MATERIAL BALANCE Input Material Quantity (kg) Output ...

MATERIAL BALANCE

Input Material Quantity (kg) Output Material Quantity(kg)

TCAP 1059 Micanazol nitrate 1000

Imidazol 424 Recovered Toluene 9250

Sodium Carbonate 848 org residue 624

Toluene 9481 Spent carbon 350

Sodium borohydride 69 Recovered Methanol 2100

TBAB 375

Effluent to

ETP(Aqueous

effluent) 22559

Caustic Soda flake 3750

DCBC 917

Hydrose 10

Carbon 350

Nitric acid 300

Methanol 2300

Water 16000

Total 35883 Total 35883

[15] DORZOLAMIDE HYDROCHLORIDE

MANUFACTURING PROCESS

(±)-Trans-5, 6-dihydro-4H-4-Ethyl amino

7-dioxide is resolute with (-)

with hydrochloric acid in presence of water to yield Dorzolamide Hydrochl

Schematic diagram of Dorzolamide

methanol are taken for solvent recovery. The process involves reaction of methanol,

acetone, n butanol, methanol, sodium hydroxide, sodium carbonate, so

reactor. Different compounds are formed which get acidified and alkalized with purification.

CHEMICAL REACTION

MATERIAL BALANCE

Input Material

(+-)- Trans -5,6 - DIHYDRO-4H

Ethyl amino-6methyltheino[2,3

N butanol

Methanol

Ethyl Acetate

Acetone

Activated carbon

Sodium Bicarbonate

Sodium Chloride

Sodium Hydroxide

Hydrochloric acid

Water

Total

[15] DORZOLAMIDE HYDROCHLORIDE

Ethyl amino-6-methylthieno [2, 3-b] thiopyran-2

)-Di-para-toluoyl-L-tartaric acid monohydrate and then reacted

with hydrochloric acid in presence of water to yield Dorzolamide Hydrochl

Schematic diagram of Dorzolamide Hydrochloride. N Butanol, ethyl acetate , acetone and


acetone, n butanol, methanol, sodium hydroxide, sodium carbonate, sodium chloride in a


Quantity (KG) Output Material

4H-4-

methyltheino[2,3-

2990 Dorzolamide Hcl

23200 Recovered N Butanol

30200 Recovered Methanol

14500 Recovered Ethyl Acetate

800 Recovered Acetone

300 Organic residue

1500 Solvent Vapor loss

1500 Effluent to ETP(Aqueous

258

Recovered intermediate

products for second crop

336

8800

84384 Total

2-Sulfonamide-7,

tartaric acid monohydrate and then reacted

with hydrochloric acid in presence of water to yield Dorzolamide Hydrochloride (Pharma).

. N Butanol, ethyl acetate , acetone and


dium chloride in a


Quantity (KG)

1000

21700

28275

Recovered Ethyl Acetate 14028

720

2666

1033

Aqueous) 12769

Recovered intermediate

products for second crop 2193

84384

[16] BOSENTAN

MANUFACTURING PROCESS Guiacol and diethyl chloromalonate were added drop wise in succession to a previously

prepared sodium ethoxide solution. The suspension was stirred at 45oC with exclusion of

moisture. Thereafter the ethanol was distilled off. The residue was taken up in toluene,wash

with water and 1% sodium hydroxide solution until organic phase gets colorless. Finally wash

with water and saturated brine solution. After drying on sodium sulfate and evaporating the

solvent, the residue was distilled to give diethyl (O-ethoxyphenoxy) malonate.Pyrimidine-2-

carboxamidine hydrochloride and diethyl (O-ethoxyphenoxy) malonate were added while

cooling with ice to a previously prepared sodium methoxide solution from sodium and

absolute methanol. Stir the reaction mixture at room temperature with the exclusion of

moisture. Solvent was evaporated under reduced pressure. The residue was taken up in

1NNaOH solution. Alkaline solution was acidified with 1N HCl. Precipitate was filtered off and

washed thoroughly with water and dried under vacuum. The 5-(2-methoxy-phenoxy)-2-

(pyrimidin-2-yl) tetrahydro-pyrimidine-4, 6-dione used in the next step without further

purification. Pyrimidinone from step-II was charged in to N, N diisopropyl-N-ethylamine.

Phosphorous pentachloride (PCl5) was added portion wise. Reflux the reaction mixture. The

mixture was then evaporated under reduced pressure. Residue was poured on to ice and

extracted with ethyl acetate.

The combined extracts were washed with water, dried andevaporated in a vacuum. The

residue was chromatographed on silica gel using ethyl acetate yielded 4, 6-dichloro-5-(2-

methoxy-phenoxy)-2, 2’-bipyrimidine. To a solution of Step-III inDMSO, p-

tertbutylbenzenesulphonamide was added. The mixture was heated at 100oC. The solution

was concentrated under vacuum. The oily residue was poured on to ice, and adjusted pH 3.

The suspension was extracted with ethyl acetate, combined organic layers and washed with

water. Dried over sodium sulphate and concentrated under reduced pressure. The residue

was chromatographed on silica gel with toluene-ethyl acetate 9:1to give4-tert-butyl-N-[6-

chloro-5-(2-methoxy-phenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]-benzenesulphonamide. To

a solution of sodium metal in ethylene glycol, charged Step 04. The mixture was heated at

100oC.After completion of reaction, the reaction mass was poured on to ice and adjusted to

pH=3 with1M tartaric acid. The suspension was extracted with ethyl acetate. Combined

organic layers were washed with water, dried over sodium sulphate and concentrated under

reduced pressure. The residue was chromatographed on silica gel with dichloromethane-

ethyl acetate9:1to yield 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-

(pyrimidin-2-yl)-pyrimidin-4-yl]-benzenesulphonamide (Bosentan)

CHEMICAL REACTION

MATERIAL BALANCE

Input material Quantity (KG) Output material Quantity (KG)

4,6 Dichloro 5 (2-

Methoxyphenoxy)2,2

Bipsimidine

726 Bosentan

Monohydrate

1000

4 Tert Butylbenzene

Sulfonamide

443 Evaporation losses 3973

Hydrochloric Acid 179 Carbon dioxide 94

Potassium Carbonate 1206 Effluent to ETP 17245

Sodium Tert Butoxide 998

Ethylene Glycol 12339

Water 6421


[17] FEBUXOSTAT


Ethyl-2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate is reacted with

hydroxylamine hydrochloride to form oxide which is dehydrated with sodium formate &

formic acid to form Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate

which on hydrolysis gives Febuxostate. Process involves formation of Ethyl 2-(3-Formyl-4-

Isobutoxyphenyl)-4-Methylthiazole-5-carboxylate,Ethyl 2-(3-Cyano-4-Isobutoxyphenyl)-4-

Methyl-5-thiazole carboxylate and finally febuxostate. The reactions are carried out in three

different reactors .Acetone is recovered and reused while aqueous effluent is taken to ETP.

