LIST OF ANNEXURES S. No Content...

Additional Information SRR Laboratories

Prepared By Rightsource Industrial Solutions Pvt. Ltd

LIST OF ANNEXURES

S. No Content Annexure

1 List of Proposed Products & By-Products Annexure - I

2 Site Plan Annexure - II

3 Manufacturing Process Description Annexure - III

4 Water Consumption Details Annexure - IV

5 Solid & Hazardous Waste Generation And

Disposal Annexure -V

6 Stack Emission Details Annexure - VI

7 Process Emission Details Annexure -VII

8 List of Raw Materials Annexure - VIII

9 Waste water Details Annexure - IX

10 Consolidated Statement- Pollution Details Annexure –X



ANNEXURE – I

LIST OF PROPOSED PRODUCTS

S

No Product name

Quantity in

Tonne /

Month

CAS no Therapeutic

category

1 Carvedilol 10 72956-09-3 Antihypertensive

2 Cyano diol hydrochloride 5 717133-25-0 Drug

intermediate

3 Dabigatran 5 211915-06-9 Anticoagulant

4 Fexofenadine hydrochloride 10 153439-40-8 Anti allergic

5 Fluconazole 10 88386-73-4 Antifungal

6 Folic acid 20 59-50-3 Hematinic (Vit-B)

7 Itraconazole 10 84625-61-6 Antifungal

8 Ketoconazole 10 65277-42-1 Antifungal

9 Levocetirizine dihydrochloride 5 130018-77-8 Antihistamine

10 Linagliptin 5 668270-12-0 Anti diabetic

11 Meropenem 5 119478-56-7 Antibacterial

12 Montelukast sodium 2 151767-02-1 Anti asthmatic

13 Rosuvastatin calcium 2 147098-20-2 Anti lipemic

agent

14 Sitagliptin Phosphate Monohydrate 5 654671-77-9 Anti Diabetic

15 Teneligliptin 5 760937-92-6 Anti Diabetic

16 Tri butyl tin chloride 5 1461-22-9 Organic Reagent

17 Valacyclovir Hydrochloride

Monohydrate 10 124832-27-5 Anti Viral

18 Vildagliptin 5 274901-16-5 Anti diabetic

Total 129

LIST OF BY-PRODUCTS

S.

No

Name of the Product

Name of the By-Product

Quantity

in Kg/Day

1

Itraconazole

Hydrochloric acid(17%) 6228

Ketoconazole

Fluconazole

Folic Acid

Fexofenadine Hydrochloride

Linagliptin

Levocetirizine Dihydrochloride

Dabigartan

Tri Butyl Tin Chloride



S.

No

Name of the Product

Name of the By-Product

Quantity

in Kg/Day

Vildagliptin

Rosuvastatin Calcium

2

Itraconazole Hydrobromic acid(17%)

960

Ketoconazole

Linagliptin

Dabigartan

3

Fluconazole Aluminium chloride Solution

(Aluminum

hydroxide+water)(12%) 1652


4 Fluconazole Triethyl amine hydrochloride 313 Levocetirizine Dihydrochloride



ANNEXURE - II SITE PLAN



ANNEXURE - III

MANUFACTURING PROCESS DESCRIPTION

1.CARVEDILOL

Process Description:

Stage-1

Phenyl hydrazine Hydrochloride reacts with 1, 3-Cyclohexanedione in the presence

of Methanol to give Stage-1 product.

Stage-2

Stage-1 product undergoes dehydrogenation by using Raney nickel as catalyst in

presence of Methanol to give Stage-2 product.

Stage-3

Stage-2 product reacts with Epichlorohydrin and sodium hydroxide in the presence

of methanol to give Stage-3 product.

Stage-4

Stage-3 product reacts with 2-(2-Methoxyphenoxy) ethyl amine in the presence of

Iso propyl alcohol to give Carvedilol product.

CARVEDILOL

Route of Synthesis:

Stage-1

NH NH2

HCl

Phenyl hydrazine Hydrochloride

C6H8N2.HCl

144.60

+ OO

1,3-Cyclohexanedione

C6H8O2

112.13

MethanolNH

O

1,2,3,9-Tetrahydro-carbazol-4-one

C12H11NO

185.22+ H2O

+

18.02

NH4Cl

.

53.49



Stage-2

NH

O

1,2,3,9-Tetrahydro-carbazol-4-one

C12H11NO

185.22

NH

OH

4-Hydroxy carbazole

MethanolRaney Nickel

KOH

C12H9NO

183.21

+

56.11

+ HCl

36.46

+ KCl

74.55

+ H2O

18.02

+ H2

2.02

Stage-3

NH

OH

4-Hydroxy carbazole

C12H9NO

183.21

Epichlorohydrin

Cl O+

C3H5ClO

92.50

NH

O O

C15H13NO2

239.27

+ NaCl + H2O

58.44 18.02

Methanol+ NaOH

40.0

4-Oxiranylmethoxy-9H-carbazole



Stage-4

NH

O O

C15H13NO2

239.27

NH2OO+

C9H13NO2

167.21

NH

O NH

OH

O

H3CO

Carvedilol

C24H26N2O4

404.48

Iso propyl alcohol

4-Oxiranylmethoxy-9H-carbazole

2-(2-Methoxy-phenoxy)-ethylamine

CARVEDILOL

Flow Chart: Phenyl hydrazine Hydrochloride1,3-CyclohexanedioneMethanolActivated carbonWater

Stage-1 Methanol RecoveryEffluent water

Stage-2Methanol RecoveryEffluent water

Stage-1Raney nickelMethanolPotassium hydroxide Hydrochloric acid Water

Stage-3Methanol RecoveryAcetone RecoveryEthyl acetate Recovery

Stage-2AcetoneEpichlorohydrinSodium hydroxideMethanolEthyl acetateWater

Stage-4 IPA RecoveryEthyl acetate Recovery

Stage-3Isopropyl alcohol2-(2-Methoxy phenoxy) ethylamineEthyl acetate

CARVEDILOL



CARVEDILOL

Material Balance:

Material balance of Carvedilol Stage-1 Batch Size: 500.0.0 Kg

Name of the input Quantity in Kg

Name of the out put Quantity In Kg

Phenyl hydrazine Hydrochloride 209.00

Stage-1 260.00

1,3-Cyclohexanedione 162.00 Methanol Recovery 760.00

Methanol 800.00 Methanol Loss 16.00

Activated carbon 10.00 Effluent water 1103.35

Water 1000.00 (Water-1000 ,Ammonium chloride-77.30, Generated Water-26.05)

Spent carbon 10.00

Organic residue (process residue-7.65, Distillation Residue-24 (Methanol)

31.65

Total 2181 Total 2181

Material balance of Carvedilol Stage-2 Batch Size: 500.0.0 Kg



Stage-1 260.00 Stage-2 244.00

Raney nickel 15.00 Methanol Recovery 950.00


Potassium hydroxide 79.00 Effluent water 1129.95

Hydrochloric acid 52.00 (Water-1000,Potasium chloride-

104.65, Generated Water -25.3)

Water 1000.00 Raney nickel Recovery 15.00

Process emission

(Hydrogen) 2.83

Organic residue (process residue-14.22 Distillation Residue-30 (Methanol)

44.22


Material balance of Carvedilol



Stage-3 Batch Size: 500.0.0 Kg



Stage-2 244.00 Stage-3 305.00

Acetone 500.00 Methanol Recovery 950.00

Epichlorohydrin 124.00 Methanol Loss 20.00

Sodium hydroxide 54.00 Acetone Recovery 475.00

Methanol 1000.00 Acetone Loss 10.00

Ethyl acetate 700.00 Ethyl acetate Recovery 665.00

Water 1000.00 Ethyl acetate Loss 14.00

Effluent water (Water-1000, Generated water-23.98, Sodium chloride-77.85)

1101.83

Organic residue (process residue-15.17 Distillation Residue-66 (Methanol-30,Acetone-15, Ethylacetate-21)

81.17


Material balance of Carvedilol Stage-4 Batch Size:500.0 Kg



Stage-3 305.00 Carvedilol 500.00 Isopropyl alcohol 1000.00 Isopropyl alcohol Recovery 950.00 2-(2-Methoxy phenoxy) ethylamine

214.00 Isopropyl alcohol Loss 20.00

Ethyl acetate 1000.00 Ethyl acetate Recovery 950.00 Ethyl acetate Loss 20.00

Organic residue (process residue-19 Distillation Residue-60 (Isopropyl alcohol-30, Ethyl acetate-30)

79.00

Total 2519.00 Total 2519.00

2.CYANO DIOL HYDROCHLORIDE


Stage-1

5-Cyano pthalide undergoes condensation with P-Fluoromagnesium bromide and

Dimethyl amino magnesium chloride in presence of Toluene to give Stage-1 Product

Stage-2

Stage-1 Product reacts with Hydrochloric acid in presence of Toluene to give

Cyano Diol Hydrochloride product



Route of synthesis:

Stage-1:

NC

O

O

5-Cyano pthalide

C9H5NO2

159.14

+

P-Fluoromagnesium bromide

F

MgBr

199.30

Dimethyl amino magnesium chloride

NH3C

H3CMgCl

+

145.91

OH

OHN

CH3

CH3

F

342.41

+ Mg(Br)OH +

121.21

Mg(Cl)OH

76.76

C6H4BrFMg C5H12ClMgN

+ 2 H2O

36.04

Toluene

4-Dimethylamino-1-(4-fluoro-phenyl)-1-(2-hydroxymethyl-

Cyano phenyl)-butan-1-ol

C20H23FN2O2

Magnesium hydroxy bromide

Magnesium hydroxy chloride

NC

Stage-2:

OH

OHN

CH3

CH3

F

342.41

4-Dimethylamino-1-(4-fluoro-phenyl)-1-(2-hydroxymethyl-Cyano

phenyl)-butan-1-ol

C20H23FN2O2

NC

+ HCl

36.46

OH

OHN

CH3

CH3

F

NC

HCl

C20H23FN2O2.HCl

378.87

Toluene

Cyano Diol Hydrochloride



Flow chart:

Stage-1

Stage-2

5-Cyano pthalideP-Fluoromagnesium bromideDimethyl amino magnesium chlorideToluene Water

Toluene RecoveryEffluent Water

Stage-1 Hydrochloric acid Toluene Water


Cyano Diol Hydrochloride

Material Balance:

Material Balance of Cyano Diol Hydrochloride Stage-1 Batch Size: 100.0 Kg


Name of the out put Quantity in Kg

5-Cyano pthalide 42.00 Stage-1 85.00

P-Fluoromagnesium bromide 53.00 Toluene Recovery 190.00

Dimethyl amino magnesium chloride

39.00 Toluene Loss 4.00

Toluene 200.00 Effluent Water 342.72

Water 300.00 (Water-290.49, Magnesium hydroxybromide-31.98, Magnesium hydroxychloride-20.25)

Organic Residue (Process residue-6.28 Distillation Residue-6 (Toluene)

12.28

Total 634 Total 634



Material Balance of Cyano Diol Hydrochloride Stage-2 Batch Size: 100.0 Kg



Stage-1 85.00 Cyano Diol Hydrochloride 100.00

Hydrochloric acid 21.00 Toluene Recovery 190.00

Toluene 200.00 Toluene Loss 4.00

Water 300.00 Effluent Water 300.00

(Water-300)

Organic Residue (Process residue-6 Distillation Residue-6 (Toluene)

12.00

Total 606 Total 606

3. DABIGARTAN

Process Description

Stage-1

Pyridin-2-ylamine reacts with Ethyl acrylate, Ammonia and Hydrochloric acid in

presence of n-Hexane to give stage-1 product

Stage-2

Step-A

4-Chloro -3-nitro benzoic acid reacts with Methyl amine in presence of Isopropyl

Alcohol and Acetic to give step –A product

Step-B

Step-A product reacts with thinly chloride in presence of Methanol to give step-B of

stage of state-2 product

Stage-3

Stage-2 and Stage-1 condensed in presence of Tri ethyl amine, Toluene and Ethanol

to give stage-3product

Stage-4

Stage-3 product undergoes reduction with Iron powder in presence of Ammonium

formate, Toluene, Ethanol, Tetra hydro furan to give stage-3 product

Stage-5

4-Amino benzonitrile reacts with 2- Bromo acetic acid in presence of water to give

stage-5 product



Stage-6

Stage-4 product reacts with stage -5 products in presence of DiChloro methane and

ethyl acetate to give stage-6 product

Stage-7

Stage-6 product reacts with Ammonium carbonate in presence of Ethanol and

Isopropyl Alcohol give stage-7 product

Stage-8

Stage-7 product reacts with Hexylchloroformate in presence of potassium carbonate

and Tetra hydro furan to give Dibgatran product

DABIGARTAN

Route of Synthesis:

Stage-1

N NH2

Pyridin-2-ylamine

C5H6N2

94.11

+

Ethyl acrylate

O

O

C5H8O2

100.12

N NH

O

O

3-(Pyridin-2-ylamino)-propionic acid ethyl ester

C10H14N2O2

194.23

n-Hexane+ NH3

17.03

+ HCl

36.46

+ NH4Cl

53.49



Stage-2

Step-A

OH

O

O2N

Cl

4-Chloro-3-nitro-benzoic acid

C7H4ClNO4

201.56

+

Methyl Amine

H2N

CH5N

31.06

Acetic acid , Isopropylalcohol

OH

O

O2N

NH

4-Methylamino-3-nitro-benzoic acid

C8H8N2O4

196.16

+ HCl

36.46Water

Step-B

OH

O

O2N

NH

4-Methylamino-3-nitro-benzoic acid

C8H8N2O4

196.16

+ HCl

36.46+ SOCl2

118.97

Methanol

Cl

O

O2N

NH

C8H7ClN2O3

+

4-Methylamino-3-nitro-benzoyl chloride

214.61SO2

64.06



Stage-3

Toluene , Ethanol

Cl

O

O2N

NH

C8H7ClN2O3

+4-Methylamino-3-nitro-

benzoyl chloride

214.61

N NH

O

O

3-(Pyridin-2-ylamino)-propionic acid ethyl ester

C10H14N2O2

194.23

+

Triethylamine

N

C6H15N

101.19

O

O2N

NH N

N O

O

3-[(4-Methylamino-3-nitro-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester

C18H20N4O5

372.38

+

Triethylamine hydrochloride

N

C6H16NCl

137.65

. HCl

Stage-4

Ammonium formate Toluene , Ethanol ,Tetrahydrofuran & Water

O

O2N

NH N

N O

O

3-[(4-Methylamino-3-nitro-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester

C18H20N4O5

372.38

+ Fe

55.84

O

H2N

NH N

N O

O

C18H22N4O3

342.39

+

3-[(3-Amino-4-methylamino-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester

Fe

55.84

+ O2

32.00



Stage-5

4-Amino benzonitrile

N NH2

C7H6N2

118.14

2-bromoacetic acid

O

OHBr

+

C2H3BrO2

138.95

NHN

O

OH

Water

(4-Cyano-phenylamino)-acetic acid

C9H8N2O2

176.17

+ HBr

80.91

STAGE-6

Dichloromethane, Ethyl acetate

O

H2N

NH N

N O

O

C18H22N4O3

342.39

3-[(3-Amino-4-methylamino-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester

+N

HN

O

OH

(4-Cyano-phenylamino)-acetic acid

C9H8N2O2

176.17

N NH

O

N

N O

O

N

N

3-({2-[(4-Cyano-phenylamino)-methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}-pyridin-2-yl-amino)-propionic acid ethyl ester

C27H26N6O3

482.53

+ 2 H2O

36.03



Stage-7

N N O

O

O

N

N

HN

N N O

O

O

N

N

HN CN (NH4)2CO3

NH2

NH

C27H26N6O3

Mol. Wt.: 482.53

Ethyl 3-(2-((4-cyanophenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-

1H-benzo[d]imidazole-5-carboxamido)propanoate

C27H29N7O3

Mol. Wt.: 499.56

Ethyl 3-(2-((4-amidinophenylamino)methyl)-1-methyl-N-(pyridin-2-

yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate

CO2+

Ethano, IPA+

Ammonium carbonate

96.09

44.0

+ NH3

17.03

+ H2O

18.0



Stage-8

N N O

O

O

N

N

HNNH2

NH

N N O

O

O

N

N

HNN

NH2

O

O

Dabigatran

Hexyl chloroformate

499.56

O

O

Cl

+

164.63

C34H41N7O5

627.73

C7H13Cl O2

3-({2-[(4-Carbamimidoyl-phenylamino)-methyl]-1-methyl-1H-benzoimidazole-5-

carbonyl}-pyridin-2-yl-amino)-propionic acid ethyl ester

C27H29N7O3

THF

+ K2CO3

138.21

+ KCl

74.55

CHKO2

84.12

+

Potassium formate

+ 0.5 O2

16.00



Flow chart:

(pyridine-2-ylamine Ethyl acrylate Ammonia Hydrochloric acid n-Hexane Water

Stage-1

n-Hexane RecoveryEffluent water

Stage-2

Acetic acid RecoveryIsopropyl alcohol RecoveryMethanol RecoveryEffluent water

4-chloro-3-nitro-benzoic acid Methyl amine Acetic acid Isopropyl alcohol Thionyl chloride Methanol Water

Stage-3

Toluene RecoveryEthanol RecoveryEffluent water

Stage-1Stage-2Triethylamine Toluene Ethanol Water

Stage-4

Toluene RecoveryEthanol RecoveryTetra hydrofuran RecoveryEffluent water

Stage-3Iron Ammonium formate Toluene Ethanol Tetra hydrofuran Water



Dabigartan

Stage-5 Effluent water

4-amino benzonitrile 2-bromoacetic acid Water

Stage-4Stage-5Dichloromethane Ethyl acetate Water

Stage-6

Dichloromethane RecoveryEthyl acetate RecoveryEffluent water

Stage-6Ammonium carbonate Ethanol Isopropyl alcohol Water

Stage-7

Ethanol RecoveryIsopropyl alcohol RecoveryEffluent water

Stage-7Hexyl chloro formate Potassium carbonate Tetrahydrofuran Water

Stage-8

Tetrahydrofuran RecoveryEffluent water

Material balance:

Material balance of Dabigartan Stage-1 Batch Size: 100.0Kg



(pyridine-2-ylamine 23.00 Stage-1 45.00

Ethyl acrylate 25.00 n-Hexane Recovery 190.00

Ammonia 5.00 n-Hexane loss 4.00

Hydrochloric acid 9.00 Effluent water 313.10

n-Hexane 200.00 (Water-300 Ammonium chloride-13.10)

Water 300.00 Organic Residue 9.90

Process residue -3.9 Distillation Residue-6 (n-Hexane )

Total 562 Total 562






4-chloro-3-nitro-benzoic acid 55.00 Stage-2 49.00

Methyl amine 9.00 Acetic acid Recovery 190.00

Acetic acid 200.00 Acetic acid loss 4.00

Isopropyl alcohol 200.00 Isopropyl alcohol Recovery 190.00

Thionyl chloride 31.00 Isopropyl alcohol loss 4.00

Methanol 200.00 Methanol Recovery 190.00

Water 300.00 Methanol loss 4.00

Effluent water 306.00

(Water-300 Isopropyl alcohol -6)

By product (Hydrochloric acid-19.04)

19.04

Process emission (Sulphur dioxide-16.25,

16.25

Organic Residue 22.71

Process residue -10.71 Distillation Residue-12 (Methanol-6, Acetic acid-6 )

Total 995 Total 995




Stage-1 45.00 Stage-3 78.00

Stage-2 49.00 Toluene Recovery 190.00

Triethylamine 24.00 Toluene loss 4.00

Toluene 200.00 Ethanol Recovery 190.00

Ethanol 200.00 Ethanol loss 4.00

Water 300.00 Effluent water 337.45

(Water-300 Toluene -6, Triethylamine hydrochloride-31.45)


