ToR Amendment Tagoor Laboratories Private Limited

ANNEXURE – I

Details of Products as per Granted ToR and Amendment Required

Production Capacity S. Ton /Month Therapeutic Product Name No As per Amendment category granted ToR Required 1 Abacavir sulfate 2.0 2.0 Anti HIV 2 Amitriptyline 5.0 10.0 Antidepressant 3 Atrovastatin Calcium 5.0 5.0 Hypercholesterolemia 4 Bupropion 5.0 5.0 Anti depressant 5 carisoprodol 2.0 2.0 Muscle Relaxant 6 Clopidogrelbisulfate 5.0 5.0 Antithrombotic 7 Cyclobenzaprine HCl 5.0 5.0 Muscle relaxant 8 Cyproheptadine HCl 5.0 10.0 Anti allergic 9 Desloratadine 5.0 5.0 Antihistamine 10 Domperidone 20.0 30.0 Anti emetic 11 Domperidone maleate 2.0 2.0 Anti emetic 12 Donepezil HCl 1.0 1.0 Alzheimer’s disease 13 Ebastine 5.0 5.0 Anti allergic 14 Esomeprazole Sodium 3.0 3.0 Anti ulcerative Esomeprazole Magnesium 3.0 3.0 Anti ulcerative 15 trihydrate 16 Fexofenadine Hydrochloride 6.0 15.0 Anti histamine 17 Haloperidol 2.0 2.0 Antipsychotic 18 Itopride Hydrochloride 2.0 2.0 Antispasmodics 19 Itraconazole 10.0 10.0 Antifungal 20 Ketrolac Tromethane 2.0 2.0 Anti Inflammatory 21 Lansoprazole 10.0 10.0 Ant ulcerative 22 Loperamide Hydrochloride 10.0 10.0 Anti diarrhea agent 23 Losartan Potassium 6.0 15.0 Anti Hypertensive 24 Nebivolol HCl 2.0 2.0 Anti Hypertensive 25 Nortriptyline HCl 2.0 2.0 Anti depressant 26 Omeprazole 40.0 40.0 Anti ulcerative 27 Omeprazole Sodium 2.0 2.0 Ant ulcerative Omeprazole Magnesium 2.0 2.0 Ant ulcerative 28 Dihydrate 29 Oxatomide 1.0 1.0 Antihistamine Pantoprazole Sodium Sesqui 10.0 20.0 Ant ulcerative 30 Hydrate 31 Pimozide 2.0 2.0 Antipsychotic 32 Pregabalin 2.0 2.0 Epileptic 33 Quetiapine Hemifumarate 2.0 2.0 Antipsychotic

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ToR Amendment Tagoor Laboratories Private Limited

Production Capacity S. Ton /Month Therapeutic Product Name No As per Amendment category granted ToR Required 34 Rabeprazole Sodium 10.0 15.0 Ant ulcerative 35 Rupatadine fumarate 2.0 2.0 Antihistamine 36 Telmisartan 2.0 2.0 Anti Hypertensive 37 Terbinafine hydrochloride 8.0 15.0 Anti fungal 38 Valsartan 2.0 2.0 Anti Hypertensive 39 1-Benzy-4-piperidone 5.0 5.0 Drug Intermediate 40 1-Benzyl-4-chloropiperidine 5.0 5.0 Drug Intermediate 41 1-Benzylpiperidin-4-ol 5.0 5.0 Drug Intermediate 42 1-Methylpiperidin-4-amine 5.0 5.0 Drug Intermediate 43 4-Aminopiperidine 5.0 5.0 Drug Intermediate 44 4-Hydroxy piperidine 5.0 5.0 Drug Intermediate 45 4-Phenylpiperidine 1.0 1.0 Drug Intermediate 46 4-piperidinopiperidine 1.0 1.0 Drug Intermediate N-tert-Butoxycarbonyl-4- 5.0 5.0 Drug Intermediate 47 hydroxy piperidine Total ( Worst Combination of any 12 Products at any 140.0 200.0 given point of time)

Note:

The above Listed Products, we will manufacture either Finished Product or any Intermediate stage of finished Product as per given quantity by not increasing the production capacity of 200 MT/Month.

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ToR Amendment Tagoor Laboratories Private Limited

List of By-Products for ToR Amendment

S. Quantity in Product Name By product No. Kg /Day Clopidogrel Bisulphate 1 Omeprazole Ammonium sulphate 3578.08 Domperidone Domperidone 2 Cyclobenzaprinehydrochloride Sodium bromide 656 Itraconazole Cyclobenzaprinehydrochloride Cyproheptadine 3 Magnesium Chloride 290 Hydrochloride Desloratadine Desloratadine 4 Potassium chloride 226 Ebastine Aluminium chloride solution 5 Ebastine 667 (12%) Itraconazole 6 Potassium bromide 84 Telmisartan Pantoprazole sodium 7 sesquihydrate Domperidone Ammonium chloride 2216 8 Desloratadine Ammonium acetate 234 Pantoprazole sodium Acetic acid 506 8 sesquihydrate Ammonium phosphate 773.50 Sodium methyl sulphate 632 Pantoprazole sodium sesquihydrate 9 Domperidone Sodium acetate 1244.45 Rabeprazole sodium Omeprazole 10 Omeprazole Sodium nitrite 545 11 Domperidone Methanol 182 12 Losartan Potassium Trityl alcohol 326 Total 12160.03

Note:

The By-Products will be produced according to the combination of required products manufacturing.

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ToR Amendment Tagoor Laboratories Private Limited

ANNEXURE – II

Details of Water Consumption as per Granted ToR and Amendment Required

Water consumptionIn KLD S.No Purpose As per granted ToR Amendment Required 1 Process 40.0 152.5 2 Washings 5.0 6.0 3 Boiler make up 58.5 70.5 4 Cooling towers make up 72.5 119.0 5 Scrubbing system 8.0 18.0 6 Domestic 5.0 6.0 7 Gardening 5.0 5.0 Total 194.00 377.0

Total Water consumption is 377 KLD. 209 KLD of water will be recovered (from Process: 90 KLD & Water Recycled from ZLD System: 119 KLD). Hence, Total fresh water requirement is 377KLD -209 KLD = 168 KLD.

Source of water As per Granted ToR: Ground Water Amendment Required: Surface water Allotment from River /Ground Water

Details of Waste Water as per Granted ToR and Amendment Required

Effluent In KLD S. No Purpose As per granted Amendment ToR Required 1 Process 48.00 98.0 2 Washings 5.00 6.0 3 Boiler Blow down 8.50 10.0 4 Cooling towers Blow down 10.50 15.5 5 Scrubbing system 8.00 15.0 6 Domestic 4.00 5.5 Total 84.00 150.0

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ANNEXURE -III

Details of Solid & Hazardous Waste Generation and Disposal as per Granted ToR and Amendment Required

Quantity S. Details As per Amendment Disposal Method No granted ToR Required Organic waste 1743 2211 Sent to Cement 1 (Process Residue) Kg/Day Kg/Day Industries 167 336 Sent to Cement 2 Spent Carbon Kg/Day Kg/Day Industries Solvent Distillation 1123 2001 Sent to Cement 3 Residue Kg/Day Kg/Day Industries 1216 725 4 Inorganic Waste Sent to TSDF Kg/Day Kg/Day Sent to authorized Spent Mixed 2465 4000 5 recyclers/Cement Solvents Kg/Day Kg/Day Industries 500 .00 500 .00 6 ETP Sludge Sent to TSDF Kg/Day Kg/Day 4387 8684 7 MEE Salts Sent to TSDF Kg/Day Kg/Day Organic Evaporative Liquid 8 0.82KLD 1560 Kg/Day Sent to Cement Industry ( from MEE Stripper) SPCB Authorized 9 Used Oils 500L/Annum 500L/Annum Agencies for Reprocessing/Recycling Detoxified 600 No’s / After Detoxification sent 800 No’s / Month 10 Containers Month to outside agencies. Send back to suppliers Used Lead Acid 11 4 No’s/ Annum 4 No’s/ Annum for buyback of New Batteries Batteries Ash from boiler 11550 Kg/Day Sent to Brick 12 17100 Kg/Day Ash from boiler Manufacturers

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ToR Amendment Tagoor Laboratories Private Limited

ANNEXURE - IV

UTILITES AS PER GRANTED TOR

Boilers: Existing: 6.0 TPH Coal fired/ Agro waste fired Boiler & 2,00,000 kcal/hr Thermo pack Boiler will be continued Proposed: 4.0 TPH Coal fired/ Agro waste fired Boiler is proposed

DG Sets: 250 KVA & 500KVA

DETAILS OF UTILITIES AS PER AMENDMENT REQUIRED

Boilers: Existing: 6.0 TPH Coal fired/ Agro waste fired Boiler will be kept as Standby The existing 2,00,000 kcal/hr. Thermo pack Boiler will be Continued Proposed: 12.0 TPH Coal fired/ Agro waste fired Boiler

DG Sets:

1000KVA X 2 no’s

STACK EMISSION DETAILS FOR 12 TPH COAL FIRED/ AGRO WASTE FIRED BOILER

Particulars Units 12.0 TPH Agro waste / Coal fired Boiler (Proposed) Type of Fuel -- Agro waste /Indian Coal Coal Consumption TPD 48 Ash Content % 35 Sulphur Content % 0.4 No. of Stacks No 1 Height of stack M 32 Diameter of Stack M 0.6 Temperature of Flue oC 220 Gas Velocity of Flue Gas m/s 15 Particulate Matter gm/sec 1.8 Sulphur dioxide gm/sec 2.67 emission Oxides of Nitrogen gm/sec 5.13 emission Pollution control - Cyclone separator followed by equipment suitable pack of Bag filters

 Note : 6.0 TPH Agro waste /Coal fired boiler (Stand by )

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ToR Amendment Tagoor Laboratories Private Limited

STACK EMISSION DETAILS FOR THERMO PACK BOILER

2,00,000 kcal/hr. Thermo pack Particulars Units Boiler (Existing) Thermo pack Boiler Capacity Kcal/hr. 2,00,000 Type of Fuel -- Agro waste/ Coal

Stack Temperature Before oC 250 Air preheater Stack Temperature After Air oC 180 preheater Stack Height m 9.0 Fuel Consumption per Day TPD 0.75 Diameter m 0.30

STACK EMISSION DETAILS FOR DG SETS

Emission Emission Emission Stack Flue Gas Stack Flue gas Capacity of SPM in Of SO2 in of NOx In dia. Temp. Height Velocity In KVA 3 3 3 O mg/Nm mg/Nm mg/Nm in m in C in m in m/sec. 1000 KVA 80 50 60 0.2 300 10 16 (Proposed) 1000 KVA 80 50 60 0.2 300 10 16 (Proposed)

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ToR Amendment Tagoor Laboratories Private Limited

ANNEXURE -VII

Details of Process Emission as per Granted ToR and Amendment Required

Quantity In S. Name of the Kg/Day No. Gas As per Amendment Treatment Method granted ToR Required Scrubbed by using 1 Sulphur dioxide 697 1724 C.S.Lye Solution Hydrogen Scrubbed by using 2 330 1183 chloride chilled water media Hydrogen Scrubbed by using C. S. 3 420 311 Bromide Lye solution Dispersed into the 4 Nitrogen 17 45 atmosphere Dispersed into the 5 Carbon dioxide 662 863 atmosphere Diffused by using 6 Hydrogen 16 34 Nitrogen through Flame arrestor Scrubbed by using 7 Ammonia 68 104 chilled water media Dispersed into the 8 Oxygen 136 794 atmosphere Scrubbed by using 9 Chloro Methane 209 242 C.S.Lye Solution

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ToR Amendment Tagoor Laboratories Private Limited

ANNEXURE – X CONSOLIDATED STATEMENT- POLLUTION DETAILS ASPER TOR AMENDMENT

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Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) Form-I

Form - 1 Appendix- I (See Paragraph-6) (I) Basic Information S. Item Details No. Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt 1 Name of the Project/s Ltd)Expansion of Existing Bulk Drugs & Intermediates manufacturing unit 5(f) Synthetic organic chemicals industry (dyes & dye intermediates; bulk drugs and intermediates excluding drug formulations; 2 S.No. in the Schedule synthetic rubbers; basic organic chemicals, other synthetic organic chemicals and chemical intermediates) Proposed capacity / area / length / tonnage to be handled /command Bulk Drugs & Intermediates – 200 Tons/Month 3 area / lease area / number of wells (ToR Amendment) to be drilled 4 New / Expansion / Modernization Expansion 10.00 TPM (As per EC vide F.No. J-11011/401/ 5 Existing Capacity / Area etc. 2014-IA-II (I) Dated : 01 Aug 2017) 6 Category of Project i.e. ‘A’ or ‘B’ A Does it attract the general 7 Not Applicable conditions? If yes, please specify Does it attract the Specific 8 Not Applicable conditions? If yes, please specify. Location Latitude 17° 9'29.66"N Longitude 81°35'23.87"E Plot / Survey / Khasra No Sy No. 29, 9 Village Tupakulagudem (V) Mandal Tallapudi (M) District West Godavari (Dist.) State Andhra Pradesh Nearest railway station / airport Kovvuru Railway station – 22.0 KMs (SE) 10 along with distance in km Rajahmundry Airport – 24.00 KMs (ESE) Nearest town, city, district 11 headquarters along with distance in Rajahmundry – 24 km (SE) km

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Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) Form-I

S. Item Details No. Village Panchayats, Zilla Parishad, 12 Municipal Corporation, Local body Tupakulagudem (V) Tallapudi (M), West (complete postal addresses with Godavari (Dist.), Andhra Pradesh telephone nos. to be given) 13 Name of the applicant P. Kasiviswanadha Raju

Plot No 99 & 100, SV Cooperative Industrial 14 Registered Address Estate, IDA, Jeedimetla, Hyderabad, Telangana Sate Duplex No: 29, Lakshmi Gayatri Enclave, Address for Correspondence Aditya Nagar, KPHB, Kukatpally, Hyderabad Telangana Sate Name P. Kasiviswanadha Raju Designation (Owner/Partner/CEO) Director Duplex No: 29, Lakshmi Gayatri Enclave, 15 Address Aditya Nagar, KPHB, Kukatpally, Hyderabad Telangana Sate Pincode 500072 E-mail [email protected], [email protected] Telephone no. +91-9989311222 Fax no. - Details of Alternate Sites examined, 16 if any. Location of these sites Not Applicable should be shown on a toposheet. 17 Interlinked Projects Not Applicable Whether separate application of 18 interlinked project has been Not Applicable submitted. 19 If yes, date of submission Not Applicable 20 If no, reason Not Applicable Whether the proposal involves approval / clearance under: if yes, details of the same and their status to be given 21 Not Applicable (a) The Forest (Conservation) Act, 1980? (b) The Wildlife (Protection) Act, 1972?

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Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) Form-I

S. Item Details No. (c) The C.R.Z. Notification, 1991? Whether there is any Government No, Government Order / Policy relevant / 22 Order / Policy relevant / relating to relating to the site are applicable. the site 23 Forest Land involved (hectares) No Forest land is involved in the project Whether there is any litigation pending against the project and / or land in which the project is proposed to set up? 24 (a) Name of the Court No litigations pending against the project. (b) Case No. (c) Orders / directions of the court, if any and its relevance with the proposed project.

(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.)

Details thereof (with approximate S. Information / Checklist Yes quantities /rates, wherever possible) No. confirmation /No with sources of information data Permanent or temporary change in The expansion proposal is within the land use, land cover or topography existing land. The total area of the unit 1.1 including increase in intensity of Yes is 11.80 Acres (47752.9 Sq.m) and land use (with respect to local land Plant layout is Enclosed. use plan). Clearance of existing land, No major tree felling or clearance of 1.2 No vegetation and buildings? buildings is envisaged. 1.3 Creation of new land uses? No None Pre-construction investigations e.g. 1.4 No Not Applicable bore holes, soil testing? Construction of various blocks Production, Stores, QC, Boiler shed, 1.5 Construction works? Yes DG set, Utility, Pollution treatment facility, Roads, solvent storage yard,

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Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) Form-I

Details thereof (with approximate S. Information / Checklist Yes quantities /rates, wherever possible) No. confirmation /No with sources of information data Green belt and others 1.6 Demolition works? No No major demolition work is envisaged Majority of the labor will be hired from nearby villages so no housing or Temporary sites used for shelter facilities required for 1.7 construction works or housing of No construction workers. However existing construction works? facilities are sufficient like drinking and sanitation facilities for workers during working hours. Above ground buildings, structures or earthworks including linear 1.8 No Not Applicable structures, cut and fill or excavations Underground works including 1.9 No Not Applicable mining or funneling? 1.10 Reclamation Works? No Not Applicable 1.11 Dredging? No Not Applicable 1.12 Offshore structures? No Not Applicable List of products, By-Products and capacities for TOR Amendment was Production and manufacturing 1.13 Yes Enclosed as in Additional Information processes? and Manufacturing Process is Enclosed as Appendix - I Common facility for storage of raw Facilities for storage of goods or 1.14 Yes materials and finished products will be materials? provided

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Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) Form-I

Details thereof (with approximate S. Information / Checklist Yes quantities /rates, wherever possible) No. confirmation /No with sources of information data

Solid Waste: The Solid & hazardous waste generated in plant will be disposed as per rules. The Details of Solid/Hazardous Waste Details as per Facilities for treatment or disposal Amendment Required enclosed as 1.15 Yes of solid waste or liquid effluents? Annexure in Additional Information File

Liquid waste: Industrial effluent of 154 KL/ day is generated and will be treated in ZLD System.

The workforce is recruited from nearby Facilities for long term housing of 1.16 No villages. No long term housing of operational workers? operational workers Road traffic is likely to increase both during construction and operation stage for transportation of man and New road, rail or sea traffic during material. However, existing transport 1.17 No construction or operation? routes are adequate for the increase in traffic. No additional transport infrastructure is required due to the proposed project New road, rail, air waterborne or other transport infrastructure No, additional transport infrastructure is 1.18 No including new or altered routes and required due to the present proposal. stations, ports, airports etc? Closure or diversion of existing transport routes or infrastructure 1.19 No Not Required leading to changes in traffic movements? New or diverted transmission lines 1.20 No Not Required or pipelines? Impoundment, damming, culverting, 1.21 realignment or other changes to the No Not Required hydrology of watercourses or

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Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) Form-I

Details thereof (with approximate S. Information / Checklist Yes quantities /rates, wherever possible) No. confirmation /No with sources of information data aquifers? 1.22 Stream crossings? No None The total water requirement is 377 KL/day for the proposed project and Abstraction or transfers of water 1.23 Yes Source of Water: Surface water from ground or surface waters? Allotment from State Government /Ground Water Changes in water bodies or the land None (There will not be any changes in 1.24 surface affecting drainage or run- No water bodies or the land surface off? affecting drainage or runoff) Transport of personnel or materials The raw materials and products will be 1.25 for construction, operation or No transported during construction and decommissioning? operation phase Long-term dismantling or 1.26 decommissioning which could have No Not Applicable an impact on the environment? Ongoing activity during 1.27 decommissioning which could have No Not Applicable an impact on the environment? The Estimated employment generation Influx of people to an area in either 1.28 Yes for this proposed project is about 135 temporarily or permanently? Direct employees. 1.29 Introduction of alien species? No No New species are introduced. Loss of native species or genetic No Loss of native species or genetic 1.30 No diversity? diversity. 1.31 Any other actions? No None envisaged

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):

Details thereof (with approximate S. Information /Checklist Yes quantities /rates, wherever possible) No. confirmation /No with sources of information data Land especially undeveloped Total 11.80 Acres (47752.9 Sq.m) is of 2.1 No or agricultural land (ha) Industrial Land 2.2 Water (expected source & Yes The total water requirement is 377 KL/day

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Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) Form-I

competing users) Unit : KLD for the proposed project and Source of Water: Surface water Allotment from River /Ground Water The Details as per Amendment Required are enclosed in Additional Information file 2.3 Minerals (MT) No Not Applicable Construction material – stone, Construction materials like stone, steel 2.4 aggregates, and / soil No aggregates, sand & cement will be sourced (expected source- MT) locally. Forests and timber (source- 2.5 No No Timber will be used. MT) Details as per Amendment Required The power requirement for the plant is 2000 KVA. Boilers: The existing 6.0 TPH Coal fired/ Agro waste fired Boiler will be kept as standby Energy including electricity and 2,00,000 kcal/hr Thermo pack Boiler and fuels (source, competing 2.6 Yes will be Continued. users) Unit : fuel (MT), energy (MW) Proposed to install 12.0 TPH Coal fired/ Agro waste fired Boiler.

DG Sets: For emergency power supply industry is proposing two no’s DG sets of 1000 KVA and Existing:250 KVA will be dropped, Any other natural resources 2.7 (use appropriate standard No None 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. S. Information /Checklist Yes Details thereof (with approximate No. confirmation /No quantities /rates, wherever possible) with sources of information data The number of chemicals will be used Use of substance or materials, which 3.1 Yes for the production of Synthetic Drugs & are hazardous (as per MSIHC rules) Intermediates which have been

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Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) Form-I

to human health or the environment mentioned in the list of raw materials (flora, fauna and water supplies). given in the Additional Information as Annexure. Changes in occurrence of disease or No such occurrence is envisaged, since 3.2 affect disease vectors (e.g. insect or No effluent generated will be treated water borne diseases) properly. The proposed expansion will generate direct and indirect employment Affect the welfare or people e.g. by opportunities during construction as well 3.3 Yes changing living conditions? as operation phase for the local people based on their qualification and work experience. Vulnerable groups of people who could be affected by the project e.g. 3.4 No None hospital patient’s, children, the elderly etc., 3.5 Any other causes No None

4. Production of solid wastes during construction or operation or decommissioning (MT/ month) S. Information / Checklist Yes Details thereof (with approximate No. confirmation /No quantities /rates, wherever possible ) with sources of information data No 4.1 Spoil, overburden or mine wastes Not Applicable

Commercial waste like empty cement bags, Iron scrap etc. will be sold to scrap buyers after the construction phase. Domestic waste like used Municipal waste (domestic and or 4.2 Yes paper, label, cartoons will be disposed commercial wastes) to the scrap buyers. Organic waste from canteen will be disposed as per the local Panchayath / Municipal disposal mechanism. Hazardous wastes (as per Hazardous wastes Details for ToR 4.3 Hazardous Waste Management Yes Amendment are Enclosed as Rules) Annexure in additional information The detailed Solid & Hazardous wastes 4.4 Other industrial process wastes Yes for ToR Amendment are Enclosed as Annexure in additional information

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Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) Form-I

S. Information / Checklist Yes Details thereof (with approximate No. confirmation /No quantities /rates, wherever possible ) with sources of information data 4.5 Surplus product No None Sewage sludge or other sludge 4.6 Yes ETP sludge is sent to TSDF from effluent treatment Minimal quantity of debris, scraps, excavated soil used cement bags, 4.7 Construction or demolition wastes No iron/steel scrap and cardboards waste could be generated during additional construction. Redundant machinery or 4.8 No None equipment Contaminated soils or other 4.9 No None materials 4.10 Agricultural wastes No None 4.11 Other solid wastes No None

5. Release of pollutants or any hazardous, toxic or noxious substances to air (Kg/hr) Details thereof (with approximate Information /Checklist Yes/ S.No. quantities /rates, wherever possible) confirmation No with sources of information data

Gaseous emission like SO2, NOx, CO and particular matter shall be generated from Emissions from Boilers and DG sets which will be combustion of fossil fuels maintained under prescribed limit. DG sets 5.1 Yes from stationary or mobile will be used during only power break down. sources Adequate stack height of Boilers and DG sets provided for effective dispersion of pollutants. Proper control measures will be adopted to Emissions from production 5.2 Yes control emission as per prescribed processes Standard Emissions from handling Fugitive emissions from material handling, 5.3 including storage and Yes loading /unloading and transport of material transport will be minimal due to closed loop system. Emissions from This will be restricted to the construction 5.4 Yes construction activities phase and to the construction site only. It

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Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) Form-I

Details thereof (with approximate Information /Checklist Yes/ S.No. quantities /rates, wherever possible) confirmation No with sources of information data including plant and will be minimized by sprinkling water. equipment Dust or odors from handling of materials Dust will be generated from loading and 5.5 including construction Yes unloading of raw material and finished materials, sewage and products. waste. Emissions from 5.6 No No incinerator is proposed. incineration of waste Emissions from burning of waste in open air (e.g. 5.7 No No waste will be burnt in open air. slash materials, construction debris) Emissions from any other Dust Emissions from Ball Mill will be 5.8 Yes sources mitigated by providing Inbuilt bag filters.

6. Generation of Noise and Vibration, and Emissions of Light and Heat: Details thereof (with approximate Information /Checklist Yes/ S.No. quantities /rates, wherever possible ) confirmation No with sources of information data Material transport shall be source of noise during construction, while transfer pumps, vacuum systems are the sources of noise during operation. The equipment in the plant are designed for noise levels not From operation of equipment exceeding 90 dB (A). Proper encasement 6.1 e.g. engines, ventilation plant, Yes of noise generating sources is done to crushers control the noise levels below 75 dB (A) at plant boundary. Maintenance of all equipment is carried out regularly to reduce noise. A proper green belt is developed which acts as a noise barrier. Pumps, motors, gearboxes etc will generate little bit of noise and will be From industrials or similar 6.2 Yes mitigated with regular maintenance. Apart processes from all these a thick plantation of green belt will be developed along the periphery

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Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) Form-I

Details thereof (with approximate Information /Checklist Yes/ S.No. quantities /rates, wherever possible ) confirmation No with sources of information data of the compound wall to arrest the noise nuisance during the operation phase. Temporary noise generation during 6.3 From construction or demolition Yes construction activities 6.4 From blasting or piling No Not Applicable From construction or operational Noise due to movement of trucks during 6.5 Yes traffic construction and operation phase Adequate Lighting shall be provided in 6.6 From lighting or cooling systems Yes unit and also local ventilation system shall be provided 6.7 From any other sources No Not Applicable

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 S. Information /Checklist Yes Details thereof (with approximate No. confirmation /No quantities /rates, wherever possible ) with sources of information data Hazardous materials will be used and stored with due safety and care at site. All the norms under the Manufacture, From handling, storage, use or 7.1 Yes Storage and Import Of Hazardous spillage of hazardous materials Chemicals (MSIHC) Rules and amendments thereafter will be complied. From discharge of sewage or other effluents to water or the land ETP will be installed and will be 7.2 No (expected mode and place of designed for zero effluent discharge discharge ) All possible air pollutants will be scrubbed/ filtered properly by various By deposition of pollutants emitted pollution control equipment before 7.3 No to air into the land or into water emitting into atmosphere. The norms will be maintained through regular monitoring and analysis of vent gases. 7.4 From any other sources No None 7.5 Is there a risk of long term build up No None

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Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) Form-I

of pollutants in the environment from these sources?

8. Risk of accidents during construction or operation of the Project, which could affect human or the environment S.No. Information /Checklist Yes/ Details thereof (with approximate confirmation No quantities /rates, wherever possible ) with sources of information data No explosions will occur during From explosions, spillages, fires construction. During production etc from storage, handling, use operations, all inbuilt safety 8.1 No or production of hazardous precautions will be adopted and there substances will not be any damage to environment or human health. 8.2 From any other causes No None As the area is plain, there are no Could the project be affected by chances of landslides & there is no natural disasters causing history of cloud burst. No natural 8.3 environmental damage (e.g. No disasters are envisaged, since site is in floods, earthquakes, landslides, an area where such occurrences do cloudburst etc)? not arise.

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 activates in the locality. Details thereof (with approximate Information /Checklist Yes S.No. quantities /rates, wherever possible ) confirmation /No with sources of information data Lead to development of supporting. facilities, ancillary development or development The proposed project will prove stimulated by the project which beneficiary for the localities as it 9.1 Yes could have impact on the provides: Additional direct and indirect environment e.g.: employment • Supporting infrastructure (roads, power supply, waste

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Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) Form-I

Details thereof (with approximate Information /Checklist Yes S.No. quantities /rates, wherever possible ) confirmation /No with sources of information data or waste-water treatment etc.)

• Housing development

• Extractive industries

• Supply industries

• Other Lead to after use of the site, 9.2 which could have an impact on No None the environment Set a precedent for later 9.3 No developments Have cumulative effects due to proximity to other existing or 9.4 No None envisaged planned projects with similar effects)

(III) Environment Sensitivity Aerial distances (within 15 km.) S. Yes Areas Proposed project location No. /No boundary. Areas protected under international conventions, national 1. or local legislation for their No - ecological, landscape, cultural or other related values. Reserve Forests • Fairly dense Jungle near Gopavaram - 1.2 KMs (WNW) Areas which are important or • Dense Mixed Jungle near sensitive for ecological reasons- Hukumpet - 4.8 KMs (NNW) • 2. Wetlands, water courses or other Yes Mixed Jungle near Rajampalem - 5.1KMs (NNW) water bodies, coastal zone, • Vinjaram R.F. -9.1 KMs(NNW) biospheres. Mountains, forests • Karakapadu RF – 9.4 KMs (NW) • Polavaram RF- 9.6 KMs (N) Water bodies • Tadipudi lift canal – 1.50 KMs (S)

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Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) Form-I

Aerial distances (within 15 km.) S. Yes Areas Proposed project location No. /No boundary. • Tank near Bhimolu – 2.65 KMs (SW) • River Godavari– 7.8 KMs (E) • Kovada kalva - 6.25 KMs (N) • Polavaram Right Canal - 3.5 KMs (WNW) • Tank near Ramannapalem – 7.80KMs(N) • Pendrala kalva - 8.4 KMs (NW) • Kovvada Kalva Reservoir – 9.62 KMs (NW) Areas used by protected, important or sensitive species of 3. flora or fauna for breeding, No None nesting, foraging, resting, over wintering, migration. Inland, coastal, marine or 4. No None underground waters 5. State, National boundaries No None Routes or facilities used by the 6. public for access to recreation or No None other tourist, pilgrim areas 7. Defense installations No None

8. Densely populated or built-up area Yes Mandal head quarter Tallapudi is 8.50 kms Areas occupied by sensitive man- made land uses (hospitals, 9. Yes Mandal head quarter Tallapudi is 8.50 schools, places of worship, kms community facilities ) Reserve Forests • Fairly dense Jungle near Gopavaram - 1.2 KMs (WNW) Areas containing important, high • Dense Mixed Jungle near quality or scarce resources Hukumpet - 4.8 KMs (NNW) 10. (ground water resources, surface Yes • Mixed Jungle near Rajampalem - resources, forestry, agriculture, 5.1KMs (NNW) fisheries, tourism, minerals) • Vinjaram R.F. -9.1 KMs(NNW) • Karakapadu RF – 9.4 KMs (NW) • Polavaram RF- 9.6 KMs (N) Water bodies

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Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) Form-I

Aerial distances (within 15 km.) S. Yes Areas Proposed project location No. /No boundary. • Tadipudi lift canal – 1.50 KMs (S) • Tank near Bhimolu – 2.65 KMs (SW) • River Godavari– 7.8 KMs (E) • Kovada kalva - 6.25 KMs (N) • Polavaram Right Canal - 3.5 KMs (WNW) • Tank near Ramannapalem – 7.80KMs(N) • Pendrala kalva - 8.4 KMs (NW) • Kovvada Kalva Reservoir – 9.62 KMs (NW) Areas already subjected to pollution or environmental 11. damage.(those where existing No None legal environmental standards are exceeded) Areas susceptible to natural The project is located in seismic zone hazard which could cause the II (Least Active) as per IS: 1893 (Part- project to present environmental 1) 2002. Therefore, possibility of 12.0 problems (Earthquakes, No earthquake is not anticipated. So subsidence, landslides, erosion, there will be no effect of natural flooding or extreme or adverse hazards on the project. climatic conditions)

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APPENDIX-I

1-BENZYL-4-CHLOROPIPERIDINE

Process Description:

Stage-1:

Benzyl amine reacts with reacts with Acryclic acid methyl ester in presence of Methanol to give stage-1 product.

Stage-2:

Staeg-1 product reacts with Sodium Methoxide in presence of Hydrochloric acid and Toluene to give satge-2 product.

Stage-3:

Stage-2 product reacts with Hydrochloric acid and water in presence of Chloroform and Caustic Solution to give 1-Benzyl-4-Chloro-Piperidone.

Route of Synthesis:

Stage-1 O O O O O O N NH2 Methanol 2 + Benzylamine Acrylic acid methyl ester 3-[Benzyl-(2-methoxycarbonyl- C H O ethyl)-amino]-propionic acid C H N 8 12 4 7 9 2X86.09=172.18 methyl ester 107.15 C15H21NO4 279.33

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Stage-2

COOCH3 O O O O N

O N Toluene + CH3ONa + HCl 3-[Benzyl-(2-methoxycarbonyl- Sodium 36.46 1-Benzyl-4-oxo-piperidine-3- ethyl)-amino]-propionic acid methoxide carboxylic acid methyl ester methyl ester 54.02 C H NO C H NO 14 17 3 15 21 4 247.29 279.33

+ 2 CH3OH + NaCl 64.08 58.44

Stage3

COOCH3 O Cl

N N

Chloroform, Caustic solution + CH OH + HCl + H2O 3 1-Benzyl-4-oxo-piperidine-3- 36.46 18.02 1-Benzyl-4-chloro 32.04 carboxylic acid methyl ester piperidone

C14H17NO3 C12H16ClN 247.29 209.72

+ CO 2 + 0.5 O2 44.01 16.00

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Flowchart:

Benzylamine Methanol Recovery Stage-1 Acryclic acid methyl ester Effluent water Methanol

Stage-1 Sodium Methoxide Stage-2 Toluene Recovery Hydrochloric acid Effluent water Toluene

1-BENZYL-4-CHLOROPIPERIDINE

1-BENZYL-4-CHLOROPIPERIDINE

Material Balance:

Material Balance of 1-Benzyl-4-Chloro-Piperidone Stage-1 Batch Size: 200.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Benzylamine 140.00 Stage-1 330.00 Acryclic acid methyl ester 224.85 Methanol Recovery 285.00 Methanol 300.00 Methanol loss 10.00 Water 400.00 Effluent water 400.00 (Water-400) 0 Organic residue 39.85 Process residue – 34.85 Distillation residue-5 (Methanol-5) Total 1064.85 Total 1064.85

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Material Balance of 1-Benzyl-4-Chloro-Piperidone Stage-2 Batch Size: 200.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 330.00 Stage-2 263.00 Sodium Methoxide 63.70 Toluene Recovery 380.00 Hydrochloric acid 43.00 Toluene loss 12.00 Toluene 400.00 Effluent water 544.54 Water 400.00 (Water-400,Sodium Chloride- 0 68.97,Methanol-75.57) Organic residue 37.16 Process residue-29.16 Distillation residue-8 (Toluene-8) Total 1236.70 Total 1236.70

Material Balance of 1-Benzyl-4-Chloro-Piperidone Stage-3 Batch Size: 200.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 263.00 1-Benzyl-4-Chloro-Piperidone 200.00 Hydrochloric acid 38.65 Chloroform Recovery 475.00 Chloroform 500.00 Chloroform Loss 25.00 Caustic solution 50.00 Effluent water 383.93 Water 300.00 (Water-300,Water from Caustic 0 solution 50,Generated Methanol- 33.93) Process emission 63.38 (carbondioxide-46.55, oxygen- 0 16.83) Organic residue 4.34 Process residue -4.34 Total 1151.65 Total 1151.65

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1-BENZYL-4-PIPERIDONE Process Description:

Stage-1:

Benzyl amine reacts with reacts with Acryclic acid methyl ester in presence of Methanol to give stage-1 product.

Stage-2:

Staeg-1 product reacts with Sodium Methoxide in presence of Hydrochloric acid and Toluene to give satge-2 product.

Stage-3:

Stage-2 product undergoes Hydrolysis with Sodium Hydroxide and Hydrochloric acid in presence of Chloroform to give 1-Benzyl-4-Piperidone.

Route of Synthesis:

Satge-1

O O O

NH O 2 O N O Methanol + 2

Benzylamine Acrylic acid methyl ester 3-[Benzyl-(2-methoxycarbonyl- C7H9N C8H12O4 ethyl)-amino]-propionic acid 107.15 2X86.09=172.18 methyl ester C15H21NO4 279.33

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Stage-2 COOCH3

O O O N O

O N Toluene + CH3ONa + HCl 3-[Benzyl-(2-methoxycarbonyl- Sodium 36.46 1-Benzyl-4-oxo-piperidine-3- ethyl)-amino]-propionic acid methoxide carboxylic acid methyl ester methyl ester 54.02 C H NO C H NO 14 17 3 15 21 4 247.29 279.33

+ 2 CH3OH + NaCl 64.08 58.44

Stage-3

COOCH3 O O

N N

Chloroform, Caustic solution + HCl + NaOH 1-Benzyl-4-oxo-piperidine-3- 36.46 40.00 1-Benzyl-4-piperidone carboxylic acid methyl ester C12H15NO C H NO 14 17 3 189.25 247.29

+ CH3OH + NaCl + CO2 32.04 58.44 44.01

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Flowchart:

Benzylamine Methanol Recovery Stage-1 Acryclic acid methyl ester Effluent water Methanol

Stage-1 Sodium Methoxide Stage-2 Toluene Recovery Hydrochloric acid Effluent water Toluene

Stage-2 Hydrochloric acid Stage-2 Chloroform Recovery Chloroform Effluent water Caustic solution Sodium Hydroxide

1-BENZYL-4-PIPERIDONE Material Balance:

Material Balance of 1-Benzyl-4- Piperidone Stage-1 Batch Size: 200.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Benzylamine 147.00 Stage-1 350.00 Acryclic acid methyl ester 236.00 Methanol Recovery 285.00 Methanol 300.00 Methanol loss 10.00 Water 400.00 Effluent water 400.00 (Water-400) 0 Organic residue 38.00 Process residue – 33 Distillation residue-5 (Methanol-5) Total 1083.00 Total 1083.00

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Material Balance of 1-Benzyl-4- Piperidone Stage-2 Batch Size: 200.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 350.00 Stage-2 285.00 Sodium Methoxide 67.55 Toluene Recovery 380.00 Hydrochloric acid 45.50 Toluene loss 12.00 Toluene 400.00 Effluent water 553.30 Water 400.00 (Water-400,Sodium Chloride- 0 73.15,Methanol-80.15) Organic residue 32.75 Process residue-24.15 Distillation residue-8 (Toluene-8) Total 1263.05 Total 1263.05

Material Balance of 1-Benzyl-4- Piperidone Stage-3 Batch Size: 200.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 285.00 1-Benzyl-4- Piperidone 200.00 Hydrochloric acid 42.00 Chloroform Recovery 475.00 Chloroform 500.00 Chloroform Loss 25.00 Caustic solution 50.00 Effluent water 454.02 Sodium Hydroxide 45.88 (Water-300,Water from Caustic solution 50,Generated Methanol- 36.76,Sodium Chloride-67.26) Water 300.00 Process emission 50.45 (carbondioxide-50.45) Organic residue 18.41 Process residue -18.41 Total 1222.88 Total 1222.88

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1-BENZYL-PIPERIDIN-4-OL

Process Description:

Stage-1:

N-Benzyl-4-Piperidone undergoes Hydrogenation with Hydrogen in presence of Palladium Carbon and Methanol to give 1-Benzyl-piperidin-4-ol

Route of Synthesis:

Stage-1 O OH

N N

Methanol, Pd/C + H2

N-Benzyl-4-piperidone 2.02 1-Benzyl-piperidin-4-ol C H NO 12 15 C12H17NO 189.25 191.27

Flowchart:

N-Benzyl-4-Piperidone Methanol Recovery Stage-1 Hydrogen Effluent water Methanol

1-BENZYL-PIPERIDIN-4-OL

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Material Balance:

Material Balance of 1-Benzyl-Piperidin-4-ol .Stage-1 Batch Size: 200.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg N-Benzyl-4-Piperidone 209.00 1-Benzyl-piperidin-4-ol 200.00 Hydrogen 2.20 Methanol Recovery 285.00 Methanol 300.00 Methanol loss 10.00 Water 400.00 Effluent water 400.00 (Water-400) 0 Organic residue 16.20 Process residue – 11.20 Distillation residue-5 (Methanol-5) Total 911.20 Total 911.20

1-METHYLPIPERIDIN-4-AMINE

Process Description:

Stage-1:

1-methylpiperidin-4-one undergoes amination with Ammonia in presence of Methanol to give 1-Methylpiperidin-4-Amine

Route of Synthesis:

Stage-1:

O NH2

NH Methanol,Methanolic ammonia + 3 + 0.5 O2 N N Raney Nickel,H2 gas CH CH3 3 1-methylpiperidin-4-one 17.03 1-methylpiperidin-4-amine 16.00 C6H11NO C6H14N2 113.16 114.19

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Flowchart:

1-methylpiperidin-4-one Methanol Recovery Stage-1 Ammonia Effluent water Methanol Raney nickel Hydrogen gas Methanolic ammonia

1-METHYLPIPERIDIN-4-AMINE

Material balance:

Material Balance of 1-Methylpiperidin-4-Amine Stage-1 Batch Size: 200.00 Kg Name of the input Quantity in Name of the out put Quantity Kg in Kg 1-methylpiperidin-4-one 209.00 1-Methylpiperidin-4-Amine 200.00 Ammonia 31.35 Methanol Recovery 385.00 Methanol 400.00 Methanol Loss 10.00 Raney nickel 10.00 Effluent water 407.00 Hydrogen gas 2.00 (Water-400,Methanolic ammonia- 0 5,Hydrogen-2) Methanolic ammonia 5.00 Raney nickel recovery 10.00 Water 400.00 Process emission 29.46 (oxygen-29.46) 0 Organic residue 15.89 Process residue -10.89 Distillation residue-5 (Methanol-5) Total 1057.35 Total 1057.35

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4-AMINO PIPERIDINE Process Description: Stage-1: N-carbethoxy-4-amino-Piperidine reacts with Sodium hydroxide and Hydrochloric acid in presence of water and Chloroform to give 4-Amino-Piperidine. Route of Synthesis: Stage-1 NH2

NH2

N Water, Chloroform + NaOH + HCl N + COOC2H5 H C2H5OH N-Carbethoxy-4- 40.00 36.46 4-Amino piperidine Ethanol amino piperidine 46.07 C5H12N2 C8H16N2O2 100.16 172.22

+ NaCl + CO2 58.44 44.01 Flowchart:

N-Carbethoxy-4-amino piperidine ChloroformRecovery Stage-1 Sodium Hydroxide Effluent water Hydrochloric acid Chloroform

4-AMINO PIPERIDINE Material Balance of 4-Amino-Piperidine. Stage-1 Batch Size: 200.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg N-Carbethoxy-4-amino piperidine 367.00 4-Amino-Piperidine 200.00 Sodium Hydroxide 85.15 Chloroform Recovery 285.00 Hydrochloric acid 77.45 Chloroform loss 15.00 Chloroform 300.00 Effluent water 622.39 Water 400.00 (Water-400, sodium chloride- 0 124.41,Ethanol-97.98) Process emission 93.58 (Carbon dioxide-93.58) 0 Organic residue 13.63 Process residue – 13.63 Total 1229.60 Total 1229.60

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4-HYDROXY PIPERIDINE

Process Description: Stage-1: N-Methyl-4-Piperidone reacts with Ethylchloroformate in presence of Toluene to give Satge-1 product. Stage-2: Stage-1 product undergoes Hydrogenation with Hydrogen gas in presence of Toluene and Raney nickel to give Stage-2 product.