CHEMICAL REACTION

MATERIAL BALANCE

Input material

KSM

Isobutyl Bromide

Potassium Carbonate

Ammonium Hydroxide Hcl

Sodium Carbonate

Sodium Hydroxide

Hydrochloric Acid

Acetone

Water

Total

Quantity (KG) Output material

1547 Febuxostat

1162 Evaporation losses

1834 Recovered Acetone

323 Effluent to ETP

314

297

289

750

1200

7716 Total

Quantity (KG)

1000

565

700

5451

7716

[18] FESOTERODINE NDMF


Stage-1 Preparation of FES/KSM/I (Ester)Reaction of Cinnamic acid with p

intermediate which on further reaction with Benzyl bromide in presence of Methanol and

base gives Ester is isolated from Methanol.

Stage-2 Preparation FES/KSM/II (Amide)Ester is hydrolyzed using Potassium hydroxide and Meth

on further reaction with Thionyl chloride followed by reaction with Diisopropylamine gives

amide. Amide is isolated from Isopropanol.

Stage-3 Preparation of FES/KSM/III (KSM)Amide on reduction with Sodium Borohydride

(Oil) having one chiral carbon and it is racemic. Racemic Amine (Oil) on resolution with

optically active acid Di p-toluoyl L

desired optical and chemical pu

CHEMICAL REACTION

[18] FESOTERODINE NDMF


1 Preparation of FES/KSM/I (Ester) Reaction of Cinnamic acid with p-Cresol in presence of Sulphuric acid gives Coumarin


base gives Ester is isolated from Methanol.

2 Preparation FES/KSM/II (Amide) Ester is hydrolyzed using Potassium hydroxide and Methanol to give Acid intermediate which


amide. Amide is isolated from Isopropanol.

3 Preparation of FES/KSM/III (KSM) Amide on reduction with Sodium Borohydride and Borontri-fluorideetherate gives Amine


toluoyl L-tartaric acid followed by crystallizations gives KSM of

desired optical and chemical purity.

Sulphuric acid gives Coumarin


anol to give Acid intermediate which


fluorideetherate gives Amine


tartaric acid followed by crystallizations gives KSM of

MATERIAL BALANCE


Benzyl Amine DPTT 5454 Festerodine NDMF 1000

Sodium Carbonate 5726 Carbon dioxide 535

Ceric Ammonium nitrate 12544 Evaporation losses 5630

Barium Borohydrate (BaBH4) 774 Effluent to ETP 19464

Fumaric Acid 1477

Hydrogen gas 13

Isobutyl Chloride 340

Triethylamine 301


[19] RIZATRIPTAN

MANUFACTURING PROCESSCharge Triazole Compound, Dimethyl amino Indole, Catalyst, Acetonitrile,Methanol, Water

in a reactor and heat by raising the temperature. Then reflux and distill out Methanol.

filter and finally dry in RCVD to get

solvents.Process involves reaction in a reactor ,filteration and drying. It involves heating and

cooling ,drying with recovery of solvents. Aqueous effluent is taken to ETP.

CHEMICAL REACTION

MATERIAL BALANCE

Input Material

Triazole Compound

Dimethyl amine Indole

Catalyst

Acetonitrile

Methanol

Water

Total

MANUFACTURING PROCESS Charge Triazole Compound, Dimethyl amino Indole, Catalyst, Acetonitrile,Methanol, Water

in a reactor and heat by raising the temperature. Then reflux and distill out Methanol.

filter and finally dry in RCVD to get Rizatriptan .Acetonitrile and methanol are recovered as


cooling ,drying with recovery of solvents. Aqueous effluent is taken to ETP.

Quantity (kg) Output Material

1250 Rizatriptan

2000 Recovered solvents

1120 Effluent to ETP

5000 Moisture loss

6250

12500

28120 Total

Charge Triazole Compound, Dimethyl amino Indole, Catalyst, Acetonitrile,Methanol, Water

in a reactor and heat by raising the temperature. Then reflux and distill out Methanol. Cool &

Acetonitrile and methanol are recovered as


Quantity(kg)

1000

13250

13250

620

28120

[20] OLANZAPINE


Charge Methyl piperazinyl Chloro

temperature by heating. Reflux the material and distill out. Add Acetonitrile cool & filter dry

in RCVD to get OLANZAPINE

distillation, refluxing and drying with recovery of solvents. Aqueous effluent is taken to ETP.

CHEMICAL REACTION

MATERIAL BALANCE

Input Material

Methyl Piperazinyl Chloro-thiano benzodiazepine N N DMA

Catalyst

Acetonitrile

Total

Charge Methyl piperazinyl Chloro-thieno benzodiazepine, N N DMA, catalyst and raise the

Reflux the material and distill out. Add Acetonitrile cool & filter dry

OLANZAPINE. Process involves reaction, heating , cooling , filtration,



1060 Olanzapine thiano benzodiazepine

933 Effluent to ETP

5330 Recovered Solvent

130 Moisture loss

4000

11453 Total

thieno benzodiazepine, N N DMA, catalyst and raise the

Reflux the material and distill out. Add Acetonitrile cool & filter dry

. Process involves reaction, heating , cooling , filtration,


Quantity(kg)

1000

3323

6800

330

11453

[21] LEVOCITRIZINE


1-[4-Chlorophenyl) phenyl methyl] piperizine is treated with L-Tartaric acid, (2

Chloroethoxy) & Acetonitrile. The mass is further treated with Sodium Carbonate, KI, n-

Butanol & Conc. HCl. The crude obtained is crystallized from ethyl acetate to give

Levocetrizine.Process involves reaction in a reactor, purification, drying and milling.

Potassium iodide, tartaric acid,n butanol, ethyl acetate are recovered and reused.

CHEMICAL REACTION

Cl OH

+ O

O

Cl

1-[4-Chlorophenyl) phenyl methyl]

piperizine

L-Tartaric acid,(2-Chloroethoxy)

Na2CO3

HCl

N N O

OH

. HCl

O

LEVOCITRIZINE HCL

N

MATERIAL BALANCE


1-[4Chlorophenyl) Phenyl

methyl] piperizine L-Tartaric acid

1820 Levocetrizine 1000

2-Chloroethoxy 620 Recovered N Butanol 2080

Acetonitrile 1450 Recovered Ethyl

Acetate 2660

Sodium Carbonate 350 Aqueous Effluent for

Potassium Iodide and

Tartaric acid Recovery

3920

Potassium Iodide 150 Solvent vapor loss 250

N-Butanol 2250

Hydrochloric Acid 320

Ethyl Acetate 2950


[22] REVAROXABAN


Stage-1: Preparation of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-

yl]phenyl}morpholin-3- one hydrochloride

2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5- yl} methyl)-1Hisoindole-

1,3(2H)-dione {Stage-II (Non-DMF)} is reacted with 40% Aqueous methyl amine in Isopropyl

alcohol to give 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} morpholin-3- one

which is further reacted with aq. HCl to give 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-

3-yl]phenyl}morpholin-3- one hydrochloride.

