121) ANISOLE (CAS Number : 100-66-3)
ROS :-
OCH 3 OH TOLUENE NaHSO4 + CH3SO4Na + sodium methyl sulfate 120gm/mole Phenol 134 Anisole Mol wt :- 94gm/mole Mol wt :- 108 gm/mole
Process :-
Take phenol, sodium methyl sulfate & toluene in Reactor. Heating reflux & Mataintane for 14-hrs at reflux temp. cool to RT. Centrifuge salt .distilled solvent product distilled .collect product & packing.
Flow diagram :-
Phenol - 500kg CH3SO4Na-712 kg
Toluene -500kg Reactor
Maintaine-110 ° C
Maintain &
Centrifuge NaHSO4 SALT - 600kg
Loss -10 kg Reactor Recover of toluene -480 kg
Product-500kg Effluents – 122 kg
Mass Balance :-
INPUT QTY OUTPUT QTY
Phenol 500 kg Product 500 kg
Toluene 500 kg Recover Toluene 480 kg
Ch3SO4Na 712 kgs NaHso4 salt 600 KG
effluent 122 kg
loss 10 kg
TOTAL 1712 KG 1712 KG
122)VERATROLE (CAS Number: 91-16-7)
ROS :-
OCH 3 OH OCH OH TOLUENE 3 2NaHSO4 + 2CH3SO4Na + sodium methyl sulfate 120gm/mole Catechol 134 Veratrole Mol wt :- 110gm/mole Mol wt :- 138 gm/mole
Process :-
Take Catechol, sodium methyl sulfate & toluene in Reactor. Heating reflux & Mataintane for 14-hrs at reflux temp. cool to RT. Centrifuge salt .distilled solvent product distilled .collect product & packing.
Flow diagram :-
Catechol - 560kg CH3SO4Na-1364 kg
Toluene -1000kg Reactor
Maintaine-110 ° C
Maintain &
Centrifuge NaHSO4 SALT - 1100kg
Reactor Recover of toluene -980 kg Loss-10 kg Effluents - 334kg Product-500kg
Mass Balance :-
INPUT QTY OUTPUT QTY
Catechol 560 kg Product 500 kg
Toluene 1000 kg Recover Toluene 980 kg
CH3SO4Na 1364 kgs NaHso4 salt 1100 KG
effluent 334 kg
loss 10 kg
TOTAL 2924 KG 2924 KG
123) 3-methoxy-4-hydroxy-benzaldehyde(Vanillin) (CAS Number : 121-33- 5)
ROS :-
OH 2NaoH (40) OH CHO OCH 3 TOLUENE OCH 3 + + 2NaHSO4 + 2H2O HOOC 2H2SO4 (18) (98) 120gm/mole OH guaiacol glyoxylic acid HOOC 124 78 3- methoxy-4-Hydroxy mandelic acid 198 METHANOL NaoH O2 GAS (40) H2SO4 (98)
OH OCH NaHSO4 3 + +CO2(44)+2H2O(18) 120gm/mole
CHO 3- methoxy-4-Hydroxy Benzaldehyde
153
Process :-
Take 50 % glyoxylic acid & water in reactor. drop wise addition of 50 % sodium hydroxide solution at 10-20 C & Take Guaiacol & water in reactor. drop wise addition of 50 % sodium hydroxide solution at 10-20 C . In this solution above solution at 10-20 C. Stir for 27 hrs at 10-20C. Set PH-4-5 By 50 % H2SO4 . centrifuge & dry .Take above stage , methanol , copper oxide & NaoH in reactor. Hetaing to reflux. Oxygen gas passed for 24 hrs. distilled solvent. Charge water set ph-1-2 by50 % H2SO4 . stir for at 0-10 C. centrifuge & dry .Packing
Flow diagram :-
Glyoxylic acid (50%)-600 kg NaoH+ Water-200 kg+200kg
Reactor
Guaiacol+ water -476kg+450 kg
NaoH+ Water-200 kg+200kg Reactor NaHSO4 SALT - 1100kg
50% H2SO4-2000kg Effluent - 1900kg Centrifuge & dry NaoH-200 kg Oxygen -50 kg Methanol -1000 kg
Copper oxide -50 kg Reactor
Water -500 kg Recover of methanol -950 kg
50% H2SO4 -1000 kg Reactor NaHSO4 SALT - 550kg
Centrifuge Effluent - 900kg Loss -15 kg & dry
Effluents - 761kg Product-500kg
Mass Balance :-
INPUT QTY OUTPUT QTY
Glyoxylic acid(50%) 600 kg Product 500 kg
Guaiacol 476 kg Recover methanol 950 kg
NaoH 600 kg Effluent 3561 kg
50 %H2SO4 3000kgs NaHso4 salt 1650 KG
WATER 900 kgs
Methanol 1000 kg loss 15 kg
Copper oxide 50 kg
Oxygen 50 kg
TOTAL 6676 KG 6676 KG
124)ETHYL VANILLIN (CAS Number : 121-32-4)
ROS :-
OH 2NaoH (40) OH CHO OC 2H5 TOLUENE OC 2H5 + + 2NaHSO4 + 2H2O HOOC 2H2SO4 (18) (98) 120gm/mole OH guaithol glyoxylic acid HOOC 138 78 3- ethoxy-4-Hydroxy mandelic acid 212 METHANOL NaoH O2 GAS (40) H2SO4 (98)
OH OC H NaHSO4 2 5 + +CO2(44)+2H2O(18) 120gm/mole
CHO 2-ethyl Vanillin
166
Process :-
