ANNEXURE 1 TERMS OF REFERENCES -...

M/s. VIHITA CHEM (P) LTD.(UNIT-II)

ANNEXURE 1

TERMS OF REFERENCES

• TOR prescribed by MoEF & CC for this sector will be taken into

account.

• To use Baseline Monitoring details of M/s. Ion Exchange Pvt Ltd.

for the month of January, February & March 2017.


ANNEXURE-2

LIST OF PRODUCTS

SR.

NO.

PRODUCTS QUANTITY

(MT/MONTH)

REMARKS

LIST OF PRODUCTS AS PER EXISTING CCA NO:-H-84112

1. 4-METHYL CATECHLO

AND/OR

7

Total Production of sr.no.1 to

8 shall not exceed 7

MT/Month in any case.

2. HYDROXY UREA

AND/OR

7

3. 4-HYDROXY BENZYL

ALCOHOL

AND/OR

7

4. BENZALDEHYDE

DIMETHYL ACETAL

AND/OR

7

5. 4-METHOXY

BENZALDEHYDE

DIMETHYL ACETAL

AND/OR

7

6. DI METHYL

FORMAMIDE DI ISO

PROPYL ACETAL

AND/OR

7

7. 2-BROMO 2’,5’-

DIMETHOXY

ACETOPHENONE

AND/OR

7

8. METHYLENE DIOXY

PHENOL

7

9. DI METHYL

FORMAMIDE DI

METHYL ACETAL

AND/OR

13

Total Production of sr.no.9 to

15 shall not exceed 13

MT/Month in any case.

10. 4-CHLORO-4’

HYDROXY

BENZOPHENONE

AND/OR

13

11. 2,3,4,5,-BIS-O-[1- 13


METHYL ETHYL

IDENE] B-D-

FRUCTOPYRANOSE

AND/OR

12. ALPHA-BROMO-2-

CHLORO PHENYL

ACETIC ACID

AND/OR

13

13. ALPHA-BROMO-2-

CHLORO PHENYL

ACETIC ACID METHYL

ESTER AND/OR

13

14. O-BENZYL HYDROXYL

AMINE

HYDROCHLORIDE

AND/OR

13

15. O-BENXYL HYDROXYL

AMINE METHANE

SULPHONIC ACID

13

LIST OF PRODUCTS AFTER PROPOSED EXPANSION

SR

NO.

NAME OF THE PRODUCT PRODUCTION

CAPACITY

MT/MONTH

GROUP-1

(Each product not more than 100 MT/Month) 1. 2,3,4,5–bis-O-[1-Methyl Ethyl idene] B-D-Fructopyranose 100

(Either/Or) 2. Di Methyl Formamide Di Methyl Acetal

3. 4-Methyl CatecholDi-acetic acid Dimethyl ester

(Sr No:-1 to 3) TOTAL: 100 MT/Month

GROUP-2

(Each product not more than 30 MT/Month) 4. 4-Methyl Catechol

30

(Either/Or)

5. Methylene dioxy phenol

6. 4-Chloro-4’Hydroxy Benzophenone

7. 2-Bromo Veratryl Bromide

8. 7-Ethyl tryptophol

9. 2 -Bromo 2’,5’ – dimethoxyacetophenone

10. Di Methyl Formamide Di Iso Propyl Acetal

11. 4-Methoxy Benzaldehyde dimethyl Acetal

12. Benzaldehyde dimethyl Acetal


13. 4-Hydroxy Benzyl Alcohol

14. O-Benzyl hydroxyl amine Hydrochloride

15. Alpha –Bromo -2-Chloro Phenyl Acetic Acid Methyl Ester

16. 3-(1-Piperaziny)-1,2-Benzisoxazole/Hydrochloride

17. 5-Chloroethyl-6-Chloro-2-Oxindole

18. 2,4,6 TrimethoxyBenzaldehyde

19. 4-Methoxy-3-nitrobenzylsulfonylacetic acid

20. (1R,2R)-1-2-bis (methane sulfonyloxy methyl)

cyclohexane

21. 4-Isopropyl catechol

22. 3-Methoxy Phenol

23. Veratrol Alcohol

24. 3,4-Dihydroxy Benzoic Acid

25. 3,4 DihydroxyBenzaldehyde

26. 4-Propyl Catechol

27. Dimethyl Acetamide Dimethyl Acetal

28. Tert-butyl(4-bromophenyl)

Methylcarbamate

29 4-[(4-Methyl-1-piperazinyl)-methyl]-benzoyl chloride

dihydrochloride

30 (2-cyclopropyl-4-(4-fluorophenyl)quinolone-3yl)methanol

31. (-) Alcohol

32. 3 –MethoxyPropiophenone


GROUP-3

(Each product not more than 20 MT/Month) 33. AfatinibDimalate

20

(Either/Or)

34. Arbutin

35. Agomelatine

36. Apixaban

37. Aripiprazole

38. Asenapine

39. Axitinib

40. Azilsartan

41. Abacavir Sulfate

42. Atorvastatin Calcium

43. Bupropion HCL

44. Bazedoxifene

45. Canagliflozin

46. Candesartan Cilexetil

47. Celecoxib

48. Clopidogrel bi sulfate

49. Dabigatran


50. Dapagliflozin

51. Darifenacin

52. Donepezil

53. Dronedarone

54. Desvenlafaxine Succinate monohydrate

55. Duloxetine Hydrochloride

56 Erlotinib

57 Etoricoxib

58 Etodolac

59 Escitalopram oxalate

60 Febuxostate

61 Felodipine

62 Fluconazol

63 Granisetron HCl

64 Gefitinib

65 Gabapentin

66 ILoperidone

67 Irbesartan

68 Itopride Hydrochloride

69 Lapatinib

70 Lurasidone Hydrochloride

71 Losartan Potassium

72 Mem Chloride

73 Minodronic Acid

74 Moclobemide

75 Modafinil

76 Metoprolol Tartrate

77 Nisoldipine

78 Omeprazole

79 O Des Venlafexine

80 Olmesartan

81 Pitavastatin

82 Piperonylic Acid

83 PramipexoleDihydrochloride Monohydrate

84 Prasugrel Hydrochloride

85 Paroxetine

86 Pinaverium Bromide

87 Pioglitazone HCl

88 QuetiapineFumarate

89 Rabeprazole Sodium

90 Rivaroxaban

91 Ropinirole Hydrochloride

92 Resperidone

93 Sertraline Hydrochloride

94 1-[3-(benzyloxy)propyl]-5-formaylindoline-7-carbonitrite


95 Solifenacin Succinate

96 Dimethylformamide di-tert-butyl Acetal

97 Tadalafil

98 Ticagrelor

99 Topiramate

100 Vilazodone Hydrochloride

101 Valsartan

102 VortioxetineHydrbromide

103 Vemurafinib

104 Warfarin Sodium clatharte

105 Ziprasidone HCl


GROUP-4

(R&D Products 5 MT/Month) 106 Various New Product developed by In –house R&D

5.0

TOTAL 5.0

Group-1+Group-2+Group-3+Group-4) 155 MT/Month


ANNEXURE-3

LIST OF DIRECTORS

Sr.

