LIST of PRODUCTS BULK DRUGS Sl. No Name of the Product Production TPM 1. Carvedilol Phosphate 2.50 2. Citalopram Hydrobromide 10

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 TPM 1 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 Toluene Br + NH2

1-(2-Bromo-ethoxy)- 2-methoxy-benzene Benzylamine C9H11BrO2 C7H9N Mol. Wt.: 231.1 Mol. Wt.: 107

O NH HBr +

Stage-1 Hydrobromic acid C16H19NO2 Mol.Wt.:81 Mol.Wt.:257

Stage-2:

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

O Cl N O OH NH + Cl O Methanol O O Stage-2 Stage-1 2-Chloromethyl-oxirane C H ClNO C16H19NO2 C3H5ClO 19 24 3 Mol. Wt.: 257 Mol. Wt.: 92 Mol. 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.

OH O K CO Cl N 2 3 OH + O N H Stage-2 9H-Carbazol-4-ol C H NO C19H24ClNO3 12 9 Mol. Wt.: 349.8 Mol. Wt.: 183 O O N OH O HCl + N H Hydrochloric Stage-3 acid C31H32N2O4 Mol.Wt.:36.5 Mol. Wt.: 496.6

Stage-4:

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

O O N H2, Pd/C OH + H2 O

N Stage-3 H Hydrogen C31H32N2O4 Mol. Wt.: 496.6 Mol. Wt.: 2 O O NH OH CH3 O + N H Toluene Carvedilol free base C7H8 C24H26N2O4 Mol. Wt.: 92 Mol. Wt.: 406.5

Stage-5:

Carvedilol free base reacts with phosphoric acid and water forms carvedilol phosphate. The reaction proceeds as per the below equation.

O O NH OH OH H2O + OH P OH +1/2 HO O 2 O NH Carvedilol free base Phosphoric acid Water C24H26N2O4 H3O4P Mol. Wt.: 406.5 Mol. Wt.: 98 Mol.Wt.: 9

O O NH OH CH3 O

. H3PO4 .1/2 H2O

Carvedilol phosphate C25H30NO8P Mol. Wt.: 513.5

FLOW CHART OF CARVEDILOL PHOSPHATE

Stage-1 1-(2-bromo ethoxy)-2-methoxy benzene benzyl amine Reactor Spent toluene to recovery Toluene

Centrifuge

Layer Seperator Forms hydrobromic acid

Stage-1

Stage-2

stage-1 product 2-chloro ethyl-oxirane Reactor Spent methanol to recovery Methanol

Centrifuge

Stage-2

Stage-3

Stage-2 9H-carbazol-4-ol Reactor HCl gas to scrubbing Potassium carbonate

Centrifuge

Layer separation

Stage-3 Stage-4

Stage-3 comound Reactor Toluene to recovery H2, Pd/C

Centrifuge

Layer separation

Cavedilol free base

Stage-5 Carvedilol free base Phosphoric acid Reactor Water

Centrifuge Waste water to recovery

Distillation

Pharma

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 F

CH3 CH3 N Phosphoric acid + .H O OH N 2 CH3 Liq.Ammonia,Toluene O OH CH NC NC 3

4-[4-Dimethylamino-1-(4-fluoro-phenyl)- 1-hydroxy-butyl]-3-hydroxymethyl-benzonitrile Stage-1 Water C H FN O C20H23FN2O2 20 22 2 Mol. Wt.: 18 Mol. Wt.: 342 Mol. Wt.: 324.4

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.

F F

CH3 IPA CH3 N + HBr O N CH3 O CH3 NC NC HBr

Stage-1 Hydro bromicacid Citalopram Hydrobromide C20H22FN2O BrH C20H22BrFN2O Mol. Wt.: 324.4 Mol. Wt.: 80.9 Mol. Wt.: 405.3

FLOW CHART OF CITALOPRAM HYDROBROMIDE

Stage-1

4-[4-Dimethylamino-1-(4-fluoro-phenyl)- 1-hydroxy-butyl]-3-hydroxymethyl-benzonitrile Phosphoric acid Reactor Toluene to recovery Liq.Ammonia,Toluene Water

Centrifuge Ammonium phosphate salt solution for sale

Stage-1

Stage-2:Pharma

Stage-1 Hydrobromic acid Spent solvent to recovery Di Isopropyl ether Reactor Iospropyl alcohol

Centrifuge Di Isopropyl ether

Stage-Pharma

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

Water NaHS + Na2CO3 NaHCO3 + Na2S

Sodium Sodium Sodiumhydrogen Sodium bicarbonate sulphide sulphide Carbonate Mol. Wt.: 84 Mol.Wt.:78 Mol. Wt.: 56 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.

Cl Cl CN –O Cl N Toluene N+ + + O NaHS H2N 2 O

CH3 CH3 1-Chloro-3-methyl parachloro -5-nitro-benzene benzyl cyanide Stage-1 Oxygen O C7H6ClNO2 C8H6ClN C15H12Cl2N2 2 Mol. Wt.: 171.6 Mol. Wt.: 151.6 Mol. Wt.: 291.2 Mol. 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 OH O I Cl CN OH Toluene/PCl + 3 Water

H2N I

CH3 2-Hydroxy-3,5-diiodo Stage-1 -benzoic acid C15H12Cl2N2 C7H4I2O3 Mol. Wt.: 291.2 Mol. Wt.: 389.9 OH O Cl C N I NH CH Cl H2O +

I CH3

Water Closantel C22H14Cl2I2N2O2 Mol. Wt.: 18 Mol. Wt.: 663.1

Stage-3:

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

OH O Cl C N I OH NaOH NH CH Cl + +

O I CH3 Closantel Formic acid Sodium Hydroxide C22H14Cl2I2N2O2 CH2O2 Mol. Wt.: 663.1 Mol. Wt.: 46 Mol. Wt.: 40

CH 3 Water + I NH Cl H2O O Acetone OH O O- Na+ Cl N Water Closantel Sodium C23H15Cl2I2N2NaO4 Mol. Wt.: 18 Mol. Wt.: 731.1

FLOW CHART OF CLOSANTEL SODIUM

Stage-1 Sodiumbicarbonate Sodium Sulphide Reactor Inorganic salt solution to waste Water 1-chloro3-methyl-2-nitro benzene parachlorobenzyl cyanide Tolouene to recovery Reactor Sodium Hydrogen Sulfide O2 gas to scrubbing Toluene

Centrifuge

Stage-1

Stage-2:

Stage-1 2-Hydroxy-3,5-diiodo-benzoic acid Toluene Reactor Toluene to recovery Phosphorus tri chloride water

Centrifuge Inorganic salt solution to waste

Stage-2

Stage-3: Closantel Formic acid Sodium Hydroxide Reactor Acetone to recovery Water Acetone

Centrifuge 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.

O H O N NH Titanium S isoperoxide + + KOH O N O MDC 5-Methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2- ylmethylsulfanyl)-1H-benzoimidazole cumene hydroperoxide Potassium C17H19N3O2S C9H12O2 Hydroxide Mol. Wt.: 329.4 Mol. Wt.: 152.2 Mol. Wt.: 56.1

O N

OH N CH3 S + H O + N CH3 O 2 O O K Phenyl-acetic acid Esomeprazole Potassium Water C8H8O2 C17H18KN3O3S Mol.Wt.:18 Mol. Wt.: 136.2 Mol. Wt.: 383.5

Stage-2:

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

N N CH3 Acetone 2 + Mg.Cl + 3 H O S 2 2 N O O O CH3 K

Esomeprazole Potassium Magnesium Water C34H36N6O6S2K2 Chloride H6O3 Mol. Wt.: 767 Mol. Wt.: 95 Mol. Wt.: 54

O N S N N O Mg

O N N S 2 KCl + N O

H O H2O H2O 2 Potassium Chloride Cl2K2 Esomeprazole Magnesium trihydrate Mol. Wt.: 149 C34H42MgN6O9S2 Mol. Wt.: 767.2

FLOW CHART OF ESOMEPRAZOLE MAGNESIUM TRIHYDRATE

Stage-1:

5-Methoxy-2-(4-methoxy-3, 5-dimethyl- pyridin-2-yl-methyl sulfanyl)-1H-benzoimidazole Cumene hydro peroxide Potassium hydroxide Reactor Solvent Mls Titanium isopropoxide Methylene Dichloride

Centrifuge Water to waste

Layer separator Phenyl acetic acid

Stage-1

Stage-2: Stage-1 Magnesium Chloride Reactor Water Acetone to recovery Acetone

Centrifuge Inorganic salt solution to waste

Pharma

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.