Process residue -8.55 Distillation Residue-6 (Ethanol -6)

Total 818 Total 818






Stage-3 78.00 Stage-4 68.00

Iron 12.00 Toluene Recovery 190.00

Ammonium formate 20.00 Toluene loss 4.00

Toluene 200.00 Ethanol Recovery 190.00

Ethanol 200.00 Ethanol loss 4.00

Tetra hydrofuran 200.00 Tetra hydrofuran Recovery 190.00

Water 300.00 Tetra hydrofuran loss 4.00


(Water-300 Toluene -6, Iron -11.70, Ammonium formate-20)

Process emission (oxygen)

6.70


Process residue -3.6 Distillation Residue-12 (Ethanol -6, Tetra hydrofuran-6)





4-amino benzonitrile 25.00 Stage-5 35.00

2-bromoacetic acid 30.00 Effluent water 300.00

Water 300.00 (Water-300)

Byproduct (Hydrobromic acid)

17.15


Total 355 Total 355




Stage-4 68.00 Stage-6 89.00

Stage-5 35.00 Dichloromethane Recovery 190.00

Dichloromethane 200.00 Dichloromethane loss 4.00


Water 300.00 Ethyl acetate loss 4.00




(Water-300 Ethyl acetate -6, Generated water -7.15


Process residue -6.85 Distillation Residue-6 (Dichloromethane -6)

Total 803 Total 803




Stage-6 89.00 Stage-7 87.00

Ammonium carbonate 18.00 Ethanol Recovery 190.00

Ethanol 200 Ethanol loss 4.00


Water 300.00 Isopropyl alcohol loss 4.00


(Water-300 Generated water -3.35)

Process emission (Carbon dioxide-8.10, Ammonia-3.13),

11.23


Process residue -5.52 Distillation Residue-12 (ethanol-6, Isopropyl alcohol-6 )

Total 807 Total 807




Stage-7 87.00 Dabigartan 100.00

Hexyl chloro formate 29.00 Tetrahydrofuran Recovery 190.00

Potassium carbonate 25.00 Tetrahydrofuran loss 4.00

Tetrahydrofuran 200.00 Effluent water 327.63

Water 300.00 (Water-300 , Potassium formate-14.65, potassium chloride-12.98)

Process emission (Oxygen)

2.78


Process residue -10.59 Distillation Residue-6 (THF )

Total 641 Total 641



4. FEXOFENADINE HYDROCHLORIDE


Stage-1

3-Chloro-2-methylprop-1-ene reacts with Sodium acetate in the presence of Dimethyl formamide to give Stage-1 product. Stage-2 Stage-1 product reacts with Aluminum chloride, Sodium hydroxide and Benzene in the presence of Toluene to give Stage-2 product. Stage-3 Stage-2 product reacts with 4-Chloro-butyryl chloride,in the presence of Dichloromehane to give Stage-3 product. Stage-4 Stage-3 product reacts with Sodium hydroxide in presence of Methanol to give Stage-4 product. Stage-5 Stage-4 product reacts with Hydrochloric acid and Potassium permanganate inpresence of water to give Stage-5 product. Stage-6 Stage-5 product reacts with Methanol and Hydrochloric acid in presence of Methanol to give Stage-6 product. Stage-7

Piperidine-4 -carboxylic acid reacts with Chloro benzene and Magnesium in

presence of THF and Toluene to give Azacyclonol.

Stage-8

Stage-6 product undergoes condensation with Stage-7 product in presence of

Sodium bicarbonate, Methyl isobutyl ketone and Ethyl acetate to give Stage-8

Product

Stage-9

Stage-8 product reduction with Sodiumborohydride, Sodium hydroxide and Acetic

acid Methanol to give Stage-9 product .

Stage-10

Stage-9 product undergoes condensation with Hydrochloric acid in presence of Iso

propyl alcohol to give Fexofenadine Hydrochloride .



FEXOFENADINE HYDROCHLORIDE

Route of Synthesis:

Stage-1:

CH3

H2C Cl + CH3COONa

+ NaCl

3-Chloro-2-methylprop-1-ene

2-methylprop-2-en-1-yl-acetate

90.55

C4H7Cl

82.03

C6H10O2

114.14

58.44

Dimethyl formamide

CH3

O

O

CH2

H3C

Stage-2:

2-methylprop-2-en-1-yl-acetate

C6H10O2

114.14

+ AlCl3

Benzene

C6H6

78.11

CH3

CH2OCOCH3H3C

C12H16O2

192.25

CH3

O

O

CH2

H3C

+

133.34

+ 3 H2O

54.05

Toluene

Acetic acid 2-methyl-2-phenyl-propyl ester

+ Al(OH)3

78.00

+ 3 HCl

109.38



Stage-3:

CH3

CH2OCOCH3H3C

C12H16O2

192.25

+Cl

Cl

O

H3C CH2OCOCH3

CH3

+ HCl

2-Methyl-2-phenylpropyl acetate

C4H6Cl2O

141.0

C16H21ClO3

296.79

36.46

4-Chloro-butyryl chloride

Dichloromethane

Cl

O

Acetic acid 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propyl ester

Stage-4:

H3C CH2OCOCH3

CH3

+

C16H21ClO3

296.79

Methanol

Cl

O

Acetic acid 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propyl ester

H3C CH2OH

CH3

NaOH

40.0

C14H18O2

+ NaCl

58.44

218.29

+ CH3COOH

60.0

O

Cyclopropyl-[4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-methanone



Stage-5:

+ HCl + KMnO4

MnO2 + KCl + H2O

86.9474.55 18.02

36.46 158.03

Water

H3C CH2OH

CH3

C14H18O2

218.29

O


+

H3C COOH

CH3

O


C14H16O3

232.28

Stage-6:

CH3OH + HCl

32.04 36.46

Methanol+

H3C COOH

CH3

O


C14H16O3

232.28

+

H3C COOCH3

CH3

O

Cl

2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid methyl ester

C15H19ClO3

282.76

H2O

18.02



Stage-7:

Piperidine-4-carboxylic acid

NH

O OH

Chloro benzene

Cl

+

2

+ Mg

HO

NH

2

+ MgCl2 + MgO

Azacyclonol Magnesium chloride

C6H11NO2C6H5Cl

C18H21NO

129.162X112.56=225.12

2X24.3=48.6

267.3695.21

40.30

THF, Toluene

Stage-8:

H3C COOCH3

CH3

O

Cl

2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid methyl ester

C15H19ClO3

282.76

+

Azacyclonol

C18H21NO

267.36

MIBK, Ethyl acetate+ NaHCO3

84.01

HN

OH

+ NaCl + CO2 + H2O

C33H39NO4

Mol. Wt.: 513.7

H3C

CH3

COOCH3

O

OH

2-(4-{4-[4-(Hydroxy-diphenyl-methyl)-piperidin-1-yl]-butyryl}-phenyl)-2-methyl

-propionic acid methyl ester

58.44 44.01 18.02



Stage-9:

+

Methanol

H3C

CH3

COOCH3

O

N

OH

C33H39NO4

Mol. Wt.: 513.7

H3C

CH3

COOH

O

N

OH

2-(4-{4-[4-(Hydroxy-diphenyl-methyl)-piperidin-1-yl]-butyryl}-phenyl)-2-methyl-

propionic acid methyl ester

37.83

+ NaOH

40.00

+ 2 CH3COOH

120.10

+ 3 H2O

54.05

2-(4-{4-[4-(Hydroxy-diphenyl-methyl)-piperidin-1-yl]-butyryl}-phenyl)-2-

methyl-propionic acid

C32H37NO4

499.64

+ H3BO3

61.83

+ 2 CH3COONa

164.07

+ CH3OH

32.04

+ 4 H2

8.00

NaBH4



Stage-10:

+ HCl

36.46

Iso propyl alcohol

.HCl


C32H38NO3ClMol. Wt.: 536.10

C32H37NO4

Mol. Wt.:499.64

H3C

CH3

COOH

O

N

OH

H3C

CH3

COOH

O

N

OH

2-(4-{4-[4-(Hydroxy-diphenyl-methyl)-piperidin-1-yl]-butyryl}-phenyl)-

2-methyl-propionic acid




Flow Chart:

Stage-1

Stage-2

Stage-3

3-Chloro-2-methylprop-1-eneSodium acetateDMFWater

DMF RecoveryEffluent water

Stage-1TolueneBenzeneAluminum chlorideWater

Toluene RecoveryEffluentb water

Stage-24-Chlorobutanoyl chlorideDichloromethane Sodium sulphateWater

Dichloromethane RecoveryEffluent water

Stage-4

Stage-5

Stage-3Sodium hydroxideMethanolWater

Stage-4Hydrochloric AcidPotassium permanganateWater

Methanol RecoveryEffluent Water

Effluent Water



Stage-6

Stage-7

Stage-8

THF RecoveryToluene RecoveryEffluent water

Ethyl Acetate RecoveryMIBK RecoveryEffluent water

Stage-9

Stage-10

Methanol RecoveryEffluent water

Isopropyl Alcohol Recovery

Stage-5MethanolHydrochloric AcidWater

Methanol RecoveryEffluent Water

Piperidine-4-carboxylic acidChloro benzeneMagnesiumTHFTolueneActivated CarbonWater

Stage-6Sodium BicarbonateStage-7Methyl isobutyl ketoneEthyl AcetateWater

Stage-8Sodium BorohydrideSodium HydroxideAcetic AcidActivated carbonMethanolWater

Stage-9Hydrochloric acidIsopropyl alcohol





Material Balance:

Material Balance of Fexofenadine Hydrochloride Stage-1 Batch Size: 500Kg



3-Chloro-2-methylprop-1-ene

108.00 Stage-1 131.00

Sodium acetate 98.00 DMF Recovery 475.00

DMF 500.00 DMF Loss 10.00


(Water-300, Sodium chloride-69.7 DMF-5)

Organic Residue Process residue-5.3 Distillation residue-10 (DMF)

15.30





Stage-1 131.00 Stage-2 215.00

Toluene 500.00 Toluene Recovery 475.00

Benzene 90.00 Toluene Loss 10.00

Aluminum chloride 153.00 By-Product

Aluminum chloride solution

(Aluminium hydroxide-89.5+Water-238)

Hydrochloric acid

327.50

125.52

Water 300.00 Organic Residue (process residue-5.98 Distillation residue-15 ( Toluene-15)

20.98





Stage-2 215.00 Stage-3 321.00

4-Chlorobutanoyl chloride 158.00 Dichloromethane Recovery 475.00



Dichloromethane 500.00 Dichloromethane Loss 10.00

Sodium sulphate 12.00 Effluent water 300.00


Inorganic solid waste (Sodium sulphate)

12.00

By product (Hydrochloric acid)

40.76

Organic Residue Process residue-11.24 Distillation Residue-15 (Dichloromethane)

26.24





Stage-3 321.00 Stage-4 232.00

Sodium hydroxide 40.00 Methanol Recovery 475.00



(Water-300,Acetic Acid-64.90 Sodium chloride-63.2)

Organic Residue (Process residue-0.9 Distillation residue-15 (Methanol)

15.90





Stage-4 232.00 Stage-5 239.00

Hydrochloric Acid 39.00 Effluent Water (Water-300, Potassium Chloride-79.25, generated water-19.15, Manganese dioxide-90.3)

488.70

Potassium permanganate 168.00


Total 739 Total 739






Stage-5 239.00 Stage-6 285.00


Hydrochloric Acid 38.00 Methanol Loss 10.00


(Water-300, generated water-18.55)

Organic Residue Process residue-6.45 Distillation Residue-15 (Methanol)

21.45





Piperidine-4-carboxylic acid

139.00 Azacyclonol (Stage-7) 269.00

Chloro benzene 234.00 THF Recovery 475.00

Magnesium 51.00 THF Loss 10.00

THF 500.00 Toluene Recovery 475.00


Activated Carbon 5.00 Effluent water 455.60

Water 300.00 (Water-300,Magnesium chloride-98.80,Magnesium oxide-41.80,THF-15

Spent Carbon 5.00

Organic Residue (Process residue-14.4 Distillation Residue-15 (Toluene)

29.40





Stage-6 285.00 Stage-8 505.00

Sodium Bicarbonate 85.00 Ethyl Acetate Recovery 760.00

Stage-7 269.00 Ethyl Acetate Loss 16.00

Methyl isobutyl ketone 600.00 MIBK Recovery 570.00



Ethyl Acetate 800.00 MIBK loss 12.00


(Water-300, Sodium Chloride-58.90 generated water-18.16, MIBk-18)

Process Emission 44.35

(Carbon dioxide)

Organic residue- (Process residue-12.59 Distillation Residue-24 (Ethyl acetate)

36.59





Stage-8 505.00 Stage-9 476.00

Sodium Borohydride 38.00 Methanol Recovery 760.00

Sodium Hydroxide 40.00 Methanol Loss 16.00

Acetic Acid 118.00 Effluent water 500.35

Activated carbon 5.00 (Water-446.85, Boric Acid-60.75, Sodium Acetate-161.25, Methanol-31.50)

Methanol 800.00 Spent Carbon 5.00

Water 300.00 Process Emissions 7.82

(Hydrogen)


40.83





Stage-9 476.00 Fexofenadine Hydrochloride 500.00

Hydrochloric acid 35.00 Isopropyl Alcohol Recovery 285.00

Isopropyl alcohol 300.00 Isopropyl Alcohol Loss 6.00

Organic Residue Process residue-11 Distillation Residue-9 (Isp propyl alcohol)

20.00

Total 811 Total 811



5.FLUCONAZOLE

Process Description

Stage-1

Step-A

1,3-Difluorobenzene reacts with Chloroacetyl Chloride in the presence of Aluminum

chloride and MDC to give step-A product .

Step-B

Step-A product reacts with 1,2,4-triazole in presence of Triethyl amine and

EthylAcetate to give DFTA(2,4-Difluoro-2-(1h- 1,2,4-Triazole-1-Yl)

Acetophenone)(Stage-1) product.

Stage-2

Stage-1 product reacts with Tri methyl sulfoxonium iodide in presence of potassium

hydroxide to give stage-4 product.

Stage-3

Stage-2 product reacts with 1, 2,4-triazole in presence of Potassium carbonate and

Toluene to get Fluconazole Technical product. Finally it is purified in Isopropyl

Alcohol pure Fluconazole

FLUCONAZOLE

Route of Synthesis:

Stage-1

Step-A

1,3-Difluorobenzene

F F +

Chloroacetyl chloride

O

ClCl

F F

Cl

O

2-Chloro-1-(2,4-difluorophenyl)ethanone

AlCl3

C6H4F2

114.09C2H2Cl2O

112.94

C8H5ClF2O

190.57

+

MDC+

133.34

+ 3H2O

54.06

Al(OH)3

78.00

4 HCl+

145.84



Step-B

F F

Cl

O

2-Chloro-1-(2,4-difluorophenyl)ethanone

C8H5ClF2O190.57

N

NN

F F

O

1,2,4-triazole

+

. HCl

C2H3N3

69.07

C10H7F2N3O

223.18

NH

NN

Triethylamine

(2,4-Difluoro-2-(1h- 1,2,4-Triazole-1-Yl) Acetophenone)

(DFTA)

Ethyl Acetate,N+

C6H15N

101.19

Triethylamine hydrochlordie

N+

C6H16NCl

137.65

Stage-2

1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)ethanone

N

NN

F F

O

C10H7F2N3O

223.18

+Trimethyl

sulfoxonium iodide

S+

O

H3C

CH3

CH3I-

+ KOH

1-[2-(2,4-di fluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-Triazole

N N

N

O

F F

C3H9IOS

220.07

56.11

C11H9F2N3O

237.21

+ (CH3)2SO + KI + H2O

Dimethyl Sulfoxide

78.13

166.0 18.02

Toluene



Stage-3

1-[2-(2,4-di fluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-Triazole

N N

N

O

F F

C11H9F2N3O

237.21

1,2,4-Triazole

NH

NN

C2H3N3

69.07

+ + K2CO3

OH

N

N

N

NN

N

F F

Fluconazole

C13H12F2N6O

306.27

138.21

+ 2 HCl

2X36.5=73.0

+ 2 KCl + H2O + CO2

149.10 18.0 44.0

DMF, IPA, Activated Carbon

FLUCONAZOLE

Flow Chart: 1,3 Difluoro benzeneChloro Acetyl chlorideAluminium ChlorideMDC1,2,4-triazoleTriethyl AmineEthyl AcetateIso propyl alcohol DM Water

Mixed Solvent(MDC + Ethyl acetate)Recovery

Stage-1Tri methyl Sulfoxonium iodidePotassium HydroxideTolueneWater


Stage-21,2,4-TriazolePotassium carbonateDMFHydrochloric AcidIPAActivated CarbonSodium sulphate DM Water

DMF RecoveryIPA RecoveryEffluent water

FLUCONAZOLE

Stage-1

Stage-2

Stage-3



FLUCONAZOLE

Material Balance:

Material Balance of Fluconazole

Stage-1 Batch Size: 100Kg



1,3 Difluoro benzene 60.00 Stage-1 80.00

Chloro Acetyl chloride 60.00 Mixed Solvent(MDC + Ethyl acetate)Recovery

352.00

Aluminium Chloride 72.00 MDC Loss 12.00

MDC 250.00 Iso propyl alcohol Recovery 114.00

1,2,4-triazole 32.00

Triethyl Amine 46.00 Iso propyl alcohol loss 2.40

Ethyl Acetate 120.00 Ethyl Acetate loss 6.00

Iso propyl alcohol 120.00 By-Products

Aluminium chloride Solution (Aluminium hydroxide-41 +Water-389)

Triethyl amine hydrochloride

Hydrochloric acid

430.00

78.00 76.68

DM Water 400.00 Organic Residue Process residue-5.32 Distillation residue -3.6 (IPA)

8.92

Total 1160.00 Total 1160.00



Name of the input Quantity

in Kg

Name of the out put Quantity

in Kg

Stage-1 80.00 Stage-2 85.00

Tri methyl Sulfoxonium iodide 80.00 Toluene Recovery 190.00

Potassium Hydroxide 20.00 Toluene Loss 4.00

Toluene 200.00 Effluent Water

(Water-400,

generated water-6.45,

Potassium iodide-59.5,

DMSO-28, Toluene-6) 499.95

Water 400.00

Organic Residue

Process residue-1.05

1.05

Total 780 Total 780






in Kg


in Kg

Stage-2 85.00 Fluconazole 100.00

1,2,4-Triazole 26.00 DMF Recovery 190.00

Potassium carbonate 49.00 DMF Loss 4.00

DMF 200.00 IPA Recovery 190.00

Hydrochloric Acid 26.00 IPA Loss 4.00

IPA 200.00 Effluent Water

(Water-400,generated water-6.45,

Potassium chloride-53.42, DMF-6,

IPA- 3) 468.87

Activated Carbon 10.00

Sodium sulphate 25.00 Spent Carbon 10.00

DM Water 400.00 Process Emission

(Carbon dioxide) 15.76

Inorganic solid waste

(Sodium sulphate) 25.00

Organic Residue

Process residue -10.37

Distillation residue – 3

(IPA) 13.37


6.FOLIC ACID

Process description:

Stage-1:

4-Nitro-benzoic acid undergoes chlorination with Thionyl chloride in presence of

Toluene , Sodium hydroxide and Dimethyl formamide to give Stage-1 product.

Stage-2:

Stage-1 product reacts with monosodium glutamate in presence of Sulfuric acid and

toluene to give Stage-2 product .

Stage-3:

Stage-2 product undergoes Hydrogenation with Hydrogen gas in presence of

palladium carbon and toluene to give Stage-3 product

Stage-4:

Acetone reacts with Chlorine gas in presence of Water to give Stage-4 product.

Stage-5:

Stage-4 product reacts with Stage-2 product in presence of acetic acid to give Folic

acid Product.



