annexure i terms of referenceenvironmentclearance.nic.in/writereaddata/online/tor/10... · 2017. 5....

M/s. ZCL Chemicals Ltd., Ankleshwar

M/s. Jyoti Om Chemical Research Centre Pvt. Ltd., Ankleshwar

ANNEXURE I

TERMS OF REFERENCE

• Standard TOR Prescribed by MoEF & CC with 5 km study area.

• Baseline data of Ion Exchange (I.)Ltd. for December 2016 to February 2017 will be taken in to account

for EIA Report preparation.



ANNEXURE II LIST OF DIRECTORS

Sr.

No. Name & Address of Directors

Designation Contact detail

1 Mr. Ajay Krishnakant Parikh

Managing

Director

20/301, Gurukrupa, Vithal

Nagar, CHS Ltd., 11th Road,

JVPD Scheme, Vile Parle (W),

Mumbai – 400 049

Phone No. - 022--61539900

2 Mr. Nihar Ajay Parikh

Executive

Director

20/301, Gurukrupa, Vithal

Nagar, CHS Ltd., 11th Road,

JVPD Scheme, Vile Parle (W),

Mumbai – 400 049

Phone No. - 022--61539906

3 Mr Dhiren Shevantilal Shah

Non-Executive

Director,

Independent

Director

Cumbala Hill post Office,

Gamdevi P.Stn, Mumbai –

400026.

Phone No. - 022--61539999

4 Mr. Piyush Maganlal Nathwani

Executive

Director

F 14, Shashwat Complex, Dahej

By Pass Road, Bharuch-392001,

Gujarat

Phone No. - 02646--619405

5

Ms. Anuja Ajay Parikh

Non-Executive

Director

20/301, Gurukrupa, Vithal Nagar

Society, 11th Road, JVPD

Scheme, Vile Parle (W),

Mumbai-400049.

Phone No. - 022—61539999

6 Mr. Hargovind Rathore

Non-Executive

Director,

Independent

Director

7 Mr. Ling Wei Ong Non-Executive

Director



ANNEXURE III A

PLANT LAYOUT



ANNEXURE III B

SITE PLAN



ANNEXURE IV

LIST OF EXISTING PRODUCTS AND THEIR PRODUCTION CAPACITY AS PER CCA

Sr.

No.

Name of Products Existing as per

CCA No.

AWH-72765

(MT/Year)

Group 1 204.3

1 Thrio Pypridil Amide 204.03

Either/ or

product will be

made

2 Ritalinic acid

3 4 - benzyloxy -3- nitrophenylace bromide

4 Zonisamide

5 Modafinil - EP/USP

6 4-Amino-N-[(2 R, 3S)- 3 Amino, 2 hydroxy, 4-

phenyl butyl ] – n – (2 Methyl propyl) benzene

sulfonamide

7 Darunavir

8 Fluvoxamine Maleate

9 Trifluoperazine

10 Methylphenidate

11 R & D Products

12 Dex Methyl Phenidate

13 Chlordiazepoxide

14 Cillastazol

15 7 Hydroxy 1,2,3,4 tetra hydro quenoline

16 Chloro Methyl cyclo propane

17 1-(2,3 dichloro phenyl) - piperazine

hydrochloride (DCPP)

18 BBQ (7-(4-Bromobutoxy)-3, 4-

dihydroquinolin-2(1H)-one)

19 T2551 - Etravirin Inter

20 Canagliflozicin Inter (n-2): 2-(4-fluorophenyl)-

5-(5-iodo-2-methylbenzyl)thiophene

21 Aripiprazole

22 BET (1-(2-Bromoethyl)-4-ethyl-1,4-dihydro-

5H-tetrazol-5-one)

23 1-Amino Indane

GROUP – 2 42.03

24 Trimethyl pyruvic Acid AND/OR 42.03



Sr.

No.


CCA No.

AWH-72765

(MT/Year)

25 4,4’-Diflurobenzhydryl Piperazine

26 2 Tri Pheno trimethyl phenothiazine

27 Levomepromazine

28 Betahistine IP / EP / USP

29 Betahistine Mesylate JP/EP

GROUP – 3 23.1

30 Phenyl 2 Piperidyl Acetamide 23.1

Either/ or

product will be

made

31 N- (1 Benzyl 4 Piperidinyl) N Phenyl

Propanamide HCL / NN Phenyl N 4 Piperidinyl

Propanamide HCl

32 N Acetyl Hydroxy Phenyl Piperazine

33 Amino Ethyl Phosphoric Acid

34 (1-Isopropyl-4-(hydroxyl Phenyl) (piperazine)

35 Memantine HCl

36 Quetiapine Fumerate

GROUP –4 23.266

37 Phenyl 2Pyridyl Acetamide 23.266

Either/ or

product will be

made

38 Zaltoprofen

39 Alprazolam

40 Mono chloro acetonitrile

GROUP –5 : Individual Product 12.48

41 BOC Nitro 0

42 (N-[4-Methoxymethyl)-1-(phenyl methyl)-4-

Piperdinyl]-N-Phenyl Propanamaide-

Ethanedioate.

0.06

43 Dex Ritalinic Acid 0.1

44 Remi N Benzyl Propeonamide eater Oxalate 0.02

45 Nebivolol 0.1

46 Flurbiprofen 0.4

47 Olanzapine 0.4

48 Levodropropizine 0.5

49 Atomoxetine 0.5

50 Felbiprofen 3

51 Clozapine 1.8

52 Diazepam 0.4

53 Oxazepam 0.4



Sr.

No.


CCA No.

AWH-72765

(MT/Year)

54 Flupirtine maleate 0.4

55 Bromazepam 0.4

56 Benzhydrl Piprazine 4

Total 304.906

Product list after expansion

Sr. No Product Name CAS No. Proposed

quantity

CNS Active API/Intermediates: 225 TPA

225 TPA

Either/ or

product will

be made

1 Thrio Pypril Amide 50288-62- 5

2 Ritalinic acid 19395-41- 6

3 Zonisamide - USP 68291-97- 4

4 Modafinil - EP/USP 68693-11- 8

5 Fluvoxamine Maleate- EP/BP/USP/JP - FLX/MDD 61718-82- 9

6 Trifluoperazine - USP/EP/BP 440-17- 5

7 Methylphenidate - USP/EP 298-59- 9

8 Dex Methyl Phenidate 19262-68- 1

9 Chlordiazepoxide 58-25-3

10 7 Hydroxy Quinoline 22246-18-0

11 1-Chloromethyl cyclopropane 5911-08-0

12 1-(2,3 dichloro phenyl) - piperazine hydrochloride (DCPP) 119532-26- 2

13 7-(4-Bromobutoxy)-3, 4-dihydroquinolin-2(1H)-one (BBQ) 129722-34-5

14 Aripiprazole 129722-12- 9

15 1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5h-tetrazol-5-one

(BET)

84501-67-7

16 1-Amino Indane 34698-41-4

17 4,4’-Diflurobenzhydryl Piperazine 27469-60- 9

18 2 Tri Pheno trimethyl phenothiazine 92-30- 8

19 Levomepromazine 7104-38- 3

20 Betahistine 5579-84- 0

21 Betahistine Mesylate JP/EP - 54856-23-4

22 Phenyl 2 Piperidyl acetamide 19395-39- 2

23 N- (1 Benzyl 4 Piperidinyl) N Phenyl Propanamide HCL /

NN Phenyl N 4 Piperidinyl Propanamide HCl - (FC

1002/1003)

5156-58- 1

24 Memantine HCl 41100-52- 1

25 Quetiapine Fumerate 111974-72- 2




quantity

26 Phenyl 2Pyridyl Acetamide 7251-52- 7

27 Alprazolam 28981-97- 7

28 Mono chloro acetonitrile 107-14-2

29 Remi N Benzyl Propeonamide eater Oxalate 61085-73- 2

30 Olanzapine 132539-06- 1

31 Benzhydrl Piprazine 841-77-0

32 Alpha-phenylpiperidine-2-acetic acid (KMP) 19395-41-6

33 Fluvoxamine Oxalate (OXA) NA

34 5-methoxy-p-trifluoromethylvalerophenone-oxime (XIA) 61747-22-6

35 1,2,4-Triazolo[4,3,a]pyridine-3(2H)-one (TZP)

36 4-amino-2-methyl-10H-thieno[2,3b] [1,5]-benzodiazepine

hydrochloride (AMB)

138564-60-0

37 Lurasidone Hydrochloride 367514-88-3

38 2-bromo-3-(2,3-dimethylphenyl)butanal (MPB) 1421259-21-3

39 Brexpiprazole 913611-97-9

40 Nicorandil 65141-46-0

41 Quinfamide 62265-68-3

Group 2- Psychodynamic Substances

42 (N-[4-Methoxymethyl)-1-(phenyl methyl)-4-Piperdinyl]-N-

Phenyl Propanamaide,- Ethanedioate. (SUE / SU 10)

61086-13- 3

25 TPA Either/ or

product will

be made

43 Dex Ritalinic Acid 1382859-13-3

44 Atomoxetine 82248-59- 7

45 Diazepam 439-14-5

46 Oxazepam 604-75-1

47 Flupirtine maleate 75507-68-5

48 Bromazepam 1812-30-2

49 Nebivolol 152520-56-4

50 Levodropropizine - EP 99291-25-5

51 Clozapine 5786-21- 0

52 Eslicarbazepine Acetate 236395-14-5

Anti Asthmatic Intermediates: 40 TPA

53 4 - benzyloxy -3- nitrophenacyl bromide 43229-01- 2 40 TPA Either/ or

product will

be made

54 4-benzyloxy-3-nitrostyreneoxide (NSO) 51582-41-3

55 2-(2[3-(3-[2-(7-chloroquinoline-2-yl)ethenyl)phenyl)-3-

hydroxy-n-propyl]phenyl)-2-propan-1-ol (SMKT)

142569-70-8

Anti Viral API/ Intermediates: 200 TPA

56 Di Amino (BOC 1/ DRV II) 169280-56-2 200 TPA Either/ or

product will

be made

57 Darunavir 635728-49-3

58 T2551 - Etravirin Intermediate 269055-15-4

59 BOC Nitro 191226-98- 9

Antidiabetic API: 100 TPA




quantity

60 Canagliflozin Inter (n-2): 2-(4-fluorophenyl)-5-(5-iodo-2-

methylbenzyl)thiophene

842133-18-0 100 TPA Either/ or

product will

be made

61 Dapagliflozin 461432-26-8

62 Empagliflozin 864070-44-0

Antiinflammatory API

63 Zaltoprofen 74711-43- 6

75 TPA Either/ or

product will

be made

64 Flurbiprofen 5104-49-4

65 Felbinac - JP/BP 5728-52- 9

66 Loxoprofen Sodium 80382-23-6

67 Naproxen Sodium 26159-34-2

Miscelleneous groups: 125 TPA

68 Mirabegron 223673-61-8

125 TPA Either/ or

product will

be made

69 Deferasirox 201530-41-8

70 Colesevelam 182815-44-7

71 Tricyclo [3.3.1 13, 7] decan-1- aminium, N, N, N-Trimethyl

hydroxide (TMA)

NA

72 N, N-Dimethyl- 3, 5-dimethyl piperidinium hydroxide (TMP) NA

73 Pirfenidone 53179-13-8

74 Apalutamide (CAP/CBF) 956104-40-8

75 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-

1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide

(BAN/Rivaroxaban)

366789-02-8

76 Trimethyl pyruvic Acid 815-17-8

77 N Acetyl Hydroxy Phenyl Piperazine 67914-60-7

78 Amino Ethyl Phosphoric Acid 071-23-4

79 (1-Isopropyl-4-(hydroxyl Phenyl) (piperazine) 67914-97-0

80 Cilastazol 73963-72- 1

81 R & D Products

Total 790 TPA

*NA-Not Available



ANNEXURE- V

DETAILS OF RAW MATERIAL CONSUMPTION

Product Name Sr.No Name of chemicals Unit

RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

Group 1- CNS Active API/Intermediates

Threo Pypridyl

Amide

1 2-Phenyl-2-[piperidine-2-yl]

acetamide Kg 2.150

30.650 638.542 2 Acetone Lit 15.550

3 Sodium bicarbonate Kg 5.550

4 Sulphuric acid Kg 2.850

5 Sodium Hydroxide Kg 4.550

Ritalinic acid

1 2-Phenyl-2-[piperidine-2-yl]

acetamide (PPAC) Kg 1.350

9.666 201.375

2 Caustic Flakes Kg 4.050

3 Hydrochloric Acid CP Kg 3.050

4 Acetone Kg 0.506

5 Act. Carbon Kg 0.020

6 Hyflow Kg 0.015

7 Liq. Ammonia Lit 0.675

Zonisamide

1 4-Hydroxycoumarin Kg 1.953

41.585 866.354

2 Hydroxylamine Hydrochloride Kg 2.930

3 Potassium Acetate Anhydrous Kg 4.130


5 Conc. Hydrochloric acid Kg 7.800

6 Chlorosulphonic Acid Kg 1.200

7 Sodium sulphate anhydrous Kg 0.782

8 Phosphorus Oxychloride Kg 0.200

9 Ammonia gas anhydrous Kg 1.300

10 Hyflowsupercell Kg 0.125

11 Activated Charcoal Kg 0.312

12 Acetone Lit 1.500

13 1,4-Dioxane Kg 0.970

14 Toluene Lit 3.000

15 1,2-Dichloroethane Kg 7.000

16 Dichloromethane Kg 4.900

17 Methanol Lit 1.530

Modafinil 1

(2-

[(diphenylmethyl)thio]acetami

de)

Kg 1.182 30.528 636.000

2 Hydrogen Peroxide (35%) Kg 0.535




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

3 Acetic acid Lit 3.546


Fluvoxamine

Maleate

1 4'-(trifluoromethyl)-5-methoxy

Valerophenone Kg 2.000

43.300 902.083

2 Hydroxyl amine hydrochloride Kg 0.800

3 2-chloro ethylamine

hydrochloride Kg 1.500

4 Sodium hydroxide Kg 3.000

5 methanol Lit 1.000

6 Di methyl formamide Lit 10.000

7 Di-chloro methane Lit 10.000

8 hexane Lit 15.000

Trifluoperazine

Hydrochloride

1 TPZ Kg 0.650

15.060 313.750

2

1-(3- Chloro Propyl)-N Methyl

Piperazine 2 Hydrochloric

Acid

Kg 1.716


4 Potassium Hydroxide Kg 0.312

5 Toluene Lit 6.400

6 Sodium Sulphide Kg 0.130

7 Diethyl Sulphoxide Kg 0.325

8 Acetic Acid Lit 0.065

9 Celite Kg 0.050


11 Methanolic Hydrochloric Acid

(10– 12%) Lit 2.294

Methylphenidate

1 PPAC Kg 1.000

5.840 121.667


3 Dry Hydrochloric Acid Kg 0.400

4 Methyl Isobutyl Ketone Kg 2.000


Dex Methyl

Phenidate

1 d-Threo ritalinic acid

hydrochloride (KMO) Kg 0.953

17.822 371.292

2 Thionyl chloride Kg 0.953

3 Methanol Kg 4.765

4 Methylene Dichloride Kg 5.718


6 Isopropyl Alcohol Kg 5.242

7 Isopropyl Alcohol-

Hydrochloric Acid Kg 0.858

Chlordiazapoxid 1 2-Amino-5- Kg 2.62 47.000 979.167




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

e chlorobenzophenone

2 Hydroxylamine hydrochloride Kg 2.46

3 Pyridine Lit 6.48

4 Ethanol Lit 1.54

5 Diethyl ether Lit 1.08

6 Petroleum Ether Lit 1.08

7 Glacial Acetic acid Lit 1.13

8 Chloroacetyl chloride Lit 1.21

9 25%Methanolic methylamine Lit 1.42

10 Methylene Dichloride Lit 10.14


12 Sodium sulphate Kg 0.2

13 Methanol Lit 7.5

7 Hydroxy

1,2,3,4 Hydroxy

Quenoline

1 3-Methoxyaniline Kg 1.600

39.260 817.917

2 3-chloropropanoyl chloride Kg 1.660

3 Toluene Kg 24.000

5 Anhydrous aluminum chloride Kg 6.400

6 Methanol Kg 4.000

7 Sodium carbonate Kg 1.600

Chloromethyl

cyclopropane

1 Cyclopropyl methanol Kg 5.000

25.500 531.250

2 N-Chloro succinimide Kg 10.200

3 Dimethyl sulfide Kg 2.800

4 Methylene dichloride Lt 2.500

5 5% Aq Sodium bicarbonate

solution Lt 5.000

1-(2,3 dichloro

phenyl) -

piperazine

hydrochloride

(DCPP)

1 DCPP Base Kg 1.020

5.590 116.458 2 Isopropyl Alcohol Kg 4.009

3 Conc. Hydrochloric Acid Kg 0.561

7-(4-

Bromobutoxy)-3,

4-

dihydroquinolin-

2(1H)-one

(BBQ)

1 7-HQ Kg 1.160

32.480 676.667

2 Potassium carbonate Kg 1.160

3 1,4-Dibromobutane Kg 4.640

4 DMF Kg 1.160

5 Toluene Kg 17.400

6 Cyclohexane Kg 6.960

Aripiprazole 1

7-Hydroxy-3,4-

dihydroquinolin-2(1H)-one (7-

HDQ)

Kg 0.770 40.591 845.646

2 1-Bromo,4-Chloro Butane Lit 4.850




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

3 n-Propanol Lit 3.850


5 Cyclohexane Lit 7.700

6 Sodium Iodide Lit 0.033

7 1-(2,3-Dichlorophenyl)

piperazine Hydrochloride Kg 1.090

8 Ethanol Lit 21.000

9 Tetra butyl ammonium

bromide Lit 0.092

10 Triethylamine Lit 0.810


1-(2-

bromoethyl)-4-

ethyl-1,4-

dihydro-5h-

tetrazol-5-one

(BET)

1 EDTO Lit 2.000

29.500 614.583

2 1,2-Dibromoethane [EDB] Lit 16.000

3 Methyl Isobutyl Ketone Lit 2.080



7 Sodium chloride Kg 3.360

1-Amino Indane

/ AMI

1 1-Indanone Lit 1.76

29.304 610.500

2 Hydroxylamine hydrochloride Lit 1.02

3 sodium hydroxide Kg 0.53


5 Raney Ni Kg



8 ammonia Lit 2.20

9 Hydrochloric Acid Lit 0.21

10 Hyflo powder Kg 0.18

4,4’-

Diflurobenzhydr

yl Piperazine

(DBP / DFBHP)

1 4,4 difluoro benzhydrol Kg 1.480

25.280 526.667

2 Thionyl Chloride Kg 1.600


4 Piperazine Anhydrous Kg 2.600



2 Tri Pheno

trimethyl

phenothiazine

(TPZ)

1 ABT Kg 0.250

3.048 63.496

2 Formic Acid Kg 0.084

3 Bromo Benzene Kg 0.484

4 Copper Carbonate Kg 0.012

5 Potassium Carbonate Lit 0.165

6 Caustic Flask Kg 0.082

7 Iodine Kg 0.006




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

8 Sulphur powder Lit 0.042

9 MCB Kg 0.136



12 Sodium Thiosulphate Kg 0.003

13 Charcoal Kg 0.004

Levomepromazi

ne Maleate

(LMM / LMZ)

1 2-Methoxy Phenothiazine Kg 2.270

27.783 578.819

2

Side Chain (3-Dimethylamino-

2-methyl propyl chloride hydro

chloride )

Kg 2.390

3 Caustic Soda Flakes Kg 1.698

4 Toluene Kg 10.862

5 Pot. Hydroxide Flakes Kg 1.112

6 Dimethyl Sulfoxide Kg 1.732

7 Sodium Chloride Kg 1.816


9 Dibenzoyl-L-tartaric acid

monohydrate Kg 2.815

10 Maleic Acid Kg 0.522

11 Acetone Kg 1.431

Betahistine

Dihydrochloride

( BST / BSI)

1 Pyridine-2-ethanol Kg 1.810

31.430 654.792

2 Phosphorus tri bromide Kg 3.980


4 Sodium bi-carbonate Kg 1.070

5 Methyl amine 40% aqueous

solution Kg 0.570

6 Isopropyl alcohol

Hydrochloric Acid (15%) Lit 7.000

7 Isopropyl alcohol Lit 6.000

Betahistine

Mesylate (BSM)

1 2-Vinylpyridine Kg 0.592

16.314 339.870

2 Monomethylamine

Hydrochloric Acid Kg 0.760

3 Chloroform Kg 2.960

4 Hydroquinone Kg 0.030

5 Acetic acid Kg 0.148


7 Isopropyl alcohol Kg 10.560

8 Methane sulphonic acid (LR

Grade) Kg 0.836

Phenyl 2

Piperidyl

1 Sulfuric Acid Lit 5.400 15.747 328.063

2 PPAN Kg 1.000




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

acetamide

(PPAC / PHA /

PAC)


5 Carbon Kg 0.218

6 Hyflow Kg 0.012

7 PPAC/02 Stage - II Kg 1.000


9 Palladium Charcoal Kg 0.208

N- (1 Benzyl 4

Piperidinyl) N

Phenyl

Propanamide

HYDROCHLOR

IC ACID / NN

Phenyl N 4

Piperidinyl

Propanamide

Hydrochloric

Acid - (FC

1002/1003)

1

N-(1-benzylpiperdin-4-yl)-N-

phenylpropanamide

Hydrochloric Acid

Kg 1.450

21.915 456.563


3 Palladium carbon Kg 0.050


5 Hydrogen gas Kg 1.450

7 1-Benzyl-N-phenylpiperidin-4-

amine Kg 1.560

8 Propanoic anhydride Kg 1.250

10 Sodium Carbonate Kg 1.005

11 Methylene chloride Lit 5.500

12 Hydrochloric acid Kg 2.150

Memantine

Hydrochloric

Acid (MMT /

MNT / MMN /

PRK / ADA)

1 Acetonitrile Lit 8.150

46.410 966.875

2 Sulphuric acid Lit 14.550

3 Toluene Lit 1.550

4 Sodium Bicarbonate Kg 1.950


6 Hexane Lit 1.560


8 Monoethylene Glycol Lit 1.550

9 Diisopropyl ether Lit 2.500

10 Hydrogen chloride gas Kg 0.750


12 1,3-Dimethyl Adamantane Kg 1.950

Quetiapine

Fumerate (QTP)

1 Dibenzo[b,f][1,4]thiazepin-

11(10H)-one Kg 1.013

40.474 843.198

2 Phosphorus Oxychloride Kg 0.753

3 N,N-Dimethyl Aniline Kg 1.055

4

1-(2- hydroxyethoxy)

ethylpiperazine

dihydrochloride

Kg 1.200

5 Toluene Lit 5.098





RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

7 Sulfolane Lit 3.979

8 Ethyl acetate Lit 5.918


10 Fumaric acid Kg 0.318

Phenyl 2Pyridyl

Acetamide

(PPA)

1 PPAN Kg 1.500

19.830 413.125 2 Sulfuric Acid 98 % Kg 6.100


4 Caustic Soda Kg 5.600

Alprazolam (

PRO / APZ)

1

7-Chloro-5-phenyl-2-thioxo-

2,3-dihydro-1H-1,4-

benzodizaepine

Kg 1.960

28.460 592.917 2 Acetohydrazide Kg 3.000




Mono chloro

acetonitrile

(MCAN)

1 Methyl chloroacetate Kg 4.80

22.400 466.667

2 Aq. Ammonia L 9.60

4 DPO L 1.40


6 10% Aq. Sodium carbonate Kg 1.90

Remi N Benzyl

Propeonamide

eater Oxalate

(RPO)

1

4- ( Phenyl Amino) 1- (Phenyl

Methyl)-4 Piperdinecarboxylic

acid

Kg 1.000

94.271 1963.979


3 Toluene Kg 23.920

4 Potassium Carbonate Kg 1.740

5 Methane Sulphonic Acid Kg 2.000

6 Con. Hydrochloric Acid Kg 6.000

7 Sodium Sulphate Kg 0.021

8 Propionic Anhydride Kg 2.000

9 Ethyl Acetate Kg 16.500

10 Anhydrous Oxalic Acid Kg 0.030

11 Hyflow Kg 1.660

12 Ammonia Kg 10.000

Olanzapine

(ZAP)

1 2-Amino-5-methylthiophene-

3-carbonitrile Kg 1.450

148.779 3099.563 2 2-fluoronitrobenzene Kg 1.520

3 Sodium hydride(60% in

mineral oil) Kg 0.690

4 Tetrahydrofuran Lit 15.550




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

5 30% Hydrochloric acid Lit 6.250

6 Methylene chloride Lit 70.465

7 Stannous chloride Kg 2.950

8 Dimethyl sulphoxide Lit 7.050

9 N-methylpiperazine Lit 5.250


11 Sodium Chloride Kg 6.500


Benzhydryl

Piperazine

(BHP)

1 BHPCL Kg 2.832

13.189 274.771

2 Toluene Lit 6.920

4 Sodium Bicarbonate Kg 1.000


6 Soda Ash Kg 0.085

7 TBAB Kg 0.400

8 Piperazine Kg 0.012


10 Carbon Kg 0.260

11 Hyflow Kg 0.030


Alpha-

phenylpiperidine

-2-acetic acid

(KMP)

