brief manufactring process, chemical reaction and mass balance

BRIEF MANUFACTRING PROCESS, CHEMICAL REACTION AND MASS BALANCE

1. Furosemide Manufacturing Process:

Lasamide, Furfuryl Amine, Sodium Bicarbonate will be added in Reactor and reaction will

be carried out at 125°C for 4 hours. Caustic solution will be added to it and then

Hydrochloric acid will be added to adjust the pH of the reaction mass. Then separate the

org. residue and transfer remaining mass into another reactor for purification by adding

carbon followed by filtration. Then chill the purified reaction mass to 0°- 5°C temp.

Precipitation takes place and centrifuge the reaction mass followed by drying to obtain

finished product.

Mass Balance:

Note: Afore mentioned quantities are in Kg

Process Flow diagram :

SS REACTOR

FILTRATION / SEPARATION

Furfuryl Amine : 32 Lasamide : 90 Sodium carbonate : 25 Caustic Flakes : 10

PURIFICATION

CHILL UPTO 0°-5°C

DM Water : 200 Carbon : 1

DRYING

CENTRIFUGE

FINISHED PRODUCT : FUROSEMIDE

: 100 KG.

Spent Carbon to BEIL for Incineration : 1

Wastewater to CETP (ETL) : 207

Evaporation Loss : 25

157

332

Furfuryl Amine ML : 25 for Recovery

Recovered Furfuryl Amine : 20 Kg.

& Dist. Residue : 2.5 Kg.

125

332

132

1. Diaminomethyleneamino(1-amino-1-iminomethylene) thiomethyl thiozole dihydrochloride [ITU]

Manufacturing Process:

Charge acetone into the reaction vessel. Chill acetone up to 10°C. Add slowly 1,3-Dichloro acetone within 1 hour maintain temp. 10 °C. Add KI (Lot-1) at 10°C and stir the reaction mass for 15 minutes. Add Guanyl thiourea by maintaining temp. 12 °C to 15 °C. Add KI (Lot-2) at 15 °C to 20 °C and maintain for 3 hours. Add acetic acid (glacial) at 20°C to 25°C temp. Heat the reaction mass to 40 °C temp. Now add thiourea and acetone under stirring at 40 °C temp. Raise the temp. of the reaction mass to 55 °C to 60 °C. Reflux the reaction mass at 55 °C to 60°C temp. for 3 hours. Cool the reaction mass to 30 °C temp. Further cool to 20 °C temp. Centrifuge the material and wash the wet cake with acetone. Unload the wet cake from the centrifuge. Dry the wet cake in dryer at 95 °C to 100 °C temperature for 9 to 10 hours. Unload the dried material and weight and packed it.

Chemical Reaction:

q

Mass Balance:

Sr. No.

Input Quantity (Kg)

Output Quantity (Kg)

1 1,3 DCA 0.435 Product 1.000

2 Guanyl Thiourea 0.413 Evaporation Loss 0.400

3 Acetone 3.100 Acetone Recover 3.000

4 Catalyst 0.004 Dist. Residue 0.074

5 Thiourea 0.261

6 Acetic Acid 0.261

Total 4.474 Total 4.474

3. N-Sulfomyl-3-chloropropionamide hydrochloride [IF] Manufacturing Process:

Charge Acrylonitrile into the reaction vessel. Add hydrogen peroxide (50 %) under stirring. Chill the reaction mass to 15°C to 20°C. Purge HCl gas at 15°C to 20°C for 38 to 40 hours at the feeding rate of 0.8-1.0 Kg/hour. After completion of gas passing, degas the reaction mass. Now Add sulfamide under stirring at RT. Cool the reaction mass to 18°C to 22°C temp. Further chill the reaction mass to 0°C to 10°C temp. Purge HCl gas at 0°C to 10°C for 8 hours at the feeding rate of 0.8-1.0 Kg/hour. Raise the temp. of the reaction mass to 15°C to 20°C within 2 hours with continue HCl gas passing. Raise the temp. of the reaction mass to 50°C to 55°C within 2 to 3 hours with continue HCl gas passing. Maintain reaction mass at 50°C to 55°C for 5 hours with continue HCl gas passing. Degas the reaction mass for 5 hours at 50°C to 55°C temp. Cool the reaction mass to 28°C to 32°C temp. Further cool the reaction mass to 18°C to 22°C. Centrifuge the material and wash the wet cake with chilled acetone. Unload the wet cake and dry the wet cake in dryer at 65°C to 70°C temp. for 5 to 6 hours. Unload the dried material and record the weight and packed.

