenylcarbamoyl)pyrrol -1- (4R,6R)-tert-Butyl-6-(2- 121 aminoethyl)-2,2-dimethyl-1,3- 125995-13-3 Atorvastatin

dioxane-4-acetate Methyl 4-(4-fluorophenyl)-6- isopropyl-2-[(N-methyl-N- 122 289042-11-1 Rosuvastatine methylsulfonyl)amino]pyrimidine-

5-carbo xylate tert-Butyl 6-[(1E)-2-[4-(4- fluorophenyl)-6-(1-methylethyl)- 123 289042-12-2 Rosuvastatine 2-[methyl(methylsulfonyl)amino]- 5-pyrimidinyl]ethenyl] -2,2 -

21

1-[Cyano-(p- 124 methoxyphenyl)methyl]cyclohexa 93413-76-4 Venlafaxine

nol

1-[2-Amino-1-(4- 125 methoxyphenyl)ethyl]cyclohexano 149289-31-6 Venlafaxine

l

126 2,3 -Dichlorobenzoylcyanide 77668 -42 -9 Lamotrigine

127 5-Chloroacetylsalicylamide 33254 -88 -5 Labetalol

128 1-(4 -Chlorobenzhydryl)piperazine 303 -26 -4 Cetrizine

129 2-Amino, 5 -methyl thiazole 7305 -71 -7 Meloxicam 4-Hydroxy, 2-methyl, 2h,1,2- 130 benzothiazine carboxylic acid 118854-48-1 Meloxicam

isopropyl ester -1,1 -dioxide 4-Hydroxy, 2-methyl, 2h,1,2- 131 benzothiazine carboxylic acid 35511-15-0 Meloxicam

methyl ester -1,1 -dioxide

132 Chloro acetyl Xylidine 1131 -01 -7 Lidocaine 2-(2-(3-(S)-(3-(2-(7-Chloro-2- quinolinyl)-ethenyl)phenyl-3- 133 142569-70-8 Montelukast methanesulphonyloxypropyl)pehe

nyl) -2-propanol 1-(Mercaptomethyl)- 134 162515-68-6 Montelukast

cyclopropane acetic acid

135 Denatonium Saccharate 90823 -38 -4 Bitterant 3-Morpholino-1-(4-(2- 136 oxopiperidin-1-yl)5,6- 545445-44-1 Apixaban

dihydropyridin -2(1h) -one z-Ethyl-2-chloro-2-(2-(4- 137 27143-07-3 Apixaban

methoxyphenyl)hydrazono)acetate 4-Chloro-7-tosyl-7h-pyrrolo[2,3- 138 479633-63-1 Tofacitanib

d]pyrimidine Bis (3R, 4R) - (1- benzyl - 4 methyl 5 139 - pipeidine - 3yl) methylamine di - 477600-70-7 Tofacitanib toluoyl - L - tartaric acid [(2S)-1-tert-butoxycarbonyl-4- 140 oxo-2-pyrrolidinylcarbonyl]-1,3- 401564-36-1 Teneligliptin

thiazolidine 1-(3-methyl-1-phenyl-5-pyrazolyl)- 141 401566-79-8 Teneligliptin

piperazine)

22

6-Chloro 4-Hydroxy 2-Methyl 2H- 142 thieno[2,3,e][1,2]thiazine-3- 70415-50-8 Lornoxicam

Carboxylate 1,1 -dioxide 4,4’-(2- 143 603-41-8 Bisacodyl

Pyridinylmethylene)bisphenol 3-Amino-4-methyl-2- 144 thiophenecarboxylic acid methyl e 85006-31-1 Articaine

ster

145 Basic cromium sulphate 15244-38-9 35 Tanning of leather TOTAL OF API INTERMEDIATES 125

(III) SPECIALITY CHEMICALS

146 Fusidic Acid 6990.06-3 2 Antibacterial

147 Vancomycine 1404-90-6 5 Antibacterial

148 Mupirocine 12650-69-0 3 Antibacterial For fibrinolytic, anti-edemic,

149 Seratiopaptidase 70851-98-8 5 and anti-inflammatory activity. Inhibitor of nucleic acid

150 Mycophenolate 24280-93-1 10 synthesis; immunomodulator. TOTAL OF SPECIALITY CHEMICALS 25

Research activity for Pharma (IV) R & D Products 0.1 molecule development for laboratory TOTAL OF API, API INTERMEDIATES, SPECIALITY 350.1 CHEMICALS & R & D Products

23

RAW MATERIAL CONSUMPTION: FOR PROPOSED PRODUCTS Sr. Raw Materials Cas No. Quantity Name of Products No (MT/MONTH) (I) ACTIVE PHARMACEUTICAL INGREDIENT (API)

1 Ibuprofen Chloro Acetic Acid 79 -11 -8 87.1 Isopropyl Alcohol 67 -63 -0 462.2

Sulphuric Acid 7664-93-9 123.4

Soda Ash 497 -19 -8 10.2

Ethylene Dichloride 107-06-2 149.1

Isobutyl Benzene 538 -93 -2 77.8

Aluminium Chloride 7446 -70 -0 51

Acetyl chloride 75-36-5 53.6

Liquor Ammonia 1336 -21 -6 0.3

Sodium Metal 7440-23-5 20.5

Caustic Soda 1310 -73 -2 53.8

Acetone 67-64-1 307.5

Sodium Dichromate 10588 -01 -9 48

Hexane 110 -54 -3 158.4

2 Aspirin Salicylic Acid 69-72-7 100 Acetic Anhydride 108 -24 -7 38

Acetic Acid 101830 188.8

Activated Carbon 7440 -44 -0 1

3 Diclofenac Sodium Caustic Soda Flakes 1310-73-2 39 Sodium Citrate 6132 -04 -3 2

2,6 - Dichlorodiphenyl 2- 15362-40-0 110 Indolenone HyfloW 61790-53-2 0.1

Activated Carbon 7440 -44 -0 0.2

1-(2,2-dimethoxyethyl)-5- - methoxy-6-

4 Dolutegravir (methoxycarbonyl)-4-oxo- 100.0 1,4-dihydropyridine-3- carboxylic acid Isobutyl chloro formate 543-27-1 47.9

N-Mehtyl morpholine 109 -02 -4 42.8

1-hydroxy benzotriazole 123333-53-9 47.9 monohydrate 72235-52-0 2,4-difluoro benzyl amine 60.4

Potassium carbonate 584-08-7 5.0

24

Sodium chloride 7440 -23 -5 0.8

Citric acid 77-92-9 4.5

Iso propyl alcohol 67 -63 -0 705.5

Ethyl acetate 141 -78 -6 2931.1

Methane sulfonic acid 75-75-2 7.6

Acetic acid 101830 95.0

3-R-amino-1- butanol 61477-40 31.5

Sodium bicarbonate 144 -55 -8 3.4

n-heptane 142-82-5 323.7

Acetonitrile 75 -05 -8 1294.8

Magnesium bromide 13446-53-2 76.1 hexahydrate Hydro chloric acid 7647-01-0 5.5

Methylene Chloride 75 -09 -2 700.3

Sodium Hydroxide 1310 -73 -2 0.5

Ethanol 64-17-5 122.5

5 Acyclovir Guanine 73 -40 -5 55.6 Acetic Anhydride 108-24-7 209.0

Acetone 67 -64 -1 425.9

Para Toluene Sulfonic Acid 104-15-4 6.0

Sodium Hydroxide 1310 -73 -2 60.4

Hydrochloric Acid 7647-01-0 24.2

Dioxolane Diacetate - 61.1

Toluene 108 -88 -3 276.2

Nitirc Acid 7697-37-2 0.3

Diethylamine 109 -89 -7 41.1

Sulfuric Acid 7664 -93 -9 16.7

Sodium Dithionite 7775 -14 -6 0.9

Hyflow 61790 -53 -2 1.8

Activated Carbon 7440-44-0 8.3

6 Valacyclovir L-Valine 72 -18 -4 19.4 Benzyl chloro formate 501-53-1 28.2

Sodium hydroxide 1310 -73 -2 13.2

Toluene 108 -88 -3 125.0

Hexane 110-54-3 83.3

Activated Carbon 7440 -44 -0 1.9

Hyflow 61790-53-2 1.3

Acyclovir 59277 -89 -3 34.7

Dicyclohexyl carbodiimide 538-75-0 31.8

Dimethyl amino pyridine 1122 -58 -3 0.1

Dichloromethane (DCM) 75 -09 -2 166.7

25

Isopropanol (IPA) 67 -63 -0 111.1

Dimethyl formamide 68-12-2 97.2

Sodium sulphate 7757 -82 -6 3.2

Hydrogen 1333 -74 -0 0.3

Methanol 67-56-1 250.0

Ethanol 64 -17 -5 250.0

10% Pd/C 1.3

Hydrochloric Acid 7647 -01 -0 11.1

7 Tenofovir Adenine 73-24-5 29.1 (r) -Propylene Carbonate 16606 -55 -6 22.0

Di methyl Formamide 68-12-2 84.1 (DMF) Toluene 108-88-3 303.0

Caustic Soda 1310 -73 -2 0.8

Diethyl-ptoluene sulphonyl 31618-90-3 62.3 oxymethyl phosphonate Hydrobromic Acid 10035 -10 -6 30.9

N-Methyl Pyrroldine (NMP) 872 -50 -4 12.1

MagnisiumTert Butoxide 32149 -57 -8 36.4

Acetic Acid 101830 31.1

Acetone 67 -64 -1 61.4

Methylene 75-09-2 275.0 Dichloride(MDC) Methanol 67-56-1 28.8

Caustic Soda Lye (48%) 1310 -73 -2 46.3

4-Chloro-2-trifluoro acetyl 173676-59-0

8 Efavirenz 50.0 aniline hydrochloride 4-Methoxy phenyl 105-13-5 26.6 methanol Cyclopropyl acetylene 6746-94-7 13.0

Tetrahydrofuran 109 -99 -9 860.0

Methyl tert-butyl ether 1634-04-4 300.0

Ammonia 1336 -21 -6 2.5

Toluene 108 -88 -3 1112.5

Heptane 142-82-5 100.0

Activated Carbon 7440 -44 -0 1.0

2,3-Dichloro-5,6-dicyano- 84-58-2 41.5 1,4-benzoquinone Sodium bicarbonate 144-55-8 20.0

Methanol 67 -56 -1 227.5

Acetic Acid 101830 3.8

Sodium chloride 7440 -23 -5 2.3

26

Sodium Hydroxide 1310 -73 -2 2.5

n-Hexane 110-54-3 725.0

Acetone 67 -64 -1 30.0

Triphosgene 32315 -10 -9 51.3

Isopropyl Alcohol 67-63-0 250.0

Hydrochloric Acid 7647 -01 -0 6.5

Sodium borohydride 16940-66-2 7.0

S - 2 - Aminobutamide 7682-20-4

9 Levetiracetam 32 hydrochloride Methylene Dichloride 75 -09 -2 88

4-chlorobutanoyl chloride 4635-59-0 43

Pottasium Hydroxide 1310 -58 -3 44

TerabutylAmmoniumbromi 1643-19-2 1 de Ethyl Acetate 141-78-6 168

10 Lamivudine L-Menthol 2216 -51 -5 125.0 Glyoxalic Acid (50%) 298 -12 -4 50.0

Sulphuric Acid 7664 -93 -9 1.5

Sodium carbonate 497 -19 -8 10.0

Cyclohexane 110-82-7 375.0

Sodium bisulphate 7681 -38 -1 17.5

Formaldehyde 50-00-0 7.5

1,4 -Dithiane -2,5 -diol 40018 -26 -6 22.5

Acetic Acid 101830 10.0

n-Hexane 110-54-3 460.0

Triethyl Amine 121 -44 -8 54.3

Toluene 108-88-3 1075.0

Methyl sulfonic acid 75 -75 -2 0.8

Dimethyl formamide 68-12-2 2.5

Thionyl chloride 7719 -09 -7 31.4

Cytosine 71-30-7 29.3

Hexamethyldisilazane 999-97-3 37.5 Ethyl Acetate 141 -78 -6 475.0

Ethyl alcohol 64-17-5 600.0

Dipotassium hydrogen 7758-11-4 36.0 phosphate Hydrochloric acid 7647 -01 -0 10.0

Sodium borohydride 16940-66-2 10.0

Activated carbon 7440 -44 -0 7.5

Salicylic Acid 69-72-7 36.3

11 Guifenesin Pyrcatechol 120 -80 -9 30.7

27

Di methyl sulfate 77 -78 -1 22.5

Sodium carbonate 497-19-8 19.0

Hydrochloric acid (36%) 7647 -01 -0 4.0

Sodium hydroxide (47%) 1310 -73 -2 30.0

Toluene 108-88-3 100.0

Epichlorohydrin 106 -89 -8 27.5

Phosphoric acid 7664-38-2 1.0

EDC 25952 -53 -8 37.5

2,2'-(cyclohexane-1,1- -

12 Gabapentin 48.3 diyl)diacetic acid Liquor Ammonia 1336-21-6 13.4

Caustic Soda Flakes 1310 -73 -2 9.7

Hydrochloric Acid 7647-01-0 48.5

Sodium Hypochlorate 7681 -52 -9 35.9

Methylene Dichloride 75 -09 -2 73.2

Methanol 67-56-1 85.4

Activated Carbon 7440 -44 -0 0.7

13 Chlorpheniramine Maleate 2-(4-chlorobenzyl)pyridine 4350-41-8 27.3 2-chloro-N,N- 4584-46-7 15.6 dimethylethanamine Sodium amide 7782 -92 -5 3.9

Ethy Acetate 141-78-6 84.4

Melic Acid 6915 -15 -7 16.9

2 Methyl 5 Nitro Imidazole 88054-22-2

14 Metronidazole 82.4 (2MNI) Glacial acetic acid 64-19-7 67.6

Acetic Anhydride 108 -24 -7 4.0

Ethylene Oxide 75 -21 -8 110.0

Sulphuric Acid 7664-93-9 80.0

Liquor Ammonia 1336 -21 -6 110.0

Activated Carbon 7440-44-0 1.0

15 Naproxen sodium β-Naphthol 135 -19 -3 41.3 Methanol 67-56-1 184.5

Sulphuric acid 7664 -93 -9 1.7

Ethylene Dichloride 107 -06 -2 297.1

C.S. Lye (48%) 1310-73-2 44.3

Aluminum Chloride 7446 -70 -0 42.1

Acetyl Chloride 75-36-5 21.5

Caustic Soda 1310 -73 -2 55.9

2-butyl chloro acetate 590-02-3 41.3

Potassium 2 -butoxide 41233 -93 -6 154.1

28

Acetic acid 101830 14.9

Hydroxylamine HCl 5470-11-1 17.2

KOH 1310 -58 -3 14.0

HCl (33%) 7647 -01 -0 44.8

Toluene 108-88-3 958.9

N-Methyl D -Glutamine 6284 -40 -8 79.1

Sodium Chloride 7440-23-5 6.2

Acetone 67 -64 -1 12.2

16 4-Aminosalicylic acid P - Nitro Salicylic Acid 619-19-2 61.7 Fe catalyst 7439 -89 -6 3.3

Hydrochloric Acid 7647 -01 -0 20.7

Hydrogen Gas 1333-74-0 2.0

Caustic Soda 1310 -73 -2 13.3

17 Ibuprofen Sodium Methanol 67-56-1 82 Ibuprofen 15687 -27 -1 42

Caustic soda Lye 1310-73-2 33

Cyclohexane 110-82-7 92

18 Lidocaine hydrochloride Diethyl Amine 109 -89 -7 99 Caustic Soda 1310-73-2 13

2,6-Dimethylphenyl 1131-01-7 45 chloroacetamide Acetone 67-64-1 97

Activated Carbon 7440-44-0 1

Hydrochloric Acid Gas 7647 -01 -0 6

4-(aminomethyl)benzoic -

19 Tranexamic Acid 150 acid Sulphate Hydrogen Gas 1333-74-0 2

Pd/C 7440 -05 -3 3

Calcium Hydroxide 1305-62-0 45

Toluene 108 -88 -3 129

20 Phenyramidol hydrochloride 2 – Amino Pyridine 504-29-0 44 Dimethyl Formamide 68-12-2 48

Caustic Soda 1310 -73 -2 8

Styrene oxide 96-09-3 20

Toluene 108 -88 -3 24

Methanol 67-56-1 53

Activated Carbon 7440 -44 -0 1

Hydrochloric Acid Gas 7647 -01 -0 7

21 Ibuprofen Lysinate Ibuprofen 15687-27-1 19.2 Hexane 110 -54 -3 36.6

Activated Carbon 7440-44-0 0.9

29

Lysine 56 -87 -1 13.8

Hyflow 68855-54-9 0.4

22 Mesalmine/Mesalazine 5 - Nitro Salicylic Acid 96 -97 -9 42.3 Pd/C catalyst 7440 -05 -3 0.7

Sodium Carbonate 497-19-8 10.6

Hydrogen Gas 1333 -74 -0 1.4

Hydrochloric Acid 7647-01-0 28.9

23 Aceclofenac Diclofenac Sodium 15307 -79 -6 30.0 t-Butyl Chloro Acetate 107-59-5 14.3

Toluene 108 -88 -3 150.0

DMF 68 -12 -2 30.0

Formic Acid 64-18-6 10.4

Activated Carbon 7440 -44 -0 3.0

24 Albendazole Methanol 67-56-1 69 methyl (5-chloro-1H- 20367-38-8 benzimidazol-2- 27

yl)carbamate sodium thiocyanate 540 -72 -7 10

Propyl Chloride 540 -54 -5 9

Sodium sulfide 1313-82-2 10

Trans 4-Amino 27489-62-9

25 Ambroxol hydrochloride 12 Cyclohexenol 2-Amino-3,5- 50910-55-9 21 dibromobenzaldehyde Methanol 67 -56 -1 75

Formic acid 64-18-6 3

Activated Carbon 7440 -44 -0 0

Hydrochloric acid 7647-01-0 3

[1,2,4]Triazolo[4,3- 6969-71-7

26 Trazodone 20.0 a]pyridin-3(2H)-one Caustic Flakes 1310 -73 -2 28.6

Isopropyl Alcohol 67-63-0 26.3

Toluene 108 -88 -3 62.9

1-(3-Chlorophenyl)- 13078-15-4 24.2 piperazine 3-Chloro -1-propanol 60827-45-4 13.9

Hydrochloric Acid 7647 -01 -0 22.3

Activated Carbon 7440-44-0 3.0

Hyflo 61790-53-2 2.6

Dimethyl Formamide 68 -12 -2 129.2

Methane Sulfomide 124-63-0 14.8 Chloride

30

Triethyl Amine 121 -44 -8 13.7

Methanol 67-56-1 759.6

2-(1-Cyano-3-methyl- 186038-82-4

27 Pregabalin butyl)- Malonic acid diethyl 113.0 ester Potassium hydroxide 1310-58-3 24.8

Ethanol 64 -17 -5 30.0

Acetic acid 101830 26.5

Raney nickel 12003 -78 -0 0.8

Iso Propyl Alcohol 67-63-0 187.5

Hydrogen gas 1333 -74 -0 1.7

(S) -Mandelic acid 17199 -29 -0 32.0

Tetrahydrofuran 109—99-9 45.0

Sodium Hydroxide 1310 -73 -2 0.8

28 Omeprazole 3,5-Lutidine 591-22-0 12.9 Hydrogen Peroxide 7722 -84 -1 9.6

Nitric acid 7697 -37 -2 32.3

Sulphuric acid 7664 -93 -9 32.3

Acetic acid 101830 60.0

Sodium methoxide 124-41-4 15.0

Sodium hydroxide 1310 -73 -2 8.4

Dimethyl sulphate 77-78-1 10.7

Methanol 67 -56 -1 225.0

Thionyl Chloride 7719 -09 -7 10.1

Toluene 108-88-3 300.0

2-Mercapto-5-methoxy 37052-78-1 15.6 Benzimidazole CS Lye 1310 -73 -2 3.6

Acetone 67-64-1 75.0

29 Esomeprazole Omeprazole 73590 -58 -6 27.0 Cumin hydro peroxide 7722-84-1 3.5

Potassium hydroxide 1310 -58 -3 1.8

N, N-diethyltryptamine 61 -50 -7 2.0 Titanium isopropoxide 546-68-9 0.2

Toluene 108 -88 -3 96.0

Methanol 67-56-1 30.0

Magnesium sulfate 7487 -88 -9 4.8

30 Pantoprazole sodium Maltol 118-71-8 25.5 Dimethyl sulphate 77 -78 -1 7.5

Potassium carbonate 584 -08 -7 0.5

Acetone 67-64-1 300.0

31

Ammonium Carbonate 506 -87 -6 19.5

Toluene 108-88-3 240.0

Phosphorous oxy chloride 10025 -87 -3 10.5

Sodium Hydroxide 1310 -73 -2 38.7

Methylenedichloride 75-09-2 855.0

Hydrogen peroxide (30%) 7722 -84 -1 15.0

Acetic acid 101830 13.5

Methanol 67 -56 -1 262.5

Acetic Anhydride 108-24-7 13.5

Chloroform 67 -66 -3 60.0

Thionyl chloride 7719 -09 -7 11.7

5-diFluoromethoxy-2- 97963-62-7 21.0 mercapto- benzimidazole Sodium hypochlorite (12%) 7681 -52 -9 30.0

Ammonium Chloride 12125 -02 -9 7.5

Activated Carbon 7440-44-0 0.3

31 Rabeprazole 2,3 -Lutidine 583 -61 -9 13.8 Hydrogen Peroxide (50%) 7722-84-1 9.9

Nitric acid 7697 -37 -2 9.0

Sulphuric acid 7664-93-9 10.6

3-Methoxy -1-Propanol 6.0

Sodium Hydroxide 1310-73-2 16.8

Toluene 108-88-3 294.0

DMSO (Dimethyl Sulfoxide) 67 -68 -5 60.0

Acetic anhydride 108-24-7 11.7

Hydrochloric acid 7647 -01 -0 6.0

Thionyl Chloride 7719 -09 -7 15.9

MDC 75 -09 -2 405.0

Sodium Sulphate 7757 -82 -6 3.0

2-Mercaptobenzimidazole 583-39-1 15.9

Sodium Hypochlorite (8%) 7681 -52 -9 98.1

Acetone 67-64-1 45.0

Sodium hydro sulphate 7681 -38 -1 3.6

MMA (Methyl 80-62-6 3.0 methacrylate ) in Methanol Isopropyl Alcohol 67-63-0 90.0

Activated Carbon 7440 -44 -0 3.0

32 Lansoprazole 2,3 -Lutidine 583 -61 -9 12.6 Acetic Acid 101830 12.0

Hydrogen Peroxide (33%) 7722 -84 -1 21.9

Sulfuric Acid 7664-93-9 30.0

32

Nitric Acid 7697 -37 -2 7.4

Sodium Hydroxide 1310-73-2 11.1

Potassium Carbonate 584 -08 -7 11.3

Tri Fluoro Ethanol 75 -89 -8 8.3

MIBK(Methyl Isobutyl 108-10-1 40.8 Ketone) Acetic Anhydride 108 -24 -7 8.4

TBAB 1643-19-2 (Tetrabutylammonium 0.4

bromide) Toluene 108 -88 -3 180.0

Hydrochloric acid (33%) 7647-01-0 9.1

Activated Carbon 7440 -44 -0 0.9

Thionyl Chloride 7719 -09 -7 9.7

Methylene Dichloride 75-09-2 30.0

2-Mercapto Benz imidazole 583 -39 -1 12.2

Isopropyl Alcohol 67-63-0 66.0

Chloroform 67 -66 -3 72.0

Acetone 67-64-1 48.0

33 Fluconazole 1,3 Difluoro benzene 372 -18 -9 15.0 Chloro Acetyl chloride 79 -04 -9 14.9

Aluminium Chloride 7446-70-0 4.5

MDC 75 -09 -2 240.0

1,2,4-triazole 288-88-0 15.0

Triethyl Amine 121 -44 -8 11.1

Ethyl Acetate 141-78-6 210.0

Trimethyl Sulfoxonium 1774-47-6 23.4 iodide Potassium Hydroxide 1310 -58 -3 6.0

Toluene 108-88-3 240.0

Cetyl tri methyl Ammonium 57-09-0 3.0 Bromide Potassium carbonate 584 -08 -7 14.1

DMF 68 -12 -2 195.0

Hydrochloric Acid 7647-01-0 7.5

Magnesium Sulfate 7487 -88 -9 1.5

IPA 67-63-0 135.0

Activated Carbon 7440 -44 -0 3.0

34 Dexibuprofen Toluene 108-88-3 53.3 Ibuprofen 15687 -27 -1 26.7

N - Octyl D-Glucamine 23323 -37 -7 20.0

Potassium Hydroxide 1310-58-3 0.1

33

solution Acetic Acid 64-19-7 0.1

Methyl-4-(butyramido)-3- -

35 Telmisartan 14.6 methyl-5-nitrobenzene Methanol 67-56-1 539.0

Palladium carbon(Wet 5% 7440-05-3 0.6 MC) Sodium hydroxide 1310-73-2 24.4

Hydrochloric acid 7647 -01 -0 16.0

N-Methylbenzene-1,2- - 6.4 diamine Poly phosphoric acid 8017-16-1 33.0

Methyl-4-methyl-1,1- - 11.4 biphenyl- 2-carboxylate 1,3-dibromo-5,5-dimethyl - 14.4 imidazolidine-2,4-dione Azo bis isobutyronitrile 78 -67 -1 0.6

Sodium meta bisulphate 7681-57-4 0.9

Chloroform 67 -66 -3 64.0

n-Hexane 110-54-3 20.0

Potassium hydroxide 1310 -58 -3 6.6

Acetone 67 -64 -1 90.0

MDC 75-09-2 240.0

Acetic acid 101830 12.0

Activated carbon 7440-44-0 2.0

Methanolic ammonia 7664-41-7 10.0

2-Cyano-4-Methyl biphenyl 114772-53-1

36 Losartan 12.0 (OTBN) Sodium Azide 26628 -22 -8 4.4

Triethylamine HCl 554 -68 -7 5.0

Hydrochloric acid 7647 -01 -0 4.6

Sodium nitrite 7632 -00 -0 4.6

Toluene 108-88-3 80.0

Trityl chloride 76-83-5 16.6

Triethylamine 121-44-8 6.0

MDC 75 -09 -2 160.0

Methanol 67-56-1 260.0

N-Bromo succinimide (NBS) 128-08-5 9.0

Sodium meta bisulphate 7681 -57 -4 2.0

Butyl chloro formyl 83857-96-9 9.0 imidazole (BCFI)

34

TBAB(Tetrabutylammoniu 1643-19-2 1.0 m bromide) IPA HCl 7647 -01 -0 60.0

Sodium hydroxide 1310-73-2 5.4

Potassium hydroxide 1310-58-3 4.0

Activated Carbon 7440-44-0 3.0

Ethyl Acetate 141 -78 -6 40.0

37 Valsartan L-Valine 72 -18 -4 9.0 Thionyl Chloride 7719-09-7 9.1

Methanol 67 -56 -1 160.0

Toluene 108-88-3 500.0

Sodium hydroxide 1310 -73 -2 8.0

4-Bromomethyl-biphenyl- 114772-54-2 16.4 2- carbonitrile Potassium carbonate 584-08-7 9.0

Valeryl Chloride 638 -29 -9 6.8

Triethylamine 121 -44 -8 4.0

Sodium bicarbonate 144 -55 -8 5.0

Sodium Sulphate 7757 -82 -6 2.0

Sodium Azide 26628-22-8 3.2

Tri butyl tin chloride 1461 -22 -9 16.0

Hydrogen 1333-74-0 0.1

Xylene 1330 -20 -7 48.0

MDC 75 -09 -2 100.0

Acetic Acid 101830 8.0

N-Hexane 110 -54 -3 40.0

Activated Carbon 7440-44-0 2.0

Diethyl 2-propyl-1H- 144689-94-1

38 Olmisartan 7.0 imidazole-4,5-dicarboxylate Methyl Iodide 74 -88 -4 8.0

Magnesium 7439-95-4 0.7

Diethyl ether 60 -29 -7 9.1

Methylchloroisothiazolinon 37.8 e 26172 -55 -4 5-(4'- 124750-51-2 (bromomethyl)biphenyl-2- 15.6

yl) -1-trityl -1H -tetrazole Dimethylacetamide 127-19-5 18.2

Potassium Hydroxide 1310-58-3 1.6

Toluene 108 -88 -3 65.1

Ethyl acetate 141-78-6 9.1

35

4-(Chloro methyl)-5- 80841-78-7 5.3 methyl-1,3-dioxol-2-one Lithium Hydroxide 1310 -65 -2 1.5

Acetic acid 64-19-7 36.4

Acetone 67-64-1 14.3

Nacl 7647-14-5 10.4

39 Candesartan cilexetil Trityl Candisartan 139481 -72 -4 38.0 Dimethyl form amide 68 -12 -2 207.0

Potassium Carbonate 584-08-7 21.0

Cyclohexyl,1-Chloro ethyl 99464-83-2 11.5 carbonate Ethyl Acetate 141 -78 -6 840.0

Sodium Chloride 7647-14-5 21.0

Sodium Sulphate 7757 -82 -6 21.6

Cyclo hexane 110-82-7 500.0

Ethyl Acetate 141 -78 -6 468.0

MDC 75 -09 -2 130.0

Methanol 67 -56 -1 208.0

Formic Acid 64 -18 -6 1.9

Sodium Bicarbonate 144-55-8 25.0

Isopropyl alcohol 67 -63 -0 86.0

2-N-Butyl-1,3-diazo 151257-01-1

40 Irbesartan spiro(4,4)non,1-ene-4-one 11.6 hydrochloride 4-Bromo methyl-1,2- 114772-54-2 13.6 Cyanobiphenyl DMF 68 -12 -2 60.0

Sodium azide 26628 -22 -8 3.2

Triethyl amine 554-68-7 6.8 Hydrochloride Toluene 108 -88 -3 70.0

Ethyl acetate 141-78-6 60.0

IPA 67 -63 -0 60.0

1-(4-methoxyphenyl)- -

41 Mebeverin hydrochloride 12.0 propan -2- one Monoethyl Amine (70%) 75-04-7 8.6

Hydrochloric acid (35%) 7647 -01 -0 15.0

Methanol 67-56-1 40.0

Sodium Hydroxide (47%) 1310 -73 -2 8.0

Hydrogen 1333-74-0 0.4

Nitrogen 7727 -37 -9 0.4

Methyl Isobutyl Ketone 108 -10 -1 30.0

36

3,4-Dimethoxybenzoic acid- - 20.0 4- bromo butyl ester Toluene 108 -88 -3 90.0

Ethyl Acetate 141-78-6 50.0

Methylene Dichloride 75-09-2 30.0

Sodium Carbonate 497-19-8 8.0

(3,4-dimethoxyphenyl)

42 Verapamil hydrochloride 93-17-4 11.7 acetonitrile 2-bomopropane 75-26-3 8.1

Potassium hydroxide 1310-58-3 3.7

Dimethyl Sulfoxide 67 -68 -5 20.0

Cyclohexane 110-82-7 2.0

Raney nickel 12635 -27 -7 0.1

Hydrogen 1333 -74 -0 0.3

Isopropanol 67-63-0 40.0

Dimethyl sulphate 77 -78 -1 8.4

Sodium hydroxide 1310-73-2 8.3

Hydrogen chloride 7647 -01 -0 4.5

Toluene 108-88-3 60.0

Acetone 67 -64 -1 60.0

1-bromo -3-chloro propane 109 -70 -6 8.8

2-(3,4-dimethoxyphenyl)-3- 20850-49-1 12.3 methylbutanenitrile Sodium amide 7782-92-5 2.2

Methanol 67 -56 -1 30.0

43 Drotaverinhydroch;loride Pyro catechol 120-80-9 30.8

Diethyl sulfate 39.2 64 -67 -5 Toluene 108-88-3 382.9

Sodium hydroxide (47%) 1310-73-2 42.0

Para formaldehyde 30525 -89 -4 8.2

Hydrochloric acid (35%) 7647-01-0 20.0

Sodium bicarbonate 144 -55 -8 2.0

7681-52- 9 (anhydrous) Sodium hypochlorite 7.0 7681-52-8 (pentahydrate) Methanol 67 -56 -1 100.0

Ammonia gas 1336 -21 -6 9.0

Hydrogen 1333-74-0 0.6

Nitrogen 7727 -37 -9 0.2

37

Raney Nickel 12635 -27 -7 1.2

Phosphorous oxy chloride 10025-87-3 27.9

IPA 67 -63 -0 70.0

N – (2, 6 – Diamino – -

44 Lisinopril hexanoyl) – pyrrolidine – 2 10.0 – carboxylic acid 2 – Oxo – 4 - Phenyl Butyric 710-11-2 14.0 acid 5% palladium carbon 7440 -05 -3 2.4

Hydrogen gas 1333-74-0 0.4

Sodium hydroxide 1310 -73 -2 6.0

Methanol 67-56-1 100.0

2-(1-carboxy-ethylamino)- -

45 Ramipril 4- phenyl-butyric acid 13.7 ethylester (cis,endo)-octahydro- - cyclopenta[b]pyrrole-2(s)- 9.4 carboxylic acid hydrochloride Ethyl acetate 141 -78 -6 24.0

Triethylamine 121-44-8 24.0

Ethanol 64 -17 -5 26.0

5% Pd/Activated carbon 7440-44-0 0.4

tert-Butyl-2-[(4R,6S)-6- - (cyanomethyl)-2,2-

46 Atorvastatin calcium 13.3 dimethyl, 1,3-dioxane-4- yl]acetate Palladium Carbon 7440 -05 -3 0.3

Methanol 67-56-1 203.2

Hyflo 61790 -53 -2 0.5

Hydrogen Gas 1333-74-0 1.0

Dimethyl Carbonate 616 -38 -6 5.4

2-Methyl 2-Butanone - 5.4

Aniline 62 -53 -3 5.4

Sulfuric Acid 7664 -93 -9 0.6

Benzaldehyde 100-52-7 5.5

Potassium Carbonate 584 -08 -7 1.0

Toluene 108-88-3 148.0

Acetone 67 -64 -1 28.0

Flouro Benzaldehyde 459-57-4 5.8

Para Toluene Sulfonic acid 104 -15 -4 0.4

IPA 67 -63 -0 144.0

38

Calcium Acetate 62 -54 -4 3.0

Activated Carbon 7440-44-0 0.2

47 Rosuvastatin calcium 4-Fluoro benzaldehyde 459 -57 -4 10.4 4-Methyl-3-oxo-pentanoic 7152-15-0 13.3 acid ethyl ester Potassium hydroxide 1310-58-3 4.7

Methyl Iodide 74 -88 -4 12.0

Methanol 67 -56 -1 110.0

S-Methyl iso thio urea - 7.0

2,3-Dichloro-5,6-dicyano - 17.0 benzoquinone Hexamethylphosphoramide 680 -31 -9 20.0

MDC 75-09-2 160.0

Meta chloro peroxy 937-14-4 23.7 benzoic acid Methyl amine 74 -89 -5 2.0

Ethanol 64-17-5 50.0

Methane sulfonyl chloride 124 -63 -0 5.9

Sodium hydride (60%) 7646-69-7 0.2

Di methoxy ethane 110 -71 -4 60.0

Hydrogen 1333 -74 -0 0.2

DIBAL-H 0.2

Toluene 108 -88 -3 160.0

Methyl(3R)-3-(tert butyl di - methyl silyloxy)-5-oxo-6- triphenyl 28.9

phosphoranylidenehexanoa te Triethyl amine 121-44-8 3.0

N,N -Dimethyl formamide 68 -12 -2 60.0

Hydrogen fluoride 7664-39-3 1.0

THF 109 -99 -9 150.0

Ethyl acetate 141-78-6 210.0

Diethyl methoxy borane 7397 -46 -8 4.0

Sodium boro hydride 16940 -66 -2 0.2

Calcium chloride 10043-52-4 2.6

4-Methoxy Phenyl 104-47-2

48 Venlafaxin hydrochloride 11.2 Acetonitrile Cyclohexanone 108 -94 -1 7.6

NaOH 1310-73-2 2.0

TBAB (Tetra-n- 1643-19-2 0.8 butylammonium bromide)

39

Toluene 108 -88 -3 120.0

Hydrogen Gas 1333-74-0 0.3

Raney Nickle 12635 -27 -7 0.8

Methanol 67 -56 -1 366.0

Formic Acid 64-18-6 6.4

Formaldehyde 50 -00 -0 4.2

MDC 75-09-2 160.0

HCl 7647 -01 -0 20.0

Ethyl Acetate 141-78-6 180.0

Sodium Sulphate 7757 -82 -6 6.0

IPA 67 -63 -0 40.0

Activated Carbon 7440-44-0 4.8

1-(3-Benzyloxy-phenyl)-2- -

49 Phenylephrin hydrochloride methylamino-ethanone 37.2 Hydrochloride Methanol 67 -56 -1 252.0

10% Palladium Carbon 7440 -05 -3 4.4

Hydrogen gas 1333 -74 -0 0.8

Sodium hydroxide 1310 -73 -2 0.3

L(+) Tartaric acid 87-69-4 15.2

Chloroform 67 -66 -3 83.2

IPA 67-63-0 400.0

Ammonia Hydroxide 1336 -21 -6 8.8

Sulfuric acid 7664 -93 -9 12.4

Hydrochloric acid 7647-01-0 1.9

Acetone 67 -64 -1 80.0

Activated Carbon 7440-44-0 4.0

Imminogunidly-2,3- -

50 Lamotrigine Dichlorobenzyl Cyanide 43.4 Phosphate Sodium Hydroxide 1310 -73 -2 9.8

n-Propyl Alcohol(n -PA) 71 -23 -8 514.3

Hydrochloricacid 7647-01-0 2.3

51 Labetalol hydrochloride Benzyl acetone 2550 -26 -7 8.8 Benzyl amine 100-46-9 6.3

Sodium borohydride 16940 -66 -2 21.1

Sodium carbonate 497 -19 -8 3.1

Hydrochloric acid 7647 -01 -0 14.3

Methanol 67 -56 -1 365.9

Toluene 108-88-3 158.5

Hydrogen 1333-74-0 0.3

IPA 67-63-0 78.7

40

Activated carbon 7440 -44 -0 1.0

LH-Bromide 7726-95-6 13.1

Pd Carbon 7440 -05 -3 5.8

P-Chloro benzhydryl 303-26-4

52 Cetrizine hydrochloride 20 Piperazine Toluene 108-88-3 59

2 - chloroethanol 107 -07 -3 6

Caustic Soda 1310 -73 -2 3

Sodium mono chloro 3926-62-3 5 acetate Dimethyl formamide 68 -12 -2 20

Acetone 67 -64 -1 44

Hydrochloric Acid 7647-01-0 3

R (-)-1-[4- 300543-56-0

53 Levocetrizine hydrochloride (Chlorophenyl)phenyl] 40 Methyl Piperazine Toluene 108 -88 -3 42

2 - chloroethanol 107 -07 -3 4

Caustic Soda 1310-73-2 2

Sodium mono chloro 3926-62-3 5 acetate Dimethyl formamide 68 -12 -2 20

Acetone 67-64-1 45

Hydrochloric Acid 7647 -01 -0 3

54 Vitamin D3 7-Dehydrocholestrol 434-16-2 25.0 1-Propanol 71 -23 -8 125.0

Methyl tert -butyl ether 1634 -04 -4 100.0

Methyl Naphthalene-1-yl- -

55 Terbinafine hydrochloride 12.4 methyl amine 1-chloro-6,6- dimethylhept- 83554-69-2 11.4 2-en-4-yne Potassium Carbonate 584 -08 -7 5.0

Toluene 108-88-3 60.0

HCl gas 7647 -01 -0 1.0

Isopropyl Alcohol ( IPA) 67 -63 -0 120.0

6- Chloro-pyrimidine-2,4- 156-83-2

56 Minoxidil 15.0 diamine Hydrogen peroxide 7722 -84 -1 3.6

Methanol 67 -56 -1 200.0

Acetic Acid 101830 80.0

Piperidine 110 -89 -4 8.4

Toluene 108-88-3 120.0

41

Hydrochloric acid 7647 -01 -0 2.0

Activated carbon 7440-44-0 1.2

Racemic Cis and Trans -

57 Sertaline hydrochloride 22.8 Sertraline Caustic Lye 1310-73-2 25.0

D(-) Mandelic acid 611-71-2 1.0

Methylene chloride 75 -09 -2 270.0

Methanol 67 -56 -1 144.0

Hydrochloric acid 7647-01-0 4.0

Activated carbon 7440 -44 -0 3.1

Methylene chloride 75-09-2 640.0

IPA 67 -63 -0 900.0

Activated carbon 7440-44-0 0.5

Hyflow 61790 -53 -2 0.4

58 Sugammadex sodium γ-cyclodextrin 17465 -86 -0 12.0 O-xylene 95-47-6 24.1

Sodium Hydride 7646 -69 -7 1.9

Bromine 7726-95-6 11.9

Methanol 67 -56 -1 32.4

3-Sulfanyl Propionic acid - 7.9

Sodium Hydroxide 1310 -73 -2 3.0

3-Morpholino-1-(4-(2- 545445-44-1

59 Apixaban oxopiperidin-1-yl)5,6- 15.6 dihydropyridin-2(1h)-one Ethyl Acetate 141 -78 -6 22.0

z-Ethyl-2-chloro-2-(2-(4- 27143-07-3 methoxyphenyl)hydrazono) 11.4

acetate Ethanol 64-17-5 85.3

Ammonia 1336-21-6 0.7

Bis (3R, 4R) - (1- benzyl - 4 - methyl - pipeidine - 3yl)

60 Tofacitinib 16.6 methylamine di - toluoyl - L - tartaric acid [KSM - I] Potassium Carbonate 584-08-7 4.4

4-chloro-7-tosyl- 479633-63-1 12.5 pyrrolo[2,3-d] Pyrimidine Methanol 67 -56 -1 24.2

Formic Acid 64-18-6 2.0

Toluene 108 -88 -3 28.3

Hydrogen Gas 1333 -74 -0 0.1

Pd/C 7440-05-3 0.2

42

n - Butanol 71 -36 -3 16.2

Ethyl Chloro Acetate 105-39-5 4.6

Citric Acid 77 -92 -9 7.9

1-(3-methyl-1-phenyl-1H- 401566-79-8

61 Teneligliptin HBr 11 pyrazol-5-yl)piperazine Methylene Dichloride 75-09-2 24

tert-butyl (2S)-4-oxo-2-(1,3- 401564-36-1 thiazolidine-3- 13 carbonyl)pyrrolidine-1- carboxylate Sodium 56553-60-7 0 triacetoxyborohydride Ethyl Acetate 141-78-6 87

Hydrobromic Acid 10035 -10 -6 3

62 Lidocaine base Diethyl Amine 45 Caustic Soda 1310-73-2 16

2,6-Dimethylphenyl 1131-01-7 20 chloroacetamide Hydrochloric acid 7647 -01 -0 0.1