1 Alpha-Ph-2-Piperidine Acetic

Acid (Kmn) Kg

1.111

2.985 62.196 2 Hydrochloric Acid CP Grade Kg 1.341

3 Caustic Soda Flakes Kg 0.533

Fluvoxamine

Oxalate (OXA)

1 4'-(Trifluoromethyl)-5-

methoxy Valerophenone Kg 0.874

38.479 801.648

2 Hydroxylamine Hydrochloric

Acid Kg 0.348

3 Sodium Carbonate Heavy

Granular Kg 0.474


5 Hexane Lit 0.956

6 Distilled Hexane of MDD

Stage-1 Lit 5.701

7 Sodium Sulphate (Anhydrous) Kg 0.437

8 Di Methyl Sulphoxide Kg 3.779

9 Potassium Hydroxide Flakes Kg 0.756

10 OXA-1 Kg 0.756

11 2-Chloro Ethyl Amine

Hydrochloric Acid-70% Kg 0.567


13 Recovered Toluene of OXA Lit 5.510




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

Stage-2

14 Oxalic Acid Kg 0.348

15 Toluene ML of OXA Stage-2 Lit 9.184

5-methoxy-p-

trifluoromethylv

alerophenone-

oxime (XIA)

1 4'-(Trifluoromethyl)-5-

methoxy Valerophenone Kg

1.180

18.926 394.292

2 Hydroxylamine Hydrochloric

Acid Kg

0.470

3 Sodium Carbonate Heavy

Granular Kg

0.640


5 Hexane Lit 1.290

6 Distilled Hexane of MDD

Stage-1 Lit

7.696

7 Sodium Sulphate (Anhydrous) Kg 0.590

1,2,4-

Triazolo[4,3,a]py

ridine-3(2H)-one

(TZP)

1 Urea Kg 1.873

14.215 296.140

2 Hydrazine hydrate Kg 1.949

3 Methanol Kg 2.918

4 TZP-I Kg 2.500

5 2-Chloropyridine Kg 1.680

6 Con H2SO4 Kg 0.125

7 2-ethoxy ethanol (2-EE) Kg 3.170

4-amino-2-

methyl-10H-

thieno[2,3b]

[1,5]-

benzodiazepine

hydrochloride

(AMB)

1 2-Amino-5-Methylthiophene-

3-Carbonitrile

Kg 0.860

84.138 1752.876

2 1-Fluoro-2-Nitrobenzene

(FNB)

Kg 0.922



5 Di Methyl Formamide Lit 0.043

6 Olanzapine Intermediate

(AMB-1)

Kg 1.569


8 Raney Nickel Catalyst Kg 0.157

9 Hydrogen Gas Cylinder Kg 0.118

10 Hydrochloric Acid CP Grade Lit 3.686


12 Hyflo Super Cell Kg 0.115

13 Hydrogenated mass of AMB Lit 5.118

14 Olanzapine Intermediate

(AMB-2)

Kg 1.177

Lurasidone

Hydrochloride

(SID)

1 BOI Kg 1.041

22.632 471.492 2 MID Kg 0.427

3 Pottasium carbonate Kg 0.390




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

4 Anisole Kg 4.122

5 Denatured alcohol Kg 3.289


7 SID-I Kg 1.020

8 METHYLENE DICHLORIDE Kg 8.553

9 Aq. Hydrochloric Acid Kg 0.255

10 Acetone Kg 3.223

2-bromo-3-(2,3-

dimethylphenyl)

butanal (MPB)

1 2,3-Dimethyl bromobenzene Kg 1.950

45.389 945.594

2 Magnesium turnings Kg 0.350

3 Tetrahydrofuran (THF) Kg 2.622

4 Toluene Kg 18.143

5 Acetone Kg 1.500

6 Heptanes Kg 1.250

7 Conc. Hydrochloric acid Kg 1.133

8 Ammonia solution Kg 0.035

9 4A° Molecular sieves Kg 0.100

10 MPB-I Kg 1.100

11 Phosphorous oxychloride Kg 2.142

12 Dimethyl formamide Kg 1.000


14 Hydrogen Kg 0.083

15 5% Palladium on carbon (50%

wet), on dried basis Kg

0.054

16 Triethyl amine Kg 0.038

17 4-Dimethylamino pyridine Kg 0.110

18 Activated charcoal Kg 0.294

19 Morpholine Kg 0.459

20 Bromine (Br2) Kg 0.900

21 Ethyl acetate Kg 8.299


23 Sodium thiosulphate x 5H2O Kg 0.110

24 Nitrogen gas Kg 1.295

25 Triethanol amine Kg 0.004

26 2,6-di-tertbutyl-4-methyl

phenol [BHT] Kg

0.004

Brexpiprazole

(REX)

1 7-Hydroxy-1H-quinolin-2-one

(HOQ) Kg

2.206

131.379 2737.065 2 Potassium carbonate Kg 2.110

3 1-Bromo-4-chlorobutane Kg 7.117

4 Methanol Kg 24.975




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)


6 Silica Gel Kg 1.434

7 REX-I Kg 0.662

8 BTP Kg 0.735

9 Sodium iodide Kg 0.441

10 DMF Kg 7.353

11 Magnesium sulfate Kg 0.152

12 REX-II Kg 1.111

13 Ethanol Kg 5.555

14 4-Chlorobenzo[b]thiophene

(BBT) Kg

0.857

15 N-Boc-piperazine (NBP) Kg 2.191

16 Sodium t-butoxide Kg 0.684

17 (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP)

Kg

0.048

18 DISOPROPYL

ALCOHOLlladium

tris(dibenzylideneacetone)

Kg

0.046

19 Toluene Kg 15.956



22 Ammonia solution Kg 0.086

23 BTP-I Kg 0.699

24 Conc Hydrochloric Acid Kg 0.288

Nicorandil

1 Toluene Lit 4.00

28.02 6305.09

2 Methanol Lit 1.19

3 Nicotinic acid Kg 1.19

4 Thionyl chloride Lit 1.43

5 Dimethyl formamide Lit 0.03


7 Liquor ammonia LR grade Lit 1.81

8 Monoethanolamine Lit 1.04

9 Nico amide Kg 1.67

10 Fuming nitric acid Kg 3.00


12 Mythelychloride Lit 4.00

13 Isopropanol Lit 4.00


Quinfamide 1 DTHQ Kg 0.88 15.99 3598.41




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

2 2-Furoic Acid Kg 0.47

3 Thionyl Chloride Kg 0.66

4 Ethylene Dichloride Lit 0.00


6 Triethylamine Lit 0.62

7 Sodium Bicarbonate Lit 0.66

8 Sodium Sulphate Anhydrous Kg 0.21

9 Caustic Lye Lit 2.35


11 Ethyl Acetate Lit 4.00


13 Activated Carbon Special

Grade Kg 0.12

Total RM of Group 1 in

worse case

28.02 6305.09

Group 2-Psychodynamic Substances

(N-[4-

Methoxymethyl)

-1-(phenyl

methyl)-4-

Piperdinyl]-N-

Phenyl

Propanamaide, -

Ethanedioate.

(SUE / SU 10)

1 Nitril Kg 5.627

384.312 8006.492

2 Con. Hydrochloric Acid Lit 12.545

3 Stage-I Kg 4.180

4 Ethylene Glycol Kg 13.330

5 Potassium hydroxide Kg 2.600




9 Stage-II Kg 3.655


11

Red AL (60-65% Solution in

toluene) Net : Sodium bis(2-

Methoxy ethoxy) aluminum

hydride

Kg 10.310

12 10% Sodium Hydroxide

solution Kg 124.050


14 Stage-III Kg 3.260

15 Benzyl triethyl ammonium

chloride Kg 0.172

16 Dimethyl sulfate Kg 1.140

17 Stage-IV Kg 2.236

18 Propionic anhydride Kg 3.636

19 Ammonia Lit 14.450

20 Stage– V Kg 0.909





RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

22 Activated Carbon Kg 0.042

23 Oxalic Acid Kg 0.312

Dex Ritalinic

Acid (KMO)

1 d,l-Threo ritalinic acid Kg 2.17

48.697 1014.521

2 Oxalic acid dihydrate Kg 1.738

3 (+)Dibenzoyl-D-tartaric acid

monohydrate Kg 3.96

4 Methanol Kg 15.99

6 Toluene Kg 8.02

7 Con Hydrochloric Acid Kg 0.854

8 Acetone Kg 15.97

Atomoxetine

(ATO)

1 N-methyl-3-Hydroxy-3-phenyl

propyl amine Kg 2.929

147.553 3074.021

2 2-Fluorotoluene Kg 5.870


4 Oxalic acid dihydrate Kg 2.284

5 S-(+)- Mandelic acid Kg 1.098

6 Sodium Hydroxide flakes Kg 0.482



9 Dimethyl sulphoxide Lit 20.500



12 Di isopropyl ether Lit 3.618

13 Acetonitrile Kg 16.310

14

Isopropyl alcohol

Hydrochloride

(NLT 22.0%)

Lit 1.206

Diazepam

1

2-N-methylamino-5-

chlorobenzo

phenone

Kg 1.600

101.960 2124.167 2 Chloro acetyl chloride Kg 1.000

3 Hexamethylene tetra amine Kg 3.360



Oxazepam

(OXP)

1 2-Amino-5-

chlorobenzophenone Kg 2.030

154.090 3210.208

2 Chloro acetyl chloride Kg 1.190

3 acetic anhydride Kg 3.300

4 acetic acid Kg 3.290

5 hydrogen peroxide Kg 1.460

6 HMTA Kg 3.330

7 Ammonium acetate Kg 1.830





RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)




13 DIMETHYL SULFOXIDE Lit 33.130

Flupirtine

Maleate (FLP)

1 ACNP Kg 1.000

43.010 896.042

2 4-Fluorobenzyl amine Kg 1.050


5 Isobutanol Lit 11.500

6 Raney Ni Kg 0.150

7 Hydrazine hydrate Kg 12.000

8 TBAB Kg 0.050

9 Ethyl chloroformate Kg 1.260

10 Maleic acid Kg 1.500


Bromazepam

(BRM)

1 2-(2-Aminobenzoyl)-pyridine Kg 1.450

96.960 2020

2 Acetic anhydride Kg 1.140

3 N-bromosuccinamide Kg 1.560

4 Conc hydrochloric acid Kg 4.730

5 Sodium metabisulfite Kg 20.220


7 Chloro acetyl chloride Kg 1.080

8 HMTA Kg 2.130






15 Dimethyl Sulfoxide Lit 4.480

Nebivolel (NBV)

1 (Isomer-A) Kg 1.72

114.504 1192.750

2 (Isomer-B) Kg 1.59

3 Isopropyl Alcohol Lit 13.50


5 Palladium on charcoal Kg 0.114

7 Methanolic Hydrochloric Acid Kg 3.18

Levodropropozin

e (LDP / LEDO)

1 1-Phenyl piperazine Kg 1.000

13.400 139.583

2 R-(-)-3-Chloro -1,2-Propane

diol Kg 0.680


4 Dichloro methane Lit 8.000

6 Toluene Lit 3.000

Clozapine (CLZ) 1 8-chloro-5,10-dihydro-11H-

dibenzo[b,e][1,4]diazepin-11-Kg 1.000 28.227 588.063




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

one

(8-CDDO)

2 Titanium Tetrachloride (TiCl4) Kg 0.777

3 Anisole Kg 0.900



6 Isopropyl Alcohol Lit 6.000


8 N-Methylpiperazine (NMP) Kg 2.450

Eslicarbazepine

Acetate (CAR)

1 Oxcarbazepine (OXC) Kg 4.000

130.356 2715.746

2 Sodium borohydride Kg 0.400

3 Isopropanol Kg 30.220


5 Acetone Kg 2.000

6 CAR-I Kg 3.800

7 L-(+)-Tartaric acid Kg 2.320


9 Phosphoric acid Kg 0.190


11 N,N-dimethyl pyridine

(Dimethyl Amine) Kg

0.083

12 Pyridine Kg 1.625

13 CAR-II Kg 2.964


15 CAR-III Kg 1.363

16 Dichloromethane (Methylene

Dichloride) Kg

23.537

17 Con sulfuric acid Kg 0.123


19 Activated carbon Kg 0.061

20 Hyflo powder Kg 0.123


worse case

384.12 8006.49

Group 3-Anti Asthmatic Intermediates

4 - benzyloxy -

3- nitrophenylace

bromide (BNB /

BNPB)

1 4-HAP Kg 1.000

24.578 81.927


3 Sodium Hydroxy Kg 0.436

4 Stage-I Kg 1.000

5 Benzoyl Chloride Kg 1.000

6 Dimethyl Amine Kg 3.600

7 Stage Ii Kg 1.000

8 EDC Kg 5.000

9 Bromine Kg 0.200




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

10 Sodium Bisulphite Kg 0.092

11 Stage - III Kg 1.000

12 Acetone Kg 4.000

4-benzyloxy-3-

nitrostyreneoxide

(NSO)

1 BNPB Kg 1.600

25.421 84.737

2 THF Kg 8.272

3 Sodium Borohydride Kg 0.055


5 Hyflow Kg 0.030

6 Methanol for precipitation Kg 15.248

2-(2[3-(3-[2-(7-

chloroquinoline-

2-

yl)ethenyl)pheny

l)-3-hydroxy-n-

propyl]phenyl)-

2-propan-1-ol

(SMKT / SMT)

1

1-{3-[-2-(7-chloroquinolin-2-

yl)ethenyl]phenyl} prop-2-en-

1-ol (Stage-02)

Kg 1.361

94.911 316.371

2 Methyl-2-Iodo benzoate (In-

house made) Kg 1.159

3 Palladium acetate Kg 0.004



6

Methyl 2-(3-(3-(2-(7-

chloroquinolin-2-yl)

vinyl)phenyl)-3-

oxopropyl)benzoate (Stage-01)

Kg 1.551

7

(-)-B-

Chlorodiisopinocampheylbora

ne 60% in Heptane

Kg 3.282

8 Diethanolamine Kg 1.430


10 Hexanes Kg 10.416



13

SMT stage-II: Methyl 2-(3-(3-

(2-(7-chloroquinolin-2-yl)

vinyl) phenyl)-3-

hydroxypropyl) benzoate

Kg 1.171

14 Cerium chloride Kg 0.760

15

Methyl magnesium

chloride(3M solution in THF)

22.0%

Kg 4.415



18 Xylene Kg 6.025



Total RM of Group 3 in 94.911 316.371




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

worse case

Group 4- Anti Viral API/ Intermediates

DRV ethanoloate

/ Darunavir

1 BOC Nitro Kg 2.230

29.071 484.517

2 Raney Ni Kg 0.112



5 Con.Hydrochloric Acid Kg 4.680

6

(3R, 3as, 6aR)

Hexahydrofuro[2,3-b] furan-3-

ol

Lit 0.490

7 Disuccimidyl carbonate Kg 1.079

8 41% Aq. Methyl amine soln. Lit 0.050

9 Acetonitrile Lit 1.290


T2551 - Etravirin

Intermediate

(ETV)

1 2,6-Dimethyl phenol Kg 1.690

50.012 833.533

2 Bromine Kg 2.113

3 Copper cyanide Kg 1.352

4 DMF Lit 2.028




8 Sodium hypochlorite Lit 2.518

9 activate carbon Kg 0.110

DRV

Intermediate /

BOC 01 / Dia

Amino

1 BOC Nitro Kg 1.560

14.055 234.250

2 Raney Nickel Kg 0.117

3 Hydrogen gas Kg 0.178

4 Methanol Kg 8.000

5 Hyflo Kg 0.024



8 Conc Hydrochloric Acid Kg 3.000

BOC N / BOC

nitro


39.410 656.833

2 TEA Kg 0.600

3 Nocil Chloride Kg 0.710

4 Na2CO3 Kg 0.200

5 Na2SO4 Kg 2.000


7 Ethyl Acetate Kg 3.600


worse case 50.012 833.533

Group 5--Antidiabetic API

Canagliflozicin 1 5-Iodo-2-methylbenzoic acid Kg 1.75 24.669 205.578




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

Inter 2 Dichloromethane Kg 12.04

3 N,N-dimethylformamide Kg 0.03


5 2-(4-fluorophenyl)thiophene

(II) Kg 1.31

6 Aluminium chloride Kg 3.11

7 Concentrated hydrochloric

acid Kg 1.75

8 Intermediate-III Kg 1.50

9 Triethyl silane (Et3SiH) Kg 1.65

10 BF3Et2O Kg 1.35

Dapagliflozin

(GLI)

1 5-Bromo-2-chloro-4'-

ethoxydiphenylmethane (BCE) Kg 1.74

199.815 1665.124

2 2,3,4,6-tetra-O-trimethyl-silyl-

β-D-glucolactone (TTSG) Kg 0.45

3 (S)-(+)-1,2-propanediol Kg 0.15



6 Activated Carbon Kg 0.10

7 Boron trifluoride diethyl

etharate [CAS no 109-63-7] Kg 0.97

8 Conc hydrochloric acid Kg 1.98



11 GLI-I Kg 1.98

12 GLI-II Kg 1.75

13 GLI-III Kg 1.45

14 GLI-IV Kg 1.02

15 Hexanes Kg 1.39

16 Hexyl lithium (2.3 M solution

in hexane] Kg 10.68

17 Hyflo powder (Celite) Kg 0.20

18 Lithium hydroxide

monohydrate Kg 0.12

19 Magnesium sulfate Kg 1.98

20 Methane sulfonic acid Kg 0.67


22 Potassium hydrogen sulfate Kg 0.15

23 Pyridine Kg 3.22

24 N,N-Dimethylpyridine Kg 0.03



27 Solvent Kg 9.50




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)


29 Toluene Kg 26.31

30 Triethyl silane [CAS No 617-

86-7] Kg 1.05

Empagliflozin

(EMP)

1

(5-Bromo-2-chlorophenyl) (4-

hydroxyphenyl)methanone

(BCM)

Kg 1.50

68.451 570.428

2 Triethylsilane (Et3SiH) Kg 3.36

3 BF3THF Kg 1.50

4 Toluene Kg 11.35



7 EMP-I Kg 1.36


9 Tertbutyl-dimethylsilyl

chloride (TBDMSCl) Kg 0.82

10 Imidazole Kg 0.51

11 EMP-II Kg 1.78

12 Tetrahydrofuran Kg 3.57

13 Hexyl lithium Kg 2.23

14 TTSG (tetrakis-trimethylsilyl-

D-gluconolactone) Kg 1.69

15 Methanol Kg 5.35

16 Methansulfonic acid Kg 0.45


18 BF3Et2O Kg 0.45

19 EMP-III Kg 1.45

20 R-3-hydroxy tetrahydrofuran Kg 0.73

21 p-toluene sulfonylchloride Kg 1.31

22 Pyridine Kg 1.32

23 N,N-dimethylformamide

(DMF) Kg 4.35

24 Cesium carbonate (Cs2CO3) Kg 1.16

25 Methyl-tettbutyl ether Kg 5.80


worse case 199.815 1665.124

Group 6--Antiinflammatory API

Zaltoprofen

(ZLT)

1 5-(1-Carboxyethyl)-2-

(phenylthio)phenylacetic acid Kg 1.589

45.853 286.581 2 Ploy phosphoric acid Kg 3.178



6 Toluene Kg 15.000




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

7 Ethanol Kg 25.260

Flurbiprofen

(RBI)

1 4-Acetyl-2-fluoro biphenyl Kg 1.250

52.993 331.206

2 Sulphur Kg 0.348

3 Morpholine Lit 1.238


5 Sulphuric acid Lit 0.971


8 Diethyl ether Lit 6.714

9 Hydrochloric acid Lit 8.143


11 Diethyl carbonate Lit 5.786

12 Sodium ethoxide Lit 3.200

13 Dimethyl sulphate Lit 0.871


15 Petroleum ether Lit 6.143

Felbinac (FLC /

FBI)

1 4-Acetyl biphenyl Kg 1.410

37.880 236.750

2 Methenol Lit 11.830

3 Sulfur Kg 0.370

4 Morpholine Kg 1.410


6 Hyflow powder Kg 0.390

7 Con Hydrochloric acid Kg 1.380



10 Hyflow powder Kg 0.350

11 Acetone Kg 17.370

Loxoprofen

Sodium (OXO)

1 2-(4-

(bromomethyl)phenyl)propioni

c acid(2-BPP)

Kg 1.450

55.810 348.815

2 Methanol Kg 1.160

3 Con.H2SO4 Kg 0.290

4 OXO-I Kg 1.500

5 2-Ethoxycarbonyl

cyclopentanone

Kg 0.960


7 Potassium hydroxide Kg 0.375

8 OXO-II Kg 1.840


10 Con Hydrochloric Acid Kg 3.680



13 Cyclo hexane Kg 5.310

14 OXO-III Kg 0.883




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)



Naproxen

Sodium

1 DL-Naproxene Kg 2.500

20.975 131.094

2 N-Octayal-Glucamine Kg 1.100

3 Isopropanol Kg 11.250

4 S-(+)-Naproxene NODG salt Kg 3.500



worse case 55.810 348.815

Group 7--Miscelleneous group

Mirabegron

(BEG)

1 4-Nitrophenyl ethylamine

hydrochloride (4-NPE)

Kg 1.210

121.604 1266.710

2 R-Mandelic acid Kg 0.956

3 HOBT Kg 0.097

4 EDC.Hydrochloric Acid Kg 3.353


6 N,N-DMF Kg 2.299

7 METHYLENE DICHLORIDE Kg 12.750

8 7% Hydrochloric Acid solution Kg 1.936

9 20% potassium carbonate

solution

Kg 3.630

10 BEG-I Kg 1.513

11 Sodium borohydride Kg 0.303

12 THF Kg 9.408

13 BF3-THF Kg 2.042


15 25% Sodium carbonate Kg 9.378



18 BEG-II Kg 1.361

19 Electrolyte iron powder Kg 0.667

20 Ammonium chloride Kg 0.640

21 EDTA Kg 0.068

22 10% sodium hydroxide

solution

Kg 11.769

23 BEG-III Kg 0.926

24 2-Aminothiazol-4-yl-acetic

acid(ATAA)

Kg 0.148

25 BEG-IV Kg 1.250





RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)


Deferasirox

(DFX)

1 Salicylamide (SLD) Kg 1.110

36.877 384.138

2 Salicyic acid (SAC) Kg 1.596


4 Methylene chloride Kg 4.761

5 Pyridine Kg 0.159

6 Toluene Kg 3.182

7 Methanol Kg 0.796

8 Ethanol Kg 18.077

9 DFX-I Kg 1.043

10 4-Hydrazino benzoic acid Kg 0.642



13 85% phosphoric acid Kg 0.101

14 DFX-II Kg 1.252

15 Liq.ammonia (30%) Kg 0.192


17 Hyflo super cell Kg 0.247

Colesevelam

1 50% Polyallylamine

hydrochloride soln. Kg 1.280

53.850 560.938

2 Sodium Hydroxide L 0.570

3 Epichlorohydrin Kg 0.030

4 Isopropyl Alcohol L 8.970

5 (6-bromohexyl) Trimethyl

Ammonium Bromide Kg 0.670

6 1-bromo Decane Kg 0.460

7 Methanol L 39.580

8 Conc. Hydrochloric acid (C.P.

Grade) Kg 0.330

9 Sodium Chloride Pure Kg 1.960

Tricyclo [3.3.1

13, 7] decan-1-

aminium, N, N,

N-Trimethyl

hydroxide

(TMA)

1 1-Adamantaneamine Kg 1.000

15.881 165.423

2 Toluene Kg 4.325

3 Dimethyl sulfate Kg 2.668

4 Sodium hydroxide pellets Kg 2.008

5 sulfuric acid ( 98% w/w;

concentrated)

Kg 0.324


N, N-Dimethyl-

3, 5-dimethyl

piperidinium

1 3, 5-Dimethylpiperidine Kg 0.365

4.388 45.703 2 Dimethyl sulfate (DMS) Kg 1.285





RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

hydroxide (TMP) 4 Sulfuric acid Kg 0.183

5 Toluene Kg 0.365


Pirfenidone

(FEN)

1 2-Amino-5-methylpyridine Kg 1.263

45.262 471.477

2 Sulphuric acid (98%) Kg 2.288

3 Sodium nitrite Kg 0.964



6 Methylene dichloride Kg 13.130


8 FEN stage-I Kg 1.074


10 Copper metal Kg 0.107

11 Bromobenzene Kg 3.850

12 Toluene Kg 9.204


14 ISOPROPYL ALCOHOL Kg 0.212

15 FEN-II Kg 1.342

Apalutamide

(CAP/CBF)

1 3-(trifluoromethy)pyridine Kg 3.900

96.601 1006.258

2 Hydrogen peroxide (30 %

solution) Kg 2.340



5 Trimethyl silyl cyanide Kg 0.975


7 Tetraethyl ammonium nitrate Kg 0.390

8 Trifluoroacetic anhydride Kg 1.560

9 Iron Kg 4.050



12 Celite (hyflo powder) Kg 0.934

13 2-Fluoro-4-nitrotoluene Kg 3.000

14 Potassium permanganate

(KMnO4) Kg 1.500

15 Con. Hydrochloric acid Kg 2.250

16 CBF-I Kg 2.500


18 N,N-DMF Kg 0.003

19 Methylamine (40% solution in

water) Kg 1.250




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

20 CBF-II Kg 2.250

21 CBF-III Kg 1.125

22 Cyclobutanone Kg 0.563

23 Sodium cyanide Kg 0.225

24 Sodium hypochlorite Kg 0.169


5-chloro-N-

({(5S)-2-oxo-3-

[4-(3-

oxomorpholin-4-

yl)phenyl]-1,3-

oxazolidin-5-

yl}methyl)thioph

ene-2-

carboxamide /

BAN /

Rivaroxaban

1 4-(4-aminophenyl)morpholin-

3-one (APM) Kg 0.775

82.844 862.959

2

2-[(2S)-2-oxiranylmethyl]-1H-

isoindole-1,3(2H)-dione

(Oxiran)

Kg 1.062


4 BAN-I Kg 1.473

5 N,N′-carbonyldiimidazole

(CDI) Kg 0.957

6 Dimethylaminopyridine

(DIMETHYL AMINEP) Kg 0.077

7 Toluene Kg 20.983

8 BAN-II Kg 1.399

9 Methylamine (40% strength in

water) Kg 1.287



12 BAN-III Kg 0.979

13 5-Chlorothiophene-2-

carboxylic acid (CTA) Kg 0.754



16 Potassium carbonate (K2CO3) Kg 1.028

17 BAN-IV Kg 1.175

18 Formic acid Kg 12.209

Trimethyl

pyruvic Acid /

Kito Acid(KTA)

1 Pinacolone Lit 1.156

15.466 161.104

3 Caustic soda flakes Kg 0.940

4 KMnO4 Kg 3.720


6 METHYLENE DICHLORIDE Lit 5.290


N Acetyl

Hydroxy Phenyl

Piperazine

(AHPP)


28.949 301.552 3 BCA Kg 1.000

4 Para Amino Phenol Kg 1.600

5 Caustic Lye Kg 2.060




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

6 Catalyst A Kg 0.001

7 Acetic Anhydride Kg 0.970


9 Catalyst B Kg 4.800

10 Carbon Kg 0.043

11 Ahpp Crude Kg 1.000


13 Catalyst B Kg 0.004

Amino Ethyl

Phosphoric Acid

(AMPA)

1 N-Hydroxy Phthalimide (Stage

I) Kg

1.000

24.876 259.125

2 HBr 48% Kg 4.000

3 Sulphuric acid conc. Lit 1.500


5 AMPA (Stage II) Kg 1.000

6 Tri Ethyl Phosphite Kg 0.520

7 AMPA (Stage III) Kg 1.000

8 Hydrazine Hydrate Kg 0.520

9 AMPA (Stage IV) Kg 1.000

10 Conc. HYDROCHLORIC

ACID C.P. Lit

2.116

11 Pyridine Kg 1.020

(1-Isopropyl-4-

(hydroxyl

Phenyl)

(piperazine)

(IHPP)

1 4- MPP Kg 1.000

14.962 155.854

2 DMF Kg 1.500


4 Iso Propyl Bromide Kg 3.837

6 Stage-01 Kg 1.000

7 HBr 45 - 50 % Solution Kg 4.000

8 lithium Bromide Kg 0.500

9 CAT-A Kg 0.100

10 Methanol for cake washing Lit 3.000

Cilastazol

1 6-Hydroxy-3-,4-dihydro-2-

quinolinone Kg 0.588

12.188 126.958

2 5-(4-chlorobutyl)-1-

cyclohexyl-1H-tetrazole Kg 0.958

3 Phase transfer catalyst(PTC) Kg 0.205


5 Toluene Kg 1.526


7 Methanol Kg 8.714

R & D Products




RM

Qty.