Chemical Reaction:

(1)

CH2 CH2CN + NH2 S NH2

OO

CH2 CH2 C

NH2

N SO2NH2

Cl

(2) (3)

(1) Acrylonitrile

(2) Sulfamide

(3) N-sulfomyl-3-chloropropionamidehydrochloride

Mass Balance:

Sr. No.

Input Quantity (Kg)


1 Acrylonitrile 1.303 Product 1.000

2 Hydrogen Peroxide 0.008 Evaporation Loss 0.556

3 HCl (Gas) 1.495 Acetone Recover 0.350

4 Sulfamide 0.500 CAN Recover 1.2907

5 Acetone 0.400 Dist. Residue 0.050

6 Dil. HCl 0.46


4. Famotidine Manufacturing Process:

STAGE-1: [FAMOTIDINE CRUDE]: Charge Methanol into the reaction vessel. Add caustic

soda flakes and reflux the reaction mass under stirring. Cool to 30°C and then chill to 20°C

to 22°C temp. Now add ITU (Diaminomethyleneamino(1-amino-1-iminomethylene)

thiomethyl thiozole dihydrochloride) and IF (N-Sulfomyl-3-chloropropionamide

hydrochloride) at 20°C to 22°C temp. Regulate the temperature to 25°C and maintain for

2 hours under stirring. Chill the reaction mass to 0°C to 5°C 22.temp. Centrifuge the

slurry. Unload the wet material from the centrifuge. Charge water into the reaction vessel

and add wet cake under stirring. Stir for 30 minutes. Centrifuge the material and wash the

wet cake with water and then wash with methanol. Load the wet cake in dryer. Dry the

wet cake at 80°C to 85°C temperature for 7 to 8 hours. Unload the dried material and

weight it.

STAGE-2: [FAMOTIDINE PURE]: Charge Water & caustic soda into the reaction vessel. Add

Famotidine Crude (Stage-1) under stirring. Heat the reaction mass to 70°C to 75°C

temperature. Check the clarity of the reaction mass. It should be clear. Now prepare the

slurry of Activated carbon in water. Add activated carbon slurry into the reaction mass at

70°C to 75°C temp. And maint. for 15 minutes. Filter the reaction mass through pressure

filter and transfer filtrate online to another reaction vessel maintaining temperature 30°C

to 40°C. Add Acetic Acid & follow out the material Now chill the filtrate to 0°C to 5°C

temp. and maintain for 30 minutes. Centrifuge the slurry and wash the wet cake with

water. Unload the wet cake and weight it. Dry the wet cake in dryer at 75°C temperature

for 5 to 6 hours. Unload the dried material and weight it and packed it as Famotidine

Pure.

Chemical Reaction:

(1) Diaminomethyleneamino(1-amino-1-iminomethylene)thiomethyl thiozole dihydrochloride

(2) N-Sulfamyl-3-chloropropionamidine hydrochloride

(8) Famotidine

S

NCH2 S C

NH

NH2 2HCl

NC

NH2

NH2

CH2 CH2 C

NH2

N SO 2NH2

Cl+NaOH

S

NCH2 S

NC

NH2

NH2

CH2 CH2 C

NH2

N SO2NH2

(2)(1)

(3)

Mass Balance:

Sr. No.

Input Quantity (Kg)


1 ITU 1.150 Product 1.000

2 IF 0.965 Methanol Recover 5.500

3 Methanol 5.710 Methanol Loss 0.200

4 NaOH 0.690 Effluent 22.305

5 Water 20.50 Evaporation Loss 0.010

6 Acetic Acid 0.200 Dist. Residue 0.200


5. Sevelamer HCl


Stage-1 Preparation of Polyallylamine Hydrochloride

Into clean reactor charge 250 Kg Hydrochloric acid at room temperature. Add 150 Kg

allylamine in 2 hrs at 5 to 10 °C. Raise the temperature 80 °C and add a solution of 2,2-

dimethyl-2,2-azopropane dihydrochloride (6.0 Kg in 44 Kg water) at 45 to 50 °C. Stir the

mass 30 hrs at 45 to 50 °C. Monitor the reaction performance by analytical methods.

After completion of reaction, cool the mass to 25 to 30 °C Stir for 1 hr at 25 to 30 °C.

Expected weight is 450 Kg.

Stage-2 Preparation of Sevelamer

Add 150 Kg Sodium hydroxide solution (75 Kg in 75 Kg water) into 450 Kg Polyallylamine

at room temperature and stir for 30 minutes. add 22.0 Kg of epichlorohydrin into above

solution at room temperature and stir for 20 minutes. Heat the mass at 25 to 50 °C in 10

to 20 minutes. Cool to 30 °C and stir for 30 minutes at 25 to 30 °C. Filter the slurry and

wash the material and finally with 3 X 1500 Kg Water. Collect the main and washing

Mother Liquor together. Unload and dry the material at 45 to 50 °C in vacuum tray drier

(VTD) till to reach the required moisture content of the product. Expected weight is 200

Kg.