Toluene 108-88-3 30

Activated Carbon 7440 -44 -0 0.2

63 Benzocaine Para Amino Benzoic Acid 150-13-0 25.0 Toluene 108 -88 -3 20.0

Sulphuric Acid 7664 -93 -9 2.3

Retarder - 6.0

Caustic Soda 1310 -73 -2 1.9

Methanol 67-56-1 23.2

Activated Carbon 7440 -44 -0 0.2

64 Procaine Para Amino Benzoic Acid 150-13-0 21 Toluene 108 -88 -3 17

Sulphuric Acid 7664 -93 -9 12

Ethanol 64-17-5 5

Caustic Soda 1310 -73 -2 2

2-diethyl amino Ethanol 100-37-8 28

HCl 7647 -01 -0 4

Sodium Ethoxide 141-52-6 1

65 Articaine Methylene Dichloride 75 -09 -2 20 2 - Chloropropionyl 7623-09-8 16 Chloride Caustic Soda 1310-73-2 6

methyl 3-amino-4- 85006-31-1 13 methylthiophene-2-

43

carboxylate N - Propylamine 107-10-8 31

66 Prilocaine hydrochloride Methylene Dichloride 75 -09 -2 20.6 2 - Chloropropionyl 7623-09-8 16.0 Chloride Caustic Soda 1310-73-2 5.8

O-Toluidine 95 -53 -4 16.0

N - Propylamine 107 -10 -8 32.0

Acivated Carbon 7440-44-0 0.2

Hydrochloric Acid Gas 7647 -01 -0 2.9

Acetone 67-64-1 19.8

67 Prilocaine base Methylene Dichloride 75 -09 -2 20.6 2 - Chloropropionyl 7623-09-8 16.0 Chloride Caustic Soda 1310-73-2 5.8

O-Toluidine 95 -53 -4 16.0

N - Propylamine 107 -10 -8 32.0

Hexane 110 -54 -3 58.7

68 Bupivacaine hydrochloride Picolinic Acid 98 -98 -6 8.7 Toluene 108-88-3 26.0

2,6 - Xylidine 87 -62 -7 8.3

Methylene Dichloride 75-09-2 30.7

N - Butyl Chloride 109 -69 -3 6.3

Sodium Hydroxide 1310 -73 -2 5.5

Acetone 67-64-1 26.7

Activated Carbon 7440 -44 -0 0.3

Hyflow 61790-53-2 0.1

Hydrochloric Gas 7647 -01 -0 2.3

69 Ropivacaine hydrochloride Picolinic Acid 98-98-6 8.7 Toluene 108 -88 -3 26.1

2,6 - Xylidine 87-62-7 8.4

Methylene Dichloride 75-09-2 30.8

N - Propyl Chloride 540 -54 -5 5.2

Sodium Hydroxide 1310-73-2 5.5

Acetone 67 -64 -1 26.7

Activated Carbon 7440-44-0 0.3

Hyflow 61790 -53 -2 0.1

Hydrochloric Gas 7647 -01 -0 2.3

70 Tetracaine hydrochloride Para Amino Benzoic Acid 150-13-0 19.5 Toluene 108 -88 -3 15.6

Sulphuric Acid 7664-93-9 10.5

44

Ethanol 64 -17 -5 4.7

Caustic Soda 1310-73-2 6.5

2-methyl amino Ethanol 109 -83 -1 18.0

HCl 7647 -01 -0 3.8

Sodium Ethoxide 141-52-6 0.5

Methylene Dichloride 75 -09 -2 28.0

N - Propyl Chloride 540-54-5 4.8

2-hydroxyquinoline-4- 84906-81-0

71 Cinchocaine hydrochloride 12.1 carboxylic acid Toluene 108 -88 -3 25.4

N1,N1-diethylethane-1,2- 100-36-7 7.6 diamine Thionyl Chloride 7719-09-7 7.6

Sodium Hydroxide 1310 -73 -2 7.9

1 - Butanol 71-36-3 4.9

Sodium Metal 7440 -23 -5 1.5

Methylene Dichloride 75 -09 -2 38.1

Isopropyl Alcohol 67 -63 -0 38.1

Activated Carbon 7440 -44 -0 0.3

Hyflow 61790-53-2 0.1

Hydrochloric acid gas 7647 -01 -0 2.2

Benzothiazine Isopropyl -

72 Meloxicam 22 Ester 2-amino 5-methyl Thiazole 7305-71-7 8

O - Xylene 95 -47 -6 96

Isopropyl Alcohol 67-63-0 34

Caustic Flakes 1310 -73 -2 9

Activated carbon 7440 -44 -0 1

Acetic Acid 101830 10

Hydrochloric acid 7647 -01 -0 10

73 Piroxicam O - Xylene 95-47-6 120 Methyl benzothiazine - 27 Isopropyl Ester Isopropyl Alcohol 67 -63 -0 31

Activated carbon 7440-44-0 0

2 - Amino Pyridine 504 -29 -0 8

74 Lornoxicam O-Xylene 95 -47 -6 50 Methyl 6 chloro-4- hydroxyl 906522-88-1 - 2- methyl- 2H –thieno 24 [2,3-e][1,2] thiazine- 3- carboxylate - 1,1 - dioxide 2 - Amino Pyridine (2 -AP) 504 -29 -0 6

45

Methanol 67 -56 -1 25

Causic Soda 1310-73-2 3

Acetic Acid 101830 9

Activated Carbon 7440 -44 -0 0.2

75 Piroxicam Betacyclodextrin Betacyclodextrin 7585-39-9 20.9 Piroxicam 36322-90-4 2.3

Caustic Soda Lye (50%) 1310 -73 -2 0.4

Hydrochloric Acid 7647-01-0 0.6

76 Sodium Picosulphate Sulphamic Acid 5329 -14 -6 8 Pyridine 110 -86 -1 36

Bisphenol 80 -05 -7 20

Methanol 67 -56 -1 133

Activated Carbon 7440-44-0 2

Soda Ash 497 -19 -8 4

77 Bisacodyl Bisphenol 80-05-7 20 Acetic Anhydride 108 -24 -7 6

Methanol 67-56-1 12

Activated Carbon 7440-44-0 1

Ice 7789 -20 -0 10

78 Alendronate Sodium 4 - Amino Butyric Acid 56-12-2 8 Phosphorus Acid 7664 -38 -2 7

Phosphorus Trichloride 10 7719 -12 -2 Soda Ash 497-19-8 4

Activated Carbon 7440 -44 -0 0.2

Ice 7789-20-0 10

2-[2-3(S)-3-[2-(7-chloro-2- - quinolinyl)-ethyl]phenyl]-3-

79 Montelukast Sodium 15 hydroxypropyl] phenyl-2- propanol Methane sulfonyl chloride 124 -63 -0 4

Toluene 108-88-3 30

Caustic Soda 1310 -73 -2 3

Methanol 67-56-1 118

2-[1-(sulfonyl methyl) - 5 cyclopropyl] acetic acid Sodium Methoxide 124 -41 -4 2

(II) ACTIVE PHARMACEUTICAL INGREDIENT (API) INTERMEDIATES

80 Isobutyl acetophenone Ethylene Dichloride 25952 -53 -8 74.6

46

Isobutyl Benzene 538 -93 -2 38.9

Aluminium Chloride 7446 -70 -0 25.5

Acetyl chloride 75 -36 -5 26.8

Liquor Ammonia 1336 -21 -6 0.2

Ice 7789 -20 -0 26.1

Caustic Soda 1310 -73 -2 80.0

81 1-(2,6 -Dichlorophenyl) -2- 3 - Indolinone 3260 -61 -5 27.8 Di chloro Phenol 120 -83 -2 30.6

Dimethyl Formamide 68 -12 -2 64.8

82 Try amino pyrimidine sulphate Methanol 67 -56 -1 105.50 Sodium Methoxide 124 -41 -4 39.50

Guanidine Nitrate 506 -93 -4 31.00

Methyl Cynoacetate 105 -34 -0 25.00

Sulphuric Acid 7664 -93 -9 35.50

Sodium Nitrite 7632 -00 -0 17.50

Caustic Soda Lye 1310 -73 -2 15.00

Hydrazine Hydrate 7803 -57 -8 32.00

Raney Nickel 12003 -78 -0 1.00

83 Guanine TAPS 29915 -38 -6 50.00 Formic Acid 64 -18 -6 250.00

Sodium Formate 141 -53 -7 28.50

Caustic Soda Flakes 1310 -73 -2 50.00

Hyflo w 61790 -53 -2 0.50

Activated Carbon 7440 -44 -0 0.50

Acetic Acid 101830 55.00

84 Adenine Aniline 62 -53 -3 56.1 Sodium nitrite 7632 -00 -0 41.6

Sulfuric acid 7664 -93 -9 64.7

malanonitrile 109 -77 -3 39.8

Sodium hydroxide 1310 -73 -2 103.4

Ammonia 1336 -21 -6 18.5

Formamide 75 -12 -7 309.1

Hydrogen gas 1333 -74 -0 1.9

Palladium carbon 7440 -05 -3 0.8

Activated carbon 7440 -44 -0 0.8

(2S)-2-aminobutanamide 1492-24-6 85 (2S)-2-aminobutanoic acid 47.7

Hydrochloride Methanol 67 -56 -1 500.0

Sodium Methoxide 124 -41 -4 25.0

Hydrochloric Acid 7647 -01 -0 95.2

Liquor Ammonia 1336 -21 -6 50.0

86 1,1 -Cyclohexane diacetic acid Glacial Acetic Acid 64 -19 -7 28 Cyclohexenone 108 -94 -1 25

47

Acetic Anhydrie 108 -24 -7 28

3,4-Dimethoxybenzoic 120-80-9 87 Catechol 18.00

acid(Veratric Acid) Dimethyl Sulphate 77 -78 -1 45.50

Causti c Soda Flakes 1310 -73 -2 15.00

Dichloro Methane (MDC) 75 -09 -2 223.00

Aluminium Chloride 7446 -70 -0 60.50

Acetyl Chloride 75 -36 -5 39.50

Actvated Carbon 7440 -44 -0 2.00

Hyflo w 61790 -53 -2 0.15

Sodium Hydrosulfite 7775 -14 -6 0.50

Hydrochloric Acid 7647 -01 -0 89.00

Ice 7789 -20 -0 5.00

7681-52- 9 (anhydrous) Sodium hypochlorite 96.00 7681-52-8 (pentahydrate) Sodium metabisulphite 007681 -57 -4 3.00

88 Para Amino Benzoic Acid P- Nitrobenzoic Acid 62.96 Pd/C 7440 -05 -3 1.85

Caustic Soda 1310 -73 -2 18.52

Hydrochloric acid 7647 -01 -0 22.96

1-(2,2-Dimethoxyethyl)-1,4- 41051-15-4 dihydro-3-methoxy-4-oxo-2,5- 89 4-Methoxyacetoacetate 45.1 pyridinedicarboxylic acid 2-methyl

ester DMFDMA (N,N- 4637-24-5 Dimethylformamide 36.8

Dimethyl Acetal ) Methanol 67 -56 -1 150.0

Aminoacetaldehydedimeth 22483 -09 -6 2.5

Dimethyl oxalate 553 -90 -2 36.4

Lithium hydride 7580 -67 -8 2.5

Lithium hydroxide 1310 -65 -2 7.4

Hydrochloric acid 7647 -01 -0 17.5

Ethyl ace tat e 141 -78 -6 375.0

Sodium hydroxide 1310 -73 -2 0.4

(S)-1-(2-Amino-5-chlorophenyl)-1- 173676-59-0 4-Chloro-2-trifluoro acetyl 90 (trifluoromethyl)-3-cyclopropyl-2- 25.0 aniline hydrochloride

propyn -1-ol 4-Methoxy phenyl 15471-26-8 13.3 methanol Cyclopropyl acetylene 6746 -94 -7 6.5

Tetrahydrofuran 109 -99 -9 305.0

48

Methyl tert -butyl ether 1634 -04 -4 150.0

Ammonia 1336 -21 -6 1.3

Toluene 108 -88 -3 556.3

Heptane 142 -82 -5 50.0

Activated Carbon 7440 -44 -0 1.3

2,3-Dichloro-5,6-dicyano- 84-58-2 20.8 1,4-benzoquinone Sodium bicarbonate 144 -55 -8 2.5

Methanol 67 -56 -1 101.3

Acetic Acid 101830 1.9

Sodium chloride 7440 -23 -5 1.1

Sodium Hydroxide 1310 -73 -2 1.3

n-Hexane 110 -54 -3 62.5

Acetone 67 -64 -1 15.0

Sodium borohydride 16940 -66 -2 3.5

(S)-5-Chloro-alpha- 173676-59-0 (cyclopropylacetenyl)-2-[((4- 4-Chloro-2-trifluoro acetyl 91 16.7 methoxyphenyl)methyl)amino]- aniline hydrochloride alpha - 4-Methoxy phenyl 15471-26-8 8.9 methanol Cyclopropyl acetylene 6746 -94 -7 4.3

Tetrahydrofuran 109 -99 -9 203.3

Methyl tert -butyl ether 1634 -04 -4 100.0

Ammonia 1336 -21 -6 0.8

Toluene 108 -88 -3 104.2

Heptane 142 -82 -5 33.3

Activated Carbon 7440 -44 -0 0.8

2216-51-5 (1R,2S,5R)-Menthyl-(2R,5S)-5-(4- 92 amino-2-oxo-2H-pyrimidin-1-yl)- L-Menthol 31.3

[1,3]oxathiolane-2-carboxylic acid Glyoxalic Acid (50%) 298 -12 -4 12.5

Sulphuric Acid 7664 -93 -9 0.4

Sodium carbonate 497 -19 -8 2.5

Cyclohexane 110 -82 -7 93.8

Sodium bisulphate 7681 -38 -1 4.4

Formaldehyde 50 -00 -0 1.9

1,4 -Dithiane -2,5 -diol 40018 -26 -6 5.6

Acetic Acid 101830 2.5

n-Hexane 110 -54 -3 115.0

Triethyl Amine 121 -44 -8 7.3

Toluene 108 -88 -3 193.8

49

Methyl sulfonic acid 75 -75 -2 0.2

Dimethyl formamide 68 -12 -2 0.6

Thionyl chloride 7719 -09 -7 7.8

Cytosine 71 -30 -7 7.3

Hexamethyldisilazane 999 -97 -3 9.4

Ethyl Acetate 141 -78 -6 43.8

2-Amino-3,5- 2-Amino-benzoic acid 134-20-3 93 15.6

dibromobenzaldehyde methyl ester Bromine gas 7726 -95 -6 16.5

Methanol 67 -56 -1 87.5

Sodium Borohydride 16940 -66 -2 3.6

Hydrochloric acid 7647 -01 -0 3.8

94 Trans -4-Aminocyclohexanol Paracetamol 103 -90 -2 63 Pd/C 7440 -05 - 3

Hydrogen Gas 1333 -74 -0 3

Caustic Soda 1310 -73 -2 17

Toluene 108 -88 -3 143

(3,4-Dimethoxyphenyl) 7647-01-0 95 Hydrochloric Acid 60.0 acetonitrile Paraformaldehyde 30525 -89 -4 8.4

Chloroform 67 -66 -3 150.0

3, 4 - Dimethoxy Benzene - 39.1

Sodium Bicarbonate 144 -55 -8 2.5

TBAB 1643-19-2 (Tetrabutylammonium 1.6

bromide ) 7681-52- Sodium Hypochlorite 9 (anhydrous) 76 9.0 81-52-8 (pentahydrate)

96 Denatonium Benzoate Lidocaine 137 -58 -6 13 Toluene 108 -88 -3 50

Benzyl Chloride 100 -44 -7 7

Caustic Soda Flakes 1310 -73 -2 7

Benzoic Acid 65 -85 -0 7

97 4-(Aminomethyl) Benzoic Acid Chlorobenzene 108 -90 -7 110 p - toluic acid 99 -94 -5 37

Chlorine 7782 -50 -5 19

Caustic Soda 1310 -73 -2 11

Liquor Ammonia 1336 -21 -6 5

Sulphuric Acid (50%) 7664 -93 -9 12

1-(3-Chlorophenyl)-4-(3- 1330-20-7 98 chloropropyl)piperazine Xylene 50.0

hydrochloride

50

3-chloro aniline 10.0 108 -42 -9 51-75-2 bis(2- 14.0 chloroethyl)methylamine Caustic Lye 1310 -73 -2 4.0

Acetone 67 -64 -1 120.0

Potassium Carbonate 584 -08 -7 9.0

1 - Bromo 3 - chloro 109-70-6 12.0 propane Toluene 108 -88 -3 30.0

(R)-(-)-3-(2-Amino-2-oxo ethyl)-5- 590-86-3 99 Isoveraldehyde 8.9

methyl hexanoic acid Cyanoacetamide 107 -91 -5 17.8

Piperidine 110 -89 -4 6.7

Sulphuric acid 7664 -93 -9 23.6

Toluene 108 -88 -3 17.8

Urea 57 -13 -6 6.5

Sodium hydroxide 1310 -73 - 4.4

Hydrochloric acid 7647 -01 -0 7.6

Activated carbon 7440 -44 -0 0.1

Chloroform 67 -66 -3 240.0

R(+) Phenyl ethyl amine 3886 -69 -9 7.3

2-Chloromethyl-4-methoxy-3,5- 101830 100 Acetic Acid 3.8

dimethylpyridine hydrochloride 3,5 Lutidine 591 -22 -0 3.6

H2O2 7722 -84 -1 2.9

Methanol 67 -56 -1 50.6

Sulphuric Acid 7664 -93 -9 12.4

Nitric acid 7697 -37 -2 7.2

Toluene 108 -88 -3 110.7

DMS 77 -78 -1 3.5

NaOH 1310 -73 -2 7.2

Ammonium per sulphate 7727 -54 -0 8.3

Carbon 7440 -44 -0 0.8

Sodium Sulphate 7757 -82 -6 2.0

Dimethyl formamide 68 -12 -2 0.2

Thionyl chloride 7719 -09 - 6.5

Acetone 67 -64 -1 6.0

5-Methoxy-2-Mercapto 4 - Methoxy 2 - Nitro 96-96-8 101 10.4

Benzimidazole aniline Sodium Hydro Sulphide 16721 -80 -5 20.8

Carbon Disulphide 5.5

Caustic Lye 1310 -73 -2 11.8

51

Hydrochloric Acid 7647 -01 -0 9.9

5-Difluromethoxy-2-Mercapto 103-90-2 102 4 Hydroxy Acetanilide 7.5

Benzimidazole Caustic soda Lye 48% 1310 -73 -2 4.0

Difluoro -chloro Methen 75 -45 -6 4.0

Acetonitrile 75 -05 -8 36.0

Chloroform 67-66-3 77.5

Nitric Acid 7697 -37 -2 3.4

Sodium Hydro sulphide 16721 -80 -5 22.2

Sodium Disulphide - 3.5

Caustic Lye 1310 -73 -2 1.3

Activated Carbon 7440 -44 -0 0.1

Hydrochloric Acid 7647 -01 -0 1.8

5-Difluoromethoxy-2-{[(3,4- 118-71-8 103 dimethoxy-2- Maltol 8.9 pyridinyl)methyl]thio} -1H - Dimethyl sulphate 77 -78 -1 2.6

Potassium carbonate 584 -08 -7 0.2

Acetone 67 -64 -1 63.2

Ammonium Carbonate 10361 -29 -2 6.8

Toluene 108 -88 -3 84.2

Phosphorous oxy chloride 10025 -87 -3 3.7

Sodium Hydroxide 1310 -73 -2 12.3

Methylene dichloride 75 -09 -2 194.7

Hydrogen peroxide (30%) 7722 -84 -1 5.3

Acetic acid 101830 4.7

Methanol 67 -56 -1 92.1

Acetic Anhydride 108 -24 -7 4.7

Chloroform 67 -66 -3 21.1

Thionyl chloride 7719 -09 -7 4.1

5-diFluoromethoxy-2- 97963-62-7 7.4 mercapto - benzimidazole 2-Chloromethyl 3,4-Dimethoxy 118-71-8 104 Maltol 13.1

Pyridine HCl Dimethyl sulphate 77 -78 -1 3.8

Potassium carbonate 584 -08 -7 0.2

Acetone 67 -64 -1 92.3

Ammonium Carbonate 10361 -29 -2 10.0

Toluene 108 -88 -3 46.2

Phosphorous oxy chloride 10025 -87 -3 5.4

Sodium Hydroxide 1310 -73 -2 14.2

Methylenedichloride 75 -09 -2 284.6

Hydrogen peroxide (30%) 7722 -84 -1 7.7

52

Acetic acid 101830 6.9

Methanol 67 -56 -1 134.6

Acetic Anhydride 108 -24 -7 6.9

Chloroform 67 -66 -3 30.8

Thionyl chloride 7719 -09 -7 6.0

105 2-Mercapto Benzimidazole Benzene 1,3 Diamine 108 -45 -2 7.4 Carbon Disulfide 75 -15 -0 6.1

Sodium Hydroxide 1310 -73 -2 2.4

Caustic Lye 1310 -73 -2 2.4

Activated Carbon 7440 -44 -0 0.2

Hydrochloric Acid 7647 -01 -0 7.4

2-Chloromethoxy-4-(3-Methoxy 583-61-9 106 2,3-Lutidine 5.8

Propoxy)-3-Methyl Pyridine Hydrogen Peroxide (50%) 7722 -84 -1 4.1

Nitric acid 7697 -37 -2 3.8

Sulphuric acid 7664 -93 -9 4.4

Acetic acid 101830 2.2

3-Methoxy -1-Propanol 1589 -49 -7 2.5

Sodium Hydroxide 1310 -73 -2 2.7

Toluene 108 -88 -3 118.8

DMSO 67 -68 -5 25.0

Acetic anhydride 108 -24 -7 4.9

Hydrochloric acid 7647 -01 -0 2.5

Thionyl Chloride 7719 -09 -7 6.6

MDC 75 -09 -2 93.8

Sodium Sulphate 7757 -82 -6 1.3

2-[[[4-(3-Methoxy Propoxy)-3- 583-61-9 107 Methyl Pyridine-2-yl] Methyl] 2,3-Lutidine 4.6

Thio] -1H -Benzimidazole Hydrogen Peroxide (50%) 7722 -84 -1 3.3

Nitric acid 7697 -37 -2 3.0

Sulphuric acid 7664 -93 -9 3.5

Acetic acid 101830 1.8

3-Methoxy -1-Propanol 1589 -49 -7 2.0

Sodium Hydroxide 1310 -73 -2 3.7

Toluene 108 -88 -3 98.0

DMSO 67 -68 -5 20.0

Acetic anhydride 108 -24 -7 3.9

Hydrochloric acid 7647 -01 -0 2.0

Thionyl Chloride 7719 -09 -7 5.3

MDC 75 -09 -2 75.0

Sodium Sulphate 7757 -82 -6 1.0

2-Mercaptobenzimidazole 583 -39 -1 5.3

53

[1,1’-Biphenyl]-2-carbonitrile,4’- 152628-01-8 [(1,4’-dimethyl -2’-propyl [2,6”-bi- Methyl-4-(butyramido)-3- 108 6.3 1H-benzimidazole ] -1’-yl) methyl methyl-5-nitrobenzene

] – (1,1 -biphenyl) -2-carbonitrile Methanol 67 -56 -1 162.2

Palladium carbon (Wet 5% 7440 -05 -3 0.3

Sodium hydroxide 1310 -73 -2 10.6

Hydrochloric acid 7647 -01 -0 7.0

N-Methylbenzene-1,2- 4760-34-3 2.8 diamine Poly phosphoric acid 8017 -16 -1 14.3

Methyl-4-methyl-1,1- 114772-34-8 5.0 biphenyl - 2-carboxylate 1,3-dibromo-5,5-dimethyl - 6.3 imidazolidine -2,4 -dione Azo bis isobutyronitrile 78 -67 -1 0.3

Sodium meta bisulphate 7681 -57 -4 0.4

Chloroform 67 -66 -3 27.8

n-Hexane 110 -54 -3 8.7

Potassium hydroxide 1310 -58 -3 2.9

Acetone 67 -64 -1 39.1

MDC 75 -09 -2 104.3

Acetic acid 101830 3.5

Activated carbon 7440 -44 -0 0.4

Methyl 4'-bromomethyl biphenyl- Methyl-4-methyl-1,1- 114772-34-8 109 7.8

2-carboxylate biphenyl- 2-carboxylate 1,3-dibromo-5,5-dimethyl - 9.8 imidazolidine -2,4 -dione Azo bis isobutyronitrile 78 -67 -1 0.4

Sodium meta bisulphate 7681 -57 -4 0.6

Chloroform 67 -66 -3 43.5

n-Hexane 110 -54 -3 13.6

2-n-propyl-4-methyl-6-(1- 152628-01-8 Methyl-4-(butyramido)-3- 110 methylbenzimidazole-2- 10.0 methyl-5-nitrobenzene

yl)benzimidazole Methanol 67 -56 -1 118.5

Palladium carbon(Wet 5% 7440 -05 -3 0.4

Sodium hydroxide 1310 -73 -2 16.7

Hydrochloric acid 7647 -01 -0 4.1

N-Methylbenzene -1,2 - 4.4

Poly phosphoric acid 8017 -16 -1 22.6

54

2n-Butyl-4-chloro-[1-(2'- 114772-53-1 2-Cyano-4-Methyl biphenyl 111 cyanobiphenyl-4-yl) methyl]-5- 8.6 (OTBN)

(hydroxymethyl) -imidazole Sodium Azide 26628 -22 -8 3.1

TEA HCl 554 -68 -7 3.6

Hydrochloric acid 7647 -01 -0 3.3

Sodium nitrite 7632 -00 -0 3.3

Toluene 108 -88 -3 57.1

5-(4'-Bromomethyl-1, 1'-biphenyl- 114772-53-1 2-Cyano-4-Methyl biphenyl 112 2-yl)-1-triphenylmethyl-1H- 4.6 (OTBN)

tetrazole (TTBB) Sodium Azide 26628 -22 -8 1.7

TEA HCl 554 -68 -7 1.9

Hydrochloric acid 7647 -01 -0 1.8

Sodium nitrite 7632 -00 -0 1.8

Toluene 108 -88 -3 30.8

Trityl chloride 76 -83 -5 6.4

TEA 121 -44 -8 2.3

MDC 75 -09 -2 61.5

Methanol 67 -56 -1 7.7

N-Bromo succinimide (NBS) 128 -08 -5 3.5

Sodium meta bisulphate 7681 -57 -4 0.8

Ethyl Acetate 141 -78 -6 15.4

2-Butyl 4-Chloro 5-Formyl 110-59-8 113 Pentanenitrile 4.7

Imidazole(BCFI) Methanol 67 -56 -1 55.6

Hydrochloric Acid Gas 7647 -01 -0 2.0

Sodium Methoxide 124 -41 -4 3.1

methyl iminoacetate - 5.0

Sulfuryl Chloride 7791 -25 -5 7.5

Sodium Hydroxide 1310 -73 -2 6.7

4-(1-Hydroxy-1-methylethyl)-2- propyl-1-[[2'-[(triphenylmethyl)- Diethyl 2-propyl-1H- 114 1H-tetrazol-5-yl][1,1'-biphenyl]-4- 144689-94-1 3.5 imidazole-4,5-dicarboxylate yl]methyl]-1H-imidazole-5-

carboxylic acid ethyl ester) Methyl Iodide 74 -88 -4 4.0

Magnesium 7439 -95 -4 0.7

Diethyl ether 60 -29 -7 3.5

Methylchloroisothiazolinon 26172-55-4 3.5 e

55

5-(4'- 124750-51-2 (bromomethyl)biphenyl-2- 7.8

yl) -1-trityl -1H -tetrazole Dimethylacetamide 127 -19 -5 3.5

Potassium tert -Butoxide 865 -47 -4 1.6

Toluene 108 -88 -3 7.1

Ethyl acetate 141 -78 -6 3.5

5-Methoxy – 2-oxo-1,3-dioxol - 4 - 144689-94-1 yl ) methyl - 4 - (1-hydroxy -1 - methylethyl -2 propyl-1- (2 –(2- Diethyl 2-propyl-1H- 115 3.2 triphenylmethyl ) -2H – tetrazole - imidazole-4,5-dicarboxylate 5 – yl ) biphenyl -4-yl ) methyl ) -

1H-imidazole – 5 – carboxylate Methyl Iodide 74 -88 -4 3.5

Magnesium 7439 -95 -4 0.6

Diethyl ether 60 -29 -7 3.2

Methylchloroisothiazolinon 3.2 e 26172 -55 -4 124750-51-2 5-(4'-(bromomethyl )biphenyl-2-yl)-1-trityl-1H- 7.0

tetrazole Dimethylacetamide 127 -19 -5 6.4

Potassium tert -Butoxide 865 -47 -4 1.4

Toluene 108 -88 -3 12.7

Ethyl acetate 141 -78 -6 3.2

4-(Chloro methyl)-5- 80841-78-7 1.9

methyl -1,3 -dioxol -2-one Lithium Hydroxide 1310 -65 -2 0.5

Methyl 1-[(2'-cyanobiphenyl-4- Methyl 2-{[(2'-cyano[1,1'- 139481-28-0 116 yl)methyl]-2-ethoxy-1H- biphenyl]-4- 9.6

benzimidazole -7-carboxylate yl)methyl]amino} -3- Methylene Dichloride 75 -09 -2 19.8

TBAB 1643-19-2 (Tetrabutylammonium 0.2

bromide ) Methoxyethane 540 -67 -0 1.6

Ethyl 2-ethoxy-1-[(2'- - ethyl 2-{[(2'-cyano[1,1'- 117 cyanobiphenyl-4-yl)methyl]-1H- 9.6 biphenyl]-4-yl)

benzimidazole -7-carboxylate methyl]amino}-3- 57113-91-4 14.3 nitrobenzoate

56

TBAB 1643-19-2 (Tetrabutylammonium 0.2

bromide ) Methoxyethane 540 -67 -0 1.5

N-[(2'-Cyanobiphenyl-4-methyl)- 72-18-4 118 (L)-Valine methyl ester L-Valine 5.0

Hydrochloride Thionyl Chloride 7719 -09 -7 5.1

Methanol 67 -56 -1 88.9

Toluene 108 -88 -3 122.2

Sodium Hydroxide 1310 -73 -2 2.2

4-Bromomethyl-biphenyl- 114772-54-2 9.1

2- carbonitrile Potassium carbonate 584 -08 -7 5.0

4'-[(2-Butyl-4-oxo-1,3- 2-N-Butyl-1,3-diazo 151257-01-1 119 6.2 diazaspiro[4.4]non-1-en-3- spiro(4,4)non,1-ene-4-one yl)methyl]biphenyl -2-carbonitrile hydrochloride 4-Bromo methyl-1,2- 114772-54-2 7.3 Cyanobiphenyl DMF 68 -12 -2 32.3

tert-Butyl (4R,6R)-2-[[[6-(2-4- - tert-Butyl-2-[(4R,6S)-6- fluorophenyl)-5-isopropyl-3- (cyanomethyl)-2,2- 120 phenyl-4- 5.0 dimethyl, 1,3-dioxane-4- (phenylcarbamoyl)pyrrol-1- yl]acetate yl]ethyl] -2,2 -dimethyl -1,3 -dioxan - Palladium Carbon 7440 -05 -3 0.1

Methanol 67 -56 -1 40.6

Hyflo w 61790 -53 -2 0.1

Hydrogen Gas 1333 -74 -0 0.4

Dimethyl Carbonate 616 -38 -6 2.1

2-Methyl 2 -Butanone 563 -80 -4 2.1

Aniline 62 -53 -3 2.1

Sulfuric Acid 7664 -93 -9 0.1

Benzaldehyde 100 -52 -7 2.1

Potassium Carbonate 584 -08 -7 0.4

Toluene 108 -88 -3 56.1

Acetone 67 -64 -1 10.6

Flouro Benzaldehyde 459 -57 -4 2.2

104-15-4 Para Toluene Sulfonic acid 6192-52-5 0.2

(monohydrate) IPA 67 -63 -0 24.2

57

(4R,6R)-tert-Butyl-6-(2- tert-Butyl-2-[(4R,6S)-6- - 121 aminoethyl)-2,2-dimethyl-1,3- (cyanomethyl)-2,2dimethyl, 10.4

dioxane -4-acetate 1,3 -dioxane -4-yl]acetate Palladium Carbon 7440 -05 -3 0.2

Methanol 67 -56 -1 62.5

Hyflow 61790 -53 -2 0.3

Hydrogen Gas 1333 -74 -0 0.8

Methyl 4-(4-fluorophenyl)-6- 459-57-4 isopropyl-2-[(N-methyl-N- 122 4-Fluoro benzaldehyde 5.5 methylsulfonyl)amino]pyrimidine-

5-carbo xylate 4-Methyl-3-oxo-pentanoic 7152-15-0 7.0 acid ethyl ester Potassium hydroxide 1310 -58 -3 2.5

Methyl Iodide 74 -88 -4 6.3

Methanol 67 -56 -1 57.9

S-Methyl iso thio urea 867 -44 -7 3.7

2,3-Dichloro-5,6-dicyano 84-58-2 8.9 benzoquinone HMPA 10.5 (Hexamethylphosphoramide ) 680 -31 -9 MDC 75 -09 -2 84.2

Meta chloro peroxy 937-14-4 12.5 benzoic acid Methyl amine 74 -89 -5 1.1

Ethanol 64 -17 -5 26.3

Methane sulfonyl chloride 124 -63 -0 3.7

Sodium hydride (60%) 7646-69-7 0.1

Di methoxy ethane 110 -71 -4 31.6

Hydrogen 1333 -74 -0 0.1

DIBAL-H (Diisobutyl 1191-15-7 0.1 aluminium hydride ) Toluene 108 -88 -3 31.6

tert-Butyl 6-[(1E)-2-[4-(4- 459-57-4 fluorophenyl)-6-(1-methylethyl)- 123 2-[methyl(methylsulfonyl)amino]- 4-Fluoro benzaldehyde 3.4 5-pyrimidinyl]ethenyl]-2,2- dimethyl -1,3 -dioxane -4-acetate 4-Methyl-3-oxo-pentanoic 7152-15-0 4.3 acid ethyl ester Potassium hydroxide 1310 -58 -3 1.5

Methyl Iodide 74 -88 -4 3.9

Methanol 67 -56 -1 35.5

S-Methyl iso thio urea 867 -44 -7 2.3

58

2,3-Dichloro-5,6-dicyano 84-58-2 5.5 benzoquinone HMPA 6.5 (Hexamethylphosphoramid 680 -31 -9 MDC 75 -09 -2 51.6

Meta chloro peroxy 937-14-4 7.7 benzoic acid Methyl amine 74 -89 -5 0.7

Ethanol 64 -17 -5 16.1

Methane sulfonyl chloride 124 -63 -0 2.3

Sodium hydride (60%) 7646 -69 -7 0.1

Di methoxy ethane 110 -71 -4 19.4

Hydrogen 1333 -74 -0 0.0

DIBAL-H (Diisobutyl 1191-15-7 0.1 aluminium hydride ) Toluene 108 -88 -3 19.4

Methyl(3R)-3-(tert butyl di 147118-35-2 methyl silyloxy)-5-oxo-6- triphenyl 9.3

phosphoranylidene hexanoate Triethyl amine 121 -44 -8 1.0

N,N -Dimethyl formamide 68 -12 -2 19.4

1-[Cyano-(p- 4-Methoxy Phenyl 124 104-47-2 6.2 methoxyphenyl)methyl]cyclohexa Acetonitrile Cyclohexanone 108 -94 -1 4.2

NaOH 1310 -73 -2 1.1

TBAB 1643-19-2 (Tetrabutylammonium 0.4

bromide ) Toluene 108 -88 -3 66.6

1-[2-Amino-1-(4- 4-Methoxy Phenyl 125 104-47-2 6.5 methoxyphenyl)ethyl]cyclohexanol Acetonitrile Cyclohexanone 108 -94 -1 4.4

NaOH 1310 -73 -2 1.2

TBAB 1643-19-2 (Tetrabutylammonium 0.5

bromide ) Toluene 108 -88 -3 69.8

Hydrogen Gas 1333 -74 -0 0.2

Raney Nickle 12635 -27 -7 0.5

Methanol 67 -56 -1 166.3

126 2,3 -Dichlorobenzoylcyanide Toluene 108 -88 -3 64

59

2,4-Dichlorobenzyl chloride 13 94-99-5 Hexane 110 - 54 -3 24

127 5-Chloroacetylsalicylamide Dichloromethane (MDC) 75 -09 -2 161.50 Nitrobenzene 98 -95 -3 26.40

Aluminium chloride 7446 -70 -0 18.00

Salicylamide 65 -45 -2 9.20

Acetyl chloride 75 -36 -5 8.00

Hydrochloric acid 7647 -01 -0 44.00

Ice 7789 -20 -0 36.70

Methanol 67 -56 -1 2.60

Sulfuryl chloride 7791 -25 -5 12.30

Acetone 67 -64 -1 52.70

128 1-(4 -Chlorobenzhydryl)piperazine p - Chloro Benzophenone 134 -85 -0 10.00 Formic Acid 64 -18 -6 1.95

Hydrochloric Acid 7647 -01 -0 9.98

Toluene 108 -88 -3 23.70

Piperazine 110 -85 -0 3.02

Caustic Soda Flakes 1310 -73 -2 3.20

129 2-Amino, 5 -methyl thiazole Propionaldehyde 123 -38 -6 8 Thiourea 62 -56 -6 7

Hydrochloric Acid 7647 -01 -0 3

Caustic Soda Flakes 1310 -73 -2 3

Toluene 108 -88 -3 10

4-Hydroxy, 2-methyl, 2h,1,2- 68-12-2 130 benzothiazine carboxylic acid Dimethyl Formamide 3

isopropyl ester -1,1 -dioxide Isopropyl ChloroAcetate 105 -48 -6 5

Sodium Saccharin 128 -44 -9 13

Sodium Carbonate 497 -19 -8 0.4

Isopropyl Alcohol (IPA) 67 -63 -0 37

Sodium Metal 7440 -23 -5 3

ICE 7789 -20 -0 2

Dimethyl Sulphate (DMS) 77 -78 -1 4

Hydrochloric Acid 7647 -01 -0 4

4-Hydroxy, 2-methyl, 2h,1,2- 68-12-2 131 benzothiazine carboxylic acid Dimethyl Formamide(DMF) 4

methyl ester -1,1 -dioxide Methyl 96-34-4 4 MonoChloroAcetate Sodium Saccharin 128 -44 -9 15

Sodium Carbonate 497 -19 -8 1

MDC 75 -09 -2 9

Methanol 67 -56 -1 10

60

Sodium Metal 7440 -23 -5 7

ICE 7789 -20 -0 5

Dimethyl Sulphate (DMS) 77 -78 -1 4

Hydrochloric Acid 7647 -01 -0 3

132 Chloro acetyl Xylidine Toluene 108 -88 -3 23 chloro acetyl chloride 79 -04 -9; 6

2,6 Xylidine 7

2-(2-(3-(S)-(3-(2-(7-Chloro-2- 75-09-2 quinolinyl)-ethenyl)phenyl-3- 133 Methylene Dichloride 17 methanesulphonyloxypropyl)pehe

nyl) -2-propanol (cyclopropane-1,1- 39590-81-3 8 diyl)dimethanol Hydrochloric Acid 7647 -01 -0 11

Toluene 108 -88 -3 18

potassium ethanethioate 10387 -40 -3 8

1-(Mercaptomethyl)- 3-[(E)-2-(7-chloroquinolin- 134 120578-03-2 7

cyclopropane acetic acid 2-yl)ethenyl]benzaldehyde Tetra Hydrofurane 109 -99 -9 13

Vinylmagnesium bromide 1826 -67 -1 3

Dimethyl Formamide 68 -12 -2 14

2-(2-chlorophenyl)propan- - 4 2-ol

135 Denatonium Saccharate Lidocaine 137 -58 -6 6 Toluene 108 -88 -3 25

Benzyl Chloride 100 -44 -7 3

Caustic Soda Flakes 1310 -73 -2 4

Saccharin 2 81-07-2 3-Morpholino-1-(4-(2- 62-53-3 136 oxopiperidin-1-yl)5,6- Aniline 5

dihydropyridin -2(1h) -one Dichloromethan (MDC) 75 -09 -2 74

Caustic Soda Flakes 1310 -73 -2 2

5-chlorovaleryl chloride 1575 -61 -7 4

Toluene 108 -88 -3 24

Hexane 110 -54 -3 27

Sulphuric Acid 7664 -93 -9 0.1

Nitric Acid 7697 -37 -2 1

Ice 7789 -20 -0 10

Sodium Bicarbonate 144 -55 -8 4

Dimethyl Formamide 68 -12 -2 10

Morpholine 110 -91 -8 1

Ethanol 64 -17 -5 23

61

Raney Nickel 12003 -78 -0 0.4

Hydrazine Hydrate 7803 -57 -8 0.5

Ethyl Acetate 141 -78 -6 33

Phosphorus Pentachloride 10026 -13 -8 3

z-Ethyl-2-chloro-2-(2-(4- 104-94-9 137 P-Anisidine 5

methoxyphenyl)hydrazono)acetate Hydrochloric Acid 7647 -01 -0 2

Sodium Nitrite 7632 -00 -0 1

Ethyl 2 -Chloro Aceto 609 -15 -4 3

Methanol 67 -56 -1 30

Isopropyl Alcohol (IPA) 67 -63 -0 20

4-Chloro-7-tosyl-7h-pyrrolo[2,3- 67-64-1 138 Acetone 11

d]pyrimidine 4-Chloropyrrolo-7H-[2,3,D] 3680-69-1 3 Pyrimidine p - Toluene sulphonic 3 chloride 98 -59 -9 Caustic Soda Flakes 1310 -73 -2 1

(3R,4R)-1-Benzyl-n,4- 67-64-1 139 Acetone 43.1

dimethylpiperidin -3-amine 3 – Amino 4 – Methyl 3430-27-1 18.8 Pyridine Acetyl chloride 75 -36 -5 1.0

Caustic Soda Lye 1310 -73 -2 0.4

Toluene 108 -88 -3 57.7

Benzyl Chlo ride 100 -44 -7 1.6

Methanol 67 -56 -1 33.4

Sodium Borohydrate 16940 -66 -2 0.5

Hydrochloric Acid 7647 -01 -0 2.3

Hexane 110 -54 -3 21.0

Caustic Soda 1310 -73 -2 1.3

Methylamine 74 -89 -5 0.4

Di - P- Toluoyl L - Tartaric 32634-66-5 2.4 acid (2S,4R)-1-(tert- - [(2S)-1-tert-butoxycarbonyl-4- butoxycarbonyl)-4-hydroxy 140 oxo-2-pyrrolidinylcarbonyl]-1,3- 4.0 pyrrolidine-2-carboxylic

thiazolidine acid Methylene Dichloride 75 -09 -2 5.1

1,3 -thiazolidine 504 -78 -9 1.5

1-(3-methyl-1-phenyl-5- tert-butyl piperazine-1- 57260-71-6 141 4.2

pyrazolyl) - piperazine) carboxylate Dimethyl Formamide 68 -12 -2 8.3

Diketene 674 -82 -8 1.8

62

Ethyl Acetate 141 -78 -6 6.3

Pyridine 110 -86 -1 11.3

Phenylhydrazine 100 -63 -0 2.3

Hydrochloric Acid 7647 -01 -0 1.4

497-19- 8 (anhydrous) Sodium Carbonate 5968-11-6 1.5

(monohydrate) 6132 -02 -1 6-Chloro 4-Hydroxy 2-Methyl 2H- 67-56-1 142 thieno[2,3,e][1,2]thiazine-3- Methanol 21

Carboxylate 1,1 -dioxide Sodium Metal 7440 -23 -5 1

Methyl 5-chloro-3-[(2- 906522-87-0 methoxy-2-oxoethyl) 6 sulfamoyl]thiophene-2- carboxylate Hydrochloric Acid 7647 -01 -0 5

Toluene 108 -88 -3 13

Dimethyl Sulphate 77 -78 -1 2

Caustic soda Lye 1310 -73 -2 4

4,4’-(2- 141-78-6 143 Ethyl Acetate 9

Pyridinylmethylene)bisphenol Phenol 108 -95 -2 3

Sulphuric Acid 7664 -93 -9 4

Caustic Soda 1310 -73 -2 2

Pyridine 2 -Aldehyde 1121 -60 -4 3

Methanol 67 -56 -1 1

3-Amino-4-methyl-2- - 144 4-methylthiophen-3-amine 3.8 thiophenecarboxylic acid methyl e Methylene Dichloride 75 -09 -2 9.4

Methyl Chloroformate 79 -22 -1 3.1

10101-53-8

145 Basic cromium sulphate Chromium Sulphate 13520-66-6 5.5 (dodecahydrate) Sodium Sulphate 7757 -82 -6 2

Sugar 57 -50 -1 2.5

Sulphuric acid 7664 -93 -9 16.5

10588-01-9 Sodium dichromate 7789-12-0

(dihydrate) 14.7 Sodium Hydroxide 1310 -73 -2 1.1

(III) SPECIALITY CHEMICALS

63

146 Fusidic Acid Spor Micro organism - 0.02 Surcrose 57 -50 -1 40.0

Caustic Soda Lye 1310 -73 -2 8.0

KH2PO4 7778 -77 -0 2.0

MgSO4 7487 -88 -9 2.0

Sheftone C - 0.8

Antifoam 8050 -81 -5 0.2

Methanol 67 -56 -1 4.0

Acetone 67 -64 -1 4.0

147 Vancomycine Spor Micro organism - 0.03 Dextrose 492 -62 -6 0.5

Dextrine 9004 -53 -9 30.0

Potato Protein 9005 -25 -8 7.2

CaCO3 471 -34 -1 0.5

Soyaflour 68513 -95 -1 7.2

Salts Minerals 0.5

Ethanol 64 -17 -5 12.5

IPA 67 -63 -0 12.5

148 Mupirocine Spor Micro organism - 0.03 Wheat Gluten 8002 -80 -0 5.7

Corn Powder 9005 -25 -8 4.8

Salts & Minerals - 2.1

Antifoam 8050 -81 -5 0.3

Ethyl Acetate 141 -78 -6 540.0

n-Haptane 142 -82 -5 7.2

149 Seratiopaptidase Spor Micro organism - 0.1 Dextrose 492 -62 -6 40.0

Soyabean Flour 68513 -95 -1 40.0

Casein 9000 -71 -9 25.0

Soya Oil 8001 -22 -7 20.0

Diammonium Phosphate 7783 -28 -0 10.0

Calcium Chloride 10043 -52 -4 0.8

Magnesium Sulphate 7487 -88 -9 0.8

Potassium Chloride 7440 -09 -7 0.8

Sodium Chloride 7440 -23 -5 1.0

IPA 67 -63 -0 250.0

Acetone 67 -64 -1 250.0

150 Mycophenolate Spor Micro organism - 0.1 Dextrose 492 -62 -6 50.0

Soyabean Flour 68513 -95 -1 40.0

Casein 9000 -71 -9 50.0

Soya Oil 8001 -22 -7 40.0

Diammonium Phosphate 7783 -28 -0 20.0

Calcium Chloride 10043 -52 -4 1.6

64

Magnesium Sulphate 7487 -88 -9 1.6

Potassium Chloride 7440 -09 -7 1.6

Sodium Chloride 7440 -23 -5 2.0

Xylene 1330 -20 -7 140.0 Isobutanol 78 -83 -1 60.0 Dipyridyl Carbonate 1659 -31 -0 1.0 Sodium Bicarbonate 144 -55 -8 0.1 Isobutyl Acetate 110 -19 -0 50.0 Carbon 7440 -44 -0 0.5 Acetone 67 -64 -1 140.0 Sodium 2Ethyl Hexanoic 19766-89-3 0.6 Acid

65

ANNEXURE-II ______LAYOUT OF MAP OF THE PLANT

66

ANNEXURE-III MANUFACTURING PROCESS, CHEMICAL REACTION & MASS BALANCE: (I) ACTIVE PHARMACEUTICAL INGREDIENT (API) 1] Ibuprofen Process Description: Monochloro acetic acid is ester with isopropyl alcohol and sulphuric acid which on work up with soda ash gave the isopropyl Chloro Acetate. Acetyl chloride is reacted with 4- isobutyl benzene in presence of aluminum chloride at 0-5 °c and decomposed with ice water. Separation of layer and work up required to get the product p- isobutyl AcetoPhenone. Sodium isopropoxide is made by dissolving sodium in isopropyl alcohol. A mix of p- isobutyl acetophenone & isopropyl chloro acetate is added. isopropyl alcohol is distilled off and the reaction mass in subjected to hydrolyser with aqueous alkali and worked up to get the compound p-lsobutyl propionaldehyde. P- iso Butyl phenyl Propionaldehyde is oxidized in acetone with sodium dichromate in Acetone and water in the presence of sulphuric acid to get ibuprofen crude which is further recrystallized from hexane to get the Ibuprofen.