(Kg/Kg)

Total RM

(Kg/Kg of

Product)

Total

RM

(MT/M)

Total RM of Group 7 553.74 5768.198

ANNEXURE- VI BREIF MANUFACTURING PROCESS:

1. Threophenyl-2-piperidyl-2-acetamide (TPA) Process:

2-Phenyl-2-[piperidine-2-yl] acetamide reacted with sodium bicarbonate in acetone and

water. Acid base using sulphuric acid and sodium.

Chemical Reaction:

Flow Diagram:

AcetoneH

NH

H2NOC

H

H

NH

H2NOCH Sodium Bicarbonate & H 2SO4

Threophenyl-2-piperidyl-2-acetamide2-Phenyl-2-[piperidine)-2)-yl]acetamide

2. Ritalinic Acid (KMN)

Process Description:

1-phenyl-1-piperidyl-2-acetamide in acidic solution gives threo-1-phenyl-1-piperidyl-2-

acetamide hydrochloride which is then treatment with sodium hydroxide affords 1-

phenyl-1-piperidin-2-acetic acid.

Chemical Reaction

NH

H

CONH2

HCl

1-Phenyl-1-piperidyl-2-acetamide

NH

H

COOHHCl

NaOHNH

H

COOH

1-Phenyl-1-piperidin-2-acetic acid

Flow Diagram:

3. Zonisamide – USP

Process:

4-Hydroxycoumarin was reacted with hydroxylamine HCl in presence of potassium

acetate anhydrous in methanol at desired temperature and appropriate condition.

Methanol distillation, basification, dichloromethane washing and later acidification

afforded Zonisamide Stage-I. Obtained solid was reacted with complex of

chlorosulphonic acid and 1, 4-dioxane in ethylene dichloride. Quenching and later

water removal and later chlorination using phosphorus oxychloride in toluene and

animation using ammonia afforded Zonisamide Stage-II. Purification of Zonisamide

Stage-II using acetone, water and activated charcoal afforded pure Zonisamide.

Chemical Reaction

ZON Stage-I

O O

OH

1,2-benzisoxazol-3-ylacetic acid

ZON Stage-II

N

O

OH

O

1,2-benzisoxazol-3-ylacetic acid

O

N

S

OH

OO

O

N

S

Cl

OO

O

N

S

NH2

OO

ZON Stage-III (Final)

O

N

S

NH2

OO

O

N

S

NH2

OO

4-Hydroxycoumarin

ZON Stage-I

ZON Stage-I

1,2-Benzisoxazol-3-yl-methanesulfonamide

ZON Stage-III (Final)

Acetone

Water

NH3

POCl 3ClSO3H

1,4-Dioxane

EDCToluene

Toluene

N

O

OH

O

Hydroxylamine HCl

Potassium Acetate

Methanol

ZON Stage-II

1,2-Benzisoxazol-3-yl-methanesulfonamide 1,2-Benzisoxazol-3-yl-methanesulfonamide

ZON Stage-II

Activated charcoal

Flow Diagram:

4. Modafinil (NIL)

Process:

[2-(diphenylmethyl)thio]acetamide was reacted with Hydrogen peroxide in presence

acetic acid at desired temperature and appropriate condition give Modafinil crude

that is purified with methanol and water afforded pure Modafinil.

Chemical Reaction

Stage 1

SNH2

O

Acetic acid

35% H2O2 S

NH2

OO

Formula Weight = 257.3507 Formula Weight = 273.3501

2-[(diphenylmethyl)sulfanyl]acetamide 2-[(diphenylmethyl)sulfinyl]acetamide

(Thio Acetamide) Modafinil Crude

Stage 2

Methanol

RO water S

NH2

OO

Formula Weight = 273.3501

2-[(diphenylmethyl)sulfinyl]acetamide

Modafinil Pure

SNH2

OO


2-[(diphenylmethyl)sulfinyl]acetamide

Modafinil Crude

Flow Diagram

5. Fluvoxamine Maleate

Process:

5-methoxy-1-(4-methylphenyl) pentan-1-one condense with hydroxylamine

hydrochloride and 2-chloroethylamine hydrochloride to give Fluvoxamine base.

Treating of free base of Fluvoxamine with Maleic acid gives Fluvoxamine Maleate.

Chemical Reaction:

F3C

O

OCH3 NH2OH . HCl

F3C

N

OCH3

O

NH2

COOH

COOH

5-methoxy-1-[4-(trifluoromethyl)phenyl]pentan-1-one 2-[({(1E)-5-methoxy-1-[4-(trifluoromethyl)phenyl]

pentylidene}amino)oxy]ethanamine

F3C

N

OCH3

O

NH2

COOH

COOH

.

Cl

NH2 HCl

Flow Diagram:

6. Trifluoperazine

Process:

Side chain and alkali solution is condensed in Toluene at RT. Toluene layer is then

treated with Sodium sulphate anhydrous.

TPZ and side chain in Toluene is then treated with Sodamide at elevated temp. to give

TFP in Toluene. Toluene is recovered then TFP is extracted in MDC and again MDC is

recovered to get crude TFP. This crude TFP is then treated with HCl gas in Acetone to

give TFP hydrochloride.

4'-(trifluoromethyl)-5-methoxy

Valerophenone

Hydroxyl amine HCl

2-chloro ethylamine

hydrochloride

Sodium hydroxide

Methanol

DMF

Methylene chloride

Hexane

Reaction

&

workup

Aqueous ML

Hexane + MDC ML

Filtration Alkali aqueous ML

Water Drying Fluvoxamine Maleate

Chemical Reaction

N

H

CF3

S+

N

N

CH2-CH2-CH2Cl

CH3

TOULENE

Trif luorophenothiazine

N

N

NF3C

S

CH3

MeOH HCl

N

N

NF3C

S

CH3

Trifluoperazine BaseTrifluoperazine Hydrochloride

.2HCl

M.W. - 267.26

M.W. -407.5

1-(3-chloropropyl)-4-methylpiperazine

M.W. -176.6

Flow Diagram:

7. Methylphenidate

Process:

Phenyl 2 Piperidine Acetamide is reacted in presence of Dry HCL. The product is

isolated after work up with MIBK.

Chemical Reaction

NH

H

CONH 2

H

Methylisobutyl ketone

Dry HCl gas

.HCl

Methylphenidate Hydrochloride

H

NH

H3COOC

H

Phenyl-2-pypiridine acetamide Flow Diagram:

8. Dex Methyl Phenidate HCl

Manufacturing Process:

d- Threo ritalinic acid hydrochloride was reacted with thionyl chloride in methanol

to give Crude Dex methylphenidate hydrochloride which is purified by acid base

treatment to obtained pure Dex methylphenidate hydrochloride.

Chemical Reaction

.

O OH

NH

H

H ClH

d-threo ritalinic acid hydrochloride

F.W.= 255.74

O OCH 3

NH

H

H . ClH

Dexmethylphenidate hydrochloride

F.W.= 269.76

Methanol

Thionyl Chloride

IPA

HCl

Flow Diagram:

Thionyl Chloride

Methanol

KMOMaintaining

under

reflux

Distillation Methanol recovery

Dry Cake of

Dexmethylphenidate

hydrochloride

Drying

Salt formation

Filtration

IPA HCl

Work up and

distillationMDC RecoveryMDC

IPA MLR

9. Chlordiazepoxide

Process:

2-Amino-5-chlorobenzophenone reacted with hydroxylamine formed hydroxylamine

derivative. It reacted with chloroacetyl chloride and gave 6-Chloro-2-chloromethyl-

4-phenylquinazoline-3-oxide HCl. It further reacted with methylamine in methanol

and gave Chlordiazepoxide. Purification using methanol gave pure

Chlordiazepoxide.

Chemical Reaction

Flow Diagram:

O

NH2

Cl

NH2

ClN OH N

N

Cl

Cl

NH2OH

Cl

O

Cl

O

CH3NH2 N

N

Cl

NH CH3

2-Amino-5-chlorobenzophenone Oxime derivative

N

N

Cl

NH CH3

Pure Chlordiazepoxide

CH3OH

Crude Chlordiazepoxide

6-Chloro-2-chloromethyl-4-phenyl

quinozoline-3-oxide

O O

HCl

HCl

10. 7-hydroxy-3,4-hydroquinolin-2(1H)-one(7-HDQ)

Process:

3-methoxy aniline condense with 3-chlorpropanoyl chloride at appropriate temp.

form HDQ-1. HDQ-1 cyclization and hydrolysis with Anh. AlCl3 give to HDQ

crude. Recrystallization with solvent to give HDQ.

Chemical Reaction:

+NaHCO3

NH2 OCH3

3-methoxyaniline

Cl

Cl

O

3-chloropropanoyl chloride

OCH3

NH

O

Cl

N-(3-methoxyphenyl)-3-chloropropionamide

Toluene

MAD CPC

HDQ-I

Anh. AlCl3

N

H

OH O

7-hydroxy-3,4-dihydroquinolin-2(1H)-one

HDQ Crude

Purification

N

H

OH O


HDQ

Flow Diagram:

11. 1-Chloromethyl cyclopropane

Process:

Cyclopropyl methanol reacted with N-chloro succinimide and dimethyl sulfide to

formed Chloromethyl cyclopropane.

Chemical Reaction:

OH Cl

N

O

O

Cl

Cyclo propyl methanol

CH3

SCH3

Chloro methyl cyclo propane

Dimethl sulfoxide

F.W.= 72.10 F.W.= 90.55

NH

O

O

+ CH3

SCH3

O

SuccinimideF.W.= 99.08 F.W.= 78.13

N-Chlorosuccinimide

Dimethyl sulfide

+

Flow Diagram:

Dimethyl sulfide

MDC

N-Chloro succinimideMaintaining

Filtration Biproducts

MDC Recovery

Cyclopropyl methanol

Fractional Distillation

Chloromethyl cyclopropane

Chloromethyl cyclopropane : Flow Diagram

12. 1-(2, 3-Dichlorophenyl) piperazine HCl

Process:

DCPP base is reacted with conc. HCl using IPA as solvent. The product is isolated

by filtration.

Chemical Reaction:

Flow Diagram:

HCl

N

NHCl

Cl

HCl

1-(2,3-dichlorophenyl)piperazine Hydrochloride

N

NHCl

Cl

1-(2,3-dichlorophenyl)piperazine



13. 7-(4-Bromobutoxy)-3, 4-dihydroquinolin-2(1H)-one (BBQ)

Process:

7-Hydroxy-3-,4-dihydroquinolin-(2H)-one was reacted with 1,4-dibromobutane in

presence of potassium carbonate and DMF at desired temperature and appropriate

condition give 7-(4-Bromobutoxy)-3,4-dihydroquinolin-2(1H)-one (Crude BBQ), it

further purified by Toluene and other solvent afforded pure 7-(4-Bromobutoxy)-3,

4-dihydroquinolin-2(1H)-one(BBQ).

Chemical Reaction:

N

HO OH

+

Br

Br

N

HO O

Br

7-hydroxy-3,4-dihydroqui

nolin-2(1H)-one K2CO3

1,4-dibromobutane

Purification

BBQ

BBQ - I

7 - HQ

DBB

N

HO O

Br

Flow Diagram:

14. Aripiprazole

Process:

Stage – I: - 7-Hydroxy-3, 4-dihydroquinolin-2(1H)-one (7-HDQ) was reacted with

1-bromo-4-chlorobutane in presence of sodium hydroxide-butanol and cyclohexane

at desired temperature and appropriate condition gives 7-(4-chloro butoxy)-3, 4-

dihydro-2(1H)-quinolinone (Stage – I)

Stage – II: - 7-(4-chloro butaoxy)-3, 4-dihydro-2(1H)-quinolinone (Stage – I)

condense with 1-(2, 3-dichlorophenyl) piperazine hydrochloride in presence of

Triethylamine with catalytic amount of sodium iodide and TBAB gives Aripiprazole

crude.

Stage – III: - Purification of Crude Aripiprazole by Acetonitrile and Iso-butanol

afforded pure Aripiprazole and further purification by ethanol (80.0%) afforded pure

Aripiprazole (Final Aripiprazole).

Chemical Reaction:

NH

OOH

Br

Cl

+ n - Propanol

NaOHNH

O OCl

7-(4-chlorobutoxy)-3,4-dihydroquinolin-2(1H)-one

Molecular Formula = C13

H16

ClNO2



Molecular Formula = C9H

9NO

2


1-bromo-4-chlorobutane

Molecular Formula = C 4H8BrCl


Stage I

Stage II

NH

O OCl

7-(4-chlorobutoxy)-3,4-dihydroquinolin-2(1H)-one

Molecular Formula = C13H16ClNO2


+N

NH Cl

Cl

1-(2,3-dichlorophenyl)piperazine hydrochloride

.HCl


Molecular Formula = C10H13Cl3N2

N

NO N

HO

Cl

Cl

Molecular Formula = C23H27Cl2N3O2


N

NO N

HO

Cl

Cl

N

NO N

HO

Cl

Cl

Purification

Stage III


H27

Cl2N

3O

2



H27

Cl2N

3O

2


Aripiprazole crude

Flow Diagram:

15. 1-(2-Bromoethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one [BET]

Process:

1-Ethyl-1,4-dihydro-5H-tetrazol-5-one [EDTO] was reacted with 1,2-dibromo

ethane in presence of sodium carbonate in MIBK at desired temperature and

appropriate condition give 1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one

[BET], , crude BET is purified by falling film distillation and pot distillation.

Chemical Reaction:

N

NNH

N

CH3

O

1-ethyl-1,4-dihydro-5H-tetrazol-5-one


N

NN

N

CH3

O

Br

1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one


Br

Br

1,2-dibromoethane

Flow Diagram:

1,2-Dibromoethane

MIBK

EDTO

MIBK

Reaction

Reaction massWater

Layer separation

MIBK Distillation

Aq. layer

Recover MIBK

Product distillation

BET pure

16. 1-Amino Indane

Process:

1-indanone is reacted with hydroxylamine hydrochloride and sodium hydroxide at

70-75°C gives 1-Indanone oxime is further react with Raney nickel and ammonia in

methanol media under hydrogen atmosphere at 40-42°C for 24.0 hrs and isolation by

acid base method following MDC extraction gives 1-aminoindane.

Chemical Reaction:

hydroxylamine hydrochloride

1-Indanone

Stage - I

ON

OH

1-indanone Oxime

Raney Nickel

NH2

1-Aminoindane

Flow Diagram:

1 - Indanone

Reaction

Maintaining

Filtration

Drying

ML Recover Methanol

Reaction

1 - Indanone oxime

Methanol

hydroxylamine hydrochloride

Sodium hydroxide

Water

1 - Indanone Oxime

Reaction

Maintaining

Filtration

Residue

ML Recover Methanol

ReactionMethanol

ammonia solution

Raney Nickel

MDC

ReactionHCl

NaOH

Sepration &

Evaporation

1 - Aminoindane

17. 4, 4’-Diflurobenzhydryl Piperazine (DFBHP)

Process:

4,4 Diflurobenzhydrol on chlorination by HCL gives 4-4 Diflurobenzhy dry /

chloride Extier Toluene and condensate with piperazine to give 4, 4” Difluro

Benzhydrryl Piperazine.

Chemical Reaction:

O

FF

NaBH4

Methanol

OH

F F

Cl

F F

SOCl2

Toluene

N

NH

F F

M.W.218.19 M.W.220.21 M.W.238.66 M.W.288.33

4,4' Diflorobenzophenonebis(4-fluorophenyl)methanol

1-[bis(4-fluorophenyl)methyl]piperazine

DFBHP

Flow Diagram:

18. 2-TrifluromethylPhenothiazine (TPZ)

Process:

3-(Trifluoromethyl) aniline react with formic acid & gives trifluoromethyl phenyl

formamide. Trifluoromethyl phenyl formamide react with bromobenzene, and

formed intermediate treated with alkali, and further treatment with sulfur results

gives TPZ [2-(trifluoromethyl)-10H-phenothiazine.

Chemical Reaction:

CF3NH2

HCOOH

CF3NH

CHO Br

CuCO3

K2CO3

N

CHO

CF3

NaOH

HClNH

CF3

N

H

CF3

S

Sulphur powder

iodine

TPZ

Trifluophenothiazine

M.W. -161.12 M.W. -189.13M.W. -265.23

M.W. -237.22

M.W. -267.26

3-(trifluoromethyl)aniline

(3-ABT) N-[3-(trifluoromethyl)phenyl]formamideN-phenyl-N-[3-(trifluoromethyl)phenyl]formamide

Flow Diagram:

19. Levomepromazine

Process:

3-Dimethylamino-2-methyl propyl chloride hydrochloride was condensed with 2-

Methoxy phenothiazine in acetone in presence of KOH at reflux temperature. This

obtained solid was resolved in toluene by resolving agent & Levomepromazine

Maleate was precipitated out from mother liquor by reacting with Maleic acid.

3-ABT

Formylation with formic acid

N-Formyl 3- ABT

Condn. With Bromobenzene using

Base and catalyst

N- Formyl diphenyl amine

Hydrolysis with alkali

Trifluro diphenyl amine

Treatment with sulphar

Crystallization in solvent

2-Trifluromethyl phenothiazine

Chemical Reaction: S

NH

OCH3

+ Cl N

CH3

CH3

CH3

N

CH3

CH3

CH3

S

N OCH3

H

COOH

COOH

.

N

CH3

CH3

CH3

S

N OCH3

H

Solvent

2 Methoxy phenothiazine3-chloro-N,N,2-trimethylpropan-1-amine

Levomapromazine Maleate

HCl

HCl

Resolving agent

MALEIC ACID

Flow Diagram:

Flow diagram of Levomepromazine Maleate:

Batch Size :0.41 Mt./Month

Acetone

2-Methoxyphenothiazine

Potassium Hydroxide Flakes

3-dimethylamino-2-methyl propyl

chloride hydrochloride (Side

chain)

RO Water

NaCl

Hydrochloric acid

Sodium Hydroxide

Reaction & Work up

Drying

20. Betahistine Dihydrochloride (BST)

Process:

Pyridine 2-ethanol reacts with phosphorus tri-bromide and than methylamine later it

converts in to Betahistine Dihydrochloride by reaction with hydrochloric acid.

Chemical Reaction: N OH

PBr3

N NHCH3

2HCl

HCl

CH 3NH 2

Flow Diagram:

Pyridine-2-ethanol

Phosphorus tribromide

Toluene

Methylamine 40% aqueous

solution

RO Water

Isopropyl alcohol HCl

Reaction & Work up

Aqueous layer

Isopropyl alcohol

Filtration

IPA mother liquor

Drying

Betahistine Dihydrochloride (Final)

Toluene

Resolving agent

Maleic acid

Reaction

Toluene

Filtration Toluene mother liquor

Drying

Levomepromazine Maleate (Final)

21. Betahistine Mesylate (BSM)

Process:

2-Vinyl pyridine was reacted with methyl amine hydrochloride in presence of

Catalyst-1 and Catalyst-2 at desired temperature and appropriate condition give

Betahistine base. Crude base is purified by high vacuum distillation. Betahistine

Mesilate was obtained by reaction of Methanesulphonic acid and base in IPA from

base. Purification by Isopropyl alcohol afforded pure Betahistine Mesilate.

Chemical Reaction:

NCH2 + CH3 NH2 HCl

Methylamine

2-Vinyl Pyridine

N NH

CH3

N-methyl-2-(pyridin-2-yl)ethanamine

Stage-I

Molecular Formula=C 7H7N

Molecular Weight=105.137

Molecular Formula=CH 6ClN


Hydrochloride

Catalyst-1

Stage-II

N NH

CH3


Molecular Formula=C 8H12N2

High Vacuum

Distillation

N-methyl-2-(pyridin-2-yl)ethanamine

N NH

CH3


Molecular Formula=C 8H12N2

CH3SO

3H

Isopropyl Alcohol+

2CH3SO3H

(BSM Stage-I)

N NH

CH3

N-methyl-2-(pyridin-2-yl)ethanaminebis(methanesulphonate

(BSM Stage-II)

Molecular Formula=C8H

12N

2.2CH

3SO

3H


(BSM Stage-I)

N NH

CH3


(BSM Stage-II)


12N

2.2CH

3SO

3H


2CH3SO3H

N NH

CH3



12N

2.2CH

3SO

3H


2CH3SO3H

Isopropyl Alcohol

Stage-III

(BSM Stage-III)

Flow Diagram:

Stage 1 Input Operation Output

Betahistine Mesilate Stage-I

Methyl amine hydrochloride

Water

Catalyst-1

Catalyst-2

2-Vinyl Pyridine

Reaction

(IPQC:1 )

Sodium Hydroxide + Water

Chloroform(fresh/recovered/all

ratio of fresh & recovered)

Quenching

&

Work-up(IPQC:2)

Aqueous layer

Chloroform Recovery

Recover chloroform

High vacuum distillation(IPQC:3)

Betahistine Mesilate Stage-I

(Send a sample to QC for Betahistine

Mesilate Stage-I Intermediate Analysis &

Recovered Chloroform Complete

Analysis)

Stage 2: Input Operation Output

Betahistine Base

Isopropyl Alcohol

Methane Sulphonic acid

Reaction

(IPQC:4)

Methanol + Acetone

N2 (g)

Isopropyl Alcohol

N2 (g)

Isolation & Filtration

Filtrate

Wet Cake

Betahistine Mesylate Stage-II

(Crude)

(Sample for Betahistine Mesylate-II

for complete analysis)

Stage 3: Input Operation Output

Isopropyl alcohol

Betahistine Mesilate

Crude Stage - II

N2

Reaction

Isopropyl alcohol

Isolation & Filtration

Mother liquor

Drying (IPQC:6)&Packing

(VTD for drying)

Betahistine Mesilate Stage-III

(Betahistine Mesilate Pure)

(Sample for Betahistine Mesilate for

complete analysis)

22. Phenyl 2 Piperidyl Acetamide (PPAC)

Process:

Phenyl-2-Piperidyl Acetonitrile on acidic hydrolysis gives amide which on

hydrogenation using Palladium Charcoal as catalyst in acetic acid gives the require

product.

