33 181)ROS :- PRASUGREL HYDROCHLORIDE
O O F F
Ethyl methyl ketone N N Aco .HCL Aco HCL(36.5) in S S isopropanol
2-Acetoxy-5-( -cyclopropylcarbony1-2- 2-Acetoxy-5-( -cyclopropylcarbony1-2-fluorobenzyl)- fluorobenzyl)-4,5,6,7-tetrahydro 4,5,6,7-tetrahydro thieno[3,2-c]pyridine hydrochloride thieno[3,2-c]pyridine MOL FOR :- C20 H21FNO 3SCl MOL WT :- 409.9 MOL FOR :- C20 H20 FNO 3S MOL WT :- 373.44
Manufacturing Process :-
The hydrochloride is Prepared by dissolving 2-acetoxy-5-( -cyclopropylcarbony1- 2-fluorobenzyl)-4,5,6,7-tetrahydro thieno[3,2-c]pyridine prasugrel in ethyl methyl ketone at 35- 40 ℃ followed by addition of IPA.HCL The solid obtained is filtered to yield 2-Acetoxy-5-( - cyclopropylcarbony1-2-fluorobenzyl)-4,5,6,7-tetrahydro thieno[3,2-c]pyridine hydrochloride (Prasugrel hydrochloride) (APl)
NAME OF Raw material :-
1) - 2-acetoxy-5-( -cyclopropylcarbony1-2-fluorobenzyl)-4,5,6,7-tetrahydro thieno[3,2- c]pyridine
2)- Ethyl methyl ketone
3) - IPA.HCL
Flow diagram :-
2-acetoxy-5-( -cyclopropylcarbony1- Ethyl methyl ketone 1000L kg
2-fluorobenzyl)-4,5,6,7-tetrahydro IPA.HCL 1000kg thieno[3,2-c]pyridine 480Kg Reactor
Chilled 10 °C
Reactor Recovery Of ethyl methyl ketone 950 kg Centrifuge Loss -20 kg Recovery Of Ipa 950 kg Salt 60 kg
Dry wt -500Kg
PRASUGREL HYDROCHLORIDE INPUT kg OUTPUT kg 2-acetoxy-5-( - 480 Recovery Of ethyl methyl ketone 950 cyclopropylcarbony1-2- fluorobenzyl)-4,5,6,7-tetrahydro thieno[3,2 -c]pyridine Ethyl methyl ketone 1000 Recovery Of Ipa 950 IPA.HCL 1000 Salt 60 Product 500 loss 20
TOTAL 2480 2480
182) Paroxitine HCL ROS :-
F SO 2CL 2 F
HO toluene O CH 2OH NaoH dimethylethylamine O O N + O O sodiume methoxide N + H2O(18) CH3 DMF CH3 Mol FOR :- C19H16FNO3 (-)trans carbinol sesamole MOL Wt :- 329 gm/mol Mol FOR :- C13H18FNO Mol FOR :- C7H6O 3 MOL Wt :- 222 gm/mol MOL Wt :- 138gm/mol
phenylchloroformate F (156.57) F toluene
O O KOH (56.10) O O O O N Paroxetine toluene HCL H N + + Mol for :-C19H20FNO3 NAOH(40) 36.5 O Mol wt:-329.5 gm/mole OPH PhOCOOK(175) toluene Mol FOR :- C26H24FNO5 F HCL MOL Wt :- 449 gm/mol
O
O O .HCL(36.5)
N H Paroxetine.HCL
Mol for :-C19H20FNO3.HCl
Mol wt:-365.5 gm/mole
Flow chart :-
Benzenesulfphonyl chloride-250 KG (-)trans carbinol-355 KG
Dimethylethylamine - Toluene-500 kg 250kg Reactor
DMF - 500 kg Recover DMF- 450 kg SMO -1.0 kg Sesamole-238 kg Reactor
toluene-500 kg Phenylchloroformate :-230kg Water -174 kg KOH-366kg Reactor Hcl Gas-58 kg Scrubber Toluene-500 kg Total -232 kg Con HCL-180kg Effluent -812 KG Reactor Recover Toluene - 1450
Effluent- 500 kg Loss -100 kg Centrifug e
Product-500kg
Manufacturing Process :-
charged Toluene charged to a clean, dry and charge trans-(-)-4-(4'- fluorophenyl)-3- hydroxymethyl-1 -methylpiperidine in Reactor. The vessel contents are cooled to 5 °C and dimethylethylamine is added, and then a nitrogen purge is attached and the vessel contents further cooled to 0 UC. A mixture of benzenesulphonyl chloride and toluene added at 0C .Charge N,N'-dimethylformamide is added. Charge solution of sesamol and sodium methoxide in N,N'-dimethylformamide added over. Water wash &The combined toluene solutions are distilled to give an anhydrous toluene solution of (-) trans 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)-l- methylpiperidine. Take