Nimp Healthcare Private Limited- form-i revised

93

GROUP-3

26) Omeprazole

BRIEF PROCESS:

2-Chloromethyl-3, 5-dimethyl-4-methoxy pyridine hydrochloride (chloro compound)

is condensed with 2-mercapto-5-methoxybenzimidazole(mercapto compound) in the

presence of sodium hydroxide as a base in aqueous methanol to get sulfide

compound.

Sulfide compound is oxidized with hydrogen peroxide in the presence of ammonium

molybdatetetrahydrate as catalyst to get omeprazole Crude. Omeprazole Crude is

further purified by acid base treatment followed by crystallization in the mixture of

methanol & DCM to get pure omeprazole as a light sensitive solid.

Omeprazole Crude is taken in DM Water and sodium hydroxide solution is added to

get omeprazole sodium as a clear solution. This solution is wash with

dichloromethane and filtered to remove the insoluble solids .To this filtrate, aqueous

ammonium acetate solution is added drop wise to isolate Omeprazole.

Chemical Reaction:

Step 1- Preparation of Sulfide

Step 3- Preparation of Omeprazole

94

Mass Balance:

Sr

No Input (Kg)

Output (Kg)

Stage- I:

1

2-Chloromethyl- 3, 5-

Dimethyl- -4-

methoxy pyridine

hydrochloride (Chloro

compound)

89.03 Sulfide comp. 106.84

2

2-mercapto-5-methoxy

benzimidazole

(Mercapto compound)

75.85 Methanol reuse 338.32

3 Sodium hydroxide 48.07 Methanol loss 14.22

4 Methanol 356.12 Effluent 290.31

5 Water 180.62

Total 749.69 Total 749.69

Sr

No Input (Kg)

Output (Kg)

Stage- II:

1 sulfide comp. 106.84 Omeprazole (crude) 70.83

2 Hydrogen peroxide 25.17 Methanol recovery 855.55

3

Ammonium molybdate

tetra hydrate

0.42 Methanol loss 35.89

4

Sodium carbonate 1.07 Dichloro methane

recovery

687.18

5 Sodium hydroxide 14.31 Dichloromethane loss 28.63

6 Acetic acid 21.37 Waste water 209.01

7 Triethyl amine 0.53

8 Water 104.14

9 Methanol 897.43

10 Dichloro methane 715.81

Total 1887.09 Total 1887.09

Sr

No Input (Kg)

Output (Kg)

Stage- III:

1 Omeprazole(crude) 70.83 Omeprazole 42.85

2

Sodium hydroxide 9.21 Dichloro methane

recovery

180.34

3 Ammonium acetate 17.70 Dichloro methane Loss 7.59

95

4 Dichloro methane 189.83 Acetone recovery 33.64

5 Acetone 35.41 Acetone loss 1.14

6 Water 132.49 Effluent 189.91


96

27) Atorvastatine Calcium

BRIEF PROCESS:

2R-trans)-5-(4-Fluorophenyl)-2-(1-Methyl)-N, 4 diphenyl-1-[2-Tetra hydroxy- 4

hydroxy-6-Oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide treated with NaOH in

IPA. The mass is treated with calcium acetate solution. The crude obtained is

crystallized from IPA to give atorvastatin calcium.

Chemical Reaction:

Mass Balance

Sr

No Input (Kg)

Output (Kg)

Stage- I:

1

(2R-trans)-5-(4-

Fluorophenyl)-2-(1-

Methyl)-N,4diphenyl-1-[2-

Tetra hydroxy-4-hydroxy- 6-

Oxo-2H-pyran-2- yl)ethyl]-

1H-pyrrole-3-carboxamide

191.00 Stage - 1 89.00

2

IPA 225.00 Aq. Effluent for IPA

Recovery

358.00

3 NaOH 31.00


97

Sr

No Input (Kg)

Output (Kg)

Stage- II:

1 Stage - 1 89.00 Stage-2 101.00

2

Calcium Acetate solution 140.00 Aq. Effluent for Calcium

Acetate solution Recovery

128.00


Sr

No Input (Kg)

Output (Kg)

Stage- III:

1 Stage - 2 101.00 Atorvastatin Calcium 100.00

2

IPA 173.00 Aq .Effluent for IPA

Recovery

155.00

Dry Loss 19.00


98

28) Zonisamide

BRIEF PROCESS:

4-Hydroxycoumarin was reacted with hydroxylamine HCl in presence of potassium

acetate anhydrous in methanol at desired temperature and appropriate condition.