Chemical Reaction: Stage –I (Preparation of Polyallylamine Hydrochloride):

CH2

NH2 + HCl

allylamine Hydrochloric acid

Polymerisation Water 25 to 80ºC

NH2

.

.

n

.HCl

Polyallylamine Hydrochloride

Stage – 2 (Preparation of Sevelamer):

NH2

.

.

n

.HCl

+

O

Cl

+ Na OH Polyallylamine Hydrochloride Epichlorohydrin Sodium Hydroxide

Cross Linking Water 25 to 50ºC

NH2

NH2

NH

NH

CH3

CH3

OH

CH3

CH3

.nHCl

.nHCl

.nHCl

.nHCl

a

bc m

Sevelamer a, b = number of primary amine groups c = number of cross linking groups n = fraction of protonated amines m = large number to indicate extended polymer network

Mass Balance:

Sr. No.

Input Quantity (Kg)


1 Allylamine 150 Product 200

2 2,2-Dimethyl-2,2-azopropane dihydrochloride

6 Effluent 2250

3 HCl 250 Evaporation Loss 172

4 Water 2119

5 Epichlorhydrin 22

6 NaOH Flakes 75

Total 2622 Total 2622

5 (a). Sevelamer Carbonate Manufacturing Process:

Charge Purified Water and Sevelamer Hydrochloride.

Charge Caustic Soda flakes.

Purge Carbon Dioxide gas.

Filter the mass and wash with Water.

Dry wet material to give Sevelamer Carbonate. Chemical Reaction: Mass Balance:

Sr. No.

Input Quantity (Kg)


1 SevelamerHCl 1.111 Product 1.000

2 Caustic soda flakes 0.333 Effluent 35.556

3 Carbon dioxide 0.278 Evaporation Loss 2.944

4 Water 37.778


6. Poly Allaylamine Hydrochloride Manufacturing Process:

Into clean reactor charge 250 Kg Concentrated hydrochloric acid at room temperature. Add 150 Kg allylamine in 2 hrs at 5 to 10 °C. Raise the temperature 80 °C and add a solution of 2,2-dimethyl-2,2-azopropane dihydrochloride (6.0 Kg in 44 Kg water) at 45 to 50 °C. Stir the mass 30 hrs at 45 to 50 °C. Monitor the reaction performance by analytical methods. After completion of reaction, cool the mass to 25 to 30 °C Stir for 1 hr at 25 to 30 °C. Expected weight is 450 Kg.

Chemical Reaction:

CH2

NH2 + HCl

allylamine Hydrochloric acid

Polymerisation Water 25 to 80ºC

NH2

.

.

n

.HCl


Mass Balance:

Sr. No.

Input Quantity (Kg)


1 Allylamine 150 Product 450

2 2,2-Dimethyl-2,2-azopropane dihydrochloride

6

3 HCl 250

4 Water 44

Total 450 Total 450

6). Fomepizole Manufacturing Process

Stage-1 Preparation of 1, 1-Diethoxy Propane

Into reactor, charge 395 Kg Ethanol and 131 Kg Propanaldehyde at room temperature.

Heat the mass to 90ºC and reflux for 15 hrs. Cool the mass to room temperature. Add

390 Kg Hexane and stir for 30 minutes at room temperature. Separate the layers. Distill

out the Hexane completely at 80ºC.

Expected weight is 300 Kg

Stage-2 Preparation of Fomepizole

Into the reactor charge 233 Kg N,N-Dimethyl formamide and 300 Kg 1,1- Diethoxy

Propane at room temperature. Add 535 Kg Phosphorus oxychloride solution

(345 Kg in 190 Kg N,N-Dimethyl formamide) into the mass in 14 hrs at 90ºC. Cool to 50ºC

and stir for 12 hrs. Monitor the reaction performance by analytical methods. After

completion of reaction cool the mass to room temperature. Into the mass add 2000 Kg

Water and 2680 Kg Dichloro methane and stir for 30 minutes. Separate the layers and

distill out Dichloro methane completely at below 50ºC.

Into the above mass, add 2010 Kg Dichloro methane and 110 Kg Hydrazine hydrate at

room temperature. Heat the mass to 100ºC reflux for 15 hrs at the reflux temperature.