product dissolved in toluene & chare a solution of phenyl chloroformate in toluene s added dropwise with stirring under nitrogen, over 25 to 30 minutes. Water wash & distilled toluene to give an anhydrous toluene solution of (-) trans 4-(4'- fluorophenyl)-3-(3',4'-methylenedioxy phenoxymethyl)-l- phenoxycarbonyl piperidine. Charge potassium hydroxide & take product a solution in toluene and the well stirred mixture is refluxed for 2 hours. &water wash. distilled toluene.& free base obtain. Charge free base in toluene in Reactor and drop wise concentrated hydrochloric acid addition in2-hrs.stirred for 2 hours at RT ¢rifuge. Dry & packing
INPUT KG/Batch MT/MT MT/DAY MT/MONTH OUTPUT KG/BATCH MT/MT MT/DAY MT/MONTH
(-)trans carbinol 355 0.71 0.4686 14.2
Dimethylethylamine 250 0.5 effluent 0.33 10 1312 2.624 1.73184 52.48 Benzenesulfphonyl chloride 250 0.5 0.33 10 Dry wt 500 1 0.66 20 Sodium methoxide (smo) 1 0.002 0.00132 0.04 Recover of DMF 450 0.9 0.594 18 Fresh DMF 50 0.1 0.066 2 0 0 0 Recover of DMF 450 0.9 0.594 18 Recover of toluene 1450 2.9 1.914 58 Fresh toluene 50 0.1 0.066 2 loss 100 0.2 0.132 4 Recover of toluene 1450 2.9 1.914 58 Hcl Gas 58 0.116 0.07656 2.32 Sesamole 238 0.476 0.31416 9.52 Phenylchloroformate 230 0.46 0.3036 9.2 KOH 366 0.732 0.48312 14.64 Con HCl 180 0.36 0.2376 7.2 TOTAL 3870 7.74 5.1084 154.8 TOTAL 3870 7.74 5.1084 154.8
M.B of scrubber
INPUT KG/Batch MT/MT MT/DAY MT/MONTH OUTPUT KG/BATCH MT/MT MT/DAY MT/MONTH HCl gas 58 0.116 0.07656 2.32 Scrubber Sol 232 0.464 0.30624 9.28 Water 174 0.348 0.22968 6.96 232 0.464 0.30624 9.28 232 0.464 0.30624 9.28
. 183) Pinavarium Bromide
ROS :-
Cl IPA CH3 OH N CH3 O NaHCO3(84) H3C H3C N O + O CO2(44)+H2O(18) + NaCL(58.5) DIHYDRONEPOL 4-(2-chloroethyl)morpholine Br MOL FOR : C17H310O2N MOL FOR : C11H170 MOL FOR : C6H12CLNO MOL WT - 281.43 Br MOL WT :- 169 MOL WT :- 149 310 Acetone OCH H3CO 3 2-bromo veratyl bromide
CH3 O H C 3 + N O Br Br
OCH 3 OCH 3 Pinavarium bormide Mol FOR :- C28H37CLN4O2S MOL WT :- 591
Flow chart :-
4-(2-chlroethyl)morpholine - dihydronepol -124 kg 186 kg
IPA-1000 kg Na2CO3-340 kg Reactor
Acetone-1000 kg Recover IPA -950 kg 2-bromo-veratyl bromide- Reactor 310 kg
Reactor Recover Acetone-950 kg
Loss – 85 kg Effluent -475 KG Centrifuge
Product-500 kg
Manufacturing Process :-
Charge of dihydronepol , Isopropyl alcohol Sodium carbonate & 4-(2- chlroethyl)morpholine in reactor &. Heating to reflux. Maintain for 14-hrs at reflux temp. filter reaction mass & distilled IPA. centrifuge & drying. Take product, 2-bromo-veratyl bromide & Acetone in reactor. Heating to reflux. Maintain for 14-hrs at reflux temp. cool to RT & Chilled to 5-10 C for 1-hrs . centrifuge .drying & Packing .
Pinavarium Bromide INPUT OUTPUT dihydronepol 124 KG Recover of IPA 950 LIT 4-(2-chlroethyl)morpholine 186 kg Dry Wt 500 KG Na2co3 340 KG SOLVENT LOSS 60 KG IPA 1000 LIT Recover of ACETONE 950 LIT Acetone 1000 lit EFFLU ENT 475 KG 2-bromo-veratyl bromide 310 kg Loss 25 kg TOTAL 2960KG 2960 KG
. 184)PIOGLITAZONE HYDROCHLORIDE
ROS :-
stage :-1 NO palladium NH 2 carbon 2 H C H C 3 + 3H2 3 N O hydrogen gas N O 4-(2-(5-ethylpyridin-2-yl) MOL WT :- ethoxyanilline 2H2O 5-ethyl-2-(2-(4-nitrophenoxy) 2.0 + ethyl)pyridine PGL-1 18 EPNB MOL WT - 242.3 MOL WT :- 272.3 stage-2 O CH3 NH2
