List of products - Welcome to Environmentenvironmentclearance.nic.in/writereaddata/Online/TOR/0_0_10_Jul... · LIST OF PRODUCTS BULK DRUGS Sl. ... Mol.Wt.:81 C16H19NO2 Mol.Wt.:257

LIST OF PRODUCTS

BULK DRUGS

Sl. No Name of the product Production TPM

1. Carvedilol phosphate 2.50

2. Citalopram Hydrobromide 10.00

3. Closantel sodium 5.00

4. Esomeprazole magnesium trihydrate 1.50

5. Fexofinadine hydrochloride 2.00

6. Fosfomycin trometamol 3.00

7. Gaba-pentin 3.00

8. Itraconozole 2.00

9. Lansoprazole 3.00

10. Lornoxicam 4.00

11. Montelukast sodium 3.00

12. Omeprazole 5.00

13. Ondansetron 3.00

14. Oxyclozanide 5.00

15. Ritonavir 3.00

16. Rosuvastatin calcium 3.00

17. Setraline hydrochloride 2.00

18. Sparfloxacin 2.00

19. Terbinafine hydrochloride 3.00

Total 65.00

INTERMEDIATES

Sl. No Name of the product Production TPM

1 Tri Chloro Salisylic Acid 3.00 2 5-AminO-2-Hydroxy Benzoic acid 2.00 3 5-Amino-2-dibenzylamino-1,6-diphenyl-hex-4-en-3-one 2.00 4 2-Amino-6-chloro-3-nitro pyridine 3.00 5 4-Chloro butyryl chloride 3.00

CHEMICALS

Sl.No Name of the product Production TPM

1 Tributyl Tin chloride 90 2 L-Menthol 90 3 Dicyclo Hexylcarbomidiimide 90

SOLVENT RECOVERY

Sl.No Name of the product Production

TPM1 All solvents 450

Industry proposes to produce

• 2.0 TPD either from bulk drug group or intermediate group • 3.0 TPD from chemicals group • 15.0 TPD solvent recovery

CARVEDILOL PHOSPHATE

Carvedilol Phosphate can be manufactured in four stages.

Stage-1:

1-(2-bromo ethoxy)-2-methoxy benzene and benzyl amine reacts together in the presence of toluene

solvent medium forms stage-1 compound.

O

OBr

1-(2-Bromo-ethoxy)-2-methoxy-benzene

C9H11BrO2Mol. Wt.: 231.1

NH2

Benzylamine

+

C7H9NMol. Wt.: 107

O

ONH

Stage-1

+HBr

Hydrobromic acidMol.Wt.:81

C16H19NO2Mol. Wt.: 257

Toluene

Stage-2:

Statge-1 compound reacts with 2-chloro ethyl-oxirane in the presence of methanol solvent medium forms

the stag-2 compound.

O

ONH

Stage-1C16H19NO2

Mol. Wt.: 257

OCl+

2-Chloromethyl-oxiraneC3H5ClO

Mol. Wt.: 92

Methanol

Stage-2

O

ONCl

OH

C19H24ClNO3Mol. Wt.: 349.8

Stage-3:

Stage-2 compound reacts with 9H-carbazol-4-ol in the presence of potassium carbonate forms the

stage-3 compound.

Stage-2

O

ONCl

OH


NH

OH

+

9H-Carbazol-4-olC12H9NO

Mol. Wt.: 183

O

ONOH

NH

O

C31H32N2O4Mol. Wt.: 496.6

+HCl

Hydrochloricacid

Stage-3

Mol.Wt.:36.5

K2CO3

Stage-4:

Stage-3 compound undergoes reduction in the presence of H2; Pd/C forms the carvedilol free base.

O

ONOH

NH

O

C31H32N2O4Mol. Wt.: 496.6

Stage-3

H2, Pd/C

C24H26N2O4Mol. Wt.: 406.5

Carvedilol free base

+

CH3

TolueneC7H8

Mol. Wt.: 92

O

ONH

OH

NH

O

+ H2

Hydrogen

Mol. Wt.: 2

Stage-5:

Carvedilol free base reacts with phosphoric acid and water forms carvedilol phosphate. The reaction

proceeds as per the below equation.

O

ONHOH

NH

O

C24H26N2O4Mol. Wt.: 406.5

Carvedilol free base Phosphoric acid

P

O

OH

OH

OH+

H3O4PMol. Wt.: 98

+ 1/2 H2O

Water

Mol.Wt.: 9

O

OH

NHO

OCH3

. H3PO4 .1/2 H2O

Carvedilol phosphateC25H30NO8P

Mol. Wt.: 513.5

H2O

FLOW CHART OF CARVEDILOL PHOSPHATE

Layer Seperator

Reactor

Stage-1

1-(2-bromo ethoxy)-2-methoxy benzenebenzyl amine

Toluene

Centrifuge

Spent toluene to recovery

Forms hydrobromic acid

Stage-1

Reactor

Stage-2

stage-1 product2-chloro ethyl-oxirane

Methanol

Centrifuge

Spent methanol to recovery

Stage-2

Stage-29H-carbazol-4-ol

Potassium carbonateReactor

Stage-3

Centrifuge

Layerseparation

Stage-3

HCl gas to scrubbing

Stage-3 comoundH2, Pd/C

Reactor

Stage-4

Centrifuge

Layerseparation

Toluene to recovery

Cavedilol free base

Carvedilol free basePhosphoric acid

WaterReactor

Centrifuge Waste water to recovery

Stage-5

Pharma

Distillation

CITALOPRAM HYDROBROMIDE

The product is manufactured in three stages.

Stage-1:

4-[4-Dimethylamino-1-(4-fluoro-phenyl)-1-hydroxy-butyl]-3-hydroxymethyl-benzonitrile on Cyclisation in

presence of Phosphoric acid and Ammonia solution produces stages-1 product.

F

NCOH

OH N

CH3

CH3

4-[4-Dimethylamino-1-(4-fluoro-phenyl)-1-hydroxy-butyl]-3-hydroxymethyl-benzonitrile

C20H23FN2O2Mol. Wt.: 342

Phosphoric acidLiq.Ammonia,Toluene O

F

NC

N

CH3

CH3

.H2O

Stage-1C20H22FN2O

Mol. Wt.: 324.4

+

Water

Mol. Wt.: 18 Stage-2: Citalopram Hydro bromide is produced when stage-1 compound reacts with Hydrobromic acid . Isopropyl

alcohol, Carbon and Di isopropyl ether is used in the process.

O

F

NC

N

CH3

CH3

Stage-1C20H22FN2O

Mol. Wt.: 324.4

+ HBrIPA

O

F

NC

N

CH3

CH3

HBr

Citalopram HydrobromideC20H22BrFN2OMol. Wt.: 405.3

BrHMol. Wt.: 80.9

Hydro bromicacid

FLOW CHART OF CITALOPRAM HYDROBROMIDE

Stage-1

4-[4-Dimethylamino-1-(4-fluoro-phenyl)-1-hydroxy-butyl]-3-hydroxymethyl-benzonitrile

Phosphoric acidLiq.Ammonia,Toluene

Water

Reactor

Centrifuge Ammonium phosphate saltsolution for sale

Stage-1

Toluene to recovery

Stage-2:Pharma

Reactor

Centrifuge

Stage-Pharma

Stage-1Hydrobromic acidDi Isopropyl etherIospropyl alcohol

Spent solvent to recovery

Di Isopropyl ether

CLOSANTEL SODIUM

The product is manufactured in three stages.

Stage-1:

Step-A:

Sodium bicarbonate and Sodium sulphide react together in presence of water to produce Sodium

hydrogen sulphide

Sodiumbicarbonate

Water

Sodiumhydrogensulphide

Mol. Wt.: 84 Mol. Wt.: 56

NaHCO3 Na2S+

Sodiumsulphide

Mol.Wt.:78

NaHS + Na2CO3

SodiumCarbonate

Mol.Wt.:106

Step-B:

This mass is made to react with 1-chloro-3-methyl-5-nitro benzene and p-Chloro Benzyl cyanide in

presence of toluene solvent medium and water to produce the stage-1 compound.

ClN

C8H6ClNMol. Wt.: 151.6

+NaHS

Cl

H2N

Cl

CH3

CN

Stage-1

Toluene

1-Chloro-3-methyl-5-nitro-benzene


parachlorobenzyl cyanide

C15H12Cl2N2Mol. Wt.: 291.2

+ O2

Oxygen

N+

–O

O

Cl

CH3

O2Mol. Wt.: 32

Stage-2:

Stage-1 on reaction with 2-Hydroxy-3, 5-diiodo-benzoicacid by means of phosphorous trichloride in

presence of toluene solvent medium and water to form the stage-2 compound

Cl

H2N

Cl

CH3

CN

Stage-1C15H12Cl2N2

Mol. Wt.: 291.2

+

2-Hydroxy-3,5-diiodo-benzoic acid

C7H4I2O3Mol. Wt.: 389.9

Toluene/PCl3Water

Closantel

+H2O

Water

Mol. Wt.: 18

Cl

Cl

CH3

CH

COHI

I

NH

O N

OH

I

I

O

OH

C22H14Cl2I2N2O2Mol. Wt.: 663.1

Stage-3:

Stage-2 compound with Formic acid and Sodium Hydroxide in Water and Acetone

Closantel

Cl

Cl

CH3

CH

COHI

I

NH

O N

C22H14Cl2I2N2O2Mol. Wt.: 663.1

+

O

OH

Formic acidCH2O2

Mol. Wt.: 46

WaterAcetone

Na+

O

NHO

O-

I

I

OH

CH3

N

Cl

Cl

C23H15Cl2I2N2NaO4Mol. Wt.: 731.1

Closantel SodiumWater

Mol. Wt.: 18

H2O +

+ NaOH

SodiumHydroxide

Mol. Wt.: 40

FLOW CHART OF CLOSANTEL SODIUM

Stage-1Sodiumbicarbonate

Sodium SulphideWater

Reactor

Reactor

1-chloro3-methyl-2-nitro benzeneparachlorobenzyl cyanideSodium Hydrogen Sulfide

Toluene

Centrifuge

Inorganic salt solution to waste

Stage-1

Tolouene to recoveryO2 gas to scrubbing

Stage-2:

Stage-12-Hydroxy-3,5-diiodo-benzoic acid

ToluenePhosphorus tri chloride

water

Reactor

Centrifuge Inorganic salt solution to waste

Stage-2

Toluene to recovery

Stage-3:Closantel

Formic acidSodium Hydroxide

WaterAcetone

Reactor

Centrifuge

Acetone to recovery

Water to waste

Final compound

ESOMEPRAZOLE MAGNESIUM TRIHYDRATE

The product is produced in two stages.

Stage-1:

5-Methoxy-2-(4-methoxy-3, 5-dimethyl-pyridin-2-yl-methyl sulfanyl)-1H-benzoimidazole reacts with

cumene hydro peroxide and potassium Hydroxide by means of titanium isopropoxide in presence of

Methylene dichloride solvent medium to form the stage-1 product.

