Product Name: -2,4 Ditertiary butyl phenyl...

Product Name: -2,4 Ditertiary butyl phenyl phosphite

Reaction: -

Procedure: -

Charge Xylene in Reactor at room temperature.and

add2,4DTBP + Base . Heat the reaction massup to 50° C . After

heatind add PCL3 in rteaction mass. Aging reaction mass

at150°C temperature . concentrate reactin mass and recover

xylene . add methanol in mass and cool reacition mass. Filtrate

mass and dry material.

Xylene

Reactor

2,4 DTBP +

Base

Heating up to 50°C

Reactor

PCl3

Aging up to

tempt 150°C

Distillation of Xylene

Q.C check for

2,4 DTBP

Addition of Methanol

Cooling , Filtration and

drying of product

FLOW CHART FOR 2,4 Ditertiary butyl phenyl phosphite

Final product: - 4-HBS

Process description of 4-HBS:

Charge sulfanilamide to reactor followed by aq.HCl. Chill the mass and add aq. Sodium

nitrite slowly. After diazotization is over; charge diazotized mass to previously

prepared chilled sodium sulfite slurry at low temperature. Heat the mass and charge

aq.HCl for hydrolysis purpose. Chill the reaction mass and filter. Purify crude crop

using appropriate solvent.

Reaction:

(Part –A)

Reactor

Reactor

Sulfanilamide

NaNO2

HCl

Chilled water Reactor

Water

Flowchart for 4 Hydrazinobenzenesulfonamide (Part –

A)

9Stae?(hydrochloride

(Part –B)

`

Organic Layer. Concentrated

U/ Vacuum.

Residue IPA

Residue HPLC Purity

TLP Stage I

Reactor

Reactor

Sodium

Sulphite

Wet Crop

Water

Part –A

Reactor

Effluent

Reactor

Reactor

Filtration

Reactor

Filtration

HCl

Crude dry

crop

Water

HCl

Effluent

Effluent

Drying (4-HBS)

Wet Crop

Water evaporates

Final product: - 4-Acetoxy styrene

Procedure-

4-Acetoxy Styrene: 4-Hydroxy benzaldehyde react with malonic acid in presence of

ethylene diamine it gives 4-hydroxy coumaric acid which on decarboxylation at

higher temperature it gives 4-hydroxy styrene. That 4-hydroxy styrene react with

acetic anhydride in presence of triethyleamine it gives 4-Acetoxy

Reaction:

stage -I

Reactor

Reactor

4-Hydroxy

Benzaldehyde

Malonic Acid

Catachol

Flow sheet of 4-Acetoxy styrene

Reactor

Reactor

Reactor

Reactor

Reactor

Reactor

Reactor

Reactor

Reactor

DMF

Ethylene diamine

Recovered DMF

Water

Ethyl Acetate

Effluent

NaHCO3+water

Solution

Effluent

Recovered E/A

NaCl +water

Solution

Effluent

Stage -II

Reactor

Reactor

Acetic anhydride

Reactor

Reactor

Reactor

Reactor

Reactor

Reactor

Reactor

Reactor

Triethylamine

NaHCO3 + water

Solution

Effluent

NaCl + water

Solution

Recovered E/A E/A

Effluent

Water

Effluent

Effluent

4-chlorophenyl hydrazine hydrochloride

Manufacturing description-

4Chloroaniline to reactor followed by aq.HCl. Chill the mass and add aq. Sodium nitrite

slowly. After diazotization is over ; charge diazotized mass to previously prepared sodium

metabisulfite and sodium hydroxide mixture at low temperature. Heat the mass and charge

aq.HCl for hydrolysis purpose. Chill the reaction mass and filter the crude crop. Purify

crude crop using appropriate solvent.

Reaction: -

Cl

NH2

Cl

N+ N Cl

Cl

NSO3Na

NHSO3Na

Cl

NH

NH2

HCl

H2O

HCl

NaHSO3

NaOH

4 chloroaniline Diazonium salt Disulfonate salt 4 chlorophenylhydrazine HCl

Mol wt 127.57 [ 179.05]

NaNO2/HCl

Chemistry of 4 chlorophenylhydrazine HCl

[175.01] [346.67]

Flowsheet:

Step I: Preparation of Diazomium salt (S-I)

4-chloro aniline

Reactor

Conc. HCl

NaNO2

Water

Reactor

Diazotized mass

Step II: Diazonium salt to 4-CPH.HCl

Sodium metabisulfite

Reactor

46% NaOH

Diazotized mass

Butanol

Reactor

Reaction mass

Water

Conc. HCl

Reaction mass

Conc. HCl

Wet crop

Filtrate Effluent

Dry crop

Water

Water

Product Name: -6 HQ

Manufacturing Process: -

STEP I : Charge P-Anisidine, NaHCo3 and Toluene in reactor under stirring and

at room temp. add mixture of 3-Chloropropionyl chloride & Toluene maintaining

the temp. below 50o C. Digest the reaction mass for one hour. Cool the mass at

room temperature and then add water & stir for 10 minutes slowly. Add HCl with

for 30 minutes stirring. Filter the mass under vacuum wet solid is suspended in

water and stir for 30 minutes .Filter the mass under vacuum. Then give toluene

washing to solid and suck dry. Unload the solid and dry under vacuum at 70 C.

STEP II: (preparation of crude 6-HQ) Charge Step-I product, Dimethyl acetamide

and start stirring. Heating the reaction mass started to get 70o C. Start addition of

AlCl3. Digest the reaction mass at 150o C. Cool the mass at 120C and quench it

into crushed ICE with stirring. Add Ice cold water to the mass and stir for 01 Hr. To

this add NaBH4 solution slowly Filter the mass under vacuum. Wash the solid with

water & Suck dry the solid and dry under vacuum oven at 80o C

STEP III - Purification of Stage II (crude 6 H.Q.): Charge crude crop of 6-HQ and

Methanol and start stirring. Heat at 65 C , clear brown solution is obtained To this

add Sodium sulphite and stir for 01 Hr .Then add of Activated Charcoal and

continue stirring for next 01 Hr. Filter the hot mass through hy-flow bed . Give hot

methanol wash to bed and collect all filtrate. Distilled out about 80 % Methanol

under vacuum and add water in reaction mass.

Filter the mass under vacuum and give water wash to solid and suck dry.

Reaction: -

O

CH3

NH2

Cl O

Cl

Cl

O

NH

O CH3

Cl

O

NH

O CH3 AlCl

3

NaBH4

HO

N O

H

+

Toluene

NaHCO3

Step - 1

Step - 2

+ CH3Cl

HCl

Dimethyl Acetamide

+ NaCl

p- Anisidine

Sodium bi

carbonate

Toluene

Reactor

Digest the reaction at elevated

temp.

Cooling the mass

Effluent stream water +

Toluene ML Wet crop

3- Chloro proponoyl chloride

+ Toluene

Water

Water wash

Filtration

Filtration

Wet crop

Dried crop step I

product

Concentrated

HCl 35 %

Toluene

Aqueous wash +

Toluene ML after

all water wash and

Toluene wash

FLOW CHART FOR 6 HQ Step I

Stage I product

N,N Dimethyl

Acetamide

Reactor

Heat at elevated Temp.

Digestion of reaction mass at

desire temp.

Quenching

Aluminum chloride.

Ice

Filtration

NaBH4 +

water

Water

2400 Kg

Wet

crop

Filtrate

Crude 6- HQ

Water

Methyl chloride

Methanol

Wash

Dry 6- HQ

Methanol

Wash

Recovered

Methanol

Wash

Distillation

Residue

Losses

Ethanolamine 20% +

Water 40% + Isopropanol

40%

Reactor

Distillation

Recovery

of

Isopropan

ol + water

for recycle

Mix of N- Methyl

ethanolamine

Hydrochloride +Unreacted

ethanolamine + Water

(Biodegradable)

FLOW CHART FOR 6 HQ Step II

Product Name- A.T.M.P

Process description: A.T.M.P

Take 60% OPA and add ammonium chloride in reactor. Take reactor temp. upto 95°c

and add 1st HCHO in 8.30 hrs in between temp.100-110°c.After 2 hrs cooking add 2nd

lot HCHO in 3.30 hrs.After 6hrs cooking take sample (NH4Cl-0.23%,OPA-1%,HCHO-

1.75%).

After 16hrs to18 hrs distillation. Give water wash (500ltr each) upto HCHO below 1%.

After Q.C check cooling the reactor and add H2o2and adjust sp. gravity 1.320-1.330

Reaction:

Product Name- ACETYL CHLORIDE

FLOW CHART FOR A.T.M.P

Water

Water

OPA

Reaction

HCl Scrubbing System-

HCL

DIL HCL

Water

Distillation

Formulation

NH4Cl

HCHO

.

A.T.M.P

HCL

.