H3C + NaNO2 + 2HBr + O N O sodium nitrate H2C methyl acrylate MOL WT - 4-(2-(5-ethylpyridin-2-yl) 69 hydrobromic acid MOL WT - ethoxyanilline 86.08 MOL WT - PGL-1 81 MOL WT - 242.3 copper oxide
O
CH 3 N2 NaBr + + 2H2O O + H C 3 WATER Br sodium nitrate Nitogen N O MOL WT - 103 MOL WT - 28 MOL WT - 18
methyl-2-bromo-3-(4-(2-(5ethylpyri din-2-yl)ethoxy)phenyl) propanoate MOL WT - 392.28 PGL-2
Stage 3 O S
CH 3 ONa H3C O H3C + + Br H2N NH N O 2 thiourea O methyl-2-bromo-3-(4-(2-(5ethylpyri sodium acetate din-2-yl)ethoxy)phenyl) propanoate MOL WT - 76.1 MOL WT - 82.03 MOL WT - 392.28 PGL-2
S NH CH3COOH CH3OH H C NaBr + + 3 N + O H N O
5-{4-{-(6-ethylpyridin-2-yl)ethoxy)ben Sodium bromide Acetic Acid methanol zyl}-2-amino-13-thinzolidin-4-one MOLWT - MOL WT - 60 MOL WT - 32 MOL WT - 355.4 103 PGL-3 Stage 4
S NH
H3C N + 2HCL + H20 + KHCO O H N O
5-{4-{-(6-ethylpyridin-2-yl)ethoxy)ben MOLWT-36.46 MOLWT -18 MOLWT - 100.11 zyl}-2-amino-13-thinzolidin-4-one MOL WT - 355.4 PGL-3
S O H C 3 N O H N O + NH4CL + KCL + H2O 5-{4-{-(6-ethylpyridin-2-yl)ethoxy)ben MOLWT -74.5 MOLWT - 18 zyl}-2-amino-13-thinzolidin-4-one MOLWT -53.5 MOL WT - 355.4 + CO2 PGL-4 MOLWT - 44 Stage 4 S O H C 3 N O H N O 5-{4-{-(6-ethylpyridin-2-yl)ethoxy)ben zyl}-2-amino-13-thinzolidin-4-one MOL WT - 356.4 PGL-4
DMF S O H C 3 N O H N O 5-{4-{-(6-ethylpyridin-2-yl)ethoxy)ben zyl}-2-amino-13-thinzolidin-4-one PGL-5 Stage 5 MOL WT - 356.4
S O H C HCL 3 N + O H 36.5 N O 5-{4-{-(6-ethylpyridin-2-yl)ethoxy)ben zyl}-2-amino-13-thinzolidin-4-one MOL WT - 356.4
S O H C 3 N O H N O HCL Pioglitazone hydrochloride MOL WT - 392.89
Flow chart :-
EPNB-347 KG palladium carbon-10 KG
-10 kg
Hydrogen gas- 6 kg Reactor CuO-50 kg
Stage-1-310 kg Sodium nitrate-88 KG -10Recover kg catalyst -10 kg HBr-207 kg Methyl acrylate-110 Reactor Effluent-40kg
Stage-2 500kg Sodium acetate-150 KG
-10 kg thiourea -97 kg NaBr -131 KG
Reactor Effluent -84 KG methano -500 kg Recover cuo -50 KG Stage-3 452kg water -500 KG
Con hcl -91 kg NaBr -131 KG RecoverAceticacid-114kg Reactor KG KHCO3 -127 kg Recover CH3OH-550kg KG Stage-4 454kg Ammonium chloride -110 KCL-130 kg DMF - 500 kg Reactor WATER - 500 kg Effluent-475 kg Stage-5 445kg Effluent -132 KG 50% ethanol- 500 kg
Con HCL - 1000kg Reactor Recover DMF- 475 kg Effluen -34 KG Effluent 500 kg Recover ethanol-250 kg Loss -10 kg CENTRIFUGE Effluent-832 kg Effluent 225 KG
Product-500 kg
Manufacturing Process :-
5-ethyl-2-(2(4-nitrophenoxy)ethyl)pyridine (EPNB) is hydrogenated in presence of palladium catalyst to produce PGL-1, which is further diazotized using sodium nitrite solution in water to get diazotized PGL-1. It is further reacted with HBR &methyl acrylate in presence of copper oxide to get PGL-2.
PGL-2 is cyclized using thiourea & sodium acetate in methanol to give PGL- 3(5-{4-{-(6-ethylpyridin-2-yl)ethoxy)ben zyl}-2-amino-13-thinzolidin-4-one)
PGL-3 is reacted with HCL in water to give PGL-4 ( 5-{4-{-(6-ethylpyridin-2- yl)ethoxy)ben zyl}-2-amino-13-thinzolidin-4-one). PGL-4 is purified in DMF & water mixture to get PURE PIOGLITAZONE. PGL-5
PGL-5 is isolatetd as a HCL salt using con HCL IN ethanol & water mixture as a solvent to give PIOGLITAZONE HYDROCHLORIDE .