Take 50 % glyoxylic acid & water in reactor. drop wise addition of 50 % sodium hydroxide solution at 10-20 C & Take Guaithol & water in reactor. drop wise addition of 50 % sodium hydroxide solution at 10-20 C . In this solution above solution at 10-20 C. Stir for 27 hrs at 10-20C. Set PH-4-5 By 50 % H2SO4 . centrifuge & dry .Take above stage , methanol , copper oxide & NaoH in reactor. Hetaing to reflux. Oxygen gas passed for 24 hrs. distilled solvent. Charge water set ph-1-2 by50 % H2SO4 . stir for at 0-10 C. centrifuge & dry .Packing
Flow diagram :-
Glyoxylic acid (50%)-565 kg NaoH+ Water-200 kg+200kg
Reactor
Guaithol+ water -500kg+450 kg
NaoH+ Water-200 kg+200kg Reactor NaHSO4 SALT - 1100kg
50% H2SO4-2000kg Effluent - 1900kg Centrifuge & dry NaoH-200 kg Oxygen -50 kg Methanol -1000 kg
Copper oxide -50 kg Reactor
Water -500 kg Recover of methanol -950 kg
50% H2SO4 -1000 kg Reactor NaHSO4 SALT - 550kg
Centrifuge Recover water - 900kg Loss -20 kg & dry
Product-500kg Effluents - 745kg
Mass Balance :-
INPUT QTY OUTPUT QTY
Glyoxylic acid(50%) 565 kg Product 500 kg
Guaithol 500 kg Recover methanol 950 kg
NaoH 600 kg effluent 3545 kg
50 %H2SO4 3000kgs NaHso4 salt 1650 KG
WATER 900 kgs
Methanol 1000 kg loss 20 kg
Copper oxide 50 kg
Oxygen 50 kg
TOTAL 6665 KG 6665 KG
125)3,4-methylenedioxy Benzaldehyde(Piperonal) (CAS Number 120- 57-0)
ROS :-
O 2NaoH (40) O CHO O O TOLUENE + + 2NaHSO4 + 2H2O HOOC 2H2SO4 (18) (98) 120gm/mole OH 1,2 -dimethylene glyoxylic acid dioxy benzene HOOC 78 122 3,4-methlene dioxy mandelic acid 182 METHANOL NaoH O2 GAS (40) H2SO4 (98)
O O NaHSO4 + +CO2(44)+2H2O(18) 120gm/mole
CHO 3,4-methylenedioxy Benzaldehyde
150
Process :-
Take 50 % glyoxylic acid & water in reactor. drop wise addition of 50 % sodium hydroxide solution at 10-20 C & Take 1,2-methylene dioxy benzene & water in reactor. drop wise addition of 50 % sodium hydroxide solution at 10-20 C . In this solution above solution at 10-20 C. Stir for 27 hrs at 10-20C. Set PH-4-5 By 50 % H2SO4 . centrifuge & dry .Take above stage , methanol , copper oxide & NaoH in reactor. Hetaing to reflux. Oxygen gas passed for 24 hrs. distilled solvent. Charge water set ph-1-2 by50 % H2SO4 . stir for at 0-10 C. centrifuge & dry .Packing Flow diagram :-
Glyoxylic acid (50%)-600 kg NaoH+ Water-200 kg+200kg
Reactor
1,2 -methylene dioxy benzene + water -476kg+450 kg
NaoH+ Water-200 kg+200kg Reactor NaHSO4 SALT - 1100kg
50% H2SO4-2000kg Effluent - 1900kg Centrifuge & dry NaoH-200 kg Oxygen -50 kg Methanol -1000 kg
Copper oxide -50 kg Reactor
Water -500 kg Recover of methanol -950 kg
50% H2SO4 -1000 kg Reactor NaHSO4 SALT - 550kg
Centrifuge Effluent - 900kg Loss -20 kg & dry
Effluents - 756kg Product-500kg
Mass Balance :-
INPUT QTY OUTPUT QTY
Glyoxylic acid(50%) 600 kg Product 500 kg
1,2-methylene dioxy benzene 476 kg Recover methanol 950 kg
NaoH 600 kg Effluent 3556 kg
50 %H2SO4 3000kgs NaHso4 salt 1650 KG
WATER 900 kgs loss 20 kg
Methanol 1000 kg
Copper oxide 50 kg
Oxygen 50 kg
TOTAL 6676 KG 6676 KG
37
126) ROS :- 1-[3-(benzyloxy)propyl]-5-formylindoline-7-Carbonitrile CHO CHO
CuCN(89.56) N + CuBr N dimetylformamide 143.45 CN Br
O O
C6H5 C6H5
1-[3-(benzyloxy)propyl]-7-bromo 1-[3-(benzyloxy)propyl]-5-formylindoline indoline-5-Carbaldehyde -7-Carbonitrile 20 20 2 2 MF:-C 19 H20 BrNO 2 MF:-C H N O FW:-374.271 FW:-320.385
Manufacturing Process :-
Reaction of 1-[3-(benzyloxy)propyl]-7-bromoindoline-5-Carbaldehyde(brom.indo) with copper(I)cyanide in dimetylformamide ,further upon work up will give crude 1-[3- (benzyloxy)propyl]-5-formylindoline-5-Carbonitrile (cyano aldehyde). Finally purification of crude will give pure 1-[3-(benzyloxy)propyl]-5-formylindoline-7-Carbonitrile (cyano aldehyde).