+

cumene hydroperoxideC9H12O2

Mol. Wt.: 152.2

Titaniumisoperoxide

KOH

O

SNO

NN

CH3

OCH3

Esomeprazole Potassium

C17H19N3O2SMol. Wt.: 329.4

Phenyl-acetic acidC8H8O2

Mol. Wt.: 136.2

+

K

H2O +

5-Methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethylsulfanyl)-1H-benzoimidazole

O

OH

WaterMol.Wt.:18

N

NHS

N

O O

C17H18KN3O3SMol. Wt.: 383.5

+

OO H

Mol. Wt.: 56.1

PotassiumHydroxide

MDC

Stage-2:

Stage-1 compound on reaction with Magnesium Chloride solution in presence of acetone solvent medium

to form the final compound

Esomeprazole PotassiumC34H36N6O6S2K2

Mol. Wt.: 767

+ Mg.Cl2

MagnesiumChloride

Mol. Wt.: 95

3 H2O2

OS

N

NN

Mg

+2 KCl

Esomeprazole Magnesium trihydratePotassium Chloride

O

SNO

N

NCH3

OCH3

K

OS

N

NN

O

O

O

O

H2O H2O H2O

Cl2K2Mol. Wt.: 149

C34H42MgN6O9S2Mol. Wt.: 767.2

+

H6O3Mol. Wt.: 54

Water

Acetone

FLOW CHART OF ESOMEPRAZOLE MAGNESIUM TRIHYDRATE

Centrifuge

Stage-1

Stage-1:

Reactor

5-Methoxy-2-(4-methoxy-3, 5-dimethyl-pyridin-2-yl-methyl sulfanyl)-1H-benzoimidazole

Cumene hydro peroxidePotassium hydroxide

Titanium isopropoxideMethylene Dichloride

Solvent Mls

Layerseparator

Phenyl acetic acid

Water to waste

Reactor

Centrifuge

Acetone to recovery

Pharma

Stage-2:

Stage-1Magnesium Chloride

WaterAcetone


FEXOFINADINE HYDROCHLORIDE

The product is produced in three stages.

Stage-1:

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

Azacyclonol and Sodium Bicarbonate by means of Methyl isobutyl ketone in presence of Ethyl alcohol

solvent medium to form the stage-1 compound.

+ + NaHCO3

SodiumBicaronate

Mol. Wt.: 84

MIBKEtOH

Stage-1

AzacyclonolC18H21NO

Mol. Wt.: 267.4

C33H39NO4Mol. Wt.: 513.7

C15H19ClO3Mol. Wt.: 282.8

OH

NH

+ NaCl

Sodium ChlorideMol.Wt.:58.5

+CO2

Carbon dioxide

Mol.Wt.:44

+H2O

Water

Mol.Wt.:18

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

OOO

Cl

OH

N

C+

CH3CH3

O

O

O CH3

Stage-2:

Stage-2 compound is produced when stage-1 compound, Sodium hydroxide and Acetic acid react together

with water in presence of Methanol solvent medium.

Stage-1

OH

N

CH3 CH3

O

O

O

+Methanol

Stage-2

NaOH

SodiumHydroxideMol.Wt.:40

+

O

HO

Acetic acidC2H4O2

Mol. Wt.: 60

+ H2O

Water

Mol.Wt.:18

OH

N

CH3 CH3

O

O

OH

C32H37NO4Mol. Wt.: 499.6

++ + Na+

O

O-

Sodium acetateC2H3NaO2

Mol. Wt.: 82

OH

MethanolCH4O

Mol. Wt.: 32Mol.Wt.:18

C33H39NO4Mol. Wt.: 513.7

Hydrogen

H2O

Stage-3:

Stage-2 compound is treated with Hydrochloric acid in presence of isopropyl alcohol solvent medium to

produce the pharma.

Stage-2

OH

N

CH3 CH3

O

O

OH

C32H37NO4Mol. Wt.: 499.6

+ HCl

Hydrochloricacid

Mol. Wt.: 36.5

IPA

.HCl

Fexofenadine HCl

OH

N

CH3 CH3

O

O

OH

C32H38ClNO4Mol. Wt.: 536

FLOW CHART OF FEXOFINADINE HYDROCHLORIDE

Reactor

Centrifuge

stage-1:

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

AzacyclonolSodium bicarbonate

Methyl isobutyl ketoneEthyl alcohol

Ethanol to recovery &CO2 gas to scrubbing


Stage-1

Stage-1 productSodium hydroxide

Acetic acidWater

Methanol

Reactor

Centrifuge

Stage-2:

Methanol to recovery

Waste water

Stage-2

Stage-3:

Stage-2 productHydrochloric acid

IsopropanolReactor

Centrifuge

Solvent recovery

Final product

FOSFOMYCIN TROMETAMOL

The product is produced in two stages.

Stage-1:

Fosfomycin phenyl ammonium salt on coupling with Trometamol produces stage-1 compound. Ethanol is the solvent used.

Reaction proceeds as per the below equation.

NH2

OHOH

OH

TrometamolC7H18NO7P

Mol. Wt.: 259.2

O

CH3 PO

OHOH .

Fosfomycin phenyl ammonium salt

+ NH2

OHOH

OH


Ethanol

Bis-Fosfomycin trometamol disaltC11H29N2O10PMol. Wt.:380.2

NH2

OHOH

OHO

CH3 PO

OHOH2

Stage-2:

Stage-1 on reaction with Fosfomycin in presence of methane sulfonic acid produces the final compound. The reaction


Bis-Fosfomycin trometamol disaltC11H29N2O10PMol. Wt.:380.2

NH2

OHOH

OHO

CH3 PO

OHOH2

O

CH3P

O

OHOH+

C3H7O4PMol. Wt.: 138.1

Fosfomycin

methane sulfonic acid

O

CH3 PO

OHOH

NH2

OHOH

OH

2

C11H29N2O10PMol. Wt.:518

Fosfomycin trometamol

FLOW CHART OF FOSFOMYCIN TROMETAMOL

Stage-1

TrometamolFosfomycin Phenyl ammonium salt

EthanolReactor

Centrifuge

Ethanol to reuse

Stage-1

Stage-2

Reactor

Centrifuge

Methane sulfonic acid to reuse

Stage-2:Pharma

Stage-1Fosfomycin

Methane sulfonic acid

GABA-PENTIN

The compound can be prepared in three stages.

Stage-1:

The cyclohexane-1, 1-diacetic acid mono amide is treated with sodium hypochlorite by means of Water in

presence of Di chloro methane solvent medium to get Stage-1 compound.

Cyclohexane-1, 1-diacetic Acid monoamide

+

sodiumhypochlorite

WaterMDC

+CO2

Carbondioxide

Mol. Wt.: 44

+ NaCl

Sodium chloride

Mol. Wt.: 58.5

+H2O

Water

Mol. Wt.:18

NH2

NH2

C10H18N2O2Mol. Wt.: 198.3

Na+

Cl O-

ClNaOMol. Wt.: 74.4

NH

O

C9H15NOMol. Wt.: 153

2-Aza-spiro[4.5]decan-3-one

OO

Stage-2:

2-Azaspiro [4, 5] decan-3-one on acid hydrolysis with concentrated hydrochloric acid in presence of

water gives Gaba-Pentin hydrochloride.

NH

O


2-Aza-spiro[4.5]decan-3-one

+ HCl

Hydrochloricacid

Mol. Wt.: 36.5

Water O

OH

NH2

(1-Aminomethyl-cyclohexyl)-acetic acid

.HCl


Stage-3:

Gaba-pentin hydrochloride on neutralization with sodium hydroxide in presence of water gives Gaba-

pentin. Finally product is purified with Carbon

O

OH

NH2


.HCl


+ NaOH

Sodium hydroxideMol. Wt.: 40

Water

OOH

NH2


+ NaCl + H2O

Sodiumchloride

Mol. Wt.: 58.5

Water

Mol. Wt.: 18C9H17NO2

Mol. Wt.: 171.2

FLOW CHART OF GABA-PENTIN

Stage-1Cyclohexane-1,1-diaceticacid monoamide

sodium hypochloriteWaterMDC

Reactor

Centrifuge

CO2 gas to scrubbingMDC to recovery

Inorganic salt solution

Stage-1

Stage-2

Stage-1HCl

WaterReactor

Centrifuge

Stage-2

Water to waste

Stage-3

Stage-2Sod.Hydroxide

CarbonWater

Reactor

Centrifuge Inorganic slt solution to waste

Pharma

ITRACONOZOLE

The product can be manufactured in ten stages.

Stage-1:

p- Methoxy phenyl piperazine HCl is condensed with p-Nitro chloro benzene in presence of DMSO solvent medium forms the stage-1 compound.

N NHOH

Cl

p-methoxy phenyl piperazine HClC11H17ClN2O

Mol. Wt.: 228.7

N+

O-

Cl

p-nitro chloro benzene

+


DMSO

N N

O

CH3

N+

O–

O

C17H19N3O3Mol. Wt.: 313

Stage-1

2 HCl

Hydrochloric acid

+

Cl2H2Mol. Wt.: 73

O

Stage-2:

Stage-1 compound is reduced with Nickel and palladium charcoal in the presence of methanol solvent medium forms the stage-2 compound.

N N

O

CH3

N+

O–

O

C17H19N3O3Mol. Wt.: 313

Stage-1

3 H2+

HydrogenMol. Wt.: 6

Ni , Pd/C

Methanol

N N

NH2

2 H2O

Stage-2C17H21N3OMol. Wt.: 283.4

+

H4O2Mol. Wt.: 36

WaterO

CH3

Stage-3:

Stage-2 compound on condensation with Phenyl chloro acetate in presence of toluene solvent medium produces stage-3 compound.

N N

O NH2

Stage-2C17H21N3O

Mol. Wt.: 283.4

phenyl chloro acetate

+Toluene

N NOH3C

NH

O

O

Cl

C O

O

C25H26N2O3Mol. Wt.: 402.5

Stage-3

+H Cl

Hydrochloricacid

Mol.Wt.:36.5

C7H5ClO2Mol. Wt.: 156.6

CH3

Stage-4:

Stage-3 product on doing reduction with Hydrazine hydrate in presence of 1, 4-dioxane at high temperatures forms the stage-4 compound.

N NO

H3C

NH

C O

O

C25H26N2O3Mol. Wt.: 402.5

Stage-3

+NH2

NH2HO

H

Hydrazine hydrateH6N2O

Mol. Wt.: 50.1

N NO NH

C O

NH

NH2

Stage-4C19H24N4O2Mol. Wt.: 340

OH

Phenol

+

C6H6OMol. Wt.: 94

+HO

H

WaterMol.Wt.:18

1,4-Dioxane

Stage-5:

Stage-4 compound on cyclization with formanidine gives Stage-5 compound in the presence of Acetic acid forms the stage-5 compound.

