27. Gabapentine Manufacturing Process: Step-I 1,1 ...

27. Gabapentine Manufacturing Process: Step-I 1,1-cyclodiacetic acid is condensed with urea in xylene. After completion, product is isolated by adjusting its pH with HCl to give stage-I. Stage 2: Stage-1 undergoes hoffman reduction with sodium hypochloride followed by cyclisation to give stage-II. Stage 3: Stage-II is converted into its hydrochloride salt with concentrate HCl. The product (Stage-III) is isolated by cooling the reaction mixture. Stage 4: Hydrochloride salt of stage-III is converted into gabapentin monohydrate by treatment with caustic solution. The product crystallises during caustic addition. Stage 5: Gabapentin monohydrate is dehydrated with methanol to get clear solution. It is treated with activated carbon and filtered. Gabapentin is isolated by cencentrating followed by cooling of reaction mixture. Product is filtered, washed and dried. Chemical Reaction:

Mass Balance:

28. ALBENDAZOLE

Manufacturing Process:

1. Charge Methanol, Ortho nitro aniline , Ammonium Thiocynate and cool to

0oC.Add Chlorine marinating temp between 0-5 oC ,then charge water and stirr for

1 hrs, centrifuge at R.T and wash with water to PH neutral.

2. Charge water , N-propanol ,charge STEP-1.Start addition of caustic lye slowly

below 40 oC and heat to 50 oC . Maintain temp between 40-50 oC for 1/2 hrs and

charge n- Propyl Bromide maintain the temperature at 50 oC . Maintain 4 Hrs at

62-65 oC .Distilled water Heat to 90 oC . Charge NACL while stirring. Settle &

separate organic layer (TOP)

3. Charge STEP-2 with methanol stirring 15 minutes and heat to 50 oC . Start addition

of NAHS slowly lot wise. Temp rises from 50 to 70 oC. Complete addition of NAHS

from 60 -65 oC . Reflux 6-8 Hrs at 80-85 oC .

4. Start methanol recovery at temp 90 oC . Charge water and heat upto 85-90oC .

Settle RM for 1 Hrs. Separate RM for 1 hrs , Separate Aqueous layer from bottom

.Collect the top organic layer in Drums. Distilled out organic layer under vacuum I

st cut removed upto temp 100 oC then distilled out product at temp upto 210 oC

out product at temp upto 210 oC .

5. Charge water and cool to 8-10 oC . Charge Hydrogen Cynamide solution. Start

simultaneous addition of MCF and Caustic lye slowly below 20 oC and PH should be

6-8 . Complete the addition below 20 oC. Stirring 1/2 Hrs. Check the absence of

unreacted Hydrogen Cynamide.

6. Charge water , HCL , PART A, ,acetone and start addition of PART B. Heat to 65 oC .

continue to reflux RM at 80-85 oC for 1HRs. Check PH of RM .It should be 4.00 to

6.0. Centrifuge Reaction mass at 80-85oC . Wash cake with Hot Water , Then wash

with Methanol and again wash with Acetone to get the pure Albendazole.

Chemical Reaction: Chemical reaction ofALBENDAZOLE

STEP-1

NH4SCN Chlorine Gas Methanol

NH4CL+HCL

Ortho Nitro Aniline MOL WT :- 138.12

Ammonium Thiocynate MOL WT :- 76.122

5-THIOCYNO-2-NITRO ANILINEMOL WT :- 195.1985

Step-2

NAOH

CH3CH2CH2Br Methanol

+ NABR +NACN

5-THIOCYNO-2-NITRO ANILINEMOL WT :- 195.1985

INTERMIDIATE 2-NITRO 4 PROPYL THIO ANILINE

STEP -3 & 4 3,4 DIAMINOPROPYL THIO ANILINE (A)

NAHS MEOH

STEP-2 Caustic Soda,

Sodium Hydrosulphide, TOLUENE, Carbon, EDTA, SODIUM META BISULPHITE, Acetone

METHANOL HCL 30%

1,2-DIAMINE-5-PROPYL THIO BENZENE

STEP -5 PART (B) (CYANAMIDE COMPLEX WITH CYANAMIDE SOLUTION)

CH2N2

NAOH

NC-NH-COOCH3

+HCL+ NAOH

CYANAMIDESOLUTION (L-500)

METHYL CHLORO FORMAT

CAUSTIC SODA METHYL CYNO ESTER ( CYNO COMPOUND )

STEP-6

NC-NH-COOCH3

1,2-DIAMINE-5-PROPYL THIO BENZENE

METHYL CYNO ESTER (CYNO COMPOUND)

CONDENSATION (A+B)=C

METHANOL ACETONE

ALBENDAZOLE

MATERIAL BALANCE

Sr No.