Route of Synthesis:

Stage-1:

COOH

NO2

4-Nitro-benzoic acid

C7H5NO4

167.12

+

Thionyl chloride

SOCl2

118.97

COCl

NO2

4-Nitro-benzoyl chlorideC7H4ClNO3

185.56

+ NaCl+ NaOH

40.058.44

+ H2O

18.02

+ SO2

64.06

DMF, Toluene

Stage-2:

COCl

NO2

4-Nitro-benzoyl chloride

C7H4ClNO3

185.56

+ HO

O O

ONaNH2

Monosodium glutamate

C5H8NNaO4

169.11

+ H2SO4

98.08

O2N

O

NH

COOH

COOHH

2-(4-Nitro-benzoylamino)-pentanedioic acid

C12H12N2O7

296.23

+ NaHSO4

120.06

+ HCl

36.46

Toluene

Stage-3:

O2N

O

NH

COOH

COOHH

2-(4-Nitro-benzoylamino)-pentanedioic acid

C12H12N2O7

296.23

+ H2H2N

O

NH

COOH

COOHH

2-(4-Amino-benzoylamino)-pentanedioic acid

C12H14N2O5

266.25

+ 2 H2O

36.0

3

6.0

Toluene



Stage-4:

H3C

O

CH3

Acetone

C3H6O

58.08

+ Cl23

Chlorine Gas

3X70.91=212.73

O

Cl

Cl Cl

1,1,3-Trichloro-propan-2-one

+ 3 HCl

3X36.5=109.5

161.41

C3H3Cl3O

Water

Stage-5:

H2N

O

NH

COOH

COOHH

2-(4-Amino-benzoylamino)-pentanedioic acid

C12H14N2O5

266.25

O

Cl

Cl Cl

1,1,3-Trichloro-propan-2-one

161.41

C3H3Cl3O

+ +

N

N

NH2

NH2

OH

H2N H2SO4

2,5,6-Triamino-4,5-dihydro-pyrimidin-4-ol;

compound with sulfuric acid

C4H11N5O5S

241.23

N

NH

N

NNH

H2N

NH

O

COOH

OH COOH

Folic acid

C19H19N7O6

441.41

+H2O

3X18=54

+SO2

64.06

+ HCl

3X36.5=109.5

3 3

Acetic acid



Flow Chart:

4-Nitro benzoic acidThionyl chlorideSodium hydroxideDimethyl formamideTolueneWater

Dimethyl Formamide RecoveryToluene RecoveryEffluent water

Stage-1

Toluene RecoveryEffluent WaterStage-2

Stage-1Monosodium glutamateSulfuric acidTolueneWater

Stage-2Catalyst(Iron Powder)Hydrogen GasTolueneSodium SulphateWater

AcetoneChlorine GasWater

Toluene RecoveryEffluent WaterStage-3

Effluent WaterStage-4

Acetic acid RecoveryEffluent WaterStage-5

Stage-3Stage-42,5,6-Triamino-4,5-dihydro-pyrimidin-4-ol ,Sulfuric acidAcetic acidWater

Folic Acid

Material Balance:

Material Balance of Folic Acid Stage-1 Batch Size: 200.0 Kg



4-Nitro benzoic acid 100.00 Stage-1 105.00

Thionyl chloride 71.25 Dimethyl Formamide Recovery 380.00

Sodium hydroxide 44.00 Dimethyl formamide Loss 8.00

Dimethyl formamide 400.00 Toluene Recovery 380.00





(Water-1000, Generated water-10.8, sodium chloride-34.97, Toluene-10 Dimethyl formamide-10, Sodium hydroxide-20)

Process emissions 38.35

(sulfur dioxide)

Organic residue 10.13

(Organic Impurities-6.13, Distillation residue-4 (DMF-2, Toluene -2)

Total 2015.25 Total 2015.25

Material Balance of Folic Acid

Stage-2 Batch Size: 200.0 Kg



Stage-1 105.00 Stage-2 153.00

Monosodium glutamate 96.00 Toluene Recovery 570.00

Sulfuric acid 56.00 Toluene Loss 12.00


Water 700.00 (Water-700, Sodium bisulfate-68, Toluene-10)

By -Product 20.65

(Hydrochloric acid )


(Organic Impurities-15.35, Distillation residue-8 (Toluene-8)






Stage-2 153.00 Stage-3 130.00

Catalyst(Iron Powder) 10.00 Toluene Recovery 760.00

Hydrogen Gas 4.00 Toluene Loss 16.00

Toluene 800.00 Spent Catalyst 10.00

Sodium Sulphate 15.00 Effluent Water 1032.00

Water 1000.00 (Water-1000, Generated Water-20, Toluene-12)

Inorganic solid waste 15.00



(Sodium sulphate)


Process residue-7 Distillation Residue 12 (Toluene-12)






Acetone 30.00 Stage-4 79.00

Chlorine Gas 110.00 Effluent Water 800.00


By -Product 56.60



Total 940 Total 940





Stage-3 130.00 Folic acid 200.00

Stage-4 79.00 Acetic acid Recovery 475.00

2,5,6-Triamino-4,5-dihydro-pyrimidin-4-ol ,Sulfuric acid

118.00 Acetic acid Loss 10.00

Acetic acid 500.00 Effluent Water 835.36

Water 800.00 (Water-800, generated water-26.36, Acetic acid-9)

By –Product (Hydrochloric acid -53.47)

53.47

Process emission 31.28

(Sulfur dioxide-31.28)


(Process residue-15.89, Distillation Residue-6 Acetic acid-6)




7.ITRACONAZOLE


Stage-1:

1-(4-Methoxyphenyl) Piperazine undergoes condensation with p-Nitro Chloro

Benzene to give Stage-1 compound in presence of Potassium Carbonate and DMF.

Stage-2:

Stage-1 Compound Hydrogenation with Hydrogen to give Stage-2 compound in

presence of Palladium on carbon and DMF

Stage-3:

Stage-2 Compound undergoes condensation with Phenyl Chloro formate to give

Stage-3 Compound in presence of Sodium bicarbonate and MDC

Stage-4:

Stage-3 Compound reacts with Hydrazine Hydrate to give Stage-4 Compound in

presence of 1,4-Dioxane

Stage-5:

Stage-4 Compound reacts with Formamidine and Acetic Acid to give Stage-5

Compound in presence of DMF

Stage-6:

Stage-5 Compound reacts with 2-Bromobutane to give Stage-6 Compound in

presence of Potassium carbonate, DMF and Methanol.

Stage-7:

Stage-6 Compound reacts with Hydro bromic acid to give Stage-7 compound in

presence of Sodium Carbonate and Methanol.

Stage-8(preparation of Cis –Bromo benzoate)

Step-A

2,4-Dichloroacetophenone undergoes condensation with Glycerol and Bromine to

give Step-A compound in presence of Para toluene sulfuric acid and n-Butanol

Step-B

Step-A compound undergoes condensation with Benzoyl chloride to give Cis –

Bromo benzoate(Stage-8) in presence of Toluene

Stage-9:

Stage-8 Compound reacts with 1,2,4-Triazole to give Stage-9 compound in

presence of Potassium carbonate ,Sodium hydroxide and DMF

Stage-10:

Stage-9 compound reacts with Methane sulfonyl chloride to give Stage-10

compound in presence of Triethylamine and MDC

Stage-11

Stage-10 compound reacts with Stage-7 compound to give Itraconazole in presence

of Potassium hydroxide and Methanol.



ITRACONAZOLE

Route of Synthesis:

Stage-1:

+

H3CO N N NO2

C11H16N2O

192.26

C6H4ClNO2

157.55

C17H19N3O3

313.35

+ 2 KCl + CO2 + H2O

149.10 44.01 18.02

HN N OCH3

1-(4-Methoxy-phenyl)-piperazine 1-Chloro-4-nitro-benzene

1-(4-Methoxy-phenyl)-4-(4-nitro-phenyl)-piperazine

Cl NO2 +DMF

WaterK2CO3

138.20

+ HCl

36.46

Stage-2:

H3CO N N NO2

C17H19N3O3

313.35

+ 3H2 pd/Catalyst

H3CO N N NH2

C17H21N3O

283.37

+ 2H2O

36.04

Hydrogen

6.05

DMF1-(4-Methoxy-phenyl)-4-(4-nitro-phenyl)-

piperazine

4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-phenylamine



Stage-3:

H3CO N N NH2

C17H21N3O

283.37

+OCl

O+ NaHCO3

Phenyl chloro formate

C7H5ClO2

156.57

84.01

H3CO N N NHCOOPh

C24H25N3O3

403.47

+ NaCl + CO2 + H2O

58.44 44.01 18.02

4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-phenylamine

{4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-phenyl}-carbamic acid phenyl ester

MDC

Stage-4:

H3CO N N NHCOOPh

C24H25N3O3

403.47

+ N2H4.H2O

Hydrazine hydrate

50.06

1,4-Dioxane

H3CO N N NHCONHNH2

C18H23N5O2

341.41

+

OH

Phenol

C6H6O

94.11

+ H2O

18.02

{4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-phenyl}-carbamic acid phenyl ester

1,3-Dimethyl-7-{2-[(1-phenyl-2-propanyl)amino]ethyl}-3,7-dihydro-1H-purine-2,6-dione



Stage-5:

H3CO N N NHCONHNH2

C18H23N5O2

341.41

+ H2N NH + 2CH3COOH

Formamidine

CH4N2

44.07

120.10

H3CO N N N

N

NH

O

C19H21N5O2

351.40

+

Ammonium acetate

2CH3COONH4

154.16

1,3-Dimethyl-7-{2-[(1-phenyl-2-propanyl)amino]ethyl}-3,7-dihydro-1H-purine-2,6-dione

2-{4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-phenyl}-2,4-dihydro-[1,2,4]triazol-3-one

Stage-6:

H3CO N N N

N

NH

O

C19H21N5O2

351.40

+ +

C4H9Br

137.02

69.10

Methanol

C23H29N5O2

407.51

+ KBr + 1/2CO2 + 1/2 H2O

119.0 22.0 9.01

2-{4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-phenyl}-2,4-dihydro-[1,2,4]triazol-3-one

H3CCH3

Br

2-Bromo-butane

1/2 K2CO3

H3CO N N NN

N

O

CH3

CH3

4-Isobutyl-2-{4-[4-(4-methoxy-phenyl)-piperazin-1-yl]-phenyl}-2,4-dihydro-[1,2,4]triazol-3-one



Stage-7:

H3CO N N N

N

N

O

CH3

CH3

C23H29N5O2

407.51

+ 2HBr + Na2CO3

Hydrobromic acid

161.82

106.0

+ CH3OH + 2NaBr +

Methanol

C22H27N5O2

393.48

32.04 205.79 44.01

4-Isobutyl-2-{4-[4-(4-methoxy-phenyl)-piperazin-1-yl]-phenyl}-2,4-dihydro-[1,2,4]triazol-3-one

HO N N NN

N

O

CH3

CH3

2-{4-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-phenyl}-4-isobutyl-2,4-dihydro-[1,2,4]triazol-3-one

CO2

Stage-8

Step-A

Cl Cl

CH3

O

2,4-Dichloro acetophenone

+

Glycerol

HO OH

OH

+ Br2

C8H6Cl2O

189.04

C3H8O3

92.09

159.81

PTSA

n-Butanol

Cl Cl

O

O

Br

OH

C11H11BrCl2O3

342.01

+ +HBr

80.91

H2O

18.02[2-Bromomethyl-2-(2,4-dichloro-

phenyl)-[1,3]dioxolan-4-yl]-methanol



Step-B

(Cis Bromo benzoate preparation)

Cl Cl

O

O

Br

OH

[2-Bromomethyl-2-(2,4-dichloro-phenyl)]-[1,3]dioxolan

-4-yl]-methanolC11H11BrCl2O3

342.01

+

Benzoyl chloride

O

Cl

C7H5ClO

140.57

Cl Cl

O

OOCOPh

Br

C18H15BrCl2O4

446.12

+

Benzoic acid 2-bromomethyl-2-(2,4-dichloro-phenyl)-[1,3]dioxolan

-4-ylmethyl ester

HCl

36.46

CIS-BROMO BENZOATE

Stage-9:

ClCl

O

O

Br

OOCC6H5

+ NN

HN

+ 1/2 K2CO3 + NaOHDMF

Water

Cis-bromo benzoate

C18H15BrCl2O4

446.12

1,2,4-Triazole

C2H3N3

69.1

Potassium carbonate

69.0

Sodium hydroxide

40.0

+

C13H13Cl2N3O3

330.17

COONa

Sodium benzoate

144.10

+ KBr + 1/2 CO2 +

119.0 22.0 9.01

O

OHO

NN

N

Cl Cl

[2-(2,4-Dichloro-phenyl)-2-[1,2,4]triazol-1-ylmethyl-[1,3]dioxolan-4-yl]-methanol

C7H5NaO2

1/2 H2O



Stage-10:

ClCl

O

O

N

HO

N

N

C13H13Cl2N3O3

330.17

+ CH3SO2Cl + (C2H5)3NMDC

Water

C14H15Cl2N3O5S

408.26

+ (C2H5)3N.HCl

Methane sulfonyl chloride

114.55

Triethyl amine

101.19

Triethyl amine hydrochloride

137.65

[2-(2,4-Dichloro-phenyl)-2-[1,2,4]triazol-1-ylmethyl-[1,3]dioxolan-4-yl]-methanol

ClCl

O

O

N

O3SH3C

N

N

1-[2-(2,4-Dichloro-phenyl)-4-ethyl-[1,3]dioxolan-2-ylmethyl]-1H-[1,2,4]triazole;



Stage-11:

ClCl

O

O

N

O3SH3C

N

N

C14H15Cl2N3O5S

408.26

C22H27N5O2

393.48

+ KOH

56.11

Potassium hydroxide

Methanol

CH3O2SOK + H2O

Methane sulfonate potassium

134.20

18.02

1-[2-(2,4-Dichloro-phenyl)-4-ethyl-[1,3]dioxolan

-2-ylmethyl]-1H-[1,2,4]triazole;(Stage-10)

+ HO N N NN

NO

CH3

CH3

2-{4-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-phenyl}-4-isobutyl-2,4-dihydro

-[1,2,4]triazol-3-one(Stage-7)

O N N NN

N

O

CH3

CH3Cl Cl

O

O

NN

N

+

C35H38Cl2N8O4

705.63

ITRACONAZOLE



ITRACONAZOLE

Flow-Chart:

1-(4-Methoxy phenyl ) Piperazine1-Chloro-4-Nitro-benzeneDMFHydrochloric acidPotassium Carbonate

Stage-1DMF RecoveryEffluent water

Stage-1Palladium CarbonDMFHydrogen Gas

Stage-2DMF RecoveryEffluent water

Stage-2Phenyl Chloro formateMethylene DichlorideSodium Bicarbonate

Stage-3MDC RecoveryEffluent water

Stage-3Hydrazine Hydrate1,4-Dioxane

Stage-4 1,4-Dioxane Recovery

Stage-4FormamidineDimethyl FormamideAcetic Acid

Stage-5 DMF RecoveryEffluent water



Stage-52-Bromo ButanePotassium CarbonateMethanolDimethyl Formamide

Stage-6DMF RecoveryMethanol Recovery

Stage-6Hydrogen BromideSodium CarbonateMethanol

Stage-7 Methanol Recovery

2,4 -DichloroacetophenoneGlycerolLiq Brominen-ButanolBenzoyl chlorideToluenep-Toluenesulfonic acid

Stage-8Toluene Recoveryn-Butanol recovery

Cis-Bromo Benzoate1,2,4-TriazoleSodium HydroxidePotassium CarbonateDimethyl Formamide

Stage-9 DMF Recovery

Stage-10

Stage-9Methane Sulfonyl ChlorideTriethylamineMethylene DichlorideIsopropyl Alcohol

MDC RecoveryIsopropyl Alcohol Recovery

Stage-11

Stage-7Stage-10Potassium HydroxideActivated CarbonDimethyl FormamideMethanol

DMF RecoveryMethanol Recovery

Itraconazole



Material Balance:

Material Balance of Itraconazole Stage-1 Batch Size:200.00Kg



1-(4-Methoxy phenyl ) Piperazine

57.00 Stage-1 92.00

1-Chloro-4-Nitro-benzene 46.30 DMF Recovery 95.00


Hydrochloric acid 10.70 Effluent Water (Water3, gen.Water-5.4 Potassium chloride-44.2)

349.60

Potassium Carbonate 40.60

Water 300.00 Process Emissions (Carbon Dioxide)

13.00

Total 554.60 Total 554.60

Material Balance of Itraconazole

Stage-2 Batch Size:200.00Kg


in Kg


in Kg

Stage-1 92.00 Stage-2 83.00

Palladium Carbon 5.00 DMF Recovery 95.00


Hydrogen Gas 1.80 Effluent Water

(Water-300,gen.Water-10.6)

310.60

Water 300.00

Spent Catalyst

(Palladium Carbon Reuse)

5.00

Organic Residue

Process residue-0.2

Distillation Residue-3

(DMF)

3.20





in Kg


in Kg

Stage-2 83.00 Stage-3 117.00

Phenyl Chloro formate 45.40 MDC Recovery 190.00

Methylene Dichloride 200.00 MDC Loss 10.00

Sodium Bicarbonate 24.40 Effluent Water 372.45



Water 350.00 (Water-350,

gen.Water-5.3,

Sodium chloride-17.15 )

Process Emissions

(Carbon Dioxide)

12.90

Organic Residue

(Process residue-0.45

0.45





in Kg


In Kg

Stage-3 117.00 Stage-4 99.00

Hydrazine Hydrate 14.55 1,4-Dioxane Recovery 190.00

1,4-Dioxane 200.00 1,4-Dioxane Loss 10.00

Water 300.00 Effluent Water

(Water-300, gen.Water-5.25)

305.25

Organic Residue

(process residue-27.3

(Phenol)

27.30





Stage-4 99.00 Stage-5 101.00

Formamidine 12.70 DMF Recovery 190.00

Dimethyl Formamide 200.00 DMF Loss 10.00

Acetic Acid 34.60 Effluent Water (Water-300, Ammonium acetate-44.70)

344.70

Water 300.00

Organic Residue Process residue-0.6

0.60







in Kg


in Kg

Stage-5 101.00 Stage-6 116.0

2-Bromo Butane 39.00 DMF Recovery 285.00

Potassium Carbonate 19.70 DMF Loss 6.00


Dimethyl Formamide 300.00 Methanol Loss 2.00


(Water-300, gen.Water-2.6,

Potassium bromide-34.2,

DMF-4)

340.80

Process Emissions

(Carbon Dioxide)

6.35

Organic Residue

(Process residue-0.55,


(Methanol-3, DMF-5)

8.55



Stage-6 116.00 Stage-7 112.00

Hydrobromic acid 46.10 Methanol Recovery 190.00

Sodium Carbonate 30.20 Methanol Loss 4.00

Methanol 200.00 Effluent Water (Water-300, Sodium bromide-58.60, Methanol-9.10)

367.70

Water 300.00

Process Emissions (Carbon Dioxide)

12.60

Organic residue Distillation Residue-6 (Methanol)

6.00


Material Balance of Itraconazole Stage-8(Cis –Bromobenzoate) Batch Size:200.00Kg

2,4 -Dichloroacetophenone 55.00 Stage-8 (Cis –Bromobenzoate) 128.00

Glycerol 26.70 n-Butanol Recovery 190.00

Liq Bromine 46.30 n-Butanol Loss 4.00

n-Butanol 200.00 Toluene Recovery 190.00



Benzoyl chloride 40.35 Toluene Loss 4.00

Toluene 200.00 By-Products (Hydrobromic acid-23.55, Hydrochloric acid -10.55, )

34.10

p-Toluenesulfonic acid 5.00

Water 300.00 Effluent water (Water-300, Generated water-5.25 p-Toluenesulfonic acid-5, n-Butanol-6)

316.25

Organic residue Process residue-1 Distillation Residue-6 (Toluene-6)

7.00

Total 1373.35 Total 1373.35



Name of the input Quantity in

Kg


in Kg

Cis-Bromo Benzoate 128.00 Stage-9 94.00

1,2,4-Triazole 19.70 DMF Recovery 95.00

Sodium Hydroxide 19.65 DMF Loss 2.00

Potassium Carbonate 11.40 Effluent Water

(Water-300, gen.Water-2.60

Potassium Bromide-34.15,

Sodium Benzoate-41.35)

378.10

Dimethyl Formamide 100.00

Water 300.00 Process Emissions

(Carbon dioxide)

6.35

Organic residue

Process residue-0.3


(DMF)

3.30







in Kg


in Kg

Stage-9 94.00 Stage-10 116.00

Methane Sulfonyl Chloride 32.55 MDC Recovery 190.00

Triethylamine 28.80 MDC Loss 4.00

Methylene Dichloride 200.00 Isopropyl Alcohol Recovery 190.00

Isopropyl Alcohol 200.00 Isopropyl Alcohol Loss 4.00


(Water-300,Triethylamine

Hydrochloride-39.20, Isopropyl

Alcohol-6)

345.20

Organic Residue



(MDC)

6.15





in Kg


in Kg

Stage-7 112.00 Itraconazole 200.00

Stage-10 116.00 Dimethyl Formamide Recovery 190.00

Potassium Hydroxide 16.00 Dimethyl Formamide Loss 4.00

Activated Carbon 8.00 Methanol Recovery 190.00

Dimethyl Formamide 200.00 Methanol Loss 4.00

Methanol 200.00 Effluent Water

(Water-300

gen.Water-5.15,

DMF-6,

Potassium Methane Sulfonate-

38.15)

349.30

Water 300.00

Spent Carbon 8.00

Organic residue



(Methanol-6)

6.70

Total 952 Total 952



8. KETOCONAZOLE


Stage-1 (Preparation of Cis – Bromo benzoate)

Step-A

2, 4-Dichloroacetophenone reacts with Glycerol and Bromine in presence of

toluene,n-butanol and PTSA to give step-A product.