INPUT KG MT/MT MT/day MT/month OUTPUT KG MT/MT MT/day MT/month EPNB 347 0.694 0.46 13.88 Recover catalyst 10 0.02 0.01 0.40 Hydrogen gas 6 0.012 0.01 0.24 NaBr salt 262 0.524 0.35 10.48 Recover Acetic palladium carbon 10 0.02 0.01 0.4 114 acid 0.228 0.15 4.56 Recover HBr 207 0.414 0.28 8.28 550 CH3OH 1.1 0.73 22.00 110 0.22 0.15 4.4 Ammonium Methyl acrylate 110 chloride salt 0.22 0.15 4.40 Sodium nitrate 88 0.176 0.12 3.52 KCL SALT 130 0.26 0.17 5.20 thiourea 97 0.194 0.13 3.88 Recover DMF 475 0.95 0.63 19.00 150 0.3 0.20 6 Sodium acetate Effluent 2322 4.644 3.10 92.88 Con hcl 91 0.182 0.12 3.64 PRODUCT 500 1 0.67 20.00 127 0.254 0.17 5.08 KHCO3 Recover ethanol 250 0.5 0.33 10.00 1000 2 1.33 40 water Loss 10 0.02 0.01 0.40 500 1 0.67 20 Recover DMF 50 copper oxide 0.1 0.07 2.00 Con hcl 1000 2 1.33 40 50 % ETHANOL 500 1 0.67 20 methanol 500 1 0.67 20 copper oxide 50 0.1 0.07 2 TOTAL 4783 9.566 6.38 191.32 TOTAL 4783 9.566 6.38 191.32
. 185)Quetiapine Fumarate
ROS :-
S S 2H2O(18) +H3PO4(98) + 2H2O+ 2NACL pocl3 (153.33) 18 58.5 chloro compound K2CO3 NH NH MOL WT - 2NAOH(40) 247.74 O Cl Ketone deri. H N MOL WT :- 227.28 OH NAOH(40) (172.71) S N O Cl H OH S (124.57) N N 2-chloro ethoxy ethanol N + H2O+NACL Na2CO3 N O 18 58.5 N quetiapine NAOH(40) HN + H2O+ NACL MOL WT - 385.99 18 58.5 ETHANOL piperzine dervi furaric acid (115.11) MOL WT -349.50 O OH S
OH N N N O O OH
quetiapine fumarate 2 MOL WT - 883.09
Flow chart :-
POCL3-110 kg KETONE -150 kg
TOLUENE-500 kg K2CO3-100 kg Reactor water-500 kg
DMSO- 250l kg Piperazine -217 kg kg toluene -500 kg Con HCL –100 kg
ethanol - 250 kg Distilled POCL3-90 kg Reactor water -500 Distilled dmso-230 kg 2-chloroethoxyethanol-74 kg toluene -500 kg
Na2co3 -90 kg Distilled toluene& reused-1400 kg
water- 500 kg Reactor Recover piperazine - 100kg
ethanol- 250 kg Furamic acid- 70kg
Effluent -440 KG Reactor Recover ethanol- 450 kg
Loss -51 kg Effluent - 1400 kg Centrifuge
Product-500 kg
Manufacturing Process :-
Charge Dibenzo[Z\/][l,4]thiazepine-l l-(10H)one (keto compound), charge phosphorus oxychloride & charge potassium carbonate at RT and heated to reflux at 100 0C ± 5°C for 6 hours. and the phosphorus oxychloride completely distilled. Charge Toluene& charge water layer separation and toluene layer distilled out.& filter reaction mass. Toluene wash. dry it.
charged Dimethylsulfoxide , charged piperazine &charged toluene at RT under nitrogen and the heated to 50 0C to 60 0C.. To it a solution of 11- chloro- dibenzo[Z\/]l,4]thiazepine (chloro compound) in toluene at RT. and stirred for 3 hours at RT.& charge water . & toluene layer separation. toluene layer distilled out. Take oil & charge Ethanol at RT Con HCL addition &chilled 0-5 C. filter reaction mass. dry it.
Charge l-piperazinyl-dibenzo[Z\/][l,4]thiazepine dihydrochloride (piperazine dervi), Charge sodium bicarbonate, Charge water , Charge 2-chloroethoxyethanol, Charge toluene . and heated to reflux at 95 0C to 100 0C. After completion of the reaction & set ph-5.4 to5.5 bi dil HCL . toluene layer distilled out.
charge Ethanol & charged into the residue at RT. heated to 45°C to 50 0C. charged Fumaric mixture. heated to reflux 80 0C and for 1-hrs. cool to RT & chilled 0-5 filter reaction mass. dry it
Quetiapine Fumarate INPUT OUTPUT KETONE 150 KG Recover of TOLUENE 1400 LIT POCL3 110 kg Dry Wt 500 KG Potassium carbonate 100KG loss 51 KG TOLUENE 1500 LIT WATER 1500 LIT Recover of Piperazine 100 KG Piperazine 217 LIT Recover of DMSO 230 lit DMSO 250 lit Recover of Pocl3 90 kg Con HCL 100 kg Recover of ethanol 450 lit 2-chloroethoxyethanol 74 kg EFFLU ENT 18 40 kg Na2co3 90 kg Furamic acid 70 kg ethanol 500 lit TOTAL 4661KG 4661 KG
. 34
186) ROS :- RABEPRAZOLE SODIUM
CH3 CH3 O O
+ H2O O NaOH(40) O Sodium hydroxide CH CH 3 Methanol 3 O N O N Toluene S S N Ethyl acetate N N N Na H Methy 1-butyl ether 2-[{4-(3-methoxypropoxy)-3- 2-[{4-(3-methoxypropoxy)-3-meth methyl-pyridine-2-yl}methylsu yl-pyridine-2-yl}methylsulfinyl]-1H lfinyl]-1H-benzimidazole -benzimidazole-1H-Sodium salt MOL FOR :- C 18 H21 N3O3S MOL FOR :- C 18 H20 N3O3SNa MOL WT :- 359.4 MOL WT :- 381.4
Manufacturing Process :-
Rabeprazole sulphoxide is reacted with sodium hydroxide in methanol to form rabeprazole Sodium.