No. Name of the Partner Address Contact No.

1. Mr. Mafatlal Maganlal

Patel

(Chairman)

2,Snehdip Socity, Near GNFC

Township, Bholaw,

Bharuch,392015,Gujarat, India

9824152333

2. Mr. Vital Mafatlal Patel

(C.E.O. & M.D.)


Township, Bholaw,


9898472111

3. Mrs. Savitaben Mafatlal

Patel

(Executive Director)


Township, Bholaw,


9824852333

4. Mrs. Neelam Vital Patel



Township, Bholaw,


9227472111

5. Ms. Tejal Mafatlal Patel



Township, Bholaw,


9924152333

09

11

10

12

13

14

08

07

05

06

16

15

19

17

18

0102

03

04

Utility Area

20D

20C

20A

20B

20E

Solid waste

storage Area

Toilet Block

GMP Ware Hose-1

Explosive Yard

Scrape Yard

WARE HOUSE-2

GREEN BELT

OPEN LAND

GREEN BELT

GREEN BELT

GR

EE

N B

EL

T

Parking

Canteen

Garden

SECURITY CABIN

& visitor Room

Under ground water Tank

GEB Yard

Production Plant-C

ETP Area

GMP Plant-D

Electrical &

Maintenance Area

GR

EE

N B

EL

T

VIHITA CHEM PVT. LTD. (UNIT-2)

GREEN BELT

VIHITA CHEM PVT. LTD. (UNIT-2) PLOT NO.-3709/2,

ANKLESHWER DIST. BHARUCH

Sr. No. PARTICULAR

AREA IN

Sqmt.

SIZE

1 & 2 SECURITY CABIN & visitor Room 12.5 5 x 2.5

3

Under ground water Tank

121.5

13.5 x 9

4 GEB Yard 67.5

9 x 7.5

5 Production Plant-C 612

36 x 17

6 ETP Area 140

20 x 7

7 GMP Plant-D

347 20.75 x 16.73

8 Electrical & Maintenance Area

34 9.20 x 3.7

9

Utility Area 160 16 x 10

10 Toilet Block

20 5 x 4

11

Solid waste storage Area 80 16 x 5

12 GMP Ware Hose-1

190 15.2 x 12.5

13

Explosive Yard 900 36 x 25

14

Scrape Yard 180 30 x 6

15 WARE HOUSE-2

240 20 x 12

16 OPEN LAND

1398.5

17

Parking 140 14 x 10

18 Canteen

45 9 x 5

19 Garden

450 25 x 18

20-A

GREEN BELT 950

111 x 4.5

20-B

70 x 3

20-C

30 x 4

20-D

30 x 4

20-E

GREEN BELT (Compony Outside) 420 60 x 7

21

ROAD AREA 712

80 x 6

21

28 x 4

21

30 x 4

22 TOTAL AREA 6800

68x100

23 GREEN BELT AREA 1400

(20.58% of total area)

PLOT NO.-3709/2,

ANKLESHWER DIST. BHARUCH

21

21

PRODUCED BY AN AUTODESK EDUCATIONAL PRODUCT

PR

OD

UC

ED

B

Y A

N A

UT

OD

ES

K E

DU

CA

TIO

NA

L P

RO

DU

CT

PRODUCED BY AN AUTODESK EDUCATIONAL PRODUCT

PR

OD

UC

ED

B

Y A

N A

UT

OD

ES

K E

DU

CA

TIO

NA

L P

RO

DU

CT

Administrator

Text Box

Administrator

Text Box

Plot No. 3709/1 &2, GIDC Ankleshwar, Dist.: Bharuch

Administrator

Text Box

1 & 2

Administrator

Line

Administrator

Text Box

N

ANNEXURE-5


LIST OF RAW MATERIALS

SR.

No

Name of Product Quantity of

Product

MT/Month

Name of Raw

Material

MT/MT OF

PRODUCT

MT/Month

1. 2,3,4,5 –bis-O-[1-Methyl

Ethyl idene] B-D-

Fructopyranose

100 B-D-Fructopyranose 0.78 78

Sulphric acid 0.422 42.2

Acetone 0.1 10

Toluene 0.04 4

TOTAL 1.342 134.2

2. Di Methyl Formamide Di

Methyl Acetal

100 Dimethyl formamide 0.66 66.0

Dimethyl sulphate 1.14 114.00

sodium methoxide 25%

solution

1.952

195.2

TOTAL 3.752 375.2

3. 4-Methyl Catechol Diacetic

acid Dimethyl ester

100 4-Methyl catechol 0.5 50.00

Sodium Hydroxide 0.64 64.0

Mono Chloro acetic

acid

0.756 75.60

Hydrochloric acid 2 200

Toluene 0.06 6.0

Methanol 0.15 15

Sulfuric Acid 0.04 4

TOTAL 4.146 414.6

4.

4-Methyl Catechol

30 Methyl Phenol 1.05 31.5

Hydro Bromic Acid 1.74 52.2

Hydrogen Peroxide 0.75 22.5

Caustic Soda 0.65 19.5

Sulphuric Acid 0.7 21

Butanol 0.09 2.7

TOTAL 4.98 149.4

5. Methylnedioxy phenol

30 Zinc Chloride 1.11 33.3

methylene

dioxybenzene 1 30

Acetic Anhydride 1.2 36

Methylene dichloride 0.08 48

Formic Acid 1.24 37.2

Toluene fresh 0.08 2.4


Methanol 0.6 18

Sodium Methoxide 1.2 36

TOTAL 5.38 161.1

6.