Reaction:

Toluene

+

NaNH2

CH2CN

2-Chloro

pyridine

Cl N

Benzyl

CH-

N

Phenyl 2-pyridyl

acetonitrile

Stage I

CH-CONH2

N

Conc. H2SO4

H2O

NaOH

CH-CONH2

N

H2 gas / Pd-C

Acetic acid

Phenyl 2-pyridyl

acetamide

Phenyl 2-piperidyl

acetamide

Flow Diagram:

BLENDING

PACKING

SSR-19

SSR-16

PPR-22

SSR-08

CF-05

TD-04 / 05

MILLING

GLR-105

GLR-12

SF-01 / 02

SSR-04

CF-02

TD-01/ 02

PF-01

SF-03

23. N-(1benzyl 4 pipridinyl) N Phenyl propanamide HCL/ NN Phenyl N 4

piperidinyl propanamide HCL (FC 1002/1003)

Process:

Brief Process for FC-1002

1-Benzyl-N-phenylpiperidin-4-amine, Propanoic anhydride reacted in methylene

chloride. Neutralization water washing and Hydrochloride salt formation affords FC-

1002.

Brief Process for FC-1003

1 N-(1-benzylpiperdin-4-yl)-N-phenyl propanamide HCl reacted with hydrogen in

presence of palladium carbon in alkaline condition. Isolation in usual way affords

FC-1003.

Reaction:

Reaction Scheme: FC-1002

+N

NH

O

OO

CH3CH3

FC 1002

N

N

O

CH3

HCl

HCl

1-benzyl-N-phenylpiperidin-4-amine

propanoic anhydride

Reaction Scheme: FC-1003

FC 1003

NH

N

O

CH3

Pd/CN

N

O

CH3

HCl

N-(1-benzylpiperidin-4-yl)-N-phenylpropanamide

Flow Diagram:

Process Flow diagram: FC-1002

1-Benzyl-N-

phenylpiperidin4-

amine

Propanoic anhydride

RO water

Sodium Carbonate

Methylene chloride

Reaction

&

Work up

Hydrochloric acid

Salt formation

Filtration Aqueous layer

Drying FC-1002

Process Flow diagram: FC-1003

N-(1-benzylpiperdin-

4-yl)-N-

phenylpropanamide

HCl

Isopropyl alcohol

Palladium carbon

Sodium carbonate

Hydrogen gas

Reaction

&

Work up

Isopropyl alcohol

RO water

Precipitation

RO water Filtration IPA+ Water mother

liquor

Drying FC-1003

24. Memantine HCL

Process:

1,3-Dimethyladamantane was reacted with acetonitrile in sulphuric acid at room

temperature. This obtained solid was reacted with sodium hydroxide in

monoethylene glycol and than Memantine HCl precipitated out by reacting with

hydrochloric acid gas.

Chemical Reaction: CH3

CH3

1,3 dimethyl adamantine

Acetonitrile, H 2SO4

Toluene,MEG,NaOHCH3

CH3

NH2

CH3

CH3

NH2 HCl

Memantine HCl

Ethanol

Diiospropylether

HCl

Hexane

KRM

Stage IFinal

Flow Diagram:

1,3-Dimethyl Adamantane

Sulphuric acid

Acetonitrile

Toluene

Hexane

Monoethylene glycol

Sodium Hydroxide

Reaction

&

Work up

Diisopropyl ether

Hydrochloric acid

Ethanol

Salt formation

Diisopropyl ether Filtration

Diisopropyl ether mother

liquor

Drying Memantine Hydrochloride

(Final)

25. Quetiapine Fumerate

Process:

Dibenzo [b,f][1,4]thiazepin-11(10H)-one , phosphorus Oxychloride reacted in

toluene in presence of N,N-Dimethyl aniline, further reacted with 1-(2-

hydroxyethoxy)ethylpiperazine Dihydrochloride in presence of potassium carbonate

in Sulfolane affords Quetiapine base. Salt formation with Fumaric acid affords

Quetiapine Fumarate.

Chemical Reaction:

NH

S

O

POCl3

dibenzo[b,f][1,4]thiazepin-11(10H)-one

N

NH

OOH

S

N

N

NO

OH

OH

OH

O

O

Quetiapine Fumarate

Fumaric acid

2

Flow diagram:

Dibenzo[b,f][1,4]thiazepin-

11(10H)-one

Phosphorus Oxychloride

N,N-Dimethyl aniline

1-(2-

hydroxyethoxy)ethylpiperazine

dihydrochloride

Toluene

Potassium carbonate

Sulfolane

Ethyl acetate

Reaction

&

Workup

&

Recovery

Recovered toluene

Recovered ethyl acetate

RO water

Methanol

Fumaric acid

Salt formation

Methanol + Water

Filtration Methanol + water MLR

Drying

Quetiapine Fumarate (Final)

26. Phenyl – 2 – Pyridyl Acetamide (PPA)

Process:

Condensation of Phenl Acetonitrile and 2 Chloro Pyridine toluene gives PPAN.

Hydrolysis of PPAN with H2SO4 gives PPA; Hydrogenation with Pd Charcoal will

convert PPA to PPAC.

Chemical Reaction:

CH2CN

+N Cl

NaNH 2

TOULENE

PPAN

NCN

H2SO4N NH2

O

NaOH N NH2

O

H2

Pd2+

N

H

NH2

O

phenylacetonitrile

M.W. 117.14 M.W. 113.54

2-chloropyridine

phenyl(pyridin-2-yl)acetonitrile

M.W. 194.23

2-phenyl-2-(pyridin-2-yl)acetamide

M.W. 212.24

2-phenyl-2-(piperidin-2-yl)acetamide

M.W. 218.29

Flow Diagram:

Phenyl acetonitrile

2-chloropyridine

Sodium amide

Toluene

Sulphuric acid

Reaction

Water Filtration Acidic aqueous ML

Drying PPA

27. Alprazolam

Process:

7-chloro-5-phenyl-2-thioxo-2,3-dihydro-1H-1,4-benzodizaepine was reacted with

acetohydrazide in presence of toluene at desired temperature and appropriate

condition give 2-(2-acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine, it

further converted in to Alprazolam crude by reacting with appropriate solvent, this

crude is purified by ethyl acetate and other solvent afforded pure Alprazolam.

Chemical Reaction:

a. Stage-I : 2-(2-acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine:

NH

NCl

S

CH3

NH NH2

O

acetohydrazide

N

NCl

NH NH

CH3

O

7-chloro-5-phenyl-2-thiazo-2,3-dihydro-1H-1,4-benzodiazepine

2-(2-acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine

Formula Weight = 286.77 Formula Weight = 326.78

Stage-II : Alprazolam crude :

N

NCl

NH NH

CH3

O

2-(2-acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine


N

N

N

N

CH3

Cl

Alprazolam crudeFormula Weight = 308.76

Stage-III: Alprazolam Pure :

Alprazolam crude


N

N

N

N

CH3

Cl

Alprazolam pure


N

N

N

N

CH3

Cl

Flow Diagram:

Reaction and Work up

Inprocess by TLC

Filtrate MLFiltration

Drying Alprazolam

(Stage - I)

2-(2-acetylhydrazino)-7-chloro

phenyl-3H-1,4-bezodiazepine

Acetohydrazide

Alprazolam Stage - I

Toluene Reaction and Work up

Inprocess by TLC

Filtration

Drying Alprazolam Crude

(Stage - II)

Alprazolam Stage - II

Methanol Dessolution

Hot Filtration


Drying Flupirtine Maleate Pure

(Stage - III)

Cooling

28. Mono chloro acetonitrile

Process:

Methyl chloroacetate reacted with ammonia formed 2-Chloroactamide. 2-

Chloroactamide treated with Thionyl chloride formed Chloro acetonitrile.

Chemical Reaction:

Cl

NH2

O

Cl

H3CO

O

methyl chloroacetate 2-chloroacetamide

Cl

N

chloroacetonitrile

[Mono chloro acetonitrile]

NH3SOCl2

Flow Diagram:

29. Remi N Benzyl Propeonamide eater Oxalate


4 – (phenyl amino) – 1- (phenyl methyl) – 4 – piperdine carboxylic acid give its ester

in methanol by methane sulfonic acid gives it propanamide on reaction with

propionic anhychide gives its oxatile by oxalic acid in methanol reaction in

ethylacetate as crude product which on purification gives pure product 1 – Benzyl –

4 (Methoxy carboxyl ) – 4 – [ C 1 – oxopropyl) phenyl amino] – piperdine oxalate.

Chemical Reaction:

N

C6H5

COOHH5C6HN

MeOH N

C6H5

COOCH 3H5C6HN

Acid Ester

N

C6H5

COOCH 3H5C6HN

CO

CH3

Propionic anhydride Oxalic Acid

N

C6H5

COOCH3H5C6HN

CO

CH3

RPO

(COOH)2

M.W. -310.39 M.W. -324.41 M.W. -381.48 M.W. -471.48

Flow Diagram:

30. Olanzapine


2-Amino-5-methylthiophene-3-carbonitrile reacted with 2-fluorobenzene and

sodium hydride in usual way. Work up ,pH adjustment and filtration affords

Olanzapine (Step-1). Olanzapine (Step-1) further reacted with N-methylpiperazine at

required temperature and condition. Isolation affords Olanzapine (Final).

Flow diagram of RPO

Batch Size : 0.008 Mt./Month

1-Benzyl-4-(phenyl amino)

piperidine-4-carboxylic acid

Methanol + methane sulphonic

acid

Propionic anhydride

Oxalic acid

Reaction

Filtration Methanol ML

Methanol Drying RPO

Chemical Reaction:

Na.H

THF

S

CH3

N

NH2

2-amino-5-methylthiophene-3-carbonitrile

NO2

F

NO2

NH

S

CH3

N

5-methyl-2-[(2-nitrophenyl)amino]thiophene-3-carbonitrile

Step:1

SnCl2 , HCl

Ethanol

DMSO

CH3

N

NH

NH

N

SCH3

CH3

N

N

2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine

(Olanzapine)

Flow Diagram:

Stage 1

2-Amino-5-

methylthiophene-3-

carbonitrile

2-

fluoronitrobenzene

Sodium Hydride

Tetrahydrofuran

Reaction

&

Work up

30% Hydrochloric

acid

Methylene chloride

pH adjustment

RO water Filtration Methylene chloride MLR

Drying

5-Methyl-2-[(2-

nitrophenyl)amino]thiophene-3-

carbonitrile (Step-1)

Stage-2

Flow diagram of Olanzapine (Final)

5-Methyl-2-[(2-

nitrophenyl)amino]thiophene-

3-carbonitrile (Step-1)

Stannous chloride

Ethanol

Dimethylsulphoxide

N-methylpiperazine

Toluene

Sodium chloride + RO Water

Reaction

&

Workup

Toluene Filtration Toluene MLR

Drying Olanzapine(Final)

31. Benzhydryl Piperazine (BHP)


Benzhydrol is reacted with conc. HCl and the chlorinated product is condensed with

piperazine using Toluene as solvent. The product is isolated by treating reaction

mass with acetic acid (dil) and dil. Sodium hydroxide.

Chemical reaction:

Toluene +

Acetic acid +

Caustic Soln

Piperazine

Benzhydryl Piperazine

OH

Benzhydro

l

Cl

CH CH

CH

HCl

Flow Diagram:

32. Alpha-phenylpiperidine-2-acetic acid (KMP)


1-phenyl-1-piperidyl-2-acetamide in acidic solution gives threo-1-phenyl-1-

piperidyl-2-acetamide hydrochloride which is then treatment with sodium hydroxide

affords 1-phenyl-1-piperidin-2-acetic acid. This when reacted with HCl and caustic

Flakes gives Alpha-phenylpiperidine-2-acetic acid (KMP).

Chemical Reaction:

Toluene

PPR-22

TANK T1

PPR-22

S/F-01

SSR-18

TANK T4

SSR-16

CF-08

TD-03 / 04

MILLING

BLENDING

PACKING

NF-01

DRUMS

TANK T2

TOLUENE

LAYER

Sod. Sulphate bed

Organic Toluene

layer

Aq. layer

Flow Diagram:

1-Phenyl-1-piperidyl-

2-acetamide

Hydrochloric acid

water

Reaction

Water Filtration Acidic aqueous ML

Sodium hydroxide pH adjustment

Water Filtration Alkali aqueous ML

Drying Ritalinic acid

HCL +

Caustic

Alpha-phenylpiperidine-

2-acetic acid (KMP)

33. Fluvoxamine Oxalate (OXA)


5-methoxy-1-(4-trifluoromethylphenyl) pentan-1-one is reacted with hydroxyl amine

hydrochloride in presence of Sodium carbonate in Methanol solvent forms Fuxia. It

is worked up and isolated in Hexane. Stage-1 is reacted with 2 chloro ethyl amine in

DMSO, work up with toluene and water and crystalized with maleic acid to form

OXA-2.

Complete chemical name of this product is 5-methoxy-4'-(trifluoromethyl)

valerophenone (E)-O-(2-aminoethyl) oxime oxalate (1:1)

Chemical Reaction:

F3C

O

OCH3

F3C

N

OCH3

ONH2

Cl

NH2HCl

KOH

F3C

N

OCH3

ONH2

.

Oxalic acid dihydrate

COOH

COOH

OXA

F3C

N

OCH3

OH

Stage-IKSM

Na2CO3

NH2OH.HCl

Flow diagram:

Stage 1:

Reaction mixtureNH2OH.Hcl

Base

KSM

Maintain

Wet Cake

Slurry wash

Filtration

Wet Cake

Drying

Washing

MLR send to effluent

XIA

Layer separationSolvent

Stage 2:

Reaction mixtureKOH

2-CEA

Stage-I

Maintain

Wet Cake

Slurry wash

Filtration

Wet Cake

Drying

Washing


OXA

Layer separationOxalic acid dihydrate

Organic layer

34. 5-methoxy-p-trifluoromethylvalerophenone-oxime (XIA)


5-methoxy-1-(4-trifluoromethylphenyl) pentan-1-one is reacted with hydroxyl amine

hydrochloride in presence of Sodium carbonate in Methanol solvent forms Fuxia.

Chemical Reaction:

F3C

O

OCH3

F3C

N

OCH3

OH

Stage-IKSM

Na2CO3

Flow Diagram:

Reaction mixtureNH2OH.Hcl

Base

KSM

Maintain

Wet Cake

Slurry wash

Filtration

Wet Cake

Drying

Washing


XIA

Layer separationSolvent

35. 1,2,4-Triazolo[4,3,a]pyridine-3(2H)-one


Urea is reacted with Hydrazine to form semicarbezide hydrochloride TZP stage-01.

TZP-I further reacted with 2-Chloropyridine in the presence of 2-ethoxy ethanol and

catalytically amount of Con H2SO4 to give TZP stage-02 (Final).

Chemical Reaction:

+2-Ethoxyethanol

Water

N

N

NH

O

NH2

O

NH

NH2

N Cl

2-Chloropyridine

HCl

Semicarbazide Hydrochloride

1,2,4-Triazolo[4,3-a]pyridin-3(2H)-one

Conc.sulfuric acid

NH2

O

NH

NH2

NH2

O

NH2+

NH2

NH2

.H2O

Urea Hydrazine hydrate

. HCl

Semicarbazide Hydrochloride TZP - II

TZP - I

Flow Diagram:

Urea

Hydrazine hydrateStirring

Heating

Maintaining

CoolingMethanol

Filtration MLR

Drying U/Vacuum

TZP-I

Washing

TZP stage-02:

TZP-I

2-CP Stirring

Heating

Maintaining

CoolingWater

Filtration MLR

Drying U/Vacuum

TZP-II

Washing

2-EE

36. 4-amino-2-methyl-10H-thieno[2,3b] [1,5]-benzodiazepine hydrochloride


AMT and FNB reaction to be performed in DMF solvent in presence of KOH to

make AMB-1. Hydrogenation of stage-1 to be performed in presence of catalyst

followed by work up and isolation to make AMB-2 from stage-1. Charcoal treatment

and purification of Stage-2 performed to form Stage-3.

Chemical Reaction:

Flow diagram:

AMB STAGE-I

INPUT

Reaction

Acetone

Potassium hydroxide

2-Fluro nitrobenzene

DMF

AMT

Process Water

Filtration

Pre chilled water

AMB-1 Wet cake

ON

ODB

AMB Stage-2

vessel

Raney Ni

Catalyst washing Process Water

Acetone

Hydrogenation

Acetone

Stage-I

Acetone

Nitrogen

Hydrogen

Hyflo

Filtration

Acetone

Ethanol

Reaction HCL

Process Water

Process water

Filtration

MDC

Purification Methanol

Wet Cake

Pre Cooled MDC

Filtration

Drying

OUTPUT

AMB-II

AMB-3

Methanol

Dissolution

AMB Stage-II

Filtration

Activated Carbon

Dissolution

Hyflow

Filtration

Methanol

Crystallization

Filtration

Methanol

Drying

AMB-3

37. Lurasidone Hydrochloride


Trans (3aR, 7aR) octahydro-[2H-isoindole-2—spiro-1’-piperazinium]-‘-(1,2-

benzisothiazol-3-yl), methansulfonate (1:1) (BOI) is reacted with bicyclo

[2,2,1]heptane-2-exo-3-exo dicarboximide (MID) in the presence of potassium

carbonate and anisole at higher temperature for 3-4 hrs. Maintaining. After

completion work up, organic layer is distilled under vacuum to recover anisole.

Denatured alcohol is added to the residual mass, followed by cooling, filtration,

drying to get Lurasidone free base as Stage-I (SID-I). SID-I is converted into

hydrochloride salt to give Lurasidone hydrochloride (SID).

The complete chemical name of this product is [3aR-

[2(1R*,2R*),3aR*,4S*,7R*,7aS*]]-2-[2-[[4-(1,2-benzisothiazol-3-yl)-1-

piperazinyl]methyl] cyclohexylmethyl] hexahydro-4,7-methano-2H-isoindole-1,3-

dione hydrochloride.

Chemical Reaction:

NH

O

O

H

H

NN+

SN

H

H

N

O

O

N

N

SN

H

H

+

Anisole

K2CO3 (Anh)

Aq. HCl

N

O

O

N

N

SN

H

H

CH3

SOO

- O

HCl

MDC

Lurasidone base

Lurasidone hydrochloride

Stage - I

Retardar /Denature ethanol

Stage - II (Final)

BOI

MID

Flow Diagram:

SID stage-01:

BOI

MID

K2CO3

Anisole

Stirring

Heating

Maintaining

CoolingProcess water

Layer Separation

Org. layer

Combined org. layer

Distillation U/Vacuum

Filtration MLR

Drying U/Vacuum

Lurasidone stage - I

SID - I

SID stage-02: SID - I

Methylene dichloride

Aq. HCl

Stirring

Organic layer

Org. layer

Combined org. layer

Distillation atmosphericMDC re cove ry

Methylene dichloride

Maintaning

Filtration MLR

Drying U/Vacuum

Layer separation

Filtered through cartridge filter

Acetone

Stirring

Lurasidone hydrochloride

38. 2-bromo-3-(2,3-dimethylphenyl)butanal


2,3-dimethyl bromobenzene reacted with magnesium in tetrahydrofuran followed by

acetone to produce 2-(2,3-Dimethylphenyl)propan-2-ol (MPB) Stage-I. It reacted

with phosphorus oxychloride and later complex of phosphorus oxychloride &

dimethylformamide to produce (2E +2Z)-3-(2,3-dimethylphenyl)-2-butenal (insitu

intermediate) [1BEBZ]. It reacted with hydrogen gas in presence of 5% palladium

on carbon in autoclave to produce β, 2, 3-trimethyl-benzenepropanal (insitu

intermediate) [1C]. It reacted with morpholine followed by bromine in solvent to

give 3-(2, 3-Dimethylphenyl)-2-bromobutanal (MPB) after isolation.

Chemical Reaction: CH3

CH3Br

+ MgTHF

CH3

CH3CH3

CH3OH

Acetone

MPB Stage-I2,3-Dimethyl bromobenzene 2-(2,3-Dimethylphenyl)propan-2-ol

KSM

POCl3

DMF

CH3

CH3

CH3

CHO

2E + 2Z of 3-(2,3-Dimethylphenyl)but-2-enal

CH3

CH3

CH3

CHO

3-(2,3-dimethylphenyl)butanal

Pd/C

H2 gas pressure

Morpholine

Br2

CH3

CH3

CH3

CHO

Br

2-bromo-3-(2,3-dimethylphenyl)butanal

MPB

[1BEBZ] [1C]

Flow Diagram:

Step-I: - MPB

THFMg turnings Stirring

2,3-Dimethyl Bromobenzene

Acetone + toluene

Conc HCl

Water Layer SeparationAq. Layer

Org. Layer

+ toluene

Aqueous ammonia

NaOH solution Layer Separation

Layer SeparationWater

Org. Layer

Org. Layer

Toluene RecoveryReco toluene + THF HeptanesReco toluene + heptanes

Filtration

Drying

MPB Stage-I

Aq. Layer

Aq. Layer

Nitrogen gas Nitrogen gas

Heptanes MLR

Step-II: - MPB

DMFMPB Stage-I Stirring

POCl3

Water Aq. Layer

Org. LayerAqueous ammonia

NaOH solution Layer Separation


Organic mass [1BEBZ]BHT

Stirring

Triethanolamine

Aq. Layer

Aq. Layer

Organic mass [1BEBZ]Activated charcoal

Stirring

Triethylamine

Org. mass

5% Pd/C

Toluene Filtration


Autoclave

4-Dimethylaminopyridine

Nitrogen gasHydrogen gas

5% HCl solution

Organic mass [1C]

Org. Layer

Layer Separation

Org. LayerWater

5% NaHCO 3 solution

Pd/C Waste

Aq.layer

Aq.layer

Org. mass

Nitrogen gas

Carbon Waste

Organic mass [1C]

Morpholine

Stirring

Org. massPurified water

Layer Separation

Sodium bicarbonate + Org. Layer

N2 gas

MPB

Concentration

Org. massBHT

Triethanolamine

Aq. layer

Toluene

WaterN2 gas

EthylacetateBromine

Stirring

Addition into bromine

Conc HClAq. layerLayer Separation

Sodium thiosulphate Aqueous solution

Water

Org. mass

Reco EtOAc+toluene

39. Brexpiprazole


7-Hydroxyquinolinone (HOQ) reacted with 1-bromo-4-chlorobutane (BCB) in

methanol in presence of potassium hydroxide to produce 7-(4-chlorobutoxy)

Hydroxyquinolinone (REX) Stage-I. 4-Chloro-1-benzothiphene (BBT) reacted with

N-Boc-piperazine (NBP) in N-methylpyrrolidinone in presence of

diisopropylethylamine base to produce Tert-butyl-4-(1-benzothiophene-4-yl)

piperazine-1-carboxylate (BTP-I). BTP-I reacted with HCl and produce 1-(1-

benzothiophene-4-yl) piperazine hydrochloride (BTP). REX-I and BTP reacted to

produce crude Brexpiprazole (REX-II). Purification of REX-II using ethanol

produced pure Brexpiprazole (REX).

Complete chemical name of this product is 7-(4-(4-(Benzo[b]thiophen-4-

yl)piperazin- 1-yl)butoxy)quinolin-2(1H)-one dihydrochloride.