Process description-

Phosphorus trichloride is reacts with acetic acid it gives

Orthophosphorus acid and acetyl chloride as a product.

Reaction:

FLOW CHART FOR H.E.D.P. WITH A/Cl

Water

`

PCl3 824 Kgs.

Reaction

A/Cl Recovery

A/A Scrubbing System

Dil A/A.

Complex

Breaking

Distillation

Product

Formulation

A/Cl

Scrubber

.

A/Cl Distillation

Rec.Acetic acid

Water

Acetic Acid

PRODUCT NAME-BENFOTIAMINE PHOSPHATE

Reaction Scheme

Brief Process;

Thiamine phosphate reacted with benzoylthiosulfate in presence of aqueous

sodium hydroxide solution to give Benfotiamine.

N

N NH2

N

O

S

OO

P

OH

O

OH

NaOHN

N

NH2

N

SO

POH

OH

O

+

Sodiumbenzoylthiosulfate

H2O

BenfotiamineThiamine Phosphate

Title : PROCESS REACTION OF PRODUCT BENFOTIAMINE PHOSPHATE

Thiamine phosphate Water Sodium hydroxide

Reaction

Filtration

Benfotamine

Filtrate (Effluent )

Sodium benzoylthiosulfate

Final product: Sodium Penta Chlorophenate

Reaction:

SPCP - : C6H5 OH + 5 Cl2 + NaOH C6Cl5 ONa + 5 HCl + H2O

Process Description: - Phenol is reacted with Chlorine at controlled condition.

Evolved HCl gas is absorbed in water .The Pentachlorophenate formed is reacted

with Caustic Lye. The product is formulated and Packed suitably.

EXCEL INDUSTRIES LTD,LOTE-PARSHURAM

FLOW CHART FOR S.P.C.P.

Chlorine

Phenol

Reactor

HCl

.

Ejector

Water

Neutralizer

Water

NaOH

Filter

Residue.

Product

Drying Drying loss Water Scrubbed

Water

Product Name: - CELECOXIB

ROUTE OF SYNTHESIS

Brief Process

4,4,4-Trifluoro-1-(4-methylphenyl)-1,3-butanedione reacts with 4 –

hydrazinobenzene sulfonamide hydrochloride to obtain Celecoxib

CF3

O O

SO2NH

2

NH-NH2. HCl

water

SO2NH

2

NNF

FF

+

4-Hydrazinobenzene sulfonamide hydrochloride

Celecoxib

4,4,4-trifluoro-1-(4-methylphenyl)- 1,3-butanedione

4-

aminobenzenesulfonamide

Conc HCl Sodium N420 Water

Reaction

Stirring

Filtration

Sodium sulfite

4-Hydrazinobenzene

sulfonamide

hydrochloride

Effluent

FLOW CHART FOR CELECOXIB

4-

hydrazinobenzenesulfonamide

hydrochloride

Water

4,4,4-trifluoro-1-(4-

methylphenyl)-1,3-

butanedione 750 kg

Reaction

Filtration

Celecoxib

Effluent

FLOW CHART FOR CELECOXIB

PRODUCT- Cetilistat

Chemical Reaction:

Brief Process Description: 5-Methylanthranilic acid reacted with

Cetylchloroformate in Tetrahydrofuran at 25-30°C to give Cetilistat.

Cl

O

NH2

COOH

N

O

O

O

O(CH3)15O +

THF, RT

(CH3)15

Cetylchloroformate 5-Methylanthranilic acid

Cetilistat

Title : PROCESS FLOW CHART OF CETILISTAT

5-Methyl anthranilic acid Pyridine Cetylchloroformate

Reaction

Filtration

Cetilistat

Filtrate

Recovery of pyridine

Effluent

PRODUCT NAME- CODEX - 551: -

Process Description: - The mixture of Di-Methyl Phosphite & Di-Methyl Maleate

reacts with Sodium Methoxide & Methyl Acrylate to form an ester. Reaction is carried

out below 5 °C. The ester formed is hydrolyzed with water to get final product &

dil.Methanol. The methanol is separated by distillation & sold as a by-product of 60

% purity.

REACTION-

I st. Ester

CH3 O CH2.COOCH3 CH3

O H

HCOOCH3

HC.COOCH3 NaOCH3

P +

P

CH3O HC.COOCH3 CH3O

O

O

Dimethyl Phosphite Dimethyl Maleate Phosphono succinic acid

tetra methyl

Ester.

II nd. Ester.

CH2.COOCH3

CH3 O CHCOO.CH3 CH3 O

CH2.CH2COOCH3

NaOCH3

P + CH2=CH.COOCH3 P C

COOCH3

CH3O CH3O

O O

CH2COOCH3

I st. Ester. II nd. Ester.

Hydrolysis.

CH3 O CHCOO.CH3 H O

CH2.CH2COOH

P COOCH3 + 5 H2O P C - COOH + 5

CH3OH

CH3O HO

O CH2.COOCH3 O CH2COOH

2 Phosphono butane 2, Phosphono butane

Methanol

bicarboxylic acid 1,2,4 tri carboxylic acid

( 1,2,4 0 pentamethyl Ester

( II nd, Ester )

EXCEL INDUSTRIES LIMITED, LOTE PARSHURAM.

FLOW CHART FOR CODEX - 551

Sodium Methoxide

Reactor Dimethyl Phosphite

Maleate.

Di - Methyl Maleate

Methyl Acrylate

174 Kgs.

Distillation

Methanol ( 66 % )

Hydrolyses

Methanol - 60 %

Concentration

Filter

Codex 551 ( 50 % )

Water

Water

Recycle to Process

Product Name- codex-661

Process description: codex 661

Take A/A in reactor and add PCL3 at rate 840kg/hr for 8 to 9 hrs.After 1hr cooking

we collect crude A/CL for 4 hrs. After completing 2nd PCL3 lot cooking reactor for half

hr and then collect 2nd crude A/CL for1.30 hrs.After that 8-9hrs. Heating/cooking then

take sample & send to Q.C. for analysis. The required crude HEDP complex OPA below

1%.After OPA checking Break the complex with addition of recover acetic acid in 3-4

hrs. After complex breaking add dil.Acetic acid & take for further distillation. In that

distillation of 8-9 hrs we recover Acetic acid & after distillation add water in reactor

and adjust specific gravity 1.440

Reaction:

FLOW CHART FOR H.E.D.P. (CODEX- 661)

Water

PCl3

Reaction

HCl

A/A Scrubbing System

Dil A/A

Complex

Breaking

Distillation

Recover A/ A

Dilute A/A

Product

Formulation

H.E.D.P

Final product: - Dibenzoyl Methane (DBM)

Reaction-

Dibenzoyl Methane (DBM), CAS Number: 120-46-7

1. Details of Chemistry and Route of Synthesis:

Process Description:

Charge Xylene. Start heating. Add sodium methoxide followed by

methyl benzoate. Heat the above reaction mass. Start the addition of

Acetophenone. Cool the reaction mass to room temperature & Adjust

pH of reaction mass acidic using HCl. Separate aqueous layer, & give

three water wash under stirring at room temperature. Distil out

complete xylene under vacuum.

Flowchart OF DBM

Reactor

Reactor

Reactor

Settling and Separation

Reaction mass

Organic Layer

Layer Separation

Xylene

Distillation

HCL 20%

Methyl benzoate

Acetophenone

water

Effluent

Crude

Effluent

Recovery of Xylene

Xylene

Sodium

methoxide

Reaction Crude

Filtration

Reaction Crude

Filtration

Crude Crop

Drying

Wash with cold

MeOH

MeOH

Crude Cake

Aq.MeOH

MeOH

Aq.MeOH

Drying loss

Recovered

MeoH

Effluent

Recovered

MeoH

Effluent

Final Product

PRODUCT NAME-DISPERCEL 32

Title:Brief Process Description and Reaction Dispercel 32 (Polymaleic Acid)

Process Description:-Take Maleic Anhydride & Xylene in the reactor. Dissolve catalyst

in Xylene & then add it to reactor. Heat the reaction mass. Decant the top Xylene layer

then remove the Xylene by distillation. Cool the mass & adjust Sp. Gravity. Drain the mass

then filter and fill in drum. Recover the decanted Xylene & re-use in next batch. Maleic

Anhydride dissolved in Xylene & polymerized by using DTBP as a catalyst to form Poly

Maleic Acid. Xylene is recovered by distillation & recycled in the process.

