LIST OF ANNEXURES S. No Content Annexure...LIST OF ANNEXURES S. No Content Annexure 1 List of Proposed Products & By-Products Annexure - I 2 Site Plan Annexure - II 3 Manufacturing

Additional Information SGR Laboratories Private Limited

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

Prepared By Rightsource Industrial Solutions Pvt. Ltd Page 1


ANNEXURE – I

LIST OF PROPOSED PRODUCTS

S. No Name of the Product Quantity in Kg/Month CAS Number Therapeutic Category

1 Atorvastatin Calcium 10000.00 134523-03-8 Antihyperlipidemic 2 Dapoxetine Hydrochloride 4000.00 129938-20-1 Premature ejaculation 3 D-penicillamine 5000.00 52-67-5 Antibiotic 4 Duloxetine Hydrochloride 5000.00 136464-34-9 Anti depressant 5 Lansoprazole 10000.00 103577-45-3 Anti ulcer 6 Lopinavir 5000.00 192725-17-0 Anti viral 7 Moxifloxacin hydrochloride 2000.00 186826-86-8 Anti bacterial 8 Nebivolol 5000.00 152520-56-4 Anti hypertensive 9 Ritonavir 5000.00 155213-67-5 Anti viral

10 Sildenafil citrate 15000.00 171599-83-0 Erective dysfunction 11 Valsartan 15000.00 137862-53-4 Anti hypertensive

Total 81000.00

LIST OF BY-PRODUCTS

S. No Name of the Product Name of the By-Product Quantity in Kg/Day

1 Dapoxetine Hydrochloride Isomer for product Recovery 138.67

2 D-penicillamine 2-Phenyl-N-(2-Phenylimino-ethyl)-acetamide 313.57

3 Duloxetine Hydrochloride Isomer for product Recovery 98.75

Mandelic acid 80.79



ANNEXURE - II SITE PLAN



ANNEXURE - III

MANUFACTURING PROCESS DESCRIPTION

1. ATORVASTATIN CALCIUM TRIHYDRATE

Process Description Stage-1 (6-Cyanomethyl-2, 2-dimethyl- [1, 3] dioxan-4-yl)-acetic acid tert-butyl ester

undergoes hydrogenation in presence of Raney Nickel and Methanol to give Stage-1

product.

Stage-2 Stage-1 reacts with 4-(4-fluorophenyl)-2-isobutyryl-3 phenyl-4-oxo-N-phenyl-

butyramide in presence of IPA and Cyclohexane to give Stage-2 product.

Stage-3 Satge-2 undergoes hydrolysis in presence of Hydrochloric acid and IPA to give

stage-3 product.

Sateg-4 Stage-3 product reacts with Calcium acetate in presence of Methanol and toluene to

give Atorvatatin calcium Trihydrate

ATORVASTATIN CALCIUM TRIHYDRATE

Route of Synthesis

Stage-1

O

OOONC

O

OOO

H2N+ 2 H2

(6-Cyanomethyl-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid

tert-butyl esterC14H23NO4

269.34

4.00[6-(2-Amino-ethyl)-2,2-dimethyl-

[1,3]dioxan-4-yl]-acetic acid tert-butyl ester

C14H27NO4

273.37



Stage-2

O

OOO

H2N

[6-(2-Amino-ethyl)-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acid

tert-butyl esterC14H27NO4

273.37

NNH

F

O CH3H3C OO

H3CCH3

OO

+

O

HN

O

O

F

+ 2 H2O

2-[2-(4-Fluoro-phenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoic acid phenylamide

C26H24FNO3

417.47

(6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-

acetic acid tert-butyl esterC40H47FN2O5

654.81

2X18=36.0

Stage-3

NNH

F

O CH3H3C OO

H3CCH3

OO

(6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-

ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid tert-butyl ester

C40H47FN2O5

654.81

H2ONN

H

F

O CH3H3C OHHO

OO

+

+

18.0 7-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid tert-butyl

esterC37H43FN2O5

614.75

O

Acetone58.08



Stage-4

NNH

F

O CH3H3C OHHO

OO

7-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-

dihydroxy-heptanoic acid tert-butyl ester

C37H43FN2O5

2X614.75=1229.5

+ Ca(COOCH3)2

(158.17)

+ 3 H2O

54.0

NNH

F

O CH3H3COHOH

O-

O

2

Ca+2. 3H2O

(1209.26)

+ OH2

(148.24)

+ 2 CH3COONa

(164)

+

(80)

2 NaOH

2

Atorvastatin calcium trihydrate 2-Methyl-propan-2-ol Sodium acetate


Flow Chart

Stage-1

Stage-2

Stage-3

Stage-4


(6-Cyanomethyl-2,2-dimethyl- [1,3]dioxan-4-yl)-acetic acid tert-butyl esterRaney NickelMethanol

Methanol Recspent catalyst

Stage-14-(4-fluorophenyl)-2-isobutyryl-3 phenyl-4-oxo-N-phenyl-butyramide cyclohexaneIsopropylalcohol

Cyclo hexane RecIsopropyl alcohol Rec

Stage-2Sodium carbonateAcetonitrileIPAHydrochloric acid

Acetonitrile RecIPA Rec

Stage-3Calcium acetate Sodium hydroxide flakes Hydrochloric acidMethanolToluene

Methanol RecToluene Rec




Material Balance:

Material balance of Atorvastatin calcium Trihydrate Stage-1 Batch Size: 500.0Kg

Name of the input Quantity in Kg

Name of the out put Quantity In Kg

(6-Cyanomethyl-2,2-dimethyl- [1,3]dioxan-4-yl)-acetic acid tert-butyl ester

252.00 Stage-1 248.00

Hydrogen 0.68 Methanol Recovery 152.00 Raney Nickel 1.00 Methanol Loss 8.00 Methanol 160.00 Spent catalyst 1.00 Organic residue 4.68 Process residue-4.68 Total 413.68 Total 413.68




Stage-1 248.00 Stage-2 570.00 4-(4-fluorophenyl)-2-isobutyryl-3 phenyl -4-oxo-N-phenyl-butyramide

378.50 Generated water 32.48

Pivalic acid 2.00 Cyclohexane Recovery 190.00 cyclohexane 200.00 Cyclohexane Loss 10.00 Isopropylalcohol 150.00 Isopropylalcohol Recovery 143.00 Isopropylalcohol Loss 7.00 Organic residue(Pivalic acid) 26.02 Process residue-26.02

(organic impurities-24.02, Pivalic acid-2)

Total 978.50 Total 978.50






Stage-2 570.00 Stage-3 522.00 Sodium carbonate 7.00 Acetonitrile Recovery +

Acetone-50.16 335.16

Acetonitrile 300.00 Acetonitrile Loss 15.00 IPA 150.00 IPA Recovery 143.00 Water 2000.00 IPA Loss 7.00 Effluent water 1991.60 (water-1984.60, Sodium

carbonate-7) 0

Organic Residue 13.24 Process residue-13.24 Total 3027.00 Total 3027.00




Stage-3 522.00 Atorvastatin calcium Trihydrate

500.00

Calcium acetate 66.82 Methanol Recovery 280.00 Sodium hydroxide flakes 33.95 Methanol Loss 15.00 Hydrochloric acid 3.36 Toluene Recovery 185.00 Methanol 300.00 Toluene Loss 10.00 Toluene 200.00 Effluent water 1549.98 Activated carbon 5.00 (water-1477.56,sodium

acetate-69.42,Toluene-3) 0

Hyflow 3.00 Spent carbon & Hyflow 8.00 Water 1500.00 Organic residue 86.15 Process residue-79.15

Organic Impurities-16.51,2-Methyl-propan-2-ol-62.64, Distillation residue-7 (Toluene-2, Methanol-5)

Total 2634.13 Total 2634.13



DAPOXETINE HYDROCHLORIDE

Process Description: Stage-1 1-Napthol reacts with 3-Phenyl propyl bromide and Potassium hydroxide in the

presence of Methanol to give Stage-1 product.

Stage-2 Step-A Stage-1 product reacts with N-Bromosuccinimide in the presence of EDC to give

Stage-2A product.

Step-B Step-2A product reacts with Di methyl amine in the presence of Ethanol to give

Stage-2B product. Stage-3 Stage-2 B product reacts with Tartaric acid in the presence of Ethanol to give Stage-

3 product.

Stage-4 Stage-3 product reacts with IPA. HCl to give Dapoxetine Hydrochloride .


Route of Synthesis: Stage-1

OH

1-NaptholC10H8O

144.17

+ Br

3-phenyl propyl bromide

C9H11Br

199.09

+ KOH

Potassium hydroxide

56.11

Methanol

O

1-(3-Phenyl-propoxy)-naphthalene

C19H18O

262.35

+ KBr

119.00

+ H2O

18.0



Stage-2

Step-A

O

1-(3-Phenyl-propoxy)-naphthalene

C19H18O262.35

+

N-Bromo succinimide

OON

Br

C4H4BrNO2

177.98

EDC

O

Br

1-(3-Bromo-3-phenyl-propoxy)-naphthalene

C19H17BrO

341.24

+

OOHN

Pyrrolidine-2,5-dione

C4H5NO2

99.09

Step-B

O

Br

1-(3-Bromo-3-phenyl-propoxy)-naphthalene

C19H17BrO

341.24

+

Dimethyl amine

HN

C2H7N

45.08

Ethanol

O

N

Dimethyl-[3-(naphthalen-1-yloxy)-1-phenyl-propyl]-amine

C21H23NO

305.41

+ HBr

80.91



Stage-3

O

N

Dimethyl-[3-(naphthalen-1-yloxy)-1-phenyl-propyl]-amine

C21H23NO

305.41

+

Tartaric acid

OH

OHO

HO

O

OH

C4H6O6

150.09

O

N

OH

OHO

HO

O

OH

Dimethyl-[3-(naphthalen-1-yloxy)-1-phenyl-propyl]-amine tartarsate

C25H29O7N

455.50Stage-4

O

N

OH

OHO

HO

O

OH

Dimethyl-[3-(naphthalen-1-yloxy)-1-phenyl-propyl]-amine tartarsate

C25H29O7N

455.50

IPA.HCl

O

N HCl

Dapoxetine Hydrochloride

C21H23NO

305.41

OH

OHO

HO

O

OH+

Tartaric acidC4H6O6

150.09




Flow Chart: 1-Naphthol3-Phenylpropyl bromidePotassium hydroxideMethanol

Stage-1 Methanol Rec

Stage-2 Ethanol RecDiethyl ether Rec

Stage-1Di methyl amineEthanolDiethylether

Stage-3 Ethanol RecStage-2EthanolTartaric acid

Stage-4 Ethyl acetate Rec

Stage-3Sodium hydroxideEthyl acetateIPA.HCl


Material Balance: Material balance of Dapoxetine Hydrochloride

Stage-1 Batch Size:100.00 Kg Name of the input Quantity

in Kg Name of the out put Quantity

In Kg 1-Naphthol 106.00 Stage-1 187.00 3-Phenylpropyl bromide 147.00 Methanol Recovery 251.00 Potassium hydroxide 42.00 Methanol Loss 13.00 Methanol 265.00 Diethyl ether Recovery 333.00 Diethyl ether 350.00 Diethyl ether Loss 17.00 Sodium sulphate 20.00 Carbon tetra hydrochloride

Recovery 238.00

Carbon tetra hydrochloride 250.00 Carbon tetra hydrochloride Loss 12.00 Water 500.00 Effluent water 600.72

(Water-500,Generated water-

13.23,Potassium bromide-87.49) 0

Inorganic solid waste 20.00 (Sodium sulfate) 0 Organic Residue 8.28 Process residue-7.28



Distillation residue-1,(Methanol-1) Total 1680.00 Total 1680.00

Material balance of Dapoxetine Hydrochloride



In Kg Stage-1 187.00 Stage-2 206.00 Di methyl amine 32.00 Ethanol Recovery 665.00 Ethanol 700.00 Ethanol Loss 35.00 Diethyl ether 700.00 Diethyl ether Recovery 665.00 Sodium sulphate 20.00 Diethyl ether Loss 35.00 N-Bromo succinamide 127.00 Effluent water 800.00 water 800.00 (Water-800) 0 Inorganic solid waste 20.00 (Sodium sulfate) 0 Process emission 56.19 (Hydrogen Bromide-56.19) 0 Organic Residue 0 Succinimide Recovery 70.63 Organic residue 13.18 Process residue-13.18 Total 2566.00 Total 2566.00




In Kg Stage-2 206.00 Stage-3 153.00 Ethanol 100.00 Ethanol Recovery 95.00 Tartaric acid 51.00 Ethanol Loss 5.00 Isomer recovery 104.00 Organic Residue Total 357.00 Total 357.00




In Kg Stage-3 153.00 Dapoxetine Hydrochloride 100.00 Sodium hydroxide 1.00 Ethyl acetate Recovery 90.00 Ethyl acetate 100.00 Ethyl acetate Loss 10.00 IPA.HCl 2.00 Effluent water 851.40

Water 800.00 (Water-800,Tartraic acid-50.40,

Sodium Hydroxide-1) 0

Organic Residue 4.60 Process residue-4.6 Total 1056.00 Total 1056.00



D-PENICILLAMINE

Process description: Stage-1 The Penilloic acid is reacted with the mixture of Aniline, Water, Acetic acid and Toluene medium , and extracting the product in to aqeous layer to give D-Penicillamine crude. The obtained crude is crystallized with methanol to give Pure D-Pencillamine

D-PENICILLAMINE Route of Synthesis: Stage-1

HN

OHN

SCH3

CH3

OOH

Penilloic acid

C15H20N2O3S

308.39

+

NH2

Aniline

C6H7N93.13

Methanol, Toluene, EDC, Acetic acid & Water

H3C

HS

CH3

OH

O

NH2H

D-PenicillamineC5H11NO2S

149.21

+

HN

O

N

2-Phenyl-N-(2-phenylimino-ethyl)-acetamide

C16H16N2O

252.31

D-PENCILLAMINE Flow chart:

Stage-1

Peniloic acidAnilineMethanolTolueneEDCAcetic acidActivated carbonHyflow Water

Methanol + Toluene (Mixed Solvents)RecoveryEDC RecoveryEffluent water

D-Penicillamine



Material balance:

Material Balance of D-Penicillamine Stage-1

Batch Size:200.00Kg Name of the input Quantity


in Kg Peniloic acid 460.00 D-Penicillamine 200.00 Aniline 139.00 By-Product

(2-Phenyl-N-(2-phenylimino-ethyl)-acetamide)

376.28

Methanol 400.00 Methanol + Toluene (Mixed Solvents)Recovery

718.00

Toluene 350.00 Methanol loss 10.00 EDC 300.00 Toluene loss 12.00 Acetic acid 89.55 EDC Recovery 295.00 Activated carbon 15.00 EDC loss 5.00 Hyflow 1.00 Effluent water 2503.00 Water 2500.00 (Water-2500,Toluene-3) 0 Spent carbon 15.00 Inorganic solid waste

(Hyflow) 1.00

Spent acetic acid 89.55 Organic residue 29.72 Process residue-22.72

Distillation residue-7 (Methanol-5,Toluene-2)

Total 4254.55 Total 4254.55



DULOXETINE HYDROCHLORIDE

Process Description: Stage-1 3-Dimethylamino-1-thiophen-2-yl-propan-1-ol reacts with Mandalic acid in the

presence of Ethyl acetate to give Stage-1 product.