Step-B

Step-A product reacts with benzoyl chloride in presence of toluene to give stage-1

cis bromo benzoate product.

Stage-2

Stage-1 reacts with 1H-Imidazole in presence of Sodium hydroxide, Methanol and

TBAB, DMF and toluene to give stage-2 product.

Stage-3

Stage-2 product reacts with p-Toluene Sulfonyl chloride in presence of sodium

carbonate, Activated carbon, Ethyl acetate and n-Hexane to give stage-3 product.

Stage-4

4-Chlorophenol undergoes condensation with Piperazine and Acetic acid in

presence of n-Butanol and Water to give stage-4 product.

Stage-5

Stage-5 compound undergoes condensation with Stgae-4 to give Ketoconazole in

presence of sodium methoxide, and Sodium hydroxide to give crude of

Ketoconazole. Further undergoes purification with Activated Carbon, Methanol and

Ethyl Acetate to give pure Ketoconazole



Route of Synthesis:

Stage-1(Preparation of Cis –Bromo benzene)

Step-A

Cl Cl

CH3

O

2,4-Dichloro acetophenone

+

Glycerol

HO OH

OH

+ Br2

C8H6Cl2O

189.04

C3H8O3

92.09

159.81

PTSA

n-Butanol

Cl Cl

O

O

Br

OH



342.01

+ +HBr

80.91

H2O

18.02

Step-B

Cl Cl

O

O

Br

OH



342.01

+

Benzoyl chloride

O

Cl

C7H5ClO

140.57

Cl Cl

O

OOCOPh

Br

C18H15BrCl2O4

446.12

+


-4-ylmethyl ester

HCl

36.46

CIS-BROMO BENZOATE



Stage-2

N

HN

+

1H-Imidazole

C3H4N2

68.08

+ NaOH

40.00

Cl Cl

O

OOH

N

N

H

C14H14Cl2N2O3

329.18

+

Cl Cl

O

OOCOPh

Br

C18H15BrCl2O4

446.12


-4-ylmethyl ester

OH

O

+

C7H6O2

122.12

Benzoic acid

NaBr

102.89Cis-2-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-yl methyl)-1,3-dioxolane-4-Methanol

TBAB

Methanol

CIS-BROMO BENZOATE



Stage-3

cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolane-4-methanol

O

O

N

N

Cl Cl

OH

para tolune sulfonyl chloride

S

O

O

ClH3C

Na2CO3+ +

(cis-Imidazole Alcohol)C14H14Cl2N2O3

329.18

C7H7ClO2S

190.65

O

O

N

N

Cl Cl

OS

O O

CH3

Toluene-4-sulfonic acid 2-(2,4-dichloro-phenyl)-2-imidazol-1-ylmethyl-[1,3]dioxolan-4-ylmethyl ester

cis-TosylateC21H20Cl2N2O5S

483.36

+ 2 NaCl + +

116.89

105.99

+ HCl

36.46

CO2

44.01

H2O

18.02

Stage-4

OH

Cl

4-Chloro-phenolC6H5ClO

128.56

+

HN NH

Piperazine

C4H10N2

86.14

+

H3C OH

O

Acetic acid

60.05

N N CH3

O

HO

1-Acetyl-4-(4-hydroxy phenyl)piperazine

C12H16N2O2

220.27

+ HCl + H2O

36.46 18.02



Stage-5

O

O

N

N

Cl Cl

OS

O O

CH3

Toluene-4-sulfonic acid 2-(2,4-dichloro-phenyl)-2-imidazol-1-ylmethyl-[1,3]dioxolan-4-ylmethyl ester

cis-Tosylate

C21H20Cl2N2O5S

483.36

+ CH3ONa + NaOH

1-Acetyl-4-(4-hydroxyphenyl)

piperazine

+

C12H16N2O2

220.27

54.02

CH3

ONNOO

O

NN

Cl

Cl + CH3OH

CH3

+

Ketoconazole

531.43

C26H28Cl2N4O4

Toluene

C7H7

91.13

32.04

+ Na2SO4

142.04

O CH3

OH

40.00



Flow Chart:

Stage-1

Stage-2

Stage-3

Stage-4

Stage-5

KETOCONAZOLE

2,4-Dichloro AcetophenoneGlycerolLiquid BromineBenzoyl chlorideMethanolToluene

Toluene RecMethanol RecEffluent water

Stage-1 (Cis -Bromo benzoate)ImidazoleSodium hydroxideMethanolTBAB

Methanol Rec

Stage-2(Cis-Imidazole alcohol)Para Toluene Sulfonyl ChlorideSodium CarbonateMethanolEthyl Acetate

Methanol RecEthyl acetate Rec

Stage-4Stage-3Sodium methoxideSodium hydroxideAcetoneMethanolEthyl Acetate

Methanol RecEthyl acetate RecAcetone Rec

4-ChlorophenolPiperazineAcetic acidn-Butanol

n-Butanol RecEffluent water

Material Balance:

Material Balance of Ketoconazole Stage-1(Cis –Bromo benzoate) Batch Size:100Kg



2,4-Dichloro Acetophenone 43.00 Stage-1(Cis –Bromo benzoate) 93.00

Glycerol 21.00 Mixed solvents (Methanol+Toluene )Recovery

570.00

Liquid Bromine 36.00 Methanol Loss 15.00

Benzoyl chloride 31.00 Toluene Loss 15.00



Methanol 300.00 n-Butanol Recovery 95.00

Toluene 300.00 n-Butanol Loss 2.00

ParaToluene Sulphonic acid 7.50 Effluent water 411.51

n-Butanol 100.00 (Water-400, Generated water-4.01, PTSA-7.5 )

Water 400.00 By-Products 25.87

(Hydrobromic acid-18.04, Hydrochloric acid-7.83)

Organic residue (Process rersidue-8.12 Distillation Residue-3 ( Butanol-3)

11.12


Material Balance of Ketoconazole

Stage-2 Batch Size:100Kg


in Kg


in Kg

Stage-1 (Cis –Bromo benzoate) 93.00 Stage-2(Cis-Imidazole alcohol) 66.00

Imidazole 15.00 Methanol Recovery 285.00

Sodium hydroxide 9.00 Methanol loss 6.00

Methanol 300.00 Effluent water 466.50

TBAB 20.00 (water-400,

Sodium bromide-21.26,

TBAB-20, Benzoic acid-25.24)

Water 400.00 Organic residue 13.50



(Methanol)

Total 837 Total 837

Material Balance of Ketoconazole Stage-3 Batch Size:100Kg



Stage-2(Cis-Imidazole alcohol)

66.00 Stage-3(Cis –Tosylate) 94.00

Para Toluene Sulfonyl Chloride

39.00 Methanol Recovery 190.00

Sodium Carbonate 22.00 Methanol Loss 10.00

Methanol 200.00 Methylene DichlorideRecovery 190.00



Methylene Dichloride 200.00 Methylene Dichloride Loss 10.00

Hydrochloric Acid 8.00 Ethyl Acetate Recovery 285.00

Ethyl Acetate 300.00 Ethyl Acetate loss 6.00

n-Hexane 300.00 n-Hexane Recovery 285.00

Activated Carbon 2.50 n-Hexane Loss 6.00

DM Water 400.00 Effluent Water 441.04

(Water-400, generated water-3.61, Sodium chloride-23.43,Ethyl acetate-9 Hexane-5)

Spent Carbon 2.50


(Carbon dioxide)

Organic residue (Process residue-5.14, Distillation Residue-4 ( Hexane-4)

9.14





4-Chlorophenol 26.00 Stage-4 43.00

Piperazine 18.00 n-Butanol Recovery 285.00

Acetic acid 12.00 n-Butanol Loss 6.00

n-Butanol 300.00 Effluent water 408.60

Water 400.00 (Water-400, Generated water-3.6, Butanol-5)

By-product 7.29

(Hydrochloric acid)

Organic residue Process Residue-2.11, Distillation Residue-4 (Butanol)

6.11

Total 756. Total 756




Stage-3 94.00 Ketoconazole 100.00

Stage-4 43.00 Acetone Recovery 285.00

Sodium methoxide 11.00 Acetone Loss 6.00


Acetone 300.00 Methanol Loss 5.00



Methanol 240.00 Ethyl Acetate Recovery 313.00

Ethyl Acetate 330.00 Ethyl Acetate Loss 7.00

Activated Carbon 3.00 Effluent Water 423.89

DM Water 400.00 (Water-400, Toluene-17.68, Methanol-6.21)


27.55

Spent Carbon 3.00

Organic Residue (Process residue-4.56 Distillation Residue-26 (Acetone-9,Methanol-7,Ethyl acetate-10)

30.56


9.LEVO CETIRIZINE DI HYDROCHLORIDE

Process Description

Stage-1

Step-A

P-Chlorobenzo phenone undergoes Amination with Ammonium formate in presence

of Toluene to give Step-A product.

Step-B

Step-A product undergoes salt formation with HCl inpresence of Methanol to give

Stage-1 Product..

Stage-2

Step-A

Stage-1product undergoes resolution with tartaric acid in presence of Sodium

hydroxide to give Step-A product

Step-B

Step-A product undergoes Hydrolysis with Sodium hydroxide in presence of

Methanol and HCl to give Stage-2 Product.

Stage-3

PTSC undergoes condensation with n,n-bis(2-chloroethyl)amine Hydrochloride in

presence of MDC and sodium htdroxide to give Stage-3 Product.

Stage-4

Stage-3 Product react with (L)-(4-chloro-phenyl)-c-phenyl-methylamine-1-methane

sulfonyl-4-methyl-benzene(2-ethyl-methyl-amine) in presence of methanol to give

Stage-4 Product.

Stage-5

Stage-4 product undergoes hydrolysis with HBr and Acetic Acid in presence of

Toluene to give Stage-5 product.

Stage-6

Stage-5 product reacts with Chloro ethanol in presence of Triethyl amine and

Toluene to give stage-6 product



Stage-7

Step-A

Stage-6 product undergoes condensation with Sodium monochloro acetate in

presence of DMF, Acetone and HCl to give Levocetrizine dihydrochloride crude.

Step-B

Levocetrizine dihydrochloride crude purified in Dichloromethane, Activated carbon &

Acetone to give Levocetrizine dihydrochloride

LEVOCETIRIZINE DIHYDROCHLORIDE Route of Synthesis:

Stage-1

Step-A

O

Cl

p-chloro benzophenone

Ammonium formate

63.06

+ Toluene Cl

NH2

C-(4-Chloro-phenyl)-C-phenyl-

methylamine

+ CO2 + H2O

44.00 18.02

NH4HCO2

C13H9ClO

216.66C13H12ClN

217.69

Step-B

Cl

NH2

+

C-(4-Chloro-phenyl)-C-phenyl-methylamine

HCl

36.46

MethanolCl

NH2

C-(4-Chloro-phenyl)-C-phenyl-methylamine Hydrochloride

HCl

C13H12ClN

217.69C13H13Cl2N

254.19

.



Stage-2(Resolution)

Step-A

Cl

NH2

C-(4-Chloro-phenyl)-C-phenyl-methylamine Hydrochloride

HCl

C13H13Cl2N

254.19 X 2=508.38

.

+

Tartaric acid

OH

OHO

OH

O

OH

C4H6O6

150.09

+ 2 NaOH

80.00

Cl

NH2 OH

OHO

OH

O

OH.

C-(4-Chloro-phenyl)-C-phenyl-methylamin 2,3-dihydroxy-succinic acid

C17H18ClNO6

367.78

+

Isomer

Cl

NH2

C13H12ClN

217.69

+ 2 NaCl

116.88

+ 2 H2O

36.02

2



Step-B (Hydrolysis)

Cl

NH2 OH

OHO

OH

O

OH.

C-(4-Chloro-phenyl)-C-phenyl-methylamin 2,3-dihydroxy-succinic acid

C17H18ClNO6

367.78

+

Cl

NH2

C13H12ClN

217.69

NaOH

40.00

+ HCl

36.46

C-(4-Chloro-phenyl)-C-phenyl-methylamine

OH

OHO

OH

O

OH

+

Tartric acid

C4H6O6

150.09

+ NaCl

58.44

+ H2O

18.02

Stage-3

para toluene sulphonyl chloride

n,n-bis( 2-chloro ethyl) amine

Hydrochloride

80.001-Methanesulfonyl-4-methyl-

benzene,(2-chloro-ethyl)-chloromethyl-

amine

CH3

SO2Cl +HN

Cl

ClHCl

+ 2NaOHMDC

CH3

SO2N

Cl

Cl

C11H15Cl2NO2S

296.21

+ 2NaCl

116.89

+ 2H2O

36.0

C7H7ClO2S

190.65

C4H10Cl3N

178.5



Stage-4

1-Methanesulfonyl-4-methyl-benzene,

(2-chloro-ethyl)-chloromethyl-amine

CH3

SO2 N

Cl

Cl

C11H15Cl2NO2S

296.21

Cl

NH2

+

(L)_(4-Chloro-phenyl)-C-phenyl-methylamine-1-methane sulfonyl

-4-methyl-benzene(2-ethyl-methyl-amine

C13H12ClN

217.69

N

Cl

N S

O

O

CH3

1-[(4-Chloro-phenyl)-phenyl-methyl]-4-(toluene-4-sulfonyl)-piperazine

+

C24H25ClN2O2S

440.99

MeOH

2HCl

72.92



Stage-5

N

Cl

N S

O

O

CH3

1-[(4-Chloro-phenyl)-phenyl-methyl]-4-(toluene-4-sulfonyl)-piperazine

C24H25ClN2O2S

440.99

+ HBr + CH3COOH

Hydrobromic acid

80.91

Acetic acid

60.05

N

HN

Cl

1-[(4-Chloro-phenyl)-phenyl-methyl]-piperazine

+ CH3COOBr +

SO2H

CH3

C17H19ClN2

286.80

Bromo acetate

138.95

pTSA

156.20

C7H8O2S



Stage-6

N

HN

Cl

1-[(4-Chloro-phenyl)-phenyl-methyl]-piperazine

C17H19ClN2

286.80

+

Chloro ethanol

C2H5ClO80.51

C19H23ClN2O

330.85

CH3

OH

Cl

1-{4-[(4-Chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethanol

CH3

NN

Cl

OH

+ HCl

+

Triethylamine

N

C6H15N

101.19

N .

Triethylamine Hydrogen chloride

C6H16ClN

137.65

Stage-7

C19H23ClN2O

330.85

1-{4-[(4-Chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethanol

CH3

NN

Cl

OH

Sodium monochloro acetate

Na+

O

O-Cl + 2HCl

DMF, MDC, Acetone, Activated Carbon ,

C2H2ClNaO2

116.48

Hydrochloric acid

2x36.46=72.92

NaCl

levocetirizine dihydrochlorideSodium chloride

58.44C21H25ClN2O3.2HCl

461.81

+

CH3

O

OO

N

N

Cl2 HCl

+



Flow Chart:

Stage - 1

Stage - 2

Stage - 3

Stage - 4

Stage - 5

p-chloro benzo phenoneAmmonium formateHydrochloric acidTolueneActivated carbonWater

Effluent waterToluene Recovery

Stage-1Sodium hydroxideTartaric acidMDCHydrochloric acidWater

MDC RecoveryEffluent Water

para toluene sulphonyl chloriden,n-bis( 2-chloro ethyl)amine HClSodium HydroxideMDCWater

MDC RecoveryEffluent Water

Stage-3Stage-2Ethyl di isopropyl amineMethanol

Methanol RecoveryEthyl di isopropyl amine Reuse

Stage-4Hydro bromic acidAcetic acidTolueneWater


Stage - 6

Stage-5Chloro ethanolTriethyl amineTolueneWater


Stage - 7

Stage-6Sodium mono chloro acetateHydrochloric acidDi methyl formamideMDCActivated CarbonAcetoneWater

MDC RecoveryAcetone RecoveryDMF RecoveryEffluent Water

LevocetirizineDi Hydrochloride



Material Balance:

Material balance of Levo Cetrizine di Hydrochloride



in kg


in Kg

p-chloro benzo phenone 125.00 Stage-1 136.00

Ammonium formate 37.00 Toluene Recovery 760.00

Hydrochloric acid 21.00 Toluene Loss 16.00


Activated carbon 5.00 (Water-400,


Toluene-12)

Water 400.00 Spent carbon 5.00

Process Emission 25.21

(Carbon dioxide)


(Process residue-11.47


(Toluene-12)

Total 1388.00 Total 1388.00

Material balance of Levocetirizine Dihydrochloride



in kg


in Kg

Stage-1 136.00 Stage-2 55.00

Sodium hydroxide 33.00 MDC Recovery 665.00

Tartaric acid 40.00 MDC Loss 14.00

MDC 700.00 Effluent Water 560.42

Hydrochloric acid 10.00 (Water-500,


Sodium Chloride-46.19)


(Process Residue-103.58

(Isomer-58, Tartaric acid-

38.74)


(MDC-21)

Total 1419.00 Total 1419.00






in kg


in Kg

para toluene sulphonyl chloride 50.00 Stage-3 74.00

n,n-bis( 2-chloro ethyl)

amine HCl

46.00 MDC Recovery 665.00

Sodium Hydroxide 21.00 MDC Loss 14.00

MDC 700.00 Effluent Water 439.37

Water 400.00 (Water-400,


Sodium chloride-30.1)


(Process Residue-3.63,


(MDC-21)

Total 1217.00 Total 1217.00




in kg


in Kg

Stage-3 74.00 Stage-4 107.00

Stage-2 55.00 Methanol Recovery 380.00

Ethyl di isopropyl amine 28.00 Methanol Loss 8.00

Methanol 400.00 Ethyl di isopropyl amine Reuse 28.00

By -product 18.24

(Hydrochloric acid)




(Methanol-12)





in kg


in Kg

Stage-4 107.00 Stage-5 67.00

Hydro bromic acid 20.00 Toluene Recovery 380.00



Acetic acid 15.00 Toluene Loss 8.00


Water 100.00

(Water-100,

Bromoacetate-33.46,

PTSA-37.61,Toluene-6)




(Toluene-6)





in kg


in Kg

Stage-5 67.00 Stage-6 74.00

Chloro ethanol 19.00 Toluene Recovery 380.00

Triethyl amine 24.00 Toluene Loss 8.00


Water 300.00 (Water-300,Toluene-6)

By –Products

(Triethyl amine hydrogen

chloride) 31.74




(Toluene-6)





in kg


in Kg

Stage-6 74.00 Levocetirizine Dihydrochloride 100.00

Sodium mono chloro acetate 26.00 MDC Recovery 237.00

Hydrochloric acid 17.00 MDC Loss 5.00

Di methyl formamide 100.00 Acetone Recovery 95.00

MDC 250.00 Acetone Loss 2.00

Activated Carbon 5.00 DMF Recovery 95.00

Acetone 100.00 DMF Loss 2.00




(Water-200,

Sodium chloride-13.04,

DMF-3)

Spent Carbon 5.00


Process Residue-3.96,


(MDC-8, Acetone-3

Total 772 Total 772

10. LINAGLIPTIN


Stage-1

8-Bromo-7-but-2-ynyl-3-methyl -3,7-dihydro-purine-2,6-dione reacts with 2-

(chloromethyl)-4-methyl quinazoline in presence of DMSO, water and Ethanol to give

Stage-1 Product.