Reaction of Dispersal - 32 ( Poly Maleic Acid ) :- DTBP + Xylene +

H H H H H H C C Heat 140 0C C C C C C C DTBP C C Solvent - Xylene C C C C O O O O O O O O O Maleic Anhydride Poly Maleic Anhydride H2O H H H H

C C C C C C COOH COOH COOH COOH

Poly Maleic Acid + Xylene

PRODUCT NAME- EXCLAR

Title : Manufacturing Process OF PRODUCT EXCLAR

In reactor add D-sorbitol & methanol. Then Stir for 15min.and add 3,4-

dimethylbenzaldehyde, ethylene glycol , PTSA , cyclohexane with stirring . Heat to

reflux temp. (56-600C) and continue it for 12 hours. Check for unreacted 3,4-dimethyl

benzaldehyde in RM. After completion of reaction filter the mass at 50°C to separate

ML and crop. Take crude material in reactor. Charge methanol and stir the mass for

30min. Add 2% sodium Bicarbonate solution slowly. Heat the above mass to 64 -700C

for 2 hrs cooking. Filter hot and give methanol wash to filtered mass. Dry the material

at 90 -95 0C.

Title : PROCESS REACTION OF PRODUCT EXCLAR

CH2OH

CHOH

CH

CHOH

CHOH

CH2OH

HO

CHO

CH3

CH3

CH

O

CH2OH

CHOH

CH

CH

CH

CH2O

H3C

H3C O

O

HC

CH3

CH3

H2O+

2-

Sorbitol (182)

3,4-Dimethylbenzaldehyde (2 x 134 = 268)

Millad-3988 (414)

2

1, 3; 2, 4 –bis (3,4-dimethyl benzylidene) sorbitol (414)

Title : Process Flow Sheet Diagram for Product EXCLAR

Dimethyl benzaldehyde

Sorbitol PTSA Ethylene Glycol

Cyclohexane Methanol

REACTION

FILTRATION

PURIFICATION

Aq. ML

Aq. MeOH NaHCO3

FILTRATION

Wet Crop

Dry Crop

Aq. ML

Product Name: - Fexofenadine

Manufacturing Process: -

FBX-10 is dissolved in methanol followed by hydrolysis using aqueous sodium

hydroxide solution. The methanolic solution is concentrated to dryness results in

residue which is dissolved in water. Alkaline solution is extracted with MDC and

separated aqueous layer is acidified with dilute HCl followed by filtration. Crude

material is purified in methanol results in product Fexofenadine

Reaction: -

OH

N

O

CH3

CH3

O

O CH3

methanol, NaOH

water, conc.HCl

OH

N

O

CH3

CH3

O

OH

FBX-10

Molecular Formula = C33

H39

NO4

Formula Weight = 513.66706

Fex intermediate


H37

NO4

Formula Weight = 499.64048

Reactor

Fex10 Methanol

NaOH & Water

Distillation

Water

Aqueous

Recovered aq. Methanol

Int Product

Aqueous layer

Layer separation

MDC

Organic layer

HCl

Filtration

Drying Wet Crop

Dry solid

Methanol ML

Effluent

Recovered

Methanol

FLOW CHART FOR Fexofenadine

Final product: - FLUROBENZENE

FLUROBENZENE Procedure:

It is recommended that benzenediazonium

fluoborate be precipitated from a solution whose total hydrogen-ion

concentration does not exceed 1 mole per liter.2 The diazonium

fluoborate has

also been prepared from aniline hydrochloride and nitrosyl

borofluoride.

Chemistry- FLUROBENZENE

Reactor

Reactor

Reactor

HCL

Aniline

Working flow sheet for FLUROBENZENE

Water

NaNO2

Reactor

Boric acid +

Hydrofluoric

acid

Filtration

Drying

Reactor

Reactor

Effluent

12025

Ice water

Ice + salt

Reactor

Distillation

Drying

With crushed CaCl2

Distillation

Reactor

Methanol +

Ethyl ether

5 times wash

NaOH 10%

Scrubbing of

Boron

Fluoride with

(ice+ water or

soda solution)

Product

FLUROBENZENE

Effluent

Residue

Effluent

Rec. Methanol

+ Rec. Ethyl

Ether

Drying loss

12025

Product Name: Lauracel


Thionyl Chloride is added to Caproic Acid and this mass is cooked. Chlorinated phenol is

added to this cooked mass. The reaction mass is cooled and drained. The sulfur dioxide gas

generated from the process is scrubbed in Caustic soda solution and the Sodium Sulfite

generated is sold. HCl gas generated from the process is scrubbed in water and 30% HCl

generated is sold.

Chemistry:

R- COOH + SOCl2 + OH + Cl2 + SO2 + HCl

Flowchart

PHENOL THIONYL CHLORIDE FATTY ACID CAPROIC ACID

COOKING

COOLING

PACKING

Sulfur Dioxide

Scrubbing

Caustic-17%

Sodium Sulfite -30%

HCl(100%)

Water

Scrubbing

HCl – 30%

CHLORINE

REACTOR

1. Name of the Item : Nizatidine (N- [4-(6-methylamino-7-nitro-2-thia-5-aza-6-

heptene-1-yl)-2-thiazolylmethyl]- N,N- dimethylamine

Route of Synthesis:

2-(Dimethylaminothio)acetamide HCl (DMATA HCl) reacts with 1,3-dichloroacetone to

give 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline which reacts

with thionyl chloride to afford 2-[(Dimethylamino)methyl]-4-(chloromethyl)thiazole

(Stage I). The said product 2-[(Dimethylamino)methyl]-4-(chloromethyl)thiazole

reacts with cysteamine HCl to give 4-{[(2-aminoethyl)thio]-methyl}-N,N-dimethyl-2-

thiazolemethanamine (Stage II). Stage II then reacts with 1-methylamino-1-

methylthio-2-nitroethene to give the title compound.

5. Process and Equipment / instrument Flow chart

Reaction

Reaction

Filtration

Filtrate

Stirring

DMATA HCl Charging

Solid residue,

Filtration

Diisopropyl ether

Sodium sulphate Sodium bicarbonate

Reaction

Reaction Thionyl chloride,

Filtration

Filtrate

Solid

Drying

Stage I

Recovered Chloroform,

Recovery of DIPE,

1,3-Dichloro acetone

Filtrate

Chloroform, Reaction

Residue

Carbon dioxide gas evolved,

Sulphur dioxide gas evolved,

Residue

Reaction

Reaction

Reaction

Layer separation

Upper organic layer

Cysteamine HCl Charging

Toluene,

Concentration

Solid drying

Weight of solid, Stage II

Water

Sodium sulphate

Sodium hydroxide,

Recovery of Toluene,

Stage I

Lower aqueous layer with Sodium

chloride and sodium sulphate


Reaction

Stirring

Reaction

Water Stage II

Layer separation

Chloroform

Organic layer

Concentration

Crude solid

Aqueous layer

1-methylamino-1-methylthio-

2-nitroethene

Acetone

Filtration

Filtrate

Recovered acetone,

Nizatidine wet solid

Drying

Nizatidine

Recovered chloroform

PRODUCT NAME- NOPA

Title: Manufacturing Process OF PRODUCT NOPA

Charge DEP to a reactor. Heat the to 140°C under continuous stirring. Add a mixture

of DEP + n-Octane + DTBP to a preheated mass, drop wise in 2 Hrs. Monitor the

reaction progress on GC, till n-Octane is consumed, which takes about 1 Hr. Cool the

reaction mass to 80°C & distill out DEP from reaction mass under vacuum. Hydrolyze

the concentrated reaction mass by 1:1 HCl at 140°C; & distill out water from aqueous

mass simultaneously. The reaction mass is further hydrolyzed with water at 170°C.

Cool the solidified mass to 60 C & add n-Hexane under stirring to form homogeneous

slurry. Cool the slurry to & keep it aside for 1 Hr. Filtered the precipitated product &

wash it with chilled n-Hexane to remove any impurities.

Title: PROCESS REACTION OF PRODUCT NOPA

P O

OC2H

5

OC2H

5

H P

O

OC2H

5

OC2H

5

P

O

OC2H

5

OC2H

5

HydrolysisP

O

OH

OH

+140C

ArbuzovRxn.

1-Octene Diethyl Phosphite Octylphosphonic acid diethyl ester

Step-1:Synthesis of Octylphosphonic acid diethyl ester.

Step-2:Hydrolysis of octylphosphonic acid diethyl ester.