Stage-3: Stage-2 product undergoes hydrolysis with sodium hydroxide in presence of Toluene to give 4-Hydroxy piperidine. Route of Synthesis: Stage-1: O O

O Cl CH N + 3 + CH3Cl N O O O

CH3 CH3 N-Methyl-4-Piperidone Ethylchloroformate 4-Oxo-piperidine-1-carboxylic acid Chloromethane ethyl ester C6H11NO C3H5ClO2 50.49 C8H13NO3 113.16 108.52 171.19 Stage-2: O OH

N N

O O O O + H2

CH3 CH3 4-Oxo-piperidine-1-carboxylic acid 2.0 4-Hydroxy-piperidine-1-carboxylic acid ethyl ester ethyl ester

C8H13NO3 C8H15NO3 171.19 173.21

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Stage-3: OH

OH N O O + 2 NaOH + C2H5OH + Na2CO3 CH3 N H 4-Hydroxy-piperidine-1-carboxylic8 0.00 4-Hydroxy Piperidine 46.07 105.99 acid ethyl ester C5H11NO 101.15 C8H15NO3 173.21 Flowchart:

N-Methyl-4-Piperidone Stage-1 Toluene Recovery Ethylchloroformate Effluent water Toluene Acetic acid C.S.Lye

Stage-1 Hydrogen Stage-2 Toluene Recovery Raney Nickel Effluent water Toluene

Stage-2 Toluene Recovery Sodium hydroxide Stage-3 Effluent water Toluene

4-HYDROXY PIPERIDINE Material Balance:

Material balance of 4-Hydroxy Piperidine Stage-1 Batch Size:100Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg N-Methyl-4-Piperidone 130.00 Stage-1 188.00 Ethylchloroformate 124.55 Toluene Recovery 375.00 Toluene 400.00 Toluene Loss 15.00

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Acetic acid 3.00 Effluent Water 359.09 C.S.Lye 2.00 (Water-350, Toluene-5, 0 Sodium acetate-4.09) Water 350.00 Process Emission 57.98 (Chloromethane-57.98) 0 Organic Residue 14.48 Process residue-9.48 Distillation residue-5 (Toluene-5) Total 1009.55 Total 1009.55

Material balance of 4-Hydroxy Piperidine Stage-2 Batch Size:100Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 188.00 Stage-2 180.00 Hydrogen 2.05 Toluene Recovery 332.00 Raney Nickel 10.00 Toluene Loss 15.00 Toluene 350.00 Raney Nickel reuse 10.00 Water 300.00 Effluent Water 302.00 (Water-300,Toluene-2) 0 Organic Residue 11.05 Process residue-10.05 Distillation residue-1 (Toluene-1) Total 850.05 Total 850.05

Material balance of 4-Hydroxy Piperidine Stage-3 Batch Size:100Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 180.00 4-Hydroxy Piperidine 100.00 Sodium hydroxide 83.20 Toluene Recovery 285.00 Toluene 300.00 Toluene Loss 10.00 Water 300.00 Effluent Water 459.68 (Water-300,Ethanol- 0 47.7,Sodium carbonate- 109.98,Toluene-2) Organic Residue 8.52 Process residue-5.52 Distillation residue-3 (Toluene-3) Total 863.20 Total 863.20

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4-PHENYLPIPERIDINE

Process Description:

Stage-1:

4-Phenyl-piperidin-4-ol reacts with Sulphuric acid and Sodium Hydroxide in presence of Toluene to give 4-Phenyl Piperidine

Route of Synthesis:

Stage-1

OH

N Toluene N H + H2SO4 + 2 NaOH H 4-Phenyl-piperidin-4-ol 98.08 80.00 4-Phenyl-piperidine

C11H15NO C11H15N 177.24 161.24

+ Na SO 2 4 + 2 H2O + 0.5 O2 Sodium 36.03 16.00 sulphate 142.04

Flowchart:

4-Phenyl-piperidin-4-ol Stage-1 Toluene Recovery Sodium Hydroxide Effluent water Sulphuric acid Toluene

4-PHENYLPIPERIDINE

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Material Balance: Material Balance of 4-Phenyl Piperidine. Stage-1 Batch Size: 100.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 4-Phenyl-piperidin-4-ol 118.00 4-Phenyl Piperidine 100.00 Sodium Hydroxide 53.25 Toluene Recovery 285.00 Sulphuric acid 65.25 Toluene loss 10.00 Toluene 300.00 Effluent water 521.47 Water 400.00 (Water-400, sodium Sulphate- 0 94.52,Generated water- 23.95,Toluene-3) Process emission 10.62 (Oxygen-10.62) 0 Organic residue 9.41 Process residue – 7.41 Distillation residue-2 (Toluene-2) Total 936.50 Total 936.50

4-PHENYLPIPERIDINE

Process Description: Stage-1: 4-Phenyl-piperidin-4-ol reacts with Sulphuric acid and Sodium Hydroxide in presence of Toluene to give 4-Phenyl Piperidine Route of Synthesis: Stage-1

OH

N Toluene N H + H2SO4 + 2 NaOH H 4-Phenyl-piperidin-4-ol 98.08 80.00 4-Phenyl-piperidine

C11H15NO C11H15N 177.24 161.24

+ Na SO 2 4 + 2 H2O + 0.5 O2 Sodium 36.03 16.00 sulphate 142.04

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Flowchart:

4-Phenyl-piperidin-4-ol Stage-1 Toluene Recovery Sodium Hydroxide Effluent water Sulphuric acid Toluene

4-PHENYLPIPERIDINE Material Balance:

Material Balance of 4-Phenyl Piperidine. Stage-1 Batch Size: 100.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 4-Phenyl-piperidin-4-ol 118.00 4-Phenyl Piperidine 100.00 Sodium Hydroxide 53.25 Toluene Recovery 285.00 Sulphuric acid 65.25 Toluene loss 10.00 Toluene 300.00 Effluent water 521.47 Water 400.00 (Water-400, sodium Sulphate- 0 94.52,Generated water- 23.95,Toluene-3) Process emission 10.62 (Oxygen-10.62) 0 Organic residue 9.41 Process residue – 7.41 Distillation residue-2 (Toluene-2) Total 936.50 Total 936.50

4-PIPERIDINOPIPERIDINE

Process Description:

Stage-1:

4-Oxo-piperidine-1-carboxylic acid ethyl ester reacts with Piperidine in presence of Hydrogen,Pd/c and Methanol to give Stage-1 product.

Staeg-2:

Staeg-1 Product undergoes Hydrolysis with Potassium Hydroxide and Hydrochloric acid in presence of IPA to give 4-Piperidinopiperidine

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Route of Synthesis:

Stage-1

O N

Pd/C, N Methanol, N 3-4Kg pressure COOC H + N 2 5 H + H2 COOC2H5 4-Oxo-piperidine-1- Piperidine 2.02 [1,4']Bipiperidinyl-1'-carboxylic carboxylic acid ethyl ester C5H11N acid ethyl ester C8H13NO3 85.15 C13H24N2O2 171.19 240.34

+ H2O 18.02

Stage-2

N N

N IPA N + KOH H COOC2H5 + HCl

[1,4']Bipiperidinyl-1'-carboxylic Potassium 36.46 4-Piperidinopiperidine acid ethyl ester hydroxide C10H20N2 C H N O 56.11 13 24 2 2 168.28 240.34

+ + C2H5OH KCl + CO2 Ethanol 74.55 44.01 46.07

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Flowchart: 4-Oxo-piperidine-1-carboxylic acid ethyl ester Methanol Recovery Piperidine Stage-1 Effluent water Methanol Palladium carbon Hydrogen

Stage-1 IPA recovery Potassium Hydroxide Stage-2 Hydrochloric acid Effluent water IPA

4-PIPERIDINOPIPERIDINE

Material Balance: Material balance of 4-Piperidinopiperidine Stage-1 Batch Size:100Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 4-Oxo-piperidine-1-carboxylic 116.00 Stage-1 152.00 acid ethyl ester Piperidine 57.65 Methanol Recovery 385.00 Methanol 400.00 Methanol Loss 10.00 Palladium carbon 1.00 Effluent Water 362.18 Hydrogen 1.25 (Water-350, Generated 0 water-12.18) Water 350.00 Organic Residue 16.72 Process residue-11.72 Distillation residue-5 (Methanol-5) Total 925.90 Total 925.90

Material balance of 4-Piperidinopiperidine Stage-2 Batch Size:100Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 152.00 4-Piperidinopiperidine 100.00 Potassium Hydroxide 35.42 IPA Recovery 385.00 Hydrochloric acid 22.95 IPA Loss 15.00 IPA 400.00 Effluent Water 426.15 Water 350.00 (Water-350, Ethanol- 0 9.03,Potassium chloride-47.12) Process Emission 27.82 (Carbondioxide-27.82) 0 Organic Residue 6.40 Process residue-6.40 Total 960.37 Total 960.37

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ABACAVIR SULFATE Process Description: Stage-1 ADT pyrimidine is reacted with ACM Tartrate and sodium carbonate in presence of Toluene to give Stage-1 product. Stage-2 Stage-1 compound is treated with Cyclo propyl amine and sodium Hydroxide in presence of IPA to give Stage-2 Product. Stage-3 Stage-2 Product reacts with Sulfuric acid in presence of IPA to give Abacavir Sulfate. Route of Synthesis:

Stage-1

Cl CO-OH H CH2OH N NH CH-OH + 1/2 N CHO 2 1 Na2CO3 + + CH-OH Sodium Cl NH2 N Carbonate COOH ADT Pyrimidine (4-Amino-cyclopent ACM Tartrate C5H4Cl2N4O -2-enyl)-methanol C4H6O6 159.0 C6H11NO 207.2 150.09 113.16

Cl COONa N N CHOH + + 1/2 1/2 NaCl + 1 CO2 + 2 H2O N CHOH H2N N HOH2C COONa

45.0 Disodium tartarate 66.0 Stage-1 58.5 C H Na O C11H12ClN5O 4 4 2 6 265.70 194.05

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Stage-2

Cl NH

N N N NH2 N

IPA H N N N + N 2 + NaOH H2N N HOH C 2 HOH2C

Stage-1 Cyclopropyl 40.0 Stage-2 amine C H ClN O C14H18N6O 11 12 5 C3H7N 286.33 265.70 57.09

+ NaCl + H2O 58.5 18.0

Stage-3

NH NH N IPA N N + H2SO4 N H2SO4 N H2N N N Sulphuric acid H2N N HOH C 2 HOH2C

Stage-2 98.0 Abacavir Sulphate C14H18N6O C14H20N6O5S 286.33 384.41

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Flow Chart: ADT Pyrimidine ACM Tartarate 4-Amino-cyclopent Stage-1 Toluene Rec -2-enyl)methanol Toluene

Stage-1 Cyclopropylamine Stage-2 IPA Rec Triethyl Orthoformate Sodium Hydroxide Isopropyl Alcohol

Abacavir Base Stage-3 IPA Rec Sulfuric Acid Isopropyl Alcohol

ABACAVIR SULFATE Material Balance:

Material Balance of Abacavir Sulfate Stage-1 Batch Size: 100Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg ADT Pyrimidine 73.00 Stage-1 85.00 ACM Tartarate 53.00 Toluene Recovery 380.00 4-Amino-cyclopent-2- 40.00 Toluene Loss 8.00 enyl)methanol Sodium Carbonate 56.00 Effluent Water 210.92 Toluene 400.00 (Water-100,Gen water-15.8,Sodium 0 chloride-20.6, Sodium tartarate- 68.52,Toluene-6) Water 100.00 Process Emissions 23.24 (Carbon Dioxide) 0 Organic residue 14.84 Process residue – 8.84 Distillation residue – 6 (Toluene -6) Total 722.00 Total 722.00

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Material Balance of Abacavir Sulfate Stage-2 Batch Size: 100Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 85.00 Stage-2 80.00 Cyclopropylamine 18.30 Triehtyl Orthoformate Recovery 257.00 Triethyl Orthoformate 270.00 Triethyl Orthoformate Loss 13.00 Sodium Hydroxide 12.80 Isopropyl Alcohol Recovery 475.00 Isopropyl Alcohol 500.00 Isopropyl Alcohol Loss 15.00 Water 100.00 Effluent Water 124.45 (Water-100,Gen water-5.75,Sodium chloride-18.7) Organic Residue 21.65 Process residue – 11.65 Distillation residue -10 (IPA- 10) Total 986.10 Total 986.10 Material Balance of Abacavir Sulfate Stage-3 Batch Size: 100Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 80.00 Abacavir Sulfate 100.00 Sulfuric Acid 30.00 Isopropyl Alcohol Recovery 285.00 Isopropyl Alcohol 300.00 Isopropyl Alcohol Loss 10.00 Organic Residue 15.00 Process residue -10 Distillation residue – 5 (IPA -5) Total 410.00 Total 410.00

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AMITRIPTYLINE HYDROCHLORIDE

Process Description:

Stage-1:

Step-A:

1-bromo-3-chloropropane (BCP) reacts with Dimethylamine (DMA) the presence of Toluene, water, C.S Lye, HCl, Potassium hydroxide and Sodium Sulphate to give Step-A product. Step-B: Step-A product reacts with Hydrochloric acid to give stage-1 Product. Stage 2: Step-A: Isobenzofuran-1,3-dione reacts with Phenyl acetic acid in presence of Sodium acetate and Potassium Hydroxide Solution to give Step-A Product.

Step-B:

Step-A Product undergoes Hydrogenation in presence of Raney nickel and Toluene to give step-b product.

Step-C:

Step-B product undergoes dehydration with Phosphorous Pent oxide and Phosphoric acid in presence of O-xylene to give Stage-2 product.

Stage-3:

Stage-2 product reacts with Stage-1 product in presence of Magnesium, Ammonium Chloride, THF and Methanol to give stage-3 product.

Stage-4:

Stage-3 product undergoes Salt formation/Dehydration with Hydrochloric acid in presence of Toluene, Carbon and Acetone to give Amitriptyline Hydrochloride

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Route of Synthesis

Stage-1:

Step-A Toluene, water, HCL CH3 Cl + HN CH NaOH Br 3 KOH, Sodium sulphate 1-bromo-3-chloropropane N-methyl methanamine sodium Hydroxide C H BrCl 40.00 3 6 C2H7N 157.44 45.08

Cl N NaBr H2O 3-chloro-N,N-dimethyl Sodium bromide 18.0 propan-1-amine 102.9 C5H12ClN 121.61 Step-B: CH 3 CH3 Cl N Cl N . HCl CH + HCl 3 CH3

3-chloro-N,N-dimethylpropan-1- 36.46 3-chloro-N,N-dimethylpropan-1- amine amine Hydrochloride C H ClN 5 12 C5H13Cl2N 121.61 158.07

Stage-2:

Step-A:

O O OH

O O CH3COONa + O O

Isobenzofuran-1,3-dione Phenyl-acetic acid 3-Benzylidene-3H- C H O C8H4O3 8 8 2 isobenzofuran-1-one C H O 148.12 136.15 15 10 2 222.24

+ CO2 + H2O 44.0 18.02

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Step-B:

O Raney Ni O + Toluene 2 H2 O OH 4.00 3-Benzylidene-3H-isobenzofuran-1-one 2-Phenethyl-benzoic acid

C15H14O2 C15H10O2 222.24 226.27 Step-C:

O

P2O5 ,H3PO4,C.S.LYE + O H2O Xylene OH 2-Phenethyl-benzoic acid Dibenzosuberone 18.0

C15H14O2 C15H12O 226.27 208.26 Stage-3:

O CH3 Cl N + Mg CH3 + + NH4Cl THF/Methanol

Dibenzosuberone 3-chloro-N,N-dimethylpropan-1- amine 24.31 53.49 C15H12O C5H12ClN 208.26 121.61

OH

N + MgCl2 + NH3 5-(3-Dimethylamino-propyl)-10,11- 95.21 dihydro-5H-dibenzo[a,d] 17.03 cyclohepten-5-ol C20H25NO 295.42

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Stage-4:

Cl OH H Acetone N + HCl N + H2O Carbon

5-(3-Dimethylamino-propyl)- 36.46 Amitriptyline Hydrochloride 18.0 10,11-dihydro-5H-dibenzo[a,d] C H ClN cyclohepten-5-ol 20 24 C20H25NO 313.86 295.42 Flow Chart 1-Bromo-3-Chloro propane Di methyl amine Toluene Sodium Hydroxide Toluene recovery Stage-1 Sodium sulfate. Effluent water Hydrochloric Acid Isobenzofuran-1,3-dione Phenyl-acetic acid Potassium hydroxide Sodium acetate Toluene Recovery Toluene Stage-2 Xylene Recovery Raney Nickel Effluent water Hydrogen Xylene CS Lye Flakes (10%)

Stage-2 Toluene Recovery 3-Chloro-N,N-dimethyl Stage-3 Methanol Recovery propan-1-amine Effluent water Ammonium Chloride Magnesium Tetra hydro furan Toluene Methanol Toluene recovery Stage-3 Stage-4 Acetone recovery Hydrochloric Acid Effluent water Toluene Acetone Activated Carbon

AMITRIPTYLINE HYDROCHLORIDE

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Material Balance:

Material Balance of Amitriptyline Hydrochloride Stage-1 BatchSize:500 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 1-Bromo-3-Chloro propane 225.00 Stage-1 205.00 Di methyl amine 65.00 Toluene Recovery 475.00 Toluene 500.00 Toluene Loss 10.00 Sodium Hydroxide 57.00 Effluent Water 580.83 Sodium sulfate. 20.00 (water-400, Generated water- 0 25.83, Sodium Bromide-147, Toluene-8) Hydrochloric Acid 50.00 Inorganic solid waste 20.00 Water 400.00 (Sodium sulfate) 0 Organic residue 26.17 Process residue-21.17 Distillation residue-5 (Toluene-5) Total 1317.00 Total 1317.00

Material Balance of Amitriptyline Hydrochloride Stage-2 BatchSize:500 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Isobenzofuran-1,3-dione 290.00 Stage-2 350.00 Phenyl-acetic acid 267.00 Xylene Recovery 385.00 Potassium hydroxide 50.00 Xylene Loss 10.00 Sodium acetate 10.00 Toluene Recovery 1140.00 Toluene 1200.00 Toluene Loss 40.00 Raney Nickel 20.00 Effluent Water 807.10 Hydrogen (water-500, Generated 0 water-67.10, Sodium acetate-10, Potassium Hydroxide-50, 7.50 Phosphoric acid-50, Phosphorous Pent oxide-30, Water from CS Lye-90,Toluene-10) Phosphorous Pent oxide 30.00 Process emission 86.14 Phosphoric acid 50.00 (carbondioxide-86.14) 0 Xylene 400.00 Organic residue 106.26 CS Lye Flakes (10%) Process residue-91.26 100.00 Distillation residue-15 (Xylene-5,Toluene-10) Water 500.00 Total 2924.50 Total 2924.50

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Material Balance of Amitriptyline Hydrochloride Stage-3 BatchSize 500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 350.00 Stage-3 480.00 3-Chloro-N,N-dimethylpropan- 205.00 Tetra hydro furan Recovery 238.00 1-amine Ammonium Chloride 90.00 Tetra hydro furan Loss 12.00 Magnesium 41.00 Toluene Recovery 95.00 Tetra hydro furan 250.00 Toluene Loss 3.00 Toluene 100.00 Methanol Recovery 190.00 Methanol 200.00 Methanol Loss 5.00 Water 500.00 Effluent Water 661.00 Water-500, Magnesium 0 Chloride-160,Toluene-1) Process Emission 28.62 (Ammonia-28.62) 0 Organic Residue 23.38 Process residue-17.38 Distillation residue-6 (Toluene-1,Methanol-5) Total 1736.00 Total 1736.00

Material Balance of Amitriptyline Hydrochloride Stage-4 BatchSize 500 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-3 480.00 Amitriptyline Hydrochloride 500.00 Hydrochloric Acid 62.00 Toluene Recovery 570.00 Toluene 600.00 Toluene Loss 12.00 Acetone 250.00 Acetone Recovery 237.00 Activated Carbon 20.00 Acetone Loss 12.00 Water 400.00 Spent Carbon 20.00 Effluent water 433.28 (water-400,Generated water- 0 29.28,Toluene-4) Organic Residue 27.72 Process residue-22.72, Distillation residue-5 (Toluene-4,Acetone-1) Total 1812.00 Total 1812.00

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ATROVASTAIN CALCIUM

Process Description:

Stage-1 tert-Butyl-2-[(4R,6S)-6-(cyano methyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate undergoes reduction with Hydrogen on Palladium Carbon in presence of Methanol to give Stage-1 Product.

Stage-2

Aniline undergoes condensation with Dimethyl Carbonate and 2-Methyl-2-butanone in presence of Methanol to give stage-2 product.

Stage-3

Stage-2 product reacts with Benzaldehyde in presence of potassium Carbonate, Acetone and Toluene media to give stage-3 product.

Stage-4

Stage-3 Product reacts with stage-1 product and Fluorobenzaldehyde in presence of Para Toulene Sulfonic acid, Isopropyl Alcohol and Toluene to give stage-4 product.

Stage-5

Stage- 4 product undergoes hydrolysis in presence of Sulfuric acid and Methanol to give Stage-5 Product.

Stage-6

Stage-5 product undergoes salt formation with Calcium Acetate in presence of Isopropyl Alcohol to give Atorvastatin Calcium.

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Route of Synthesis:

Stage-1

H3C CH3 H3C CH3 O O O CH 3 O O O CN CH3 CH3 Methanol CH3 O CH3 + 2 H NH2 O CH3 tert-Butyl-2[(4R,6S)-6-(cyano methyl) 2 -2,2-dimethyl-1,3-dioxan-4yl] acetate 4.0 tert-Butyl-2[(4R,6S)-6-(amino ethyl) -2,2-dimethyl-1,3-dioxan-4yl] acetate C14H23NO4 C14H27NO4 269.34 273.37 Stage-2

CH3 O H3C CH3 H NH2 N Methanol CH O + 3 + O O O + 2 CH3OH H3C O 2-Methyl-2-butanone 4-Methyl-3-oxo-N-phenyl Aniline Dimethyl carbonate 64.08 pentanamide C3H6O3 C5H10O C6H7N C12H15NO2 93.13 90.08 86.13 205.25

Stage-3 CH3 O H N CH 3 H Acetone, Toluene + + K CO + O O 2 3 2 HCl

4-Methyl-3-oxo-N-phenyl Benzaldehyde 138.20 pentanamide 72.92 C7H6O C12H15NO2 106.12 CH 205.25 3 H3C O O

+ CO + NH 2KCl + 2 2 H2O

2-Benzylidene-4-methyl-3-oxo- 149.10 44.01 36.04 pentanoic acid phenylamide C19H19NO2 293.36

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Stage-4

CH3 O H3C CH3 H3C O O O O O CH H + 3 CH3 + IPA NH NH2 O CH3 F Toluene 2-Benzylidene-4-methyl-3-oxo- tert-Butyl-2[(4R,6S)-6-(amino ethyl) Fluorobenzaldehyde pentanoic acid phenylamide -2,2-dimethyl-1,3-dioxan-4yl] acetate C7H5FO C19H19NO2 C14H27NO4 124.03 293.36 273.37

H C H3C CH O 3 CH 3 3 O O O N CH3 H N O C CH3 + 2 H2O CH3 36.04

F Atorvastatin Ester

C40H47FN2O5 654.81

Stage-5

H C H C CH H C O 3 CH 3 3 O 3 3 O O O CH3 CH OH OH O N 3 N H N O C CH3 Methanol H N OH CH 3 + 2 H2O

F 36.0 Atorvastatin Ester F Atorvastain C40H47FN2O5 C33H35FN2O5 654.81 558.64 CH3 H C CH + 3 3 + OH C CH3

CH3 O Acetone tert-Butanol

C3H6O C4H10O 58.08 74.12

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Stage-6 H C O 3 CH 3 OH OH O N 2 H N OH + Iso Propyl alcohol CH3COOCa

Atorvastain F Calcium Acetate C H FN O 33 35 2 5 99.12 1117.28

H C O 3 CH 3 OH OH O N H N OH + CH3COOH Ca2+ 60.04

F 2 Atorvastatin calcium

C66H68CaF2N4O10 1155.36

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Flow Chart: Tert-Butyl-2-[(4R,6S)-6-(cyano methyl)-2,2-dimethyl-1,3-d ioxane-4-yl]Acetate Methanol Recovery Palladium Carbon Stage-1 Palladoum carbon recovery Hydrogen Methanol

Aniline Dimethyl Carbonate Methanol Recovery 2-Methyl-2-Butanone Stage-2 Effluent water Sulfuric Acid Methanol Stage-2 Benzaldehyde Acetone Recovery Potassium Carbonate Toluene Recovery Hydrochloric acid Stage-3 Effluent water Acetone Toluene Stage-3 Stage-1 Toluene Recovery Fluorobenzaldehyde Isopropyl alcohol Recovery Toluene Stage-4 Effluent water Para Toluene Sulfonic Acid Isopropyl Alcohol

Stage-4 Methanol Recovery Sulfuric Acid Stage-5 Effluent water Methanol

Calcium Acetate Isopropyl Alcohol IPA Recovery Activated Carbon Stage-6 Acetic acid recovery

ATORVASTATIN CALCIUM

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Material Balance:

Material Balance of Atorvastatin Calcium Stage-1 Batch Size:200Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Tert-Butyl-2-[(4R,6S)-6- 131.00 Stage-1 122.00 (cyanomethyl)-2,2-dimethyl-1,3- dioxane-4-yl]Acetate Palladium Carbon 1.00 Methanol Recovery 380.00 Hydrogen 1.85 Methanol Loss 15.00 Methanol 400.00 Palladium Carbon 1.00 Organic residue- 15.85 Process residue-10.85 Distillation residue-5 (Methanol-5) Total 533.85 Total 533.85

Material Balance of Atorvastatin Calcium Stage-2 Batch Size:200Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Aniline 50.00 Stage-2 100.00 Dimethyl Carbonate 48.35 Methanol Recovery + generated 177.40 Methanol 2-Methyl-2-Butanone 46.00 Methanol Loss 4.00 Sulfuric Acid 0.80 Effluent Water 300.80 Methanol 150.00 (Water-300,Sulfuric acid-0.8) 0 Water 300.00 Organic Residue 12.95 Process residue-9.95 Distillation residue-3 (Methanol-3) Total 595.15 Total 595.15

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Material Balance of Atorvastatin Calcium Stage-3 Batch Size:200Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 100.00 Stage-3 131.00 Benzaldehyde 51.50 Acetone Recovery 190.00 Potassium Carbonate 67.00 Acetone Loss 5.00 Hydrochloric acid 35.50 Toluene Recovery 285.00 Acetone 200.00 Toluene Loss 8.00 Toluene 300.00 Effluent Water 494.10 Water 400.00 (Water-400,Generated water- 0 17.50,Potassium Chloride-72.60, Toluene-4) Process Emission 21.40 (Carbon dioxide- 21.40) 0 Organic residue 19.50 Process residue-11.50 Distillation residue-8 (Toluene-3, Acetone-5) Total 1154.00 Total 1154.00

Material Balance of Atorvastatin Calcium Stage-4 Batch Size:200Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-3 131.00 Stage-4 268.00 Stage-1 122.00 Isopropyl Alcohol Recovery 285.00 Fluorobenzaldehyde 55.00 Isopropyl Alcohol Loss 10.00 Toluene 500.00 Toluene Recovery 475.00 Para Toluene Sulfonic Acid 2.00 Toluene Loss 10.00 Isopropyl Alcohol 300.00 Effluent Water 425.98 Water 400.00 (Water-400,Generated water- 15.98, para Toluene Sulfonic acid- 2, Toluene-8) Organic Residue 36.02 Process residue-24.02 Distillation residue-12 (Toluene-7, Isopropyl alcohol-5) Total 1510.00 Total 1510.00

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Material Balance of Atorvastatin Calcium Stage-5 Batch Size:200Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-4 268.00 Stage-5 210.00 Sulfuric Acid 2.50 Mixed Solvent Rceovery 433.86 (Methanol + Acetone-23.58,Tert- butanol-30.28) Methanol 400.00 Methanol Loss 8.00 Water 300.00 Effluent Water 288.03 (Water-285.53,Sulfuric acid-2.5) 0 Organic residue 30.61 Process residue -18.61 Distillation residue-12 (Methanol-12) Total 970.5 Total 970.50

Material Balance of Atorvastatin Calcium Stage-6 Batch Size:200Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-5 210.00 Atorvastain Calcium 200.00 Calcium Acetate 18.48 Acetic acid Recovery 11.13 Isopropyl Alcohol 400.00 Isopropyl Alcohol Recovery 380.00 Activated Carbon 10.00 Isopropyl Alcohol Loss 20.00 Spent Carbon Recovery 10.00 Organic residue 17.35 Process residue-17.35 Total 638.48 Total 638.48

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BUPROPION Route of synthesis: Stage-1 1-(3-Chloro-phenyl)-propan-1-one undergoes Bromination with in presence of MDC and Water to give Stage-1 Product. Stage-2 Stage-1 product undergoes condensation with tertiary-Butyl amine in presence of Toluene and Ethyl acetate to give Bupropion. Route of synthesis: Stage-1 Cl O MDC Br Water Cl + HBr + Br 2 O CH3 3-Bromo-1-(3-chloro-phenyl) 1-(3-Chloro-phenyl) 159.81 80.91 -propan-1-one -propan-1-one C9H8BrClO C9H9ClO 247.52 168.62 Stage-2 H3C O CH3 CH Toluene 3 H3C CH3 H3C NH Br Ethyl acetate Cl + HBr Cl + NH CH3 O 2 BUPROPION 3-Bromo-1-(3-chloro- Tertiary butyl 80.91 C H ClNO phenyl)-propan-1-one amine 13 18 C H BrClO 239.74 9 8 C4H11N 247.52 73.14

Flow Chart: 1-(3-Chloro-phenyl)- Acetic acid Recovery propan-1-one Stage-1 MDC Recovery Liquid Bromine Effluent water Acetic acid MDC

Stage-1 teritiary-Butyl amine Stage-2 Toluene Recovery Toluene Ethyl acetate Recovery Ethyl acetate Effluent water

BUPROPION

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Material Balance:

Material Balance of Bupropion Stage-1 Batch Size: 200.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 1-(3-Chloro-phenyl)-propan-1- Stage-1 230.000 175.000 one Liquid Bromine 165.70 Acetic acid Recovery 285.00 Acetic acid 300.00 Acetic acid loss 10.00 MDC 250.00 MDC Recovery 238.00 Water 400.00 MDC loss 8.00 Effluent water 400.00 (Water-400) 0 Process emission 83.82 (Hydrogen bromide – 83.82) 0 Organic residue 35.88 Process residue – 26.88 Distillation residue-9 (Aceticacid-5,MDC-4) Total 1290.70 Total 1290.70

Material Balance of Bupropion Stage-2 Batch Size: 200.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 230.00 Bupropion 200.00 teritiary-Butyl amine 68.00 Toluene Recovery 190.00 Toluene 200.00 Toluene loss 5.00 Ethyl acetate 200.00 Ethyl acetate Recovery 190.00 Water 300.00 Ethyl acetate loss 5.00 Effluent water 306.00 (water-300, Toluene-3, ethyl 0 acetate-3) Process emission 74.98 (Hydrogen bromide – 74.98) 0 Organic residue 27.02 Process residue -23.02 Distillation residue-4 (Ethyl acetate-2,Toluene-2) Total 998.00 Total 998.00

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CARISOPRODOL

Process Description:

Stage-1

2-Methyl-2-propyl-1,3-propane diol undergo cyclisation with Dimethyl carbonate in the presence of Toluene and Sodium methoxide to give Stage-1 product.

Stage-2

Stage-1 undergo condensation with Isopropylamine to give stage-2 product.

Stage-3

Stage-2 reacts with sodium cyanate and Hydrochloric acid in the presence of chloroform to give Stage-3 product.

Stage-4

Stage-3 Product undergoes recystallisation by using methanol to give Carisoprodol

Route of synthesis:

Stage-1 O O OH O Toluene H C H3C 3 OH + H3C CH3 O O O H3C NaOMe H3C

2-Methyl-2-Propyl-1,3-Propane diol Dimethyl carbonate 5-Methyl-5-propyl-[1,3]dioxan-2-one C3H6O3 C7H16O2 C H O 90.07 8 14 3 132.20 158.19

+ 2 CH3OH

Methanol 2X32.04=64.08

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Stage-2 H O N CH3

O O NH2 O CH3 H C H3C + 3 O H C CH OH 3 3 H C H3C 3

5-Methyl-5-propyl-[1,3]dioxan-2-one Isopropyl amine Isopropyl-carbamic acid 2-hydroxymethyl -2-methyl-pentyl ester C8H14O3 C3H9N C H NO 158.19 59.11 11 23 3 217.30

Stage-3 H O N CH3

O CH3 Toluene NaOCN + HCl H3C + OH H3C

Isopropyl-carbamic acid 2-hydroxymethyl Sodium cyanate Hydrochloric acid -2-methyl-pentyl ester 65.00 36.5 C11H23NO3 217.30

H O N CH3

O CH3

H3C + NaCl O NH2 H3C O

Carisoprodol(Tech) Sodium chloride 58.44 C12H24N2O4 260.32

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Stage-4 H H O N CH3 O N CH3 O CH3 O CH3 Methanol H3C H3C O NH2 O NH2 Purification H3C H3C O O

Carisoprodol(Pharma) Carisoprodol(Tech) C12H24N2O4 C12H24N2O4 260.32 260.32

Flow Chart:

2-Methyl-2-propyl- 1,3-propane diol Stage-1 Dimethyl carbonate Toluene Rec Toluene

Stage-1 Isopropylamine Stage-2 Isopropyl amine Rec

Stage-2 Sodium cyanate Stage-3 Chlorofom Rec Chloroform Toluene Rec Toluene

Carisoprodol (Tech) Methanol Stage-4 Methanol Rec Activated carbon Spent carbon

CARSIPRODOL

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Material Balance:

Material Balance of Carisoprodol Stage-1 Batch Size: 100.0 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 2-Methyl-2-propyl-1,3-propane 64.00 Stage-1 72.00 diol 43.50 Mixed Solvent 415.97 Dimethyl carbonate (Toluene Recovery + Generated methanol-30.97) Toluene 400.00 Toluene Loss 10.00 Sodium methoxide 6.00 Organic Residue 15.53 Process residue-10.53 Organic impurities-4.53 (Sodium methoxide-6) Distillation residue-5 (Toluene-5) Total 513.50 Total 513.50

Material Balance of Carisoprodol Stage-2 Batch Size: 100.0 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 72.00 Stage-2 93.00 Isopropylamine 147.00 Isopropylamine Recovery 114.00 Isopropylamine Loss 3.00 Organic Residue 9.00 Process residue -6 Distillation residue-3 (Isopropyl Amine-3) Total 219.00 Total 219.00

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Material Balance of Carisoprodol Stage-3 Batch Size: 100.0 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 93.00 Stage-3 105.00 Sodium cyanate 27.80 Chloroform Recovery 475.00 Chloroform 500.00 Chloroform Loss 20.00 Toluene 400.00 Toluene Recovery 385.00 Hydrochloric acid (35%) 45.00 Toluene Loss 10.00 Sulphuric acid 10.00 Effluent water 517.42 Water 450.00 (Water-450,Sodium chloride- 0 24.92, water from HCl- 29.5,Sulfuric Acid-10,Toluene-3) Organic Residue 13.38 Process residue-6.38 Distillation residue-7 (Chloroform-5,Toluene-2) Total 1525.80 Total 1525.80

Material Balance of Carisoprodol Stage-4 Batch Size: 100.0Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage -3 105.00 Carisoprodol 100.00 Methanol 300.00 Methanol Recovery 285.00 Activated carbon 5.00 Methanol Loss 10.00 Water 400.00 Effluent water 400.00 (Water-400) 0 Spent carbon 5.00 Organic Residue 10.00 Process residue-5 Distillation residue-5 (Methanol-5) Total 810.00 Total 810.00

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CLOPIDOGREL BISULPHATE

Process Description:

Stage-1:

2-Amino-2-(2-chlorophenyl) acetic acid reacts with sulphuric acid and Methanol in presence of Ammonia and Toluene to give Stage-1 Product.