NAME OF Raw material :-
1) - Rabeprazole sulphoxide
2)- NaOH
3) - Water
4)- Methanol
5)- Toluene
Flow diagram :-
Rabeprazole sulphoxide 500Kg 405KgNaOH+600kg Water
Methanol 1000 kg
Reactor
Recovery Of Meoh 950 kg Centrifuge Effluent 1030 kg
Dry wt-510Kg
Technical 510Kg Toluene100 0kg Reactor
Loss -75 kg Centrifuge Recovery Of Toluene 950kg
Dry wt -500Kg
RABEPRAZOLE SODIUM INPUT kg OUTPUT kg Rabeprazole sulphoxide 500 Recovery Of Meoh 950 NaOH 405 Effluent 1030 Water 600 Recovery Of Toluene 950 Methanol 1000 Product 500 Toluene 1000 loss 75
TOTAL 3505 3505
35
187)ROS :- RIVAROXABAN
O OH O O O Cl S NH N O Cl S O N 5-Chlorothiophene-2-Cacoxylic H2N HCL O acid(162.59) N O HCL N NAOH(40) O Sodium Acetate O +36.5 O 5-Chloro-N-({(5S)-2-oxo-3-[4- O (3-oxo-4-morpholinyl)phenyl]- 4-{4-[(5S)-5-(aminomethyl)-2- 1,3-oxazolidin-5-yl}methyl)-2- oxo-1,3-oxazolidin-3-yl]phenyl thiophene-Carboxamide }morpholin-3-one.HCL MOL FOR :- C19 H18 ClN 3O5S MOL FOR :- C14 H18 N3O4Cl MOL WT :- 435.8 MOL WT :- 327.8
O O O O NH N NH N Cl S Cl S O O Acetic acid O N O N O O O O Rivaroxaban 5-Chloro-N-({(5S)-2-oxo-3-[4- (3-oxo-4-morpholinyl)phenyl]- MOL FOR :- C19 H18 ClN 3O5S 1,3-oxazolidin-5-yl}methyl)-2- MOL WT :- 435.8 thiophene-Carboxamide MOL FOR :- C19 H18 ClN 3O5S MOL WT :- 435.8
Manufacturing Process :-
Stage :- 1
5-Chlorothiophene-2-Carboxylchloride which is further reacted with 4-{4-[(5S)-5- (aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one.HCL in Presence of Sodium acetate in Process Water / sulfolane to give 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene-Carboxamide
Stage :-2 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5- yl}methyl)-2-thiophene-Carboxamide is Crystallized from Acetic acid to give Rivaroxaban.
NAME OF Raw material :-
1) - 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one.HCL
2)- 5-Chlorothiophene-2-Carboxylchloride
3) - Sodium Acetate
4)- Water
5)- Acetic Acid
Flow diagram :-
5-Chlorothiophene-2- 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3- Carboxylchloride 225 kg oxazolidin-3-yl]phenyl}morpholin-3- Sodium Acetate 600 Kg + Water 800 kg one.HCL 405 kg Water-135 kg Reactor
Hcl Gas -45 kg Scrubber Centrifuge Effluent-1120 kg Salt-200kg Total-180 kg
Technical DRY WT -515KG Acetic Acid-1000 kg Technical wt: 515kg Reactor
Recovery ofAcetic Acid-950 kg Loss-50 kg Centrifuge Residue-30kg
DRY wt -500kg
RIVAROXABAN INPUT kg OUTPUT kg 4-{4-[(5S)-5-(aminomethyl)-2- 405 Effluent 1300 oxo-1,3-oxazolidin-3- yl]phenyl}morpholin-3-one.HCL 5-Chlorothiophene-2- 225 Salt 200 Carboxylchloride Sodium Acetate 600 Recover Acetic Acid 950 Water 800 Residue 30 Acetic Acid 1000 Product 500 loss 50
TOTAL 3030 3030
36
188)ROS :-ROPINIROLE HYDROCHLORIDE
CH CH H3C 3 H3C 3 H2(2) N N HCL 10%pd/c, Methanol HCL
Ethanol OH Methylene chloride Triethylamime O +H2O(18) +O2g(32) O Ethanolic HCL N NO 2 H Ethyl-2-nitro-6-(N,N-di-n-propylamino) Ropinirole hydrohchloride ethylphenyl)acetic acid hydrochloride MOL FOR :- C 16 H24 N2O .HCL MOL FOR :- C 16 H24 N2O4 HCL MOL WT :-296.84 MOL WT :- 344.84
CH H3C 3 CH H3C 3 N N HCL HCL
Purification O Mixture of Ethyl Acetate & Ethanol* O Ethanolic HCL,Ethyl acetate N N H H Ropinirole hydrohchloride Ropinirole hydrohchloride MOL FOR :- C 16 H24 N2O .HCL MOL FOR :- C 16 H24 N2O .HCL MOL WT :-296.84 MOL WT :-296.84 Manufacturing Process :-
(2-nitro-6-(N,N-di-n-prethyl)phenyl)acitic acid HCL in presence of 10%palladium on cabon using D solvent givesRopinirole HCL tech acid base purifaction of ropinirole HCL tech using ethylacetate/sodiumbicarbonte/ethanolic HCL gives Ropinirole Haydrochloride
Flow diagram :-
Ethyl-2-nitro-6-(N,N-di-n- Methanol 1250 kg propylaminoethylphenyl)acetic acid.HCL-625kg 10% Pdc-65kg
Reactor
Sparkler filter 10% Pdc-70kg Reused