Monitor the reaction performance by analytical methods. After completion of reaction

cool the mass to room temperature. Add 2000 Kg Water into the mass and adjust the pH

to 7.0 using Potassium carbonate solution (75 Kg in 750 Kg Water). Separate the layers

and wash the dichloro methane layer with 1000 Kg Water. Distill out Dichloro methane

completely under vacuum at below 40ºC.

Add 425 Kg Di isopropyl ether and stir for 30 minutes at room temperature. Add 15 Kg

Carbon and stir for 30 to 40 minutes at room temperature. Filter and wash with

73 Kg Di isopropyl ether. Distill out Di isopropyl ether completely under vacuum at below

50ºC. Release the vacuum and unload the liquid Fomepizole.

Chemical Reaction

Stage – 1 (Preparation of 1,1-Diethoxy Propane)

CH3 OH +

CH3

H

O

Hexane / 90ºC

CH3OOCH3

CH3 Ethanol Propanaldehyde 1,1-Diethoxy Propane Stage-2 (Preparation of Fomepizole)

CH3OOCH3

CH3 +

ClP

Cl

ClO

+ NH2 NH2. H2O 1,1-Diethoxy Propane Phosphorous Hydrazine Hydrate Oxychloride N,N-Dimethyl Formamide (DMF) Dichloro Methane (MDC) Water 50ºC/ 90ºC 100ºC

NH

N

CH3 Fomepizole

Mass Balance:

Sr. No.

Input Quantity (Kg)


Step-1

1 Propanaldehyde 131 Step-1 300

2 Ethanol 395 Ethanol Recover 378

3 Hexane 390 Ethanol Loss 15

4 Hexane Recover 375

5 Hexane Loss 15

6 Dist. Residue 2

Total 916 Total 916

Sr. No.

Input Quantity (Kg)


Step-2

1 Step-I 300 Product 100

2 Phosphorus oxychloride

345

Dichloro methane 4670

3 Hydrazine Hydrate 110 Dichloro methane loss 20

4 Potassium Carbonate 75 Dimethyl formamide 30

5 Carbon 15 Di isopropyl ether 480

6 Di isopropyl Ether 498 Di isopropyl ether loss 18

7 N,N-Dimethyl Formamide

423

Carbon 15

8 Dichloro Methane 4690 Water 6470

9 Water 5750 Dimethyl formamide 383

10

Dimethyl formamide loss

10

11 Dist. Residue 10


7. COLESEVELAM Manufacturing Process

Stage-1 Preparation of Polyallylamine

Into clean reactor charge 301 Kg Concentrated hydrochloric acid at room temperature.

Add 156 Kg Monoallylamine in 2 hrs at 5 to 10ºC. Raise the temperature and distill out

water and excess hydrochloric acid under vacuum at below 60ºC. Add 95 Kg Water into

the mass at room temperature. Raise the mass temperature to 45 to 50ºC and add a

solution of 2,2-dimethyl-2,2-azopropane dihydrochloride (3 Kg in 10 Kg water) at 45 to

50ºC. Stir the mass 30 hrs at 45 to 50ºC. Monitor the reaction performance by

analytical methods. After completion of reaction, cool the mass to 25 to 30ºC and

transferred into 1354 Kg Methanol. Stir for 1 hr at 25 to 30ºC. Filter the slurry and wash

the material with 395 Kg Methanol. Collect the main and washing Mother Liquor

together. Unload and dry the material at 45 to 50ºC in vacuum tray drier (VTD) till to

reach the required LOD (Loss On Drying) of the product.


Stage-2 Preparation of Colesevelam

Add 200 Kg Sodium hydroxide solution (50 Kg in 150 Kg water) into 245 Kg

Polyallylamine at room temperature and stir for 30 minutes. In a separate reactor, add 2

Kg of Epichlorohydrin, 4 Kg n-Decylchloride and 4 Kg Trimethyl ammonium hexylchloride

into 63 Kg of above solution and at room temperature and stir for 20 minutes. Add this

solution into the above remaining mass at 25 to 50ºC in 10 to 20 minutes. Cool to 30ºC

and stir for 30 minutes at 25 to 30ºC. Filter the slurry and wash the material with 32 Kg

Methanol, 100 Kg Water, 20 Kg Sodium hydroxide solution (1Kg in 19 Kg Water) and

finally with 400 Kg Water. Collect the main and washing Mother Liquor together. Unload

and dry the material at 45 to 50ºC in vacuum tray drier (VTD) till to reach the required

moisture content of the product.


Chemical Reaction

Stage – 1 (Preparation of Polyallylamine)

CH2

NH2 + HCl

Monoallylamine Hydrochloric acid

Polymerisation 45 to 50ºC Water

NH2

.

.

n

.HCl


Stage-2 (Preparation of Colsevelam HCl)

NH2

.