4-Chloro-4’ HYDROXY

BENZOPHENONE(Route-1)

30 Phenol 0.426 12.78

1,2 Dichloro benzene 0.06 48

Aluminium Chloride 0.6 18

4-Chlore Benzo 1.054 31.62

ANNEXURE-5


trochloride

TOTAL 3.68 110.4

6 4-CHLORO-4’ HYDROXY

BENZOPHENONE (Route-2)

30 Phenol 0.43 12.9

1,2 Dichloro benzene 0.05 1.5


4-Chlore Benzoyl

chloride 0.8 24

Methanol 0.05 1.5

TOTAL 2.03 60.9

7. 2-Bromo Veratryl Bromide

30 Veratrol 0.5 15.000

Hydro Bromide 0.64 19.200

Methyl Di Choride 0.1 3.000


P-Formaldehyde 0.106 3.180

Toluene 0.08 2.400

Hydro Bromide in

Acetic acid

1 30.000

Acetic Acid 0.22 6.600

TOTAL 2.9 88.38

8. 7-Ethyl trptophol

30 2

EthylphenylhyDrazine

Hydrochloride 1.332 39.96

Dimethyl acetamide 0.6 18

Con Sulfuric Acid 0.532 15.96

2,3-dihydrofuran 0.532 15.96

Toluene 0.1 2

TOTAL 4.496 134.88

9. 2 -Bromo 2’,5’ –

dimethoxyacetophenone

30 Hydroquinone 0.70 21

Caustic soda 0.48 14.4

Methylne Chloride 0.10 3

DiMethyl Chloride 0.70 21

Zinc Chloride 0.60 18

Acetic Anhydride 0.65 19.5

Hydrogenperoxide 0.24 7.2

Hydro bromic acid 0.58 17.34

TOTAL 4.05 121.44

10. Di Methyl Formamide Di Iso

Propyl Acetal

30 Iso propyl alcohol 0.72 21.6

di methyl formamide di

methyl acetal 0.72 21.6

TOTAL 1.4 43.2

11. 4-Methoxy Benzaldehyde

dimethyl Acetal

30 4-Methoxy

benzaldehyde 0.76 22.8

methanol 1.4 42

tri methyleorthoformate 0.6 18

caustic soda flakes 0.222 6.66

TOTAL 2.982 89.46

12. Benzaldehyde dimethyl

Acetal

30 benzaldehyde 0.76 22.8

methanol 1.4 42

ANNEXURE-5


tri methyleorthoformate 0.662 19.86

caustic soda flakes 0.274 8.22

TOTAL 3.1 92.9

13. 4-Hydroxy Benzyl Alcohol

30 4-hydroxy

benzaldehyde 1.016 30.48

Methanol 0.084 2.52

paladium/charcoal 0.004 0.12

Hydrogen 0.016 0.48

TOTAL 1.12 33.6

14. O-Benzyl hydroxyl amine

Hydrochloride

30 Benzyl Hydrochloride 0.8 24

N-Hydroxyphthalimide 1.03 30.9

Methylene Dichloride 0.15 4.5

Sodium carbonate 0.6

18

TABA catalyst 0.02 0.6

Toluene 0.05 1.5

Hydrazine Hydrate 0.38 11.4

Methanol 0.1 3

Hydrochloric acid 0.5 15

TOTAL 3.63 108.9

15. Alpha-Bromo-2-Chloro

Phenyl Acetic Acid Methyl

Ester

30 2-Chlorophenyl

Acetonitrile 1 30


Methyle Di chloride 0.1 3

Toluene 0.2 6

N-BromoSuccinimide 0.672 20.16

Methanol 0.1 3

Chlorobenzene 0.1 3

50% sulfuric acid 3 90

Catalyst 0.02 0.6

TOTAL 6.316 189.48

16. 3-(1-Piperaziny)-1,2-

Benzisoxazole /

Hydrochloirde

30 2, 2'-Dithiosalicylic

acid 1.8 54

Methanol 7.096 212.88

Sulfuric Acid 0.06 1.8

Sodium methoxide 0.364 10.92

HydroChloride 1.2 36

Phosphoryl chloride 0.81 24.3

Piperazine 0.44 13.2

Toluene 7.83 234.9

Acetamide 0.33 9.9

TOTAL 19.93 597.9

17. 5-chloroethyl-6-chloro-2-

oxindole

30 Di Methyl malonate 1.042 31.26

Di methyl sulphoxide 0.1 3.0

2,5 dichloro

nitrobenzene

1.042 31.3

pottasium carbonate 0.75 22.5

Hydrochloric Acid 0.6 18.0

Acetic Acid 0.1 3.0

ANNEXURE-5


Iron 0.306 9.2

Methanol 0.06 1.8

Chloro acetyl chloride 0.6 18.0

Zinc chloride 0.746 22.4

Methylne dichloride 0.1 3.0

Tri ethyl silane 0.63 18.9

TOTAL 6.076 182.36

18. 2,4,6 Tri

Methoxybenzaldehyde

30 Dimethylmethanamide 0.84 25.2

Phosphoryl chloride 0.8 24

1,3,5 Tri methoxy

benzene 0.86 25.8

Methanol 0.08 2.4

Sodium carbonate 1.2 36

TOTAL 3.78 113.4

19. 4-METHOXY-3-NITRO

BENZYL SULFONYL

ACETIC ACID

30 N-Bromosuccinimide 0.9 27

3-Nitro-4-Methoxy

Toluene 0.76 22.8

Chloro Benzene 0.12 3.6

Benzoyl peroxide 0.01 0.3

Thioglycolic Acid 0.38 11.4

Methanol 0.15 4.5


Sodium Peroxide 0.164 4.92

Acetic acid 0.1 3

TOTAL 3.844 115.32

20. (1R,2R)-1-2-bis

(methanesulfonyloxymethyl)