Stage-II: Preparation of 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-

oxazolidin-5-yl}methyl)-2-thiophene-carboxamide

5-Chlorothiophene-2-carboxylic acid (RM-III) is reacted with Oxalyl chloride with catalytic

amount of DMF in THF to give 5-Chlorothiophene-2-carboxylchloride which is further reacted

with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3- yl]phenyl}morpholin-3-

onehydrochloride 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-

thiophenecarboxamide

Stage3

Preparation of 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-

yl}methyl)-2-thiophene-carboxamide

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.

CHEMICAL REACTION

MATERIAL BALANCE

Input material Quantity

(KG)

Output

material

Quantity

(KG)

(4-4-Aminophenyl)-

morpholin-3-one 1410

Revaroxaban 1000

Glycidyl Phthalimide 1640

Carbon

dioxide 410

4-

Dimethylaminoopyridine

(DMAP)

10 Solvent

vapor losses 200

Carbonyldiimidazole 4030 Effluent to

ETP(aqueous) 12040

5-Chlorothiophene-2-

cacoxylic acid 1230

Sodium Acetate 1480

Oxalyl Chloride 1500

Methyl Amine(Aqueous) 1630


Acetic Acid 40


[23] CIPROFLOXACIN


Fluoro quonlinic acid & piperizine treated in presence of dimethyl sulphoxide. Caustic lye is

added, to forma base. Treated with HCl to give Ciprofloxacin. Purified using Methanol filtered

& dried to give Ciprofloxacin.

CHEMICAL REACTION

MATERIAL BALANCE

Input Material Quantity (KG) Output Material Quantity (KG)

Flouro Quinolic acid 1000 Ciprofloxacin 1000

Piperazine 400 Recovered Methanol 800

Dimethyl Sulphoxide 50 Recovered

Piperazine

160

Causitc lye 950 Drying loss 240

Hydrochloric Acid 600 Aqueous effluent to

ETP

3000

Methanol 1400

Water 800


[24] AGOMELATINE


Catalytic hydrogenation of (7

Ammonia gives 2-(7-Methoxy-1

naphthyl) ethanamine with acetyl chloride in p

This on purification gives final Agomelatine. Process involves catalytic hydrogenation,

condensation and purification.IPA and acetic acid are recovered .Processes are carried

carried out in reaction vessels.

CHEMICAL REACTION

Catalytic hydrogenation of (7-Methoxy-1-naphthyl) acetonitrile using Methanol and

1-naphthyl) ethanamine. Condensation of 2-(7

naphthyl) ethanamine with acetyl chloride in presence of base gives crude Agom

tion gives final Agomelatine. Process involves catalytic hydrogenation,

and purification.IPA and acetic acid are recovered .Processes are carried

naphthyl) acetonitrile using Methanol and

(7-Methoxy-1-

resence of base gives crude Agomelatine.

tion gives final Agomelatine. Process involves catalytic hydrogenation,

and purification.IPA and acetic acid are recovered .Processes are carried

MATERIAL BALANCE


2-(7-methoxy-1-napthyl-napthyl)

Acetonitrile

1000 Agomelatine 1000

Hydrogen Gas 20 Recovered Isopropyl

Alcohol

560

Isopropyl Alcohol 740 Organic Residue 100

Sodium Acetate (Anhydrous) 420 Solvent vapor losses 20

Acetic Acid (Anhydrous) 510 Recovered Acetic

Acid 490

Sodium chloride 520


[25] BRINZOLAMIDE


4(S)-4-hydroxy-6-sulfonamide dioxide react with Methane sulfonic anhydride and ethyl

amine in the presence of aq. ammonia and IPA media at 50 degrees and compound isolating

with adjusting the mass PH with HCl in the presence of IPA to give Brinzolamide.process

involves reaction of raw materials in a reactor, with heating at 50 degree C, cooling, PH

adjustment and isolation of the compound.IPA and Tetrahydrofuran are recovered as

solvents for use as recovered solvents .Aqueous effluent is sent to ETP for treatment.

MATERIAL BALANCE


4(S)-4-hydroxy-6- sulfonamide

dioxide

2610 Brinzolomide 1000

Methanol sulfonic anhydride 600 Recovered

Tetrahydrofuran

9195

Ethyl amine 330 Recovered Isopropyl

Alcohol 9770

Ammonia liquor 200 Organic Residue 4386

Hydrochloric Acid 101 Solvent vapor losses 94

Sodium Hydroxide 110 Effluent to ETP 13100

Pyridine 200

Tetrahydrofuran 10050

Isopropyl Alcohol 10950

Sodium Bicarbonate 101

Activated Carbon 101

Hyflow 101

Water 12000


[26] ATORVASTATIN CALCIUM


Stage 1

2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)

with tert-butyl 2-((4R, 6R)-6-

presence of pivolic acid. cyclohexane and Isopropyl alcohol gives tert

(2-(4-fluorophenyl)-5-isopropyl-3

1,3-dioxan-4-yl)acetate.

Stage 2

Tert-butyl2-((4R,6R) – 6-(2-(2

(phenylcarbamoyl)-1H-pyrrol-1-yl)

presence of Acetonitrile, Hydrochloric a

(2-(4- fluorophenyl)-5-isopropyl

dihydroxy heptanoate.

Stage 3

(3R,5R)-tert butyl 7-(2-

1Hpyrrol-1-yl)-3,5-dihydroxyheptanoate reacts with water and calcium acetate in presence

of Acetonitrile, Ethyl acetate and sodium hydroxide gives mono calcium mono (3R,5R)

(4-Fluorophenyl)-5-isopropyl-3-phenyl

heptanoate).