Stage-2:

Stage-1 Product undergoes resolution with L-(+) tartaric acid in presence of Methanol and Acetone to give Stage-2 Product.

Stage-3:

2-(thiophen-2-yl)ethanol reacts with Para Toluene Sulphonyl chloride in presence of Sodium hydrate and Toluene to give Stage-3 Product.

Stage-4:

Stage-3 Product reacts with Stage-2 product in presence of MDC, Ethyl acetate and Ammonia to give Stage-4 Product.

Stage-5:

Stage-4 Product reacts with Formaldehyde, sulphuric acid in presence of Acetone and Sodium bicarbonate to give Stage-5 Product.

Stage-6:

Stage-5 Product undergoes recrystalisation in presence of Acetone, Acetonitrile and Methanol to give Clopidogrel Bisulphate.

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CLOPIDOGREL BISULPHATE

Route of Synthesis:

Stage-1: Cl O

OH

NH MDC,Toluene 2 + H2SO4 + CH3OH + 2NH3

2-Amino-2-(2-chlorophenyl) 98.08 32.04 34.06 acetic acid

C8H8ClNO2 185.61 Cl O

OCH3 NH2 + (NH ) SO 4 2 4 + H2O Methyl 2-amino-2 Ammonium sulphate 18.02 -(2-chlorophenyl)acetate 132.14 C9H10ClNO2 199.63 Stage-2: OH O Cl OH O O Cl HO O HO Methanol OH OCH3 OH . Acetone NH + O OH O OH 2 OCH3

Methyl 2-amino-2-(2- L-(+) -Tartaric acid NH2 chlorophenyl)acetate C H O C H ClNO 4 6 6 (S)-Methyl 2-amino-2-(2-chlorophenyl) 9 10 2 acetate (2S,3S)-2,3-dihydroxysuccinate 199.63 150.09 C13H16ClNO8 349.72

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Stage-3: O Cl S S O OH Toluene + H3C + NaOH

2-(thiophen-2-yl)ethanol p-Toluene 40.00 sulphonyl chloride C6H8OS C7H7ClO2S 128.19 190.65

S O

O S CH3 O

2-(Thiophen-2-yl)ethyl 4- + NaCl + H2O methylbenzenesulfonate 58.44 18.02 C13H14O3S2 282.38

Stage-4:

OH O S O Cl HO O OH O S CH3 . O OH + K HPO O OCH3 2 4 + NH2 2-(Thiophen-2-yl)ethyl 4-methyl Dipotassoium benzenesulfonate (S)-Methyl 2-amino-2-(2-chlorophenyl) acetate Tartarate ortho phosphate C13H14O3S2 C H ClNO 174.18 282.38 13 16 8 349.72 + 2 NH3 + HCl

MDC, Ethyl acetate, IPA 34.06 36.46

O OCH3 O OK OH O S HN + O S -O NH4 NH + O- .HCl 4 CH Cl + + 3 O OH (S)-Methyl 2-(2-chlorophenyl)- Ammonium tartarate Potassium salt of p- 2-((2-(thiophen-2- toluene sulfonic acid C H N O yl)ethyl)amino)acetate 4 12 2 6 C7H7KO3S hydrochloride 184.15 210.29 C15H17Cl2NO2S 346.27

+ KH2PO4 Monopotassium phosphate 136.09

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Stage-5

O OCH3

HN S .HCl + CH O + + Cl 2 H2SO4 NaHCO3 Acetone, MDC

(S)-Methyl 2-(2-chlorophenyl)- Formaldehdye 98.08 84.01 2-((2-(thiophen-2-yl)ethyl)amino) acetate hydrochloride 30.03

C15H17Cl2NO2S

346.27 O OCH3

N . H2SO4 Cl + 2H O + NaCl + CO S 2 2

(S)-Methyl 2-(2-chlorophenyl)-2-(6,7- 36.03 58.44 44.01 dihydrothieno [3,2-c]pyridin-5(4H)-yl)acetate sulfate

C16H18ClNO6S2 419.90

Stage-6 OCH O OCH3 O 3

N N . H SO . H2SO4 2 4 Acetonitrile,Methanol, Cl Cl Acetone S S Clopidogrel bi sulphate(Crude) Clopidogrel bi sulphate(pure)

C16H18ClNO6S2 C16H18ClNO6S2 419.90 419.90

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Flow Chart: 2-Amino-2-(2-chlorophenyl) acetic acid Sulphuric acid Stage-1 MDC recovery Methanol Toluene recovery Liq. Ammonia MDC Toluene Sodium sulphate Stage-1 L-(+)-Tartaric acid Methanol recovery Stage-2 Methanol Acetone recovery Acetone 2-(thiophen-2-yl)ethanol PTSC Sodium hydroxide Stage-3 Sodium sulphate Toluene Recovery Toluene Stage-2 Stage-3(intermediate-1) Liq. Ammonia Hydrochloric acid IPA Recovery MDC Stage-4 MDC Recovery IPA Ethyl acetate recovery Ethyl acetate Activated carbon Hyflow Sodium sulfate Stage-4 Formaldehyde Sulfuric acid Stage-5 MDC recovery Sodium bi carbonate Acetone recovery Acetone MDC Activated carbon Sodium sulfate Stage-5 Methanol recovery Acetone Stage-6 Acetone recovery Methanol Acetonitrile Recovery Acetonitrile

Clopidogrel Bisulphate

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Material Balance: Material Balance of Clopidogrel Bisulphate Stage-1 Batch Size: 200.0 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 2-Amino-2-(2-chlorophenyl)acetic Stage-1 150.00 149.00 acid Sulphuric acid 78.50 Methylene Dichloride Recovery 475.00 Methanol 25.50 Methylene Dichloride Loss 15.00 Liq. Ammonia 27.50 Toluene Recovery 285.00 Methylene Dichloride 500.00 Toluene loss 7.00 Toluene 300.00 Inorganic solid waste 125.94 (Sodium sulfate-20, Ammonium Sodium sulphate 20.00 sulphate-105.94 ) Water 400.00 Effluent water 418.47 (Water-400,Generated water-

14.47,Toluene-4) Organic Residue 24.09 Process Residue-15.09 Distillation Residue-9 (MDC-5,Toluene-4) Total 1500.50 Total 1500.50

Material Balance of Clopidogrel Bisulphate Stage-2 Batch Size: 200.0 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 150.00 Stage-2 247.00 L-(+)-Tartaric acid 112.65 Methanol Recovery 475.00 Methanol 500.00 Methanol loss 15.00 Acetone 150.00 Acetone Recovery 143.00 Acetone loss 5.00 Organic residue 27.65 Process residue-15.65, Distillation residue-12 ( Methanol-10,Acetone-2) Total 912.65 Total 912.65

Material Balance of Clopidogrel Bisulphate Stage-3 Batch Size: 200.0 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 2-(thiophen-2-yl)ethanol 97.00 Stage-3 199.00 ParaTolueneSulfonylChloride 144.50 Toluene Recovery 333.00 Sodium hydroxide 30.20 Toluene loss 7.00

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Sodium sulphate 10.00 Effluent water 262.71 (Water-200,Generated water- 0 Toluene 350.00 13.58, Sodium chloride-44.13, Toluene-5 ) Water 200.00 Inorganic residue 10.00 (Sodium sulfate) 0 Organic residue 19.99 Process Residue-14.99 Distillation Residue-5 (Toluene-5) Total 831.70 Total 831.70

Material Balance of Clopidogrel Bisulphate Stage-4 Batch Size: 200.0 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-3 199.00 Stage-4 185.00 Stage-2 247.00 MDC Recovery 380.00 Liq. Ammonia 23.80 MDC loss 8.00 Dipotassium ortho phosphate 122.50 IPA Recovery 333.00 Hydrochloric acid 25.68 IPA loss 7.00 MDC 400.00 Ethyl acetate Recovery 380.00 IPA 350.00 Ethyl acetate loss 8.00 Ethyl acetate 400.00 Effluent water 303.72 (Water-200, Mono potassium 0 Activated carbon 2.50 phosphate-95.72, Ethyl acetate- 8) Hyflow 0.50 Spent carbon & Hyflow 3.00 Sodium sulfate 10.00 Inorganic solid waste 10.00 Water 200.00 (Sodium sulfate) 0 Organic residue 363.26 Process Residue- Organic impurities-59.47 (Ammonium tartarate-129.74, Potassium salt of para-toluene sulfonic acid-148.05, Distillation Residue-26 (MDC-12, IPA-10, Ethylacetate- 4) Total 1980.98 Total 1980.98

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Material Balance of Clopidogrel Bisulphate Stage-5 Batch Size: 200.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-4 185.00 Stage-5 210.00 Formaldehyde 16.00 MDC Recovery 665.00 Sulfuric acid 53.00 MDC loss 15.00 Sodium bi carbonate 44.75 Acetone Recovery 570.00 Acetone 600.00 Acetone loss 12.00 MDC 700.00 Effluent water 350.32 (Water-300, Generated water- Activated carbon 10.00 19.24,Sodium chloride-31.08) Sodium sulfate 20.00 Process emission 23.49 Water 300.00 (Carbon dioxide-23.49) Spent carbon 10.00 Inorganic solid waste 20.00 (Sodium sulfate) Organic residue 52.94 Process Residue-14.94, Distillation Residue-38 ( MDC-20, Acetone-18 ) Total 1928.75 Total 1928.75

Material Balance of Clopidogrel Bisulphate Stage-6 Batch Size: 200.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-5 210.00 Clopidogrel Bisulphate 200.00 Acetone 250.00 Acetonitrile Recovery 190.00 Methanol 150.00 Acetonitrile Loss 5.00 Acetonitrile 200.00 Acetone Recovery 238.00 Acetone Loss 7.00 Methanol Recovery 143.00 Methanol Loss 5.00 Organic Residue 22.00 Process residue-10, Distillation residue-12 (Acetonitrile-5,Acetone-5, Methanol-2) Total 810.00 Total 810.00

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CYCLOBENZAPRINE HYDROCHLORIDE

Process Description:

Stage-1:

1-bromo-3-chloropropane reacts with Dimethyl amine in presence of Sodium Hydroxide,Toluene and water to give Steage-1 Product.

Stage-2:

Step-A:

Phenyl acetic acid reacts with Pthalic anhydride in prrsence of Methanol and sodium acetate to give stage-A product.

Step-B:

Stage-A Product reacts with Hydrogen in presence of sodium hydroxide and rabey- nickel to give Step-B Product.

Step-C:

Step-B product undergoes cyclisation in presence of Xylene, P2O5 and Phosphoric acid to give Stage-2 Product.

Stage-3:

Stage-2 Product reacts with Stage-1 Product in presence of Magnesium, THF, Toluene and Methanol to give Stage-3 Product.

Stage-4:

Stage-3 Product undergoes Dehydration with Hydrochloric acid in presence of Toluene and Acetone to give Cyclobenzaprine Hydrochloride

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Route of Synthesis

Stage-1: H N Toluene, water, HCl Br Cl + H3C CH3 + NaOH KOH, Sodium sulphate 1-bromo-3-chloro Dimethyl amine 40.00 propane C2H7N C H BrCl 3 6 45.08 157.44 CH3 Cl N CH 3 + NaBr + H2O 3-chloro-N,N-dimethyl 102.9 18.02 propan-1-amine

C5H12ClN 121.61

Stage-2:

Step-A:

COOH O

O O

+ O Phenyl-acetic acid Phthalic anhydride O 3-Benzylidene-3H- C H O 8 8 2 C8H4O3 isobenzofuran-1-one 136.15 148.12 C15H10O2 222.24

+ H2O + CO2 18.02 44.01

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Step-B:

O NaOH solution, OH HCl solution, + H Raney nickel O 2 O 3-Benzylidene-3H- 2.02 2-Styryl-benzoic acid isobenzofuran-1-one C15H12O2 C15H10O2 224.25 222.24

Step-C:

OH + H2O P2O5, H3PO4 O O Xylene 2-Styryl-benzoic acid Dibenzosuberenone 18.02

C15H12O2 C15H10O 206.24 224.25

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Stage-3: O

CH3 + Cl N + + NH Cl CH3 Mg 4 THF/Methanol Dibenzosuberenone 3-chloro-N,N-Dimethyl 24.31 53.49 propan-1-amine C15H10O C H ClN 206.24 5 12 121.61 N

OH

+ 5-(3-Dimethylamino-propyl)-5H- MgCl2 + NH3 dibenzo[a,d]cyclohepten-5-ol 95.21 17.03

C20H23NO 293.40

Stage-4:

N

OH N

. HCl + H2O + HCl Acetone Carbon 5-(3-Dimethylamino-propyl)-5H- 36.46 Cyclobenzaprine Hydrochloride dibenzo[a,d]cyclohepten-5-ol 18.02 C20H22ClN C20H23NO 311.85 293.40

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Flow Chart 1-Bromo-3-Chloro propane Di methyl amine Toluene Stage-1 Toluene Recovery Sodium Hydroxide Effluent water Hydrochloric Acid Potassium hydroxide Sodium sulfate. Phenyl acetic acid Pthalic anhydride Stage-2 Toluene Recovery Sodium acetate tri hydrate Methanol Recovery Methanol Effluent water Raney Nickel Sodium Hydroxide Solution Hydrochloric acid Solution Toluene Hydrogen gas Phosphoric acid O-Xylene Phosphorous penta oxide

Stage-2 Stage-1 Magnesium Stage-3 Toluene Recovery Ethyl Bromide Methanol Recovery Ammonium Chloride Effluent water Sodium Hydroxide (10%) Dil Hydrochloric Acid Tetra hydra furan Toluene Methanol Stage-2 Hydrochloric Acid IPA Recovery Stage-4 Activated Carbon Acetone Recovery Acetone Effluent water Toluene IPA IPA HCl CYCLOBENZAPRINE HYDROCHLORIDE

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Material Balance Material Balance of Cyclobenzaprine Hydrochloride Stage-1 BatchSize:200 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 1-Bromo-3-Chloro propane 123.00 Stage-1 90.00 Di methyl amine 35.20 Toluene Recovery 232.00 Toluene 250.00 Toluene Loss 12.00 Sodium Hydroxide 31.25 Effluent Water 600.34 Hydrochloric Acid 10.00 (water-500, Generated water- 14.02 ,Sodium Bromide-80.32, potassium hydroxide- 5, Toluene-1) Potassium hydroxide 5.00 Inorganic solid waste 5.00 Sodium sulfate. 5.00 (Sodium sulfate) Water 500.00 Organic Residue 20.11 (Process residue-15.11, Distillation residue -5 (Toluene-5) Total 959.45 Total 959.45

Material balance of Cyclobenzaprine Hydrochloride Stage-2 Batch Size: 500.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Phenyl acetic acid 71.00 Stage-2 90.00 Pthalic anhydride 77.20 Methanol recovery 475.00 Sodium acetate tri hydrate 10.00 Methanol Loss 15.00 Methanol 500.00 Toluene recovery 475.00 Raney Nickel 5.00 Toluene Loss 10.00 Sodium Hydroxide Solution 100.00 O-Xylene Recovery 475.00 Hydrochloric acid Solution 50.00 O-Xylene Loss 25.00 Toluene 500.00 Raney Nickel Recovery 5.00 Hydrogen gas 1.00 Effluent water 875.69

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Phosphoric acid 50.00 (Water-600,Generated 0 water-17.69,Toluene- 8,Sodium hydroxide Solution-100,HydroChloroc acid-50,Phosphaorous pentoxide-50,Phosphoric acid-50) O-Xylene 500.00 Process emission 22.93 Phosphorous penta oxide 50.00 (Carbon dioxide-22.93) 0 Water 600.00 Organic residue 45.58 Process residue -28.58 Distillation residue-17 (Methanol-10,Toluene-7)

Total 2514.20 Total 2514.20

Material Balance of Cyclobenzaprine Hydrochloride Stage-3 BatchSize:200 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 150.00 Stage-2 200.00 Stage-1 90.00 Toluene Recovery 104.00 Magnesium 18.00 Toluene Loss 6.00 Ethyl Bromide 1.00 Methanol Recovery 187.00 Ammonium Chloride 40.00 Methanol Loss 10.00 Sodium Hydroxide (10%) 100.00 THF Recovery 283.00 Dil Hydrochloric Acid 9.00 THF Loss 15.00 Tetra hydra furan 300.00 Effluent Water 973.64 Toluene 120.00 (water-800,Magnesium Chloride- 0 69.24, Sodium chloride-14.4, water from NaOH-90) Methanol 200.00 Process Emission 12.38 Water 800.00 (Ammonia-12.38) 0 Organic Residue 36.98 Process residue-21.98 Distillation residue-15 (Toluene-10,Methanol-3,THF-2) Total 1828.00 Total 1828.00

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Material Balance of Cyclobenzaprine Hydrochloride Stage-4 BatchSize:200Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 200.00 Cyclobenzaprine Hydrochloride 200.00 Hydrochloric Acid 25.00 Toluene Recovery 698.00 Activated Carbon 20.00 Toluene Loss 37.00 Acetone 250.00 Acetone Recovery 237.00 Toluene 750.00 Acetone Loss 12.00 IPA 1200.00 IPA Recovery 1152.00 IPA HCl 10.00 IPA Loss 58.00 Water 800.00 Effluent Water 823.28 (Water-800,generated water- 18.28, Toluene-5) Spent Carbon 20.00 Organic Residue 17.72 Process residue-6.72 Distillation residue -11 (Toluene-10,Acetone-1) Total 3255.00 Total 3255.00

CYPROHEPTADINE HYDROCHLORIDE Process Description:

Stage-1:

Step-A:

Phenyl acetic acid reacts with Pthalic anhydride in prrsence of Methanol and sodium acetate to give stage-A product.

Step-B:

Stage-A Product reacts with Hydrogen in presence of sodium hydroxide and rabey- nickel to give Step-B Product.

Step-C:

Step-B product undergoes cyclisation in presence of Xylene, P2O5 and Phosphoric acid to give Stage-1 Product.

Stage-2:

Stage-1 Product undergoes Hydrogenation with hydrogen in presence of Methanol and Raney Nickel to give Stage-2 Product.

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Stage-3:

Stage-2 Product undergoes Chlorination with Thionyl chloride in presence of Toluene, Chloform and Sodium Hydroxide to give stage-3 Product.

Stage-4:

Stage-3 product reacts with N-methyl-4-Chloro Piperidine in presnec of Magnesium, THF, Methanol, Toluene and Ammonia to give Staeg-4 product.

Stage-5:

Stage-4 product undergoes Dehydration in presence of Hydrochloric acid, Toluene, IPA and water to give Cyproheptadine Hydrochloride Route of Synthesis:

Stage-1

Step-A:

COOH O

O O

+ O Phenyl-acetic acid Phthalic anhydride O 3-Benzylidene-3H- C H O 8 8 2 C8H4O3 isobenzofuran-1-one 136.15 148.12 C15H10O2 222.24

+ H2O + CO2 18.02 44.01

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Step-B:

O NaOH solution, OH HCl solution, + H Raney nickel O 2 O 3-Benzylidene-3H- 2.02 2-Styryl-benzoic acid isobenzofuran-1-one C15H12O2 C15H10O2 224.25 222.24

Step-C:

OH + H2O P2O5, H3PO4 O O Xylene 2-Styryl-benzoic acid Dibenzosuberenone 18.02

C15H12O2 C15H10O 206.24 224.25

Stage-2:

O OH

Methanol + H2 N N

CH3 CH3

N-Methyl4-piperidone 2.02 N-Methyl 4-Hydroxy piperidine C H NO 6 11 C6H13NO 113.16 115.17

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Stage-3:

OH Cl

Toluene Chloroform + + H O + N N NaCl 2 SO2 + SOCl2 + NaOH Na2CO3 CH3 CH3 18.0 64.06 N-Methyl-4-Hydroxy 118.97 40.0 N-Methyl-4-chloro 58.5 piperidine piperidine C H ClN C6H13NO 6 12 133.62 115.17

Stage-4: Cl

N + Mg + NH4Cl THF/Methanol O + CH3 Dibenzosuberenone N-Methyl-4-Chloro 24.31 53.49

C15H10O Piperidine

206.24 C6H12ClN 133.62

OH

N + MgCl2 + NH3 5-(1-Methyl-piperidin-4-yl)-5H- dibenzo[a,d]cyclohepten-5-ol 95.21 17.03

C21H23NO 305.41

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Stage-5:

Step-A:

Cl H OH 1 1/ H2O + HCl + 1 1/2H2O N 2 N

5-(1-Methyl-piperidin-4-yl)-5H- 36.46 27.0 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)- dibenzo[a,d]cyclohepten-5-ol 1-methylpiperidine hydrochloride Sesquihydrate C21H23NO C21H21N·HCl·1.5H2O 305.41 350.86

+ H2O

18.02

Step-B:

Cl Cl H H IPA HCl 1 1/ H2O N 2 N 1 1/2H2O

4-(5H-dibenzo[a,d][7]annulen-5-ylidene)- Cyproheptadine HClsesquihydrate 1-methylpiperidine hydrochloride Sesquihydrate C21H21N·HCl·1.5H2O

C21H21N·HCl·1.5H2O 350.86 350.86

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Flowchart: Phenyl acetic acid Pthalic anhydride Sodium acetate tri hydrate Methanol Raney Nickel Toluene recovery Sodium Hydroxide Solution Stage-1 Methanol recovery Hydrochloric acid Solution Effluent water Toluene Hydrogen gas Phosphoric acid O-Xylene Phosphorous penta oxide N -Methyl-4-Piperidone Hydrogen Stage-2 Methanol recovery Methanol Effluent water Stage-2 Thionyl chloride Stage-3 Toluene Recovery Sodium Hydroxide Chloroform Recovery Sodium bicarbonate Effluent Water Toluene Chloroform Stage-1 Magnesium Lithium bromide Toluene Recovery N-methyl-4-Chloro piperidine Stage-4 Methanol Recovery Ethyl bromide Effluent water Ammonium Chloride Tetrahydrafuran Methanol Toluene IPA Recovery Stage-4 Stage-5 Effluent water IPAHCl(30%)

CYPROHEPTADINE HYDROCHLORIDE

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Material Balance:

Material balance of Cyproheptadine Hydrochloride Stage-1 Batch Size: 500.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Phenyl acetic acid 260.00 Stage-1 332.00 Pthalic anhydride 283.00 Methanol recovery 475.00 Sodium acetate tri hydrate 10.00 Methanol Loss 15.00 Methanol 500.00 Toluene recovery 475.00 Raney Nickel 5.00 Toluene Loss 10.00 Sodium Hydroxide Solution 100.00 O-Xylene Recovery 475.00 Hydrochloric acid Solution 50.00 O-Xylene Loss 25.00 Toluene 500.00 Raney Nickel Recovery 5.00 Hydrogen gas 4.00 Effluent water 922.82 Phosphoric acid 50.00 (Water-600,Generated 0 water-64.82,Toluene- 8,Sodium hydroxide Solution-100,HydroChloroc acid-50,Phosphaorous pentoxide-50,Phosphoric acid-50)

O-Xylene 500.00 Process emission 84.00 Phosphorous penta oxide 50.00 (Carbon dioxide-84) 0 Water 600.00 Organic residue 93.18 Process residue -76.18 Distillation residue-17 (Methanol-10,Toluene-7) Total 2912 Total 2912.00

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Material Balance of Cyproheptadine Hydrochloride Stage-2 BatchSize:500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg N –Methyl-4-Piperidone 205.00 Stage-2 200.00 Hydrogen 4.00 Methanol Recovery 570.00 Methanol 600.00 Methanol Loss 12.00 Water 800.00 Effluent Water 800.00 (Water-800) 0 Organic residue 27.00 Process residue-9 Distillation residue-18 (Methanol-18) Total 1609.00 Total 1609.00

Material Balance of Cyproheptadine Hydrochloride Stage-3 BatchSize:500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 200.00 Stage-3 216.00 Thionyl chloride 207.00 Toluene Recovery 570.00 Sodium Hydroxide 70.00 Toluene Loss 12.00 Sodium bicarbonate 20.00 Chloroform Recovery 475.00 Toluene 600.00 Chloroform Loss 25.00 Chloroform 500.00 Effluent Water 963.26 Water 800.00 (Water-800,Sodium chloride- 0 102,Generated water- 31.26,Toluene-10,Sodium bicarbonate-20) Process emission 111.24 (Sulphur dioxide-111.24) 0 Organic residue 24.50 Process residue-16.5 Distillation residue-8 (Toluene-8) Total 2397.00 Total 2397.00

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Material Balance of Cyproheptadine Hydrochloride Stage-4 BatchSize:500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 332.00 Stage-4 462.00 Magnesium 40.00 THF Recovery 331.00 Lithium bromide 5.00 THF Loss 17.00 N-methyl-4-Chloro piperidine 216.00 Methanol Recovery 190.00 Ethyl bromide 1.00 Methanol Loss 10.00 Ammonium Chloride 87.00 Toluene Recovery 774.00 Tetrahydrafuran 350.00 Toluene Loss 40.00 Methanol 200.00 Effluent Water 1662.26 Toluene 820.00 (Water-1500,Magnesium 0 Chloride-153.26,Lithium Bromide-5,Ethyl Bromide- 1,Toluene-3) Water 1500.00 Process Emission 27.41 (Ammonia-27.41) Organic Residue 37.33 Process residue-33.33 Distillation residue-4 ( Toluene-2,THF-2) Total 3551.00 Total 3551.00

Material Balance of Cyproheptadine Hydrochloride Stage-5 BatchSize:500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-4 462.00 Cyproheptadine Hydrochloride 500.00 IPAHCl(30%) 786.00 IPA Recovery 570.00 Water 800.00 IPA Loss 12.00 Effluent Water 916.26 (Water-759,generated water- 0 27.26,water from HCl-130) Organic residue 49.74 Process residue-31.74 Distillation residue- (IPA-18) Total 2048.00 Total 2048.00

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DESLORATADINE

Process Description:

Stage-1

3-[2-(3-chlorophenyl)-ethyl] pyridine-2-carbonitrile reacts with Potassium hydroxide, Hydrochloric acid in presence of n-Butanol to give Stage-1 product.

Stage-2

Staeg-1 product undergoes cyclisation with Phosphorous penta chloride to give Stage-2 product.

Stage-3

Stage-2 product reacts with 4-Chloro-1-methyl piperdine, Magnesium, Hydrochloric acid in the presence of THF to give Stage-3 product.

Stage-4

Stage-3 Product undergoes dehydaration with Sulfuric acid and Sodium Hydroxide in presence of Ethyl acetate and n-Hexane to give Stage-4 product.

Stage-5

Stage-4 product reacts with ethyl chloro formate in the presence of Toluene and Cyclo hexane to give Stage-5 product.

Stage-6

Stage-5 product reacts with Sodium hydroxide, Hydrochloric acid in the presence of Methanol to give Desloratadine .

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DESLORATADINE

Route of Synthesis:

Stage-1:

Cl

N CN + KOH + 2HCl + H2O 3-[2-(3-Chlorophenyl)-ethyl]-pyridine 56.11 -2-carbonitrile 72.00 18.0

C14H11ClN2

242.70 Cl

N COOH + KCl + NH4Cl 3-[2-(3-Chloro-phenyl)-ethyl]-pyridine 74.55 53.49 -2-carboxylic acid

C14H12ClNO2 261.70

Stage-2:

Cl Cl PCl5 N

N COOH + H2O O 3-[2-(3-Chloro-phenyl)-ethyl]-pyridine 8-Chloro-5,6-dihydro-benzo[5,6] 18.0 -2-carboxylic acid cyclohepta[1,2-b]pyridin-11-one C H ClNO 14 12 2 C14H10ClNO 261.70 243.69

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Stage-3:

Cl

N N Cl + + Mg + HCl O 8-Chloro-5,6-dihydro-benzo[5,6] 4-Chloro-1-methyl cyclohepta[1,2-b]pyridin-11-one Magnesium Hydrochloric -piperidine acid C H ClNO 24.31 14 10 C6H12ClN 36.5 243.69 133.62

THF

Cl

N OH

N + MgCl2

CH3 8-Chloro-11(1-methyl-piperidine-4-yl) 95.21 -6,11-dihydro-5H-benzo[5,6]cyclohepta [1,2-b]pyriidn-11-ol

C20H23ClN2O 342.86

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Stage-4:

Cl

N OH

Ethyl acetate N + H2SO4 + 2 NaOH n-Hexane CH3 8-Chloro-11(1-methyl-piperidine-4-yl) 98.08 80.00 -6,11-dihydro-5H-benzo[5,6]cyclohepta [1,2-b]pyriidn-11-ol

C20H23ClN2O 342.86 Cl N

N + Na SO 2 4 + 3 H2O

CH3

8-Chloro-11(1-methyl-piperidine-4-yl) 142.04 54.06 -6,11-dihydro-5H-benzo[5,6]cyclohepta [1,2-b]pyridine

[N-Methyl Desloratadine]

C20H21ClN2 324.85

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Stage-5:

Cl Cl N N O

Toluene + N N O Cl COOC2H5 CH3 8-Chloro-11(1-methyl-piperidine-4-yl) Ethyl chloroformate 4-(8-Chloro-5,6-dihydro-benzo[5,6] -6,11-dihydro-5H-benzo cyclohepta[1,2-b]pyridin-11-ylidene) C3H5ClO2 [5,6]cyclohepta[1,2-b]pyridine -piperidine-1-carboxylic acid ethyl ester 108.52 C H ClN O [N-Methyl Desloratadine] 22 23 2 2 382.88 C20H21ClN2

324.85 + CH3Cl Chlormethane 50.49

Stage-6:

Cl Cl N N

10 % Aq.MeOH + NaOH + HCl N N H COOC2H5 4-(8-Chloro-5,6-dihydro-benzo[5,6] 40.0 36.46 Desloratadine cyclohepta[1,2-b]pyridin-11-ylidene) C H ClN -piperidine-1-carboxylic acid ethyl ester 19 19 2 310.82 C22H23ClN2O2 382.88

+ C2H5OH + NaCl + CO2 46.07 58.5 44.0

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Flow Chart:

3-[2-(3-Chloro phenyl)-ethyl]- pyridine-2-carbonitrile Stage-1 Ammonium chloride Potassium hydroxide Hydrochloric acid

Stage-1 Phosphorous Stage-2 DCM Rec pentachloride DCM

Stage-2 4-Chloro-1-methyl- Stage-3 THF Rec piperidine THF

Stage-3 Stage-4 Generated water Sulfuric acid

Stage-4 Ethyl chloroformate Stage-5 Toluene Rec Toluene

Stage-5 Sodium hydroxide Stage-6 Methanol Rec Methanol

DESLORATADINE

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Material Balance

Material Balance of Desloratadine Stage-1 Batch Size: 200.00Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 3-[2-(3-Chlorophenyl)-ethyl]- Stage-1 287.00 296.00 pyridine-2-carbonitrile Potassium hydroxide 68.50 n-Butanol Recovery 90.00 n-Butanol 100.00 n-Butanol Loss 10.00 Hydrochloric acid 87.50 Effluent water 634.09 Water 500.00 (Water-478.10, Potassium chloride-90.87, Ammonium chloride-65.12) Organic Residue 30.91 Process residue -30.91 Total 1052.00 Total 1052.00

Material Balance of Desloratadine Stage-2 Batch Size: 200.00Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 287.00 Stage-2 240.00 Methylene dichloride 200.00 Methylene dichloride Recovery 190.00 Phosphorous Pentachloride 228.00 Methylene dichloride Loss 10.00 Hydrochloric acid 30.00 Ethyl acetate Recovery 475.00 Ethyl acetate 500.00 Ethyl acetate Loss 10.00 Activated carbon 5.00 n-Hexane Recovery 90.00 Hyflow 5.00 n-Hexane Loss 5.00 n-Hexane 100.00 Spent carbon & Hyflow Recovery 10.00 Water 300.00 Effluent water 585.50 (Water-300, Generated water- 0 19.50, Hydrochloric acid-30, Ethyl

acetate-8, Phosphorous Pentachloride -228) Organic Residue 39.50 Process residue -27.50 Distillatiojn residue-12 (n-Hecxane-5, Ethyl acetate-7) Total 1655.00 Total 1655.00 Material Balance of Desloratadine Stage-3 Batch Size: 200.00Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg

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Stage-2 240.00 Stage-3 304.00 4-chloro-1-methyl-piperidine 131.50 Tetrahydrofuran Recovery 475.00 Tetrahydrofuran 500.00 Tetrahydrofuran Loss 15.00 Magnesium metal 23.75 EthyleneDiBromide Recovery 90.00 EthyleneDiBromide 100.00 EthyleneDiBromide Loss 10.00 Ethyl acetate 500.00 Ethyl acetate Recovery 475.00 n-Hexane 100.00 Ethyl acetate Loss 10.00 Acetonitrile 150.00 Acetonitrile Recovery 143.00 Isopropyl alcohol 100.00 Acetonitrile Loss 7.00 Hydrochloric acid 35.75 Isopropyl alcohol Recovery 95.00 Water 500.00 Isopropyl alcohol Loss 5.00 n-Hexane Recovery 90.00 n-Hexane Loss 3.00 Effluent water 613.60 (Water-500,Magnesium chloride -93.60,THF-10, Ethyl acetate-8, n-Hexane-2) Organic Residue 45.40 Process residue-33.40 Distillation residue-12 (n-Hexane-5, Ethyl acetate-7) Total 2381.00 Total 2381.00

Material Balance of Desloratadine Stage-4 Batch Size: 200.00Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-3 304.00 Stage-4 259.00 Sulphuric acid 88.00 Ethyl acetate Recovery 475.00 Ethyl acetate 500.00 Ethyl acetate Loss 10.00 Sodium hydroxide 70.85 n-Hexane Recovery 475.00 n-Hexane 500.00 n-Hexane Loss 25.00 Hyflow 5.00 Effluent water 678.57 (Water-500, generated water- 0 Activated carbon 2.00 47.72, Sodium sulfate- 125.85,Ethyl acetate-5 Water 500.00 Spent carbon & Hyflow Recovery 7.00 Organic Residue 40.28 Process residue -30.28 Distillation residue (Ethyl acetate-10) Total 1969.85 Total 1969.85

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Material Balance of Desloratadine Stage-5 Batch Size: 200.00Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-4 259.00 Stage-5 274.00 Triethyl amine 80.00 Toluene Recovery 475.00 Ethyl chloro formate 86.50 Toluene Loss 10.00 Cyclo hexane 400.00 Cyclohexane Recovery 380.00 Toluene 500.00 Cyclohexane Loss 20.00 Water 400.00 Effluent water 488.00 (Water-400, Triethylamine-80, ,Toluene-8) Process emission 40.14 (Chloro Methane-40.14) Organic Residue 38.36 Process residue-31.36 Distillation residue – 7 (Toluene-7) Total 1725.50 Total 1725.50

Material Balance of Desloratadine Stage-6 Batch Size: 200.0Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-5 274.00 Desloratadine 200.00 Methanol Recovery+ ethanol- 270.88 Sodium hydroxide flakes 28.50 32.88 Methanol 250.00 Methanol Loss 12.00 Toluene 300.00 Toluene Recovery 285.00 Cyclo hexane 400.00 Toluene Loss 10.00 Activated carbon 3.00 Cyclo hexane Recovery 380.00 Hydrochloric acid 26.00 Cyclo hexane Loss 20.00 Water 500.00 Effluent water 544.64 (Water-500,Toluene-3,Sodium 0

Chloride-41.64) Process Emissions 31.23 (Carbon dioxide-31.23) 0 Spent carbon 3.00 Organic Residue 24.75 Process residue -22.75 Distillation residue- (Toluene-2) Total 1781.50 Total 1781.50

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DOMPERIDONE MALEATE

Process Description: Stage-1 5-Chloro-1-{1-[3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propyl]-piperidin-4-yl}- 1,3-dihydro-benzoimidazol-2-one(Domeperidone) Product reacts with Maleic acid Product in presence of Methanol to give Domperidone Maleate Route of synthesis:

Stage-1:

N O N N Cl O OH O N O NH H + OH Methanol Maleic acid 5-Chloro-1-{1-[3-(2-oxo-2,3-dihydro- benzoimidazol-1-yl)-propyl]-piperidin-4-yl}-1,3- C4H4O4 dihydro-benzoimidazol-2-one 116.07 (Domperidone)

C22H24ClN5O2 425.91 Cl

N N NH O O O OH N O NH OH

Domperidone Maleate

C26H28ClN5O6 541.98

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Flowchart:

5-Chloro-1-{1-[3-(2-oxo-2,3-dihydro- benzoimidazol-1-yl)-propyl]-piperidin-4-yl}- 1,3-dihydro-benzoimidazol-2-one Stage-10 (Domeperidone) Methanol Recovery Maleic acid Methanol

DOMPERIDONE MALEATE

Material Balance:

Material balance of Domperidone Maleate Stage-1 Batch Size:500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 5-Chloro-1-{1-[3-(2-oxo-2,3- 400.00 Domperidone Maleate 500.00 dihydro-benzoimidazol-1-yl)- propyl]-piperidin-4-yl}-1,3- dihydro-benzoimidazol-2- one(Domeperidone) Maleic acid 110.00 Methanol Recovery 475.00 Methanol 500.00 Methanol Loss 15.00 Organic residue 20.00 Process residue-10 Distillation residue-10 (Methanol) Total 1010.00 Total 1010.00

DOMPERIDONE Process description Stage-1 Methyl acrylate reacts with Methylamie in presence fo Methanol to give Stage-1 product Stage-2 Step-A Stage-1 product reacts with Sodium methoxide in presence of water and Chloroform to give Step-A product

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Step-B Step-A product undergoes Hydrolysis with water in presence of Chloroform to give Stage-2 Product Stage-3 Stage-2 product reacts with Ethylchkloroformate in presence of Toluene to give Stage-3 product Stage-4 Step-A Stage-3 product undergoes Hydrogenation with Hydrogen gas in presence of Raney Nickel and Methanol to give Step-A product Step-B Step-A product undergoes Amination with Ammonium and Sulphuric acid in presence of Methanol to give Stage-4 product .