MATERIAL INPUT Input MATERIAL OUTPUT Output

STEP-1 (in Kgs) (in Kgs)

1 Ortho Nitro Aniline 1000 CRUDE 5-THIOCYNO-2-

NITRO ANILINE 1400

2 Ammonium Thiocynate 1168 HCL 888

4 Methanol 5520 NH4CL 600

5 Chlorine Gas 720 METHANOL 5520

6 WATER 1000 ML TO ETP 1000

Total Input 9408 Total Output 9408

STEP 2

1 step-1 1400 ML TO ETP 8910

2 Caustic Soda 860 NaBr 600

3 N- Propanol 3600 STEP-2 OUTPUT 1400

4 N-Propyl Bromide 850 RECOVERED

METHANOL 3325

5 Toluene 3600 LOSS 175

6 METHANOL 3500 RECOVERED TOLUENE

3420

7 Sodium Hydrosulphide DILUTED 4200 LOSS TOLUENE 180

TOTAL 18010 TOTAL 18010

STEP -3

1 CYAANAMIDE SOLUTION (L-500) 495 RECOVERD ACETONE

2344

2 CAUSTIC SODA 742 LOSS ACETONE 176

3 METHYL CHLORO FORMAT 608 ML TO ETP 3000

4 STEP 2 1400 RESIDUE 105

5 ACETONE 2520 OUTPUT QTY ABZ 940

6 WATER 800

TOTAL 6565 TOTAL 6565

30. Cetrazine diHCl and its intermediates: MANUFACTURING PROCESS and CHEMICAL REACTION: Step-I P-chlorobenzophenone A charge chlorobenzene 100 Kg and Benzoile chloride 125 Kg and Aluminum chloride4 1kg at A RT, Then heat to 70-75 oC Stir 30min. Add Ice 120 kg then stir 1 hour , add slowly sodium hydroxide 35kg Stir 30min. , then centrifuge wet cake 175Kg. Dry Output 145.

Cl

+

ClO

O

Cl

STEP-1

NaCl+

Step-II 4-Chloro benzhydrol A charge p-chloro benzophenone 100 Kg and add methyl alcohol 135 Kg and sodium boro hydrate 7 Kg and caustic soda 1Kg at A RT, Stir 30min. Heat to reflux temp 600C ,Then add 100lit water cool to RT , wet cake 120 Kg, Dry 60-700C Out put dry :-100Kg

STEP-2

O

Cl

OH

Cl Step-III N- (4-chloro benzhydrol),N-(2-hydroxy ethyl) piperazine A charge 4-chloro benzhydrol 100 Kg and add toluen 235 Kg and thionyl chloride 85 Kg and scrubber caustic soda lye 200Kg and 100kg water at A RT, Stir 30min. Heat to reflux temp 600C ,Then add 80kg 2-hydroxy ethyl piperazine Stir 30min. Heat to reflux temp 600C ,then recovery of toluene, then add 100 lit Water then stir 1 hour , cool to RT ,centrifuge, the wet cake 120 Kg, Dry 60-700C Output dry :-100Kg

STEP-3

OH

Cl

Cl

Cl

N

Cl

NOH

+NH

N

OH

Step-IV Cetrazine Base A charge N- (4-chloro benzhydrol),N-(2-hydroxy ethyl) piperazine100 Kg and add Sodium mono chloro acetic acid 38 Kgand Dimethyl formamide 185 Kg and Caustic potash 65 Kg at a RT, Stir 30min. Heat to temp 600C ,Then cool to 5 0C Stir 30min.add water 300kg ,centrifuge , the wet cake;-112 Kg, Dry 50-550C Output dry :-100Kg. STEP-4

N

Cl

NOH

+ Na

OCl N

Cl

NO

OH

O

+ NaCl

Step-V Cetrazine Di HCl API A charge Cetrazine base 100 Kg and acetone 400kg at a RT , Then heat to clear solution temp 65-700C, then add activated charcoal 2kg stir 1 hour, filter and cool to RT, then child to 5-100C 1hour maintain. Then start HCl gas 20kg pursing solid product isolated then check pH acidic , centrifuge, wet cake146 kg, Dry 110Kg

STEP-5

+

OH

O

N

Cl

NO

N

Cl

NO

OH

O

HCl2HCl.

MATERIAL BALANCE:

Material Input Qty(Kg) Material Output Qty(Kg)

Step-1

Chloro Benzene 100 Effluent 316

Benzoile Chloride 125 Drying Loss 30

Aluminium Chloride 1 P-Chloro benzophenone 145

Sodium Hydroxide 35

Ice 220

Water 10

Total 491 Total 491

Step-2

P-Chloro benzophenone 100 Effluent 243

Methyl Alcohol 135 Drying Loss 345

Sodium Borohydrate 7 4-Chloro Benzhydrol 100

Sodium Hydroxide 1

Water 100

Total 343 Total 343

Step-3

4-Chloro Benzhydrol 100 Effluent 230

Toluene 235 Scrubber waste water 315

Thionyl Chloride 85 Drying Loss 20

Hydroxy Ethyl Piperazine 80 Reuse Toluene 215

Sodium Hydroxide Lye 200 Loss Toluene 20

Water 200 N-(4-Chloro Benzhydrol),N-(2-Hydroxy Ethyl)Piperazine

100

Total 900 Total 900

Step-4

N-(4-Chloro Benzhydrol),N-(2-Hydroxy Ethyl)Piperazine

100 Effluent 418

Sodium Mono Chloro Acetate 38 Cetrazine Base 120

Dimethyl Formamide 185

Potassium Hydroxide 65

Water 300

Total 538 Total 538

Step-5

Acetone 400 Waste Carbon 2

Activated carbon 2 Reuse Acetone 340

HCl gas 20 Loss Acetone 36

Cetrazine Base 100 Drying Loss 30

Bottam 4

Cetrazine Dihydrochloride 110

Total 522 Total 522

31. Lasamide Manufacturing Process: 2,4 Dichloro Benzoic acid is reacted with Chlorosulfonic acid(CSA) at elevated temperature. The product formed is isolated by quenching in ice water, the product is filtered and subjected to ammoniation to get Lasamide. Chemical Reaction: C7H4Cl2O2 + 2ClSO3H C7H3Cl3O4S + H2SO4 + HCl 2,4 Dichloro Benzoic acid CSA 2,4 Dichloro Benzoic acid Sulfonyl Chloride C7H3Cl3O4S + 3NH3 C7H8Cl2N2O4S + NH4Cl C7H8Cl2N2O4S + HCl C7H5Cl2NO4S + NH4Cl Mass Balance:

Input Qty. (kg) Output Qty. (kg)

2,4 Dichloro Benzoic acid 950 Product 1000

Chlorosulfonic acid 4720 Effluent 1810

Ammonia 720 Dil. Sulphuric Acid 1316

HCl 1296 Dil. HCl 4150

Water 2320 Ammonium Chloride 1730

Total 10006 Total 10006

32. PIOGLITAZONE HYDROCHLORIDE

Process Description

5-Ethyl-2-(2-(4- Nitro phenoxy)ethyl)pyridine (EPNB) is hydrogenated in presence of palladium

catalyst to produce PGL-I, which is further diazotized using sodium nitrite solution in water to get

diazotized PGL-I. It is further reacted with hydrogen bromide and methyl acrylate in presence of

copper oxide (I) to get PGL-II.

PGL-II is cyclized using thiourea and sodium acetate in methanol to give PGL-III (5-({4-[2-(5-

ethylpyridin-2-yl) ethoxy]benzyl}-2-imino-1,3-thiazolidin-4-one).

PGL-III is reacted with hydrochloric acid in water to give PGL-IV ((5-({4-[2-(5-ethylpyridin-2-yl)

ethoxy]benzyl}-1,3-thiazolidin-2,4-dione).

PGL-IV is purified in DMF and water mixture to get PGL-V (pure Pioglitazone).

PGL-V is isolated as a hydrochloride salt using concentrated Hydrochloride acid in ethanol water

mixture as a solvent to get Pioglitazone hydrochloride.

Chemical Equation

Stage IA- Preparation of PGL-I

H 3 C NO 2

+ 3 H 2

N O Hydrogen gas

5-ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine

MW = 2.0 MW = 272.3

EPNB

Palladium carbon

H 3 C N H 2

+ 2 H 2 O

N

O

4-[2-(5-ethylpyridin-2-yl)ethoxy]aniline MW = 242.3 MW = 18

P G L - I

Stage IB- Preparation of PGL-II

H 3 C

N H 2 O

C H 3

+ NaNO 2

+ 2 HBr +

N O H 2 C O

4-[2-(5-ethylpyridin-2-yl)ethoxy]aniline Sodium nitrite Hydrobromic Acid Methyl acrylate MW= 242.3 MW= 69 MW= 81 MW= 86.08

P G L - I

Copper oxide(I)

O

H 3 C

O

C H 3 + NaBr + N 2

+

2H 2 O

B r

N O m e th y l 2 - b ro m o - 3 - {4 - [2 -

Sodium bromide Nitrogen gas

Water (5 - e th y lp y rid in - 2 - y l)e th o x y ]p h e n y l}p ro p a n o a te

MW = 392.28 MW = 103 MW = 28 MW = 18

P G L - II

Stage IC- Preparation of PGL-III O

H 3 C

O

C H 3 S + H 3 C

ONa

B r +

O

N O H 2 N N H 2 m e t h y l 2 - b r o m o - 3 - { 4 - [ 2 -

( 5 - e t h y l p y r i d i n - 2 - y l ) e t h o x y ] p h e n y l } p r o p a n o a t e Thiourea Sodium Acetate

MW= 392.28 MW= 76.1 MW= 82.03

P G L - I I

H 3 C

N O

O 5 - { 4 - [ 2 - ( 5 - e t h y l p y r i d i n - 2 - y l) e t h o x y ] b e n z y l } - 2 - i m i n o - 1 , 3 - t h i a z o l i d i n - 4 - o n e

MW= 355.4 P G L - I I I

Stage II- Preparation of PGL-IV H 3 C

N O

O 5 - { 4 - [ 2 - ( 5 - e t h y l p y r i d i n - 2 - y l ) e t h o x y ] b e n z y l } - 2 - i m i n o - 1 , 3 - t h i a z o l i d i n - 4 - o n e

MW= 355.4 P G L - I I I

S N H

+ H 2 O+

+ 2 HCl KHCO 3 N

H

Potassium Bicarbonate

MW= 36.46 MW = 18 MW= 100.11

S O

H 3 C

N

+ NH 4 Cl + KCl N O

H

Potassiumchloride

O AmmoniumChloride

5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1, MW= 53.5 MW= 74.5 3-thiazolidine-2,4-dione

+

+

MW= 356.43

CO 2

H 2 O

P G L - I V

Carbondioxide

MW= 44 MW= 18

S N H

N + NaBr + H 3 C O H + CH 3 OH

H O

Sodium Bromide Acetic Acid Methanol

MW= 103 MW= 60.0 MW= 32.0

Stage III- Preparation of PGL-V

S

O S

O H3C

H3C

N DMF

N

N

O N O H

H

O O

5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1, 5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,

3-thiazolidine-2,4-dione

3-thiazolidine-2,4-dione

MW= 356.43 MW= 356.43 PGL-IV PGL-V

Stage IV- Preparation of Pioglitazone Hydrochloride

S

O

H 3 C

N O N

+ HCl O H

5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1, Hydrochloride 3-thiazolidine-2,4-dione