N NO

H3C

NH

C O

NH

NH2Stage-4C19H24N4O2Mol. Wt.: 340

+ CH3 C

O

O NH CH

NH

FormanidineC3H6N2O2

Mol. Wt.: 102.1

AcOH

N NO

H3C

C19H21N5O2Mol. Wt.: 351

Stage-5

+ 2 NH3 +CH3COOH

AmmoniaH6N2

Mol. Wt.: 34.1C2H4O2

Mol. Wt.: 60

Acetic acid

NH

NN

O

Stage-6:

Stage-5 compound undergoes condensation with 2-Bromo butane in presence of dimethyl sulfoxide medium gives stage-6 compound.

+ CH2 CH

Br

CH3CH3

C4H9BrMol. Wt.: 137

2-Bromo butane

+ K2CO3

Potassiumcarbonate

Mol. Wt.: 138

DMSOKOH

C23H29N5O2Mol. Wt.: 407.5

Stage-6

+KHCO3+KBr

Mol. Wt.: 100

Potassiumbicarbonate

Mol. Wt.: 119

Potassiumbromide

N NO

H3C

C19H21N5O2Mol. Wt.: 351

Stage-5

NH

NN

O

N NO

H3CN

NN

OCH

H3C

CH2

H3C

Stage-7:

Stage-6 on doing hydrolysis with aqueous hydrogen bromide under refluxing water forms stage-7 compound which is an intermediate (A)

C23H29N5O2Mol. Wt.: 407.5

Stage-6

+ aq. HBr

Hydrogenbromide

Mol.Wt.:81

stage-7C22H27N5O2

Mol. Wt.: 393.5

+CH3Br

Methyl bromideCH3Br

Mol. Wt.: 95

WaterN NO

H3CN

NN

OCH

H3C

CH2

CH3

N NHO

N

NN

OCH

H3C

CH2

CH3

Stage-8:

Benzoic acid-2-bromo-2-(3,5-dichloro phenyl)-[1,3]dioxolan-4-yl ester on treatment with 1,2,4-triazole with potassium carbonate and water in the presence of sodium hydroxide forms stage-8 compound.

Cl

ClO

O

O C

OBr

Benzoic acid 2-bromo-2-(3,5-dichloro-phenyl)-[1,3]dioxolan-4-yl ester

NH

NN

1,2,4-triazole

+

C2H3N3Mol. Wt.: 69.1

C16H11BrCl2O4Mol. Wt.: 418.1

+ K2CO3

Potassiumcarbonate

Mol. Wt.: 138 Cl

ClO

O

OH

NN

N

C11H9Cl2N3O3Mol. Wt.: 302

Stage-8

+ KBr +KHCO3

Potassiumbromide

Mol. Wt.: 119

Potassiumbicarbonate

Mol. Wt.: 100

+ H2O

water

Mol.Wt.:18

C

O

OH +

C7H6O2Mol. Wt.: 122

Benzoic acid

NaOH

Stage-9:

Stage-8 compound on condensation with Methane sulphonyl chloride forms the stage-9 compound which is an intermediate (B).

Cl

ClO

O

OH

NN

N


Stage-8

CH3 S

O

O

Cl

CH3ClO2SMol. Wt.: 114.6

Methanesulfonyl chloride

+

Cl

ClO

O

ON

N

N

SO

OCH3

C12H11Cl2N3O5SMol. Wt.: 380

Stage-9

HCl

Hydrochloricacid

+

Mol.Wt.:36.5

Tri ethyl amine

Stage-10:

Intermediate (A) on condensation with intermediate (B) with KOH in the presence of DMF as a solvent medium forms the Itraconozole crude and the product is finally purified with solvent.

N NOH N

NN

OCH

CH3 CH2

CH3stage-7C22H27N5O2

Mol. Wt.: 393.5

Cl

ClO

O

O

NN

NS

O

O

CH3

+

C12H11Cl2N3O5SMol. Wt.: 380

Stage-9

Cl

ClO

O

O

NN

N

S

O

O

CH3OH

N N N

NN

OCH

CH3 CH2

CH3

C33H34Cl2N8O4Mol. Wt.: 677.6

Itraconozole

+

CH4O3SMol. Wt.: 96

Methanesulfonic acid

Methanol

FLOW CHART OF ITRACONOZOLE

Methoxy phenyl piperazine HClp-Nitro chloro Benzene

Di-methyl sulphoxideReactor

Centrifuge

DMSO to recoveryHCl gas to scrubbing

Stage-1

Stage-1

Stage-1 productNickle catalyst

PalladiumMethanol

Reactor

Centrifuge Water to waste

Stage-2

Stage-2

Spent nickle catalystFiletaration


Stage-2 productPhenyl chloro acetate

TolueneReactor

Centrifuge

Toluene to recoveryHCl gas to scrubbing

Stage-3

Stage-3

Stage-3 productHydrazine hydrate

1,4-DioxaneReactor

Stage-4

Stage-4

Spent dioxane

Centrifuge Phenol

Stage-4 productFormanidine

Acetic acidReactor

Centrifuge

Stage-5

Stage-5

Spent Acetic acidRelease of ammonia

Acetic acid

Stage-5 product2-bromo butane

DMSOPotassium carbonatePotassium hydroxide

Reactor

Centrifuge

Stage-6

Stage-6

Filetaration

Spent DMSO

Potassium bicarbonate& potassiunm bromide

Stage-6 productAqueous hydrogen bromide

WaterReactor

Centrifuge

Stage-7

Stage-7

Methyl bromide

Waste water to recovery

Reactor

Centrifuge

Stage-8

Stage-8

Filetaration

Benzoic acid-2-bromo-2-(3,5-dichloro phenyl)-[1,3]dioxolan-4-yl ester

1,2,4-triazolePotassium carbonate

WaterSodium hydroxide

Forms Potassium bicarbonatePotassium bromide &Benzoic acid

Stage-8 productMethane sulphonyl chloride

Tri ethyl amineReactor

Centrifuge

Stage-9

Stage-9

Spent Tri ethyl amine to recoveryHCl gas to scrubbing

Stage-7 productStage-9 product

MethanolReactor

Centrifuge

Stage-10

Stage-10


Methane sulfonic acid

LANSOPRAZOLE

The product can be manufactured in five stages

Stage-1:

The condensation of 2, 3-dimethyl-4-nitropyridine with 2, 2, 2-trifluoroethanol by means of Potassium carbonate in presence of hot HMPT to form 2, 3-dimethyl-4-(2, 2, 2-trifluoroethoxy) pyridine N-oxide

NO

H3C

CH3

N+

O–

O

C7H8N2O3Mol. Wt.: 168.2

2,3-dimethyl-4-nitropyridineN-oxide

+

2,2,2-trifluoroethanol

FF

FOH

C2H3F3OMol. Wt.: 100

K2CO3HMPT

NO

H3C

CH3

O CF3

C9H10F3NO2Mol. Wt.: 221.2

KNO2+

+

Potassiumcarbonate

CK2O3Mol. Wt.: 138

Potassium nitriteKNO2

Mol. Wt.: 85

+KOH

Potassiumhydroxide

Mol. Wt.: 56

+CO2

Carbondioxide

Mol. Wt.: 44

Stage-1

Stage-2:

Stage-1 compound undergoes isomerisation in presence of acetic anhydride to form the 2 - (hydroxyl methyl)-3-methyl-4-(2, 2, 2-trifluoroethoxy) pyridine

NO

H3C

CH3

O CF3

Stage-1

(CH3CO)2ON

CH2

CH3

O CF3HO



Stage-2

Stage-3:

Stage-2 compound undergoes reaction with thionyl chloride in presence of Chloroform to form the corresponding chloromethyl derivative.

N

CH2

CH3

O CF3HO


Stage-2

+ SOCl2

Thionylchloride

Mol. Wt.: 119

CHCl3

N

CH2

CH3

O CF3Cl

C9H9ClF3NOMol. Wt.: 239.6

Srage-3

+SO2

Sulfurdioxide

Mol. Wt.: 64.1

+ HCl

Hydrochloricacid

Mol. Wt.: 36.5

Stage-4:

Stage-3 compound undergoes condensation with 2-mercaptobenzimidazole by means of sodium methoxide in presence of methanol solvent medium to form 2 - (2-benzimidazolylthiomethyl) -3-methyl-4-(2,2,2-trifluoroethoxy) pyridine

N

CH2 CH3

O CF3Cl

C9H9ClF3NOMol. Wt.: 239.6

Srage-3 2-mercaptobenzimidazole

N

HN

SH

C7H6N2SMol. Wt.: 150

+

N

CH2 CH3

O CF3S

N

HN

C16H14F3N3OSMol. Wt.: 353.4

Stage-4

+HCl

Hydrochloricacid

Mol. Wt.: 36.5

MethanolNaOMe

.

Stage-5:

Finally, Stage-4 compound is oxidised with m-Chloro per benzoic acid in presence of chloroform to form the stage-4 compound.

N

CH2

CH3

O CF3S

N

HN

C16H14F3N3OSMol. Wt.: 353.4

Lansoprazole

+CHCl3

N

CH2

CH3

O CF3S

N

HN

(O)

oxygenMol. Wt.: 16

m-CPBA

O

C16H14F3N3O2SMol. Wt.: 369.4

Stage-4

FLOW CHART OF LANSOPRAZOLE

2, 3-dimethyl-4-nitropyridine2, 2, 2-trifluoroethanol

Potassium carbonateHMPT

Reactor

Centrifuge

CO2 gas to scrubbing

KOH & KNO2 for use

Stage-1:

Stage-1

Stage-1Acetic anhydride Reactor

Stage-2:

Finished product

Stage-2Thionyl chloride

Chloroform

Stage-3:

Reactor

Centrifuge SO2 to scrubbing& HCl to reuse

Stage-3 product

Stage-32-mercaptobenzimidazole

Sodium methoxideMethanol

Stage-4:

Reactor

Centrifuge


HCl to use

Stage-4 product

Stage-4m-CPBA

Chloroform

Stage-5:

Reactor

Centrifuge

Chloroform to reuse

Final compound

LORNOXICAM

The product is manufactured in six stages.

Stage-1:

2, 5-dichlorothiophene and Chlorosulfonic acid undergoes condensation produces stage-1 compound.

Chloroform is the solvent used in the process.

2,5-dichlorothiophene

S

Cl

Cl

C4H2Cl2SMol. Wt.: 153

+

Cl

SO O

OH

Chloro sulfonic acidClHO3S

Mol. Wt.: 116.5

Chloroform

S

Cl

Cl

SO O

Cl

C4HCl3O2S2Mol. Wt.: 251.5

Stage-1

+ H2O

Water

Mol. Wt.: 18

Stage-2:

Stage-1 compound reacts with Mono methyl amine in presence of chloroform solvent medium forms the

stage-2 compound.