Stage-5 Stage-4 product undergoes Condensation with 1, 4-Dichloro-2-nitrobenzene in presence of Water and Soda Ash to give Stgae-5 product Stage-6 Stage-5 product undergoes Hydrogenation with Hydrogen in presence of Raney Nickel and Methanol to give Stage-6 product Stage-7 Step-A Stage-6 product reacts with Urea in presence of Water and Ammonium hydroxide to give Step-A product Step-B Step-A product undergoes Hydrolysis with Water and Soduium hydroxide in presence of Water to give Stage-7 product Stage-8 Orthophenylene diamie reacts with Methylacetoacetate in presence of O- Xylene , Sodium hydroxide and water to give Stage-8 product Stage-9 Stage-8 product reacts with 1-Bromo-3-Chloro-propane in presence of Sodium hydroxide , TBAB & Water to give Stage-9 product

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Stage-10 Stage-9 product reacts with Hydrochloric acid in presence of Methanol to give Stage-10 product Stage-11 Stage-7 product condensed with Stage-10 product in presence of Ammonium hydroxide and MIBK to give Domperidone product Route of synthesis: Stage-1 O CH3 O

O CH3N O NH2 Methanol 2 + CH3 O O Methyl acrylate Methylamine CH C H O 31.06 3 4 6 2 3-[(2-Methoxycarbonyl-ethyl)-methyl-amino]- 2X86.09=172.18 propionic acid methyl ester C9H17NO4 203.24

Stage-2 Step-A

O CH3 O Na O CH3N CH3 CH3N O O

O Chloroform CH3O O & water + CH3ONa CH3 Sodium 4-methoxy-3-(methoxy 3-[(2-Methoxycarbonyl-ethyl)-methyl- Sodium methoxide carbonyl)-1-methylpiperidin- amino]-propionic acid methyl ester 54.02 4-olate C9H17NO4 C9H16NNaO4 203.24 225.22

+ CH3OH

32.04

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Step-B: Na O O CH3 N CH3 O

O Chloroform N CH O + H O 3 2 + Distillation CH3 CH3COONa

Sodium 4-methoxy-3-(methoxy 18.0 N-Methyl-piperidin-4-one 82.03 carbonyl)-1-methylpiperidin- 4-olate C6H11NO C9H16NNaO4 113.16 225.22 + CH3OH + 1/2 O2

32.04 16.0 Stage-3:

O O

O N N Toluene CH O O CH3 + CH Cl 3 + O Cl 3 4-Oxo-piperidine-1- 50.49 N-Methyl4-piperidone Ethyl chloroformate carboxylic acid C H NO 6 11 C3H5ClO2 ethyl ester 113.16 108.52 C8H13NO3 171.19

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Stage-4: Step-A

O OH

N N

O O CH + Raney Nickel &Methanol O O 3 H2 CH3

4-Oxo-piperidine-1- 2.02 4-Hydroxy-piperidine- carboxylic acid 1-carboxylic acid ethyl ester ethyl ester C8H13NO3 C8H15NO3 171.19 173.21

Step-B OH NH2

N N O O Methanol CH3 CH + 3 NH3 + H2SO4 O O 3 4-Hydroxy-piperidine- 51.09 98.08 4-Amino-piperidine- 1-carboxylic acid 1-carboxylic acid ethyl ester ethyl ester C8H15NO3 C8H16N2O2 173.21 172.22 H O + (NH4)2SO4 + 2 132.14 18.02

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Stage-5 NH2

Cl NO N 2 Soda Ash Water Cl O O CH3 +

4-Amino-piperidine- 1,4-Dichloro-2- 1-carboxylic acid nitro-benzene ethyl ester C6H3Cl2NO2 Cl C8H16N2O2 192.00 172.22 O2N NH

N

O O CH3 + HCl 4-(4-Chloro-2-nitro-phenylamino) 36.46 -piperidine-1-carboxylic acid ethyl ester

C14H18ClN3O4 327.76

Stage-6

Cl Cl

O2N H2N NH NH

N Methanol N O O CH3 Raney Nickel O O CH3 + H2 4-(4-Chloro-2-nitro-phenylamino) 2.02 4-(2-Amino-4-chloro-phenylamino)- -piperidine-1-carboxylic acid ethyl ester piperidine-1-carboxylic acid ethyl ester

C14H20ClN3O2 C14H18ClN3O4 297.78 327.76

+ O2 32.00

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Stage-7

Step-A Cl

H2N NH

NH2 N H2N O O O CH3 + + NH4OH + HCl Urea 4-(2-Amino-4-chloro-phenylamino)- 35.05 36.46 piperidine-1-carboxylic acid ethyl ester CH4N2O C14H20ClN3O2 60.06 297.78

Activated carbon Water

CH3 O O HN N N O

+ NH Cl + H O + 2 NH Cl 4 2 3 4-(5-Chloro-2-oxo-2,3-dihydro-benzoimidazol-1 -yl)-piperidine-1-carboxylic acid ethyl ester 53.49 18.02 34.06 C15H18ClN3O3 323.77

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Step-B:

HN

H O Cl N O O N Cl N N + NaOH O N H

4-(5-Chloro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)- 40.00 5-Chloro-1-piperidin-4-yl-1,3 piperidine-1-carboxylic acid ethyl ester -dihydro-benzoimidazol-2-one C15H18ClN3O3 C H ClN O 323.77 12 14 3 251.71

CO + C2H5ONa + 2 68.05 44.00

Stage-8: O O NH2 O-Xylene H3C O Water NH2 + + NaOH + HCl CH3 ortho phenylene di amine Methyl aceto acetate 40.00 36.46

C6H8N2 C5H8O3 108.14 116.12

H3C CH2 N O N H + H O + NaCl + 2 + 3 H2 CO2

1-Isopropenyl-1,3-dihydro- 58.44 18.02 6.0 44.0 benzoimidazol-2-one

C10H10N2O 174.2

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Stage-9

H3C CH2 N O TBAB,WATER N + Br Cl H + NaOH 1-Isopropenyl-1,3-dihydro- 1-Bromo-3-chloro-propane 40.00 benzoimidazol-2-one 157.44 C10H10N2O

174.2 H3C CH2 N O N

Cl + NaBr + H2O 1-(3-Chloro-propyl)-3-isopropenyl- 102.89 1,3-dihydro-benzoimidazol-2-one 18.02

C13H15ClN2O 250.72

Stage-10 H C H 3 N CH2 O N N O N Cl Methanol + HCl Cl 1-(3-Chloro-propyl)-1,3-dihydro- 1-(3-Chloro-propyl)-3-isopropenyl- 36.5 benzoimidazol-2-one 1,3-dihydro-benzoimidazol-2-one C10H11ClN2O C13H15ClN2O 210.66 250.72

H3C CH2 + Cl 2-Chloro-propene

C3H5Cl 76.52

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Stage-11 H Cl N O H N N O N Ammonium chloride , N Cl MIBK, Sodium hydroxide H + + NH4OH & Water

5-Chloro-1-piperidin-4-yl-1,3 1-(3-chloropropyl)-1,3-dihydro 35.05 -dihydro-benzoimidazol-2-one -2H-(Benzimidazole-2-one) C10H11ClN2O C12H14ClN3O 251.71 210.66

O O NH N HN N N Cl + NH4Cl + H2O 53.49 18.02 Domperidone

C22H24ClN5O2

425.91

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Flow chart:

Methyl acrylate Methanol loss Mono methyl amine Stage-1 Organic residue Methanol

Stage -1 Chloroform recovery Sodium methoxide Stage-2 Chloroform Effluent water Water

Stage -2 Ethylchloroformate Stage-3 Toluene recovery Toluene

Stage -3 Methanol Ammonia Generated water Sulphuric acid Stage-4 Methanol recovery Raney Nickel Hydrogen

Stage -4 1,4-Dichloro-2-nitro- benzene (DCNB) Stage-5 Effluent water Soda ash Water Stage -5 Methanol Raney nickel Methanol recovery Hydrogen Stage-6 Toluene recovery Toluene Water Stage-6 Urea Effluent water Ammonium hydroxide Stage-7 Hydrochloric acid Activated carbon Sodium hydroxide Water

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Ortho phenylene diamine(OPDA) Methyl Aceto Acetate (MAA) O -xylene recovery Sodium hydroxide Stage-8 effluent water Hydrochloric acid (10%) O-Xylene Water Stage-8 1-Bromo-3- chloro -propane Stage-9 Effluent water Sodium hydroxide TBAB Water

Stage-9 Hydrochloric acid (12%) Methanol Recovery Stage-10 Methanol Effluent water Water

Stage -7 Stage-10 Methyl iso butyl ketone Stage-11 Effluent water Ammonium hydroxide (30%) Sodium hydroxide Ammonium chloride Water

Domperidone

Material Balance:

Material Balance of Domperidone Stage-1 Batch Size: 840Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Methyl acrylate 411.00 Stage -1 483.00 Mono methyl amine 76.00 Methanol loss 100.00 Methanol 100.00 Organic residue 4.00 Total 587 Total 587

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Material Balance of Domperidone Stage-2 Batch Size: 840Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage -1 483.00 Stage -2 211.00 Sodium methoxide 169.00 Chloroform recovery 6745.00 Chloroform 7100.00 Chloroform loss 355.00 Water 4830.00 Effluent water 4787.00 (Water-4787) By products 445.98 (Sodium acetate -195, Methanol-250.98) Process emission 38.02 (Oxygen) Total 12582 Total 12582

Material Balance of Domperidone Stage-3 Batch Size: 840Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage -2 211.00 Stage -3 275.00 Ethylchloroformate 259.25 Toluene recovery 1074.00 Toluene 1130.00 Toluene loss 56.00 Process emission 94.14 (Chloromethane) Organic residue 101.11 Total 1600.25 Total 1600.25

Material Balance of Domperidone Stage-4 Batch Size: 840Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage -3 275.00 Stage -4 258.00 Methanol 250.00 Spent raney nickel 5.00 recovery Ammonia 56.20 By product 95.00 (Ammonia sulphate) Sulphuric acid 70.20 Generated water 29.00 Raney Nickel 5.00 Methanol recovery 238.00 Hydrogen 4.00 Methanol loss 12.00 Organic residue 23.40 Total 660.4 Total 660.4

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Material Balance of Domperidone Stage-5 Batch Size: 840Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage -4 258.00 Stage -5 544.00 1,4-Dichloro-2-nitro-benzene 310.00 Effluent water 2403.50 (DCNB) (Water-2300 Soda ash -103.5) Soda ash 103.50 Process emission 24.00 (Hydrogen Chloride) Water 2300.00

Total 2971.5 Total 2971.5

Material Balance of Domperidone Stage-6 Batch Size: 840Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage -5 544.00 Stage-6 389.00 Methanol 820.00 Methanol recovery 779.00 Raney nickel 5.00 Methanol loss 17.00 Hydrogen 4.00 Toluene recovery 494.00 Toluene 520.00 Toluene loss 10.00 Water 300.00 Effluent water 316.00 (Water-300, Toluene-16) Raney nickel recovery 5.00 Process emission 53.11 (Oxygen) Organic residue 129.89 Process residue-105.89 Distillation Residue-24 (Methanol-24) Total 2193 Total 2193

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Material Balance of Domperidone Stage-7 Batch Size: 840Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-6 389.00 Stage-7 550.00 Urea 138.00 Effluent water 2112.43 (Water-2000, Generated Water-23.54 Sodium acetate-88.89) Ammonium hydroxide 444.00 By-product 565.50 (Ammonium chloride- 565.50 ) Hydrochloric acid 306.00 Process emission 102.07 (Ammonia-44.60, Carbon dioxide-57.47) Activated carbon 35.00 Spent carbon 35.00 Sodium hydroxide 53.00 Water 2000.00 Total 3365 Total 3365

Material Balance of Domperidone Stage-8 Batch Size: 840Kg Name of the input Quantity Name of the output Quantity in in Kg Kg Ortho phenylene 344.00 Stage-8 516.00 diamine(OPDA) Methyl Aceto Acetate (MAA) 386.00 O –xylene recovery 2869.00 Sodium hydroxide 413.00 O –xylene loss 151.00 Hydrochloric acid (10%) 1270.00 Effluent water 7038.00 (Water-5300, Generated Water-58, Water from hydrochloric acid - 1143,excess sodium hydroxide-235, Sodium chloride-302) O-Xylene 3020.00 Process emission 159.00 (Hydrogen-19.06, Carbon dioxide-139.94) Water 5300.00 Total 10733 Total 10733

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Material Balance of Domperidone Stage-9 Batch Size: 840Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-8 516.00 Stage-9 608.00 1-Bromo-3- chloro -propane 471.00 Effluent water 3536.00 (Water-3440 , Generated Water-54, TBAB-42) Sodium hydroxide 291.00 By-product 604.00 (Sodium bromide ) TBAB 42.00 Organic residue 12.00 Water 3440.00 Total 4760 Total 4760

Material Balance of Domperidone Stage-10 Batch Size: 840Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-9 608.00 Stage-10 462.00 Hydrochloric acid (12%) 730.00 Methanol Recovery 475.00 Methanol 500.00 Methanol loss 25.00 Water 2645.00 Effluent water 3473.00 (Water-2645,2-chloro propene- 186, water from Hydrochloric acid-642 ) Organic residue 48.00 Total 4483 Total 4483

Material Balance of Domperidone Stage-11 Batch Size: 840Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage -7 550.00 Domperidone 840.00 Stage-10 462.00 Effluent water 7660.00 (Water-5000, Methyl iso butyl ketone-200, Sodium hydroxide-2000, Generated water-40, Water from Ammonium hydroxide 420) Methyl iso butyl ketone 200.00 By product (Ammonium 1017.00 chloride-1017) Ammonium hydroxide (30%) 600.00 Organic residue 195.00 Sodium hydroxide 2000.00 Ammonium chloride 900.00 Water 5000.00 Total 9712 Total 9712

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DONEPEZIL HYDROCHLORIDE

Process Description:

Stage-1:

5,6 Dimethoxy-2-(Piperidin-4-yl) methyl)Indan-1-one reacts with Chloromethyl Benzene in presence of Sodium bicarbonate , Iso propyl alcohol, Tetra butyl ammonium bromide,Toluene, Methanol, IPA-HCl, Sodium hydroxide (NaOH),Con HCl, Carbon and Water to give Stage–1 product

Stage-2:

Stage-1 product undergoes purification with Methylene dichloride, Acetone and Carbon to give Donepezil HCl.

Route of Synthesis

Stage-1:

O O Cl Methanol O + NH TBAB/Toluene

5,6-dimethoxy-2-(piperidin-4-yl- (chloromethyl)benzene methyl)indan-1-one C7H7Cl C17H23NO3 126.58 289.37 O O

O

N + HCl

2-(1-Benzyl-piperidin-4-ylmethyl)-5,6- 36.46 dimethoxy-indan-1-one

C24H29NO3 379.49

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Stage-2:

O O O O O Cl O H N MDC/Acetone + HCl N

2-(1-Benzyl-piperidin-4-ylmethyl)-5,6- 36.46 DONEPEZIL HCl dimethoxy-indan-1-one C24H30ClNO3 C24H29NO3 415.95 379.49

Flow Chart 5,6 Dimethoxy-2-(Piperidin-4-yl) methyl)Indan-1-one Toluene Recovery Chloromethyl Benzene Methanol Recovery Activated Carbon Stage-1 Isopropyl alcohol Sodium hydroxide Recovery TBAB Effluent water Toluene Isopropyl alcohol Methanol

Stage-1 MDC Recovery Stage-2 Activated Carbon Acetone Recovery Methylene Dichloride Acetone Hydrochloric Acid

DONEPEZIL HYDROCHLORIDE

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Material Balance

Material Balance of Donepezil Hydrochloride Stage-1 BatchSize:100.00Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 5,6 Dimethoxy-2-(Piperidin-4-yl) 87.00 Stage-1 102.00 methyl)Indan-1-one Chloromethyl Benzene 38.00 Toluene Recovery 285.00 Activated Carbon 10.00 Toluene Loss 10.00 Sodium hydroxide 15.00 Isopropyl alcohol Recovery 333.00 TBAB 2.00 Isopropyl alcohol Loss 18.00 Toluene 300.00 Methanol Recovery 190.00 Isopropyl alcohol 350.00 Methanol Loss 5.00 Methanol 200.00 Effluent Water 505.00 Water 500.00 (Water-500,Toluene-3,TBAB-2) 0.00 Process emission 10.88 (Hydrogen Chloride-10.88) 0 Spent Carbon 10.00 Organic Residue 33.12 (Process residue-17.12, Distillation residue -16 (Toluene-2, Isopropyl alcohol- 9,Methanol-5) Total 1502.00 Total 1502.00

Material Balance of Donepezil Hydrochloride Stage-2 BatchSize:100.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 102.00 Donepezil Hydrochloride 100.00 Activated Carbon 10.00 Methylene Dichloride Recovery 760.00 Methylene Dichloride 800.00 Methylene Dichloride Loss 16.00 Acetone 300.00 Acetone Recovery 285.00 Hydrochloric Acid 9.72 Acetone Loss 10.00 Spent Carbon 10.00 Organic Residue 40.72 Process residue-11.72 Distillation residue-29 (Acetone-5,MDC-24) Total 1221.72 Total 1221.72

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EBASTINE

Process Description:

Stage-1:

4-Benzhydryloxy-piperidine-1-carboxylic acid ethyl ester undergoes Hydrolysis with Potassium Hydroxide in presence of IPA, Hydrochloric acid and Acetone to give Stage-1 product. Stage-2: Stage-1 Product undergoes salt formation with Hydrochloric acid in presence of Toluene to give Stage-2 product. Stage-3: Tert-Butyl-benzene reacts with 4-Chloro-Butyryl Chloride in presence of Dichloromethane ,Aluminium chloride, Ice water and water to give stage-3 Product.

Stage-4:

Stage-3 Product reacts with stage-1 product in presence of Methanol, Toluene and TBAB to give stage-4 Product.

Stage-5:

Stage-4 Product undergoes Purification in presence of Carbon to give Ebastine.

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Route of Synthesis: Stage-1

O

N O

O Chloroform, Isopropylalcohol& Acetone CH3 + KOH + HCl 4-Benzhydryloxy-piperidine-1- 56.11 carboxylic acid ethyl ester 36.46

C21H25NO3 339.43

O + + 0.5 O + O O KCl 2 N H 4-Benzhydryloxy-piperidine Ethyl formate 74.55 16.00 C H NO 18 21 C3H6O2 267.37 74.08 Stage-2:

O O + HCl . HCl N N H H 36.46 4-Benzhydryloxy-piperidine 4-Benzhydryloxy-piperidine Hydrochloride

C18H21NO C18H22ClNO 267.37 303.83

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Stage-3

CH3

H3C CH3

Cl Cl + O + AlCl3 + 3 H2O tert-Butyl-benzene 4-Chloro-butyryl chloride 133.34 C H Cl O 54.05 C10H14 4 6 2 134.22 141.0

Dichloromethane, n-Hexane, Ice water & DM water

CH3 O

H3C

CH3 4 HCl Cl + + Al(OH)3 1-(4-tert-Butyl-phenyl)-4- 145.84 78.00 chloro-butan-1-one C14H19ClO 238.75 Stage-4:

CH3 O

H3C O CH 3 0.5 K CO Cl + NH + 2 3 1-(4-tert-Butyl-phenyl)-4- 4-Benzhydryloxy-piperidine 69.10 chloro-butan-1-one C18H21NO C14H19ClO 267.37 238.75

Methanol, Toluene ,TBAB, Potassium iodide

CH O N 3 CH3 O CH KCl 3 + + 0.5 CO2 + 0.5 H2O 4-(4-Benzhydryloxy-piperidin-1-yl)-1- 74.55 22.00 9.01 (4-tert-butyl-phenyl)-butan-1-one

C32H39NO2 469.66

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Stage-5:

CH Methanol O N 3 CH3 Activated Carbon O CH3 4-(4-Benzhydryloxy-piperidin-1-yl)-1- (4-tert-butyl-phenyl)-butan-1-one

C32H39NO2 469.66 CH O N 3 CH3 O CH3

Ebastine

C32H39NO2 469.66

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Flowchart: 4-Benzhydryloxy-piperidine-1- carboxylic acid ethyl ester Potassium Hydroxide IPA Recovery Hydrochloric acid Stage-1 Acetone Recovery Chloroform Effluent water IPA Acetone

Stage-1 Hydrochloric acid Stage-2 Toluene Recovery Toluene Effluent water

Stage-2 4-Chloro-butyryl chloride Aluminum chloride n-Hexane Recovery Dichloromethane Recovery Dichlorormethane Stage-3 n-Hexane Effluent water

Stage-3 4-Benzyhydroloxy-piperidne Potassium carbonate Toluene Recovery Methanol Stage-4 Toluene Methanol Recovery TBAB Effluent water Potassium Iodide

Stage-4 Methanol Activated carbon Stage-5 IPA Recovery IPA

EBASTINE

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Material Balance: Material Balance of Ebastine Stage-1 Batch Size: 500.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 4-Benzhydryloxy-piperidine-1- Stage-1 314.00 420.00 carboxylic acid ethyl ester Potassium Hydroxide 70.00 Acetone Recovery 385.00 Hydrochloric acid 45.00 Acetone Loss 10.0 Chloroform 400.00 Chloroform Recovery 385.00 IPA 400.00 Chloroform Loss 10.00 Acetone 400.00 IPA Recovery 385.00 Water 400.00 IPA Loss 10.00 Effluent water 584.24 (Water-400,Potassium chloride- 0 92.24,Ethyl formate-92) Process emission 20.00 (Oxygen-20) 0 Organic residue 31.76 Process residue –16.76 Distillation residue-15 (Acetone-5,Chloroform-5,IPA-5) Total 2135.00 Total 2135.00

Material Balance of Ebastine Stage-2 Batch Size: 500.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 314.00 Stage-2 340.00 Hydrochloric acid 43.00 Toluene Recovery 385.00 Toluene 400.00 Toluene Loss 10.0 Water 400.00 Effluent water 403.00 (Water-400,Toluene-3) 0 Organic residue 19.00 Process residue –17 Distillation residue-2 (Toluene-2) Total 1157.00 Total 1157.00

Material Balance of Ebastine Stage-3 Batch Size: 500.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 165.00 Stage-3 280.00 4-Chloro-butyryl chloride 173.00 n-Hexane Recovery 385.00 Aluminum chloride 164.00 n-Hexane Loss 10.0

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Dichlorormethane 400.00 Dichloromethane Recovery 385.00 n-Hexane 400.00 Dichloromethane Loss 10.00 Water 400.00 Effluent water 429.00 (Water-333,Aluminium 0 Hydroxide-96) Process emission 179.00 (Hydrogenchloride-179) 0 Organic residue 24.00 Process residue –14 Distillation residue-10 (n-Hexane-5,Dichloromethane-5) Total 1702 Total 1702.00

Material Balance of Ebastine Stage-4 Batch Size: 500.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-3 280.00 Stage-4 525.00 4-Benzyhydroloxy-piperidne 314.00 Toluene Recovery 385.00 Potassium carbonate 81.00 Toluene Loss 10.00 Methanol 400.00 Methanol Recovery 385.00 Toluene 400.00 Methanol Loss 10.00 TBAB 5.00 Effluent water 515.99 Potassium Iodide 10.00 (Water-400,Generated water- 0 10.56,Potassium Chloride- 87.43,Toluene-3,TBAB- 5,Potassium Iodide-10) Water 400.00 Process emission 26.00 (Carbon dioxide-26) 0 Organic residue 33.01 Process residue –26.01 Distillation residue-7 (Methanol-5,Toluene-2) Total 1890.00 Total 1890.00

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Material Balance of Ebastine Stage-5 Batch Size: 500.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-4 525.00 Ebastine 500.00 Methanol 400.00 Methanol Recovery 385.00 Activated carbon 5.00 Methanol Loss 10.00 IPA 400.00 IPA Recovery 385.00 IPA Loss 10.00 Spent carbon 5.00 Organic residue 35.00 Process residue –25 Distillation residue-10 (Methanol-5,IPA-5) Total 1330.00 Total 1330.00

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ESOMEPRAZOLE MAGNESIUM TRIHYDRATE Process Description: Stage-1 Omeprazole sulfide reacts with cumin hydro peroxide and magnesium chloride hexa hydrate in the presence of Toluene to give Esomeprazole Magnesium Route of Synthesis: Stage-1:

CH3 OH OCH3 H3C O H3C CH3 2 N OCH3 + + Toluene N C S MgCl2. 6H2O H2 N H

5-Methoxy-2-[(4-methoxy-3,5-dimethyl-pyridin Cumin hydroperoxide Magnesium chloride -2-ylmethyl Thio]-1H -Benzoimidazole C9H12O2 Hexahydrate C17H19N3O2S 2X152.19=304.38 203.00 2X329.41=658.82

CH3 OCH3 H C OH H3C CH3 3 Mg 3H O + 2 + 3H2O + 2HCl O N OCH3 2 N C S H 2 N 2

Esomeprazole Magnesium Tri Hydrate Cumin hydroxide 54.00 72.92

C9H12O C17H18N3O3S.Mg3H2O 2X136.19=272.38 767.15

Flow Chart:

Omeprazole sulphide Toluene Stage-1 Methanol Rec D(-)-Diethyl tartrate N,N-Diisopropyl ethylamine Methanol

ESOMEPRAZOLE MAGNESIUM TRIHYDRATE

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Material Balance:

Material balance of Esomeprazole Magnesium Trihydrate Stage-1 Batch Size: 100.00 Kg Name of the input Quantity Name of the out put Quantity in Kg In Kg Omeprazole sulphide 90.00 Esomeprazole Magnesium Tri 100.00 hydrate Toluene 400.00 Toluene Recovery 385.00 D(-)-Diethyl tartrate 12.00 Toluene Loss 15.00 Titanium tetra iso propoxide 7.50 Methanol Recovery 285.00 N,N-Di isopropyl ethylamine 5.00 Methanol Loss 15.00 Cumin hydro peroxide 42.00 Dichloromethane Recovery 385.00 Potassium hydroxide 44.00 Dichloromethane Loss 15.00 Methanol 300.00 Ethyl acetate Recovery 385.00 Dichloromethane 400.00 Ethyl acetate Loss 15.00 Acetic acid 15.00 Effluent water 1335.87 Sodium sulfate 10.00 (Water-1200,Generated water- 0 7.29,Potassium hydroxide-44, Acetic acid-15,Titanium tetra isopropoxide-7.5,N,N- Diisopropylethylamine-5,D(-) Diethyl tartarate-12,Cumin hydroxide-37.17,Hydrochloric acid-7.91) MgCl2 6H2O 27.75 Inorganic Residue 10.00 Ethyl acetate 400.00 (Sodium sulphate-10) water 1200.00 Organic Residue 7.38 Process residue-7.38 Total 2953.25 Total 2953.25

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ESOMEPRAZOLE SODIUM. Process Description Stage-1 5-Methoxy-2-[(4-Methoxy-3,5-Dimethyl-2-pyridinyl)MethylThio]-1H-Benzimidazole reacts with Cumin hydro peroxide and Potassium hydroxide in the presence of Toluene to give stage-1 product. Stage-2 Stage-1 reacts with acetic acid and sodium hydroxide in the presence of MDC to give Esomeprazole Sodium. . Route of synthesis: Stage-1: OCH 3 CH3 OH H3C CH3 H3C O OCH N 3 Toluene KOH N C S + + H 2 N H

5-Methoxy-2-[(4-methoxy-3,5-dimethyl-pyridin Cumin hydroperoxide Potassium hydroxide -2-ylmethyl Thio]-1H -Benzoimidazole C9H12O2 56.10 C17H19N3O2S 152.19 329.41

OCH3 CH3 H C CH 3 3 H3C OH O N OCH3 N C S H O + H 2 2 N K+

Esomeprazole potassium salt.Monohydrate Cumin hydroxide

C9H12O C17H20KN3O4S 136.19 401.52

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Stage-2: OCH3

H3C CH3 O O N OCH3 MDC + + NaOH N C S H O H 2 H3C OH 2 N K+ Esomeprazole potassium salt.Monohydrate Acetic acid Sodium hydroxide 40.00 C17H20KN3O4S 60.05 401.52

OCH3

H3C CH3

O N OCH3 H O N C S + CH3COOK + 2 H2O H2 N Na

Esomeprazole Sodium Potassium acetate 18.00 98.14 C17H18N3NaO3S.H2O 385.41 Flowchart: 5-Methoxy-2-[(4-Methoxy-3,5 -Dimethyl-2-pyridinyl)Methyl Toluene Recovery Thio]-1H-Benzimidazole Stage-1 Cumin hydroxide Cumin hydroperoxide Potassium hydroxide Toluene

Stage-1 Acetic acid MDC Recovery MDC Stage-2 Potassium acetate Sodium hydroxide

ESOMEPRAZOLE SODIUM

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Material Balance:

Material Balance Of Esomeprazole sodium Stage-1 Batch Size: 100Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Omeprazole sulfide 96.00 Stage-1 110.00 Cumin Hydroperoxide 44.35 Toluene Recovery 285.00 Potassium hydroxide 16.35 Toluene Loss 10.00 DET 11.30 Methanol Recovery 95.00 Ti(IV)Isopropoxide 2.50 Methanol Loss 3.00 NEDIPA 4.50 NEDIPA Loss 4.50 Toluene 300.00 Organic Residue 67.50 Methanol 100.00 Process residue-60.50 Organic impurities-7.06( Ti(IV)Isopropoxide-2.5, Cumin hydroxide-39.64,DET- 11.3) Distillation residue-7 (Toluene-5,Methanol-2) Total 575.00 Total 575.00

Material Balance Of Esomeprazole sodium Stage-2 Batch Size: 100Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage -1 110.00 Esomeprazole Sodium 100.00 Acetic acid 16.40 MDC Recovery 285.00 Sodium hydroxide 10.90 MDC Loss 10.00 MDC 300.00 Ethyl acetate Recovery 143.00 Ethyl acetate 150.00 Ethyl acetate Loss 2.00 Activated carbon 5.00 Effluent water 834.68 Water 800.00 (Water-800,Generated water 0 -4.84,Potassium acetate- 26.84,Ethyl acetate-3) Spent carbon 5.00 Organic residue 12.62 Process residue-5.62 Distillation residue-7 MDC-5,Ethyl acetate -2) Total 1392.30 Total 1392.30

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FEXOFENADINE HYDROCHLORIDE

Process Description:

Stage-1

2-[4-(4-Chloro-butyryl)-cyclohexyl]-2-methyl-propionic acid methyl ester on undergoes condensation with Azacyclonol in presence of Sodium bicarbonate and MIBK to give stage-1 product.

Stage-2

Stage-1 product undergoes reduction with, Sodiumborohydride and water in presence of Methanol to give stage-2 product.

Stage-3

Stage-2 product undergoes salt formation with HCl in presence of IPA to give Fexofenadine Hydrochloride

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FEXOFENADINE HYDROCHLORIDE

Route of Synthesis:

Stage-1

H3C COOCH 3 H N

CH3 Cl OH MIBK O + + NaHCO3 2-[4-(4-Chloro-butyryl)-phenyl]- Azacyclonol 84.01 2-methyl-propionic acid methyl ester C18H21NO C H ClO 15 19 3 267.37 282.10

H3C COOCH3

N CH3 O

OH + NaCl + CO2 + H2O

2-(4-{4-[4-(Hydroxy-diphenyl-methyl)- 58.44 44.0 18.02 piperidin-1-yl]-butyryl}-phenyl)-2-methyl- propionic acid methyl ester C33H39NO4 513.67

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Stage-2

H3C COOCH3

CH N 3 O

OH Methanol + NaBH4 + 4 H2O 2-(4-{4-[4-(Hydroxy-diphenyl- 37.83 72.06 methyl)-piperidin-1-yl]-butyryl}-phenyl) -2-methyl-propionic acid methyl ester C33H39NO4 513.67

H3C COOH

CH N 3 OH

OH + 3 H2 + H3BO3 + CH3ONa

Fexofenadine 61.83 54.02 6.00 C32H39NO4 501.66

Stage-3

H3C H3C COOH COOH

CH3 CH N N 3 OH OH IPA OH + HCl OH HCl Fexofenadine 36.46 Fexofenadine hydrochloride C32H39NO4 501.66 C32H40ClNO4 538.12

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FEXOFENADINE HYDROCHLORIDE

Flow Chart:

Dimethyl phenyl acetate Sodium Bicarbonate Stage-1 Ethyl acetate Rec Azacyclonol Methyl isobutyl ketone Ethyl Acetate

Stage-1 Sodium Borohydride Stage-2 Methanol Rec Sodium Hydroxide Acetic Acid Methanol

Stage-2 Stage-3 Hydrochloric acid IPA Rec Isopropyl alcohol

FEXOFENADINE HYDROCHLORIDE Material Balance:

Material Balance of Fexofenadine Hydrochloride Stage-1 Batch Size: 200Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 2-[4-(4-Chloro-butyryl)- 136.00 Stage-1 227.00 cyclohexyl]-2-methyl-propionic acid methyl ester Sodium Bicarbonate 40.40 Ethyl Acetate recovery 665.00 Azacyclonol 129.00 Ethyl Acetate Loss 14.00 Methyl isobutyl ketone 200.00 Methyl Isobutyl Ketone Recovery 190.00 Ethyl Acetate 700.00 Methyl Isobutyl Ketone Loss 8.00 Water 600.00 Effluent water 641.71 (Water-600,Generated water- 8.56,Sodium chloride-28.15, Ethyl acetate-5) Process Emission 21.08 (Carbon dioxide -21.08) Organic Residue 38.61 (Process Residue-20.61, Distillation Residue-18, (Ethyl acetate-16,MIBK-2) Total 1805.40 Total 1805.40

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Material Balance of Fexofenadine Hydrochloride Stage-2 Batch Size: 200Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 227.00 Stage-2 203.00 Sodium Borohydride 16.50 Methanol recovery 760.00 Activated carbon 10.00 Methanol Loss 16.00 Methanol 800.00 Effluent Water 519.30 Water 500.00 (Water-468.22, Boric acid-27.24, 0 Sodium methoxide-23.84) Spent Carbon 10.00 Process Emissions 2.49 (Hydrogen-2.49) 0 Organic Residue 42.71 Process Residue-22.71 Organic Impurities-12.31 (Sodium methoxide-10.4) Distillation Residue-24 (Methanol-24) Total 1553.50 Total 1553.50

Material Balance of Fexofenadine Hydrochloride Stage-3 Batch Size: 200Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 203.00 Fexofenadine Hydrochloride 200.00 Hydrochloric acid 14.50 Isopropyl Alcohol Recovery 760.00 Isopropyl alcohol 800.00 Isopropyl Alcohol Loss 16.00 Organic Residue 41.50 Process Residue-17.50 Distillation Residue-24 (IPA-24) Total 1017.50 Total 1017.50

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HALOPERIDOL Process description: Stage-1: 1-4-Fluoro Phenyl-pentan-1-one reacts with 4-(Chloro phenyl)piperidine 4-ol in presence of Potassiumcarbonate, Toluene , Cholofrom, Potassium Iodide &Water to give Stage-1 Product Stage-2: Stage-1 Product undergoes purification in Methanol & activated carbon to give of Haloperidol. Route of Synthesis: Stage-1 Cl O HO

+ K CO + 2 HCl + F + N 2 3 H2O H 1-(4-Fluoro-phenyl)-pentan-1-one 4-(4-Chloro-phenyl)- 138.21 72.92 18.02 piperidin-4-ol C H ClNO C11H13FO 11 14 180.22 211.69 Toluene, Chloroform,

Activated carbon, Potassium iodide,

Cl

O OH N + + CH OH + 2 KCl + H2CO3 H2 F 3 2.02 Haloperidol(Crude) 32.04 149.10 62.02

C21H23ClFNO2 375.86

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Stage-2 Cl Cl

O O Activated carbon, OH OH N N Methanol F F Haloperidol(Crude) Haloperidol(Pure)

C21H23ClFNO2 C21H23ClFNO2 375.86 375.86 Flowchart: 1-4-Fluoro Phenyl-pentan-1-one 4-(Chloro phenyl)piperidine 4-ol Potassium carbonate Toluene Recovery Potassium Iodide Stage-1 Chlorofrom recovery Hydrochloric acid Effluent water Toluene Chloroform

Stage-1 Methanol Recovery Spent Carbon Stage-2 Spent carbon Recovery Methanol

Haloperidol Material Balance:

Material Balance of Haloperidol Stage-1 Batch Size: 100 Kg Name of the input Quantity Name of the out put Quantity in in Kg Kg 1-4-Fluoro Phenyl-pentan-1- 57.00 Stage-I 110.00 one 4-(Chloro phenyl)piperidine 4-ol 67.00 Mixed solvent (Toluene Recovery + Generated 390.08 Methanol ) Potassium carbonate 44.00 Toluene loss 8.00 Potassium Iodide 2.00 Chloroform Recovery 285.00 Hydrochloric acid 23.00 Chloroform loss 15.00 Toluene 400.00 Effluent water 567.10 Chloroform 300.00 (water -494.36, Potassium 0 Chloride-47.14, Carbonic acid- 19.60, Toluene-6) Water 500.00 Process emission 0.62

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(Hydrogen-0.62) 0 Organic residue 17.20 Process residue-11.20 Distillation residue-6 (Toluene-6) Total 1393.00 Total 1393.00

Material Balance of Haloperidol Stage-2 Batch Size: 100 Kg Name of the input Quantity Name of the out put Quantity in in Kg Kg Stage-1 110.00 Haloperidol 100.00 Spent Carbon 4.00 Methanol Recovery 570.00 Methanol 600.00 Methanol Loss 12.00 Spent carbon Recovery 4.00 Organic residue 28.00 Process residue- 10 Distillation residue-18 (Methanol-18) Total 714.00 Total 714.00

ITOPRIDE HYDROCHLORIDE Process Description Stage-1 4-Hydroxy benzaldehyde reacts with (2-Chloroethyl)-dimethylamine hydrochloride and Triethyl amine in presence of Chloroform to give stage-1 product. Stage-2 Stage-1 product reacts with Hydroxyl amine sulfate and Hydrogen gas in presence of Raney Nickel in presence of Methanol to give Stage-2 product. Stage-3 Stage-2 product undergoes condensation with 3, 4-Dimethoxy benzoyl chloride in presence of Toluene to give stage-3 product. Stage-4 Stage-3 product undergoes purification in presence of Methanol and Isopropyl alcohol to give Itopride Hydrochloride.

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Route of Synthesis Stage-1:

H H3C Cl HO N Cl N O + CH3 H + 2 Chloroform

4-Hydroxy-benzaldehyde (2-Chloro-ethyl)-dimethyl Triethyl-amine -amine Hydrochoride C H N C7H6O2 6 15 C4H11Cl2N 122.12 202.00 144.04

H O O . HCl H3C N 2 N CH3 +

4-(2-Dimethylamino -ethoxy)-benzaldehyde Triethyl amine Hydrochloride C11H15NO2 193.24 C6H16ClN 275.30 Stage-2: H O O H C N 3 Raney Ni CH3 + (NH2OH)H2SO4 + 2 H2 Methanol 4.00 4-(2-Dimethylamino Hydroxyl amine sulphate -ethoxy)-benzaldehyde 131.11 C11H15NO2 193.24 O

NH2

H3C N CH + H SO 3 2 4 + 2 H2O [2-(4-Aminomethyl-phenoxy) Sulfuric acid 36.00 -ethyl]-dimethyl-amine 98.00 C11H18N2O 194.27

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Stage-3: O

O Cl

NH2 H CO H3C N 3 Toluene OCH CH3 + 3

[2-(4-Aminomethyl-phenoxy) 3,4-Dimethoxy- -ethyl]-dimethyl-amine benzoyl chloride OCH3 C H ClO C11H18N2O 9 9 3 194.27 200.62 OCH3

HN

H3C N O O CH 3 HCl

Itopride Hydrochloride (Crude)

C20H27ClN2O4 394.89

Stage-4:

OCH3 OCH3 OCH3 OCH3 HN H3C N O O Methanol HN CH3 H3C N O O HCl CH 3 HCl Itopride Hydrochloride (Crude) Itopride Hydrochloride C20H27ClN2O4 394.89 C20H27ClN2O4 394.89

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Flow Chart: 4-Hydroxy benzaldehyde (2-Chloroethyl)-dimethylamine hydrochloride Stage-1 Chloroform Rec Triethyl amine Chloroform

Stage-1 Hydroxyl amine sulfate Stage-2 Methanol Rec Raney Ni Methanol

Stage-2 3, 4-Dimethoxy Stage-3 Toluene Rec benzoyl chloride Toluene

Stage-3 Stage-4 Methanol Rec Methanol IPA Rec Isopropyl alcohol

ITOPRIDE HYDROCHLORIDE

Material Balance:

Material Balance of Itopride Hydrochloride Stage-1 Batch Size: 100.0Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 4-Hydroxy benzaldehyde 37.00 Stage-1 56.00 (2-Chloro ethyl)-dimethyl Chloroform Recovery 475.00 43.60 hydrochloride Triethylamine 61.20 Chloroform Loss 25.00 Chloroform 500.00 Effluent water 383.40 (Water-300, Triethyl amine HCl- 0 Water 300.00 83.40) Organic residue 2.40 Process residue-2.4 Total 941.80 Total 941.80

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Material Balance of Itopride Hydrochloride Stage-2 Batch Size: 100.0Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 56.00 Stage-2 54.00 Hydroxyl amine sulphate 38.00 Methanol Recovery 570.00 Methanol 600.00 Methanol Loss 12.00 Raney nickel 5.00 Effluent water 338.0 (Water-300,Generated water- 0 Hydrogen gas 1.12 10.41,Sulfuric acid-28.39) Water 300.00 Spent Raney Nickel Recovered 5.00 Organic residue 21.12 Process residue-3.12

Distillation residue-18 (Methanol-18) Total 1000.12 Total 1000.12

Material Balance of Itopride Hydrochloride Stage-3 Batch Size: 100.0Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 54.00 Stage-3 105.00 3,4-Dimethoxy benzoyl chloride 55.50 Toluene Recovery 380.00 Toluene 400.00 Toluene Loss 12.00 Water 200.00 Effluent water 204.00 (Water-200,Toluene-4) 0 Organic Residue 8.50 Process residue-4.50

Distillation residue-4 (Toluene-4) Total 709.50 Total 709.50

Material Balance of Itopride Hydrochloride Stage-4 Batch Size: 100.0Kg Name of the input Quantity in Kg Name of the out put Quantity in Kg Stage-3 105.00 Itopride Hydrochloride 100.00 Methanol 500.00 Methanol Recovery 475.00 Isopropyl alcohol 500.00 Methanol Loss 10.00 Isopropyl alcohol 475.00 Activated carbon 3.50 Recovery Water 200.00 Isopropyl alcohol Loss 10.00 Effluent water 200.00 (Water-200) 0 Spent carbon 3.50 Organic residue 35.00 Process residue-5 Distillation residue-30

(Methanol-15, Isopropyl alcohol-15) Total 1308.5 Total 1308.50

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ITRACONAZOLE

Process Description: Stage-1 1-(4-Methoxy-Phenyl)-piperazine reacts with 1-Bromo-4-nitro-benzene in presence of MDC and Methanol to give Stage-1 Product. Stage-2: Stage-1 Product reacts with Hydrogen in presence of Pd/c catalyst and DMF to give Stage-2 Product. Stage-3: Stage-2 product reacts with Phenyl Chloro formate in presence of Sodium bicarbonate and MDC to give Stage-3 product. Stage-4: Stage-3 product reacts with Hydrazine hydrate in presence of 1,4-Dioxane to give Stage-4 product. Stage-5: Stage-4 Product reacts with Formamidine in presence of Acetic acid and acetone to give Stage-5 product. Stage-6: Stage-5 product reacts with 2-Bromo-Butane in presence of Potassium carbonate and Methanol to give Stage-6 product. Stage-7: Stage-6 product reacts with Hydrobromic acid in presence of Sodium carbonate nd Methanol to give stage-7 Product. Stage-8: Step-A: 2,4Dichloroacetopheneone reacts with Glycerol and Bromine in presence of Toluene, PTSA and n-Butanol to give Step-A product.