Stage-2 Stage-1 product undergoes reaction with Sodium carbonate in the presence of MDC

to give Stage-2 product.

Stage-3 Stage-2 product reacts with 1-Fluoro naphthalene, Oxalic acid in the presence of

DMSO to give Stage-3 product.

Stage-4 Stage-3 product reacts with Phenyl chloro formate in the presence of Toluene a to

give Stage-4 product.

Stage-5 Stage-4 product reacts with Hydrochloric acid in the presence of Ethyl acetate to

give Duloxetine Hydrochloride product.

DULOXETINE HYDROCHLORIDE Route of synthesis: Stage-1:

SN

CH3

CH3

OH

SN

CH3

CH3

+OH

O

OH

OHO

OH

3-Dimethylamino-1-thiophen-2-yl-propan-1-ol

C9H15NOS

2 X185.29 = 370.58

L(+)-Mandelic acidC8H8O3

152.15

3-Dimethylamino-1-thiophen-2-yl-propan-1-ol,Mandelate

C17H23NO4S

337.43

Ethyl acetate

OH

2

SN

CH3

CH3

OH

Isomer

185.30

+



Stage-2:

SN

CH3

CH3

OH

OHO

OH

3-Dimethylamino-1-thiophen-2-yl-propan-1-ol,Mandelate

C17H23NO4S

337.43

MDC

10%Na2CO3 SN

CH3

CH3

OH

OHO

OH+

3-Dimethylamino-1-thiophen-2-yl-propan-1-olC9H15NOS

185.29

C8H8O3

152.15

Mandelic acid

Stage-3:

Step-A:

SN

CH3

CH3

OH

3-Dimethylamino-1-thiophen-2-yl-propan-1-ol

C9H15NOS

185.29

+

F

1-Fluoro-naphthalene

C10H7F

146.16

NaOH

DMSO

SN

CH3

CH3

O

C19H21NOS

311.44

+ HF

Hydrofluoride

20.01

Dimethyl-[3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-amine



Step-B:

+

Oxalic acid

O OH

OHO

C2H2O4

90.03

NaOH

DMSO

SN

CH3

CH3

OO OH

OHO

C21H23NO5S

401.48

Dimethyl-[3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-amine Oxalate

SN

CH3

CH3

O

Dimethyl-[3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-amine

311.44

C19H21NOS

Stage-4:

SN

CH3

CH3

O O OH

OHO

C21H23NO5S

401.48

Dimethyl-[3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-amine Oxalate

+OCl

O

C7H5ClO2

156.57

Phenyl chloro formate

+ H2O

18.00

NaOH

S

HN

CH3

O O OH

OHO

Methyl-[3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-amine; compound with oxalic acid

C20H21NO5S

387.45

+

OH

Phenol

94.11

+ CH3Cl

50.49

Methyl chloride

+ CO2

Carbon dioxide44.00



Stage-5:

S

HN

CH3

O O OH

OHO

Methyl-[3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-amine; compound with oxalic acid

C20H21NO5S

387.45

+ HCl

Hydrochloric acid36.5

Aq.NH3

Ethyl acetate

S

HN

CH3

O

HCl

O OH

OHO

Duloxetine Hydrochloride

C18H20ClNOS

333.88

Oxalic acid

90.03

+




Flow Chart:

Stage-13-Dimethylamino-1-thiophen-2-yl-propan-1-olL(+) Mandelic acidEthyl acetate

Ethyl acetate Rec

Stage-2 MDC RecStage-1DichloromethaneSodium carbonate

Stage-3 DMSO RecToluene Rec

Stage-21-FluoroNapthaleneOxalic acidDMSOToluene

Stage-4 Toluene Rec

Stage-3Phenyl chloroformateSodium carbonateToluene

Stage-5 Ethyl acetate Rec

Stage-4Hydrochloric acidEthyl acetate



Material Balance:

Material balance of Duloxetine Hydrochloride Stage-1 Batch Size: 200.0Kg Name of the input Quantity


In Kg 3-Dimethylamino-1-thiophen-2-yl-propan-1-ol

237.00 Stage-1 215.00

L(+) Mandelic acid 98.00 Ethyl acetate Recovery 340.00 Ethyl acetate 360.00 Ethyl acetate Loss 18.00 Isomer recovery 118.50 Organic Residue 3.50



Process residue-1.5 Distillation residue-2 (Ethyl acetate-2)




In Kg Stage-1 215.00 Stage-2 118.00 Dichloromethane 200.00 Dichloromethane Recovery 185.00 Sodium carbonate 5.00 Dichloromethane Loss 10.00 Sodium chloride 10.00 Cyclo hexane Recovery 361.00 Cyclo hexane 380.00 Cyclo hexane Loss 19.00 Water 1000.00 Effluent water 1015.00 (Water-1000,Sodium carbonate-

5,Sodium chloride-10) 0

Mandelic acid recovery 96.95 Organic Residue 5.05 Process residue-0.05

Distillation residue-5 (DCM-5)

Total 1810.00 Total 1810.00



In Kg Stage-2 118.00 Stage-3 255.00 1-FluoroNapthalene 93.00 Toluene Recovery 945.00 Oxalic acid 58.00 Toluene Loss 50.00 Sodium hydroxide 10.00 Isopropyl alcohol Recovery 285.00 DMSO 5.00 Isopropyl alcohol Loss 15.00 TBAB 3.00 Effluent water 1020.00 Toluene 1000.00 (Water-1000,DMSO-5,

TBAB-3,Sodium hydroxide-10, Toluene-2)

0

Isopropyl alcohol 300.00 Process emission 12.62 Water 1000.00 (Hydrogen Flouride-12.62) 0 Organic Residue 4.38 Process residue-1.38

Distillation residue -3 (Toluene-3)

Total 2587.00 Total 2587.00





In Kg Stage-3 255.00 Stage-4 240.00 Phenyl chloroformate 100.00 Toluene Recovery 940.00 Sodium carbonate 0.60 Toluene Loss 50.00 Sodium sulfate 10.00 Ethyl acetate Recovery 1045.00 Sodium hydroxide 6.70 Ethyl acetate Loss 55.00 DMSO 2.00 Effluent water 1374.07 TEA 5.00 (Water-1288,DMSO-2,

Oxalic Acid-10 ,TEA-5, Phenol-59.77, Toluene-2,sodium carbonate-0.6,sodium hydroxide-6.7)

0

Oxalic acid 10.00 Inorganic Residue 10.00 Toluene 1000.00 (Sodium sulphate-10) 0 Ethyl acetate 1100.00 Process Emission 60.02 DM. water 1300.00 (Carbon dioxide-27.94,Methyl

chloride-32.06,) 0

Organic Residue 15.21 Process residue-7.21

Distillation residue (Toluene-8)

Total 3789.30 Total 3789.30



In Kg Stage-4 240.00 Duloxetine Hydrochloride 200.00 Hydrochloric acid 23.00 Ethyl acetate Recovery 95.00 Ethyl acetate 100.00 Ethyl acetate Loss 5.00 Methanol 4.00 Methanol Recovery 4.00 Oxalic acid Recovery 56.00 Organic Residue 7.00 Process residue-7 Total 367.00 Total 367.00



LANSOPRAZOLE

Process Description

Stage-1

2, 3-Lutidine reacts with Hydrogen Peroxide and Nitric Acid in Presence of Acetic

acid to give stage-1 product.

Stage-2

Stage-1 Product reacts with 1, 1, 2- trifluoroethanol and Acetic Anhydride in

presence of Potassium Carbonate to give stage-2 product.

Stage-3

Stage-2 product undergoes chlorination with Thionyl Chloride in presence of Toluene to give stage-3 product.

Stage-4

Stage-3 product undergoes condensation with 1H-Benzoimidazole-2-thiol in

presence of Sodium Hydroxide to give stage-4 product.

Stage-5

Stage-4 product undergoes oxidation with Hydrogen peroxide in presence of IPA to

give Lansoprazole.



LANSOPRAZOLE

Route of Synthesis:

Stage-1

2,3-Lutidine

107.15

+

H2O2

34.00

+ HNO3

63.00

+ 2 H2O

C7H9N

36.044-Nitro-2,3-Dimethyl pyridine-N-Oxide

168.15

C7H8N2O3

N+

O-

H3C

H3C

NO2

NCH3

CH3

Hydrogen Peroxide

HO OH

Stage-2

+

4-Nitro-2,3-Dimethyl pyridine-N-Oxide

168.15

CF3CH2OH

+ K2CO3+

C4H6O3

+ + HCl

100.04 102.09

N

OCH2CF3

CH3

CH2OH

. HCl

257.64

+ KHCO3

100.12

+ KNO2

85.10

+CH3COONa

82.03

CH3COOH

C7H8N2O3

C9H11ClF3NO2

OO

OOHF

F

F

N+

O-

H3C

H3C

NO2

1,1,2-Trifluoro-ethanol Acetic anhydride 138.21

NaOH

40.00 36.46

60.05

+

[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol



Stage-3

N

OCH2CF3

CH3

CH2OH

. HCl

257.64

+

C9H11ClF3NO2

[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol

+

SOCl2

Thionyl chloride

118.97

N

OCH2CF3

CH3

CH2Cl

. HCl

276.08

SO2

64.06

+ HCl

36.46

C9H10Cl2F3NO

S

O

Cl

Cl

2-Chloromethyl-3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridine Hydrochloride

Stage-4

N

OCH2CF3

CH3

CH2Cl

. HCl

276.08

C9H10Cl2F3NO

2-Chloromethyl-3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridine Hydrochloride

+N

HN

HS + 2 NaoH

80.00

150.20

N

OCH2CF3

CH3

CH2 SN

HN

+ 2 NaCl

116.88

+ 2 H2O

36.04

C7H6N2S

C16H14F3N3OS

353.36

1H-Benzoimidazole-2-thiol

2-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethylthio]-1H-benzo[d]imidazole



Stage-5

N

OCH2CF3

CH3

CH2 SN

HN

+

C16H14F3N3OS

353.36

2-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethylthio]-1H-benzo[d]imidazole

+

H2O2

Hydrogen peroxide

N

OCH2CF3

CH3

CH2 SN

HN

O

Lansoprazole

369.36

H2O

18.02C16H14F3N3O2S

HO OH

34.01

LANSOPRAZOLE



Flow Chart:

Stage-1

Stage-2

Stage-3

Stage-4

Stage-5

2,3-LutidineAcetic AcidHydrogen Peroxide (50%)Sulfuric AcidNitric Acid Effluent water

Stage-1Sodium HydroxidePotassium Carbonate1,1,2-Tri Fluoro EthanolMIBKAcetic AnhydrideTEBACTolueneHydrogen Chloride Activated Carbon

Stage-2Methylene DichlorideTolueneThionyl Chloride

Stage-3Sodium Hydroxide1H-Benzoimidazole-2thiol

Stage-4Isopropyl AlcoholHydrogen Peroxide (50%)CatalystChloroformAcetone

Isopropyl alcohol RecoveryAcetone recoveryEffluent water

Effluent water

Toluene recoveryMethylene Dichloride RecoveryEffluent water

MIBK RecoveryToluene RecoveryEffluent water

LANSOPRAZOLE

LANSOPRAZOLE



MATERIAL BALANCE:

Material Balance of Lansoprazole Stage-1 Batch Size:500Kg


Name of the out put Quantity in Kg

2,3-Lutidine 188.00 Stage-1 280.00 Acetic Acid 46.00 Spent Sulfuric Acid 50.00 Hydrogen Peroxide (50%) 120.00 Effluent water 969.23 Sulfuric Acid 50.00 (Water-800, Generatedwater-

63.23,water from hydrogen peroxide-60, Acetic Acid - 46)

0

Nitric Acid 111.00 Organic Residue 15.77 Water 800.00 Process residue – 15.77 Total 1315.00 Total 1315.00




Stage-1 280.00 Stage-2 405.00 Sodium Hydroxide 67.00 MIBK Recovery 140.00 Potassium Carbonate 230.00 MIBK Loss 5.00 1,1,2-Tri Fluoro Ethanol 167.00 Toluene Recovery 380.00 MIBK 150.00 Toluene Loss 10.00 Acetic Anhydride 170.00 Effluent Water 1041.59 TEBAC 1.00 (Water-800, Sodium Acetate-136.59,