Chemical reaction:

N

H

O OHCl Br+

1-bromo-4-chlorobutane

KOH

N

H

O O ClMeOH

(HOQ) (BCB) (REX-I)

7-hydroxyquinolin-2(1H)-one 7-(4-chlorobutoxy)quinolin-2(1H)-one

ClH

S

N

N

H

1-(1-benzothiophene-4-yl)

(BTP)

N

H

O ON

SN

Brexpiprazole (crude)

(REX-II)

N

H

O ON

SN

Brexpiprazole (pure)

(REX)

Purification

Ethanol

piperazine HCl

S

Cl

+

N

N

H

Boc

Tert-butylpiperazine

DIPEA

N-methyl-2-

S

N

N

Boc

-1-carboxylate

4-Chloro-1-

benzothiophene

Tert-butyl-4-(1-benzothiophene-4-yl)

piperazine-1-carboxylate

(BBT) (NBP) (BTP-I)

HCl

S

N

N

H

ClH

1-(1-benzothiophene-4-yl)

piperazine Hydrochloride

(BTP)

pyrrolidinone

Flow diagram:

Step-I: - REX-I

7-Hydroxyquinolin-2H-one

1-Bromo-4-chlorobutaneStirring

Methanol

Potassium hydroxide

Methanol Filtration Methanol MLR

MDC + Methanol [100:3] Silica Gel Chromatography

Drying

REX-I

MDC + MethanolSpent

Step-II: - REX-II

REX-IBTP

Stirring DMFPotassium carbonate

Water Filtration DMF + Water MLR

MDC

Sodium iodide

MDC + Methanol [100:3] Silica Gel Chromatography

Stirring Methanol Drying with MgSO 4MgSO 4

Waste MgSO 4

Solvent distillationRecoveredMethanol + MDC

SpentMethanol + MDC

Wet cake

Residue

REX-II

Step-III: - REX

Purification

Filtration

Drying

REX

Ethanol MLR

EthanolREX-II

Ethanol

Step-I: - BTP-I

4-ChlorobenzothiopheneN-Boc-piperazine

Sodium-t-butoxide

Org. mass

dipalladium tris

Water

ExtractionEthyl acetate

StirringR-BINAP

Nitrogen gas

Nitrogen gas

Organic mass

Org. Layer

Layer Separation

Combined Org. Layer

Water

Aq. layer

[dibenzylideneacetone]Toluene

Layer Separation Aq. layer

Org. Layer

Aq. layer

MgSO 4

Org. Layer

Solvent distilation

Silica Gel ChromatographyMDC + Methanol +

25% NH3 water [100:10:1] BTP-I

Reco Etyl acetate

Waste MgSO 4

Step-II: - BTP

BTP-IMethanolConc HCl

IsolationEthyl acetate

Stirring

Wet cake Purification

Filtration

Solvent distillation Reco Methanol

Ethyl acetate MLR

Methanol

Drying

FiltrationMethanol

Ethyl acetate

Methanol MLR

BTP

40. Nicorandil


The process, in brief, involves the coupling of nicotinic acid methyl ester (prepared

by the treatment of nicotinic acid with thionyl chloride and methanol) with

monoethanolamine to form N-(2-hydroxyethyl)nicotinamide. This amide is then

reacted with fuming nitric acid to give nicorandil (crude) which is then crystallized

from isopropylalcohol-water to furnish the pure product. This page gives the brief

outline (flow chart) of the manufacturing method.

Nicotinic acid (IV) is converted in to its corresponding methyl ester (V) by treatment

with thionyl chloride and methanol in the presence of toluene.

The nicotinic acid methyl ester (V) is coupled with monoethanolamine to form N-

(2-hydroxyethyl) nicotinamide (VI) which after treatment with fuming nitric acid

produces nicorandil crude (I).

Nicorandil crude is crystallised by Isopropyl alcohol, water to yield the pure product

(Scheme – II).

Chemical Reaction:

N

OH

OO

N

OMe

NH2

OH

O

N

NOH

H

O

N

NONO

2

H

SCHEME - II

C

(IV)

Thionyl Chloride,

Methanol, Toluene

(V)

Monoethanolamine

(VI)(I)

Fuming Nitric acid

Crystallisation Isopropanol, Water

NICORANDIL PURE

NICORANDIL CRUDE

Flow Diagram:

41. Quinfamide


It involves condensation of dichloroacetyl tetroxyquin (DTHQ) with 2-furoyl

chloride to give Quinfamide.

Synthesis of Intermediates :

Synthesis of 1-dichloroacetyl-1,2,3,4-tetrahydro-6-quinolinol (II) called as dichloroacetyl

tetroxyquin (DTHQ).

I. 6-methoxy quinoline (V) :

p-Anisidine (IV) in presence of p-nitroanisole (which can be made from p-chloro

nitro-benzene & methanol) undergoes Skraup’s reaction with glycerine and

Sulphuric acid to give the title compound (V).

II. 6-Methoxytetrahydroquinoline (VI) :

The title compound is prepared by hydrogenation of (V) in presense of Raney Ni.

III. 6- Hydroxytetrahydroquinoline (Tetroxyquin ) (VII) :

Compound VI is demethylated using aqueous hydrobromic acid to give compound

VII.

STARTING MATERIAL

NICOTINIC ACID

NICOTINIC ACID METHYL ESTER

N-(2-HYDROXYETHYL)NICOTINAMIDE

NICORANDIL CRUDE

NICORANDIL PURE

Thionyl Chloride, Methanol, Toluene

Monoethanolamine

Fuming Nitric Acid

Isopropyl alcohol, Water

IV. 1-dichloroacetyl-1,2,3,4-tetrahydro-6-quinolinol (II) also called dichloroacetyl

tetroxyquin (DTHQ) :

The title compound (II) is prepared by reacting 6-hydroxy tetrahydroquinoline VII,

with dichloroacetyl chloride.

a. Synthesis of 2-furoyl chloride (III) :

Furoic acid (VIII) is reacted with thionyl chloride to give the title compound.

Chemical reaction:

Chain I

Step I

Step II

Step III

Step IV

CH3O

NH

aq. HBr HO

NH

-methoxy tetrahydroquinoline Tetroxyquin6

HO

NH

Cl2CHCOCl HO

N

COCHCl2

TetroxyquinDTHQ

H2 CH

3O

N

-methoxyquinoline

CH3O

NH

-methoxy tetrahydroquinoline6 6

CH3O

NH2

CH3O

N

p-Anisidine -methoxyquinoline

CH2OH

CHOH

CH2OH

Sulphuric acid

6

Chain II Step I

CHAIN I CHAIN II

Step IV Step I

NEt3

Quinfamide (Crude) Ethyl Acetate

O COOHCOClO

SOCl2

-Furoic acid-Furoyl Chloride

22

HO

N

COCHCl2

O COCl

-Furoyl Chloride

+

2

C

O

O

N

COCHCl2

Quinfamide (pure)

O

DTHQ

Flow Diagram:

42. (N-[4-Methoxymethyl)-1-(phenyl methyl)-4-Piperdinyl]-N-Phenyl

Propanamaide,-Ethanedioate


Cyano compound (nitrile) on acid hydrolysis gives its amide in ethylene glycol,

potassium hydroxide at proper temp. gives its acid, which gives alcohol on treatment

with Red – AL 3 M solution in toluene. This alcohol converted to ether in toluene

by caustic in presence of benzyl tri ethyl ammonium chloride react with propionic

anhydride forms propanamide, which on treating with oxalic acid solution in ethyl

acetate yield its oxalate which on purifications in ethyl acetate and methanol yield

final pure product.

Chemical Reaction:

1-benzyl-4-(phenylamino)piperidine-4-carbonitrile

N

CNPhHN

Ph

H2SO4

KOHN

CH2OHPhHN

Ph

Toluene NaOH

Benzyl triethyl amino chloride

O

OHO

OH

Ph

N

CH2OCH 3NPh

CH3

O

N-[(4-methoxy methyl-1-benzyl)-4-piperidinyl]-N-phenyl propanamideethanedioate SU-10

Stage-I

Flow Diagram:

Stage-1

1-Benzyl-4-(phenyl

amino)Piperidine-4-carbnitrile

Sulphuric acid

Potassium hydroxide + water

Reaction


Water Drying SU-10 Stage-I

Stage-2

SU-10 Stage-I

Toluene

Red Al 3M solution

Propionic anhydride

Oxalic acid

Reaction & workup

Aqueous layer


Water + toluene Drying SU-10 Final

43. Dex Ritalinic Acid


D, l-Threo ritalinic was reacted with dibenzoyl-D tartaric acid to give dibenzoyl-D-

tartrate salt. Dibenzoyl-D-tartrate salt of d-threo ritalinic acid was reacted with conc.

HCl in toluene to give d-threo ritalinic acid hydrochloride.

Chemical Reaction:

d, l -Threo ritalinic acid O OH

O OH

OO

O

O.

O OH

NH

H

H

O OH

NH

H

H

Dibenzoyl-D-tartrate salt of d-threo ritalinic acid

(D-DBT Salt)

Dibenzoyl-D-tartaric acid

Con HCl

Toluene

O OH

NH

H

H ClH

d-threo ritalinic acid hydrochloride

Flow Diagram:

Stage 1

d,l-Threo ritalinic acid

Methanol

Water

Dibenzoyl-D-tartaric acid

Maintaining

Filtration MLR + Washing MLR

Wet Cake

Dry Cake

of

KMO-I

Drying

Stage 2 Final

KMO-I

Toluene

Water

Conc. HClAcetone

Maintaining

Distillation,

Isolation,

Filtration

Wet Cake

Dry Cake of KMO-II

(d-Threo ritalinic acid

hydrochloride Final)

Drying

44. Atomoxetine


N-methyl-3-hydroxy-3-phenylpropyl amine was reacted with 2-Fluorotoluene in the

presence of potassium hydroxide in the mixture of toluene and dimethyl sulphoxide

afforded Atomoxetine racemic base which was purified by oxalate salt formation.

Oxalate salt than resolved by S-(+) mandelic acid and later converted in crude

Atomoxetine Hydrochloride. Acetonitrile purification afforded Atomoxetine

Hydrochloride.

Chemical Reaction:

NH

CH3

OH

NH

CH3

O

CH3

DMSO, KOH Oxalic acid

F CH3

NH

CH3

O

CH3

Racemic Oxalate salt

Stage-I

Mwt. 165.23

Mwt. 110.13Mwt. 255.35

Mwt. 345.38

COOH

COOH

NH

CH3

O

CH3

COOH

COOH

Racemic Oxalate salt

Stage-IMwt. 345.38

NH

CH3

O

CH3

NH

CH3

O

CH3

Water: Toluene

K2CO3

S - (+) Mandelic acid

Toluene: EtOAC

(R) - ATO S -(+)Mandelate salt

COOHOH

Stage - II

M.Wt 407.50

Stage - II

Stage - I

Stage - III

Stage -IV

NH

CH3

O

CH3

COOHOH

Stage - II

(R) - ATO S -(+)Mandelate salt

M.Wt 407.50

1) NaOH/ H2O: Toluene

2) DIPE/ ACN , IPA .HCl NH

CH3

O

CH3

. HCl

Racemic free base

(R)- Atomoxetine Hydrochloride

M.wt: 291.98

Stage - III

IPA

Crude ATO.HCl

NH

CH3

O

CH3

. HCl


M.wt: 291.98

Stage - III

Crude ATO.HCl

NH

CH3

O

CH3

. HCl


M.wt: 291.98

Stage - IV

Acetonitrile

NH

CH3

O

CH3

. HCl


M.wt: 291.98

Stage - IV

Crude ATO.HCl

NH

CH3

O

CH3

. HCl


M.wt: 291.98

Stage - V

Acetonitrile

Stage - V

3-(methylamino)-1-phenylpropan-1-ol

Flow Diagram:

Stage-1

Stage-2

Input Operation Output

Atomoxetine Hydrochloride (ATO) Stage-I from N-methyl-3-hydroxy-3-

phenylpropylamine (KSM)

Dimethyl sulphoxide

Potassium Hydroxide

Flakes

N-methyl-3-hydroxy-3-

phenyl propylamine (KSM)

Toluene + 2-FT (fresh/

reco)

2-Fluorotoluene

Reaction

Distilled water (discard)

IPQC: 1 Reaction mass

Unreacted 3-(Methyl amino)-

1-phenylpropane -1-ol

by HPLC (by area

normalization): Limit Should

not be more than 6.0%

Process water

Toluene (fresh/ reco) Layer separation

& Toluene extraction

Upper toluene layer-I-II (

product)

Aqueous layer ( discarded)

Process water Water washing to

combine toluene layer

Aqueous layer (discard),pH

~ 10-13

Oxalic acid Dehydrate soln

in Isopropyl alcohol

Combine toluene layer

Maintaining

Toluene (fresh/ reco)

Isopropyl Alcohol

Filtration and washing

MLR (sent for toluene + 2-

Fluorotoluene recovery)

Drying u/vacuum IPQC:2 LOD Limit: NMT

3.0%

Atomoxetine HCl

(ATO) Stage-I

(Yield: 1.65w/w of

KSM)

Complete Analysis of

Intermediate as per

Specification


Atomoxetine Hydrochloride (ATO) Stage-II from Atomoxetine Hydrochloride (ATO) Stage-I

Process water

Potassium carbonate


Atomoxetine HCl

(ATO)Stage-I

Reaction

IPQC: 3 pH of aqueous layer,

Limit: Between 7.5 to 8.5

Toluene (fresh/ reco.) Work-up


product)


Process water Water washing Aq. layer (discard), pH :7 to 8

Toluene recovery

/vacuum

Reco. toluene (Complete

analysis)

Degassing /vacuum IPQC:4 Purity NLT 96.0% by

area & %Toluene: NMT

10.0%w/w

Ethyl acetate

Toluene

(S)-(+)-Mandelic acid

Cooling

(Oily mass)

Stirring

Ethyl acetate (chilled) Filtration and washing MLR sent for racemisation

Drying under vacuum IPQC:5 LOD Limit: NMT 1.0%

Atomoxetine HCl (ATO)

Stage-II

(Yield: 0.412w/w of

Stage-I)


Inter

mediate as per

Specification

Stage-3


Atomoxetine Hydrochloride (ATO) Stage-III from Atomoxetine Hydrochloride (ATO)

Stage-II

Process water

Toluene (fresh/reco.)


Stage-II

20% NaOH Solution

Reaction

IPQC: 6 pH of the lower

Aqueous layer, Limit: Between

11.5 to 13.5

Toluene (fresh/ reco.) Layer separation


(SSR)


product)


Process water Water washing Aq. layer (discard)

Toluene recovery

/vacuum

Reco toluene (Send for

analysis)

Degassing u/vacuum

Di isopropyl ether

Acetonitrile

Cooling (Oily mass) IPQC:7 pH of rxn mass Limit:

NMT 2.0

In plant material transfer from technical area to pharma are via filtration (clarification)

Isopropyl alcohol HCl HCl formation

Stirring

Diisopropylether Filtration and washing MLR (spent )

Drying u/vacuum IPQC:8 Water content & LOD

Limit: NMT 0.5% & NMT1.0%

Atomoxetine HCl

(ATO) Stage-III (Yield:

0.60w/w of Stage-II)


Inter

mediate as per

Specification

Stage-4


Atomoxetine Hydrochloride (ATO) Stage-IV from Atomoxetine Hydrochloride (ATO) Stage-III

Acetonitrile

Atomoxetine HCl(ATO)

Stage-III

Reaction

Crystallization

Cooling

Maintaining

Filtration

Acetonitrile Washing Acetonitrile MLR

Spinning/Shuck well IPQC:9 LOD Limit: NMT

10%

Atomoxetine HCl

(ATO) Stage-IV

(Yield: 0.90w/w of

Stage-III)


Intermediate as per

Specification

Stage-5 (Final)


Atomoxetine Hydrochloride (ATO) Stage-V (Final) from Atomoxetine Hydrochloride

(ATO) Stage-IV

Acetonitrile


Stage-IV

Reaction

Crystallization

Cooling

Maintaining

Filtration

Acetonitrile Washing Acetonitrile MLR

Drying under

vacuum IPQC:10 LOD Limit:NMT0.5%

Milling &

Shifting

Drying under

vacuum

Atomoxetine

HCl (ATO)

Stage-V (Final)

(Yield: 0.94w/w

of Stage-IV)

Complete

Analysis of

Finish Product as

per Specification

Process flow diagram for Racemization of Atomoxetine Hydrochloride (ATO)

from Stage-II MLR


Atomoxetine Hydrochloride Racemization Stage-I from Stage-II Mother Liquor

Atomoxetine HCl (ATO) Stage-

II MLR

5% Sodium hydroxide solution

Reaction

Layer separation Upper organic layer (product)


Process water

Organic layer distn

u/vacuum

Recover Ethyl acetate+ Toluene


Di methyl sulphoxide

Potassium Hydroxide

Residue

Heating

Send the sample as per IPQC:11 for

SOR: Limit: (-)-1.5 to + 2.0°

Process water


Layer separation


Upper toluene layer-I-II ( product)


Process water Water washing to combine

toluene layer

Aqueous layer (discard),pH ~ 10-

13

Oxalic acid Dehydrate soln in

Isopropyl alcohol

Note: Hot solution addition

Combine toluene layer

Maintaining


Isopropyl Alcohol Filtration and washing MLR (sent for toluene recovery)

Drying u/vacuum IPQC:2 LOD Limit: NMT 3.0%


Stage-I

(Yield: 1.25w/w of Input

Stage-II MLR residue )


Intermediate as per

Specification

45. Diazepam


2-N-methylamino-5-chlorobenzophenone was reacted with Chloro acetyl chloride in

presence of toluene at elevated temperature and appropriate condition give

Diazepam stage-I. Further it reacts with Hexamethylene tetra amine give Diazepam

crude. Purification by solvent afforded pure Diazepam.

Chemical Reaction: NH

O

CH3

Cl

N

NCl

OCH3

2-N-methylamino-5-chlorobenzophenone


+ Cl

Cl

O

chloroacetic acid


OCl

Cl

CH3

O

2-N-methyl-chloroacetamido-5-chlorobenzophenone


Diazepam


Hexamethylenetetraamine

Toluene

Flow diagram:

Stage-1

2-N-methylamino-5-

chlorobenzophenone

Chloroacetyl chloride

Toluene

Reaction

&

Work up

In process TLC

Filtration

Drying Diazepam, stage-I

Stage-2

Diazepam stage-I

Hexamethylenetetramine

Methanol

Reaction

&

Work up

In process TLC

Filtration

Mother liquor

Drying Diazepam stage-II

Stage-3

Diazepam stage-II

Methanol

Reaction

&

Work up

Maintaining

Filtration

Mother liquor

Drying Diazepam stage-III

46. Oxazepam (OXP)


2-amino-5-chlorobenzophenone (KSM) react with chloro acetyl chloride in presence

of toluene gives Oxazepam stage-I than follow by cyclization using HMTA gives

Oxazepam stage-II which was further oxidation using per acetic acid gives

Oxazepam stage-III than acetylation of stage-III gives oxazepam stage-IV follow by

hydrolysis gives crude Oxazepam. Purification of crude OXP gives final Oxazepam.

The complete chemical name of this product is 5-methoxy-4'-(trifluoromethyl)

valerophenone (E)-O-(2-aminoethyl) oxime oxalate (1:1)

Chemical Reaction:

O

NH2

Cl

1 Chloro acetyl chloride

2 Toluene

3 methanol

O

NH

Cl

Cl

O

2-chloro-N-[4-chloro-2-(phenylcarbonyl)phenyl]acetamide

M.wt 308.15

(2-amino-5-chlorophenyl)(phenyl)methanone

M. Wt 231.67

OXP - I2 - ACP

1 HMTA

2 Methanol

3 NH 4OAC

4 Toluene

NH

Cl N

O

7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one

M. wt 270.71OXP - II

1 Per acetic acid

2 MDC

3 Methanol

1 Acetic anhydride

2 Water

NH

Cl N

O

O CH3

O

M Wt: 328.74

OXP - IV

1 NaOH

2 Methanol3 Acetic acid

NH

Cl N

O

OH

M w t 286.71

OXP - V

Purification

M w t 286.71

OXP - IV

NH

Cl N

O

O

M w t 286.71

OXP - III

NH

Cl N

O

OH

Process Flow diagram:

Stage-1

2-amino-5-chlorobenzophenone

Chloro acetyl chloride

Toluene

Reaction monitoringReactor

layer separation

solvent distillation

Filtration

OXP - I

Methanol

Stage-2 OXP - I

HMTA

Amonium actate



Filtration

OXP - II

Methanol

Stage-3 OXP - II

Per acetic acid

MDC



Filtration

OXP - III

Methanol

Stage-4

OXP - III

Acetic anhydride Reaction monitoringReactor

Filtration

OXP - IV

Water

Stage-5

OXP - IV

Sodium hydroxide Reaction monitoringReactor

Filtration

OXP - V

Acetic acid

Methanol

Water

Water

Stage-6 OXP - V

DMSO Reactor

Filtration

OXP - VI

Methanol

47. Flupirtine maleate


2-Amino-6-chloro-3-nitropyridine was reacted with 4-flurobenzyl amine in presence

of base at elevated temperature and appropriate condition to give Flupirtine Maleate

stage-I. Further it reacts with Raney Ni, hydrazine hydrate, Ethyl chloro formate and

tri ethyl amine gives Flupirtine Maleate crude. Purification by solvent afforded pure

Flupirtine Maleate.

The complete chemical name of this product is 2-Amino-6-([(4-fluorophenyl)

methyl] amino)-3-pyridinyl-carbamic acid ethyl ester maleate.

Chemical Reaction:

Water

N NH2

NO

O

Cl

ACNP

F

N NH2

NO

NH

O

4-FBA

F

NH2

+Sod. carbonate

ANFP

4-Fluoro benzylamine2-Amino-6-Chloro-3-nitropyridine

2-Amino-6-(4-fluorobenzylamino)-3-nitropyridine

1. Isobutanol

2. Raney Ni

3. Hydrazine hydrate Cl

O

O CH3

1. Ethyl chloroformate

Maleic acid, Water

O

O

OH

OH

(I) (II) (III)

Methanol

Purification

F

N NH2

NH

NH

O O CH3

Flupirtine maleate

(V)

O

O

OH

OH

F

N NH2

NH

NH

O O CH3

Flupirtine maleate (Crude)

(IV) O

O

OH

OH

HClF

N NH2

NH

NH

O O CH3

Flupirtine hydrochloride

Flow Diagram: 2-Amino-6-chloro-3-nitropyridine

4 - flourobenzylamine Reaction and Work up

Inprocess by TLC


Drying Flupirtine Maleate

(Stage - I)

Flupirtine Maleate Stage - I

Raney Ni

Reaction and Work up

Inprocess by TLC

Filtrate ML

Filtration

Filtration

Ethyl chloro formate

Solvent

Salt formationMaleic Acid

Drying Flupirtine Maleate Crude

(Stage - II)

Flupirtine Maleate Stage - II

Methanol Dessolution

Hot Filtration


Drying Flupirtine Maleate Pure

(Stage - III)

Cooling

48. Bromazepam


2-(2-Aminobenzoyl)pyridine was react with acetic anhydride and NBS in presence

of MDC give Bromazepam intermediate stage-I follow by hydrolysis and further

react with Chloro acetyl chloride gives Bromazepam intermediate stage-II further

cyclization with HMTA gives crude Bromazepam followed by purification gives

final Bromazepam.

Chemical Reaction:

NH2

O

N

1. (CH3CO)2ONH

O

N

CH3O

Formula Weight = 198.2206Formula Weight = 240.25728

NH

O

N

CH3O

Br


1. Aq.HCl

NH2

O

N

Br


NH

N

Br OCl

O

Bromazepam (Crude)

N

H

N

N

Br

O

Bromazepam

Purification

2 - ABP

Formula weight 316.15

Formula weight 316.15

(1) (2)

(3)

(4)

(5)

ClCl

OBRM - IV

1. HMTA2. Methanol

3. 2N HCl

4. Water

N

H

N

N

Br

O

(6)

2. Methanol

3. NaOH

2. MDC

1.NBS

2. Con HCl

BRM - I

BRM - IIBRM - III

Formula weight = 353.59

Flow diagram:

Stage-1

Reaction

2 - (aminobenzoyl)pyridine

Methylene dichliride

Acetic anhydride

Reaction monitoring

BRM - I

N - bromo succinimide

Con Hydrochloric acid

sodium carbonate

Reaction monitoring

Filteration

BRM stage - I

Stage-2

Reactor

BRM stage - I

Methanol

Con HCl

Toluene

CAC

Reaction monitoring

Extraction & layer separation

organic layer

layer separationwater addition

Reaction monitoring

BRM - II

Filteration

solvent distillation methanol

Stage-3

Reaction

BRM - IIMethanol

HMTA Reaction monitoring

Cool to 0 - 5°C

Filteration

BRM stage - I

2N HClH2O

Stage-4

Reaction

BRM - IIIMethanol

DMSO

Heat to 70 - 75°C

Filteration

BRM stage - IV

Cool to 0 - 5°C

49. Nebivolol


(Isomer-A) was reacted with benzyl amine in alcohol to give NBV-I which was

further reacted with (Isomer-B) to give Nebivolol hydrochloride crude. Further crude

was purified to give pure Nebivolol hydrochloride.

Chemical Reacton:

O

F

O

+

NH2

O

F

N O

OH OH

F

O

F

NH

OH

O

F

NH O

F

OH OH

Isomer-A

Isomer-B

Pd/C

Benzylated Base

Nebivolol Base

Benzyl amine

HCl

O

F

NH O

F

OH OH

F.W.= 441.89

Nebivolol hydrochloride

ClH

NBV-I

Flow Diagram: Stage-1

Benzyl amine

IPA

Isomer-A Maintaining

Filtration

Wet Cake

Dry Cake

of

NBV-I

Drying

MLR

Stage-2

Isomer-B

Methanol

NBV-I Maintaining

Hydrogenation

Filtration

Wet Cake

Dry Cake of

NBV-II

Pd/CH2

HCl

Drying

MLR

Stage-3 (FINAL)

NBV-II

AlcoholMaintaining

Filtration

Wet Cake

Dry Cake of

NBV-III

Drying

MLR

50. Levodropropizine


N-phenyl piparazine is react with R-(-)-3-Chloro-1, 2-propandiol using base sodium

carbonate and solvent as a Water heat up to reflux. Monitoring by TLC. The product

isolate with MDC and water.