S

Cl

Cl

SO O

Cl

C4HCl3O2S2Mol. Wt.: 251.5

Stage-1

+Chloroform

Mono methyl amine

H2N CH3

CH5NMol. Wt.: 31.1

S

Cl

Cl

SO O

NH CH3

C5H5Cl2NO2S2Mol. Wt.: 246

Stage-2

+ HCl

Hydrochloric acid

Mol. Wt.: 36.5

Stage-3:

Stage-2 compound reacts with Carbon dioxide and hydrogen in presence of Butyl lithium forms the Stage-3 compound. Methanol is the solvent used in this process.

SCl

Cl

SO O

HN CH3

C5H5Cl2NO2S2Mol. Wt.: 246

Stage-2

++ CO2

Carbon Dioxide

Mol. Wt.: 44

+ 2 H

Hydrogen

Mol. Wt.: 2

S

S NH

O OCH3

O

OH

ClBuLiMeOH

HCl

Hydrochloric acid

Mol. Wt.: 36.5C6H6ClNO4S2Mol. Wt.: 255.7

Stage-3

Stage-4:

Stage-3 compound undergoes reaction with methanol in presence of Phosphorous pentachloride and methanol solvent medium forms the stage-4 compound.

S

S NH

O OCH3

O

OH

Cl

C6H6ClNO4S2Mol. Wt.: 255.7

Stage-3

PCl5MeOH S

S NH

O OCH3

O

O

Cl

CH3


+

MethanolCH4O

Mol. Wt.: 32

Stage-4

+ H2O

Water

Mol.Wt.: 18

Methanol

Stage-5:

Stage-4 compound reacts with Methyl iodo acetate in presence of a strong base; sodium hydride undergoes the following reaction and forms the stage-5 compound.

S

S NH

O OCH3

O

O

Cl

CH3


Stage-4C3H5IO2

Mol. Wt.: 200

+NaH

S

S N

O O

CH3O

O

Cl

CH3


Stage-5

+ HI

Hydrogen Iodide

Mol. Wt.: 127.9

OCH3

OIO

CH3O

Methyl iodo acetate

Stage-6:

Stage-5 product undergoes cyclization in presence of sodium methoxide forms the stage-6 compound.

The reacdtion proceeds as per the below equation.

S

S N

O O

CH3O

O

Cl

CH3


Stage-5

OCH3

OS

SN

O OCH3

HO

Cl


Stage-6

NaOMe H2O+

Water

Mol. Wt.: 18

H2O

Water

Mol. Wt.: 18

+ + CH3OH

MethanolMol.Wt.: 32

O

OCH3

Stage-7:

Stage-6 compound undergoes reaction with Pyridine-2-ylamine forms the final compound Lornoxicam

which undergoes as per the below equation. Methanol is the solvent used in this process.

N

H2N

C5H6N2Mol. Wt.: 94

Pyridin-2-ylamine

+

N

HN

S

SN

O OCH3

HO

Cl


Stage-6

O

OCH3

S

SN

O OCH3

HO

Cl

O

CH3OH

Methanol

Mol. Wt.: 32C13H10ClN3O4S2Mol. Wt.: 371.8

Lornoxicam

+Methanol

FLOW CHART OF LORNOXICAM

2, 5-dichlorothiopheneChlorosulfonic acid

ChloroformReactor

Water Waste water ro recoveryCentrifuge

Stage-1

Stage-1

Reactor

Centrifuge

Stage-2

Stage-2

Stage-1Mono methyl amine

Chloroform

Waste HCl to recovery

Reactor

Centrifuge

Stage-3

Stage-3

Stage-2Carbon Dioxide

HydrogenButyl lithium

Methanol


Waste HCl to recovery

Reactor

Centrifuge

Stage-4

Stage-4

Stage-3Methanol

PCl5


Water Waste water to recovery

Reactor

Centrifuge

Stage-5

Stage-5

Stage-4Methyl iodo acetate

Sodium Hydride

Hydrogen Iodide

Reactor

Centrifuge

Stage-6

Stage-6

Stage-5Sodium methoxide

Water

Waste water & Methanol to recovery

Reactor

Centrifuge

Stage-7

Stage-6Pyridine-2-ylamine

MethanolMethanol to recovery

Final product

MONTELUKAST SODIUM

Montelukast Sodium is produced in 6 stages.

Stage-:1:

On condensation of 7-Chloro-2-methyl quinoline with Benzene-1, 3-dicarbaldehyde by means of acetic anhydride in presence of acetic acid solvent medium to form the stage-1 product.

C8H6O2Mol.Wt.: 134

+ +


O

H

Benzene 1,3-dicarbaldehyde

C18H12ClNOMol. Wt.: 293.7

3-[2-(7-Chloro-quinolin-3-yl)-vinyl]-benzaldehyde

H2O

Mol. Wt.: 18

Water

HONCl CH3

7-Chloro-2-methylquinoline

NCl

O H

Ac2O

AcOH

Stage-2:

Stage-1 compound on reacting with Vinyl Magnesium Bromide and water by means of sodium chloride and ammonium acetate is used as a catalyst in presence of toluene solvent medium to form the stage-2 product.


NCl

O H

+Mg CH2

Br

Vinylmagnesiumbromide Water

+

C2H3BrMgMol. Wt.: 131

NaCl

NCl

OH


Stage-1

Stage-2

MgBrOH

hydroxy magnesium bromideBrHMgO

Mol. Wt.: 121

H2O+

H2OMol. Wt.: 18

CH3COONH4

Toluene

Stage-3:

Stage-2 compound on condensation with 1-(2-Iodophenyl) ethanone in presence of Palladium acetate and water in presence of acetonitrile solvent medium to obtain the stage-3 product

NCl

OH


Stage-2

+O

I

1-(2-iodo phenyl ) ethanoneC8H7IO

Mol. Wt.: 246

Pd(OCOCH3)

CH3CN

NCl

OH

O


Stage-3Hydrogen Iodide

H I +

Mol. Wt.:127.9

Stage-4:

Stage-3 reacts with Methyl magnesium bromide and water by means of CeCl3 in Acetonitrile solvent medium to attain the stage-4 product.

NCl

OH

O


Stage-3Methyl magnesium

bromide

Hydroxy Magnesiumbromide

+

Water

Acetonitrile

CeCl3CH3BrMg+

CH3BrMgMol. Wt.: 119

H2O+

Mol. Wt.: 18

NCl

OH

OH


Stage-4

MgBrOH

Mol. Wt.: 121

Stage-5:

Stage-4 reacts with Methane sulfonyl chloride in the presence of n, n- Di isopropyl ethylamine and toluene solvent medium to form the stage-5 compound.

NCl

OH

OH


Stage-4

+

CH3

SO O

Cl N,N,Diisopropylethylamine

+ HCl

Hydrochloric acid

Toluene

Methanesulfonyl chlorideCH3ClO2S

Mol. Wt.: 114.6

NCl

OH

CH3

S OO

O

C30H30ClNO4SMol. Wt.: 536.1

Stage-5

Mol. Wt.: 36.5

Stage-6:

Stage-5 product on reaction with (1-Mercapto methyl cyclopropyl) acetic acid with butyl lithium in presence of tetra hydro furan solvent medium to form the final compound

NCl

OH

CH3

S OO

O

C30H30ClNO4SMol. Wt.: 536.1

Stage-5

+

Methanesulfonic acid

O

OHSH

C6H10O2SMol. Wt.: 146

(1-Mercaptomethyl-cyclopropyl)acetic acid

NCl

OH

CH3

S OO

OH

Stage-5

S

O

O

+

CH4O3SMol. Wt.: 96

+ NaOH

Sodiumhydroxide

Mol. Wt.: 40

n-BuLi

THFNa

+H2O

Water

Mol. Wt.: 18C35H35ClNNaO3S

Mol. Wt.: 608.2

FLOW CHART

7-chloro-2-methyl quinolineBenzene-1,3-dicarbaldehyde

Acetic anhydrideAcetic acid

Stage-1

Reactor

Reactor

Centrifuge

Stage-1

Acetic acid to recovery

Waste water

Stage-2

Stage-1Vinylmagnesiumbromide

AmmoniumacetateWater

TolueneSodium chloride

Reactor

Hydroxy magnesiumbromide to disposal

Toluene to recovery

Centrifuge

Filteration Sodium chloride solution

Reactor

Stage-2

Stage-3

Stage-22-Iodophenyl ethanone

Palladium acetateAcetonitrile

Palladium acetate solution to waste

Reactor

Centrifuge

Stage-3

Acetonitrile to recovery

Water

Stage-4

Stage-3Methylmagnesiumbromide

AcetonitrileCeriumchloride

Water

Acetonitrile to recoveryReactor

Centrifuge

Stage-4

Cerium chloride solution to waste

Filteration Hydroxy magnesium bromide to disposal

Stage-5

Stage-4Methyl sulfonyl Chloride

n,n-Di isopropyl EthylamineToluene

Reactor

Centrifuge

Stage-5

Toluene to recovery

Waste HCl

Stage-6

Stage-5Mercapto methylcyclopropane acetic acid

Sodium Hydroxiden-Butyl lithium

Tetra hydro furan

Reactor

Centrifuge

Pharma

THF to recovery

Waste water

OMEPRAZOLE

The product is produced in five stages.

Stage-1:

3, 5-Lutidine undergoes oxidation with Hydrogen peroxide initially in Acetic acid. Then the reaction mass

will be subjected to Nitration with Nitric acid and Sulfuric acid mixture.

3,5-Lutidine

+ H2O2 + HNO3

Hydrogen Peroxide

Mol. Wt.:34Nitric acid

Mol. Wt.: 63

N+O-

CH3CH3

N+O

O-

Stage-1C7H8N2O3

Mol. Wt.: 168.

+ 2 H2O

Water

Mol. Wt.:36

N

H3C CH3

C7H9NMol. Wt.: 107

H2O, H2SO4Acetic acid

Stage-2:

Stage-1 compound on reaction with Sodium methoxide, Sodium Hydroxide and Dimethyl sulfate in presence

of methanol solvent medium by means of water produces stage-2 compound. The reaction proceeds as

per the below equation.

NO

CH3CH3

NO

OStage-1

C7H8N2O3Mol. Wt.: 168.2

+

Sod.methoxideMol. Wt.:54

+ 2 NaOH

Sodium hydroxideMol. Wt.: 80

MeOH

+NaNO2+H2O

Sodium NitriteWater

NO

CH3CH3

COOH

Stage-2C8H9NO3

Mol. Wt.: 167.2

CH3ONa + (CH3)2SO4

Di methyl sulfoxideMol. Wt.:126

Water

+Na2SO4

Sod.Sulphate

+CH3OH

MethanolNNaO2

Mol. Wt.: 69H2O

Mol. Wt.: 18Na2O4S

Mol. Wt.: 142CH4O

Mol. Wt.: 32

Stage-3:

Stage-2 product on reaction with Thionyl chloride & sodium hydroxide produces stage-3 compound in

presence of toluene solvent medium.