30 (1R,2R)-1,2-

Cyclohexane di

carboxylic Acid 0.6 18

Tetra Hydrogen Floride 0.04 1.2

Sodium Borohydride 0.054 1.62


Methelene Dichloride 0.08 2.4

Methane

sulfonylchloride 0.43 12.9

Tri ethyl Amine 0.4 12

TOTAL 1.624 48.72

21. 4-Isopropyl catechol

30 P- Cumidine 1.1 33

Sodium Nitrite 0.56 16.8

Sulphuric Acid 1.52 45.6

Copper Sulfate 0.1 3

Methylne di chloride 0.1 3

Hydrogen Bromide 1.24 37.2

Hydro Peroxide 0.5 15


Copper 0.02 0.6

n-Butanol 0.06 1.8

TOTAL 5.8 173.4

22. 3-Methoxy Phenol 30 Resorcinol 0.95 28.5

Toluene 0.1 3

ANNEXURE-5


Sodium Carbonate 1.1 33

Dimethyl sulfate 1.1 33

50% Sodium Hydroxide

sol wash 1.5 45

50% Sulfuric Acid 0.8 24

TOTAL 5.55 166.5

23. Veratrol Alcohol

30 Vanillin 0.94 28.2

Toluene 0.26 7.8

Dimethyl sulphate 1.324 39.72

Sodium Carbonate 1.324 39.72


Sodium Borohydride 0.12 3.6

Methanol 0.1 3

Methylne di chloride 0.1 3

TOTAL 4.356 130.68

24. 3,4- Dihydroxy Benzoic Acid

30 Veratric Acid 1.25 37.5

Hydrogen Bromide (48

%) 5 150

Acetic acid 0.13 3.9

TOTAL 6.38 191.4

25. 3,4- Dihydroxy Benzaldehyde

30 Veratric Acid 1.25 37.5

Hydrogen Bromide (48

%) 2.5 75


TOTAL 3.88 116.4

26. 4-Propyl catechol

30 4-Propyl Phenol 1 30

Methyl Di Chloride 0.1 3


Hydrogen Peroxide

(50%) 0.5 15


Copper 0.02 0.6

Sulfuric Acid 0.72 21.6

Bromo Phenol 1.54 46.2

n-Butanol 0.06 1.8

TOTAL 5.76 172.8

27. DimetylAcetamide Dimethyl

Acertal

30 Dimethyl Aceamide 0.654 19.62

Dimethyl Sulphate 0.948 28.44


Methanol 1 30

TOTAL 4.554 136.62

28. Tert-butyl (4-bromophenyl)

Methylcarbamate

30 N-Methyl aniline 0.426 12.78

N-Bromosuccinimide 0.716 21.48

Di-t-butyl dicarbonate 0.784 23.52

Caustic 0.29 8.7


TOTAL 2.316 69.48

4-[(4-Methyl-1-Piperazinyl)- 30 4-cyano benzyl bromide 0.84 25.2

ANNEXURE-5


29.

methyl]-benzoyl chloride

dihydrochloride

Chloroform 0.1 3

N-methyl piperazine 1.18 35.4

Con Hydrochloric Acid 4 120

Dimethylformamide 0.1 3

Thionyl Chloride 0.1 3

Methylene Dichloride 0.1 3

TOTAL 6.42 192.6

30. 2-Cyclopropyl-4-

4fluorophenytl quinolone-3-yi

menthanol

30 2-amino-4-fluoro

benzophenone 0.772 23.16

3-cyclopropyl-3-oxo

propionic acid methyl

ester 0.57 17.1

Methanol 1.2 36

Con sulfuric acid 0.04 1.2

Toluene 1 30

Hydrochloric Acid 2 60

Cyclohexane 1 30

10% Sodium

bicarbonate 4 120

TOTAL 10.6 197.46

31. (-) Alcohol 30 4-Fiuoro Benzaldehyde 1.24 37.2

malonic acid 1.4 42

Pyridine 0.05 1.5

Con Hydrochloride 1 30

Thionyl chloride 0.05 1.5

Dimethylformamide 0.02 0.6

Diethyl malonate 1.4 42

Potassium t butoxide 1.032 30.96

Sodium

tetrahydridoborate 0.7 21

Boron trifluorideethrate 0.1 3

Tartaric acid 1 30

Iso Propyl Alcohol 0.1 3

Methyl amine 0.3 9

TOTAL 8.392 251.76

32. 3- MethoxyPropiophenone 30 Propiophenone 0.8 24

Ethylene Dichloride 0.1 3

Aluminium chloride 0.22 6.6

Bromine 0.974 29.22

Toluene 0.1 3

25% Sodium methoxide 1.5 45

Di Methyl formamide 0.1 3

Cuprous chloride 0.1 3

Dil Sulfuric acid 2 60

TOTAL 5.894 176.82

33. AfatinibDimalate

20 (S,E)-N-(4-(3-Chloro-

4-fluorophenylamino)-

7-(tetrahydrofuran-3-

yloxy)quinazolin-6-yl)-

0.61 12.2

ANNEXURE-5


4-(dimethylamino)but-

2-enamide Afatinib

Maleic acid 0.24 4.8

Methanol 0.18 3.6

TOTAL 1.03 20.6

34. Arbutin 20 Monoacetyl

hydroquinone

0.5 10

Boron

trifluorideetherate

0.01 0.2

Dichloromethane 0.09 1.8

Pentaacetyl-B-D-

glucose

1.56 31.2

Tri ethyl amine 0.408 8.16

Sodium Methoxide 0.02 0.4

Methanol 0.07 1.4

TOTAL 2.658 53.16

35. Agomelatine

20 2-(7-Methoxy-1-

naphthyl) acetonitrile

0.89 17.8

Methanol + Ammonia 0.1 2

Raney Ni 0.1 2

Acetyl chloride 0.29 5.8

Methanol 0.1 2

TOTAL 1.48 29.6

36. Apixaban

20 Ethyl 1-(4-

methoxyphenyl)-7-oxo-

6-(4-(2-oxopiperidine-

1-yl)phenyl)-4,5,6,7

tetrahydro-1H-

pyrazolo[3,4-

c]pyridine-3-

Carboxylate

1.11 22.2

Ethylene glycol 0.1 2

Amonnium solution 2.8 56

TOTAL 4.01 80.2

37. Aripiprazole

20 7-(4-Chlorobutoxy)-

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

quinolinone

0.85 17

1-(2,3-

dichlorophenyl)piperazi

ne HCL

0.652 13.04

N,N-

dimethylformamide

fresh

1.7 34

Potassiumcarbonate 0.68 13.6

Acetonitrile 0.1 2

Iso Propyl Alcohol 0.14 2.8

Charcoal 0.1 2

TOTAL 4.222 84.44

38. Asenapine 20 Trans-2-methyl-5-nitro- 0.790 15.800

ANNEXURE-5


2, 3, 3a, 12b-tetrahydro-

1H-dibenz [2, 3:6, 7]