HCl

112 138 250.2

250.2 194.2

Octylphosphonic acid diethyl ester n-Octyl-1-phosphonic acid

EXCEL INDUSTRIES LTD, LOTE-PARSHURAM

Title : Process Flow Sheet Diagram for Product NOPA

DEP n-Octane DTBP

REACTION

Hydrolysis

PURIFICATION 2162 kg

HCL + Water

n-Hexane

FILTRATION

Wet Crop

Dry Crop

HCL

Water

n-Hexane + Water

DISTILLATION of Hexane layer

Residue Recovered n- Hexane

SCRUBBER

Effluent

Product Name : OXO

Reaction:

OXO Step I chemistry :

OXO Step II chemistry :

OXO Step III chemistry:

Theoretical per MT quantity of N-tert-butoxycarbonyl-L-trans-4-oxoproline


Trans-4 hydroxy L-proline is undergoes with Boc unhydride in presence of ethyl

acetate is solvent it produce N-tert butoxycarnyl L-trans-4-hydroxyproline.(Step-I)

In further process N-tert butoxycarnyl L-trans-4-hydroxyproline reacts with sodium

hypochlorite in presence of Dichloromethane as solvent and TEMPO as reagent it

afford N-tert-butoxycarbonyl-L- trans-4-oxoproline.( Step-II)

Dicyclohexyl carbodimide and 1,3 – Thiazolidine reacts with N-tert-butoxycarbonyl-

L- trans-4-oxoproline with tolune as solvent it produce 3-((S)-1-tertbutoxycarbonyl-

4-oxopyrrolidin-2-yl-carbonyl ) thiazolidine.

Reaction Mass

Reaction Mass

Reactor

Reaction Mass

Conc. Mass

Settling & separation

Trans-4-hydroxy-

L-Proline

Boc anhydride

HCL

Sodium

hydroxide

solution

Ethyl Acetate

Working flow sheet for OXO (Stage –I)

Reactor Water

Brine Solution

Effluent

Reaction Mass

Settling & separation Effluent

Concentration

Rec. Ethyl Acetate

Conc Reaction

Mass

Filtration

Mintroleum+Ethyl

Acetate

Cake

Drying

Mintroleum

Drying loss

Reactor MDC

Stage –I

Reactor

Tempo

Filtration

Sodium

Hypochloride

WetCake

Drying

Potassium Hydrogen

Sulphate

Water

OXO Stage II

OXO Stage II

ML

Layer Separation

MDC ML Effluent

Recovered

MDC

Drying loss

Effluent

Reactor

Reaction Mass

Reactor

Reaction Mass

Filtration

Cake

Toluene Stage-II

Settling & Seperation

1,3 Thiazolidine

Organic Layer

.

Settling & Separation

TLP Stage I

Working flow sheet for OXO (Stage –III)

Water

DCC+ Toluene

Filtrate

Toluene

Effluent Potassium Hydrogen

Sulphate + Water

Effluent

Cake

Drying

Filtration

Organic Layer

Organic Layer

Cocentration

Organic Layer

Concentrated Reaction

Mass

Concentrated Reaction Mass

Silica Gel

Filtration

Rec.IPA+ Rec.Mintroleum

Final PRODUCT

Sodium

Sulphate

Sodium

Sulphate ML

Recovered

Toluene

IPA

Mintroleum

Silic Gel

Drying Drying loss

Effluent

Effluent

Effluent

Final product: - Phenyl Hydrazine Hydrochloride

Process description of Phenylhydrazine hydrochloride:

Charge aniline to reactor followed by aq.HCl. Chill the mass and add aq. Sodium nitrite

slowly. After diazotization is over; charge diazotized mass to previously prepared

sodium metabisulfite and sodium hydroxide mixture at low temperature. Heat the

mass and charge aq.HCl for hydrolysis purpose. Chill the reaction mass and filter the

crude crop. Purify crude crop using appropriate solvent.

Reaction:-

Reactor

Reactor

Reactor

Codex HCL Aniline

flowsheet for Phenyl Hydrazine Hydrochloride

Chilled water

Water

NaNO2

Reactor

Reactor

Filtration

Reactor

Drying

Effluent

Part – A

Wet crop

Reactor

Water SMBS

Water

NaOH

Codex HCL

.

Reactor

Drying (Phenyl Hydrazine Hydrochloride)

Filtration

HCL

Water

Crude dry crop

Wet crop Effluent

Water (evaporates)

Final product: - Phenyl Hydrazine

Phenyl hydrazine Procedure:

Charge aniline to reactor followed by aq.HCl. Chill the mass and add aq. Sodium nitrite

slowly. After diazotization is over; charge diazotized mass to previously prepared

sodium metabisulfite and sodium hydroxide mixture at low temperature. Heat the

mass and charge aq.HCl for hydrolysis purpose. Chill the reaction mass and filter. Add

water to crude crop followed by toluene. Charge caustic lye to make pH basic.

Separate organic layer and distill out toluene followed by phenyl hydrazine.

Chemistry-Phenyl Hydrazine

Excel Industries Limited

Lote –Parshuram.

Phenylhydrazine :

Chemistry :

Reactor

Reactor

Reactor

HCL Aniline

Working flow sheet for Phenyl Hydrazine

Chilled water

Water

NaNO2

Reactor

Reactor

Reactor

Water Na2S2O3

Part- A

Reactor

Decantation

Reactor

Reactor

Filtration

Organic Layer

Reactor

Caustic Lye 48%

Caustic Lye 48%

Toluene

Effluent

Rec.Toluene

Effluent

Distillation

Final Distillation (Phenyl Hydrazine)

HCL

Wet crop

Water

Residue

Distiln

Residue

Effluent

Product Name : PMPA

Chemistry :

N

N

N

N

NH2

O O

O

CH3

H

N

N

N

N

NH2

OH

+

Adenine RPC HPA

DMA, NaOH

-CO2

N

N

N

N

O POH

OHO

NH2

.H2O

N

N

N

N

NH2

OH

SO2O C

H2

P

OO

O

C2H

5

C2H

5

N

N

N

N

NH2

O PO

OO

C2H

5

C2H

5

N

N

N

N

NH2

O PO

OO

C2H

5

C2H

5

+MTB

HBr

R-9-[2-(hydroxyl)propyl]adenine (HPA)

Diethyl[[(p-toluenesulfonyl)oxy]methyl]phosphonate (DESMP)

DMF, Toluene

PMPE

PMPE (R)-9-[2-(phosphonomethoxy)propyl]adenine.

Process Description :

In a reactor add N, N Dimethyl Acetamide (DMA) at room temperature and start stirring. Then add

Adenine, powdered NaOH and remaining N,N Dimethyl Acetamide (DMA). Heat the reaction mixture and

add R-Propylene Carbonate to the reaction mass. draw a sample to check the absence of Adenine at

appropriate intervals. Cool the reaction mixture. Then transfer the reaction mixture slowly with stirring to

the reactor containing Isopropyl Alcohol (IPA). Stir the reaction mixture at 15oC for 25 min. Filter the

slurry to isolate crude crop of HPA and organic mass. Give washings with Isopropyl Alcohol - IPA to the

filtered crude cake of HPA. Dry the wet cake in oven.

In a reactor add DMF & Toluene & cool with stirring. Cool the mass. Then add 2-Hydroxy propyl adenine

(HPA) followed by Magnesium Tertiary Butoxide & stir. Add Di-ethyl[[(p-

toluenesulfonyl)oxy]methyl]phosphonate (DESMP) slowly under stirring. Slowly heat the reaction mixture.

After heating monitor the Reaction mass quantitatively to see whether HPA is present or not. Continue

aging the mass till HPA comes within desired limit. Stop the heating & cool the reaction mass. Add acetic

acid in the reaction mass and Stir.

Hydrolysis: Add HBr & stir the reaction mass. Then heat the reaction mass with continuous distillation.

Collect the volatile Liquid. Cool the mass. After cooling -keep the reaction mass -in ice bath to precipitate

solid material. Filter the solid & give water washing. To the filtrate add MDC & stir for extraction. After

that take the material in separating Vessel & separate the aqueous & MDC layer. Adjust the required pH

of aqueous layer with sodium hydroxide. Keep the reaction mass in ice bath to get white silky solid material

PMPA. Filter the solid PMPA & give washings with chilled water.

Recrystallization: Take the crude wet PMPA cake for recrystallization. Add water to it & heat. Then cool the

reaction mass to room temperature. White solid starts precipitating. Filter the mass, give washing with DM

water followed by Acetone wash. Dry the solid .check the quality in QC & repack.