CHEMICAL REACTION

[26] ATORVASTATIN CALCIUM

phenylethyl)-4-methyl-3-oxo-N-phenylpentanamide reacts

-(2-aminoethyl)-2, 2-dimethyl-1, 3-dioxan-4-yl)acetate in

presence of pivolic acid. cyclohexane and Isopropyl alcohol gives tert-butyl2-((4R,6R)

3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-2,2

(2-(4 – fluorophenyl)-5 – isopropyl – 3

yl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate reacts with water

presence of Acetonitrile, Hydrochloric acid and Sodium carbonate gives (3R,5R)

isopropyl-3-phenyl-4-(phenyl carbamoyl)- 1H- pyrrol

-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)

dihydroxyheptanoate reacts with water and calcium acetate in presence

of Acetonitrile, Ethyl acetate and sodium hydroxide gives mono calcium mono (3R,5R)

phenyl-4--(phenylcarbamoyl)- 1H-pyrrol-1-yl)-3,5

phenylpentanamide reacts

yl)acetate in

((4R,6R)-6- (2-

2,2- dimethyl-

3 – phenyl-4

yl)acetate reacts with water in

cid and Sodium carbonate gives (3R,5R)-tert butyl 7-

pyrrol-1-yl)- 3,5-

(phenylcarbamoyl)-

dihydroxyheptanoate reacts with water and calcium acetate in presence

of Acetonitrile, Ethyl acetate and sodium hydroxide gives mono calcium mono (3R,5R)-7- (2-

3,5- dihydroxy

MATERIAL BALANCE


1, 1--dimethyl ethyl-6-

(2- aminoethyl)

770 Atorvastatin Calcium 1000

4- Fluoro-2-methyl-1-oxopropyl 1176 Recovered Isopropyl

Alcohol

2388

Cyclohexane 3000 Recovered

Acetonitrile 3235

Isopropyl Alcohol 2501 Recovered

Cyclohexane 2760

Hydrochloric Acid 70 Organic Residue 1707

Acetonitrile 3500 Solvent vapor loss 117

Sodium Hydroxide 146 Calcium

Acetate(byproduct) 42

Calcium Acetate 179 Sodium

Acetate(byproduct) 34

Hyflow 12 Effluent to ETP 6269

Water 6198


[27] CAPACITABINE


2,3-di-o-acetyl-5-deoxy-5-fluorocytidine is condensed with n

Methylene chloride to give Capacitabine

Chloroformate, Sodium Hydroxide, sodium Bicarbonate, Hydrochloric Acid, Methylene

Chloride(MDC), Methanol, Ethyl Acetate

reaction vessel. MDC, Methanol and ethyl acetate are taken for solvent recovery for

recovery and further reuse. Effluent is taken for further treatment to ETP. Activated carbon

is disposed as organic residue. The process mainly involves c

CHEMICAL REACTION

fluorocytidine is condensed with n-Pentyl chloro

Methylene chloride to give Capacitabine. 2,3 di-o-actyl-5-dexy-5-fluorocytidine,

Sodium Hydroxide, sodium Bicarbonate, Hydrochloric Acid, Methylene

Chloride(MDC), Methanol, Ethyl Acetate, Activated carbon and water are reacted in a

MDC, Methanol and ethyl acetate are taken for solvent recovery for


is disposed as organic residue. The process mainly involves condensation.

chloro formate in

fluorocytidine, n-Pentyl

Sodium Hydroxide, sodium Bicarbonate, Hydrochloric Acid, Methylene

are reacted in a

MDC, Methanol and ethyl acetate are taken for solvent recovery for


MATERIAL BALANCE


2,3 di-o-actyl-5-dexy-5-

fluorocytidine

1247 Capacitabine 1000

n-Pentyl Chloroformate 570 Recovered

Methylene

Chloride(MDC)

3881

Sodium Hydroxide 415 Recovered Methanol 2419

Sodium Bicarbonate 50 Recovered ethyl

Acetate 5308

Hydrochloric Acid 75 Organic Residue 868

Methylene Chloride(MDC) 4000 Solvent vapor loss 52

Methanol 2500 Material recovered

for second crop 446

Ethyl Acetate 5500 Effluent to ETP 1183

Activated Carbon 50

Water 750


[28] DIACEREIN


Aloe emodine is oxidized using chromic acid and tetrahydrofuran as a solvent to give

I(4,5-(Hydroxy)-9,10-dihydro-9, 10

acetic anhydride in presence of sulfuric acid to get Diacerein crude and which is first purified

with NMP & methanol mixture and then with NMP & wate

Methyl pyrolidone,methanol and acetone are sent for solvent recovery.

reaction in reactors in two stages.In stage 1

Sulphuric Acid, Sodium Hydroxide ,Tetrahydrofuran (THF), Acetone a

of water.In stage two the reacted mass is further reacted with Acetic anhydride ,Sulphuric

acid, Sodium hydroxide, N-Methyl pyrolidone, Methanol and Acetone to give diacerein.

Aqueous effluent is taken to ETP for further treatment.

CHEMICAL REACTION

Aloe emodine is oxidized using chromic acid and tetrahydrofuran as a solvent to give

9, 10-dioxo-2-anthracenecarboxylic acid). DCN-I is reacted with


with NMP & methanol mixture and then with NMP & water mixture to give diacerein.

Methyl pyrolidone,methanol and acetone are sent for solvent recovery. Process involves

reaction in reactors in two stages.In stage 1 Aloe emodine, Sodium dichromate

Sulphuric Acid, Sodium Hydroxide ,Tetrahydrofuran (THF), Acetone are reacted in presence


Methyl pyrolidone, Methanol and Acetone to give diacerein.

Aqueous effluent is taken to ETP for further treatment.

Aloe emodine is oxidized using chromic acid and tetrahydrofuran as a solvent to give DCN-

I is reacted with


e diacerein. N-

Process involves

Aloe emodine, Sodium dichromate, dihydro,

re reacted in presence


Methyl pyrolidone, Methanol and Acetone to give diacerein.

MATERIAL BALANCE


Aloe emodine 1966 Diacerein 1000

Sodium dichromate dihydro 2168 Sodium Sulphate

(byproduct)

1034

Sulphuric Acid 814 Recovered

Tetrahydrofuran 21120

Sodium Hydroxide 122 Recovered Acetone 5890

Tetrahydrofuran 22000 Recovered N Methyl

pyrolidone 3342

Acetone 6200 Recovered Methanol 2112

Acetic Anhydride 1018 Material recovered

for second crop 480

N Methyl pyrolidone 3498 Organic Residue

(Including Spent

Carbon)

1900

Methanol 2200 Solvent vapor losses 156

Activated Carbon 200 Effluent to ETP 11602

Celite 200

Water 8250


[29] DABIGATRAN


Stage 1

The propionic acid methyl ester derivate of formulae

acid, hydrogenated with damp Pd/C at RT at 2 bar hydrogen pressure. After completion of

the reaction the catalyst is filtered off and dissolved in ethanol was added to filtrate. To get

formulae-II precipitated out this was filtered off and dried.

Stage 2

The Tosylate salt obtained in the stage I was dissolved in acetone and the mixture is

combined with hexylchloroformate in presence of potassium hydroxide at temperature15

degree Centigrade. After completion of the reaction the precipitated

and washed with acetone mixture. The resulting crude is crystallized with water.