Acetic Acid-100,Toluene-5) 0

Toluene 400.00 Inorganic solid waste 308.70 Hydrogen Chloride 61.00 (Potassium Nitrite-141.70, Potassium

Bicarbonate-167) 0

Activated Carbon 5.00 Spent Carbon 5.00 Water 800.00 Organic Residue 35.71 Process Residue-25.71

Distillation Residue-10 (MIBK-5,Toluene-5)

Total 2331.00 Total 2331.00






Stage-2 405.00 Stage-3 415.00 Methylene Dichloride 400.00 Toluene Recovery 475.00 Toluene 500.00 Toluene Loss 15 Thionyl Chloride 180.00 Methylene Dichloride Recovery 380.00 Methylene Dichloride Loss 12.00 Process Emissions 152.68 (Sulfur Dioxide-97.50,Hydrogen

Chloride-55.18) 0

Organic Residue 35.32 Process residue- 17.32

Distillation Residue-18 (Toluene-10, Methylene Dichloride -8)

Total 1485.00 Total 1485.00




Stage-3 415.00 Stage-4 505.00 Sodium Hydroxide 121.00 Effluent Water 829.88 1H-Benzoimidazole-2thiol 226.00 (Water-600, Generated Water-

54.18,Sodium Chloride-175.70) 0

Water 600.00 Organic Residue 27.12 (Process Residue-27.12) Total 1362.00 Total 1362.00

Material Balance of Lansoprazole



Stage-5 Batch Size:500Kg Name of the input Quantity


in Kg Stage-4 505.00 Lansoprazole 500.00 Isopropyl Alcohol 250.00 Isopropyl Alcohol Recovery 238.00 Hydrogen Peroxide (50%) 98.00 Isopropyl Alcohol Loss 5.00 Catalyst 1.00 Chloroform Recovery 384.00 Chloroform 400.00 Chloroform Loss 12.00 Acetone 150.00 Acetone Recovery 143.00 Water 600.00 Acetone Loss 3.00 Effluent Water 674.75 (Water-600, Generated Water-

25.75, Water from Hydrogen peroxide-49)

0

Catalyst Reuse 1.00 Organic Residue 43.25 Process residue-28.25

Distillation residue-15 (IPA-7, Chloroform-4,Acetone-4)

Total 2004.00 Total 2004.00



LOPINAVIR Process Description Stage-1 Step-A (R)-2-amino-3-phenyl propanoic acid reacts with benzyl chloride ,Potassium

carbonate in presence of Ethanol to give Stage-A product.

Step-B Stage-A Product reacts with Acetonitrile, Sodium amide and citric acid monohydrate

in presence of MTBE to give Stage-1 product.

Stage-2 Satge-1 reacts with Benzyl magnesium chloride in presence of THF, MTBE to give

Stage-2 product.

Stage-3 Step-A Stage-2 product reacts with sodium borohydride in presence of Methane sulphonic

acid, TEA and 1, 2-DME to give step-A as product.

Step-B Valina reacts with Methyl chloro formate and Acrylonitrile to give Stage-3B as

product.

Step-C Stage-3C Product undergoes Hydrogenation by using Raney nickel as catalyst and

methanol to give Stage-3C product.

Step-D (2S)- (1-Tetra hydro pyramid-2-one)-3-methyl butanoic acid reacts with Imidazole in

presence of THF to give Step-D product.

Step-E Step-A reacts with Step-D in presence of Ethyl acetate to give Step-E product.

Step-F Step-E reacts with Ammonium formate in presence of Palladium carbon and

Methanol to give Step-F product.

Step-G



Step-F product reacts with L-Pyro glutamic acid in presence of DMF, Ethyl acetate to

give (2S, 3S, 5S)-2-Amino-3-hydroxy-5-(1-tetra hydro pyrmid-2-onyl)-3-methyl

butanoyl) amino-1, 6-diphenyl hexane-S-pyro glutamate (THP).

Stage-4 N-(4-Amino-1-benzyl-3-hydroxy-5-phenyl-pentyl)-3-methyl-2-(2-oxo-

tetrahydropyrimidin-1-yl)-butyramide (S)-5-oxo-pyrrolidine-2-carboxylate reacts with

2,6-Dimethyl phenoxy acetyl chloride and sodium bicarbonate in the presence of

Ethyl acetate to give stage-4 as product.

Stage-5 Stage-4 undergoes purification with ethanol to give Lopinavir (pure).

LOPINAVIR

Route of Synthesis:

Stage-1

Step-A

(R)-2-amino-3-phenyl propanoic acid

O

OH

H2N

+

Benzyl Chloride

Cl

(R) -benzyl 2-(dibenzyl amino)-3-phenyl propanoate

OO

N

3 + K2CO3

Potassium Carbonate

C9H11NO2

165.19

C7H7Cl

3X126.58=379.74138.21

+ 2 KCl + +

C30H29NO2

435.56

2X74.55=149.10

Ethanol

Potassium Chloride

HCl

36.46

Hydrogen Chloride

CO2

44.01

+ H2O

18.02Carbon dioxide



Step-B

Monosodium citrate

(R) -benzyl 2-(dibenzyl amino)-3-phenyl propanoate

C30H29NO2

435.56

+ CH3CN + NaNH2 +

C6H10O8

Acetonitrile Sodium Amide Citric Acid Monohydrate

41.05 39.01 210.14

MTBE

OH

1-Imino-4-(N,N-dibenzylamino)5-phenyl-3-oxo-pent-1-ene

C25H24N2O

368.47

+ + + NH3

Benzyl Alcohol Ammonia

C7H8O

108.14 214.11

C6H7O7Na

OO

N

C

ON

NH

HO

OOH

O OH

OHOH2O

Na+

HO

OO-

O OH

O

HO + H2O

17.03

18.0



Stage-2

1-Imino-4-(N,N dibenzylamino)-5-phenyl-3-oxo-pent-1-ene

C

ON

NH

C25H24N2O

368.47

Benzyl Magnesium Chloride

MgCl

+

Citric Acid monohydrate

(R,Z)-5-amino-2-(dibenzyl amino)-1,6-diphenyl hex-4-en-3-one

ON

NH2

Magnesium Chloride

+ + NaCl

58.44

C7H7MgCl

150.89210.14

C32H32N2O

460.61

+ MgCl2

95.21

+

C6H7O7Na

Monosodium Citrate

+ H2O

214.11

18.02

THF/MTBE

HO

O

OH

O OH

O

HO. H2O

Sodium Chloride

C6H10O8

Na+

HO

OO-

O OH

O

HO



Stage-3 Step-A


ON

NH2

C32H32N2O

460.61

(2R)-5-amino-2-(dibenzyl amino)-1,6-diphenyl hexane-3-ol

OHN

NH2

+ NaBH4 + 3H2O

37.83

54.06

C32H36N2O

464.64

+ H3BO3

61.83

MSA

TEA/1,2 DMEsodium

Borohydride

+HCl

36.46

Hydrochloric acid

Boric acid

+ NaCl

58.44

Sodium chloride

2 H2

4.04

+

Step-B

HO

O

NH2

CH3H3C

valina

C5H11NO2

117.15

+

Methylchloroformate

O

OClCH3

C2H3ClO2

94.50

+

Acrylonitrile

CH2

N

C3H3N

53.06

N-(2-Cyanoethyl)-N-(methoxycarbonyl)-L-valine

CN

N OCH3

OH3C CH3

HO

O

C10H16N2O4

228.25

+ HCl

Hydrochloric acid

36.5



Step-C

N-(2-Cyanoethyl)-N-(methoxycarbonyl)-L-valine

CN

N OCH3

OH3C CH3

HO

O

C10H16N2O4

228.25

Raney Ni

Methanol,NaOH

N NH

OH3C CH3

HO

O

3-Methyl-2-(2-oxo-tetrahydro-pyrimidin-1-yl)-butyric acid

C9H16N2O3

200.23

+ 2H2

4.00

+ CH3OH

32.04

Metahnol

Step-D

N

N

(2S)-(1-Tetrahydropyramid-2-one)-3-methylbutanoic acid

N

NH

O

OH

O

Imidazole

+N

NH

O

O

C9H16N2O3

C3H4N2 C12H18N4O2

200.2368.07 250.30

+H2O

18.02

N

HN

1-[1-(Imidazole-1-carbonyl)-2-methyl-propyl]-tetrahydro-pyrimidin-2-one

THF



Step-E

N NN NH

O

O

1-[1-(4,5-Dihydro-imidazole-1-carbonyl)-2-methyl-propyl]-tetrahydro-pyrimidin-2-one

OHN

NH

N NH

N NH

O

O

Imidazole

OHN

NH2

5-Amino-2-dibenzylamino-1,6-diphenyl-hexan-3-ol

+

N-(1-Benzyl-4-dibenzylamino-3-hydroxy-5-phenyl-pentyl)-3-methyl-2-(2-oxo-tetrahydro

-pyrimidin-1-yl)-butyramideC41H50N4O3

+

646.86

C3H4N2

68.08

C32H36N2O

464.64

Ethyl acetate

Water

C12H18N4O2

250.30

Step-F

OHN

NH

N NH

O

O

N-(1-Benzyl-4-dibenzylamino-3-hydroxy-5-phenyl-pentyl)-3-methyl-2-(2-oxo-tetrahydro

-pyrimidin-1-yl)-butyramide

C41H50N4O3

646.86

+

Pd/C

OHH2N

NH

N NH

O

O

N-(4-Amino-1-benzyl-3-hydroxy-5-phenyl-pentyl)-3-methyl-2-(2-oxo-tetrahydro-pyrimidin-1-yl)-

butyramide

+

Ammonium formate

63.06

C27H38N4O3

466.62

TolueneC7H8

2 X 92.14=184.28

+ NH3

Ammonia

17.03

+

Carbondioxide

44.01

MeoHNH4

+

O-O

CH5NO2

CO2

+ H2

2.02

2



Step-G

OHH2N

NH

N NH

O

O

N-(4-Amino-1-benzyl-3-hydroxy-5-phenyl-pentyl)-3-methyl-2-(2-oxo-tetrahydro-pyrimidin-1-yl)-

butyramide

C27H38N4O3

466.62

+

L-Pyroglutamic acid

HN

O

O

OH

C5H7NO3

129.11

DMF

Ethyl acetate

OHH2N

NH

N NH

O

O

HN

O

O

OH

(2S, 3S, 5S)-2-Amino-3-hydroxy-5-(1-tetra hydro pyrmid-2-onyl)-3-methyl butanoyl) amino-1, 6

-diphenyl hexane-S-pyro glutamate (THP)

C32H45N5O6

595.73



Stage-4

H2N

OH

NH

N

O

NH

O

NH

O

H

COOH

C32H45N5O6

595.72

+

CH3

CH3

OHN

ONH

OHN

H3C CH3

ONH

O

2,6-Dimethyl phenoxy acetyl chloride

O

CH3

CH3

O

Cl

C10H11ClO2

198.64

+

SodiumCarbonate

NaHCO3

84.00

C37H48N4O5

628.80

+NH

H

COOHO

5-Oxo-pyrrolidine-2-carboxylic acid

C5H7NO3

129.11

+ NaCl

+ H2O + CO2

Sodium chloride

58.44

18.00 44.00

Ethyl acetate

N-{1-Benzyl-4-[2-(2,6-dimethyl-phenoxy)-acetylamino]-3-hydroxy-5-phenyl-pentyl}-3-methyl-2-(2-oxo-tetrahydro-

pyrimidin-1-yl)-butyramide (Lopinavir Crude)

N-(4-Amino-1-benzyl-3-hydroxy-5-phenyl-pentyl)-3-methyl-2-(2-oxo-tetrahydro-pyrimidin-1-yl)-butyramide;

compound with 5-oxo-pyrrolidine-2-carboxylic acid



Stage-5

CH3

CH3

O

HN

O

NH

OH

N

H3C CH3

O

NH

O

N-{1-Benzyl-4-[2-(2,6-dimethyl-phenoxy)-acetylamino]-3-hydroxy-5-phenyl-pentyl}-3-methyl-2-(2-oxo-tetrahydro-

pyrimidin-1-yl)-butyramide(Lopinavir Crude)

C37H48N4O5

628.80CH3

CH3

O

HN

O

NH

OH

N

H3C CH3

O

NH

O

Ethanol

C37H48N4O5

628.80

Lopinavir (pure)



LOPINAVIR

Flow Chart:

Stage-1

Stage-2

Stage-3

Stage-4

LOPINAVIR

(R)-2-amino-3-phenyl propanoic acidPotassium carbonateBenzyl chlorideEthanoln-HeptaneMethanolSodamideAcetonitrileCitric acid monohydrateMTBE

MTBE RecoveryEthanol RecoveryElluent water

MTBE RecoveryTHF Recoveryeffluent water

Methanol RecoveryEthyl acetaet RecoveryEffluent water

Acetone RecoveryEthyl acetate RecoveryEffluent water

Stage-5 Spent Carbon

Benzyl magnesium chlorideCitric acid monohydrateTHFSodium chlorideEthanolMTBESodium Boro hydrideMethane sulphonic acidImidazoleTPATHFEthyl acetateAmmonium formateMethanolPalladium carbon

2,6-Dimethyl phenoxy acetyl chloride (DPC)Ethyl acetateSodium bicarbonate (10%)Sodium chloride (10%)Sodium sulphateAcetone

EthanolActivated carbonHyflow

LOPINAVIR



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



(R)-2-amino-3-phenyl propanoic acid

103.00 Stage-1 210.00

Potassium carbonate 86.00 n-Heptane Recovery 238.00 Benzyl chloride 237.00 n-Heptane Loss 12.00 Ethanol 500.00 MTBE Recovery 475.00 n-Heptane 250.00 MTBE Loss 25.00 Methanol 400.00 Methanol Recovery 380.00 Sodamide 23.00 Methanol Loss 10.00 Acetonitrile 24.35 Ethanol Recovery 475.00 Citric acid monohydrate 124.85 Ethanol Loss 15.00 MTBE 500.00 Effluent water 452.00 Water 250.00 (Water-250,Generated Water-