Stage-2

Stage-1 Product reacts with Boc-3 Amino Piperidine in presence of DMSO, Iso

propyl ether and Ethyl acetate to give Stage-2 Product.

Stage-3:

Stage-2 Product undergoes Hydrolysis with water in presence of MDC, Methanol

and Ethanol to give Stage-3 Product.

Stage-4

Stage-3 Product undergoes Purification in Methanol ,IPA and Activated Carbon to

give Linagliptin.



LINAGLIPTIN

Route of Synthesis:

Stage-1

N

NN

HN

O

O

CH3

CH3

Br

N

N

CH3

Cl

2-(chloromethyl)-4-methyl quinazoline

N

NN

N

O

N

N

CH3 CH3

CH3

Br

8-bromo-7-(but-2-yn-1yl)-3-methyl-1-[(4-methyl quinazolin-2-yl)methyl]-3,4,5,7-

tetrahydro-1H-purine-2,6-dione

C20H19BrN6O2

455.31

O

DMSO ,Ethanol

8-Bromo-7-but-2-ynyl-3-methyl-3,7-dihydro-purine-2,6-dione

C10H9BrN4O2

297.11

+

C10H9ClN2

192.64

+ H2O

18.02

+ HCl

36.46

+ 0.5 O2

16.00



Stage-2

N

NN

N

O

N

N

CH3 CH3

CH3

Br

8-bromo-7-(but-2-yn-1yl)-3-methyl-1-[(4-methyl quinazolin-2-yl)methyl]-3,4,5,7-

tetrahydro-1H-purine-2,6-dione

C20H19BrN6O2

455.31

O

Boc-3-Amino piperidine

NHNH

O

O+

C10H20N2O2

200.28

N

NN

N

O

N

N

CH3 CH3

CH3O

HN

N

O

O

CH3

CH3

CH3

N-BOC-Linagliptin

C30H36N8O4

572.66

(R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate

+ HBr

80.91

+ H2

2.02

DMSO, Iso propyl ether, Ethyl acetate



Stage-3

N

NN

N

O

N

N

CH3 CH3

CH3O

HN

N

O

O

CH3

CH3

CH3

N-BOC-Linagliptin

C30H36N8O4

572.66

(R)-tert-butyl (1-(7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)carbamate

MDC, Methanol Ethanol

N

NN

N

O

N

N

CH3 CH3

CH3O

H2N

N

(R)-8-(3-aminopiperidin-1-yl)-7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)

-1H-purine-2,6(3H,7H)-dione

C25H28N8O2

472.54

O

O

CH3

CH3

CH3

HO

Carbonic acid mono-tert-butyl ester

+

C5H10O3

118.13

+ H2O

18.02

Stage-4:

N

NN

N

O

N

N

CH3 CH3

CH3O

H2N

N

(R)-8-(3-aminopiperidin-1-yl)-7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)

-1H-purine-2,6(3H,7H)-dione

C25H28N8O2

472.54

Methanol, IPA, Activated Carbon

N

NN

N

O

N

N

CH3 CH3

CH3O

H2N

N

Linagliptin

C25H28N8O2

472.54



LINAGLIPTIN

Flow chart:

8-Bromo-7-but-2-ynyl-3-methyl-3,7-dihydro-purine-2,6-dione2- Chloromethyl-4- methyl quinazolineDimethyl sulfoxideEthanolWater

Stage-1Boc-3- amino piperidineDimethyl sulfoxideIsopropyl etherEthyl acetateActivated carbonWater

Dimethyl sulfoxide RecoveryIsopropyl ether recoveryEthyl acetate recoveryEffluent water

Stage-2Sodium sulphateEthanolMethanolMethylene chlorideWater

Methylene chloride Recovery Ethanol RecoveryMethanol RecoveryEffluent water

Stage-1

Stage-2

Stage-3

Dimethy sulfoxide Recovery Ethanol RecoveryEffluent water

Stage-3Isopropyl AlcoholActivated CarbonMethanol

Isopropyl Alcohol RecoveryMethanol Recovery

Stage-4

Linagliptin



Material Balance:

Material balance of Linagliptin Stage-1 Batch size : 100kg


in kg


in kg

8-Bromo-7-but-2-ynyl-3-methyl-3,7-dihydro-purine-2,6-dione

72.00 Stage-I 107.00

2- Chloromethyl-4- methyl quinazoline

47.00 Dimethy sulfoxide Recovery 190.00

Dimethyl sulfoxide 200.00 Dimethy sulfoxide Loss 10.00

Ethanol 200.00 Ethanol Recovery 190.00

Water 300.00 Ethanol Loss 4.00

EffulentWater 295.64

(Water -295.64)

By- Product (Hydrochloric acid-8.83)

8.83


(Oxygen-3.87)


Process Residue-3.66 Distillation Residue-6 ( Ethanol-6)

Total 819 Total 819

Material balance of Linagliptin

Stage-2 Batch size : 100kg


in kg


in kg

Stage-1 107.00 Stage-2 130.00

Boc-3- amino piperidine 47.00 Dimethyl sulfoxide Recovery 190.00

Dimethyl sulfoxide 200.00 Dimethyl sulfoxide loss 10.00

Isopropyl ether 200.00 Isopropyl ether recovery 190.00

Ethyl acetate 200.00 Isopropyl ether loss 10.00

Activated carbon 5.00 Ethyl acetate recovery 190.00

Water 300.00 Ethyl acetate loss 4.00

Effluent water

(Water-300)

300.00

By –product

(Hydrobromic acid-19.01)

19.01

Spent Carbon 5.00




(Hydrogen-0.47)


Process Residue-4.52,


(Ethyl acetate-6)





in kg


in kg

Stage-2 130.00 Stage-3 104.00

Sodium sulphate 25.00 Methylene chloride Recovery 190.00

Ethanol 200.00 Methylene chloride Loss 10.00

Methanol 200.00 Ethanol Recovery 190.00

Methylene chloride 200.00 Ethanol Loss 10.00

Water 300.00 Methanol Recovery 190.00

Methanol Loss 10.00


(Water-295.9, Carbonic

acidmono-tert-butylester-26.82)


(Sodium sulphate)






in kg


in kg

Stage-3 104.00 Linagliptin 100.00

Isopropyl Alcohol 300.00 Isopropyl Alcohol Recovery 285.00

Activated Carbon 5.00 Isopropyl Alcohol Loss 6.00


Methanol Loss 6.00

Spent Carbon 5.00


Process Residue-4,




(Methanol-9,IPA-9)

Total 709 Total 709

11. MEROPENEM


Stage-1

3-(Diphenoxy-phosphoroloxy)-6-(1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicycle[3.2.0 ] hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester reacts with 2- Dimethylcarbamoyl-4-mercapto-pyrrolidine-1-carboxylic acid 4-nitro-benzyl ester in presence of Sodium Hydroxide, TEA and MDC to give stage-1 product.

Stage-2

Stage-1 product undergoes Hydrogenation with Hydrogen in presence of Palladium

carbon , Iso propyl alcohol , n-Hexane and Ethyl acetate to give Meropenem.



Route of Synthesis:

Stage-1

O

O

N

NO2

O

H3C

OH

H HCH3

O P

O

OPh

OPh

3-(Diphenoxy-phosphoryloxy)-6-(1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-

carboxylic acid 4-nitro-benzyl ester

C29H27N2O10P

594.51

+

ON

OMe2N

SH

O

NO2

2-Dimethylcarbamoyl-4-mercapto-pyrrolidine-1-carboxylic acid

4-nitro-benzyl ester

C15H19N3O5S

353.39

+

Triethylamine

N

C6H15N

101.19

NaOH

40.00

+ 2 HCl

72.92

O

O

N

NO2

O

H3C

OHH H CH3

S

+

O

N

O

Me2N

O NO2

3-[5-Dimethylcarbamoyl-1-(4-nitro-benzyloxycarbonyl)-pyrrolidin-

3-ylsulfanyl]-6-(1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]

hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester

C32H35N5O11S

697.71

HO P

O

OPh

OPh

Phosphoric acid diphenyl ester

+

C12H11O4P

250.19

+

137.65

+ NaCl

58.44

+ H2O

18.02Triethyl amine Hydrochloride

Acetonitrile , Dichloromethane

N HCl



Stage-2

O

O

N

NO2

O

H3C

OHH H CH3

S

O

N

O

Me2N

O NO2

3-[5-Dimethylcarbamoyl-1-(4-nitro-benzyloxycarbonyl)-pyrrolidin-3-yl

sulfonyl]-6-(1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]

hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester

C32H35N5O11S

697.71

Ethyl acetate,Pd/C, Iso propyl alcohol

& n-Hexane

OH

O

N

O

H3C

OH

H HCH3

S NH

O

Me2N CH3

NO2

O

O NO2H

1-Methyl-4-nitro-benzeneMeropenem

C17H25N3O5S

383.46

+

C8H7NO4

181.15

+

C7H7NO2

137.14

Formic acid 4-nitro-benzyl ester

+ 2 H2

4.03



Flow Chart:

3-(Diphenoxy-phosphoryloxy)-6- (1-hydroxy-ethyl)-4-methyl-7-oxo- 1-aza-bicyclo[3.2.0]hept-2-ene-2- carboxylic acid 4-nitro-benzyl ester2-Dimethylcarbamoyl-4-mercapto- pyrrolidine-1-carboxylic acid 4-nitro-benzyl esterTriethyl amineSodium hydroxide Hydrochloric acid Acetonitrile Dichloromethane Water

Stage-1

Stage-2

Acetonitrile RecoveryDichloromethane RecoveryEffluent Water

Stage-1Hydrogen Ethyl acetate Iso propyl alcohol n-Hexane Palladium on carbon Water

Ethyl acetate RecoveryIso propyl alcohol Recoveryn-Hexane RecoveryPalladium on carbon Recovery Effluent Water

Meropenem

Material balance:

Material Balance of Meropenem Stage-1 Batch Size: 250Kg



3-(Diphenoxy-phosphoryloxy)-6- (1-hydroxy-ethyl)-4-methyl-7-oxo- 1-aza-bicyclo[3.2.0]hept-2-ene-2- carboxylic acid 4-nitro-benzyl ester

430.00 Stage-I 479.00

2-Dimethylcarbamoyl-4-mercapto- pyrrolidine-1-carboxylic acid 4-nitro-benzyl ester

256.00 Acetonitrile Recovery 475.00

Triethyl amine 74.00 Acetonitrile Loss 10.00

Sodium hydroxide 29.00 Dichloromethane Recovery 475.00

Hydrochloric acid 53.00 Dichloromethane Loss 10.00

Acetonitrile 500.00 Effluent Water 570.29



Dichloromethane 500.00 (Water-500,Sodium chloride-42.26, Generated water-13.03, Acetonitrie-15)

Water 500.00 Organic Solid Waste (Process residue-307.71 Phosphoric acid diphenyl ester-180.95, triethylaminehydrochloride-99.56, Organic impurities-27.2) ]Distillation Residue-15 (Dichloromethan-15)

322.71


Material Balance of Meropenem Stage-2 Batch Size: 250Kg



Stage-1 479.00 Meropenem 250.00

Hydrogen 3.00 Ethyl acetate Recovery 570.00

Ethyl acetate 600.00 Ethyl acetate Loss 12.00

Iso propyl alcohol 500.00 Iso propyl alcohol Recovery 475.00

n-Hexane 500.00 Iso propyl alcohol Loss 10.00

Palladium on carbon 10.00 n-Hexane Recovery 475.00

Water 500.00 n-Hexane Loss 10.00

Palladium on carbon Recovery 10.00

Effluent Water (Water-500, n-Hexane-15)

515.00

Organic Solid Waste (Process residue-232 Formic acid 4-nitrobenzyl ester -124.36, 1-methyl 4-nitro-benzene-94.15, Organic impurities-13.49) Distillation Residue-33 (Ethyl acetate-18, Iso propyl alcohol-15)

265.00




12.MONTELUKAST SODIUM


Stage-1

Step-A

1-{3-[2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]

propan-1-ol reacts with Methane sulfonyl chloride and Diisopropylethylamine in

presence of Toluene & n-Hexane to give Step-A product.

Step-B

Step-A reacts with (1-Mercaptomethyl cyclopropyl)acetic acid and Tert Butylamine in

presence of Toluene & n-Hexane to give Stage-1 product.

Stage-2

Stage -1 product undergoes reacts with Acetic acid in presence of Methanol & MDC

to give Stage-2 product.

Stage-3

Stage-2 product reacts with Sodium hydroxide in presence of Methanol to give

Montelukast sodium product.

Route of Synthesis:

Stage-1:

Step-A

NCl

OH

H3C

OHH3C

1-{3-[2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(1-hydroxy-1-methyl-

ethyl)-phenyl]-propan-1-ol

C29H28ClNO2

457.99

+


CH3SO2Cl +

Diisopropylethyl amine

N

CH3

CH3H3C

CH3

114.55C8H19N

129.24

NCl

O

H3C

OHH3C

SO O

CH3

C30H30ClNO4S

536.08

Methanesulfonic acid 1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(1-hydroxy-1-methyl-

ethyl)-phenyl]-propyl ester

+

Diisopropylamine Hydrochloride

HCl

C8H19N.HCl

165.70

Toluene & n-Hexane

CH3

N

CH3

CH2H3C

CH3

CH3



Step-B

+

H3CH3C

H3C

NH2

tert-Butylamine

C4H11N

73.14

NCl

O

H3C

OHH3C

SO O

CH3

C30H30ClNO4S

536.08

Methanesulfonic acid 1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(1-hydroxy

-1-methyl-ethyl)-phenyl]-propyl ester

+

(1-Mercaptomethyl cyclopropyl)acetic acid

HOOC

HS

C6H10O2S

146.20

NCl

S

H3C

OHH3C

COOH

CH3SO3Na

+

C39H47ClN2O3S

659.32

Toluene & n-Hexane

(1-{1-{3-[2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-propylsulfanylmethyl}-

cyclopropyl)-acetic acid

+ CH3ONa

54.02

Sodium Methane Sulfonate

118.09

+CH3OH

32.04

H3CH3C

H3C

NH2

Na+

SO O

O-



Stage-2:

NCl

S

H3C

OHH3C

COOH

C39H47ClN2O3S

659.32

(1-{1-{3-[2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-propylsulfanylmethyl}-cyclopropyl)-

acetic acid

H3C

H3C

H3C

NH2

+ H3C OH

O

Acetic acid

60.05

Methanol

MDC

H3C

H3C

H3C

NH2H3C OH

ONCl

S

H3C

OHH3C

COOH



C35H36ClNO3S

586.18

133.19

Tert Butylamine salt of Acetic acid

+



Stage-3:

NCl

S

H3C

OHH3C

COOH



C35H36ClNO3S

586.18

+ NaOH

40.00

Methanol

NCl

S

H3C

OHH3C

COONa

C35H35ClNNaO3S

608.17

Montelukast Sodium

+ H2O

18.00



MONTELUKAST SODIUM

Flow Chart:

Stage-1

1-{3-[2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-propan-1-ol TolueneMethane sulfonyl chlorideDiisopropyl ethyl amineSodium methoxide Tert . butyl amine (1-Mercaptomethyl cyclopropyl)acetic acid n-Hexane Water

n-Hexane RecoveryToluene RecoveryEffluent water

MONTELUKAST SODIUM

Stage-3Stage-2MethanolSodium hydroxideActivated carbonn-HeptaneWater

Methanol Recoveryn-Heptane RecoveryEffluent water

Stage-2Stage-1DichloromethaneAcetic acidMethanolActivated carbonWater

Dichloromethane RecoveryMethanol RecoveryEffluent water

Material Balance:

Material balance of Montelukast sodium Stage-1 Batch Size: 100.0Kg



1-{3-[2-(7-Chloro-quinolin-2-yl)-

vinyl]-phenyl}-3-[2-(1-hydroxy-1-

methyl-ethyl)-phenyl]-propan-1-ol

(MON10)

90.00 Stage-1 119.00

Toluene 500.00 n-Hexane Recovery 285.00

Methane sulfonyl chloride 23.00 n-Hexane Loss 6.00

Diisopropyl ethyl amine 26.00 Toluene Recovery 475.00

Sodium methoxide 10.50 Toluene Loss 10.00

Tert . butyl amine 14.00 Effluent water

(Water-500,Diisopropylamine hydrochloride-32.55, n-Hexane-9,

584.82



Toluene-15, Sodium methane sulfonate -22.25, Methanol-6.02)

(1-Mercaptomethyl

cyclopropyl)acetic acid

28.00 Organic residue 11.68

n-Hexane 300.00

Water 500.00


Material balance of Montelukast sodium Stage-2 Batch Size: 100.0Kg



Stage-1 119.00 Stage-2 101.00

Dichloromethane 500.00 Dichloromethane Recovery 475.00

Acetic acid 11.00 Dichloromethane Loss 10.00


Activated carbon 5.00 Methanol Loss 10.00


(Water-500,Tert butylamine salt of acetic acid-24.03)

Spent carbon 5.00


Process residue-4.97 Distillation Residue-30 (Methanol-15, Dichloromethane-15)


Material balance of Montelukast sodium Stage-3 Batch Size:100.0Kg



Stage-2 101.00 Montelukast sodium 100.00


Sodium hydroxide 7.00 Methanol Loss 6.00

Activated carbon 3.00 n-Heptane Recovery 285.00

n-Heptane 300.00 n-Heptane Loss 6.00

Water 500.00 Effluent water (Water-500, Generated water-3.10)

503.10

Spent carbon 3.00


Process residue-4.9 Distillation residue-18 (Methanol-9, n-Heptane-9)




13.ROSUVASTATIN CALCIUM

Process Description

Stage-1

4-Fluoro-Benzadehyde reacts with 4-Methyl-3-oxo-pentanoic acid ethyl ester,

Potassium hydroxide in presence of Methanol to give Stage-1 product.