Flow

DESMP

Reactor

Dry HCl Mg-t-butoxide DMF

Acetic Acid

Reactor

Caustic Lye

Dry PMPA

HBr By-Product Ethyl

Bromide

Filtration Wash of Chilled Water By Product Mg-Acetate

Reactor MDC

MDC Layer

Reactor

Filtration: Crude crop

By Product NaBr Solution

Water

Acetone

By Product NaBr Solution Filtrate

See Annexure 2

Acetone See Annexure 3

Reaction Vessel

Adenine NaOH flakes

Cooking

DMA

RPC

Reaction mass

Cooling & Filtration

IPA

Crude HPA

Filtrate ML

Wash of Cold

IPA

Drying

Loss on Drying

HPA Toluene

Filtration: Crude crop

Filtration: Crude crop Moisture Loss

See Annexure 1

Process Flow Sheet Diagram For DMA and IPA Recovery Annexure 1

Filtrate ML

Distillation

Residue

Recovered DMA 4650 Kg for Recycle

Loss of DMA

Residue

Process Flow Sheet For Recovery Of MDC. Annexure 2

MDC Layer

Distillation Recovered MDC

Loss

Residue

Process Flow Sheet For Recovery Of Acetone. Annexure 3

Acetone

Distillation Recovered

Loss

Residue

Product Name: PPZ

Chemistry:

Stage I

:

Stage II :


Stage I:

3-Amino crotonitrile reacts with Phenyl hydrazine in aqueous HCl to afford 3-

Methyl-1-phenyl-1H-pyrazol-5-amine which then reacts with Bis(2-

chloroethyl)amine Hydrochloride in presence of Sodium hydride and N,N-

Dimethyl acetamide solvent to afford 1-(3-Methyl-1-phenyl-5-

pyrazolyl)piperazine

Stage II:

Amino pyrazol (Stage - I) , Sodium hydride and Bis (2-chloroethyl) amine. HCL

react in presence of a N,N-Dimethyl N,N-Dimethylacetamide. The obtained

product further purified with Methylene Dichloride and pH of the product is

adjusted with Ammonia solution. The obtained product filtered and dried at

defined temperature under vacuum. Then packed the product in drums lined

with poly bags.

Reactor

Conc.HCL Water

Reactor

Reaction Mass

Reaction Mass

Quenching

Water

Reaction Mass

Filtration

Wet Cake

Water

3-Amino Crotonitri

le

Phenyl Hydrazine

NaOH Flakes

Effluent

Stage I

FLOW CHART PPZ

Reactor

PPZ Stage I

Reaction mass

Reactor

DMA

Drying

Stage II

Sodium Hydride

Bis

(2-chloroethyl) amine

HCL

Reaction mass

Quenching

Water

Filtration

Effluent

Wet Cake

Reactor

MDC

Drying loss

EXCEL INDUSTRIES LTD, LOTE-PARSHURM

Reactor

HCl

Reactor

Layer Separation

Effluent

Organic .Layer

Organic .Layer

Ammonia solution

Filtration

Effluent

Wet Cake

Drying

Dry Cake

Drying loss

44. Product Name: - Pregabelin

Process Reaction:-

Manufacturing Procedure: -

Concentrate the reaction mixture of sovaleraldehyde, Ethylcyanoacetate, Diethyl

Malonate, Di-n-propylamine, n-Hexane and Conc. HCl and recovere Hexan (By-

Product) from reaction mixture. Add Toluene and Water in mass And seperate

layer. Recover Toluene from Organic Layer.

O

O

CN

O

n-Pr2NH

n-heptaneO

O

CNO

O

O

O n-Pr2NH

OO

O

O

O

O

CN

OO O

OH O

NH2

O

OHH

5C

2OOC

COOC2H

5

CH3COCl

NH3, HCl

OH O

O

NH2

NaOBr

OH O

NH2

Tartaric acid

+ +HCl

H2O

Isovaleraldehyde

Diethyl

Malonate

Ethylcyanoacetate

Recovered Hexane

Reaction

Toluene

Concentration

Layer separation

Product

3-isobutyl glutaric acid

Dil HCL By Product

Recovered Toluene

Di-n-

propylamine

n-Hexane

Conc.

HCl

By Product

Water

Toluene

By Product

3-isobutyl glutaric

acid

Water

Acetyl Chloride

Recovered Acetyl Chloride

By-Product

Reaction

Aqueous Ammonia

Concentration

Stirring to Reaction

Mass

Product

(±)-3-(Carbamoylmethyl)-5-

methylhexanoic acid

Filtrate

Filter

Ethyl acetate

Recovered ethyl

acetate, By Product

Aqueous Effluent,

(±)-3-(Carbamoylmethyl)-5-

methylhexanoic acid

R-(1)-Phenylethylamine

Chloroform

Filtrate ML

Reaction under

Stirring

Crude Product

for Recycle

Filtration

Solid 1600 kg

Filtration

Recovered R-(1)-

Phenylethylamine,

Reaction, NaOH soln,

Bromine

Recovered chloroform

Wet Product

(S)-3-(aminomethyl)-5-methylhexanoic acid

(Solid Pregabelin) Scrubber Loss

Effluent

Final product: - Sertaconazole

Reaction:


Stage I & Stage II

1. Charged Chloro thiophenol in Toluene at RT. Charged sodium hydroxide

solution to the reaction mixture. Charged 2-chloro acetone . Charged

water to reaction mixture. Layers separated. charged water to the reaction

mass. Layers separated. charged 10% brine solution to the upper organic

layer .Layers separated.Charged Toluene to the Reactor. charged

Polyphosphoric acid to reaction mixture then heated

2. Charged the Toluene layer to the Poly phosphoric acid. Charged reaction

mixture in ice chilled water .Layers separated. Charged 10% brine solution

.Layers separated. charged water to the upper organic then Layers

separated.

3. Charged water to the upper organic layer.Layers separated. Concentrated

Toluene from the Organic mass.

Stage III

1. Charged Stage II in MDC. Charged N-bromosuccinimide and α, α-

Azoisobutyronitrile. Reaction mixture heated, stirred .

2. Charged water to reaction mixture, Layers separated. Charged 5 %

Sodium thiosulfate solution to the lower organic layer. layers separated.

Charged water to the lower organic layer .Layers separated Filtered the

mass. Concentrated MDC completely at 45-50°C atmospherically. Charged

n-hexane to the obtained residue. Concentrated n-hexane completely

.charged n-hexane to the obtained residue. Cooled the mass. Stirred. Solid

filtered, washed n-hexane and suck dried. Charged n-hexane to the suck

dried solid.

3. washed with n-hexane and suck dried. Dry the mass.

FlowChart of Sertaconazole

Reactor

Reactor

Reactor

Reactor

Reactor

Reactor (Layer Separation)

Organic Layer

Toluene

2-Chlorothiophenol

Water

NaoH+ Water

Water

2-Chloro acetone

Effluent


Organic Layer

Organic Layer (Stage-I)


Effluent

Effluent

Stage-I

Water

Reactor

Reactor

Reactor

Reactor (Layer Sepration)

Reactor

Reactor


PPA

Toluene

NaCl + Water

Water

Stage-I

Water

Ice +Water

Effluent

Reactor

Reactor (Layer Sepration)

Reactor

Effluent

Recovered Toluene

Effluent

Stage-II

Reactor

Reactor

Reactor

Reactor

Reactor

Reactor

Reactor

Stage-II

MDC

Water

N-Bromosuccinimide

)

Reactor

Reactor

Filtration

Reactor

Effluent

Effluent

Stage-III

5% Sodium

thiosulfate solution

Water

Effluent

Stripping

Reactor

Reactor

Filtration

Reactor

Filtration

Reactor

n-hexane

Distillation

n-hexane

Reactor

Filtration

Drying

n-hexane

n-hexane

Recovered n-

hexane

Recovered MDC

n-hexane

Water

evaporates in

drying

Effluent

PRODUCT NAME-SILODOSIN


Addition of Oil (R)-2,3-dihydro-1-(3-hydroxypropyl ) 5-[2-[[2-[2-(2,2,2-trifluoro ethoxy) phenoxy]

ethyl] amino]propyl]-1H-indole-7-carbonitrile, Dimethyl sulfoxide, Sodium Hydroxide , Water and 30

% Hydrogen peroxide solution in reactor. Concentrate the reaction mixture and Recovered

Dimethyl sulfoxide. Then add Ethyl acetate and Water + HCl 5 % soln in Reaction mass. Separate

Aqueous Layer and Organic Layer. Recover Ethyl Acetate from Organic Layer.

Title : PROCESS REACTION OF PRODUCT SILODOSIN ……………

(R)-2,3-dihydro-1-(3-benzyloxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoro ethoxy) phenoxy] ethyl] amino] propyl]-1H-indole-7-carbonitrile.

Methanol

Sodium hydroxide

Reaction

Concentration

Water Ethyl acetate

Layer separation

Oil 1000 Kg . (R)-2,3-dihydro-1-(3-hydroxypropyl ) 5-[2-[[2-[2-(2,2,2-trifluoro ethoxy) phenoxy] ethyl] amino]propyl]-1H-indole-7-carbonitrile

Ethyl acetate layer

Aqueous Layer

Recovered Ethyl acetate

Concentration

Reaction mass

Recovered Methanol

Water

http://www.futuregenerics.com/scripts/atlasgate.dll/foldb/W3Page_ResultShortListRun?xSession_Id=HzcEaUVTUXWxm&xLanguage_Id=ENG&xAction=SHORTLIST_DISPLAYFICHE&xdocid=897774

http://www.futuregenerics.com/scripts/atlasgate.dll/foldb/W3Page_ResultShortListRun?xSession_Id=HzcEaUVTUXWxm&xLanguage_Id=ENG&xAction=SHORTLIST_DISPLAYFICHE&xdocid=897774

Dimethyl sulfoxide

Sodium Hydroxide

Reaction

Concentration

Water + HCl 5 % soln Ethyl acetate

Layer separation

Silodosin

Ethyl acetate layer

Aqueous Layer

Recovered Ethyl acetate Concentration

Reaction mass

Recovered Dimethyl sulfoxide

Water 30 % Hydrogen peroxide solution

Oil (R)-2,3-dihydro-1-(3-hydroxypropyl ) 5-[2-[[2-[2-(2,2,2-trifluoro ethoxy) phenoxy] ethyl] amino]propyl]-1H-indole-7-carbonitrile

Product Name : SIPM


Take 1 mole of IPA into the Reactor. Then add Chlorosulphonic Acid 1.3 moles

into the same reactor.