Solvents are recovered for reuse and aqueous effluent is sent to ETP.

CHEMICAL REACTION

MATERIAL BALANCE

Input Material

3-[(1-Methyl-2-{[4-(5-oxo-4,5-

dihydro-[1,2,4] oxadiazol-3-yl)-

phenylamino]-methyl)-1H-

benzoimidazole-5-carbonyl)-

pyridin-2-yl amino]-propionic

acidethyl ester

Para toluene sulphonic acid

Acetic acid

Ethanol

Hexa Chlorofomate

The propionic acid methyl ester derivate of formulae-I is dissolved in ethanol and acetic

with damp Pd/C at RT at 2 bar hydrogen pressure. After completion of


II precipitated out this was filtered off and dried.

obtained in the stage I was dissolved in acetone and the mixture is


degree Centigrade. After completion of the reaction the precipitated , product is filtered off

ed with acetone mixture. The resulting crude is crystallized with water.

Solvents are recovered for reuse and aqueous effluent is sent to ETP.

Quantity (KG) Output Material Quantity (KG)

970 Dabigatran

250 Carbon dioxide

200 Recovered

Ethanol

25000 Recovered

Acetone

280 Organic residue

I is dissolved in ethanol and acetic

with damp Pd/C at RT at 2 bar hydrogen pressure. After completion of


obtained in the stage I was dissolved in acetone and the mixture is


product is filtered off

ed with acetone mixture. The resulting crude is crystallized with water.

Quantity (KG)

1000

74

24500

11905

892

Acetone

12000

Solvent Vapor

loss 174

Potassium Hydroxide 96

Effluent to ETP

(Aqueous

Effluent )

3255

Hydrochloric acid 4

Water 3000


[30] VILAZODONE HYDROCHLORIDE


Stage 1

5-{4-[4-(5-Cyano-1H-indol-3-yl)-

methylester reacts with methanolic ammonia to yield 5

piperazin-1-yl}-benzofuran-2-carboxylic acid amide

Stage 2

5-{4-[4-(5-Cyano-1H-indol-3-yl)-butyl]

reacts with IPA/HCl in methanol and water to yield Vilazodone hydrochloride

Solvents are recovered and reused.

CHEMICAL REACTION

MATERIAL BALANCE

Input Material

5-{4-(5-Cyano-1H-indol-3-

yl)-butyl]-piperazin-1-yl}-

benzofuran-2carboxylicacid

methyl ester

Ammonia

Methanol

Hydrochloric acid

[30] VILAZODONE HYDROCHLORIDE

-butyl]-piperazin-1-yl}-benzofuran-2-carboxylicacid

methylester reacts with methanolic ammonia to yield 5-{4-[4-(5-Cyano-1H-indol

carboxylic acid amide

butyl]-piperazin-1-yl}-benzofuran-2carboxylicacidamide

reacts with IPA/HCl in methanol and water to yield Vilazodone hydrochloride.

Solvents are recovered and reused. Effluent is sent to ETP.


1510 Vilazodone Hcl


16100

Recovered Isopropyl

Alcohol

110 Solvent Vapor loss

carboxylicacid

indol-3-yl)-butyl]-

2carboxylicacidamide

Quantity(kg)

1000

15800

11640

878

Sodium Hydroxide 30% 122 Organic Residue 1042

Isopropyl Alcohol 12000 Effluent to ETP 14380

Activated Carbon 200 Activated carbon 200

Water 14000 Sodium chloride 53


[31] POSACONAZOLE


N-{4-[4-(4-Hydroxy-phenyl)-piperazin

with Formic acid N'-(2-benzyloxy

difluorophenyl)-5-(1,2,4-triazol-1

presence of Tetrahydrofuran and Formic acid to yield Posaconazole .

Chloro-2- Quinolinyl)-ethenyl]pheny]

methyl) cyclopropyl}acetic acid, Methane sulfonyl chloride, sodium hydroxide, N,N

Disopropyletylamie, Hydrochloric acid, Sodium chloride, Acetic acid ,Toluene, Acetonitrile

and Methanol are reacted in a reaction vessel. Solvent

effluent is sent to ETP.

CHEMICAL REACTION

MATERIAL BALANCE

Input material

2-[2-[3(S)-[3-[2-(7-Chloro-2-

Quinolinyl)-ethenyl ]pheny]-3

hydroxy propyl] phenyl-2-

Propanol

2-[1-(sulfonyl

methyl) cyclopropyl} acetic

acid

Methane sulfonyl chloride

piperazin-1-yl]-phenyl}-carbonic acid phenyl ester is condensed

benzyloxy-1-ethyl-propyl)-hydrazine and (5R

1-ylmethyl)tetrahydrofuran-3-methanol tosylate ester in the

presence of Tetrahydrofuran and Formic acid to yield Posaconazole . 2-[2-[3(S)

ethenyl]pheny]-3-hydroxypropyl]phenyl-2- Propanol, 2

methyl) cyclopropyl}acetic acid, Methane sulfonyl chloride, sodium hydroxide, N,N


and Methanol are reacted in a reaction vessel. Solvents are sent for solvent recovery and

Quantity

(KG)

Output material Quantity

1326

Posaconazole

423 Methane Sulphonic Acid

(byproduct)

332 Recovered

Acetonitrile

carbonic acid phenyl ester is condensed

(5R-cis)-5-(2,4-

methanol tosylate ester in the

[3(S)-[3-[2-(7-

Propanol, 2-[1-(sulfonyl

methyl) cyclopropyl}acetic acid, Methane sulfonyl chloride, sodium hydroxide, N,N-


s are sent for solvent recovery and

Quantity

(KG)

1000

158

821

sodium hydroxide 182 Recovered Toluene 947

N,N-Disopropyletylamine 7 Recovered n Hexane 1646

Hydrochloric acid 46 Recovered Methanol 1262

Sodium chloride 7 Solvent Vapor losses 51

Acetic acid 13 Organic Residue 1095

Toluene 1000 Effluent to ETP 1835

Acetonitrile 867

Methanol 1333

n-Hexane 1733

Activated carbon 13

Water 1533


[32] DAPOXETINE HYDROCHLORIDE


β-(dimethyl amino) benzene propanol is reacted with 1

sodium hydroxide, followed by treated with hydrochloric aci

Dapoxetine Hydrochloride.Process involves reaction of

1-fluoronaphthalene, sodium hydroxide

Propanol, and Activatd carbon in

Dapoxetine Hydrochloride. Process mainly involves reaction,filteration,washing,centrifuging

and drying. DMSO and propanol are sent for solvent recovery while aqueous effluent stre

is sent to ETP for further treatment.