Stage-2

Stage-1 product reacts with S-Methyl iso thio urea and 2, 3Dichloro-5, 6-dicyano benzo quinone in presence of HMPA and MDC to give stage-2 product. Stage-3 Stage-2 product reacts with meta-chloro peroxy benzoic acid in presence of MDC to give Stage-3 as product. Stage-4 Stage-3 product reacts with methyl amine in presence of Ethanol and Methanol to give Stage-4 product. Stage-5 Stage-4 product reacts with Methane sulfonyl chloride in presence of Dimethoxy ethane to give Stage-5 product. Stage-6 Stage-5 product undergoes reduction with Diisobutylaluminium in presence of Toluene to give Stage-6 product. Stage-7 Stage-6 product reacts with methyl (3R)-3-(ert-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidene hexanoate in presence of DMF to give Stage-7 product Stage-8 Stage-7 product reacts with Hydrogen fluoride in presence of THF and Ethyl acetate to give Stage-8 as product. Stage-9 Stage-8 product undergoes reduction with Hydrogen in presence of Sodium Boro hydride, THF and Dimethoxy borene to give Sage-9 product. Stage-10

Stage-9 product reacts with Calcium chloride undergoes saponification in presence

of Toluene and Ethyl acetate to give Rosuvastatin Calcium as product.



ROSUVASTATIN CALCIUM Route of Synthesis:

Stage-1

F

CHO

4-Fluoro-benzaldehyde

+

4-Methyl-3-oxo-pentanoic acid ethyl ester

FCOOC2H5

CH3

O

H2O

2-(4-Fluoro-benzylidene)-4-methyl-3-oxo-pentanoic acid ethyl ester

C7H5F0

124.11

C8H14O3

158.19

C15H17FO3

264.29

18.0

C CH2

O

CHH3C

H3CCOOC2H5

CH3

MeOH

+

Stage-2

FCOOC2H5

CH3

O

2-(4-Fluoro-benzylidene)-4-methyl-3-oxo-pentanoic acid ethyl ester

C15H17FO3

264.29

S-methylisothiourea

NH

SH2NCH3

+

2,3-Dichloro-5,6-dicyano-p-benzoquinone

O

O

Cl

Cl

NC

NC

+

FCOOC2H5

N N

CH3

CH3

SCH3

OH

OH

Cl

Cl

NC

NC

4-(4-Fluoro-phenyl)-6-isopropyl-2-methylsulfanyl-pyrimidine

-5-carboxylic acid ethyl ester

HMPA

+

C2H6N2S

90.15

C8Cl2N2O2

227.0

C17H19FN2O2S

334.41

2,3-Dichloro-5,6-dicyano-p-benzoquinol

+ H2O

C8H2Cl2N2O2

229.02

18.0

CH3

MDC



Stage-3

FCOOC2H5

N N

CH3

CH3

SCH3

4-(4-Fluoro-phenyl)-6-isopropyl-2-methylsulfanyl-pyrimidine

-5-carboxylic acid ethyl ester

C17H19FN2O2S

334.41

FCOOC2H5

N N

CH3

CH3

SO2CH3

meta-Chloroperoxybenzoic acid

O

O

OH

Cl

+

+

meta-Chlorobenzoic acid

O

HO

Cl

4-(4-Fluoro-phenyl)-6-isopropyl-2-methanesulfonyl-pyrimidine-5

-carboxylic acid ethyl ester

C17H19FN2O4S

366.41

2

C7H5ClO2

2x156.57=313.14

C7H5ClO3

2

2x172.57=345.14

MDC



Stage-4

FCOOC2H5

N N

CH3

CH3

SO2CH3

4-(4-Fluoro-phenyl)-6-isopropyl-2-methanesulfonyl-pyrimidine-5

-carboxylic acid ethyl ester

C17H19FN2O4S

366.41

CH3

SO OH

Methanesulfonic acid

+

Methylamine

H2N CH3

FCOOC2H5

N N

CH3

CH3

NHCH3

Ethanol

4-(4-Fluoro-phenyl)-6-isopropyl-2-methylamino-pyrimidine-5-carboxylic acid ethyl ester

+

C17H20FN3O2

317.36

CH5N

31.06

CH4O2S

80.11

MeOH

Stage-5

FCOOC2H5

N N

CH3

CH3

NHCH3

4-(4-Fluoro-phenyl)-6-isopropyl-2-methylamino-pyrimidine-5-carboxylic acid ethyl ester

C17H20FN3O2

317.36


CH3

SO O

Cl

CH3ClO2S

114.55

FCOOC2H5

N N

CH3

CH3

N

SO2CH3

CH3

4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl

-amino)-pyrimidine-5-carboxylic acid ethyl ester

C18H22FN3O4S

395.45

HCl

36.5

Dimethoxy ethane

++



Stage-6

FCOOC2H5

N N

CH3

CH3

N

SO2CH3

CH3

4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl

-amino)-pyrimidine-5-carboxylic acid ethyl ester

C18H22FN3O4S

395.45

FCHO

N N

CH3

CH3

N

SO2CH3

CH3

+

N-[4-(4-Fluoro-phenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-N-methyl

-methanesulfonamide

C16H18FN3O3S

351.40

TolueneAl

H

Diisobutylaluminium hydride

142.22

+Al

OC2H5

Diisobutylaluminiumethoxide

186.27

Stage-7

FCHO

N N

CH3

CH3

N

SO2CH3

CH3

N-[4-(4-Fluoro-phenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-N-methyl

-methanesulfonamide

C16H18FN3O3S

351.40

Methyl (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidenehexanoate

O

O

P

O

O

Si CH3H3CH3C

H3CCH3

CH3

+

C31H39O4PSi

534.70

F

N

N

CH3

CH3NH3CO2S

CH3

COOCH3

O O

Si

CH3

CH3

CH3

CH3

CH3

3-(tert-Butyl-dimethyl-silanyloxy)-7-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)

-pyrimidin-5-yl]-5-oxo-hept-6-enoic acid methyl ester

C29H42FN3O6SSi

607.81

+ O P

Triphenylphosphine oxide

C18H15OP

278.28

TEA

N,N-DMFKI



Stage-8

F

N

N

CH3

CH3NH3CO2S

CH3

COOCH3

O O

Si

CH3

CH3

CH3

CH3

CH3

3-(tert-Butyl-dimethyl-silanyloxy)-7-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)

-pyrimidin-5-yl]-5-oxo-hept-6-enoic acid methyl ester

C29H42FN3O6SSi

607.81

+ HFTHF/Ethyl acetate

Hydrogen fluoride

20.01

F

N

N

CH3

CH3NH3CO2S

CH3

COOCH3

O OHSi

CH3

CH3

CH3

CH3

CH3

7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3-hydroxy

-5-oxo-hept-6-enoic acid methyl ester

+ F

tert-Butyl-fluoro-dimethyl-silane

C23H28FN3O6S

493.55

C6H15FSi

134.27



Stage-9

F

N

N

CH3

CH3NH3CO2S

CH3

COOCH3

O OH

7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3-hydroxy

-5-oxo-hept-6-enoic acid methyl esterC23H28FN3O6S

493.55

NaBH4

F

N

N

CH3

CH3NH3CO2S

CH3

COOCH3

OH OH

7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-

hept-6-enoic acid methyl ester

C23H30FN3O6S

495.56

+

37.83

+ HCl

36.5

+ NaCl

58.44

+ H3BO3

Diethyl methoxy borane

THF

61.83

+ 3 H2O

3X18=54.0

+ 3 H2

6.05



Stage-10

F

N

N

CH3

CH3NH3CO2S

CH3

COOCH3

OH OH

7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-

hept-6-enoic acid methyl ester

C23H30FN3O6S

2x495.56=991.12

+2

110.98

Water

F

N

N

CH3

CH3NH3CO2S

CH3

COO-

OH OH

2 Ca 2+

Rosuvastatin calcium

(C22H27FN3O6S)Ca

1001.14

+ 2 CH3Cl

Calcium chloride

100.98

Methyl chloride

C2H6Cl2

CaCl2Toluene,Ethyl acetate



ROSUVASTATIN CALCIUM

Flow-Chart:

Stage-1

Stage-2

Stage-3

4-Fluoro benzaldehyde4-Methyl-3-oxo-pentanoic acid ethyl esterMethanolWater

Methanol RecoveryEffluent water

Stage-1S-Methyl iso thio urea2,3-Dichloro-5,6-dicyano benzoquinoneHMPAMDCWater

MDC RecoveryHMPA RecoveryEffluent water

Stage-2Meta chloro peroxy benzoic acidMDCWater

MDC RecoveryEffluent water

Stage-4

Stage-5

Stage-3Methyl amineEthanolMethanolWater

Ethanol RecoveryMethanol RecoveryEffluent water

Stage-4Methane sulfonyl chlorideDi methoxy ethane

Di methoxy ethane Recovery

Stage-5Diisobutylaluminium hydride Toluene

Toluene RecoveryStage-6



Stage-7

Stage-8

Stage-9

N,N-Dimethyl formamide RecoveryEffluent water

Stage-7Hydrogen fluorideTHFEthyl acetate

THF RecoveryEthyl acetate Recovery

Stage-8Sodium boro hydrideDiethyl methoxy boraneEthyl acetateHydrochloric acidTHFWater

Ethyl acetate RecoveryTHF RecoveryEffluent water

Stage-10

Stage-9Calcium chlorideTolueneEthyl acetateWater

Toluene RecoveryEthyl acetate RecoveryEffluent water

Stage-6Methyl(3R)-3-(tert butyl di methyl silyloxy)-5-oxo-6-triphenyl phosphoranylidene hexanoateTriethyl amineN,N-Dimethyl formamideWater

ROSUVASTATIN CALCIUM

Material Balance:

Material Balance of Rosuvastatin Calcium Stage-1 Batch Size: 100.0 Kg



4-Fluoro benzaldehyde 41.00 Stage-1 85.00

4-Methyl-3-oxo-pentanoic acid ethyl ester

53.00 Methanol Recovery 238.00



(Water-300,gen water-5.95)


10.05

Total 644 Total 644






Stage-1 85.00 Stage-2 105.50

S-Methyl iso thio urea 29.00 MDC Recovery 285.00

2,3-Dichloro-5,6-dicyano benzoquinone

73.00 MDC Loss 6.00

HMPA 100.00 HMPA Recovery 95.00

MDC 300.00 HMPA Loss 2.00


(Water-300,gen water-5.79, , 2,3-Dichloro-5,6-Dicyano-benzoquinol-73.65)


(Process residue-2.06 Distillation Residue-12 (HMPA-3, MDC-9)

Total 887 Total 887




Stage-2 105.50 Stage-3 96.00

Meta chloro peroxy benzoic acid

109.00 MDC Recovery 285.00

MDC 300.00 MDC Loss 6.00


(Water-300, Meta chlorobenzoic acid-98.78 )


(Process residue-19.72, Distillation Residue-9 (MDC))





Stage-3 96.00 Stage-4 81.00

Methyl amine 9.00 Ethanol Recovery 238.00

Ethanol 250.00 Ethanol Loss 5.00


Water 300.00 Methanol Loss 9.00




(Water-300,Methane sulfonic acid-17.7)

Organic Residue Process residue-3.3 Distillation Residue-16 (Ethanol-7, Methanol-9)

19.30

Total 955 Total 955




Stage-4 81.00 Stage-5 95.00

Methane sulfonyl chloride 30.00 Di methoxy ethane Recovery 285.00

Di methoxy ethane 300.00 Di methoxy ethane Loss 6.00

By - Product 9.30

(Hydrochloric acid)

Organic Residue Process residue-6.7 Distillation Residue-9 (Di methoxy ethane)

15.70

Total 411 Total 411




Stage-5 95.00 Stage-6 82.00

Diisobutylaluminium hydride 35.00 Toluene Recovery 285.00



(Process residue-48 Organic Impurities-3 diisobutylaluminium ethoxide-45 Distillation Residue-9 (Toluene)

Total 430 Total 430






Stage-6 82.00 Stage-7 136.00

Methyl(3R)-3-(tert butyl di methyl silyloxy)-5-oxo-6-triphenyl phosphoranylidene hexanoate

125.00 N,N-Dimethyl formamide Recovery

285.00

Triethyl amine 10.00 N,N-Dimethyl formamide Loss 6.00

N,N-Dimethyl formamide 300.00 Effluent water 319.00

Water 300.00 (Water-300, Triethyl amine-10, DMF-9)


(Process residue- Organic Impurities-6, Triphenyl phosphine oxide-65)

Total 817 Total 817




Stage-7 136.00 Stage-8 107.00

Hydrogen fluoride 4.50 THF Recovery 285.00

THF 300.00 THF Loss 6.00


Ethyl acetate Loss 6.00


(Process residue-33.5 Organic Impurities-3.5, Tert-butyl-fluoro-dimethyl silane-30) Distillation Residue-18 (THF-9, Ethyl acetate-9)





Stage-8 107.00 Stage-9 102.00

Sodium boro hydride 8.20 Ethyl acetate Recovery 285.00

Diethyl methoxy borane 20.00 Ethyl acetate Loss 6.00

Ethyl acetate 300.00 THF Recovery 285.00

Hydrochloric acid 8.00 THF Loss 6.00



THF 300.00 Effluent water 343.34

Water 300.00 (water-288.28, Sodium chloride-12.66 Dimethoxy borane-20, Boric acid-13.40, THF-9)

Process Emissions 1.31

(Hydrogen)

Organic Residue Process residue-5.55 Distillation Residue-9 (Ethyl acetate-9)

14.55





Stage-9 102.00 Rosuvastatin Calcium 100.00

Calcium chloride 11.50 Toluene Recovery 285.00



Water 300.00 Ethyl acetate Loss 6.00


(Water-300, Toluene-9)

Process emission ((Chloromethane)

10.39


(Process residue-3.11 Distillation Residue-9 (Ethyl acetate-9)




14.SITAGLIPTIN PHOSPHATE MONOHYDRATE Process Description

Stage-1

Step-A

(2, 4, 5-Trifluoro-phenyl) acetic acid undergoes Chlorination with Thionyl chloride

and Meldrums acid in presence of Sodium Hydroxide, MDC, Methanol and Ethyl

acetate to give Step-A product

Step-B

Step-A product reacts with 3-(Trifluoro methyl) 5, 6, 7, 8-tetra hydro-[1,2,4]triazolo

(4, 3-a) pyrazine hydrochloride in presence of Methane sulphonic acid , Sodium

carbonate, Methanol, Toluene and IPA to give Stage-1 product

Stage-2

Stage-1 compound reacts with Hydroxy-phenyl acetic acid and sodium borohydride

in presence of acetic acid, MDC and IPA to give stage-2 product

Stage-3

Stage-2 compound reacts with sodium hydroxide, phosphoric acid and water in

presence of Toluene, MDC and IPA to give Sitagliptin Phosphate Monohydrate.

SITAGLIPTIN PHOSPHATE MONOHYDRATE

Route of synthesis

Stage-1

Step-A F

F

F

OH

O

(2,4,5-Trifluoro-phenyl)-acetic acid

C8H5F3O2

190.12

+ SOCl2

118.97

+

O O

OO

CH3H3C

Meldrums acid

C6H8O4

144.13

+ 2 NaOH

80.00

F

F

FOH

O

O

O

OCH3

C14H11F3O5

316.23

+ SO2 + 2 NaCl

64.06 2X58.4=116.8

+ 2H2O

36.02

CH3

5-[1-Hydroxy-2-(2,4,5-trifluoro-phenyl)-ethylidene]-2,2-dimethyl-[1,3]

dioxane-4,6-dione

MDC, Methanol, Ethyl acetate



Step-B

F

F

FOH

O

O

O

OCH3

C14H11F3O5

316.23

CH3

5-[1-Hydroxy-2-(2,4,5-trifluoro-phenyl)-ethylidene]-2,2-dimethyl-[1,3]

dioxane-4,6-dione

+

HN

NN

N

CF3

HCl

C6H8ClF3N4

228.60

+

3-Trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]

pyrazine Hydrochloride

+CH3SO3H

96.11

NaHCO3

+ NH3

17.03

84.01

F

F

FNH2 O

N

NN

N

CF3

3-Amino-1-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-

trifluoro-phenyl)-but-2-en-1-one

C16H13F6N5O

405.30

+

NaCl

58.44

+ SO2

64.06

+ O2

32.00

Propanetriol

OHHO

HO

C3H8O3

92.09

+

Lactic acid

OH

OOH

C3H6O3

90.08

+

Methanol, Toluene, IPA



Stage-2

F

F

FNH2 O

N

NN

N

CF3

3-Amino-1-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-

trifluoro-phenyl)-but-2-en-1-one

C16H13F6N5O

405.30

+ NaBH4

37.83

+ CH3COOH

60.05

+

O

OH

OH

Hydroxy-phenyl-acetic acid

C8H8O3

152.15

F

F

FNH2 O

N

NN

N

CF3

O

OH

OH

3-Amino-1-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-

(2,4,5-trifluoro-phenyl)-but-2-en-1-one Hydroxy phenyl acetate

C24H23F6N5O4

559.46

+ CH3COONa

82.03

+

+ H3BO3

61.83

3 H2O

54.05

+ 4 H2

8.00



Stage-3

F

F

FNH2 O

N

NN

N

CF3

O

OH

OH

3-Amino-1-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-

(2,4,5-trifluoro-phenyl)-but-2-en-1-one Hydroxy phenyl acetate

C24H23F6N5O4

559.46

+ NaOH

40.00

+ H3PO4

98.00

H3PO4 H2O

Sitagliptin Phosphate monohydrate

C16H20F6N5O6P

523.32

O

OH

ONa

+

Sodium mandelate

C8H7NaO3

174.13

F

F

F

NH2

N

N

N

N

CF3

O

MDC, IPA



Flow Chart

2,4,5-Trifluro phenyl acetic acid3-(trifluoromethyl)-5,6,7,8-tetrahydro(1,2,4)triazole(4,3,-a)Pyrazine hydrochlorideMethane sulfonic acidThionyl chlorideMeldrum acidSodium hydroxideSodium sulphateSodium bicarbonateMethylene dichlorideAmmonia Ethyl acetateMethanolWater

Stage-1Sodium borohydrateHydroxyl phenyl acetic acidAcetic acidIsopropyl alcoholTolueneMethylene chlorideWater

Methylene dichloride RecoveryToluene RecoveryIsopropyl alcohol RecoveryEffluent water

Methylene dichloride RecoveryIsopropyl alcohol RecoveryEffluent water

Stage-1

Stage-2

Stage-3

Methylene dichloride RecoveryEthyl acetate RecoveryMethanol RecoveryEffluent water

Stage-2Sodium hydroxidePhosphoric acidSodium sulphateMethylene chlorideIsopropyl alcoholWater

Sitagliptin Phosphate Monohydrate



Material Balance

Material balance of Sitagliptin Phosphate Monohydrate



in kg


in kg

2,4,5-Trifluro phenyl acetic acid 41.00 Stage-1 82.00

3-(trifluoromethyl)-5,6,7,8-

tetrahydro(1,2,4)triazole(4,3,-

a)Pyrazine hydrochloride

48.00 Methylene dichloride

Recovery

190.00

Methane sulfonic acid 20.00 Methylene dichloride Loss 4.00

Thionyl chloride 26.00 Ethyl acetate Recovery 190.00

Meldrum acid 31.10 Ethyl acetate Loss 4.00


Sodium sulphate 10.00 Methanol Loss 4.00

Sodium bicarbonate 18.00 Effluent water 389.21

Methylene dichloride 200.00 (Water-300,

Generated water-7.8,

Sodium chloride-37.4,

Lactic acid-18.8,

Propanetriol-19.21,

Ethyl acetate-6)

Ammonia 3.60 Inorganic solid waste 10.00

Ethyl acetate 200.00 (Sodium sulphate)

Methanol 200.00 Process emission 33.84

Water 300.00 (Sulphur dioxide-27.17,

Oxygen-6.67)


Process residue -6.15

Distillation residue- 12

(MDC-6, Methanol-6)







In kg


In kg

Stage-1 82.00 Stage-2 110.00

Sodium borohydrate 8.00 Mixed Solvents(Methylene

dichloride+ Toluene)

Recovery

380.00

Hydroxyl phenyl acetic acid 31.00 Methylene dichloride Loss 10.00

Acetic acid 12.20 Toluene Loss 10.00


Toluene 200.00 Isopropyl alcohol Loss 4.00

Methylene chloride 200.00 Effluent water 318.10

Water 300.00 (Water-289, Sodium acetate-

16.6, Boric acid-12.5)


(Hydrogen)



Distillation residue - 6

( IPA-6)

Total 1033.2 Total 1033.20




In kg


In kg

Stage-2 110.00 Sitagliptin Phosphate

Monohydrate

100.00

Sodium hydroxide 8.00 Methylene dichloride

Recovery

190.00

Phosphoric acid 20.00 Methylene dichloride Loss 10.00

Sodium sulphate 10.00 Isopropyl alcohol Recovery 190.00

Methylene chloride 200.00 Isopropyl alcohol Loss 4.00

Isopropyl alcohol 200.00 Effluent water 206.00

Water 200.00 (Water-200,IPA-6)


(Sodium sulphate)


Process residue -38



(Sodium mandelate-34.25,

Organic impurities-3.75)

Total 748 Total 748

15.TENELIGLIPTIN HYDROBROMIDE HYDRATE


Stage-1

1-(3-Methyl-1-phenyl-1H-Pyrazol-5-yl) piperazine reacts with 4-Benzenesulfonyloxy-

2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in presence of

DMF and Ethyl acetate to give Stage-1 Product.