10.62, Benzyl Alcohol-64.23, Monosodium citrate-127.15)

0

Inorganic solid waste 92.90 (Potassium chloride-92.90) 0 Process Emissions 60.15 (Carbon dioxide-27.39, Hydrogen

chloride-22.66,Ammonia-10.10) 0

Organic Residue 53.15 Orgnanic Impurities-33.15

Distillation residue-20 (Methanol-10,Ethanol-10)

Total 2498.20 Total 2498.20

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



Stage-1 210.00 Stage-2 252.00 Benzyl magnesium chloride 85.90 Ethanol Recovery 380.00 Citric acid monohydrate 119.70 Ethanol Loss 10.00 THF 400.00 MTBE Recovery 570.00 Sodium chloride 33.20 MTBE Loss 30.00 Ethanol 400.00 THF Recovery 380.00 MTBE 600.00 THF Loss 10.00 Water 300.00 Effluent water 486.27 (Water-300, Generated water-

10.08, Monosodium citrate-122.01, Magnesium chloride-54.18)

0

Organic Residue 30.53 Process residue-10.53

Distillation residue-20 (Ethanol-10,THF-10)



Total 2148.80 Total 2148.80

Material Balance of Lopinavir Stage-3 Batch Size: 250Kg



Stage-2 252.00 (2S, 3S, 5S)-2-Amino-3-hydroxy-5-(1-tetra hydro pyrmid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenyl hexane-S-pyro glutamate (THP)

257.00

Sodium Boro hydride 20.65 1,2-Dimethoxy ethane Recovery 285.00 Methane sulphonic acid 7.00 1,2-Dimethoxy ethane Loss 15.00 Triethyl amine 96.00 MTBE Recovery 238.00 1,2-Dimethoxy ethane 300.00 MTBE Loss 12.00 MTBE 250.00 THF Recovery 475.00 Ammonium chloride 200.00 THF Loss 15.00 Imidazole 39.65 IPA Recovery 285.00 TPA 55.00 IPA Loss 15.000 THF 500.00 Ethyl acetate Recovery 760.00 Ethyl acetate 800.00 Ethyl acetate Loss 24.00 Ammonium formate 29.48 Methanol Recovery 475.00 Methanol 500.00 Methanol Loss 15.00 Palladium carbon 20.60 DMF Recovery 285.00 L-Pyro glutamic acid 57.96 DMF Loss 15.00 DMF 300.00 MDC Recovery 570.00 Hydrochloric acid 20.00 MDC Loss 12.00 IPA 300.00 Dimethyl Acetamide recovery 152.00 Dimethyl acetamide 160.00 Dimethyl Acetamide Loss 8.00 MDC 600.00 Triethyl amine Reuse 96.00 Valina 75.00 Effluent water 692.91 Methyl chloro formate 60.45 (Water-470.52,Generated water-

10.42,Boric acid-33.75, Sodium Chloride-31.75 Methane sulphonic acid-7,imidazole-35.47,Ethyl acetate-8,TEA-96)

0

Acrylonitrile 34.00 Spent Catalysts 25.60 Hydrogen gas 3.29 (Palladium carbon Recovered-20.60,

Raney Nickel Recovered-5.00) 0

Raney Nickel 5.00 (Toluene Recovery + Methanol recovery) Mixed Solvent

106.25

Water 500.00 Process Emissions 71.99 (Hydrogen-20.1,Carbondioxide-

20.67,Ammonia-7.90,Hydrochloric acid-23.32 )

0

Inorganic Solid Waste 200.00 (Ammonium Chloride) 0 Organic Residue 80.33



Process residue-34.33 Distillation residue-46 (Methanol-10,Ethyl acetate-8,THF-10,MDC-18)

Total 5186.08 Total 5186.08

Material Balance of Lopinavir Stage-4 Batch Size: 250.0 Kg



THP(Lopinavir Intermediate) 257.00 Stage-4 260.00 2,6-Dimethyl phenoxy acetyl chloride (DPC)

85.50 Ethyl acetate Recovery 760.00

Ethyl acetate 800.00 Ethyl acetate Loss 40.00 Sodium bicarbonate (10%) 362.50 Acetone Recovery 473.00 Sodium chloride (10%) 100.00 Acetone Loss 25.00 Sodium sulphate 20.00 Effluent Water 1004.36 Acetone 500.00 (Water-500,generated water-

7.71,Sodium chloride-25.20 water from Sodium bicarbonate-326.25 ,water from Sodium chloride-90, Pyroglutamic acid-55.20)

0

Activated carbon 2.50 Spent Carbon 2.50 Water 500.00 Inorganic Solid Waste 20.00 (Sodium Sulfate) 0 Process Emissions 18.76 (Carbon dioxide-18.76) 0 Organic Residue 23.88

Process residue-21.88

Distillation residue-2 (Acetone-2)

Total 2627.50 Total 2627.50

Material Balance of Lopinavir Stage-5 Batch Size: 250.0 Kg



Stage-4 260.00 Lopinavir(pure) 250.00 Ethanol 500.00 Ethanol Recovery 475.00 Activated carbon 3.50 Ethanol Loss 20.00 Hyflow 5.00 Spent carbon & Hyflow 8.50 Water 500.00 Effluent Water 500.00 (Water-500) 0 Organic Residue 15.00

Process residue-10 Distillation residue-5(Ethanol-5)

Total 1268.50 Total 1268.50



MOXIFLOXACIN HYDROCHLORIDE Process Description: Stage-1 Moxifloxacin Q-acid is reacted with 2, 8-Diazobicycloc (4.3.0) nonane in presence of

Triethylamine in Acetone and Dimethylformamide to give stage-1 Product.

Stage-2 Stage-1 Product reacts with Hydrochloric acid in presence of Methanol to give

Moxifloxacin Hydrochloride.

MOXIFLOXACIN HYDROCHLORIDE

Route of Synthesis:

Stage-1

NF

F

OCH3

O

COOH

+

NH

NH

H

H

+

(C2H5)3N

Acetone

N

F

OCH3

O

COOH

NH

N

H

H

Moxifloxacin Q-acid

C14H11F2NO4

295.24

2,8-Diazobicyclo(4.3.0)nonane

C7H14N2

126.20

Triethylamine

101.19

Moxifloxacin Base

C21H24FN3O4

401.43

+

(C2H5)3N.HF

Triethyl amine Hydrofluoride

121.20

N HF.

N



Stage-2:

N

F

OCH3

COOHNH

N

H

H

Moxifloxacin Base

C21H24FN3O4

401.43

+ HCl

Hydrochloric acid36.5

Methanol

N

F

OCH3

OCOOH

NH

N

H

H

Moxifloxacin Hydrochloride

HCl

C21H25FClN3O4

437.89

O


Flow Chart:

Moxifloxacin Q-Acid2,8-Diazobicyclo(4.3.0)nonaneTriethylamineAcetoneDimethylformamide

Stage-1 Acetone RecDMF Rec

Stage-2

Moxifloxacin BaseHydrochloric acidMethanolEDTA

Methanol Rec

MOXIFLOXACIN HDYROCHLORIDE




Material Balance:

Material Balance of Moxifloxacin Hydrochloride Stage-1 Batch Size:100Kg



Moxifloxacin Q-Acid 80.00 Stage-1 97.00 2,8-Diazobicyclo(4.3.0) nonane 34.50 Acetone Recovery 190.00 Triethylamine 27.35 Acetone Loss 10.00 Acetone 200.00 Dimethylformamide Recovery 95.00 Dimethylformamide 100.00 Dimethylformamide Loss 5.00 Organic residue 44.85 Process residue-12.05

(Triethyl amine hydro fluoride-32.80)


Material Balance of Moxifloxacin Hydrochloride Stage-2 Batch Size: 100Kg



Moxifloxacin Base 97.00 Moxifloxacin Hydrochloride 100.00 Hydrochloric acid 10.00 Methanol Recovery 475.00 Methanol 500.00 Methanol Loss 25.00 EDTA 1.00 Effluent Water 1504.00 Activated Carbon 5.00 (Water-1500,EDTA-1,Methanol-3) 0 Water 1500.00 Spent Carbon 5.00 Organic Residue 4.00 Process residue-4 Total 2113.00 Total 2113.00



NEBIVOLOL HYDROCHLORIDE Process Description: Stage-1: 6-Fluoro-2-oxiranyl-chroman undergoes column separation to give Stage-1 product. Stage-2: Stage-1 reacts with Benzyl amine in presence of IPA to give Stage-2 product. Stage-3: Stage-2 reacts with 6-Fluoro-2-o-Oxiranyl-chroman in presence of Methanol to give

Stage-3 product.

Stage-4: Stage-3 reacts with Hydrochloric acid in presence of Pd/C to give Nebivolol

Hydrochloride.

NEBIVOLOL HYDROCHLORIDE

Route of synthesis:

Stage-1:

O O

F

O O

F

6-Fluoro-2-oxiranyl-chroman

C11H11FO2

194.20

Column seperation


C11H11FO2

388.40

O O

F


C11H11FO2

194.20

+2

Stage-2:

O O

F

6-Fluoro-2-oxiranyl-chromanC11H11FO2

194.20

NH2

BenzylamineC7H9N107.15

+IPA

2-Benzylamino-1-(6-fluoro-chroman-2-yl)-ethanol

C18H20FNO2

301.36

O

HN

F

OH



Stage-3:

2-Benzylamino-1-(6-fluoro-chroman-2-yl)-ethanol

C18H20FNO2

O

F

O


C11H11FO2

194.20

O

HN

O

N O

F

OHOH

F

495.56

C29H31F2NO4

+Methanol

301.36

FOH

PhH2C

2-{Benzyl-[2-(6-fluoro-chroman-2-yl)-2-hydroxy-ethyl]-amino}-1

-(6-fluoro-chroman-2-yl)-ethanol

Stage-4:

O

N O

F

OH

OH

F

2-{Benzyl-[2-(6-fluoro-chroman-2-yl)-2-hydroxy-ethyl]-amino}-1-(6-fluoro-chroman-2-yl)-ethanol

495.56

C29H31F2NO4

HCl

96.56

+

O

HN O

F

OH

OH

F

HCl

C22H26ClF2NO4

441.90

Nebivolol Hydrochloride

Isopropyl alcohol Hydrochloride

CH3

CH3

HO

CH3

CH3

HO+

Isopropyl alcohol

60.10

Methanol

+ H2

Hydrogen

2.00

+

Toluene

CH3

92.14

Pd/C



NEBIVOLOL HYDROCHLORIDE Flow chart:

6-Fluoro-2-oxiranyl-chromanSilica gelEthyl acetate

Stage-2Benzyl amineIPA

Stage-36-Fluro-2-oxiranyl-chromanMethanol

Stage-4Hydrochloric acidPd/Carbon


Stage-1

Stage-2

Stage-3

Stage-4

IPA Rec

Methanol RecEffluent water

Effluent water

Ethyl acetate RecoveryEffluent water


Material Balance:

Material Balance of Nebivolol HCl Stage-1 Batch Size: 200.00Kgs



6-Fluoro-2-oxiranyl-chroman 198.00 Stage-1 96.00 Silicagel 20.00 Hexane Recovery 285.00 Hexane 300.00 Hexane Loss 15.00 Ethyl acetate 300.00 Ethyl acetate Recovery 283.00 Ethyl acetate Loss 15.00 Inorganic solid waste

(Silicagel-20) 20.00

Organic Residue 104.00 Process residue- 102

(6-Fluoro-2-Oxiranyl-chroman-99) Distillation residue (Ethyl acetate-2)




Material Balance of Nebivolol HCl Stage-2 Batch Size:200.00 Kgs



Stage-1 96.00 Stage-2 144.00 Benzylamine 52.90 IPA Recovery 283.00 IPA 300.00 IPA Loss 15.00 Organic Residue 6.90 Process residue-4.9

Distillation residue (IPA-2)


Material Balance of Nebivolol HCl Stage-3 Batch Size:200.00 Kgs



Stage-2 144.00 Stage-3 230.00 Stage-1 96.00 Methanol Recovery 283.00 Methanol 300.00 Methanol Loss 15.00

DIPE 300.00 DIPE Recovery 285.00 Acetonitrile 250.00 DIPE Loss 15.00 Acetonitrile Recovery 237.50 Acetonitrile Loss 12.50 Organic Residue 12.00 Process residue-10

Distillation residue-2 Methanol-2)

0

Total 1090.00 Total 1090.00

Material Balance of Nebivolol HCl Stage-4 Batch Size: 200.00 Kgs



Stage-3 230.00 Nebivolol Hydrochloride 200.00 IPA.HCl 44.62 (Methanol + IPA + Toluene )

mixed Solvent 355.38

Hydrogen 0.92 Methanol Loss 15.00 Palladium Catalyst 2.00 Spent hyflow 7.66 Hyflow 0.50 Organic Residue-7.66

(Process residue-7.66)

Methanol 300.00 Total 578.04 Total 578.04



RITONAVIR Process description: Stage-1 (R,Z)-5-Amino-2-(dibenzyl amino)-1,6-diphenyl hex-4-en-3-one reacts with sodium borohydride in presence of methanol , HCl and water to give (2R)-5-amino-2-(dibenzyl amino)-1,6-diphenyl hexane-3-ol. Stage-2 Stage-1 product reacts with di-tert-butyl oxydiformate in presence of MTBE, Potassium carbonate and HCl to give stage-2 product. Stage-3 Stage-2 product reacts with ammonium farmate in presence of Methanol to give Stage-3 Product. Stage-4 Stage-3 Product reacts with succinic acid in presence of IPA, Acetic acid and sodium hydroxide to give stage-4 product. Stage-5 Step-A Thiourea reacts with 2-chloro-3-oxo-propionic acid ethyl ester in presence of isoamyl nitrite to give stage-5 product. Step-B Step-A product reacts with sodium borohydride in presence of methanol and HCl to give step-B product. Step-C Step-B product reacts with hydrogen in presence of methanol and Pd/C to give step-c product of stage-5. Stage-6 Stage-5 product reacts with 4-Nitro phenyl chloro formate in presence of pyridine and sodium bicarbonate to give stage-6 product. Stage-7 Stage-6 product undergoes condensation with stage-4 product in presence of toluene and methanol to give stage-7 product. Stage-8 Isobutyramide reacts with phosphorus penta sulphide in presence of toluene and sodium hydroxide to give stage-8 product. Stage-9 Stage-8 product reacts with 1,3-dichloro acetone & monomethyl amine in presence of sodium hydroxide and toluene to give stage-9 product. Stage-10 Stage-9 product reacts with (S)-methyl-3-methyl-2-((4-Nitrophenoxy)carbonyl amino)butanoate in presence of LiOH and methanol to give stage-10 product. Stage-11 N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine reacts with (1-Benzyl-4-tert-butoxycarbonylamino-2-hydroxy-5-phenyl-pentyl)-carbamic acid thiazol-5-ylmethyl ester of THF to give Ritonavir product.