Cl MIBK + NH + NaHCO3 EtOH O OH O O

2-[4-(4-Chloro-butyryl)-phenyl]- 2-methyl-propionic acid methyl ester Azacyclonol Sodium C H ClO Bicaronate 15 19 3 C18H21NO Mol. Wt.: 282.8 Mol. Wt.: 267.4 Mol. Wt.: 84

CH3 CH3 O CH3 N O O

+ + NaCl + C H2O + CO2 OH

Stage-1 Water Carbon dioxide Sodium Chloride C33H39NO4 Mol.Wt.:18 Mol.Wt.:44 Mol.Wt.:58.5 Mol. Wt.: 513.7

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.

CH3 CH3 O

N O O Methanol + + NaOH HO + H2O OH O Sodium Acetic acid Stage-1 Water Hydroxide C H NO C2H4O2 33 39 4 Mol.Wt.:18 Mol. Wt.: 513.7 Mol.Wt.:40 Mol. Wt.: 60

CH3 CH 3 OH

O N O Na+ - H2O + OH + O + O OH

Stage-2 Hydrogen Methanol Sodium acetate CH4O C2H3NaO2 C32H37NO4 Mol.Wt.:18 Mol. Wt.: 32 Mol.Wt.:82 Mol. Wt.: 499.6

Stage-3:

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

CH CH 3 3 CH3 CH3 OH OH O O N O N O IPA + HCl OH OH

.HCl

Stage-2 Hydrochloric Fexofenadine HCl acid C32H37NO4 C32H38ClNO4 Mol. Wt.: 499.6 Mol. Wt.: 36.5 Mol. Wt.: 536

FLOW CHART OF FEXOFINADINE HYDROCHLORIDE

stage-1: 2-[4-(4-Chloro-butyryl)-phenyl]- 2-methyl-propionic acid methyl ester Ethanol to recovery & Azacyclonol Reactor Sodium bicarbonate CO2 gas to scrubbing Methyl isobutyl ketone Ethyl alcohol

Centrifuge Inorganic salt solution to waste

Stage-1

Stage-2:

Stage-1 product Sodium hydroxide Acetic acid Reactor Methanol to recovery Water Methanol

Centrifuge Waste water

Stage-2

Stage-3:

Stage-2 product Hydrochloric acid Reactor Solvent recovery Isopropanol

Centrifuge

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.

O OH OH O OH O O Ethanol P NH CH3 NH2 + 2 CH P NH OH . OH 3 OH 2 OH OH OH OH OH OH OH 2

Fosfomycin phenyl ammonium salt Trometamol Bis-Fosfomycin trometamol disalt C7H18NO7P C4H11NO3 C11H29N2O10P Mol. Wt.: 259.2 Mol. Wt.: 121 Mol. Wt.:380.2

Stage-2:

Stage-1 on reaction with Fosfomycin in presence of methane sulfonic acid produces the final compound. The reaction proceeds as per the below equation.

O methane OH O OH O O O sulfonic acid O 2 NH2 + P CH3 P P CH3 CH3 NH2 OH OH OH OH OH OH OH OH OH OH 2 Bis-Fosfomycin trometamol disalt Fosfomycin Fosfomycin trometamol C11H29N2O10P C11H29N2O10P C3H7O4P Mol. Wt.:380.2 Mol. Wt.: 138.1 Mol. Wt.:518

FLOW CHART OF FOSFOMYCIN TROMETAMOL

Stage-1 Trometamol Fosfomycin Phenyl ammonium salt Reactor Ethanol to reuse Ethanol

Centrifuge

Stage-1

Stage-2

Stage-1 Fosfomycin Reactor Methane sulfonic acid to reuse Methane sulfonic acid

Centrifuge

Stage-2:Pharma

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.

NH2 O O - Water + Cl O MDC Na+ NH2

Cyclohexane-1, 1-diacetic sodium Acid monoamide hypochlorite C10H18N2O2 ClNaO Mol. Wt.: 198.3 Mol. Wt.: 74.4 O

NH H2O + CO2 + NaCl +

2-Aza-spiro[4.5] Carbon Sodium decan-3-one Water dioxide chloride C9H15NO Mol. Wt.:18 Mol. Wt.: 44 Mol. Wt.: 58.5 Mol. Wt.: 153

Stage-2:

2-Azaspiro [4, 5] decan-3-one on acid hydrolysis with concentrated hydrochloric acid in presence of water gives Gaba-Pentin hydrochloride.

OH O Water + HCl O NH NH2 .HCl

2-Aza-spiro[4.5] (1-Aminomethyl-cyclohexyl)- decan-3-one Hydrochloric acetic acid C9H15NO acid C9H18ClNO2 Mol. Wt.: 153 Mol. Wt.: 36.5 Mol. Wt.: 207.7

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 OH

Water NH O + NaOH 2 + NaCl + H2O NH2 .HCl

(1-Aminomethyl-cyclohexyl)- (1-Aminomethyl-cyclohexyl)- Sodium acetic acid Sodium acetic acid chloride Water C H ClNO hydroxide C9H17NO2 9 18 2 Mol. Wt.: 58.5 Mol. Wt.: 18 Mol. Wt.: 207.7 Mol. Wt.: 40 Mol. Wt.: 171.2

FLOW CHART OF GABA-PENTIN

Stage-1 Cyclohexane-1,1-diaceticacid monoamide CO2 gas to scrubbing sodium hypochlorite Reactor Water MDC to recovery MDC

Centrifuge Inorganic salt solution

Stage-1

Stage-2

Stage-1 HCl Reactor Water

Centrifuge Water to waste

Stage-2

Stage-3

Stage-2 Sod.Hydroxide Carbon Reactor Water

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.

O H + DMSO O NNH+ N Cl Cl O-

p-methoxy phenyl p-nitro chloro piperazine HCl benzene C11H17ClN2O C6H4ClNO2 Mol. Wt.: 228.7 Mol. Wt.: 157.6 NN

2 HCl + O O N+ CH3 – Hydrochloric acid Stage-1 O Cl2H2 C17H19N3O3 Mol. Wt.: 73 Mol. Wt.: 313 Stage-2:

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

NN Ni , Pd/C + 3 H2 O Methanol O N+ Stage-1 CH3 – Hydrogen C17H19N3O3 O Mol. Wt.: 313 Mol. Wt.: 6

+ 2 H2O O NH Water Stage-2 2 H O C H N O 4 2 CH3 17 21 3 Mol. Wt.: 36 Mol. Wt.: 283.4

Stage-3:

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

NN O Cl + Toluene O NH2

CH3 Stage-2 phenyl chloro acetate C17H21N3O C7H5ClO2 Mol. Wt.: 283.4 Mol. Wt.: 156.6

O NN NH HCl + H3C C O O

Hydrochloric Stage-3 acid C25H26N2O3 Mol.Wt.:36.5 Mol.Wt.:402.5 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.

O NN NH O NH 1,4-Dioxane + 2 H H NH2 H3C C O O

Stage-3 Hydrazine hydrate C25H26N2O3 H6N2O Mol. Wt.: 402.5 Mol. Wt.: 50.1

O O NN NH H H + OH + C O

NH Phenol Stage-4 Water C6H6O C19H24N4O2 Mol.Wt.:18 Mol.Wt.:94 Mol. Wt.: 340 NH2

Stage-5:

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

O NN NH O NH AcOH C O + CH3 C O NH CH H3C NH

Stage-4 NH2 Formanidine C H N O C19H24N4O2 3 6 2 2 Mol. Wt.: 340 Mol. Wt.: 102.1

CH COOH + 2 NH + O NN N 3 3 N H C 3 N O H Acetic acid Ammonia Stage-5 C2H4O2 H6N2 C19H21N5O2 Mol. Wt.: 60 Mol. Wt.: 34.1 Mol. Wt.: 351

Stage-6:

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

O NN CH CH2 DMSO N + + K CO 2 3 KOH H C N 3 CH3 CH3 N O H Stage-5 2-Bromo butane Potassium C19H21N5O2 C4H9Br carbonate Mol. Wt.: 351 Mol. Wt.: 137 Mol. Wt.: 138

O NN N N KBr + KHCO3 + H3C N O CH CH2 Potassium H C Potassium Stage-6 3 H3C bromide bicarbonate C23H29N5O2 Mol. Wt.: 119 Mol. Wt.: 100 Mol. Wt.: 407.5

Stage-7:

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

O NN N Water H3C N + aq. HBr N O CH CH2 Hydrogen Stage-6 bromide H C C23H29N5O2 3 CH3 Mol.Wt.:81 Mol. Wt.: 407.5

HO NN N CH3Br + N N O Methyl bromide stage-7 CH CH2 CH Br C22H27N5O2 3 H3C Mol. Wt.: 95 Mol. Wt.: 393.5 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.