oxepino [4, 5-c]-pyrrole

10% palladium charcoal 0.080 1.600

Hydrogen Pressure (8-

10 kg/cm2

0.030 0.600

Methanol 0.100 2.000

Dichloromethane 0.100 2.000

Dilute Sodium

Hydroxide Solution

1.200 24.000

Sodium nitrite 0.180 3.600

Cuprous Chloride in

con. Hydrochloride

0.480 9.600

Con. Hydrochloride 0.122 2.440

carbon 0.3 6

Ethyl acetate 0.1 2

Lit liq Ammonia 0.35 7

n-Butyl alcohol 0.2 4

Maleic acid 0.3 6

TOTAL 4.332 86.640

39. Axitinib

20 AxitinibSolveate 1.05 21

Dimethyl sulfoxide 1 20

TOTAL 2.05 41

40. Azilsartan

20 Azilsartan 0.82 16.4

4-Hydroxymethyl-5-

methyl-1,3-dioxol-2-

one

0.22

4.4

Potassium Carbonate 0.78 15.6

di methyl acetal 0.8 16

P-Toluenesultonyl

Chloride

0.52

10.4


Ethyl Acetate 0.2 4


Acetone 0.05 1

Potassium ethyl

Hexanate 0.38 7.6

TOTAL 4.012 80.24

41. Abcavirsulphate 20 N-(2-amino-4,6-

dichloro-5-

pyrimidiyl)formaide 1 20

Sodium carbonate 2 40

(1S,2R)-4-amino-2-

cyclopentene-1-

methanol HCl 0.9 18

Iso propyl Alcohol 4 80

Con Hydrochloric Acid 0.74 14.8

Triethylorthoformate 4 80

Acetone 0.4 8

ANNEXURE-5


75% Isopropoyl

Alcohol 2 40


Triethylamine 1.68 33.6

Cyclopropyl amine 0.6 12

TOTAL 17.608 352.16

42. Atrovastatin Calcium 20 Diketo compound 0.36 7.2

ATR-1 0.234 4.68

Sodium bicarbonate 0.3 6

Iso propyl Alcohol 0.05 1

Pivalic acid 0.088 1.76

Cyclohexane 0.05 1

SodiumHydroxide 0.04 0.8

Calcium acetate 0.14 2.8

Dil Hydrochloric Acid 1.5 30

Ethyl acetate 0.05 1

Methanol 0.09 1.8

t-bytyl ether 0.5 10

Methyl ethyl ketone 0.25 5

TOTAL 3.652 73.04

43. Bupropion Hydrochloric Acid 20 3-Chloropropiophenone 0.64 12.8

Bromine 0.6 12

Methyle Dichloride 0.1 2


10% Hydrochloric Acid 1 20


T-Butyl amine 0.4 8

TOTAL 2.84 56.8

44. Bazedoxifene

20 5-(Benzyloxy)-2-[4-

(benzyloxy)phenyl-3-1-

[4-(2-

hexaMethylneimine-1-

yl-ethoxy)benzyl]-1H-

indole

1.08 21.6

palladium on carbon 0.12 2.4

Hydrogen 0.02 0.4


Acetone 0.1 2

TOTAL 1.4 28.8

45. Canagliflozin

20 1-(2,3,4,6-Tetra-O-

propionyl--D-

glucopyranosyl)-4-

methyl-3-[5(4-

fluorophenyl)-2-

thienylmethyl]benzene

1.322 26.44


Methanol 0.1 2

Ethyl Acetate 0.1 2

Toluene 0.05 1

ANNEXURE-5


Heptane 0.05 1

TOTAL 1.692 33.84

46. Candesartan Cilexetil 20 KSM 1 0.8 16

Triethyl amine 0.18 3.6

Dichloromethane 0.2 4

Trityl phenyl Chloride 0.498 9.96

DMSO Acetonitrile 0.14 2.8


Cyclohexyl 1-

chloroethyl carbonate

0.54 10.8

Acetonitrile 0.1 2

Sodium bicarbonate 0.18 3.6

Methanolic

Hydrochloride

0.6 12

Acetone 0.05 1

TOTAL 3.35 66.96

47. Celecoxib 20 (4-

Sulfamoylphenyl)Hydra

zine

0.620 12.400

1-(4-methylphenyl)

4,4,4-Tifluorobutane,3-

dione

0.640 12.800

12.5% aqueous Iso

Propyl Alcohol

0.250 5.000

30% Iso propyl Alcohol 0.600 12.000

TOTAL 0.620 42.2

48. Clopidogrel Bi Sulfate 20 2 Chlorophenylglycine 0.6 12

Thionyl Chloride 0.25 5

Methanol 0.2 4

Sodium Bicarbonate 0.22 4.4


L-tartaric acid 0.476 9.52

Methyl Di Chloride 0.22 4.4


PotasiumPhospate 0.38 7.6

2-Thiophene ethanol 0.46 9.2

Formaldehyde 1.3 26

Con. Hydrochloric Acid 0.36 7.2

TOTAL 6.188 123.76

49. Dabigatran 20 3-[(3-Amino-4-

methylaminobenzoyl)p

yridin-2-

ylamino]propionic acid

ethyl ester

0.580 11.600

Acetic Acid 1.200 24.000

N-(4-

Cyanophenyl)glycine

0.300 6.000

N,NCarbonyldiimidazol 0.272 5.440

Tetra Hydrofloride 0.300 6.000

ANNEXURE-5


Hydrochloride 0.800 16.000


Ammonium Carbonate 0.192 3.840


TOTAL 4.1 81.3

50. Dapagliflozin

20 4-Chloro-7-methoxy-6-

(3-morpholin-4-

ylpropoxy)quinazoline

1.05 21.0

Methanol 0.1 2.0


TOTAL 2.21 44.2

51. Derifenacin

20 3(S)-(+)-(1-Carbamoyl-

1,1diphenylmethyl)

pyrrolidine L-(+)-

tartrate

0.140 2.797


5-(2-Bromoethyl)-2,3-

dihydrobenzofuran

0.074 1.483

Dimethyl formamide 0.014 0.280

Acetone 0.014 0.280


Methyle Di Chloride 0.280 5.594

1-(3-Chlorophenyl)

piperazine

0.597 11.944

1-Bromo-3-chloro

propane

0.503 10.055

Hydrochloric acid 0.225 4.492

Caustic Lye 0.351 7.025

Acetone 0.004 0.073

Toluene 0.068 1.365


TOTAL 2.446 48.923

52.