.

n

.HCl

+ NaOH + + Polyallylamine Hydrochloride n-Decyl chloride

O

Cl

+

ClN

+

CH3

CH3

CH3

Epichlorohydrin Trimethylammoniumhexylchloride

Cross Linking 25 to 50ºC

NHCH2 N+CH3

CH3CH3

CH2NH CH3

CH2 NH2

n

O

Cl .HCl

Colesevelam Hydrochloride

http://www.chemblink.com/products/1002-69-3.htm

Mass Balance:

Sr. No.

Input Quantity (Kg)


Step-1

1 Monoallylamine 156 Step-1 245

2 2,2-dimethyl-2,2-azopropane dihydrochloride

3 Methanol Recover 1696

3 Concentrated Hydrochloric acid

301 Methanol Loss 52

4 Methanol 1749 Effluent 321

5 Water 105


Sr. No.

Input Quantity (Kg)


Step-2

1 Polyallylamine 245 Product 260

2 Epichlorohydrin 2 Efflunet 788

3 n-Decylchloride 4 Sodium chloride 172

4 Trimethylammoniumhexylchloride

4 Methanol 32

5 Sodium hydroxide 116

6 Methanol 32

7 Water 849

8

9

10

11


9. Glimepiride

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

Charged 3 Ethyl 4 methyl Pyrroline and toluene is SSR. Charged slowly 2 Phenyl

Isocyante in it. Heat the RM to reflux for 2 hrs.

Cool and then chilled the rm. Filter the mass and dry it.

Charged Chloro Sulfonic Acid in Reactor at RT and chilled it. Charged Amide derivative

in above reaction mixture in chilling condition.

The reaction mixture was heated and stirred. The reaction mixture was very slowly

quenched in chilled ammonia solution. Filter the solid mass, wash with water and dry

it.

Charged EDC and above crude product in Reactor at RT. The reaction mixture was

heated and stirred the chilled to 0-5oC. Filter the solid mass under chilling condition

and dry it.

Chemical Reaction:

Mass Balance:

Sr. No.

Input Quantity (Kg)


1 3 Ethyl methyl Pyrroline

0.40 Product

1.00

2 2 Phenyl ethyl isocyanate

0.40

Toluene Recover 3.35

3 Toluene 3.50 EDC Recover 1.70

4 Chloro Sulfonic Acid 1.00 Distillation + Drying loss 0.83

5 Ammonia Solution 3.10 Residue 0.03

6 EDC 2.00 Effluent 4.38

7 Water 1.00


10. Furosemide Manufacturing Process:

To Furfurylamine, 2,4-Dichloro-5-Sulfamoyl Benzoic acid (Lasamide) will be added below 60°C. Gradually, temperature of the reaction mixture, under Nitrogen atmosphere will be raised to 117- 120°C and maintained for several hrs. The reaction mass will be cooled and passing of Nitrogen gas will be stopped and diluted with Isopropyl Alcohol. Subsequently the pH of reaction mass will be adjusted to highly alkaline with solution of sodium hydroxide & cooled to 0°C for several hours. When the crude sodium Frusemide separates out, it will be centrifuged. The sodium salt of Frusemide will be dissolved in DM water, charcolised and filtered. pH of clear solution will be adjusted to acidic when pure Frusemide separates out. It will be centrifuged, washed with DM water & dried. Dried product will be milled blended, shifted and packed. Chemical Reaction:

Mass Balance:

Sr. No.

Input Quantity (Kg)


1 Furfuryl Amine 1564 Product 1000

2 Lasamide 850

Furfuryl Amine Recover

1210

3 Caustic Flake 234 Loss 450

4 IPA 5920 Dist. Residue 20

5 Carbon 80 Spent Carbon 70

6 Water 7396 Effluent 7593

7 Acetic Acid 220 IPA Recover 5680

8 IPA Loss 240


11. Betahistine Dihydrocloride:


2-vinyl pyridine react with methylamine hydrochloride in presence of acetic acid to form

betahistidine Base isolated by high vacuum distillation. Betahistidine Base react with IPA

Hcl to form Betahistidine dihydrochloride.

Chemical Reaction:

NCH3

+ CH3 NH2 ClH

NNH

CH3

Molecular Formula: C7H9NFormula Weight: 107.15306

Molecular Formula: CH6ClN

Formula Weight: 67.51804

Molecular Formula: C8H12N2


NNH

CH3

Molecular Formula: C8H12N2


IPA HCl

NNH

CH3

ClH

Molecular Formula: C8H14Cl2N2

Formula Weight: 209

2

Mass Balance:

Sr. No.