MW= 356.43 MW=36.5 PGL-V

S O

H 3 C

N

O N

H

HCl O

MW= 392.89 Pioglitazone Hydrochloride

Mass Balance:

Step-1 - PZ1 PREPARATION INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs MEP 4.86 Mass 8.31 Methanol 1.35 PFA 1.84 Formic 0.25 Charcoal 0.01 Total 8.31 Total 8.31 INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Mass 8.31 P2 1 1.08

MEP 3.45 Methanol 0.56 Loss Methanol 0.79 Residue to Inc. * 2.43

Total 8.31 Total 8.31 Step2- PZ 2 PREPARATION INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs P2 1 1.08 Mass 6.54 Toluene 3.71 TEA 0.84 MSC 0.91 Total 6.54 Total 6.54 INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Water 10.80 Mass 6.33 Mass 6.54 Aqueons Layer to ETP * 11.01 Total 17.340 Total 17.340 Step 3 - PZ3 PREPARATION INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs PZ 2 6.33 Mass 12.45 IPA 3.41 H 2 O 0.29 4OH benzaldehyde 1.00 K 2 CO 3 1.42 Total 12.45 Total 12.45

INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Mass 12.45 Aqueous to ETP * 16.60 Water 10.80 Mass 8.71 Toluene 2.06 Total 25.31 Total 25.31 INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Mass 8.710 Aqueous to ETP * 8.75 NaOH 0.36 Mass 8.71 H 2 O 8.39 Total 17.46 Total 17.46

Step 4 - PZ 4 PREPARATION INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs H 2 O 4.81 Evaporation Loss 0.24 Acetic Acid 1.25 Mass 6.78 Thio Urea 0.96 Total 7.02 Total 7.02

INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Mass 6.780 ML to ETP * 6.27 Water 0.960 Wet Cake 1.47 Total 7.740 Total 7.740 INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Wet Cake 1.47 Vapours 0.22

Dry Cake 1.25 Total 1.47 Total 1.47

Reaction

( 8 days)

Distillation

Reaction

Water Washing

Reaction

Water Washing

Caustic Washing

Reaction

Filtration

Drying

Step 5- PZ 5 PREPARATION

INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Mass 8.71 Toluene Rec. 4.44 Methanol 18.73 Distillation Loss 1.33

Mass 21.67 Total 27.44 Total 27.44

INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Mass 21.67 Mass 23.20 PZ4 1.25 Piperidue 0.28 Total 23.20 Total 23.20 INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Mass 23.20 Loss 9.86 Water 2.39 MeOH Rec. 13.51 Methanol 0.57 Wet Cake 1.44

Reidue to Inc * 1.35 Total 26.16 Total 26.16 INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Wet Cake 1.44 Vapours Loss 0.21

Dry Cake 1.23 Total 1.44 Total 1.44 Step 6- PZ6 PREPARATION INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs PZ5 1.23 Mass 27.97 THF 3.73 DMG 0.16 Cobaltous Ch. 0.01 NaOH 0.10 Na BH4 0.26 DMF 3.28 Water 19.20 Total 27.97 Total 27.97 INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Mass 27.97 EA Rec. 8.30 Ethyl Acetate 16.60 Mass 36.27

Loss 0.88 Residue to Inc * 0.88

Total 44.57 Total 44.57 INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Mass 36.27 Mass 38.85 Acetic Acid 2.58 Total 38.85 Total 38.85 INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Mass 38.85 ML to ETP * 38.45 IPA 0.98 Wet Cake 1.38 Total 39.83 Total 39.83

INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Wet Cake 1.38 Dry Cake 1.11

Vapour 0.27 Total 1.38 Total 1.38

Step 7- PZ HCl PREPARATION INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs PZ6 1.11 Mass 8.06 Methanol 6.07 HCL 0.85 Carbon 0.03 Total 8.06 Total 8.06 INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Mass 8.06 Cake to Incin. * 0.05 Hyflow 0.01 Filterate 8.02 Total 8.07 Total 8.07

Reaction

Filtration & Solvent

Recovery

Drying

Distillation

Extraction & Solvent recovery

Precipitation

Fitration

Reaction

Drying

Sparkler Filtration

Reaction

INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Filterate 8.02 Distillation 3.30

Distillation Loss 0.33 Mass 4.39

Total 8.02 Total 8.02

INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Mass 4.39 MeOH Rec.. 1.71 MeOH Wash 0.82 Loss 1.87

Residue to Inc. * 0.43 Wet Cake 1.20


INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Wet Cake 1.20 Vapour 0.18

Dry Cake 1.02 Total 1.20 Total 1.20

INPUT : OUTPUT : Raw Material Input , Kgs Product Output, Kgs Dry Cake 1.02 Loss 0.02

PZ Pure 1.00 Total 1.02 Total 1.02

Sparkler Filtration

Crystallisation

Centrifuge & Solvent

Recovery

Drying

Sifter & Micronisation

33. MESALMINE BRIEF MANUFACTURING PROCESS

STEP 1 Preparation of 2-Hydroxy-5-Nitro Benzoic Acid With Nitration of Ortho Chloro Toluene receive the Ortho Chloro Benzoic Acid again the

nitration of the Ortho Chloro Benzoic Acid we will receive the 2-chloro-5- nitro benzoic acid.