CHEMICAL REACTION

MATERIAL BALANCE

Input material

ᵦ- (dimethylamino)

benzenepropanol

1-fluoronaphthalene

sodium hydroxide

Hydrochloric acid

Di methyl Sulphoxide (DMSO)

n-Propanol

Activated Carbon

Water

Total

[32] DAPOXETINE HYDROCHLORIDE

(dimethyl amino) benzene propanol is reacted with 1-fluoronaphthalene in presence of

followed by treated with hydrochloric acid in dimethyl sulfoxide to give

Process involves reaction of ᵦ- (dimethylamino)benzenepropanol,

hydroxide, Hydrochloric acid, Dimethy1 Sulfoxide (DMSO), n

l, and Activatd carbon in a reaction in presence of water to finally obtain


and drying. DMSO and propanol are sent for solvent recovery while aqueous effluent stre

is sent to ETP for further treatment.

Quantity

(KG)


1062 Dapoxetine Hydrochloride 1000

865 Recovered Dimethyl

Sulphoxide 11875

357 Recovered n Propanol 9650

325 Organic Residue 1035

12500 Solvent vapor loss

10000 Material Recovered for

Second crop 1039

250 Effluent to ETP 15635

15000

40359 Total 40359

fluoronaphthalene in presence of

d in dimethyl sulfoxide to give

(dimethylamino)benzenepropanol,

, Hydrochloric acid, Dimethy1 Sulfoxide (DMSO), n-

a reaction in presence of water to finally obtain


and drying. DMSO and propanol are sent for solvent recovery while aqueous effluent stream

Quantity

(KG)

1000

11875

9650

1035

125

1039

15635

40359

[33] CANAGLIFLOZIN


2-(5-bromo-2-methyl benzyl)-5-(4

the presence of Methanol media and potassium carbonate catalyst and compound isolate in

Acetone media to give pure Canagliflozin

flurophenyl)thiophene, silyl D-gloconolactone, Methanol, Acetone ,Potassium carbonate

and water are reacted in a reactor followed by filteration,

Methanol and Acetone are sent for solvent recovery

for further treatment.

CHEMICAL REACTION

MATERIAL BALANCE

Input material

2-(5-bromo-2-methylbenzil)-

5-(4-flurophenyl)thiophene

silyl D-gloconolactone

Methanol

Acetone

Potassium Carbonate

Water

Total

(4-flurophenyl) thiophene react with silyl-Dgloconolactonein


Acetone media to give pure Canagliflozin. 2-(5-bromo-2-methylbenzil)

gloconolactone, Methanol, Acetone ,Potassium carbonate

and water are reacted in a reactor followed by filteration, centrifuging and drying.

Methanol and Acetone are sent for solvent recovery while aqueous effluent is sent to ETP

Quantity

(KG)


2123 Canagliflozin


15400

16667 Recovered Acetone 23250

25000 Material recovered for

second crop

333 Solvent Vapor Losses

5055 Organic residue

Effluent to ETP

51948 Total 51948

Dgloconolactonein


methylbenzil)-5-(4-

gloconolactone, Methanol, Acetone ,Potassium carbonate

centrifuging and drying.

while aqueous effluent is sent to ETP

Quantity

(KG)

1000

15400

23250

2567

142

3754

5835

51948

[34] BRONOPOL (BP)


Charge methanol in a Reactor and then charge formaldehyde, charge caustic lye slowly to

the mixture. This is maintained for 3 hours at 200 degree Centigrade, after that charge

bromine and maintain for 4 hours at 60 degree centigrade and then methanol is recovered.

After total methanol recovery, charge water &

carbon is filtered & water is distilled. The reaction

Centigrade. The material is centrifuged & dried

collected separately.

CHEMICAL REACTION

MATERIAL BALANCE

Input material

Nitro Methane

Methanol

caustic

Formaldehyde

Carbon

Bromine

Water

Total


This is maintained for 3 hours at 200 degree Centigrade, after that charge

4 hours at 60 degree centigrade and then methanol is recovered.

After total methanol recovery, charge water & Carbon into this and then stir for 1 Hr. Then

carbon is filtered & water is distilled. The reaction mixture is chilled to 100 degree

Centigrade. The material is centrifuged & dried. ML is sodium bromide solution & it is

Quantity

(KG)


333 Bronopol (BP)


233 Waste water(recycled)

733

Sodium Bromide

17

Drying loss

883

1667

5533 Total


This is maintained for 3 hours at 200 degree Centigrade, after that charge

4 hours at 60 degree centigrade and then methanol is recovered.

Carbon into this and then stir for 1 Hr. Then

mixture is chilled to 100 degree

is sodium bromide solution & it is

Quantity

(KG)

1000

2083

1667

267

516

5533

[35] CARBAMAZEPINE


Charge Methanol, Iminostilbene carbonyl chloride, ammonia & purified water in to reactor,

stir & heat the content to desired temperature. After completion of reaction centrifuge the

reaction mass followed by washing the wet cake with purified water. Charge Acetone,

Hyflow, wet cake, activated carbon in to another reactor & heat the content up to desire

temperature. Cool the reaction mass and filter it through sparkler followed by micr

Transfer the filtrate in to another reactor, stir & cool the content. Centrifuge the reaction

mass followed washing of wet cake with acetone and then lastly dry the product in fluid

drier.

CHEMICAL REACTION

MATERIAL BALANCE

Input material

Methanol

Imino stilbene carbonyl

Chloride

Ammonia Liquor

Acetone





temperature. Cool the reaction mass and filter it through sparkler followed by micr


mass followed washing of wet cake with acetone and then lastly dry the product in fluid

Quantity

(KG)


1014

Carbamezapine

1282 Losses to air

( Scrubber)


6504 Spent Carbon





temperature. Cool the reaction mass and filter it through sparkler followed by micron.


mass followed washing of wet cake with acetone and then lastly dry the product in fluid bed

Quantity

(KG)

1000

216

17154

31

Toluene 40 Recovered Acetone 6179

Caustic lye 406 Recovered Methanol 963

Hyflow 13 Organic residue 445

Activated Carbon 12 Solvent vapor losses 303

Water 14218


[36] CEFSULODINE SODIUM


Stage 1

RS-a- Sulfophenyl Acetic Acid react with S- Methyl Benzyl Amine in the presence of

Acetonitrile media at room temperature to give complex stage-I.

Stage 2

1-Hydroxy Benzotraizole react with Methansulphonyl Chloride in the presence of

sodiumbicarbonate base and MDC media at 50 degrees then mass adjusting the PH with

sodium bicarbonate and at room temperature and compound isolate in Hexane media to

give stage-II solid.