Recovery of Methanol 1200 kg Reactor Residue-60kg MDC-1000 kg Triethyl amine-185 KG
Reactor
Recovery Of MDC- 950-kg Centrifuge Effluent-290kg
Technical Dry
wt -510kg Technical 510Kg Ethyl acetate- 1000 kg
Reactor
Recover Of Ethyl acetate 95kg Loss -65 kg Centrifuge Residue 40Kg
Dry wt-500kg
NAME OF Raw material :-
1) - Ethyl-2-nitro-6-(N,N-di-n-propylaminoethylphenyl)acetic acid.HCL
2)- Methanol
3) - 10% Pdc
4)- MDC
5)- Triethyl amine
6) - Ethyl acetate
ROPINIROLE HYDROCHLORIDE INPUT kg OUTPUT kg Ethyl-2-nitro-6-(N,N-di-n- 625 10% Pdc-60kg Reused 70 propylaminoethylphenyl)acetic acid.HCL Methanol 1250 Recovery of Methanol 1200 10% Pdc 65 Residue 100 MDC 1000 MDC 950 Triethyl amine 185 Efflu ent 290 Ethyl acetate 1000 Ethyl acetate 950 Product 500 loss 65
TOTAL 4125 4125
189)Resperidone
ROS :-
N O N O O Cl
N + K2CO3(138) O N HN N CH3 DMF F F N 3-(2-chloroethyl-6,7,8,9-tet rahydro-2-methyl-4h-pyrid 6-fluoro-3-(4-piperidinyl o(1,2.a)pyridimidine 4-one N CH3 1,2 benzisooxazole + KCL(74.5) MOL WT :- 220 MOL WT :- 226.5 RISPERIDONE + CO2(44) MOL WT - 410
Flow chart :-
3-(2-chloroethyl-6,7,8,9-tetrahydro-2-methyl-4h- 6-fluoro-3-(4-piperidinyl1,2 pyrido(1,2.a)pyridimidine 4-one-275 benzisooxazole-268 KG
DMF-1000 kg K2CO3-358 kg Reactor
Reactor
Recover DMF -975 kg Loss -20 kg Centrifuge Effluent -406 KG
Product-500 kg
Manufacturing Process :-
Charge of 6-fluoro-3-(4-piperidinyl1,2 benzisooxazole ,DMF, potassium carbonate & 3-(2-chloroethyl-6,7,8,9-tetrahydro-2-methyl-4h-pyrido(1,2.a)pyridimidine 4-one in reactor. Heating to reflux. Maintain for 12-hrs at reflux temp. filter reaction mass . Tak cool to RT& chilled 0-10C For 1-hrs maintain. centrifuge & drying..
Resperidone INPUT OUTPUT 6-fluoro-3-(4-piperidinyl1,2 268 KG Recover of DMF 975 LIT benzisooxazole 3-(2-chloroethyl-6,7,8,9-tetrahydro- 275kg Dry Wt 500 KG 2-methyl-4h- pyrido(1,2.a)pyridimidine 4-one potassium carbonate 358KG EFFLUENT 406 KG DMF 1000 LIT Loss 20 kg
TOTAL 1901KG TOTAL 1901 KG
. 190)Sertraline Hydrochloride
ROS :-
CH3 O N CH3 NH H2(2) + CH3NH2 Pd/Baso4 H2O(18) MOL WT :- 31 +
Cl Cl Cl ketamine Cl Cl sertralone Cl MOL WT - MOL WT :- 291 304 (+/-)sertraline base MOL WT :- 306
mandelate acid(152)
CH3 CH CH 3 3 NH NH NH H H OH HCL H HCL(36.5) NaoH
COOH mandelate acid(152)
Cl Cl Cl Cl Cl Cl sertraline HCL cis (+)sertraline base cis(+) sertraline mandelate MOL WT :- MOL WT :- 342 306 MOL WT :- 458
Flow chart :-
Setralone-425 kg mono methylamine -50 kg
Water-500 kg Reactor
Hydrogen -4 kg Methanol-500 kg RecoverPb/BaSO4 – 60 kg
Pb/BaSO4-50 kg Reactor ethyl acetate-500kg D-(-)-Mandelic acid -225 kg
10 % NAOH -500 kg Reactor Recover methanol-475 kg
Acetonitrile - 1000 kg
HCL -100 kg Effluent - 500KG Reactor Recover ethyl acetate- 475 kg
Effluent - 850 kg Loss -44 kg Centrifuge
Recover acetonitrile- 950 kg Product-500 kg
Manufacturing Process :-
setralone, aqueous mono methylamine solution in reactor. The mixture is heated to 75-90 0C under stirring for 40 hours,cooled to 20-25 0C, filtered, washed with water to ketamine obtain. Charge ketamine in methanol is hydrogenated in the presence of catalyst Pd/BaSO4 at rt and at a pressure of 4 kg for 8 hours. filtration through bed, washed thee with methanol. Distilled methanol to sertraline base obtain. sertraline base reacted The ethyl acetate solution is treated with D-(-)-Mandelic acid . cool to RT & filtrate mass to obtain cis (+)sertraline mandelate salt obtain. cis mandelate salt in ethyl acetate & charge 10% NaOH solution ðyl acetate distilled out to obtain cis(+) sertraline free base. The cis (+) sertraline free base & charge acetonitrile .HCL gas purging at 20-25C and hydrogen chloride is bubbled through the solution at 25-27°C. During the addition of HCl, the temperature of the reaction mixture raises form 25 to 25 0C. chilled to 10C. filtrate. dry & packing.