NAME OF Raw material :-
1) - 1-[3-(benzyloxy)propyl]-7-bromoindoline-5-Carbaldehyde
2)- DMF
3) - Coppercyanide
4)- Methanol
Flow diagram :-
1-[3-(benzyloxy)propyl]-7- DMF 1000 kg bromoindoline-5-Carbaldehyde 625 kg Coppercyanide 150 kg
Reactor
Efflu ent -300 kg Centrifuge Recovery of DMF -950 kg Salt 120 kg
Technical Dry wt 510 kg
Technical 510 kg Methanol 10 00 kg
Reactor
Recovery of Methanol -950 kg Loss-35 kg Centrifuge Residue 40 kg Dry wt 500 kg
1-[3-(benzyloxy)propyl]-5-formylindoline-7-Carbonitrile INPUT kg OUTPUT kg 1-[3-(benzyloxy)propyl]-7- 625 Effluent 300 bromoindoline-5-Carbaldehyde DMF 1000 Recovery of DMF 950 Coppercyanide 150 Salt 120 Methanol 1000 Recovery of Methanol 950 Residue 40 Product 500 loss 35
TOTAL 2775 2775
127)ROS :- dimethyl formamide di-tert- butyl Acetal
Step :-1
H C O O 3 H3C N CHO N CHO . H C OS O + H3C OS O 3 H3C H C O 3 O H C N, N Di-methyl formamide H3C 3 MOL FOR :- C 3H7NO Dimethyl sulfate DMF.DMS Complex
MOL WT :- 73 gm/mole MOL FOR :- C 2H6O4S MOL FOR :- C 2H6O4S MOL WT :- 126 gm/mol MOL WT :- 199 gm/mole
Step :-2 CH3 tert-Butanol H3C O (74.21) N H C H3C 3 H3C CH3 N CHO . H3C OS O + OK O O CH H C H C 3 3 O H C 3 3 CH CH3 H3C 3 CH3 Potassium-tert -butoxide dimethyl formamide di-tert- DMF.DMS Complex butyl Acetal MOL FOR :- C 4H9OK MOL FOR :- C 2H6O4S MOL FOR :- C 11 H25 O2 N MOL WT :- 112.21 gm/mole MOL WT :- 199 gm/mole MOL WT :- 203.52 gm/mole
O
H3C OS O + KOH(56) O H3C
MOL WT :- 126 gm/mol
Manufacturing Process :-
Take DMF in Rector and drop wise addition DMS for 3-hrs at RT. Heating to 85 ˚C. Maintaining for 3 hours at 85 ˚C.Cool to RT. Take t-butanol and Potassium tert- buoxide U/N 2 .Heating to 65-70 ˚C for 30 min. drop wise addition DMF-DMS complex for 3-hrs at 30-35 ˚C for 3 hours U/N 2.stirr for 30 min. Heating to reflux 80-85 ˚C. Maintaining for 40 hours at 80-85 ˚C.cool to RT.Filter the rxm . bed wash with t-butanol. Fractional distillation. t-butanol reused.
NAME OF Raw material :-
1) - N,N Dimethtyl formimade-203 KG
2)- Dimethyl sulfate
3) - t-butanol
4)- DMF-DMS Complex
5)- Potassium tert- buoxide
Flow diagram :-
N,N Dimethtyl formimade-203 KG Dimethyl sulfate-350 kg
Reactor
Reactor
DMF - DMS Complex - 553 kg t-butanol -1500 kg DMF-DMS Complex-553 kg
Potassium tert- Reactor buoxide- 320 kg
Reactor
Centrifuge SALT-400kg
Recover Of t-butanol- 1450 kg reused Reactor Loss- 3 kg Residue 20Kg
Product- 500kg
Dimethyl formamide di-tert- butyl Acetal INPUT kg OUTPUT kg N,N Dimethtyl formimade 203 Recover Of t-butanol 1450 Dimethyl sulfate 350 Residue 20 t-butanol 1500 SALT 400 Potassium tert- buoxide 320 Product 500 loss 3
TOTAL 2373 2373
54
128) ROS :- AFATINIB DIMALEATE
F F O Cl NH NMe 2 O NH Cl NH NMe 2 N 2Maleic acid (116), NH Ethanol N N O N O HO O O O 2 (S,E)-N-(4-(3-Chloro-4-fluorophenyla O OH mino)-7-(tetrahydrofuran-3-yloxy)qui nazolin-6-yl)-4-(dimethylamino)but-2 Afatinib dimaleate -enamide Afatinib 718 486
Manufacturing Process :-
To a Solution of Afatinib in Methanolis added maleic acid in Methanol slowly. The Separated Solid is filtered and Washed with ethanol to get Afatinib dimaleate.