Stage-2

Stage-1 Product reacts with Trifluoro acetic acid in presence of MDC to give

Teneligliptin.

Stage-3

Teneligliptin undergoes salt formation with Hydrobromide hydrate in presence of

MDC, Ethyl acetate and IPA to give Teneligliptan Penta Hydrobromide Hydrate.

Route oh Synthesis:

Stage-1

N

O

O

O

S

N

SO

OO

N

HN

N N

1-(3-Methyl-1-phenyl-1H-pyrazol-5-

yl)piperazine

C14H18N4

242.32

+

4-Benzenesulfonyloxy-2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid

tert-butyl ester

C19H26N2O6S2

442.55

N

O

O

O

S

N

NN

NN

C27H38N6O3S526.69

(2S,4S)-tert-butyl 4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-

yl)-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate

SO

OOH

Benzenesulfonic acid

C6H6O3S

158.18

+

DMF, Ethy acetate



Stage-2

N

O

O

O

SN

NNNN

C27H38N6O3S526.69

(2S,4S)-tert-butyl 4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-

yl)-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate

Tri Fluoro Acetic acid

O

OH

Formic acid tert-butyl ester

NH

O

SN

NNNN

Teneligliptin

C22H30N6OS

426.58

+

C5H10O2102.13

MDC



Stage-3

MDC, Ethyl acetate, IPA

NH

O

SN

NNNN

Teneligliptin

C22H30N6OS

426.58 X 2=853.16

Hydrobromide hydrate

+

NH

O

SN

NNNN

5 HBr H2O

[C22H30N6OS ]2 5HBr H2O

422.57

Teneligliptin Penta hydrobromide hydrate

2

2

HBr5

H2O

1275.74

x



TENELIGLIPTIN PENTA HYDROBROMIDE HYDRATE

Flow chart

1-(3-methyl-1-phenyl-1H-pyrazo-5-yl) piperazine4-Benzenesulfonyloxy-2-(thiazolidine -3-carbonyl)-pyrrolidine-1-carboxylic acidtert-butyl esterDimethyl form amideEthyl acetateWater

Ethyl acetate RecoveryDimethyl formamide RecoveryEffluent water

Stage-1

Methylene chloride RecoveryEffluent water

Stage-2

Methylene chloride RecoveryEthyl acetate RecoveryIsopropyl alcohol RecoverySpent carbon Effluent water

Stage-3

Stage-1Sodium sulphateTrifluoro acetic acidMethylene chlorideWater

Stage-2Aqueous hydrobromic acid Isopropyl alcoholEthyl acetateMethylene chlorideActivated carbonWater

Teneligliptin Hydrobromide Hydrate



TENELIGLIPTIN HYDROBROMIDE HYDRATE

Material balance:

Material balance of Teneligliptin Hydrobromide Hydrate

Stage-1 Batch size : 100.00kg


In kg


In kg

1-(3-methyl-1-phenyl-1H-pyrazo-

5-yl) piperazine

42.00 Stage-1 88.00

4-Benzenesulfonyloxy-2-

(thiazolidine -3-carbonyl)-

pyrrolidine-1-carboxylic acid tert-

butyl ester

77.00 Ethyl acetate Recovery 95.00

Dimethyl form amide 200.00 Ethyl acetate Loss 5.00

Ethyl acetate 100.00 Dimethyl formamide

Recovery

190.00

Water 200.00 Dimethyl formamide Loss 4.00


(Water- 200, DMF-6)


Process residue-14

(benzene sulfonic acid-

27.45, Organic impurities-

3.55)

Total 619 Total 619




in kg


in kg

Stage-1 88.00 Stage-2 69.00

Sodium sulphate 20.00 Methylene chloride Recovery 190.00

Trifluoro acetic acid 5.00 Methylene chloride Loss 10.00

Methylene chloride 200.00 Inorganic solid waste 20.00

Water 200.00 (Sodium sulphate-20)

Effluent Water 205.00

(Water-200, Trifluoro acetic acid-5)


Process residue19

(Formic acid tert-butylester-17.10,



Organic impurities-1.9)

Total 513 Total 513


Stage-3 Batch size : 100.00kg


In kg


In kg

Stage-2 69.00 Teneligliptin hydrobromide hydrate 100.00

Aqueous hydrobromic acid 35.00 Methylene chloride Recovery 190.00

Isopropyl alcohol 200.00 Methylene chloride Loss 10.00


Methylene chloride 200.00 Ethyl acetate Loss 4.00

Activated carbon 10.00 Isopropyl alcohol Recovery 190.00

Water 200.00 Isopropyl alcohol Loss 4.00

Spent carbon 10.00


(Water-200, Isopropyl alcohol-6, Ethyl

acetate-6)

0


Total 914 Total 914

16.TRI BUTYL TIN CHLORIDE

Process description:

Stage-1

n-Butyl chloride undergoes Grignard reaction with Magnesium and Tin Chloride in

presence of Diethyl ether to give Tri Butyl tin Chloride product.



Route of Synthesis:

Stage-1

n-Butyl Chloride

CH3Cl

C4H9Cl

92.57X3=277.71

+ SnCl2

189.62

+ Mg

24.31

Diethyl ether3

ClSn CH3

CH3

H3C

Tri Butyl Tin Chloride

+ H2O

18.02

C12H27ClSn

325.51

+ MgCl2

95.21

+ 2 HCl

72.92

+ 0.5 O2

16.00

Flow chart:

n-Butyl ChlorideTin(II) chlorideMagnesium Diethyl ether Toluene Ammonium chloride IodineEthylene di bromideWater

Mixed Solvents(Diethyl ether +Toluene ) RecoveryEffluent water

Stage-1

Tri Butyl Tin ChlorideMaterial Balance:

Material balance of Tri Butyl Tin Chloride Stage-1 Batch Size: 500.0.0 Kg



n-Butyl Chloride 450.00 Tri Butyl Tin Chloride 500.00

Tin(II) chloride 308.00

Mixed Solvents (Diethyl ether +Toluene ) Recovery

713.00

Magnesium 40.00 Toluene loss 30.00

Diethyl ether 150.00 Diethyl ether loss 7.00

Toluene 600.00 Effluent water 1374.47

Ammonium chloride 50.00 (Water-1170 ,Ammonium chloride-50, Magnesium chloride-154.27, Iodine-0.1, Ethylene

0



dibromide-0.1)

Iodine 0.100 Process emission (Oxygen-25.92)

25.92

Ethylene di bromide 0.100 By –product (Hydrochloric acid -118.15)

118.15

Water 1200.00 Organic residue 29.66


17.VALACYCLOVIR HYDROCHLORIDE MONOHYDRATE


Stage-1

Acetic acid 2-(2-acetylamino-6- oxo-1,6-dihydro-purin-9-ylmethoxy)-ethyl ester

undergoes condensation with 3-Methyl-2-(phenoxycarbonyl methyl-amino)-butyric

acid in presence of Dimethylformamide, Dimethyl amine , Acetone & ehanol to give

Stage-1

Product.

Stage-2

Stage-1 product undergoes reduction with Hydrogen Gas in presence of palladium

on carbon as catalysed and further Reacted with Hydrochloric acid and water to give

Valcyclovir Hydrochloride monohydrate.



VALACYCLOVIR HYDROCHLORIDE MONOHYDRATE

Route of Synthesis:

Stage-1

C12H15N5O5

309.28

3-Methyl-2-(phenoxycarbonylmethyl-amino)-butyric acid

C13H17NO4

251.28

+

Dimethyl formamide , Dimethylamine ,

Acetone & Ethanol

2-Benzyloxycarbonylamino-3-methyl-butyric acid 2-(2-amino-6-oxo-1,6-dihydro-purin-9-yl

methoxy)-ethyl ester

C21H26N6O6

458.47

+ 2CH3COOH

120.10

+ H2O

18.0

HN

N N

N

OO CH3

O

O

NH

H3C

O

Acetic acid 2-(2-acetylamino-6-oxo-1,6-dihydro-purin-9-ylmethoxy)-ethyl ester

H3C

O

OH

NCH3O

O

CH3

HN

N N

N

OO

O

O

H2NHN

O

O



Stage-2

Palladium on Carbon, Methanol & Ethanol

2-Benzyloxycarbonylamino-3-methyl-butyric acid 2-(2-amino-6-oxo-1,6-dihydro-purin-9-yl

methoxy)-ethyl ester

C21H26N6O6

458.47

HN

N N

N

OO

O

O

H2NHN

O

O

+

Valcyclovir Hydrochloride Monohydrate

C13H23ClN6O5

378.81

C8H8O2

136.15

+ HCl

36.46

+ H2O

18.02

+ H2

2.02

HN

N N

N

OO

O

O

H2NNH2

O

O

Formic acid benzyl ester

. H2O . HCl

Flow Chart:

Stage-1

Stage-2

Dimethyl amine RecoveryDimethyl formamide RecoveryAcetone RecoveryEthanol RecoveryEffluent Water

Stage-IPalladium on CarbonHydrochloric acid MethanolEthanolHydrogenActivated carbonDM Water

Methanol RecoveryEthanol RecoveryPalladium on Carbon RecoveryEffluent Water

Acetic acid 2-(2-acetylamino-6- oxo-1,6-dihydro-purin-9-ylmethoxy)-ethyl ester3-Methyl-2-(phenoxy carbonyl methylamino)-butyric acidDimethyl amineDimethyl formamideAcetoneEthanolSodium sulphate Water

Valcyclovir Hydrochloride Monohydrate



Material Balance

Material Balance of Valcyclovir Hydrochloride Monohydrate Stage-1 Batch Size: 500Kg



Acetic acid 2-(2-acetylamino-6- oxo-1,6-dihydro-purin-9-ylmethoxy)-ethyl ester

453.00 Stage-I 637.00

3-Methyl-2-(phenoxy carbonyl methylamino)-butyric acid

368.00 Dimethyl amine Recovery 190.00

Dimethyl amine 200.00 Dimethyl amine Loss 4.00

Dimethyl formamide 500.00 Dimethyl formamide Recovery 475.00

Acetone 500.00 Dimethyl formamide Loss 10.00

Ethanol 500.00 Acetone Recovery 475.00

Sodium sulphate 25.00 Acetone Loss 10.00

Water 500.00 Ethanol Recovery 475.00

Ethanol Loss 10.00

Effluent Water 670.51

(Water-473.61, Acetic acid-175.90, Dimethylamine-6 Dimethyl formamide-15)


25.00

Organic Solid Waste (Process residue-34.49 Distillation Residue-30 (Acetone -15, Ethanol-15)

64.49


Material Balance of Valcyclovir Hydrochloride Monohydrate



in Kg

Name of the out put Quantity in

Kg

Stage-I 637.00 Valcyclovir Hydrochloride

Monohydrate

500.00

Palladium on Carbon 15.00 Methanol Recovery 475.00

Hydrochloric acid 51.00 Methanol Loss 10.00

Methanol 500.00 Ethanol Recovery 475.00

Ethanol 500.00 Ethanol Loss 10.00

Hydrogen 3.00 Palladium on Carbon

Recovery

15.00



Activated carbon 5.00 Effluent Water 475.00

DM Water 500.00 (Water-475)

Spent Carbon 5.00

Organic residue-

Process residue-216

(Formic acid methyl ester -

189.16, Organic impurities-

26.84)

Distillation residue-30

(Methanol-15, ethanol-15

246.00


18.VILDAGLIPTIN


Stage-1

Pyrrolidine-2-carboxylic acid reacts with chloro-acetyl chloride in presence of MDC

and IPA to give Stage-1 Product.

Stage-2

Stage-1 product reacts with Ammonium carbonate in presence of MDC and IPA to

give stage-2 Product.

Stage-3

Stage-2 product reacts with Trifluoro acetic anhydride in presence of MDC and IPA

to give Stage-3 Product.

Stage-4

Stage-3 Product reacts with 3-Amoino- adam -1-ol in presence of MDC and Acetone

to give Vildagliptin.



VILDAGLIPTIN

Route of Synthesis:

Stage-1

+

Chloro-acetyl chloride

C2H2Cl2O

112.94

C5H9NO2

115.13

MDC, IPA

HN

O

OH

Pyrrolidine-2-carboxylic acid

ClCl

O N O

OH

(S)-1-(2-chloroacetyl)pyrrolidine

-2-carboxylic acid

C7H10ClNO3

191.61

O

Cl

+ HCl

36.46

Stage-2

MDC, IPA

N O

OH

(S)-1-(2-chloroacetyl)pyrrolidine

-2-carboxylic acid

C7H10ClNO3

191.61

O

Cl

+ (NH4)2CO3

96.09

N O

NH2

(S)-1-(2-chloroacetyl)pyrrolidine-2-carboxamide

ClO

C7H11ClN2O2

190.63

+ CO2

44.01

+ NH3

17.03

H2O+

36.02

2

Stage-3



N O

NH2

(S)-1-(2-chloroacetyl)pyrrolidine-2-carboxamide

ClO

C7H11ClN2O2

190.63

+

Tri fluoro acetic anhydride

F3C O CF3

O O

C4F6O3

210.03

N

ClO

CN

1-(2-chloroacetyl)pyrrolidine

-2-carbonitrile

C7H9ClN2O

172.61

+

Tri fluoro acetic acid

OO F

FF

C2HF3O2

114.02 X2=228.04

+ 3 H2

6.06

2

IPA, MDC

Stage-4

N

ClO

CN

C7H9ClN2O

172.61

OHH2N

1-(2-Chloro-acetyl)-pyrrolidine

-2-carbonitrile

3-Amino-adamantan-1-ol

N

O

CN

OH

C17H25N3O2

303.40

NH

+

C10H17NO

167.25

Vildagliptin

MDC, Acetone+ HCl

36.46

Flow Chart:



Pyrrolidine -2-carboxlic acidChloro acetyl chlorideSodium sulphateSodium chlorideIsopropyl etherMethylene dichloride

Stage-1Ammonium bicarbonateIsopropyl alcoholMethylene dichloride Isopropyl ether

Methylene dichloride recoveryIsopropyl alcohol recoveryIsopropyl ether recovery

Stage-33- amino-1- adamantanolePotassium carbonatePotassium iodideActivated carbonHyflowSodium sulphateSodium chlorideMethylene chlorideAcetone

Tetrahydrofuran RecoveryMethylene chloride RecoveryIsopropyl alcohol Recovery

Stage-1

Stage-2

Stage-3

Methylene dichloride recoveryIsopropyl ether recovery

Stage-4

Stage-2Trifluoro acetic anhydrideAmmonium bicarbonateSodium chlorideSodium sulphateIsopropyl alcoholTetrahydrofuranMethylene chloride

Vildagliptin

Acetone Recovery Methylene chloride Recovery

VILDAGLIPTIN

Material Balance:



Material balance of Vildagliptin



In kg


In kg

Pyrrolidine -2-carboxlic acid 44.00 Stage-1 71.00

Chloro acetyl chloride 44.00 Methylene dichloride

Recovery

190.00

Isopropyl ether 0200.00 Methylene dichloride Loss 10.00

Methylene dichloride 200.00 Isopropyl ether Recovery 190.00

Water 200.00 Isopropyl ether Loss 10.00


(Water-200)

By -product 13.93

(Hydrochloric acid)


Total 688 Total 688

Material balance of Vildagliptin



In kg


In kg

Stage-1 71.00 Stage2 68.00

Ammonium bicarbonate 36.00 Methylene dichloride

recovery

190.00

Isopropyl alcohol 100.00 Methylene dichloride Loss 10.00

Methylene dichloride (MDC) 200.00 Isopropyl alcohol Recovery 95.00

Isopropyl ether 200.00 Isopropyl alcohol Loss 5.00

Isopropyl ether Recovery 190.00

Isopropyl ether Loss 10.00

Generated water 13.35


(Carbon dioxide-16.3,

Ammonia-6.3)


Total 607 Total 607



Material balance of Vildagliptin Stage-3 Batch size : 100kg

Name of the input Quantity In kg

Name of the out put Quantity In kg

Stage-2 68.00 Stage-3 57.00

Trifluoro acetic anhydride 75.00 Tetrahydrofuran Recovery 190.00

Isopropyl alcohol 200.00 Tetrahydrofuran Loss 4.00

Tetrahydrofuran 200.00 Methylene chloride Recovery 190.00

Methylene chloride 200.00 Methylene chloride Loss 10.00

Water 200.00 Isopropyl alcohol Recovery 190.00

Isopropyl alcohol Loss 4.00


(Water -200, THF-6, Tri fluoroacetic acid -81.35)

Process emission (Hydrogen)

2.15


Process Residue-2.5 Distillation residue- 6 (Isopropyl alcohol -6)

Total 943 Total 943

Material balance of Vildagliptin Stage-4 Batch size :100kg

Name of the input Quantity In kg

Name of the out put Quantity In kg

Stage-3 59.00 Vildagliptin 100.00

3- amino-1- adamantanole 58.00 Acetone Recovery 190.00

Activated carbon 5.00 Acetone Loss 4.00

Methylene chloride 200.00 Methylene chloride Recovery

190.00

Acetone 200.00 Methylene chloride Loss 10.00


(Water -300)

Spent carbon 5.00

By product 12.46



Process residue-4.54 Distillation residue-6 (Acetone-6)

Total 822 Total 822



ANNEXURE – IV

WATER CONSUMPTION DETAILS

S.No Purpose Water input KLD

1 Process 52

2 Washings 5

3 Boiler make up 42

4 Cooling towers make up 79

5 Scrubbing system 7

6 Domestic 4

7 Gardening 5

Total 194



ANNEXURE -V

SOLID & HAZARDOUS WASTE GENERATION AND DISPOSAL

S. No Name of the

Hazardous Waste Quantity Kg/Day

Disposal Method

1 Organic Solid Waste 1657

Sent to Cement Industries

2 Spent Carbon 145

3 Solvent distillation residue

1091

4 Organic Evaporate liquid from MEE stripper

640

5 Mixed Solvents 3945 Sent to paint industries

6 ETP Sludge 1000 Sent to TSDF 7 Inorganic solid waste 359

8 MEE Salts 3151

9 Used Oils 500 Ltrs/Annum SPCB Authorized Agencies for Reprocessing/Recycling

10 Detoxified Containers 500 No’s/Month After Detoxification sent back to suppliers/sent to outside Parties

11 Used Lead Acid Batteries 2 No’s/Year Send back to suppliers for buyback of New Batteries

Solid Waste Details

12 Fly ash from boiler 7700

Kg/Day Sent to Brick Manufacturers



ANNEXURE - VI

STACK EMISSION DETAILS FOR PROPOSED BOILER

Particulars Units 3.0TPH Coal Fired Boiler

4.0TPH Coal Fired Boiler

Type of Fuel -- Indian Coal Indian Coal

Coal /Fuel Consumption TPD 12 16

Ash Content % 35 35

Sulphur Content % 0.4 0.4

No. of Stacks No 1 1

Height of stack M 30 32

Diameter of Stack M 0.5 0.6

Temperature of Flue Gas oC 200 220

Velocity of Flue Gas m/s 12 14

Particulate Matter at outlet of Bag filter

gm/sec 0.50 0.75

Sulphur dioxide emission gm/sec 0.78 1.04

Oxides of Nitrogen emission

gm/sec 2.05 2.74

Pollution control equipments

Cyclone separator followed by suitable pack of Bag filters

STACK EMISSION DETAILS FOR DG SETS

Capacity In KVA

Emission of SPM in mg/Nm3

Emission Of SO2 in mg/Nm3

Emission of NOx

in mg/Nm3

Stack dia. in m

Flue Gas Temp. in

OC

Stack Height in m

Flue gas Velocity in m/sec.