Chemical Reaction:

Mass Balance: Input material Quantity Output material Quantity (MT/MT ) (MT/MT ) Chloro Acetic Acid 0.871 Ibuprofen 1.00 Isopropyl Alcohol 4.622 IPA Recovery 3.967 Sulphuric Acid 1.234 EDC Recovery 1.405 Soda Ash 0.102 Acetone recovery 2.928 Ethylene Dichloride 1.491 Hexane Recovery 1.516 Isobutyl Benzene 0.778 Aluminium Chloride Solution (8-10%) 4.490 Aluminium Chloride 0.510 Evaporation Loss 0.3 57 Acetyl chloride 0.536 Effluent 11.956 Liquor Ammonia 0.003 Distillation Residue 0.013 Water 18.572 Cromium Sulfate Solution (8 -10%) 3.7 Ice 0.521 Dilute Caustic Lye Solution 5.0 Sodium Metal 0.205 IBAP isomer (Cas No. 38861 -78 -8) 0.062 Isomer of Aldehyde (Cas No. 51407- Caustic Soda 1.870 46-6) 0.06 Acetone 3.075 Sodium Dichromate 0.480 Hexane 1.584

Total 36.454 Total 36.454

68

2. Aspirin Process Description: Charge ML Crude, Salicylic acid and Acetic Anhydride in to the reactor and heat to reflux. Maintain reflux for specified time and cool to Room Temperature. Centrifuge reaction mass. Wash cake with Acetic acid and dry the material. Charge Acetic acid, ML (Pure) and dried material in reactor and heat till clear solution observed. Add Activated Carbon. Filter the reaction mass. Clear filtrate is charged in reactor and cooled. The reaction mass is than centrifuged and dried.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Salicylic Acid 1.000 Product 1.000 Acetic Anhydride 0.380 Acetic Acid Recovered 2.016 Acetic Acid 1.888 ML (Crude) 0.560 ML Crude 0.560 ML (Pure) 0.540 ML (Pure) 0.540 Distillation Residue 0.003 Actvated Carbon 0.010 Spent Carbon 0.015 Evaporation Loss 0.244

Total 4.378 Total 4.378

69

3. Diclofenac Sodium Process Description: Charge Water, 2,6 - Dichlorodiphenyl 2- Indolenone, Caustic Soda flakes and Citric acid in to the reactor and heat to reflux. Maintain reflux for specified time and cool to Room Temperature. Centrifuge reaction mass. Wash cake with water and dry the material. Add Water, dried material, Caustic Soda flakes and Citric acid in reactor and heat till clear solution observed. Add Activated Carbon. Filter the reaction mass through hyflo. Clear filtrate is charged in reactor and cooled. The reaction mass is than centrifuged and dried.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Water 3.02 Product 1.00 Caustic Soda Flakes 0.39 Effluent 3.45 Sodium Citrate 0.02 Carbon Waste 0.003 2,6 - Dichlorodiphenyl 2- 1.10 Loss 0.08 Indolenone Hyflo 0.00 1

Activated Carbon 0.002

Total 4.533 Total 4.533

70

4. Dolutegravir Process Description: 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid was treated with 2,4-difluoro benzyl amine in presence of Isobutyl chloro formate, N-Mehtyl morpholine and 1-hydroxy benzotriazole mono hydrate to give stage-I. Bis demethylation of Stage-I with Methane sulfonic acid/acetic acid followed by Cyclization with 3-R- amino-1- Butanol to afford Stage-II. Stage-II was reacted with Magnesium bromide hexahydrate and Hydro chloric acid to produce Dolutegravir.

Chemical Reaction:

71

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 1-(2,2-dimethoxyethyl)-5-methoxy-6- (methoxycarbonyl)-4-oxo-1,4- 2.000 Product 1.000 dihydropyridine-3-carboxylic acid Isobutyl chloro formate 0.958 Citric acid Rec 0.207 N-Mehtyl morpholine 0.855 N-Mehtyl morpholine: Rec 0.829 1-hydroxy benzotriazole 1-hydroxy benzotriazole monohydrate 0.958 1.265 monohydrate: Rec 2,4-difluoro benzyl amine 1.209 Iso propyl alcohol Rec. 13.752 Potassium carbonate 0.100 Ethyl Acetate Recovery 56.277 Sodium chloride 0.015 Carbon Dioxide 0.188 Citric acid 0.089 Acetic acid: Rec 1.826 Water 1.735 Acetonitrile rec 24.861 Iso propyl alcohol 14.110 n-heptane rec 6.215 Ethyl acetate 58.622 Methylene chloride Rec 13.347 Methane sulfonic acid 0.153 Ethanol Rec. 2.388 Acetic acid 1.900 Water rec 0.060 3-R-amino-1- butanol 0.629 Effluent 11.298 Sodium bicarbonate 0.068 Residue 0.019 n-heptane 6.474 Evaporation Loss 0.336 Acetonitrile 25.897 Magnesium bromide hexahydrate 1.521

Hydro chloric acid 0.110

Methylene Chloride 14.006 Sodium Hydroxide 0.009 Ethanol 2.451 Total 133.86 Total 133.86

72

5. Acyclovir Process Description: Guanine reacts with acetic anhydride gives Diacetyl Guanine. Diacetyl Guanine reacts with Dioxolanediacetate in presence of Para Toluene Sulphonic acid (PTSA) in Toluene gives Diacetyl acyclovir. Hydrolysis of Diacetyl acyclovir in presence of dimethyl amine gives Acyclovir crude. Acyclovir crude on purification, with activated carbon, Sodium dithionite in water gives acyclovir.

Chemical Reaction:

73

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Guanine 1.112 Acyclovir 1.000 Acetic Anhydride 4.180 Acetic acid 1.440 Acetone 8.518 Acetic Anhydride Recovered 3.169 Para Toluene Sulfonic Acid 0.119 Acetone Recovered 8.229 Water 4.100 Toluene Recovered 5.303 Sodium Hydroxide 1.207 Residue 0.107 Hydrochloric Acid 0.484 Waste Water 8.518 Dioxolane Diacetate 1.223 Evaporation Loss 0.081 Toluene 5.524

Nitirc Acid 0.006

Diethylamine 0.821

Sulfuric Acid 0.333

Sodium Dithionite 0.018

Hyflow 0.036 Activated Carbon 0.167 Total 27.847 Total 27.847

74

6. Valacyclovir Process Description: Condensation of L-Valine with Benzyl chloro format in presence of Sodium hydroxide and Toluene followed by crystallization from Hexane gives N- Benzyloxycarbonyl-L-Valine (CBZ-L-Valine). Condensation of Acyclovir with CBZ-L-Valine in presence of Dicyclohexyl carbodiimide, Dimethyl amino pyridine as catalyst and Dimethyl formamide as solvent gives 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9yl)methoxy]ethyl-N- (benzyloxycarbonyl)- L- Valine ester. Reduction of 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin- 9yl)methoxy]ethyl-N- (benzyloxycarbonyl)-L- Valine ester in presence of Methanol and Hydrogen gas using Palldium on carbon followed by saltification with hydrochloric acid gives 2-[(2-amino-1,6- dihydro-6-oxo-9H- purin-9yl)methoxy]ethyl-L-Valine ester hydrochloride (Valacyclovir hydrochloride).

Chemical Reaction:

75

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) L-Valine 0.387 Valacyclovir hydrochloride 1.000 Benzyl chloro formate 0.564 Toluene Recovered 2.413 Sodium hydroxide 0.264 Hexane Recovered 1.613 Toluene 2.500 DCM Recovered 3.284 Hexane 1.667 IPA Recovered 2.144 Activated Carbon 0.039 DMF Recovered 1.877 Hyflow 0.025 Methanol Recovered 4.890 Water 3.390 Ethanol Recovered 4.910 Acyclovir 0.694 Residue 0.026 Dicyclohexyl carbodiimide 0.636 Waste Water 5.391 Dimethyl amino pyridine 0.003 PD/C recovery 0.025 Dichloromethane (DCM) 3.333 Spent Carbon 0.033 Isopropanol (IPA) 2.222 Evaporation Loss 0.378 Dimethyl formamide 1.944 Sodium sulphate 0.064 Hydrogen 0.006

Methanol 5.000 Ethanol 5.000 10% Pd/C 0.025 Hydrochloric Acid 0.222 Total 27.984 Total 27.984

76

7. Tenofovir Process Description: The reaction of (R)-Propylene carbonate with Adenine in presence of base in Dimethyl Formamide yields ®- 9-(2- Hydroxypropyl) adenine. (R)-9-(2-Hydroxypropyl) adenine is condensed with Diethyl-ptoluene sulphonyl oxymethyl phosphonate (DESMP) in presence of the magnesium tert. butoxide in DMF gives Diethyl ester of intermediate, which is further hydrolyzed with Aqueous Hydrobromic acid yields (R)-9-[2- (phosphonomethoxy)propyl] adenine.

Chemical Reaction:

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Adenine 0.582 Tenofovir 1.000 (r)-Propylene Carbonate 0.440 DMF Recovered 1.623 Di methyl Formamide (DMF) 1.682 Toluene Recovered 5.806

77

Toluene 6.061 Acetone Recovered 1.166 Caustic Soda 0.015 MDC Recovered 5.280 Water 4.275 Methanol Recovered 0.553 DESMP 1.246 Carbon Dioxide 0.170 Hydrobromic Acid 0.618 Residue 0.016 N-Methyl Pyrroldine (NMP) 0.242 Waste Water 9.053 MagnisiumTert Butoxide 0.727 Evaporation Loss 0.072 Acetic Acid 0.621 Acetone 1.227

Methylene Dichloride(MDC) 5.500

Methanol 0.576 Caustic Soda Lye (48%) 0.926 Total 24.739 Total 24.739

8. Efavirenz Process Description: 4-Chloro-2-trifluoro acetyl aniline hydrochloride reacts with 4-methoxy phenyl methanol, Cyclopropyl acetylene in the presence of MTBE, THF as a solvent media to gives Stage-1 Compound. Stage-1 Compound reacts with DDQ in the presence of Toluene, Methanol to get Stage-2 Compound in Methanol Stage-2 Compound reacts with sodium borohydride in the presence of sodium hydroxide in methanol, Toluene to get Stage-3 Compound. Stage-3 Compound reacts with Triphosgene in the presence of Ethyl Acetate and N Hexane Solvent Media to gives Efavirenz.

Chemical Reaction:

78

79

Stage-4

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 4-Chloro-2-trifluoro acetyl 1.000 Efavirenz 1.000 aniline hydrochloride 4-Methoxy phenyl methanol 0.532 THF Recovery 16.230 Cyclopropyl acetylene 0.260 MTBE Recovery 5.650 Tetrahydrofuran 17.200 Toluene Recovery 21.020 Methyl tert-butyl ether 6.000 Heptane Recovery 1.920 Ammonia 0.050 Effluent Water 9.580 Toluene 22.250 Spent Carbon 0.020 Heptane 2.000 Organic Residue 0.027 Activated Carbon 0.020 Evaporation Loss 3.653 Water 6.500 DDHQ Recycle 0.837 DDQ 0.830 Methanol Recovery 4.260 Sodium bicarbonate 0.400 n-Hexane Recovery 13.680 Methanol 4.550 Acetone Recovery 0.570 Acetic Acid 0.075 IPA Recovery 4.710 Sodium chloride 0.045 Sodium Hydroxide 0.050

80 n-Hexane 14.500 Acetone 0.600 Triphosgene 1.025 Isopropyl Alcohol 5.000 Hydrochloric Acid 0.130 Sodium borohydride 0.140 Total 83.157 Total 83.157

81

9. Levetiracetam

Process Description: Charge Methylene Dichloride, S - 2 - Aminobutamide hydrochloride, Potassium Hydroxide and Tetrabutyl Ammonium bromide in reactor. The reaction mass is cooled to specified temperature. Addition of 4 – chloro butanoyl chloride is done by maintaining the temperature. Reaction mass is centrifuged and dried to get levetiracetam crude. It is purified by using ethyl acetate, centrifuged and dried.

Chemical Reaction:

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) S - 2 - Aminobutamide 0.647 Levetiracetam 1.000 hydrochloride Methylene Dichloride 1.765 Methylene Dichloride Recovery 1.713 4-chlorobutanoyl chloride 0.853 Ethyl Acetate Recovery 3.232 Pottasium Hydroxide 0.882 Evaporation Loss 0.375 Water 0.825 Effluent 1.971 TerabutylAmmoniumbromide 0.029 Distillation Residue 0.063 Ethyl Acetate 3.353 Total 8.354 Total 8.354

82

10. Lamivudine Process Description: L (-) Menthol is reacted with glyoxylic acid in the presence of catalytic amount of sulphuric acid, in cyclohexane media to give L (-) menthylglyoxilate, which is purified with sodium bisulfite and formaldehyde to give pure L (-)- Menthylglyoxillate hydrate. L (-) Menthylglyoxilate is reacted with 1,4-Dithiane-2,5-diol in the presence of acetic acid and Toluene as media, to give L-menthyl-5-hydroxy-1,3-oxathiolane-2- carboxylate. Menthyl-5-hydroxy-1,3- oxathiolane-2-carboxylate is reacted with thionyl chloride in the presence of di methyl form amide and methane sulfonic acid in Toluene as media to give chloro compound, which is reacted with silyl cytosine complex in the presence of triethylamine to give crude compound, which is leached with ethyl acetate and D.M. water to give pure Cyclohexyl Ester of Lamivudine. Cyclo hexyl ester of Lamivudine reduced with sodium boro hydride, di potassium hydrogen phosphate in the presence of catalytic amount of sodium hydroxide and rectified spirit to give lamivudine base which is treated with salicylic acid to give Lamivudine Salicylate. Lamivudine Salicylate is treated with triethylamine in the presence of absolute alcohol. This compound is then treated with activated carbon and lamivudine is isolated from ethyl acetate.

Chemical Reaction:

83

84

85

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) L-Menthol 2.500 Lamivudine 1.000 Glyoxalic Acid (50%) 1.000 Cyclohexane + menthol Recovery 8.630 Sulphuric Acid 0.030 Toluene Recovery 21.180 Sodium carbonate 0.200 n-Hexane Recovery 8.740 Cyclohexane 7.500 Ethyl acetate Recovery 9.197 Sodium bisulphate 0.350 HMDS Recovery 0.750 Formaldehyde 0.150 Ethyl Alcohol Recovery 11.545 Water 4.000 Dipotassium Hydrogen Phosphate Reuse 0.720 1,4-Dithiane-2,5-diol 0.450 Residue 0.082 Acetic Acid 0.200 Waste Water 8.432 n-Hexane 9.200 Evaporation Loss 3.411 Triethyl Amine 1.085 Toluene 21.500

Methyl sulfonic acid 0.015 Dimethyl formamide 0.050 Thionyl chloride 0.627

Cytosine 0.585 HMDS 0.750 Ethyl Acetate 9.500 Ethyl alcohol 12.000 Dipotassium hydrogen 0.720 phosphate Hydrochloric acid 0.200 Sodium borohydride 0.200 Activated carbon 0.150 Salicylic Acid 0.725 Total 73.687 Total 73.687

86

11. Guifenesin Process Description: Pyro catechol reacts with Dimethyl sulfate and Sodium carbonate to give Step-A as product. Step-A Product reacts with Sodium hydroxide to give Step-B (Stage-1) as product. Stage-1 reacts with Epichlorohydrine and water in the presence of Toluene as solvent media to give Guifenesin as product.

Chemical Reaction:

87

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Pyrcatechol 0.614 Guaifenesin 1.000 Di methyl sulfate 0.450 Toluene Recovery 1.910 Sodium carbonate 0.380 EDC Recovery 0.713 Hydrochloric acid (36%) 0.080 Residue 0.055 Sodium hydroxide (47%) 0.600 Waste Water 4.492 Toluene 2.000 Evaporation Loss 0.275 Water 3.000 Epichlorohydrin 0.550

Phosphoric acid 0.020

EDC 0.750 Total 8.444 Total 8.444

88

12. Gabapentin Process Description: Charge 2,2'-(cyclohexane-1,1-diyl) diacetic acid In SS reactor followed by liquor Ammonia. Heat the reaction mass slowly to 45°C. Maintain the reaction mass at 45°C for 3 hr with contineous stirring. Cool to 30 °C and charge water. Charge Caustic soda. Temperature will rise up to 50°C. (If temperature rise more than 50°C than apply cooling up to 50°C.) Stir the reaction mass till clear solution observed. Cool the reaction mass to 10 – 15°C. Start addition of Hydrochloric acid at 15 – 20°C. Cool the reaction mass to 5 – 10°C. Centrifuge the reaction mass and dry the material. Charge Sodium hypochlorite solution in reactor followed by addition of [1-(2-amino-2-oxoethyl) cyclohexyl] acetic acid under cooling. Heat to reflux. Maintain reflux for 4 hr and cool. Charge Methylene dichloride, Stir and settled for 30 min. Separate Organic layer and charge it in GLR. Distill off Methylene Dichloride and cool the reaction mass. Charge Hydrochloric acid and water. Heat the reaction mass to reflux. Distill out water completely. Cool the reaction mass and charge Methanol and heat till clear solution observed. Charge Activated Carbon and Stir. Filter via sparkler filter. Charge filtrate in clean reactor and distill out methanol. Cool the reaction mass, Centrifuge and Dry.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2,2'-(cyclohexane-1,1- 0.966 Product 1.000 diyl)diacetic acid Liquor Ammonia 0.267 MDC recovery 1.415 Caustic Soda Flakes 0.193 Water Recovery 0.927 Hydrochloric Acid 0.971 Methanol Recovery 1.646 Sodium Hypochlorate 0.717 Waste Water 2.080 Methylene Dichloride 1.463 Spent Carbon 0.020 Methanol 1.707 Evaporation loss 0.447 Activated Carbon 0.015 Distillation Residue 0.022 Water 1.258 Total 7.55 Total 7.55

89

13. Chlorpheniramine Maleate Process Description: Preparation of Chlorpheniramine maleate from 2-(4-chlorobenzyl)pyridine and condense with 2- chloro-N,N- dimethyl ethanamine in presence of sodium amide and Ammonia Water, after completion of reaction isolate Chlorpheniramine base in ethyl acetate and further prepared malate salt using malic acid.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2-(4-chlorobenzyl)pyridine 0.545 CPM (Product) 1.000 2-chloro-N,N- 0.312 Hydrochloric acid (28 - 30%) 0.265 dimethylethanamine Sodium amide 0.078 Ethyl Acetate Recovery 1.622 Ethy Acetate 1.688 Distillation Residue 0.029 Water 0.169 Evaporation loss 0.214 Melic Acid 0.338 Total 3.130 Total 3.130

90

14. Metronidazole Process Description: 2 Methyl 5 Nitro Imidazole (2MNI) is treated with Acetic Acid, ethylene oxide, sulphuric acid, liq nh3, activated carbon at R.T. The mixture is treated with NaOH to get pH of 2.1 to separate crude Metronidazole which is washed on centrifuge, thus obtained crude product is crystallized with water produce Pharmaceutical grade Metronidazole in powder form.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2 Methyl 5 Nitro Imidazole 1.648 Metronidazole 1.000 (2MNI) GlA .Acid 1.352 2 Methyl 5 Nitro Imidazole Recovered 0.432 Acetic Anhydride 0.080 Spent Carbon 0.020 Ethylene Oxide 2.200 Waste Water 9.852 Sulphuric Acid 1.600 Liquor Ammonia 2.200

Water 2.204

Activated Carbon 0.020 Total 11.304 Total 11.304

91

15. Naproxen sodium Process Description: Acetyl methoxy Napthalene is reacts with Sec-potassium Butoxide and Sec-Butyl chloro acetate in the presence of potassium Hydroxide and Hydroxylamine Sulfate in Sec-Butanol media to get Stage-I intermediate. Stage-I inter mediate is reacts with Sulfuric acid in the presence of sodium Hydroxide and Water to get DL-Naproxen. DL- Naproxen is reacts With NOG in the presence of Sodium Hydroxide in Toluene Solvent media to get D-Naproxen NOG. DL-Naproxen is reacts with Sulfuric acid in the presence of sodium Hydroxide and water to get Naproxen (crude). Naproxen (crude) is purified in the presence of carbon in Isopropyl alcohol media toget Naproxen (Pure).

Chemical Reaction:

92

93

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) β-Naphthol 0.825 Naproxen 1.000 Methanol 3.690 Methanol Rec 3.364 Sulphuric acid 0.033 EDC Recovery 5.780 Water 6.472 Beta Naphthol recovery 0.041 EDC 5.941 Hydrochloric Acid (28 - 30%) 0.694 C.S. Lye (48%) 0.886 CO2 ↑ 0.217 Aluminum Chloride 0.841 2-butanol Rec. 3.245 Acetyl Chloride 0.429 Liquor ammonia 1.734 Ice 0.200 Acetone Recovery 0.203 Caustic Soda 1.118 N-Methyl D-Glutamine Recovered 1.540 2-butyl chloro acetate 0.826 Stage - V recovered 0.248 Potassium 2-butoxide 3.081 Evaporation Loss 0.735 Acetic acid 0.297 Residue 0.076 Hydroxylamine HCl 0.344 Effluent 9.660 KOH 0.280 Toluene recovery 18.748 HCl (33%) 0.896

Toluene 19.178 N-Methyl D-Glutamine 1.581 Sodium Chloride 0.124 Acetone 0.243 Total 47.285 Total 47.285

94

16. 4-Aminosalicylic acid

Process Description: Hydrogenation of p – Nitro salicylic acid is done in presence of Fe catalyst to give p – Amino salicylic acid. Purification of p – amino benzoic acid is done by using Hydrochloric acid and caustic soda solution.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) P - Nitro Salicylic Acid 1.233 Product 1.000 Fe catalyst 0.066 Catalyst Recovery 0.066 Hydrochloric Acid 0.413 Effluent 3.018 Water 2.466 Evaporation Loss 0.400 Hydrogen Gas 0.040 Caustic Soda 0.266 Total 4.484 Total 4.484

95

17. Ibuprofen Sodium

Process Description: Methanol is charged to a reaction vessel at room temperature followed by charging of Ibuprofen. Reaction mass is stirred to till clarity. Reaction mass is heated & aq. Sodium Hydroxide solution is added. Reaction mass is maintained under heating till reaction completion. After that methanol is distilled out followed by addition of cyclohexane. Cyclohexane is again distilled azeotropically. Reaction mass is cooled to RT & solid is filtered & dried to give Ibuprofen sodium.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Methanol 1.633 Ibuprofen Sodium 1.000 Ibuprofen 0.837 Methanol Recovery 1.573 Caustic soda Lye 0.653 Cyclohexane Recovery 1.777 Cyclohexane 1.837 Evaporation Loss 0.220 Distillation Residue 0.073 Waste Water 0.315 Total 4.959 Total 4.959

96

18. Lidocaine hydrochloride Process Description: Diethyl amine and caustic soda is charged in reactor. The reaction mass is cooled and 2, 6 -dimethylphenyl chloroacetamide is added. Heat the reaction mass and maintain. Distill off Diethyl amine. Cool the reaction mass and centrifuge. Wash wet cake with water. Wet cake and Acetone are Charged in Reactor. Heat the reaction mass to get clear solution. Add Activated Carbon and filter. The pH of reaction mass is adjusted with Hydrochloric Acid, cooled, centrifuged and dried.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Diethyl Amine 1.970 Product 1.000 Caustic Soda 0.257 Diethyl Aminne Recovery 1.736 2,6-Dimethylphenyl 0.894 Acetone Recovery 1.890 chloroacetamide Water 1.926 Spent Carbon 0.012 Acetone 1.930 Distillation Residue 0.026 Activated Carbon 0.010 Waste water 2.360 Hydrochloric Acid Gas 0.126 Evaporation Loss 0.089 Total 7.113 Total 7.113

97

19. Tranexamic Acid

Process Description: Hydrogenation of 4-(Methylamino) benzoic acid sulphate in water is done in presence of 5% Pd/c. Reaction mass is filtered to remove the 5% Pd/c. The reaction mass is transferred to reactor and calcium hydroxide is added till specific pH observed. Distill off specified quantity of water and cool to 60 °C. Charge Toluene and stir. Stop stirring and let the layers to settle down. Remove aqueous layer. Cool the reaction mass to 0 – 5°C. The reaction mass is than centrifuged. Wash with chilled Toluene during centrifuge. Dry the material.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 4-(aminomethyl)benzoic acid 3.000 Product 1.000 Sulphate Water 16.000 Recovered Pd/C 0.050 Hydrogen Gas 0.040 Toluene Recovery 2.542 Pd/C 0.050 Water recovery 14.000 Calcium Hydroxide 0.900 Waste Water 4.811 Toluene 2.585 Distillation Residue 0.080 Evaporation Loss 0.092 Total 22.575 Total 22.575

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20. Phenyramidol hydrochloride

Process Description: Dimethyl formamide, 2 – Amino pyridine and Caustic Soda are charged in reactor. Heat the reaction mass and add styrene oxide and stir at elevated temperature. Distill out the DMF completely. Add Toluene and Water in reaction mass. Collect the Toluene layer and discard aqueous layer. Apply vacuum and distill out toluene. Add Methanol in residue (after distillation) and stir until the reaction mass become clear. The reaction mass is than treated with activated carbon and filtered. The pH of filtrate is than adjusted with Hydrochloric acid which results in precipitates of Phenyramidol Hydrochloride. The reaction mass is than centrifuged and dried.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2 – Amino Pyridine 0.875 Product 1.000 Dimethyl Formamide 0.960 DMF Recoverey 0.936 Caustic Soda 0.150 Toluene Recovery 0.466 Styrene oxide 0.391 Waste Water 1.023 Water 0.500 Methanol Recovery 0.985 Toluene 0.480 Spent Carbon 0.027 Methanol 1.060 Distillation Residue 0.053 Activated Carbon 0.025 Evaporation Loss 0.099 Hydrochloric Acid Gas 0.148 Total 4.589 Total 4.589

99

21. Ibuprofen Lysinate

Process Description: Ibuprofen solution was obtained by dissolving ibuprofen in Hexane, treated with activated carbon and filtered. Similarly, DL-Lysine solution was prepared by dissolving DL-lysine in water, treated with activated carbon and followed by filtration. Add dropwise lysine solution in Ibuprofen solution dropwise. Obtained solid filtered to give Ibuprofen Lysinate.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Ibuprofen 0.640 Ibuprofen Lysinate 1.000 Hexane 1.220 Haxane Recovery 1.170 Activated Carbon 0.030 Spent Carbon 0.043 Water 0.610 Effluent Water 0.687 Lysine 0.460 Organic Residue 0.015 Hyflo 0.012 Evaporation Loss 0.058 Total 2.972 Total 2.972

100

22. Mesalmine/Mesalazine

Process Description: Demineralized water and 5 – amino salicylic acid (crude) is charged in reactor and heated. Add hydrochloric acid till the reaction mass become clear. The reaction mass is treated with activated carbon and filtered. Clear filtrate is charged in reactor and specific pH is adjusted with caustic soda which results in crystallization of Mesalamine. The crystals are than dried.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 5 - Nitro Salicylic Acid 1.408 Product 1.000 Pd/C catalyst 0.023 Catalyst Recovery 0.023 Sodium Carbonate 0.352 CO2 0.072 Water 2.817 Evaporation Loss 0.141 Hydrogen Gas 0.046 Effluent 4.374 Hydrochloric Acid 0.962 Total 5.610 Total 5.610

23. Aceclofenac Process Description: Diclofenac sodium on condensation with t-Butyl chloro acetate, produces stage-1 product. Toluene is the solvent used in the process. Intermediate is purified with water wash and recovery of Toluene. Reaction proceeds as per the below equation. Above stage on hydrolysis produces pharma. Formic acid is used in the process. Pharma is obtained on purification with Carbon.

101

Chemical Reaction:

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Diclofenac Sodium 1.000 Aceclofenac 1.000 t-Butyl Chloro Acetate 0.475 Toluene Recovery 4.650 Toluene 5.000 DMF Recovery 0.950 DMF 1.000 Residue 0.145 Water 2.000 Evaporation Loss 0.250 Formic Acid 0.348 Effluent Water 2.928 Activated Carbon 0.100 Total 9.923 Total 9.923

24. Albendazole Process Description: 4-Cl-2-Benzimidazole Methyl Carbomate and Sodium Thiocynate reacted in presence of Methanol whioch is reacted with Na2S and Propyl Bromide by which produced Albendazole. Recovered Methanol is distilled and recycled to next batch. Step-II recovered Sodium Thiocynate recycled to next batch.

102

Chemical Reaction:

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Methanol 2.308 Albendazole 1.000 methyl (5-chloro-1H- 0.885 Methanol Recovery 2.218 benzimidazol-2-yl)carbamate sodium thiocyanate 0.327 Residue 0.416 Propyl Chloride 0.308 Evaporation Loss 0.433 Sodium sulfide 0.327 Total 4.154 Total 4.154

25. Ambroxol hydrochloride Process Description: 2-Amino-3,5-dibromobenzaldehyde and Trans 4-aminocyclohexanol are charged in reactor followed by water. Heat the reaction mass to reflux and maintain for 8 hr. Cool the reaction mass and maintain the reaction mass at 0 – 5 ºC. Centrifuge the material. Charge the wet cake in reactor followed by Methanol and stir till clear solution observed. Cool the reaction mass to 0 – 5°C. Add Formic acid slowly below 25 °C. Maintain then reaction mass for 2 hr at 5 – 10 °C. Add activated carbon and filter. Charge the clear filtrate in reactor and add Hydrochloric acid gas till specified pH is observed. Cool the reaction mass to 0 – 5 ºC. Centrifuge the material lot wise. Washing of chilled methanol to be given during Centrifuge process. Dry the material in dryer.

103

Chemical Reaction:

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Trans 4-Amino Cyclohexenol 0.400 Product 1.000 2-Amino-3,5- 0.700 Methanol Recovery 2.445 dibromobenzaldehyde Water 0.650 Spent Carbon 0.019 Methanol 2.500 Distillation Residue 0.037 Formic acid 0.110 Waste Water 0.890 Activated Carbon 0.010 Evaporation Loss 0.069 Hydrochloric acid 0.090 Total 4.460 Total 4.460

26. Trazodone Process Description: [1,2,4]Triazolo[4,3-a]pyridin-3(2H)-one (KSM-01) is reacted with aq. Caustic solution in presence of IPA and convert in to Stage-I. Product precipitate by stirring the reaction mass at lower temperature. Isolate the solid by filtration. Dry the wet material to get stage-I product. 1-(3-Chlorophenyl) piperazine (KSM-02) is condensed with 3-Chloro-1-propanol in presence of sodium iodide and triethyl amine in Toluene to give Stage-II. Give water wash to the reaction mass and acidify organic layer with aq. HCl solution. Charolaise the mass & filter thru hyflow bed.

104

Crystallize solid stage-II by adjusting alkaline pH with aq. caustic solution. Isolate the solid by filtration. Dry the wet material to get stage-I product. Trazodone hydrochloride stage-II is reacted with methane sulfonyl chloride in presence of Triethyl amine in presence of DMF to give mesyl TRZ-A. Filter the reaction mass and isolate inorganic salt. Charge Stage-I in filtrate and stir the reaction mass to convert in to stage-III. Remove solvent by distillation. Dissolve product in Methanol and precipice the product by adding water. Isolate the solid by filtration. Dry the wet material to get stage-III product. Trazodone hydrochloride stage-III is dissolved in methanol and provide Carbon treatment. Filter the reaction mass to remove charcoal. Slowly add hydrochloride to filtrate to convert in to trazodone hydrochloride salt. Isolate the solid by filtration. Dry the wet material to get stage-IV product. Trazodone hydrochloride stage- IV is purified with methanol to give Trazodone hydrochloride. Precipitate the product by stirring the reaction mass at lower temperature. Isolate the solid by filtration. Wet material dissolve in methanol. Filter the clear reaction mass. Precipitate the material by cooling and stirring of reaction mass. Isolate the solid by filtration. Dry the wet material to get stage-IV product.

Chemical Reaction:

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Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) [1,2,4]Triazolo[4,3-a]pyridin- 0.667 Trazadone HCl 1.000 3(2H)-one Caustic Flakes 1.0 IPA Recovered 2.895 Isopropyl Alcohol 0.877 Toluene Recovered 2.098 Toluene 2.098 Methanol Recovery 24.798 1-(3-Chlorophenyl)-piperazine 0.807 Evaporation Loss 1.047 3-Chloro -1-propanol 0.465 Residue 0.199 Hydrochloric Acid 0.744 Effluent 4.549 Activated Carbon 0.100 DMF Recovery 4.298 Hyflow 0.088 Dimethyl Formamide 4.305 Methane Sulfomide Chloride 0.493 Triethyl Amine 0.458 Methanol 25.319 Water 3.509 Total 40.884 Total 40.884

106

27. Pregabalin Process Description: 2-(1-Cyano-3-methyl-butyl)-Malonic acid diethyl ester reacts with Hydrogen in presence of Raney Nickel, Potassium hydroxide, Acetic acid and Water to give Stage-1 product. Stage-1 product reacts with Mandelic acid in presence of Iso propyl Alcohol to give Stage-2 product. Stage-2 product reacts with Sodium hydroxide in presence of Tetra Hydro Furan to give Pregabalin product.

Chemical Reaction:

107

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2-(1-Cyano-3-methyl-butyl)- 3.765 Pregabalin 1.000 Malonic acid diethyl ester Potassium hydroxide 0.825 Ethanol Recovery 2.305 Ethanol 1.000 Iso Propyl Alcohol Recovery 5.965 Acetic acid 0.885 R-Isomer recovery 1.113 Raney nickel 0.025 Tetrahydrofuran Recovery 1.425 Iso Propyl Alcohol 6.250 Mandelic acid recovery- 1.008 Hydrogen gas 0.057 Residue 0.076 Water 1.050 Carbon Dioxide 0.648 (S)-Mandelic acid 1.065 Raney Nickel Reuse 0.025 Tetrahydrofuran 1.500 Evapouration Loss 0.310 Sodium Hydroxide 0.025 Effluent water 2.572 Total 16.446 Total 16.446

28. Omeprazole Process Description: 3, 5-Lutidine undergoes oxidation with Hydrogen peroxide initially in Acetic acid. Then the reaction mass will be subjected to Nitration with Nitric acid and Sulphuric acid mixture. Below is the equation. Above stage compound on reaction with Sodium methoxide, Sodium Hydroxide and Dimethyl sulphate in Methanol and water produces stage-2 product. Reaction takes place as per the equation. A Stage-2 product on reaction with Thionyl chloride, APS and sodium hydroxide produces stage-3 compound. Toluene is the solvent used in the process. Below is the equation. Stage-3 product on condensation with 5-Methoxy -2-Mercapto benzimidazole in presence of C.S. Lye Produces stage-4. Toluene is the solvent medium Above stage-4 compound on reaction with Hydrogen Peroxide produces omeprazole pharma. Methanol and Acetone are used in the process.

Chemical Reaction:

108

109

110

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 3,5-Lutidine 0.430 Omeprazole 1.000 Hydrogen Peroxide 0.320 Methanol Recovery 7.025 Nitric acid 1.075 Toluene Recovery 9.250 Sulphuric acid 1.075 Acetone Recovery 2.375 Acetic acid 2.000 Effluent Water 7.131 Water 1.058 Residue 0.105 Sodium methoxide 0.500 Evaporation Loss 1.185 Sodium hydroxide 0.279 Dimethyl sulphate 0.355 Methanol 7.500 Thionyl Chloride 0.338 Toluene 10.000 2-Mercapto-5-methoxy 0.521 Benzimidazole CS Lye 0.120 Acetone 2.500 Total 28.071 Total 28.071

111

29. Esomeprazole Process Description: 5-Methoxy-2-[(4-Methoxy-3,5-Dimethyl-2-pyridinyl) Methyl Thio]-1H-Benzimidazole reacts with Cumin hydroperoxide and Potassium hydroxide in the presence of Toluene as a solvent media to give stage-1 as product. Stage-1 undergoes hydrolysis with Magnesium sulfate in the presence of Toluene as a solvent media to give Esomeprazole Magnesium Trihydrate as product.