O Cl Br O O NH NaOH + + K2CO3 + H2O O C N N

Benzoic acid 2-bromo-2-(3,5-dichloro-phenyl) water -[1,3]dioxolan-4-yl ester 1,2,4-triazole Potassium carbonate C H BrCl O C2H3N3 16 11 2 4 Mol.Wt.:18 Cl Mol. Wt.: 418.1 Mol. Wt.: 69.1 Mol. Wt.: 138

O O Cl N C OH + KHCO + KBr + O 3 N OH N Benzoic acid Potassium Potassium Stage-8 bromide C7H6O2 bicarbonate C11H9Cl2N3O3 Mol. Wt.: 122 Mol. Wt.: 100 Mol. Wt.: 119 Mol. Wt.: 302

Stage-9:

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

Cl Cl

O Cl O O O Cl Tri ethyl amine N O + CH3 S Cl + HCl N O N O S CH3 N O OH O N N

Stage-8 Methanesulfonyl chloride Stage-9 Hydrochloric C11H9Cl2N3O3 CH3ClO2S C12H11Cl2N3O5S acid Mol. Wt.: 302 Mol. Wt.: 114.6 Mol. Wt.: 380 Mol.Wt.:36.5 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.

OH NN N N Cl O O N + O Methanol N O CH N CH O S CH3 3 CH2 N CH O stage-7 3 Stage-9 C22H27N5O2 C12H11Cl2N3O5S Mol. Wt.: 393.5 Mol. Wt.: 380

O + Cl O OH S CH3 N O N O NN N O N N O N Methanesulfonic acid Itraconozole CH CH4O3S C33H34Cl2N8O4 CH Mol. Wt.: 96 Mol. Wt.: 677.6 3 CH2

CH3

FLOW CHART OF ITRACONOZOLE

Stage-1 Methoxy phenyl piperazine HCl DMSO to recovery p-Nitro chloro Benzene Reactor HCl gas to scrubbing Di-methyl sulphoxide

Centrifuge

Stage-1

Stage-2 Stage-1 product Nickle catalyst Reactor Methanol to recovery Palladium Methanol

Centrifuge Water to waste

Filetaration Spent nickle catalyst

Stage-2

Stage-3

Stage-2 product Reactor Toluene to recovery Phenyl chloro acetate HCl gas to scrubbing Toluene

Centrifuge

Stage-3 Stage-4 Stage-3 product Hydrazine hydrate Reactor Spent dioxane 1,4-Dioxane

Centrifuge Phenol

Stage-4 Stage-5

Stage-4 product Spent Acetic acid Formanidine Reactor Release of ammonia Acetic acid

Centrifuge Acetic acid

Stage-5 Stage-6 Stage-5 product 2-bromo butane DMSO Reactor Spent DMSO Potassium carbonate Potassium hydroxide

Centrifuge

Potassium bicarbonate Filetaration & potassiunm bromide

Stage-6

Stage-7

Stage-6 product Aqueous hydrogen bromide Reactor Waste water to recovery Water

Centrifuge Methyl bromide

Stage-7 Stage-8

Benzoic acid-2-bromo-2-(3,5-dichloro phenyl)- [1,3]dioxolan-4-yl ester 1,2,4-triazole Reactor Potassium carbonate Water Sodium hydroxide Forms Potassium bicarbonate Centrifuge Potassium bromide & Benzoic acid

Filetaration

Stage-8 Stage-9

Stage-8 product Spent Tri ethyl amine to recovery Methane sulphonyl chloride Reactor HCl gas to scrubbing Tri ethyl amine

Centrifuge

Stage-9

Stage-10

Stage-7 product Stage-9 product Reactor Methanol to recovery Methanol

Centrifuge Methane sulfonic acid

Stage-10

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

O N F OH HMPT O + + K CO + F 2 3 H3C N F – CH3 O

2,3-dimethyl-4-nitropyridine 2,2,2-trifluoroethanol Potassium N-oxide carbonate C7H8N2O3 C2H3F3O CK2O3 Mol. Wt.: 168.2 Mol. Wt.: 100 Mol. Wt.: 138

O N

+ KOH + H C O CF3 CO2 + KNO2 3 CH3

Carbon Potassium Potassium nitrite Stage-1 dioxide hydroxide KNO2 C9H10F3NO2 Mol. Wt.: 44 Mol. Wt.: 56 Mol. Wt.: 85 Mol. Wt.: 221.2 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

O N N (CH CO) O 3 2 HO O CF O CF C 3 H3C 3 H2 CH3 CH3 Stage-1 Stage-2 C9H10F3NO2 C9H10F3NO2 Mol. Wt.: 221.2 Mol. Wt.: 221.2

Stage-3:

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

HO CHCl3 C O CF3 + SOCl2 H2 CH3 Stage-2 Thionyl C9H10F3NO2 chloride Mol. Wt.: 221.2 Mol. Wt.: 119

SO2 + HCl + Cl C O CF3 H2 CH3

Sulfur Hydrochloric Srage-3 dioxide acid C9H9ClF3NO Mol. Wt.: 64.1 Mol. Wt.: 36.5 Mol. Wt.: 239.6 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 H N Cl Methanol C O CF SH 3 + NaOMe H2 N CH3 Srage-3 2-mercaptobenzimidazole C9H9ClF3NO C7H6N2S Mol. Wt.: 239.6 Mol. Wt.: 150

H N N S HCl + C O CF3 N H2 CH3

Hydrochloric Stage-4 acid C16H14F3N3OS Mol. Wt.: 36.5 Mol.Wt.:353.4 .

Stage-5:

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

H H O N N N N m-CPBA S S C O CF C O CF3 + (O) 3 N H CHCl N H2 2 3 CH CH3 3 Lansoprazole Stage-4 oxygen C16H14F3N3OS C16H14F3N3O2S Mol. Wt.: 353.4 Mol. Wt.: 16 Mol. Wt.: 369.4

FLOW CHART OF LANSOPRAZOLE

Stage-1:

2, 3-dimethyl-4-nitropyridine 2, 2, 2-trifluoroethanol Potassium carbonate Reactor CO2 gas to scrubbing HMPT

Centrifuge KOH & KNO2 for use

Stage-1 Stage-2:

Stage-1 Acetic anhydride Reactor Finished product

Stage-3:

Stage-2 Thionyl chloride Reactor Chloroform

SO to scrubbing Centrifuge 2 & HCl to reuse

Stage-3 product

Stage-4:

Stage-3 2-mercaptobenzimidazole Methanol to recovery Sodium methoxide Reactor Methanol

Centrifuge HCl to use

Stage-4 product Stage-5:

Stage-4 m-CPBA Reactor Chloroform to reuse Chloroform

Centrifuge

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.

OOS OH Cl Chloroform OOS Cl + + H2O S S Cl Cl Cl 2,5-dichlorothiophene Stage-1 Chloro sulfonic acid Water C4H2Cl2S ClHO3S C4HCl3O2S2 Mol. Wt.: 153 Mol. Wt.: 116.5 Mol. Wt.: 251.5 Mol. Wt.: 18

Stage-2:

Stage-1 compound reacts with Mono methyl amine in presence of chloroform solvent medium forms the stage-2 compound.

NH CH3 Cl OOS OOS

Chloroform Cl + HCl Cl + H2NCH3 S S Cl Cl

Stage-1 Mono methyl amine Stage-2 Hydrochloric acid C4HCl3O2S2 CH5N C5H5Cl2NO2S2 Mol. Wt.: 251.5 Mol. Wt.: 31.1 Mol.Wt.:246 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.

HN CH3 O O OOS S CH3 N Cl H BuLi Cl + CO2 + 2 H S O + HCl S MeOH Cl OH Stage-2 Stage-3 Carbon Dioxide Hydrogen Hydrochloric acid C5H5Cl2NO2S2 C6H6ClNO4S2 Mol. Wt.: 246 Mol. Wt.: 44 Mol. Wt.: 2 Mol. Wt.: 255.7 Mol. Wt.: 36.5 Stage-4:

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

O O O O CH S CH3 S 3 N N H Cl H Cl PCl O + 5 S O S MeOH +H2O Methanol OH O CH3 Stage-4 Stage-3 Methanol Water C6H6ClNO4S2 CH4O C7H8ClNO4S2 Mol. Wt.: 255.7 Mol. Wt.: 32 Mol. Wt.: 269.7 Mol.Wt.: 18 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.

O O O O S O S CH3 N CH3 N O NaH Cl O Cl H + I CH3 S CH3 +HI S O O O O O CH3 CH3 Stage-4 Methyl iodo acetate Stage-5 Hydrogen Iodide C7H8ClNO4S2 C3H5IO2 C10H12ClNO6S2 Mol. Wt.: 269.7 Mol. Wt.: 200 Mol. Wt.: 341.8 Mol. Wt.: 127.9

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.