Heat the mass under continuous stirring. Cool the reaction mass & add 15

moles methanol. Filter the reaction mass by using Sparkler filter and transfer

the mass to another Reactor. Then reflux mass and after cooling add DMF.

and Thionyl Chloride to the reactor. Reflux and Cool the reaction mass. Add

Sodium Sulphate &Cool.

Filter the mass and Centrifuge.

For first purification add process water and then add caustic lye to adjust the

pH. Heat and then filter the mass through sparkler filter & transfer the mass to

another vessel for crystallization. Crystallize the mass in reactor and then

centrifuge the mass to get solid product.

Repeat the same process for second purification. Dry the mass and Pack the

material.

Chemical Reaction

COOH

COOH

COOH

COOHHO3S

COOH

COOHHO3S

COOCH3

COOCH3HO

3S

COOCH3

COOCH3HO

3S

COOCH3

COOCH3NaO

3S

ClSO3H+

Isophthalic acid 5- Sulfoisophthalic acid.

(166) (246)

Step-I )

Step-II)

+ 2 CH3OH + 2H2O

5-Sulfo isophthalic acid. Methanol 5-sulfoisophthalic acid

dimethyl ester.(246) 2(32)(274) 2(18)

Step-III)

2 + Na2SO4

5-Sulfoisophthalic acid

dimethyl ester

Dimethyl-5- sulfoisophthalate

sodium salt

2

2(274)(142)

2(296)

+ H2SO4

(98)

Esterification :-

Salt Preparation :-

Sulphonation :-

+

(36.5)(116.5)

Sulfuric acid

HCl

Chlorosulphonic acid

Sulphonation

Isophthalic Acid

Esterification, Filtration

Chlorosulphonic Acid

Reaction Mass

Filtration of Crude

Washing & Centrifuging

Water 17948 Kg

First Purification.

Filtration

Drying

Dry Product

DMF 5.58 Kg

Methanol

Na2SO4

HCl Scrubber

Filter ML

H2O

Filter ML

Water Distil.

Second Purification

Filtration

Third Purification

Filtration

Water 8974 Kg

Water 6730 Kg

Filter ML

Water Distil.

Filter ML

Water Distil.

Methanol Distil.

Recovered

Methanol

Water

Distill.

Distilled Water ML Crop.

By-product

Spent acid

Distilled Water

Recovered Methanol Water Distillation

Distilled Water

By-product

Spent acid

Distilled Water Used For First Purification.

Recovered Methanol Is Used For Esterification

In Next Charge

Filtration of Crude

Centrifuging

Filter ML

Filter ML

Methanol Distill.

Reaction Mass

(Crude Mass)

Product Name: Sitagliptin.

Process Decription :

Take 2-chloro-5-(trifluoromethyl) -1, 3,4-oxadiazole with methanol and ethylene

diamine in reactor stir the mix and HCL extracted from the mix. Heat the mix and

recover methanol from this mix. Add IPA in the mix and filter the mix. Dry the

wetcake and recover IPA from the filtrate.

Process Reaction:-

O

F

F F

O

O

F

F F

NH

NH2NH

2 NH2

TEACl

O

ClO

F

F F

NH

NH

O

Cl

POCl3

NN

O CF3

Cl

NH2

NH2

NH

N

NN

F3C

Ethyltrifluoro acetate

b.p : 62°C

+

trifluoroacetic acid hydrazide

m.p 112°C

+

+

Step - I

Step - II

Step - III Step - IV

2-chloro-5-(trifluoromethyl)-1,3,4- oxadiazole

3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo [4,3-a]pyrazine hydrochloride

EXCEL INDUSTRIES LTD, LOTE-PARSHURAM

Flowchart:

Reaction

Stirring

Ethylene diamine,

Conc. HCl

Heating

Recovery Recovered methanol

Reaction

IPA

Filtration Filtrate

Recovered IPA

Effluent Product

Drying Product: 3- (trifluoromethyl) -5,6,7,8-tetrahydro-[1,2,4] Triazolo [4,3-a] pyrazine hydrochloride. (Sitagliptin)

Moisture Loss

2-chloro-5-(trifluoromethyl) -1, 3,4-oxadiazole

1250 Kg

Methanol

Name of Product: SOLIFENACIN

Chemical Reaction:

Route of Synthesis:


Solifenacin succinate treated with Sodium carbonate and then isolated to give

Solifenacin base.

Flow chart:

,

Ethyl acetate

Reaction

Reaction

Layer separation

Stirring

Lower aqueous layer

Settling

Lower Aqueous layer

Solifenacin succinate,

Layer separation

20% Sodium carbonate solution

(750 kg Na2CO3 in water)

Ethyl acetate

Organic layer

Combined organic

layers

Upper organic

layer

Water

Effluent

Stirring

Settling

Aqueous layer

Layer separation

Organic layer

Concentartion

Solid n-heptane

Reaction

Filtration

Drying

Solifenacin,

ethyl acetate recovery

Filtrate

n-heptane recovery

Name of the Item: SOLIFENACIN SUCCINATE

Chemical Reaction:

Route of Synthesis:


Stage IV reacted with ethyl chloroformate in presence of triethylamine to afford (1S)-

ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinoline carboxylate (Stage V) which then

undergoes transesterification reaction with (R)-quinclidin-3-ol in the presence of

sodium hydride to give solifenacin base. The base is then treated with succinic acid to

give Solifenacin succinate.

Flow chart:

,

Reaction

Reaction

Triethylamine,

Reaction

Stirring

Reaction

(1S)-1-Phenyl-1,2,3,4-

tetrahydroisoquinoline

Stirring

Aqueous layer

Toluene 1

Layer separation

Ethyl chloro formate

Water

Organic layer 5% HCl solution,

Stirring

Settling

Effluent

,

10% Sodium bicarbonate

solution Reactor

Reaction (R)-3-Quinclidinol,

Reaction

Stirring

Toluene layer

Reaction

Toluene 7900 kg & water

Stirring

Sodium hydride,

Layer separation Organic layer

Aqueous layer Toluene

Stirring

Layer separation

Organic layer

Aqueous

layer

Effluent

Combined organic

layers Water

Stirring

Toluene layer Succinic acid

Stirring

Filtration Filtrate

Solifenacin succinate

Drying Distillation

Rec. Toluene

Product Name: T1

Chemistry:

N

OH

P

O

SH

O

S

S NH2

OH

C2H

5OH P

S

OH

OH

OH+ + 3 H2O + 2 +

p-Cyanophenol E-DTA 4-Hydroxy thiobenzamide Thiophosphoric acidEthanol


Charge O-O-Diethyl Hydrogen Di thio Phosphate ( E-DTA) under nitrogen

condition in a reactor. Add 4-Cynophenol and stir for 15 min, then add 70 ml water.

Start Heating to reach the temp 50 ± 5 °C. Digest the material for 10 Hr at 50 ± 5

°C. Check the 4-cynophenol on HPLC ( 4-CP % = Below 0.5 by external standard).

Cool the mass below 20°C. Adjust the PH by using 10% NaHCO3 Solution ( PH-6

on PH paper). Stir the mass 0.5 Hr. Then add 50 ml MDC to reaction mass & stir

for 15 min. Filter the reaction mass & separate out crude crop. Wash the crude

crop by 300 ml water. Dry the product at 70 °C under vacuum.