Chemical Reaction:

112

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Omeprazole 0.900 Esomeprazole Magnesium trihydrate 1.000 Cumin hydro peroxide 0.116 Toluene Recovery 3.050 Potassium hydroxide 0.059 Methanol Recovery 0.950 DET 0.065 Organic Residue 0.079 Titanium isopropoxide 0.005 Evaporation Loss 0.200 Toluene 3.200 Effluent water 1.826 Methanol 1.000 Magnesium sulfate 0.160 Water 1.600 Total 7.105 Total 7.105

30. Pantoprazole sodium Process Description: Maltol and Dimethyl sulphate condense in Acetone solvent medium. Excess Dimethyl sulphate is removed by treating the reaction mass with Potassium Carbonate. Reaction takes place as per the below equation. Stage-1 compound on treating with Liquor Ammonia solution stage-2 compound is formed. Reaction proceeds as per the below equation Stage-2 compound on reaction with Phosphorous oxy chloride produces stage-3 compound. Further reaction is stopped by treating the reaction mass with water. Final product is extracted with MDC and after distilling out MDC compound is obtained. Below is the reaction scheme. Stage- 3 compound when reacts with Hydrogen peroxide in presence of Acetic acid, stage-4 compound is obtained. Methanol is the solvent

113 employed. Stage-4 compound on reaction with Methanol in sodium hydroxide presence produces stage-5 compound. Execs Methanol is used. Below is the reaction Above stage compound on reaction with Acetic anhydride produces an intermediate. MDC used as solvent. Product is precipitated with C.S. Flakes. Stage-6 compound when reacts with Thionyl chloride an intermediate is formed. MDC is used as solvent. Product is crystallized in Methanol. Finally, product is purified with Acetone. When 2- Chloromethyl-3, 4-dimethoxy-pyridine Hydrochloride reacts with 5-diFluoro methoxy-2-mercapto- benzimidazole, in presence of Sodium hydroxide, product is formed. Mythylene dichloride is the solvent. Stage-8 is treated with Sodium hypochlorite in presence of Sodium hydroxide, to produce the Pantoprazole sodium. This is purified in Acetone. Methylene dichloride is used as solvent.

Chemical Reaction:

114

115

116

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Maltol 0.850 Pantoprazole Sodium 1.000 Dimethyl sulphate 0.250 Acetone Recovery 9.544 Potassium carbonate 0.015 Toluene Recovery 7.520 Acetone 10.000 MDC Recovery 27.140 Ammonium Carbonate 0.650 Methanol Recovery 8.104 Toluene 8.000 Chloroform + Acetic Anhydride Recovery 1.988 Water 3.340 Carbon Dioxide 0.417 Phosphorous oxy chloride 0.350 Residue 0.120 Sodium Hydroxide 1.290 Evaporation Loss 2.997 Methylenedichloride 28.500 Effluent Water 8.905 Hydrogen peroxide (30%) 0.500 Spent carbon 0.010 Acetic acid 0.450 Methanol 8.750 Acetic Anhydride 0.450 Chloroform 2.000 Thionyl chloride 0.390 5-diFluoromethoxy-2- 0.700 mercapto- benzimidazole Sodium hypochlorite (12%) 1.000 Ammonium Chloride 0.250 Activated Carbon 0.010 Total 67.745 Total 67.745

117

31. Rabeprazole Process Description: 2, 3-Lutidine is reacted with Hydrogen Peroxide in presence of Acetic Acid to give N Oxide it further reacts with Nitration mixture (Nitric Acid + Sulfuric Acid) to give Stage-1. Stage-1 is reacted with 3-Methoxy-1- Propanol and Sodium Hydroxide to get Stage-2 Compound. Stage-2 Compound is reacted with Acetic Anhydride, Sodium Hydroxide and Hydrochloric Acid to get Stage-3 Compound. Stage-3 Compound is reacted with Thionyl Chloride, in the presence of MDC as solvent media to give Stage-4 as product. Stage-4 product reacts with 2Mercapto benzimidazole and sodium hydroxide in the presence of Toluene as a solvent media to give stage-5 as product. Stage-5 Compound is reacted with Sodium Hypochlorite to get Rabeprazole Base. Stage-6 reacts with Sodium hydroxide to get Rabeprazole Sodium.

Chemical Reaction:

118

119

120

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2,3-Lutidine 0.460 Rabeprazole Sodium 1.000 Hydrogen Peroxide (50%) 0.330 Toluene Recovery 12.775 Nitric acid 0.300 DMSO Recovery 1.921 Sulphuric acid 0.352 MDC Recovery 12.800 Water 6.256 Acetone Recovery 1.370 3-Methoxy-1-Propanol 0.200 IPA Recovery 2.800 Sodium Hydroxide 0.561 Spent carbon 0.100 Toluene 9.800 Effluent Water 8.844 DMSO 2.000 Evaporation Loss 1.831 Acetic anhydride 0.390 Residue 0.158 Hydrochloric acid 0.200 Thionyl Chloride 0.530 MDC 13.500 Sodium Sulphate 0.100 2-Mercaptobenzimidazole 0.530 Sodium Hypochlorite (8%) 3.270 Acetone 1.500 Sodium hydro sulphate 0.120 MMA in Methanol 0.100 Isopropyl Alcohol 3.000 Activated Carbon 0.100 Total 43.599 Total 43.599

121

32. Lansoprazole Process Description: 2, 3-Lutidine oxidized with Hydrogen Peroxide in the Presence of Acetic acid and subsequently on Nitration with Nitric Acid, Sulfuric Acid to produces stage-1. Stage-1 Product reacts with 2, 2, 2- tri fluoro ethanol and Sodium hydroxide to give Stage-2A reaction mass. Reaction Mass (Stage-2A) reacts with Acetic Anhydride in presence of Acetic Acid, an intermediate is formed. Further it is treated with dry hydrochloric acid and Sodium hydroxide to give stage-2 Compound. Above compound Chlorinated with Thionyl chloride in presence of Toluene solvent media to give stage-3 Chloro compound. Stage-3 Condensed with 2-Mercapto benzimidazole in Presence of Sodium Hydroxide and Toluene solvent media to give Stage-4 Compound. Stage-4 Compound reacts with Hydrogen peroxide in presence of IPA produces Pharma. The product is further purified with carbon and Water to get pure compound of Lansoprazole.

Chemical Reaction:

122

123

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2,3-Lutidine 0.420 Lansoprazole 1.000 Acetic Acid 0.400 Acetic Acid Recovery 0.400 Hydrogen Peroxide (33%) 0.730 MIBK Recovery 1.300 Sulfuric Acid 1.000 Toluene Recovery 5.680 Nitric Acid 0.247 MDC Recovery 0.950 Water 2.184 Isopropyl Alcohol Recovery 2.090 Sodium Hydroxide 0.369 Chloroform Recovery 2.280 Potassium Carbonate 0.378 Acetone Recovery 1.510 Tri Fluoro Ethanol 0.275 Effluent Water 5.606 MIBK 1.360 Organic Residue 0.019 Acetic Anhydride 0.279 Spent Carbon 0.030 TBAB 0.012 Evaporation Loss 1.051 Toluene 6.000 Hydrochloric acid (33%) 0.303 Activated Carbon 0.030 Thionyl Chloride 0.323 Methylene Dichloride 1.000 2-Mercapto Benz imidazole 0.406 Isopropyl Alcohol 2.200 Chloroform 2.400 Acetone 1.600

124

Total 21.915 Total 21.915 33. Fluconazole Process Description: 1, 3-Difluorobenzene reacts with Chloro acetyl Chloride in the presence of Aluminium chloride to get 2- Chloro-1- (2, 4-difluorophenyl) ethanone. 2-Chloro-1-(2,4-difluorophenyl)ethanone reacts with 1,2,4-triazole in the presence of Triethyl amine and Ethyl Acetate as a Solvent media to get 1-(2,4- ifluorophenyl)-2- (1,2,4- triazol-1- yl)ethanone. 1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)ethanone reacts with Tri methyl sulfoxonium iodide in the presence of potassium hydroxide to get 1-[2-(2,4-difluorophenyl)-2,3- epoxypropyl]-1H-1,2,4-Triazole. 1-[2-(2, 4- difluorophenyl)-2, 3-epoxypropyl]-1H-1, 2, 4-Triazole reacts with 1, 2, 4- triazole in the presence of Potassium carbonate and Toluene solvent media to get Fluconazole Tech. Finally Purified with Isopropyl Alcohol in the presence of Magnesium sulfate to get pure Fluconazole.

Chemical Reaction:

125

126

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 1,3 Difluoro benzene 0.500 Fluconazole 1.000 Chloro Acetyl chloride 0.495 MDC Recovery 7.500 Aluminium Chloride 0.150 Ethyl Acetate Recovery 6.640 MDC 8.000 Toluene Recovery 7.380 Water 2.900 DMF Recovery 6.000 1,2,4-triazole 0.500 IPA Recovery 4.275 Triethyl Amine 0.370 Spent Carbon 0.100 Ethyl Acetate 7.000 Carbon Dioxide 0.150 Trimethyl Sulfoxonium iodide 0.780 Effluent Water 5.950 Potassium Hydroxide 0.200 Evaporation Loss 1.700 Toluene 8.000 Organic Residue 0.170 Cetyl tri methyl Ammonium 0.100 Bromide Potassium carbonate 0.470 DMF 6.500 Hydrochloric Acid 0.250 Magnesium Sulfate 0.050 IPA 4.500 Activated Carbon 0.100 Total 40.865 Total 40.865

34. Dexibuprofen Process Description: Toluene is charged to a reaction vessel followed by Ibuprofen. Temperature of reaction mass is increased and N- octyl D Glucamine is charged. Reaction mass is further heated to get a clear solution. Reaction mass is cooled to room temperature & solid is filtered & dried to give N-octyl D Glucamine salt of Ibuprofen. Mother liquor is stored to recover undesired isomer (Stage – 1). Water is charged to a reaction vessel at room temperature followed by stage-1 material. Aq. Solution of KOH is added slowly & reaction mass is stirred for 2 hrs at same temperature. Solid is filtered to give N-octyl-D Glucamine, which is dried, tested & reused in next batch. Mother liquor is charged to another reaction vessel & pH is adjusted with acetic acid. Solid is filtered to give Dex Ibuprofen. Material is dried & submitted for complete analysis.

Chemical Reaction:

127

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Toluene 2.667 Dexibuprofen 1.000 Ibuprofen 1.333 N - Octyl D-Glucamine Recovery 0.967 N - Octyl D-Glucamine 1.000 Toluene Recovery 2.601 Potassium Hydroxide solution 0.400 Evaporation Loss 0.272 Acetic Acid 0.533 Organic Residue 0.280 Water 3.000 Waste Water 3.813 Total 8.933 Total 8.933

35. Telmisartan Process Description: Methyl-4-(butyramido)3-methyl-5-nitrobenzoate undergoes hydrogenation in the presence of Palladium carbon as catalyst by using Methanol as solvent media to give Stage-1A as product. Stage-1A product reacts with sodium hydroxide and hydrochloric acid to give Stage-1B as product. Stage-1 B product reacts with N- Methylbenzene- 1,2-diamine in the presence of Sodium hydroxide and polyphosphoric acid to give Stage -2 as product. Stage-2 product reacts with 1, 3-dibromo-5, 5-dimethylimidazolidine-2,4-dione in the presence of Chloroform as solvent media to give Stage-3 as product. Stage-2 product reacts with Stage-3 and potassium hydroxide in the presence of acetone as solvent media to give Stage-4 as product. Stage-5 Stage- 4 product reacts with potassium hydroxide and hydrochloric acid in the presence of MDC as solvent media to give stage-5 as product. Stage-5 product undergoes purification with Methanolic ammonia, acetic acid and activated carbon in the presence of methanol as solvent media to give Telmisartan as product.

Chemical Reaction:

128

129

130

131

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Methyl-4-(butyramido)-3- 0.730 Telmisartan 1.000 methyl-5-nitrobenzene Methanol 26.950 Methanol Recovery 26.030 Palladium carbon(Wet 5% 0.030 Chloroform Recovery 3.040 MC) Sodium hydroxide 1.220 n-Hexane Recovery 0.950 Hydrochloric acid 0.800 Acetone Recovery 4.270

132

Water 4.750 MDC Recovery 11.380 N-Methylbenzene-1,2-diamine 0.320 Palladium Carbon Reuse 0.030 Poly phosphoric acid 1.650 Spent Carbon 0.100 Methyl-4-methyl-1,1-biphenyl- 0.570 Residue 0.231 2-carboxylate 1,3-dibromo-5,5-dimethyl 0.720 Effluent water 10.498 imidazolidine-2,4-dione Azo bis isobutyronitrile 0.029 Evaporation Loss 2.513 Sodium meta bisulphate 0.043 Chloroform 3.200 n-Hexane 1.000 Potassium hydroxide 0.330 Acetone 4.500 MDC 12.000 Acetic acid 0.600 Activated carbon 0.100 Methanolic ammonia 0.500 Total 60.042 Total 60.042

36. Losartan Process Description: OTBN and Sodium nitrate are made to react together in Toluene solvent medium using TEA HCl as catalyst. Product is isolated by using Hydrochloric acid. Reaction proceeds as per the below equation. The Above stage-1 material is treated with Trityl chloride. Methylene dichloride is used as solvent. Product is washed with water and crystallized in Methanol. Stage-2 is dissolved in Methylene dichloride and treated with N- Bromo succinimide (NBS). Methylene dichloride is distilled-off to obtain the product. Finally the product is treated with Sodium Metabisulhite solution. The product is washed with Ethyl acetate while centrifuging. Stage-3 mass is dissolved in sodium boro hydride solution. Butyl Chloro formyl imidazole (BCFI), TBAB is made to react with stage-3 solution. Finally treated the mass is dissolved in IPA and HCL mixture. The mass is isolated by precipitated with water. The reaction mass pH is adjusted with NaOH to get the Losartan Base. The stage-4 mass is treated with Potassium hydroxide in Methanol solvent medium.Product is purified with Carbon. Pharma is isolated by distilling of Methanol.

Chemical Reaction:Stage-I

133

134

135

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2-Cyano-4-Methyl biphenyl 0.600 Losartan Potassium 1.000 (OTBN) Sodium Azide 0.220 Toluene Recovery 3.770 TEA HCl 0.250 MDC Recovery 7.600 Hydrochloric acid 0.230 Methanol Recovery 12.200 Sodium nitrite 0.230 IPA Recovery 2.680 Toluene 4.000 Ethyl Acetate Recovery 1.900 Water 9.600 Spent Carbon 0.150 Trityl chloride 0.830 Effluent water 12.904 TEA 0.300 Organic Residue 0.174 MDC 8.000 Evaporation Loss 1.552 Methanol 13.000 N-Bromo succinimide (NBS) 0.450 Sodium meta bisulphate 0.100 Butyl chloro formyl imidazole 0.450 (BCFI) TBAB 0.050 IPA HCl 3.000 Sodium hydroxide 0.270 Potassium hydroxide 0.200 Activated Carbon 0.150 Ethyl Acetate 2.000 Total 43.930 Total 43.930

37. Valsartan Process Description: L-Valine reacts with Methanol in presence of Methanol as solvent media to give Stage-1 as product. Stage-1 product reacts with 4-Bromomethyl-biphenyl-2-carbonitrile in presence of Methanol as solvent media to give Stage-2 as product. Stage-2 product reacts with Valeryl chloride in presence of Methanol as solvent media to give Stage-3 as product. Stage-3 product reacts with Sodium azide, Tri butyl tin chloride undergoes Hydrogenation in presence of Methanol as solvent media t give Valsartan as product.

Chemical Reaction:

136

137

138

139

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) L-Valine 0.450 Valsartan 1.000 Thionyl Chloride 0.457 Methanol Recovery 7.580 Methanol 8.000 Toluene Recovery 23.590 Toluene 25.000 MDC Recovery 4.750 Water 1.750 Xylene Recovery 2.280 Sodium hydroxide 0.400 N-Hexane Recovery 1.900 4-Bromomethyl-biphenyl-2- 0.820 Carbon Dioxide 0.253 carbonitrile Potassium carbonate 0.450 Evaporation Loss 2.120 Valeryl Chloride 0.340 Residue 0.201 TEA 0.200 Effluent Water 5.432 Sodium bicarbonate 0.250 Spent Carbon 0.100 Sodium Sulphate 0.100 Sodium Azide 0.160 Tri butyl tin chloride 0.800 Hydrogen 0.005 Xylene 2.400 MDC 5.000 Acetic Acid 0.400 N-Hexane 2.000 Activated Carbon 0.100 Total 49 Total 49

38. Olmisartan Process Description: Methylation of Diethyl 2-propyl-1-imidazole- 4,5-dicarboxylate is done with methyl iodide to get Ethyl 4-(2- Hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate. Ethyl 4-(2-Hydroxypropan-2-yl)-2-propyl-1H- imidazole-5-carboxylate is condensate with 5-(4'-(bromomethyl) biphenyl-2-yl)- 1-trityl-1H-tetrazole in presence of Potassium tert butoxide to give Ethyl 4-(2-Hydroxy propan-2-yl)-2-propyl-1- ((2'-(1-trityl-1H- tetrazole-5-yl)biphenyl-4-yl) methyl)-1H-imidazole-5-carboxylate. Ethyl 4-(2-Hydroxy propan-2-yl)-2- propyl- 1- ((2'-(1-trityl-1H-tetrazole-5-yl)biphenyl-4-yl) methyl)-1H-imidazole-5-carboxylate is reacted with 4- Chloromethyl)-5-methyl- 1,3-dioxol-2-one in presence of Lithium hydroxide, DMAc and Toluene to give (5- methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(2-hydroxypropan-2-yl)-2-propyl-1- ((2'-(1-trityl-1H-tetrazol-5-yl) biphenyl - 4-yl) methyl)-1H-imidazole-5-carboxylate. (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl 4-(2- hydroxypropan-2-yl)-2-propyl-1- ((2'-(1-trityl-1H-tetrazol-5-yl) biphenyl - 4-yl) methyl)-1H-imidazole-5- carboxylate is react with water using acetic acid as solvent to give Olmisartan.

140

Chemical Reaction:

141

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Diethyl 2-propyl-1H- 0.350 Olmisartan 1.000 imidazole-4,5-dicarboxylate Methyl Iodide 0.402 Organic Residue 0.081 Magnesium 0.037 Diethyl Ether Recovery 0.433 Water 5.579 MCI Recovery 1.808 Diethyl ether 0.455 Toluene recovery 3.108 MCl 1.890 Ethyl acetate recovery 0.410 5-(4'-(bromomethyl)biphenyl- 0.780 DMAC recovery 0.725 2-yl)-1-trityl-1H-tetrazole DMAC 0.911 Evaporation Loss 0.473 Potassium Hydroxide 0.080 Acetone recovery 0.683 Toluene 3.256 Effluent 8.874 Ethyl acetate 0.455 4-(Chloro methyl)-5- methyl- 0.266 1,3-dioxol-2-one Lithium Hydroxide 0.075 Acetic acid 1.821 Acetone 0.717 Nacl 0.520 Total 17.59 Total 17.59

39. Candesartan cilexetil Process Description: Trityl Candisartan is reacted with 1-chloro-ethyl cyclohexyl carbonate using cyclohexane as solvent to give stage – 1. Stage – 1 is reacted with formic acid and water to give candesartan Cilexetil as product.

Chemical Reaction:

142

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Trityl Candisartan 1.900 Candesartan cilexetil 1.000 Dimethyl form amide 10.350 Dimethyl form amide Recovery 9.600 Potassium Carbonate 1.050 Cyclo hexane Recovery 23.750 Cyclohexyl,1-Chloro ethyl 0.575 Ethyl Acetate Recovery 62.150 carbonate Ethyl Acetate 42.000 MDC Recovery 6.200 Sodium Chloride 1.050 Isopropyl alcohol Recovery 4.000 Sodium Sulphate 1.079 Methanol Recovery 9.650 Cyclo hexane 25.000 Carbondioxide 0.094 Water 0.700 Organic Residue 0.041 Ethyl Acetate 23.400 Effluent Water 8.963 MDC 6.500 Evaporation Loss 4.200 Methanol 10.400 Total 129.648 Formic Acid 0.094 Sodium Bicarbonate 1.250 Isopropyl alcohol 4.300 Total 129.648

143

40. Irbesartan Process Description: 2-Butyl-1,3-diaza-spiro[4.4]non-1-en-4-one hydrochloride reacts with 4- Bromomethyl-biphenyl-2- carbonitrile in presence of DMF to give Stage-1 product. Stage-1 product reacts with Sodium azide and Triethyl amine Hydrochloride in presence Toluene and ethyl acetate to give Irbesartan product.

Chemical Reaction:

144

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2-N-Butyl-1,3-diazo spiro(4,4)non,1-ene-4-one 0.580 Irbesartan 1.000 hydrochloride 4-Bromo methyl-1,2- 0.680 DMF Recovery 2.850 Cyanobiphenyl DMF 3.000 Toluene Recovery 3.330 Water 8.700 Ethyl acetate Recovery 2.850 Sodium azide 0.160 IPA Recovery 2.850 Triethyl amine Hydrochloride 0.340 Effluent water 9.254 Toluene 3.500 Evaporation Loss 0.826 Ethyl acetate 3.000 IPA 3.000 Total 22.960 Total 22.960

145

41. Mebeverin hydrochloride Process Description: 1-(4-methoxyphenyl)-propan-2-one undergoes reductive amino ethylation with Hydrogen gas in presence of Pd/C Methanol as a solvent media to give Stage-1 as a product. 3,4-Dimethoxy benzoic caid-4-bromo butyl ester reacts with Stage-1 ,Sodium carbonate in presence of MIBK as a solvent media to give Mebeverine Hydrochloride as a product.

Chemical Reaction:

146

147

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 1-(4-methoxyphenyl)-propan- 0.600 Mebeverine HCl 1.000 2- one Monoethyl Amine (70%) 0.430 Methanol Recovery 1.850 Hydrochloric acid (35%) 0.750 Toluene Recovery 4.220 Methanol 2.000 Ethyl Acetate Recovery 2.350 Sodium Hydroxide (47%) 0.400 Methyl Isobutyl Ketone Recovery 1.410 Hydrogen 0.020 Methylene Dichloride Recovery 1.420 Nitrogen 0.020 Effluent water 4.968 Methyl Isobutyl Ketone 1.500 Evaporation Loss 0.653 Water 2.350 Organic Residue 0.099 3,4-Dimethoxybenzoic acid-4- 1.000 bromo butyl ester Toluene 4.500 Ethyl Acetate 2.500 Methylene Dichloride 1.500 Sodium Carbonate 0.400 Total 17.970 Total 17.970

42. Verapamil hydrochloride Process Description: (3,4-dimethoxyphenyl) acetonitrile is reacted with 2-bromopropane and potassium hydroxide using Dimethyl sulfoxide and cyclohexane as solvent to get stage – I. Hydrogenation of stage -1 in presence of Isopropanol using Palladium carbon as catalyst gives 2-(3,4-dimethyoxyphenyl) ethanamine (Stage – 2). Methylation of Stage -2 is carried out by using Dimethyl sulphate to give stage – III product. Stage – III product is reacted with 1 – bromo – 3 chloro propane and 2-(3,4 dimethoxyphenyl) 3 – methyl butane nitrile to give verapamil hydrochloride.

Chemical Reaction:

148

149

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) (3,4-dimethoxyphenyl) acetonitrile 0.585 Verapamil hydrochloride 1.000 2-bomopropane 0.406 Dimethyl sulfoxide Recovery 0.950 Potassium hydroxide 0.185 Isopropanol Recovery 1.900 Dimethyl Sulfoxide 1.000 Raney Nickel Recovery 0.005 Cyclohexane 0.100 Toluene Recovery 2.850 Water 4.650 Methanol Recovery 1.425 Raney nickel 0.005 Acetone Recovery 2.850 Hydrogen 0.016 Effluent water 7.330 Isopropanol 2.000 Organic Residue 0.100 Dimethyl sulphate 0.418 Evaporation Loss 0.258 Sodium hydroxide 0.415 Total 18.668 Hydrogen chloride 0.223 Toluene 3.000 Acetone 3.000 1-bromo-3-chloro propane 0.442 2-(3,4-dimethoxyphenyl)-3- methylbutanenitrile 0.615 Sodium amide 0.109 Methanol 1.500 Total 18.668

43. Drotaverinhydroch;loride Process Description: Pyro catechol reacts with Diethyl sulphate and sodium hydroxide in the presence of Toluene as solvent media to give Stage-1 as product. Stage-1 product reacts with Para formaldehyde and Hydrochloric acid in the presence of Toluene as solvent media to give Stage-2 as product. Stage-2 product reacts with Sodium cyanide in water media to give Stage-3 as product. Stage-3 product undergoes hydrogenation by using Raney Nickel as catalyst in the presence of Methanol as solvent media to give Stage-4 as product. 3, 4-Diethoxy benzyl cyanide reacts with Sodium hydroxide and Hydrochloric acid in the presence of Toluene as solvent media to give Stage-5 as product. Stage-5 product reacts with Stage-4 in the presence of Toluene as solvent media to give Stage-6 as product. Stage-6 product reacts with Phosphorous oxychloride and Sodium hydroxide by using Toluene as solvent media to give Stage-7 as product. Stage-7 product undergoes purification by using IPA as solvent media to give Drotaverine Hydrochloride as product.

Chemical Reaction:

150

151

152

153

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Pyro catechol 1.538 Drotaverine Hydrochloride 1.000 Diethyl sulfate 1.960 Toluene Recovery 18.305 Toluene 19.147 Methanol Recovery 4.720 Sodium hydroxide (47%) 2.100 IPA Recovery 3.320 Water 1.702 Effluent water 10.275 Para formaldehyde 0.410 Residue 0.138 Hydrochloric acid (35%) 1.000 Carbon Dioxide 0.108 Sodium bicarbonate 0.100 Evaporation Loss 1.385 Sodium cyanide 0.558 Raney Nickel Reuse 0.060 Sodium hypochlorite 0.350 Methanol 5.000 Ammonia gas 0.450 Hydrogen 0.030 Nitrogen 0.010 Raney Nickel 0.060 Phosphorous oxy chloride 1.397 IPA 3.500 Total 39.311 Total 39.311

154

44. Lisinopril Process Description: N – (2, 6 – Diamino – hexanoyl) – pyrrolidine – 2 – carboxylic acid Hydrogenated with 5% palladium Carbon Catalyst & Water. The mass is further treated with 2 – Oxo – 4 – Phenyl Butyric acid and Sodium Hydroxide. The resultant mass is crystallized from methanol to get Lisinopril.

Chemical Reaction:

155

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) N – (2, 6 – Diamino – hexanoyl) – 0.500 Lisinopril 1.000 pyrrolidine – 2 – carboxylic acid 2 – Oxo – 4 - Phenyl Butyric acid 0.700 Methanol Recovery 4.750 5% palladium carbon 0.120 Palladium carbon reuse 0.120 Hydrogen gas 0.020 Effluent Water 2.367 Sodium hydroxide 0.300 Residue 0.303 Methanol 5.000 Evaporation Loss 0.100 Water 2.000 Total 8.640 Total 8.640

45. Ramipril Process Description: 2-(1-carboxy-ethylamino)-4-phenyl-butyric acid ethyl ester undergoes condensation with (cis, endo)- octahydro- cyclopenta[b]pyrrole-2(s)-carboxylic acid to give Stage-1 compound in presence of Ethyl acetate and Triethylamine. Stage-1 compound Purification with Ethanol to give Ramipril

Chemical Reaction:

156

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2-(1-carboxy-ethylamino)-4- 0.686 Ramipril 1.000 phenyl-butyric acid ethylester (cis,endo)-octahydro- cyclopenta[b]pyrrole-2(s)- 0.472 Triethyl amine Hydrochloride 1.290 carboxylic acid hydrochloride Ethyl acetate 1.200 Ethyl acetate Recovery 1.140 Triethylamine 1.200 Evaporation Loss 0.124 Water 0.300 Effluent water 0.344 Ethanol 1.300 Organic residue 0.024 5% Pd/Activated carbon 0.020 Ethanol recovery 1.236 Spent 5% Pd/Activated carbon 0.020 Total 5.178 Total 5.178

46. Atorvastatin calcium Process Description: tert-Butyl-2-[(4R,6S)-6-(cyano methyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate reduction with Hydrogen on Palladium Carbon in presence of Methanol gives tert-Butyl-2- [(4R,6S)-6-(amino ethyl)-2,2-dimethyl-1,3- dioxan-4- yl]acetate. Aniline on condensed with Di methyl Carbonate and 2-Methyl-2-butanone in presence of Methanol gives 4-Methyl-3-oxo-N-phenyl pentanamide. 4-Methoyl-3-oxo-N-Phenyl pentaamide upon reaction with Benzaldehyde in presence of potassium Carbonate, Acetone and Toluene media gives Atorvastatin ester. 2- Benzylidene-4-methyl-3-oxo pentanoic acid phenyl amide on reaction with tert- Butyl- 2-[(4R,6S)-6(amino ethyl)- 2-dimethyl-1,3-dioxan-4-yl] acetate and Fluoro benzaldehyde in presence of para Toulene Sulfonic acid, Isopropyl Alcohol and Toluene media gives Atorvastatin ester. Atrovastatin ester undergoes hydrolysis in presence of Sulfuric acid and methanol gives Atorvastatin. Atorvastatin upon salt formation with Calcium Acetate in presence of Isopropyl Alcohol gives Atorvastatin Calcium. Chemical Reaction:

157

158

159

160

161

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) tert-Butyl-2-[(4R,6S)-6-(cyanomethyl)- 0.664 Atorvastatin Calcium 1.000 2,2-dimethyl, 1,3-dioxane-4-yl]acetate Palladium Carbon 0.013 Methanol Recovery 9.720 Methanol 10.160 Acetone Recovery 1.430 Hyflo 0.027 Toluene Recovery 7.048 Hydrogen Gas 0.050 IPA Recovery 6.808 Dimethyl Carbonate 0.272 Effluent 9.301 2-Methyl 2-Butanone 0.272 Organic Residue 0.231 Aniline 0.272 Evaporation Loss 1.248 Sulfuric Acid 0.032 Spent Carbon 0.018 Water 8.280 Spent Catalyst 0.032 Benzaldehyde 0.276 Potassium Carbonate 0.050 Toluene 7.400 Acetone 1.400 Flouro Benzaldehyde 0.288 Para Toluene Sulfonic acid 0.020 IPA 7.200 Calcium Acetate 0.150 Activated Carbon 0.01 Total 36.836 Total 36.836

47. Rosuvastatin calcium Process Description: 4-Fluoro-Benzadehyde reacts with 4-Methyl-3-oxo-pentanoic acid ethyl ester in presence of Base to give Stage-1 as product. Stage-1 product reacts with S-Methyl iso thio urea and 2, 3Dichloro-5, 6-dicyano benzo quinone in presence of HMPA to give stage-2 as product. Stage-2 product reacts with meta-chloro peroxy benzoic acid to give Stage-4 as product and Meta chloro benzoic acid as by-product. Stage-3 product reacts with methyl amine in presence of Ethanol s solvent media to give Stage-4 as product. Stage-4 product reacts with Methane sulfonyl chloride in presence of Sodium hydride as catalyst to give Stage-5 as product. Stage- 5 product undergoes reduction and oxidation in presence of Hydrogen gas to give Stage-6 as product. Stage-6 product reacts with methyl (3R)-3-(ert-butyldimethylsilyloxy)-5-oxo-6- triphenyl phosphoranylidene hexanoate. Stage-7 product reacts with Hydrogen fluoride in presence of Acetonitrile as solvent media to give Stage-8 as product. Stage-8 product reacts with Sodium Boro hydride undergoes hydrogenation to give Sage-9 as product. Stage-9 product reacts with Calcium chloride undergoes saponification to give Rosuvastatin Calcium as product.

162

Chemical Reaction:

163

164

165

166

167

168

169

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 4-Fluoro benzaldehyde 0.520 Rosuvastatin Calcium 1.000 4-Methyl-3-oxo-pentanoic acid ethyl ester 0.663 Methanol Recovery 5.215 Potassium hydroxide 0.235 MDC Recovery 7.585 Methyl Iodide 0.600 HMPA Recovery 0.945 Methanol 5.500 Ethanol Recovery 2.380

170

Water 2.100 Di methoxy ethane Recovery 2.895 S-Methyl iso thio urea 0.350 Toluene Recovery 7.575 N,N-Dimethyl formamide 2,3-Dichloro-5,6-dicyano benzoquinone 0.850 2.800 Recovery HMPA 1.000 THF Recovery 7.136 MDC 8.000 Ethyl acetate Recovery 10.024 Meta chloro peroxy benzoic acid 1.187 Hydrochloric acid (28-30%) 0.112 Methyl amine 0.102 Effluent water 7.283 Ethanol 2.500 Organic Residue 0.454 Methane sulfonyl chloride 0.295 Evaporation Loss 2.456 Sodium hydride (60%) 0.010 Di methoxy ethane 3.000 Hydrogen 0.010 DIBAL-H 0.010 Toluene 8.000 Methyl(3R)-3-(tert butyl di methyl silyloxy)-5-oxo-6- triphenyl 1.446 phosphoranylidene hexanoate Triethyl amine 0.150 N,N-Dimethyl formamide 3.000 Hydrogen fluoride 0.051 THF 7.500 Ethyl acetate 10.500 Diethyl methoxy borane 0.200 Sodium boro hydride 0.010 Calcium chloride 0.130 Total 57.919 Total 57.859

48. Venlafaxin hydrochloride Process Description: 4-Methoxy phenyl acetonitrile reacts with Cyclohexanone in the presence of Sodium hydroxide as base and Toluene as a solvent media to give stage-1 as product. Stage-1 undergoes reduction with Raney nickel in the presence of Toluene as a solvent media to give stage-2 as product. Stage-2 reacts with Formic acid and Formaldehyde in the presence of Ethyl acetate and MDC as a solvent media to give stage-3 as product. Stage-3 undergoes purification in the presence of Ethyl acetate as a solvent media to give Venlafaxine Hydrochloride as product.

Chemical Reaction:

171

172

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 4-Methoxy Phenyl Acetonitrile 0.560 Venlafaxine 1.000 Cyclohexanone 0.380 Toluene Recovery 5.500 NaOH 0.100 Effluent 2.605 TBAB 0.040 Methanol Recovery 17.405 Toluene 6.000 MDC Recovery 7.500 Water 1.000 Ethyl Acetate Recovery 8.600 Hydrogen Gas 0.015 IPA Recovery 1.800 Raney Nickle 0.040 Evaporation Loss 2.443 Methanol 18.300 Organic Residue 0.370 Formic Acid 0.320 Spent Carbon 0.240 Formaldehyde 0.208 Spent Catalyst 0.040 MDC 8.000 HCl 1.000 Ethyl Acetate 9.000 Sodium Sulphate 0.300 IPA 2.000 Activated Carbon 0.240 Total 47.503 Total 47.503

49. Phenylephrin hydrochloride Process Description: Debenzylation of 1-(3-Benzyloxy-phenyl)-2-methylamino-ethanone Hydrochloride in presence of 10% Pd/c and methanol to get Stage-1 as product. Stage-1 compound Resolution of L-tartaric acid in the presence of methanol to get stage-2 as product. Stage-2 compound reacts with Ammonium hydroxide to get Stage-3 as Product. Stage-3 compound reacts with hydrochloric acid in presence of IPA to get Phenylephrine HCl as product.

Chemical Reaction:

173

174

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 1-(3-Benzyloxy-phenyl)-2- methylamino- 1.860 Phenylephrine HCl 1.000 ethanone Hydrochloride Methanol 12.600 Methanol Recovery 11.960 10% Palladium Carbon 0.220 Toluene Recovery 0.587 Hydrogen gas 0.042 Palladium Carbon Recycle 0.220 Sodium hydroxide 0.017 Chloroform Recovery 3.940 L(+) Tartaric acid 0.759 IPA Recovery 19.000 Chloroform 4.160 L-Tartaric Acid Recovery 0.945 IPA 20.000 Acetone Recovery 3.800 Ammonia Hydroxide 0.440 Residue 0.252 Sulfuric acid 0.620 Evaporation Loss 1.963 Hydrochloric acid 0.097 Effluent Water 2.028 Acetone 4.000 Spent Carbon 0.200 Activated Carbon 0.200 Water 0.880 Total 45.895 Total 45.895

50. Lamotrigine

Process Description: (2, 3 – dichloro phenyl) – Oxo-acetonitrile reacts with Phosphoric acid and amino guanidine in the presences of poly phosphoric acid gives Open form phosphate of lamotrigine. Open form phosphate of lamotrigine is treated with Sodium Hydroxide Solution in presence of propanal to get 6-(2, 3-dichlorophenyl)-1, 2, 4- triazine-3, 5- diamine or Lamotrigine.

175

Chemical Reaction:

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Imminogunidly-2,3- Dichlorobenzyl Cyanide 2.170 Lamotrigine 1.000 Phosphate Sodium Hydroxide 0.490 Sodium Phosphate 0.644 n-Propyl Alcohol(n-PA) 25.714 n-PA Recovered 24.888 Water 0.490 Organic Residue 0.099 Hydrochloricacid 0.116 Effluent Water 1.960 Evaporation Loss 0.389 Total 28.980 Total 28.980

176

51. Labetalol hydrochloride Process Description: Benzyl acetone is reacted with Benzyl amine in presence Methanol, Toluene and Isopropyl alcohol to get stage-I compound. Stage-I compound is reacted with LH-Bromide and Hydrochloric acid in presence of Methanol to get stage-II compound. Stage-II compound is reacted with Hydrogen in presence of Methanol to get Labetalol hydrochloride.

Chemical Reaction:

177

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Benzyl acetone 0.438 Labetalol. HCl 1.001 Benzyl amine 0.317 Methanol Recovery 17.851 Sodium borohydride 1.056 Toluene Recovery 7.919 Sodium carbonate 0.156 IPA Recovery 3.913 Hydrochloric acid 0.717 Effluent 2.760 Methanol 18.297 Spent carbon 0.051 Toluene 7.925 Evaporation Loss 0.637 Water 0.788 Pd/C Recovery 0.291 Hydrogen 0.016 Hydrobromic acid 0.222 IPA 3.937 Total 34.645 Activated carbon 0.050 LH-Bromide 0.656 Pd Carbon 0.292 Total 34.645

52. Cetrizine hydrochloride Process Description: P-Chlorobenzhydryl piperazine react with 2-Chloro ethanol in presence of Sodium hydroxide in toluene solvent. After reaction completion toluene distill out under vacuum give crud product P-Chlorobenzhydryl piperazine ethanol. Stage -1 compound react with Sodium monochloro acetate in Dimethyl formamide. After complete reaction start Centrifuge wet product dry product cetirizine base. Cetirizine base and Acetone are Charged in Reactor. Heat the reaction mass to get clear solution. The pH of reaction mass is adjusted with Hydrochloric Acid gas, cooled, centrifuged and dried.

Chemical Reaction:

178

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) P-Chloro benzhydryl Piperazine 1.000 Product 1.000 Toluene 2.972 Toluene Recovery 2.804 2 - chloroethanol 0.277 DMF Recovery 0.961 Water 2.395 Acetone Recovery 2.109 Caustic Soda 0.139 Distillation Residue 0.089 Sodium mono chloro acetate 0.267 Waste water 3.276 Dimethyl formamide 0.991 Evaporation Loss 0.177 Acetone 2.215 Hydrochloric Acid 0.160 Total 10.416 Total 10.416

53. Levocetrizine hydrochloride Process Description: R (-)-1-[4-(Chlorophenyl)phenyl] Methyl piperazine react with 2-Chloro ethanol in presence of Sodium hydroxide in toluene solvent. After reaction completion toluene distil out under vacuum give crude product Stage - I. Stage - 1 compound react with Sodium monochloro acetate in Dimethyl formamide. After complete reaction start Cf wet product dry product Levocetirizine base. Levocetirizine base and Acetone are Charged in Reactor. Heat the reaction mass to get clear solution. The pH of reaction mass is adjusted with Hydrochloric Acid gas, cooled, centrifuged and dried.

Chemical Reaction:

179

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) R (-)-1-[4-(Chlorophenyl)phenyl] Methyl Piperazine 2.000 Product 1.000 Toluene 2.122 Acetone Recovery 2.152 2 - chloroethanol 0.202 Toluene Recovery 1.960 Water 0.800 DMF Recovery 0.980 Caustic Soda 0.101 Waste water 2.452 Sodium mono chloro acetate 0.273 Distillation Residue 0.112 Dimethyl formamide 1.010 Evaporation Loss 0.275 Acetone 2.260 Total 8.931 Hydrochloric Acid 0.163 Total 8.931

54. Vitamin D3 Process Description: 7 – Hydro cholesterol is treated with methyl tert-butyl ether in presence of UV light by using 1- propanol as solvent to give Cholecalciferol.

Chemical Reaction:

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 7-Dehydrocholestrol 1.250 cholecalciferol 1.000 1-Propanol 6.250 1-propanol Recovery 5.850 Methyl tert-butyl ether 5.000 Evaporation Loss 1.250 Methyl tert-butyl ether Recovery 4.150 Distillation Residue 0.250 Total 12.500 Total 12.500

55. Terbinafine hydrochloride Process Description: Methyl Naphthalene-1-yl-methyl amine on condensation with 1-chloro-6,6- dimethylhept-2-en-4-yne in presence of Potassium carbonate and Toluene as a solvent gives Terbinafine. Terbinafine on reaction with Hydrochloric acid gives Terbinafine hydrochloride.

180

Chemical Reaction:

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Methyl Naphthalene-1-yl-methyl amine 0.621 Toluene Recovery 3.202 1-chloro-6,6- dimethylhept-2-en-4-yne 0.568 Evaporation Loss 0.125 Potassium Carbonate 0.250 Effluent 0.797 Toluene 3.000 Distillation Residue 0.295 Water 0.750 Terbinafine Hydrochloride 1.000 HCl gas 0.050 IPA Recovered 5.820 Isopropyl Alcohol(IPA) 6.000 Total 11.239 Total 11.239

181

56. Minoxidil Process Description: 6-Chloro-pyrimidine-2,4-diamineundergoesOxidationwithHydrogenperoxideinpresenceofmethanol andaceticacidtogiveStage-1product.Stage-1compoundReactwithPiperidineinpresenceofToluene andWatertogiveMinoxidil.

Chemical Reaction:

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 6- Chloro-pyrimidine-2,4-diamine 0.750 Minoxidil 1.000 Hydrogen peroxide 0.180 Methanol Recovery 9.500 Methanol 10.000 Acetic Acid Recovery 3.800 Acetic Acid 4.000 Toluene Recovery 5.700 Water 0.700 Effluent water 1.676 Piperidine 0.420 Organic residue 0.074 Toluene 6.000 Evaporation Loss 0.400 Hydrochloric acid 0.100 Spent carbon 0.060 Activated carbon 0.060 Total 22.210 Total 22.210

182

57. Sertaline hydrochloride Process Description: Racemic Cis & Trans Mixture of Sertraline undergo Resolution with D(-) Mandelic acid in the presence of Methanol as a solvent media to give stage-1 as product. Stage-1 reacts with Hydrochloric acid in the presence of Methylene chloride as a solvent media to give Sertraline Hydrochloride as product.

Chemical Reaction:

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Racemic Cis and Trans Sertraline 1.140 Methylene chloride Recovery 43.230 Caustic Lye 0.750 Evaporation Loss 4.860 D(-) Mandelic acid 0.050 Methanol Recovery 6.840 Methylene chloride 13.500 Effluent 1.800 Methanol 7.200 Organic Residue 0.275 Water 0.400 IPA Recovery 42.735 Hydrochloric acid 0.200 Spent carbon 0.198 Caustic lye 0.500 Sertraline Hydrochloride (pure) 1.000

183

Activated carbon 0.153 Methylene chloride 32.000 IPA 45.000 Activated carbon 0.025 Hyflow 0.020 Total 100.938 Total 100.938

58. Sugammadex sodium Process Description: γ-cyclodextrin reacted with sodium hydride and bromine using Toluene as solvent to give intermediate. The intermediate reaction with methyl-3-mercaptopropionate in methanol to give ester followed by sodium hydroxide solution to get sugammadex sodium.