O O O O S O N CH3 S CH3 N Cl O NaOMe Cl CH3 + H2O + H2O + CH3OH S O S O CH3 O HO O CH3 Stage-5 Stage-6 Water Water Methanol C10H12ClNO6S2 C9H8ClNO5S2 Mol. Wt.: 341.8 Mol. Wt.: 18 Mol. Wt.: 309.7 Mol. Wt.: 18 Mol.Wt.: 32

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.

O O O O S CH3 S CH N 3 H N H2N Cl Cl + Methanol N + CH3OH O S S CH N 3 HO O N HO O

Stage-6 Pyridin-2-ylamine Lornoxicam Methanol C9H8ClNO5S2 C5H6N2 C13H10ClN3O4S2 Mol. Wt.: 309.7 Mol. Wt.: 94 Mol. Wt.: 371.8 Mol. Wt.: 32

FLOW CHART OF LORNOXICAM

Stage-1

2, 5-dichlorothiophene Chlorosulfonic acid Reactor Chloroform

Water Centrifuge Waste water ro recovery

Stage-1

Stage-2

Stage-1 Mono methyl amine Reactor Chloroform

Centrifuge Waste HCl to recovery

Stage-2

Stage-3

Stage-2 Carbon Dioxide Hydrogen Reactor Spent solvent to recovery Butyl lithium Methanol

Centrifuge Waste HCl to recovery

Stage-3 Stage-4 Stage-3 Methanol Reactor Spent solvent to recovery PCl5

Water Centrifuge Waste water to recovery

Stage-4

Stage-5

Stage-4 Methyl iodo acetate Reactor Sodium Hydride

Centrifuge Hydrogen Iodide

Stage-5

Stage-6

Stage-5 Sodium methoxide Reactor Water

Centrifuge Waste water & Methanol to recovery

Stage-6

Stage-7

Stage-6 Pyridine-2-ylamine Reactor Methanol to recovery Methanol

Centrifuge

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.

O Cl N + Ac O 2 + H2O Cl N CH 3 O AcOH H O H 3-[2-(7-Chloro-quinolin-3-yl)-vinyl]- 7-Chloro-2-methyl Benzene Water quinoline 1,3-dicarbaldehyde benzaldehyde C10H8ClN C8H6O2 C18H12ClNO Mol. Wt.: 177.6 Mol.Wt.: 134 Mol. Wt.: 293.7 Mol.Wt.:18

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.

Cl N Toluene + Br NaCl Mg CH2 + H2O CH COONH O H 3 4

Vinylmagnesium Stage-1 bromide Water C18H12ClNO C2H3BrMg H2O Mol. Wt.: 293.7 Mol. Wt.: 131 Mol. Wt.: 18

Mg OH + OH Br Cl N

hydroxy magnesium bromide Stage-2 BrHMgO C20H16ClNO Mol.Wt.:121 Mol. Wt.: 321.1

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

I OH Pd(OCOCH3) N Cl + CH CN O 3

Stage-2 1-(2-iodo phenyl ) ethanone C20H16ClNO C8H7IO Mol. Wt.: 321.1 Mol. Wt.: 246

HI + Cl N

Hydrogen Iodide O Stage-3 C28H24ClNO2 Mol. Wt.:127.9 Mol. Wt.: 441.9

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.

OH Cl N Acetonitrile + CH3BrMg + H2O CeCl3 O Methyl magnesium Water Stage-3 bromide C28H24ClNO2 CH3BrMg Mol. Wt.: 442 Mol. Wt.: 119 Mol. Wt.: 18

Mg OH + OH Br Cl N

OH Hydroxy Magnesium Stage-4 bromide C29H28ClNO2 Mol. Wt.: 121 Mol. Wt.: 458

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.

CH3

O S O OH Cl N,N,Diisopropyl O Cl N ethylamine + OOS Toluene Cl N + HCl OH CH3 Stage-4 Methanesulfonyl chloride Stage-5 OH C H ClNO Hydrochloric acid 29 28 2 CH3ClO2S C30H30ClNO4S Mol. Wt.: 458 Mol. Wt.: 114.6 Mol. Wt.: 536.1 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

CH3 O S O

O O N + NaOH Cl + SH OH

OH (1-Mercaptomethyl-cyclopropyl) Stage-5 acetic acid Sodium C30H30ClNO4S C6H10O2S hydroxide Mol. Wt.: 536.1 Mol. Wt.: 146 Mol. Wt.: 40

n-BuLi Na O THF

O CH3 S + H2O O S O + Cl N OH

Water Methanesulfonic acid Stage-5 OH CH4O3S C H ClNNaO S Mol. Wt.: 96 35 35 3 Mol. Wt.: 18 Mol. Wt.: 608.2

FLOW CHART

Stage-1 7-chloro-2-methyl quinoline Benzene-1,3-dicarbaldehyde Reactor Acetic acid to recovery Acetic anhydride Acetic acid

Reactor Waste water

Centrifuge

Stage-1 Stage-2 Stage-1 Vinylmagnesiumbromide Ammoniumacetate Reactor Water Toluene Sodium chloride Filteration Sodium chloride solution

Reactor Toluene to recovery

Centrifuge Hydroxy magnesiumbromide to disposal

Stage-2 Stage-3 Stage-2 2-Iodophenyl ethanone Reactor Acetonitrile to recovery Palladium acetate Acetonitrile

Water Centrifuge Palladium acetate solution to waste

Stage-3

Stage-4 Stage-3 Methylmagnesiumbromide Acetonitrile Reactor Acetonitrile to recovery Ceriumchloride Water

Centrifuge Cerium chloride solution to waste

Filteration Hydroxy magnesium bromide to disposal

Stage-4

Stage-5

Stage-4 Methyl sulfonyl Chloride Toluene to recovery n,n-Di isopropyl Ethylamine Reactor Toluene

Centrifuge Waste HCl

Stage-5

Stage-6

Stage-5 Mercapto methylcyclopropane acetic acid Sodium Hydroxide Reactor THF to recovery n-Butyl lithium Tetra hydro furan

Centrifuge Waste water

Pharma

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.

CH CH N 3 3 H2O, H2SO4 O + H2O2 + HNO3 - + + Acetic acid O N N + 2 H2O O- H3CCH3 3,5-Lutidine Hydrogen Stage-1 Water Nitric acid C7H9N Peroxide C7H8N2O3 Mol. Wt.: 107 Mol. Wt.:34 Mol. Wt.: 63 Mol. Wt.: 168. Mol. Wt.:36

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.

CH3 CH3 O MeOH O N N + CH ONa + 2 NaOH + (CH3)2SO4 3 Water O Stage-1 Sod.methoxide Sodium hydroxide Di methyl sulfoxide C7H8N2O3 Mol. Wt.: 168.2 Mol. Wt.:54 Mol. Wt.: 80 Mol. Wt.:126

CH3 CH3

Na SO + H2O + NaNO + CH3OH + 2 4 2 O N COOH

Methanol Sod.Sulphate Water Sodium Nitrite Stage-2 CH4O Na2O4S H2O NNaO2 C8H9NO3 Mol. Wt.: 32 Mol. Wt.: 142 Mol. Wt.: 18 Mol. Wt.: 69 Mol. Wt.: 167.2

Stage-3:

Stage-2 product on reaction with Thionyl chloride & sodium hydroxide produces stage-3 compound in presence of toluene solvent medium.

CH3 CH3 Toluene SOCl + NaOH O N COOH + 2

Stage-2 Thionyl Chloride Sodium Hydroxide HNaO C8H9NO3 Cl2OS Mol. Wt.: 167.2 Mol. Wt.: 119 Mol. Wt.: 40

CH3 CH3

SO + O N COCl NaCl + H2O + 2

Sodium Chloride Water Sulphur dioxide Stage-3 ClNa H2O O2S C8H8ClNO2 Mol. Wt.: 58 Mol. Wt.: 18 Mol. Wt.: 64.1 Mol. Wt.: 185.6

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

CH3 CH3 NH HS Toluene O N COCl + CH3 C.S.Lye N O

2-Mercapto-5-methoxy Stage-3 benzimidazole C8H8ClNO2 C8H8N2OS Mol. Wt.: 185.6 Mol. Wt.: 180

O + HCl N

NH CH3 Hydrochloric S acid N Mol. Wt.:36.5 O O CH3 OCH3

C16H17N3O3S Mol. Wt.: 331 Stage-4

Stage-5: Omeprazole

Above stage-4 compound on reaction with Hydrogen Peroxide produces stage-5 pharma. Methanol and Acetone are used in the process.