Step-B: Step-A product reacts with Benzyl Chloride in presence of Toluene and Methanol to give Stage-8 Product. Stage-9: Stage-8 Product reacts with 1,2,4-Triazole in presence of Potassium Carbonate , Sodium Hydroxide ,DMF and water to giveStage-9 Product.

Stage-10: Stage-9 Product reacts with Methanol Sulfanyl Chloride in presence of TEA, MDC and water to give Stage-10 product. Stage-11: Stage-10 Product undergoes condensation with Stage-7 Product in presence of potassium hydroxide and Methanol to give Itraconazole.

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Route of Synthesis Stage-1:

MDC HN N OCH3 + O2N Br Methanol

1-(4-Methoxy-phenyl)-piperazine 1-Bromo-4-nitro-benzene C H BrNO C11H16N2O 6 4 2 192.26 202.01

O2N N N OCH3 + HBr

1-(4-Methoxy-phenyl)-4-(4-nitro-phenyl)- piperazine 80.91

C17H17N3O3 313.35 Stage-2: 3H H3CO N N NO2 + 2 pd/Catalyst DMF 1-(4-Methoxy-phenyl)-4-(4-nitro-phenyl)- Hydrogen piperazine 6.05 C17H19N3O3 313.35 H3CO N N NH2 + 2H2O

4-[4-(4-Methoxy-phenyl)-piperazin-1-yl] 36.04 -phenylamine C17H21N3O 283.37

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Stage-3:

O H CO N N NH + + NaHCO3 3 2 Cl O MDC

4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]- Phenyl chloro formate 84.01 phenylamine C H ClO C H N O 7 5 2 17 21 3 156.57 283.37

CO H3CO N N NHCOOPh + NaCl + 2 + H2O

44.01 18.02 {4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-phenyl} 58.44 -carbamic acid phenyl ester C24H25N3O3 403.47

Stage-4:

H CO N N NHCOOPh 1,4-Dioxane 3 + N2H4.H2O

{4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-phenyl}- Hydrazine hydrate carbamic acid phenyl ester 50.06 C24H25N3O3 403.47 OH

+ H2O H3CO N N NHCONHNH2 +

1,3-Dimethyl-7-{2-[(1-phenyl-2-propanyl)amino]ethyl} Phenol 18.02 -3,7-dihydro-1H-purine-2,6-dione C6H6O C H N O 18 23 5 2 94.11 341.41

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Stage-5:

H3CO N N NHCONHNH2 + H N NH 2 + 2CH3COOH

1,3-Dimethyl-7-{2-[(1-phenyl-2-propanyl)amino]ethyl} Formamidine 120.10 -3,7-dihydro-1H-purine-2,6-dione CH4N2 C18H23N5O2 44.07 341.41

O NH H3CO N N N + 2CH3COONH4 N 2-{4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-phenyl} Ammonium acetate -2,4-dihydro-[1,2,4]triazol-3-one 154.16 C19H21N5O2 351.40 Stage-6: O Br NH H3C + CH + 1/ K CO H3CO N N N 3 2 2 3 N 2-{4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-phenyl} 2-Bromo-butane 69.10 -2,4-dihydro-[1,2,4]triazol-3-one C4H9Br C H N O 19 21 5 2 137.02 351.40

Methanol

O CH3 N + KBr + 1/2CO + 1/2 H3CO N N N CH3 2 H2O N 4-Isobutyl-2-{4-[4-(4-methoxy-phenyl)-piperazin-1-yl] 119.0 22.0 9.01 -phenyl}-2,4-dihydro-[1,2,4]triazol-3-one C23H29N5O2 407.51

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Stage-7: O CH3 N H CO N N N CH 3 3 + 2HBr + Na2CO3 N Methanol 4-Isobutyl-2-{4-[4-(4-methoxy-phenyl)-piperazin-1-yl]-phenyl} Hydrobromic acid 106.0 -2,4-dihydro-[1,2,4]triazol-3-one 161.82 C23H29N5O2 407.51

O CH3 N HO N N N + CH OH + 2NaBr + CO CH3 3 2 N 2-{4-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-phenyl} 32.04 205.79 44.01 -4-isobutyl-2,4-dihydro-[1,2,4]triazol-3-one C22H27N5O2 393.48 Stage-8: Step-A O

CH 3 OH PTSA + Br Cl Cl + HO OH 2 n-Butanol 159.81 2,4-Dichloro Glycerol acetophenone C H O O 3 8 3 OH C8H6Cl2O 92.09 189.04 O Br + HBr + H2O Cl Cl 18.02 [2-Bromomethyl-2-(2,4-dichloro- 80.91 phenyl)-[1,3]dioxolan-4- yl]-methanol

C11H11BrCl2O3 342.01 Step-B: O O Br OH O O Cl OOCC6H5 Br O Cl Cl + + HCl [2-Bromomethyl-2-(2,4-dichloro Benzoyl chloride Cl Cl Benzoic acid 2-bromomethyl-2-(2,4- 36.46 -phenyl)]-[1,3]dioxolan C7H5ClO dichloro-phenyl)-[1,3]dioxolan -4-yl]-methanol 140.57 -4-ylmethyl ester

C11H11BrCl2O3 Cis-bromo benzoate

342.01 C18H15BrCl2O4 446.12

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Stage-9: Br O OOCC6H5 H O N DMF N NaOH + 1/2 K2CO3 + Cl Cl + N Water Potassium Sodium Cis-bromo benzoate 1,2,4-Triazole carbonate hydroxide C18H15BrCl2O4 C2H3N3 69.0 40.0 446.12 N 69.1 N N O COONa

HO O + + KBr + 1/2 CO2 + 1/2 H2O Cl Cl [2-(2,4-Dichloro-phenyl)-2-[1,2,4]triazol Sodium 119.0 22.0 9.01 -1-ylmethyl-[1,3]dioxolan-4-yl]-methanol benzoate C H Cl N O 13 13 2 3 3 C7H5NaO2 330.17 144.10

Stage-10: N N N O HO O MDC + + CH3SO2Cl (C2H5)3N Cl Cl Water [2-(2,4-Dichloro-phenyl)-2-[1,2,4]triazol Methane sulfonyl Triethyl amine -1-ylmethyl-[1,3]dioxolan-4-yl]-methanol chloride 101.19 114.55 C13H13Cl2N3O3 N 330.17 N N O O3SH3C O

+ (C2H5)3N.HCl Cl Cl 1-[2-(2,4-Dichloro-phenyl)-4-ethyl-[1,3]dioxolan Triethyl amine hydrochloride -2-ylmethyl]-1H-[1,2,4]triazole; 137.65 C14H15Cl2N3O5S 408.26

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Stage-11:

N N N O O3SH3C O CH3 O N + HO N N N CH3 + KOH Methanol Cl Cl N 1-[2-(2,4-Dichloro-phenyl)-4-ethy 2-{4-[4-(4-Hydroxy-phenyl)-piperazin- 56.11 l-[1,3]dioxolan 1-yl]-phenyl}-4-isobutyl-2,4-dihydro -2-ylmethyl]-1H-[1,2,4]triazole;(Stage-10) -[1,2,4]triazol-3-one(Stage-7) C H Cl N O S 14 15 2 3 5 C22H27N5O2 408.26 393.48

Cl Cl O CH3 N + CH3O2SOK + H2O O O N N N CH3 N O N Methane sulfonate 18.02 N ITRACONAZOLE N potassium C35H38Cl2N8O4 705.63 134.20

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Flowchart: 1-(4-Methoxy-phenyl)-piperazine 1-Bromo-4-Nitro-benzene MDC recovery MDC Stage-1 Methanol recovery Methanol Effluent water Stage-1 Palladium Carbon DMF DMF Recovery Hydrogen Gas Stage-2 Effluent water

Stage-2 Phenyl Chloro formate Methylene Dichloride Recovery Methylene Dichloride Stage-3 Effluent water Sodium Bicarbonate

Stage-3 1,4-Dioxane Recovery Hydrazine Hydrate Stage-4 Effluent water 1,4-Dioxane

Stage-4 Formamidine Dimethyl Formamide Recovery Dimethyl Formamide Stage-5 Effluent water Acetic Acid

Stage-5 2-Bromo Butane Potassium Carbonate Dimethyl Formamide Recovery Stage-6 Methanol Effluent water Dimethyl Formamide

Stage-6 Hydrogen Bromide Methanol recovery Sodium Carbonate Stage-7 Effluent water Methanol

2,4 -Dichloroacetophenone n-Butanol recovery Glycerol Toluene Recovery Liq Bromine Stage-8 Effluent water Benzoyl chloride Toluene n-Butanol p-Toluenesulfonic acid

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Stage-8 1,2,4-Triazole Sodium Hydroxide Stage-9 Dimethyl Formamide recovery Potassium Carbonate Effluent water Dimethyl Formamide Stage-9 Methane Sulfonyl Chloride Triethylamine Isopropyl alcohol Recovery Stage-10 Methylene Dichloride Effluent water Isopropyl Alcohol

Stage-10 Stage-7 Dimethyl formamide Recovery Potassium Hydroxide Stage-11 MethanolRecovery Activated Carbon Effluent water Dimethyl Formamide Methanol ITRACONAZOLE

Material Balance:

Material Balance of Itraconazole Stage-1 Batch Size:500.00Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 1-(4-Methoxy-phenyl)- 208.00 Stage-1 322.00 piperazine 1-Bromo-4-Nitro-benzene 219.00 Methanol Recovery 95.00 MDC 250.00 Methanol Loss 5.00 Methanol 100.00 MDC Recovery 238.00 Water 500.00 MDC Loss 5.00 Effluent Water 500.00 (Water-500) 0 Process Emissions 87.53 (Hydrogen Bromide-87.53) 0 Organic residue 24.47 Process residue -17.47 (Distillation Residue-7 (MDC-7) Total 1277.00 Total 1277.00

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Material Balance of Itraconazole Stage-2 Batch Size:500.00Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 322.00 Stage-2 277.00 Palladium Carbon 5.00 DMF Recovery 665.00 DMF 700.00 DMF Loss 15.00 Hydrogen Gas 6.30 Effluent Water 337.03 Water 300.00 (Water-300,Generated Water- 37.03) Spent Catalyst 5.00 (Palladium Carbon Reuse) Organic Residue 34.27 Process residue- 14.27 Distillation Residue-20 (DMF-20) Total 1333.30 Total 1333.30

Material Balance of Itraconazole Stage-3 Batch Size:500.00Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 277.00 Stage-3 375.00 Phenyl Chloro formate 154.00 MDC Recovery 475.00 Methylene Dichloride 500.00 MDC Loss 10.00 Sodium Bicarbonate 83.00 Effluent Water 424.73 Water 350.00 (Water-350, GeneratedWater-17.60 Sodium chloride-57.13 ) Process Emissions 43.00 (Carbon Dioxide-43) Organic Residue 36.27 Process residue-21.27 Distillation Residue-15 ( MDC) Total 1364.00 Total 1364.00

Material Balance of Itraconazole Stage-4 Batch Size:500.00Kg Name of the input Quantity Name of the out put Quantity in Kg In Kg Stage-3 375.00 Stage-4 300.00 Hydrazine Hydrate 47.00 1,4-Dioxane Recovery 475.00 1,4-Dioxane 500.00 1,4-Dioxane Loss 10.00 Water 500.00 Effluent Water 605.06 (Water-500, GeneratedWater- 17.60, Phenol-87.46)

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Organic Residue 31.94 Process residue-16.94 Distillation Residue-15 (1,4-Dioxane-15) Total 1422.00 Total 1422.00

Material Balance of Itraconazole Stage-5 Batch Size:500.00Kg Name of the input Quantity Name of the out put Quantity in Kg In Kg Stage-4 300.00 Stage-5 290.00 Formamidine 39.00 DMF Recovery 238.00 Dimethyl Formamide 250.00 DMF Loss 5.00 Acetic Acid 106.00 Effluent Water 635.46 Water 500.00 (Water-500, 0 Ammonium acetate-135.46) Organic Residue 26.54 Process residue – 19.54 Distillation Residue-7 (DMF-7) Total 1195.00 Total 1195.00

Material Balance of Itraconazole Stage-6 Batch Size:500.00Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-5 290.00 Stage-6 320.00 2-Bromo Butane 113.00 DMF Recovery 285.00 Potassium Carbonate 57.00 DMF Loss 10.00 Methanol 450.00 Methanol Recovery 427.00 Dimethyl Formamide 300.00 Methanol Loss 9.00 Water 300.00 Effluent Water 405.44 (Water-300, Generated Water- 0 7.44, Potassium bromide-98) Process Emissions 18.15 (Carbon Dioxide-18.15) 0 Organic Residue 35.41 (Process residue-16.41, Distillation Residue-19 (Methanol-14, DMF-5) Total 1510.00 Total 1510.00

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Material Balance of Itraconazole Stage-7 Batch Size:500.00Kg Stage-6 320.00 Stage-7 294.00 Hydrogen Bromide 128.00 Methanol Recovery+ Generated 414.56 Methanol Sodium Carbonate 83.00 Methanol Loss 12.00 Methanol 400.00 Effluent Water 611.59 Water 450.00 (Water-450, 0 Sodium bromide-161.59) Process emission 34.56 (Carbondioxide-34.56) 0 Organic residue 14.29 Process residue -6.29 Distillation Residue-8 (Methanol-8) Total 1381.00 Total 1381.00

Material Balance of Itraconazole Stage-8 Batch Size:500.00Kg 2,4 -Dichloroacetophenone 215.00 Stage-8 370.00 Glycerol 105.00 n-Butanol Recovery 475.00 Liq Bromine 182.00 n-Butanol Loss 15.00 Benzoyl chloride 152.00 Toluene recovery 380.00 Toluene 400.00 Toluene Loss 10.00 n-Butanol 500.00 Effluent water 630.49 p-Toluenesulfonic acid 5.00 (Effluent water-600, Generated 0 water-20.49,Toluene-5, Paratoluene Sulfonic acid-5) Water 600.00 Process Emissions 145.30 (Hydrogen bromide-92, 0 Hydrogen Chloride-53.30) Organic residue 133.21 Process residue-118.21 Distillation Residue-15 (n-Butanol-10,Toluene-5) Total 2159.00 Total 2159.00

Material Balance of Itraconazole Stage-9 Batch Size:500.00Kg Name of the input Quantity in Name of the out put Quantity Kg in Kg Stage-8 370.00 Stage-9 260.00 1,2,4-Triazole 58.00 DMF Recovery 95.00 Sodium Hydroxide 34.00 DMF Loss 2.00 Potassium Carbonate 58.00 Effluent Water 725.66

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Dimethyl Formamide 100.00 (Water-500, Generated Water- 0 7.47 Potassium Bromide-98.69, Sodium Benzoate-119.50) Water 500.00 Process Emission 18.24 (Carbon dioxide-18.24) 0 Organic residue 19.10 Process residue-16.1 Distillation Residue-3 (DMF-3) Total 1120.00 Total 1120.00

Material Balance of Itraconazole Stage-10 Batch Size:500.00Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-9 260.00 Stage-10 305.00 Methane Sulfonyl Chloride 91.00 MDC Recovery 570.00 Triethylamine 80.00 MDC Loss 12.00 Methylene Dichloride 600.00 Isopropyl Alcohol Recovery 570.00 Isopropyl Alcohol 600.00 Isopropyl Alcohol Loss 12.00 Water 500.00 Effluent Water 608.40 (Water-500,Triethylamine 0 Hydrochloride-108.40) Organic Residue 53.60 Process residue-17.60 Distillation Residue-36 (MDC-18,IPA-18) Total 2131.00 Total 2131.00

Material Balance of Itraconazole Stage-11 Batch Size:500.00Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-10 305.00 Itraconazole 500.00 Stage-7 294.00 Dimethyl Formamide Recovery 285.00 Potassium Hydroxide 42.00 Dimethyl Formamide Loss 10.00 Activated Carbon 8.00 Methanol Recovery 380.00 Dimethyl Formamide 300.00 Methanol Loss 12.00 Methanol 400.00 Effluent Water 613.71 Water 500.00 (Water-500, Generated Water- 13.46 Potassium Methane Sulfonate-100.25) Spent Carbon 8.00 Organic residue 40.29 Process residue-27.29 Distillation Residue-13 (Methanol-8, DMF-5) Total 1849.00 Total 1849.00

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KETOROLAC TROMETHAMINE Process Description Stage-1 5-chloro-2-benzoylpyrrole reacts with Methyl-gama-methoxy –butanoate in presence of Acetone to give Stage-1 product.

Stage-2 Stage-1 Product undergoes condensation with Tromethamine in presence of Acetone to give Ketorolac Tromethamine. Route of synthesis Stage-1

O H O N Cl O CH H C O 3 + NaOH Acetone + 3 5-Chloro-2-benzoyl pyrrole methyl-gama-methoxybutanoate 40.00

C11H8ClNO C6H12O3 205.64 132.16

O

N COOH + NaCl + 2 CH3OH

Ketorolac 58.44 64.08

C15H13NO3 255.27 Stage-2

NH O 2

N COOH Acetone HO OH + NH OH 2 O Ketorolac Tromethamine N . C15H13NO3 C4H11NO3 COOH HO OH 255.27 121.14 OH ketorolac tromethamine

C19H24N2O6 376.40

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Flow chart:

5-chloro-2-benzoylpyrrole Methyl-gama-methoxy Acetone Recovery butanonate Stage-1 Sodium hydroxide Acetone

Stage-1 Acetone Stage-2 Tromethamine Acetone Recovery Carbon & hyflow

Ketorolac Tromethamine

KETOROLAC TROMETHAMINE

Material Balance

Material Balance of Ketorolac Tromethamine Stage-1 Batch Size: 100Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 5-chloro-2-benzoylpyrrole 59.00 Stage-1 70.00 Methyl-gama-methoxy 37.85 Acetone Recovery 475.00 butanonate Sodium hydroxide 11.45 Acetone Loss 15.00 Acetone 500.00 Methanol Recovery 16.75 Water 500.00 Effluent water 516.75 (water-500,Sodium chloride- 0 16.75) Organic Residue 14.80 Process residue-4.8, Distillation residue -10 ( Acetone-10) Total 1108.30 Total 1108.30

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Material Balance of Ketorolac Tromethamine Stage-2 Batch Size: 100Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 70.00 Ketorolac Tromethamine 100.00 Acetone 300.00 Acetone Recovery 285.00 Tromethamine 34.00 Acetone Loss 7.00 Carbon & hyflow 10.00 Effluent water 400.00 Water 400.00 (water-400) 0 Spent carbon & hyflow 10.00 Organic residue 12.00 Process residue-4 Distillation residue – 8 (Acetone-8) Total 814.00 Total 814.00

LANSOPRAZOLE

Process Description Stage-1 2, 3-Lutidine reacts with Hydrogen Peroxide and Nitric Acid in Presence of Acetic acid to give stage-1 product. Stage-2 Stage-1 Product reacts with 1, 1, 2- trifluoroethanol and Acetic Anhydride in presence of Potassium Carbonate to give stage-2 product. Stage-3 Stage-2 product undergoes chlorination with Thionyl Chloride in presence of Toluene to give stage-3 product. Stage-4 Stage-3 product undergoes condensation with 1H-Benzoimidazole-2-thiol in presence of Sodium Hydroxide to give stage-4 product. Stage-5 Stage-4 product undergoes oxidation with Hydrogen peroxide in presence of IPA to give Lansoprazole.

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LANSOPRAZOLE Route of Synthesis:

Stage-1

NO2 H C CH3 3

CH3 N H C N+ 3 + 2 H2O HNO + HO OH + 3 O- 4-Nitro-2,3-Dimethyl 36.04 2,3-Lutidine Hydrogen Peroxide 63.00 pyridine-N-Oxide H2O2 C7H9N C7H8N2O3 107.15 34.00 168.15

Stage-2

NO2

H3C F O O + + F + K2CO3 + NaOH + HCl H C + F 3 N OH O O- Acetic anhydride 36.46 4-Nitro-2,3-Dimethyl 1,1,2-Trifluoro-ethanol 138.21 40.00 pyridine-N-Oxide C4H6O3 CF3CH2OH 102.09 C7H8N2O3 100.04 168.15

OCH2CF3

CH3 . HCl + + + CH3COONa CH3COOH KHCO3 + KNO2 CH OH N 2 82.03 60.05 100.12 85.10 [3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]- methanol

C9H11ClF3NO2 257.64

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Stage-3

OCH2CF3 OCH2CF3

O CH3 CH3 . . HCl + Cl S HCl

CH OH CH2Cl N 2 Cl N [3-Methyl-4-(2,2,2-trifluoro-ethoxy) Thionyl chloride 2-Chloromethyl-3-methyl-4-(2,2,2-trifluoro- ethoxy)-pyridine Hydrochloride -pyridin-2-yl]-methanol SOCl2 C9H11ClF3NO2 118.97 C9H10Cl2F3NO 257.64 276.08

HCl + SO2 + 64.06 36.46

Stage-4 OCH2CF3

CH 3 H . HCl N + HS + 2 NaoH CH Cl N N 2 2-Chloromethyl-3-methyl-4-(2,2,2-trifluoro- 1H-Benzoimidazole-2-thiol 80.00 ethoxy)-pyridine Hydrochloride C7H6N2S C9H10Cl2F3NO 150.20 276.08 OCH2CF3

CH3

H N CH + 2 NaCl + N 2 S 2 H2O N

2-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl 116.88 36.04 methylthio]-1H-benzo[d]imidazole

C16H14F3N3OS 353.36

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Stage-5

OCH2CF3

CH3

H N CH N 2 S + HO OH N

2-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl Hydrogen peroxide

methylthio]-1H-benzo[d]imidazole H2O2 34.01 C16H14F3N3OS 353.36 OCH2CF3

CH3

O H N CH + H O N 2 S 2 N

Lansoprazole 18.02 C16H14F3N3O2S

369.36 LANSOPRAZOLE

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Flow Chart: 2,3-Lutidine Acetic Acid Hydrogen Peroxide (50%) Sulfuric Acid Nitric Acid Stage-1 Effluent water Stage-1 Sodium Hydroxide Potassium Carbonate 1,1,2-Tri Fluoro Ethanol MIBK Recovery MIBK Stage-2 Toluene Recovery Acetic Anhydride Effluent water TEBAC Toluene Hydrogen Chloride Activated Carbon Stage-2 Toluene recovery Methylene Dichloride Stage-3 Methylene Dichloride Recovery Toluene Effluent water Thionyl Chloride

Stage-3 Sodium Hydroxide Stage-4 Effluent water 1H-Benzoimidazole-2thiol

Stage-4 Isopropyl Alcohol Hydrogen Peroxide (50%) Catalyst Isopropyl alcohol Recovery Stage-5 Chloroform Acetone recovery Acetone Effluent water

LANSOPRAZOLE

LANSOPRAZOLE

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MATERIAL BALANCE:

Material Balance of Lansoprazole Stage-1 Batch Size:500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 2,3-Lutidine 188.00 Stage-1 280.00 Acetic Acid 46.00 Spent Sulfuric Acid 50.00 Hydrogen Peroxide (50%) 120.00 Effluent water 969.23 Sulfuric Acid 50.00 (Water-800, Generatedwater- 0 63.23,water from hydrogen peroxide- 60, Acetic Acid - 46) Nitric Acid 111.00 Organic Residue 15.77 Water 800.00 Process residue – 15.77 Total 1315.00 Total 1315.00

Material Balance of Lansoprazole Stage-2 Batch Size:500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 280.00 Stage-2 405.00 Sodium Hydroxide 67.00 MIBK Recovery 140.00 Potassium Carbonate 230.00 MIBK Loss 5.00 1,1,2-Tri Fluoro Ethanol 167.00 Toluene Recovery 380.00 MIBK 150.00 Toluene Loss 10.00 Acetic Anhydride 170.00 Effluent Water 1041.59 TEBAC 1.00 (Water-800, Sodium Acetate-136.59, 0 Acetic Acid-100,Toluene-5) Toluene 400.00 Inorganic solid waste 308.70 Hydrogen Chloride 61.00 (Potassium Nitrite-141.70, Potassium 0 Bicarbonate-167) Activated Carbon 5.00 Spent Carbon 5.00 Water 800.00 Organic Residue 35.71 Process Residue-25.71 Distillation Residue-10 (MIBK-5,Toluene-5) Total 2331.00 Total 2331.00

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Material Balance of Lansoprazole Stage-3 Batch Size:500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 405.00 Stage-3 415.00 Methylene Dichloride 400.00 Toluene Recovery 475.00 Toluene 500.00 Toluene Loss 15 Thionyl Chloride 180.00 Methylene Dichloride Recovery 380.00 Methylene Dichloride Loss 12.00 Process Emissions 152.68 (Sulfur Dioxide-97.50,Hydrogen 0 Chloride-55.18) Organic Residue 35.32 Process residue- 17.32 Distillation Residue-18 (Toluene-10, Methylene Dichloride -8) Total 1485.00 Total 1485.00

Material Balance of Lansoprazole Stage-4 Batch Size:500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-3 415.00 Stage-4 505.00 Sodium Hydroxide 121.00 Effluent Water 829.88 1H-Benzoimidazole-2thiol 226.00 (Water-600, Generated Water- 0 54.18,Sodium Chloride-175.70) Water 600.00 Organic Residue 27.12 (Process Residue-27.12) Total 1362.00 Total 1362.00

Material Balance of Lansoprazole Stage-5 Batch Size:500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-4 505.00 Lansoprazole 500.00 Isopropyl Alcohol 250.00 Isopropyl Alcohol Recovery 238.00 Hydrogen Peroxide (50%) 98.00 Isopropyl Alcohol Loss 5.00 Catalyst 1.00 Chloroform Recovery 384.00 Chloroform 400.00 Chloroform Loss 12.00 Acetone 150.00 Acetone Recovery 143.00 Water 600.00 Acetone Loss 3.00

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Effluent Water 674.75 (Water-600, Generated Water- 0 25.75, Water from Hydrogen peroxide-49) Catalyst Reuse 1.00 Organic Residue 43.25 Process residue-28.25 Distillation residue-15 (IPA-7, Chloroform-4,Acetone-4) Total 2004.00 Total 2004.00

LOPERAMIDE HCL Process Description:

Stage-1: Diphenyl acetonitrile reacts with 1, 2-Dichloroethane in presence of TBAB, Toluene and Methanol to give Stage-1 Product.

Stage-2: Stage-1 product reacts with Sulphuric acid and water in presence of Acetic acid and IPA to give Staeg-2 product.

Stage-3: Stage-2 Product reacts with Hydrobromic acid in presence of Acetic acid to give Stage-3 Product.

Stage-4:

Stage-3 product reacts with Thionyl chloride in presence of Toluene to give Stage-4 product.

Stage-5:

Stage-4 Product reacts with Dimethyl amine in presence of Toluene, water to give Stage-5 product.

Stage-6:

Step-A:

4-Chloro Phenyl magnesium bromide reacts with 4-oxo-piperidine-1-carboxylic acid ethyl ester in presence of Toluene and Hydrobromic acid to give Step-A Product.

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Step-B:

Step-A Product reacts with Sodium hydroxide in presence of Methanol, Toluene to give Stage-6 Product.

Stage-7:

Stage-5 reacts with stage-6 in presence of Potassium Carbonate, Potassium Iodide and acetone to give stage-7 Product.

Stage-8:

Stage-7 Product undergoes Salt formation with Hydrochloric acid in presence of Acetone to give Loperamide Hydrochloride.

Route of Synthesis.

Stage-1 Cl N N

Cl TBAB + Cl + HCl

Diphenyl-acetonitrile 1,2-Dichloro-ethane 4-Chloro-2,2-diphenyl-butyronitrile36.46 C H Cl C14H11N 2 4 2 C H ClN 193.24 98.96 16 14 255.74

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Stage-2 Cl N

H O + H2SO4 + 2 Acetic acid

4-Chloro-2,2-diphenyl-butyronitrile Sulphuric acid 18.0

C16H14ClN 98.08 255.74 O

O

NH Cl + 4 + SO2 + 1/2 O2

3,3-Diphenyl-dihydro- 53.49 64.06 16.0 furan-2-one

C16H14O2 238.28

Stage-3 Br O HO

O O

CH3COOH + HBr

3,3-Diphenyl-dihydro- 4-Bromo-2,2-diphenyl- 80.91 furan-2-one butyric acid (Loperamide-III)

C16H14O2 C16H15BrO2 238.28 319.19

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Stage-4: Br Br OH O COCl

+ SOCl2 Toluene + SO2 + HCl 4-Bromo-2,2-diphenyl- Thionyl chloride 4-Bromo-2,2-diphenyl- 64.06 36.46 butyric acid (Loperamide-III) 118.97 butyryl chloride C16H15BrO2 C16H14BrClO 319.19 337.64

Stage-5: H C 3 CH3 Br N Br

COCl O H N Toluene + H3C CH3 Water 4-Bromo-2,2-diphenyl- + HCl Dimethylamine (Dihydro-N,N-dimethyl-3,3-diphenyl butyryl chloride -2(3H)-furaniminium bromide) 36.46 C2H7N C H BrClO 16 14 45.08 or 337.64 4-Bromo-N,N-dimethyl-2,2- diphenyl-butyramide

C18H20BrNO 346.26

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Stage-6:

Step-A:

Toluene, BrMg Cl + HCl solution O N COOC2H5 + HBr

4-Chloro phenyl 4-Oxo-piperidine-1- magnesium bromide carboxylic acid ethyl ester 80.91

C6H4BrClMg C8H13NO3 215.76 171.19 HO

Cl N COOC2H5 + MgBr2

184.11 4-(4-Chloro-phenyl)-4- hydroxy-piperidine-1- carboxylic acid ethyl ester

C14H18ClNO3 283.75

Step-B: HO Methanol, Cl N COOC H 2 5 + NaOH + HCl Toluene

4-(4-Chloro-phenyl)-4- 40.00 36.46 hydroxy-piperidine-1- carboxylic acid ethyl ester

C14H18ClNO3 283.75 HO

Cl NH + C2H5OH + NaCl + CO2 Ethanol 58.44 44.01 46.07 4-(4-Chlorophenyl)-4- hydroxy piperidine

C11H14ClNO 211.69

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Stage-7:

H3C CH N 3 Br OH O K CO,KI HN 2 Acetone Cl (Dihydro-N,N-dimethyl-3,3- + 4-(4-Chloro-phenyl) diphenyl-2(3H)- -piperidin-4-ol furaniminium bromide) or C11H14ClNO 4-Bromo-N,N-dimethyl-2,2- 211.69 diphenyl-butyramide OH N C H BrNO 18 20 O N Cl 346.26

4-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]- + HBr N,N-dimethyl-2,2-diphenyl-butyramide 80.91

C29H33ClN2O2 477.04

Stage-8:

OH OH N N O O Cl N Cl N Acetone

+ HCl . HCl

4-[4-(4-Chloro-phenyl)-4-hydroxy- 36.46 Loperamide Hydrochloride piperidin-1-yl]-N,N-dimethyl- 2,2-diphenyl-butyramide C29H34Cl2N2O2

C29H33ClN2O2 513.50 477.04

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Flowchart:

Di phenyl acetonitrile 1,2-Dichloro ethane Methanol Recovery TBAB Stage-1 Toluene Recovery C.S.LYE Effluent water Acetic acid Toluene Methanol

Acetic Acid Isopropyl alcohol Recovery Stage-2 Sulfuric acid Effluent water Soda ash (10%) Isopropyl alcohol

HBr In Acetic acid (40%) Toluene Recovery Toluene Stage-3 Effluent water

Thionyl chloride Toluene Recovery Stage-4 Toluene Effluent water

Sodium carbonate Dimethylamine Toluene Recovery Toluene Stage-5 Effluent water

4-Chloro Phenyl Magnesium Bromide Hydrobromic acid Toluene Recovery Sodium Hydroxide Stage-6 Methanol Recovery Hydrochloric acid Effluent water Methanol Toluene 4-(4-Chloro-phenyl)- piperidin-4-ol Acetone recovery Potassium Iodide Stage-7 Effluent water Potassium carbonate Activated Carbon Acetone

Hydrochloric acid Acetone Recovery Acetone Stage-8

LOPERAMIDE HCL

LOPERAMIDE HCL

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Material Balance:

Material balance of Loperamide HCl Stage-1 Batch Size: 200.0 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Di phenyl acetonitrile 114.00 Stage-1 142.00 1,2-Dichloro ethane 260.00 Dichloro ethane Recovery 190.00 TBAB 6.00 Dichloro ethane Loss 5.00 C.S.LYE 15.00 Toluene Recovery 285.00 Acetic acid 0.50 Toluene Loss 5.00 Toluene 300.00 Methanol recovery 190.00 Methanol 200.00 Methanol Loss 5.00 Water 500.00 Effluent water 526.50 (Water-500,Acetic acid- 0.5,C.S.lye-15, TBAB-6, Toluene-5) Process emission 21.50 (Hydrogen Chloride-21.50) Organic Residue 25.50 Process residue-9.5, Distillation residue-16 (Dichloro ethane - 6,Toluene-5,Methanol-5) Total 1395.50 Total 1395.50

Material balance of Material balance of Loperamide HCl Stage-2 Batch Size: 200.0 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 142.00 Stage-2 125.00 Acetic Acid 55.00 Effluent water 474.70 Sulfuric acid 55.00 (Water-290, Acetic acid- 55, soda ash solution-100, Ammonium chloride- 29.70) Soda ash (10%) 100.00 Isopropyl alcohol 143.00 Recovery Isopropyl alcohol 150.00 Isopropyl alcohol Loss 5.00 Water 300.00 Process Emission 44.44 (Sulphur dioxide-35.56, Oxygen-8.88) Organic Residue 9.86 Process residue-7.86 Distillation residue-2 (Isopropyl alcohol-2) Total 802.00 Total 802.00

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Material balance of Material balance of Loperamide HCl Stage-3 Batch Size: 200.0 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 125.00 Stage-3 160.00 HBr In Acetic acid (40%) 108.00 Toluene Recovery 238.00 Toluene 250.00 Toluene Loss 7.00 Water 300.00 Effluent water 369.80 (Water-300, Acetic acid- 64.8,Toluene-5) Organic Residue 8.20 Process residue-3.2, Distillation residue-5 (Toluene-5) Total 783.00 Total 783.00

Material Balance of Loperamide HCl Stage-4 Batch Size:200Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-3 160.00 Stage-4 160.00 Thionyl chloride 60.00 Toluene recovery 190.00 Toluene 200.00 Toluene loss 5.00 Process Emission 50.38 (Sulphur dioxide-32.11, Hydrogen Chloride-18.27 Organic residue 14.62 Process residue-9.62 Distillation residue-5 (Toluene-5) Total 420.00 Total 420.00

Material Balance of Loperamide HCl Stage-5 Batch Size:200Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-4 160.00 Stage-5 152.00 Sodium carbonate 40.00 Toluene Recovery 190.00 Dimethylamine 26.00 Toluene Loss 5.00 Toluene 200.00 Effluent Water 343.00 Water 300.00 (Water-300,Sodium Carbonate-40,Toluene-3) Process emission 17.27 (Hydrogen Chloride-17.27) Organic residue 18.73 Process residue-16.73 Distillation residue-2 (Toluene-2) Total 726.00 Total 726.00

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Material Balance of Loperamide HCl Stage-6 Batch Size:200Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 4-Chloro Phenyl Magnesium 106.00 Stage-6 94.00 Bromide 4-Oxo-Piperidine-1-Carboxylic 85.00 Methanol Recovery 285.00 acid ethyl ester Hydrobromic acid 40.00 Methanol Loss 10.00 Sodium Hydroxide 19.00 (Mixed solvent) 211.59 Toluene Recovery + Generated Ethanol Hydrochloric acid 18.00 Toluene Loss 5.00 Methanol 300.00 Effluent water 520.84 Toluene 200.00 (Water-400, Magnesium Bromide-90.45,Sodium Chloride-27.39,Toluene-3) Water 400.00 Process emission 20.62 (carbondioxide-20.62) Organic residue 20.95 Process residue-13.95 Distillation residue-7 (Methanol-5,Toluene-2) Total 1168.00 Total 1168.00

Material Balance of Loperamide HCl Stage-7: Batch Size:200Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-6 152.00 Stage-7 200.00 4-(4-Chloro-phenyl)- 94.00 Acetone recovery 190.00 piperidin-4-ol Potassium Iodide 20.00 Acetone loss 5.00 Potassium carbonate 40.00 Effluent Water 460.00 Activated Carbon 10.00 (Water-400,Potassium Iodide-20, Potassium Carbonate-40) Acetone 200.00 Spent carbon 10.00 Water 400.00 Process emission 35.52 (Hydrogen Bromide-35.52 Organic Residue 15.48 Process residue-10.48 Distillation residue-5 (Acetone-5) Total 916.00 Total 916.00

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Material Balance of Loperamide HCl Stage-8: Batch Size:200Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-7 200.00 Loperamide HCl 200.00 Hydrochloric acid 15.00 Acetone recovery 190.00 Acetone 200.00 Acetone loss 5.00 Organic residue 20.00 Process residue-15 Distillation residue-5 (Acetone-5) Total 415.00 Total 415.00

LOSARTAN POTASSIUM Process Description Stage-1 Orthototylbenzonitrile and Sodium nitrate reacts with Sodium azide and sodium nitrite in presence of Toluene and Hcl to give Stage-1 product. Stage-2 Stage-1 product reacts with trityl chloride in presence of MDC to give Stage-2 product. Stage-3 Stage-2 product undergoes bromination with N-Bromasuccinimiode in presence of MDC and Ethyl acetate to give stage-3 product.