Chemical Reaction:

184

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) γ-cyclodextrin 0.602 Sugammadex Sodium 1.000 O-xylene 1.204 O-xylene Recovery 1.182 Sodium Hydride 0.093 Methanol Recovery 1.560 Bromine 0.593 Effluent Water 0.512 Methanol 1.620 Hydrobromic acid (45 - 48%) 0.924 3-Sulfanyl Propionic acid 0.394 Evaporation Loss 0.100 Sodium Hydroxide 0.148 Water 0.625 Total 5.278 Total 5.278

59. Apixaban Process Description: The reaction of 3-Morpholino-1-(4-(2-oxopiperidin-1-yl)5,6-dihydropyridine-2(1h)-one with z-Ethyl-2- chloro-2-(2- (4-methoxyphenyl)hydrazono)acetate using ethyl acetate as solvent to give intermediate. Intermediate is reacted with ammonia using ethanol as solvent to give Apixaban.

Chemical Reaction:

185

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 3-Morpholino-1-(4-(2-oxopiperidin-1- 0.782 Apixaban 1.000 yl)5,6-dihydropyridin-2(1h)-one Ethyl Acetate 1.099 Ethyl Acetate Recovery 1.056 z-Ethyl-2-chloro-2-(2-(4- 0.571 Ethanol Recovery 4.208 methoxyphenyl)hydrazono)acetate Ethanol 4.264 Evaporation Loss 0.201 Ammonia 0.037 Distilation Residue 0.207 Water 0.199 Hydrochloric acid (28 - 30%) 0.281 Total 6.953 Total 6.953

60. Tofacitinib Process Description: Condensation of Bis (3R, 4R) - (1- benzyl - 4 methyl - pipeidine - 3yl) methylamine di - toluoyl - L - tartaric acid [KSM - I] and 4-chloro-7-tosyl-pyrrolo[2,3-d] Pyrimidine gives Stage – 1 material. Stage – 1 reacted with Formic acid using methanol as solvent to give stage – 2. Hydrogenation of stage – 2 material is done using Pd/C catalyst resulting formation of Stage – 3 material. Stage -3 material is reacted with ethyl cyanoacetate and Citric acid using n – Butanol as solvent to give tofacitinib citrate.

Chemical Reaction:

186

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Bis (3R, 4R) - (1- benzyl - 4 methyl - pipeidine - 3yl) methylamine di - toluoyl - 0.832 Tofacitinib Citrate 1.000 L - tartaric acid [KSM - I] Water 2.121 Methanol Recovery 1.167 Potassium Carbonate 0.222 Toluene Recovery 1.399 4-chloro-7-tosyl-pyrrolo[2,3-d] 0.626 n - Butanol Recovery 0.802 Pyrimidine Methanol 1.212 Effluent 2.695 Formic Acid 0.101 Carbon Dioxide 0.081 Toluene 1.414 Hydrochloric acid (28 - 30%) 0.142 Hydrogen Gas 0.004 Organic Residue 0.464 Pd/C 0.010 Evaporation Loss 0.219 n - Butanol 0.808 Pd/C Recovery 0.010 Ethyl Chloro Acetate 0.232 Citric Acid 0.394 Total 7.978 Total 7.978

187

61. Teneligliptin HBr Process Description: 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine and tert-butyl (2S)-4-oxo-2-(1,3-thiazolidine-3- carbonyl) pyrrolidine-1-carboxylate are reacted in presence of Sodium triacetoxy borohydride using Methylene Dichloride as solvent to get Intermediate – 1. Reaction mass is centrifuged and dried. The dried material is charged in reactor with ethyl Acetate followed by Hydrobromic acid. The reaction mass is centrifuged to get teneligliptin Hydrobromide. The wet cake from centrifuge is dried.

Chemical Reaction:

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 1-(3-methyl-1-phenyl-1H-pyrazol-5- 0.543 Teneligliptin 1.000 yl)piperazine Methylene Dichloride 1.188 Methylene Dichloride Recovery 1.131 tert-butyl (2S)-4-oxo-2-(1,3-thiazolidine- 0.642 Ethyl Acetate Recovery 4.130 3-carbonyl)pyrrolidine-1-carboxylate Sodium triacetoxyborohydride 0.020 Evaporation Loss 0.391 Ethyl Acetate 4.356 Distillation Residue 0.257 Hydrobromic Acid 0.160 Total 6.909 Total 6.909

62. Lidocaine base Process Description: Diethyl amine and caustic soda is charged in reactor. The reaction mass is cooled and 2, 6 -dimethylphenyl chloroacetamide is added. Heat the reaction mass and maintain. Distill off Diethyl amine. Cool the reaction mass and centrifuge. Wash wet cake with water. Dry the material. Charge the material in reactor followed by water. Adjust pH with Hydrochloric acid and charge toluene. Heat the reaction mass to get clear solution. Add Activated Carbon and filter. The pH of reaction mass is adjusted with Caustic Soda flakes, cooled, centrifuged and dried.

188

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Diethyl Amine 2.250 Product 1.000 Caustic Soda 0.793 Diethyl Aminne Recovery 1.982 2,6-Dimethylphenyl chloroacetamide 1.021 Toluene Recovery 1.458 Water 2.450 Waste Water 3.429 Hydrochloric acid 0.005 Spent Carbon 0.011 Toluene 1.500 Distillation Residue 0.012 Activated Carbon 0.010 Evapouration Loss 0.137 Total 8.029 Total 8.029

63. Benzocaine Process Description: Para Amino Benzoic Acid, Toluene and Retarder charged in reactor. Cool the reaction mass and add Sulfuric Acid in slowly. The reaction mass is than heated and cooled with continuous stirring. The specific pH of reaction mass is adjusted with slowly addition of Caustic soda solution. Heat the reaction mass and stop the stirring. Settled and separate the aqueous layer. Apply vacuum and distill out toluene. Add water in reaction mass and cooled. The reaction mass is than centrifuged and wet cake (Benzocaine Crude) is collected and dried. Methanol and Benzocaine Crude charged in reactor. Heat the reaction mass and stir until the reaction mass become clear. The reaction mass is treated with activated carbon and filtered. Apply vacuum and distill out the Methanol and cooled with continuous stirring. The Reaction mass is centrifuged and dried.

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Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Para Amino Benzoic Acid 1.25 Product 1.00 Toluene 1.00 Toluene Recovery 0.91 Sulphuric Acid 0.12 Methanol Recovery 1.16 Retarder 0.30 Waste Water 2.42 Caustic Soda 0.10 Spent Carbon 0.01 Water 1.70 Distillation Residue 0.02 Methanol 1.16 Evaporation Loss 0.12 Activated Carbon 0.01 Total 5.63 Total 5.63

64. Procaine Process Description:

Para Amino Benzoic Acid, Toluene and Retarder charged in reactor. Cool the reaction mass and add Sulfuric Acid in slowly. The reaction mass is than heated and cooled with continuous stirring. The specific pH of reaction mass is adjusted with slowly addition of Caustic soda solution. Heat the reaction mass and stop the stirring. Settled and separate the aqueous layer. Apply vacuum and distill out toluene. Add water in reaction mass and cooled. The reaction mass is than centrifuged and wet cake (stage - I) is collected and dried. Stage– I and 2 Di-ethyl amino Ethanol is reacted in presence of sulphuric acid, Hydrochloric acid and sodium ethoxide in vessel. Ethanol is recovered during process. Then mass is dried and product is collected at the end.

Chemical Reaction:

190

Mass Balance:

Input material Quantity (MT/MT) Output material Quantity (MT/MT) Para Amino Benzoic Acid 1.07 Procaine 1.00 Toluene 0.86 Toluene Recovery 0.78 Sulphuric Acid 0.58 Ethanol Recovery 0.26 Ethanol 0.26 Effluent 3.63 Caustic Soda 0.08 Evaporation Loss 0.17 Water 1.35 Distillation Residue 0.01 2-diethyl amino Ethanol 1.42 HCl 0.21 Sodium Ethoxide 0.03 Total 5.85 Total 5.85

65. Articaine Process Description: methyl 3-amino-4-methylthio phene-2-carboxylate and 2 – chloro propionyl chloride are reacted using methylene dichloride as solvent to give methyl 3-[(1-chloro-1-oxopropan-2-yl)amino] -4- methylthiophene- 2-carboxylate(Stage-1). Stage – 1 is reacted with N – Propylamine to give Articaine.

191

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Methylene Dichloride 1.011 Articaine 1.000 2 - Chloropropionyl Chloride 0.784 MDC recovery 0.989 Caustic Soda 0.282 NPA recovery 1.199 methyl 3-amino-4-methylthiophene-2- 0.637 Waste water 3.081 carboxylate Water 2.116 Evaporation Loss 0.127 N - Propylamine 1.567 Total 6.396 Total 6.396

66. Prilocaine hydrochloride Process Description: 2 – Chloropropionyl Chloride and Methylene dichloride are charged in reactor and stir at lower temperature. O – Toludine is charged and kept at elevated temperature for specific time. Distill off Methylene Dichloride. The reaction mass is than cooled and water is added. The reaction mass is than filtered. Wash cake with water and dried. N – Propylamine is charged in reactor in which the Intermediate I is added slowly. The reaction mass is than heated and maintained. Distilled off N –

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Propylamine. The reaction mass is cooled with continuous stirring. Sodium hydroxide solution is added to adjust specific pH. The reaction mass is than centrifuged. Wash cake with water and dried. Acetone is charged in reactor in which prilocaine crude is added slowly with continuous stirring. The clear reaction mass is than treated with activated carbon. The reaction mass is filtered and filtrate is collected in reactor. The specific pH of reaction mass is adjusted with addition of Hydrochloric acid. Centrifuge and dry.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Methylene Dichloride 1.032 Product 1.000 2 - Chloropropionyl Chloride 0.800 MDC recovery 1.010 Caustic Soda 0.288 NPA recovery 1.224 O-Toluidine 0.800 Acetone Recovery 0.943 Water 0.780 Spent Carbon 0.011 N - Propylamine 1.600 Waste water 1.769 Acivated Carbon 0.010 Distillation Residue 0.133 Hydrochloric Acid Gas 0.145 Evaporation Loss 0.355 Acetone 0.990 Total 6.445 Total 6.445

193

67. Prilocaine base Process Description: 2 – Chloropropionyl Chloride and Methylene dichloride are charged in reactor and stir at lower temperature. O – Toludine is charged and kept at elevated temperature for specific time. Distill off Methylene Dichloride. The reaction mass is than cooled and water is added. The reaction mass is than filtered. Wash cake with water and dried. N – Propylamine is charged in reactor in which the Intermediate I is added slowly. The reaction mass is than heated and maintained. Distilled off N – Propylamine. The reaction mass is cooled with continuous stirring. Sodium hydroxide solution is added to adjust specific pH. The reaction mass is than centrifuged. Wash cake with water and dried. Prilocaine crude and Hexane charged in Reactor and stir at room temperature. If clarity is ok then chill at lower temperature. The reaction mass is filtered and Reaction mass is centrifuge wash with Hexane and wet cake is collected and dried.

Chemical Reaction:

194

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Methylene Dichloride 1.032 Product 1.000 2 - Chloropropionyl Chloride 0.800 MDC recovery 1.010 Caustic Soda 0.288 NPA recovery 1.224 O-Toluidine 0.800 Hexane Recovery 2.814 Water 0.780 Waste water 1.769 N - Propylamine 1.600 Distillation Residue 0.145 Hexane 2.934 Evaporation Loss 0.272 Total 8.234 Total 8.234

68. Bupivacaine hydrochloride Process Description: 2,6 Xylidine reacted with Picolinic acid using toluene as solvent to give stage – 1 material. Stage – 1 is reacted with N-Butyl chloride using methylene dichloride as solvent to give Bupivacaine base. Bupivacaine base is dissolved in acetone and treated with activated carbon and then reacted with Hydrochloric acid gas to give Bupivacaine hydrochloride.

Chemical Reaction: Water CH CH 3 Toluene 3 NH NH2 OH N + N - H O (18.01) H 2 O H CH CH3 O 3

2,6 - Xylidine Picolinic Acid Stage - I Molecular Formula: C H NO Molecular Formula: C H N O Molecular Formula: C 8H11 N 6 11 2 14 20 2 Formula Weight: 121.17964 Formula Weight: 129.15704 Formula Weight: 232.3214

Methylene Dichloride CH Cl 3 CH3 NH NaOH (39.99) N NH N O + - NaCl (58.44) H CH3 O CH3 CH3 - H 2O (18.01) CH3

N Butyl Chloride Stage - I Bupivacaine Molecular Formula: C H N O 14 20 2 Molecular Formula: C 4H9Cl Molecular Formula: C 18 H28 N2O Formula Weight: 232.3214 Formula Weight: 92.56726 Formula Weight: 288.42772

CH CH3 3 NH NH N Acetone N ClH O O HCl (36.46) CH CH3 3

CH CH3 3

Bupivacaine Bupivacaine Hydrochloride

Molecular Formula: C 18 H29 ClN 2O Molecular Formula: C 18 H28 N2O Formula Weight: 288.42772 Formula Weight: 324.88866

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Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Picolinic Acid 0.433 Bupivacaine Hydrochloride 1.000 Toluene 1.300 Toluene Recovery 1.266 2,6 - Xylidine 0.417 MDC Recovery 1.469 Water 1.200 Acetone Recovery 1.236 Methylene Dichloride 1.533 Evaporation Loss 0.352 N - Butyl Chloride 0.317 Organic Residue 0.154 Sodium Hydroxide 0.273 Effluent Water 1.447 Acetone 1.333 Spent Carbon 0.023 Activated Carbon 0.017 Hyflo 0.007 Hydrochloric Gas 0.117 Total 6.947 Total 6.947

69. Ropivacaine hydrochloride Process Description: 2,6 Xylidine reacted with Picolinic acid using toluene as solvent to give stage – 1 material. Stage – 1 is reacted with N-propyl chloride using methylene dichloride as solvent to give Ropivacaine base. Ropivacaine base is dissolved in acetone and treated with activated carbon and then reacted with Hydrochloric acid gas to give Ropivacaine hydrochloride.

Water CH Chemical Reaction: CH3 3 Toluene NH NH2 OH N + N - H O (18.01) H 2 O H CH CH3 O 3

2,6 - Xylidine Picolinic Acid Stage - I Molecular Formula: C H NO Molecular Formula: C H N O Molecular Formula: C 8H11 N 6 11 2 14 20 2 Formula Weight: 121.17964 Formula Weight: 129.15704 Formula Weight: 232.3214

Methylene Dichloride CH Cl 3 CH3 NH NaOH (39.99) N NH N O + - NaCl (58.44) H CH3 CH3 O - H O (18.01) CH3 2 CH3

N Propyl Chloride Stage - I Ropivacaine Molecular Formula: C H N O 14 20 2 Molecular Formula: C 17 H26 N2O Formula Weight: 232.3214 Formula Weight: 78.54068 Formula Weight: 274.40114

CH CH3 3 HCl (36.46) NH NH N Acetone N ClH O O CH3 CH3 CH CH3 3

Ropivacaine Hydrochloride Ropivacaine

Molecular Formula: C 17 H27 ClN 2O Molecular Formula: C 18 H28 N2O Formula Weight: 274.40114 Formula Weight: 310.86208

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Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Picolinic Acid 0.435 Bupivacaine Hydrochloride 1.000 Toluene 1.304 Toluene Recovery 1.270 2,6 - Xylidine 0.418 MDC Recovery 1.473 Water 1.204 Acetone Recovery 1.221 Methylene Dichloride 1.538 Evaporation Loss 0.341 N - Propyl Chloride 0.261 Organic Residue 0.147 Sodium Hydroxide 0.274 Effluent Water 1.436 Acetone 1.337 Spent Carbon 0.023 Activated Carbon 0.017 Hyflo 0.007 Hydrochloric Gas 0.117 Total 6.911 Total 6.911

70. Tetracaine hydrochloride Process Description: Para Amino Benzoic Acid, Toluene and Retarder charged in reactor. Cool the reaction mass and add Sulfuric Acid in slowly. The reaction mass is than heated and cooled with continuous stirring. The specific pH of reaction mass is adjusted with slowly addition of Caustic soda solution. Heat the reaction mass and stop the stirring. Settled and separate the aqueous layer. Apply vacuum and distill out toluene. Add water in reaction mass and cooled. The reaction mass is than centrifuged and wet cake (stage - I) is collected and dried. Stage– I and 2 Di-methyl amino Ethanol is reacted in presence of sulphuric acid, Hydrochloric acid and sodium ethoxide in vessel to give stage - 2. Ethanol is recovered during process. Stage – 2 is reacted with N – butyl chloride using methylene dichloride as solvent to give Tetracaine. Then mass is dried and product is collected at the end.

197

Chemical Reaction:

198

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Para Amino Benzoic Acid 0.98 Tetracaine 1.00 Toluene 0.78 Toluene Recovery 0.71 Sulphuric Acid 0.53 Ethanol Recovery 0.23 Ethanol 0.23 MDC Recovery 1.34 Caustic Soda 0.32 Effluent 2.60 Water 0.74 Evaporation Loss 0.37 2-methyl amino Ethanol 0.90 Distillation Residue 0.09 HCl 0.19 Sodium Ethoxide 0.02 Methylene Dichloride 1.40 N - Propyl Chloride 0.24 Total 6.34 Total 6.34

71. Cinchocaine hydrochloride Process Description: 2 – hydroxy quinoline- 4 – carboxylic acid is reacted with N, N – Diethylethane-1,2 – diamine using toluene as solvent to give stage – 1 material. Sodium metal is dissolved in 1 – butanol which is reacted with stage – 1 to get Cinchocaine base. Cinchocaine base is dissolved in acetone and treated with activated carbon and then reacted with Hydrochloric acid gas to give Cinchocaine hydrochloride.

Chemical Reaction:

199

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2-hydroxyquinoline-4-carboxylic acid 0.603 Cinchocaine Hydrochloride 1.000 Toluene 1.270 Toluene Recovery 1.227 N1,N1-diethylethane-1,2-diamine 0.381 MDC recovery 1.836 Thionyl Chloride 0.381 IPA recovery 1.849 Water 1.111 Organic Residue 0.223 Sodium Hydroxide 0.397 Evaporation Loss 0.251 1 - Butanol 0.244 Effluent Water 1.994 Sodium Metal 0.076 Spent Carbon 0.025 Methylene Dichloride 1.905 Isopropyl Alcohol 1.905 Activated Carbon 0.016 Hyflo 0.006 Hydrochloric acid gas 0.111 Total 8.406 Total 8.406

72. Meloxicam Process Description: In a clean and dry flask, charge O - xylene & Methyl benzothiazine Isopropyl Ester. Heat it to 50 °c temperature followed by add 2-amino 5-methyl Thiazole. Reflux mixture at 140°C temperature for 24 hrs. In between distilled out o-xylene and Isopropyl Alcohol. Cool reaction mixture to room temperature. Centrifuge the product. Dissolve technical Meloxicam in Isopropyl Alcohol in presence of caustic lye at RT. Add carbon stir for 1 hr. Filter the product and adjust pH to 4.5 with mixture of acetic acid & hydrochloric acid. Filter the product, wash with distilled water and dry the product at 70°C Temperature.

Chemical Reaction:

200

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Benzothiazine Isopropyl Ester 1.100 Product 1.000 2-amino 5-methyl Thiazole 0.422 O-Xylene Recovery 4.686 O - Xylene 4.800 Isopropyl alcohol Recovery 1.685 Isopropyl Alcohol 1.688 Distillation Residue 0.102 Caustic Flakes 0.450 Evaporation loss 0.159 Water 0.100 Spent Carbon 0.045 Activated carbon 0.041 Waste Water 1.924 Acetic Acid 0.500 Hydrochloric acid 0.500 Total 9.601 Total 9.601

73. Piroxicam Process Description: In reactor charge O - Xylene followed by Methyl benzothiazine Isopropyl Ester & 2 –Amino Pyridine. Heat the reaction mass to 140 °C. Reflux it for 3 Hrs. Distil out O - Xylene and Isopropyl Alcohol. Cool to room temperature & centrifuge. Unload the crude cake and charge in reactor followed by Isopropyl Alcohol and stir. Add activated Carbon & reflux for 1 Hr and filter. Cool the filtrate to 10 °C. Wash with chilled Isopropyl Alcohol.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) O - Xylene 6.000 Product 1.000 Methyl benzothiazine Isopropyl Ester 1.327 O - Xylene Recovery 5.884 Isopropyl Alcohol 1.550 Distillation Residue 0.086 Activated carbon 0.020 Isopropyl Alcohol Recovery 1.725 Water 0.500 Waste Water 0.958 2 - Amino Pyridine 0.420 Spent Carbon 0.025

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Total 9.817 Evaporation loss 0.139 O - Xylene 6.000 Methyl benzothiazine Isopropyl Ester 1.327 Isopropyl Alcohol 1.550 Activated carbon 0.020 Water 0.500 2 - Amino Pyridine 0.420 Total 9.817 Total 9.817

74. Lornoxicam Process Description: Methyl 6 chloro-4- hydroxy- 2- methyl- 2H –thieno [2,3-e][1,2] thiazine- 3- carboxylate- 1,1- dioxide and 2- amino pyridine are dissolved in O-Xylene and condensate. Caustic solution and methanol is added in Crude wet cake, charcolized, pH is adjusted with acetic acid, centrifuged and dried.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) O-Xylene 2.500 Product 1.000 Methyl 6 chloro-4- hydroxy- 2- methyl- 2H –thieno [2,3-e][1,2] thiazine- 3- 1.200 O-Xylene Recovery 2.445 carboxylate- 1,1- dioxide 2 - Amino Pyridine (2-AP) 0.300 Methanol Recovery 1.249 Methanol 1.250 Distillation Residue 0.095 Causic Soda 0.150 Spent Carbon 0.018 Water 1.000 Waste Water 1.950 Acetic Acid 0.459 Evaporation Loss 0.112 Activated Carbon 0.010 Total 6.869 Total 6.869

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75. Piroxicam Betacyclodextrin Process Description: Piroxicam and Beta Cyclodextrin are dissolved in Water using Caustic Soda and Filtered. pH is adjusted with Hydrochloric acid, centrifuged and dried.

Chemical Reaction:

203

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Betacyclodextrin 1.043 Product 1.000 Piroxicam 0.117 Waste Water 2.060 Water 2.100 Loss 0.250 Caustic Soda Lye (50%) 0.020 Hydrochloric Acid 0.030 Total 3.310 Total 3.310

76. Sodium Picosulphate Process Description: In a clean and dry glass flask, charge pyridine and Bisphenol respectively. Heat it to 80°C temperature. Add Sulphamicaciddropwise&maintaintemperatureofabout80- 85°C.Coolthereactionmixturetoroom temperature. Add solvent, filter the Sulphamic acid complex. Then Add caustic solution in to reaction mixture at room temperature. Warm the mixture at 50°C temperature. Filter Sodium Pico sulphate Technical and dry at65- 70°ctemperature.DissolvetechnicalPicosulphateinsolventat45-50°Ctemperature.Thenadd activatedcarbon&warmto40- 45°Ctemperature.FilteractivatedcarbonandDistilledout50%ofsolvent fromreactionmixture.Coolreactionmixtureto10°C.Centrifugethepureproduct&dryitat70-75°c temperature.

Chemical Reaction:

204

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Sulphamic Acid 0.400 Product 1.000 Pyridine 1.800 Methanol Recovery 6.396 Bisphenol 1.000 Pyridine recovery 1.651 Methanol 6.640 Spent Carbon 0.082 Activated Carbon 0.080 Waste Water 1.623 Water 1.000 Distillation Residue 0.077 Soda Ash 0.180 Evaporaion Loss 0.271 Total 11.100 Total 11.100

77. Bisacodyl Process Description: In to a clean and dry glass flask, charge bisphenol and acetic anhydride. Chill the mixture to 0 °C.Maintain 5-10°c temperature for 3hrs. Now allow it to cool down til la ttain room temperature and maintain it for 10 hrs. Quench reaction mixture in ice+water and stir it for 3hrs. Filter the product wash with water till neutral pH. Filter the slurry, unload, dry and weigh. In a clear flask, charge Methanol and add wet technical Bisacodyl. Heatittorefluxandmakeclearsolution.AddsomeActivatedcarbonandrefluxfor1/2hr.Filter.Distille d out50%ofMethanolcharged.Chillthereactionmixtureto5°candmaintainitfor1hr.Filterthepure product,washwithchilledMethanol.Drytheproductat65-70°C.

Chemical Reaction:

205

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Bisphenol 1.000 Product 1.000 Acetic Anhydride 0.285 Methanol recovery 0.605 Water 1.200 Spent Carbon 0.045 Methanol 0.620 Waste Water 1.887 Activated Carbon 0.040 Distillation Residue 0.010 Ice 0.500 Evaporation Loss 0.098 Total 3.645 Total 3.645

78. Alendronate Sodium Process Description: In a clean & dry Glass reactor, charge Gamma Amino Butyric Acid and Phosphorus Acid. Chlorination of reaction mass takes place in presence of phosphorus trichloride at temperature of 60-65 °C. Add Hydrolyze reaction mixture in ice-cold water. Take Hydrolyzed reaction mixture, heat to 110 °C temperature for few hours. Cool reaction mixture to 60 °C temperature. Add activated carbon. Filter reaction mixture at room temperature. Add Soda Ash to reaction mixture and adjust pH at 5.5-5.6. Cool reaction mixture to 10 °C. Filter the Product, with little amount of distilled water. Dry the product at 70-75 °c temperature.

206

Chemical Reaction:

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 4 - Amino Butyric Acid 0.375 Product 1.000 Phosphorus Acid 0.354 Hydrochloric Acid (28 - 30%) 1.560 Phosphorus Trichloride 0.500 Spent Carbon 0.012 Soda Ash 0.200 Waste Water 1.465 Activated Carbon 0.010 Evaporation Loss 0.063 Ice 0.500 Water 2.160 Total 4.099 Total 4.099

79. Montelukast Sodium Process Description: 2-[2-3(S)-3-[2-(7-chloro-2-quinolinyl)-ethyl]phenyl]-3-hydroxypropyl] phenyl-2-propanol will be reacted with methane sulfonyl chloride in the presence of toluene to form 2-[2-3(S)-3-[2-(7- chloro-2-quinolinyl)- ethenyl]phenyl-3-methanesulfonyloxypropyl]phenyl-2-propanol. 2- [2- 3(S)-3- [2-(7-chloro-2-quinolinyl)- ethenyl] phenyl-3-methanesulfonyloxypropyl]phenyl-2- propanol will be reacted with 2-[1-(sulfonyl methyl) cyclopropyl] acetic acid in the presence of

207

Methanol to give 1-[[[(1R)-1-[3-(1E)-2-(7-chloro-2- quinolinyl)ethynyl]phenyl]-3-[2-(1-hydroxy-1- methyl ethyl phenyl] propyl] thio] methyl] cyclo propane acetic acid. (Montelukast). 1-[[[(1R)-1- [3-(1E)-2-(7-chloro-2-quinolinyl)ethynyl]phenyl]-3-[2-(1-hydroxy-1-methyl ethyl phenyl]propyl]thio]methyl] cyclo propane acetic acid. (Montelukast) will be reacted withsodium methoxide in the presence of Methanol to give 1-[[[(1R)-1-[3-(1E)-2-(7-chloro-2-quinolinyl) ethynyl] phenyl]- 3-[2-(1-hydroxy-1-methyl ethyl phenyl] propyl] thio] methyl] cyclo propane acetic acid, sodium salt. (Montelukast Sodium).

Chemical Reaction:

208

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2-[2-3(S)-3-[2-(7-chloro-2-quinolinyl)- ethyl]phenyl]-3-hydroxypropyl] phenyl-2- 0.757 Montelukast Sodium 1.000 propanol Methane sulfonyl chloride 0.189 Toluene Recovery 1.455 Toluene 1.500 Methanol Recovery 0.995 Water 0.260 Methanol Recovery 4.816 Caustic Soda 0.130 Evaporation Loss 0.374 Methanol 0.990 Effuent 0.390 2-[1-(sulfonyl methyl) cyclopropyl] acetic 0.247 Distillation Residue 0.033 acid Methanol 4.900 Sodium Methoxide 0.090 Total 9.063 Total 9.063

209

(II) ACTIVE PHARMACEUTICAL INGREDIENT (API) INTERMEDIATES 80) Isobutyl acetophenone Process Description: Acetyl chloride is reacted with 4- isobutyl benzene in presence of aluminum chloride at 0-5 °c and decomposed with ice water. Separation of layer and work up required to get the product p- isobutyl AcetoPhenone.

Chemical Reaction: CH3

CH CH3 3 Ethylene Dichloride CH Cl 3 Aluminium chloride Liquor Ammonia

+ 2CH OH

- HCl (36.46) O CH3

Isobutyl Acetophenone Isobutyl Benzene Acetyl Chloride C H O C H ClO 12 16 C10 H14 2 3 176.25 78.49 134.22

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Ethylene Dichloride 1.491 Isobutyl Acetophenone 1.081 Isobutyl Benzene 0.778 EDC Recovery 1.421 Aluminium Chloride Solution (8- Aluminium Chloride 0.510 4.474 10%) Acetyl chloride 0.536 Evaporation Loss 0.051 Liquor Ammonia 0.003 Distillation Residue 0.013 Water 4.036 IBAP isomer (Cas No. 38861-78-8) 0.049 Ice 0.521 Dilute Caustic Lye Solution 1.054 Caustic Soda 0.268 Total 8.143 Total 8.143

210

81) 1-(2,6-Dichlorophenyl)-2-indolinone Process Description: Condensation of 2 – indolinone and 2,6 – Dichloro phenol is done by using Dimethyl Formamide as solvent to get 1-(2,6-Dichlorophenyl)-2-indolinone

Chemical Reaction:

O OH N Dimethyl Formamide Cl Cl Cl Cl O N + - H 2O (18.01) H

2 - Indolinone 2,6 - Dichloro Phenol 1-(2,6-Dichlorophenyl)-2-indolinone Molecular Formula: C H Cl O Molecular Formula: C 8H7NO 6 4 2 Molecular Formula: C 14 H9Cl 2NO Formula Weight: 133.14728 Formula Weight: 163.00136 Formula Weight: 278.13336

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 1-(2,6-Dichlorophenyl)-2- 3 - Indolinone 0.556 1.000 indolinone Di chloro Phenol 0.611 Evaporation Loss 0.182 Dimethyl Formamide 1.296 DMF Recovery 1.247 Distillatin Residue 0.034 Total 2.463 Total 2.463

82) Try amino pyrimidine sulphate Process Description: Charge Methanol, Sodium Methoxide and Guanidine Nitrate in the reactor. Cool the reaction mass. Add Methyl Cyano acetate slowly. Heat to reflux and maintain it. Cool to room tempetrature and add water and Adjust pH with sulphuric acid. Centrifuge the reaction mass. Wash cake with water. Charge the wet cake in reactor folloewed by Caustic sodalye, Hydraxzine hydrate and raney Nickel. Heat the reaction mass to reflux. Filter the reaction mass to remove ranay Nickel. Adjust pH of reaction mass with sulphuric acid. Centrifuge the reaction mass. Wash cake with water. Dry the material.

211

Chemical Reaction: OH Methanol O OCH 3 NH2 NO Sodium Methoxide N NO 2 + Sodium Nitrate N NH H2N NH2 Water H2N 2 CN H Sulphuric Acid Guanidine Nitrate Methyl Cyano Acetate 2,6-diamino-5-nitroso-1,4-dihydro pyrimidin-4-ol

M.F. : CH 7N4O2 M.W.: C 4H5NO 2 M.F.: C 4H7N5O2 M.W.: 107.09 M.W. : 99.08 M.W.: 157.13

OH OH Hydrazine Hydrate NH2 NO Ni N N H SO Caustic Soda lye 2 4 N NH N NH Water H2N 2 H2N 2 H H Sulphuric Acid

2,6-diamino-5-nitroso-1,4-dihydro Try Amino Pyrimidine Sulphate pyrimidin-4-ol

M.F.: C 4H9N5O6S M.F.: C 4H7N5O2 M.W.: 255.20 M.W.: 157.13

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Methanol 2.11 Product 1.00 Sodium Methoxide 0.79 Methanol Recovery 1.90 Guanidine Nitrate 0.62 Raney Nickle Recovery 0.02 Methyl Cynoacetate 0.50 Effluent 7.23 Water 4.22 Loss 0.11 Sulphuric Acid 0.71 Sodium Nitrite 0.35 Caustic Soda Lye 0.30 Hydrazine Hydrate 0.64 Raney Nickel 0.02 Total 10.26 Total 10.26

212

83) Guanine Process Description: Charge Try amino pyrimidine sulphate, Formic Acid, Sodium Format Caustic Soda flakes and Water in reactor. Heat the reaction mass to reflux and maintain. Charge Activated carbon and pass through Hyflo bed. Charge clear filtrate in reactor. Adjust specified pH with Acetic acid. The material is centrifuged and dried.

Chemical Reaction: OH O

NH2 Sodium Format N N N HCOOH H2SO 4 N N NH Caustic Soda H2N N H2N 2 H H H Water Acetic Acid Try Amino Pyrimidine Sulphate Guanine

Molecular Formula: C 4H9N5O6S Molecular Formula: C 5H5N5O2

Formula Weight: 255.20916 Formula Weight: 167.1255

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) TAPS 1.00 Product 1.00 Formic Acid 5.00 Formic Acid Recovery 2.44 Sodium Formate 0.57 Carbon Waste 0.02 Caustic Soda Flakes 1.00 Effluent 6.07 Water 1.00 Loss 0.16 Hyflo 0.01 Activated Carbon 0.01 Acetic Acid 1.10 Total 9.69 Total 9.69

84) Adenine Process Description: Aniline is carried diazotization with sodium nitrite and sulfuric acid mixture. The diazomass is reacted with mano nitrile to get stage-1.Stage -1 is reacted with formamide and ammonia to get stage-2 product and is isolatedfrom mother liquors and centrifuged.Stage-2 is hydrogenated in hydrogenator in the presence of palladium carbon and water.The aniline is isolated and used for stage-1. The stage-4 product is isolated from waterand centrifuged.Stage-4 is reacted with formamide to get adenine crude. The product is isolated frommother liquors and centrifuged.Adenine crude is recrystallized in acid base neutralization and carbon treatment is carried.Pure adenine is centrifuged and dried.

213

Chemical Reaction: N

N NaOH (39.99) NH2 N NaNO 2 (68.99) N N H SO (98.0) + 2 4 N - 3 H 2O (18.01) - Na SO (142.04) Aniline Malanonitrile 2 4 [( E)-phenyldiazenyl]propanedinitrile Molecular Formula: C H N 6 7 Molecular Formula: C 3H2N2 Molecular Formula: C 9H6N4 Formula Weight: 93.12648 Formula Weight: 66.06138 Formula Weight: 170.17074

N H2N N

O N NH (17.03) N 3 N N + N NH N - H 2O (18.01) 2 NH2

E [( E)-phenyldiazenyl]propanedinitrile Formamide 5-[( )-phenyldiazenyl]pyrimidine-4,6-diamine Molecular Formula: C H N Molecular Formula: C 9H6N4 Molecular Formula: CH 3NO 10 10 6 Formula Weight: 170.17074 Formula Weight: 45.04062 Formula Weight: 214.2266

H2N N

H2N N N 2 H (2.01) N 2 N Pd/C H N N NH2 2 Water NH2 - Aniline (93.12)

pyrimidine-4,5,6-triamine 5-[( E)-phenyldiazenyl]pyrimidine-4,6-diamine

Molecular Formula: C 4H7N5 Molecular Formula: C 10 H10 N6 Formula Weight: 214.2266 Formula Weight: 125.13188

214

H N N NH2 2 O H Water N N + N H N Sodiium Hydroxide 2 NH 2 Sulfuric Acid N NH N 2 Activated Carbon

Adenine pyrimidine-4,5,6-triamine Formamide

Molecular Formula: C 5H5N5 Molecular Formula: C 4H7N5 Molecular Formula: CH 3NO Formula Weight: 125.13188 Formula Weight: 45.04062 Formula Weight: 135.1267

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Aniline 1.122 Adenine 1.000 Sodium nitrite 0.832 Formamide 5.246 Sulfuric acid 1.295 Palladium carbon 0.015 malanonitrile 0.796 Spent carbon 0.016 Sodium hydroxide 2.067 Effluent 8.258 water 2.724 Loss 0.089 Ammonia 0.370 Residue 0.028 Formamide 6.183 Aniline 0.805 Hydrogen gas 0.037 Palladium carbon 0.015 Activated carbon 0.016 Total 15.456 Total 15.456

215

85) (2S)-2-aminobutanamide Hydrochloride Process Description: (2S)-2-aminobutanoic acid is reacted with sodium methoxide to give methyl (2s)-2- aminobutanoate (stage -1). Stage -1 is reacted with hydrochloric acid and ammonia to give (2S)- 2-aminobutanamide hydrochloride.

Chemical Reaction:

O HCl (36.46) O

CH 3ONa (54.03) CH3 H3C OH H3C O - NaCl (-58.44)

NH2 NH - H 2O (18.01) 2 (2 S)-2-aminobutanoic acid methyl (2 S)-2-aminobutanoate Formula Weight: 103.11976 Formula Weight: 117.14634

Molecular Formula: C 5H11 NO 2 Molecular Formula: C 4H9NO 2

O O HCl (36.46)

NH 3 (17.04) CH3 H3C NH2 H3C O - CH 3OH (32.04) NH2 ClH NH2 S methyl (2 S)-2-aminobutanoate (2 )-2-aminobutanamide Hydrochloride Formula Weight: 117.14634 Formula Weight: 138.59594 Molecular Formula: C H ClN O Molecular Formula: C 5H11 NO 2 4 11 2

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) (2S)-2-aminobutanamide (2S)-2-aminobutanoic acid 0.955 1.000 Hydrochloride Methanol 10.000 Methanol Recovery 9.268 Sodium Methoxide 0.500 Evaporation Loss 1.646 Hydrochloric Acid 1.904 Effluent 2.444 Liquor Ammonia 1.000 Total 14.359 Total 14.359

216

86) 1,1-Cyclohexane diacetic acid Process Description: Cyclohexanone and Acetic anhydried is reacted together in presence of glacial acetic acid to get 2,2'-(cyclohexane-1,1-diyl) diacetic acid. The specified quentity of Acetic acid is distilled off. Reaction mass is cooled, centrifuged and dried.

Chemical Reaction: COOH COOH O OO Acetic Acid + H3C O CH3

2,2'-(cyclohexane-1,1-d Acetic Anhydried cyclohexanone iyl)diacetic acid Molecular Formula: C H O Molecular Formula: C H O 6 10 4 6 3 M.F.: C 10 H16 O4 Formula Weight: 98.143 Formula Weight: 102.08864 M.W.: 200.23

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Glacial Acetic Acid 0.550 Product 1.000 Cyclohexenone 0.500 Acetic Acid Recovery 0.485 Acetic Anhydried 0.550 Evaporation Loss 0.115 Total 1.600 Total 1.600

87) 3,4-Dimethoxybenzoic acid (Veratric Acid) Process Description: In reactor charge Catechol, Caustic Soda flakes, Dimethyl sulphate and Water. Heat the reaction mass to reflux and maintain. Cool the reaction mass and Centrifuge. Charge the wet material from centrifuge in reactor followed by Dichloro methane. Cool the reaction mass. Add Acetyl chloride in reaction mass slowly below 25 ºC. Quench the reaction mass in to the mixture of Hydrochloric acid and Ice –Water. Stop stirring and let the layers to settle. Keep organic layer in reactor. Distill off Dichloro methane completely. Charge Sodium hypochlorite in to reactor. Heat the reaction mass till clear solution observed. The reaction mass is cooled, centrifuged and dried.

217

Chemical Reaction: OCH 3 OCH Methylene Dichloride 3 OCH OH DMS (126.13) 3 Acetyl chloride (78.49) OCH OH 2 NaOH (39.99) 3 - HCl (36.46) - 2 H 2O (18.01) 3CH O - Na 2SO 4 (142.04) MF= C H O 8 10 2 MF= C 10 H12 O3 MF= C 6H6O2 MW= 138.1 MW= 180.2 MW= 110.1 1-(3,4-dimethoxyphenyl) Veratrole Catechol ethanone

OCH 3 OCH 3 H2O (18.01) OCH 3 OCH 3 NaOCl (74.44)

- CH 3OH (32.04) - NaCl (58.4) OH O 3CH O

MF= C 9H10 O4 MF= C 10 H12 O3 MW= 180.2 MW= 182.2 1-(3,4-dimethoxyphenyl) Veratric acid ethanone

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 3,4-Dimethoxybenzoic acid Catechol 0.36 1.00 (Veratric Acid) Dimethyl Sulphate 0.91 MDC Recovery 4.01 Causti Soda Flakes 0.30 Water Recovery 1.26 Water 3.13 Dilute HCl 1.98 Dichloro Methane (MDC) 4.46 Carbon Waste 0.04 Aluminium Chloride 1.21 Effluent 6.73 Acetyl Chloride 0.79 Loss 0.05 Actvated Carbon 0.04 Hyflo 0.00 Sodium Hydrosulfite 0.01 Hydrochloric Acid 1.78 Ice 0.10 Sodium hypochlorite 1.92 Sodium metabisulphite 0.06 Total 15.07 Total 15.07

218

88) Para Amino Benzoic Acid Process Description: Hydrogenation of p – nitrobenzoic acid by using Pd/C as catalyst gives p – Aminobenzoic acid.