O N N NH CH3 NH CH3 MeOH S S + H2O2 Acetone + H2O O N O CH3 OCH3 O N O CH3 OCH3 Stage-4 Hydrogen CH3 omeprazole Water C16H17N3O3S Peroxide C17H19N3O3S Mol. Wt.: 331 Mol.Wt.:34 Mol. Wt.: 345. Mol. Wt.: 18

FLOW CHART OF OMEPRAZOLE

Stage-1 3,5-Lutidine Hydrogen Peroxide Nitric acid Reactor Sulphuric acid Acetic acid Water

Centrifuge Waste water

Stage-1

Stage-2 Stage-1 Methanol Sod.Methoxide Dimethylsulphate Reactor Methanol to recovery Sodium Hydroxide Water

Centrifuge Inorganic solid waste solution

Stage-2

Stage-3 Stage-2 Thionylchloride Ammoniumpersulphate Reactor Sulphurdioxide Toluene HCl to scrubber Water

Layer seperator Toluene to recovery

Centrifuge Waste water

Stage-3 Stage-4 Stage-3 5-Methoxy mercapto benzimidazole Reactor C.S.Lye Toluene Layer seperator Toluene to recovery

Water Centrifuge Waste water

Stage-4

Stage-5 Stage-5 Methanol Reactor Acetone IPA to recovery Hydrogen peroxide

Centrifuge Acetone to recovery

Pharma

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.

O O Br Br Methanol + + H2O N NH2 O H

Cyclohexane-1,3-dione 2-Bromo Aniline Stage-1 Water C6H6BrN C6H8O2 C12H12BrNO Mol. Wt.: 172 Mol. Wt.: 112 Mol. Wt.: 266 Mol. Wt.: 18

Stage-2:

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

O O Br Br NaH + HI + H3CI C6H6 N N H CH3 Stage-1 Methyl Iodide Stage-2 Hydrogen Iodide C12H12BrNO CH3I C13H14BrNO HI Mol. Wt.: 266 Mol. Wt.: 141.9 Mol.Wt.:280.2 Mol. Wt.: 127.9

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.

O O Br CH3 Br H3C I N LDA + HI + N CH2 THF N CH3 N H3C CH3 CH3 Dimethyl amio Stage-2 methylene iodide Stage-3 Hydrogen iodide C13H14BrNO C3H8IN C H BrN O HI Mol. Wt.: 185 16 21 2 Mol. Wt.: 280.2 Mol.Wt.:337.3 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.

O Br CH 3 DMF N HN N + N CH3 CH3 CH3

Stage-3 2-methyl indole C16H21BrN2O C4H6N2 Mol. Wt.: 337.3 Mol. Wt.: 82 O Br H N N N + H C CH 3 3 N CH3

CH3 N, N-dimethyl amine Stage-4 C2H7N C18H20BrN3O Mol. Wt.: 45.1 Mol. Wt.: 374.3

Stage-5:

Stage-4 compound undergoes cyclization by means of palladium acetate and triethyl amine in presence of acetonitrile forms the final compound.

O O Br Pd(OAc) N N N N 2 + HBr Et3N CH3CN N N CH3 CH3 CH3 CH3 Stage-4 Ondansetron Hydrobromic C18H20BrN3O C18H19N3O acid Mol. Wt.: 374.3 Mol.Wt.:293.4 Mol. Wt.: 80.9

FLOW CHART OF ONDANSETRN

Stage-1

2-bromo aniline cyclohexane-1,3-dione Reactor Spent methanol to recovery Methanol

Centrifuge Waste water

Stage-1

Stage-2

Stage-1 Spent MLs to recovery& Iodo methane Reactor Sodium hydride HI gas to scrubbing Benzene

Centrifuge

Stage-2

Stage-3 Stage-2 THF to recovery & dimethyl amio methylene iodide Reactor lithium di isopropyl amide HI gas to scrubbing THF

Centrifuge

Stage-3 Stage-4

Stage-3 2-methyl indole Reactor Spent DMF to recovery DMF

Centrifuge N,N-dimethyl amine

Stage-4

Stage-5

Stage-4 palladium acetate Acetonitrile to recovery & Reactor triethyl amine HBr gas to scrubbing acetonitrile

Centrifuge

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 OH Cl Cl NO2 Water + H2O + HNO3

Cl Cl 2,4-Dichloro-Nitrophenol 2,4-Dichloro-phenol Nitric acid Water C H Cl O C6H3Cl2NO3 6 4 2 Mol. Wt.: 63 Mol. Wt.: 208 Mol. Wt.: 18 Mol. Wt.: 163

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 SO + H2O 2 NaOH + H2O + 3 S Na2S2 + H2 + 2

Sodium Sodium Sulphur Water Hydroxide Sulphide Hydrgen dioxide Water Mol.Wt.:80 Mol.Wt.:18 Mol.Wt.:96 Mol.Wt.:110 Mol.Wt.:2 Mol.Wt.:64 Mol.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 OH Cl O2N Cl NH2 Na S Water + Na S O + 2 2 + H2O 2 2 3 MCB

Cl Cl 2,4-Dichloro Nitrophenol Sodium sulphide Water Stasge-2 Sodium C6H3Cl2NO3 Na2S2 C6H5Cl2NO dithionate Mol. Wt.: 208 Mol. Wt.: 110 Mol. Wt.: 18 Mol. Wt.: 178 Mol. Wt.: 158

Stage‐3:

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

HO Cl HO Cl O O O MCB + + Cl S + SO2 HCl Cl HO Cl Cl Cl Cl Cl

3,5,6-trichlorosalicylic acid Thionyl chloride Stage-3 Sulphur dioxide Hydrochloric acid C7H3Cl3O3 Cl2OS C7H2Cl4O2 O2S Mol. Wt.: 241.5 Mol. Wt.: 119 Mol. Wt.: 259.9 Mol. Wt.: 64.1 Mol.Wt.:36.5

Stage‐4:

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

OH O Cl OH O Cl Cl Cl + MCB N Cl H + HCl Cl H N Cl OH 2 Cl Cl OH Cl

Stage-3 Stasge-2 Stage-4 Hydrochloric C H Cl O acid 7 2 4 2 C6H5Cl2NO C13H6Cl5NO3 Mol. Wt.: 259.9 Mol. Wt.: 178 Mol. Wt.: 401.5 Mol. Wt.: 36.5

Staeg‐5:

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

Cl Cl

OH O OH O Cl Cl N Cl Acetone N Cl H Carbon H OH OH Cl Cl Cl Cl Stage-4 Oxyclozanide C H Cl NO 13 6 5 3 C13H6Cl5NO3 Mol. Wt.: 401.5 Mol. Wt.: 401.5

FLOW CHART OF OXYCLOZANIDE

Stage-1

2, 4-Dichlorophenol Nitric acid Reactor Water

Centrifuge Water to waste

Stage-1

Stage-2 Sodium hydroxide Hydrogen & Sulfur Reactor sulfur gasses to scrubbing Water

Centrifuge Inorganic salt solution to waste

2,4-Dichloro nitro phenol Sodium sulfide Reactor Spent MLs Water Mono chloro benzene

Centrifuge Inorganic salt solution to waste

Stage-2

Stage-3

3,5,6-Trichloro Salicylic acid Spent MLs & Thionyl chloride Reactor SO2 & HCl gasses to scrubbing Mono chloro benzene

Centrifuge

Stage-3

Stage-4

Stage-2 Spent MLs Raector Stage-3 HCl gas to scrubbing Mono chloro benzene

Centrifuge

Stage-4

Stage-5

Stage-2 Stage-3 Raector Acetone to recovery Mono chloro benzene

Centrifuge Spent carbon

Final product

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.

CH3 CH3 O O CH3 O O NH COOH O H O NH2 S NaOH 2 + NO2 + NaHCO3 + OH CH2 N CH2 COOH (2S,3S,5S)-2-amino-3-hydroxy-5-(tert- butyloxycarbonyl) amino-1,6-diphenyl Carbnic acid.4-nitrophenyl- Sodim Sodium hexane hemi succinic acid salt 5-thiazolylmethyl ester bicarbonate hydroxide C27H38N2O7 C11H8N2O5S CHNaO3 HNaO Mol. Wt.: 502.6 Mol. Wt.: 280.3 Mol. Wt.: 84 Mol. Wt.: 40

CH3 CH3 NO 2 O O CH3 O NH + H O + + NH CO2 + CH3COONa 2 2 O OH

OH S N Carbon Dioxide Sodium acetate p-nitro phenol Stage-1 C H Na O Water CO2 4 6 2 4 C6H5NO3 C28H35N3O5S Mol. Wt.: 44 Mol. Wt.: 164 Mol. wt.:34 Mol. Wt.: 139 Mol. Wt.: 525.7

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.