Methanol distillation, basification, dichloromethane washing and later acidification

afforded Zonisamide Stage-I.

Obtained solid was reacted with complex of chloro sulphonic acid and 1, 4-dioxane in

ethylene dichloride. Quenching and later water removal and later chlorination using

phosphorus oxychloride in toluene and animation using ammonia afforded

Zonisamide Stage-II.

Purification of Zonisamide Stage-II using acetone, water and activated charcoal

afforded pure Zonisamide.

Chemical Reaction:

Stage- 1:

Stage-2:

Stage-3:

99

Mass Balance:

Sr

No Input (Kg)

Output (Kg)

Stage- I:

1 Methanol 153.00 Stage-1 214.00

2 4Hydroxy Coumarin 195.30 Methanol Recovery 137.7

3

Hydroxylamine

hydrochloride

193.00 Methanol loss 15.3

4 Potassium acetate 213.00 Effluent 1238.30

5 NaOH 20.00 Dry loss 30.00

6 MDC 290.00 Organic Residue 29.00

7 HCL 100.00

8 Water 500.00

Total 1664.30 Total 1664.30

Sr

No Input (Kg)

Output (Kg)

Stage- II:

1 Stage-1 214.00 Stage-2 171.00

2 EDC 856.00 HCL gas 20.00

3 1,4 Dioxane 97.00 EDC Recovery 770.0

4 CSA 120.00 Ammonia gas 130.00

5 Sodium Sulphate 78.00 Toluene recovery 270.00

6 Toluene 300.00 Aq. Effluent 803.40

7 Phosphorus Oxychloride 20.00 Solvent loss 115.60

8 Water 500.00 Dry loss 35.00

9 Ammonia Gas 130.00

Total 2315.00 Total 2315.00

Sr

No Input (Kg)

Output (Kg)

Stage- III:

1 Zonisamide (Crude) 180.00 zonisamide 125.00

2 Ethyl Acelate 1445 Ml CF 1454.00

3 Carbon 7.00 Carbon + Hyflow 25.00

4 Hyflow 7.00 Dry In Loss 35.00

Total 1639.00 Total 1639.00

100

29) Meloxicam

BRIEF PROCESS:

Methyl Benzothiazine Isopropyl Ester and 2-amino 5-methyl thiazole is reacted in

presence of O-xylene. The contents are heated to reflux. The contents are stirred at

140-150 C for 24 hours with simultaneous distillation of O-xylene. The reaction mass

is then cooled to 75-80 C and transferred to another reactor. The reaction mass is

chilled to 0-5C and the product obtained is filtered on a buckner filter.

The wet material obtained charged into the reactor containing methanol and the

contents are stirred for 30 minutes. The reaction mass is filtered on buckner filter.

This methanol purified material is charged into the reactor containing DMF. The

activated charcoal and alumina are charged into the reaction mass by making a slurry

in DMF. The contents are heated to 100-110 C and the temperature is maintained for

30 minutes at 100-110 C. The contents are filtered through hyflo bed on buckner

filter. The clear solution obtained is charged into the another reactor and heated to

100 C. the DM water is charged into the filtrate. Then the reaction mass is cooled to

30 C and further chilled to 0-5 C. the temperature is maintained for 1 hour.

The product obtained is filtered on buckner filter. The product is suck dried for 1 hour

washed with filtered methanol. And suck dried. The product is dried in Vacuum Tray

Dryer under vacuum at 75-80 C for 8 hours. The product is micronised using jet mill.

The product is sifted through 20sieve prior to final packing.