NO

CH3CH3

COOH

Stage-2C8H9NO3

Mol. Wt.: 167.2

+ SOCl2

Thionyl Chloride

Toluene

NO

CH3CH3

COCl

Stage-3

+SO2+NaCl

Sulphur dioxideSodium Chloride

+ H2O

Water

+ NaOH

Sodium HydroxideCl2OS

Mol. Wt.: 119HNaO

Mol. Wt.: 40

O2SMol. Wt.: 64.1

H2OMol. Wt.: 18

ClNaMol. Wt.: 58


Stage-4:

Stage-3 product on condensation with 5-Methoxy -2-Mercapto benzimidazole in presence of C.S. Lye

Produces stage-4.Toluene is the solvent medium

NO

CH3CH3

COCl

Stage-3

N

NH

OCH3

HS

2-Mercapto-5-methoxy benzimidazoleC8H8N2OS

Mol. Wt.: 180

+Toluene

SN

NH

N

CH3

O CH3CH3

O+

Stage-4

C16H17N3O3SMol. Wt.: 331

Mol. Wt.:36.5

C.S.Lye

HCl

O

Hydrochloricacid

O


Stage-5: Omeprazole

Above stage-4 compound on reaction with Hydrogen Peroxide produces stage-5 pharma. Methanol and

Acetone are used in the process.

SN

NHN

CH3

O CH3CH3

O

+

Stage-4C16H17N3O3SMol. Wt.: 331

Oomeprazole

C17H19N3O3SMol. Wt.: 345.

+ H2O2

HydrogenPeroxide

Mol. Wt.: 34

MeOHAcetone S

NO

CH3

NHN

CH3

O CH3CH3

H2O

WaterMol. Wt.: 18

O O

FLOW CHART OF OMEPRAZOLE

Stage-1 3,5-LutidineHydrogen Peroxide

Nitric acidSulphuric acid

Acetic acidWater

Reactor

Stage-1

Waste waterCentrifuge

Stage-2Stage-1

MethanolSod.Methoxide

DimethylsulphateSodium Hydroxide

Water

Reactor

Stage-2

Inorganic solid waste solutionCentrifuge

Stage-3


Stage-2Thionylchloride

AmmoniumpersulphateToluene

Water

Reactor

Stage-3

Waste waterCentrifuge

SulphurdioxideHCl to scrubber

Layerseperator Toluene to recovery

Stage-4Stage-3

5-Methoxy mercaptobenzimidazole

C.S.LyeToluene

Reactor

Layerseperator

CentrifugeWater Waste water

Stage-4

Stage-5Stage-5

MethanolAcetone

Hydrogen peroxide

Reactor

Centrifuge Acetone to recovery

Pharma

IPA to recovery

Toluene to recovery

ONDANSETRON

The compound can be prepared in five stages.

Stage-1:

Condensation of 2-bromo aniline with cyclohexane-1,3-dione gives bromo enaminone in presence of

methanol solvent medium.

2-Bromo Aniline Cyclohexane-1,3-dione

+ + H2O

Water

Mol. Wt.: 18

O

ONH2

Br

C6H6BrNMol. Wt.: 172

C6H8O2Mol. Wt.: 112

Methanol

NH

BrO

C12H12BrNOMol. Wt.: 266

Stage-1

Stage-2:

Staeg-1 compound is N-methylated with Iodo methane by means of NaH in presence of benzene medium

affording tertiary enaminone.

NH

BrO

C12H12BrNOMol. Wt.: 266

Stage-1

+

Methyl Iodide

H3C I

CH3IMol. Wt.: 141.9

NaH

N

BrO

CH3

C13H14BrNOMol. Wt.: 280.2

Stage-2

+ HI

HIMol. Wt.: 127.9

Hydrogen Iodide

C6H6

Stage-3:

Stage-2 compound is treated with dimethyl amio methylene iodide (Eschenmoser salt) by means of lithium

di isopropyl amide in presence of THF solvent medium affords dimethyl amino methyl derivative.

N

BrO

CH3

C13H14BrNOMol. Wt.: 280.2

Stage-2

N

H3C

H3C

CH2

I

+

C3H8INMol. Wt.: 185

Dimethyl amiomethylene iodide

LDATHF N

BrO

CH3

N

CH3

CH3

C16H21BrN2OMol. Wt.: 337.3

Stage-3

+ HI

Hydrogen iodideHI

Mol. Wt.: 127.9

Stage-4:

Stage-3 compound is then coupled with 2-methyl indole in presence of DMF solvent medium to form the

stage-4 compound.

N

BrO

CH3

N

CH3

CH3


Stage-3

+NHN

CH3

C4H6N2Mol. Wt.: 82

2-methyl indole

N

BrO

CH3

N N

CH3

DMF

N, N-dimethyl amine

HN

CH3H3C+

C2H7NMol. Wt.: 45.1


Stage-4

Stage-5:

Stage-4 compound undergoes cyclization by means of palladium acetate and triethyl amine in presence of

acetonitrile forms the final compound.

N

BrO

CH3

N N

CH3


Stage-4

+Pd(OAc)2

Et3NN

O

CH3

N N

CH3

C18H19N3OMol. Wt.: 293.4

Ondansetron

HBr

Hydrobromicacid

Mol. Wt.: 80.9

CH3CN

FLOW CHART OF ONDANSETRN

2-bromo anilinecyclohexane-1,3-dione

MethanolReactor

Centrifuge

Spent methanol to recovery

Waste water

Stage-1

Stage-1

Stage-1Iodo methane

Sodium hydrideBenzene

Reactor

Centrifuge

Spent MLs to recovery&HI gas to scrubbing

Stage-2

Stage-2

Stage-2dimethyl amio methylene iodide

lithium di isopropyl amideTHF

Reactor

Centrifuge

THF to recovery &HI gas to scrubbing

Stage-3

Stage-3

Reactor

Centrifuge

Stage-32-methyl indole

DMFSpent DMF to recovery

N,N-dimethyl amine

Stage-4

Stage-4

Reactor

Centrifuge

Stage-4palladium acetate

triethyl amineacetonitrile

Stage-5

Acetonitrile to recovery &HBr gas to scrubbing

Final compound

OXYCLOZANIDE

The compound can be prepared in five stages.

Stage‐1:

2, 4‐Dichlorophenol is treated with Nitric acid in presence of water to produce stage‐1 compound.

OH

Cl

Cl

C6H4Cl2OMol. Wt.: 163

2,4-Dichloro-phenol

+ HNO3

Nitric acid

Water

OH

Cl

Cl

C6H3Cl2NO3Mol. Wt.: 208

2,4-Dichloro-Nitrophenol

+NO2

H2O

Water

Mol. Wt.: 18Mol. Wt.: 63

Stage‐2:

STEP‐A

Sodium hydroxide, Sulfur and water react together in presence of water medium to form the sodium sulfide. The reaction proceeds as per the below equation.

Water

SodiumHydroxide

2 NaOH

Mol.Wt.:80

+ + + + +H2O

WaterMol.Wt.:18

3 S

Mol.Wt.:96

Na2S2

SodiumSulphide

Mol.Wt.:110

H2

Hydrgen

SO2

Sulphurdioxide

Mol.Wt.:2 Mol.Wt.:64

H2O

WaterMol.Wt.:18

STEP‐B

Sodium sulfide reacts with 2,4‐Dichloro nitro phenol and water in presence of mono chloro benzene forms the stage‐2 compound.

OH

Cl

Cl

C6H3Cl2NO3Mol. Wt.: 208

2,4-Dichloro Nitrophenol

+

O2NNa2S2

Sodium sulphide

+ H2O

Water

Mol. Wt.: 18

WaterMCB

OH

Cl

ClNH2

Stasge-2C6H5Cl2NO

Mol. Wt.: 178

+ Na2S2O3

Sodiumdithionate

Mol. Wt.: 158Na2S2

Mol. Wt.: 110

Stage‐3:

3,5,6‐Trichloro Salicylic acid is treated with Thionyl chloride in presence of Mono chloro benzene to produce stage‐3product.

Thionyl chloride3,5,6-trichlorosalicylic acid

+

Sulphur dioxide

SO2+ + HCl

Hydrochloricacid

Mol.Wt.:36.5

HO

O

HO

Cl Cl

Cl

C7H3Cl3O3Mol. Wt.: 241.5

S

O

Cl

Cl

Cl2OSMol. Wt.: 119

MCB

HO

O

Cl

Cl Cl

Cl


Stage-3O2S

Mol. Wt.: 64.1

Stage‐4:

Stage‐2 & stage‐3 products react together in presence of mono chloro benzene to form stage‐4.

Stasge-2C6H5Cl2NO

Mol. Wt.: 178

+

Stage-3C7H2Cl4O2

Mol. Wt.: 259.9

MCB

Stage-4

HCl

Hydrochloricacid

Mol. Wt.: 36.5

OH

Cl

Cl

Cl

Cl

O

OH

Cl

Cl

H2N

OH

Cl

Cl

Cl

O

OH

Cl

Cl

NH

C13H6Cl5NO3Mol. Wt.: 401.5

+

Staeg‐5:

Stage‐4 product on purification with Carbon in presence of Acetone produces Oxyclozanide.

Stage-4

OH

Cl

Cl

Cl

O

OH

Cl

Cl

NH


AcetoneCarbon

OH

Cl

Cl

Cl

O

OH

Cl

Cl

NH


Oxyclozanide

FLOW CHART OF OXYCLOZANIDE

2, 4-DichlorophenolNitric acid

WaterReactor

Centrifuge Water to waste

Stage-1

Stage-1

Sodium hydroxideSulfurWater

Reactor Hydrogen & sulfur gasses to scrubbing


Reactor

2,4-Dichloro nitro phenolSodium sulfide

WaterMono chloro benzene

Spent MLs


Stage-2

Stage-2

3,5,6-Trichloro Salicylic acidThionyl chloride

Mono chloro benzeneReactor

Centrifuge

Spent MLs &SO2 & HCl gasses to scrubbing

Stage-3

Stage-3

Stage-2Stage-3

Mono chloro benzeneRaector

Centrifuge

Spent MLsHCl gas to scrubbing

Stage-4

Stage-4

Stage-2Stage-3

Mono chloro benzeneRaector

Centrifuge

Acetone to recovery

Spent carbon

Final product

Stage-5

RITONAVIR

The product can be prepared in five stages

Stage-1:

(2S, 3S, 5S)-2-amino-3-hydroxy-5-(tert-butyl oxy carbonyl) amino-1,6-diphenylhexane hemi succinic acid salt and Carbnic acid.4-nitrophenyl-5-thiazolyl methyl ester condense to produce stage-1 compound. Sodium bicarbonate and Sodium hydroxide are used in the condensation.