CH3 CH3 O O CH3 O NH NH 1,4-Dioxane O + H2O + HCl OH n-Hexane

S N Stage-1 Water Hydrochloric acid C28H35N3O5S Mol. Wt.: 525.7 Mol. Wt.: 18 Mol. Wt.: 36.5

O O CH3 CH NH NH2 .HCl 3 O OH + HO O CH3

S N Stage-2 C23H28ClN3O3S C5H10O3 Mol. Wt.: 462 Mol. Wt.: 118 Stage-3:

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

O NH2 O NH NH NH2 .HCl O OH OH NaCl + H O O H2O + 2 + NaOH S S N N Stage-2 Sodium Free base Sodium Water C23H28ClN3O3S hydroxide C23H27N3O3S chloride Mol. Wt.: 462 Mol. wt.:40 Mol. Wt.: 425.5 Mol. wt.:58.5 Mol. wt.:18

Step-B:

CH3 CH CH 3 3 CH3 O CH3 N O CH3 N Li NH N S + HCl NH N S + LiCl O OH O O CH CH CH3 CH3 3 3 N-((N-Methyl-N- Free acid Lithium chloride ((2-isopropyl-4-thiazolyl)methyl Hydrochloric acid amino)carbonyl) C14H23N3O3S -L-valine.Lithium salt Mol.Wt.:36.5 Mol. wt.:313.00 Mol. wt.:42 C14H22LiN3O3S Mol. wt.:319 Step-C:

CH3 CH CH 3 3 CH CH3 CH 3 O CH3 N O O O 3 N S CH3 NH N CH2 CH NH N S OH + Cl O O O CH3 O CH3 CH3 O CH CH CH 3 3 Free acid Isobutylchloroformate 3 C H N O S C H O Cl 14 23 3 3 5 9 2 C19H31N3O4S Mol. wt.:313 Mol. wt.:136.5 Mol. wt.:397 +

HCl Hydrochloric acid Mol. wt.:36.5

Stage-4:

CH3 CH3 CH CH 3 3 S S N CH3CH3 N CH3CH3 O O O O Ethyl acetate NH NH n-heptane N NH NH O N NH NH O RIT-form-II(seedling) CH3 O OH S CH3 O OH S N N Ritonavir crude Ritonavir form-II C H N O S C37H48N6O5S2 37 48 6 5 2 Mol. wt.:720.1 Mol. wt.:720.1

Step-5:

CH3 CH CH3 3 CH3 S Ethyl acetate N CH3CH3 S O O N CH CH n-heptane 3 3 NH O O RIT-form-I(seedling) N NH NH O NH N NH NH O CH3 O OH S CH3 O OH S N N Ritonavir form-II Ritonavir form-I C37H48N6O5S2 C37H48N6O5S2 Mol. wt.:720.1 Mol. wt.:720.1

FLOW CHART OF RITONAVIR

Stage-1 (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 Reactor Sodiumbicarbonate Water to recovery Sodium hydroxide Water

Centri fuge Water to waste

Stage-1

Stage-2 Satge-1 1,4-Di oxane HCl Reactor Toluene to recovery n-hexane Water Layer saparate Water to waste

Centri fuge Tolene to recovery

Stage-2 stage-3 Stage-2 Sodium hydroxide HCl Reactor Water to recovery Isobutyl chloro formate Water Layer saparate Water to waste

Centri fuge salt solution

Stage-3 Stage-4 Satge-3 n-Heptane Ethyl acetate Reactor n-heptene to recovery Water

Layer saparate Water to waste

Centri fuge Ethyl acetate to recovery

Stage-4 Stage-5 Satge-4 n-Heptane n-heptene to recovery Ethyl acetate Reactor Water

Layer saparate Water to waste

Centrifuge Ethyl acetate to recovery

Stage-5

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.

O F O O F Piperidine/AcOH + O + H2O O Benzene CHO O 4-methyl-3-oxopentanoic 4-fluoro benzaldehyde acid ethyl ester Stage-1 Water C7H5FO C8H14O3 C15H17FO3 Mol. Wt.: 124 Mol. Wt.: 158.2 Mol. Wt.: 264.3 Mol. Wt.: 18

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.

O Cl CN F O O H2N NH Toluene + + S Cl CN CH 3 O O Stage-1 S-methyl iso thio urea DDQ C15H17FO3 C2H6N2S C8Cl2N2O2 Mol. Wt.: 264.3 Mol. Wt.: 90 Mol. Wt.: 227

F O O OH Cl CN + + H2O N N Cl CN OH S CH 2,3-dichloro-5,6-dicyano 3 hydroquinone Stage-2 Water C8H2Cl2N2O2 C17H19FN2O2S Mol. Wt.: 18 Mol. Wt.: 229 Mol. Wt.: 334

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.

F O O F O O m-CPBA/H O + 2 (O) 2 2 Aq.NaOH N N N N S O CH3 S O CH3 Stage-2 Stage-3 Oxygen C17H19FN2O2S C17H19FN2O4S Mol. Wt.: 334 Mol. Wt.: 32 Mol. Wt.: 366

Stage-4:

Stage-3 compound is treated with methyl amine in presence of methane sulfonyl chloride gives the stage- 4 compound.

F O O F O O

N N Me SO Cl N N + MeNH 2 + H 2 O N 2 S S CH3 O CH3 CH O O 3 Stage-3 Stage-4 Methhyl amine Hydrogen C17H19FN2O4S CH5N C18H22FN3O4S Mol. Wt.: 366 Mol. Wt.: 31.1 Mol. Wt.: 395.5 Mol. 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.

F O O F O H CH3 CH3

CH3 CH3 H2 N N DIBAL H N N C + H2 + H3C OH O N O N S CH3 S CH3 CH3 O O CH3 Ethanol Stage-4 Stage-5 Hydrogen C H O C18H22FN3O4S C16H18FN3O3S 2 6 Mol. Wt.: 395.5 Mol.Wt.: 2 Mol. Wt.: 351 Mol. Wt.: 46.1

Stage-6:

Stage-5 compound is submitted to a Wittig condensation with the phosphorane in dry THF to give the stage-6 product.

TBDMSO O CH3 O O F O H CH3 F CH3 TBDMSO O CH3 CH3 CH3 O N N Dry THF N N + O + Ph3PO O N CH3 O N S (Ph3)P S CH3 O CH3 O CH3 Tri phenyl Stage-5 Phosphorane compound Stage-6 phosphine oxide C H OP C16H18FN3O3S C31H39O4PSi C29H42FN3O6SSi 18 15 Mol. Wt.: 351 Mol. Wt.: 534.7 Mol. Wt.: 607.8 Mol. Wt.: 278.3

Stage-7:

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

HO O TBDMSO O CH3 CH3 O O O O F CH3 CH F CH H3C 3 3 Si CH3 F CH3 THF N N N N + HF + O N O N S CH3 S CH3 O CH3 O CH3 Tert-butyl dimethyl Stage-6 Hydrogen Stage-7 silyl fluoride C29H42FN3O6SSi fluoride C23H28FN3O6S C6H15FSi Mol. Wt.: 607.8 Mol. Wt.: 20 Mol. Wt.: 493.5 Mol. Wt.: 134.3

Stage-8:

The controlled reduction of stage-7 product with sodium boro hydride in diethyl methoxy borane affords the stage-8 compound.

HO O HO O CH CH3 3 O O O OH

F F CH CH3 3 CH CH3 3 Et2BOMe/NaBH4 N N + 2 (H) N N O O N N CH S CH3 S 3 O CH3 O CH3

Stage-7 Stage-8 Hydrogen C H FN O S C23H28FN3O6S 23 30 3 6 Mol. Wt.: 493.5 Mol. Wt.: 2 Mol. Wt.: 495.6

Stage-9:

Stage-8 is hydrolyzed with NaOH in presence of ethanol solvent medium yielding the corresponding sodium salt. The reaction showed as below.

HO ONa HO O CH3 O O OH OH F CH F 3 CH3 CH3 CH 3 N N N N Ethanol + NaOH O N + H3COH CH O N S 3 S CH3 O CH3 O CH3 Stage-8 Stage-9 Methanol C H FN O S Sodiumhydroxide 23 30 3 6 C22H27FN3NaO6S CH4O Mol. Wt.: 495.6 Mol. Wt.: 40 Mol.Wt.:503.5 Mol. Wt.: 32

Stage-10:

Stage-9 compound is finally treated with calcium chloride in water yields the final compound. The reaction proceeds as per the below equation.