Chemical Reaction: COOH COOH

Pd/C

Water

NO 2 NH2 p - Nitro Benzoicacid p - Amino Benzoicacid

Molecular Formula: C 7H7NO 2 Molecular Formula: C 7H5NO 4 Formula Weight: 137.13598 Formula Weight: 167.1189

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) P- Nitrobenzoic Acid 1.26 Para Amino Benzoic Acid 1.00 Pd/C 0.04 Pd/C recovery 0.04 Water 1.48 Effluent 2.47 Caustic Soda 0.37 Evaporation Loss 0.10 Hydrochloric acid 0.46 Total 3.61 Total 3.61

89) 1-(2,2-Dimethoxyethyl)-1,4-dihydro-3-methoxy-4-oxo-2,5-pyridinedicarboxylic acid 2- methyl ester Process Description: A mixture of methyl 4-methoxyacetoacetate and DMFDMA was stirred at room temperatureand diluted with Methanol and amino acetaldehyde dimethyl acetal was added. Dimethyloxalate was charged followed by portion-wise addition of Lithium hydride to produce 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3- carboxylicacid. And hydrolyzed the material with Lithium hydroxide to affords 1-(2,2- Dimethoxyethyl)-1,4-dihydro-3-methoxy-4-oxo-2,5-pyridinedicarboxylic acid 2-methyl ester. Chemical Reaction:

219

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 1-[2,2-bis(methyloxy)ethyl]-5- [methyloxy)-6- 4-Methoxyacetoacetate 1.802 [(methyloxy)carbonyl]-4- oxo- 1.000 1,4-dihydro-3- pyridine carboxylic acid DMFDMA 1.470 Methanol recovered 5.700 Methanol 6.000 EA recovered 14.250 Aminoacetaldehydedimethylacetal 0.100 Organic Residue 0.018 Dimethyl oxalate 1.455 DMFDMA 0.933 Lithium hydride 0.100 Effluent Water 5.935 Lithium hydroxide 0.295 Evaporation Loss 0.601 Hydrochloric acid 0.700 Ethylaceate 15.000 Water 1.500 Sodium hydroxide 0.015 Total 28.437 Total 28.437

90) (S)-1-(2-Amino-5-chlorophenyl)-1-(trifluoromethyl)-3-cyclopropyl-2-propyn-1-ol Process Description: 4-Chloro-2-trifluoro acetyl aniline hydrochloride reacts with 4-methoxy phenyl methanol,Cyclopropyl acetylene in the presence of MTBE, THF as a solvent media to givesStage- 1 Compound.Stage-1 Compound reacts with DDQ in the presence of Toluene, Methanol to getStage-2 Compound in MethanolStage-2 Compound reacts with sodium borohydride in the presence of sodiumhydroxide in methanol, Toluene to get (S)-1-(2-Amino-5-chlorophenyl)-1- (trifluoromethyl)-3-cyclopropyl-2-propyn-1-ol.

220

Chemical Reaction:

221

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) (S)-1-(2-Amino-5-chlorophenyl)- 4-Chloro-2-trifluoro acetyl aniline 1.000 1-(trifluoromethyl)-3-cyclopropyl- 1.000 hydrochloride 2-propyn-1-ol 4-Methoxy phenyl methanol 0.532 THF Recovery 11.500 Cyclopropyl acetylene 0.260 MTBE Recovery 5.650 Tetrahydrofuran 12.200 Toluene Recovery 21.020 Methyl tert-butyl ether 6.000 Heptane Recovery 1.920 Ammonia 0.050 Effluent Water 3.093 Toluene 22.250 Spent Carbon 0.050 Heptane 2.000 Organic Residue 0.131 Activated Carbon 0.050 Evaporation Loss 2.401 Water 1.600 DDHQ Recycle 0.837 DDQ 0.830 Methanol Recovery 3.780 Sodium bicarbonate 0.100 n-Hexane Recovery 2.380 Methanol 4.050 Acetone Recovery 0.570 Acetic Acid 0.075 Sodium chloride 0.045 Sodium Hydroxide 0.050 n-Hexane 2.500 Acetone 0.600 Sodium borohydride 0.140 Total 54.332 Total 54.332

222

91) (S)-5-Chloro-alpha-(cyclopropylacetenyl)-2-[((4-methoxyphenyl)methyl)amino]-alpha- (trifluoromethyl)benzenemethanol

Process Description: 4-Chloro-2-trifluoro acetyl aniline hydrochloride reacts with 4-methoxy phenyl methanol,Cyclopropyl acetylene in the presence of MTBE, THF as a solvent media to gives80.(S)-5-Chloro-alpha-(cyclopropylacetenyl)-2-[((4-methoxyphenyl)methyl)amino]-alpha- (trifluoromethyl)benzenemethanol.

Chemical Reaction:

223

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) (S)-5-Chloro-alpha-(cyclopropylacetenyl)-2- 4-Chloro-2-trifluoro acetyl aniline 0.667 [((4-methoxyphenyl)methyl)amino]-alpha- 1.000 hydrochloride (trifluoromethyl)benzenemethanol 4-Methoxy phenyl methanol 0.355 THF Recovery 7.667 Cyclopropyl acetylene 0.173 MTBE Recovery 3.767 Tetrahydrofuran 8.133 Toluene Recovery 3.947 Methyl tert-butyl ether 4.000 Heptane Recovery 1.280 Ammonia 0.033 Effluent Water 8.186 Toluene 4.167 Spent Carbon 0.033 Heptane 1.333 Organic Residue 0.162 Activated Carbon 0.033 Evaporation Loss 0.853 Water 8.000 Total 26.895 Total 26.895

92) (1R,2S,5R)-Menthyl-(2R,5S)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-[1,3]oxathiolane-2- carboxylic acid

Process Description: L (-) Menthol is reacted with glyoxylic acid in the presence of catalytic amount ofsulphuric acid, in cyclohexane media to give L (-) menthylglyoxilate, which is purifiedwith sodium bisulfite and formaldehyde to give pure L (-)-Menthylglyoxillate hydrate.L (-) Menthylglyoxilate is reacted with 1,4-Dithiane-2,5-diol in the presence of aceticacid and Toluene as media, to give L- menthyl-5-hydroxy-1,3-oxathiolane-2-carboxylate.Menthyl-5-hydroxy-1,3-oxathiolane-2- carboxylate is reacted with thionyl chloride inthe presence of di methyl form amide and methane sulfonic acid in Toluene as mediato give chloro compound, which is reacted with silyl cytosine complex in the presenceof triethylamine to give crude compound, which is leached with ethyl acetate andD.M.water to give(1R,2S,5R)-Menthyl-(2R,5S)-5-(4-amino-2-oxo-2H- pyrimidin-1-yl)-[1,3]oxathiolane-2-carboxylic acid.

Chemical Reaction:

224

225

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 1R,2S,5R)-Menthyl-(2R,5S)-5- (4-amino-2-oxo-2H-pyrimidin-1- L-Menthol 1.250 1.000 yl)-[1,3]oxathiolane-2-carboxylic acid Cyclohexane + menthol Glyoxalic Acid (50%) 0.500 4.315 Recovery Sulphuric Acid 0.015 Toluene Recovery 7.350 Sodium carbonate 0.100 n-Hexane Recovery 4.370 Cyclohexane 3.750 Ethyl acetate Recovery 1.665 Sodium bisulphate 0.175 HMDS Recovery 0.375 Formaldehyde 0.075 Residue 0.393 Water 1.000 Waste Water 2.033 1,4-Dithiane-2,5-diol 0.225 Evaporation Loss 1.095 Acetic Acid 0.100 Total 22.59 n-Hexane 4.600 Triethyl Amine 0.293 Toluene 7.750 Methyl sulfonic acid 0.008 Dimethyl formamide 0.025 Thionyl chloride 0.314 Cytosine 0.293 HMDS 0.375 Ethyl Acetate 1.750 Total 22.59

93) 2-Amino-3,5-dibromobenzaldehyde Process Description: 2- Amino benzoic acid methyl ester reacts with Bromine in presence of Methanol to give stage- 1 product. Stage-1 product reacts with Sodium borohydride in presence of Hydrochloric acid, water and methanol to give Stage-2 product.

Chemical Reaction:

226

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2-Amino-3, 5-Dibromo- 2-Amino-benzoic acid methyl ester 0.625 1.000 Benzaldehyde Bromine gas 0.661 Methanol recovery 3.446 Methanol 3.500 Effluent water 4.752 Water 4.500 Organic residue 0.253 Sodium Borohydride 0.143 Evaporation Loss 0.130 Hydrochloric acid 0.152 Total 9.581 Total 9.581

94) Trans-4-Aminocyclohexanol Process Description: Charge Water, Paracetamol and Pd/C in autoclave. Take pressure reaction with hydrogen gas till stop consuming. Filter to remove Pd/C. Charge the filtrate in reactor followed by Caustic Soda lye. Heat the reaction mass. Cool the reaction mass and centrifuge. Charge wet cake with toluene and heat. Stop stirring and let the layers to separate. Keep Organic layer in reactor. Cool the reaction mass. Centrifuge the reaction mass. Wash cake with toluene. Dry the material.

227

Chemical Reaction: OH OH OH

3 H 2 NaOH (39.99)

Pd/C Toluene

- CH 3COONa (82.03) NHCOCH 3 NHCOCH 3 NH2

4-Acetylaminophenol Trans 4-Acetylaminocyclohexanol Trans-4-Aminocyclohexanol

MW : 151.16 MW: 157.21 MW : 115.17

MF : C H NO MF : C H NO MF : C 6H13 NO 8 9 2 8 15 2

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Paracetamol 2.500 Product 1.000 Water 6.000 Pd/C Recovery 0.099 Pd/C 0.100 Toluene Recovery 5.586 Hydrogen Gas 0.100 Distillation Residue 0.018 Caustic Soda 0.662 Waste Water 8.306 Toluene 5.730 Evaporation Loss 0.083 Total 15.092 Total 15.092

95) (3,4-Dimethoxyphenyl)acetonitrile Process Description: Charge Hydrochloric acid CP and chloroform and paraformaldehyde in to the reactor at 25- 35°C. Cool the reaction mass and add Veratrol in to the glass line reactor. Stir the reaction mass until desired product. Then Settle the content for 1 Hr. Separate out aqueous layer .Collect Organic layer in to a separate glass addition vessel connected with cynation reactor. In to a separate SS reactor charge water and sodium cyanide with all safety precautions at 25-35°C.and stir for 15-30 min. Heat up to 60-65°C and add Veratrol chloride (Intermediate) in chloroform solution from glass addition vessel. Maintain temperature 60-65°C for 6-10 hrs.After reaction over add water and Settle. Separate out Aq. layer as effluent and collect in to separate Tank. Add hydrogen peroxide + water + Caustic soda lye or sodium hypochlorite to detoxify. Organic layer collected into Drum and weigh it. Take above crude product for further distillation stage to get Pure (Homoveratontrile)(3,4-Dimethoxyphenyl) acetonitrile.

Chemical Reaction:

228

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) (3,4- Hydrochloric Acid 2.400 1.000 Dimethoxyphenyl)acetonitrile Paraformaldehyde 0.335 Chloroform Recovery 5.761 Chloroform 6.000 Effluent Water 5.624 3, 4 - Dimethoxy Benzene 1.565 Evaporation Loss 0.100 Water 1.300 Organic Residue 0.039 Sodium Bicarbonate 0.100 TBAB 0.064 Sodium Cyanide 0.400 Sodium Hyypochlorite 0.360 Total 12.524 Total 12.524

96) Denatonium Benzoate Process Description: Charge Water and Lidocaine in reactor. Heat to get clear solution. Add benzyl chloride slowly. Heat to reflux and maintain. Cool reaction mass. Charge Toluene and stir. Stop stirring and let the layer to settle. Remove organic layer. Adjust pH with caustic Solution. Centrifuge the material. Charge Wet cake with toluene and Benzoic acid. Heat reaction mass to reflux and maintain. Cool the reaction mass and centrifuge. Dry the material.

229

Chemical Reaction: CH 3 CH3 Toluene NaOH NH NH + Water - CH O N OH + 3 CH3O N Cl - NaCl (58.4) CH 3 CH3 CH 3 CH3

Lidocaine Benzyl Chloride 2-Diethyl Benzyl amino-N- (2,6-dimethylphenyl)acetamide

M.F. : C 14 H22 N2O M.W. : C H Cl 7 7 Molecular Formula: C 21 H30 N2O2 F.W. : 234.33 M.W. : 126.58 Formula Weight: 342.4751

CH - 3 CH3 OO O OH NH NH

- OH + CH O N + + 3 - H 2O (18.01) CH3O N CH 3 CH3 CH 3 CH3 2-Diethyl Benzyl amino-N- Benzoic Acid Denatonium Benzoate (2,6-dimethylphenyl)acetamide M.F. : C H O M.W. : C H N O M.F. : C 21 H29 N2O 7 6 2 28 34 2 3 M.W. : 325.46 F.W. : 122.12 M.W. : 446.58

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Lidocaine 0.500 Product 1.000 Water 2.960 Toluene Recovery 1.890 Toluene 2.000 Distillation Residue 0.024 Benzyl Chloride 0.270 Waste Water 3.259 Caustic Soda Flakes 0.290 Evaporation Loss 0.121 Benzoic Acid 0.274 Total 6.294 Total 6.294

97) 4-(Aminomethyl) Benzoic Acid Process Description: Charge Chlorobenzene and p-Toluic acid in reactor. Cool the reaction mass. Pass chlorine gas in reaction mass till specific pH observed. Maintain the reaction mass and Centrifuge. Dry the material. Charge Water, 4- Chloromethyl) Benzoic Acid and Caustic soda in reactor. Cool the reaction mass. Add Liquor Ammonia Slowly till neutral pH observed. Heat the reaction mass to reflux. Cool the reaction mass. Centrifuge the reaction mass. Wash wet cake with water. Charge the wet material in reactor with water. Adjust pH of reaction mass with sulphuric acid. Distill off specified quantity of water. The reaction mass is centrifuged and dried.

230

Chemical Reaction: COOH COOH Chlorobenzene Pd/C + Cl 2 - HCl (36.46)

CH3 CH 2Cl p - Toluic acid Chlorine Gas 4-(chloromethyl)benzoic acid Molecular Formula: Cl M.F.: C 8H7ClO 2 Molecular Formula: C 8H8O2 2 Formula Weight: 136.14792 Formula Weight: 70.906 M.W.: 170.59

COOH COOH Water NaOH (39.99)

H2SO 4 (M.W.: 98.08) + NH3 - NaCl (58.44)

- H O (18.01) CH 2NH 3.HSO 4 CH 2Cl 2 4-(aminomethyl) benzoic 4-(chloromethyl)benzoic acid Ammonia acid sulfate M.F.: C H NO S M.F.: C 8H7ClO 2 M.F.: H 3N 8 11 6 M.W.: 249.24 M.W.: 170.59 M.W.: 17.03

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Chlorobenzene 4.38 Product 1.00 p - toluic acid 1.46 Chlorobenzene Recovery 4.28 Chlorine 0.76 Water Recovery 5.00 Water 6.53 30% HCl 1.52 Caustic Soda 0.42 Distillation Residue 0.02 Liquor Ammonia 0.18 Waste Water 2.07 Sulphuric Acid (50%) 0.46 Evaporation Loss 0.30 Total 14.20 Total 14.20

98) 1-(3-Chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride Process Description: Charge xylene & 3-Chloro Aniline and BCA in G.L.R. Heat and reflux for 24 hour. Cool to Room Temperature &charge water & caustic lye up to 10-12 pH. Separate out equal layer & give water wash 200-300 liter of xylene layer (product) 3 to 4 times. Distill out xylene & distill out product through high vacuum. Product charge in GLR & Acetone & cool. Add 1-Bromo –3 chloro-1-propane in room temperature maintain 8-10 hr& distill out Acetone. Charge water & toluene &separate aqueous layer. Give water wash 200-300 liter 3 to 4 times toluene layer (product). In toluene layer charge HCl & chill. Centrifuge the material & give Acetone wash & dry.

231

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 1-(3-Chlorophenyl)-4-(3- Xylene 5.000 chloropropyl)piperazine 1.200 hydrochloride 3-chloro aniline 1.000 Xylene Recovery 4.720 BCA 1.400 Acetone Recovery 11.480 Caustic Lye 0.400 Toluene Recovery 2.927 Water 4.400 Organic Residue 0.350 Acetone 12.000 Evaporation Loss 1.140 Potassium Carbonate 0.900 Effluent Water 7.483 1 - Bromo 3 - chloro propane 1.200 Toluene 3.000 Total 29.300 Total 29.300

232

99) (R)-(-)-3-(2-Amino-2-oxo ethyl)-5-methyl hexanoic acid Process Description: Isoveraldehyde, Cyanoacetamide and piperidine is reacted at 100-110C for 12 hours in presence of sulfuric acid. After completion of reaction, water is added and washed with Toluene. Toluene layer is distilled out to get Isobutyl glutaric acid. Isobutyl glutaric acid is reacted with urea at 140-145 C. Reaction mass is added with water and sodium hydroxide. pH of reaction mass is adjusted with Hydrochloric acid between 1-3 to get 3-(Carbamoylmethyl)-5- methyl hexanoic acid. R(-)-3-Carbomylmehtly-5-methyl hexanoic acid 3-Carbomylmehtly-5- methyl hexanoic acid dissolve in Chloroform with R(+)-1-Phenyl ethylamine and salt is brak in presence of caustic solution to obtain R(-)-3-(Carbomylmethyl)-5-methyl hexanoic acid. Caustic layer is treated with Hydrochloric acid to get R(-)-3-Carbomylmehtly-5-methyl hexanoic acid.

Chemical Reaction:

233

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) (R)-(-)-3-(2-Amino-2-oxo ethyl)- Isoveraldehyde 0.889 1.000 5-methyl hexanoic acid Cyanoacetamide 1.778 Toluene recovery 1.689 Piperidine 0.667 Chlroform recovery 23.219 Sulphuric acid 2.356 R(-) Phenylethyl amine recovery 0.696 Toluene 1.778 Spent Carbon 0.011 Urea 0.649 Evaporation Loss 0.284 Sodium hydroxide 0.444 Residue 0.196 Hydrochloric acid 0.756 Waste Water 10.410 Activated carbon 0.011 Chlroform 24.000 R(+) Phenyl ethyl amine 0.733 Water 3.444 Total 37.504 Total 37.504

234

100) 2-Chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride Process Description: 3, 5-Lutidine is reacted with Hydrogen peroxide in presence of Acetic acid to yield 3, 5-Dimethyl Pyridine-N-Oxide. 3,5-Dimethyl Pyridine-N-Oxide is further reacted with Nitric acid and Sulphuric acid followed by PH adjustment with Ammonia gas and wash with water and Methanol to yield 3,5 Dimethyl-4- Nitro Pyridine – N- Oxide. 3,5 Dimethyl -4- Nitro Pyridine-N- Oxide is reacted with Methanol in presence of Sodium hydroxide followed by neutralization with Acetic acid to yield 3,5-Dimethyl – 4- MethoxyPyridine-N-Oxide. It is further reacted with Dimethyl sulphate using Toluene as solvent to yield 2, 3-Diethyl -4-Methoxy Pyridine-1- Methoxy sulphate salt. 2, 3-Diethyl -4-Methoxy Pyridine-1-Methoxy sulphate salt. Is reacted with Methanol in presence of Ammonium per sulphate using Toluene as solvent followed by pH adjustment to basic Sodium hydroxide to yield 2-Hydroxy methyl -3, 5-Dimethyl-4-methoxy pyridine. 2-Hydroxy methyl-3, 5-Dimethyl-4-methpxy pyridine is further reacted with Thionyl chloride in presence of Dimethyl form amide in Toluene followed by washings with Toluene and Acetone to yield 2-Chloromethyl-3, 5-Dimethyl-4-methoxy pyridine HCl.

Chemical Reaction:

235

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2-Chloromethyl-3,5- Dimethyl-4- Acetic Acid 0.377 1.000 Methoxy Pyridine HCl 3,5 Lutidine 0.362 Methanol 4.686 H2O2 0.290 Toluene 15.241 Methanol 5.063 Acetone 0.400 Sulphuric Acid 1.237 Effluent Water 9.420 Nitric acid 0.715 Evaporation Loss 0.898 Water 9.385 Residue 0.296 Toluene 11.068 DMS 0.348 NaOH 0.719 Ammonium per sulphate 0.835 Carbon 0.077 Sodium Sulphate 0.200 Dimethyl formamide 0.016 Thionyl chloride 0.650 Acetone 0.600 Total 31.942 Total 31.942

101) 5-Methoxy-2-Mercapto Benzimidazole Process Description: 4-Methoxy-2-Nitro-Aniline. Reacts with Sodium Hydrosulphide, undergoes reduction reaction to yield 4-Methoxy-2-Amino Aniline. 4-Methoxy-2-Amino Aniline. Reacts with, Process water, Sodium Hydroxide lye, Carbon disulphide, undergoes cyclization reaction to yield 2-Mercapto-5- Methoxy-Benzimidazole crude. Crude 2-Mercapto-5-Methoxy-Benzimidazole is purified by Filtration in presence of, RO water Sodium Hydroxide and Activated Carbon & the filtrate is Treated With Sodium Hydrosulphite, than acidified with Hydrochloric Acid , than the reaction mixture is slurry and it is centrifuged and washed with RO water and dried to yield pure 2- Mercapto-5-Methoxy-Benzimidazole.

Chemical Reaction:

236

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 5-Methoxy-2-Mercapto 4 - Methoxy 2 - Nitro aniline 1.040 1.000 Benzimidazole Sodium Hydro Sulphide 2.079 Effluent Water 10.039 Carbon Disulphide 0.554 Spent Carbon 0.005 Water 5.446 Evaporation Loss 0.248 Caustic Lye 1.178 Activated Carbon 0.005 Hydrochloric Acid 0.990 Total 11.292 Total 11.292

102) 5-Difluromethoxy-2-Mercapto Benzimidazole Process Description: 4 Hydroxy Acetanilide reacts with diflouro chloro methane in presence of Sodium Hydroxideand Acetonitrile at temp 35 0C to 55 0C yield, 4 Diflouro methoxy Acetanilide.Acetonitriledistil out at up to 110 0C. 4 Diflouro methoxy Acetanilide reacts with Nitric acid underNitration Reaction in presence of Chloroform and then hydrolysis Reaction to yield 4-Diflouro Methoxy 2 Nitro aniline. Chloroform Distil out at Temp up to 110 0C. 4-Diflouro Methoxy-2-Nitro-Aniline Reacts with Sodium Hydrosulphide, undergoes reductionreaction at Temp up to 70 0C to yield 4- Difluoro Methoxy-2-Amino Aniline. 4-DifluoroMethoxy-2-Amino Aniline. Reacts with Carbon

237 disulphide, undergoes cyclization reaction atTemp up to 55 0C to yield 5 Difluoro Methoxy 2Mercapto Benzimidazole crude.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 5-Difluromethoxy-2-Mercapto 4 Hydroxy Acetanilide 0.750 1.000 Benzimidazole Caustic soda Lye 48% 0.400 Acetonitrile Recovery 3.500 Difluoro-chloro Methen 0.400 Chloroform Recovery 7.625 Acetonitrile 3.600 Evaporation Loss 0.093

238

Chloroform 7.750 Waste Water 6.088 Nitric Acid 0.338 Spent Carbon 0.013 Water 2.200 Sodium Hydro sulphide 2.218 Sodium Disulphide 0.350 Caustic Lye 0.125 Activated Carbon 0.013 Hydrochloric Acid 0.175 Total 18.318 Total 18.318

103) 5-Difluoromethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]thio}-1H-benzimidazole Process Description: Maltol and Dimethyl sulphate condense in Acetone solvent medium. ExcessDimethyl sulphate is removed by treating the reaction mass with PotassiumCarbonate. Reaction takes place as per the below equation.Stage-1 compound on treating with Liquor Ammonia solution stage-2 compound isformed. Reaction proceeds as per the below equationStage-2 compound on reaction with Phosphorous oxy chloride produces stage-3compound. Further reaction is stopped by treating the reaction mass with water.Final product is extracted with MDC and after distilling out MDC compound isobtained. Below is the reaction scheme.Stage-3 compound when reacts with Hydrogen peroxide in presence of Acetic acid,stage-4 compound is obtained. Methanol is the solvent employed.Stage-4 compound on reaction with Methanol in sodium hydroxide presenceproduces stage-5 compound. Execs Methanol is used. Below is the reactionAbove stage compound on reaction with Acetic anhydride produces anintermediate.MDC used as solvent. Product is precipitated with C.S. Flakes. Stage-6 compound when reacts with Thionyl chloride an intermediate is formed.MDCis used as solvent. Product is crystallized in Methanol. Finally, product is purified withAcetone.When 2- Chloromethyl-3, 4-dimethoxy-pyridine Hydrochloride reacts with 5-diFluoromethoxy-2- mercapto-benzimidazole, in presence of Sodium hydroxide, product isformed.

Chemical Reaction:

239

240

241

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 5-Difluoromethoxy-2-{[(3,4-dimethoxy-2- Maltol 0.895 1.000 pyridinyl)methyl]thio}-1H-benzimidazole Dimethyl sulphate 0.263 Acetone Recovery 6.067 Potassium carbonate 0.016 Toluene Recovery 7.916 Acetone 6.316 MDC Recovery 18.568 Ammonium Carbonate 0.684 Methanol Recovery 8.531 Chloroform + Acetic Anhydride Toluene 8.421 2.093 Recovery Water 2.989 Carbon Dioxide 0.439 Phosphorous oxy chloride 0.368 Residue 0.121 Sodium Hydroxide 1.232 Evaporation Loss 2.418 Methylenedichloride 19.474 Effluent Water 7.442 Hydrogen peroxide (30%) 0.526 Acetic acid 0.474 Methanol 9.211 Acetic Anhydride 0.474 Chloroform 2.105 Thionyl chloride 0.411 5-diFluoromethoxy-2- mercapto- 0.737 benzimidazole Total 54.595 Total 54.595

104) 2-Chloromethyl 3,4-Dimethoxy Pyridine HCl Process Description: Maltol and Dimethyl sulphate condense in Acetone solvent medium. ExcessDimethyl sulphate is removed by treating the reaction mass with PotassiumCarbonate. Reaction takes place as per the below equation.Stage-1 compound on treating with Liquor Ammonia solution stage-2 compound isformed. Reaction proceeds as per the below equationStage-2 compound on reaction with Phosphorous oxy chloride produces stage-3compound. Further reaction is stopped by treating the reaction mass with water.Final product is extracted with MDC and after distilling out MDC compound isobtained. Below is the reaction scheme.Stage-3 compound

242 when reacts with Hydrogen peroxide in presence of Acetic acid,stage-4 compound is obtained. Methanol is the solvent employed.Stage-4 compound on reaction with Methanol in sodium hydroxide presenceproduces stage-5 compound. Execs Methanol is used. Below is the reactionAbove stage compound on reaction with Acetic anhydride produces anintermediate.MDC used as solvent. Product is precipitated with C.S. Flakes. Stage-6 compound when reacts with Thionyl chloride an intermediate is formed.MDCis used as solvent. Product is crystallized in Methanol. Finally, product is purified with Acetone.

Chemical Reaction:

243

244

245

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2-Chloromethyl 3,4-Dimethoxy Maltol 1.308 1.000 Pyridine HCl Dimethyl sulphate 0.385 Acetone Recovery 8.868 Potassium carbonate 0.023 Toluene Recovery 4.308 Acetone 9.231 MDC Recovery 27.138 Ammonium Carbonate 1.000 Methanol Recovery 12.468 Chloroform + Acetic Anhydride Toluene 4.615 3.058 Recovery Water 3.600 Carbon Dioxide 0.642 Phosphorous oxy chloride 0.538 Residue 0.165 Sodium Hydroxide 1.415 Evaporation Loss 3.149 Methylenedichloride 28.462 Effluent Water 9.074 Hydrogen peroxide (30%) 0.769 Acetic acid 0.692 Methanol 13.462 Acetic Anhydride 0.692 Chloroform 3.077 Thionyl chloride 0.600 Total 69.869 Total 69.869

105) 2-Mercapto Benzimidazole Process Description: Charge OPDA & Carbon Disulfide along with water in the reactor. Add caustic flakes atelevated temperature. During reaction H2S gas shall be evolved which shall be absorbed incaustic scrubber. Now increase the temperature of mass up to 100 OC & then cool it to40 OC. Dump the reaction mass in vacuum nautch & wash it with water till pH 7.0 to 8.0 to getcrude MBI. Charge crude MBI in PP/FRP vessel & add caustic flakes solution to dissolve crudMBI. Filter the solution after giving carbon treatment. Add HCl to maintain pH 5.0 to 6.0.Dump the product in vacuum nautch filter. After filtration, centrifuge the mass to get wet cake of the product & ML shall go to ETP. Dry the cake in dryer to get finish product.

Chemical Reaction:

246

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Water 2.963 2-Mercapto Benzimidazole 1.000 Benzene 1,3 Diamine 0.741 Effluent Water 4.498 Carbon Disulfide 0.611 Spent Carbon 0.019 Sodium Hydroxide 0.241 Evaporation Loss 0.039 Caustic Lye 0.241 Activated Carbon 0.019 Hydrochloric Acid 0.741 Total 5.556 Total 5.556

106) 2-Chloromethoxy-4-(3-Methoxy Propoxy)-3-Methyl Pyridine Process Description: 2, 3-Lutidine is reacted with Hydrogen Peroxide in presence of Acetic Acid to give NOxideit further reacts with Nitration mixture (Nitric Acid + Sulfuric Acid) to giveStage-1. Stage-1 is reacted with 3-Methoxy-1-Propanol and Sodium Hydroxide to get Stage-2Compound. Stage-2 Compound is reacted with Acetic Anhydride, Sodium Hydroxide andHydrochloric Acid to get Stage-3 Compound. Stage-3 Compound is reacted with Thionyl Chloride,in the presence of MDC assolvent media to give 2-Chloromethoxy-4-(3-Methoxy Propoxy)-3-Methyl Pyridine.

247

Chemical Reaction:

248

249

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2-Chloromethoxy-4-(3-Methoxy 2,3-Lutidine 0.575 1.000 Propoxy)-3-Methyl Pyridine Hydrogen Peroxide (50%) 0.413 Toluene Recovery 11.281 Nitric acid 0.375 DMSO Recovery 2.401 Sulphuric acid 0.440 MDC Recovery 8.875 Acetic acid 0.223 Effluent Water 4.384 Water 1.570 Evaporation Loss 1.351 3-Methoxy-1-Propanol 0.250 Residue 0.100 Sodium Hydroxide 0.273 Toluene 11.875 DMSO 2.500 Acetic anhydride 0.488 Hydrochloric acid 0.250 Thionyl Chloride 0.663 MDC 9.375 Sodium Sulphate 0.125 Total 29.393 Total 29.393

107) 2-[[[4-(3-Methoxy Propoxy)-3-Methyl Pyridine-2-yl] Methyl] Thio]-1H-Benzimidazole Process Description: 2, 3-Lutidine is reacted with Hydrogen Peroxide in presence of Acetic Acid to give N Oxide it further reacts with Nitration mixture (Nitric Acid + Sulfuric Acid) to give Stage-1. Stage-1 is reacted with 3-Methoxy-1-Propanol and Sodium Hydroxide to get Stage-2 Compound. Stage-2 Compound is reacted with Acetic Anhydride, Sodium Hydroxide and Hydrochloric Acid to get Stage-3 Compound. Stage-3 Compound is reacted with Thionyl Chloride, in the presence of MDC as solvent media to give Stage-4 as product. Stage-4 product reacts with 2Mercapto benzimidazole and sodium hydroxide in the presence of Toluene as a solvent media to give 2- [[[4-(3-Methoxy Propoxy)-3-Methyl Pyridine-2-yl] Methyl] Thio]-1H-Benzimidazole.

Chemical Reaction:

250

251

252

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2-[[[4-(3-Methoxy Propoxy)-3-Methyl 2,3-Lutidine 0.460 Pyridine-2-yl] Methyl] Thio]-1H- 1.000 Benzimidazole Hydrogen Peroxide (50%) 0.330 Toluene Recovery 12.775 Nitric acid 0.300 DMSO Recovery 1.921 Sulphuric acid 0.352 MDC Recovery 7.100 Acetic acid 0.178 Effluent Water 4.332 Water 5.256 Evaporation Loss 1.281 3-Methoxy-1-Propanol 0.200 Residue 0.085 Sodium Hydroxide 0.368 Toluene 9.800 DMSO 2.000 Acetic anhydride 0.390 Hydrochloric acid 0.200 Thionyl Chloride 0.530 MDC 7.500 Sodium Sulphate 0.100 2-Mercaptobenzimidazole 0.530 Total 28.494 Total 28.494

108) [1,1’-Biphenyl]-2-carbonitrile,4’-[(1,4’-dimethyl -2’-propyl [2,6”-bi-1H-benzimidazole ] - 1’-yl) methyl ] – (1,1-biphenyl)-2-carbonitrile Process Description: Methyl-4-(butyramido)3-methyl-5-nitrobenzoate undergoes hydrogenation in thepresence of Palladium carbon as catalyst by using Methanol as solvent media togive Stage-1A as product.Stage-1A product reacts with sodium hydroxide and hydrochloric acid to give Stage-1B as product.Stage-1 B product reacts with N-Methylbenzene-1,2-diamine in the presence ofSodium hydroxide and polyphosphoric acid to give Stage -2 as product.Stage-2 product reacts with 1, 3-dibromo-5, 5-dimethylimidazolidine-2,4-dione in thepresence of Chloroform as solvent media to give Stage-3 as product.Stage-2 product reacts with Stage-3 and potassium hydroxide in the presence ofacetone as solvent media to give Stage-4 as product.Stage-4 product reacts with potassium hydroxide and hydrochloric acid in thepresence of MDC as solvent media to give stage-5 as product.

Chemical Reaction:

253

254

255

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) [1,1’-Biphenyl]-2-carbonitrile,4’- Methyl-4-(butyramido)-3- methyl-5- [(1,4’-dimethyl -2’-propyl [2,6”-bi- 0.635 1.000 nitrobenzene 1H-benzimidazole ] -1’-yl) methyl ] – (1,1-biphenyl)-2-carbonitrile Methanol 16.217 Methanol Recovery 15.391 Palladium carbon(Wet 5% MC) 0.026 Chloroform Recovery 2.643 Sodium hydroxide 1.061 n-Hexane Recovery 0.826 Hydrochloric acid 0.696 Acetone Recovery 3.713 Water 22.870 MDC Recovery 9.896 N-Methylbenzene-1,2-diamine 0.278 Palladium Carbon Reuse 0.026 Poly phosphoric acid 1.435 Spent Carbon 0.043 Methyl-4-methyl-1,1-biphenyl- 2- 0.496 Residue 0.091 carboxylate 1,3-dibromo-5,5-dimethyl imidazolidine- 0.626 Effluent water 27.673 2,4-dione Azo bis isobutyronitrile 0.025 Evaporation Loss 1.777 Sodium meta bisulphate 0.037 Chloroform 2.783 n-Hexane 0.870 Potassium hydroxide 0.287 Acetone 3.913 MDC 10.435 Acetic acid 0.348 Activated carbon 0.043 Total 63.080 Total 63.080

256

109) Methyl 4'-bromomethyl biphenyl-2-carboxylate Process Description: Methyl-4-methyl-1,1-biphenyl 2-carboxylate reacts with 1, 3-dibromo-5, 5- dimethylimidazolidine-2,4-dione in thepresence of Chloroform as solvent media to give Methyl 4'-bromomethyl biphenyl-2-carboxylateas product Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Methyl-4-methyl-1,1-biphenyl- 2- Methyl 4'-bromomethyl biphenyl- 0.776 1.000 carboxylate 2-carboxylate 1,3-dibromo-5,5-dimethyl imidazolidine- 0.980 Chloroform Recovery 4.136 2,4-dione Azo bis isobutyronitrile 0.039 n-Hexane Recovery 1.293 Sodium meta bisulphate 0.059 Residue 0.755 Chloroform 4.354 Effluent water 5.540 n-Hexane 1.361 Evaporation Loss 0.286 Water 5.442 Total 13.010 Total 13.010

257

110) 2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)benzimidazole Process Description: Methyl-4-(butyramido)3-methyl-5-nitrobenzoate undergoes hydrogenation in thepresence of Palladium carbon as catalyst by using Methanol as solvent media togive Stage-1A as product.Stage-1A product reacts with sodium hydroxide and hydrochloric acid to give Stage-1B as product.Stage-1 B product reacts with N-Methylbenzene-1,2-diamine in the presence ofSodium hydroxide and polyphosphoric acid to give2-n-propyl-4-methyl-6-(1- methylbenzimidazole-2-yl)benzimidazole. Chemical Reaction:

258

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2-n-propyl-4-methyl-6-(1-methyl Methyl-4-(butyramido)-3- methyl-5- 1.000 benzimidazole-2-yl) 1.000 nitrobenzene benzimidazole Methanol 11.849 Methanol Recovery 11.260 Palladium carbon(Wet 5% MC) 0.041 Palladium Carbon Reuse 0.041 Sodium hydroxide 1.671 Residue 0.046 Hydrochloric acid 0.411 Effluent Water 8.319 Water 3.699 Evaporation Loss 0.703 N-Methylbenzene-1,2-diamine 0.438 Poly phosphoric acid 2.260 Total 21.370 Total 21.370

259

111) 2n-Butyl-4-chloro-[1-(2'-cyanobiphenyl-4-yl) methyl]-5-(hydroxymethyl)-imidazole Process Description: OTBN and Sodium nitrate are made to react together in Toluene solvent mediumusing TEA HCl as catalyst. Product is isolated by using Hydrochloric acid2n-Butyl-4-chloro-[1-(2'- cyanobiphenyl-4-yl) methyl]-5-(hydroxymethyl)-imidazole.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2n-Butyl-4-chloro-[1-(2'- 2-Cyano-4-Methyl biphenyl (OTBN) 0.857 cyanobiphenyl-4-yl) methyl]-5- 1.000 (hydroxyl methyl)-imidazole Sodium Azide 0.314 Toluene Recovery 5.386 TEA HCl 0.357 Effluent water 15.270 Hydrochloric acid 0.329 Organic Residue 0.120 Sodium nitrite 0.329 Evaporation Loss 0.410 Toluene 5.714 Water 14.286 Total 22.186 Total 22.186

260

112) 5-(4'-Bromomethyl-1, 1'-biphenyl-2-yl)-1-triphenylmethyl-1H-tetrazole (TTBB) Process Description: OTBN and Sodium nitrate are made to react together in Toluene solvent mediumusing TEA HCl as catalyst. Product is isolated by using Hydrochloric acid. Reactionproceeds as per the below equation.The Above stage-1 material is treated with Trityl chloride. Methylene dichloride isused as solvent. Product is washed with water and crystallized in Methanol. Stage-2 is dissolved in Methylene dichloride and treated with N-Bromo succinimide(NBS). Methylene dichloride is distilled-off to obtain the 5-(4'-Bromomethyl-1, 1'-biphenyl-2-yl)-1-triphenylmethyl-1H- tetrazole (TTBB). Chemical Reaction:

261

262

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 5-(4'-Bromomethyl-1,1'biphenyl-2-yl)- 2-Cyano-4-Methyl biphenyl (OTBN) 0.462 1.000 1-triphenylmethyl-1H-tetrazole Sodium Azide 0.169 Toluene Recovery 2.900 TEA HCl 0.192 MDC Recovery 5.846 Hydrochloric acid 0.177 Methanol Recovery 0.692 Sodium nitrite 0.177 Ethyl Acetate Recovery 1.462 Toluene 3.077 Effluent water 15.748 Water 14.615 Organic Residue 0.282 Trityl chloride 0.638 Evaporation Loss 0.694 TEA 0.231 MDC 6.154 Methanol 0.769 N-Bromo succinimide (NBS) 0.346 Sodium meta bisulphate 0.077 Ethyl Acetate 1.538 Total 28.623 Total 28.623

113) 2-Butyl 4-Chloro 5-Formyl Imidazole(BCFI) Process Description: Pantanenitrile and sodium methoxide is reacted using Methanol as solvent to get Methyl pentanimidate. Methyl Pentanenitrile is reacted with methyl iminoacetate and sulfuryl chloride using methanol as solvent to give 2-butyl 4-chloro 5-formyl Imidazole.