Flow diagram :-
305Kg (S,E)-N-(4-(3-Chloro-4- maleic acid +Methanol fluorophenylamino)-7- 120Kg+120 kg (tetrahydrofuran-3-yloxy)quinazolin- 6-yl)-4-(dimethylamino)but-2- enamide Afatinib Reactor Methanol 600KG
Centrifuge Recover of MeOH 630 KG
Loss 15 KG
Dry Wt :- 500 kg
NAME OF Raw material :-
1)- (S,E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3- yloxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide
2)- Methanol
3)- maleic acid
Mass Balance :-
AFATINIB DIMALEATE INPUT kg OUTPUT kg (S,E)-N-(4-(3-Chloro-4- 305 Recover of MeOH 630 fluorophenylamino)-7- (tetrahydrofuran-3- yloxy)quinazolin-6-yl)-4- (dimethylamino)but-2-enamide Afatinib
Maleic Acid 120 Dry Wt 500 Methanol 720 loss 15
TOTAL 1145 1145
129) ROS :- Arbutin
AC O BF3 AC O O OAC O OAC Etherate O AC O OH + OAC TEA + OAC AC O OAC OAC MDC O2(g) Monoacetyl hydroquinone OAC Pentaacetyl-B-D-glucose 32 MOL FOR :- C7H8O2 Penta acetyl arbutine C16 H22 O11 MOL WT :- 124.14 g/mol MOL FOR :- MOL FOR :- C22 H26 O12 MOL WT :- 390.34 g/mol MOL WT :- 482 g/mol
NaoH
5H2O(18)
HO O O OH 5CH3COOH + OH 60 HO HO Arbutin MOL FOR :- C12 H16 O7 MOL WT :- 272.25 g/mol
Manufacturing process:- Arbutin
Take Pentaacetyl-B-D-glucose and Monoacetyl hydroquinone in dried MDC stirr it make Clear solu Add Triethyl amine Chill to 20 ℃ Add BF3 etherate Soln Reflux for 24 hours chill to 20 ℃ Add Water Separate Organic & Aq Layer give Water Wash to organic Layer Distill out MDC Recrystallise in Toluene mp – 145 – 148 ℃
Take This Product in Methanol Add Sodium Methoxide 25% Solu Reflux for 6 hours distill out Methanol this is Tech Product Add Water and isolate the Product.
FLOW CHART :- Arbutin
BF3 - etherate 5 kg MDC 1000 kg
Pentaacetyl-B-D-glucose 780 kg Monoacetyl hydroquinone 250 kg Tri ethyl amine 204 kg GLR Water 500 Lit
MDC -900 kgReuse Isolation 925 kg LOSS -180 kg Sodium Methoxide 10 kg Methanol 800 kg
Product Recover methanol-720 kg Reuse Water 500 Lit Loss -180 kg Isolation Effluent -900 kg Reuse
Effluent 849 kg Arbutin 500 kg
NAME OF Raw material :- Arbutin
1)- Monoacetyl hydroquinone 2)- Pentaacetyl-B-D-glucose 3)- BF3 - etherate
4)- TEA ( Tri ethyl amine)
5)- MDC
6)- Sodium Methoxide Mass Balance Arbutin INPUT kg OUTPUT kg Monoacetyl hydroquinone 250 Dry Wt 500 BF3 - etherate 5 Recover of MDC 900
Pentaacetyl-B-D-glucose 780 Recover Methanol 720
MDC 1000 loss 180 Tri ethyl amine 204 Sodium Methoxide 10 Effluent 1749 Water 1000 Methanol 800 TOTAL 4049 4049
1
130) ROS :- AGOMELATINE
CH 2CN CH 2CH 2NHCOCH 3 CH 2-CH 2-NH 2 OMe OMe H3CO Raney Ni + HCL(36.5) 2H2(2) CH3COCl 7-Methoxy-1-naphthylacetonitrile 78.5 Agomelatine 201 197 243
Manufacturing Process :-
Catalytic hydrogenation of (7-Methoxy-1-naphthyl) acetonitrile using Methanol and Ammonia gives 2-(7-Methoxy-1-naphthyl) ethanamine. Condensation of 2-(7-Methoxy-1- naphthyl) ethanamine with acetyl chloride in presence of base gives crude Agolelatine. Which on purification gives final Agomelatine API.