Donepezil

20 Diene 1.100 22.000


Hydrogen gas 0.020 0.400

Platinum oxide 0.120 2.400

Methyle Di Chloride 0.100 2.000

Diisopropyl ether 0.100 2.000

Charcoal 0.12 2.4

TOTAL 1.61 32.2

53. Dronedarone

20 2-n-Butyl-3-[4-(3-di-n-

butyl

aminopropoxy)Benzoyl

]-5-aminobenzofurn

dioxalate

1.320 26.400

Aqeous Ammonia

solution (25%)

1.620 32.400

Carbon 0.100 2.000

Methansulmide 0.180 3.600

ANNEXURE-5


Ethyl Acetate 3.560 71.200

Piridine 0.110 2.200

TOTAL 6.89 137.8

54. Desvenlafaxine Succinate

monohydrate

20 Venlafaxine 0.768 15.36

DMSO 0.1 2

Sodium Hydride 0.28 5.6

Acetonitrile 0.1 2

Thiophenol 0.026 0.52

Succinate Monohydrate 0.36 7.2

TOTAL 1.634 32.68

55. Duloxetine Hydrochloride 20 DTP.HCL 0.694 13.88

NaBH4 0.12 2.4

water 1 20

Methanol 0.15 3

1-fluronaphthalene 0.462 9.24

Oxalic acid 0.398 7.96

sodamide 0.124 2.48

DMSO 0.05 1

Liq-NH3 5.8 116

Ethyl acetate 1 20

DiIsopropyl amine 0.05 1

Phenyl chloroformate 0.53 10.6

DBIA 1.18 23.6

ethyl acetate HCL 2 40

Acetone 0.05 1

56. Erlotinib 20 KSM 0.77 15.4

3-Ethylaniline 0.29 5.8

Methyle Di Chloride 0.1 2

Methanol 1.8 36

Methanol

Hydrochloride

1.15 23

TOTAL 4.11 82.2

57. Etoricoxib 20 Ketosulfone 0.870 17.400

3-amino-2-

Chloroacrolein

0.320 6.400

Tetra Hydro Floride 0.100 2.000

Potassium tert-

Butoxide

0.340 6.800

Trifluro Acetic Acid 0.380 7.600

Toluene 0.100 2.000

Iso Propyl

Alcohol+Hexane

0.100 2.000

TOTAL 2.210 44.200

58. Etodolac 20 7-Ethyl tryptophol 1 20

Methyl-9-

oxopentanoate 0.818 16.36


Methanol 0.1 2

ANNEXURE-5



Dil Hydrochloride 2 40

TOTAL 1 20

59. Escitalopram Oxalate 20 Citalopram 2.04 40.8

Di-P-toluoyl-D-tartaric

acid 0.48 9.6

Methanol 0.1 2

25% liq ammonia 0.9 18

Methyle Di Chloride 1.5 30

Toluene 0.1 2

Triethanolamine 0.26 5.2

Methan sulfonyl

chloride 0.28 5.6



TOTAL 6 120

60. Febuxostate 20 Ethyl2-[3-Cyano-4-(2-

methylpropoxy)phenyl]

-4-methyl-5-

thiazoleCarboxylate 1.17 23.4

Hydroxylamine

hydrochloride

0.38

7.6

Methanol 0.1 2


Con.Hydro Chloric

Acid

0.34

6.8

Acetone+ D.M water 0.1 2

TOTAL 2.43 48.6

61. Felodipine

20 2,3-dichloro

Benzaldehyde

0.50 10

Methyl aceto acetate 0.242 4.84

Piperidine 0.242 4.84

Formic acid 0.10 2

3-amino Crotonic acid 0.33 6.6

Cyclohexane: Isopropyl

alcohol

0.10 2

TOTAL 1.514 30.280

62. Fluconazol 20 1,3-difuoro benzene 0.392 7.84

Chloroacetyl chloride 0.4 8


Methanol 0.1 2

ETHYAL ACETATE 2 40

Dil Hydrochloric acid 2 40

10 % Potassium

carbonate 1 20

Sodium nitrate 0.2 4

4H-amino-l,2,4- trizole 0.288 5.76

trimethylsulfoxoniumio

dide 0.76 15.2

ANNEXURE-5


Potassium Hydroxide 0.1 2

TOTAL 7.74 154.8

63. Garnisetron 20 Endo-9-methyl-9-

azabicyclo[3.3.1]nonyla

mine HCl 1.19 23.8


Dichloromethane 2 40

N-methyl -indazole-3-

Carboxylic acid 0.784 15.68

Thinoyl chloride 1.568 31.36

Dimethyl fumarate 0.156 3.12

Triethanolamine 0.57 11.4

Sodium hydrogen

carbonate 1 20

Iso Propyl Alcohol 2 40

Iso Propyl Alcohol

Hydrochloride (25 %) 1 20

TOTAL 11.458 229.16

64. Giftinib 20 KSM 0.820 16.400

isopropyl alcohol 0.100 2.000

3-Chloro-4-

fluoroaniline

0.350 7.000

Conc. HCl 0.300 6.000

N-Propanol 0.100 2.000

TOTAL 1.670 33.400

65. Gabapentine 20 gabapentin lactam 0.96 19.2

50 % Hydro Bromide 2 40


Acetone 0.1 2

Diethylamine 0.46 9.2

Methanol 0.05 1

TOTAL 3.62 72.4

66. Iloperidone 20 1-(4-hydroxy-3-

methoxyphenyl)

ethanone

0.4 8

1-bromo-3-

Chloropropane

0.38 7.6


6-fluoro-3(4-

piperidinyl)-1,2-

benzisoxazole

hydrochloride

0.62 12.4

Tartaric acid 0.36 7.2

Ammonia 1.2 24

TOTAL 3.32 66.400

67. Irbesatan 20 2-(n-butyl)-3-(2’-

Cynobiphenyl-4-

ylmethyl)-4-oxo-1,3-

diazaspiro [4.4] non-

0.992 19.84

ANNEXURE-5


1ene

tributyltin Chloride 0.65 13

Sodiumazide 0.54 10.8

Xylene 0.1 2



Methyl-t-butyl ether 0.1 2

Charcoal 0.1 2


TOTAL 4.122 82.440

68. Itopride Hydrochloride 20 Vertroyl chloride 0.54 10.8

2-(4-aminomethyl)