750 KVA 80.0 190.0 235.0 0.30 225 10 15



ANNEXURE -VII

PROCESS EMISSION DETAILS

S. No Name of the Gas Quantity

in Kg/Day Treatment Method

1 Carbon dioxide 280 Dispersed into the atmosphere

2 Oxygen 42 Dispersed into the atmosphere

3 Ammonia 16 Scrubbed by using Chilled water media

4 Sulfur dioxide 305 Scrubbed by using C.S.Lye Solution

5 Hydrogen 15 Diffused by using Nitrogen through Flame arrestor

6 Chloro methane 7 Scrubbed by using C.S.Lye Solution



ANNEXURE - VIII

LIST OF RAW MATERIALS

1. CARVEDILOL

S. No. Raw Material Consumption/ Batch in Kgs

Consumption/ Day in Kgs

1 Phenyl hydrazine Hydrochloride 209.00 139.33

2 1,3-Cyclohexanedione 162.00 108.00 3 2-(2-Methoxy phenoxy)

ethylamine 214.00 142.67

4 Acetone 500.00 333.33 5 Activated carbon 10.00 6.67 6 Epichlorohydrin 124.00 82.67 7 Ethyl acetate 1700.00 1133.33 8 Hydrochloric acid 52.00 34.67 9 Isopropyl alcohol 1000.00 666.67 10 Methanol 2800.00 1866.67 11 Potassium hydroxide 79.00 52.67 12 Raney nickel 15.00 10.00 13 Sodium hydroxide 54.00 36.00

2.CYANO DIOL HYDROCHLORIDE



1 5-Cyano pthalide 42.00 70.00

2 Dimethyl amino magnesium chloride

39.00 65.00

3 Hydrochloric acid 21.00 35.00

4 P-Fluoromagnesium bromide

53.00 88.33

5 Toluene 400.00 666.67

3. DABIGARTAN



1 Pyridine -2-ylamine 23.00 38.33 2 2-bromoacetic acid 30.00 50.00

3 4-amino benzonitrile 25.00 41.67 4 4-chloro-3-nitro-benzoic

acid 55.00

91.67 5 Acetic acid 200.00 333.33 6 Ammonia 5.00 8.33 7 Ammonium carbonate 18.00 30.00 8 Ammonium formate 20.00 33.33





9 Dichloromethane 200.00 333.33 10 Ethanol 600.00 1000.0 11 Ethyl acetate 200.00 333.33 12 Ethyl acrylate 25.00 41.67 13 Hexyl chloro formate 29.00 48.33 14 Hydrochloric acid 9.00 15.00 15 Iron 12.00 20.00 16 Isopropyl alcohol 400.00 666.67 17 Methanol 200.00 333.33 18 Methyl amine 9.00 15.00

19 n-Hexane 200.00 333.33 20 Potassium carbonate 25.00 41.67

21 Tetra hydrofuran 400.00 666.67 22 Thionyl chloride 31.00 51.67 23 Toluene 400.00 666.67 24 Triethylamine 24.00 40.00

4.FEXOFENADINE HYDROCHLORIDE

S. No.

Raw Material Consumption/ Batch in Kgs


1 3-Chloro-2-methylprop-1-ene

108.00 72.00

2 4-Chlorobutanoyl chloride 158.00 105.33 3 Acetic Acid 118.00 78.67 4 Activated Carbon 10.00 6.67 5 Aluminum chloride 153.00 102.00 6 Benzene 90.00 60.00 7 Chloro benzene 234.00 156.00

8 Dichloromethane 500.00 333.33 9 Dimethyl formamide 500.00 333.33 10 Ethyl Acetate 800.00 533.33 11 Hydrochloric Acid 112.00 74.66 12 Isopropyl alcohol 300.00 200.00 13 Magnesium 51.00 34.00 14 Methanol 1033.00 688.67 15 Methyl isobutyl ketone 600.00 400.00 16 Methyl isobutyl ketone 600.00 400.00 17 Piperidine-4-carboxylic

acid 139.00

92.67 18 Potassium permanganate 168.00 112.00 19 Sodium acetate 98.00 65.33 20 Sodium Bicarbonate 85.00 56.67

21 Sodium Borohydride 38.00 25.33 22 Sodium hydroxide 80.00 53.33 23 Sodium sulphate 12.00 8.00



S. No.



24 THF 500.00 333.33 25 Toluene 1000.00 666.67

5.FLUCONAZOLE



1 1,3 Difluoro benzene 60.00 200.00 2 1,2,4-triazole 58.00 193.33 3 Activated Carbon 10.00 33.33

4 Aluminium Chloride 72.00 240.00 5 Chloro Acetyl chloride 60.00 200.00 6 DMF 200.00 666.67 7 Ethyl Acetate 120.00 400.00

8 Hydrochloric Acid 26.00 86.67 9 Iso propyl alcohol 320.00 1066.67 10 MDC 250.00 833.33 11 Potassium carbonate 49.00 163.33 12 Potassium Hydroxide 20.00 66.67 13 Sodium sulphate 25.00 83.33 14 Toluene 200.00 666.67 15 Tri methyl Sulfoxonium

iodide 80.00 266.67 16 Triethyl Amine 46.00 153.33

6.FOLIC ACID

S. No.



1 4-Nitro benzoic acid 100.00 333.33 2 2,5,6-Triamino-4,5-

dihydro-pyrimidin-4-ol ,Sulfuric acid

118.00

393.33

3 Acetic acid 500.00 1666.67 4 Acetone 30.00 100.00 5 Catalyst(Iron Powder) 10.00 33.33 6 Chlorine Gas 110.00 366.67 7 Dimethyl formamide 400.00 1333.33 8 Hydrogen Gas 4.00 13.33 9 Monosodium glutamate 96.00 320.00 10 Sodium hydroxide 44.00 146.67 11 Sodium Sulphate 15.00 50.00 12 Sulfuric acid 56.00 186.67 13 Thionyl chloride 71.25 237.50 14 Toluene 1800.00 6000.00



7.ITRACONAZOLE



1 1-(4-Methoxy phenyl ) Piperazine 57.00 95.00

2 1,2,4-Triazole 19.70 32.83 3 1,4-Dioxane 200.00 333.33

4 1-Chloro-4-Nitro-benzene 46.30 77.17 5 2,4 -

Dichloroacetophenone 55.00 91.67 6 2-Bromo Butane 39.00 65.00

7 Acetic Acid 34.60 57.66 8 Activated Carbon 8.00 13.33 9 Benzoyl chloride 40.35 67.25 10 Cis-Bromo Benzoate 128.00 213.33 11 Dimethyl Formamide 700.00 1166.67 12 Formamidine 12.70 21.17 13 Glycerol 26.70 44.50 14 Hydrazine Hydrate 14.55 24.25 15 Hydrochloric acid 10.70 17.83 16 Hydrobromic acid 46.10 76.83 17 Hydrogen Gas 1.80 3.00

18 Liq Bromine 46.30 77.17 19 Methane Sulfonyl Chloride 32.55 54.25 20 Methanol 500.00 833.33 21 Methylene Dichloride 400.00 666.67 22 n-Butanol 200.00 333.33 23 Palladium Carbon 5.00 8.33 24 Phenyl Chloro formate 45.40 75.67 25 Potassium Carbonate 71.70 119.50 26 Potassium Hydroxide 16.00 26.67 27 p-Toluenesulfonic acid 5.00 8.33 28 Sodium Bicarbonate 24.40 40.67 29 Sodium Carbonate 30.20 50.33 30 Sodium Hydroxide 19.65 32.75

31 Toluene 200.00 333.33 32 Triethylamine 28.80 48.00

8.KETOCONAZOLE



1 2,4-Dichloro Acetophenone 43.00 143.33

2 4-Chlorophenol 26.00 86.67 3 Acetic acid 12.00 40.00





4 Acetone 300.00 1000.00 5 Activated Carbon 5.50 18.33 6 Benzoyl chloride 31.00 103.33

7 Ethyl Acetate 630.00 2100.00 8 Glycerol 21.00 70.00 9 Hydrochloric Acid 8.00 26.67 10 Imidazole 15.00 50.00 11 Liquid Bromine 36.00 120.00 12 Methanol 740.00 2466.67 13 Methanol 300.00 1000.00

14 Methylene Dichloride 200.00 666.67 15 n-Butanol 100.00 333.33 16 n-Butanol 300.00 1000.00 17 n-Hexane 300.00 1000.00 18 Para Toluene Sulfonyl

Chloride 39.00 130.00 19 ParaToluene Sulphonic

acid 7.50 25.00 20 Piperazine 18.00 60.00

21 Sodium Carbonate 22.00 73.33 22 Sodium hydroxide 17.00 56.67 23 Sodium methoxide 11.00 36.67 24 TBAB 20.00 66.67 25 Toluene 300.00 1000.00

9.LEVO CETIRIZINE DI HYDROCHLORIDE



1 p-chloro benzo phenone 125.00 208.33 2 Acetic acid 15.00 25.00 3 Acetone 100.00 166.67

4 Activated carbon 10.00 16.67 5 Ammonium formate 37.00 61.67 6 Chloro ethanol 19.00 31.67 7 Di methyl formamide 100.00 166.67 8 Ethyl di isopropyl amine 28.00 46.67 9 Hydro bromic acid 20.00 33.33 10 Hydrochloric acid 48.00 80.00

11 MDC 1650.00 2750.00 12 Methanol 400.00 666.67 13 n,n-bis( 2-chloro ethyl)

amine HCl 46.00 76.67 14 para toluene sulphonyl

chloride 50.00 83.33





15 Sodium hydroxide 33.00 55.00 16 Sodium Hydroxide 21.00 35.00 17 Sodium mono chloro

acetate 26.00 43.33

18 Tartaric acid 40.00 66.67 19 Toluene 1600.00 2666.67 20 Triethyl amine 24.00 40.00

10.LINAGLIPTIN



1 8-Bromo-7-but-2-ynyl-3-methyl-3,7-dihydro-purine-2,6-dione 72.00 120.00

2 2- Chloromethyl-4- methyl quinazoline 47.00 78.33

3 Activated carbon 5.00 8.33 4 Activated Carbon 5.00 8.33 5 Boc-3- amino piperidine 47.00 78.33 6 Dimethyl sulfoxide 400.00 666.66 7 Ethanol 400.00 666.66 8 Ethyl acetate 200.00 333.33 9 Isopropyl Alcohol 300.00 500.00

10 Isopropyl ether 200.00 333.33 11 Methanol 500.00 833.33 12 Methylene chloride 200.00 333.33 13 Sodium sulphate 25.00 41.67

11.MEROPENEM



1 3-(Diphenoxy-phosphoryloxy)-6- (1-hydroxy-ethyl)-4-methyl-7-oxo- 1-aza-bicyclo[3.2.0]hept-2-ene-2- carboxylic acid 4-nitro-benzyl ester 430.00 286.67

2 2-Dimethylcarbamoyl-4-mercapto- pyrrolidine-1-carboxylic acid 4-nitro-benzyl ester 256.00 170.67





3 Acetonitrile 500.00 333.33 4 Dichloromethane 500.00 333.33 5 Ethyl acetate 600.00 400.00

6 Hydrochloric acid 53.00 35.33 7 Hydrogen 3.00 2.00 8 Iso propyl alcohol 500.00 333.33 9 n-Hexane 500.00 333.33 10 Palladium on carbon 10.00 6.67 11 Sodium hydroxide 29.00 19.33 12 Triethyl amine 74.00 49.33

12.MONTELUKAST SODIUM



1 1-{3-[2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-propan-1-ol (MON10) 90.00 60.00

2 (1-Mercaptomethyl cyclopropyl)acetic acid 28.00 18.67

3 Acetic acid 11.00 7.33 4 Activated carbon 8.00 5.33 5 Dichloromethane 500.00 333.33 6 Diisopropyl ethyl amine 26.00 17.33 7 Methane sulfonyl chloride 23.00 15.33 8 Methanol 800.00 533.33 9 n-Heptane 300.00 200.00

10 n-Hexane 300.00 200.00 11 Sodium hydroxide 7.00 4.67 12 Sodium methoxide 10.50 7.00

13 Tert . butyl amine 14.00 9.33 14 Toluene 500.00 333.33

13.ROSUVASTATIN CALCIUM





1 4-Fluoro benzaldehyde 41.00 27.33 2 2,3-Dichloro-5,6-dicyano

benzoquinone 73.00 48.67 3 4-Methyl-3-oxo-pentanoic

acid ethyl ester 53.00 35.33

4 Calcium chloride 11.50 7.67 5 Di methoxy ethane 300.00 200.00 6 Diethyl methoxy borane 20.00 13.33 7 Diisobutylaluminium

hydride 35.00 23.33 8 Ethanol 250.00 166.67 9 Ethyl acetate 900.00 600.00 10 HMPA 100.00 66.67 11 Hydrochloric acid 8.00 5.33 12 Hydrogen fluoride 4.50 3.00 13 MDC 600.00 400.00 14 Meta chloro peroxy

benzoic acid 109.00 72.67 15 Methane sulfonyl chloride 30.00 20.00 16 Methanol 550.00 366.67 17 Methyl amine 9.00 6.00

18 Methyl(3R)-3-(tert butyl di methyl silyloxy)-5-oxo-6-triphenyl phosphoranylidene hexanoate 125.00 83.33

19 N,N-Dimethyl formamide 300.00 200.00 20 S-Methyl iso thio urea 29.00 19.33 21 Sodium boro hydride 8.20 5.47 22 THF 600.00 400.00 23 Toluene 600.00 400.00 24 Triethyl amine 10.00 6.67

14.SITAGLIPTIN PHOSPHATE MONOHYDRATE



1 2,4,5-Trifluro phenyl acetic acid 41.00 68.33

2 3-(trifluoromethyl)-5,6,7,8-tetrahydro(1,2,4)triazole(4,3,-a)Pyrazine hydrochloride 48.00 80.00

3 Acetic acid 12.20 20.33 4 Ammonia 3.60 6.00 5 Ethyl acetate 200.00 333.33





6 Hydroxyl phenyl acetic acid 31.00 51.67 7 Isopropyl alcohol 400.00 666.67 8 Meldrum acid 31.10 51.83

9 Methane sulfonic acid 20.00 33.33 10 Methanol 200.00 333.33 11 Methylene chloride 400.00 666.67 12 Methylene dichloride 200.00 333.33 13 Phosphoric acid 20.00 33.33 14 Sodium bicarbonate 18.00 30.00 15 Sodium borohydrate 8.00 13.33

16 Sodium hydroxide 25.50 42.50 17 Sodium sulphate 20.00 33.33 18 Thionyl chloride 26.00 43.33 19 Toluene 200.00 333.33

15.TENELIGLIPTIN HYDROBROMIDE HYDRATE



1 1-(3-methyl-1-phenyl-1H-pyrazo-5-yl) piperazine 42.00 70.00

2 4-Benzenesulfonyloxy-2-(thiazolidine -3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester 77.00 128.33

3 Activated carbon 10.00 16.67 4 Aqueous hydrobromic acid 35.00 58.33

5 Dimethyl form amide 200.00 333.33 6 Ethyl acetate 300.00 500.00 7 Isopropyl alcohol 200.00 333.33 8 Methylene chloride 400.00 666.67 9 Sodium sulphate 20.00 33.33

10 Trifluoro acetic acid 5.00 8.33

16.TRI BUTYL TIN CHLORIDE



1 n-Butyl Chloride 450.00 150.00 2 Ammonium chloride 50.00 16.67 3 Diethyl ether 150.00 50.00 4 Ethylene di bromide 0.100 0.03 5 Iodine 0.100 0.03 6 Magnesium 40.00 13.33





7 Tin(II) chloride 308.00 102.67 8 Toluene 600.00 200.00

17.VALACYCLOVIR HYDROCHLORIDE MONOHYDRATE



1 Acetic acid 2-(2-acetylamino-6- oxo-1,6-dihydro-purin-9-ylmethoxy)-ethyl ester 453.00 302.00

2 3-Methyl-2-(phenoxy carbonyl methylamino)-butyric acid 368.00 245.33

3 Acetone 500.00 333.33 4 Activated carbon 5.00 3.33 5 Dimethyl amine 200.00 133.33 6 Dimethyl formamide 500.00 333.33 7 Ethanol 1000.00 666.67 8 Hydrochloric acid 51.00 34.00

9 Hydrogen 3.00 2.00 10 Methanol 500.00 333.33 11 Palladium on Carbon 15.00 10.00 12 Sodium sulphate 25.00 16.67

18.VILDAGLIPTIN



1 Pyrrolidine -2-carboxlic acid 44.00 73.33

2 3- amino-1- adamantanole 58.00 96.67

3 Acetone 200.00 333.33

4 Activated carbon 5.00 8.33

5 Ammonium bicarbonate 36.00 60.00

6 Chloro acetyl chloride 44.00 73.33

7 Isopropyl alcohol 300.00 500.00

8 Isopropyl ether 200.00 333.33

9 Isopropyl ether 200.00 333.33

10 Methylene chloride 400.00 666.67

11 Methylene dichloride 400.00 666.67

12 Tetrahydrofuran 200.00 333.33

13 Trifluoro acetic anhydride 75.00 125.00

ANNEXURE – IX



WASTE WATER DETAILS

S.No Purpose Effluent Water KLD

1 Process 55

2 Washings 5

3 Boiler Blow down 6

4 Cooling towers Blow down 11

5 Scrubbing system 2

6 Domestic 3.8

Total 82.8

HTDS & LTDS DETAILS

S. No

Purpose HTDS KLD

LTDS KLD

Total Effluent in

KLD

Disposal Method

1 Process 30 25 55

ZLD System

2 Washings 0 5 5

3 Boiler Blow down 0 6 6

4 Cooling towers blow down

0 11 11

5 Scrubbing system 2 0 2

6 Domestic 0 3.8 3.8

Total 32 50.8 82.8



ANNEXURE – X

CONSOLIDATED STATEMENT- POLLUTION DETAILS



LIST OF ENCLOSURES

S. No Content Enclosures

1 Sale Agreement Enclosure - I

2

Topomap Showing Inter-State Booundary[

Telangana State – Andhra Pradesh Interstate

Boundary – 400 meters (NE)] Within 5 Kms

Radius

Enclosure - II

Enclosure-II FIGURE: TOPOMAP SHOWING INTER-STATE BOOUNDARY WITHIN 5 KMS RADIUS

Telangana State – Andhra Pradesh Inter-state Boundary – 400 meters (NE)

LIST OF ANNEXURES S. No Content...

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