Stage-4 Stage-3 product undergoes condensation eith Butyl Chloroformyl imidazole in presence of Sodium hydroxide and Methanol to give Stage-4 product..

Stage-5 Stage-4 product undergoes salt formation with POTASSIUM Hydroxide in presence of Methanol to give Losartan potassium.

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Route of Synthesis:

Stage-1

CH3 CH3

+ NaN NaNO 2 HCl N 3 + 2 + NH CN N N

Ortho tolylbenzonitrile Sodium Azide Sodium nitrite Hydrochloric Acid 5-(4'-Methyl-biphenyl -2-yl)-2H-tetrazole

C14H11N 65.0 69.0 2X36.46=72.92 C14H12N4 193.24 236.27

+ 2 NaCl + H2O + N2

2X58.44=116.89 18.0 28.0

Stage-2

CH3

CH3

N NH N + Cl N + HCl N N N N

5-(4'-Methyl-biphenyl trityl chloride -2-yl)-2H-tetrazole 5-(4'-Methyl-biphenyl-2-yl)-2-trityl 36.46 -2H-tetrazole

C14H12N4 C19H15Cl C33H26N4 236.27 278.78 478.59

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Stage-3

CH 3 CH2Br

Br

N N N N + O O N N N N N

5-(4'-Methyl-biphenyl-2-yl)-2-trityl N-Bromosuccinimide 5-(4'-Bromomethyl-biphenyl-2-yl)-2-trityl -2H-tetrazole -2H-tetrazole C33H26N4 C H BrNO 4 4 2 C33H25BrN4 478.59 177.98 557.48

H N O O +

Succinimide

C4H5NO2 99.09

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Stage-4

CH2Br

N HO N N + + NaOH N CH3 N Cl N H

5-(4'-Bromomethyl-biphenyl-2-yl)-2-trityl Butylchloroformyl imidazole Sodium hydroxide -2H-tetrazole 40.0 C H BrN 33 25 4 C8H13ClN2O 557.48 188.65

HO N N

HN N Cl N + OH + NaBr N

Losartan Base trityl alcohol Sodium bromide

C22H23ClN6O C19H16O 102.89 422.91 260.33

Stage-5

HO N N HO N N HN N N KN N Cl N + KOH Cl N + H O N 2

Losartan Base Potassium hydroxide Losartan Potassium 18.0

C22H23ClN6O 56.11 C22H22ClKN6O 422.91 461.00

Flow Chart:

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Ortho tolylbenzonitrile Sodium Azide Toluene Recovery Hydrochloric acid Stage-1 Effluent water Sodium nitrite Toluene

Stage-1 Trityl chloride MDC Recovery TEA Stage-2 Methanol Recovery MDC Effluent water Methanol

Stage-2 N-Bromosuccinimide (NBS) Methylene dichlorie Recovery Sodium meta bisulphate Stage-3 Ethyl acetate Recovery Methylenedichloride Effluent water Ethyl Acetate

Stage-3 Butyl chloro formyl imidazole Methanol Recovery TBAB Stage-4 Methanol Effluent water Sodium hydroxide

Stage-4 Potassium hydroxide Methanol Recovery Methanol Stage-5 Effluent water Activated Carbon

LOSARTAN POTASSIUM LOSARTAN POTASSIUM

Material Balance:

Material Balance Of Losartan Potassium Stage-1 Batch Size:100kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Ortho tolylbenzonitrile 62.00 Stage-1 70.00 Sodium Azide 20.85 Toluene Recovery 380.00 Hydrochloric acid 23.50 Toluene Loss 8.00 Sodium nitrite 22.15 Effluent water 645.21 Toluene 400.00 (Water-600, 0 Generated water-5.76, Sodium chloride-37.45,

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Toluene-2) Water 600.00 Process Emission 8.92 (Nitrogen-8.92) 0 Organic Residue 16.37 Process residue-6.37 Distillation Residue-10 (Toluene-10) Total 1128.50 Total 1128.50

Material Balance Of Losartan Potassium Stage-2 Batch Size:100kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 70.00 Stage-2 130.00 Trityl chloride 82.50 MDC Recovery 475.00 TEA 30.00 MDC Loss 10.00 MDC 500.00 Methanol Recovery 475.00 Methanol 500.00 Methanol Loss 10.00 Water 500.00 Effluent Water 530.00 (Water-500,TEA-30) 0 Process emission 10.78 (Hydrogen chloride-10.78) 0 Organic Residue 41.72 Process residue-11.72 Distillation Residue-30 (Methanol-15,MDC-15) Total 1682.50 Total 1682.50

Material Balance Of Losartan Potassium Stage-3 Batch Size:100kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 130.00 Stage-3 140.00 N-Bromosuccinimide (NBS) 48.25 Methylenedichloride 380.00 Recovery Sodium meta bisulphate 10.00 Methylenedichloride Loss 8.00 Methylenedichloride 400.00 Ethyl Acetate Recovery 190.00 Ethyl Acetate 200.00 Ethyl Acetate Loss 4.00 Water 600.00 Effluent Water 613.00 (Water-600, 0 Sodium meta bisulphate-10, Ethyl acetate-3,) Organic Residue 53.25

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Process residue-38.25 (Organic impurities-11.34 succinimide-26.91) Distillation Residue-15 (Ethyl acetate-3,MDC-12) Total 1388.25 Total 1388.25

Material Balance Of Losartan Potassium Stage-4 Batch Size:100kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-3 140.00 Stage-4 99.00 Butyl chloro formyl imidazole 47.35 Methanol Recovery 760.00 (BCFI) TBAB 5.00 Methanol Loss 20.00 Methanol 800.00 Effluent Water 730.76 Sodium hydroxide 9.95 (Water-700, 0 Sodium bromide-25.76, TBAB-5) Water 700.00 By-Product 65.24 (trityl alcohol-65.24) 0 Organic Residue 7.30 Process residue- 7.30 Distillation Residue-20 (Methanol-20) Total 1702.3 Total 1695

Material Balance Of Losartan Potassium Stage-5: Batch Size:100kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-4 99.00 Losartan Potassium 100.00 Potassium hydroxide 13.05 Methanol Recovery 380.00 Methanol 400.00 Methanol Loss 10.00 Activated Carbon 15.00 Effluent Water 406.15 Water 400.00 (Water-400, 0 Generated water-4.15) Spent Carbon 15.00 Organic Residue 15.90 Process residue-5.90 Distillation residue-10 (Methanol-10) Total 927.05 Total 927.05

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NEBIVOLOL HYDROCHLORIDE Process Description: Stage-1: (R)-2-(benzyl amino)-1-(6-fluro-3, 4-dihydro-2H-chromen-2-yl) ethanol react with 6- Fluro-3, 4-dihydro-2-(oxiran-2- yl)-2H chromene in presence of diisopropylethylamine, Methanol,HCl to form NBL/Stage-1. Stage-2: NBL/Stage-I reacts with Pd/C in presence of methanol and treated with IPA HCL to form Nebivolol hydrochloride Pharma (Stage-2).

Route of synthesis Stage-1

NH O O O OH HCl Methanol F + F HCl 6-fluoro-3,4-dihydro-2-((R)- 36.5 R ( )-2-(benzylamino)-1-(6-fluoro-3,4- oxiran-2-yl)-2H-chromene dihydro-2H-chromen-2-yl)ethanol C H FO C H FNO 11 11 2 18 20 2 194.2 301.36 OH N O O OH F HCl F 2-{Benzyl-[2-(6-fluoro-chroman- 2-yl)-2-hydroxy-ethyl]-amino}- 1-(6-fluoro-chroman-2-yl)- ethanol Hydrochloride

C29H32ClF2NO4 532.02 Stage-2

OH HCl H OH N O N O O O OH F Pd/C, MeoH OH F HCl F + H2 IPA HCl F 2-{Benzyl-[2-(6-fluoro-chroman- 2.00 Nebivolol Hydrochloride 2-yl)-2-hydroxy-ethyl]-amino}- C H F NO HCL 1-(6-fluoro-chroman-2-yl)- 22 25 2 4 ethanol Hydrochloride 442.03

C29H32ClF2NO4 CH3 532.02

Toluene

C7H8 92.14

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Flow Chart (R)-2-(benzyl amino)-1-(6-fluro-3,4- dihydro-2H-chromen-2-yl) ethanol 6-Fluro-3,4-dihydro-2-(oxiran-2- yl)- Stage-1 Methanol Rec 2Hchromene Diiso propyl ether Methanol

Stage-1 Stage-2 Methanol Methanol Rec Pd/carbon

NEBIVOLOL HYDROCHLORIDE

Material Balance

Material Balance of Nebivolol Hydrochloride Stage-1 BatchSize:200.0Kg Name of the input Quantity in Name of the out put Quantity in Kg Kg (R)-2-(benzyl amino)-1-(6-fluro-3,4- 169.00 Stage-1 268.00 dihydro-2H-chromen-2-yl) ethanol 6-Fluro-3,4-dihydro-2-(oxiran-2- Methanol Recovery yl)-2Hchromene 108.85 550.00 Diiso propyl ether 400.00 Methanol Loss 30.00 Methanol 600.00 Diiso propyl ether 380.00 Recovery Hydrochloric acid 20.45 Diiso propyl ether Loss 20.00 Organic Residue 50.30 Process residue -30.3, Distillation residue -20 Methanol-20) Total 1298.30 Total 1298.30

Material Balance of Nebivolol Hydrochloride Stage-2 BatchSize:200.0Kg Name of the input Quantity in Name of the out put Quantity in Kg Kg Stage-1 Nebivolol Hydrochloride 200.00 268.00

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Methanol 800.00 Mixed solvent 806.36 (Methanol Recovery + Toluene Recovery) Pd/carbon 2.00 Methanol Loss 20.00 Hydrogen 0.80 Pd/carbon 2.00 IPA HCl 80.00 IPA Recovery 50.00 IPA Loss 30.00 Organic residue 42.44 Process residue -22.44 Distillation residue-20 (Methanol-20) Total 1150.80 Total 1150.80

NORTRIPTYLINE HYDROCHLORIDE

Process Description:

Stage-1:

[3-(10,11-Dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-dimethyl-amine Hydrochloride reacts with ethyl chloro formate in presence of Sodium Hydroxide and toluene to give Stage-1 product.

Stage-2:

Stage-1 Product undergoes Hydrolysis with Potassium Hydroxide in presence of Isopropyl alcohol an Hydrochloric acid to give Stage-2 product.

Stage-3:

Stage-2 product undergoes Salt formation in presence of IPA.HCl and Acetone to give Nortriptyline Hydrochloride.

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Route of Synthesis Satge-1:

CH N 3 O CH3 . HCl Sodium Sulphate, Toluene , + + O Cl NaOH DM water [3-(10,11-Dihydro-dibenzo[a,d] Ethyl chloroformate 40.00 cyclohepten-5-ylidene) C3H5Cl -propyl]-dimethyl-amine O2 hydrochloride 108.52 C H ClN 20 24 O 313.86 N O CH3 CH3 + NaCl + HCl + CH3OH [3-(10,11-Dihydro-dibenzo[a,d]cyclohepten- 58.44 36.46 32.04 5-ylidene)-propyl]-methyl-carbamic acid ethyl ester C22H25NO2 335.44 Stage-2

O

N O CH3 CH3 Chloroform + KOH + HCl + H2O Isopropylalcohol [3-(10,11-Dihydro-dibenzo[a,d]cyclohepten- 56.11 36.46 18.02 5-ylidene)-propyl]-methyl-carbamic acid ethyl ester C22H25NO2 335.44

CH3 N H O O + H3C + KCl + CH3OH + 0.5 O2 [3-(10,11-Dihydro-dibenzo[a,d] Methyl formate 74.55 32.04 16.00 cyclohepten-5-ylidene)-propyl]- C2H4O2 methyl-amine 60.05 C19H21N 263.38

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Stage-3

CH 3 CH3 N Acetone, N H Activated carbon H + HCl . HCl

[3-(10,11-Dihydro-dibenzo[a,d] 36.46 cyclohepten-5-ylidene)-propyl]- methyl-amine Nortriptyline HCl C19H21N C19H22ClN 263.38 299.84

Flowchart: [3-(10,11-Dihydro-dibenzo[a,d]cyclohep ten-5-ylidene)-propyl]-dimethy l-amine Hydrochloride Stage-1 Toluene Recovery Ethyl chloroformate Effluent water Sodium hydroxide Sodium sulphate Toluene

Stage-1 Potassium Hydroxide Stage-2 IPA Recovery Hydrochloric acid Effluent water Chloroform IPA

Stage-2 Hydrochloric Acid Acetone Recovery Acetone Stage-3 Activated carbon Effluent water

NORTRIPTYLINE HYDROCHLORIDE

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Material Balance:

Material Balance of Nortriptyline Hydrochloride Stage-1 Batch Size: 200.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg [3-(10,11-Dihydro- Stage-1 245.00 dibenzo[a,d]cyclohepten-5- 240.00 ylidene)-propyl]-dimethyl-amine Hydrochloride Ethyl chloroformate 83.00 Toluene Recovery 385.00 Sodium hydroxide 31.00 Toluene Loss 10.00 Sodium sulphate 20.00 Effluent water 472.50 Toluene 400.00 (water-400,Sodium chloride- 0 45,Methanol-24.5,Toluene-3) Water 400.00 Inorganic solid waste 20.00 (Sodium sulphate-20) 0 Process emission 28.00 (Hydrogen Chloride-28) 0 Organic residue 13.50 Process residue -11.5 Distillation residue-2 (Toluene-2) Total 1174.00 Total 1174.00

Material Balance of Nortriptyline Hydrochloride Stage-2 Batch Size: 200.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 245.00 Stage-2 183.00 Potassium Hydroxide 41.00 Chloroform Recovery 385.00 Hydrochloric acid 27.00 Chloroform Loss 15.00 Chloroform 400.00 IPA Recovery 385.00 IPA 400.00 IPA Loss 10.00 Water 400.00 Effluent water 507.85 (water-386,Potassium chloride- 0 54.45,Methyl formate- 44,Methanol-23.40) Process emission 12.00 (Oxygen-12) 0 Organic residue 15.15 Process residue -10.15 Distillation residue-5 (IPA-5) Total 1513.00 Total 1513.00

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Material Balance of Nortriptyline Hydrochloride Stage-3 Batch Size: 200.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 183.00 Nortriptyline Hydrochloride 200.00 Hydrochloric Acid 26.00 Acetone Recovery 190.00 Acetone 200.00 Acetone Loss 5.00 Activated carbon 5.00 Effluent water 300.00 Water 300.00 (water-300) Spent carbon recovery 5.00 Organic residue 14.00 Process residue -9 Distillation residue-5 (Acetone-5) Total 714.00 Total 714.00

N-TERT-BUTOXYCARBONYL-4-HYDROXY PIPERIDINE

Process Description:

Stage-1:

N-Carbethoxy-4-Piperidone reacts with Di-tert butyl dicarbonate in presence of water Toluene to give N-Tert-Butoxycarbonyl-4-Hydroxy Piperidine.

Route of Synthesis:

Stage-1

O O O CH3 H3C O N H3C CH3 O + O O O Water H3C CH3 + 2 H2O N-Carbethoxy-4-piperidone Di-tert butyl dicarbonate 36.03 C H NO 8 13 3 C10H18O5 171.19 218.25 CH3

O CH3 O O H C HO N 3 CH CH3 3 O + HO O O + C2H5OH + 0.5 O2 CH3 N-tert butoxy carbonyl-4- Tert butyl pyrocarbonate Ethanol 16.00 hydroxy piperidine C H O 46.07 C H NO 6 10 5 10 19 3 162.14 201.26

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Flowchart:

N-Carbethoxy-4-amino piperidine Stage-1 Toluene Recovery di-tert butyl dicarbonate Effluent water Toluene

N-TERT-BUTOXYCARBONYL-4-HYDROXY PIPERIDINE

Material Balance:

Material Balance of N-Tert-Butoxycarbonyl-4-Hydroxy Piperidine. Stage-1 Batch Size: 100.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg N-Tert-Butoxycarbonyl-4-Hydroxy 100.00 N-Carbethoxy-4-amino piperidine 90.00 Piperidine. di-tert butyl dicarbonate 114.66 Toluene Recovery 385.00 Toluene 400.00 Toluene Loss 10.00 Water 400.00 Effluent water 493.53 (Water-381.10, Ethanol- 0 24.20,Toluene-3, Tert butyl pyrocarbonate-85.23) Process emission 8.37 (Oxygen-8.37) 0 Organic residue 7.76 Process residue – 5.76 Distillation residue-2 (Toluene-2) Total 1004.66 Total 1004.66

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OMEPRAZOLE MAGNESIUM DIHYDRATE Process Description: Stage-1: Omeprazole reacts with Ammonium hydroxide and Magnesium sulfates to give Omeprazole Magnesium dihydrate.

Route of Synthesis: Stage-1: OCH3

H3C CH3 O N OCH3 2 + MgSO S + NH4OH 4 N N H

Omeprazole Ammonium hydroxide Magnesium sulphate C17H19N3O3S 35.04 120.36 2X345.41=690.82

OCH3

H3C CH3 O N OCH3 Mg+2 2H O + (NH4)2SO4 S 2 N -N 2

Omeprazole Magnesium Dihydrate Ammonium sulfate +2 132.13 C17H18N3O3S.Mg .2H2O 749.12

Flowchart:

Omeprazole Ammonium hydroxide (20%) Stage-1 Effluent water Magnesium sulfate Activated carbon

OMEPRAZOLE MAGNESIUM DIHYDRATE

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Material Balance: Material Balance Of Omeprazole Magnesium Dihydrate Stage-1 Batch Size: 100.0Kgs Name of the input Quantity Name of the out put Quantity in Kg in Kg Omeprazole 103.00 Omeprazole Magnesium 100.00 Dihydrate Ammonium hydroxide (20%) 25.75 Effluent water 540.27 Magnesium sulfate 17.90 (Water-500,Water from ammonium hydroxide-20.60, Ammonium sulfate-19.67) Activated carbon 5.00 Spent carbon 5.00 Water 500.00 Organic Residue 6.38 (Process residue-6.38) Total 651.65 Total 651.65

OMEPRAZOLE SODIUM

Process Description

5-Methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethanesulfinyl)-1H- benzoimidazole (Omeprazole) Product reacts with sodium hydroxide in the presence of Methanol to give Omeprazole sodium.

OMEPRAZOLE SODIUM Stage-1: O H N S N Methanol + NaOH O N O 5-Methoxy-2-(4-methoxy-3,5- 40.00 dimethyl-pyridin-2-ylmethanesulfinyl)- 1H-benzoimidazole OCH3 H C CH (Omeprazole) 3 3 O N OCH3 C17H19N3O3S S H2O N N 345.42 Na Omeprazole Sodium

C17H19N3NaO3S.H2O 385.41

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Flow Chart: 5-Methoxy-2-(4-methoxy-3,5-dimethyl- pyridin-2-ylmethanesulfinyl)-1H- benzoimidazole (Omeprazole) Sodium hydroxide Stage-1 Methanol Recovery Methanol

OMEPRAZOLE SODIUM

OMEPRAZOLE SODIUM

Material Balance:

Material Balance of Omeprazole Sodium Stage-1 Batch Size: 500.00Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 5-Methoxy-2-(4-methoxy-3,5- 462.00 Omeprazole Sodium 500.00 dimethyl-pyridin-2- ylmethanesulfinyl)-1H- benzoimidazole (Omeprazole) Sodium hydroxide 54.00 Methanol Recovery 380.00 Methanol 400.00 Methanol Loss 10.00 Organic Residue 26.00 Process residue-16 Distillation residue-10 (Methanol-10) Total 916.00 Total 916.00

OMEPRAZOLE

Process description:

Stage-1

3,5-Dimethyl-pyridine undergoes Oxidation with Hydrogen peroxide in presence of Acetic acid to give Stage-1 product

Stage-2

Stage-1 product undergoes Nitration with Nitric acid in presence of Sulphuric acid & Methanol to give Stage-2 product

Stage-3

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Stage-2 product reacts with Dimethylsulphate in presence of Chloroform & Methanol to give Stage-3 product

Stage-4

Stage-3 product reacts with Ammonium persulphate and Ammonium sulphate in presence of Toluene & Methanol to give Stage-4 product

Stage-5

Stage-4 product undergoes Chlorination with Thionyl chloride in presence of Toluene , IPA & Acetone to give Stage-5 product

Stage-6

Stage-5 product undergoes Condensation with 2-Mercapto-5-methoxy benzimidazole in presence of Toluene, Sodium hydroxide & Water to give Stage-6 product

Stage-7

Stage-6 product undergoes Oxidation with Hydrogen peroxide in presence of Acetic acid & Dichloromethane to give Omeprazole product

Route of Synthesis:

Stage-1

N+ N Acetic acid + H2O2 O- + H2O 3,5-Dimethyl- 34.01 3,5-Dimethyl-pyridine 18.02 pyridine 1-oxide

C7H9N C7H9NO 123.15 107.15

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Stage-2

N+ Methanol O- + 2 NH3 + H2SO4 + HNO3 3,5-Dimethyl-pyridine 34.06 98.08 63.01 1-oxide

C7H9NO

123.15 NO2

+ NH4 O N+ -O S O- O- + + O NH4 + H2O 3,5-Dimethyl-4-nitro- Ammonium sulphate 18.02 pyridine 1-oxide (NH4)2SO4 C H N O 7 8 2 3 132.14 168.15 Stage-3

NO2

O + O N S - O O + O + 2 NaOH+ CH3COOH + CH3OH 3,5-Dimethyl-4-nitro- Dimethylsulphate pyridine 1-oxide 80.00 60.05 C2H6O4S 32.04 C7H8N2O3 126.13 168.15 OMe Methanol, Chloroform

+ N - CH3SO4 O + CH3COONa + NaNO2 + 2 H2O Methyl sulphate salt formation of 82.03 69.00 36.03 1,4-Dimethoxy-3,5- dimethyl-pyridinium

C10H17NO6S

279.31

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Stage-4 OMe + NH4- O O S O O O N+ O CH SO - S 3 4 + O O- NH + O 4 + 2 NH4OH + H2O2 1,4-Dimethoxy-3,5- Ammonium perSulphate, 35.04X2=70.08 34.02 dimethyl-pyridinium H8N2O8S2 methyl sulphate 228.20 C10H17NO6S 279.31 Ammonium Sulphate, Toluene & mehanol OMe + O NH4 -O S O- OH + + 2 O NH4 + SO + 1.5 O N + CH3OH + 2 H2O 2 2 (4-Methoxy-3,5-dimethyl- Ammonium Sulphate, 32.02 36.03 64.06 48 pyridin-2-yl)-methanol H8N2O4S C9H13NO2 132.14X2=264.28 167.21

Stage-5

O

Isopropyl alcohol Toluene ,ice , Acetone , OH + SOCl Sodium sulphate N 2 Activated carbon & Hyflow 2-Hydroxy methyl-3,5- 118.97 dimethyl-4- O methoxypyridine . C9H13NO2 HCl 167.21 Cl + SO N 2 2-Chloromethyl-4-methoxy-3, 64.06 5-dimethyl-pyridine Hydrochloride

C9H13Cl2NO 222.11

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Stage-6

O H N . HCl HS Cl Toluene & Water N + N O + 2 NaOH

2-Chloromethyl-4-methoxy-3 2-Mercapto-5-methoxy 80.00 ,5-dimethyl pyridine benzimidazole Hydrochloride C8H8N2OS C H Cl NO 9 13 2 180.23 222.11 N O N CH3 S N H C H 3 OCH3 + 2 NaCl + 2 H2O

5-Methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-yl 116.89 36.04 methylthio)-1H-benzo[d]imidazole

C17H19N3O2S 329.42 Stage-7 N O N CH3 S EDTA, CS Flakes , Acetic acid , Hydrose , N H C Activated carbon, Dichloromethane H 3 OCH3 + HO OH

5-Methoxy-2-(4-methoxy-3,5-dimethyl 34.01 -pyridin-2-ylmethylthio)-1H- benzo[d]imidazole

C17H19N3O2S 329.42 O

H + H2O N S N O N O 18.01

Omeprazole

C17H19N3O3S 345.42

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Flow chart:

3,5- Lutidine Hydrogen peroxide Water from hydrogen peroxide+ Acetic acid Stage-1 Acetic acid Sodium tungstate Sodium tungstate Recovery Stage-1 Sulphuric acid Nitric acid (72%) Ammonia gas Stage-2 Methanol Effluent Water Water Stage-2 Dimethylsulphate Sodium hydroxid flakes Chloroform Recovery Methanol Stage-3 Methanol recovery Acetic acid Effluent Water Chloroform Water Stage-3 Ammonium persulphate Toluene Recovery Ammonium sulphate Stage-4 Methanol recovery Hydrogen peroxide Effluent Water Methanol Toluene Ammonium hydroxide Hyflow Carbon Water Stage-4 Thionyl chloride Isopropylalcohol Iso propyl alcohol recovery Acetone recovery Toluene Stage-5 Acetone Effluent Water Sodium sulphate Hyflow Carbon Hydrochloric acid Liq Ammonia (15 %) Ice Stage-5 2-Mercapto-5-methoxy benzimidazole Toluene Recovery Stage-6 Caustic lye Effluent Water Toluene Water

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Stage-6 Hydrogen peroxide Sodium Hydroxide flakes Ammonia Acetic acid Dichloromethane Hydrose Activated carbon Dichloromethane Recovery Stage-7 EDTA Effluent Water Triethylamine Water

Omeprazole

OMEPRAZOLE

Material Balance

Material Balance of Omeprazole Stage-1 Batch Size: 920Kg Name of the input Quantity Name of the output Quantity in Kg in Kg 3,5- Lutidine 765.00 Stage-1 878.00 Hydrogen peroxide 691.00 Water from hydrogen 723.00 peroxide+ Acetic acid Acetic acid 145.00 Sodium tungstate 5.00 Recovery Sodium tungstate 5.00 Total 1606 Total 1606

Material Balance of Omeprazole Stage-2 Batch Size: 920Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-1 878.00 Stage-2 915.00 Sulphuric acid 3059.00 Effluent Water 1339.00 Nitric acid (72%) 1535.00 (Water-730.5Generated 0 water-128.5, Water from Nitric acid-430, Methanol- 50) Ammonia gas 1275.00 By product 942.00 (Ammonium sulphate) Methanol 50.00 Water Recovery 21000.00 Water 18000.00 Water evaporation loss 600.00 Total 24796 Total 24796

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Material Balance of Omeprazole Stage-3 Batch Size: 920Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-2 915.00 Stage-3 2385.00 Dimethylsulphate 637.00 Chloroform Recovery 21000.00 Sodium hydroxid flakes 266.00 Chloroform loss 1000.00 Methanol 7000.00 Methanol recovery 6485.00 Acetic acid 80.00 Methanol loss 341.00 Chloroform 22000.00 Effluent Water 264.00 Water 4200.00 (Water-68, Generated 0 water-196) Water recovery 2800.00 By product 823.00 (Sodium nitrite-376, Sodium acetate-447 )) Total 35098 Total 35098

Material Balance of Omeprazole Stage-4 Batch Size: 920Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-3 2385.00 Stage-4 742.00 Ammonium persulphate 160.00 Toluene Recovery 1763.00 Ammonium sulphate 1193.00 Toluene loss 37.00 Hydrogen peroxide 581.00 Methanol recovery 6798.00 Methanol 7155.00 Methanol loss 143.00 Toluene 1855.00 Effluent Water 1543.84 Ammonium hydroxide 614.00 ( Generated water-307.65, 0 Methanol-273.41,Toluene- 55, Water from hydrogen peroxide-907.78) Hyflow 2.00 Water recovery 11500.00 Carbon 25.00 Evaporation loss 867.00 Water 12000.00 Spent Carbon & hyflow 27.00 By products 1378.30 (Ammonium sulphate) Process emissions 956.86 (sulphur dioxide-547, Oxygen-409.86) Organic Residue 214.00 Distillation Residue-214 (Methanol-214) Total 25970 Total 25970

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Material Balance of Omeprazole Stage-5 Batch Size: 920Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-4 742.00 Stage-5 715.00 Thionyl chloride 742.00 Toluene Loss 200.00 Isopropylalcohol 265.00 Iso propyl alcohol 265.00 recovery Toluene 200.00 Acetone recovery 250.00 Acetone 250.00 Effluent Water 589.80 Sodium sulphate 50.00 (Ice-196.6, 0 Water from Ammonia- 190, Water from Hydrochloric acid-203.2) Hyflow 3.00 Water recovery 3700.00 Carbon 15.00 Spent Carbon & hyflow 18.00 Hydrochloric acid 1975.00 Inorganic solid waste 50.00 (Sodium sulphate) Liq Ammonia (15 %) 1325.00 Process emissions 779.20 (sulphur dioxide-284.30, Hydrogen chloride-494.9) Ice 1000.00 Total 6567 Total 6567

Material Balance of Omeprazole Stage-6 Batch Size: 920Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-5 715.00 Stage-6 1000.00 2-Mercapto-5-methoxy 615.00 Toluene Recovery 3800.00 benzimidazole Caustic lye 630.00 Toluene Loss 80.00 Toluene 4000.00 Effluent Water 1431.00 Water 5000.00 (Water-500, 0 Generated water-116 Sodium chloride-377, Toluene-60, Water form Caustic lye-378) Water recovery 4589.00 Organic Residue 60.00 Distillation Residue-60 (Toluene ) Total 10960 Total 10960

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Material Balance of Omeprazole Stage-7 Batch Size: 920Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-6 1000.00 Omeprazole 920.00 Hydrogen peroxide 230.00 Dichloromethane 2375.00 Recovery Sodium Hydroxide flakes 150.00 Dichloromethane Loss 50.00 Ammonia 4.00 Effluent Water 831.00 Acetic acid 250.00 (Water-200, 0 Generated water-55 Sodium hydroxide flakes- 150,Ammonia-4, Acetic acid -250, Hydrose-10, Triethylamine-30, EDTA- 5, Water from hydrogen peroxide-127) Dichloromethane 2500.00 Water recovery 5900.00 Hydrose 10.00 Spent carbon 5.00 Activated carbon 5.00 Organic Residue 103.00 EDTA 5.00 Process residue-28 Distillation Residue-75 (Dichloromethane ) Triethylamine 30.00 Water 6000.00 Total 10184 Total 10184

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OXATOMIDE

Description: Stage-1: 1- (diphenyl methyl) piperazine reacts with 1-(3-chloropropyl)1,3-dihydro-2H- benzimidazol-2-one, in presence of Methyl Iso butyl ketone ,Soda ash, Water, sodium hydroxide, Con HCl, to give Staeg-1 product. Stage-2:

Stage-1 Product undergoes purification with Methanol and Carbon to give Oxatomide.

Route of Synthesis

Stage-1:

H N O N + N + 1/2 Na2CO3 MIBK/Sodium hydroxide

N Cl HCl H 1- (diphenyl methyl) piperazine 1-(3-Chloro-propyl)-1,3-dihydro- 53.0 benzoimidazol-2-one C17H20N2 C10H11ClN2O 252.35 210.66

N N N O N H

1-[3-(4-Benzhydryl-piperazin-1-yl)-propyl] + NaCl + 1/2 CO2 + 1/2 H2O -1,3-dihydro-benzoimidazol-2-one 58.44 22.0 9.0 C27H30N4O 426.55

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Stage-2:

N N N N N N Methanol O N H O N H

1-[3-(4-Benzhydryl-piperazin-1-yl)-propyl] 1-[3-(4-Benzhydryl-piperazin-1-yl)-propyl] -1,3-dihydro-benzoimidazol-2-one -1,3-dihydro-benzoimidazol-2-one

C H N O C27H30N4O 27 30 4 426.55 426.55

Flow Chart

1-(diphenyl methyl) piperazine 1-(3-chloropropyl)1,3-dihydro- 2H-benzimidazol-2-one Stage-1 MIBK Recovery Sodium carbonate Effluent water Dil. Hydrochloride MIBK

Stage-1 Stage-2 Methanol Recovery Activated Carbon Spent carbon Methanol

OXTOMIDE

Material Balance

Material Balance of Oxtomide Stage-1 BatchSize:100 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 1-(diphenyl methyl) piperazine 65.00 Stage-1 105.00 1-(3-chloropropyl)1,3-dihydro-2H- 54.25 MIBK Recovery 283.00 benzimidazol-2-one Sodium carbonate 13.65 MIBK Loss 15.00 Dil. Hydrochloride 10.00 Effluent Water 627.32 MIBK 300.00 (Water-600,Generated wtaer- 0 2.28, Sodium chloride-15.04, Water from HCl-10 Water 600.00 Process Emission 5.65 (Carbon dioxide-5.65) 0

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Organic Residue 6.93 (Process residue -4.93, Distillation residue -2 (MIBK-2) Total 1042.90 Total 1042.90

Material Balance of Oxtomide Stage-2 BatchSize:100 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 105.00 Oxtomide 100.00 Activated Carbon 10.00 Methanol Recovery 475.00 Methanol 500.00 Methanol Loss 10.00 Spent Carbon 10.00 Organic Residue 20.00 Process residue-5 Distillation residue-15 (Methanol-15) Total 615.00 Total 615.00

PANTOPRAZOLE SODIUM SESQUIHYDRATE Process description: Stage-1 Maltol reacts with Dimethylsulphate and Sodium hydroxide in presence of Water and Chloroform to give Stage-1 product

Stage-2 Stage-1 product reacts with Ammonium hydroxide in presence of Water to give Stage-2 product

Stage-3 Stage-2 product reacts with Phosphorous oxychloride in presence of Ammonium hydroxide & Water to give Stage-3 product

Stage-4 Stage-3 product reacts with Hydrogen peroxide in presence of Acetic acid, Chloroform & Ammonium hydroxide to give Stage-4 product

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Stage-5 Stage-4 product reacts with Sodium hydroxide, Methanol & Acetic anhydride in presence of Methanol, Toluene & Chloroform to give Stage-5 product

Stage-6 Stage-5 product reacts with Sodium hydroxide in presence of Water & Chloroform to give Stage-6 product

Stage-7 Stage-6 product undergoes Chlorination with Thionyl chloride in presence of Methanol & Acetone to give Stage-7 product

Stage-8 Stage-7 product reacts with 5-Difluoromethoxy-2-mercapto-1H-benzimidazole in presence of Water , Sodium hydroxide & Dichloromethane to give Stage-8 product

Stage-9 Step-A Stage-8 product reacts with Sodium oxy chloride in presence of Acetone & Ethyl acetate to give Step-A product

Step-B Step-A product reacts with Sodium hydroxide in presence of Acetone & Ethyl acetate to give Step-B product

Step-C Step-B product reacts with Water in presence of Acetone & Ethyl acetate to give Pantoprazole Sodium Sesquihydrate product

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Route of Synthesis:

Stage-1 O OH

O CH3 + (CH3)2SO4 + 2 NaOH + HCl Chloroform & water Maltol Dimethyl sulphate 80.00 36.46 C6H6O3 126.13 126.11 O

OCH 3 Na+ -O O S O O CH3 + O + NaCl + 2 H2O 3-Methoxy-2-methyl Sodium methyl 58.44 36.03 -pyran-4-one sulphate C7H8O3 CH3NaSO4 140.14 134.09

Stage-2:

O O

OCH3 OCH3

O CH3 + NH4OH N CH3 H + 2 H2O 3-Methoxy-2-methyl 35.05 3-Methoxy-2-methyl 36.03 -pyran-4-one -1H-pyridin-4-one

C7H8O3 C7H9NO2 140.14 139.15

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Stage-3 O Cl OCH 3 OCH Water 3 + POCl3 + 4NH4OH N CH3 H N CH3 Phosphorous 3-Methoxy-2-methyl- 4-Chloro-3-methoxy oxychloride 4X35.04=140.16 1H-pyridin-4-one -2-methyl-pyridine C7H9NO2 153.33 C7H8ClNO 139.15 157.60

NH Cl + HCl + 2H2O + (NH4)3PO4 + 4 Ammonium Ammonium 36.46 2X18.01=36.02 phosphate chloride 149 53.49

Stage-4: Cl Chloroform , OCH3 Sodium tungstate & Methnol + H O + 2 2 NH4OH + CH3COOH N CH3 4-Chloro-3-methoxy-2-methyl- Hydrogen peroxide 35.05 60.05 pyridine 34.01 C7H8ClNO Cl 157.60

OCH3

+ NH4 + - N CH3 O

- O O + + 2 H2O 3-methoxy-2-methyl-4- Ammonium acetate chloro pyridine-N-oxide 36.03 C2H7NO2 C7H8ClNO 173.60 77.08

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Stage-5:

Cl

OCH3

+ N CH3 O O methanol , Chloroform , - + O Toluene & Acetic acid O + NaOH + CH3OH Aceticanhydride 3-methoxy-2-methyl-4- 40.00 32.04 chloro pyridine-N-oxide C4H6O3 C H ClNO 7 8 2 102.09 173.60

OCH3

OCH3

N CH2

O O

+ CH3COOH + NaCl + H2O CH3 Acetic acid 3,4-dimethoxy-2- 58.44 18.02 methylene-2H-pyridin-1-yl ester 60.05

C10H13NO4 211.21

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STAGE-6

OCH3

OCH3

N CH2

O O Activated carbon , Chloroform , Sodium sulphate & Water CH3 + NaOH Acetic acid 3,4-dimethoxy-2- 40.00 methylene-2H-pyridin-1-yl ester OCH C10H13NO4 3 211.21 OCH3

OH CH COONa N + 3

(3,4-Dimethoxy-pyridin-2-yl)-methanol 82.03

C8H11NO3 169.18

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Stage-7:

OCH3

OCH3

OH Methanol & Acetone N + SOCl2

(3,4-Dimethoxy-pyridin-2-yl)-methanol 118.97

OCH3 C8H11NO3

169.18 OCH3

Cl . HCl N + SO2

2-Chloromethyl-3,4-dimethoxy- 64.06 pyridine; Hydrochloride

C8H11Cl2NO2

224.08

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Stage-8:

H N OCH3 SH OCH3 O N

Cl . HCl F F N + + 2 NaOH 2-Chloromethyl-3,4-dimethoxy- 5-Difluoromethoxy-2- pyridine; Hydrochloride mercapto-1H-benzimidazole 80.00

C8H11Cl2NO2 C8H6F2N2OS

224.08 216.21

Dichloromethane & water

OCH3

OCH3 H N

N CH2 S F N O + 2 NaCl + 2 H2O F 5-Difluoromethoxy-2-(3,4-dimethoxy-pyridin- 116.89 36.03 2-ylmethylsulfanyl)-1H-benzoimidazole

C16H15F2N3O3S

367.37

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Stage-9:

Step-A OCH3

OCH3 H N

N CH2 S F N O F + NaOCl 5-Difluoromethoxy-2-(3,4-dimethoxy-pyridin- 2-ylmethylsulfanyl)-1H-benzoimidazole 74.44

C16H15F2N3O3S

367.37 Hypo , Acetone & Ethyl acetate

OCH3 OCH 3 O H N

N CH2 S F N O F + NaCl 5-Difluoromethoxy-2-(3,4-dimethoxy-pyridin- 2-ylmethanesulfinyl)-1H-benzoimidazole 58.44