Input Quantity (Kg) Output Quantity (Kg)

1 2- vinyl pyridine 0.63 Product 1.00

2 Methylamine hydrochloride 0.80 Effluent 2.22

3 water 0.31 Chloroform Recovery 2.90

4 Chloroform 3.13 Chloroform Loss 0.23

5 Sodium hydroxide 0.45 IPA Recovery 2.40

6 Acetic Acid 0.06 IPA Loss 0.10

7 IPA 2.50 Distillation residue 0.40

8 IPA HCl(20%) 1.38


12. Adapalene Manufacturing Process:

Charge THF & start nitrogen purging until water quenching. Charge Mg turnings. Heat the

mass up to reflux 60-65°C . Prepare solution of adamentanol & p- bromomphenol in MDC

inn a clean container. Add above prepared solution through the addition funnel in 10 – 15

min at 60-65°C. Prepare solution of Adamentanol in MDC in clean container. Add above

prepared solution of in THF in 45-60 min at 60-65°C. Reflux the reaction mass for 60 min.

Cool the reaction mass. Charge MDC to the reaction mass. Cool the reaction mass. Charge

6-Bromo-2-methyl naphthoate at 15-20°C. Maintain the reaction mass for 30 min at 40-

45°C. Take purified water in RBF & cool it 20-25. Prepare HCl water solution Add the HCl

water solution slowly. Stir the reaction mass. Wash with purified water. Suck dry well.

Unload the material of crude stage C wet cake & take for purification. Dry the wet cake at

70 – 75°C.

Chemical Reaction:

Step-2

Step-3

Step-4

Mass Balance:

Sr. No.


1 Adamentanol 24 Product 50

2 Para Bromo Phenol 15 Effluent 442.5

3 THF 30 MDC Recovery 65

4 Mg Turning 3 MDC Loss 2

5 MDC 68 THF Recovery 29

6 6-Bromo-2-methyl naphthoate 36 THF Loss 0.5

7 HCl 66 Distillation residue 3

8 Water 350

Total 592 Total 592

13. Telmisartan and Its Intermediate Manufacturing Process:

4-Amino-3-benzoic acid is esterifies to gives methyl-4-amino-3-bezoate, which reacted with butryl chloride to produce butyramide derivative, which nitrated with fuming nitric acid to produced nitro derivative, which reduced in presence of Palladium on charcoal and then hydrolyzed to gives Benzimidazole derivative. Benzimidazole is reacted with n-methyl o-pheniline Diamine to gives condensed product, which is reacted with bromo ester to gives telmi ester, which hydrolyzed with potassium hydroxide to gives Telmisartan. Chemical Reaction:

CH3

NH2

O

OH

CH3

CH3

O

O

NH2

CH3

CH3

O

O

NH2

CH3 Cl

O CH3

CH3

O

O

NH CH3

O

CH3

CH3

O

O

NH CH3

OCH3

CH3

O

O

NH CH3

O

NO2

CH3

CH3

O

O

NH CH3

O

NO2

Pd/CharcoalAcetic Acid

CH3

CH3

CH3

O

O

NH

N

CH3

CH3

CH3

O

O

NH

N

CH3

CH3

H

O

O

NH

N

10% NaOH Sol.

Methanol

CH3

CH3

H

O

O

NH

N

CH3

CH3NH

N

N

N

CH3Polyphospheric Acid

NH2

NHCH3

TS-1M wt - 165

TS-2

M wt - 235

TS-3M wt - 280

TS-5M wt - 232

TS-6M wt - 218

TS-7M wt - 304

CH3OH/H 2SO4

65°C

Fuming HNO 3

-20 to -25°C

0 to 5°C

80°C

140 to 145°C

Yield 94 %

Yield 96 %

Yield 93 %

Yield 86 %

Yield 96 %

TEA/MDC

CH3

NH2

O

OH

CH3

CH3

O

O

NH2

CH3

CH3

O

O

NH2

CH3 Cl

O CH3

CH3

O

O

NH CH3

O

CH3

CH3

O

O

NH CH3

OCH3

CH3

O

O

NH CH3

O

NO2

CH3

CH3

O

O

NH CH3

O

NO2

Pd/CharcoalAcetic Acid

CH3

CH3

CH3

O

O

NH

N

CH3

CH3

CH3

O

O

NH

N

CH3

CH3

H

O

O

NH

N

10% NaOH Sol.