NH2

NH

O O

CH3 CH3

CH3

OHCOOH

CH2CH2

COOH

SN

O

O

O

NO2

NHNH

O O

CH3 CH3

CH3

OHO

O

SN

+ + NaOH

Sodiumhydroxide

Sodimbicarbonate

Carbnic acid.4-nitrophenyl-5-thiazolylmethyl ester

(2S,3S,5S)-2-amino-3-hydroxy-5-(tert-butyloxycarbonyl) amino-1,6-diphenyl

hexane hemi succinic acid salt

+CH3COONa + H2O2

Water

Mol. wt.:34

Stage-1Sodium acetate

+

NaHCO3+

p-nitro phenol

H2O

NO2

OH

C27H38N2O7Mol. Wt.: 502.6

C11H8N2O5SMol. Wt.: 280.3

CHNaO3Mol. Wt.: 84

HNaOMol. Wt.: 40

C28H35N3O5SMol. Wt.: 525.7


C4H6Na2O4Mol. Wt.: 164

+CO2

CO2Mol. Wt.: 44

Carbon Dioxide

Stage-2:

Stag-1 is subjected to cyclization with water and hydrochloride in presence of n-Hexane and 1, 4-Dioxane to form the stage-2 compound.

NHNH

O O

CH3 CH3

CH3

OHO

O

SN Stage-1

C28H35N3O5SMol. Wt.: 525.7

NH NH2 .HClOHO

O

SN

1,4-Dioxane

Stage-2

+

CH3 CH3

CH3

+ H2O

Water

Mol. Wt.: 18

+ HCl

Mol. Wt.: 36.5

Hydrochloric acid

n-Hexane

OHO

O

C5H10O3Mol. Wt.: 118

C23H28ClN3O3SMol. Wt.: 462

Stage-3:

Step-A: Stage-2 compound undergoes base hydrolysis to form the free base compound.

NH NH2 .HClOHO

O

SN Stage-2

C23H28ClN3O3SMol. Wt.: 462

++

NaOHNaCl + H2O

WaterSodiumchloride

Sodiumhydroxide

Free base

Mol. wt.:40 Mol. wt.:58.5 Mol. wt.:18

H2O

NHNH2

OHO

O

SN

C23H27N3O3SMol. Wt.: 425.5

Step-B:

LiO

O

CH3

NH

CH3O

NCH3

SN

CH3CH3

+ HCl + LiCl

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

amino)carbonyl)-L-valine.Lithium salt

Mol. wt.:319C14H22LiN3O3S

Mol. wt.:313.00C14H23N3O3S

OH

O

CH3

NH

CH3O

NCH3

SN

CH3CH3

Mol. wt.:42

Lithium chlorideFree acidHydrochloricacid

Mol.Wt.:36.5

Step-C:

OH

O

CH3

NH

CH3O

NCH3

SN

CH3CH3

O

O

CH3

NH

CH3

O

N

CH3S

NCH3

CH3

OO

CH3

CH3

HCl

+

Cl

O

OCH2 CH

CH3

CH3+

Mol. wt.:397C19H31N3O4S

Mol. wt.:36.5Hydrochloric acid

Mol. wt.:313C14H23N3O3S

Free acid Isobutylchloroformate

Mol. wt.:136.5C5H9O2Cl

Stage-4:

NS

CH3CH3

N

O

NH

CH3CH3

NH

O OHNH

O

O

N

SCH3

Ritonavir crudeC37H48N6O5S2Mol. wt.:720.1

C37H48N6O5S2Mol. wt.:720.1

Ritonavir form-II

NS

CH3CH3

N

O

NH

CH3CH3

NH

O OHNH

O

O

N

SCH3

Ethyl acetaten-heptane

RIT-form-II(seedling)

Step-5:

NS

CH3CH3

N

O

NH

CH3 CH3

NH

O OHNH

O

O

N

SCH3

NS

CH3CH3

N

O

NH

CH3CH3

NH

O OHNH

O

O

N

SCH3

C37H48N6O5S2Mol. wt.:720.1

C37H48N6O5S2Mol. wt.:720.1

Ethyl acetaten-heptane

RIT-form-I(seedling)

Ritonavir form-II Ritonavir form-I

FLOW CHART OF RITONAVIR

Stage-1

Reactor Water to recovery

Centri fuge

Stage-1

Water to waste

(2S,3S,5S)-2-amino-3-hydroxy-5-(tert-butyloxycarbonyl) amino-1,6-diphenylhexane hemi succinic acid

Carbnic acid.4-nitrophenyl-5-thiazolyl methyl ester SodiumbicarbonateSodium hydroxide

Water

Reactor Toluene to recovery

Centri fuge

Stage-2

Water to waste

Layer saparate

Tolene to recovery

Satge-11,4-Di oxane

HCln-hexane

Water

Stage-2

Reactor Water to recovery

Centri fuge

Water to wasteLayer

saparate

salt solution

Stage-2Sodium hydroxide

HClIsobutyl chloro formate

Water

stage-3

Stage-3

Reactor n-heptene to recovery

Centri fuge

Stage-4

Water to wasteLayer

saparate

Ethyl acetate to recovery

Satge-3n-Heptane

Ethyl acetateWater

Stage-4

Stage-5

Reactor n-heptene to recovery

Centrifuge

Stage-5

Water to wasteLayer

saparate


Satge-4n-Heptane

Ethyl acetateWater

ROSUVASTATIN CALCIUM

The product can be prepared in ten stages.

Stage-1:

The condensation of 4-fluoro benzaldehyde with 4-methyl-3-oxo pentanoic acid ethyl ester by means of

Piperidine and acetic acid in presence of benzene solvent medium gives the stage-1 compound.

CHO

F +

4-methyl-3-oxopentanoic acid ethyl ester

O

OO

C8H14O3Mol. Wt.: 158.2

C7H5FOMol. Wt.: 124

4-fluoro benzaldehyde

Piperidine/AcOHO

Benzene

F

O

O

C15H17FO3Mol. Wt.: 264.3

Stage-1

H2O

Mol. Wt.: 18Water

+

Stage-2:

Stage-1 is cyclized with S-methyl iso thio urea and oxidized with DDQ in presence of toluene solvent

medium affords the stage-2 compound. The reaction proceeds as per the below equation.

OF

O

O

C15H17FO3Mol. Wt.: 264.3

Stage-1

SCH3

NHH2N

C2H6N2SMol. Wt.: 90

S-methyl iso thio urea

+

OF O

N N

SCH3

C17H19FN2O2SMol. Wt.: 334

Stage-2

+

O

O

Cl

Cl

CN

CN

DDQC8Cl2N2O2

Mol. Wt.: 227

+Toluene

OH

OH

Cl

Cl

CN

CN


2,3-dichloro-5,6-dicyanohydroquinone

+H2O

WaterMol. Wt.: 18

Stage-3:

The oxidation of stage-2 compound with m-Chloro per benzoic acid with hydrogen peroxide in presence of

aqueous sodium hydroxide gives the stage-3 compound.

OF O

N N

SCH3


Stage-2

m-CPBA/H2O2

Aq.NaOH

OF O

N N

SCH3O

O


Stage-3

2 (O)+

OxygenMol. Wt.: 32

Stage-4:

Stage-3 compound is treated with methyl amine in presence of methane sulfonyl chloride gives the stage-

4 compound.

OF O

N N

SCH3O

O


Stage-3

MeNH2

CH5NMol. Wt.: 31.1

+

Methhyl amine

Me SO2Cl

OF O

N N

SCH3

O

O

N CH3

C18H22FN3O4SMol. Wt.: 395.5

Stage-4

H2+

HydrogenMol. Wt.: 2

Stage-5:

The reduction of ester group of stage-4 compound with DIBAL H (Di-isobutyl aluminum hydride) in

presence of toluene solvent medium affords the resulting aldehyde.

OF

CH3

CH3O

N N

SCH3

O

O

N CH3


Stage-4

DIBAL H

HF

CH3

CH3O

N N

SCH3

O

O

N CH3

H3C

H2C

OH

EthanolC2H6O

Mol. Wt.: 46.1

H2 +


Stage-5

+

HydrogenMol.Wt.: 2

Stage-6:

Stage-5 compound is submitted to a Wittig condensation with the phosphorane in dry THF to give the

stage-6 product.

HF

CH3

CH3O

N N

SCH3

O

O

N CH3


Stage-5

OO

TBDMSO

(Ph3)P

OCH3

C31H39O4PSiMol. Wt.: 534.7

+

Phosphorane compound

F

CH3

CH3

N N

SCH3

O

O

NCH3

OO

TBDMSO OCH3

C29H42FN3O6SSiMol. Wt.: 607.8

Stage-6

Dry THF Ph3P O+

Tri phenylphosphine oxide

C18H15OPMol. Wt.: 278.3

Stage-7:

The deprotection of stage-6 compound with HF in presence of THF solvent medium forms the Stage-7

compound.

F

CH3

CH3

N N

SCH3

O

O

NCH3

OO

TBDMSO OCH3

C29H42FN3O6SSiMol. Wt.: 607.8

Stage-6

HF

Hydrogen fluoride

Mol. Wt.: 20

+THF

F

CH3

CH3

N N

SCH3

O

O

NCH3

OO

HO OCH3

SiH3C CH3

F

C6H15FSiMol. Wt.: 134.3

Tert-butyl dimethyl silyl fluoride


Stage-7

+

Stage-8:

The controlled reduction of stage-7 product with sodium boro hydride in diethyl methoxy borane affords

the stage-8 compound.

F

CH3

CH3

N N

SCH3

O

O

N CH3

OO

HO OCH3


Stage-7

Et2BOMe/NaBH42 (H)

HydrogenMol. Wt.: 2

+

F

CH3

CH3

N N

SCH3

O

O

N CH3

OHO

HO OCH3


Stage-8

Stage-9:

Stage-8 is hydrolyzed with NaOH in presence of ethanol solvent medium yielding the corresponding

sodium salt. The reaction showed as below.

F

CH3

CH3

N N

SCH3

O

O

NCH3

OHO

HO OCH3


Stage-8

+ NaOH

SodiumhydroxideMol. Wt.: 40

Ethanol

F

CH3

CH3

N N

SCH3

O

O

N CH3

OHO

HO ONa

C22H27FN3NaO6SMol. Wt.: 503.5

Stage-9

H3C OH+

CH4OMol. Wt.: 32

Methanol

Stage-10:

Stage-9 compound is finally treated with calcium chloride in water yields the final compound. The reaction


F

CH3

CH3

N N

SCH3

O

O

N CH3

OHO

HO ONa

C44H54F2N6Na2O12S2Mol. Wt.: 1007

Stage-9

+ CaCl2

Calcium chlorideCaCl2

Mol. Wt.: 111

Water

F

CH3

CH3

N N

SCH3

O

O

N CH3

OHO

HO O

Ca2+

C44H54F2N6O12S2Ca2+

Mol. Wt.: 1001

Rosuvastatin calcium

2 NaCl+

2

2

Cl2Na2Mol. Wt.: 116.9

Sodium chloride

FLOW CHART OF ROSUVASTATIN CALCIUM

4-fluoro benzaldehyde4-methyl-3-oxo pentanoic acid ethyl ester

PiperidineAcetic acid

benzene

Reactor

Centrifuge

Solvent ml's to recovery

Waste water

Stage-1

Stage-1

Stage-1S-methyl iso thio urea

DDQToluene

Reactor

Centrifuge

Toluene to recovery

Waste water

Stage-2

Stage-2

Layerseparator 2,3-dichloro-5,6-dicyano

hydro quinone

stage-2Oxygen

m-CPBAHydrogen peroxideSodium hydroxide

Reactor

Stage-3

Stage-3

solvent ml's to recovery

Stage-3Methyl amine

Methane sulfonyl chlorideReactor

Centrifuge

Stage-4

Stage-4

solvent ml's to recovery

Hydrogen emission to scrubber

Stage-4Hydrogen DIBAL H

Reactor

Centrifuge

Stage-5

Stage-5

Ethanol

Stage-5Phosphorane compound

Dry THFReactor

Centrifuge

Stage-6

Stage-6


Triphenyl phosphine oxide

Stage-6Hydrogen fluorideTetra hydro furan

Reactor

Centrifuge

Stage-7

Stage-7


Tert-butyl dimethyl silyl fluoride

Stage-7Hydrogen

Diethyl methoxy boraneSodium boro hydride

Reactor

Centrifuge

Stage-8

Stage-8

Stage-8Sodium hydroxide

EthanolReactor

Centrifuge

Stage-9

Stage-9


Ethanol to recovery

Stage-9Calcium chloride

WaterReactor

Centrifuge

Stage-10

Inorganic waste

Waste water

Final compound

SETRALINE HYDROCHLORIDE

The product is manufactured in four stages

Stage-1:

α -Naphthol when reacts with Dichloro Benzene in presence of Anhydrous Aluminum chloride produces

stage-1 compound. Methanol is the solvent used.