C16H15F2N3O4S 383.37

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Step-B

OCH3 OCH 3 O H N N CH S 2 F Hypo , N O Acetone & Ethyl acetate F + NaOH 5-Difluoromethoxy-2-(3,4-dimethoxy-pyridin- 2-ylmethanesulfinyl)-1H-benzoimidazole 40.00

C16H15F2N3O4S 383.37

OCH3 OCH 3 O N

N CH2 S F N O Na F + H2O

Pantoprazole Sodium 18.02

C16H14F2N3NaO4S

405.35

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Step-C

OCH3 OCH3 O N Acetone N CH2 S F + 1.5 H O N O 2 Na F 27.00 Pantoprazole sodium

C16H14F2N3NaO4S OCH3 405.35 OCH3 O N N CH2 S F . N O 1.5 H2O Na F

Pantoprazole Sodium Sesqui Hydrate

C16H17F2N3NaO6S 432.37

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Flow chart: Maltol Sodium hydroxide Dimethyl sulphate Chloroform recovery Chloroform Stage-1 Effluent water Hydrochloric acid Water

Stage-1 Ammonium hydroxide Stage-2 Effluent Water

Stage-2 Phosphorous oxy chloride Ammonium hydroxide Stage-3 Effluent Water Water

Stage-3 Hydrogen peroxide Methanol Chloroform recovery Acetic acid Stage-4 Methanol recovery Ammonium hydroxide Effluent Water Chloroform Sodium tungstate

Stage-4 Sodium hydroxide Chloroform recovery Acetic anhydride Methanol recovery Stage-5 Acetic acid Toluene recovery Chloroform Methanol Toluene

Stage-5 Caustic lye Chloroform recovery Activated carbon Stage-6 Effluent Water Chloroform Sodium sulphate Water

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Stage-6 Thionyl chloride Methanol Recovery Methanol Stage-7 Acetone recovery Acetone

Stage-7 5-Difluoromethoxy-2 -mercapto-1H-benzimidazole Dichloromethane Recovery Stage-8 Sodium hydroxide Effluent Water Dichloromethane Water

Stage-8 Sodium hypochlorite Ethyl acetate Recovery Stage-9 Sodium Hydroxide flakes Acetone Recovery Ethyl acetate Effluent Water Acetone Water

Pantoprazole Sodium Sesquihydrtae

PANTOPRAZOLE SODIUM SESQUIHYDRATE

Material balance

Material Balance of Pantoprazole Sodium Sesquihydrtae Stage-1 Batch Size: 750Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Maltol 557.00 Stage-1 557.00 Sodium hydroxide 483.00 Chloroform recovery 2660.00 Dimethyl sulphate 669.00 Chloroform loss 140.00 Chloroform 2800.00 Effluent water 689.10 (Water -268 generated water-163, Sodium chloride-258.1) Hydrochloric acid 33.00 Water recovery 2182.00 Water 2450.00 By product 711.00 (Sodium methyl sulphate- 711) Organic residue 52.90 Total 6992 Total 6992

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Material Balance of Pantoprazole Sodium Sesquihydrtae Stage-2 Batch Size: 750Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-1 557.00 Stage-2 557.00 Ammonium hydroxide 836.00 Effluent water 836.00 (generated water- 143.20Watre from ammonium hydroxide- 692.8) Total 1393 Total 1393

Material Balance of Pantoprazole Sodium Sesquihydrtae Stage-3 Batch Size: 750Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-2 557.00 Stage-3 537.00 Phosphorous oxy chloride 896.00 Effluent water 674.86 (generated water- 144.18,Water from Ammonium hydroxide- 530.68) Ammonium hydroxide 1592.00 Water recovery 3840.00 Water 3342.00 By product 1189.20 (Ammonium Phosphate- 870 Ammonium chloride - 312.20) Process emission 145.94 (Hydrogen chloride) Total 6387 Total 6387

Material Balance of Pantoprazole Sodium Sesquihydrtae Stage-4 Batch Size: 750Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-3 537.00 Stage-4 557.00 Hydrogen peroxide 583.00 Chloroform recovery 2645.00 Methanol 567.00 Chloroform loss 140.00 Acetic acid 58.00 Methanol recovery 539.00 Ammonium hydroxide 179.00 Methanol loss 11.00 Chloroform 2785.00 Effluent water 555.00 (generated water-123, Sodium tungstate-18, Water from hydrogen peroxide-414) Sodium tungstate 18.00 By product 263.00 (Ammonium acetate )

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Organic residue 17.00 Distillation Residue-17 (Methanol) Total 4727 Total 4727

Material Balance of Pantoprazole Sodium Sesquihydrtae Stage-5 Batch Size: 750Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-4 557.00 Stage-5 557.00 Sodium hydroxide 140.00 Chloroform recovery 346.00 Acetic anhydride 335.00 Chloroform loss 18.00 Acetic acid 220.00 Methanol recovery 1226.00 Chloroform 364.00 Methanol loss 28.00 Methanol 1393.00 Toluene recovery 133.00 Toluene 140.00 Toluene loss 7.00 By product 569.00 (Acetic acid -569,) Effluent water 202.81 (Generated water -57.81, Sodium chloride-145) Organic residue 62.19 Process residue-26.19 Distillation Residue-36 (Methanol) Total 3149 Total 3149

Material Balance of Pantoprazole Sodium Sesquihydrtae Stage-6 Batch Size: 750Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-5 557.00 Stage-6 429.00 Caustic lye 995.00 Chloroform recovery 3838.00 Activated carbon 15.00 Chloroform loss 202.00 Chloroform 4040.00 Effluent water 875.00 (Water from Sodium hydroxide-875) Sodium sulphate 30.00 Water recovery 3180.00 Water 3180.00 By product 248.00 (Sodium acetate) Spent carbon 15.00 Inorganic solid waste 30.00 (Sodium sulphate) Total 8817 Total 8817

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Material Balance of Pantoprazole Sodium Sesquihydrtae Stage-7 Batch Size: 750Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-6 429.00 Stage-7 500.00 Thionyl chloride 378.00 Methanol Recovery 713.00 Methanol 750.00 Methanol loss 15.00 Acetone 1275.00 Acetone recovery 1211.00 Acetone loss 26.00 Process emission 162.44 (sulphur dioxide-162.44) Organic Residue 204.56 Process residue-144.56 Distillation Residue-60 (Methanol-22, Acetone- 38) Total 2832 Total 2832

Material Balance of Pantoprazole Sodium Sesquihydrtae Stage-8 Batch Size: 750Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-7 500.00 Stage-8 825.00 5-Difluoromethoxy-2- 500.00 Dichloromethane 4750.00 mercapto-1H-benzimidazole Recovery Sodium hydroxide 225.00 Dichloromethane loss 100.00 Dichloromethane 5000.00 Effluent Water 5400.00 Water 5000.00 (Water-5000 0 Generated water-80.39 , Sodium chloride-319.61) Organic Residue 150.00 Distillation Residue-150 (Dichloromethane) Total 11225 Total 11225

Material Balance of Pantoprazole Sodium Sesquihydrtae Stage-9 Batch Size: 750Kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-8 825.00 Pantoprazole Sodium 750.00 Sesquihydrtae Sodium hypochlorite 7500.00 Ethyl acetate Recovery 1900.00 Sodium Hydroxide flakes 80.00 Ethyl acetate Loss 40.00 Ethyl acetate 2000.00 Acetone Recovery 3800.00 Acetone 4000.00 Acetone Loss 80.00 Water 5000.00 Effluent Water 1715.00 (Water-1169, Generated 0

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water-40.46 , Ethyl acetate-60, Sodium chloride-445.54) Water recovery 11000.00 Organic Residue 120.00 Distillation Residue-120 (Acetone-120) Total 19405 Total 19405

PIMOZIDE

Process Description: Stage-1: 4-chloro-1, 1-bis (4-fluorophenyl) butane (PIM-III) react with 1-(piperidin-4-yl) 1H- benza imidazole-2(3H)-one (Keto-9) in presence of sodium carbonate, tetrabutyl ammonium bromide, MIBK to give Stage-1 product Stage-2: Stage-1 Product undergoes Purification with Methanol and carbon to form Pimozide. Route of synthesis Stage-1 Cl H N O F N MIBK + + 1/2 Na2CO3 N TBAB F H 4-chloro-1,1-bis(4- 1-(piperidin-4-yl)-1H-benzo 53.0 fluorophenyl)butane [d]imidazol-2(3H)-one

C16H15ClF2 C12H15N3O 280.74 217.27 F O N HN N

F

1-(1-(4,4-bis(4-fluorophenyl) + NaCl + 1/ H O + 1/ CO butyl)piperidin-4-yl)-1H- 2 2 2 2 58.44 benzo[d]imidazol-2(3H)-one 9.0 22.0

C28H29F2N3O 461.55

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Stage-2

F

O F N HN N O N Methanol HN N F Activated Carbon F 1-(1-(4,4-bis(4-fluorophenyl) butyl)piperidin-4-yl)-1H-benzo Pimozide [d]imidazol-2(3H)-one C28H29F2N3O (Pimozide Crude) 461.55 C28H29F2N3O 461.55

Flow Chart

4-chloro-1, 1-bis (4-fluorophenyl) butane (PIM-III) 1-(piperidin-4-yl) 1H-benza imidazole -2(3H)-one (Keto-9) MIBKl Recovery Sodium carbonate (25%) Stage-1 Effluent water Potassium Iodide Tetra butyl ammonium bromide MIBK

Stage-1 Activated Carbon Stage-2 Methanol recovery Methanol Spent carbon

PIMOZIDE

Material Balance

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Material Balance of Pimozide Stage-1 BatchSize:100 Kg Name of the input Quantity in Name of the out put Quantity Kg in Kg 4-chloro-1, 1-bis (4-fluorophenyl) 67.00 Stage-1 105.00 butane (PIM-III) 1-(piperidin-4-yl) 1H-benza imidazole- 52.00 MIBK Recovery 285.00 2(3H)-one (Keto-9) Sodium carbonate (25%) 50.00 MIBK Loss 12.00 Potassium Iodide 1.00 Effluent Water 457.09 Tetra butyl ammonium bromide 2.50 (Water-400,Generated water- 2.14,water form Sodium carbonate- 37.5,Sodium Chloride-13.95, Potassium Iodide-1,TBAB-2.5) MIBK 300.00 Process Emission 5.22 Water 400.00 (Carbon dioxide-5.22) Organic Residue 8.19 (Process residue -5.19, Distillation residue-3 MIBK-3) Total 872.50 Total 872.50

Material Balance of Pimozide Stage-2 BatchSize:100 Kg Name of the input Quantity in Name of the out put Quantity Kg in Kg Stage-1 105.00 Pimozide 100.00 Activated Carbon 5.00 Methanol Recovery 285.00 Methanol 300.00 Methanol Loss 10.00 Spent Carbon 5.00 Organic Residue 10.00 Process residue-5 Distillation residue -5 Methanol-5 Total 410.00 Total 410.00

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PREGABALIN

Process Description: Stage-1 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-2 Stage-1 product reacts with Mandelic acid in presence of IPA to give Stage-2 product. Stage-3 Stage-2 product reacts with Sodium hydroxide in presence of THF to give Pregabalin product.

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PREGABALIN Route of Synthesis: Stage –1 N

CH3 O

C OC2H5 H3C + + 2H2 + KOH CH3COOH + H2O C OC2H5

O 2-(1-Cyano-3-methyl-butyl)-malonic acid diethyl 2X2=4.0 56.11 60.05 18.00 ester

C13H21NO4 255.31

Raney Nickel Methanol

H3C

NH2 H C 3 + + CH3COOK 2 C2H5OH + CO2

COOH

3-Aminomethyl 5 -methyl 98.14 2 X46.07=92.14 44.00 hexanoic acid C8H17NO2 159.23

Stage –2 H3C H3C NH OH + 2 NH3 2 HO H3C H C + COOH IPA 3 -OOC COOH COOH 3-Aminomethyl 5 -methyl Mandelic acid hexanoic acid S(+)Pregabalin mandalate salt C8H8O3 C8H17NO2 C16H25NO5 152.15 2 x 159.23 = 318.46 311.37

+ (R)-Isomer 159.23

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Stage –3 H3C NH + 3 H3C OH HO H C 3 THF NH2 CO -OOC NaOH H3C + OH COOH COOH S(+)Pregabalin mandalate salt S(+)Pregabalin Mandelic acid C16H25NO5 C H O 311.37 C8H17NO2 8 8 3 159.23 152.14 Flow Chart:

2-(1-Cyano-3-methyl-butyl)- malonic acid diethyl ester Ethanol Potassium hydroxide Acetic acid Raney nickel stage-1 Ethanol Recovery IPA IPA Recovery Hydrogen gas

Stage-1 (S)-Mandelic acid stage-2 IPA Recovery Isopropyl alcohol

Stage -2 Tetrahydrofuran stage-3 THF Recovery Isopropyl alcohol IPA Recovery

Pregabalin

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PREGABALIN Material Balance:

Material Balance Of Pregabalin Stage-1 Batch Size: 200.0Kgs Name of the input Quantity Name of the out put Quantity in Kg in Kg 2-(1-Cyano-3-methyl-butyl)- 753.00 Stage-1 445.00 malonic acid diethyl ester Ethanol 200.00 Ethanol Recovery 461.08 Potassium hydroxide 165.00 Ethanol loss 10.00 Acetic acid 176.95 IPA Recovery 333.00 Raney nickel 5.00 IPA Loss 12.00 IPA 350.00 Raney Nickel Reuse 5.00 Hydrogen gas 11.30 Effluent water 836.44 Water 600.00 (Water-547.29,Poatassium acetate-289.15) Process emission 129.52 (Carbon dioxide-129.52) 0 Organic residue 29.21 Process residue-24.21 Distillation residue-5 (IPA-5) Total 2261.25 Total 2261.25

Material Balance Of Pregabalin Stage-2 Batch Size: 200.0Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 445.00 Stage -2 413.00 (S)-Mandelic acid 213.00 IPA Recovery 475.00 Isopropyl alcohol 500.00 IPA Loss 10.00 Water 300.00 Effluent water 300.00 (Water-300) Organic residue 260.00 Process residue- 245,organic impurities-22.5 (R-Isomer Recycle-222.5) Distillation residue-15 (IPA-15) Total 1458.00 Total 1458.00

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Material Balance Of Pregabalin Stage-3 Batch Size:200.0Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage -2 413.00 Pregabalin 200.00 Tetrahydrofuran 300.00 THF Recovery 285.00 Isopropyl alcohol 400.00 THF Loss 15.00 Sodium Hydroxide 5.00 IPA Recovery 385.00 Water 500.00 IPA Loss 15.00 Effluent water 505.00 (Water-500,Sodium 0 hydroxide-5) Organic residue 213.00 Process residue-213 (Organic impurities-11.46 Mandelic acid recovery- 201.54) Distillation residue-5 (IPA-5) Total 1618.00 Total 1618.00

QUETIAPINE FUMARATE

Process Description:

Stage-1:

11-Piperazin-1-yl-4a,11a-dihydro-dibenzo[b,f] [1,4]thiazepine Di hydrochloride reacts with 2-Chloroethoxy ethanol in presence of Sodium carbonate, Toluene and water to give Stage-1 product.

Stage-2:

Stage-1 product reacts with Fumaric acid in presence of Acetone to give Quetiapine Fumarate.

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Route of Synthesis:

Stage-1

NH . 2 HCl

N N O + HO Cl + Toluene S Na2CO3 11-Piperazin-1-yl-4a,11a-dihydro-dibenzo[b,f] 2-Chloroethoxy ethanol 105.99 [1,4]thiazepine Di hydrochloride C4H9ClO2 124.57 C17H21Cl2N3S 370.34 O N OH

N N

S CO 2-{2-[1-(4a,11a-Dihydro-dibenzo[b,f][1,4]thiazepin-11-yl)- + 2 NaCl + 2 + H2O + HCl piperidin-4-yl]-ethoxy}-ethanol(Quetiapine) 116.89 44.01 18.02 36.46 C21H27N3O2S

385.52

Stage-2 O N OH N O N HO OH 2 + Acetone S O

2-{2-[1-(4a,11a-Dihydro-dibenzo[b,f][1,4] Fumaric acid thiazepin-11-yl)-piperidin-4-yl]-ethoxy}- C4H4O4 ethanol(Quetiapine) 116.07 C H N O S O 21 27 3 2 N OH 771.00 N O N HO OH . O S 2 Quetiapine Fumarate C46H58N6O8S2 887.12

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Flowchart:

11-Piperazin-1-yl-4a,11a-dihydro-dibe Toluene recovery Stage-1 nzo[b,f][1,4]thiazepine Dihydrochloride Effluent water 2-Chloroethoxy ethanol Sodium carbonate Toluene

Stage-1 Acetone Recovery Fumaric acid Stage-2 Effluent water Acetone

QUETIAPINE FUMARATE

Material Balance:

Material Balance of Quetiapine Fumarate. Stage-1 Batch Size: 100.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 11-Piperazin-1-yl-4a,11a-dihydro- Stage-1 90.00 dibenzo[b,f] [1,4]thiazepine Di 90.00 hydrochloride 2-Chloroethoxy ethanol 30.25 Toluene Recovery 285.00 Sodium carbonate 25.75 Toluene loss 10.00 Toluene 300.00 Effluent water 434.59 Water 400.00 (Water-400, Generated water – 4.32, Sodium chloride- 27.27,Toluene-3) Process emission 19.44 (Hydrogen Chloride– 8.82, Carbon dioxide-10.62) Organic residue 6.97 Process residue – 4.97 Distillation residue-2 ((Toluene-2) Total 846.00 Total 846.00 Material Balance of Quetiapine Fumarate. Stage-2 Batch Size: 100.00 Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg

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Stage-1 90.00 Quetiapine Fumarate. 100.00 Fumaric acid 13.50 Acetone Recovery 285.00 Acetone 300.00 Acetone loss 10.00 Water 400.00 Effluent water 400.00 (Water-400) 0 Organic residue 8.50 Process residue – 3.50 Distillation residue-5 (Acetone-5) Total 803.50 Total 803.50

RABEPRAZOLE SODIUM

Process Description

Stage-1

2, 3-Lutidine reacts with Hydrogen Peroxide and Nitric acid in presence of Sulfuric Acid and water to give Stage-1Product.

Stage-2

Stage-1 Product reacts with 3-Methoxy-1-Propanol and Sodium Hydroxide in presence of Toluene and DMSO to give Stage-2 Product.

Stage-3

Stage-2 Product reacts with Acetic Anhydride in presence of Sodium Hydroxide, Toluene and Hydrochloric Acid to give Stage-3 Product.

Stage-4

Stage-3 Product reacts with Thionyl Chloride in the presence of Toluene,Methanol and MDC to giveStage-4 Product.

Stage-5

Stage-4 Product reacts with 2-Mercapto Benzimidazole, in presence of Toluene, methanol to give Stage-5 Product.

Stage-6

Stage-5 Product reacts with Sodium Hypochlorite in presence of MDC and Toluene to give Stage-6 product.

Stage-7

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Stage-6 product reacts with Sodium hydroxide in presence of Acetone to get Rabeprazole Sodium

Route of Synthesis:

Stage-1

NO2 CH3 H3C H2SO4 + H2O2 + HNO3 + 2H2O N CH3 + H3C N - 2,3-Lutidine O 36.0 2,3-Dimethyl-4-nitro C7H9N 34.01 63.0 107.15 -pyridine 1-oxide C7H8N2O3 168.15 Stage-2

NO2 O O H C 3 H3C Toluene + NaOH + HO O DMSO H C N+ + 3 H3C N - O O- 4-Nitro-2,3-Dimethyl 3-Methoxy-1-Propanol 40.0 4-(3-Methoxy-propoxy)-2,3-dimethyl pyridine-N-oxide C4H10O2 -pyridine 1-oxide C7H8N2O3 90.12 C11H17NO3 168.15 211.26

+ NaNO2 + H2O

Sodium Nitrite 18.0 69.0

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Stage-3

O O

H3C O O + H C N+ + NaOH + HCl Toluene 3 O O- Methanol Acetic anhydride 4-(3-Methoxy-propoxy)-2,3-dimethyl 40.0 36.5 -pyridine 1-oxide C4H6O3 C H NO 11 17 3 102.09 211.26

O O

N . HCl + CH3COONa + CH3COOH OH 82.0 60.0 4(3-methoxy propoxy)-2-hydroxy methyl -3-methyl pyridine hydrochloride

C11H17NO3 HCl 247.72 Stage-4

O O O O

N Toluene N . . HCl HCl + SOCl2 Methanol OH Cl 4(3-methoxy propoxy)-2-hydroxy methyl Thionyl Chloride 2-(chloromethyl)-4-(3-methoxypropoxy)- -3-methyl pyridine hydrochloride 118.97 3-methylpyridine hydrochloride

C11H17NO3 HCl C11H17Cl2NO2 247.72 266.16

+ SO2 + HCl

64.0 36.46

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Stage-5

O O H N Toluene N . HCl + HS + 2 NaOH N Methanol Cl 2-(chloromethyl)-4-(3-methoxypropoxy)- 2-Mercapto benzimidazole 80.00 3-methylpyridine hydrochloride C7H6N2S C H Cl NO 11 17 2 2 150.25 266.16 O O

N S C N H + N 2 + 2 NaCl 2 H2O H 116.89 36.03 2-[4-(3-Methoxy-propoxy)-3-methyl-pyridin- 2-ylmethylthio]-1H-benzo[d]imidazole

C18H21N3O2S 343.44 Stage-6

O O

Toluene N + NaOCl S C N MDC N H2 H 2-[4-(3-Methoxy-propoxy)-3-methyl-pyridin-Sodium Hypochlorite 2-ylmethylthio]-1H-benzo[d]imidazole 74.44 O O C18H21N3O2S 343.44 O N + NaCl S C N 58.5 N H2 H 2-[4-(3-Methoxy-propoxy)-3-methyl-pyridin-2- ylmethanesulfinyl]-1H-benzoimidazole

C18H21N3O3S 359.44

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Stage-7

O O O O

O Acetone O N N + NaOH S C N S CH N N H2 N H H Na

2-[4-(3-Methoxy-propoxy)-3-methyl-pyridin 40.0 + H2O Rabeprazole Sodium -2-ylmethanesulfinyl]-1H-benzoimidazole 18.0 C18H20N3NaO3S C H N O S 18 21 3 3 381.42 359.44

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RABEPRAZOLE SODIUM

Flow Chart: 2,3-Lutidine Hydrogen Peroxide (50%) Nitric acid Stage-1 Effluent water Sulphuric acid Acetic acid Stage-1 3-Methoxy-1-Propanol Toluene Recovery Stage-2 Sodium Hydroxide DMSO Recovery Toluene Generated water DMSO Stage-2 Acetic anhydride Toluene Recovery Sodium Hydroxide Stage-3 Mthanol Recovery Hydrochloric acid Effluent water Toluene Methanol Stage-3 Methanol Recovery Thionyl Chloride Stage-4 MDC Recovery MDC Effluent water Sodium Sulphate Toluene Methanol Stage-4 Toluene Recovery 2-Mercaptobenzimidazole Stage-5 Methanol Recovery Sodium hydroxide Effluent water Toluene Methanol Stage-5 Sodium Hypochlorite (8%) MDC Recovery Stage-6 MDC Effluent water Toluene Sodium hydro sulphate MMA in Methanol

Stage-6 Acetone Recovery Generated Sodium Hydroxide Stage-7 water Acetone Activated Carbon

RABEPRAZOLE SODIUM

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RABEPRAZOLE SODIUM

Material Balance:

Material balance of Rabeprazole Sodium Stage-1 Batch Size: 500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg 2,3-Lutidine 210.00 Stage-1 310.00 Hydrogen Peroxide (50%) 135.00 Spent Acids for sale 140.00 Nitric acid 124.00 (Sulfuric Acid-100,Acetic Acid-40) Sulphuric acid 108.00 Effluent Water 552.55 Acetic acid 46.00 (Water-400,Sulfuric Acid- 8,Acetic Acid- 6,Generated water- 70.55,Water from Hydrogen peroxide-68) Water 400.00 Organic Residue 20.45 Process resiue-20.45 Total 1023.00 Total 1023.00

Material balance of Rabeprazole Sodium Stage-2 Batch Size: 500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 310.00 Stage-2 370.00 3-Methoxy-1-Propanol 167.00 Toluene Recovery 235.00 Sodium Hydroxide 74.00 Toluene Loss 12.00 Toluene 250.00 DMSO Recovery 188.00 DMSO 200.00 DMSO Loss 10.00 Generated water 33.18 Inorganic Solid Waste 127.20 (Sodium Nitrite-127.20) 0 Organic residue 25.62 Process residue-20.62 Distillation residue-5 (Toluene-3,DMSO-2) Total 1001.00 Total 1001.00

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Material balance of Rabeprazole Sodium Stage-3 Batch Size: 500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 370.00 Stage-3 412.00 Acetic anhydride 179.00 Toluene Recovery 380.00 Sodium Hydroxide 70.00 Toluene Loss 10.00 Hydrochloric acid 64.00 Methanol Recovery 475.00 Toluene 400.00 Methanol Loss 15.00 Methanol 500.00 Effluent Water 653.61 Water 400.00 (Water-400,Sodium 0.00 Acetate-143.61,Acetic Acid-105, Toluene-5) Organic Residue 37.39 Process residue-22.39 Distillation residue-15 (Toluene-5,Methanol- 10) Total 1983.00 Total 1983.00

Material balance of Rabeprazole Sodium Stage-4 Batch Size: 500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-3 412.00 Stage-4 420.00 Thionyl Chloride 198.00 MDC Recovery 710.00 MDC 750.00 MDC Loss 37.00 Sodium Sulphate 10.00 Toluene Recovery 475.00 Toluene 500.00 Toluene Loss 10.00 Methanol 500.00 Methanol Recovery 475.00 Water 500.00 Methanol Loss 15.00 Effluent Water 508.00 (Water-500,Toluene-8) 0 Inorganic Solid Waste 10.00 (Sodium Sulphate) 0 Process Emission 167.08 (sulfur dioxide-106.44, 0 Hydrogen chloride- 60.64) Organic Residue 42.92 Process residue -22.92 Distillation residue-20 (Methanol-10, Toluene- 7, MDC-3) Total 2870.00 Total 2870.00

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Material balance of Rabeprazole Sodium Stage-5 Batch Size: 500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-4 420.00 Stage-5 510.00 2-Mercaptobenzimidazole 240.00 Toluene Recovery 380.00 Sodium hydroxide 127.00 Toluene Loss 10.00 Toluene 400.00 Methanol Recovery 380.00 Methanol 400.00 Methanol Loss 10.00 Water 400.00 Effluent Water 646.31 (Water-400,Sodium 0 chloride- 184.45,Generated water-56.86,Toluene-5) Organic Residue 50.69 Process residue-35.69, Distillation residue-15 (Toluene-5, Methanol- 10) Total 1987.00 Total 1987.00

Material balance of Rabeprazole Sodium Stage-6 Batch Size: 500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-5 510.00 Stage-6 500.00 Sodium Hypochlorite (8%) 1388.00 MDC Recovery 570.00 MDC 600.00 MDC Loss 30.00 Toluene 150.00 Toluene Recovery 143.00 Sodium hydro sulphate 12.00 Toluene Loss 5.00 MMA in Methanol 10.00 Effluent Water 1775.87 Water 400.00 (Water-400,Sodium Chloride-86.87,water from sodium hypochlorite-1277, ,MMA-10, Toluene-2) Organic Solid Waste 46.13 Process residue-43.13 Distillation residue-3 (Toluene-3) Total 3070.00 Total 3070.00

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Material balance of Rabeprazole Sodium Stage-7 Batch Size: 500Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-6 500.00 Rabeprazole Sodium 500.00 Sodium Hydroxide 56.00 Acetone Recovery 280.00 Acetone 300.00 Acetone Loss 15.00 Activated Carbon 10.00 Generated water 25.00 Spent carbon 10.00 Organic Residue 36.00 (Process residue-31, Distillation residue-5 (Acetone-5) Total 866.00 Total 866.00

RUPATADINE FUMERATE

Process Description:

Stage-1:

8-chloro-6,11-dihydro-11-(4-piperdinylidene)-5H-benzo(5,6)cyclohepta(1,2-b)pyridine react with 3-chloromethyl-5-methylpyridine in presence of sodium hydroxide, water, TBAB, Ethyl acetate to give stage-1 product.

Stage-2 :

Stage-1 product reacts with But-2-enedioic acid in presence of Methanol, Acetone to give Rupatadine Fumerate

Route of synthesis

Stage-1

N Cl N + Cl Sodium hydroxide,TBAB N Cl N Ethyl acetate N N H 8-chloro-6,11-dihydro-11-(4- 3-(chloromethyl)-5 8-Chloro-6,11-dihydro-11-[1-[(5-methyl- piperdinylidene)- 5H-benzo -methylpyridine 3-pyridinyl)methyl]-4-piperidinylidene]- [5,6]cyclohepta[1,2-b]pyridine C7H8ClN 5H-benzo[5,6]cyclohepta[1,2-b]pyridine 141.6 C H Cl C H ClN 26 26 19 19 2 N 310.82 415.396

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Stage-2

N

N H COOH Methanol,Acetone Cl +

N HOOC H 8-Chloro-6,11-dihydro-11-[1-[(5-methyl- But-2-enedioic acid 3-pyridinyl)methyl]-4-piperidinylidene]- C4H4O4 5H-benzo[5,6]cyclohepta[1,2-b]pyridine N 116.07 C26H26ClN3 H COOH 415.96 N Cl HOOC H N

8-Chloro-6,11-dihydro-11-[1-[(5-methyl- 3-pyridinyl)methyl]-4-piperidinylidene]- 5H-benzo[5,6]cyclohepta[1,2-b] pyridine fumeric acid

C30H30ClN3O4 532.03 Flow Chart 8-chloro-6,11-dihydro-11-(4- piperdinylidene)-5H-benzo (5,6)cyclohepta(1,2-b) pyridine Ethyl acetate Recovery 3-chloromethyl-5-methylpyridine Stage-1 Effluent water Ethyl acetate Sodium hydroxide TBAB Stage-1 Stage-2 Methanol recovery But-2-enedioic acid Acetone recovery Methanol Acetone Activated carbon RUPATADINE FUMERATE

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RUPATADINE FUMERATE

Material Balance

Material Balance of Rupatadine Fumerate Stage-1 BatchSize:100.0Kg Name of the input Quantity in Name of the out put Quantity in Kg Kg 8-chloro-6,11-dihydro-11-(4- 62.00 Stage-1 80.00 piperdinylidene)-5H- benzo(5,6)cyclohepta(1,2- b)pyridine(DLRD) 3-chloromethyl-5- 28.20 Ethyl acetate Recovery 190.00 methylpyridine Ethyl acetate 200.00 Ethyl acetate Loss 5.00 Sodium hydroxide 20.00 Effluent water 625.00 TBAB 2.00 (Water-600,TBAB-2, 0 Sodium hydroxide-20, Ethyl acetate-3) Water 600.00 Organic Residue 12.20 Process residue-10.20 Distillation residue-2 (Ethyl acetate-2) Total 912.20 Total 912.20

Material Balance of Rupatadine Fumerate Stage-2 BatchSize:100.0Kg Name of the input Quantity Name of the out put Quantity in in Kg Kg Stage-1 80.00 Rupatadine Fumerate 100.0 But-2-enedioic acid 22.30 Acetone Recovery 93.00 Methanol 150.00 Acetone Loss 5.00 Acetone 100.00 Methanol Recovery 143.00 Activated carbon 5.00 Methanol Loss 4.00 Spent carbon 5.00 Organic residue 7.30 Process residue-2.30 Distillation residue-5 ( Acetone-2,Methanol-3) Total 357.30 Total 357.30

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TELMISARTAN

Process Description

Stage-1

4-Methyl-biphenyl-2-carbonitrile undergoes hydrolysis with Potassium Hydroxide inpresence of Ethylene glycol and HCl to give Stage-1 product. Stage-2

Step-A

Stage-1product undergoes methylation with Dimethyl sulphate in presence of Potassium carbonate and MDC to give step-A product.

Step-B

Step-A product undergoes Bromination with DDH in presence of Acetone and Cyclo hexane to give Stage-2 product.

Stage-3

Stage-2 product undergoes condensation with 1,7’-Dimethyl-2’-propyl- 3’a,4’,5’,6’,7’,7’,a-hexahydro-1H,3’H-[2,5’]bibenzoimidazolyl in presence of potassium hydroxide and acetone to give stage-3 product..

Stage-4

Stage-3 product undergoes hydrolysis with Potassium Hydroxide in presence of water and Acetic acid to give Telmisartan.

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Route of Synthesis:

Stage-1

CH3

CN

+ HO OH + KOH + HCl + H2O 4'-Methyl-biphenyl- Ethylene glycol 56.11 2-carbonitrile 36.46 18.02 C2H6O2 C H N 14 11 62.07

193.24 CH3

COOH

+ CH3COOH + KCl + NH3 + H2 4'-Methyl-biphenyl-2- 60.05 74.55 17.03 2.02 carboxylic acid C14H12O2 212.24 Stage-2

Step-A

CH3 CH3

COOH COOCH3 + C2H6SO4 + K2CO3 4'-Methyl-biphenyl- 138.21 Dimethyl sulphate 4'-Methyl-biphenyl-2-carboxylic 2-carboxylic acid acid methyl ester C14H12O2 126.13 C H O 212.24 15 14 2 226.27

+ CH3OH + K2SO4 + CO2 32.04 174.26 44.00

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Step-B

CH3 Br H2C

O COOCH3 Br N CH3 COOCH3 + O N CH3 Br 4'-Methyl-biphenyl-2-carboxylic Dibromodimethyl 4'-Bromomethyl-biphenyl-2- acid methyl ester Hydantoin carboxylic acid methyl ester C H Br N O C15H14O2 5 6 2 2 2 C15H13O2Br 226.27 285.92 305.17

O H N CH + 3 O N CH3 Br 1-Bromo-5,5-dimethyl-imidazo lidine-2,4-dione

C5H7BrN2O2 207.03

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Stage-3:

CH3 Br N H2C H3C NH

CH N N 3 COOCH3 + + KOH

4'-Bromomethyl-biphenyl-2- 1,7'-Dimethyl-2'-propyl-3' 56.11 carboxylic acid methyl ester a,4',5',6',7',7'a-hexahydro-1H, 3'H-[2,5']bibenzoimidazolyl C15H13O2Br C H N 305.17 19 26 4 310.44 CH3 N H3C N

COOCH3 N N CH3 KBr + + H2O

Telmisartan Ester 119 18.02

C34H32N4O2 534.69 Stage-4

CH3 N CH3 H3C N H C N 3 N MDC COOCH3 + KOH + N N CH3 CH3COOH COOH Water N N CH3

Telmisartan Ester 56.11 60.05 Telmisartan C34H32N4O2 C33H36N4O2 534.69 520.66 + + CH3OH CH3COOK 32.04 Potassium Acetate 98.14

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Flow Chart:

4-methyl-biphenyl-2-carbonitrile Ethylene glycol Stage-1 Effluent water Potassium Hydroxide Hydrochloric acid Stage-1 Di methyl sulphate Dibromodimethyl Hydantoin Acetone Recovery Potassium Carbonate MDC recovery Acetone Stage-2 Effluent water Cyclohexane Activated Carbon MDC Stage-2 1,7'-Dimethyl-2'-propyl-3' Acetone Recovery a,4',5',6',7',7'a-hexahydro-1H, Stage-3 Effluent water 3'H-[2,5']bibenzoimidazolyl Potassium Hydroxide Acetone

Stage-3 MDC Recovery Potassium Hydroxide Methanol Recovery Acetic acid Stage-4 Effluent water DMF Methanol MDC Activated Carbon

TELMISARTAN

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Material Balance: Material, balance of Telmisartan Stage-1 Batch Size:100kg Name of the input Quantity Name of the output Quantity in Kg in Kg 4-methyl-biphenyl-2- 52.00 Stage-1 53.00 carbonitrile Ethylene glycol 16.70 Effluent Water 631.31 Potassium Hydroxide 15.08 (Water-595.17, 0 Potassium chloride-20.02, Acetic acid-16.12) Hydrochloric acid 9.77 Process Emission 5.09 Water 600.00 (Ammonia-4.57,Hydrogen- 0.52) Organic Residue 4.15 Process Residue-4.15 Total 693.55 Total 693.55

Material, balance of Telmisartan Stage-2 Batch Size:100kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-1 53.00 Stage-2 67.00 Di methyl sulphate 31.50 MDC Recovery 570.00 Dibromodimethyl Hydantoin 66.95 MDC Loss 12.00 Potassium Carbonate 34.50 Acetone Recovery+ 387.95 Methanol Acetone 400.00 Acetone Loss 10.00 Cyclohexane 200.00 Cyclohexane Recovery 190.00 Activated Carbon 5.00 Cyclohexane Loss 5.00 MDC 600.00 Effluent Water 843.50 Water 800.00 (Water-800,Potassium 0 sulphate-43.50) Spent Carbon 5.00 Process Emission 10.98 (Carbon dioxide-10.98) 0 Organic Residue 89.52 Process Residue-56.52 Organic impurities-8.08 (1-Bromo-5,5-dimethyl- imidazolidine-2,4-dione- 48.44) Distillation Residue-33 (Acetone-10,Cyclo hexane-5,MDC-18) Total 2190.95 Total 2190.95

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Material, balance of Telmisartan Stage-3 Batch Size:100kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-2 67.00 Stage-3 110.00 1,7'-Dimethyl-2'-propyl-3' 68.15 Acetone recovery 475.00 a,4',5',6',7',7'a-hexahydro-1H, 3'H-[2,5']bibenzoimidazolyl Potassium Hydroxide 12.25 Acetone loss 15.00 Acetone 500.00 Effluent water 430.00 Water 400.00 (Water-400, 0 Generated water-3.95, Potassium bromide- 26.05) Organic Residue 17.40 Process Residue-7.40 Distillation Residue-10 (Acetone-10) Total 1047.40 Total 1047.40

Material, balance of Telmisartan Stage-4 Batch Size:100kg Name of the input Quantity Name of the output Quantity in Kg in Kg Stage-3 110.00 Telmisartan 100.00 Potassium Hydroxide 11.45 Methanol Recovery+ 386.49 Generated Methanol Acetic acid 12.32 Methanol Loss 12.00 DMF 100.00 MDC Recovery 380.00 Methanol 400.00 MDC Loss 8.00 MDC 400.00 DMF Recovery 95.00 Activated Carbon 5.00 DMF Loss 2.00 Water 600.00 Effluent water 620.13 (Water-600, Potassium Acetate-20.13) Spent Carbon 5.00 Organic Residue 30.15 Process Residue-7.15 Distillation Residue-23 (MDC-12,Methanol- 8,DMF-3) Total 1638.77 Total 1638.77

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TERBINAFINE HYDROCHLORIDE

Process Description: Stage-1 Napthyl methyl chloride reacts with Methyl amine in the presence of to give stage-1 product. Stage-2 Pinacolone undergoes Alkylation in the presence of Potassium carbonate, Acetone and Hydrochloric acid to give stage-2 product. Stage-3 Stage-2 Product reacts with acrolein in the presence of DIPE to give stage-3 product. Stage-4 Step-A: Stage-3 Product reacts with Isopropyl alcohol in presence of Aluminium Isopropoxide to give Step-A Product. Step-B: Step-A product reacts with Hydrochloric acid in presence of Toluene and Methanol to give stage-4 Product. Stage-5 Stage-4 Product reacts with Stage-1 in presence of Potassium Carbonate, Methanol, Toluene and Ethyl acetate to give Terbinafine Hydochloride

TERBINAFINE HYDROCHLORIDE

Route of synthesis:

Stage-1: Cl H3C CH3 N

+ Methanol . H2N CH3 HCl Napthyl methyl chlorideMethyl amine N-Methyl-1-napthalene C11H9Cl 31.06 methylamine HCl 176.64 C12H14ClN 207.70

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Stage-2: O H3C H3C + K CO + 2 HCl CH CH3 2 3 Acetone H3C + H3C 2 KCl H3C H3C Pinacolone 138.20 72.92 3,3-Dimethyl-but-1-yne 149.10 C6H12O C6H10 100.15 82.14

+ 2 H2O + CO2 36.04 44.01 Stage-3:

H3C H3C CH H C DIPE CHO H3C + 2 O H3C H3C H3C + H2 3,3-Dimethyl-but-1-yne Acrolein 6,6-Dimethyl-hept-2-en-4-ynal 2.00 C6H10 C3H4O C9H12O 82.14 56.06 136.19

Stage-4:

Step-A

H3C OH Aluminium CHO H3C H3C isopropoxide H3C OH H3C CH H3C + 3 H3C Isopropyl alcohol 6,6-Dimethyl-hept-2-en-4-ynal 6,6-Dimethyl-hept-

C9H12O C3H8O 2-en-4-yn-1-ol 136.19 60.09 C9H14O 138.20 O

+ H3C CH3 Acetone

C3H6O 58.07

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Step-B H C H C 3 3 + H O H C OH H3C Cl 2 3 + HCl H3C H3C 18.0 6,6-Dimethyl-hept- 36.5 1-Chloro-6,6-dimethyl 2-en-4-yn-1-ol -hept-2-en-4-yne C9H13Cl C9H14O 156.65 138.20

Stage-5:

H3C CH3 N

CH3 H3C . HCl + H C Toluene 3 Cl + 1/2K2CO3 N-Methyl-1-napthalene 1-Chloro-6,6-Dimethyl 69.10 methylamine HCl Hept-2-ene-4-yne C12H14ClN C9H13Cl 207.70 156.65

N

CH3 . HCl + + 1/2CO H C CH KCl 2 + 1/2H2 3 3 O CH3 74.55 22.0 9.0 Terbinafine Hydrochloride

C21H26ClN 327.89

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Flow Chart

Toluene Recovery Napthyl methyl chloride Stage-1 MDC Recovery Mono methyl amine Effluent water Toluene MDC

Pinacolone Potassium carboante Acetone Recovery Stage-2 Hydrochloric acid Effluent water Acetone

Stage-2 Acrolein Stage-3 DIPE Recovery DIPE Effluent water

Stage-3 Isopropyl alcohol Hydrochloric acid Isopropyl alcohol Recovery Toluene Stage-4 Toluene Recovery Methanol Effluent water Aluminium Isopropoxide

Stage-1 Stage-4 Toluene Toluene Recovery Potassium carbonate Stage-5 Metahnol Recovery Methanol Effluent water Ethyl acetate

TERBINAFINE HYDOCHLORIDE

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Material Balance:

Material Balance of Terbinafine Hydrochloride Stage-1 Batch Size: 250.0Kgs Name of the input Quantity Name of the out put Quantity in Kg in Kg Napthyl methyl chloride 150.00 Stage-1 166.00 Mono methyl amine 27.00 Toluene Recovery 285.00 Toluene 300.00 Toluene Loss 10.00 MDC 500.00 MDC Recovery 475.00 Water 450.00 MDC Loss 15.00 Effluent water 453.00 (Water-450, Toluene-3) 0 Organic Residue 23.00 Process residue-11 Distillation residue-12 (Toluene-2, MDC-10) Total 1427.00 Total 1427.00

Material Balance of Terbinafine Hydrochloride Stage-2 Batch Size: 250.0Kgs Name of the input Quantity Name of the out put Quantity in Kg in Kg Pinacolone 100.00 Stage-3 77.00 Potassium carboante 138.00 Acetone Recovery 190.00 Hydrochloric acid 73.00 Acetone Loss 5.00 Acetone 200.00 Effluent water 584.85 Water 400.00 (Water-400,Generated water-35.98, Potassium chloride-148.87) Process emission 43.94 (Carbondioxide-43.94) Organic Residue 10.21 Process residue-5.21 Distillation residue-5 (Acetone-5) Total 911.00 Total 911.00

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Material Balance of Terbinafine Hydrochloride Stage-3 Batch Size: 250.0Kgs Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 77.00 Stage-2 122.00 Acrolein 52.55 DIPE Recovery 475.00 DIPE 500.00 DIPE Loss 25.00 Water 400.00 Effluent water 400.00 (Water-400) Process emission 1.88 (Hydrogen -1.88) Organic Residue 5.67 Process residue-5.67 Total 1029.55 Total 1029.55

Material Balance of Terbinafine Hydrochloride Stage-4 Batch Size: 250.00Kgs Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-3 122.00 Stge-4 126.00 Isopropyl alcohol 250.00 Isopropyl alcohol Recovery 190.00 Hydrochloric acid 31.00 Isopropyl alcohol Loss 5.00 Toluene 400.00 (Mixed Solvent) 432.00 Toluene recovery + Generated Acetone Methanol 400.00 Toluene Loss 12.00 Aluminium Isopropoxide 20.00 Methanol Recovery 380.00 Water 500.00 Methanol Loss 10.00 Effluent water 538.23 (Water-500, Generated water- 0 15.23,Toluene-3,Aluminium isopropoxide-20) Organic Residue 29.77 Process residue-13.77 Distillation residue-16 (Toluene-5, Methanol- 10,Isopropylalcohol-1) Total 1723.00 Total 1723.00

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Material Balance of Terbinafine Hydrochloride Stage-5 Batch Size: 250.00Kgs Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 166.00 Terbinafine Hydrochloride 250.00 Stage-4 126.00 Toluene Recovery 475.00 Toluene 500.00 Toluene Loss 15.00 Potassium carbonate 56.00 Methanol recovery 380.00 Methanol 400.00 Methanol Loss 10.00 Ethyl acetate 500.00 Ethyl acetate Recovery 475.00 Water 450.00 Ethyl acetate Loss 15.00 Inorganic solid waste 59.58 (Potassium chloride-59.58) Effluent water 467.19 (Water-450, Generated water-7.19, Toluene-5, Ethyl acetae-5) Process Emission 17.58 (Carbon dioxide-17.58) Organic Residue 33.65 Process residue-13.65 Distillation residue-20 (Toluene-5, Ethyl acetate -5, Methanol-10) Total 2198.00 Total 2198.00

VALSARTAN Process Description: Stage-1 Step-A:

L-Valine reacts with Thionyl chloride in presence of Toluene to give Step-A product.

Step-B:

Step-A Product reacts with Methanol in presence of water to give Stage-1 Product.

Stage-2:

Stage-1 product reacts with 4-Bromomethyl-biphenyl-2-carbonitrile in presence of Toluene to give Stage-2 product.

Stage-3

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Stage-2 product reacts with Valeryl chloride in presence of Toluene to give Stage-3 product.

Stage-4

Stage-3 product reacts with Sodium azide, Tri butyl tin chloride undergoes Hydrogenation in presence of Toluene, MDC and n-Hexane t give Valsartan.

Route of Synthesis:

Stage-1

Step-A

NH2 NH2 H C OH Toluene H3C Cl 3 + SO + SOCl2 Cl 2 H CH3 O CH3 O

L-Valine Thionyl Chloride 2-Amino-3-methyl-butyryl chloride 64.06 118.97 hydrochloride C5H11NO2 C5H11Cl2NO 117.15 172.0 5

Step-B

NH2 NH2 H3C OCH3 H3C Cl Methanol Cl + HCl Cl + CH3OH H H CH3 O CH3 O

2-Amino-3-methyl-butyryl 32.04 2-Amino-3-methyl-butyric Acid 36.46 chloride methyl ester hydrochloride hydrochloride C6H14NO2Cl C5H11Cl2NO 167.63 172.05

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Stage-2

N

NH2

H3C OCH3 Toluene Cl + + K2CO3 H CH3 O Br

2-Amino-3-methyl-butyric Acid 4-Bromomethyl-biphenyl- Potassium Carbonate methyl ester hydrochloride 2-carbonitrile C H NO Cl 138.21 6 14 2 C14H10BrN 167.63 272.14

N

+ KBr + KCl + CO2 + H2O NH

O

O 18.0 2-[(2-Cyano-biphenyl-4-ylmethyl)-amino]- 119.0 74.55 44.0 3-methyl-butyric acid methyl ester

C20H22N2O2 322.40

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Stage-3 N

O Toluene NH + + NaHCO3 O Cl

O 2-[(2-Cyano-biphenyl-4-ylmethyl)-amino]- Valeryl Chloride Sodium bicarbonate 3-methyl-butyric acid methyl ester

C20H22N2O2 C5H9ClO 84.0 322.40 120.58

N

O O

N + NaCl + CO2 + H2O O

2-[(2-Cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]- 58.44 44.0 18.0 3-methyl-butyric acid methyl ester

C25H30N2O3 406.52

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Stage-4

N

O O Cl Sn N + H2 + NaN3 + O

2-[(2-Cyano-biphenyl-4-ylmethyl)-pentanoyl- Sodium Tributyl tin chloride amino]-3-methyl-butyric acid methyl ester Hydrogen Azide C25H30N2O3 2.0 65.0 C12H27ClSn 406.52 325.5 MDC Toluene

N HN N N

H C N 3 NaCl + Sn + O OH O

Valsartan Tributyl methyl stannane 58.46

C24H29N5O3 C13H30Sn 435.5 305.0

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Flow-Chart L-Valine Thionyl Chloride Methanol Methanol Recovery Toluene Stage-1 Toluene Recovery

Stage-1 4-Bromomethyl-biphenyl- 2-carbonitrile Potassium carbonate Toluene Recovery Stage-2 Toluene Effluent water

Stage-2 Valeryl Chloride Toluene TEA Toluene Recovery Sodium bicarbonate Stage-3 Effluent water Sodium Sulphate Stage-3 Sodium Azide Tri butyl tin chloride Xylene Recovery Hydrogen MDC Recovery Stage-4 Sodium hydroxide Toluene Recovery Xylene Effluent watetr Toluene MDC N-Hexane VALSARTAN Activated Carbon

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VALSARTAN

Material Balance:

Material Balance of Valsartan Stage-1 Batch Size: 100Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg L-Valine 45.00 Stgae-1 51.00 Thionyl Chloride 45.67 Methanol Recovery 380.00 Methanol 409.00 Methanol Loss 12.00 Toluene 400.00 Toluene Recovery 380.00 Toluene Loss 12.00 Process Emission 34.06 (Sulfur dioxide-24.57, Hydrogen 0 Chloride-9.49) Organic Residue 30.61 Process residue -14.61, Distillation residue -16 (Methanol-8, Toluene-8) Total 899.67 Total 899.67

Material Balance of Valsartan Stage-2 Batch Size: 100Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-1 51.00 Stage-2 87.00 4-Bromomethyl-biphenyl-2- 82.77 Toluene Recovery 570.0 carbonitrile Potassium carbonate 42.02 Toluene Loss 20.00 Toluene 600.00 Effluent Water 569.04 Water 500.00 (Water-500,Generated water-5.45, 0 Potassium chloride-22.44, Potassium Bromide-36.15, Toluene-5) Process Emission 13.36 (Carbon dioxide-13.36) 0 Organic Residue 16.39 Process residue -11.39 Distillation residue -5 (Toluene-5) Total 1275.79 Total 1275.79

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Material Balance of Valsartan Stage-3 Batch Size: 100Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-2 87.00 Stage-3 104.00 Valeryl Chloride 32.53 Toluene Recovery 665.00 Toluene 700.00 Toluene Loss 20.00 TEA 20.00 Effluent Water 448.52 Sodium bicarbonate 22.62 (Water-400,Generated water- 4.78, Sodium chloride-15.74, TEA-20,Toluene-8) Sodium Sulphate 10.00 Inorganic Solid Waste 10.00 Water 400.00 (Sodium Sulphate) Process Emission 11.83 (Carbon dioxide-11.83) Organic Residue 12.80 Process residue -5.8, Distillation residue -7 (Toluene-7) Total 1272.15 Total 1272.15

Material Balance of Valsartan Stage-4 Batch Size: 100Kg Name of the input Quantity Name of the out put Quantity in Kg in Kg Stage-3 104.00 Valsartan Pharma 100.00 Sodium Azide 16.55 Toluene Recovery 665.00 Tri butyl tin chloride 83.20 Toluene Loss 20.00 Hydrogen 0.42 MDC Recovery 475.00 Sodium hydroxide 20.00 MDC Loss 15.00 Xylene 240.00 Xylene Recovery 228.00 Toluene 700.00 Xylene Loss 12.00 MDC 500.00 N-Hexane Recovery 190.00 N-Hexane 200.00 N-Hexane Loss 10.00 Activated Carbon 10.00 Effluent Water 832.87 Water 800.00 (Water-800, Sodium Chloride- 0 14.87,Toluene-8, Acetic Acid-10) Spent Carbon 10.00 Organic Residue 116.30 Process residue –99.3 Organic Impurities-21.3, (Tri butyl- methyl –stannane-78) Distillation residue- 17 (Toluene-7, MDC-10) Total 2674.17 Total 2674.17

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ToR AMENDMENT

PRE - FEASIBILITY REPORT

For

EXPANSION OF EXISTING BULK DRUGS & INTERMEDIATES MANUFACTURING UNIT at Survey No: 29, Tupakulagudem (Village), Tallapudi (Mandal), West Godavari (Dist.), Andhra Pradesh

By Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd)

Office address: Duplex No: 29, Lakshmi Gayatri Enclave, Aditya Nagar, KPHB, Kukatpally, Hyderabad

MAY - 2018 Contents

S. No. Description Page no. 1.0 Executive Summary 1 2.0 Introduction of the Proposed Project 2 2.1 Project Proponent 2 2.2 Brief description of the project 3 Need for the project and its importance to the country and or 2.3 3-4 region 2.4 Demand-Supply Gap. 4-5 Employment Generation(Direct and Indirect) due to the 2.5 5 project 3.0 Project description 5 3.1 Product and Production Capacity 8 3.2 Raw materials required and Quantities 11 3.3 Manufacturing Process 11 3.4 Resource – Utilize and Recycling 12 3.4.1 Water 12 3.4.2 Power Requirement 12 3.4.3 Fuel Requirement 12 3.5 Quantity of wastes generated 12 3.5.1 Waste Water Generation and utilization 12 - 13 3.5.2 Solid waste generation and Disposal 13 Schematic representations of the feasibility drawing which 3.6 14 give information of EIA purpose 4.0 Site Analysis 15 4.1 Connectivity 15 4.2 Land Form, Land use and Land ownership. 15 4.3 Existing Infrastructure 15 4.4 Soil classification 15 4.5 Climatic data from secondary sources 15 4.6 Social Infrastructure available 16 5.0 Planning in brief 16 6.0 Proposed infrastructure 16 6.1 Industrial Area 16 6.2 Residential Area 16 6.3 Green Belt 16 6.4 Social Infrastructure 16 - 17 6.5 Water management 17 6.6 Sewerage System 17 6.7 Industrial Waste Management 17 7.0 Rehabilitation and Resettlement (R&R) Plan 17 8.0 Project Schedule and Cost estimate 17 9.0 Analysis of project 17

LIST OF TABLES

Table No Description Page no. 3.1 Proposed Products and Existing Products and their 8 - 10 Production Capacities 3.2 List of By-Products 10 - 11 3.3 Water Requirement Details 13 3.4 Wastewater generation and Treatment Method 13 3.5 Solid and hazardous waste generation and Disposal 13 -14

LIST OF FIGURES

Figure No Description Page no. 1.1 Location Map 6 1.2 Google Earth Map Showing Tagoor Laboratories Private 7 Limited

LIST OF FLOW CHART

Flow Description Page no. Chart No 3.1 Generalized Flow Chart for Bulk Drug Manufacturing 11

Tagoor Laboratories Private Limited Pre Feasibility Report

1.0 EXECUTIVE SUMMARY

Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) is a partnership firm and it is registered office at Duplex No: 29, Lakshmi Gayatri Enclave, Aditya Nagar, KPHB, Kukatpally, Hyderabad Telangana State.

S. No Parameter Description 1 Project Location Survey No: 29, Tupakulagudem (V) Tallapudi (M), West Godavari (Dist.), Andhra Pradesh Category of Project as per 2 EIA Notification & 5(f) “A” Amendments As per Granted ToR: 42 Cores 3 Project cost Amendment Required : 45 Cores 4 Plot area 11.80 Acres (47752.9 Sq.m)

5 Proposed Products Proposed Products List is mentioned in section 3.1 Resources

6 (I)Electricity 2000 KVA Requirement 7 Source of electricity Andhra Pradesh Southern Power Distribution Company Limited (APSPDCL) As per Granted ToR Existing: 250 KVA (Continued) Proposed: 500 KVA D. G. Sets Amendment Required : Existing: 250 KVA (Dropped) Proposed: 1000 KVAX 2 No’S As per Granted ToR: 194.0 KL/day Amendment Required : 377.0 KL/day (II) Water consumption (Water Recovered from Process is 90 KLD & Water Recycled from ZLD System is 119 KLD)

Fresh Water Requirement: 168 KLD As per Granted ToR: Ground Water 8 Source of water Amendment Required : Surface water Allotment from State Government /Ground Water Waste water generation As per Granted ToR: 84.0 KL/day

Page 1 Tagoor Laboratories Private Limited Pre Feasibility Report

Amendment Required : 150.0 KL/day As per Granted ToR: Existing: 6.0 TPH Coal fired/ Agro waste fired Boiler, 2,00,000 kcal/hr. Thermo pack Boiler (Continued); Proposed: 4.0 TPH Coal fired/ Agro waste fired Boiler

(III)Boiler Amendment Required : Existing: 6.0 TPH Coal fired/ Agro waste fired Boiler will be kept as Standby The existing 2,00,000 kcal/hr. Thermo pack Boiler will be Continued Proposed: 12.0 TPH Coal fired/ Agro waste fired Boiler Coal Requirement 9 (IV)Fuel As per Granted ToR: 33.00 TPD Amendment Required : 48.75 TPD 10 Mode of disposal Zero Liquid Discharge System 11 Solid waste generation Mentioned in Para 3.5.2 of report 12 Nearest Highway National Highway NH - 16: 26 KMs (SE) (Rajahmundry – Anakapalle) 13 Nearest Railway Station Kovvuru Railway station – 22.0 KMs (SE) 14 Nearest Airport Rajahmundry Airport – 24.00 KMs (ESE)

2.0 INTRODUCTION OF THE PROJECT The objective of this pre- feasibility study is to provide information on proposed to Expansion of Existing Bulk Drug & Intermediate manufacturing unit of Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) located at Survey No: 29, Tupakulagudem (V) Tallapudi (M), West Godavari (Dist.), Andhra Pradesh.

2.1 Project Proponent

Mr. Penmetsa Subramanyam Raju, Managing partner of the company is young and energetic personality with vast experience in pharmaceutical industry Mr. Subramanya Raju has work experience of more than 18 years in bulk drugs industry. He has worked in senior position as Director-manufacturing in Vasudha group of industries and helped to emerge as one of the leading group in bulk drug

Page 2

Tagoor Laboratories Private Limited Pre Feasibility Report

industry. During his tenure in Vasudha Pharma Chem Limited, he had managed 3 units situated in jeedimetla, kazipally, and Visakhapatnam looking after production, research and development, packing, dispatch of the finished intermediates and APIs at right time, conforming to the specifications. Added to this, he is actively involved in discussing with the customers for extracting business by increasing the yields and reducing production cost to meet the demand of the customers. He has visited many countries in Europe & Asia for exhibiting the bulk drug products. Mr. Subramanyam Raju is also Managing Partner of Sri Venkateswara Industries which manufactures the intermediates & bulk drugs, situated in Hyderabad. Considering his skills and abilities, M/s Shree Jaya Laboratories Pvt Ltd., have offered him the post of Director during February 2012 and he assumed charge of the Director during February 2012 and has taken charge as Chairman during April 2013 looking after the entire production, research and development activities of the organization. He has improved the turnover of the company from 28 crores to 120 crores within a short span of one year.

Mr. Subramanyam Raju is experienced in manufacturing, process development, project management, scale up to operations, quality systems and the aqua culturing technically.

Mr. Subramanyam Raju was also awarded Hon. Doctorate by the international university in Colombo during November 2013. He has also acquired more than 20acres of land in west Godavari district of Tallapudi Mandal for establishment of Vensar and Vensub laboratories for manufacturing APIs. All the relevant licenses for commencement of the units were obtained and the land is made ready for construction works.

Dr. Pericherla Kasiviswanadharaju, the partner of the company is technically qualified person, having rich experience in organic synthesis. He recently finished his Ph. D from prestigious institute BITS Pilani, Rajasthan and his technical background is an additional asset to the industry. Presently, he is involved in purchase, marketing and research and development departments.

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Tagoor Laboratories Private Limited Pre Feasibility Report

2.2 Brief description of the project Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) is proposed to expansion of Existing Bulk Drug & Intermediate manufacturing unit at Survey No: 29, Tupakulagudem (V) Tallapudi (M), West Godavari (Dist.), Andhra Pradesh.

2.3 Need for the project and its importance to the country and region Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) is proposed to expansion of existing Bulk Drug & Intermediate manufacturing unit at Survey No: 29, Tupakulagudem (V) Tallapudi (M), West Godavari (Dist.), Andhra Pradesh.

• Availability of the well-connected road and railway network for easy transportation of the construction equipments and materials, Raw materials and finished products. • Easy availability of skilled and unskilled labor for construction of Plant and its operation. The Indian pharmaceutical industry currently tops the chart amongst India's science- based industries with wide ranging capabilities in the complex field of drug manufacture and technology. A highly organized sector, the Indian pharmaceutical industry is estimated to be worth $ 4.5 billion, growing at about 8 to 9 percent annually. It ranks very high amongst all the third world countries, in terms of technology, quality and the vast range of medicines that are manufactured. It ranges from simple headache pills to sophisticated antibiotics and complex cardiac compounds; almost every type of medicine is now made in the Indian pharmaceutical industry. The Indian pharmaceutical sector is highly fragmented with more than 20,000 registered units. It has expanded drastically in the last two decades. The Pharmaceutical and Chemical industry in India is an extremely fragmented market with severe price competition and government price control The Pharmaceutical industry in India meets around 70% of the country's demand for bulk drugs, drug intermediates, pharmaceutical formulations, chemicals, tablets, capsules, orals, and injectibles. There are approximately 250 large units and about 8000 Small Scale Units, which form the core of the pharmaceutical industry in India (including 5 Central Public Sector Units).

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Tagoor Laboratories Private Limited Pre Feasibility Report

The Indian pharma industry, which is expected to grow over 16 per cent per annum between 2017 and 2020, will outperform the global pharma industry, which is set to grow at an annual rate of 5 per cent between the same period!. The market is expected to grow to US$ 55 billion by 2020, thereby emerging as the sixth largest pharmaceutical market globally by absolute size, as stated Indian Ambassador to the US. Branded generics dominate the pharmaceuticals market, constituting nearly 80 per cent of the market share (in terms of revenues). India has also maintained its lead over China in pharmaceutical exports with a year- on-year growth of 11.44 per cent to US$ 12.91 billion in FY 2015-16, according to data from the Ministry of Commerce and Industry. Imports of pharmaceutical products rose marginally by 0.80 per cent year-on-year to US$ 1,641.15 million. Overall drug approvals given by the US Food and Drug Administration (USFDA) to Indian companies have nearly doubled to 201 in FY 2015-16 from 109 in FY 2014- 15. The country accounts for around 30 per cent (by volume) and about 10 per cent (value) in the US$ 70-80 billion US generics market.

2.4 Demand-Supply Gap.

There is a quite considerable gap between supply and demand for, fine chemicals, bulk drugs and intermediates. Very few players are in the market who can offer continuous supply. The company wants to bridge this gap between demand and supply by expanding the production capacity and thereby, making good business. Company's marketing edge comes from its direct and close contact with the customers. Their products are major strength of their customers. Each stage of their product is been monitored /checked for their quality to ensure quality product reaches their customer. They plan to launch new products every year to satisfy the need of their customers as per the market demand.

2.5 Employment Generation (Direct and Indirect) due to the project Approximate employment generation due to proposed unit is 135. Apart from this there will be significant non estimated employment generation at the supplier firms and service industry providing services to the company. Company shall be giving preference to people from economically weaker sections for employment in various semi-skilled/unskilled jobs thereby contributing to their upliftment.

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Tagoor Laboratories Private Limited Pre Feasibility Report

3.0 Project Description

Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) is proposing the Expansion of existing Bulk Drug and Intermediates Manufacturing Unit with production capacity of 200.0TPM

The Location map is shown at Figure - 3.1 and Google earth map showing Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) plant is shown at Figure - 3.2.

The site central GPS - coordinates are

Latitude: 17009’30.20” North

Longitude: 81035’23.36” East.

The project site does not offer any negative impact on the local area, but rather it has a positive impact on socio economic conditions of the habitants around it because of employment to locals.

The Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) is 26 kms away from National Highway NH – 16 and 22 kms from Kovvuru Railway station.

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Tagoor Laboratories Private Limited Pre Feasibility Report

FIGURE 1.1: LOCATION MAP

Project Site

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Tagoor Laboratories Private Limited Pre Feasibility Report

FIGURE 1.2: GOOGLE EARTH MAP SHOWING TAGOOR LABORATORIES PRIVATE LIMITED

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Tagoor Laboratories Private Limited Pre Feasibility Report

3.1 Proposed Products and Existing Products and their Production Capacities Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) is proposing to Expansion of existing Bulk Drug and Intermediates Manufacturing Unit Capacity of 200.0 TPM and the list of proposed products and Existing Products are shown in Table 3.1 & 3.2.

Table 3.1: Proposed Products and Quantities as per Required TOR Amendment

Production S. Capacity Therapeutic Product Name CAS No. No. Ton / category Month 1 Abacavir sulfate 2.00 188062-50-2 Anti HIV 2 Amitriptyline 10.00 549-18-8 Antidepressant 3 Atrovastatin Calcium 5.00 134523-03-8 Hypercholesterolemia 4 Bupropion 5.00 34841-39-9 Anti depressant 5 carisoprodol 2.00 78-44-4 Muscle Relaxant 6 Clopidogrelbisulfate 5.00 135046-48-9 Antithrombotic 7 Cyclobenzaprine HCl 5.00 6202-23-9 Muscle relaxant 8 Cyproheptadine HCl 10.00 41354-29-4 Anti allergic 9 Desloratadine 5.00 100649-74-8 Antihistamine 10 Domperidone 30.00 57808-69-9 Anti emetic 11 Domperidone maleate 2.00 99497-03-7 Anti emetic 12 Donepezil HCl 1.00 12004-70-3 Alzheimer’s disease 13 Ebastine 5.00 90729-43-4 Anti allergic 14 Esomeprazole Sodium 3.00 161796-78-7 Anti ulcerative Esomeprazole Magnesium 15 3.00 217087-09-7 Anti ulcerative trihydrate 16 Fexofenadine Hydrochloride 15.00 143439-40-8 Anti histamine 17 Haloperidol 2.00 52-86-8 Antipsychotic 18 Itopride Hydrochloride 2.00 122892-31-3 Antispasmodics 19 Itraconazole 10.00 84625-61-6 Antifungal 20 Ketrolac Tromethane 2.00 74103-07-4 Anti Inflammatory 21 Lansoprazole 10.00 103577-45-3 Ant ulcerative 22 Loperamide Hydrochloride 10.00 34552-83-5 Anti diarrhea agent 23 Losartan Potassium 15.00 124750-99-8 Anti Hypertensive 24 Nebivolol HCl 2.00 99200-09-6 Anti Hypertensive 25 Nortriptyline HCl 2.00 894-71-3 Anti depressant 26 Omeprazole 40.00 73590-58-6 Anti ulcerative 27 Omeprazole Sodium 2.00 95510-70-6 Ant ulcerative 28 Omeprazole Magnesium 2.00 95382-33-5 Ant ulcerative

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Production S. Capacity Therapeutic Product Name CAS No. No. Ton / category Month Dihydrate 29 Oxatomide 1.00 60607-34-3 Antihistamine Pantoprazole Sodium 30 20.00 164579-32-2 Ant ulcerative Sesqui Hydrate 31 Pimozide 2.00 2062-78-4 Antipsychotic 32 Pregabalin 2.00 148553-50-8 Epileptic 33 Quetiapine Hemifumarate 2.00 111974-72-2 Antipsychotic 34 Rabeprazole Sodium 15.00 117976-90-6 Ant ulcerative 35 Rupatadine fumarate 2.00 182349-12-8 Antihistamine 36 Telmisartan 2.00 144701-48-4 Anti Hypertensive 37 Terbinafine hydrochloride 15.00 78628-80-5 Anti fungal 38 Valsartan 2.00 137862-59-4 Anti Hypertensive 39 1-Benzy-4-piperidone 5.00 3612-20-2 Drug Intermediate 40 1-Benzyl-4-chloropiperidine 5.00 67848-71-9 Drug Intermediate 41 1-Benzylpiperidin-4-ol 5.00 4727-72-4 Drug Intermediate 42 1-Methylpiperidin-4-amine 5.00 41838-46-4 Drug Intermediate 43 4-Aminopiperidine 5.00 13035-19-3 Drug Intermediate 44 4-Hydroxy piperidine 5.00 5382-16-1 Drug Intermediate 45 4-Phenylpiperidine 1.00 771-99-3 Drug Intermediate 46 4-piperidinopiperidine 1.00 4897-50-1 Drug Intermediate N-tert-Butoxycarbonyl-4- 47 5.00 109384-19-2 Drug Intermediate hydroxy piperidine Total ( Worst Combination of any 12 Products at any 200.00

given point of time)

Note:

The above Listed Products, we will manufacture either Finished Product or any Intermediate stage of finished Product as per given quantity by not increasing the production capacity of 200 MT/Month.

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Table – 3.2. List of By-Products

S. Quantity in Product Name By product No. Kg /Day Clopidogrel Bisulphate 1 Omeprazole Ammonium sulphate 3578.08 Domperidone Domperidone 2 Cyclobenzaprinehydrochloride Sodium bromide 656 Itraconazole Cyclobenzaprinehydrochloride Cyproheptadine 3 Magnesium Chloride 290 Hydrochloride Desloratadine Desloratadine 4 Potassium chloride 226 Ebastine Aluminium chloride solution 5 Ebastine 667 (12%) Itraconazole 6 Potassium bromide 84 Telmisartan Pantoprazole sodium 7 sesquihydrate Domperidone Ammonium chloride 2216 8 Desloratadine Ammonium acetate 234 Pantoprazole sodium Acetic acid 506 8 sesquihydrate Ammonium phosphate 773.50 Sodium methyl sulphate 632 Pantoprazole sodium sesquihydrate 9 Domperidone Sodium acetate 1244.45 Rabeprazole sodium Omeprazole 10 Omeprazole Sodium nitrite 545 11 Domperidone Methanol 182 12 Losartan Potassium Trityl alcohol 326 Total 12160.03

Note:

The By-Products will be produced according to the combination of required products manufacturing.

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3.2 Raw materials required and Quantities

All the raw materials required for manufacturing of above products will be sourced from local market.

3.3 Manufacturing Process The manufacturing process of bulk drugs and Intermediates consists of chemical synthesis extending to stages of processing involving different type of chemical reactions. The generalized Flow chart for bulk drug manufacturing is shown in Flow chart 3.1. Flow Chart 3.1: Generalized Flow Chart for Bulk Drug Manufacturing

3.4 Resource – Utilize & Recycling 3.4.1 Water Water requirement of the project for domestic and industrial activity during operation phase will be 377 KLD. The water requirement will be met through Surface water Allotment from State Government / Ground water sources. The detailed water requirement shown in below Table 3.3

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Table 3.3: WATER CONSUMPTION DETAILS

S.No Purpose Water consumption In KLD 1 Process 152.5 2 Washings 6.0 3 Boiler make up 70.5 4 Cooling towers make up 119.0 5 Scrubbing system 18.0 6 Domestic 6.0 7 Gardening 5.0 Total 377.0 Total Water consumption of 377 KLD. 209 KLD of water will be recovered (from Process: 90 KLD & Water Recycled from ZLD System: 119 KLD). Hence, Total fresh water requirement is 377KLD -209 KLD = 168 KLD.

3.4.2 Power Requirement Power requirement of proposed project will be made available through Andhra Pradesh Southern Power Distribution Company Limited (APSPDCL). The total power requirement for the unit is 2000 KVA respectively

D.G. sets of Existing 250 KVA will be dropped and Proposed to install 1000 KVA DG Set 2 no’s to meet the emergency power requirement of the plant.

3.4.3 Fuel Requirement The existing 6.0 TPH Coal fired/ Agro waste fired Boiler will be kept as standby and 2,00,000 kcal/hr Thermo pack Boiler will be Continued.

Proposed to install 12.0 TPH Coal fired/ Agro waste fired Boiler and total fuel requirement of coal will be around 48.75 MT /Day and it will be procured from local sources.

3.5 Quantity of wastes to be generated

3.5.1 Waste Water Generation and utilization

Total effluent will generate in the project is 150.0 KLD. The treated water will be reused for plant operations.

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The HTDS waste water from Process after neutralization taken for treatment in stripper followed by MEE and ATFD, vapor condensate collected and transferred to Biological Treatment. LTDS waste water including domestic sewage, floor Washes, Utilities waste water taken along with Vapour Condensate from MEE & ATFD for Biological Treatment. Treated effluent from BTP sent to RO, RO permeate collected and RO rejects are sent to MEE followed by ATFD for evaporation and separation of salts. Evaporation salts collected and sent to TSDF. MEE & ATFD vapour condensates collected & reused along with RO permeate in plant operations.

Table 3.4: Waste water generation and Treatment Method Unit HTDS LTDS Effluent Treatment Method KLD KLD Generation in KLD Process 63 35 98 HTDS effluent sent to ETP with MEE System Washings 0 6 6 LTDS effluents treated in Boiler Blow down 0 10 10 ETP – RO Plant / RO Cooling towers Blow Rejects to MEE System 0 15.5 15.5 down and RO permeate to reuse, Condensate from MEE to Scrubbing system 15 0 15 reuse and MEE residue to Domestic 0 5.5 5.5 ATFD. Total 78 72 150

3.5.2 Proposed Solid and Hazardous waste generation and Disposal The types of Solid and Hazardous wastes generated from the project, method of disposal is shown in below table 3.5.

Table 3.5: Proposed Solid / Hazardous waste generation and Disposal

Name of the Quantity S. No Disposal Method Hazardous Waste Organic waste (Process 2211 1 Sent to Cement Industries Residue) Kg/Day 336 2 Spent Carbon Sent to Cement Industries Kg/Day 2001 3 Solvent Distillation Residue Sent to Cement Industries Kg/Day 725 4 Inorganic Waste Sent to TSDF Kg/Day 5 Spent Mixed Solvents 4000 Sent to authorized

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Name of the Quantity S. No Disposal Method Hazardous Waste Kg/Day recyclers/Cement Industries 500 .00 6 ETP Sludge Sent to TSDF Kg/Day 8684 7 MEE Salts Sent to TSDF Kg/Day Organic Evaporative Liquid ( 8 1560 Kg/Day Sent to Cement Industry from MEE Stripper) SPCB Authorized 9 Used Oils 500L/Annum Agencies for Reprocessing/Recycling 800 No’s / After Detoxification sent to Detoxified Containers 10 Month outside agencies. 4 No’s/ Send back to suppliers for 11 Used Lead Acid Batteries Annum buyback of New Batteries Solid waste generation and Disposal 17100 Sent to Brick 12 Ash from boilers Kg/Day Manufacturers

3.6 Schematic representations of the feasibility drawing which give information of EIA purpose.

The applicability of the S.O.1533 for the proposed project was explored by considering different possibilities & provision made in the said notification. Considering the products & project location of the proposed project it is noticed that the proposed project falls under Category 5 (f) “A” of the Schedule-I of EIA Notification S.O.1533.

As per the provision of the SO 1533, it is necessary to get Environmental Clearance by applying to MoEF&CC along with the Environmental Impacts Assessment Study Report for the proposed project prior to commissioning of the project activities. Therefore the EIA is required to conduct to comply with provisions of SO 1533 made for Category 5 (f) “A” of schedule –I of the notification.

4.0. Site Analysis 4.1 Connectivity Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd) located at Survey No: 29, Tupakulagudem (V) Tallapudi (M), West Godavari (Dist.), Andhra Pradesh.

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• Gopavaram village is at a distance of 1.43 KMs in N Direction from the site. • Kovvur is a Town; it is at a distance of 20 KMs in SE side from the project site.

• Site is at a distance of 24 KMs from Rajahmundry in SE direction.

• Nearest State Highway from the site is SH-42 (Koyyalagudem- Nallajerla) at a

distance of 17 KMs in W side from the project site.

• Nearest National Highway from the site is NH-5 (Rajahmundry - Anakapalle) at a

distance of 26 KMs in SE side from the project site.

4.2 Land Form, Land use and Land ownership. The land use of the Area of 11.8 Acres (47752.9 Sq.m) will be permanently changed to industrial purpose.

4.3 Existing Infrastructure.

The Proposed project proposed to Expansion of existing Bulk Drug and Intermediates Manufacturing Unit which is 26 kms away from NH-17 and Mandal head quarter Tallapudi is 8.50 kms (ESE) from the project site.

4.4 Soil classification

The predominant soils in the district are Sandy loams, black cotton soils and coastal sands.

4.5 Climatic data from secondary sources. Annual Max Temp is 36.80C

Annual Min Temp is 19.50C

Normal Annual Rainfall is 1078 mm

4.6 Social Infrastructure available.

Well developed social infrastructure facilities are available at nearby Habitations.

5.0 Planning Brief

Proposed plant activities will be started after getting statutory clearance form related authorities. The project will be completed within two years. Further project

Page 15 Tagoor Laboratories Private Limited Pre Feasibility Report management will take care of all the rules and regulation of statutory authority and provide all necessary control measures

6.0 Proposed Infrastructure

6.1 Industrial Area The infrastructure and other facilities are already well developed in Tallapudi, which is a Mandal head quarter.

6.2 Residential Area The employees who will work in the industry are from nearby villages and hence no proposal for residential area for employees.

6.3 Green Belt: 16461.5 SQM (34.50 %) of Green Belt will be developed and maintained.

6.4 Social Infrastructure: Facilities like roads, communication, Banks, ATM's and medical facilities are available.

Amenities:

Education Schools including middle, secondary and higher secondary schools, social welfare hostels

Medical and Health Community Health Centre & Primary Health center are available in Tallapudi which is 8.50 kms ESE of proposed project site.

Power and water- All the villages are electrified and drinking water facilities are extended to all villages.

Rail and Road- The project site is very well connected by road through National Highway No. 16 and nearest railway station is Kovvur.

6.5 Water management Water requirement will be met through ground water.

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6.6 Sewerage System: There will be no discharge of industrial effluent as company proposing Zero Liquid Discharge (ZLD) system. The treated effluent will be reused.

6.7 Industrial Waste Management: Due to proposed project, the effluent from cooling and Plant/Equipment washing will be generated and treated in the well designed Effluent Treatment Plant. The treated effluent will be reused.

7.0 Rehabilitation and Resettlement (R & R) Plan Rehabilitation & Resettlement (R & R) plan is not applicable to this proposed project.

8.0 Project Schedule & Cost Estimates

Proposed project activities will be started after getting statutory clearance form related authorities. The project will be completed within two years.

The project cost for proposed Project is 4500 Lakhs (45 Crores) will be used for constructing additional building, Equipments & misc.

9.0 Analysis of Benefits to proposal  Local people will get direct financial benefit by way of employment.  Local people will get some contracts of supply and services to get indirect income.  Company will contribute in improving education and health facilities in nearby area.

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