Chemical Reaction: 3CH O Methanol N 3CH 3CH 3CH Na HCl (36.46) NH + O

- NaCl (58.44) Methyl pentanimidate Pentanenitrile Sodium Methoxide Molecular Formula: C H NO Molecular Formula: CH NaO 6 13 Molecular Formula: C 5H9N 3 Formula Weight: 115.17352 Formula Weight: 83.13166 Formula Weight: 54.023689

O Cl NH Methanol CH 3 NaOH (39.99) 3 N O NH SO 2Cl 2 (134.96) 3CH 3CH + NH O O - CH 3OH (32.04) CH3

- NaCl (58.44) Methyl pentanimidate methyl iminoacetate 2-Butyl 4-Chloro 5-Formyl Imidazole - Na SO (142.04) Molecular Formula: C H ClN O Molecular Formula: C 3H5NO 2 2 4 8 13 2 Molecular Formula: C 6H13 NO - 2 H 2O (18.01) Formula Weight: 115.17352 Formula Weight: 87.0773 Formula Weight: 188.65462

263

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2-Butyl 4-Chloro 5-Formyl Pentanenitrile 0.472 1.000 Imidazole Methanol 5.556 Methanol Recovery 5.441 Hydrochloric Acid Gas 0.200 Residue 0.467 Sodium Methoxide 0.306 Evaporation Loss 0.325 methyl iminoacetate 0.500 Effluent Water 2.551 Sulfuryl Chloride 0.750 Water 1.333 Sodium Hydroxide 0.667 Total 9.783 Total 9.783

114) 4-(1-Hydroxy-1-methylethyl)-2-propyl-1-[[2'-[(triphenylmethyl)-1H-tetrazol-5-yl][1,1'- biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylic acid ethyl ester) Process Description: Methylation of Diethyl 2-propyl-1-imidazole-4,5-dicarboxylate is done with methyl iodide to get Ethyl 4-(2-Hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate. Ethyl 4-(2- Hydroxy propan -2-yl)-2-propyl-1H-imidazole-5-carboxylate is condensate with 5-(4'-(bromomethyl) biphenyl-2-yl)-1-trityl-1H-tetrazole in presence of Potassium tert butoxide to give 4-(1-Hydroxy- 1-methylethyl)-2-propyl-1-[[2'-[(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]- 1H- imidazole-5-carboxylic acid ethyl ester)[Ethyl 4-(2-Hydroxy propan-2-yl)-2-propyl-1-((2'-(1- trityl-1H-tetrazole-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate. Chemical Reaction:

264

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 4-(1-Hydroxy-1-methylethyl)-2- propyl-1-[[2'-[(triphenylmethyl)- Diethyl 2-propyl-1H- imidazole-4,5- 0.355 1H-tetrazol-5-yl][1,1'-biphenyl]-4- 1.000 dicarboxylate yl]methyl]-1H-imidazole-5- carboxylic acid ethyl ester) Methyl Iodide 0.396 Organic Residue 0.508 Magnesium 0.068 Diethyl Ether Recovery 0.337 Water 0.025 MCI Recovery 0.340 Diethyl ether 0.355 Effluent water 0.166 MCl 0.355 Butanol rec 0.103 5-(4'-(bromomethyl)biphenyl-2-yl)-1- 0.777 Toluene recovery 0.674 trityl-1H-tetrazole DMAC 0.355 Ethyl acetate recovery 0.319 Potassium tert-Butoxide 0.156 DMAC recovery 0.284 Toluene 0.709 Evaporation Loss 0.173 Ethyl acetate 0.355 Total 3.905 Total 3.905

115) 5-Methoxy – 2-oxo-1,3-dioxol - 4 - yl ) methyl - 4 - (1-hydroxy -1 - methylethyl -2 propyl- 1- (2 –(2-triphenylmethyl ) -2H – tetrazole -5 – yl ) biphenyl -4-yl ) methyl ) -1H-imidazole – 5 – carboxylate Process Description: Methylation of Diethyl 2-propyl-1-imidazole-4,5-dicarboxylate is done with methyl iodide to get Ethyl 4-(2-Hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate. Ethyl 4-(2- Hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate is condensate with 5-(4'- (bromomethyl)biphenyl-2-yl)-1-trityl-1H-tetrazole in presence of Potassium tert butoxide to give Ethyl 4-(2-Hydroxy propan-2-yl)-2-propyl-1-((2'-(1-trityl -1H-tetrazole-5-yl) biphenyl-4- yl)methyl)-1H-imidazole-5-carboxylate. Ethyl 4-(2-Hydroxy propan-2-yl)-2-propyl-1-((2'-(1-trityl- 1H-tetrazole-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate is reacted with 4- Chloromethyl)-5-methyl-1,3-dioxol-2-one in presence of Lithium hydroxide, DMAc and Toluene to give (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl4-(2-hydroxypropan-2-yl)-2-propyl-1-((2'-(1-trityl- 1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate. Chemical Reaction:

265

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) (5-methyl-2-oxo-1,3-dioxol-4- yl)methyl 4-(2-hydroxypropan-2- Diethyl 2-propyl-1H- imidazole-4,5- yl)-2-propyl-1-((2'-(1-trityl-1H- 0.318 1.000 dicarboxylate tetrazol-5-yl)biphenyl-4-yl) methyl)-1H-imidazole-5- carboxylate Methyl Iodide 0.354 Waste Water 0.455 Magnesium 0.061 Diethyl Ether Recovery 0.302 Water 0.023 MCI Recovery 0.305 Diethyl ether 0.318 Organic Residue 0.202 MCl 0.318 Butanol rec 0.092 5-(4'-(bromomethyl)biphenyl-2-yl)-1- 0.696 Toluene recovery 1.207 trityl-1H-tetrazole DMAC 0.635 Ethyl acetate recovery 0.286 Potassium tert-Butoxide 0.140 DMAC recovery 0.530 Toluene 1.270 Evaporation Loss 0.251 Ethyl acetate 0.318 Ethanol recovery 0.057 4-(Chloro methyl)-5- methyl-1,3-dioxol- 0.185 2-one Lithium Hydroxide 0.052 Total 4.687 Total 4.687

266

116) Methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylate Process Description: Methyl 2-{[(2'-cyano [1,1'-biphenyl]-4-yl)methyl] camino}-3-nitro benzoateand Methoxyethane reacted in presence of TBAB using Methylene dichloride as solvent to get Methyl 1-[(2'- cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylate. Chemical Reaction: COOCH 3

COOCH 3 N Methylene Dichloride N N NH O CH TBAB N 3 O NO 2 + 3CH CH3 - 2 H 2O (18.01)

Methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]- Methyl 2-{[(2'-cyano[1,1'-biphenyl]-4-yl) Methoxyethane 2-ethoxy-1H-benzimidazole-7-carboxylate methyl]amino}-3-nitrobenzoate Molecular Formula: C 25 H21 N3O3 Molecular Formula: C 3H8O Molecular Formula: C 22 H17 N3O4 Formula Weight: 411.45254 Formula Weight: 387.38808 Formula Weight: 60.09502

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Methyl 1-[(2'-cyanobiphenyl-4- Methyl 2-{[(2'-cyano[1,1'-biphenyl]-4- 0.963 yl)methyl]-2-ethoxy-1H- 1.000 yl)methyl]amino}-3-nitrobenzoate benzimidazole-7-carboxylate Methylene Dichloride 1.975 MDC Recovery 1.879 TBAB 0.025 Evaporation Loss 0.084 Methoxyethane 0.160 Organic Residue 0.037 Effluent 0.123 Total 3.123 Total 3.123

117) Ethyl 2-ethoxy-1-[(2'-cyanobiphenyl-4-yl)methyl]-1H-benzimidazole-7-carboxylate Process Description: Ethyl 2-{[(2'-cyano [1,1'-biphenyl] -4-yl)methyl] amino}-3-nitro benzoate and Methoxy ethane reacted in presence of TBAB using Methylene dichloride as solvent to get Ethyl 2-ethoxy-1-[(2'- cyanobiphenyl-4-yl)methyl]-1H-benzimidazole-7-carboxylate.

Chemical Reaction:

267

O

O O

O CH Methylene Dichloride N 3 N N NH CH3 N O CH3 TBAB NO O 2 + 3CH CH - 2 H 2O (18.01) 3

Ethyl 2-ethoxy-1-[(2'-cyanobiphenyl-4-yl) ethyl 2-{[(2'-cyano[1,1'-biphenyl]-4-yl) Methoxyethane methyl]-1H-benzimidazole-7-carboxylate methyl]amino}-3-nitrobenzoate Molecular Formula: C 26 H23 N3O3 Molecular Formula: C H O Molecular Formula: C 23 H19 N3O4 3 8 Formula Weight: 425.47912 Formula Weight: 401.41466 Formula Weight: 60.09502

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Ethyl 2-ethoxy-1-[(2'- ethyl 2-{[(2'-cyano[1,1'-biphenyl]-4-yl) 0.964 cyanobiphenyl-4-yl)methyl]-1H- 1.000 benzimidazole-7-carboxylate methyl]amino}-3-nitrobenzoate 1.429 MDC Recovery 1.364 TBAB 0.024 Evaporation Loss 0.055 Methoxyethane 0.155 Organic Residue 0.033 Effluent 0.119 Total 2.571 Total 2.571

118) N-[(2'-Cyanobiphenyl-4-methyl)-(L)-Valine methyl ester Hydrochloride Process Description: L-Valine reacts with Methanol in presence of Methanol as solvent media to give Stage-1 as product. Stage-1 product reacts with 4-Bromomethyl-biphenyl-2-carbonitrile and HCl in presence of Tolueneas solvent media to give N-[(2'-Cyanobiphenyl-4-methyl)-(L)-Valine methyl ester Hydrochloride.

Chemical Reaction:

268

269

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 2-[(2-Cyano-biphenyl-4- L-Valine 0.500 ylmethyl)-amino]- 3-methyl- 1.000 butyric acid methyl ester Thionyl Chloride 0.508 Methanol Recovery 8.422 Methanol 8.889 Toluene Recovery 11.544 Toluene 12.222 Carbon Dioxide 0.144 Water 9.333 Evaporation Loss 1.056 Sodium Hydroxide 0.222 Organic Residue 0.195 4-Bromomethyl-biphenyl-2- carbonitrile 0.911 Effluent Water 10.724 Potassium carbonate 0.500 Total 33.086 Total 33.086

119) 4'-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]biphenyl-2-carbonitrile Process Description: 2-Butyl-1,3-diaza-spiro[4.4]non-1-en-4-one hydrochloride reacts with 4-Bromomethyl-biphenyl- 2-carbonitrile in presence of DMF to give4'-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3- yl)methyl]biphenyl-2-carbonitrile.

Chemical Reaction:

270

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 4'-[(2-Butyl-4-oxo-1,3- 2-N-Butyl-1,3-diazo spiro(4,4)non,1- 0.624 diazaspiro[4.4]non-1-en-3- 1.000 ene-4-one hydrochloride yl)methyl]biphenyl-2-carbonitrile 4-Bromo methyl-1,2- Cyanobiphenyl 0.731 DMF Recovery 3.065 DMF 3.226 Effluent water 6.172 Water 6.129 Evaporation Loss 0.473 Total 10.710 Total 10.710

120) tert-Butyl (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4(phenylcarbamoyl) pyrrol -1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl]acetate Process Description: tert-Butyl-2-[(4R,6S)-6-(cyano methyl) -2,2-dimethyl-1,3-dioxan-4-yl]acetate reduction with Hydrogen on Palladium Carbon in presence of Methanol gives tert-Butyl-2-[(4R,6S)-6-(amino ethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate.Aniline on condensed with Di methyl Carbonate and 2-Methyl-2-butanone inpresence of Methanol gives 4-Methyl-3-oxo-N-phenyl pentanamide.4- Methoyl-3-oxo-N-Phenyl pentaamide upon reaction with Benzaldehyde inpresence of potassium Carbonate, Acetone and Toluene media gives Atorvastatinester.2-Benzylidene-4- methyl-3-oxo pentanoic acid phenyl amide on reaction with tert-Butyl-2-[(4R,6S)-6(amino ethyl)-2-dimethyl-1,3-dioxan-4-yl] acetate and Fluorobenzaldehyde in presence of para Toulene Sulfonic acid, Isopropyl Alcohol andToluene media gives Atorvastatin ester.

Chemical Reaction:

271

272

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) tert-Butyl (4R,6R)-2-[[[6-(2-4- fluorophenyl)-5-isopropyl-3- tert-Butyl-2-[(4R,6S)-6-(cyanomethyl)- phenyl-4- 0.503 1.000 2,2-dimethyl, 1,3-dioxane-4-yl]acetate (phenylcarbamoyl)pyrrol-1- yl]ethyl]-2,2-dimethyl-1,3-dioxan- 4-yl]acetate Palladium Carbon 0.010 Methanol Recovery 3.939 Methanol 4.061 Acetone Recovery 1.000 Hyflo 0.014 Toluene Recovery 5.339 Hydrogen Gas 0.038 IPA Recovery 2.279 Dimethyl Carbonate 0.206 Effluent 12.964 2-Methyl 2-Butanone 0.206 Organic Residue 0.452 Aniline 0.206 Evaporation Loss 0.612 Sulfuric Acid 0.006 Spent Catalyst 0.024

273

Water 12.788 Benzaldehyde 0.209 Potassium Carbonate 0.038 Toluene 5.606 Acetone 1.061 Flouro Benzaldehyde 0.218 Para Toluene Sulfonic acid 0.015 IPA 2.424 Total 27.609 Total 27.609

121) (4R,6R)-tert-Butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate Process Description: tert-Butyl-2-[(4R,6S)-6-(cyano methyl)-2,2-dimethyl -1,3-dioxan-4-yl] acetate reductionwith Hydrogen on Palladium Carbon in presence of Methanol gives tert-Butyl-2-[(4R,6S)-6-(amino ethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) (4R,6R)-tert-Butyl-6-(2- tert-Butyl-2-[(4R,6S)-6-(cyanomethyl)- 1.038 aminoethyl)-2,2-dimethyl-1,3- 1.000 2,2-dimethyl, 1,3-dioxane-4-yl]acetate dioxane-4-acetate Palladium Carbon 0.020 Methanol Recovery 5.875 Methanol 6.250 Organic Residue 0.116 Hyflo 0.030 Evaporation Loss 0.375 Hydrogen Gas 0.078 Spent Catalyst 0.050 Total 7.416 Total 7.416

274

122) Methyl 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-Nmethylsulfonyl)amino]pyrimidine- 5-carboxylate Process Description: 4-Fluoro-Benzadehyde reacts with 4-Methyl-3-oxo-pentanoic acid ethyl ester inpresence of Base to give Stage-1 as product.Stage-1 product reacts with S-Methyl iso thio urea and 2, 3Dichloro-5, 6-dicyanobenzo quinone in presence of HMPA to give stage-2 as product.Stage-2 product reacts with meta-chloro peroxy benzoic acid to give Stage-4 asproduct and Meta chloro benzoic acid as by-product.Stage-3 product reacts with methyl amine in presence of Ethanol s solvent media togive Stage-4 as product.Stage-4 product reacts with Methane sulfonyl chloride in presence of Sodium hydrideas catalyst to give Stage-5 as product.Stage-5 product undergoes reduction and oxidation in presence of Hydrogen gas togive Methyl 4-(4-fluorophenyl)-6- isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5-carboxylate.

Chemical Reaction:

275

276

277

278

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Methyl 4-(4-fluorophenyl)-6- isopropyl-2-[(N-methyl-N- 4-Fluoro benzaldehyde 0.547 1.000 methylsulfonyl)amino]pyrimidine- 5-carboxylate 4-Methyl-3-oxo-pentanoic acid ethyl 0.698 Methanol Recovery 5.489 ester Potassium hydroxide 0.247 MDC Recovery 7.984 Methyl Iodide 0.632 HMPA Recovery 0.995 Methanol 5.789 Meta chloro benzoic acid Reuse 1.133 Water 16.842 Ethanol Recovery 2.505 S-Methyl iso thio urea 0.368 Di methoxy ethane Recovery 3.000 2,3-Dichloro-5,6-dicyano benzoquinone 0.895 Toluene Recovery 2.989 2,3-Dichloro-5,6-Dicyano- HMPA 1.053 0.902 benzoquinol MDC 8.421 Hydrochloric acid 0.117 Meta chloro peroxy benzoic acid 1.249 Effluent water 18.170 Methyl amine 0.107 Organic Residue 0.685 Ethanol 2.632 Evaporation Loss 1.221 Methane sulfonyl chloride 0.368 Sodium hydride (60%) 0.011 Di methoxy ethane 3.158 Hydrogen 0.006 DIBAL-H 0.011 Toluene 3.158 Total 46.192 Total 46.192

279

123) tert-Butyl 6-[(1E)-2-[4-(4-fluorophenyl)-6-(1-methylethyl)-2[methyl(methylsulfonyl) amino] -5-pyrimidinyl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetate Process Description: 4-Fluoro-Benzadehyde reacts with 4-Methyl-3-oxo-pentanoic acid ethyl ester inpresence of Base to give Stage-1 as product.Stage-1 product reacts with S-Methyl iso thio urea and 2, 3Dichloro-5, 6-dicyanobenzo quinone in presence of HMPA to give stage-2 as product.Stage-2 product reacts with meta-chloro peroxy benzoic acid to give Stage-4 asproduct and Meta chloro benzoic acid as by-product.Stage-3 product reacts with methyl amine in presence of Ethanol s solvent media togive Stage-4 as product.Stage-4 product reacts with Methane sulfonyl chloride in presence of Sodium hydrideas catalyst to give Stage-5 as product.Stage-5 product undergoes reduction and oxidation in presence of Hydrogen gas togive Stage-6 as product.Stage-6 product reacts with methyl (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidene hexanoate to give tert-Butyl 6-[(1E)-2-[4-(4-fluorophenyl)-6-(1-methylethyl)-2- [methyl(methylsulfonyl)amino]-5-pyrimidinyl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetate.

Chemical Reaction:

280

281

282

283

284

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) tert-Butyl 6-[(1E)-2-[4-(4- fluorophenyl)-6-(1-methylethyl)- 4-Fluoro benzaldehyde 0.335 2-[methyl(methylsulfonyl)amino]- 1.000 5-pyrimidinyl]ethenyl]-2,2- dimethyl-1,3-dioxane-4-acetate 4-Methyl-3-oxo-pentanoic acid ethyl 0.428 Methanol Recovery 3.365

285

ester Potassium hydroxide 0.152 MDC Recovery 4.894 Methyl Iodide 0.387 HMPA Recovery 0.610 Methanol 3.548 Meta chloro benzoic acid Reuse 0.695 Water 12.258 Ethanol Recovery 1.535 S-Methyl iso thio urea 0.226 Di methoxy ethane Recovery 1.839 2,3-Dichloro-5,6-dicyano benzoquinone 0.548 Toluene Recovery 1.832 N,N-Dimethyl formamide HMPA 0.645 1.806 Recovery 2,3-Dichloro-5,6-Dicyano- MDC 5.161 0.553 benzoquinol Meta chloro peroxy benzoic acid 0.766 Hydrochloric acid 0.072 Methyl amine 0.066 Effluent water 13.201 Ethanol 1.613 Organic Residue 0.962 Methane sulfonyl chloride 0.226 Evaporation Loss 0.849 Sodium hydride (60%) 0.006 Di methoxy ethane 1.935 Hydrogen 0.004 DIBAL-H 0.006 Toluene 1.935 Methyl(3R)-3-(tert butyl di methyl silyloxy)-5-oxo-6- triphenyl 0.933 phosphoranylidene hexanoate Triethyl amine 0.097 N,N-Dimethyl formamide 1.935 Total 33.212 Total 33.212

286

124) 1-[Cyano-(p-methoxyphenyl) methyl]cyclohexanol Process Description: 4-Methoxy phenyl acetonitrile reacts with Cyclohexanone in the presence of Sodiumhydroxide as base and Toluene as a solvent media to give 1-[Cyano-(p-methoxyphenyl)methyl] cyclohexanol.

Chemical Reaction:

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 1-[Cyano-(p- 4-Methoxy Phenyl Acetonitrile 0.622 1.000 methoxyphenyl)methyl]cyclohexanol Cyclohexanone 0.422 Toluene Recovery 6.108 NaOH 0.111 Effluent 4.709 TBAB 0.044 Evaporation Loss 0.333 Toluene 6.664 Distillation Residue 0.155 Water 4.442 Total 12.305 Total 12.305

125) 1-[2-Amino-1-(4-methoxyphenyl)ethyl]cyclohexanol Process Description: 4-Methoxy phenyl acetonitrile reacts with Cyclohexanone in the presence of Sodiumhydroxide as base and Toluene as a solvent media to give stage-1 as product.Stage-1 undergoes reduction with Raney nickel in the presence of Toluene as asolvent media to give 1-[2-Amino-1-(4- methoxyphenyl)ethyl]cyclohexanol.

Chemical Reaction:

287

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 1-[2-Amino-1-(4- 4-Methoxy Phenyl Acetonitrile 0.651 1.000 methoxyphenyl)ethyl]cyclohexanol Cyclohexanone 0.442 Toluene Recovery 6.395 NaOH 0.116 Effluent 4.930 TBAB 0.047 Methanol Recovery 15.698 Toluene 6.977 Evaporation Loss 1.163 Water 4.651 Distillation Residue 0.343 Hydrogen Gas 0.017 Spent Catalyst 0.047 Raney Nickle 0.047 Methanol 16.628 Total 29.575 Total 29.575

126) 2,3-Dichlorobenzoylcyanide Process Description: Charge Toluene, 2,3-Dichlorobenzoyl Chloride and Sodium cyanide in reactor. Heat the reaction mass to reflux and maintain. Add water and stirr. Stop stirring and let the layers to separate. Remove aqueous layer. Distill of toluene completely. Chage hexane. Heat to reflux. The reaction mass is cooled, centrifuged and dried.

Chemical Reaction: O O Cl Toluene Cl Cl Sodium Cyanide (49.0) Cl N Cl Hexane - NaCl (58.44) 2,3-Dichlorobenzoyl Chloride 2,3-Dichlorobenzoyl Cyanide

M.F:C 7H3Cl 3O M.F:C 8H3Cl 2NO M.W: 209.46 M.W: 200.02

288

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Toluene 6.400 Product 1.000 Sodium Cyanide 0.334 Toluene Recovery 6.234 2,4-Dichlorobenzyl chloride 1.333 Hexane Recovery 2.283 Water 1.000 Waste Water 1.753 Hexane 2.358 Distillation Residue 0.017 Evaporation loss 0.139 Total 11.425 Total 11.425

127) 5-Chloroacetylsalicylamide Process Description: Salicylamide, Nitrobenzene, Methylene dichloride and Aluminium Chloride are charged in glass lined reactor and stired at lawer temperature. The reaction mass is than added in to mixure of hydrochloric acid and ice. The material is than washed with water, centrifuged and dried. Material from stage I with methylene dichloride and sulphuryl chloride are charged in glass line reactor and maintain at lawer temperature. The reaction mass is than centrifuged and washed with acetone (purification). After washing the material is centrifuged and dried.

Chemical Reaction: O CH3 Nitrobenzene Methylene Dichloride Aluminium Trichloride NH NH2 2 Hydrochloric Acid OH O OH O Ice

Molecular Formula: C 9H9NO 3 Molecular Formula: C 7H7NO 2 Formula Weight: 179.17 Formula Weight: 137.13 5 -Acetyle Salicylamide Salicylamide

O CH O 3 Cl Methylene Dichloride

Sulfuryl Chloride NH NH2 2 Acetone OH O OH O Methanol

Molecular Formula: C 9H9NO 3 Molecular Formula: C 9H8ClNO 3 Formula Weight: 179.17 Formula Weight: 213.61 5 -Acetyle Salicylamide 5 - Chloro Acetyl Salicylamide

289

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Dichloromethane (MDC) 16.15 5-Chloroacetylsalicylamide 1.00 Nitrobenzene 2.64 MDC Recovery 14.58 Aluminium chloride 1.80 Acetone Recovery 4.83 Salicylamide 0.92 Niro Benzene Recovery 2.43 Acetyl chloride 0.80 30% HCl 1.11 Hydrochloric acid 4.40 Effluent 24.40 Ice 3.67 Distillation Residue 0.57 Water 12.00 Loss 0.22 Methanol 0.26 Sulfuryl chloride 1.23 Acetone 5.27 Total 49.14 Total 49.14

128) 1-(4-Chlorobenzhydryl) piperazine Process Description: Charge p – Chloro Benzophenone and water in to the reactor. Cool the reaction mass. Add Formic acid below 15 °C. Add hydrochloric acid to adjust specified pH. The reaction mass is cooled, centrifuged and dried. Charge 4- chlorobenzhydryl chloride, Toluene and Piperazine in reactor. Heat to reflux and maintain. Cool the reaction mass and let the layers to settle. Charge organic layer. Charge hydrochloric acid and water. Stop stirring and let the layers to settle. Remove organic layer. Charge aqueous layer in reactor and add caustic soda flakes and water. The reaction mass is centrifuged and dried.

Chemical Reaction: Cl Cl HCOOH (46.01) Cl O HCl (36.46)

- 2 H 2O (18.01)

- CO 2 (44.00)

p - Chloro Benzophenone 4-Chlorobenzhydryl Chloride M.F.: C H Cl M.F.: C 13 H9ClO 13 10 2 M.W.: 216.66 M.W. : 237.12

290

Cl Cl NH

Cl N NH Toluene

+ NH Hydrochloric acid Caustic Soda Water

4-Chlorobenzhydryl Chloride Piperazine - HCl (36.46) 4-Chlorobenzhydryl Piperazine

M.F.: C H N MF: C 17 H19 CIN 2 M.F.: C 13 H10 Cl 2 4 10 2 MW: 286.8 M.W. : 237.12 M.W.: 86.13

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 1-(4-Chlorobenzhydryl) p - Chloro Benzophenone 1.000 1.000 piperazine Water 2.032 Waste Water 3.250 Formic Acid 0.195 Hydrochloric Acid (28 - 30%) 0.425 Hydrochloric Acid 0.998 Toluene Recovery 2.332 Toluene 2.370 Distillation Residue 0.034 Piperazine 0.302 Evaporation Loss 0.176 Caustic Soda Flakes 0.320 Total 7.217 Total 7.217

129) 2-Amino, 5-methyl thiazole Process Description: In reactor charge water and propionaldehyde and stir to get clear solution. In other reactor charge. Thiourea, water and hydrochloric acid. Heat the reaction mass and charge Propionaldehyde aqueous solution slowly. Cool the reaction mass. pH of reaction mass is adjusted with caustic soda solution. The reaction mass is centrifuged. Charge toluene, cake from centrifuge process and Water in reactor and stir. Heat the reaction mass to 60 – 65 °C. Separate the organic layer and discard the aqueous layer. The organic layer is cooled, centrifuged and dried.

Chemical Reaction: Hydrochloric Acid H N Caustic Soda H N C NH Water H2N H3C CH2 CHO 2 2 + S S - H 2O CH3

Propionaldehyde Thiourea 2 - Amino 5 - methyl thiazole Molecular Formula: C H N S M. F.= CH N S 4 8 2 M. F. = C 3H6O 4 2 M. W.= 76.12 Formula Weight: 116.18472 M. W.= 58.07

291

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Propionaldehyde 0.800 Product 1.000 Thiourea 0.675 Toluene Recovery 0.968 Water 3.845 Waste Water 4.740 Hydrochloric Acid 0.254 Distillation Residue 0.064 Caustic Soda Flakes 0.318 Evaporation Loss 0.105 Toluene 0.985 Total 6.877 Total 6.877

130) 4-Hydroxy, 2-methyl, 2h,1,2-benzothiazine carboxylic acid isopropyl ester-1,1-dioxide

Process Description: Dimethyl formamide, isopropyl chloro acetate, Water and sodium saccharine are charged in Reactor and heated. pH of material is adjusted with sodium Carbonate. Material is than centrifuged and dried. In Reactor sodium metal and isopropyl alcohol are charged and heated till clear solution observed. Add dried material lot wise in reactor. Maintain the mass at elevated temperature for Specific time. Distill off Isopropyl alcohol. Dimethyl sulphate and Ice are added and pH is adjusted with HCl. Centrifuge the material. Wash cake with water. Dried material and Isopropyl alcohol are charged in Reactor. Reaction mass heated to reflux. Reaction mass is cooled, centrifuged and dried.

292

Chemical Reaction: 3CH O O O CH3 O CH3 Dimethylformamide O N Na + N S O CH3 Na 2CO 3 S O O Cl Water O O

Mol. Wt.= 205.16 Mol. Wt. = 136.58 Mol. Wt. = 283.30 C H ClO C H O SN C7H4NNaO 3S 5 9 2 12 13 5 Sodium Saccharin Isopropyl chlororoacetate Intermediate

CH3

3CH Isopropyl alcohol OH O CH3 O O CH3 4 Na (22.98) O 2 HCl (36.46) O N (CH 3)2SO 4 (126.13) N S S CH3 O - 2 H 2 (2.0) O OO -2 NaCl (58.44) Mol. Wt. = 283.30 Mol.Wt. 297.32 - Na 2SO 4 (142.04) C12 H13 O5SN C13 H15 NO 5S Intermediate Methyl Benzothiazine Isopropyl Ester Crude

CH3

OH CH OH O CH3 3 O O CH3 N Isopropyl Alcohol S N O S CH3 O O CH3 OO

Mol.Wt. 297.32 Mol.Wt. 297.32

C13 H15 NO 5S C13 H15 NO 5S Methyl Benzothiazine Isopropyl Ester Crude Methyl Benzothiazine Isopropyl Ester

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Dimethyl Formamide 0.25 Product 1.00 Isopropyl ChloroAcetate 0.46 DMF Recovery 0.24 Sodium Saccharin 1.26 IPA Recovery 3.63 Sodium Carbonate 0.04 Waste Water 2.05 Water 0.14 Distillation Residue 0.03 Isopropyl Alcohol (IPA) 3.71 Evaporation Loss 0.18 Sodium Metal 0.28

293

ICE 0.20 Dimethyl Sulphate (DMS) 0.43 Hydrochloric Acid 0.36 Total 7.13 Total 7.13

131) 4-Hydroxy, 2-methyl, 2h,1,2-benzothiazine carboxylic acid methyl ester-1,1-dioxide Process Description: Dimethyl formamide, Methyl Monochloro acetate, Water and sodium saccharine are charged in Reactor and heated. pH of material is adjusted with sodium Carbonate. Material is than centrifuged and dried.In Reactor sodium metal and Methanol are charged and heated till clear solution observed. Add dried material lot wise in reactor. Maintain the mass at elevated temperature for Specific time. Methanol is distilled out. Dimethyl sulphate and Ice are added and pH is adjusted with HCl. Centrifuge the material. Wash cake with water. Dried material and Methylene Dichloride are charged in Reactor. Reaction mass heated to reflux. Reaction mass is cooled, centrifuged and dried.

Chemical Reaction: Water O Dimethylformamide O O CH3 O Sodium Carbonate O N Na CH + 3 N O S - NaCl (58.44) S O Cl O O O

Mol. Wt.= 205.16 Mol. Wt. = 108.52 Mol. Wt. = 255.25 C3H5ClO 2 C H O SN C7H4NNaO 3S 10 9 5 Sodium Saccharin Methyl Mono chlororoacetate Intermediate

CH3 Methanol OH O

4 Na (22.98) O O CH O 3 2 HCl (36.46) O (CH ) SO (126.13) N 3 2 4 S CH 2 N 3 - 2 H (2.0) S 2 OO O -2 NaCl (58.44) O Mol.Wt. 269.27 - Na SO (142.04) Molecular Formula: C H NO S Mol. Wt. = 255.25 2 4 11 11 5 4-hydroxy, 2- methyl, 2h, C10 H9O5SN 1,2-benzothiazine carboxylic acid Intermediate Methyl ester-1,1- dioxide crude

CH3 OH O OH

O CH3 O Methanol

N S N O S CH3 O CH OO O 3

Mol.Wt. 269.27 Mol.Wt. 269.27 Molecular Formula: C H NO S 11 11 5 Molecular Formula: C 11 H11 NO 5S 4-hydroxy, 2- methyl, 2h, 4-hydroxy, 2- methyl, 2h, 1,2-benzothiazine carboxylic acid 1,2-benzothiazine carboxylic acid Methyl ester-1,1- dioxide crude Methyl ester-1,1- dioxide

294

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Dimethyl Formamide(DMF) 0.356 Product 1.000 Methyl MonoChloroAcetate 0.410 DMF Recovery 0.347 Sodium Saccharin 1.529 Methanol Recovery 0.931 Sodium Carbonate 0.073 MDC Recovery 0.881 Water 0.600 Waste Water 3.251 MDC 0.900 Distillation Residue 0.034 Methanol 0.958 Evaporation Loss 0.209 Sodium Metal 0.657 ICE 0.500 Dimethyl Sulphate (DMS) 0.420 Hydrochloric Acid 0.250 Total 6.653 Total 6.653

132) Chloro acetyl Xylidine Process Description: Charge Toluene and 2,6 – Xylidine in reactor and stir. Cool the reaction mass and add Chloroacetyl Chloride. Heat the reaction mass at specified temperature and maintain for 3 hrs. Cool the reaction mass and centrifuge. Wash wet cake with water during centrifuge. Dry the material.

Chemical Reaction: NH CH3 2 Cl Cl NH H3C CH3 Toluene + Cl Water O H O CH3 HCl

2, 6 - Xylidine Chloro Acetyl Chloride Chloroacetyl Xylidine Molecular Formula: C H Cl NO Molecular Formula: C 8H11 N Molecular Formula: C 2H2Cl 2O 10 13 2 Formula Weight: 121.17964 Formula Weight: 112.94268 Formula Weight: 234.12232

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Toluene 2.301 Product 1.000 chloro acetyl chloride 0.607 Toluene Recovery 2.266 Water 0.100 Distillation Residue 0.020 2,6 Xylidine 0.667 Waste Water 0.274 Evaporation Loss 0.115 Total 3.675 Total 3.675

295

133) 2-(2-(3-(S)-(3-(2-(7-Chloro-2-quinolinyl)-ethenyl)phenyl-3- methanesulphonyloxypropyl)pehenyl)-2-propanol Process Description: 3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl]benzaldehyde and Tetrahydrofuran is charged in reactor. The reaction mass is cooled to specified temperature. Vinylmegnesium bromide is added in the reaction mass slowly below specified temperature to get 1-{3-[(E)-2-(7- chloroquinolin-2-yl)ethenyl] phenyl}prop-2-en-1-ol. Water is added in the reaction mass, cooled and centrifuged. The material is dried. The dried material is charged in dimethyl Formamide followed by 2-(2-chlorophenyl) propan-2-ol to get 2-[2-3(S)-3-[2-(7-chloro-2- quinolinyl)-ethyl] phenyl]-3-hydroxypropyl] phenyl-2-propanol. The reaction mass is than centrifuged and dried.

Chemical Reaction:

Tetrahydro Furane

MgBr H2O (18.01) N CH OH NO + CH2 - Mg(OH) 2 (58.32) Cl CH2 - HBr (80.91) Cl

1-{3-[( E)-2-(7-chloroquinolin-2-yl)ethenyl] 3-[(E)-2-(7-chloroquinolin-2-yl)ethe Vinylmagnesium bromide phenyl}prop-2-en-1-ol nyl]benzaldehyde

C2H3BrMg C20 H16 ClNO C18 H12 ClNO 131.25 321.80 293.74

Cl Dimethyl Formamide CH3 N OH + OH N CH OH CH CH3 - HCl (36.46) Cl 3 OH Cl CH2 CH3

1-{3-[( E)-2-(7-chloroquinolin-2-yl)ethenyl] 2-(2-chlorophenyl)propanol 2-[2-3(S)-3-[2-(7-chloro-2-quinolinyl)-ethyl]ph phenyl}prop-2-en-1-ol enyl]-3-hydroxypropyl] phenyl-2-propanol C9H11 ClO C H ClNO 20 16 C H ClNO 172.63 29 28 2 321.80 457.99

296

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Methylene Dichloride 1.724 Product 1.000 (cyclopropane-1,1-diyl)dimethanol 0.759 MDC recovery 1.645 Sodium Cyanide 0.345 Toluene Recovery 1.641 Hydrochloric Acid 1.083 Effluent 3.993 Toluene 1.793 Distillation Residue 0.072 Water 2.028 Evaporation Loss 0.172 potassium ethanethioate 0.793 Total 8.524 Total 8.524

134) 1-(Mercaptomethyl)-cyclopropane acetic acid Process Description: (cyclopropane-1,1-diyl) dimethanol is charged in reactor with Methylene Dichloride followed by Sodium Cyanide and Hydrochloric acid to get [1-(hydroxymethyl)cyclopropyl] acetonitrile monohydrate. The organic layer of separated and charged in reacted. Methylene dichloride is distilled off. Charge toluene in reaction mass followed by potassium ethanethioate to get 2-[1- (Mercaptomethyl) cyclopropyl] acetic acid. Charge water in reaction mass to remove the salt. Separate the aqueous layer. The reaction mass is cooled and centrifuged followed by drying to get finished product. Chemical Reaction: Methylene Dichloride

HCl (36.46) OH OH OH CN NaCN (49.0)

. H 2O - NaCl (58.44)

[1-(hydroxymethyl)cyclopropyl] (cyclopropane-1,1-diyl)dimethanol acetonitrile monohydrate Formula Weight: 102.1317 C6H11 NO 2

Molecular Formula: C 5H10 O2 130.15

OH CN O Toluene SH COOH

. H O + 2 CH 3COOK (98.14) 3CH SK

[1-(hydroxymethyl)cyclopropyl] potassium ethanethioate 2-[1-(Mercaptomethyl) acetonitrile monohydrate cyclopropyl] acetic acid

C2H3KOS C6H10 O2S C6H11 NO 2 114.20 146.20 130.15

297

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) 3-[(E)-2-(7-chloroquinolin-2- 0.659 Product 1.000 yl)ethenyl]benzaldehyde Tetra Hydrofurane 1.319 Tetra Hydro furane recovery 1.254 Vinylmagnesium bromide 0.297 DMF Recovery 1.319 Water 0.728 Hydrobromic acid 0.549 Dimethyl Formamide 1.429 Hydrochloric Acid 0.347 2-(2-chlorophenyl)propan-2-ol 0.385 Evaporation Loss 0.251 Distillation Residue 0.097 Total 4.817 Total 4.817

135) Denatonium Saccharate Process Description: Charge Water and Lidocaine in reactor. Heat to get clear solution. Add benzyl chloride slowly. Heat to reflux and maintain. Cool reaction mass. Charge Toluene and stir. Stop stirring and let the layer to settle. Remove organic layer. Adjust pH with caustic Solution. Centrifuge the material. Charge Wet cake with toluene and Saccharin (Saccharic acid). Heat reaction mass to reflux and maintain. Cool the reaction mass and centrifuge. Dry the material.

Chemical Reaction:

298

CH 3 CH3 Toluene NaOH NH NH + Water – OH + CH3O N CH O N Cl - NaCl (58.4) 3 CH 3 CH3 CH 3 CH3

Lidocaine Benzyl Chloride 2-Diethyl Benzyl amino-N- (2,6-dimethylphenyl)acetamide

M.F. : C 14 H22 N2O M.W. : C H Cl 7 7 Molecular Formula: C 21 H30 N2O2 F.W. : 234.33 M.W. : 126.58 Formula Weight: 342.4751

CH OH OH OH OH 3 CH3

NH O OH NH O OH OH – OH OH + + CH3O N + OH OH - H 2O (18.01) CH3O N CH OH – 3 CH3 O CH3 CH O 3 O 2-Diethyl Benzyl amino-N- Saccharin (Saccharic acid) Denatonium Saccharate (2,6-dimethylphenyl)acetamide Molecular Formula: C H N O M.F. : C 21 H29 N2O Molecular Formula: C 6H10 O8 27 38 2 9 Formula Weight: 534.59862 M.W. : 325.46 Formula Weight: 210.1388 Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Lidocaine 0.616 Product 1.000 Water 3.645 Toluene Recovery 2.328 Toluene 2.463 Distillation Residue 0.116 Benzyl Chloride 0.333 Waste Water 4.014 Caustic Soda Flakes 0.357 Evaporation Loss 0.149 Saccharin 0.153 Total 7.567 Total 7.606

136) 3-Morpholino-1-(4-(2-oxopiperidin-1-yl)5,6-dihydropyridin-2(1h)-one Process Description: Aniline react 5-chloronaiteryl chloride in Presence of Sodium hydroxide using methylene dichloride on a solvent. Separation water to organic layer. Distilled out Solvent. Add toluene and then hexane centrifuged, washing with hexane drying to get lactam intermediate. Nitration of lactam intermediate by sulphuric acid and citric acid quenching in ice water. centrifuged, get Nitro lactam intermediate. Take lactam intermediate in toluene and charge phosphoric Penta chloride after completion of reaction quenching it in ice water neutralized by sodium bicarbonate. Centrifuged and drying get nitro chloro lactam intermediate. Take nitro chloro lactam DMF and Morpholine heating and string washing get nitro Morpholine intermediate.

299

Take nitro chloro lactam intermediate in Ethanol and Water redaction with raney nickel and addition of hydrazine hydrate filtration of catalyst. Distilled out solvent and charge ethyl acetate cool and centrifuge, washing, drying get Amino Morpholine lactam intermediate. Amino Morpholine lactam intermediate React with 5-Chloro valeryl chloride un presence of Sodium hydroxide using Methylene chloride separation washing with water to organic layer. Distilled out solvent and Isolate the material by Ethyl acetate centrifuging, washing and drying to get 3-Morpholino-1-(4-Oxopiperidine-1-yl)5,6-Dihydropyridine-2(1h)-One.

Chemical Reaction:

300

NH2 N O N O Sulfuric Acid 2 NaOH (39.99) HNO 3 (63.01) + - 2 NaCl (58.4) - H 2O (18.01) Cl O Cl - 2 H 2O (18.01)

NO 2 Aniline 5 - Chlorovalerylchloride Amide Intermediate Nitrolactum Intermediate M.F.: C H N M.F.: C H Cl O M.W.: C H NO 6 7 5 8 2 11 13 M.F.: C 11 H12 N2O3 M.W.: 93.12 M.W.: 155.02 M.W.: 175.22 M.W.: 220.22 O Cl 3 Water (18.01) H N 3 Na 2CO 3 (105.98) Cl N N O PCl 5 (208.24) N O N O - Na 3PO 3 (147.94) O (87.12) - 3 NaCl (58.4) - 2 HCl (36.46) - 3 H 2O (18.01) - 3 CO 2 (44.01) NO 2 - H (2.0) NO 2 2 NO 2 Nitrolactum Intermediate Nitro chloro lactum intermediate Nitro morpholine lactum intermediate M.F.: C 11 H12 N2O3 Molecular Formula: C 11 H10 Cl 2N2O3 Molecular Formula: C 15 H17 N3O4 M.W.: 220.22 Formula Weight: 289.11 Formula Weight: 303.31

O O O N N N (155.2) Raney Ni Cl Cl O N O N O N O N2H4 (32.04) 2 NaOH (39.99) - 2 NaCl (58.4) - H 2O2 (34.01) - 2 H O (18.01) - N 2 (28.0) 2

NO 2 NH2 N O Nitro morpholine lactum intermediate Nitro morpholine lactum intermediate

Molecular Formula: C 15 H17 N3O4 Molecular Formula: C 15 H19N3O2 Formula Weight: 303.31 Formula Weight: 273.33 3-Morpholino-1-(4-Oxopiperidine-1-yl) 5,6-Dihydropyridine-2(1h)-One)

Molecular Formula: C 20 H25 N3O3 Formula Weight: 355.4308

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Aniline 0.930 Product 1.000 Dichloromethan (MDC) 14.728 MDC Recovery 14.312 Caustic Soda Flakes 0.353 Toluene Recovery 4.805

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Water 3.918 Hexane Recovery 5.158 5-chlorovaleryl chloride 0.880 DMF Recovery 1.945 Toluene 4.884 30% HCl 0.479 Hexane 5.367 Ethanol Recovery 4.079 Sulphuric Acid 0.012 Ethyl Acetate Recovery 6.256 Nitric Acid 0.178 Ni Recovery 0.078 Ice 2.000 Water Recovery 0.159 Sodium Bicarbonate 0.896 Distillation Residue 0.165 Dimethyl Formamide 1.987 Waste Water 9.228 Morpholine 0.247 Evaporation Loss 0.667 Ethanol 4.529 Raney Nickel 0.079 Hydrazine Hydrate 0.092 Ethyl Acetate 6.661 Phosphorus Pentachloride 0.589 Total 48.330 Total 48.330

137) z-Ethyl-2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate Process Description: Anisidine react with Ethyl-2-chloroacetoacetate in Presence of hydrochloric acid Sodium Nitrate using solvent is Methanol to Form hydrozonyl chloride purified in isopropyl alcohol centrifuged,washing and drying to get (Z)-Ethyl 22-chloro-2-(2-(4- methoxyphenyl)hydrazono)acetate.

Chemical Reaction: Cl O O Cl Methanol NH2 N O NaNO 2 (68.99) NH CH H3C O HCl (36.46) 3 + O - CH 3COOH (60.05) OCH - NaCl (58.4) 3 H3C H3CO - H 2O (18.01) (Z)-Ethyl 22-chloro-2-(2-(4- Para anisidine Ethyl 2-chloroacetoacetate methoxyphenyl)hydrazono)acetate

M.F.: C H ClO Molecular Formula: C 11 H13 ClN 2O3 M.F.: C 7H9NO 6 9 3 Formula Weight: 256.68552 M.W.: 123.15 M.W.: 164.58

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Water 1.920 Product 1.000 P-Anisidine 0.916 IPA Recovered 3.807 Hydrochloric Acid 0.332 Methanol recovery 5.681 Sodium Nitrite 0.270 Distillation Residue 0.110

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Ethyl 2-Chloro Aceto Acetate 0.643 Waste Water 3.137 Methanol 5.920 Evaporation Loss 0.183 Isopropyl Alcohol (IPA) 3.917 Total 13.918 Total 13.918

138) 4-Chloro-7-tosyl-7h-pyrrolo[2,3-d]pyrimidine Process Description: Charge Acetone and 4- Chloro pyrrolo pyrimidine in a reactor and stir the reaction mass. Charge p – Toluenesulfonyl chloride and add sodium hydroxide solution with continuous stirring. The reaction mass is than Centrifuged, washed with mixture of Acetone and Water (1 : 1) and dried.