Stage 3

7-Amino Cephalosporonic Acid react with tert-butyl acetate in the presence of Boron

Trifluoroetharate catalyst and Hexane media at 65 degrees to give stage-III solid.

Stage 4

Stage-I react with stage-II and stage-III in the presence of Zinc Chloride catalyst and

Triethylamine base in MDC media and compound isolate in Ethyl Acetate and Hexane and

Diisopropyl Ether media to give stage-IV solid.

Stage 5

Stage –IV react with Dimethyl Amine Formamine in the presence of Pyridine-4-

Carboxamide and Sodium Iodide catalyst in Ethanol media then compound isolating with

Using concentrated hydrochloric acid.

Stage 6

Stage-V reacts with sodium acetate at 40 degrees and compound isolating ethanol media to

give Cefsulodine pure compound.

CHEMICAL PROCESS

MATERIAL BALANCE


RS-a-Sulfophenyl acetic acid 515 Cefsulodine Sodium 1000

(S)-a-Methyl benzyl amine 288 Recovered Acetonitrile 5904

Acetonitrile 6150 Recovered Methylene

Dichloride 4859

1-Hydroxy benzotriazole 309 Recovered Hexane 2622

Methane sulphonyl chloride 261 Recovered ethyl Acetate 979

Sodium bicarbonate 100 Recovered Ethanol 1662

Methylene dichloride 5125 Recovered Di isopropyl ether 470

Hexane 3000 Recovered DMF and Acetic

Acid 1650

Sodium hydroxide 86 Recovered Diethyl ether 2175

7-Amino cephalosporic acid 598 Material recovered for second

crop 1656

Boron triflouride etherate 1875 Solvent Vapor losses 170

Tert-butyl acetate 255 Organic residue 1927

Hyflow 50 Hyflow (inorganic residue) 50

Zinc chloride 25 Acetic Acid (Byproduct) 128

Triethyl amine 25 Effluent to ETP 11442

Ethyl acetate 1025

Di isopropyl ether 500

Pyridine -4-carboxamide 242

Sodium Iodide 200

Dimethyl formamine 276


Ethanol 1750

Sodium hydroxide 27

Sodium acetate 161

DMF 1500

Diethyl ether 2250

Water 10076


[37] CLINIDIPINE


Charge Methanol heat and reflux. distilled out IPA Add Methyl cello solve, CinamylAceto

Acetate , 3 Nitro Benzaldhyde, Methanol co

Methanol, 2 Methoxy Ethyl Acetoac

and Ammonium Carbonate are reacted in a reaction vessel. Process involves heating ,

distillation, cooling, filtration and drying.

aqueous effluent is sent to ETP for further treatment.

CHEMICAL REACTION

reflux. distilled out IPA Add Methyl cello solve, CinamylAceto

Acetate , 3 Nitro Benzaldhyde, Methanol cool & Filters dry in RCVD to give

Methanol, 2 Methoxy Ethyl Acetoacetate, Cinramyl Aceto Acetate, 3 Nitro Benzaldehyde,

nate are reacted in a reaction vessel. Process involves heating ,

distillation, cooling, filtration and drying. Solvent is recovered for further reuse while

aqueous effluent is sent to ETP for further treatment.

reflux. distilled out IPA Add Methyl cello solve, CinamylAceto

ol & Filters dry in RCVD to give Cilinidipine.

, Cinramyl Aceto Acetate, 3 Nitro Benzaldehyde,

nate are reacted in a reaction vessel. Process involves heating , reflux,

Solvent is recovered for further reuse while

MATERIAL BALANCE

Input material Quantity

(KG)


(KG)

Methanol

7500 clinidipine 1000

2 Methoxy Ethyl Acetoacetate

3250 Recovered Methanol 6500

Cinramyl Aceto Acetate

1000 Recovered methyl cello

solution

2100

3 Nitro Benzaldehyde

750 Moisture loss on drying 300

Ammonium Carbonate



[38] NEBIVOLOL


Benzopyran-2-Carboxaldehyde Derivative treated with Trimethyl sulfoxonium iodide In

presence of Potassium hydroxide & Water. The mass is further treated with Benzyl

& Toluene, Ammonium formate using Pd/Catalyst. The mass is crystallized from

filtered & dried to give Nebivolol.

CHEMICAL REACTION

MATERIAL BALANCE

Input material

Benzopyran-2-

Carboxaldehyde Deri

Trimethyl sulfoxonium Iodide

Potassium hydroxide

Water

Benzylamine

Toluene

Ammonium formate

(Hydrogen source) Pd/C

Methanol

Total

Carboxaldehyde Derivative treated with Trimethyl sulfoxonium iodide In

presence of Potassium hydroxide & Water. The mass is further treated with Benzyl

& Toluene, Ammonium formate using Pd/Catalyst. The mass is crystallized from Methanol,

filtered & dried to give Nebivolol.

Quantity (KG) Output material Quantity (KG)

1.4 Aqueous Effluent for KI (1.1

Kg) recovery

1.15 Methanol

0.56 Solventloss

3.0 Toluene Recovery

0.4 Drying loss

3.0 Carbon dioxide

0.6 Nebivolol

0.01

5.2

15.32 Total

Carboxaldehyde Derivative treated with Trimethyl sulfoxonium iodide In

presence of Potassium hydroxide & Water. The mass is further treated with Benzyl amine

Methanol,

Quantity (KG)

5.3

4.6

0.7

3.0

0.3

0.4

1.0

15.32

[39] NEBIVOLOL HCL


Stage-I :

(25) 6-Fluro –[(25) (oxiran-2yl)-3,4 dihydro-2H Chromene is reacted with benyl amine in IPA

to get Stage I product.

Stage-II :

Stage I product is hydrogenated in methanol in presence of palladium catalyst.

Stage-III :

StageI I product is reacted in Isopropyl alcohol hydrochloride to get NEBIVOLOL HCL

CHEMICAL REACTION

Stage-I : Prepartion of NB-IX (NE-3)

Stage-II : Prepartion of NB-IX (NE-3)

O

F

N O

F

OH OH

Benzyl Nebivolol HCl

NE 3

Pd/C, H2

MethanolIPA HCl

.HCl.HCl

O

F

NH O

F

OH OH

Nebivolol HClNL 1

MATERIAL BALANCE


Stage-I

Stage-VIII (NE-2) 0.009 Dry Product 0.0148

NSR-19C 0.0058 MeOH Recovery 0.0405

Methanol 0.045 CFML 0.055

Acetonitrile 0.01756 Losses 0.01

Diisopropyl ether 0.03526

HCl (CP) 0.0036

Total 0.12 Total 0.12

Stage-II

Stage-IX (NE-3) 0.02 MeOH Recovery 0.765

Methanol 0.85 Dry wet 0.0059

NSR-19D 0.002 CFML 0.04

IPA HCl (20%) 0.02 Losses MeOH 0.085

Hyflow 0.01

Total 0.9 Total 0.9

[40] DONEPEZIL HYDROCHLORIDE


Stage-I:

Methyl aplha bromo-2-chlorophenyl acetate is reacted with 4,5,6,7-tetra hydro thieno

pyridine (3,2,C) pyridine HCl in methanol.Product is taken in chloroform and reacted with

camphor sulphonic acid to get Stage I product.