+Al Cl3MeOH

alpha naphtholC10H8O

Mol. Wt.: 144.2

dichloro benzeneC6H4Cl2

Mol. Wt.: 147C16H9Cl2O

Mol. Wt.: 289.2

OH

O

Cl

Cl

+ H2

HydrogenMol.Wt.:2

Stage-1

ClCl

Stage-2:

Stage-1 compound on condensation with Monomethylamine produces the stage-2 compound. Methanol is

used as the solvent. Reaction proceeds as follows.

O

Cl

Cl

+ H2O

WaterMol.Wt.:18

Stage-1

+ NH2 CH3

Methyl amineCH5N

Mol. Wt.: 31.1

MeOH

N

Cl

Cl

CH3

Stage-2C17H13Cl2N

Mol. Wt.: 302.2C16H10Cl2O

Mol. Wt.: 289.2

Stage-3:

Stage-3 compound is obtained when stage-2 product undergoes reduction reaction in acidic medium in

presence of Sodium boro hydride. Methanol is used as solvent.

N

Cl

Cl

CH3

Stage-2C17H13Cl2N

Mol. Wt.: 302.2

NaBH4

NH

Cl

Cl

CH3

HCl

C17H14Cl3NMol. Wt.: 338.7

Stage-3

MeOH+ HCl

Hydrochloricacid

Mol. Wt.: 36.5

Stage-4:

Finally pharma is obtained when stag-3 product is treated with D (-) Mandelic acid in Ethyl Acetate

medium. The compound is purified with carbon and water. The pharma is crystallized in Methanol.

NH

Cl

Cl

CH3

HCl

C17H14Cl3NMol. Wt.: 338.7

Stage-3

Ethyl AcetateD(-)Mandelic acid

NH

Cl

Cl

CH3

HCl

Sertraline HClC17H14Cl3N

Mol. Wt.: 338.7

FLOW CHART OF SERTRALINE HCl

Reactor

Stage-1

Stage-1:

alpha-NaptholDichloro Benzene

Aluminum chlorideMethanol


Centrifuge

Stage-2Stage-1

MonomethylamineMethanol

Reactor

Centrifuge


Water to recovery

Stage-2 product

Stage-2Sodium borohydride

Hydrochloric acidMethanol

Stage-3:

Reactor

Centrifuge


Inorganic salt solutionWater

Stage-3 product

Stage-3Mandelic acid

Ethyl acetate

Stage-4:

Reactor

Centrifuge


Final compound

SPARFLOXACIN

The compound can be prepared in seven stages.

Stage-1:

The reaction of ethyl penta fluoro benzoyl acetate with ethyl ortho formate in refluxing acetic anhydride in presence of acetic acid solvent medium forms the stage-1 compound.

F

F

F

F

F

O

COOEt

C11H7F5O3Mol. Wt.: 282.2

ethyl pentafluorobenzoylacetate

CH

OEt

EtO OEt

C7H16O3Mol. Wt.: 148

Triethyl ortho formate

+Ac2O

F

F

F

F

F

O

COOEt

CH

OEt

OEt

C16H17F5O5Mol. Wt.: 384

Stage-1

+ H3C OH

C2H6OMol. Wt.: 46.1

Ethanol

AcOH

Stage-2:

Stage-1 compound reacts with cyclopropyl amine in presence of ether solvent medium to form the amino methylene derivative as stage-2 product.

F

F

F

F

F

O

COOEt

CH

OEt

OEt

C16H17F5O5Mol. Wt.: 384

Reaction mass

NH2

+

C3H7NMol. Wt.: 57.1

Cyclopropyl amine

F

F

F

F

NH

O

COOEt

EtO

H3C OH

C2H6OMol. Wt.: 46.1

Ethanol

EtherF

+

C17H18F5NO4Mol. Wt.: 395

Stage-2

Stage-3:

Stage-2 compound undergoes cyclization by means of NaH in presence of Tetra hydro furan solvent medium to attain the stage-3 compound.

HF

Mol. Wt.: 20

F

F

F

F

NH

O

COOEt

EtO

H3C OH

C2H6OMol. Wt.: 46.1

Ethanol

F+


Stage-2

NaH

THF

F

F

F

F

N

O

COOEt


Stage-3

+

Hydrogen Fluoride

Stage-4:

Stage-3 compound reacts with benzyl amine by means of potassium carbonate in presence of acetonitrile solvent medium to obtain the stage-4 compound.

F

F

F

F

N

O

COOEt


Stage-3

NH2

Benzyl amineC7H9N

Mol. Wt.: 107.

+K2CO3

Acetonitrile

NH

F

F

F

N

O

COOEt

HF+

HydrogenfluorideC22H19F3N2O3

Mol. Wt.: 416.4

Stage-4

Mol. Wt.: 20

Stage-5:

Stage-4 is deprotected by hydrogenation with H2 over Pd/C in ethanol solvent medium to form the stage-5 compound.

NH

F

F

F

N

O

COOEt

C22H19F3N2O3Mol. Wt.: 416.4

Stage-4

2 (H)+

Hydrogen

Mol. Wt.: 2

H2,Pd/C

NH2

F

F

F

N

O

COOEt

C15H13F3N2O3Mol. Wt.: 326.3

Stage-5

+

TolueneC7H8

Mol. Wt.: 92

Ethanol

CH3

Stage-6:

Stage-5 product undergoes acid hydrolysis with hot sulfuric acid yields the acid compound as stage-6.

NH2

F

F

F

N

O

COOEt

C15H13F3N2O3Mol. Wt.: 326.3

Stage-5

H2SO4H2O+

Water

Mol. Wt.: 18

NH2

F

F

F

N

O

COOH

C13H9F3N2O3Mol. Wt.: 298

Stage-6

C2H5OH+

EthanolC2H6O

Mol. Wt.: 46.1

Stage-7:

Stage-6 is finally condensed with cis-2, 6-dimethylpiperazine in presence of DMF solvent medium to obtain the final product.

NH2

F

F

F

N

O

COOH


Stage-6

DMFNH

HN

H3C CH3+

cis-2, 6-dimethylpiperazineC6H14N2

Mol. Wt.: 114.2

NH2

F

N

F

N

O

COOH

HN

H3C

CH3


Sparfloxacin

+ HF

HydrogenFluoride

Mol. Wt.: 20

FLOW CHART OF SPARFLOXACIN

ethyl penta fluoro benzoyl acetateTri ethyl ortho formate

Acetic anhydrideAcetic acid

Reactor

Centrifuge

Acetic acid to recovery

Waste ethanol

Stage-1

Stage-1

Stage-1Cyclopropyl amine

EtherReactor

Centrifuge

Ether to recovery

Waste ethanol

Stage-2 product

Stage-2

Stage-2Sodium hydride

THFReactor

Centrifuge

THF to recovery

Waste ethanol andHydrogen fluoride

Stage-3 product

Stage-3

Stage-3Benzyl amine

Potassium carbonateAcetonitrile

Reactor

Centrifuge

Acetonitrile to recovery

Hydrogen Fluoride

Stage-4

Stage-4

Stage-4Hydrogen Pressure

Pd/CEthanol

Reactor

Centrifuge

Ethanol to recovery

Hydrogen Fluoride

Stage-5 compound

Stage-5

Stage-5Water

Sulphuric acidReactor

Centrifuge Waste ethanol

Stage-6

Stage-6

Stage-6cis-2, 6-dimethylpiperazine

DMFReactor

Centrifuge Hydrogen Fluoride

Final compound

Stage-7

DMF to recovery

TERBINAFINE HYDROCHLORIDE

The product can be prepared in six stages.

Stage-1:

The Grignard reaction of 1-bromo naphthalene with Mg in presence of THF solvent medium and then reacts

with carbon dioxide with water gives the corresponding naphthoic acid as stsge-1 compound.

Br

C10H7BrMol. Wt.: 207.1

1-bromo naphthalene

+ Mg

MagnesiumMol. Wt.: 24

THF

MgBr

C10H7BrMgMol. Wt.: 231.4

1-Naphthyl magnesium bromide

CO2+

Carbon dioxideMol. Wt.: 44

+ H2O

Water

Mol.Wt.: 18

O OH

C11H8O2Mol. Wt.: 172.2

Stage-1

+Mg(OH)Br

Hydroxy magnesiumbromide

Mol. Wt.: 121

Stage-2:

STEP-A

Stage-1 compound reacts with SOCl2 in presence of MDC solvent medium forms the acid chloride

compound.

O OH

C11H8O2Mol. Wt.: 172.2

Stage-1

SOCl2+

Thionyl chlorideCl2OS

Mol. Wt.: 119

MDC

O Cl

C11H7ClOMol. Wt.: 190.6

Reaction mass

SO2

Sulphur dioxide

+ + HCl

Hydrochloric acidO2S

Mol. Wt.: 64.1ClH

Mol. Wt.: 36.5

STEP-B

The reaction mass formed in STEP-A reacts with methyl amine in presence of acetone solvent medium

forms the stage-2 compound.

+ MeNH2

OHN

CH3


Stage-2

HCl

Hydrochloric acid

+

Methyl amineCH5N

Mol. Wt.: 31.1

O Cl

C11H7ClOMol. Wt.: 190.6

Reaction mass

Acetone

ClHMol. Wt.: 36.5

Stage-3:

Stage-2 product undergoes reduction with LiAlH4 in presence of THF solvent medium affords the

corresponding amine as stage-3 product.