Chemical Reaction: CH Cl 3 Cl Acetone : Water

N NaOH (39.99) N CH3 + N - NaCl (58.4) N N N S H - H 2O (18.01) ClS O O O O

4-chloro pyrrolo p - Toluene sulphonic 4-chloro-7-tosyl-pyrrolo[2,3-d] pyrimidine chloride Pyrimidine

M.F. : C H ClO S M.F. : C 13 H10 ClN 3O2S M.F. : C 6H4ClN 3 7 7 2 M.W. : 190.64 M.W. : 307.75 M.W. : 153.56

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Acetone 2.179 Product 1.000 4-Chloropyrrolo-7H-[2,3,D] Pyrimidine 0.537 Acetone Recovery 1.923 p - Toluene sulphonic chloride 0.625 Waste Water 1.134 Caustic Soda Flakes 0.130 Evaporation Loss 0.148 Water 0.775 Distillation Residue 0.041 Total 4.246 Total 4.246

139) Bis (3R, 4R) - (1- benzyl - 4 methyl - pipeidine - 3yl) methylamine di - toluoyl - L - tartaric acid Process Description: Charge Acetone and 3 – Amino- 4 – methyl pyridine and cool the reaction mass. Add Acetyl chloride with stirring and cool the reaction mass. Add aqueous ammonia solution and maintain the specific pH of reaction mass. Filter off the inorganic salt bed wash with Acetone. Collect the filtrate and distill out Acetone under vacuum. Cool the reaction mass and charge Toluene followed by addition of Benzyl chloride in to the in soluble reaction mass. Raise the

303 temperature and maintain for specific time period. Cool the reaction mass, charge water and stir. Separate out aqueous layer and charge methanol in the aqueous layer. Cool the reaction mass and add sodium borohydride. Charge water, distill out methanol under vacuum. Stir the reaction mass and cool. Centrifuge the reaction mass and dry. Add Hydrochloric acid heat, cool centrifuge and dried material are charged in reactor. Raise temperature, maintain for specific time and cool. Charge Hexane and add Sodium hydroxide to maintain the pH. Stir the reaction mass and separate out Hexane layer. Distill out the Hexane under vacuum and cool. Charge Methanol and maintain the reaction mass for specific time. Add slowly methanolic methyl amine solution with stirring. Charge Di Toluoyl L – Tartaric Acid. Gradually cool the reaction mass. Centrifuge and bed wash with Methanol and dry.

Chemical Reaction: CH3

NH CH3

+ O CH N CH3 3 - NH CH Benzyl Chloride Cl NH2 Acetyl Chloride 3 (78.49) (126.58) Acetone O Toluene N N - HCl (36.46) Quartemized salt of 3 - Amino - 4 - 2 - acetylamino - 4 - Amino pyridine derivative Methyl Pyridine Methyl Pyridine M.F.: C 15 H17 ClN 2O M.F.: C H N M.F: C 8H10 N2O 6 8 2 M.W.: 274.76 M.W.: 108.14 F.W.: 150.17 Methanol - Boric acid (61.83) Sodium Borohydride (37.83) - NaCl (58.44)

3 H 2O CH 3 CH3 O Hydrochloric Acid NH CH3

H2O (18.01) O N N - Acetamide (61.07)

M.F.: C H NO (n-(1-benzyl-4-methyl-1,2,5,6-tetrah 13 17 ydropyridine-3-yl)acetylamine) MW.: 203.28 (Intermediate-I)

N-Benzyl-4-methyl M.F.: C 15 H22 N2O piperidin-3-one M.W.: 246.35 Hexane - H 2O (18.01) Methanol NaOH (31.06 ) CH 3-NH 2

CH3 CH3 NH NH CH3 CH3

DTTA (390.34) N N 1 /2 DTTA

CH 3OH

Bis (3R, 4R) - (1- benzyl - 4 methyl - 1-Benzyl-N,4-dimethylpiperidin- pipeidine - 3yl) methylamine di - toluoyl - 3-amine L - tartaric acid [KSM - I]

M.F.: C 14 H22N2 M.F.: C 24 H31 N2O4 F.W.: 216.33 F.W.: 411.50 Mass Balance:

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Input material Quantity Output material Quantity (MT/MT) (MT/MT) Acetone 8.618 Product 1.000 3 – Amino 4 – Methyl Pyridine 3.750 Acetone Recovery 8.310 Acetyl chloride 0.193 Toluene Recovery 11.270 Caustic Soda Lye 0.086 Hexane Recovery 4.095 Toluene 11.547 Methanol Recovery 6.471 Benzyl Chloeride 0.311 30% HCl 0.349 Methanol 6.678 Waste Water 8.519 Sodium Borohydrate 0.100 Distillation Residue 0.143 Water 3.727 Evaporation Loss 0.331 Hydrochloric Acid 0.460 Hexane 4.200 Caustic Soda 0.267 Methylamine 0.076 Di - P- Toluoyl L - Tartaric acid 0.475 Total 40.488 Total 40.488

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140) [(2S)-1-tert-butoxycarbonyl-4- oxo-2-pyrrolidinylcarbonyl]-1,3-thiazolidine Process Description: (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy pyrrolidine-2-carboxylic acid is reacted with 1, 3 – thiazolidine and Hydrogen peroxide using Methylene Dichloride as solvent to get [(2S)-1-tert- butoxycarbonyl-4- oxo-2-pyrrolidinylcarbonyl]-1,3-thiazolidine. Chemical Reaction: O O S Methylene Dichloride OH N CH3 CH3 H2O2 (34.01) N O OH N O + NH O CH3 CH3 S - 3 H O (18.01) H C 2 H3C O 3 O [(2S)-1-tert-butoxycarbonyl-4- (2 S,4 R)-1-( tert -butoxycarbonyl)-4- 1,3-thiazolidine oxo-2-pyrrolidinylcarbonyl]-1,3-thiazolidine hydroxy pyrrolidine-2-carboxylic acid Molecular Formula: C 13 H20 N2O4S M.F. : C 13 H24 N2O5S Molecular Formula: C 10 H17 NO 5 Formula Weight: 300.3739 Formula Weight: 231.24568 F.W. : 89.16

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) [(2S)-1-tert-butoxycarbonyl-4- (2S,4R)-1-(tert-butoxycarbonyl)-4- 0.797 oxo-2-pyrrolidinylcarbonyl]-1,3- 1.000 hydroxy pyrrolidine-2-carboxylic acid thiazolidine Methylene Dichloride 1.017 MDC Recovery 0.967 1,3-thiazolidine 0.305 Effluent Water 0.050 Evaporation Loss 0.102 Total 2.119 Total 2.119

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141) 1-(3-methyl-1-phenyl-5-pyrazolyl)- piperazine) Process Description: Tert-butyl piperazine-1-carboxylate and Diketene is reacted in DMF and Ethyl Acetate to give tert-butyl 4-(3-oxobutanoyl)piperazine (intermediate). The Intermediate is reacted with phenylhydrazine to get 1-(3-methyl-1-phenyl-5-pyrazolyl)- piperazine). Chemical Reaction: O 3CH CH3 O CH O 3 CH N O 3 O DMF CH3 N O + 3CH N CH3 Ethyl Acetate NH 2CH OO

tert -butyl 4-(3-oxobutanoyl)piperazine tert -butyl piperazine-1-carboxylate Diketene -1-carboxylate Molecular Formula: C H O Molecular Formula: C 9H18 N2O2 4 4 2 Molecular Formula: C 13 H22 N2O4 Formula Weight: 186.25142 Formula Weight: 84.07336 Formula Weight: 270.32478

NH O 3CH CH N CH NH2 3 3 NH N O CH NN 3 Pyridine 3CH N + - 2 H 2O (18.01) OO - tert butyl Formate (100.13) tert -butyl 4-(3-oxobutanoyl)piperazine phenylhydrazine 1-(3-methyl-1-phenyl-5-pyrazolyl)- piperazine) -1-carboxylate

Molecular Formula: C 6H8N2 Molecular Formula: C 14 H18 N4 Molecular Formula: C 13 H22 N2O4 Formula Weight: 242.31952 Formula Weight: 270.32 Formula Weight: 108.14112

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) 1-(3-methyl-1-phenyl-5- tert-butyl piperazine-1-carboxylate 0.833 1.000 pyrazolyl)- piperazine) Dimethyl Formamide 1.667 DMF recovery 1.612 Diketene 0.354 Ethyl Acetate Recovery 1.198 Ethyl Acetate 1.250 Organic Residue 0.083 Pyridine 2.250 Evaporation Loss 0.088 Phenylhydrazine 0.458 Pyridine Recovery 2.185 Hydrochloric Acid 0.271 Evaporation Loss 0.100 Sodium Cabonate 0.308 Effuent Water 1.128 Total 7.392 Total 7.392

307

142) 6-Chloro 4-Hydroxy 2-Methyl 2H-thieno[2,3,e][1,2]thiazine-3-Carboxylate 1,1-dioxide Process Description: Methonol and Sodium metal are charge in the reactor and heated till all metal get dissolved. Methyl 5-chloro-3-((2-methoxy-2-oxoethyl)suplfamoyl) thiophene-2-carboxylate is added slowly under specific temperature. The pH of reaction mass is adjusted with hydrochloric acid. The reaction mass is centrifuged and dried to get stage-1. Stage – 1 material is charge in toluene followed ny dimethyl sulphate. The reaction is maintain for perticuler time. The pH of reaction mass is adjusted with caustic soda solution. The reaction mass is seperated. Organic layer is collected in reactor. Toluene is distilled off. Add water and stirr. Centrifuge the reaction mass. The wet cake form centrifuge process is dried to get 6 chloro-4- hydroxy- 2- methyl- 2H thieno [2,3-e] [1,2] thiazine- 3- carboxylate- 1,1- dioxide. Chemical Reaction: Methanol O O O O S O 2 Na (22.98) S NH CH3 NH Cl 2 HCl (36.46) Cl O O O S CH S 3 - CH 3OH (32.04) CH3 O - 2 NaCl (58.44) OH O Methyl 5-chloro-3-[(2-methoxy-2-oxoethyl) 6-Chloro-hydroxy-2-methyl-N-2-Pyridinyl-2H-thia sulfamoyl]thiophene-2-carboxylate zine-3-carboxamide 1,1 dioxide

Molecular Formula: C 9H10 ClNO 6S2 Formula Weight: 297.73582

Formula Weight: 327.7618 Molecular Formula: C 8H8ClNO 5S2

O O Toluene O O S (CH 3)2SO 4 (126.13) NH S CH3 N Cl 2 NaOH (39.99) 2 O 2 Cl S O CH3 - Na 2SO 4 (142.04) S CH3 OH O - 2 H 2O (18.01) OH O 6-Chloro-hydroxy-2-methyl-N-2-Pyridinyl-2H-thia 6 chloro-4- hydroxy- 2- methyl- 2H thieno [2,3-e] zine-3-carboxamide 1,1 dioxide [1,2] thiazine- 3- carboxylate- 1,1- dioxide Formula Weight: 297.73582 Formula Weight: 311.74652 Molecular Formula: C H ClNO S 8 8 5 2 Molecular Formula: C 9H8ClNO 5S2

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Methanol 4.260 Product 1.000 Sodium Metal 0.150 Methanol Recovery 4.217 Methyl 5-chloro-3-[(2-methoxy-2- oxoethyl) sulfamoyl]thiophene-2- 1.100 Toluene recovery 2.516 carboxylate Hydrochloric Acid 1.020 Effluent 3.874

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Toluene 2.581 Evaporation Loss 0.632 Dimethyl Sulphate 0.419 Water 1.936 Caustic soda Lye 0.774 Total 12.240 Total 12.240

143) 4,4’-(2-Pyridinylmethylene) bisphenol Process Description: In a clean & dry glass flask, charge phenol followed by ethyl acetate and cooled to 10°C. Add sulfuric acid in such a way that mass temperature should not exceed than 25 °C. After completion of addition, maintain mixture temperature of 15°C for 3 hrs. Now add mixture of pyridine 2- aldehyde and ethyl acetate then maintain the temperature of reaction mixture below 20 °C for 15 hrs with stirring. Then allow it to cool down temperature to achieve temperature of 15°C & at that temperature add water, stir it for 15 minutes. By Maintaining temperature of 15°C adjust the pH using the caustic solution. Filter the product and wash with little amount of Methanol. Dry the Product. Chemical Reaction:

Sulphuric Acid Caustic Soda N OH CHO Ethyl Acetate Water CH N 2 + Methanol

- H 2O OH OH

Phenol Pyridine 2 - Aldehide M.W. : 18 4,4'-(2-Pyridinylmethylene) Bisphenol M.F.: C H O M.F. : C H NO 6 6 6 5 M.F. : C 18 H15 NO 2 F.M. : 94.11 F.M. : 107.11 F.W. : 277.32

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Ethyl Acetate 1.870 Product 1.000 Phenol 0.680 Ethyl Acetate Recovery 1.830 Sulphuric Acid 0.750 Evaporation Loss 0.120 Caustic Soda 0.306 Distillation Residue 0.059 Pyridine 2-Aldehyde 0.667 Waste Water 1.670 Methanol 0.100 Water 0.306 Total 4.679 Total 4.679

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144) 3-Amino-4-methyl-2-thiophenecarboxylic acid methyl ester Process Description: 4-methyl thiophen-3-amine and Methyl chloroformate are reacted using methylene dichloride as solvent to give methyl 3-amino-4-methylthiophene-2-carboxylate. Chemical Reaction: O

CH3 S S Methylene Dichloride O O

+ CH3 Cl O NH2 3CH - HCl (36.46) 3CH NH2

Methyl Chloroformate methyl 3-amino-4-methylthio 4-methylthiophen-3-amine phene-2-carboxylate Molecular Formula: C H ClO Molecular Formula: C 5H7NS 2 3 2 Molecular Formula: C 7H9NO 2S Formula Weight: 94.49702 Formula Weight: 113.18078 Formula Weight: 171.21686

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) methyl 3-amino-4- 4-methylthiophen-3-amine 0.750 1.000 methylthiophene-2-carboxylate Methylene Dichloride 1.875 MDC recovery 1.788 Methyl Chloroformate 0.625 Evaporation Loss 0.150 Water 0.531 Organic Residue 0.088 Hydrochloric acid (30%) 0.756 Total 3.781 Total 3.781

145) Basic chromium sulphate

Process Description: Chromium sulphate, Sodium sulphate, Sugar, Sulphuric acid, Sodium dichromate andsodium hydroxide are reacted in a reactor along with water. After reaction completion,Basic chromium suphate and Sodium sulphate solution is formed with carbon dioxideemission.product is sent for drying and Dried Basic Chromium sulphate is obtained as amain product. Chemical Reaction:

310

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Chromium Sulphate 0.157 Basic chromium sulphate 1.000 Sodium Sulphate 0.057 Carbon Dioxide 0.106 Water 0.050 Evaporation Loss 0.151 Sugar 0.072 Sulphuric acid 0.470 Sodium dichromate 0.419 Sodium Hydroxide 0.032 Total 1.257 Total 1.257

(III) FERMENTATION PRODUCTS

146) Fusidic Acid Process Description: Fermentation process is carried out using spore micro organism in microbial growth media containing sucrose, Caustic soda lye, Potassium hydrogen phosphate, Magnesium sulphate and water to get fusidic acid. Crystallization of fusidic acid is done by using methanol and acetone as solvent. Chemical Reaction:

Microbial Growth + Spore Microorganism → Media

Fusidic Acid Molecular Formula: C31H48O6 Molecular Weight: 516.709

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Spor Micro organism 0.01 Fusidic Acid 1 Surcrose 20 Effluent 50 Caustic Soda Lye 4 Methanol Recovery 1.9 KH2PO4 1 Acetone Recovery 1.9 MgSO4 1 Evaporation Loss 0.06 Sheftone C 0.4 Distillation Residue 0.02 Antifoam 0.1 Water 25 Methanol 2

311

Acetone 2 Total 55 Total 55 147) Vancomycine

Process Description: Fermentation process is carried out using spore microorganism in microbial growth media containing Dextrose, Dextrin, Potato protein, calcium carbonate, soya flour, salt minerals and water to get Vancomycin . Crystallization of Vancomycin is done by using ethanol and Isopropyl alcohol as solvent.

Chemical Reaction:

Microbial Spore + → Growth Media Microorganism

Vancomycin C66 H75 Cl 2N9O24 1449.3 g.mol −1 g·mol−1

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Spor Micro organism 0.005 Vancomycin 1.000 Dextrose 0.100 Effluent 28.175 Dextrine 6.000 Ethanol Recovery 2.375 Potato Protein 1.440 IPA Recovery 2.375 CaCO3 0.090 Evaporation Loss 0.200 Soyaflour 1.440 Distillation Residue 0.050 Salts Minerals 0.100 Water 20.000 Ethanol 2.500 IPA 2.500 Total 34.175 Total 34.175

312

148) Mupirocine

Process Description: Fermentation process is carried out using spore microorganism in microbial growth media containing Wheat gluten, corn powder, salts & minerals, Anti foam and water to get Mupirocin. Crystallization of Mupirocin is done by using Ethyl acetate and n - heptane as solvent.

Chemical Reaction:

Microbial Spore Growth + → Microorganism Media

Mupirocin C26 H44 O9 500.629 g/mol g·mol −1

Mass Balance:

Input material Quantity Output material Quantity (MT/MT) (MT/MT) Spor Micro organism 0.010 Mupirocin 1.000 Wheat Gluten 1.900 Effluent 25.310 Corn Powder 1.600 Ethyl Acetate Recovery 171.000 Salts & Minerals 0.700 n-Haptane Recovery 2.280 Antifoam 0.100 Evaporation Loss 6.840 Water 20.000 Distillation Residue 0.280 Ethyl Acetate 180.000 n-Haptane 2.400 Total 206.710 Total 206.710

149) Seratiopaptidase

Process Description: Fermentation process is carried out using spore microorganism in microbial growth media containing Dextrose, soybean flour, casein, Diammonium phosphate, calcium chloride, magnesium sulphate, potassium chloride, sodium chloride and water to get Seratiopeptidase . Crystallization of Seratiopeptidase is done by using Isopropyl alcohol and Acetone as solvent.

Chemical Reaction:

Microbial Growth Spore + → Seratiopaptidase Media Microorganism

313

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Spor Micro organism 0.010 Serratiopeptidase 1.000 Dextrose 8.000 Effluent 47.690 Soyabean Flour 8.000 IPA Recovery 47.500 Casein 5.000 Acetone Recovery 47.500 Soya Oil 4.000 Evaporation Loss 3.750 Diammonium Phosphate 2.000 Distillation Residue 0.250 Calcium Chloride 0.160 Magnesium Sulphate 0.160 Potassium Chloride 0.160 Sodium Chloride 0.200 Water 20.000 IPA 50.000 Acetone 50.000 Total 147.690 Total 147.690

150) Mycophenolate Process Description: Fermentation process is carried out using spore microorganism in microbial growth media containing Dextrose, soybean flour, casein, Diammonium phosphate, calcium chloride, magnesium sulphate, potassium chloride, sodium chloride and water to get Mycophenol ic acid browth. Mycophenolic acid is reacted with Dipyridyl carbonate and sodium bicarbonate using xylene and Isobutanol as media to give Mycophenolic acid. Mycophenolic acid is treated with activated carbon in presence of isobutyl acetate and acetone to ge t Mycophenolate mofetil. Mycophenolate mofetilis reacted with sodium – 2 – ethyl Hexenoic acid to get Mycophenolate sodium.

Chemical Reaction:

Microbial Growth Spore + → Media Microorganism

Mycophenolate C17 H20 O6 320.34 g/mol g·mol −1

Mass Balance: Input material Quantity Output material Quantity (MT/MT) (MT/MT) Mycophenolic Spor Micro organism 0.010 1.000 Acid/Mofetil/Sodium Dextrose 5.000 Effluent 30.142 Soyabean Flour 4.000 Xylene Recovery 13.300

314

Casein 5.000 Isobutanol Recovery 5.700 Soya Oil 4.000 Acetone Recovery 13.300 Diammonium Phosphate 2.000 Isobutyl Acetate Recovery 4.750 Calcium Chloride 0.160 Evaporation Loss 1.550 Magnesium Sulphate 0.160 Distillation Residue 0.118 Potassium Chloride 0.160 Spent Carbon 0.050 Sodium Chloride 0.200 Water 10.000 Xylene 14.000 Isobutanol 6.000 Dipyridyl Carbonate 0.100 Sodium Bicarbonate 0.010 Isobutyl Acetate 5.000 Carbon 0.050 Acetone 14.000 Sodium 2Ethyl Hexanoic Acid 0.060 Total 69.910 Total 69.910

315

Annexure -IV Details of Water Consumption and Wastewater generation

Sr. Category Proposed Scenario KL/day Remarks No. Water Waste water consumption generation 1 Industrial Process 107.64 164.47 ‰ Stream-I: 171.74 KL/day low COD & TDS stream (from process, Boiler, Boiler 90 19 cooling, washing, R & D & caustic Cooling 45 8 lye) will be treated in ETP giving Washing 15 15 primary & secondary treatment then sent to deep sea disposal through Scrubbing 20.79 29.27 GIDC pipeline. Other (R & D) 0.2 0.17 ‰ Stream-II: 10 KL/day high COD & TDS stream (from process) will be

given primary treatment than sent to Common MEE of M/s BEIL, Dahej. ‰ Stream-III: 30 KL/day distilled water stream will be recovered & Total (Industrial) 278.63 235.91 reuse by process distillation in process water. ‰ 24 KL/day scrubbing media will be sold to authorized end user registered under Rule-9. 2. Gardening 5.0 0.0 3 Domestic 10.0 8.0 Total 293.63 243.91

316

WATER BALANCE (PROPOSED):

Note: All figures are in KL/day

Total Water: 293.63 KLD (fresh water: 263.63 + Distilled water: 30)

Domestic: 10.0 Industrial: 278.63 Gardening: 5.0

Sewage: 8.0

Stream -III: 30 KLD Distilled

water recovery Process: 107.64 Cooling: 45 Scrubbing: 20.79 Other Boiler: 90 Washing: 15 & reuse by (R & D) : 0.2 Process distillation Process: 134.47 Caustic Lye 0.17 Boiler: 19 Cooling: 8 Washing: 15 sol.: 5.27 124.47

Stream -II: 10 KLD

high COD & TDS stream

Stream -I: 171.91 KLD low COD & TDS stream 24 ETP (Primary treatment) Scrubbing media- Liquor ammonia: 2.9 KLD Common MEE of ETP (Primary & HBr sol. (45-47%): 0.8 KLD M/s BEIL, Dahej secondary treatment) HCl sol. (28-30%): 7.3 KLD Sodium bisulfite: 6.5 KLD Deep sea disposal HCl sol. (30%): 6.5 KLD through GIDC will be sold to authorized pipeline end user registered under Rule-9.

317

Annexure -V Details of ETP:

PROCESS DESCRIPTION: ETP (EFFLUENT TREATMENT PLANT) The details of the ETP are as under: Stream I (Low COD & TDS Stream) (171.91 KLD)

First all non-toxic and biodegradable streams (low COD & TDS) of wastewater shall be collected in Collection cum Equalization Tank-01 (CET-01). Pipe grid is provided at bottom of the CET-01 to keep all suspended solids in suspension and to provide proper mixing. 2 nos. of Air Blowers (1W+1 stand-by) shall supply air through to pipe grid. Then after, equalized wastewater shall be pumped to Neutralization Tank-1 (NT-01) where the continuous addition and stirring of Lime solution is done to maintain neutral pH of wastewater from Lime Dosing Tanks (LDT-01-A/B) as per requirement with help of Lime Dosing Pumps. Then after, neutralized wastewater shall go to Flash Mixer (FM-01) by gravity. Alum shall be dosed from Alum Dosing Tanks (ADT-01-A/B) with help of Dosing Pumps. Then coagulated effluent shall be collected in Flocculator (FL-01) where Polyelectrolyte shall be dosed from Polyelectrolyte Dosing Tank-1 (PEDT-01) with help of pumps to carry out flocculation with help of Flocculator Mechanism. Then after, coagulated wastewater shall be settled in Primary Clarifier-1 (PCL-01). Clear supernatant from PCL-01 shall be passed in Aeration Tank-1 (AT-01). Here, Condensate from MEE and ATFT through condensate storage tank (CST-01) mix with effluent. Here, biodegradation of organic matter of the wastewater shall be carried out by bacteria (suspended growth) in the AT-01 and for that oxygen shall be supplied by 2 nos. of air blowers (B-02) through diffusers. Air blowers also keep MLSS in suspension. Then after, wastewater shall go to Secondary Clarifier-1 (SCL-01). Here, the suspended solids shall be settled. Sludge shall be removed from bottom of SCL-01 and pumped to AT-1 to maintain MLSS and excess activated sludge shall be sent to Sludge Sump (SS-01). Clear supernatant from SCL-01 shall go to Aeration Tank-2 (AT-02). Here biodegradation of left out organic matter of the wastewater shall be carried out by bacteria (suspended growth) and for that oxygen shall be supplied by two nos. of blowers (B-03) with help of diffusers. Then after, wastewater shall go to Secondary Clarifier-2 (SCL-02) from AT-2. Here, the suspended solids shall be settled. Activated sludge shall be removed from bottom of SCL-02 and pumped to AT-02 to maintain MLSS and remaining will be sent to SS. Nutrients will be added from Nutrient Dosing Tanks (NDTs-01) to Aeration Tank-1 & 2 for growth of Bacteria. Clear effluent is the collected in Treated Effluent Sump (TES-01) before sent to CETP Dahej for further treatment. Sludge settled in PCL-01, PST-01 and excess sludge from SCL-01-B/02-B shall be collected in Sludge Sumps (SSs-01-A/B) then sludge shall be pumped to Centrifuge (CF-01) where poly shall be mixed from poly Dosing Tank-2 (PDT-02) with sludge to increase efficiency of centrifuge sludge dewatering. Then, dewatered sludge shall be stored in in HWSA and then ultimate disposal to TSDF. Leachate from CF-01 sent back to CET-01 for further treatment.

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Stream II (High TDS stream) (10 KLD Process) First all streams of wastewater shall be collected in Equalization cum Neutralization tank (ENT- 01)where the continuous addition and stirring of Caustic solution is done to maintain neutral pH of wastewater from Lime Dosing Tank (LDT-01) as per requirement by gravity. Mixer is provided in the ENT-01 to keep all suspended solids in suspension and for proper mixing. Then, neutralized wastewater shall be pump to Flash Mixer (FM-01) where Alum and Polyelectrolyte shall be dosed from Alum Dosing Tank (ADT-01) and Polyelectrolyte Dosing Tank (PEDT-01) respectively by gravity. Then it will go into PST-01 where solids are allowed to settle and Clear supernatant from PST-01 shall be collected in Treated Effluent Sump (TES-01) before sent to Common MEE of M/s BEIL, Dahej for further treatment.

NAME AND SIZE OF ETP UNITS (FOR LOW COD & TDS STREAMS) (171.91 KLD)

Sr. Size in Meters Name of Unit Tag No. Nos. MOC No. (L X B X (LD+FB) Inlet Units Collection cum RCC M30+ A/A 1. CET-01 5.0 x 3.0 x (3.0+0.5) 1 Equalization Tank Bk. Lining Primary Treatment 2. Neutralization Tank -1 NT -01 1.7 x 1.7 x (2.0 + 0.5) 1 RCC M30 3. Flash Mixer -1 FM -01 2.0 x 2.0 x (1.8 + 0.5) 1 RCC M30 4. Flocculator FL -01 2.0 x 2.0 x (1.6 + 0.5) 1 RCC M30 4.3 Dia x (3.0 SWD + RCC M30 5. Primary Clarifier -1 PCL-01 1 0.5) Secondary Treatment 6. Aeration Tank -1 AT -01 8.0 x 4.0 (5.0 + 0.5) 1 RCC M30 4.8 Dia x (3.0 SWD + RCC M30 7. Secondary Clarifier-1 SCL-01 1 0.5) 8. Aeration Tank-2 AT-02 7.0 x 3.5 (5.0 + 0.5) 1 RCC M30 4.3 Dia x (3.0 SWD + 9. Secondary Clarifier-2 SCL-02 1 RCC M30 0.5) 10. Treated Effluent Sump TESs -01 8.0 x 5.0 (4.0 + 0.3) 1 RCC M30 11. Sludge Sump SS -01 3.0 x 3.0 x (2.0+0.5) 1 RCC M30 12. Centrifuge CFG-01/02 35 m3/D 1 SS304 13. Drain Pit DP -01 3.0 x 3.0 x (3.0+0.3) 1 RCC M30 14. Lime Dosing Tanks LDTs -01 3000 Lit. 2 HDPE/PP 15. Alum Dosing Tank ADT -01 2500 Lit 2 HDPE/PP 16. Poly Dosing Tanks PDT-01/02 1000 Lit 2 HDPE 17. Nutrient Dosing Tanks NDTs -01 1000 Lit 2 HDPE

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DETAILS OF UNITS: (FOR HIGH COD & TDS STREAMS) (10 KLD Process)

Sr. Size in Meters Name of Unit Tag No. Nos. MOC No. (L X B X (LD+FB) Inlet Units Equalization cum RCC M30+ A/A 1. ENT-01 3.0 x 1.5 (2.0 + 0.5) 1 Neutralization Tank Bk. Lining Primary Treatment RCC M25+ A/A 2. Flash Mixer-2 FM-02 1.0 x 1.0 x (1.0 + 0.5) 1 Bk. Lining Primary Settling RCC M30 3. PST-01 1.5 x 0.7 x (1.5 + 0.5) 1 Tank Treated Effluent RCC M30 4. TES-02 3.0 x 2.0 x (2.0 + 0.5) 1 Sump -02

EFFLUENT TREATMENT PLANT FLOW DIAGRAM

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CHARACTERISTICS OF WASTEWATER BEFORE & AFTER TREATEMENT. STREAM I (Low COD & TDS Stream: 171.91 KLD)

Sr. Parameter Characteristics (mg/L) Deep sea disposal No. Untreated Secondary treated Inlet Norms 1. pH 4.5 -8.5 6.5 -8.5 6.5 -8.5 6.5 -8.5 2. TDS 6000 -7000 2100 1000 -2000 2100 3. COD 8000 -10000 250 15 0-200 250

4. BOD 3 1500 -2000 100 50 -80 100 5. Ammonical 50 50 150-200 100-150 Nitrogen

STREAM II (High COD & TDS Stream: 10 KLD) Sr. No. Parameter Characteristics (mg/L) Untreated Treated water 1. pH 4.5 -8.5 6.5 -8.5 2. TDS 50000 -60000 50000 -60000 3. COD 35000 -40000 30000 -35000

4. BOD 3 8000 - 10 000 7000 -88 00

STREAM III (Distilled water Stream: 30 KLD) Sr. No. Parameter Characteristics (mg/L) Distilled water 1. pH 6.5-8.5 2. TDS - 3. COD >100

4. BOD 3 >100

Note: Company will reuse the distilled water in same stage (in next batch) of same production for which distillation carried out.

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Annexure -VI Details of hazardous waste generation, storage & disposal:

Proposed Sr. Type of Source of quantity Disposal Method Category No. waste generation (MT per Month ) Collection, Storage, transportation Sch -I 1 ETP Sludge ETP 98 and dispose common TSDF site of (35.3) BEIL, Ankleshwar. Discarded Collection, decontamination, Storage & handling Sch -I 2 Drums/Bags 4.4 Storage, transportation, & Sale to of Raw Materials (33.1) / Liners GPCB approved recyclers/vendors. Collection, Storage, transportation Equipment & Sch -I & Sale to GPCB approved recyclers 3 Used oil 0.3 Machineries (5.1) or use as lubricant within unit’s premises. Mfg. Process Collection, Storage, transportation Spent Sch -I 4 (Product No. 3,6,33, 14.1 and disposal to TSDF Site of M/s. carbon (28.3) 48,87,90,108) BEIL, Ankleshwar. Collection, Storage, Transportation Mfg. Process of & Disposal at TSDF-Site (M/s. BEIL, Spent (Product No. 16, Sch -I 5 14.65 Ank.) or return back to supplier for catalyst 27,51,88,94,125 & (28.2) regeneration or reuse in the 136) premises. Collection, Storage, transportation and disposal by co processing in Distillation Sch -I 6 Distillation Process 48.18 cement industry or at common Residue (36.1) incinerator site of M/s. BEIL, Ankleshwar. Collection, Storage, Transportation Mfg. Process and sent for co-processing in Organic Sch -I 7 (Product No. 8,33, 32 cement industries or incineration at Residue (28.1) 60, 93,123 & 141) common incinerator site of M/s. BEIL, Ankleshwar. Dilute Scrubber Sch -I Collection, Storage & sent to ETP 8 Caustic Lye 158.1 (Product No. 1 & 80) (28.1) for further treatment Solution Collection, Storage, Transportation, Liquor Scrubber Sch -I 9 87 disposal by selling to authorized ammonia (Product No. 15) (28.1) end user registered under Rule -9.

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Scrubber Collection, Storage, Transportation, HBr sol. (45- Sch -I 10 (Product No. 58 & 24 disposal by selling to authorized 47%) (28.1) 134 ) end user registered under Rule -9. Scrubber Sch-II- Collection, Storage, Transportation, HCl sol. (28- 11 (Product No. 15, 78, Class- B 219 disposal by selling to authorized 30%) 87, 97, 127 & 144 ) (15) end user registered under Rule -9. Scrubber Sch-II- Collection, Storage, Transportation, HCl sol. 12 (Product No. 10, 31, Class- B 195 disposal by selling to authorized (30%) 71, 92 & 100) (15) end user registered under Rule -9. Scrubber Collection, Storage, Transportation, Sodium Sch -I 13 (Product No. 10, 31, 195 disposal by selling to authorized bisulfite (28.1) 71, 92 & 100) end user registered under Rule-9. Spent Sch -I Collection, Storage, management & 14 Mfg. Process 12399 Solvent (28.6) recovery within the premises. Aluminium Mfg. Process Sch -I Collection, Storage, Transportation, 15 Chloride (Ibuprofen &Isobutyl (28.1) 672.7 disposal by selling to authorized Sol. (8 -10%) acetophenone ) end user registered under Rule -9. Chromium Collection, Storage, Transportation, Mfg. Process Sch -I 16 Sulfate Sol. 370 disposal by selling to authorized (Ibuprofen) (28.1) (8 -10%) end user registered under Rule -9. Collection, Storage, Transportation, Mfg. Process Sch -I 17 Acetic acid 72 disposal by selling to authorized (Acyclovir) (28.1) end user registered under Rule -9. Collection, Storage, Transportation, Sodium Mfg. Process Sch -I 18 12.9 disposal by selling to authorized Phosphate (Lamotrigine) (28.1) end user registered under Rule -9. IBAP isomer Mfg. Process Collection, Storage, Transportation, Sch -I 19 (Cas No. (Ibuprofen &Isobutyl 8.7 disposal by selling to authorized (28.1) 38861-78-8) acetophenone ) end user registered under Rule-9. Isomer of Collection, Storage, Transportation, Aldehyde Mfg. Process Sch -I 20 6.0 disposal by selling to authorized (Cas No. (Ibuprofen) (28.1) end user registered under Rule-9. 51407 -46 -6) Collection, Storage, Transportation Off Process (Batch Sch -I & send for co-processing or 21 specificatio 2 .0 failure) (28.4) common incinerator Site of M/s. n product BEIL, Ankleshwar. Collection, Storage, Transportation Off Sch -I & send for co-processing or 22 specificatio R&D 0.03 (28.4) common incinerator Site of M/s. n product BEIL, Ankleshwar. Spent Sch -I Collection, Storage, management & 23 R&D 10 Solvent (28.6) recovery within the premises.

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Collection, Storage, transportation and sent for co-processing in Spent Sch -I 24 R&D 0.05 cement industries or incineration at carbon (28.3) common incinerator Site of M/s. BEIL, Ankleshwar. Collection, Storage, Transportation & Disposal at TSDF-Site (M/s. BEIL, Spent Sch -I 25 R&D 0.05 Ank.) or return back to supplier for catalyst (28.2) regeneration or reuse in the premises . Collection, Storage, transportation and disposal by co processing in Distillation Sch -I 26 R&D 0.1 cement industry or at common Residue (36.1) incinerator site of M/s. BEIL, Ankleshwar.

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Annexure -VII

Details of flue gas & proposed pollution control equipment:

PROPOSED: Flue gas emissions

Stack Air pollution Fuel used Permissible Particulars height control Parameter with Qty. Limit Above GL Measures Briquettes= 700 Multicyclone Kg/Hour Separator, Steam Boiler Bag Filter SPM 150 mg/Nm 3 13 m or (Capacity: 2000 kg/hr) or SO 2 100 ppm Natural Gas Adequate NO x 50 ppm = 230 stack height SCM/hour

Natural Adequate Thermic fluid heater SPM 150 mg/Nm 3 13 m gas= 250 stack height (Capacity: 6 lakh kcal/hr. SO 100 ppm SCM/Hour 2 NO x 50 ppm

150 mg/Nm 3 DG Set (150 KVA) in Diesel= 20 Adequate SPM 10 m 100 ppm emergency case only Liters/hour stack height SO 2 50 ppm NO x

Process Vents

Particulars (Name of Product & Stack height Air Pollution Permissible Parameter Process) Above GL Control Measure Limit Process Vent 1 Two Stage Water (Product No. 15,78,87,97,127 &144 15 Meters HCl 20 mg/Nm 3 Scrubber & Chlorination ) Process Vent 2 Two Stage Water + SO 40 mg/Nm 3 (Product No. 10, 31, 71, 92 & 100, 15 meters 2 Alkali scrubber HCl 20 mg/Nm 3 Sulphonation & Chlorination) Process Vent 3 Two Stage Water (Product No. 58 & 134 & 15 meters HBr 30 mg/Nm 3 Scrubber Bromination) Process Vent 4 Two Stage Water 15 meters NH 175 mg/Nm 3 (Product No. 15 & Ammonification) Scrubber 3

Process Vent 5 Two Stage Alkali 15 meters HCl 20 mg/Nm 3 (Product No. 1, 80 & Chlorination) Scrubber

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Annexure –VIII

Storage Details of Hazardous Chemicals

Name of the Hazardous Maximum Type of Possible type of Sr. No of Vessel Substance Storage Storage & Hazards No. Vessels Capacity (MT/week) MOC 1 Isopropyl Alcohol 10 1 10 MS Tank Flammable/Toxic Methylene Chloride/ 2 Methylene 20 2 10 MS Tank Flammable Dichloride(MDC) 3 Toluene 20 2 10 MS Tank Flammable/Toxic 4 Ethyl Acetate 20 2 10 MS Tank Flammable 5 Methanol 10 1 10 MS Tank Flammable/Toxic 6 Acetone 10 1 10 MS Tank Flammable 7 Ethanol 5 50 200 lit Drums Flammable 8 Ethylene Dichloride 4 50 200 lit Drums Flammable/Toxic 9 Sulphuric Acid 4 50 200 lit Drums Corrosive Irritant and 10 Acetic Acid 4 20 200 lit Drums corrosive 11 Liquor Ammonia 4 20 200 lit Drums Toxic 12 Acetonitrile 4 20 200 lit Drums Flammable 13 Hydrochloric acid 4 20 200 lit Drums Corrosive 20 Flammable 14 Xylene 4 200 lit Drums / Toxic 15 Hexane 3 20 200 lit Drums Flammable 16 Tetrahydrofuran 3 20 200 lit Drums Flammable/Toxic 17 Cyclohexane 3 20 200 lit Drums Flammable 18 Dimethyl formamide 3 15 200 lit Drums Flammable/Toxic 19 Aniline 2 10 200 lit Drums Flammable/Toxic 20 Acetic Anhydride 2 10 200 lit Drums Flammable/ Toxic 21 Thionyl chloride 2 10 200 lit Drums Corrosive 22 Chloroform 2 10 200 lit Drums Toxic 23 n-heptane 2 10 200 lit Drums Flammable Hydrogen Bank (75 Cylinder) 429 Flammable & 24 Hydrogen Gas 0.75 m3 explosive 25 Ammonia gas 0.5 50 10 kg Cylinder Toxic 26 Bromine gas 0.9 300 3 kg Bottle Toxic 27 Chlorine gas 1.8 2 0.9 MT Tonner Toxic

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Annexure – IX

Socio - Economic Impacts

1) Employment Opportunities The manpower requirement for the proposed expansion project is being expected to generate some permanent jobs and some secondary jobs for the operation and maintenance of plant. This will increase direct / indirect employment opportunities and ancillary business development to some extent for the local population. The project is expected to create a beneficial impact on the local socio-economic environment. 2) Industries Required raw materials and skilled and unskilled laborers will be utilized maximum from the local area. The increasing industrial activity will boost the commercial and economical status of the locality, to some extent. 3) Public Health The company regularly examines, inspects health of its workers. There is use of hazardous chemicals for which all safety norms such as safety during handling, use of PPEs will be followed strictly. All measures will be taken to control process gas emissions so health of the people will not be adversely affected. Hence, there will not be any significant change in the status of sanitation and the community health of the area, as sufficient measures will be taken as proposed under the EMP.

4) Transportation and Communication Since the existing industry is having proper linkage for the transport and communication, the development of this project will not cause any additional impact. In brief, as a result of the proposed project there will be no adverse impact on sanitation, communication and community health, as sufficient measures have been proposed to be taken under the EMP. The proposed scenario is not expected to make any significant change in the existing status of the socio - economic environment of this region.

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Annexure-X ______Proposed Terms of Reference for EIA Studies

1. Project Description • Justification of project. • Promoters and their back ground • Project site location along with site map of 5 km area and site details providing various industries, surface water bodies, forests etc. • Project cost • Project location and Plant layout. • Existing infrastructure facilities • Water source and utilization including proposed water balance. • List of Products & their capacity • Details of manufacturing process of proposed products • List of hazardous chemicals • Mass balance of each product • Storage and Transportation of raw materials and products.

2. Description of the Environment and Baseline Data Collection • Micrometeorological data for wind speed, direction, temperature, humidity and rainfall in 10 km area. • Existing environmental status Vis a Vis air, water, noise, soil in 10 km area from the project site. • Ground water quality at 8 locations within 10 km. • Complete water balance

3. Socio Economic Data • Existing socio-economic status, land use pattern and infrastructure facilities available in the study area were surveyed.

4. Impacts Identification And Mitigatory Measures • Identification of impacting activities from the proposed project during construction and operational phase. • Impact on air and mitigation measures including green belt • Impact on water environment and mitigation measures • Soil pollution source and mitigation measures • Noise generation and control. • Solid waste quantification and disposal. • Control of fugitive emissions

5. Environmental Management Plan • Details of pollution control measures

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• Environment management team • Proposed schedule for environmental monitoring including post project

6. Risk Assessment • Objectives, Philosophy and methodology of risk assessment • Details on storage facilities • Process safety, transportation, fire fighting systems, safety features and emergency capabilities to be adopted. • Identification of hazards • Consequence analysis • Recommendations on the basis of risk assessment done • Disaster Management Plan.

7. Information for Control of Fugitive Emissions 8. Post Project Monitoring Plan for Air, Water, Soil and Noise. 9. Information on Rain Water Harvesting 10. Green Belt Development plan

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Annexure-XI ______GIDC Plot Allotment Letter

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Annexure-XIV ______Toposheet

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