HO O HO ONa O O OH OH F CH3 F 2+ 2 CH3 Ca CH3 CH3 N N Water + CaCl2 + 2 NaCl N N O N S CH3 O N CH S CH3 O 3 O CH3 2

Stage-9 Calcium chloride Rosuvastatin calcium Sodium chloride C H F N O S Ca2+ Cl Na C44H54F2N6Na2O12S2 CaCl2 44 54 2 6 12 2 2 2 Mol. Wt.: 1007 Mol. Wt.: 111 Mol. Wt.: 1001 Mol. Wt.: 116.9 FLOW CHART OF ROSUVASTATIN CALCIUM

Stage-1

4-fluoro benzaldehyde 4-methyl-3-oxo pentanoic acid ethyl ester Piperidine Reactor Solvent ml's to recovery Acetic acid benzene

Centrifuge Waste water

Stage-1

Stage-2

Stage-1 S-methyl iso thio urea Reactor Toluene to recovery DDQ Toluene

Centrifuge Waste water

Layer separator 2,3-dichloro-5,6-dicyano hydro quinone

Stage-2

Stage-3

stage-2 Oxygen m-CPBA Reactor solvent ml's to recovery Hydrogen peroxide Sodium hydroxide Stage-3 Stage-4

Stage-3 Methyl amine Reactor solvent ml's to recovery Methane sulfonyl chloride

Centrifuge Hydrogen emission to scrubber

Stage-4

Stage-5

Stage-4 Hydrogen Reactor DIBAL H

Centrifuge Ethanol

Stage-5

Stage-6

Stage-5 Phosphorane compound Reactor Solvent ml's to recovery Dry THF

Centrifuge Triphenyl phosphine oxide

Stage-6

Stage-7

Stage-6 Hydrogen fluoride Reactor Solvent ml's to recovery Tetra hydro furan

Centrifuge Tert-butyl dimethyl silyl fluoride

Stage-7 Stage-8

Stage-7 Hydrogen Reactor Diethyl methoxy borane Sodium boro hydride

Centrifuge

Stage-8

Stage-9

Stage-8 Sodium hydroxide Reactor Methanol to recovery Ethanol

Centrifuge Ethanol to recovery

Stage-9

Stage-10

Stage-9 Calcium chloride Reactor Waste water Water

Centrifuge Inorganic waste

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.

Cl OH Cl

Al Cl3 + + H2 MeOH Cl Cl alpha naphthol dichloro benzene Stage-1 Hydrogen C10H8O C6H4Cl2 C16H9Cl2O Mol. Wt.: 144.2 Mol. Wt.: 147 Mol. Wt.: 289.2 Mol.Wt.:2

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 CH3 N

MeOH + NH2 CH3 + H2O

Cl Cl Cl Cl Stage-1 Methyl amine Stage-2 Water C16H10Cl2O CH5N C17H13Cl2N Mol. Wt.: 289.2 Mol. Wt.: 31.1 Mol.Wt.:302.2 Mol.Wt.:18

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.

CH CH3 3 N NH

NaBH + HCl 4 MeOH

Cl Cl Cl Cl HCl Stage-2 Hydrochloric Stage-3 C17H13Cl2N acid C17H14Cl3N Mol. Wt.: 302.2 Mol. Wt.: 36.5 Mol. Wt.: 338.7

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.

CH3 CH3 NH NH

D(-)Mandelic acid Ethyl Acetate

Cl Cl Cl Cl HCl HCl Stage-3 Sertraline HCl C H Cl N C17H14Cl3N 17 14 3 Mol. Wt.: 338.7 Mol. Wt.: 338.7 FLOW CHART OF SERTRALINE HCl

Stage-1: alpha-Napthol Dichloro Benzene Reactor Aluminum chloride Methanol to recovery Methanol

Centrifuge

Stage-1

Stage-2 Stage-1 Monomethylamine Reactor Methanol to recovery Methanol

Centrifuge Water to recovery

Stage-2 product

Stage-3: Stage-2 Sodium borohydride Reactor Methanol to recovery Hydrochloric acid Methanol

Water Centrifuge Inorganic salt solution

Stage-3 product

Stage-4: Stage-3 Mandelic acid Reactor Ethyl acetate to recovery Ethyl acetate

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 O F O F COOEt F EtO OEt COOEt CH Ac2O CH OEt + H C OH F F + 3 OEt AcOH F F F F OEt ethyl pentafluoro benzoylacetate Triethyl ortho formate Stage-1 Ethanol C11H7F5O3 C7H16O3 C16H17F5O5 C2H6O Mol. Wt.: 282.2 Mol. Wt.: 148 Mol. Wt.: 384 Mol.Wt.:46.1 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 O F O F COOEt F COOEt NH2 Ether + + H C OH CH OEt F F NH 3 F F EtO OEt F F Reaction mass Cyclopropyl amine Stage-2 Ethanol C16H17F5O5 C3H7N C17H18F5NO4 C2H6O Mol. Wt.: 384 Mol. Wt.: 57.1 Mol. Wt.: 395 Mol. Wt.: 46.1

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.

F O F O F COOEt F COOEt NaH + HF + H3C OH F F NH THF F N EtO F F

Stage-2 Stage-3 Hydrogen Ethanol C17H18F5NO4 C15H11F4NO3 Fluoride C2H6O Mol. Wt.: 395 Mol. Wt.: 329 Mol.Wt.:20 Mol. Wt.: 46.1 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 O NH O NH2 F COOEt F COOEt

K2CO3 F N + F N Acetonitrile + HF F F

Stage-3 Benzyl amine Stage-4 Hydrogen C15H11F4NO3 C7H9N C22H19F3N2O3 fluoride Mol. Wt.: 329 Mol. Wt.: 107. Mol.Wt.:416.4 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 O NH2 O F COOEt F COOEt CH H ,Pd/C 3 + 2 (H) 2 F N + F N Ethanol F F

Stage-4 Hydrogen Stage-5 Toluene C H C22H19F3N2O3 C15H13F3N2O3 7 8 Mol. Wt.: 416.4 Mol.Wt.:2 Mol. Wt.: 326.3 Mol. Wt.: 92 Stage-6:

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

NH2 O NH2 O F COOH F COOEt + C H OH + H O H2SO4 2 5 2 F N F N F F

Stage-5 Water Stage-6 Ethanol C2H6O C15H13F3N2O3 C13H9F3N2O3 Mol. Wt.: 326.3 Mol. Wt.: 18 Mol. Wt.: 298 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 O

NH2 O F COOH H F COOH N H3C N N + DMF + HF H C N CH HN F F N 3 H 3 F CH3

Stage-6 cis-2, 6-dimethylpiperazine Sparfloxacin Hydrogen Fluoride C13H9F3N2O3 C6H14N2 C19H22F2N4O3 Mol. Wt.: 298 Mol. Wt.: 114.2 Mol. Wt.: 392 Mol. Wt.: 20

FLOW CHART OF SPARFLOXACIN

Stage-1 ethyl penta fluoro benzoyl acetate Tri ethyl ortho formate Acetic acid to recovery Acetic anhydride Reactor Acetic acid

Centrifuge Waste ethanol

Stage-1

Stage-2 Stage-1 Cyclopropyl amine Reactor Ether to recovery Ether

Centrifuge Waste ethanol

Stage-2 product

Stage-3 Stage-2 Sodium hydride Reactor THF to recovery THF

Centrifuge Waste ethanol and Hydrogen fluoride

Stage-3 product

Stage-4 Stage-3 Benzyl amine Reactor Acetonitrile to recovery Potassium carbonate Acetonitrile

Centrifuge Hydrogen Fluoride

Stage-4 Stage-5

Stage-4 Hydrogen Pressure Reactor Ethanol to recovery Pd/C Ethanol

Centrifuge Hydrogen Fluoride

Stage-5 compound Stage-6 Stage-5 Water Reactor Sulphuric acid

Centrifuge Waste ethanol

Stage-6 Stage-7

Stage-6 cis-2, 6-dimethylpiperazine Reactor DMF to recovery DMF

Centrifuge Hydrogen Fluoride

Final compound

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 MgBr

THF + Mg + CO2 + H2O

1-Naphthyl magnesium bromide 1-bromo naphthalene Magnesium C H BrMg Carbon dioxide Water C10H7Br 10 7 Mol. Wt.: 207.1 Mol. Wt.: 24 Mol. Wt.: 231.4 Mol. Wt.: 44 Mol.Wt.: 18

O OH

Mg(OH)Br +

Hydroxy magnesium Stage-1 bromide C11H8O2 Mol. Wt.: 121 Mol. Wt.: 172.2

Stage-2:

STEP-A

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

O OH O Cl

MDC + SO + HCl + SOCl2 2

Stage-1 Thionyl chloride Reaction mass Sulphur dioxide Hydrochloric acid C11H8O2 Cl2OS C11H7ClO O2S ClH Mol. Wt.: 172.2 Mol. Wt.: 119 Mol. Wt.: 190.6 Mol. Wt.: 64.1 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.