To a stirred solution of potassium hydroxide (70 kg, 1250 mol) and water (250 l) was added 2-

chloro-5- nitro benzoic acid (50 kg ,248 mol) over a period of 20 minutes between 25 to 30 0C in

an autoclave. The reaction mixture was heated to 125-130oC , stirred At the same temperature

for 5 hours under 2.5 kg /cm2. The reaction mass was cooled to 25 oC and acidify to PH 1.0-2.0

using hydrochloric acid (85 L) , stirred for 1 hour. The precipitated solid was filtered and washed

with water (150 L) , and the cake slurried in water (300 L) at 30 Oc for 1 hour, filtered, washed

with water ( 150 L) and dried at 65 oC for 10 hours to afford product 43.5 kg

yield :- 43.5 kg (96 % ) purity :- 99.87 %

1H NMR ( 400 MHZ, DMSO): DELTA 11.2 (s,1H), 8.5 (m,2H), 7.3 ( s ,1H),5.2 (s,1H).MS m/z 183;

Anal Calcd.for C7H5NO5

STEP 2

Preparation of 5-amino-2-hydroxy benzoic acid

2-Hydroxy-5-Nitro Benzoic Acid (40 kg,218 mol) was added slowly to a stirred mixture of water

(320 L ) and sodium carbonate (16.3 kg, 153 mol) . stirred for 30 minutes and the mass ph

maintained between 8.0 and 9.5 . 10 % Raney Nickel (8 L) along with water (80 L) was added to

the above solution. The resultant mixture( 130 L) was added to the mass at 25oC , Stirred for 30

minutes . The catalyst was filtered through celite , and washed with water (80L) . the solution was

acidified to Ph 2.5-3.0 with hydrochloric acid (33L) and stirred for 1 hour. The obtained compound

was filtered , washed with water (40 L ). To the solution of wet cake and water (560 l ) and

hydrochloric acid (41 L) . active charcoal (2.8 kg) was added, and the contents were heated to 70

oC , maintained at the same temperature for 2 hours. Filtered the total solution through celite,

washed with water (28 L) . Active charcoal (2.8 kg) was added to the filtrate, stirred at a

temperature of 70 oC for 2 hours, filtered through celite and washed with water (28L) . to the

obtained filtrate, Ph was adjusted to 3.0-3.5 with aq.sodium bicarbonate solution (15 L ) , stirred

for 1 hour, filtered the solid and washed with water (42 L), dried the solid at 80 OC for 9 hours to

give the product as off white colored powder.

Yield :- 27.5 kg (82 % ) Purity : -(99.9%)

CHEMICAL REACTION

2-chloro-5- nitro benzoic acid

+

KOH

+

HYDROCHLORIC ACID

→

2-Hydroxy-5-Nitro Benzoic

Acid

2-Hydroxy-5-Nitro Benzoic Acid

+

Sodium carbonate+

Raney nickel +

Sodium hydroxide +

Hydrochloric acid +

Charcoal +

sodium bicarbonate

→

MESALAMINE CAS number :- 89-57-6

Formula :- C7H7NO3

(5-amino-2-hydroxy benzoic acid)

MATERIAL BALANCE

Sr. No. MATERIAL INPUT

INPUT IN KG MATERIAL OUTPUT

OUTPUT IN KG

STEP 1 KG

1 POTASSIUM HYDROXIDE 70.00 crude 43.5

2 2-chloro-5- nitro benzoic acid 50.00 WATER 150

3 HYDROCHLORIC ACID 85.00 HCL 74

4 WATER 150.00 SOLID WASTE 87

TOTAL 355.00 354.5

STEP 2

1 step 1 crude 43.50

2 SODIUM CARBONATE 16.30 SODIUM CARBONATE 16.9

3 RANEY NICKEL 8.00 RANEY NICKEL 8

4 SODIUM HYDROXIDE 130.00 SODIUM HYDROXIDE 130

http://en.wikipedia.org/wiki/CAS_registry_number

http://en.wikipedia.org/wiki/Chemical_formula

http://en.wikipedia.org/wiki/Carbon

http://en.wikipedia.org/wiki/Hydrogen

http://en.wikipedia.org/wiki/Nitrogen

http://en.wikipedia.org/wiki/Nitrogen

5 HYDROCHLORIC ACID 74.00 WATER 110

6 CHARCOAL 5.60 mesalamine crude 27.5

7 SODIUM BICARBONATE 15.00 TOTAL 292.4 TOTAL 292.4

33. Rabeprazole Sodium

Manufacturing Process:

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

Chemical Reaction:

Mass Balance:

34. FEBUXOSTAT

Process Description

Ethyl-2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate (NV07-3) is hydrolyzed with sodium

hydroxide solution in isopropyl alcohol to furnish the product. The pH is adjusted with hydrochloric acid and

solid is separated by filtration as Febuxostat crude.

Febuxostat (crude) is dissolved in acetone and charcoalized. After filtration, acetone is distilled out and solid

is filtered to give Febuxostat.

Chemical Equation

Mass Balance:

Sr. No.

Particular Input Qty (kg)

Particular Output Qty (kg)

1 Ethyl-2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate

1.250 Product 1

2 Methanol 12.50 Methanol Recover 12.00

3 Toluene 7.50 Methanol Loss 0.50

4 Caustic soda flakes 0.125 Toluene Recover 7.25

5 HCl 0.250 Toluene Loss 0.25

6 Water 5.000 Effluent 4.375

7 Dist. Residue 0.750

8 Loss 0.500


35. ITOPRIDE HYDROCHLORIDE

Process Description

Verateric acid and Thionyl Chloride is reacted in toluene medium. At the end of the reaction any excess of

thionyl chloride is removed by purging nitrogen in the solution. The crude VC (Vertroyl Chloride) obtained is

used as such in the next step.