NAME OF Raw material :-
1)- 2-(7-Methoxy-1-naphthyl) acetonitrile
2)- 2-(7-Methoxy-1-naphthyl) ethanamine
3)- Methanol
4)- Ammonia
5)- Raney Ni
6)- Acetyl chloride
Flow diagram :-
2-(7-Methoxy-1-naphthyl) acetonitrile Methanol + Ammonia 1500Kg
445Kg Raney Ni 50Kg
Auto Clave
Sparkles filter
Distiled Recover Meoh+NH 3 1450 kg Reactor 425Kg Recover catalyst 60 Kg 2-(7-Methoxy-1-naphthyl) ethanamine TechnicalAcetyl chloride Wate- 246 kg 425Kg 145Kg GLR Scrubber HCl gas-82 kg
Chilled Total -328 kg Centrifuge Residue 20Kg
Agomelatine - Crude 511 Kg Agomelatine-Crude 511 Kg MeoH 1500Lit
Reactor
Chilled 5 to10 Centrifuge Recover Meoh 1450 Lit Effluent-495Kg
Wet cake LOSS- 90Kg
Dry wt 500Kg
AGOMELATINE INPUT kg OUTPUT kg 2-(7-Methoxy-1-naphthyl) 445 Recover Meoh+NH 3 1450 acetonitrile 2-(7-Methoxy-1-naphthyl) 425 Re use catalyst 60 ethanamine Methanol + Ammonia 1500 Residue 20 Raney Ni 50 Recover Meoh 1450 Meoh 1500 Product 500 Acetyl chloride 145 effluent 495 Loss 90 TOTAL 4065 4065
50
131)ROS :- APIXABAN
CH CH O 3 O 3
N N O O Ethylene Glycol N O N O N N N NH 3(17) N H2O O
COOEt H2N Ethyl Apixaban 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxo MOL FOR :- C25 H25 N5O4 piperidine-1-yl)phenyl)-4,5,6,7 MOL WT :- 459.71 tetrahydro-1H-pyrazolo[3,4-c]pyridine- 3-Carboxylate + CH3CH3OH MOL FOR :- C27 H28 N4O5 47 MOL WT :- 488.53
Manufacturing Process :-
Ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidine-1-yl)phenyl)-4,5,6,7 tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-Carboxylate reacts with Ammonia in Presence of Ethylene glycol to give an intermediate which gets converted into Apixaban under ammonia Pressure.
NAME OF Raw material :-
1) - Ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidine-1- yl)phenyl)-4,5,6,7 tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-Carboxylate
2)- Ethylene glycol
3) - Ammonia
4)- Water
Flow diagram :-
Ethyl 1 -(4 -methoxyphenyl) -7-oxo - Ethylene glycol -1000kg 6-(4-(2-oxopiperidine-1-yl)phenyl)- NH3 solu 1400kg 4,5,6,7 tetrahydro-1H-pyrazolo[3,4- c]pyridine-3-Carboxylate Reactor 555 kg
Recovery of Ethylene glycol -950 kg Loss 25 kg Centrifuge effluent -1480Lit
DRY WT -500 KG Mass Balance :-
APIXABAN INPUT kg OUTPUT kg Ethyl 1-(4-methoxyphenyl)-7- 555 Recovery of Ethylene glycol 950 oxo-6-(4-(2-oxopiperidine-1- yl)phenyl)-4,5,6,7 tetrahydro- 1H-pyrazolo[3,4-c]pyridine-3- Carboxylate Ethylene glycol 1000 effluent 1480 NH3 solu 1400 Product 500 loss 25
TOTAL 2955 2955
2 132 )ROS :- Aripiprazole
+ Nal l NaCl N + Cl OO OON H H 7-(4-Chlorobutoxy)-3,4-dihydro- Sodium iodide 7-(4-iodobtoxy)-3,4-dihydro- Sodium Chloride 2(1H)-quinolinone 2(1H)quinolinone MOL FOR :- Nal MOL FOR :- NaCl MOL FOR :- C13 H16 ClNO 2 MOL FOR :- C13 H16 lNO 2 MOL WT :- 149.89 MOL WT :- 58.5 MOL WT :- 253.72 MOL WT :- 345.18
HN Cl Cl Potossium N Carbonate Cl N l DMF/Process N + HCL. OO Cl N H Water O N O 1-(2,3-Dichlorophenyl Aripiprazole-Crude H 7-(4-iodobtoxy)-3,4-dihydro- piperazine hydrochloride 2(1H)quinolinone MOL FOR :- C23 H27 Cl 2N3O2 MOL FOR :- C10 H13 Cl 3N2 MOL FOR :- C13 H16 lNO 2 HI(128) MOL WT :- 264.58 MOL WT :- 448.39 + MOL WT :- 345.18 + HCL(36.5)
Acetonitrile Cl N Cl N Cl N O O N Cl N H O N O Aripiprazole-Crude H Aripiprazole-Technical MOL FOR :- C23 H27 Cl 2N3O2 MOL FOR :- C23 H27 Cl 2N3O2 MOL WT :- 448.39 MOL WT :- 448.39
Ethyl alcohol/DM Water Cl N Activated charcoal/Hyflo Cl N Cl N N O Cl N O O N O H H Aripiprazole-Technical Aripiprazole MOL FOR :- C23 H27 Cl 2N3O2 MOL FOR :- C23 H27 Cl 2N3O2 MOL WT :- 448.39 MOL WT :- 448.39
Manufacturing Process :-
Stage :- 1 :- Preparation of Aripiprazole crude
7-(4-Chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone Condenses with 1-(2,3- dichlorophenyl)piperazine hydrochloride in presence of potassium carbonate, N,N- dimethylformamide and sodium iodide to yield Aripiprazole crude.
Stage :- 2 :- Preparation of Aripiprazole technical
Aripiprazole crude in heated with acetonitrile to yield pure Aripiprazole technical.
Stage :- 3 :- Purification of Aripiprazole
Aripiprazole technical obtained is purified with ethanol to yield pure Aripiprazole .