Flow Chart :

Reactor

Water E-DTA

4-cyanophenol

Filtration

Crude crop

Effluent stream

Slurry below 20°C

Precipitated product

Filter

Wet Crop

Effluent stream Filtrate

Dry Product

Water for slurry preparation Sodium hydroxide solution (48 %)

.Hydrochloric Acid (35 %)

Effluent stream

Product Name: T2

Chemistry:

S NH2

OH

O

O

O

ClOH

S

N

O

OIsopropyl alcohol

+ + H2O +

p-Hydroxythiobenzamide

ethyl-2-chloroacetoacetate

ethyl-2-(4-hydroxyphenyl)-4-methyl-1,3-thiazloe-5-carboxylate

HCl


Charge Febuxostat T1 into reactor. Charge ethyl-2-choloroacetoacetate to

reactor followed by isopropyl alcohol. Digest the reaction mass at room

temperature for 30 minutes. Heat the reaction mass to attain the temp. 65- 70

OC. During heating reaction mass clarifies followed by precipitation. Continue the

digestion at 65-70OC till free Febuxostat T1 in reaction mass below 0.5 %. Distill

out Isopropyl alcohol (About 80- 85 % of input) taking care of flow ability of

reaction mass and cool the mass below 40O C. Add water in it and stir for one to

two hour for make the mass homogeneous. Filter the mass and dry in oven at 80

C to get moisture content below 0.5 %

Flow Chart:

Febuxostat T1 Ethyl-2-chloro aceto

acetate

Isopropyl alcohol

Reactor

Reactor

Distillation of IPA

Distillate Cool the mass

Stirring

Drying

Finished product

Effluent

Water for making

slurry

HCL

Residue Recovered

IPA

DISTILLATION

Final product: Febuxostat T-3

Chemistry:

S NH2

OH

O

O

O

ClOH

S

N

O

OIsopropyl alcohol

+ + H2O +

p-Hydroxythiobenzamide

ethyl-2-chloroacetoacetate

ethyl-2-(4-hydroxyphenyl)-4-methyl-1,3-thiazloe-5-carboxylate

HCl

MANUFACTURING PROCESS:

Charge Febuxostat T1 into reactor. Charge ethyl-2-choloroacetoacetate to reactor

followed by isopropyl alcohol. Digest the reaction mass at room temperature for 30

minutes. Heat the reaction mass to attain the temp. 65- 70 OC. During heating reaction

mass clarifies followed by precipitation. Continue the digestion at 65-70OC till free

Febuxostat T1 in reaction mass below 0.5 %. Distill out Isopropyl alcohol (About 80-

85 % of input) taking care of flow ability of reaction mass and cool the mass below

40O C. Add water in it and stir for one to two hour for make the mass homogeneous.

Filter the mass and dry in oven at 80 C to get moisture content below 0.5 %

Flow sheet of T3

Reaction

Febuxostat T2 Methane sulphonic

acid

3000 3000

Quenching

Filtration

pH Adjustment

Filtration

Drying

Final Dry Crop

Hexamine

Sodium bicarbonate Water

10000

Effluent

PPA

Water

Effluent

Effluent

Product Name: T4

Chemistry:

HON

S

CH3

O

O

CH3

O

Me

Me

Br

N

S

CH3

O

O

CH3

O

OMe

Me

+

FEB T3m.w. = 291 Isobutyl Bromide m.w. = 137

FEB T4 m.w. = 347

Solvent

K2CO3

+ KBr + KHCO3

(119) (100)


Charge FEB T3 into reactor followed by DMF and stirring started. Then charge

potassium carbonate to the reactor followed by Isobutyl bromide under stirring.

Digest the reaction mass for 10 minutes. Heating of the reaction mass started to

get 80 -85o C. Digestion of reaction mass continues at 80 -85 oC. Cool the

reaction mass to 75 o C. Then add Toluene to the reaction mass under stirring and

mix well for 5 minutes. Add water to the reaction mass under stirring. Layer

separation is to be done and upper layer is toluene layer and bottom layer is

aqueous layer .Upper toluene layer is again washed with water. Toluene layer is

chilled and then Filter the solid from toluene under vacuum and suck dry well

Flow Chart:

Febuxostat T3 N,N Dimethyl

Formamide

Potassium carbonate

Reactor

Reactor

Effluent after all

washing

Organic layer after all

washing

Isobutyl bromide

Toluene

Water washes

Seperation

Filtration

Wet crop Organic mass for

recovery

Finished product

after drying

Distillate

Rec. Toluene

Organic mass for

recovery

Distillation Residue

FEBUXOSTATE –T5

2. Process Reaction

S

N

OMe

Me

O

O

CH3

CH3

O

S

N

OMe

Me

O

O

CH3

CH3

OH .HCl

-HCl

CNH2N

-2 H2O

3. Process Description:

Charge T3 Hydroxyl amine hydrochloride, sodium formate & formic acid in reactor

with constant stirring at RT. Start Heating to reach the temp 105 ± 2 °C. Digest the

material for 04 Hr at 105 ± 2 °C. Cool the mass & Add 150 ml Ethyl acetate to

reaction mass & stir for 15 min. then Add 90 ml water & digest for 0.5 hr . Separate

out the lower aq. layer . Organic Layer is chilled to 5°C for 0.5 Hr. Filter the reaction

mass & separate out crop. Wash the crop by ethyl acetate. Dry the product at under

vacuum.


Quenching

Purification el

Layer Seperation

Organic Layer

Water

Water

Ethyl Acetate

Effluent

Process flow of Febuxostat T5

Reaction

Dried T3 stirring at RT

1250

Potassium carbonate

Dimethyl formamide

Iso butyl Bromide

Hydroxyl amine HCL

Acetyl Chloride

Filtration

Drying

Filtration el

Effluent

Organic Layer

Ethyl Acetate ML

Final product: Febuxostat T-6

Process Description : :

Charge T5 in reactor with methanol and sodium Hydroxide stir fir 30 min. Add water

in the mixture and filter the mix. Again and water with HCL and filter the mixture

and Dry the wet cake to get product. Recovered methanol from Filterate

Réaction :

Ethyl 2-(3-formyl-4-hydroxyphenyl)-4- methyl-1,3thiazole-5carboxylate:

Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4- methyl-1,3 thiazole-5 carboxylate:

(Febuxostat - T5)

Febuxostat: (2-(3-cyano-4-isobutoxy phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid)

OHC

OH

N

S

CH3

O

O

CH3

N

S

CH3

O

O

CH3

OCH3

CH3

NC

3 Ethyl Acetate

1. K2CO3, DMF, Isobutyl Bromide

2. NH2OH.HCl, AcCl

Ethyl-2-(3-Formyl 4-Hydroxy phenyl)4-Methyl-1,3 Thiozole 5-Carboxylate M.W.-291.32

Ethyl 2-(3-Cyano 4-isobutoxy phenyl)4-methyl-1,3 thiozole-5-Carboxylate M.W.-344.42

NC

OCH3

CH3

S

N

O CH3

O

CH3

NaOH

MethanolNC

OCH3

CH3

S

N

OH

O

CH3

Ethyl -2 -( 3 -cyano -4 -isobutoxyphenyl)

-4 -methyl -1, 3 -thiazole -5 -carboxylate 2 -( 3 -Cyano -4 -isobutoxyphenyl)

-4 -methyl -1, 3 -thiazole -5 -carboxylic acid

Molecular formula = C18H20O3N2S Molecular formula = C16H16O3N2S

Molecular wt = 344 Molecular wt = 316

Flow Chart:

Filtration

Charge T5 with methanol and NaoH

Reaction Mass

Clear Filtrate

Reaction Mass

Filtration

Drying

Filtrate

Drying (Final Product)

To recovery of MeOH

Water

Water

Recovered

Methanol

(Recycle)

Effluent

MeOH T 5 NaOH

HCl

Drying loss

Final product: - Teneligliptin

Chemistry:


1-(3-Methyl-1-phenyl-5-pyrazolyl)piperazine (PPZ Stage II) undergoes reductive

amination with 3-[(S)-1-tertbutoxycarbonyl-4-oxopyrrolidin-2-ylcarbonyl]

thiazolidine (OXO stage III) in presence of sodium triacetoxyborohydride as

reagent and toluene as solvent to afford tert-butyl (2S,4S)-4-[4-(3-methyl-1-phenyl-

1H- pyrazoyl) piperazine-1-yl]-2- (1,3-thiazolidin-3-ylcarbonyl) pyrrolidine-1-

carboxylate (TLP Stage I).

tert-butyl (2S,4S)-[4-(3-methyl-1-phenyl-1H- pyrazoyl)piperazine-1-yl]-2- (1,3-

thiazolidin-3-ylcarbonyl)pyrrolidine-1-carboxylate (TLP Stage I) was further

subjected to deprotection using aqueous HBr to afford Teneligliptin

hydrobromide hydrate (TLP Stage II).


Flow sheet of Teneligliptin :

Reactor

Toluene PPZ intermediate

Reactor

Layer Separation

Concentration

Reaction Mass

Distillation

Reaction Mass

Water

Isopropnol

Isopropanol

Reaction mixture 48% aqueous Hydrobromic

acid solution

Filtration

Dryer

Dry Mass

Rec.Isopropanol + Effluent

Filtration

Ethanol

Dryer

Teneligliptin hemipentahydrobromide hydrate

Effluent

Recovered Toluene

Rec.Isopropanol + Effluent

Ethanol

Water

Ethanol ML

Drying loss

Ethanol

Effluent

Distil.loss

Sodium triacetoxy borihydride

OXO

Process Details:

4 – Hydroxy Aceto Phenone and Phenol are reacted using HCl gas as catalyst. The product is

purified by using solvents and dried to get finished product. The solvents are recovered and

recycled in the process.