ITO ((2-[4 - aminomethyl) phenoxy] N,N-dimethyl ethanamine) is reacted with VC solution. The crude

product is isolated by removal of the solvent.

Crude product (Itopride Base) is treated with carbon in hot acetone. After removal of carbon, addition of

acetone HCl leads to formation of the Itopride HCl.

Chemical Equation

Mass Balance:

Sr. No.



1 Veratric acid 0.667 Product 1

2 Thionyl chloride 0.667 Toluene Recover 3.111

3 Toluene 3.270 Toluene Loss 0.159

4 4-[2-(Dimethylamino) ethoxy]Benzyl amine

0.667 IPA Recover 2.794

5 Caustic soda flakes 0.095 IPA Loss 0.063

6 IPA 2.857 Dist. Residue 0.467

7 IPA HCl 0.317 Effluent 9.445

8 Methanol 0.159 HCl Gas 0.147

9 Acetone 0.635 SO2 Gas 0.234

10 Water 8.095


36. Celecoxib M a n u f a c t u r i n g P r o c e s s

Charged water in Reactor at RT. Charged 4 SPH and Dione Deri in Reactor. The reaction

mixture was heated and stirred well. Cool the RM and Filter the Product.

Charged Toluene and wet cake in above reactor again. Heat the RM and stir well for

several time. The organic layer were washed with water add Activated carbon at stirred

under heating.

Filter the RM with Sparkler. The filtrate was cooled. The separated solid was filtered and

dried

Chemical Reaction:

Mass Balance:

Sr. No.

Input Quantity (Kg) Output Quantity (Kg)

1 4 SPH 0.70 Final Product 1.00 2 Dione Deri 0.65 Toluene (Recd) 2.65 3 Toluene 2.80 Distillation + Drying Loss 0.19 4 Carbon 0.01 Residue 0.03 5 Water 1.60 Carbon Waste 0.02 6

Effluent 1.88


37. CLOPIDOGREL BISULPHATE

MANUFACTURING PROCESS: STAGE 1:

Starting materials amino(2-chlorophenyl)acetic acid ,methanol, Sulfuric acid are added into

the reaction vessel and agitated until reaction is completed.

Methanol is recovered from the reaction mass by distillation and some of the same is lost as

vapor during the operation.

Water and Dichloro methane are added into the reaction mass and adjust PH to neutral

with liquor ammonia.

Two layers namely MDC layer and aqueous layer are obtained.

Aqueous layer is sent to ETP.

MDC (Dichloro methane) layer is then distilled to recover MDC wherein vapor loss occurs

during the operation.

Stage 1 product is further isolated by continuing distillation.

STAGE 2:

Starting materials thiophene-2-ethanol, toluene, p – toluene sulphonyl chloride, water,

sodium hydroxide solution are added into the reaction vessel and stirred until reaction is

completed.

Two layers toluene layer and aqueous layer are obtained. Aqueous layer is further sent to

ETP.

Toluene layer is then distilled to recover toluene wherein vapor loss occurs during the

operation.


STAGE 3:

Starting materials Stage 1 product, stage 2 product, acetonitrile, dipotassium phosphate are

added into the reactor and stirred until the reaction is completed.

Acetonitrile is recovered from the reaction mass by distillation and some of the same is lost

as vapor during the operation.

Ethyl acetate is added into to the reaction mass and agitated to clear solution.

Further water is added to obtain layer separation.

Two layes namely ethyl acetate layer and water layer are obtained. And water layer is sent

to ETP.

Further conc. Hydrochloric acid is added to the ethyl acetate layer for precipitation and then

filtered through centrifugal filter.

The wet cake so obtained is dried to obtain final product.

Filtrate is then distilled to obtain ethyl acetate and remaining effluent is sent to ETP.

STAGE 4:

Starting materials couple ester, water, paraformaldehyde is charged into the reaction vessel

and is agitated.

Further dichloro methane and water are added to the reaction mass and then adjust PH

acidic with liquor ammonia.

Namely MDC layer and water layer are obtained.

Water layer is sent to the ETP.

MDC layer is then distilled to recover MDC. Wherein vapor loss occurs during the operation.


STAGE 5:

Starting raw materials stage 4 product, acetone, Tartaric Acid are charged into the reaction

vessel and are stirred for longer time.

Entire mass is then filtered by centrifugal filter and wet cake so obtained is dried to obtain

dry cake..

The filtrate is sent for solvent recovery.

Water and dichloro methane are charged into the reaction vessel & then dry cake obtained

is charged.

Further PH is adjust to alkaline by sodium carbonate solution to obtain layer separation.

Namely MDC layer & water layer are obtained.

Water layer is sent to ETP.MDC layer is then distilled to recover MDC wherein vapor loss

occurs during the operation.

Stage 2 products are further isolated by continuing distillation.

STAGE 6[Final]:

Stage 2 product, acetone, activated carbon are charged into the reaction vessel and entire

mass of the reaction vessel is filtered through the neutch filter.

Further con. Sulfuric acid is added slowly to the reaction mass for crystallization.

It is further filter through centrifugal filter.

The wet cake so obtained is dried to obtain final product.

The filtrate is used in next batch for obtaining second crop.

The dried product is finally packed.