Stage-12 Ritonavir undergoes recrystallisation in n-Heptane to give Ritonavir product.

RITONAVIR

Route of Synthesis:

Stage-1


ON

NH2

C32H32N2O

460.61


OHN

NH2

+ NaBH4 + 3H2O

37.83

54.06

C32H36N2O

464.64

+ H3BO3

61.83

MSA

TEA/1,2 DMEsodium

Borohydride

+HCl

36.46

Hydrochloric acid

Boric acid

+ NaCl

58.44

Sodium chloride

2 H2

4.04

+



Stage-2


OHN

NH2

C32H36N2O

464.64

OHN

HN C

OO

CH3

CH3

CH3

(1-Benzyl-4-dibenzylamino-3-hydroxy-5-phenyl-pentyl)-carbamic acid tert-butyl ester

O

O

KO

H3C CH3

CH3

Di Potassium tert-butylcarbonate

Di-tert-butyl oxydiformate

O

O

O

O

O++ K2CO3

MTBE

C10H18O5

218.25

138.21

+ + CO2 + KCl

C37H44N2O3

564.76

C5H9KO3

156.22

44.01 74.55

Water+ HCl

36.46

+ H2O

18.02



Stage-3

OHN

HN C

OO

CH3CH3

CH3

(1-Benzyl-4-dibenzylamino-3-hydroxy-5-phenyl-pentyl)-carbamic

acid tert-butyl esterC37H44N2O3

564.76

OHH2N

HN C

OO

CH3CH3CH3

(4-Amino-1-benzyl-3-hydroxy-5-phenyl-pentyl)-carbamic acid

tert-butyl ester

+

CH5NO2

Ammonium formate

+ + + NH3

Toluene

63.06

C23H32N2O3

384.51

2X92.14=184.28

44.01 17.03

Methanol

CO2

CH3

OH4NO + H2

2.02

Carbondioxide Ammonia

C7H8



Stage-4

OHH2N

HN C

OO

CH3CH3CH3

(4-Amino-1-benzyl-3-hydroxy-5-phenyl-pentyl)-carbamic acid

tert-butyl esterC23H32N2O3

384.51

Succinic Acid

O

OHO

HO

+ + CH3COOH + NaOH

C4H6O4

118.09X0.5=59.045

60.05

40.0

OHH2N

HN C

O

OCH3CH3

CH3 O

OHO

HO0.5

(4-Amino-1-benzyl-3-hydroxy-5-phenyl-pentyl)-carbamic acid tert-butyl ester hemi succinic acid

C25H35N2O5

443.56

+ CH3COONa + H2O

82.0318.02

IPA,DMA0.5

Acetic acid

Sodium acetate



Stage-5 (5HMT) Step-A

H2N NH2

S

CH4N2S

76.12

+

OH

OO

C2H5

C5H7ClO3

150.56

Isoamyl nitrite SN

C2H5O2C

Cl2-Chloro-3-oxo-propionic

acid ethyl esterThiourea

NH2

2-Amino-thiazole-5-carboxylic acid ethyl ester

C6H8N2O2S

172.20

+ H2O

36.46

+ HCl

18.02

Hydrogen Chloride

Step-B

MethanolS

N

C2H5O2C

NH2

2-Amino-thiazole-5-carboxylic acid ethyl ester

C6H8N2O2S

172.20

+

3H2O

+ NaCl

NaBH4+

37.83

SN

NH2

OH

(2-Amino-thiazol-5-yl)-methanol

+ HCl

36.46

C4H6N2OS

130.17

58.44

H3BO3

61.83

+

+ C2H5OH

46.07

54.05

+ 2 H2

4.03

Sodium Borohydride Hydrochloric acid

Boric acid Sodium chloride Ethanol



Step-C

+S

N

NH2

OH

(2-Amino-thiazol-5-yl)-methanol

C4H6N2OS

130.17

H2

2.02

Pd/C,Methanol

C4H5NOS

115.15

5-Hydroxymethylthiazole(5HMT)

S

NHO

+ NH3

17.03

Ammonia

Stage-6

S

NHO

5-Hydroxymethyl thiazole

C4H5NOS

115.15

+

NO2

O C

O

Cl

4-Nitro phenyl chloro formate

C7H4O4ClN

201.56

+ NaHCO3

84.01

Pyridine

NO2

O CO

OS

N

Carbonic acid,4-Nitrophenyl-5-thiazolyl methyl ester

C11H8O5N2S

280.26

+ NaCl + H2O+ CO2

18.0244.058.44

Sodium Bicarbonate

Carbon dioxideSodium chloride



Stage-7

NO2

O CO

O S

N

Carbonic acid,4-Nitrophenyl-5-thiazolyl methyl ester

C11H8O5N2S

280.26

+

OHH2N

HN C

OO

CH3CH3CH3 O

OHO

HO1/2

(4-Amino-1-benzyl-3-hydroxy-5-phenyl-pentyl)-carbamic acid tert-butyl ester

hemi succinic acid

C25H35N2O5443.55

NO2

OH

O

SN

OHHN

HN C

OO

CH3CH3CH3

O

+ +

O

OHO

HO1/2

59.04

Hemisuccinic acid4-Nitro-phenolC6H5NO3

139.11

(1-Benzyl-4-tert-butoxycarbonylamino-2-hydroxy-5-phenyl-pentyl)-carbamic acid thiazol-5-ylmethyl ester

C28H35N3O5S525.66

C2H3O2

Stage-8

Isobutyramide

H3C

H3C O

NH2 + 1/2 P4S105+ 6 NaOH

H3C

H3C S

NH2

Thioisobutyramide

5

Phosphorus penta sulphideC4H9NO

5 X 87.12 = 435.6 1/2 X 444.55 = 222.27

6X40=240C4H9NS

5X103.19=515.95

+ 2 Na3PO4 + 3 H2O

2X163.94 = 327.88

Sodium Phosphate 3X18=54



Stage-9

H3C

H3C S

NH2

ThioisobutyramideC4H9NS103.19

+

1,3-dichloro acetone

O

Cl Cl

C3H4OCl2126.97

+ CH3NH2

Monomethyl Amine

+ 3 NaOH

31.06 3X40=120.0

1-(2-Isopropylthiazol-4-yl)-N-methyl methanamine

HN

H3C

S

N

CH3

CH3

C8H14N2S170.28

+ 3 NaCl +4 H2O

175.33

72.06

+ NH4Cl

53.49

+NH3

17.03

Ammonium Chloride

Sodium Hydroxide

Sodium Chloride

Ammonia

Stage-10

1-(2-Isopropylthiazol-4-yl)-N-methyl methanamine

HN

H3C

S

N

CH3

CH3

C8H14N2S

170.28

(S)- methyl-3-methyl-2-((4-Nitrophenoxy)carbonyl amino)

butanoate

OO

HN

OO

N+

O

-O

+

(S)-2-(3-((2-Isopropylthiazol-4-yl)methyl)-3-methylureido)-3-methylbutanoic acid

NH

ON

H3C

S

NH3C

CH3

+

C13H16N2O6

296.28

23.95

4-Nitro-phenol

O2N OH+ + LiCl + CH3OH

C14H23N3O3S

313.42

C6H5NO3139.1

42.39 32.04

LiOH + HCl

36.46

H3C CH3

OH

O



Stage-11

O

SN

OHHN

HN C

OO

CH3CH3

CH3O

(1-Benzyl-4-tert-butoxycarbonylamino-2-hydroxy-5-phenyl-pentyl)-carbamic acid

Thiazol-5-ylmethyl esterC28H35N3O5S

525.66

N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)

amino)carbonyl)-L-valine

HNO

HOONS

N

NH

O

O

NH

ONH

N

O

SN

HO

SN

+

RitanovirC37H48N6O5S2

720.94

+

C14H23N3O3S

313.42

THF

Tert butanol

OH

C4H10O

74.12

+ CO2

44.0

Stage-12

NH

O

O

NH

O NH

N

O

SN

HO

SN

Ritanovir crudeC37H48N6O5S2

720.94

n-Heptane

NH

O

O

NH

O NH

N

O

SN

HO

SN

Ritanovir PureC37H48N6O5S2

720.94



RITONAVIR

Flow chart:

Stage-1

Stage-2

Stage-3

Stage-4

(R,Z)-5-amino-2-(dibenzyl amino) -1,6-diphenyl hex-4-en-3-oneSodium Boro HydrideHydrochloric AcidMethanol

Methanol Recovery

Stage-1Di -tert-Butyl oxydiformatePotassium carbonateMTBE Methanol

Methanol RecoveryMTBE Recovery

Stage-2Ammonium Formate Methanol Methanol Recovery

Stage-3Succinic acidAcetic acidSodium hydroxideIPADMA

IPA RecoveryDMA Recovery

Stage-6

Stage-54-nitro phenyl chloro formateSodium bi carbonatePyridine Ethyl acetateToluene

Toluene RecoveryEthyl aceate Recovery

Stage-5

Thiourea 2-chloro-3-oxo-propionicacid ethyl ester Sodium boro hydride Hydrochloric acid HydrogenIso amyl nitrite Methanol Palladium on Carbon

Methanol Recovery Iso amyl ntrite Recovery



Stage-7

Stage-8

Stage-9

Stage-10

Stage-6Stage-4Methanol Toluene

Toluene RecoveryMethanol Recovery

Iso butyramidePhosphorus pentasulfideSodium hydroxideToluene

Toluene Recovery

Stage-81,3-Dichloro acetoneMono methyl amine Sodium hydroxideAmmonium chlorideToluene

Toluene Recovery

Stage-9(S)- methyl-3-methyl-2- ((4-Nitrophenoxy) carbonyl amino) butanoateLithium hydroxide Hydrochloric acidMethanol

Methanol Recovery

Stage-11Stage-10Stage-7THF Methanol

Methanol RecoveryTHF Recovery

Stage-12

Stage-11n-Heptane Activated carbon hyflow

n-Heptane Recovery

Ritonavir



RITONAVIR Material Balance

Material Balance Ritonavir Stage-1 Batch Size:250.0 Kg



(R,Z)-5-amino-2-(dibenzyl amino) -1,6-diphenyl hex-4-en-3-one

238.00 Stage-1 228.00

Sodium Boro Hydride 19.50 Methanol Recovery 475.00 Hydrochloric Acid 18.80 Methanol loss 15.00 Methanol 500.00 Effluent water 834.03 Water 800.00 (Water-772.16

Boric acid-31.89 sodium chloride-29.98)

0

Process emission 1.90 (Hydrogen-1.90) 0 Organic Residue 22.37 Process Residue-12.37

Distillation Residue-10 (Methanol -10)

Total 1576.30 Total 1576.30




Stage-1 228.00 Stage-2 262.00 Di –tert-Butyl oxydiformate 107.00 Methanol Recovery 475.00 Potassium carbonate 67.72 Methanol loss 15.00 MTBE 400.00 MTBE recovery 380.00 Methanol 500.00 MTBE loss 8.00 Hydrochloric acid 17.78 Effluent water 921.74 Water 800.00 (Water-800, Generated

water-8.66 dipotassium tert-butyl carbonate-76.60 , Potassium chloride-36.48)

0

Process emission 21.43 (Carbon dioxide-21.43) 0 Organic Residue 37.33 Process Residue-15.33

Distillation Residue-22 (Methanol -10,MTBE-12)

Total 2120.50 Total 2120.50






Stage-2 262.00 Stage-3 169.00 Ammonium Formate 29.00 Methanol Recovery +

Toluene Recovery 85.40 560.40

Hydrogen gas 0.78 Methanol loss 15.00 Methanol 500.00 Effluent water 800.00 Water 800.00 (Water-800) 0 Process emission 28.03 (Carbon dioxide-20.17

Ammonia-7.86) 0

Organic Residue 19.35 Process Residue-9.35

Distillation Residue-10 (Methanol -10)

Total 1591.78 Total 1591.78




Stage-3 169.00 Stage-4 184.00 Succinic acid 25.85 IPA Recovery 475.00 Acetic acid 26.35 IPA loss 15.00 Sodium hydroxide 17.58 DMA Recovery 475.00 IPA 500.00 DMA loss 15.00 DMA 500.00 Effluent water 643.77 Water 600.00 (Water-600, Generated water-

7.78, Sodium Acetate-35.99) 0


Distillation Residue-20 (IPA -10,DMA-10)