phenoxy) N,N dimethyl

ethanamine)- 0.52 10.4


Toluene 0.05 1

Acetone 0.05 1

Con Hydrochloric Acid 1.1 22

TOTAL 2.94 58.8

69. Lapatinib 20 N-[3-Chloro-4-(3-

fluorobenzyloxy)phenyl

]-6-iodoquinazolin-4-

amine

0.74

14.8

Diisopropyl ethylamine 0.4 8

Methanol 0.4 8

2

(methylsulfonyl)ethana

mine HCl

0.182

3.64

Sodiumetriacetoxyboro

hydride 0.332 6.64

P-toluene sulfonic acid 1.15 23

Tetrahydrofuran 0.2 4

TOTAL 3.404 68.08

70. Lurasidone Hydrochloride 20 (1R,2R)-1,2-

bis(methanesulfonyloxy

methyl) cyclohexane

0.786

15.72

Sodium carbonate 0.25 5

3-(1-Plperazinyl)-1,2-

benzisothiazole 0.59

11.8

Acetonitrile 0.1 2

Tetrabutyl ammonium-

Hydrogen Sulfate 0.68 13.6

Xylene (Fresh) 0.1 2

Bicyclo[2,2,1]hep-tane-

2,3-exo-dicarboximide 0.33 6.6


Methanol 0.1 50

Hydrochloric Acid 0.6 12

TOTAL 4.4 712.3

ANNEXURE-5


71. Losartan Potassium 20 KSM 1.21 24.2

Potassium hydroxide 0.22 4.4

Methanol 0.1 2

Charcoal 0.12 2.4

TOTAL 1.65 33

72. Mem Chloride 20 Paraformaldehyde 0.25 5

Methyl Cellulose 0.63 12.6

1,3,5Trioxane 0.1 2

Thionyl Chloride 0.99 19.8

TOTAL 1.97 39.4

73. Minodronic Acid 20 KSM 0.63 12.6

Phosphorous acid 0.196 3.92

Phosphorous trichloride 1.74 34.8

Tetramethylurea 0.23 4.6

Dil. Hydrochloric Acid 1.44 28.8

TOTAL 4.236 84.72

74. Moclobemide 20 KSM 1.07 21.4

Sodium Carbonate 1.06 21.2

Toluene 0.1 2


Charcoal 0.1 2

TOTAL 2.43 48.6

75. Modafinil 20 Benzhydrol 0.8 16

Thiourea 0.288 5.76

Hydrogem Bromide 2.4 48

Ammonia Solution 1.46 29.2

Sulfuric acid 0.29 5.8

Acetic Acid 0.1 2


TOTAL 5.428 108.56

76. Metoprolol Tartrate 20 4-2 methoxyethyl

phenol 0.372 7.44

Sodium Hydroxide 0.1 2

Toluene fresh 0.11 2.2

Epichlorohydrin 0.398 7.96

Isopropyl amine 0.2 4

Acetone 0.05 1

Tartaric acid 2.17 43.4

TOTAL 3.4 68

77. Nisoldipine 20 2-nitrobenzylidine

acetoaceticacid isobutyl

ester 0.81 16.2

Di methyl

aminopyridine 0.34 6.8

3-amino crotonic acid

methyl eater 0.32 6.4

Toluene 0.1 2

Di Sodium

hydiogenPhosphate 0.39 7.8

ANNEXURE-5


Acetone 0.05 1

TOTAL 2.01 40.2

78. Omeprazole 20 Chloro comp 0.68 13.6

Macraptocomo 0.55 11


Methanol 1 20

Ammonium

molybdatetetrahydrate 0.2 4


Sodium acetate 0.234 4.68

acetone 0.05 1

TOTAL 3.194 63.88

79. O Des Venlafexine 20 Venlafaxine

Hydrochloric acid 1.28 25.6

Ethanthial 0.1 2

Acetic acid 0.2 4

Dimethylmethanamide 0.1 2

Sodium hydroxide 0.088 1.76

Toluene 0.1 2


Methanol 0.1 2

TOTAL 3.448 68.96

80. Olmesartan 20 OlmesartanMedoxomil 1.08 21.6

Triphenyl methyl ether 0.53 10.6

Tritanol 0.52 10.4

Methanol 0.1 2


Acetone 0 0

TOTAL 3.25 65

81.