Sertraline Hydrochloride INPUT OUTPUT Setralone 425 KG Recover of ETHYL ACETATE 475 LIT mono methylamine 50 kg Dry Wt 500 KG Water 500 lit Recover of Methnol 475 KG ETHYL ACETATE 500 LIT Methanol 500 LIT EFFLU ENT 1350 KG Hyrogen 4.0 kg Recover of acetonirile 950 lit Pb/BaSO4 50 kg Recover Pb/Baso4 60 kg D-(-)-Mandelic acid 225 KG Loss 44 kg 10 % NAOH 500 LIT Acetonitrile 1000 LIT HCL 100 KG TOTAL 3854KG 3854 KG
. 47
191) ROS :- SOLIFENACIN SUCCINATE
O ONa NH NH O O CO + H2O CH O OH + 2 N 3 O Na2CO3(106) N CH3 O + O ONa CN CN CF 3 CF 3 MOL FOR :- 2 MOL FOR :- H2O O OH MOL FOR :- C2HNa 2O4 CO O O (1-[3-(Benzyloxy)propyl]-5-{(2 MOL WT :- 44 MOL WT :- 18 R)-2-[2-(2,2,2-trifluoroethoxy) MOL WT :- 134 (1-[3-(Benzyloxy)propyl]-5-{(2 -phenoxy]ethyl}amino)propyl] H C R)-2-[2-(2,2,2-trifluoroethoxy)- 5 6 H5C6 indoline-7-Carbonitrile phenoxy]ethyl}amino)propyl]in MOL FOR :- doline-7-Carbonitrile Oxalate C32 H36 F3N3O3 MOL WT :- 567.64 MOL FOR :- C34 H38 F3N3O7 MOL WT :- 657.67
NH NH O O H2O 2H2O2.DMSO + N CH CH 3 O N 3 O NaOH (18) CONH CN 2 CF 3 CF 3 (1-[3-(Benzyloxy)propyl]-5-{(2 1-[3-(benzyloxy)propyl]-5-{(2R) O O R)-2-[2-(2,2,2-trifluoroethoxy) -2-({2-(2,2,2-trifluoroethoxy)-ph -phenoxy]ethyl}amino)propyl] enoxy]ethyl}amino)propyl]indoli indoline-7-Carbonitrile H5C6 ne-7-Carboxamide) H5C6 MOL FOR :- C32 H36 F3N3O3 Benzyl silodosin MOL WT :- 567.64 MOL FOR :- C32 H38 F3N3O4 MOL WT :- 585.65
Manufacturing Process :-
(1-[3-(Benzyloxy)propyl]-5-{(2R)-2-[2-(2,2,2-trifluoroethoxy)- phenoxy]ethyl}amino)propyl]indoline-7-Carbonitrile Oxalate is Converted to Free base, Which Oxidized to 1-[3-(benzyloxy)propyl]-5-{(2R)-2-({2-(2,2,2-trifluoroethoxy)- phenoxy]ethyl}amino)propyl]indoline-7-Carboxamide) (Benzyl Silodosin) in Presence of Hydrogen Peroxide and Dimethylsulphoxide.
NAME OF Raw material :-
1) - (1-[3-(Benzyloxy)propyl]-5-{(2R)-2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyl]indoline-7-Carbonitrile Oxalate
2)- Sodium bicarbonate
3) - Hydrogen Peroxide
4)- Dimethyl sulfoxide Flow diagram :- sx`x`x`x` Sodium bicarbonate 106 kg
+ Water -200 kg (1-[3-(Benzyloxy)propyl]-5-{(2R)-2- [2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyl]indolin Reactor e-7-Carbonitrile Oxalate -595 kg
Centrifuge Effluent- 400 kg
Free Base -485 kg
Free Base 485 kg Hydrogen peroxide – 582 kg
Reactor Dimethyl sulfoxide -1000 kg
Loss -33 kg Recovery of DMSO - 950 kg Centrifuge Effluent- 600 kg
Dry wt 500 kg
SOLIFENACIN SUCCINATE INPUT kg OUTPUT kg (1-[3-(Benzyloxy)propyl]-5-{(2R)- 595 Effluent 1000 2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethyl}am ino)propyl]indoline-7-Carbonitrile Oxalate Sodium bicarbonate 106 Recovered DMSO 950 Hydrogen Peroxide 582 Product 500 Dimethyl sulfoxide 1000 loss 33 water 200
TOTAL 2483 2483
38 192) ROS :- TADALAFIL
O CH3 O N CH3 NH N
Methanol/Hyflo N N Cl H C NH O + 3 2 H N O H O
O O
O Tadalafil Crude (1R,3R)-methyl-1,2,3,4-tetrahydro-2-ch Methylamine MOL FOR :- C22 H19 N3O4 loroacetyl-1-(3,4-metylenedioxyphenyl) MOL FOR :- CH 5N -9H-pyrido[Chloroacetyl intermediate] MOL WT :- 389.40 MOL WT :- 31.06 + MOL FOR :- C22 H19 ClN 2O5 NH4CL(53.5) MOL WT :- 411.85
O CH3 O N CH3 N N
Methanol / Dichloromethane N N O H N O Isopropanol / Activated carbon / H Hyflo O O O
O Tadalafil Crude Tadalafil Crude MOL FOR :- C22 H19 N3O4 MOL WT :- MOL FOR :- C22 H19 N3O4 389.40 MOL WT :- 389.40
Manufacturing Process :-
Stage :- 1 :- Preparation of Tadalafil Crude
Cis Carboline reacts with Chloroacetyl Chloride Presence of Sodium bicarbonate and dichloromethane to form Corresponding Chloroacetyl Carboline derivative, Which reacts with methylamine and Undergoes Cyclisation reaction in methanol medium to yield Tadalafil Crude. Stage :- 2 :- Purification of Tadalafil
Tadalafil Crude is dissolved in a mixture of Methanol and Dichloromethane and further purified in Isopropyl alcohol to yield pure Tadalafil. Flow diagram :-
KSM 590 kg Methyl Amine 45 kg
Methanol 1200 kg
Reactor
Sparkler Filter
Reactor
Recovery of Methanol -1150 kg Centrifuge Efflu ent - 160 kg
Technical 510 kg Technical 510 kg IPA 1000 kg
Carbon 50 kg Reactor
Sparkler Filter
Reactor
Chilled
Recovery of IPA -97 0 kg Loss -5 kg Centrifuge Salt 80 kg
Dry wt 500 kg
NAME OF Raw material :-
1) - KSM
2)- Methanol
3) - Methyl Amine
4)- IPA
5)- Carbon
TADALAFIL INPUT kg OUTPUT kg KSM 590 Methanol 1150 Methanol 1200 Effluent 18 0 Methyl Amine 45 IPA 970 IPA 1000 carbon 80 Carbon 50 Product 500 loss 5
TOTAL 2885 2885
39
193)ROS :- TICAGRELOR
F F HN HN OH OH N N F F N N N N H2O(18) Conc.HCL N N O N S O N S Methanol
Ethylacetate HOHO OO Cyclohexane CH3 CH3 CH3 Ticagrelor H3C 562.63 522.56 + (CH3)2CHOH(60)
Isopropylidene Ticagrelor Manufacturing Process :-
This is Isopropylidene Ticagrelor reacted with Conc. HCL and methanol to get the title Compound Ticagrelor.