Total 1838.78 Total 1838.78




Thiourea 40.00 Stage-5 50.00 2-chloro-3-oxo-propionicacid ethyl ester

79.00 Methanol Recovery + Ethanol-22.42

497.42

Sodium boro hydride 18.40 Methanol loss 15.00 Hydrochloric acid 17.72 Iso amyl ntrite Recovery 285.00 Hydrogen 0.90 Iso amyl nitrite loss 6.00



Iso amyl nitrite 300.00 Spent palladium on carbon 10.00 Methanol 500.00 Effluent Water 691.78 Palladium on Carbon 10.00 (Water-633.15

Generated water-9.44 Sodium chloride-28.48, Boric acid-30.15)

0

Water 650.00 Process emission 28.86 (Ammonia-7.80

Hydrogen-1.94 Hydrogen chloride-19.12)

0

Organic Residue 31.96 (Process Residue-12.96

Distillation Residue-19 (Methanol -10,Iso amyl Nitrite -9)

Total 1616.02 Total 1616.02




Stage-5 50.00 Stage-6 116.00 4-nitro phenyl chloro formate 87.50 Toluene Recovery 475.00 Sodium bi carbonate 36.45 Toluene loss 10.00 Pyridine 10.00 Ethyl acetate Recovery 475.00 Ethyl acetate 500.00 Ethyl acetate loss 10.00 Toluene 500.00 Effluent water 553.15 Water 500.00 (Water-500,

Generated water-7.80, Sodium chloride-25.35 Pyridine-10 Toluene-5, Ethyl acetate -5)

0

Process emission 19.10 (Carbon dioxide-19.10) 0 Organic Residue 25.70 Process Residue-5.70

Distillation Residue-20 (Toluene -10,Ethylacetate-10)

Total 1683.95 Total 1683.95




Stage-6 116.00 Stage-7 205.00 Stage-4 184.00 Toluene Recovery 475.00 Methanol 500.00 Toluene loss 10.00



Toluene 500.00 Methanol Recovery 475.00 Water 1000.00 Methanol loss 15.00 Effluent water 1029.36 (Water-1000,

Hemi succnic acid-24.36, Toluene-5)

0


Organic impurities -13.11 (4-nitrophenol-57.53) Distillation Residue-20 (Toluene -10,Methanol-10)

Total 2300.00 Total 2300.00




Iso butyramide 40.00 Stage-8 45.00 Phosphorus pentasulfide 20.40 Toluene Recovery 475.00 Sodium hydroxide 22.00 Toluene loss 10.00 Toluene 500.00 Effluent water 540.00 Water 500.00 (Water-500,

Generated water-4.92, Sodium phosphate-30.08, Toluene-5)

0


Distillation Residue-10 (Toluene -10)

Total 1082.40 Total 1082.40




Stage-8 45.00 Stage-9 70.00 1,3-Dichloro acetone 55.35 Toluene Recovery 475.00 Mono methyl amine 13.50 Toluene loss 10.00 Sodium hydroxide 52.30 Effluent water 912.87 Ammonium chloride 23.30 (Water-800,

Generated water-31.42 Sodium chloride-76.45, Toluene-5)

0

Toluene 500.00 Process emission 7.42 Water 800.00 (Ammonia -7.42) 0 Organic Residue 14.16



Process Residue-4.16 Distillation Residue-10 (Toluene -10)

Total 1489.45 Total 1489.45




Stage-9 70.00 Stage-10 122.00 (S)- methyl-3-methyl-2- ((4-Nitrophenoxy) carbonyl amino) butanoate

122.00 Methanol Recovery 475.00

Lithium hydroxide 9.80 Methanol loss 10.00 Hydrochloric acid 14.98 Toluene Recovery 285.00 Methanol 500.00 Toluene Loss 10.00 Toluene 300.00 Effluent water 520.36 Water 500.00 (Water-500,

Lithium chloride-17.36,Toluene-3)

0


Organic impurities-20.3 (4-Nitro phenol-57.12) Distillation Residue-17 (Methanol-15,Toluene-2)

Total 1516.78 Total 1516.78




Stage-10 122.00 Stage-11 265.00 Stage-7 205.00 THF Recovery 475.00 THF 500.00 THF loss 15.00 Methanol 400.00 Methanol Recovery 380.00 Water 500.00 Methanol loss 10.00 Effluent water 528.80 (Water-500,

tert Butanol-28.80) 0

Process emission 17.08 (carbon dioxide-17.08) 0 Organic Residue 36.12 Process Residue-16.12

Distillation Residue-20 (THF-10,Methanol-10)

Total 1727.00 Total 1727.00






Stage-11 265.00 Ritonavir 250.00 n-Heptane 500.00 n-Heptane Recovery 475.00 Activated carbon 10.00 n-Heptane loss 10.00 hyflow 5.00 Effluent water 500.00 Water 500.00 (Water-500) 0 Spent carbon & hyflow 15.00 Organic Residue 30.00 Process Residue-15

Distillation Residue-15 (n-Heptane -15)

Total 1280.00 Total 1280.00



SILDENAFIL CITRATE Process Description: Stage-1 Step-A 5-Propyl-2H pyrazole-3- carboxylic acid ethyl ester reacts with Dimethyl sulphate in presence of MDC and Methanol to give Step-A Product. Step-B Step-A Product reacts with Sodium hydroxide in presence of Methanol to give Stage-2 Product. Stage-2 Stage-1 Product reacts with Nitric acid in presence of Sulfuric acid and water to give stage-2 Product. Stage-3 Stage-2 Product reacts with Thionyl chloride and Ammonium Hydroxide to give Stage-3 product. Step-4 Stage-3 Product reacts with stannous chloride in presence of Ethanol and HCl to give Stage-4 Product. Stage-5 Stage-4 Product reacts with 2-Ethoxy benzoyl chloride in presence of MDC to give Stage-5 Product. Stage-6 Stage-5 Product reacts with 5-(2-Aminomethoxy-phenyl)1—methyl-3-propyl-1,6-dihydro-pyrazol[4,3-d]pyrimidin-7-one in presence of Methanol to give stage-6 Product. Stage-7 Stage-6 Product reacts with Chloro sulfonic acid in presence of Methanol to give stage-7 Product. Stage-8 Stage-7 product condensed with 1-Methyl piperazine in presence of Toluene to give stage-8 Product. Stage-9 Stage-8 product undergoes salt formation with citric acid in presence of Methanol to give Sildenafil Citrate.

SILDENAFIL CITRATE

Route of Synthesis: Stage-1 Step-A



N

HN

CH3

O

OH3C

C9H14N2O2

182.22

+

Dimethyl sulphate

SO

OOCH3H3CO

126.13

N

CH3N

CH3

O

OH3C

SO

OOHH3CO

Methyl bisulfate

112.11

+

2-Methyl-5-propyl-2H-pyrazole-3-carboxylic acid ethyl ester

C10H16N2O2

196.25

5-Propyl-2H-pyrazole-3-carboxylic acid ethyl ester C2H6O4S

CH4O4S

Methanol, MDC

Step-B

N

CH3N

CH3

O

OH3C

C10H16N2O2

196.25

+ NaOH

40.0

N

CH3N

CH3

O

HO

CH3CH2ONa+

Sodium ethoxide68.05

C8H12N2O2

168.19

2-Methyl-5-propyl-2H-pyrazole-3-carboxylic acid

ethyl ester

2-Methyl-5-propyl-2H-pyrazole-3-carboxylic acid



Stage-2

N

CH3N

CH3

O

HO

C8H12N2O2

168.19

+ HNO3

Nitric acid

63.01

N

CH3N

CH3

O

HO

O2N

C8H11N3O4

213.19

+ H2O

18.02

2-Methyl-5-propyl-2H-pyrazole-3-

carboxylic acid

2-Methyl-4-nitro-5-propyl-2H-pyrazole-3-carboxylic acid

Stage-3

N

CH3N

CH3

O

HO

O2N

C8H11N3O4213.19

+ NH4OH

35.05Ammonium hydroxide

+ SOCl2

Thionyl chloride

118.97

N

CH3N

CH3

O

H2N

O2N

C8H12N4O3

212.21

+ SO2

64.06

+ 2 HCl

2X36.5=73.0

+ H2O

18.02

2-Methyl-4-nitro-5-propyl-2H-pyrazole-3-carboxylic acid

2-Methyl-4-nitro-5-propyl-2H-pyrazole-3-

carboxylic acid amide



Stage-4

N

CH3N

CH3

O

H2N

O2N

C8H12N4O3

212.22

+ SnCl2

Stannous chloride189.62

+ 2 HCl

2X36.5=73.0

N

CH3N

CH3

O

H2N

H2N

C8H14N4O182.22

+ SnCl4

260.52

Stannic chloride

Ethanol

+ O2

32.0

2-Methyl-4-nitro-5-propyl-2H-pyrazole-3-

carboxylic acid amide

4-Amino-2-methyl-5-propyl-2H-pyrazole-

3-carboxylic acid amide

Stage-5

N

CH3N

CH3

O

H2N

H2N

C8H14N4O

182.22

+O

CH3

Cl

O

2-Ethoxy-benzoyl chloride

C9H9ClO2

184.62

NN

H2N O

CH3NH

O

O

CH3

CH3

4-(2-Ethoxy-benzoylamino)-2-methyl-5-propyl-2H-pyrazole-

3-carboxylic acid amide

C17H22N4O3

330.38

+ HCl

36.5

4-Amino-2-methyl-5-propyl-2H-pyrazole-3-carboxylic acid amide

Hydrogenchloride



Stage-6

NN

H2NO

CH3NH

O

O

CH3

CH3

4-(2-Ethoxy-benzoylamino)-2-methyl-5-propyl-2H-pyrazole-

3-carboxylic acid amideC17H22N4O3

330.38

O

CH3

N

HN

O

NN

CH3

CH3

5-(2-Aminomethoxy-phenyl)-1-methyl-3-propyl-1,6-dihydro-pyrazolo[4,3-d]

pyrimidin-7-oneC17H20N4O2

312.37

Methanol + H2O

18.02

Stage-7

O

CH3

N

HN

O

NN

CH3

CH3

5-(2-Aminomethoxy-phenyl)-1-methyl-3-propyl-1,6-dihydro-pyrazolo[4,3-d]

pyrimidin-7-oneC17H20N4O2

312.37

Chloro Sulfonic acid

Cl

SO O

OH

+

ClHO3S

116.52

O

CH3

N

HN

O

NN

CH3

CH3

SOO

Cl

4-Ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-

benzenesulfonyl chloride

C17H19ClN4O4S

410.88+ H2O

18.02



Stage-8

O

CH3

N

HN

O

NN

CH3

CH3

SOO

Cl

4-Ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-

benzenesulfonyl chlorideC17H19ClN4O4S

410.88

+N

NH

H3C

1-Methyl-piperazineC5H12N2

100.16

O

CH3

N

HN

O

NN

CH3

CH3

SOO

N

NH3C

Sildenafil

C22H30N6O4S

474.58

+ HCl

36.46



Stage-9

O

CH3

N

HN

O

NN

CH3

CH3

SOO

N

NH3C

Sildenafil

C22H30N6O4S

474.58

+

Citric acid

HO

OOH

O OH

O

HO

C6H8O7

192.12

Methanol

O

CH3

N

HN

O

NN

CH3

CH3

SOO

N

NH3C . HO

OOH

O OH

O

HO

C28H38N6O11S

666.70

Sildenafil Citrate



SILDENAFIL CITRATE Flow chart: 4-Propyl -1h-pyrrole-2-carboxylic acid ethyl esterDi methylsulphateMethylene di chloride Methanol Sodium hydroxide

Stage-1Nitric acidSulfuric acid

Effluent Water

Stage-3Stannous ChlorideHydrochloric acidEthanolToluene

Effluent water

Stage-1

Stage-2

Stage-3

Methanol RecoveryMethylene di chloride Recovery

Ethanol RecoveryToluene Recovery

Stage-4

Stage-2Thionyl chloride Ammonium Hydroxide



Stage-42-Ethoxy-benzoyl chlorideMDC

MDC RecoveryStage-5

Methanol RecoveryToluene Recovery

Stage-6

Toluene RecoveryEffluent Water

Stage-7

Toluene RecoveryEffluent Water

Stage-8

Methanol RecoveryEffluent WaterStage-9

Stage-5MethanolToluene

Stage-6Chloro sulfonic acidToluene

Stage-71-methyl-piperazineToluene

Stage-8Citric acidMethanolActivated CarbonHyflow

Sildenafil Citrate



SILDENAFIL CITRATE

Material Balance:

Material balance of Sildenafil Citrate Stage-1 Batch size : 500kg

Name of the input Quantity in kg

Name of the out put Quantity in kg

4-Propyl -1h-pyrrole-2-carboxylic acid ethyl ester 375.00 Stage-1 297.00

Di methylsulphate 259.50 Methanol Recovery 475.00 Methylene di chloride 800.00 Methanol Loss 15.00 Methanol 500.00 Methylene di chloride Recovery 760.00 Sodium hydroxide 78.35 Methylene di chloride Loss 24.00

Water 425.00 Effluent water 789.17

(Water-425, Sodium methoxide-133.55 Methyl bi sulfate-230.62)

0

Organic residue 77.68

Process residue-51.68 Organic impurities-51.68 Distillation residue- 26 (MDC-16, Methanol-10)

Total 2437.85 Total 2437.85

Material balance of Sildenafil Citrate Stage-2 Batch size : 500kg



Stage-1 297.00 Stage-2 338.00 Nitric acid 112.00 Effluent Water 431.78

Sulfuric acid 300.00 (Water-400,Generatedwater-31.78)

0

Water + Ice 400.00 Spent Sulfuric acid 300.00 Organic residue 39.22 Process residue-39.22 Total 1109.00 Total 1109.00

Material balance of Sildenafil Citrate Stage-3 Batch size : 500.00kg



Stage-2 338.00 Stage-3 302.00 Thionyl chloride 188.60 Effluent water 328.39

Ammonium Hydroxide 55.45 (Water-300, Generatedwater-28.39)