Methanol

CH3

CH3

H

O

O

NH

N

CH3

CH3NH

N

N

N

CH3Polyphospheric Acid

NH2

NHCH3

TS-1M wt - 165

TS-2

M wt - 235

TS-3M wt - 280

TS-5M wt - 232

TS-6M wt - 218

TS-7M wt - 304

CH3OH/H 2SO4

65°C

Fuming HNO 3

-20 to -25°C

0 to 5°C

80°C

140 to 145°C

Yield 94 %

Yield 96 %

Yield 93 %

Yield 86 %

Yield 96 %

TEA/MDC

Mass Balance:

Qty (Kg) Raw material Material Qty(Kg)

3.53 Methanol ML to ETP 7.574

1.484 4-Amino 3-Methylbenzoic acid

1.423 Conc. Sulphuric acid

2.968 Liq. NH3

9.410 Total Output 1.53 Loss 0.31


1.53 TS-1 Soduim Sulpahte 0.387

5.670 MDC Aqs. Layer 12.240

1.314 TEA Recovered MDC+Hexane 6.084 1.287 Butryl chloride ML to ETP 7.705 0.153 Sodium Bicarbonate

0.387 Sodium Sulphate

12.240 Water

5.094 Hexane



0.90 TS-2 ML to ETP 12.748

4.050 Fuming Nitric acid

0.090 Sodium Bicarbonate

9.000 DM Water


INPUT OUTPUT

TS-01

INPUT OUTPUT

TS-02

INPUT OUTPUT

TS-03

14) Tapentadol Hydrochloride Manufacturing Process:

Charge isopropyl alcohol, 3-methoxy propiophenone, dimethyl amine hydrochloride, Paraformaldehyde. Heat the reaction mass. Maintain the reaction mass and distill out isopropyl alcohol. Charge Purified water and sodium hydroxide.

Charge dichloromethane and separate out layers. Charge dichloromethane layer into the reactor and distill out dichloromethane. Charge IPA and charge L (-) Dibenzoyl tartaric acid. Maintain the reaction mass and filter it. Charge Purified water and above wet cake.

Charge sodium carbonate and Dichloromethane. Separate out layers. Charge dichloromethane layer into the reactor and distill out dichloromethane and charge Tetrahydrofuran. Charge magnesium turning and ethyl acetate. Maintain the reaction mass and distill out Tetrahydrofuran. Charge Purified water and Acetic acid. Add ammonium solution and Dichloromethane. Stir the reaction mass and separate out layers. Charge Product layer into a reactor and distill out dichloromethane. Charge Ethyl acetate into the above reactor and cool the reaction mass. Charge Trifluoroacetic anhydride and maintain the reaction mass. Unload the reaction mass.

Charge palladium and apply hydrogen pressure. Maintain the reaction mass. Filter the reaction mass and collect filtrate. Charge hydrobromic acid into the reaction mass. Heat the reaction mass and maintain the reaction mass charge ammonia solution and ethyl acetate. Separate out layers. Distill out ethyl acetate and charge Isopropyl alcohol. Add IPA HCl. Maintain the reaction mass. Centrifuge the reaction mass.Dry it to give Tapentadol Hydrochloride.

Chemical Reaction:

Mass Balance:

Sr. No.


1 3-methoxy propiophenone 1.412 Product 1.00

2 IPA 7.530 IPA Recover 7.15

3 Dimethyl Amine HCL 1.059 IPA Loss 0.35

4 Paraformadehyde 0.588 MDC Recover 9.60

5 Sodium Hydroxide 0.376 MDC Loss 0.35

6 MDC 10.00 THF Recover 3.42

7 L (-) Dibenzoyl tartaric acid 1.412 THF Loss 0.08

8 THF 3.530 Ethyl Acetate Rec. 5.65

9 Mg Turning 0.171 Ethyl Acetate Loss 0.23

10 Ethyl Bromide 0.588 Palladium Recover 0.06

11 Acetic Acid 0.118 Palladium Loss 0.01

12 Ammonium Solution 0.506 Acetone Recover 6.21

13 Ethyl Acetate 5.883 Acetone Loss 0.26

14 Trifluroacetic anhydride 0.882 Effluent 25.827

15 Palladium 0.070 Dist. Residue 0.407

16 Acetone 6.470 Process Waste 0.235

17 HBr 1.765 Loss 0.05

18 IPA HCl 0.882

19 Water 17.647


15. Colistimethate Sodium Manufacturing Process: Stage 1:

Take Colistin sulphate and water. Filter and remove insoluble material. Charge sodium bi

carbonate solution. Add sodium carbonate for adjusting pH. Get white precipitation.