CHEMICAL REACTION: STAGE 1:

OHOCl

NH2

Methanol/H2SO4

OOCl

NH2

CH3

amino(2-chlorophenyl)acetic acid methyl amino(2-chlorophenyl)acetate

STAGE 2:

SOH

CH3

S

O

O

Cl+

Thiophene-2-Ethanol para toluene sulphonyl chloride

OS

O

O

CH3

S

Chloro phenyl glycine methyl ester tartarate salt

STAGE 3:

Cl

NH2

O OCH3

+OS

O

O

CH3

S

methyl amino(2-chlorophenyl)acetate 2-(2-thienyl)ethyl 4-methylbenzenesulphonate

Ethyl acetate/HCL

S

O

O

Cl

NH

CH3

methyl (2R)-(2-chlorophenyl){[2-(2-thienyl)ehtyl]amino}acetate hydrochloride

.HCL

STAGE -4 :

S

O

O

Cl

NH

CH3

P-Formaldehyde

S

O

O

Cl

N

CH3

methyl (2-chlorophenyl)(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetatestage 3

STAGE – 5 :

S

O

O

Cl

N

CH3

Tartaric Acid

S

O

O

Cl

N

CH3

methyl (2R)-(2-chlorophenyl)(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)ethanoateStage 4

STAGE – 6: Material Balance:

S-r No. Material INPUT

Qty(in kg)

Sr No. Material OUTPUT

Qty(in kg)

STAGE 1

1 amino(2-chlorophenyl)acetic acid 1.25 1 Recovered Methanol 3.75

2 methanol 3.95 2 Loss Methanol 0.20

3 Potassium salt 0.7 3 Recovered MDC 4.48

4 Water 5.30 4 Loss MDC 0.5

5 MDC 4.98 5 ML to ETP 6.87

6 Liq. ammonia 0.62 6 Stage 1 Output 1.00

TOTAL 16.80 TOTAL 16.80

STAGE 2

1 Thiophene-2-Ethanol 0.5 1 Recovered Toluene 2.93

2 p-toluene sulphonyl chloride 1.05 2 Loss Toluene 0.16

3 Toluene 3.12 3 ML to ETP 6.30

4 Water 4.5 4 Stage 2 Output 1.00

5 Sodium hydroxide 1.25 5 Residue 0.03


STAGE 3

1 Stage 1 1.25 1 Recovered Acetonitrile 5.98

2 Stage 2 1.00 2 Loss Acetonitrile 0.32

3 Acetonitrile 6.30 3 Recovered Ethyl acetate 5.26

4 Dipotassium phosphate 0.87 4 Loss Ethyl acetate 0.28

5 Ethyl acetate 5.60 5 ML to ETP 4.97

6 water 2.00 6 Residue 0.06

7 HCL 0.85 7 Stage 3 Output 1.00


STAGE 4

1 Stage 3 1.50 1 Recovered MDC 10.71


3 P-Formaldehyde 0.53 3 ML to ETP 13.53

4 MDC 11.9 4 Stage 4 product 1.10

5 Liq. Ammonia 0.60


STAGE 5

1 Stage 4 1.10 1 Recovered Acetone 9.90

2 Acetone 11.00 2 Loss Acetone 1.10

3 Tartaric acid 0.82 3 Recovered MDC 5.98


5 MDC 6.65 5 ML to ETP 4.32

6 Sodium carbonate 0.70 6 Stage 5 Output 1.00


STAGE 6

1 Stage 5 1.00 1 Recovered Acetone 4.50

2 Acetone 4.74 2 Loss Acetone 0.24

3 Activated carbon 0.15 3 Spent carbon 0.46

4 Sulfuric acid 0.31 4 Stage 6 Output 1.00


38. Amrodafinil Manufacturing Process The manufacturing process for the above mentioned products involves chemical synthesis

utilizing mainly organic chemicals as raw materials in batch process. These batch processes are

used to produce active pharma ingredients with unique physical and pharmacological

properties. Typically, a series of chemical reactions are performed in multi-purpose reactors

and the products are isolated by extraction, crystallization and filtration. The finished products

are usually dried, and milled.

Chemical Reaction:

Mass Balance:

39. QUETIAPINE FUMARATE: MANUFACTURING PROCESS: Quetiapine stage-1 & 2 2-Amino dimethyl sulfide reacts with phenylchloro formate to give carbamate product which cyclize in the presence of phosphoric acid to give quetiapine stage 1 & 2. Quetiapine stage-F Quetiapinefumarate stage – 2 reacts with N,N-Dimethyl aniline in presence of phosphorous oxychloride will further reacts with 1-hydroxy ethoxy ethyl piperazine using triethanolamine as catalyst in toluene as media. Finally product will be isolated by distillation of toluene and addition of Methanol and fumaric acid solution to form Quetiapine fumarate. CHEMICAL REACTION:

NH2

SO

O

Cl

NH

S

O

Molecular Formula = C12H11NSFormula Weight = 201.29

2-(phenylsulfanyl)aniline

Formula Weight:156.57Molecular Formula:C7H5ClO2

Phenyl chloroformate

OH

HCl

Formula Weight = 227.28166

Molecular Formula = C13H9NOSQuetiapine stage-1 & 2

Formula Weight:94.11

Molecular Formula:C6H6OPhenol Hydrochloric acid

Formula Weight:36.5Molecular Formula:HCl

+

+ +

MASS BALANCE:

Input ton Output ton

2- Amino diphenyle sulfide 1.11 Air Waste 0.06

Sodium Hydroxide flakes 0.32 Aqueous waste 19.99

Process water 7.80 Toluene Recovery 6.33

Toluene 6.67 Toluene Loss 0.33

Phenyl chloroformate 1.27 Acetone Recovery 3.33

Hydrochloric acid 0.66 Acetone Loss 0.14

Polyphospheric acid 8.89 distillation residue 0.33

Acetone 3.48 Product 1.00


MASS BALANCE :

Input Ton Output Ton

Dibenzo [b,f] [1,4] Thiazepin -11(1 OH)- ONE 0.6 Air Waste 0.03

N,N- Dimethyl ANILINE 0.4 Aqueous waste 8.42

Phosphorous oxychloride 0.3 Toluene Recovery 4.90

Hydrochloric acid 0.5 Toluene Loss 0.26

Sodium Sulphate 0.1 Methanol Recovery 7.43

Process water 6.5 Methanol Loss 0.31

Toluene 5.2 distillation residue 0.19

Triethanolamine 0.4 Spent hyflow 0.03

Hydroxy ethoxyrthyl piparazine 0.4 Product 1.00

Sodium bicarbonate 0.1

1 N HCl 0.1

Hyflosupercel 0.0

Methanol 7.7

Fumaric acid 0.2


40. ATORVASTATIN

MANUFACTURING PROCESS Stage: 1 Preparation of (5R)-1,1-Dimethylethyl 6-Cyano-5hydroxy 3-oxo-hexanoate (ATVS1) (R)-4Cyano-3-hydroxy butyric acid, ethyl ester is reacted with tert butyl acetate in the presence of LDA at low temp to get ATVS1. Stage: 2 Preparation of [R-(R*, R*)]-1, 1-Dimethylethyl 6-Cyano-3, 5-dihydroxy hexonate (ATVS2), ATVS1 is reacted with Sodium Borohydride in THF and MeOH in the presence of Diethyl Methoxy Borane. After completion of reaction, reaction mass is quenched with acetic acid. After work up affords ATVS2. Stage: 3 Preparation of (4R-Cis)-1, 1-Dimethylethyl 6-Cyanomethyl-2, 2-dimethyl-1, 3-dioxane-4-acetate (ATVS3), ATVS2 is reacted with Acetone in presence of Methane Sulphonic Acid using 2,2- Di Methoxy propane. And then it is neutralized with 5% NaHCO3 solution then extracted with Ethyl Acetate. After distillation of Ethyl Acetate MeOH & Water to get ATVS3.

Stage: 4 Preparation of (4R-Cis)-1,1-Dimethylethyl 6-(2-amino ethyl)-2,2-dimethyl-1, 3-dioxane-4-acetate (ATVS4), ATVS3 is reduced with Methanolic Ammonia in presence of Raney Nickel and Hydrogen gas, then catalyst is filtered off and the filtrate is concentrated to give oily mass ATVS4.

Stage: 5 Preparation of [R-(R*, R*)]-2(4-Fluorophenyl)-, 8-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino)Carbonyl]-1H-Pyrrol-1tert –butyl heptanoic ester (ATV8), ATVS4 is

condensed with (+) 4-fluoro--2-methyl-1-oxopropyl]-oxo-N-- Diphenyl-benzene butane amide in presence of Pivalic acid using Toluene, Heptane and THF at. After completion of reaction work up is done with 0.1N NaOH & 0.1N HCl. Organic layer is evaporated which is crystallized in IPA and Water to get ATV8.

Stage: 6 Preparation of Atorvastatin Calcium

Acidic and basic hydrolysis of ATV8 with HCl and NaOH gives sodium salt of Atorvastatin, which is treated with Aqs Calcium Acetate to give Atorvastatin Calcium in Aqs Methanol.

CHEMICAL REACTION

MATERIAL BALANCE

Sr. No.


Sr. No.


1 Ethyl-4-Cyano-3-hydroxy butanaote 1.00 1 Product 1.85

2 THF 17.567 2 THF Recovered 17.04

3 Diisopropyl amine 1.22 3 THF Loss 0.527

4 N-Butyl Lithium 13.60 4 N-Butyl Lithium Recovery 12.92

5 Tert-Butyl acetate 1.68 5 N-Butyl Lithium Loss 0.68

6 HCl 0.76 6 H2 gas 0.09

7 Ethyl Acetate 31.57 7 Spent Catalyst 1.5

8 NaCl 1.20 8 Spent Carbon 0.05

9 Methanol 25.243 9 Ethyl Acetate Recovered 30.94

10 DEMB (50 % Soln) 0.70 10 Ethyl Acetate Loss 0.63

11 Sodium Borohydride 0.44 11 Methanol Recovered 24.61

12 Acetic Acid 0.98 12 Methanol Loss 0.63

13 Dimethoxy Propane 1.81 13 n-Hexane Recovered 5.12

14 Methane Sulphonic Acid 0.03 14 n-Hexane Loss 0.08

15 Sodium Bicarbonate 2.00 15 Toluene Recovered 9.19

16 n-Hexane 5.20 16 Toluene Loss 0.189

17 DM Water 22.38 17 Methyl Tert Butyl Recovered

7.04

18 Raney Nickel 1.00 18 Methyl Tert Butyl Loss 0.37

19 Pivalic Acid 0.240 19 Effluent 32.04

20 Toluene 9.379

21 Activated Carbon 0.100

22 Methyl Tert Butyl 7.410

Total 145.496 Total 145.496

27. Gabapentine Manufacturing Process: Step-I 1,1 ...

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