Ice + Water 300.00 Process emission 217.00



(Sulfur dioxide-101.40, Hydrogen chloride-115.6)

Organic residue 34.66 Process residue-34.66 Total 882.05 Total 882.05

Material balance of Sildenafil Citrate Stage-4 Batch size:500.00kg



Stage-3 302.00 Stage-4 233.00 Stannous Chloride 269.65 Ethanol Recovery 475.00 Hydrochloric acid 103.58 Ethanol Loss 15.00 Ethanol 500.00 Toluene Recovery 570.00 Toluene 600.00 Toluene Loss 12.00

Water 300.00 Effluent Water 675.55

(Water-300,Stannicchloride-370.55, Toluene-5)

0

Process Emission 45.30 (Oxygen-45.30) 0 Organic Residue 49.38


Distillation Residue-23 (Ethanol-10, Toluene-13)

Total 2075.23 Total 2075.23




Stage-4 233.00 Stage-5 380.00 2-Ethoxy-benzoyl chloride 236.00 MDC Recovery 570.00 MDC 600.00 MDC Loss 12.00 Water 500.00 Effluent Water 500.00 (Water-500) 0 Process Emission 46.60 (Hydrogen Chloride-46.60) 0 Organic Residue 60.40


Distillation residue-18 (MDC-18)

Total 1569.00 Total 1569.00






Stage-5 380.00 Stage-6 323.00 Methanol 500.00 Methanol Recovery 475.00 Toluene 600.00 Methanol Loss 10.00 Water 300.00 Toluene Recovery 570.00 Toluene Loss 12.00

Effluent Water 325.52

(Water-300,Generatedwater-20.52, Toluene-5)

0

Organic Residue 64.48


Distillation residue- 28 (Methanol-15, Toluene-13)

Total 1780.00 Total 1780.00




Stage-6 323.00 Stage-7 382.00 Chloro sulfonic acid 120.45 Toluene Recovery 570.00 Toluene 600.00 Toluene Loss 12.00 Water 300.00 Effluent Water 323.42

(Water-300,Generated water-18.42, Toluene-5)

0



Distillation residue-13 (Toluene-13)

Total 1343.45 Total 1343.45




Stage-7 382.00 Stage-8 396.00 1-methyl-piperazine 92.82 Toluene Recovery 570.00 Toluene 600.00 Toluene Loss 12.00 Water 300.00 Effluent Water 305.00 (Water-300, Toluene-5) 0 Process emission 33.62



(Hydrogen Chloride-33.62) 0 Organic Residue 58.20


Distillation residue- 13 (Toluene-13)

Total 1374.82 Total 1374.82




Stage-8 396.00 Sildenafil Citrate 500.00 Citric acid 160.00 Methanol Recovery 475.00 Methanol 500.00 Methanol Loss 10.00 Activated Carbon 10.00 Effluent Water 300.00 Hyflow 5.00 (Water-300) 0 Water 300.00 Spent Carbon & Hyflow 15.00


Process residue-56,

Distillation residue- 15 (Methanol-15)

Total 1371.00 Total 1371.00



VALSARTAN Process Description:

Stage-1

Step-A:

L-Valine reacts with Thionyl chloride in presence of Toluene to give Step-A product.

Step-B:

Step-A Product reacts with Methanol in presence of water to give Stage-1 Product.

Stage-2:

Stage-1 product reacts with 4-Bromomethyl-biphenyl-2-carbonitrile in presence of Toluene to give Stage-2 product.

Stage-3

Stage-2 product reacts with Valeryl chloride in presence of Toluene to give Stage-3 product.

Stage-4

Stage-3 product reacts with Sodium azide, Tri butyl tin chloride undergoes Hydrogenation in presence of Toluene, MDC and n-Hexane t give Valsartan.

Route of Synthesis:

Stage-1

Step-A

L-Valine

C5H11NO2

117.15

NH2

CH3

H3C OH

O

+ SOCl2

NH2

CH3

H3C Cl

O+ SO2

HCl

Thionyl Chloride

118.972-Amino-3-methyl-butyryl chloride

hydrochlorideC5H11Cl2NO

172.05

64.06

Toluene



Step-B

NH2

CH3

H3C Cl

O

+H

Cl

2-Amino-3-methyl-butyryl chloride

hydrochlorideC5H11Cl2NO

172.05

CH3OH

NH2

CH3

H3C OCH3

O HCl + HCl

32.04 2-Amino-3-methyl-butyric Acid methyl ester hydrochloride

36.46

C6H14NO2Cl

167.63

Methanol

Stage-2

NH2

CH3

H3C OCH3

O HCl

2-Amino-3-methyl-butyric Acid methyl ester hydrochloride

C6H14NO2Cl

167.63

4-Bromomethyl-biphenyl-2-carbonitrile

N

Br

+

N

O

O

NH

2-[(2-Cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid methyl ester

C14H10BrN

272.14

+

Potassium Carbonate

138.21

Toluene

C20H22N2O2

322.40

+ KBr +

K2CO3

KCl + CO2 + H2O

119.0 74.55 44.0 18.0



Stage-3

N

O

O

NH

2-[(2-Cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid methyl ester

C20H22N2O2

322.40

Valeryl Chloride

O

Cl+ + NaHCO3

Sodium bicarbonate

Toluene

C5H9ClO

120.58

84.0

OO

N

N

O

2-[(2-Cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric acid methyl ester

C25H30N2O3

406.52

+ NaCl + CO2 + H2O

58.44 44.0 18.0



Stage-4

O

O

N

N

O

2-[(2-Cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric acid methyl ester

C25H30N2O3

406.52

O

OH

N

O

NN

HN

N

+ NaN3 +

Tributyl tin chloride

SnCl

+ H2

Hydrogen Sodium Azide

2.0 65.0 C12H27ClSn

325.5

Valsartan

C24H29N5O3

435.5

+ SnH3C

+ NaCl

Tributyl methyl stannane

C13H30Sn

305.0

58.46

TolueneMDC



Flow-Chart

Stage-1

Stage-2

L-ValineThionyl ChlorideMethanolToluene

Methanol RecoveryToluene Recovery

Stage-14-Bromomethyl-biphenyl-2-carbonitrilePotassium carbonateToluene

Toluene RecoveryEffluent water

Stage-2Valeryl ChlorideTolueneTEASodium bicarbonateSodium Sulphate

Stage-3Toluene RecoveryEffluent water

Stage-3Sodium AzideTri butyl tin chlorideHydrogen Sodium hydroxideXyleneTolueneMDCN-HexaneActivated Carbon

Stage-4

Xylene RecoveryMDC RecoveryToluene RecoveryEffluent watetr

VALSARTAN

VALSARTAN Material Balance:

Material Balance of Valsartan Stage-1 Batch Size: 500Kg



L-Valine 154.00 Stgae-1 208.00 Thionyl Chloride 157.00 Methanol Recovery 475.00 Methanol 541.00 Methanol Loss 10.00 Toluene 400.00 Toluene Recovery 380.00 Toluene Loss 10.00 Process Emission 130.83 (Sulfur dioxide-84.21, Hydrogen

Chloride-46.62) 0




Process residue -13.17, Distillation residue -25 (Methanol-15, Toluene-10)

Total 1252.00 Total 1252.00




Stage-1 208.00 Stage-2 390.00 4-Bromomethyl-biphenyl-2-carbonitrile

338.00 Toluene Recovery 570.0

Potassium carbonate 172.00 Toluene Loss 20.00 Toluene 600.00 Effluent Water 1067.48 Water 800.00 (Water-800,Generated water-22.33,

Potassium chloride-92.50, Potassium Bromide-147.65, Toluene-5)

0

Process Emission 54.60 (Carbon dioxide-54.60) 0 Organic Residue 15.92 Process residue -10.92


Total 2118.00 Total 2118.00




Stage-2 390.00 Stage-3 480.00 Valeryl Chloride 146.00 Toluene Recovery 665.00 Toluene 700.00 Toluene Loss 20.00 TEA 20.00 Effluent Water 820.77 Sodium bicarbonate 102.00 (Water-700,Generated water-

21.77, Sodium chloride-71, TEA-20,Toluene-8)

0

Sodium Sulphate 10.00 Inorganic Solid Waste 10.00 Water 700.00 (Sodium Sulphate) 0 Process Emission 53.22 (Carbon dioxide-53.22) 0 Organic Residue 19.01 Process residue -12.01


Total 2068.00 Total 2068.00



Material Balance of Valsartan Stage-4

Batch Size: 500Kg Name of the input Quantity


in Kg Stage-3 480.00 Valsartan Pharma 500.00 Sodium Azide 77.00 Toluene Recovery 665.00 Tri butyl tin chloride 385.00 Toluene Loss 20.00 Hydrogen 2.50 MDC Recovery 475.00 Sodium hydroxide 20.00 MDC Loss 15.00 Xylene 240.00 Xylene Recovery 228.00 Toluene 700.00 Xylene Loss 12.00 MDC 500.00 N-Hexane Recovery 190.00 N-Hexane 200.00 N-Hexane Loss 10.00 Activated Carbon 10.00 Effluent Water 1087.00 Water 1000.00 (Water-1000, Sodium Chloride-

69,Toluene-8, Acetic Acid-10) 0

Spent Carbon 10.00 Organic Residue 402.50 Process residue –385.50

Organic Impurities-25.50 (Tri butyl-methyl –stannane-360) Distillation residue- 17 (Toluene-7, MDC-10)

Total 3614.50 Total 3614.50



ANNEXURE – IV

WATER CONSUMPTION DETAILS

S. No Purpose Water Input in KLD 1 Process 26.80 2 Washings 5.00 3 Boiler make up 30.00 4 Cooling towers make up 63.00 5 Scrubbing system 3.00 6 Domestic 5.00 7 Gardening 3.00

Total 135.80



ANNEXURE -V

SOLID & HAZARDOUS WASTE GENERATION AND DISPOSAL

S. No Name of the Hazardous Waste

Quantity Disposal Method

1 Organic waste (Process Residue) 1398 Kg/Day Sent to Cement Industries

2 Spent Carbon 82 Kg/Day Sent to Cement Industries 3 Solvent Distillation Residue 489 Kg/Day Sent to Cement Industries 4 Inorganic Waste 555 Kg/Day Sent to TSDF 5 ETP Sludge 350 Kg/Day Sent to TSDF 6 MEE Salts 2390 Kg/Day Sent to TSDF

7 Organic Evaporative Liquid ( from MEE Stripper) 434 Kg/Day Sent to Cement Industry

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

9 Detoxified Containers 500 No’s / Month

After Detoxification sent to outside agencies.

10 Used Lead Acid Batteries 2 No’s/ Annum Send back to suppliers for

buyback of New Batteries

11 Fly ash from boiler 5425 Kg/Day Sent to Brick Manufacturers

12 Spent Mixed Solvents 2 KL/Day Sent to authorized

recyclers



ANNEXURE - VI

STACK EMISSION DETAILS FOR BOILER

Particulars Units 2.0 TPH Coal fired Boiler

3.0 TPH Coal fired Boiler

Type of Fuel -- Indian Coal Indian Coal Coal Consumption TPD 8.00 7.50 Ash Content % 35 35 Sulphur Content % 0.8 0.8 No. of Stacks No 1 1 Height of stack M 30 30 Diameter of Stack M 0.40 0.50 Temperature of Flue Gas oC 175 200 Velocity of Flue Gas m/s 10.0 12.0 Particulate Matter at outlet of Bag filter gm/sec 0.22 0.43

Sulphur dioxide emission gm/sec 0.52 0.49 Oxides of Nitrogen emission gm/sec 1.37 1.28

Pollution control equipment - Cyclone separator

followed by suitable pack of Bag filters

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.

500 KVA 80.0 190.0 235.0 0.30 220 12 23.20



ANNEXURE -VII

PROCESS EMISSION DETAILS

S. No. Name of the Gas Quantity In

Kg/Day Treatment Method

1 Sulphur dioxide 250 Scrubbed by using C.S.Lye Solution 2 Hydrogen chloride 333 Scrubbed by using chilled water media 3 Hydrogen Bromide 153 Scrubbed by using C. S. Lye solution 4 Carbon dioxide 251 Dispersed into the atmosphere

5 Hydrogen 20 Diffused by using Nitrogen through Flame arrestor

6 Ammonia 34 Scrubbed by using chilled water media 7 Oxygen 57 Dispersed into the atmosphere 8 Hydrogen fluoride 10 Scrubbed by using C.S.Lye Solution 9 Chloromethane 26 Scrubbed by using C.S.Lye Solution



ANNEXURE - VIII

LIST OF RAW MATERIALS

1. ATORVASTATIN CALCIUM S .No. Raw Material Consumption/

Batch in Kgs Consumption/

Day in Kgs 1 (6-Cyanomethyl-2,2-dimethyl-

[1,3]dioxan-4-yl)-acetic acid tert-butyl ester

252.00

168.00 2 4-(4-fluorophenyl)-2-isobutyryl-3 phenyl

-4-oxo-N-phenyl-butyramide 378.50

252.33 3 Acetonitrile 300.00 200.00 4 Activated carbon 5.00 3.33 5 Calcium acetate 66.82 44.55 6 cyclohexane 200.00 133.33 7 Hydrochloric acid 3.36 2.24 8 Hydrogen 0.68 0.45 9 Hyflow 3.00 2.00

10 IPA 150.00 100.00 11 Isopropylalcohol 150.00 100.00 12 Methanol 460.00 306.67 13 Pivalic acid 2.00 1.33 14 Raney Nickel 1.00 0.67 15 Sodium carbonate 7.00 4.67 16 Sodium hydroxide flakes 33.95 22.63 17 Toluene 200.00 133.33