The complete chemical name of this product is (2S)-3-(4-Phenylpiperazine-1-

yl)propane-1,2-diol

Chemical Reaction:

+N

NH

Cl OH

OHN

N OH

OH

1-phenylpiperazine(2R)-3-chloropropane-1,2-diol

(2R)-3-(4-phenylpiperazin-1-yl)propane-1,2-diol

Na2CO3

R O Water

(NPP) (CPD)

(LEVODROPROPIZINE)


H14

N2


Molecular Formula = C3H

7ClO

2



H20

N2O

2


Flow diagram of Levodropropizine

1-Phenyl Piperazine

3-Chloro-1,2-propane diol

Sodium Hydroxide

Water

Reaction

&

Work up

Salt formation

Evaporate

Drying Levodropropizine (Crude)

51. Clozapine


Stage – I: - 8-chloro-5, 10-dihydro-11H-dibenzo [b, e] [1, 4] diazepin-11-one (8-

CDDO) was reacted with 1-methylpiperazine in presence of Titanium Tetrachloride

and Toluene at desired temperature and appropriate condition gives 8-chloro-11-(4-

methylpiperazin-1-yl)-5H-dibenzo [b,e][1, 4] diazepine (Crude Clozapine) further

purified in Isopropyl alcohol give Final Clozapine.

The complete chemical name of this product is 8-Chloro-11-(4-methylpiperazin-1-

yl)-5H-dibenzo[b,e][1,4] diazepine.

Chemical Reaction:

NH

NH

O

ClNH

N

Cl

Cl

8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one

8,11-dichloro-5H-dibenzo[b,e][1,4]diazepine

NH

N

CH3

1-methylpiperazine

NH

NN

Cl

N

CH3

8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine

Clozapin (Crude)

Purification

IPA

NH

NN

Cl

N

CH3

Clozapin

TiCl 4

Anisole/Toluene

8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine

Flow Diagram: Stage – 1: Preparation of 8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine from 8-

chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one.


Stage – I: Preparation of 8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine from 8-

chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one.

Toluene

Anisole

TiCl4

NMP

SS Reactor

Heat

Maintaining IPQC-1 (TLC)

Work-Up

HCl RXM

Filter MLR (send for Toluene

recovery)

MDC

C. S. Lye Aq. Layer (pH= 1-2)

Layer separation Aq. Layer (pH= 10-

12)

MDC Layer

Distillation

IPA Crude Clozapine

Purification in IPA with

Charcoal

Final Clozapine

52. Eslicarbazepine Acetate


Oxcarbazepine (OXC) is reacted with sodium borohydride in mixture of isopropyl

alcohol and water to give Racemic 10, 11-dihydro-10-hydroxy-5H-

dibenz[b,f]azepine-5-carboxamide CAR-I. L-(+)-tartaric acid is treated with acetic

anhydride to give Diacetyl-L-(+)-tartaric acid anhydride. CAR-I is reacted with

Diacetyl-L-(+)-tartaric acid anhydride in presence of pyridine in dichloromethane to

give CAR-II. CAR-II is treated with aqueous NaOH solution in methanol Sodium

tartarate formed is filtered out and methanol is distilled out u/vacuum water is added

to the reaction mass and filtered to get CAR-III. CAR-III is reacted with acetic

anhydride in presence pyridine to form CAR-IV. As per the work-up procedure

charcoal treatment given to the CAR-IV solution. CAR-IV is crystalize in

isopropanol to get the desire purity.

The complete chemical name of this product is S-(−)-10-Acetoxy-10,11-dihydro-

5H-dibenz[b,f]azepine-5-carboxamide.

Chemical Reaction:

N

NH2O

O

N

NH2O

OH

N

NH2

O

O

O H

O

O

H O

OHO

O

Oxcarbazepine (OXC)

NaBH4

CAR-I

L(+)-Tartaric acid

Acetic anhydride

Con H 2SO4

N

NH2O

O

CH3

O

Eslicarbazepine acetate (CAR)

CAR - II

NaOH

N

NH2

O

OH

CAR-III

Acetic anhydride

MDC, Methanol

Water, Methanol

Pyridine

MDC, IPA

Flow Diagram:

Stage-1: CAR-I IPA

O XC

Sodium borohydride

AcetoneIPA Re covery

Distil lation

Fil tration

CAR - I

W ate r

Sodium hydroxideW ate rStirring

Aqueous ML

Stage-2: - CAR-II

Acetic anhydride

L (+) Tartaric acid

Tolue ne

Distil lation u/vacuum

MDC

MDC Recove ry

Maintaining

Fli trate MLR

AC2O +AcO H Recove ry

CAR - I

DMAP

Pyridine

Me thanolMDC:Me O H washing

Distil lation

Tolue ne re cove ry

Stirring

O rg. Fi ltrate MLFil tration

DALTAA

Stirring

Distil lation u/vacuum

Stirring

Fil tration

C AR- II

Stage-3: CAR-III

Methanol

CAR-II (wet cake)

Sodium hydroxide

Methanol

Recovered methanolDistillation

Filtration

Filtration

CAR - III

Flitrate MLR

Water

Disodium tartarate salt (By-product)

Filtrate MLR

Water washing

Wet cake

Solution

Stirring

Organic ML

Stirring

Stage-4: CAR-IV

MDC

CAR-III

H2SO4 (0.2M in H 2O) O) Aq. layer

Organic layer

Layer separation

Organic layer

NaHCO 3 Sol

Water washing

Pyridine

Layer separation

Aq. layer

Distillation MDC Recovery

IPA Filtration Organic ML

Solution

Stiring

Stiring

StiringAq. layer

Acetic anhydride

Layer separation

Stiring

Organic layer

CAR-IV

(CAR)

53. 4 - benzyloxy -3- nitrophenacyl bromide


4-HAP (4-Hydroxy acetophenone) is nitrated with HNO3 / H2SO4 (4-HNAP). P-

hydroxy 3-nitro acetophenone so formed is converted to its Sodium salt and Sodium

part is further reacted with Benzyl Chloride using Dimethyl aniline in alkaline

medium to get 4-Benzyloxy-3-nitro acetophenone which is brominated with liquid

bromine to get final prodct BNPB as 4-Benzyloxy-3-Nitro phenacyl bromide.

Chemical Reaction:

COCH3

p-Hydroxy

Acetophenone

OH

COCH3

NO2

HNO3

H2SO4

OH

NaOH

C6H5CH2Cl

COCH3

NO2

OCH2C6H5 COCH2Br

NO2

OCH2C6H5

Br2 EDC

Crude Product

Methanol

COCH2Br

NO2

OCH2C6H5

4-Benzyloxy 3-

nitroacetophenone

3-Nitro-4-

Hydroxy

Acetophenone

COCH2Br

NO2

OCH2C6H5

Pure 4-Benzyloxy 3-

nitroacetophenone

BNPB (Pure)

Purification

with Acetone

Flow Diagram:

Benzyloxy derivative

PHAP

HNO3

70%

Reactor

Quencher

CF

ICE, H2O

Reactor

CF

H2SO4

ML to ETP

NaOH Cake

ML ETP

Dryer

CF

DMF

C6H5CH2Cl

Quencher

Water

CF EDC for recovery

Crystallizer

Reactor

EDC

Bromine HBr scrubber

54. 4-benzyloxy-3-nitrostyreneoxide


4-Benzyloxy-3-Nitro Phenacyl Bromide (BNPB) on reduction with Sodium

Borohydride and treated by caustic solution gives 4-Benzyloxy-3-Nitro styrene

Oxide (NSO).

Chemical Reaction:

N+

O-

O

Br

O

O

1-[4-(benzyloxy)-3-nitrophenyl]-2-bromoethanone



H12

BrNO4

NaBH4

NaOHN

+

O-

O

O

O

2-[4-(benzyloxy)-3-nitrophenyl]oxirane


H13

NO4


4-Bezyloxy-3-nitrostyrene oxide (NSO)

Flow Diagram:

Reactor

Solvent

Sodium

Borohydride

BNPB

Sodium Hydroxide

Solution

Distillation of solvents

Water

Centrifuge

Water

Mother

Liquor

NSO

55. 2-(2[3-(3-[2-(7-chloroquinoline-2-yl)ethenyl)phenyl)-3-hydroxy-n-

propyl]phenyl)-2-propan-1-ol (SMKT)


1-{3-[-2-(7-chloroquinolin-2-yl) ethenyl] phenyl} prop-2-en-1-ol is reacted with

Methyl-2-iodobenzoate in the presence of Triethyl amine and palladium acetate in

acetonitrile media at 80°C for 24 hrs. & after completion of the reaction inorganic

salt was filtered out and filtrate MLR cool to 0-5°C and filtration, water slurry

washing to give SMT stage-01(SMT-I). Stage-01 is reacted with (-)-B-

Chlorodiisopinocampheylborane and Tetrahydrofuran at 0 ± 5°C, maintain the

reaction mixture, after completion of reaction water and diethanol amine was added,

stir and separate layer, organic layer gives water wash then distilled out completely.

To this residue product is isolating by adding Isopropyl alcohol and hexanes and

material is isolated by filtration to give SMT- stage-02 (monohydrate) SMT-II.

Stage-02 under Grignard reaction and after completion of reaction acetic acid

followed by sodium carbonate and finally water wash given to the reaction mixture.

Organic layer is distilled out completely and to this residue product is isolating by

adding Isopropyl alcohol and cyclohexane and material is isolated by filtration to

give SMT- stage-03 (SMT).

Chemical Reaction:

MeMgCl

NCl

OH

CH3

OHCH3

NCl

OHCH2

I

O O

CH3NCl

O

O O

CH3

(-) B- Chlorodiisopinocampheylborane

NCl

OH

O O

CH3

[CAS No 142569-70-8]

methyl 2-iodobenzoate

.H2O

(I)

(II)

(III)

(III)

(IV)

(IV)

(V)

(VI)

SMT-I

SMT-II

SMT

Flow Diagram:

Stage-01:

Reaction mixtureSMT-II

TEA

Acetonitrile

Palladium acetate

Heat up to 78-84°C

Maintain 13-15 hrs

Hot filtration

Wet Cake

Slurry wash

Filtration

Wet Cake

Drying

Process water

Aq. MLR send to effluent

SMT stage-III

Stage-02:

Reaction mixture

THF

(-)-DIPCl

Cool to -5 to +5°C

Maintaining

SMT-III + THF solutionN2 (g) atmosphere

Process water

Reaction mixture

Layer sepration Organic layer-1

Aqueous layer

Layer separation aqueous layer

MDC

Distillation U/vacuum

ResidueIPA

Cool to 0-5°C

Maintain & filter

Wet cake

Drying in VTD at 55-65°C SMT stage-IV

Recovered solvent

Stage-03

Reaction mixture

N2 (g) atmosphere

Cool to 0-5°C

Maintain the mass

Addition of SMT

stage-IV solution

Methyl mgnesium

chloride solution in THF

Stirring & layer

separation

Organic layer

Stir & separationAqueous layer

Water wash

Organic layer Dist, U/V

Residue

Maintain

Filter

Toluene

Cyclo hexane

MLR taken for recovery

SMT stage-V (Final)Wet cake

Drying 56. Di Amino(BOC 1/DRV II)


Reduction of Boc Nitro in presence of Raney Ni under hydrogen pressure to obtain

Boc Amine ,it further hydrolyzed in presence of Con HCl to obtain 4-Amino-N-[(2

R, 3S)- 3 Amino, 2 hydroxy, 4- phenyl butyl ] – n – (2 Methyl propyl) benzene

sulfonamide (DRV-II).

The complete chemical name of this product is 4-Amino-N-[(2 R, 3S)- 3 Amino, 2

hydroxy, 4- phenyl butyl ] – n – (2 Methyl propyl) benzene sulfonamide (Diamino).

Chemical Reaction:

NH

OH

N

CH3

CH3

S

N

O

O

O

OO

OCH3

CH3

CH3

BOC Nitro

Raney Ni

NH

OH

N

CH3

CH3

S

NH2

O

OO

OCH3

CH3

CH3

Con HCl

Reflux

NH2

OH

N

CH3

CH3

S

NH2

O

O

Diamine



BOC Amine


(Stage-I)

(Stage-II)


Boc nitro

Raney Ni

MethanolReaction Mixture (under H 2 Atm)

Maintaining

Filtration

DRV-I

Stage-02

DRV - ICon HCl

Maintainig

NaOH solution

Filtration

DRV-II

57. Darunavir


Reduction of Boc Nitro in presence of Raney Ni under hydrogen pressure to obtain

Boc Amine which further hydrolyzed in presence of Con HCl to obtain 4-Amino-N-

[(2 R, 3S)- 3 Amino, 2 hydroxy, 4- phenyl butyl ] – n – (2 Methyl propyl) benzene

sulfonamide (DRV-II).It react with 1-({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-

3-yloxy] carbonyl} oxy)pyrrolidine-2,5-dione to obtain Darunavir(crude).which is

purify in ethanol to get Darunavir(pure)

The complete chemical name of this product is (3R,3AS,6ar)-hexahydrofuro[2,3-

b]furan-3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-

hydroxypropylcarbamate.

Chemical Reaction:

NH

OH

N

CH3

CH3

S

N

O

O

O

OO

OCH3

CH3

CH3

BOC Nitro

Raney Ni NH

OH

N

CH3

CH3

S

NH2

O

OO

OCH3

CH3

CH3

Conc HCl

NH2

OH

N

CH3

CH3

S

NH2

O

O

Diamine

Methanol

O

OH

H

OH

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol

NO O

N

O

O

O

O

O

+

disuccimidyl carbonate

Solvent

Sidechain Complex

Base

NH2

OH

N

CH3

CH3

S

NH2

O

O

Methyl amine

41% Aq. Ethanol

O

OH

HO

O

NH

OH

N

CH3

CH3

S

NH2

O

O

Darunavir Ethanolate

BOC Amine

CH3 OH

O

OH

HO

O

ON

O

O

(DRV Stage-I)

(DRV Stage-II)

Diamine (DRV Stage-II)

Base

Flow Diagram:

Stage-01

Boc nitro

Raney Ni

MethanolReaction Mixture (under H 2 Atm)

Maintaining

Filtration

DRV-I

Stage-02

DRV - ICon HCl

Maintainig

NaOH solution

Filtration

DRV-II

Stage-03

DRV - IISide chain complex

Maintainig

Extraction

Distilation

DRV-III

Methylamine

Stage-04

Maintainig

Filtration

DRV-IV

DRV - II

EthanolReaction mass

58. T2551 - Etravirin Intermediate


2, 6-Dimethyl phenol is reacted with Bromine at 25-30°C gives ETV-I.ETV-I is

further react with copper cyanide in DMF media under nitrogen atmosphere at 155-

160°C for 5-7 hrs and isolation by acid base method to gives ETV-II(Crude).

Purification of ETV-II (Crude) in toluene gives ETV (Final).

The complete chemical name of this product is 4-Hydroxy-3,5-dimethyl benzonitrile

Chemical Reaction:

CH3 CH3

OHCH3 CH3

OH

N

BromineCH3 CH3

OH

Br

CuCN

2,6-dimethylphenol

4-bromo-2,6-dimethylphenol4-hydroxy-3,5-dimethyl

benzonitrile

MDCDMF

DMPHStage - I

ETV


2,6 - Xylenol

MDC

Bromine

Reaction mixture

0 - 10

Maintaining 25 - 30

layer separation

Organic layer

Distillation

Residue

Residue

Filtration

ETV - I

Methanol

Methanol/Water

Aq. layer

Recovered MDC

Recovered Methanol

MLR

Water

Sodium bisulfite

Stage-2

ETV - I

DMF

CuCN

Reaction mixture

150 - 160

Maintaining 5 hrs

Maintaining 1 hrs

Filtration

Layer separation

Filtration

MLR

Filtration

Toluene Extraction

Charcoal

CuBr Biproduct

Toluene

MLR

Sodium hypochlorite

Sodium Hydroxide

Wet cake

ETV - II

Con HCl

Stage-3

ETV - II

TolueneReaction mixture

Maintaining

Hot filtration

Filtrate MLR

Cool

Filtration &Toluene

Solid waste (Hyflo + carbon)Toluene

MLR

Drying

(ETV )

Activated carbon

Stirring

Heat to clear solution

4-hydroxy-3,5

-dimethyl benzonitrile

washing

59. BOC Nitro


Tetra butyl (IS, 2R)-1-benzyl 2Hyroxy 3-(isobutyl amino) Propyl carbamate react

with nosyl choride in the presence of Triethylamine gives the product Boc Nitro.

The Complete chemical name of this product is ([1S,2R]-(1-benzyl-2-hydroxy-3-

(isobutyl-(4-nitrobenzenesulfonyl)amino)propyl)) carbamic acid tert-butylester.

Chemical Reaction:

O

O

NH

OH

NH

CH3 CH3

CH3

CH3

CH3

TEA/MDC

S

O

O

N+

O-

O

Cl

SO O

N+

O-

O

O

O

NH

OH

N

CH3 CH3

CH3

CH3

CH3

BOC-NitroKRM

Flow Diagram:

60. Canagliflozin Inter (n-2): 2-(4-fluorophenyl)-5-(5-iodo-2-

methylbenzyl)thiophene


Stage-1: 5-Iodo-2-methylbenzoic acid was reacted with Thionyl chloride to give 5-

iodo-2-methylbenzoyl chloride. Further In-situ condensation reaction with 2-(4-

fluorophenyl) thiophene in presence of Aluminum chloride (Anhydrous) at desired

temperature and appropriate condition give [5-(4-fluorophenyl) thiophen-2-yl] (5-

iodo-2-methylphenyl) methadone.

KRM of BOC Nitro

Triethylamine

Methylene chloride

Nosyl chloride

Reaction

Methanol

Filtration

MDC + TEA ML

Methanol ML

Drying

Product

Stage-2: [5-(4-fluorophenyl) thiophen-2-yl](5-iodo-2-methylphenyl) methanone

react with Triethylsilane and Boron trifloride-ethyl ether to give 2-(4-fluorophenyl)-

5-(5-iodo-2-methylbenzyl) thiophene.

Chemical Reaction: a. Stage-I :

I

CH3 O

OH

I

CH3 O

Cl

MDC, DMF

S

F

2-(4-fluorophenyl)thiophene

I

CH3 O

SF

AlCl3

5-iodo-2-methylbenzoic acid


Thionyl chloride

MDC


5-iodo-2-methylbenzoyl chloride

[5-(4-fluorophenyl)thiophen-2-yl](5-iodo-2-methylphenyl)methanone


b. Stage-II :

I

CH3 O

SF

[5-(4-fluorophenyl)thiophen-2-yl](5-iodo-2-methylphenyl)methanone


(CH3CH2)3SiH

BF3.Et2O

CH3

I

SF

2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene



5-Iodo-2-methylbenzoic acid

Solvent

Thionyl chloride

Isolation and reaction

Reaction

Work up

(Insitu reaction)

Solvent

Alluminium chloride

Work up

Isolation Stage-I

Stage-2

Reaction

Suspension

Extraction

Distilltion

Cooling

Stage-I

Solvent

Boron trifloride-ethyl ether

Triethylsilane

Filtrate MLIsolation

Drying

Sodium bicarbonate

Solvent Aq. Layer

Recover Solvent

Solvent

Stage-II

61. Dapagliflozin


5-Bromo-2-chloro-4’-ethoxydiphenyl methane (BCE) treated with n-hexyllithium in

mixture of Toluene and THF. 2,3,4,6-tetrakis-o-trimethylsilyl-β-D-gluconolactone

(TTSG) is added to the reaction mass. Methane sulfonic acid in methanol is added to

the reaction mass to give GLI-I. GLI-I reacted with triethylsilane in presence of

BF3Et2O to give GLI-II. GLI-II reacted Ac2O in presence of DMAP in MDC to

form GLI-III. Hydrolysisi of GLI-III in presence of lithium hydroxide in mixture of

THF, Methanol and water to give GLI-IV. GLI-IV treated with S-(+)-1,2,-

propanediol to give Dapagliflozine propanediol monohydrate (GLI).

The correct chemical name of this product is (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-

ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

propanediol monohydrate.

Chemical Reaction:

HexLithium Cl

Br

O

O

OH

OH

OH

OH

O

Cl

O

O

O

O

O

OCl

O

O

O

O

O

O

OH

OH

OH

OHCl O

GLI-IV

O

O

O

O

O

O

Si

SiSi

Si

TTSGGLI-I

O

OH

OH

OH

OHCl O

OH

OHOH

OHOH2

GLIDapagliflozin propanediol monohydrate

SPD

THF : Toluene

Me3SO3H, MeOH

Et3SiH, BF3.Et2OMDC:ACN

O

OH

OH

OH

OHCl

OGLI-II

DMAPPyridineAc2OMDC

LiOH . H2OTHF:MeOH:H2O

BCE

+

GLI-III

Flow Diagram:

Step-I: - GLI-I

BCMHexyl-Lithium

Stirring Toluene, THF

TTSGCH3SO3H, Methanol

Sodium bicarbonate Water

Layer Spearation Aq. Layer

Distilation

Org. Layer

GLI-I

Step-II: - GLI-II

Sodium bicarbonate Water


Distilation

Org. Layer

GLI-ITriethylsilane (Et 3SIH)

BF3Et2O

MDC + ACN

Stirring

GLI-II

Step-III: - GLI-III

WaterLayer Spearation Aq. Layer

Distilation

Org. Layer

GLI-II

Stirring

GLI-III

Acetic anhydride

Pyridine + DMAP

MDC

Step-IV:- GLI-IV


Distilation

Org. Layer

GLI-III

Stirring

GLI-IV

Lithium hydroxide H 2O

THF:MeOHWater

Ethylacetate

Step-V: - GLI

Stirring

GLI

Isopropanol

Water

GLI-IVS-(+)-1,2,-propanediol

Crystalization Filtrate ML

Drying & packing

62. Empagliflozin


(5-Bromo-2-chlorophenyl)(4-hydroxyphenyl)methanone (BCM) react with triethyl

silane (Et3SiH) in presence of BF3THF to give EMP-I. EMP-I is treated with tert-

butyldimethylsilyl chloride (TBDMSCl) to give EMP-II. EMP-II treated with hexyl

lithium and later it react with TTSG, followed with methanol methane sulfonic acid

then triethylsilane (Et3SiH) and BF3.Et2O to give EMP-III. EMP-III react with

HTF-tosylate (R-3-hydroxy tetrahydrofuran and p-toluene sulfonylchloride) to give

Empagliflozin (EMP).

The complete chemical name of this product is (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-

[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol.

Chemical Reaction:

OO

O

O

O

O

Si

Si

Si

Si

Br

Cl

OSi

CH3

CH3

CH3CH3

CH3

TTSG

Br

Cl

OH

O

Br

Cl

OH

Et3SiH

BF3 THF

TBDMSCl

4-(5-bromo-2-chlorobenzyl) phenol (EMP-I)(5-bromo-2-chlorophenyl)

(4-hydroxyphenyl)methanone (BCM)

[4-(5-bromo-2-chlorobenzyl)phenoxy] tert butyl dimethylsilane (EMP-II)

Hexyl lithium THF/Toluene

MethanolCH3SO3H

Cl

OH

OOH

OH

OHOH

OCH3

EMP-III

O

OS

O

O

CsCO3DMF

HTF Tosylate

Cl

O

O

OH

OH

OHOH

O

Empagliflozin

Flow Diagram:

Step-I: - EMP BCM

Stirring

Sodium bicarbonate

W ate rLaye r Spe aration Aq. Laye r

Distilation

O rg. Laye r

Trie thyl si lane (Et3SiH)

BF3THF

Tolue ne

C yclohexane

EMP-I

Fil trationO rg ML

Step-II: - EMP-II

Stirring

Water Laye r Spearation Aq. Layer

Distilation

O rg. Layer

EMP-II

EMP-I

TBDMSCl

Im idazole

Dichlorme thane

MDC re cove ry

Step-III: - EMP-III EMP-II

Stirring

Tolue ne + THF

He xayl l ith ium

TTSG

Stirring

Me thanol

C H3SO3H

Trie thyl si lane

BF3.Et2O

Stirring

Sodium bicarbonate

W ate r

Laye r Se paration Aq. layer

O rg. layer

Solve nts recove ryDistilation

Fil tration

Tolue ne

He xane s

EMP-III

Step-IV: - EMP-IV

Laye r Spe aration Aq. Laye r

O rg. Laye r

R-3-hydroxy te trahydrofuran

Stirring

p-tolue ne sul fonylchloride

W ate r

Pyridine

EMP-III

DMF

C s2C O3

Stirring

Laye r Spe arationW ate r

Ethyl ace tateAq. Laye r

O rg. Laye r

EMP

MTBEFil tration O rg. Laye r

63. Zaltoprofen


5-(1-Carboxyethyl)-2-phenylthio-phenylacetic acid was reacted with Polyphosphoric

acid at room temperature. Sodium Hydroxide solution quenching, washing and

purification afforded Zaltoprofen.

The complete chemical name of this product is (2RS)-2-(10-Oxo-10, 11-

Dihydrodibenzo[b,f] thiepin-2-yl) Propanoic acid.