NAME OF Raw material :-
1)- 7-(4-Chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone
2)- 1-(2,3-dichlorophenyl)piperazine HCL
3)- N,N-dimethylformamide
4)- Potassiumcarbonate
5)- Water
6)- Acetonitrile
7)- IPA
8)- Charcol
9)- Hyflow
Flow diagram :- step:-1
425Kg 326Kg 7-(4-Chlorobutoxy)-3,4-dihydro- 1-(2,3-dichlorophenyl)piperazine HCL
2(1H)-quinolinone Potassiumcarbonate N,N-dimethylformamide Reactor 170Kg 850 lit Water 850 Lit Reactor
Recover of dmf 800 Lit Centrifuge Effluent 1250 Kg
Wet cake
Dry Wt 525 kg
Flow diagram :- step:-2
525Kg 1050 Lit Acetonitrile Aripiprazole crude
step:-1 Water -183 kg Potassiumcarbonate Reactor 170Kg Hcl gas -61 kg Scrubber Cool& chill
Recover of acetonitrile 1000Lit Total-244 kg Centrifuge Residue 30kg
Wet cake Loss -56 kg Effluent -51 kg
Dry Wt 511 kg
Flow diagram :- step:-3
511 Kg 1550Lit Aripiprazole crude IPA step:-2 Charcol 50Kg Reactor
Hyflow Heating
Sparkler filter
Chling 5 to 10 Recover of Ipa 1480 Lit Reactor Residue 50 Kg
Centrifuge
Wet cake
Dry Wt 500 kg Mass Balance
Aripiprazole INPUT kg OUTPUT kg 7-(4-Chlorobutoxy)-3,4-dihydro- 425 Recover of dmf 820 2(1H)-quinolinone
1-(2,3-dichlorophenyl)piperazine 326 Recover of Ipa 1480 HCL N,N -dimethylformamide 850 Efflu ent 1545 Potassiumcarbonate 170 Recover of acetonitrile 1000 Water 850 Residue 80 Charcol 50 Carbon 60 Acetonitrile 1050 Dry Wt 500 Potassiumcarbonate 170 loss 56 IPA 1550
TOTAL 5441 5441
1
133) ROS :- ASENAPINE
O O O NaNO2 Conc.HCL(36.5) Cl H H O N H H 2 Pd/(10%),3H2(2) H2N H H Cuprous Chloride +NH4CL Ethyl acetate,Liq Ammoni N 53 N Methanol,Sodium gel,Cyclohexane,Ethyl hydroxide,Dichloro N acetate for Purification by CH CH methane 3 3 CH3 Columm Trans-5-Chloro-2-methyl-2,3,3a, Trans-2-methyl-5-nitro-2,3,3a, Trans-2-methyl-5-amino-2,3,3a, Chromatography,n-Butyl 12b-tetrahydro-1H-dibenz[2,3:6, 12b-tetrahydro-1H-dibenz[2,3: 12b-tetrahydro-1H-dibenz[2,3:6, alocohol 7]oxepino[4,5-c]-pyrrole 6,7]oxepino[4,5-c]-pyrrole 7]oxepino[4,5-c]-pyrrole 2H2O MOL FOR :- C17 H16 ClNO + MOL WT :- 285.76 MOL FOR :- C17 H16 N2O3 MOL FOR :- C17 H18 N2O3 36 MOL WT :- 296.32 MOL WT :- 266.33 Maleic acid(116) Activated carbon n-Butyl alcohol
O
Cl H H COOH
N
CH3 COOH Trans-5-Chloro-2-methyl-2,3,3a,12 b-tetrahydro-1H-dibenz[2,3:6,7]oxe pino[4,5-c]-pyrrole maleate(crude) MOL FOR :- C21 H20 ClNO 5 MOL WT :- 401.84 O O
n-Butyl alcohol H H Cl COOH H H Cl COOH Activated Carbon N N COOH CH3 COOH CH3 Trans-5-Chloro-2-methyl-2,3,3a,12 Trans-5-Chloro-2-methyl-2,3,3a,12 b-tetrahydro-1H-dibenz[2,3:6,7]oxe b-tetrahydro-1H-dibenz[2,3:6,7]oxe pino[4,5-c]-pyrrole maleate pino[4,5-c]-pyrrole maleate(crude) MOL FOR :- C21 H20 ClNO 5 MOL FOR :- C21 H20 ClNO 5 MOL WT :- 401.84 MOL WT :- 401.84
Manufacturing Process :-
Stage :- 1 :- Preparation of Trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H- dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole maleate(Crude)
Trans-2-methyl-5-nitro-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]- pyrrole in Methanol, is added 10% palladium charcoal (50% wet) and hydrogenated under hydrogen pressure (8-10 kg/cm 2 at 25-30 ℃ till the completion of reaction. The Catalyst is removed by filtration through Hyflow and filtrate is distilled out under vacuum to give residue, which is Partitioned between dichloromethane and dilute Sodium hydroxide. Distillation of organic layer under vacuum yielded Trans -2-methyl-5-amino-2,3,3a,12b- tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole as an oil. Dichloromethane is stripped out with Process Water from the oil, the oil is taken in Conc. Hydrochloric acid and a Solution of Sodium nitrite in Process Water is added to it at 0-5℃ (Diazonium Solution) Meanwhile a Solution of Cuprous Chloride in Conc. Hydrochloric acid is Prepared and above diazonium Solution is added at 0-5℃ Reaction mixture is allowed to stir at 20-25 ℃ till the Completion of reaction. Reaction is quenched with simultaneous addition of ethyl acetate and liq. Ammonia to bring basic pH. Organic layer is Separated, Stirred with activated Carbon and filtered through Hyflow bed Distillation of organic layer under vacuum gave crude free base, which is purified by column Chromatography using 35% ethyl acetate in Cyclohexane as an eluent. The pure free base Preparation of Trans-5-chloro-2-methyl- 2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole is obtained as an oil, which is unloaded in n-Butyl alcohol for the next reaction. The oil in n-Butyl alcohol is heated to 60-65 ℃ after adding activated Carbon and filtered through Hyflow bed. This Solution is added slowly to Previously prepared solution of Maleic acid in n-Butyl alcohol at 40-45 ℃ After maintaining for 30 min. at same temperature, the reaction mixture is cooled gradually to 25-35 ℃ within 3-4 hrs and followed by addition of seed crystal of standard Asenapine maleate gave solid The obtained Asenapine maleate crude is filtered and washed with n- Butyl alcohol and dried.