Add 400 ml sodium bi carbonates solution. Add dematerialized water and adjust pH by

adding sodium carbonate. Continue stirring 2 hours. Filter the reaction mass under

nitrogen gas. Unloaded wet cake and charge dematerialized water. Add slowly sodium bi

sulfite solution for adjust pH. Maintain 1 hour. Add remaining solution in reaction mass

for pH. Stirring for 2 hours. Add acetic acid. Adjust pH. Stir for 1 hour. Add industrial

solvent. Start a zeotropic distillation. Strip out 2 times from industrial solvents. Thick

slurry mass is obtained. Add acetone for make free flowing slurry. Maintain 6 hours. Filter

and unload wet cake. Dry under vacuum.

Final Stage:

Take crude stage-1 and methanol, add industrial solvent. Filter with flow bed. Wash with

methanol. Distill out methanol under vacuum. Add Industrial solvent under stirring and

get uniform slurry. Distill out methanol under vacuum. After complete distillation, add

industrial solvent and maintain for 2 hours at 25 to 30oC temperature. Filter and wash

with Industrial solvent. Dry under vacuum at 25 to 30 oC temperature for 4 hours. After

drying continue 6 hours on 45 to 60oC temperature. Getting final material.

Chemical Reaction:

Mass Balance:

Sr. No.


Step-I

1 Colistin Sulphate 100 Step-I 155

2 Sodium Bicarbonate 50 Solvent Recover 2015

3 Sodium Carbonate 25 Solvent Loss 85

4 Formaldehyde 100 Acetone Recover 3230

5 Sodium Bisulfite 230 Acetone Loss 170

6 Acetic Acid 12 Dist. Residue 50

7 Solvent 2100 Effluent 3227

8 Acetone 3400 Drying Loss 85

9 Water 3000


Step-II

9 Step-I 155 Product 75

10 Methanol 5800 Methanol Recover 5510

11 Water 1340 Methanol Loss 250

12

Effluent 1430

13

Solid Waste 30


16. Chlorohexidine Base MANUFACTURING PROCESS: First charge the Hexamethelinediamine and butanol then added concentrated hydrochloric acid and sodiumdicyamide into the reactor Heat the mass and distill out water then reflux at desire temperature, cool and charged parachloroaniline and reflux. Charge Sodium hydroxide flaks and water then separated the layers, Chilled the Organic phase and centrifuge. Wet material further subjected to purification in methanol, chill, and centrifuge followed by washing with methanol and dried it.

CHEMICAL REACTION:

NH2

NH2 + 2 HCl NH2

NH2HCl.

.HCl

Hexametheline diamineM.W.116.2M.F. C6H16N2

[1 Eq.]

Hydrochloric acidM.W.36.5M.F. HCl

[2 Eq.]

Hexametheline diamine dihydrochlorideM.W.189.2

M.F. C6H18N2Cl2[1 Eq.]

NH2

NH2HClHClHexametheline diamine dihydrochloride

M.W.189.2M.F. C6H18N2Cl2

[1 Eq.]

+ NNa

N

N

SodiumdicynamideM.W.89.03M.F. C2N3Na

2

[2 Eq.]

NH

NH

NHN

NHNH

N

NH+ 2 NaCl

1,1'-hexane-1,6-diylbis(3-cyanoguanidine)M.W.250.3

M.F. C10H18N8

[1Eq.]

Sodium chlorideM.W.58.2M.F. NaCl

[2Eq.]

NH

NH

NHN

NHNH

N

NH+

NH2

Cl

1,1'-hexane-1,6-diylbis(3-cyanoguanidine)M.W.250.3M.F.C10H18N8

[1Eq]

Parachloroaniline HydrochlorideM.W.164

M.F.C6H7NCl2

[2Eq]

2 HCl

.2HCl

M.W.578.4

M.F.C22H32Cl4N10

[1Eq]

Chlorhexidine dihydrochloride

2NaOHSodium hydroxideM.W.40[2Eq]

Chlorhexidine BaseM.W.505.4

M.F.C22H30Cl2N10

[1Eq]+

2H2O

+2NaCl

water Sodium chloride

M.W.18 M.W.58.5

[2Eq] [2Eq]

Cl

NHNH NH

NH

NH

NH

NH

NHCl

NH

NH

Cl

NHNH NH

NH

NH

NH

NH

NHCl

NH

NH

MASS BALANCE:

Sr. No. Input Quantity (Kg) (Kg)

Output Quantity (Kg) 1 Hexamethelinediamine 100 Effluent 1250 2 Butanol 1170 Residue 103.70 3 Hydrochloric acid 210 Butanol Recover 1117 4 Sodiumdicynamide 153.40 Butanol Loss 53 5 Parachloroaniline HCl 283.30 Methanol

Recover 793

6 Sodium hydroxide 70 Methanol Loss 37 7 Water 870 Chlorhexidine

base 333

8 Methanol 830 Total 3686.7 Total 3686.7

brief manufactring process, chemical reaction and mass balance

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