OHN

CH3


Stage-2

4 (H)+

HydrogenMol. Wt.: 4

LiAlH4

THF

HN

CH3

C12H13NMol. Wt.: 171

Stage-3

H2O+

Water

Mol.wt.: 18

Stage-4:

The condensation of propenal with tert-butyl acetylene by means of butyl lithium forms the stage-4

compound. The reaction proceeds as per the below equation.

CH+

C3H4OMol. Wt.: 56.1

Propenal Tert-butyl acetylene

CH3

BuLi

CH3

CHO

OH

C9H14OMol. Wt.: 138

Stage-4C6H10

Mol. Wt.: 82

Stage-5:

Stage-4 compound is rearranged with HBr in presence of acetone solvent medium forms the stage-5

product. The rearrangement takes place under the following equation.

CH

CH3

OH

C9H14OMol. Wt.: 138

Stage-4

HBr+ Acetone

CH

CH3

Br

C9H13BrMol. Wt.: 201

Stage-5Hydrogenbromide

Mol. Wt.: 81

H2O+

WaterMol. Wt.: 18

Stage-6:

Finally, the stage-3 product reacts with stage-5 product and also with hydrochloric acid in presence of

sodium carbonate affords Terbinafine hydrogen chloride. The reaction proceeds as per the below

equation.

CH

CH3

Br

C9H13BrMol. Wt.: 201

Stage-5

HN

CH3

C12H13NMol. Wt.: 171

Stage-3

+ Na2CO3HCl

Hydrochloric acid

Mol. Wt.: 36.5

+

N

CH3

CH

H3C CH3

CH3

Terbinafine HCl

. HCl


+HBr

Hydrobromicacid

Mol Wt.: 81

FLOW CHART OF TERBINAFINE HCl

1-bromo naphthaleneMagnesium

THFReactor

ReactorCarbon dioxixe

Water Hydroxy magnesium bromide

Stage-1


Stage-1

Stage-1 productThionyl chloride

MDCReactor

Reactor

Stage-2

Stage-2

Solvent ml's to recoverySO2 & HCl emissions to scrubber

Methyl amineSpent acetone to recoveryHCl gas to scrubbing

Centrifuge

Stage-2Hydrogen

LiAlH4THF

Reactor

Stage-3

Stage-3

Centrifuge


Waste water

PropenalTert-butyl acetylene

Butyl lithiumReactor

Stage-4

Stage-4

Centrifuge

Stage-4Hydrogen bromide

AcetoneReactor

Stage-5

Stage-5


Acetone to recovery

Stage-3Stage-5

Hydrochloric acidSodium carbonate

Reactor

Stage-6

Centrifuge Inorganic salt solution

Final product

Water

TRI CHLORO SALISYLIC ACID

The product can be manufactured in two stages.

Stage-1:

Salicylic acid undergoes chlorination in presence of acetic acid to form the stage-1 compound.

OH

COOH+

Salicylic acidC7H6O3

Mol. Wt.: 138

+2 Cl2

ChlorineCl4

Mol. Wt.: 141.8

CH3COOH

OH

C

Cl Cl

OH

O

C7H4Cl2O3Mol. Wt.: 207

3,5-dichloro salicylic acid

2 HCl

Hydrochloric acid

Mol. Wt.: 73

Stage-2:

3, 5-dichloro salicylic acid undergoes chlorination by passing chlorine gas in presence of oleum to form

the trichloro salicylic acid

+

OH

C

Cl Cl

OH

O

C7H4Cl2O3Mol. Wt.: 207

3,5-dichloro salicylic acid

OleumCl2

ChlorineCl2

Mol. Wt.: 70.9

OH

C

Cl Cl

OH

O

Cl


Trichloro salicylic acid

+ HCl

Hydrochloric acid

Mol. Wt.: 36.5

FLOW CHART OF TRICHLORO SALICYLIC ACID

Salicylic acidChlorine gaas

Acetic acidReactor

Centrifuge

Stage-1:

HCl gas to scrubber

Acetic acid MLs

Stage-1 product

Stage-1 productChlorine gas

OleumReactor

Centrifuge

Stage-2:

HCl gas to scrubber

Spent MLs

Final product

5-AMINO-2-HYDROXY BENZOIC ACID

Stage-1:

2-Chloro-5-Nitro Benzoic acid undergoes hydrolysis with sodium hydroxide in presence of water forms the stage-1 compound.

Cl

O2N

O OH


2-Chloro-5-Nitro benzoic acid Sodium hydroxide

NaOH+

Mol. Wt.: 40

H2OOH

O2N

O OH


Stage-1

NaCl+

Sodium chloride

Mol. Wt.: 58.5

Stage-2:

Stage-1 product undergoes hydrogenation with hydrogen pressure in presence of Raney nickel catalyst to form 5-Amino-2-Hydroxy Benzoic acid.

OH

O2N

O OH


Stage-1

3 H2+

Hydrogen

Mol.Wt.: 6

Raney Ni/H2

OH

H2N

O OH

5-Amino-2-Hydroxy Benzoic acidC7H7NO3

Mol. Wt.: 153

+ 2 H2O

Water

Mol.Wt.: 36

FLOW CHART OF 5-AMINO-2-HYDROXY BENZOIC ACID

2-Chloro-5-Nitro Benzoic acidsodium hydroxide

waterReactor

Centrifuge Inorganic salt solution

Stage-1

Stage-1

Stage-1Raney nickle

Hydrogen pressureReactor

Centrifuge

Final product

Stage-2

Waste water to recovery

5-AMINO-2-DIBENZYLAMINO-1,6-DIPHENYL-HEX-4-EN-3-ONE

The product can be prepared in three stages.

Stage-1:

The reaction of L-phenyl alanine with benzyl bromide and potassium carbonate in ethanol forms the

stage-1 compound. The reaction undergoes as follows.

Ph

H2NOH

O

+

C9H11NO2Mol. Wt.: 165.2

Benzyl chlorideC21H21Cl3

Mol. Wt.: 379.8

L-Phenyl alanine

Ph

NO

O

Ph

Stage-1

+ 3 HCl

Hydrochloricacid

Mol. Wt.: 109.5

K2CO3Ethanol

Ph

Ph

H2C ClPh3

C30H29NO2Mol. Wt.: 435.6

Stage-2:

Stage-1 compound is condensed with acetonitrile by means of sodamide in presence of tetra hydro furan

solvent medium forms the stage-2 compound.

Ph

NO

O

Ph

Stage-1

Ph

Ph

H3C CN+

AcetonitrileC2H3N

Mol. Wt.: 41

NaNH2

THF Ph

NO

Ph

Ph

CN

C25H24N2OMol. Wt.: 368.5

Stage-2

HO Ph+

C7H8OMol. Wt.: 108

Benzyl alcoholC30H29NO2

Mol. Wt.: 435.6

Stage-3:

The reaction of stage-2 compound with benzyl magnesium chloride and water in presence of THF solvent

medium forms the required intermediate.

Ph

NO

Ph

Ph

CN

C25H24N2OMol. Wt.: 368.5

Stage-2

+

H2CPh MgCl

C7H7ClMgMol. Wt.: 151.9

Benzyl magnesium chloride

THF

NO

Ph

Ph

C33H35NOMol. Wt.: 461.6

Stage-3

+Mg(OH)Cl

+

Magnesium hydroxychloride

Mol. Wt.: 76.8

H2O

Water

Mol. Wt.: 18

FLOW CHART

L-phenyl alanineBenzyl chloride

Potassium carbonateEthanol

Reactor

Centrifuge

Ethanol solvent to recovery

Inorganic waste

Stage-1

Stage-1

Stage-1Acetonitrile

SodamideTetra hydro furan

Reactor

Centrifuge

THF solvent to recovery

Stage-2

Benzyl alcohol

Stage-2

Stage-2Benzyl magnesium chloride

WaterTHF

Reactor

Centrifuge

THF solvent to recovery

Stage-3

Inorganic waste

Final product

2-AMINO-6-CHLORO-3-NITRO PYRIDINE

Stage-1:

The compound can be prepared in two steps.

STEP-A:

2, 6-dichloro pyridine undergoes nitration with nitrating mixture i.e.; conc.HNO3 and conc.H2SO4 forms 2,

6-dichloro-3-nitro pyridine. The reaction proceeds as per the below equation.

N ClCl

2,6-dichloro pyridine

Conc. HNO3+

Nitric acidHNO3

Mol. Wt.: 63C5H3Cl2N

Mol. Wt.: 148

Conc. H2SO4+

Sulphuric acidH2O4S

Mol. Wt.: 98.1

N ClCl

NO2


2,6-dichloro-3-nitro pyridine Sulphuric acidH2O4S

Mol. Wt.: 98.1

+ H2O

WaterMol.Wt.:18

+H2SO4

STEP-B:

2, 6-dichloro-3-nitro pyridine on reaction with aqueous ammonia in the presence of isopropanol forms 2-

amino-6-chloro-3-nitro pyridine. The reaction proceeds as follows.

N ClCl

NO2


2,6-dichloro-3-nitro pyridine

+ Aq. NH3

AmmoniaH3N

Mol. Wt.: 17

IPAN NH2Cl

NO2

C5H4ClN3O2Mol. Wt.: 173.6

2-amino-6-chloro-3-nitro pyridine

+ HCl

Hydrochloric acid

Mol. Wt.: 36.5

FLOW CHART OF 2-AMINO-6-CHLORO-3-NITRO PYRIDINE

Stage-1

2,6-dichloro pyridineConc.H2SO4Conc.HNO3

Reactor

Quencher


Aqueous ammoniaIso propyl alcohol Reactor

Centrifuge Waste HCl to recovery


Filteration

Final product

4-CHLORO BUTYRYL CHLORIDE

Stage-1:

γ- Butyro lactone undergoes reduction in presence of Zinc Amalgam and Hydrochloric acid and then

reacts with Thionyl chloride to form 4-chloro butyryl chloride.

Thionyl chloride

SO

ClCl+

Cl2OSMol. Wt.: 119

O

+ 2 HCl

Gamma butyro lactone

O

C4H6O2Mol. Wt.: 86.1

2 Zn (Hg) +

Zinc amalgamZn

Mol. Wt.: 130.8

Hydrochloricacid

Mol. Wt.: 73

ClCl

C4H8Cl2Mol. Wt.: 127

4-chloro butyryl chloride

+ZnCl2

Zinc chlorideCl2Zn

Mol. Wt.: 136

+SO2

Sulfur dioxideO2S

Mol. Wt.: 64.1

+ZnO

Zinc oxideOZn

Mol. Wt.: 81.4

H2O

FLOW CHART

Gamma butyro lactoneZinc Amalgam

Hydrochloric acidThionyl chloride

Reactor

CentrifugeWater

SO2 to scrubber

ZnO & ZnCl2 to Waste Water

Final product

List of products - Welcome to Environmentenvironmentclearance.nic.in/writereaddata/Online/TOR/0_0_10_Jul... · LIST OF PRODUCTS BULK DRUGS Sl. ... Mol.Wt.:81 C16H19NO2 Mol.Wt.:257

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