Chemical Reaction:

CH3

COOH

S

COOH

CH3

COOH

S

O

phosphoric acid

2-[3-(carboxymethyl)-4-(phenylsulfanyl)phenyl]propanoic acid Crude Zaltoprofen

NaOH

Purification

PolyCH3

COOH

S

O

Zaltoprofen/Final

Flow Diagram:

64. Flurbiprofen


4-Acetyl-2-fluoro biphenyl, Sulphur, Morpholine reacted in presence of sulphuric

acid and later on hydrolyze by acetic acid. Work up and isolation affords

Flurbiprofen (Step-1). It reacts with diethyl carbonate and Dimethyl sulphate and

later on hydrolysis by sodium hydroxide affords Flurbiprofen (Final).

Chemical Reaction:

Sulphur

COOH

CH3

FF COCH 3

ONH

H2SO4F O CH3

O

Ethanol

Diethyl

Carbonate

DMSO

NaOH

4-Acetyl-2-fluoro-biphenyl Flurbiprofen (Step-1) Flurbiprofen

5-(1-Carboxyethyl)-2-

phenylthio-phenylacetic acid

Polyphosphoric acid

Sodium Hydroxide solution

Methylene chloride

Reaction

&

Work up

Ethyl acetate

Purification

Ethyl acetate Filtration Ethyl acetate mother liquor

Drying Zaltoprofen (Final)

Flow Diagram:

Flow diagram of Flurbiprofen (Step-1)

4-Acetyl-2-fluoro-biphenyl

Morpholine

Sulphur

Acetic acid

Sulphuric acid

Ethanol

Reaction

RO water

Sodium carbonate

Diethyl ether

Hydrochloric acid

Work up

&

Filtration

Aqueous layer

Drying Flurbiprofen (Step-1)

Flurbiprofen (Step-1)

Diethyl carbonate

Sodium ethoxide

Dimethyl sulphate

Acetic acid

RO water

Reaction & Workup

Sodium Hydroxide

Ethanol

Hydrochloric acid

Petroleum ether

Precipitation

Filtration Ethanol + Pet ether MLR

Drying Flurbiprofen (Final)

65. Felbinac - JP/BP


4-acetyl biphenyl reacted with morpholine and sulphur at high temp to give

thioacetomopholide. Theo acetomorpholide is treated with aqueous sodium

hydroxide to form Felbinac. Crude Felbinac purified to give Felbinac.

The complete chemical name of this product is Biphenyl-4-yl-acetic acid.

Chemical Reaction:

O CH3

+

O

NH

Sulphur

Methanol

N

O

S

4-acetyl biphenyl MorpholineThio acetomorpholide

O

OH

RO water

50% NaOH solution

Felbinac

Flow Diagram:

Stage-1

Stirring

4-Acetyl biphenyl

Morpholine

Sulphur

Methanol Stirring

Filtration Org MLR for

Methanol recovery

Drying

Thio aceto-

morpholide

Methanol

Stage-2

Stirring

Stirring

Filtration Aqueous MLR

Methanol recovery

Drying

FLC Crude

Aq. NaOH solution

Thio acetomorpholide

Con HCl

Stage-3

Stirring

Filtration

FLC (Crude)

Gl. Acetic acid

Activated Charcoal

Stirring

ORG ML

FLC Technical

Filtration

Drying

Solid waste

(hyflo + Carbon)

Stage-4

Stirring

Filtration

FLC (Technical)

Acetone

Water

ORG + Aq. ML

Drying

Felbinac

66. Loxoprofen Sodium


2-[4-(bromomethyl) phenyl] propanoic acid(2-BPP) was reacted with Sulfuric acid

in presence of methanol, the mixture was worked up as per process and separate

layers, after acid-base treatment, Organic layer completely distilled to give Methyl

2-[4-(bromomethyl) phenyl] propanoate(OXO-I) ,OXO-I reacts with ethyl-2-

oxocyclopentanecarboxylate(ECP), with DMF , the mixture was worked up as per

process and separate layers, Organic layer completely distilled to give Ethyl 1-[4-(1-

methoxy-1-oxopropan-2-yl) benzyl]-2-oxocyclopentanecarboxylate(OXO-II),OXO-

II reacts with glacial acetic acid and Con.HCl, the mixture was worked up as per

process and separate layers. Organic layer completely distilled and isolation to give

crude 2-{4-[(2-oxocyclopentyl) methyl] phenyl} propanoic acid (OXO-III),OXO-III

reacts with sodium hydroxide and water, in presence of IPA, mantain reaction mass

and cool, filtration give Loxoprofen Sodium(OXO-IV).

The complete chemical name of this product is Monosodium 2-{4-[(2-

oxocyclopentry)methyl]-phenyl}propanoate dehydrate.

Chemical Reaction:

Br

CH3 COOH

Br

CH3 COOCH 3

Methanol

H2SO

4

OXO-I (Ester)

2-[4-(bromomethyl)phenyl]propanoic acid

(2-BPP)

methyl 2-[4-(bromomethyl)phenyl]propanoate

COOEt

O

O

CH3

COOCH 3

COOEt

OXO-II (Diester)

Ethyl 2-oxocyclopentane

carboxylate (ECP)

ethyl 1-[4-(1-methoxy-1-oxopropan-2-yl)benzyl]-

2-oxocyclopentanecarboxylate

O

CH3

COOH

OXO-III (Base)

HCl/Acetic acid

2-{4-[(2-oxocyclopentyl)methyl]phenyl}

propanoic acid

O

CH3

COONa

OXO-Pure

NaOH-Water

2H2O

Loxoprofen sodium dihydrate

Solvent

Flow Diagram:

Process Flow Diagram:

Step-OXO-I

2-BPP

H2SO4

Process water

Work up

Organic Layer

Toluene

seperate layer

Organic layerNaOH solnseperate layer

Process water Organic layer

seperate layer

Organic layer

seperate layerProcess water

Distillation

Methanol

Maintaining

Reactor

Reactor

Aqueous Layer

Aqueous Layer

Aqueous Layer

Aqueous Layer

OXO-I

Step-II:-OXO-II

DMF

KOH

Reactor

Cooling

Maintaining

Work upAqueous Layer

OXO - II

seperate layer

Organic layer

Distillation

Ethyl-2-oxocyclopentanecarboxylate

Toluene

Process water

OXO-I

Step-III: - OXO-III

OXO-II

Acetic acid

WaterReactor

Toluene

Organic layer

NaOH soln

Process water

Organic layer

seperate layer

Distillation

Con HCl

Cooling

Toluene

seperate layer

Aqueous Layer

seperate layer

Toluene

Con HCl

Maintaining

Organic Layer-1

Aqueous layer-1

seperate layer Aqueous layer

Organic layerWater

Adjust pH

Aqueous layer

Organic layer

Adjust pH

Aqueous layer

Distillation

Stage-III Crude OilEthyl acetate

Cyclo hexane

Purification

OXO-III

Drying

Step-IV:- OXO-IV

IPA

OXO - IIIReactor

Maintaining

Aq. NaOH soln.

Heating & Filtration

IPA Mass

Maintaining

CoolingEthyl acetate

Filtration

Drying

Loxoprofen Sodium

67. Naproxen Sodium


DL-Naproxene is treated with n-octyl-D-glucamine in mixture of water and

isopropylalcohol to form diastereomeric salt S-(+) Naproxene NODG salt. S-(+)

Naproxene NODG salt split with aqueous sodium hydroxide solution to give S-(+)-

Naproxene sodium.

The Complete chemical name of this product is (S)-6-Methoxy-alpha-methyl-2-

naphthaleneacetic acid sodium salt or (2S)-2-(6-methoxynaphthalen-2-yl)propanoic

acid

Chemical Reaction:

+

OO

OH

H

N-Octyl-D-glucamine

(VIII)

S-(+)Naproxen NODG SaltOH

H OHH OH

HOHOHH

NH

OH

H OHH OH

HOHOHH

NH

NaOH

OO

ONa

(IX)

S(+)Naproxene Sodium

OO

OH

DL-Naproxen

Resolution

IPA water

Flow Diagram:

Step-I: -

Stirring

Water

Filtration Aqeous MLOrganic ML

DL-Naproxene

N-octyl-glucamineIsopropyl alcohol

S-(+)Naproxene NODG salt

Step-III: -

Stirring

S(+)-Naproxene NODG salt

water

Sodium hydroxide

Filtration Aqeous filtrate ML

S-(+)-Naproxene sodium

68. Mirabegron


4-nitrophenyl ethylamine hydrochloride (4-NPE) is reacted with R-Mandelic acid in

presence of EDC.HCl, HOBT and DMF to give (2R)-2-hydroxy-N-[2-(4-

nitrophenyl) ethyl]-2-phenylacetamide (BEG-I). BEG-I is treated with NaBH4 in

presence of BF3-THF to give (1R)-2-{[2-(4-nitrophenyl) ethyl] amino}-1-

phenylethanol (BEG-II). BEG-III is reacted with Fe in methanol: water and

aq.NaOH to give (1R)-2-{[2-(4-aminophenyl) ethyl] amino}-1-phenylethanol

hydrochloride (BEG-III). BEG-III is reacted with 2-Aminothiazol-4-yl-acetic acid

(ATAA) in presence of EDC.HCl to give Mirabegron Crude (BEG-IV). Purification

of BEG-IV from methanol and isopropyl alcohol to give Mirabegron (BEG-V).

The Complete chemical name of this product is 2-(2-amino-1,3-thiazol-4-yl)-N-[4-

(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide

Chemical Reaction:

+CO O H

OH

(R)-2-hydroxy-2-phenyl

acetic acid (RMA)

NO2

NH2

2-(4-nitrophenyl)propan-1-amine

hydrochloride(4-NPE)

NH

O

OH

NO2

(2R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]

-2-phenylacetamide(BEG-I)

ClH

EDC HCl

MDC, Toluene

NH

OH

NO2

(1R)-2-{[2-(4-nitrophenyl)ethyl]amino}

-1-phenylethanol(BEG-II)

NaBH4BF3-THF

NH

OH

NH2

(1R)-2-{[2-(4-aminophenyl)ethyl]amino}

-1-phenylethanol(BEG-III)

Fe/NaOH solution

S

N

NH2

OH

O

NH

OH

NH

S

N

NH2

O

Mirabegron crude (BEG-IV)

EDC HCl

(2-amino-1,3-thiazol-

4-yl)acetic acid

Puri fication

NH

OH

NH

S

N

NH2

O

Mirabegron (BEG-V)

Flow Diagram:

Step-BEG-I

DMF

(R) Mande lic acid

EDC.HCl

2-(4-nitrophe nyl )e thylam ine hydrochloride

TEA

1-Hydroxy be nz triazole

Water

Con HCl

Dichlorome thane Layer separation

Organic layer

K2C O3

Aq layer

Water

Stirring

Layer separationAq layer

Organic layer

Layer separationAq layer

Organic layer

Distillation

Recover toluene

Tolue neRecover MDC

Drying

BEG-I

Fil tration

Step-II:-BEG-II

BEG-I

THFMaintaining

Cooling

BF3-THF

NaBH4

Cooling

Water

Con HCl

Maintainig

Ethyl acetate

Na2CO3

Seprate layer Organic layer-IEthyl acetate

Seprate layerOrganic layer-II

Combine organic

layerWater Aq. layer

organic layer

Distillation

BEG-II (residue)Toluene

Cooling

CF & Drying

BEG-II

Step-III: - BEG-III

Methanol

BEG-II

Maintaining Fe

Ammonium chloride

Methanol

Water

Cool & Filter

Distillation

Cool Water

NaOH

FiltrationWater

Wet MaterialIPA

Cool & Filter

Drying

BEG-III

Step-IV: - BEG-IV

Con.HCl

Water

2-aminothiazole-4-yl

-acetic acid

BEG-III

Maintaining

Cooling Sodium hydroxide

EDC.HCl

Filtration

BEG-IV wet cakeWater

Maintaining

Filtration

BEG-IV wet cakeWater Filter ml

BEG-IV wet cakeMDC Filter ml

BEG-IV

Maintaining

Drying

Step-V: - BEG-V

Methanol

BEG-IV

Maintaining

filtration

Distillation

IPA Residue

Filtration

IPA wash Wet cake MLR and washing MLR

BEG

Drying

IPA Maintaining

69. Deferasirox


Chlorination reaction of Salicylic acid (SAC) by Thionyl chloride to give the

Salicylic acidchloride which is then condensed with Salicylamide (SLD) in order to

obtain the intermediate 2-(2-Hydroxyphenyl)-4H Benzo[e][1,3]oxazin-4-one(DFX-

I). Intermediate is reacted with 4-hydrazino benzoic acid (HBA) to give crude

Deferasirox (DFX-II). Purification of Deferasirox crude to be done in appropriate

solvent to give Deferasirox (DFX).

The complete chemical name of this product is 4-[3,5-bis(2-hydroxyphenyl)-1H-

1,2,4-triazole-1-yl]benzoic acid.

Chemical Reaction:

OOH

OH

COCl

OH

ONH2

OHN

O

OH

O

(SAC)

(SLD)

(DFX-I)

N

OH

N N

OH

HOO C

N

OH

N N

OH

HOO C (HBA)

(DFX-II)(DFX)

Purification

Salicylic acid

Salicylamide

OH O

NH

NH2

4-Hydrazino benzoic acid

Deferasirox

Flow Diagram:

Step-DFX-I

Solvent

Reaction

Distillation Recovered Solvent

Salicylamide

Thionyl chloride

Salicylic acid

Reaction

Solvent

Centrifuge Filter mlSolvent

DFX-I

Distillation Recovered Solvent

Step-II:-DFX-II

SolventReaction

4-Hydrazino benzoicacid

DFX - I

Maintain Dimethylformamide

Activated charcoal

Sparkler

Precipitation

Filter mlCentrifugeWater

Solvent

DFX-II

Step-III: - DFX-III

SolventReaction

DFX - II

Sparkler

Liquid Ammonia

Water

Precipitation

Activated charcoal

Filter ml

Deferasirox

Centrifuge

Drying

Acetic acid

Water

Solvent

70. Colesevelam


Stage-1: Preparation of poly(allylmine-co-N,N’-diallyl-1,3-diamino-2-

hydroxypropane)hydrochloride salt – Polyallylamine Hydrochloride 50% is diluted

with DM water and then partially neutralized (10.0-10.5) by using 50% Sodium

Hydrochloride Soln. Then reaction mass cross-linked with Epichlorohydrin to get

poly(allylmine-co-N,N’-diallyl-1,3-diamino-2-hydroxypropane)hydrochloride salt.

Stage-2: Preparation of Allylamine polymer with 1-chloro-2,3-epoxypropane,[6-

(allylamino)-hexy]trimethylammonium chlorideand N-allyldecylamine,

hydrochloride (Colesevelam Hydrochloride) - poly(allylmine-co-N,N’-diallyl-1,3-

diamino-2-hydroxypropane)hydrochloride salt treated with 1-bromo decane and 6-

bromohexyl Trimethyl Ammonium Bromide & 50% Sodium Hydroxide in

Methanol. Then after completion, reaction mixture was neutralized by HCl and solid

filtered and washed by Methanol. 2 M sodium chloride soln.and D.M. Water to get

Colesevalam Hydrochloride.

Chemical Reaction:

Flow Diagram:

71. Tricyclo [3.3.1 13, 7] decan-1- aminium, N, N, N-Trimethyl hydroxide

(TMA)


1-Adamantanamine reacted with dimethyl sulfate in toluene to give mono-methyl

aminium salt. Mono-methyl aminium salt reacted with dimethyl sulfate in presence

of sodium hydroxide to give Tri-methylaminium salt. Tri-methylaminium salt treated

with sulfuric acid to give Trimethyl Aminium sulfate salt. Trimethyl Aminium

sulfate salt treated with sodium hydroxide in aqueous isopropyl alcohol as a solvent

to give Trimethyl Aminium hydroxide.

Chemical Reaction:

Flow Diagram:

1-Admantamine TMA

Toluene

Dimethyl sulfate

Stirring

36% Sodium hydroxide

1-Admantinamine

Process water

Organic Layer

TMA

Layer separation

Isopropyl alcoholFiltration By-product

sod. sulfate

Filtrate

Distilation Recovered IPA + Water

72. N, N-Dimethyl- 3, 5-dimethyl piperidinium hydroxide (TMP)


3, 5-Dimethylpiperidine is reacted with dimethyl sulfate in the presence of sodium

hydroxide in toluene to give 1, 1, 3, 5-Tetramethylpiperidin-1-ium methyl sulfate.

1,1,3,5-Tetramethylpiperidin-1-ium methyl sulfate treated with aqueous sulfuric acid

in toluene at to give 1,1,3,5-Tetramethylpiperidin-1-ium hydrogen sulfate. 1,1,3,5-

Tetramethylpiperidin-1-ium hydrogen sulfate treated with aqueous sodium

hydroxide in isopropyl alcohol to produce 1,1,3,5-tetramethylpiperidin-1-ium

hydroxide.

Chemical Reaction:

Flow Diagram:

Reaction

Toluene

3,5-Dimethylpiperidine

Dimethyl sulfate

Sodium hydroxide (Aq.)

Maintaining

Sulfuric acid (Aq.)

Distillation

Residue

Isopropyl alcohol

Sodium hydroxide (Aq.)

Filtration Byproduct Sodium sulphate

Filtrate MLR

Distillation

1,1,3,5-Tetramethylpip

eridin-1-ium hydroxide

[TMP]

Recovered toluene

Recovered IPA + Water

73. Pirfenidone


2-Amino-5-methylpyridine (2-AMP) under diazotization with sodium nitrite in

water. After completion of the reaction neutralize with sodium hydroxide solution

and extracted product in methylene dichloride followed distillation of solvent and

product is isolated by filtration to form Stage-01 (FEN-I).FEN-I is treated with

bromobenzene in the presence of potassium carbonate and copper(I) iodide as

catalyst at higher temperature for 10-12 hrs. After completion of the reaction toluene

is added and filtered the mass and separate out inorganic salt. Filtrate MLR further

distillation under vacuum. Product is isolated by adding toluene and cyclohexane

from residue to form Pirfenidone stage-02 (FEN-II). FEN-II is crystalize in purified

water and TBAB heat to get clear solution which is further gradually cooling and

FEN is separated by filtration.

The complete chemical name of this product is 5-methyl- 1-phenyl- 2(1H)-

pyridinone

Chemical Reaction:

N

H

O

5-methylpyridin-2(1H)-one

N NH2

NaNO 2

5-methylpyridin-2-amine

Br

N O

5-methyl-1-phenylpyridin-2(1H)-one

bromobenzene

Cu /K2CO3

(FEN-I)

(FEN-II)

N O

Pirfenidone

(FEN)

Purification

Flow Diagram:

Flow chart of Pirfenidone stage-01 (FEN-I)

RBFWater

2-AMP

NaNO 2 Solution

-5°C to +5°C

-5°C to +5°C

Maintaining

MDC

Layer separation

Reaction mixture

Reaction mixture

Distillation of organic layer Recovered MDC

Residue

Cooling

Filtration

Ethyl aceate

Ethyl acetate for washing

FEN-IDrying

(Temp: 28°C to 38°C)

Flow chart of Pirfenidone stage-02 (FEN-II)

Bromo benzene

FEN-I

K2CO3

CuI

RBF

Heating

Maintaining

Reaction mixtureToluene

Filtration In organic salt

Distillation Recovered Toluene + bromobenzene

ResidueToluene

IPA

Heat to clearCyclohexane

Cooling

Filtration

Drying

FEN-II

MLR

Flow chart of Pirfenidone stage-03 (FEN-III)

RBF

Heating

Cooling

Filtration

Drying

FEN-III

FEN-II

Purified water

(Final)

74. Apalutamide (CAP/CBF)

Manufacturing Process of Apalutamide (CAP):

3-(trifluoromethyl)pyridine react with hydrogen peroxide in dichloromethane to

form Cap-I. CAP-I in-situ react with trimethyl silyl cyanide in presence of TEA to

give CAP-II. CAP-II react with tetraethyl ammonium nitrate to in presence of

trifluroacetic acid anhydride followed by reduction of iron in acetic acid to give

CAP.

Chemical Reaction:

N

F

FF

3-(trifluoromethyl)pyridine

H2O2

DCM N

F

FF

O

Trimethylsilyl cyanide

N

F

FF

N

TEA

tetraethyl ammonium nitrate

(CF3CO)2O

Iron powderCH3COOHN

F

FF

N

NH2

2-Cyano-3-(trifluoromethyl)-5-aminopyridine

CAP-I

CAP-IICAP

Flow Diagram:

Stirring

3-(trifluoromethyl)pyridine

Hydrogen peroxideDichloromethane

CAP-ITrimethylsilyl cyanide

Triethylamine

Layer separation Aq. Layer

CAP-II

Organic layer

Water

Tetraethylammonium nitrate

(CF3CO) 2O

Iron

Acetic acid

Water

Sodium hydroxide

Acetic acid recovery

Filtration Solid waste (Celite + Iron)Cellite (hyflo powder)

Stirring

Filtration Aq. filtrate ML

CAP

Manufacturing Process of Apalutamide (CBF):

2-Fluoro-4-nitrotoluene (I) treated with pot. Permanganate to give 2-fluroro-4-

nitrobenzoic acid (CBF-I). II is treated with thionyl chloride in presence of N,N-

DMF and later it reacts with methylamine solution to give N-methyl-2-fluoro-4-

nitrobenzamide (CBF-II). Reduction of CBF-II carried out in presence of Iron and

acetic acid to give N-methyl-04-fluroro-4-aminobenzamide CBF-III. CBF-III is

reacted with cyclobutanone in presence of sodium cyanide to give 4-[(1-

cyanocyclobutyl)amino]-2-fluoro-N-methyl]-benzamide (CBF).

Chemical Reaction:

F

NO2

Oxidation (Liquid phase)

F

COOH

NO2

(i) SOCl 2, CH 2Cl2

(ii) CH 3NH2

F

CONH-CH 3

NO2

IRON, Acetic acid

F

CONH-CH 3

NH2

NaCN

Cyclobutanone

O

F

CONH-CH 3

NH

N

KMNO 4, NaOH

4-[(1-cyanocyclobutyl)amino]-2-fluoro-N-methylbenzamide

CBF-II

CBF

2-Fluoro-4-nitrotoluene CBF-I

CBF-III

Flow Diagram:

Step-I: - CBF-I

Stirring

Filtration

CBF-I

2-Fluoro-4-nitrotoluene

(KMnO4)

Water

CelliteSolid waste (Cellite + MNO 2)

HCl Filtration Aq.filtrate

Step-II: - CBF-II

Stirring

Methylamine (40% soln) Sitrring

Water Filtration

CBF-II

Aq. layer

CBF-II

Thionyl chloride

N,N-DMF

DichloromethaneDistilation

MDC + Thionyl chloride recovery

Step-III: CBF-III

Stirring

CBF-II

IRON

Acetic acid

Filtration Solid waste (Cellite + Fe)Cellite

Distilation Recovered acetic acid

Water

NaOHStirring

FiltrationAq. Filtrate ML

CBF-III

Step-IV: CBF

Stirring

FiltrationWater

CBF-III

Sodium cyanide

Cyclobutanone

Aqueous filtrate ML

CBF

75. 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-

yl}methyl)thiophene-2-carboxamide (BAN/Rivaroxaban)


4-(4-Aminophenyl) morpholin-3-one (APM) is reacted with 2-[(2S)-oxiran-2-

ylmethyl]-1H-isoindole-1,3(2H)-dione (OXIRAN) in aqueous Isopropanol (IPA) ,

the mixture was worked up to isolate wet (BAN-1). BAN-1 is reacted with N, N’-

Carbonyldiimidazole (CDI) in presence of 4-Dimethylamino pyridine (DMAP) in

toluene, to give (BAN-2). BAN-2 in methanol is treated with 40% methylamine

aqueous solution to give (BAN-3).

5-chlorothiophene-2-carboxylic acid (CTA) is reacted with thionyl chloride in

toluene, excess thionyl chloride and toluene are distilled out. The residue is diluted

with MDC to obtain solution of 5-chlorothiophene-2-carbonyl chloride (CTC-MDC

mass). (BAN-3) is reacted with 5-chlorothiophene-2-carbonyl chloride (CTC) in

presence of K2CO3 in MDC to give crude Rivaroxaban (BAN-4). BAN-4 was

dissolved in formic acid and IPA, filtered to remove any insoluble and the filtrate is

chilled and filtered to give pure Rivaroxaban (BAN).

The complete chemical name of this product is 5-chloro-N-({(5S)-2-oxo-3-[4-(3-

oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide

(BAN).