Stage :- 2 :- Preparation of Trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H- dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole maleate
Trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5- c]-pyrrole maleate is purified by taking it into n-Butyl alcohol and heated at 60-70 ℃ till clear or hazy Solution. The activated Carbon is added and allowed to stir the reaction mixture at same temperature. Carbon is removed by filtration though Hyflow bed and filtrated is allowed to stir at 25-30 ℃. The obtained solid is filtered and Washed with n-Butyl alcohol and dried to give Asenapine maleate.
Flow diagram :-
Trans-2-methyl-5-nitro-2,3,3a,12b- tetrahydro-1H- 395Kg 40Kg 10% palladium charcoal(50% wet) dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole 15Kg H2 Pressure(8-10 kg/cm 2
Auto Clave 1200Lit Methanol
sparkler Filter Distill of
Distillation
Reactor Recover of Meoh 1150 Lit
1200Litr Dichloromethane Dilute NaoH soln 600Lit(10% Reactor
Distillation Recover of MDC 1150Litr Oil 340Kg Residue 80Kg Effluent 650Lit
61 Kg Con. HCL
Reactor
Sodium nitrite 90Kg+250Lit water Reactor CuCL in con.HCL RT 120Kg+120Lit 75 Kg NaCl Reactor 175 Lit liq NH3 Ethyl acetate 700Lit Quenched 69 KgNH4Cl Reactor 125 Kg Cu(OH)
Carbon 50 Kg Sepration Reactor
50 -55 c
Sparkler filter
Distillation
Reactor 650Lit Recover of Ethyl acetate
Crude Base Effluent- 600Lit Residue-50Kg Flow diagram :-
Crude Base Ethyl Acetate +Cycloh exane 175kg +325kg
columns
Reactor Recover Ethyl Acetate + Cyclohexane 450 kg
Pure Base 360Kg Trans-5-Chloro-2-methyl- 360Kg 2,3,3a,12b-tetrahydro-1H- dibenz[2,3:6,7]oxepino[4,5- n-Butyl alcohol 700kg c] -pyrrole Reactor Carbon 50Kg 60 -65
Sparkler filter Maleic acid +Water
150Kg+200kg 40 -45c
GLR
Cool To RT Reactor
Recover n-Butyl alcohol 650kg Centrifuge Effluent
Dry Wet : 510Kg
Purification Crude 510Kg n-Butanol1000kg
Reactor Carbon 50Kg
65 -70c Sparkler filter
25 -30c Reactor
Loss -162 kg Recover n-Butanol 950kg Centrifuge Residue -70Kg
Dry Wet=500Kg
NAME OF Raw material :-
1)- Trans-2-methyl-5-nitro-2,3,3a,12b-tetrahydro-1H- dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole
2)- 10% palladium charcoal(50% wet)
3)- H2 Pressure
4)- Methanol
5)- Dichloromethane
6)- Dilute NaoH soln
7)- Sodium nitrite
8)- water
9)- CuCL in con.HCL
10)- Ethyl acetate
11)- liq NH3
12)- Carbon
13)- Cyclohexane
14)- Trans-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole 15)- Maleic acid
16)- n-Butanol
ASENAPINE INPUT kg OUTPUT kg Trans -2-Methyl -5-Nitro -2,3,3a,12b - 395 Residue 200 Tetrahydro-1H- Dibenz[2,3:6,7]Oxepino[4,5-C]- Pyrrole Palladium Charcoal 40 Effluent 1535 H2 Pressure 15 Nacl 75 Methanol 1200 NH4Cl 69
Dichloromethane 1200 Cu(OH) 125 Dilute Naoh 600 Ethyl Acetate 650 Con. HCL 61 Ethyl Acetate +Cyclohexane 450 Sodium Nitrite 90 Methanol 1150 Cucl In Con.HCL 240 Mdc 1150 Ethyl Acetate 700 N-Butyl Alcohol 650 Carbon 150 N-Butanol 950 Lit Liq NH3 175 Product 500 Ethyl Acetate +Cyclohexane 500 Loss 162 Maleic Acid 150 Water 450 Butanol 1000 N-Butyl Alcohol 700
Total 7666 7666
53
134)ROS :- AXITINIB
N N
N DMSO / D M Water N S N H S N H HN O HN O CH3 CH3
Axitinib Solvate Axitinib API MOL FOR :- C22 H16 N4OS MOL WT :- 386.46 MOL FOR :- C22 H16 N4OS MOL WT :- 386.46
Manufacturing Process :-