H O Cl O N CH3

Acetone + HCl + MeNH2

Reaction mass Methyl amine Stage-2 Hydrochloric acid C11H7ClO CH5N C12H11NO ClH Mol. Wt.: 190.6 Mol. Wt.: 31.1 Mol.Wt.:185 Mol. 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.

H H O N N CH3 CH3

LiAlH + H O + 4 (H) 4 2 THF Stage-2 Stage-3 Water Hydrogen C12H11NO C12H13N Mol. Wt.: 185 Mol. Wt.: 4 Mol. Wt.: 171 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.

CH3 CH3 BuLi CHO + CH

Propenal Tert-butyl acetylene Stage-4 C3H4O C6H10 C9H14O Mol. Wt.: 56.1 Mol. Wt.: 82 Mol. Wt.: 138

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.

CH3 CH3

Acetone CH + HBr Br + H O C 2 OH H

Stage-4 Hydrogen Stage-5 Water C9H14O bromide C9H13Br Mol. Wt.: 138 Mol. Wt.: 81 Mol. Wt.: 201 Mol. 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 H 3 N CH3

Br + Na2CO3 + C HCl H

Stage-3 Stage-5 Hydrochloric acid C12H13N C9H13Br Mol. Wt.: 171 Mol. Wt.: 201 Mol. Wt.: 36.5

H3C CH3

CH3 CH3 N C H . HCl HBr +

Hydrobromic Terbinafine HCl acid C21H26ClN Mol Wt.: 81 Mol. Wt.: 327.9

FLOW CHART OF TERBINAFINE HCl

Stage-1

1-bromo naphthalene Magnesium Reactor Spent solvent to recovery THF

Carbon dioxixe Water Reactor Hydroxy magnesium bromide

Stage-1

Stage-2

Stage-1 product Solvent ml's to recovery Thionyl chloride Reactor SO2 & HCl emissions to scrubber MDC

Spent acetone to recovery Methyl amine Reactor HCl gas to scrubbing

Centrifuge

Stage-2

Stage-3

Stage-2 Hydrogen Reactor Solvent ml's to recovery LiAlH4 THF

Centrifuge Waste water

Stage-3 Stage-4 Propenal Tert-butyl acetylene Reactor Butyl lithium

Centrifuge

Stage-4

Stage-5

Stage-4 Hydrogen bromide Reactor Acetone to recovery Acetone

Centrifuge Waste water to recovery

Stage-5

Stage-6 Stage-3 Stage-5 Reactor Hydrochloric acid Sodium carbonate

Water Centrifuge Inorganic salt solution

Final product

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 OH O COOH C CH3COOH OH + 2 Cl2 + 2 HCl

Cl Cl Salicylic acid Chlorine 3,5-dichloro salicylic acid Hydrochloric acid C7H6O3 Cl4 C7H4Cl2O3 Mol. Wt.: 138 Mol. Wt.: 141.8 Mol.Wt.:207 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 O OH O C Cl C OH Oleum OH + Cl2 + HCl Cl Cl Cl Cl 3,5-dichloro salicylic acid Chlorine Trichloro salicylic acid Hydrochloric acid C7H4Cl2O3 Cl2 C7H3Cl3O3 Mol. Wt.: 207 Mol. Wt.: 70.9 Mol. Wt.: 241.5 Mol. Wt.: 36.5

FLOW CHART OF TRICHLORO SALICYLIC ACID

Stage-1: Salicylic acid Chlorine gaas Reactor Acetic acid MLs Acetic acid

Centrifuge HCl gas to scrubber

Stage-1 product

Stage-2:

Stage-1 product Chlorine gas Reactor Spent MLs Oleum

Centrifuge HCl gas to scrubber

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.

O OH O OH

Cl OH H2O + NaOH + NaCl

O2N O2N 2-Chloro-5-Nitro benzoic acid Sodium hydroxide Stage-1 Sodium chloride C7H4ClNO4 C7H5NO5 Mol. Wt.: 201.6 Mol. Wt.: 40 Mol. Wt.: 183 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.

O OH O OH

OH OH Raney Ni/H2 + 2 H2O + 3 H2 H2N O2N 5-Amino-2-Hydroxy Benzoic acid Stage-1 Hydrogen Water C7H5NO5 C7H7NO3 Mol. Wt.: 183 Mol.Wt.: 6 Mol. Wt.: 153 Mol.Wt.: 36

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

Stage-1

2-Chloro-5-Nitro Benzoic acid sodium hydroxide Reactor water

Centrifuge Inorganic salt solution

Stage-1

Stage-2

Stage-1 Raney nickle Reactor Hydrogen pressure

Centrifuge Waste water to recovery

Final product

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 O O H H2N 2 Ph N K2CO3 O Ph +3 HCl OH + 3 Ph CCl Ethanol Ph Ph L-Phenyl alanine Benzyl chloride Stage-1 Hydrochloric C H Cl C9H11NO2 21 21 3 C30H29NO2 acid Mol. Wt.: 165.2 Mol. Wt.: 379.8 Mol. Wt.: 435.6 Mol. Wt.: 109.5

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 Ph O O Ph N CN Ph N NaNH2 O Ph + H3CCN + HO Ph THF Ph Ph Stage-1 Acetonitrile Stage-2 Benzyl alcohol C H N O C30H29NO2 C2H3N 25 24 2 C7H8O Mol. Wt.: 435.6 Mol. Wt.: 41 Mol. Wt.: 368.5 Mol. Wt.: 108

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 O H2 Ph N CN THF Ph C MgCl + H O + 2 Ph

Stage-2 Benzyl magnesium chloride Water C25H24N2O C7H7ClMg Mol. Wt.: 368.5 Mol. Wt.: 151.9 Mol. Wt.: 18

Ph O Ph N

Mg(OH)Cl +

Magnesium hydroxy Stage-3 chloride C33H35NO Mol. Wt.: 76.8 Mol. Wt.: 461.6

FLOW CHART

Stage-1

L-phenyl alanine Benzyl chloride Potassium carbonate Reactor Ethanol solvent to recovery Ethanol

Centrifuge Inorganic waste

Stage-1

Stage-2

Stage-1 Acetonitrile Sodamide Reactor THF solvent to recovery Tetra hydro furan

Centrifuge Benzyl alcohol

Stage-2

Stage-3

Stage-2 Benzyl magnesium chloride Water Reactor THF solvent to recovery THF

Centrifuge 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.

NO2

+ Conc. HNO + Conc. H SO + H2SO4 + H O 3 2 4 Cl NCl 2 Cl NCl

2,6-dichloro pyridine Nitric acid Sulphuric acid 2,6-dichloro-3-nitro pyridine Sulphuric acid Water C5H3Cl2N HNO3 H2O4S C5H2Cl2N2O2 H2O4S Mol. Wt.: 148 Mol. Wt.: 63 Mol. Wt.: 98.1 Mol. Wt.: 193 Mol. Wt.: 98.1 Mol.Wt.:18

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.

NO NO2 2 IPA + Aq. NH3 + HCl Cl NCl Cl NNH2

2,6-dichloro-3-nitro pyridine Ammonia 2-amino-6-chloro-3-nitro pyridine Hydrochloric acid C H ClN O C5H2Cl2N2O2 H3N 5 4 3 2 Mol. Wt.: 193 Mol. Wt.: 17 Mol. Wt.: 173.6 Mol. Wt.: 36.5

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

Stage-1 2,6-dichloro pyridine Conc.H2SO4 Reactor Conc.HNO3

Quencher

Centrifuge Waste water to recovery

Aqueous ammonia Reactor Spent solvent to recovery Iso propyl alcohol

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.

O H2O + 2 Zn (Hg) + 2 HCl + Cl S

O O Cl Gamma butyro lactone Zinc amalgam Hydrochloric Thionyl chloride C4H6O2 Zn acid Cl2OS Mol. Wt.: 86.1 Mol. Wt.: 130.8 Mol. Wt.: 73 Mol. Wt.: 119

+ Cl ZnO + SO2 + ZnCl2 Cl

Zinc oxide Sulfur dioxide Zinc chloride 4-chloro butyryl chloride OZn O2S Cl2Zn C4H8Cl2 Mol. Wt.: 81.4 Mol. Wt.: 64.1 Mol.Wt.:136 Mol. Wt.: 127

FLOW CHART

Gamma butyro lactone Zinc Amalgam SO to scrubber Hydrochloric acid Reactor 2 Thionyl chloride

Water Centrifuge ZnO & ZnCl2 to Waste Water

Final product