Chemical Reaction:

5-chlorothiophene-2-

carboxylic acid

SCl

O

OH SCl

O

Cl

(CTA) (CTC)

Toluene

Thionyl chloride

N

OO

NH2

4-(4-aminophenyl)morpholin

-3-one

N

O

O O

N

O

OOH

N

O

ONH

N

O

OO

NO

O

N

O

DMAP

NH2

O

NO

O

N

O

NH

O

NO

O

N

O

SCl

O

40% Methyl amine

IPA : H 2O

Methanol

ClH

NH

O

NO

O

N

O

SCl

O

Formic acid

Rivaroxaban

MDC Anhy. K2CO3

IPA

2-[(2S)-oxiran-2-ylmethyl]

-1H-isoindole-1,3(2H)-dione

(APM)

(BAN-1)

(OXIRAN)

(BAN-2)(BAN-3)

(BAN crude)(BAN)

+

Toluene

CDI

+

5-chlorothiophene-2-

carbonyl chloride

(BAN-4)

Flow Diagram:

Step-BAN-I

Isopropyl alcohol

4-(4-aminophenyl)morpholin-3-one

Water

2-[(2S)-oxiran-2-ylmethyl]-1H-indene-1,3(2H)-dione

Isopropyl alcohol

Maintaining

Cooling

Filter ml

BAN-I

Centrifuge

Step-BAN-II

Cabonyl diimidazole (CDI)

Toluene

BAN-I Wet cake

Toluene Azeotropically

distillation

4-Dimethyl aminopyridine (DMAP)

Maintaining

Cooling

Filtration Filter ml

Water

BAN-II

Step-III: - BAN-III

Methanol

40% Methylamine solution

BAN-II

Maintaining

Cooling

Con. HCl Maintaining

Filter ml

Filtration

BAN-III

Step-IV: - BAN-IV

Toluene

5-Chlorothiophene-2-carboxylic acid (CTA)

Thionyl chloride

Maintaining

Distillaiton of toluene and

thionyl chloride Mixture of recover toluene

and thionyl chloride

MDCMDC mass containing

5-Chlorothiophene-2-carbonyl

chloride (CTC)

BAN-III

MDC

Potassium carbonate

Maintaining

Purified Water

Maintaining

Filtration

BAN-IVMethanol washing

Filter ml

Washing MLR

Step-V: - BAN-V

Formic acid

BAN-IV Wet cake

Maintaining

Hot filtration

Cool

IPA wash

Filter mlFiltration

BAN

76. Trimethyl Pyruvic Acid (Kito Acid, KTA)


Pinacolone is oxidized by Potassium Permanganate in alkaline condition to give

Keto Acid.

Chemical Reaction:

CH3

CH3

CH3

CH3

O

Pinacolone

Oxidizing Agent

NaOH

CH3

CH3

CH3 O

O

OH

Keto acid

Flow Diagram:

Pinacolone

Oxidizing agent

Sodium hydroxide +water

Reaction


Water Clarification Keto Acid

77. N Acetyl Hydroxy Phenyl Piperazine


Para Amino Phenol is reacted with BCA HCl in aqueous Methanol and the product

formed is reacted with acetic anhydride and the crude product isolated is purified

using Methanol as solvent.

The Complete chemical name of this product is 1-acetyl-4-(4-hydroxy phenyl)

piperazine.

Chemical Reaction:

N-Acetyl-4-(4-Hydroxyphenyl) Piperazine

Cl.CH2.CH2

Cl.CH2.CH2

NH2

NH.HCl

p-Amino Phenol

OH

BCA.HCl

+

Methanol NaOH -2HCL

N

N

COCH3

OH

AHPP

N

NH

OH

(CH3CO)2O + Methanol + Cat A + caustic soln

Flow Diagram:

78. Amino Ethyl Phosphoric Acid


N-Hydroxy phthalimide is reacted with 48% HBr to get AMPA stage II in solid

form, which is further reacted with Triethyl phosphite to get stage III. Stage III is

further reacted with hydrazine hydrate and hydrolysis further to give final product

viz. Amino ethyl phosphoric acid.

GLR-10

SSR-03

STAR FILTER

SSR-11

CF-01

GLR-20

TD-05

PACKING

GLR-15

CF-06

Methanol slurry

Drying N/D

Water washing

Chemical Reaction:

NH

NH

O

O

NCH2OH

HBr

solution

O

NCH2Br

O

AMPA Stage II AMPA Stage I

NCH2P-(OEt)2

O

O

AMPA Stage III

P(OEt)3

Tri Ethyl

Phosphite + C2H5Br

NH2CH2P-(OEt)2

+

O

O

AMPA Stage IV

O

NH2CH2P-(OH)2

AMPA Stage V

Hydrolysis

Amino methyl phosphoric acid

NH2NH2

Flow Diagram:

79. (1-Isopropyl-4-(hydroxyl Phenyl) (piperazine)


4 – Methoxy Phenyl Piperazine base reacts with Iso Propyl Bromide in DMF solvent

gives MPEMP. This on Hydrolysis with Hydrobromic acid gives IHPP. (HPEMP).

Chemical Reaction:

N

NH

OCH3

+

CH3

CH3

Br

Toluene

Sodium BicarbonateN

N

OCH3

CH3 CH3

NaOH

N

N

OH

CH3 CH3

IHPP

1-(4-methoxyphenyl)piperazine

Methanol / Water

GLR-105

PPNF-01

TD-01

SSR-05

CF-03

Wash by Methanol

Drying

SSR-05

CF-02

TD-02

Distillation

Drying

Flow Diagram:

4-Methoxyphenyl piperazine

Isopropyl bromide

Sodium Bicarbonate

Toluene

Sodium hydroxide

Methanol Water

Reaction

Water Filtration Alkali aqueous ML + toluene

Drying IHPP

80. Cilastazol


6-Hydroxy-3-,4-dihydro-2-quinolinone react with 5-(4-chlorobutyl)-1-cyclohexyl-

1H-tetrazole using sodium hydroxide in presence of Catalyst in water / solvent

mixture at 85-90°C for 15 hrs. to form crude Cilostazol, Purification by methanol

afforded pure Cilostazol.

The complete chemical name of this product is 6-[4-(1-cyclohexyl-1H-tetrazol-

5yl)butoxy]-3,4-dihydro carbostyril.

Chemical Reaction:

N

H

O

O N

N

N

NCilostazol (Crude)

N

H

O

OH Cl

N

N

N

N

+

NaOH

Catalyst

Water

6-HQ

CBCHT

Purification

Cilostazol

Solvent

Solvent


6 - HQ

CBCHT

Catalyst

Water/Solvent

Reaction mixture,

Heat to 85 - 90°C

Cool to 5 - 10 °C

Filtration

ZOL - I

MLRSolvent

Maintain 15 hrs

Stage-2

Reaction mixture

Heat to 40 - 45°C

Clear solution

Cool to 25 - 30°

Fitration

ZOL - II

ZOL - I

Water/solvent

SolventMLR

81. R & D Product

These are lab scale products produced out of R& D Activities



ANNEXURE- VII

DETAILS OF WATER CONSUMPTION

• Source of water: GIDC

Particulars Existing water

consumption

(KL/Day)

Proposed

consumption

(KL/Day)

After expansion

consumption

(KL/Day)

i) Domestic+

Others

(gardening etc)

21.2 0 21.2

Process 25 15 40

Boiler 12 40.5 52.5

Cooling 64.8 119.5 184.3

Washing 42 26 68

Total 165 201 366

.

DETAILS OF WASTEWATER GENERATION

Particulars Existing Wastewater

generation (KL/Day)

Proposed

Wastewater

generation (KL /Day)

After Expansion

Wastewater generation

(KL /Day)

i) Domestic+

Others

(gardening etc)

10 0 10

i) Industrial

Process 14 16 30

Boiler 4 0 3

Cooling 3 0 4

Washing 24 44 68

RO reject 0 25 25

Total 55 85 140



Water Balance Diagram

Total water requirement

366 KLD

Domestic &

Gardening

21.2 KLD

Process

40 KLD

Boiler

52.5 KLD Cooling Tower

184.3 KLD

Washing

68 KLD

Soak Pit

10 KLD

Process Effluent

30 KLD

Blow Down

3 KLD

Blow Down

4 KLD

MEE & ETP Plant 140 KLD

To NCT

55 KLD

RO

85 KLD

RO Permeate

60 KLD

55 KLD

Recycle 60 KLD

Recycle 60 KLD

RO reject to MEE 25 KL



ANNEXURE-VIII

EFFLUENT TREATMENT PLANT

HIGH STRENGTH EFFLUENT STREAM:

Following measures shall be adopted to reduce the strength of waste water— � PRE-TREATMENT

The effluents from various plants will be collected in individual sumps/tanks and will be equalized in Collection

Tank. They will be neutralized in Neutralization tank by using acid or alkali as per requirement till required pH

range obtained. This neutralized effluent will be filtered through Filter Press. This will be passed through

clarifier after pH increase by alkali and Settleable solids will be separated out. The supernatant will be

neutralized using acid and fed to stripper. � TREATMENT

The filtered effluent will be fed to Solvent Stripper for Recovery of solvents. This stream afterwards shall be

subjected to Multiple Effect Evaporator (MEE) (Under Vacuum Evaporation). Condensate shall be transferred

in O & G Chamber for further treatment at ETP. The concentrated stream (recycle) will be transferred to

Agitated Thin Film Dryer (ATFD) for drying salts and bagging. This will be stored in hazardous Waste Storage

Yard and disposed of for landfilling to TSDF’s as per requirement.

LEAN STRENGTH STREAM EFFLUENT:

The lean effluents will comprise of utility blowdown, MEE condensate, Reject water, etc. They shall be mixed

with other streams and the combined effluent shall be subjected to following treatment cycle.

� PRIMARY TREATMENT

1. Screen, Oil and solvent trap: - This will ensure removal of free and floating material, oily material and

solvents. These are to be removed manually. The oil and solvent trap unit operation shall work on gravity

separation principle.

2. Equalization cum Neutralization tank: - The effluent after removal of screenings, oily matter / solvents shall

be collected in equalization cum neutralization tank. Suitable mixing device (flash mixer) shall be used to mix

the contents of the tank. Acid and alkali shall be used as per the incoming effluent pH. A pH of 7 to 8 shall be

maintained here.

3. Tube Settler: - This will be used to remove the Settleable solids from the effluent by sedimentation process

and the effluent will be further transferred to Anoxic tank.

� SECONDARY TREATMENT

Biological Treatment: The biological treatment consist of an Anoxic tank to remove excess Ammonical

nitrogen from effluents. It will be followed by Aerobic process. There are two aeration tanks with diffused

aeration system. The oxygen supply shall be done by use of air blower and air bubble diffusers. Suitable levels

of mixed liquor suspended solids (MLSS) shall be maintained in the aeration system as per detailed biological

process design. The excess biological sludge shall be discharged over to the sludge handling system via two

clarifiers connected with each aeration tank.



� TERTIARY TREATMENT

Partial Quantity of treated effluent after biological treatment shall be collected and transferred to Treated

Effluent Collection Tank for disposal to FETP. This will be pumped in overground pressurized pipelines to

GIDC pumping stations. Rest of the treated effluent shall pass through Activated carbon filter, Multi Grade

Sand filter. This effluent will be fed to UF and RO plants. The reject will be added to MEE feed and permeate

will be recycled back to Cooling Towers, Scrubbers, water ejectors, etc. for further reuse. � SALT/SLUDGE TREATMENT

Salt/Sludge handling system: The system shall consist of VTFD, filter press and decanter centrifuge. The

salt/sludge shall be dewatered/dried and salts/sludge cake shall be bagged. They shall be stored in Hazardous

Waste Storage Yard and disposed of to TSDF’s as per requirement. � HAZARDOUS WASTE TREATMENT

The Hazardous waste generated from various plant processes will be collected, segregated and stored at

Hazardous Waste Storage Yard. They will be disposed to TSDF’s, Registered Recyclers, Refiners, Co-

processing Units, etc. complying all legal requirements.

MEE OPERATION PROCEDURE

Effluent Feeding:

Neutralized effluent (High COD) from neutralization tank after passing through filter press shall be brought for

treatment through pipeline in balance tank at MEE plant.

Pre Heaters

This effluent will be pumped to Pre-heater 3, 2, 1 in series and finally to stripper column via MEE feed pump

with a flow of 1900-1950 Lit/Hr. and finally to solvent stripper column through pumping under vacuum.

Main Steam application

After starting feed pump gradually open TVR Valve and maintain high steam pressure around 4.0 Kg/Cm2.

Solvent stripper Unit

Start Solvent stripper column pump and maintain solvent stripper column level (Half level of side glass)

through adjustment of valve of Reboiler & recycle valve. Open Low pressure steam valve gradually for solvent

stripper column/re-boiler and maintain Temp around 85 oC. When desired temp. attained in stripper

column/Reboiler start condensate pump and transfer low boiler vapor condensate via surface condensers to

Stripper condensate collection tanks. The residual high boiler effluent will be transferred to Calendria 1.

Calendria’s

After receiving high boiler effluent start Calendria pump No. 01, 2, and 3 in successions after necessary level is

maintained in calendria’s. During level maintenance apply steam gradually and maintain upto 8.0 Kg/cm2.



Condensate Pump

After full steam is applied in MEE, MEE condensate pump is started and the condensate received via MEE

surface condensor (primary and secondary) is recirculated back in balance tank till colour of the condensate is

clear, colourless & free from any suspended solids. Then transfer this condensate water in MEE O/L collection

tank via MEE condensate pump.

Recycle Pump

The remaining concentrated mass will be transferred after checking Baume (specific gravity) in VTFD Balance

Tank via recycle pump for further drying process in VTFD.

VTFD Unit

Start VTFD vacuum pump ensuring cooling circulation via vacuum Syntax pump.

The concentrated mass is kept agitated in VTFD Balance tank and is fed in VTFD agitator via VTFD feed

pump. Simultaneously open high pressure steam valve for VTFD and Maintain steam pressure 8.0 – 8.5 Kg/cm2

gradually.

Start main VTFD Agitator and set the valve opening such that dry powder/salt is received at the bottom end.

Start Condensate pump and transfer condensate received from VTFD surface condensor to E.T.P.

Collect dry powder/salt in drum from VTFD bottom hopper. Fill this powder/salt in empty bags and shift to Haz

Waste storage yard and dispose to TSDF time to time.

TABLE: 11

DEMENTIONAL DETAILS OF ETP UNITS

DIMENSIONAL DETAILS OF ETP UNITS

Sr.

No. Name of Equipment Capacity

Retention

time in Hrs. MOC

1 Collection Tank 66 KL 26.4 RCC

2 Neutralization Tank 41 KL 16.4 RCC

3 Filter Press 10 M3/hr - MS

4 Filter Press Tank 05 KL

� RCC

5 MEE Plant – Old 40 M3/Day - SS

6 MEE Plant - New 80 M3/Day SS




Sr.


Retention

time in Hrs. MOC

7 Stripper I/L Clarifier 26 KL

RCC

8 O & G Chamber 1.70 KL

RCC

9 Neutralization Tank 3 KL

RCC

10 MEE O/L Collection Tank (New Eq.

Tank)

61 KL 14.4 RCC

11 Tube Settler 27 KL 0.17

RCC

12 Anoxic Tank 19 KL

RCC

13 Aeration tank-1 463 KL 84

RCC

14 Primary Clarifier 26 KL

RCC

15 Aeration Tank-2 409 KL

RCC

16 Secondary Clarifier 26 KL

RCC

17 New Final Treated Effluent Tank 10 KL

RCC

18 Activated Carbon Filter (ACF) FRP *** *** FRP

19 Multi Grade Filter (MGF) FRP *** *** FRP

20 Ultrafiltration Plant (UF) (PVDF) 100 M3/Day SS

21 UF Permeate Tank 5 KL HDPE

22 Reverse Osmosis Plant (RO) 100 M3/Day SS

23 RO Permeate Tank 5 KL HDPE

24 Secondary O/L Collection tank 40 KL RCC

25 Holding Tank 12 KL 2.4 MS

26 Treated Effluent Tank 165 KL 72 RCC

27 MEE Cooling Tower - Old 70 TR RCC

28 MEE Cooling Tower - New 400 TR RCC




Sr.


Retention

time in Hrs. MOC

29 VTFD – Old 160 Kg/Hr. SS

30 VTFD – New 215 Kg/Hr. SS

31 Decanter Centrifuge 2 M3/Hr. SS

32 Decanter Feed tank 2 KL RCC



FIGURE:3

FLOW DIAGRAM OF ETP

Dosing System

Stripper Condensate to Incineration / MEE C.T

MEE Condensate to New Eq. Tank (L.COD)

MEE Concentrate to VTFD / Storage Tanks

VTFD Salt to TSDF after bagaging

EFFLUENT TREATMENT SCHEME - ZCL CHEMICALS LIMITED

By gravity from

QC and R & D

and from U-3 & U-

1 sump via

pumping

LCOD effluent

from U-4

U-4 H.COD &

L.COD Sumps via

pumping

Sewage Effluent

From U-3 & U-1

sump via

pumping

REJECT

EFFLUENT

TO MEE

PERMEATE TO

REUSE IN C.T.'S,

UTILITIES

U-2 (NPC) sumps

via pumping

Low COD

Effluent from

Utilities

To Final

Discharge

Tank

(165 KL)

U-2 (NPC)

Sumps via

pumping

Sludge to

TSDF

To NCT (FETP)To Deep Sea

Decanter Feed

Tank

Sludge after

bagaging to

TSDF

Decanter

Centrate to

Low or High

COD Eq. Tank

To GIDC

Pumping

Station-B

Collection Tank(66 kl)

U-3 + U-1 effluent

tank T-03(10 kl)

Unit-2 effluent

tank T-02(10 kl)

Unit-2 effluent

tank T-01(10 kl)

Neutralization Tank(41 kl)

MEE PLANT with solvent stripper &

ATFD(80 KL/Day)

MEE PLANT with solvent stripper &

VTFD

Low COD Equalisation Tank

Neutralization Tank

with flash mixer

O & G Chamber

Aeration tank-1 (463 KL)

Anoxic Tank

(19 KL)

Settler(27 KL)

Primary Clarifier(26 KL)

Aeration tank-2 (409 KL)

Secondary Clarifier

Treated Effluent

Collection Tank

M

G

F

A

C

F

UF & RO Unit

Decanter

Centrifuge

QC + Unit-1 +

R & D + effluent

tank T-07(10 kl)



FIGURE :4

FLOW DIAGRAM OF EXISTING MEE (40 KLD)



NEW MEE PLANT (80 KLD)



ANNEXURE-IX

ELECTRICITY AND FUEL CONSUMPTIONS

Sr.

No.

Particulars Existing as per

Consent Quantity

Proposed

Quantity

Total Quantity Source

1.

Natural Gas for

Boiler & Thermic

Fluid Heater

290 M3/Hrs NO

CHANGE 290 M3/Hrs. Gujarat Gas

2. Diesel For DG Sets 117 Lit./Day NO

CHANGE 117 Lit./Day

Local

Supplier

3. Energy-Electricity 1900 KVA NO

CHANGE 1900 KVA DGVCL



ANNEXURE- X

DETAILS OF FLUE GAS EMISSIONS

Sr.

No.

Stack

Attached

To

Stack

Heigh

t

Stack

Diameter

Fuel

Consumption

Air

Pollution

Control

System

Type

of

Emission

Permissible

Limit

Existing Flue gas Emission As per CCA

1. Boiler

3TPH 30 m

0.45m

(Top) Natural gas --

PM

SO2

NOx

150

mg/NM3

100 PPM

50 PPM

2. Thermic

fluid heater 22 m

0.5m


3. DG Set-1

(250 KVA) 7 0.15m Diesel --

4. DG Set-2

(750 KVA) 8 0.2m Diesel --

After Expansion Flue gas Emission

1.

Boiler*

5TPH

(Stand By) 30 m

0.45m

(Top)

Natural gas --

PM

SO2

NOx

150

mg/NM3

100 PPM

50 PPM

2. Boiler

3TPH Natural gas --

3. Thermic

fluid heater 22 m

0.5m


4. DG Set-1

(250 KVA) 7 0.15m Diesel --

5. DG Set-2

(750 KVA) 8 0.2m Diesel --

6. DG Set-3*

(1010 KVA) 30 m 0.2 m Diesel --

* Boiler (5TPH)(Stand By) and DG Set-3 (1010 KVA) applied for CTE. The application No. is 118851 in XGN



PROCESS EMISSIONS

Note: There will be no change in proposed process emissions due to Proposed Project.

DETAILS OF AIR POLLUTION CONTROL SYSTEM

Unit has 2 Scrubbers installed at site. One is located at U-2 and second is located at U-4.

Sr.

No.

Stack

Attached

To

Stack

Height

(m)

Stack

Diameter

(m)

Air Pollution

Control System

Type of

Emission

Permissible

Limit

As per Existing

1.

Reactor Vessel

Plant – 4

25 0.15 Water Scrubber +

Caustic Scrubber

Hydrochl

oric Acid

SO2

CL2

20 mg/Nm3

40 mg/Nm3

9 mg/Nm3

2. Reactor

Vessel Plant –

2

15 0.15 Water Scrubber +

Caustic Scrubber

Hydrochl

oric Acid

CL2

NH3

20 mg/Nm3

9 mg/Nm3

175 mg/Nm3



ANNEXURE- XI

DETAILS OF HAZARDOUS WASTE

Sr.

No.

Processes as per

Schedule-1

Name of Waste

as per

Schedule-1

Type of waste Cat.

Quantity for Financial

Year

Method of disposal Existing

quantity

in

MT/year

After

Expansion

Quantity in

MT/year

1 Purification and

treatment of exhaust

air/gases, water and

waste water from the

processes in this

schedule and

common industrial

effluent treatment

plants (CETP’s)

Chemical sludge

from waste water

treatment

ETP Sludge 35.3 339 550 Generation, collection,

storage within factory

premises, transportation and

Disposal at TSDF operated

by M/s BEIL, Ankleshwar

or any other authorized

TSDF.

2 Purification process

for organic

compounds /solvents

Spent carbon or

filter medium

Carbon Waste 36.2 18.25 50 Generation, collection,



Disposal through co-

processing at cement plants

like M/s Ambuja cement or

TSDF like M/s RSPL.

Incineration/co-processing

at TSDF like M/s BEIL,

Ankleshwar.



3 Production and/or

industrial use of

solvents

Distillation

residues

Distillation

residue

20.3 36.5 105 Generation, collection,



disposal through GPCB

authorized agencies for co-

processing or Incineration

like m/s RSPL, M/s BEIL,

M/s Ambuja Cement, other

Cement mfg. Industries.

4 Handling of

hazardous chemicals

and wastes

Empty barrels/

containers/liners

contaminated

with hazardous

chemicals/wastes

Discarded

containers/liners

33.1 350.04 350.04 Generation, collection,

storage with in factory


Sale to Authorized agencies

like M/s Chirag Packaging,

Ankleshwar, M/s Rhythm

Chemicals Pvt. Ltd. Sachin,

Surat, M/s BEIL,

Ankleshwar. Disposal to

TSDF like M/s BEIL.

5 Hazardous waste

treatment processes,

e.g. pre-processing,

incineration and

concentration

Concentration or

evaporation

residues

Distillation

residue from

contaminated

organic solvents

37.3 0.73 7 Generation, collection,



Disposal through co-

processing at cements plants

like M/s Ambuja cement or

TSDF like M/s RSPL.


at TSDF like M/s BEIL.



6 Industrial operations

using mineral or

synthetic oil as

lubricant in hydraulic

systems or other

applications

Used or spent oil Used / Waste Oil 5.1 1.83 10 Generation, collection,

storage, treatment within

factory premises,

transportation and Sale to

authorized recyclers /

refiners or Incineration/co-

processing at TSDF like

BEIL or Co-processing at

cement plants like M/s

Ambuja Cements.

7 Production and/or

industrial use of

solvents

Contaminated

aromatic,

aliphatic or

naphthenic

solvents may or

may not be fit

for reuse.

Contaminated

solvents not fit

for originally

intended use

20.1 2000 2000 Generation, collection,



Can be disposed of by sale

to GPCB authorized

agencies like M/s Acquire

Chemicals, Ankleshwar,

M/s Mahakali Traders,

Ankleshwar

8 Spent solvents Spent solvent 20.2 73 73 Generation, collection,



disposal through GPCB

authorized agencies for co-

processing or Incineration

like m/s RSPL, M/s BEIL,

M/s Ambuja Cement, other

Cement mfg. Industries.



9 Spent solvents Spent solvents 20.2 540 540 Generation, collection of

High COD waste from MEE

Stripper Column, storage

within factory premises,

transportation and Disposal

through co-processing at

cements plants like M/s

Ambuja cement or TSDF

like M/s RSPL.


at TSDF like M/s BEIL.

10 Industrial operations

using mineral or

synthetic oil as

lubricant in hydraulic

systems or other

applications

Wastes or

residues

containing oil

Wastes or

residues

containing oil

5.2 NIL 0.5 Generation, collection,

storage, transportation and

Sale to authorized recyclers /

refiners or Incineration/co-

processing at TSDF like



Ambuja Cements.

11 Production /

formulation of drugs/

pharmaceutical and

health care product

Off specification

products

Off specification

products

28.4 NIL 5 Generation, collection,



incineration at TSDF like



Ambuja Cements.

12 Date-expired

products

Date-expired

products

28.5 NIL 5 Generation, collection,



incineration at TSDF like



Ambuja Cements..



ANNEXURE- XII

LIST OF HAZARDOUS CHEMICALS

Sr.No. Name of Chemical

Flammable chemicals

1 Methylene Dichloride (METHYLENE

DICHLORIDE)

2 Toluene

3 Ethyl Acetate

4 Methanol

5 Hexane

6 Acetone

Toxic and corrosive chemicals

7 Ammonia

8 Caustic Soda Lye

9 Hydrochloric Acid

10 Phosphorous Pentoxide

11 Sulphuric Acid

12 Thionyl Chloride

13 Raney Nickel

14 Pd charcoal

15 Aniline

annexure i terms of referenceenvironmentclearance.nic.in/writereaddata/online/tor/10... · 2017. 5....

Documents