Dissolve Axitinib Solvate in DMSO and Precipitated D M Water to give Axitinib (API)
NAME OF Raw material :-
1)- Axitinib Solvate 2)- Dimethyl sulfoxide (DMSO) 3)- D M Water
Flow diagram :-
525Kg Axitinib Solvate Dimethyl sulfoxide (DMSO ) 500Lit
Reactor D M Water 500Lit
Recover of Dimethyl sulfoxide 500 Lit Centrifuge
Loss -25 kg Effluent 550 Lit
Dry Wt :- 500 kg
AXITINIB INPUT kg OUTPUT kg Axitinib Solvate 525 Dimethyl Sulfoxide 450 Dimethyl Sulfoxide (DMSO) 500 Effluent 550 D M Water 500 Product 500 Loss 25
TOTAL 1525 1525
135)ROS :- AZILSARTAN
H3C H3C O O N N O O O O O H2O N NH + N NH N N p-TSCl 18 OO K2CO3 O OH + DMAc O O DMAP CH3 Acetic acid O Ethyl acetate O OH MDC O MOL FOR :- C9H6O4 H3C + MOL FOR :- C25 H20 N4O5 Azilsartan Medoxomil(Technical) MOL WT :- 458.45 MOL WT :- 130.10 MOL FOR :- C30 H24 N4O8
H3C MOL WT :- 568.53 O N
O H3C O O N NH N N Acetone O O O N NH O Water N
O O O O
O O H3C O Azilsartan Medoxomil(Technical) O H C MOL FOR :- C30 H24 N4O8 3 Azilsartan Medoxomil MOL WT :- 568.53 MOL FOR :- C30 H24 N4O8 MOL WT :- 568.53 H3C O H3C N O N O O - + O O N N K Potassium N H C N NH 2-ethylhexa 3 N noate(182) O O + O O O Ethyl acetate O H3C OH O O O O O H3C H C 3 Azilsartan Medoxomil 2-ethylhex anoic acid Azilsartan Medoxomil Mono Potassoium salt MOL FOR :- C9H16 O2 MOL FOR :- C30 H24 KN 4O8 MOL FOR :- C30 H24 N4O8 MOL WT :- 144.21 MOL WT :- 606.62 MOL WT :- 568.53
Manufacturing Process :-
Stage :- 1 :- Azilsartan Medoxomil
Azilsartan is reacted with 4-Hydroxymethyl-5-methyl-1,3-dioxol-2-one,p-TSCl and DMAP,K2CO3 in DMAc as a solvent to give Azilsartan Medoxomil(Technical) after pouring in the Process Water.
Azilsartan Medoxomil(Technical) is purified using mixture of acetone and water.
Stage :- 2 :- Azilsartan Medoxomil monopotassium salt.
Azilsartan Medoxomil is treated with Potassium 2-ethyl hexanoate in presence of ethyl acetate as a solvent to give potassium salt of Azilsartan Medoxomil.
NAME OF Raw material :-
1) - Azilsartan
2)- 4-Hydroxymethyl-5-methyl-1,3-dioxol-2-one
3) - p-toluene thionylchloride
4)- K2CO3
5)- DMAP
6) - DMAc
7)- Di chloro methane
8)- Ethyal acetate
9)- Acetone
10)- Water
11) potassium ethyl Hexanate
Flow diagram :- K2CO 3+ di methyl acetal 390 Kg + 400Lit Azilsartan 410 Kg P-TSCl 260Kg 4-Hydroxymethyl-5- methyl-1,3-dioxol-2-one 71 Kg Acetic acid Reactor 110Kg 800 Lit Ethyl Acetate
MDC Reactor 800 Lit P.TSA 400Lit Recover Ethyl Acetate 750 Lit
75Kg KCL Effluent 500Lit Technical 485Kg Recover of MDC 750 Lit Residue 150Kg
500Lit Acetone Technical 485 Kg Reactor 500Lit Water
Chilled 0 -10 950 Lit Recover of Acetone+ Water Centrifuge Effluent :- 780 kg
Dry Wet 475Kg
AzilsartMedoxomil 475Kg 190Kg potassium ethyl Hexanate
Reactor 700Lit1000Lit Ethyl Acetate
Chilled 5-10C
950Lit Recover Ethyl Acetate Loss -81kg Centrifuge 125Kg 2 -ethylhexanoic acid
32Kg Residue
Dry Wet=500Kg
AZILSARTAN INPUT kg OUTPUT kg Azilsartan 410 Recover Ethyl Acetate 750 4-Hydroxymethyl-5-Methyl-1,3- 110 KCL 75 Dioxol-2-One 110Kg
K2co 3 390 Recover Of Mdc 750 P-Tscl 260 Recover Of Acetone+ Water 950 Acetic Acid 71 Residue 32 Ethyl Acetate 800 Recover Ethyl Acetate 950 Mdc 800 2-Ethylhexanoic Acid 163 Acetone 500 Ptsa 400 Water 500 Effluent 780 Potassium Ethyl Hexanate 190 Product 500 Ethyl Acetate 1000 Loss 81 Di Methyl Acetal 400
TOTAL 5431 5431