Chemical Reaction:

Stage- 1:

NH2

OH OH

ONH

CH3

(CH3Co)2O

( I )

N-(4-hydroxycyclohexyl)acetamide

4-aminocyclohexanol

Trans -

+ + CH3COOH

Stage-2:

OH

ONH

CH3

ONH

CH3

O

Na2Cr2O7 H2SO4

( I ) ( II )

N-(4-oxocyclohexyl)acetamideN-(4-hydroxycyclohexyl)acetamide

++ +2Na2SO4+

H2Cr2O7+H2O+ H2O

101

Stage-3 :

ONH

CH3

O

Br2

ONH

CH3

O

Br

BrH

+ NH2 NH2

S

O

NH

CH3

N

S

NH2 BrH

( II ) ( III )

N-(4-oxocyclohexyl)acetamide

thioureaN-(2-amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)acetamide

N-(3-bromo-4-oxocyclohexyl)acetamide hydrobromide

+ HBr + +

Mass Balance:

Sr

No Input (Kg)

Output (Kg)

Stage- I:

1

Methyl Benzothiazine

Isopropyl Ester 27.96

Stage-1 Product 63.45

2 2-amino 5-methyl thiazole 64 Isopropyl alcohol recovery 307.54

3 O-xylene 57 Isopropyl alcohol loss 12.92

4 Potassium iodide 1.18 MDC recovery 567.45

5 Caustic lye 19.55 MDC loss 23.64

6 Sodium sulphate (Na2SO4) 13.98 Waste Water 551.23

7 Conc. Hydrochloric acid 25.93 Carbon celite residue 11.89

8 Isopropyl alcohol 323.43

9 MDC 592.64

10 Water 400.56

11 Activated carbon 5.19

12 Celite 6.7

Total 1538.12 Total 1538.12

Sr

No Input (Kg)

Output (Kg)

Stage- II:

1 Stage-1 Product 63.45 Meloxicam 57.14

2 Methanol 276.01 Methanol recovery 262.14

Methanol loss 11.05

Waste water 9.13


102

30) Olanzapine

BRIEF PROCESS:

Charge Methyl piperazinyl Chloro-thieno benzodiazepine, N N DMA, catalyst heat

and reflux distilled out. Add Acetonitrile cool & filters dry in RCVD to get Olanzapine

Chemical Reaction:

Mass Balance:

Sr

No Input (Kg)

Output (Kg)

Stage- I:

1 Methyl piperazinyl 80.00 Olanzapine 75.00

2

Chloro-thieno

benzodiazepine

100.00 Aq. Effluent 280.00

3 N N DMA 400.00 Process loss 25.00

4 Catalyst 10.00 Solvent Recovery 510.00

5 Acetonitrile 300.00


103

31) Montekulast Sodium

BRIEF PROCESS:

Stage-I:

1-(Hydoxy methyl) cyclo propane Acetonitrile (MEC-4) is reacted with methane

sulfonyl chloride in presence of Diisoprpylethyl amine, and the product is further

treated with Thiol acetic acid to give MAN.

Stage-II:

Condensation of MAN and (2-(2-(3(S)-(3-(2-(7-Chloro-2-quinolinyl) ethenyl) phenyl-3-

(methane sulfonyloxy) propyl)-2-propanol) (QUID-8) in the presence with n-butyl

lithium in the presence of toluene and Dimethyl foramide which on further

hydrolysis with Caustic lye to give MOK-1 –Nitrile

Stage-III & IV:

MOK-1 Nitrile underwent sodium hydroxide hydrolysis in the presence of toluene to

give MOK-1. MOK-1 treated with t-butyl amine protection with acetone acid to give

MOK-2 butyl amine.

Stage- V:

MOK-2 t-butylamine on further treatment with caustic flakes to give sodium

Montelukast (MOK-3). On further carbon purification with methanol to give Pure

MK-3 salt (Montelukast Sodium).

Chemical Reaction:

Stage-I

Stage-II

Stage-III

104

Stage-IV

Stage-V

Mass Balance:

Sr

No Input (Kg)

Output (Kg)

Stage- I:

1 N-vinyl pyrolidone 108.1 Stage-I 96.5

2 Thiol acetic acid 74 Acetic acid 45.6

3 Di isopropyl ethylamine 6 Toluene recovered 1447.5

4 Toluene 1500 Toluene loss 7.5

5 Water 200 Toluene residue 45

6 Methane sulfonyl Chloride 15 N-vinyl pyrrolidone 23.7

Thiol acetic acid 16.3

Di isopropyl ethylamine 6

Methane sulfonyl chloride 15

Effluent 200


Sr

No Input (Kg)

Output (Kg)

Stage- II:

1 Stage-I 96.5 Stage-II 350.6

2 Thiophene-2-ethylamine 347.4

Water generated during

reaction 11.1

3 Toluene 2000 Toluene recovered 1940

4 Water 200 Toluene loss 10

5 Acetic acid 10 Toluene residue 50

6 Sodium chloride 50 Stage-I 17.9

105

7 Carbon 5 Thiophene-2-ethylamine 64.3

Acetic acid 10

Carbon 5

Sodium chloride 50

Water 200


Sr

No Input (Kg)

Output (Kg)

Stage- III:

1 Stage-II 350.6

Stage-III (Crude

Nateglinide Form H) 235.6

2 Sodium hydroxide 24.7 Sodium methoxide 21.7

3 Methanol 1219.8 Ammonia 6.8

4 Toluene 1700 Methanol recovered 1152

5 Water 200 Methanol loss 6

6 Acetic acid 30 Methanol wastewater 12

7 Sodium chloride 70 Methanol residue 30

8 HCl for NaOH neutralization 7.9 Toluene recovered 1632

Toluene loss 6.8

Toluene residue 61.2

Stage-II 122.7

Methanol 6.9

Acetic acid 30

Sodium hydroxide 8.7

Sodium chloride 70

Water 184

NaCl from NaOH

neutralization 12.7

Water from NaOH

neutralization 3.9

Total 3803 Total 3803

Sr

No Input (Kg)

Output (Kg)

Stage- IV:

1 Stage-III 235.6 Stage-IV 198.7

2 Tertiary butyl amine 29.4 Acetone recovered 1536

3 Acetone 1600 Acetone loss 7.2

4 Toluene 2000 Acetone residue 56.8

5 Carbon 5 Toluene recovered 1920

Toluene loss 10

Toluene residue 70

Stage-III 58.9

106

Tertiary butyl amine 7.4

Carbon 5

Total 3870 Total 3870

Sr

No Input (Kg)

Output (Kg)

Stage- V:

1 Stage-IV 198.7 Montekulast Sodium 150

2 Sodium hydroxide 62.1 Tert-butylamine 18

3 MDC 1800

Water generated during

reaction 4.4

4 Acetic acid 25 MDC recovered 1737

5 Water 200 MDC loss 9

6 Methanol 1000 MDC residue 54

7 Carbon 5 Methanol recovered 970

8 HCl for NaOH neutralization 47.6 Methanol loss 4

Methanol residue 26

Stage- IV 36.1

Acetic acid 25

Carbon 5

Sodium hydroxide 52.2

Water 247.9

NaCl from NaOH

neutralization 76.3

Water from NaOH

neutralization 23.5


107

32) Tamulosin HCl

BRIEF PROCESS:

Stage-1

(S)-5-(2-Amino propyl)-2-methoxy benzene sulfonamide is reacted with 2-(Oethoxy

phenoxy) ethyl bromide in presence of 50% sodium hydroxide solution and further

Hydrochloride salt formation with Ethanolic HCl gives Tamsulosin HCl.

Stage-2

Product is purified using Methanol and Ethanol

Chemical Reaction:

Mass Balance:

Sr

No Input (Kg)

Output (Kg)

Stage- I:

1

(S)-5-(2-aminopropyl)-2-

methoxybenzene

sulfonamide

8.68 Stage-I 15.82

2

2-(O-Ethoxy Phenoxy)ethyl

Bromide

12.74 Methanol Recovery 165.78

3 Methanol 173.88 Methanol Loss 7.0

4 n-Haxane 52.22 n-Hexane Recovery 49.56

5 50% lye Solution 5.60 n-Hexane Loss 2.66

6 Ethyl acetate 200.0 Ethyl acetate Recovery 189.90

108

7 Ethanol 104.3 Ethyl acetate Loss 9.75

8 Ethanolic HCl 17.36 Ethanol Recovery 114.64

9 DM Water 171.68 Ethanol Loss 5.18

Effluent 186.17


Sr

No Input (Kg)

Output (Kg)

Stage- II:

1 Stage-I 15.82 Tamsulosin HCl 14.28

2 Methanol 52.62 Methanol Recovery 48.85

3 Absolute ethanol 78.12 Methanol Loss 3.77

Ethanol Recovery 74.2

Ethanol Loss 5.46


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