Stage-II:

Stage I product is converted in Clopidogrel bisulfate by reacting with sodium carbonate and

then with sulphuric acid in presence of sodium sulfate.

CHEMICAL REACTION

Stage-I : Preparation of Enone from NSR-10A and NSR-10B

Stage:II Preparation of Donepezil Hydrochloride from Enone

Stage:III Purification of Donepezil Hydrochloride from crude

MeO

MeO

O

+N

OHCNaOMe

Methanol

MeO

MeO

O

N

M W = 377.47

5,6-dimethoxy-2,3-dihydro-1H-inden-1-one

1-benzylpiperidine-4-carbaldehydeM W = 192.21

M W = 203.28

MeO

MeO

O

N

MeO

MeO

O

N

. HCl

Donepezil Hydrochloride

M W = 416

Enone

M W = 377.47

Pd/C, H2

Ethylacetate

MeO

MeO

O

N

. HCl

Donepezil Hydrochloride

M W = 416

MATERIAL BALANCE


Stage-I

NSR-10A 0.0029 CF ML Final 0.19298

NSR-10B 0.0025 Dry wet 0.003

Sodium methoxide solution (30%) 0.00283 Loss in Drying 0.0005

Methanol 0.0762

Hydrochloric acid 0.0008

D M Water 0.1

Total 0.2 Total 0.2

Stage-II

Enone (stage-I) 0.0055 Methanol recovery 0.17

NSR-10C 0.0014 CFML -1 0.01323

Recycled NSR-10C from Donepezil

Hydrochloride crude (cycle-1)

0.00011

Aq layer all 0.2

Recycled NSR-10C from Donepezil

Hydrochloride crude (cycle-2)

0.00022

Dry wet 0.0034

Hydrochloric acid 0.0036 Loss of MeOH in rec &

LOD 0.0265

Ammonia solution 0.0295 Org Layer EA recovery 0.0918

Ethyl acetate 0.108 Loss in Aq layer 0.0162

Hydrogen gas 0.002

Hyflo super cel 0.002

Methanol 0.265

D M Water (Purified water) 0.059

Total 0.5 Total 0.5

Stage-III

Donepezil hydrochloride crude

(wet)

0.0034

CF ML 0.07643

Methanol 0.0295 Dry wet 0.0018

Methyl tertiary butyl ether 0.04318 Loss in Drying 0.0002

Activated charcoal 0.0002

Hyflo super cel 0.0005

Donepezil Hydrochloride seed 0.000042

D M Water (purified water) 0.0005

Total 0.1 Total 0.1

[41] BRIMONIDINE TARTRATE


6-Amino-5-bromo quinoxaline get reacted to Benzoyl chloride and Ammonium Thiocyanate

to form stage-1 intermediate, which further reacts with Ethylenediamine and O-

Dichlorobenzene to form crude material, which is further purified using Ethyl acetate and

Activated carbon to get BRIMONIDINE TARTRATE.

CHEMICAL REACTION

Stage-I : Preparation of 5-Bromo-6-thiouredo Quinoxaline from NSR-2A

Stage-II : Preparation Brimonidine Crude from stage-I

N

N

Br

NH 2

N

N NH NH 2

S

Br

Benzoyl chloride

NH 4SCN

Acetone

C 8H 4BrN 3

M W = 217

C 9H 7BrN 4S

M W = 282

N

N N H N H 2

S

B r

C 9 H 7 BrN 4 S

M W = 282

N

N N S

B r

N

N N H N H

N H 2

S

B r

N

N N H

N

NH

B r

C 11 H 10 BrN 5

M W = 292 .

Chlorobenzene

Heat

EthylenediamineIPA

Stage-III : Purification of Crude Brimonidine

MATERIAL BALANCE


Stage-I

NSR-2A 1000 Acetone recovery 2700 Benzoyl chloride 760 Dry wet 1000 NSR-2B 420 Filtrate + WML 264000 Acetone 3000 Acetone loss 300 D M Water 258600 Sodium Hydroxide Flakes 900 Hydrochloric acid 2000 Hyflo supercel 1020 Total 267700 Total 268000

Stage-II

Stage-I 0.5 Recovery CB+IPA 13.8 Ethylenediamine 0.41 Dry wet 0.4 Chlorobenzene 11.1 Loss in ML rec + wet cake 1 Isopropyl alcohol 3 Total 15 Total 15

Stage-III

Brimonidine crude 0.4 Aq layer 27 Hydrochloric acid 1.42 Dry wet 0.2 Sodium Hydroxide flakes 14.4 Filtrate + WML 86 Ethylacetate 27.72 Ethyl acetate recovery 25 Hyflo supercel 0.82 Ethyl rec loss + LOD Loss 2.772 D M Water 95.6

Total 140 Total 140

[42] CAPTOPRIL


Methyl Methycrylic acid is reacted with Thioacetic acid to form stahe-1 intermediate, which

further get reacted L Proline to form crude which will be further purified using water and

the isolated material further reacted with ammonia and hydrochloric acid in presence of Zn

to get the finished product.

CHEMICAL REACTION

Stage-I : Preparation of acid chloride

Stage-II : Preparation d-Amide Crude from Acid Chloride

Stage-III : Purification of d-Amide Crude

CH2

CH3

COOH

+

2-methylprop-2-enoic acid

M W = 86Methyl methacrylic acid

CH3

SH

O

ethanethioic S-acid

M W = 76Thioacetic acid

Thionyl chloride

MethanolCH3

S

O

COCl

CH3

S-(3-chloro-2-methyl-3-oxopropyl) ethanethioateM W =180.65

CH3S

O

COCl

CH3

S-(3-chloro-2-methyl-3-oxopropyl) ethanethioate

M W =180.65

+ NH

COOH

(2S)-pyrrolidine-2-carboxylic acidM W = 115.13L

-Proline

N,N-Dimethyl aniline

MDCCH3

S

O

CH3

N

COOHO

(2S)-1-[(2S)-3-(acetylsulfanyl)-2-methylpropanoyl]pyrrolidine-2-carboxylic acid

M W = 259.32

d - Amide

CH3S

O

CH3

N

COOHO

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