2. DAPOXETINE HYDROCHLORIDE

S .No. Raw Material Consumption/ Batch in Kgs

Consumption/ Day in Kgs

1 1-Naphthol 106.00 141.33 2 3-Phenylpropyl bromide 147.00 196.00 3 Carbon tetra hydrochloride 250.00 333.33 4 Di methyl amine 32.00 42.67 5 Diethyl ether 1050.00 1400.00 6 Ethanol 800.00 1066.67 7 Ethyl acetate 100.00 133.33 8 IPA.HCl 2.00 2.67 9 Methanol 265.00 353.33

10 N-Bromo succinamide 127.00 169.33 11 Potassium hydroxide 42.00 56.00 12 Sodium hydroxide 1.00 1.33 13 Sodium sulphate 40.00 53.33 14 Tartaric acid 51.00 68.00



3. D-PENICILLAMINE



1 Peniloic acid 460.00 383.33 2 Acetic acid 89.55 74.63 3 Activated carbon 15.00 12.50 4 Aniline 139.00 115.83 5 EDC 300.00 250.00 6 Hyflow 1.00 0.83 7 Methanol 400.00 333.33 8 Toluene 300.00 250.00

4. DULOXETINE HYDROCHLORIDE



1 3-Dimethylamino-1-thiophen-2-yl-propan-1-ol

237.00 197.50

2 1-FluoroNapthalene 93.00 77.50 3 Cyclo hexane 380.00 316.67 4 Dichloromethane 200.00 166.67 5 DMSO 7.00 5.83 6 Ethyl acetate 1560.00 1300.00 7 Hydrochloric acid 23.00 19.17 8 Isopropyl alcohol 300.00 250.00 9 L(+) Mandelic acid 98.00 81.67

10 Methanol 4.00 3.33 11 Oxalic acid 68.00 56.67 12 Phenyl chloroformate 100.00 83.33 13 Sodium carbonate 5.60 4.67 14 Sodium chloride 10.00 8.33 15 Sodium hydroxide 16.70 13.92 16 Sodium sulfate 10.00 8.33 17 TBAB 3.00 2.50 18 TEA 5.00 4.17 19 Toluene 2000.00 1666.67

5. LANSOPRAZOLE



1 2,3-Lutidine 188.00 125.33 2 1,1,2-Tri Fluoro Ethanol 167.00 111.33 3 1H-Benzoimidazole-2thiol 226.00 150.67 4 Acetic Acid 46.00 30.67 5 Acetic Anhydride 170.00 113.33





6 Acetone 150.00 100.00 7 Activated Carbon 5.00 3.33 8 Catalyst 1.00 0.67 9 Chloroform 400.00 266.67

10 Hydrogen Chloride 61.00 40.67 11 Hydrogen Peroxide (50%) 178.00 118.67 12 Isopropyl Alcohol 250.00 166.67 13 Methylene Dichloride 400.00 266.67 14 MIBK 150.00 100.00 15 Nitric Acid 111.00 74.00 16 Potassium Carbonate 230.00 153.33 17 Sodium Hydroxide 188.00 125.33 18 Sulfuric Acid 50.00 33.33 19 TEBAC 1.00 0.67 20 Thionyl Chloride 180.00 120.00 21 Toluene 900.00 600.00

6. LOPINAVIR



1 (R)-2-amino-3-phenyl propanoic acid 103.00 85.83 2 1,2-Dimethoxy ethane 300.00 250.00 3 2,6-Dimethyl phenoxy acetyl chloride

(DPC) 85.50

71.25 4 Acetone 500.00 416.67 5 Acetonitrile 58.35 48.63 6 Activated carbon 20.00 16.67 7 Ammonium chloride 200.00 166.67 8 Ammonium formate 29.48 24.57 9 Benzyl chloride 237.00 197.50

10 Benzyl magnesium chloride 85.90 71.58 11 Citric acid monohydrate 124.85 104.04 12 Citric acid monohydrate 119.70 99.75 13 Dimethyl acetamide 160.00 133.33 14 DMF 300.00 250.00 15 Ethanol 1400.00 1166.67 16 Ethyl acetate 1600.00 1333.33 17 Hydrochloric acid 20.00 16.67 18 Hydrogen gas 3.29 2.74 19 Hyflow 5.00 4.17 20 Imidazole 39.65 33.04 21 IPA 300.00 250.00 22 L-Pyro glutamic acid 57.96 48.30 23 MDC 600.00 500.00 24 Methane sulphonic acid 7.00 5.83





25 Methanol 900.00 750.00 26 Methyl chloro formate 60.45 50.38 27 MTBE 1350.00 1125.00 28 n-Heptane 250.00 208.33 29 Palladium carbon 20.60 17.17 30 Potassium carbonate 86.00 71.67 31 Raney Nickel 5.00 4.17 32 Sodamide 23.00 19.17 33 Sodium bicarbonate (10%) 362.50 302.08 34 Sodium Boro hydride 20.65 17.21 35 Sodium chloride 133.20 111.00 36 Sodium sulphate 20.00 16.67 37 THF 900.00 750.00 38 TPA 55.00 45.83 39 Triethyl amine 96.00 80.00 40 Valina 75.00 62.50

7. MOXIFLOXACIN HYDROCHLORIDE



1 Moxifloxacin Q-Acid 80.00 53.33 2 2,8-

Diazobicyclo(4.3.0) nonane

34.50

23.00 3 Acetone 200.00 133.33 4 Activated Carbon 5.00 3.33 5 Dimethylformamide 100.00 66.67 6 EDTA 1.00 0.67 7 Hydrochloric acid 10.00 6.67 8 Methanol 500.00 333.33 9 Triethylamine 27.35 18.23

8. NEBIVOLOL HYDROCHLORIDE



1 6-Fluoro-2-oxiranyl-chroman

198.00 165.00

2 Acetonitrile 250.00 208.33 3 Benzylamine 52.90 44.08 4 DIPE 300.00 250.00 5 Ethyl acetate 300.00 250.00 6 Hexane 300.00 250.00 7 Hydrogen 0.92 0.77





9 Hyflow 0.50 0.42 10 IPA 300.00 250.00 11 IPA.HCl 44.62 37.18 12 Methanol 600.00 500.00 13 Palladium Catalyst 2.00 1.67 14 Silicagel 20.00 16.67

9. RITONAVIR



1 (R,Z)-5-amino-2-(dibenzyl amino) -1,6-diphenyl hex-4-en-3-one

238.00 198.33

2 (S)- methyl-3-methyl-2- ((4-Nitrophenoxy) carbonyl amino) butanoate

122.00

101.67 3 1,3-Dichloro acetone 55.35 46.13 4 2-chloro-3-oxo-propionicacid ethyl ester 79.00 65.83 5 4-nitro phenyl chloro formate 87.50 72.92 6 Acetic acid 26.35 21.96 7 Activated carbon 10.00 8.33 8 Ammonium chloride 23.30 19.42 9 Ammonium Formate 29.00 24.17

10 Di –tert-Butyl oxydiformate 107.00 89.17 11 DMA 500.00 416.67 12 Ethyl acetate 500.00 416.67 13 Hydrochloric Acid 69.28 57.73 14 Hydrogen 1.68 1.40 15 hyflow 5.00 4.17 16 IPA 500.00 416.67 17 Iso amyl nitrite 300.00 250.00 18 Iso butyramide 40.00 33.33 19 Lithium hydroxide 9.80 8.17 20 Methanol 3400.00 2833.33 21 Mono methyl amine 13.50 11.25 22 MTBE 400.00 333.33 23 n-Heptane 500.00 416.67 24 Palladium on Carbon 10.00 8.33 25 Phosphorus pentasulfide 20.40 17.00 26 Potassium carbonate 67.72 56.43 27 Pyridine 10.00 8.33 28 Sodium bi carbonate 36.45 30.38 29 Sodium Boro Hydride 37.90 31.58 30 Sodium hydroxide 91.88 76.57 31 Succinic acid 25.85 21.54 32 THF 500.00 416.67



33 Thiourea 40.00 33.33 34 Toluene 2300.00 1916.67

10. SILDENAFIL CITRATE



1 4-Propyl -1h-pyrrole-2-carboxylic acid ethyl ester 375.00 375.00

2 1-methyl-piperazine 92.82 92.82 3 2-Ethoxy-benzoyl chloride 236.00 236.00 4 Activated Carbon 10.00 10.00 5 Ammonium Hydroxide 55.45 55.45 6 Chloro sulfonic acid 120.45 120.45 7 Citric acid 160.00 160.00 8 Di methylsulphate 259.50 259.50 9 Ethanol 500.00 500.00

10 Hydrochloric acid 103.58 103.58 11 Hyflow 5.00 5.00 12 MDC 600.00 600.00 13 Methanol 1500.00 1500.00 14 Methylene di chloride 800.00 800.00 15 Nitric acid 112.00 112.00 16 Sodium hydroxide 78.35 78.35 17 Stannous Chloride 269.65 269.65 18 Sulfuric acid 300.00 300.00 19 Thionyl chloride 188.60 188.60 20 Toluene 2400.00 2400.00

11. VALSARTAN



1 L-Valine 154.00 154.00 2 4-Bromomethyl-

biphenyl-2-carbonitrile 338.00 338.00

3 Activated Carbon 10.00 10.00 4 Hydrogen 2.50 2.50 5 MDC 500.00 500.00 6 Methanol 541.00 541.00 7 N-Hexane 200.00 200.00 8 Potassium carbonate 172.00 172.00 9 Sodium Azide 77.00 77.00

10 Sodium bicarbonate 102.00 102.00 11 Sodium hydroxide 20.00 20.00 12 Sodium Sulphate 10.00 10.00 13 TEA 20.00 20.00



14 Thionyl Chloride 157.00 157.00 15 Toluene 2400.00 2400.00 16 Tri butyl tin chloride 385.00 385.00 17 Valeryl Chloride 146.00 146.00 18 Xylene 240.00 240.00

ANNEXURE – IX

WASTE WATER DETAILS

S. No Purpose Effluent in KLD 1 Process 30.00 2 Washings 5.00 3 Boiler Blow down 5.00 4 Cooling towers blow down 7.00 5 Scrubbing System 3.00 6 Domestic 4.50

Total 54.50

HTDS & LTDS DETAILS

Unit HTDS KLD

LTDS KLD

Effluent Generation

in KLD Treatment Method

Process 18.70 11.30 30.00 HTDS Effluent sent to stripper followed by MEE system.

LTDS effluents treated in ETP along with MEE condensate. Treated effluent is sent to RO, RO permeate water is recycled and RO rejects taken for evaporation in MEE followed by ATFD to collect evaporation salts for disposal to TSDF.

Washings 0.00 5.00 5.00 Boiler Blow down 0.00 5.00 5.00 Cooling towers blow down 0.00 7.00 7.00 Scrubbing system 3.00 0.00 3.00

Domestic 0.00 4.50 4.50

Total 21.70 32.80 54.50



ANNEXURE – X

CONSOLIDATED STATEMENT- POLLUTION DETAILS

S.No Product Name Productioncapacity

kg/ Month

Effluent in kg/day Solid waste Details in Kg/day Distillation Residue in

Kg /Day

Emissions in Kg/day

Water Input

Water In Effluent

Inorganics in water

Organics in water TDS COD HTDS LTDS Total

Effluent Organic Inorganic Spent carbon Process Fugitive

1 Atorvastatin Calcium 10000.00 2333.33 2329.76 4.67 48.28 4.67 42.35 1327.73 1054.97 2382.71 82.06 0.00 6.00 4.67 0.00 48.00

2 Dapoxetine Hydrochloride 4000.00 2800.00 2817.64 185.19 0.00 185.19 0.00 1936.16 1066.67 3002.83 33.41 53.33 1.33 1.33 74.92 169.33

3 D-penicillamine 5000.00 2083.33 2083.33 0.00 2.50 0.00 2.61 0.00 2085.83 2085.83 18.93 0.83 12.50 5.83 0.00 16.67

4 Duloxetine Hydrochloride 5000.00 2750.00 2740.00 26.92 71.48 26.92 151.92 2838.39 0.00 2838.39 14.28 8.33 0.00 15.00 60.53 188.33

5 Lansoprazole 10000.00 1866.67 2034.77 123.80 191.73 123.80 121.41 1247.65 1102.65 2350.30 76.11 205.80 3.33 28.67 101.79 41.33 6 Lopinavir 5000.00 1708.33 2062.50 463.28 86.67 463.28 244.00 2151.13 416.67 2567.80 91.58 260.75 5.00 77.50 125.75 273.33

7 Moxifloxacin hydrochloride 2000.00 1000.00 1000.00 0.67 2.00 0.67 3.00 0.00 1002.67 1002.67 32.30 0.00 3.33 0.00 0.00 26.67

8 Nebivolol 5000.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 103.80 16.67 0.00 5.00 0.00 62.92 9 Ritonavir 5000.00 6625.00 6638.24 347.65 77.33 347.65 160.76 5002.74 2060.42 7063.16 218.72 0.00 20.83 160.83 103.18 186.67

10 Sildenafil citrate 15000.00 3125.00 3224.11 734.72 20.00 734.72 62.60 1234.10 2514.11 3748.21 305.05 0.00 15.00 136.00 342.52 134.00 11 Valsartan 15000.00 2500.00 2544.10 380.15 51.00 380.15 133.43 2975.25 0.00 2975.25 421.60 10.00 15.00 54.00 238.65 117.00 Total 81000.00 26791.67 27474.46 2267.04 550.97 2267.04 922.07 18713.16 11303.99 30017.14 1397.85 555.72 82.33 488.83 1047.34 1264.25

Prodn/Month

Water Input

TDS

Total Effluent

HTDS

LTDS

Organic

Inorganic

Spent carbon



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LIST OF ANNEXURES S. No Content Annexure...LIST OF ANNEXURES S. No Content Annexure 1 List of Proposed Products & By-Products Annexure - I 2 Site Plan Annexure - II 3 Manufacturing