NAME OF Raw material :-
1) - Isopropylidene Ticagrelor
2)- Methanol
3) - Con. HCL
4)- Cyclohexane
Flow diagram :-
Isopropylidene Ticagrelor 495 kg Con. HCL 470 kg
Methanol 1000 kg
Reactor
Recovery of Methanol -950 kg Centrifuge Efflu ent - 500 kg
Technical Dry wt 510 kg Technical 510 kg Cyclohexane 1000 kg
Reactor
Recovery of Cyclohexane -950 kg Centrifuge Loss -15 kg Effluent -50 kg
Dry wt 500 kg
TICAGRELOR INPUT kg OUTPUT kg Isopropylidene Ticagrelor 495 Methanol 950 Methanol 1000 Effluent 550 Con. HCL 470 Cyclohexane 950 Cyclohexane 1000 Product 500 loss 15
TOTAL 2965 2965
194) Topiramate
ROS :-
NH2 O CH OH O-Xylene S 2 O O O CH Sulfuryl chloride(135) 3 O CH Pyridine O 3 O O O CH3 O Ammonia(17) HCL CH3 + 36.5 H3C Tetrahydrofuran O CH O 3 n-Hexane 2,3:4,5-bis-o-(1-methyl ethyl idene) O H3C B-D-fructopyranose(pure) CH3 Topiramate(Technical) MOL F:- C 12 H 20 O 6 MOL W t:- 260.28 gm/mole MOL F:- C 12 H21 NO 8S MOL W t:- 339.36gm/mole
Flow chart :-
BME-DFP-500kg O-Xylene -1000kg Water-210 kg Sulfuryl chloride-348 kg Pyridine-214 kg Reactor kg HCl Gas-70kg Scrubber Ammonia gas- 50 kg Terahydrofuran-1000 kg Recover o-xylene- 950 kg Total-280 kg Water-1000 kg Reactor Recover THF- 1450 kg
Terahydrofuran-500 kg Disitillation n-Hexane-3000 kg Reactor Recover n-hexane-2850 kg Effluent -950 kg
Effluent -570 KG Loss -62 kg Centrifuge
Product-500 kg Manufacturing Process :-
Charge of o-xylene in reactor & charge sulfuryl chloride at 20 0C. Chill below -10 to -5 0C, slow addition of solution A (2,3:4,5-BIS-O-[1-Methyl Ethyl idene] B-D-Fructopyranose + O-Xylene + Pyridine )for 3-4 hours at -10 to -5 0C. stir for 2 hours .Check TLC .TLC O.K Water wash. Take Organic mass charged in Reactor & charged Tetrahydrofuran . Ammonia gas pass and set Ph-9 to10. Stir for 3-hrs at 35-40 0C. Check TLC .TLC O.K Water wash. Distilled out Terahydrofuran & O-xylene .Charge Terahydrofuran and Charge n-hexane the products obtain &. Chilled 5-10 0C and centrifuge .drying.
Topiramate INPUT OUTPUT BME-DFP 500 KG Recover of O-XYLENE 950 LIT
O-xylene 1000 LIT Dry Wt 500 KG sulfuryl chloride 348 KG loss 62 KG Pyridine 214 KG Recover of THF 1450LIT
THF 1500 Recover of N-HEXANE 2850 LIT
WATER 1000 Ammonia gas 50 EFFLU ENT 1800 KG n-hexane 3000
TOTAL 7612 kg 7612 KG
. 41
195 )ROS :- VILAZODONE HYDROCHLORIDE
H2N H2N O O CN CN O O + Conc.HCL Formic acid N N 36.5 N N NH NH HCL
MOL FOR :- C26 H28 ClN 5O2 MOL FOR :- C26 H21 N5O2 MOL WT :- 477.98 MOL WT :- 441.52
Manufacturing Process :-
The hydrochloride formation and amorphous form Conversion done in VILAZODONE, formic acid and Conc. HCL using spray dryer.
Flow diagram :-
Con. HCL 45 kg
VILAZODONE -485 kg Formic Acid 800 kg
Reactor
Salt 70 kg Centrifuge Loss -10 kg Effluent - 75 0 kg
Dry wt 50 0 kg
NAME OF Raw material :-
1) - VILAZODONE
2)- Con. HCL
3) - Formic Acid
VILAZODONE HYDROCHLORIDE INPUT kg OUTPUT kg VILAZODONE 485 Efflu ent 750 Con. HCL 45 Salt 70 Formic Acid 800 Product 500 loss 10
TOTAL 1330 1330