Final product: - THPE

Reaction:

OH O= C – CH3

3MPA, Dry HCL, NaHCO3

+

OH

( Phenol ) OH

(4-HAP)

OH

OH C CH3 + H2O

OH

(T.H.P.E.)

EXCEL INDUSTRIES LTD.LOTE-PARSHURAM

Flowchart Of THPE:

4- HAP Phenol 3-MPA

Reaction

NaHCO3

Filtration

Phenolic ML

1564 kg

Crude THPE

Hot Aq. Methanol

Wash

Dissolution

Precipitation

Filtration

Wet THPE

Drying & Blending

Final Product

DRY

HCL GAS

Effluent

Methanol

Aq. Methanol ML

Recovered Methanol

Water wash

Aq. Methanol

Distillation

Water

Recovered

Methanol

Phenol

Recovered

Phenol

PCl3 HCl

Reaction

OPA

Distillation

Residue

Distillation

HCl Scrubbing

HCl

(30%)

Water

Drying loss

Effluent

Tricresyl Phosphonate

Process Description

Mixed cresol reacted with Caustic lye in toluene media , formed salt reacted

with Phosphorus oxychloride gives crude product . crude product on

distillation gives Tricresyl Phosphonate .

Process Reaction :

O Cl

Cl

Cl

P +

O H

.

C H 3 NaOH

Toluene +

3 3 Cl Na

phosphorus oxychloride Mixed Cresol Tricresyl phosphonate

[ 153.33 ] 3 [58.44 ] [ 108.14 ]

C H 3

C H 3 C H 3 O

O

O

O P

[ 368.37 ]

Tricresyl Phosphonate: Process flow sheet

EMD

Processing

Distillation

Separation

Tricresyl phosphonate

Conc. mass

EMD

Mix Cresol

POCl3

NaOH + Water

Toluene

Separation

Aqueous layer

Rec. Toluene

Triethyl Phosphate :


Take POCl3 , ethanol and toluene in reactor and stir the mix hence HCL gas

liberated from the mix. Heat the mix and distilled out toluene from the mix.

Concentrate the mass and take the product

Process Reaction :

Process :

Phosphorus trichloride reacted with ethanol, followed by degassing & distillation

gives Triethyl phosphate

Cl

Cl

Cl

O

P + OHCH2CH3

OC2H5

H5C2O

H5C2O

O

P + ClH3

phosphoric trichloride ethanol triethyl phosphate hydrogen chloride

(M.W.= 153.33) (M.W.= 46.06 ) (M.W.= 182.15 ) (M.W.= 36.5 )

3

Triethyl Phosphate: Process flow sheet

EMD

Processing

Distillation

Degassing

Triethyl Phosphate

Conc. mass

HCl gas

Water

EMD 30% HCl

Ethanol

POCl3

Toluene

Rec. Toluene

Prduct Name: - Z 7 Formyl

Manufacvturing Process: -

To a chilled suspension of sodium bicarbonate, potassium bromide and TEMPO

in MDC, add a solution of Z7 dissolved in MDC. Add sodium hypochlorite solution

to the above suspension under controlled condition of temperature. After

completion, organic & aqueous layers were separated and extract the aqueous

layer with MDC. Combined MDC layer is finally washed with sodium sulphite

solution followed by water. MDC layer is concentrated followed by suspension of

residue in hexane results in product isolation after filtration.

Reaction: -

N

N

CH3 CH3

N

S

CH3

OO

CH3F

OH

TEMPO, KBr, MDC

sodium hypochlorite

sodium bicarbonate

N

N

CH3 CH3

N

S

CH3

OO

CH3F

O

H

N-[4-(4-fluorophenyl)-5-formyl-6-(propan-2-yl)pyrimidin-2-yl]-N-methylmethanesulfonamide


H18

FN3O

3S

Formula Weight = 351.3958232Formula Weight = 353.4117032


H20

FN3O

3S

N-[4-(4-fluorophenyl)-5-(hydroxymethyl)-6-(propan-2-yl)pyrimidin-2-yl]-N-methylmethanesulfonamide

Reactor

Z7 MDC

NaHCO3

Reactor

Aqueous layer

Separation &

Distillation

KBr & TEMPO

sodium hypochlorite

Layer separation

MDC layer

MDC layer

n & Drying

MDC

Layer separation

Effluent Aqueous layer

Sodium sulphite

Water

Recovered MDC 17400 kg

Product

Hexane

Filtration

Hexane

Drying

Dry solid

Hexane ML

Effluent

Recovered

Hexane

Distillation

Residue

FLOW CHART FOR Z 7 Formyl

Product Name: - Z 7 Br

Manufacturing Process

Charge Z-7, Toluene, & HBr (48%) in a reactor. Stir the mass & add remaining 175

ml Toluene at RT. Heat the mass up to 110°C. Reflux & cook the mass at 110°C for

3 Hr. Check Z-7 % on HPLC (Z-7 % = ND). Then Cool the mass at RT. In another

reactor, prepared 8% NaHCO3 Solution . Cool the Sodium bicarbonate solution to

20°C. Add above reaction mass slowly to sodium bicarbonate solution at temp 20 –

25°C (About 0.5 Hr) After complete addition stir the mass at 25°C for 0.5 Hr. Settled

the reaction mass to separate out the Aq. Layer & Toluene layer. (Take the Emulsion

in Aq. Layer) Give the two wash of Toluene to the Aq. Layer & this Toluene layer

mixed in First Toluene Layer. Give the two water wash to the Toluene Layer . Give

the two saturated NaCl wash (175 ml X 02 ) to the Toluene layer & separate out the

toluene layer. Dry the mass and pack it.

Reaction: -

N

N OH

N

F

S

O

O

N

N

N

F

S

O

OBr

+ HBr + H2O

Z7 Z7-Br

Z7 Toluene

Aq. HBr 48 %

Heating at elevated temp.

Digest reaction mass at elevated temp.

RT

Cooling of reaction mass

Separation of Aq. and Organic mass

Effluent stream Aq. Mass Organic mass

Separation of aq.

and organic mass

Separation of organic mass

Effluent stream

9 % NaHCO3

Toluene washes

of

Water washes

of

Organic mass

after two water

wash

Sat. sodium

chloride wash of

two times

Effluent stream Sodium

chloride first wash

Effluent streams NaCl

second wash

Filtration through sodium

sulphate

Vacuum distillation

of organic mass

Dried product

Toluene

Effluent stream

Aq. First wash

Effluent stream Aq.

second wash 2000 Kg

Distillation

Residue Recovered

Toluene

FLOW CHART FOR Z 7 Br

Product Name: - Z 8.2


In a GLV Charge Z-7, Toluene, HBr (48%) . Stir the mass & add remaining Toluene

at RT. Heat the mass till reflux started & water collection. Reflux & cook the mass at

for 3 Hr. Check Z-7 % on HPLC. Cool the mass at RT. In another reactor prepared

5% NaHCO3 Solution. Cool the Sodium bicarbonate solution to 20°C. Add above

reaction mass slowly to sodium bicarbonate solution. After complete addition stir the

mass for 0.5 Hr. Settled the reaction mass & take the mass in separating tank to

separate out the Aq. Layer & Toluene layer. Give the two wash of Toluene to the Aq.

Layer & this Toluene layer mixed in First Toluene Layer. Give the two water wash to

the Toluene Layer Give the two saturated NaCl wash to the Toluene layer & separate

out the toluene layer.

Take above Toluene Layer (Z7-Br) in a reactor and Heat the mass up to reflux &

separate out traces of water content. Cool the mass and add TPP in Reaction mass

at & Heat the mass. Cool the mass at RT & Filter the mass. Give Toluene wash to

the crude mass. Dry the product at temp 70°C for 3.0 Hr. & Weigh the product

Reaction: -

N

N OH

N

F

S

O

O

N

N

N

F

S

O

OBr

P

N

N

N

F

S

O

OP

+ HBr + H2O

+Br-

Z7

Z8.2

Z7-Br

Z7 –Br Toluene

Triphenyl phosphine

Heat at elevated temp.

Digest reaction mass at

Elevated temp.

Cooling of reaction mass

Filtration of reaction

mass

Toluene ML Crude Mass

Dry in oven at 70C

finished product Z8.2

Filtrate

Toluene

washes

Distillation

Residual

mass

Recovered

Toluene

FLOW CHART FOR Z 8.2

Product Name: -2,4 Ditertiary butyl phenyl...

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