Pitavastatin calcium

20 triphenyl(2-

cyclopropyl-4-(4-

fluorophenyl)quinoline-

3-yl)-phosphonium

bromide 1.4 28

Potassium carbonate 0.47 9.4

tert-butyl 2-((4R,6S)-6-

formyl-2,2-dimethyl-

1,3-dioxan-4-yl)acetate 0.62 12.4

Dimethyl sulfoxide 0.1 2

Methanol 0.1 2


sodium Carbonate 0.56 11.2

Toluene 0.1 2

10 % Hydro chloric

acid 0.4 8

Dichloromethane 0.1 2

10 % Sodium Hdroxide 0.52 10.4

Calcium chloride 0.3 6

t-butyl Acetate 0.1 2

ANNEXURE-5


TOTAL 5.478 109.56

82. Pinylperoic acid

20 Sodium Hypochlorite

(NaOCl) 10 200

1,2-methylene

dioxyAcetophenone 1.1 22

Hydrochloric Acid 1 20

TOTAL 12.1 242

83. Pramipexole hydrochloride

20 (6S)-N6-Propyl-4,5,6,7-

tetrahydro-1,3-

benzothiazole-2,6-

diamine 0.74 14.8

Methanol 1.5 30

Methanol. Hydrochloric

acid 0.1 2

TOTAL 2.34 46.8

84. Prasugrel Hydrochloride 20 2-acetoxy-5-(-

cyclopropylcarbony1-2-

fluorobenzyl)-4,5,6,7-

tetrahydro thieno[3,2-

c]pyridine

0.96 19.2

Ethyl methyl ketone 0.1 2

Iso Propyl alcohol 0.1 2

TOTAL 1.16 23.2

85. Paroxetine 20 trans carbinol 0.71 14.2

Dimethylethylamine 0.5 10

Benzenesulfphonyl

chloride

0.5 10

Toluene 0.1 2

Dimethylmethanamide 0.1 2

SMO 0.002 0.04

Sesamole 0.476 9.52

Potassium hydroxide 1.08 21.6

Con Hydrochloric acid 0.36 7.2

Phenylchloroformate 0.5 9.2

TOTAL 4.288 85.76

86. Pinaverium Bromide 20 Dihydronepol 0.248 4.96

4-(2-

chlroethyl)morpholine 0.372 7.44

sodium carbonate 0.68 13.6


Acetone 0.1 2

2-bromo-veratyl

bromide 0.62 12.4

TOTAL 2.1 42.4

87. Pioglitazone HCl 20 EPNB 0.694 13.88

Hydrogen gas 0.012 0.24

palladium carbon 0.02 0.4

Hydrogen bromide 0.414 8.28

Methyl acrylate 0.22 4.4

ANNEXURE-5


Sodium nitrate 0.176 3.52

thiourea 0.194 3.88

Sodium acetate 0.3 6

Con HCl 0.182 3.64

Potassium bicarbonate 0.254 5.08

Di methyl floide 0.05 1

Con HCl 2 40

50 % ETHANOL 0.5 10

Methanol 0.1 2

Copper oxide 0.1 2

TOTAL 5.216 104.32

ANNEXURE-5

LIST OF RAW MATERIALS

88 Quetiapine Fumarate 20 DMSO 0.04 0.8

2-Chloroethoxyethanol 0.148 2.96

Na2CO3 0.18 3.6

Furamic acid 0.14 2.8

Acetone (Fresh) 0.2 4

2-bromo-veratyl

bromide 0.2 4

Keton 0.3 6

POCl3 Fresh 0.04 0.8

Ethanol fresh 0.1 2

Con HCl 0.2 4

Piperazine fresh 0.234 4.68

Pottasium carbonate 0.2 4

Toluene fresh 0.2 4

TOTAL 1.54 30.8

89 Rabeprazole Sodium 20 Rabeprazolesulphoxide 1 20

NaOH 0.81 16.2

Methanol 0.1 2

Toluene 0.1 2

TOTAL 2.01 40.2

90. Rivaroxaban 20 4-{4-[(5S)-5-

(aminomethyl)-2-oxo-

1,3-oxazolidin-3-

yl]phenyl}morpholin-3-

one.HCL 0.81 16.2

5-Chlorothiophene-2-

Carboxylchloride 0.45 9

Sodium Acetate 1.2 24

Acetic acid 0.1 2

TOTAL 2.56 51.2

91. Ropinirole Hydrochloride 20 Ethyl-2-nitro-6-(N,N-

di-n-

propylaminoethylpheny

l)acetic acid.HCL 1.25 25

Methanol 0.1 2

10% Pdc 0.01 0.2

MDC 0.1 2

Triethyl amine 0.37 7.4

Ethyl acetate 0.1 2

TOTAL 1.93 38.6

92. Resperidone 20 6-Fluoro-3-(4-

piperidinyl 1,2

benzisooxazole 0.536 10.72

3-(2-chloroethyl-

6,7,8,9-tetrahydro-2-

methyl-4h-pyrido 0.55 11

K2CO3 0.716 14.32

ANNEXURE-5

DMF fresh 0.05 1

TOTAL 1.852 37.04

93. Sertraline Hydrochloride 20 Setralone 0.85 17

Mono methylamine 0.1 2


Methanol 0.05 1

Hydrogen 0.008 0.16

Pb/Baso4 0.1 2

D--Mandelia acid 0.45 9

10% NAOH 1 20

Acetonitrile 0.1 2

HCl 0.2 4

TOTAL 6.7 134

94. 1-[3-(benzyloxy)propyl]-5-

formaylindoline-7-

carbonitrite

20 1-[3-

(benzyloxy)propyl}-7-

bromoindoline-5-

carbaldehyde 1.25 25

DMF 0.1 2

Coppercyanide 0.3 6

Methanol 0.1 2

TOTAL 1.75 35

95. Solifenacin Succinate 20 (1-[3-

(Benzyloxy)propyl]-5-

{(2R)-2-[2-(2,2,2-

trifluoroethoxy)

phenoxy]ethyl}amino)p

ropyl]indoline-7-

Carbonitrile Oxalate 1.19 23.8


Hydrogen peroxide 1.164 23.28

Dimethyl sulfoxide 0.1 2

TOTAL 5.55 111

96 Dimethylformamide di-tert-

butyl Acetal

20 N,N,Dimethtylformima

de 0.406 8.12

Dimethyl sulfate 0.7 14

T-Butanol 0.1 2

Potassium tert-buoxide 0.64 12.8

TOTAL 1.846 36.92

97 Tadalafil 20 KSM 1.18 23.6

Methyl Amine 0.09 1.8

Methanol 0.1 2

IPA 0.1 2

carbon 0.1 2

TOTAL 1.57 31.4

98 Ticagrelor 20 KSM 0.99 19.8

Con. HCl 0.94 18.8

Methanol 0.1 2

Cyclohexane 0.1 2

TOTAL 2.13 42.6

ANNEXURE-5

99 Topiramate 20 BME-DFP 1 20

Pyridine 0.428 8.56

O-Xylene (Fresh) 0.1 2

THF (Fresh) 0.1 2

Sulfuryl chloride 0.696 13.92

n-Hexane (Fresh) 0.3 6

Ammonia Gas 0.1 2

TOTAL 2.7 54.5

100 Vilazodone Hydrochloride 20 KSM 0.97 19.4

Con. HCl 0.09 1.8

Formic Acid 1.6 32

TOTAL 2.66 53.2

101 Valsartan 20 Calcium Valsartan 1.16 23.2

HCl 1.42 28.4

Ethyl Acetate 0.1 2

Di isopropyl ether 0.1 2

TOTAL 2.78 55.6

102 VortioxetineHydrbromide 20 Tert-butyl-4-{2-[(2,4-

dimethylphenyl)sulfany

l]phenyl}-3,5-

dioxopiperazine-1-

Carboxylate 1.47 29.4

Borane DMS 1.85 37

THF 0.1 2

HCL 3 60

HBr 1.6 32

TOTAL 8.02 160.4

103 Vemurafinib 20 N-{3-[(5-bromo-1H-

pyrrolo[2,3-b]pyridin-

3-yl)Carbonyl]-2,4-

diflorophenyl}propane-

1-Sulfonamide 0.98 19.6

4-Chlorophenylboronic

acid 0.34 6.8

Tetrakistriphenylphosp

hinepalladium 0.06 1.2

Acetonitrile 0.1 2

TOTAL 1.48 29.6

104 Warfarin Sodium clatharte 20 Warfarin Acid 0.44 8.8

IPA 0.12 2.4

Methanol 0.48 9.6

TOTAL 1.04 20.8

105 Ziprasidone HCl 20 3-(1-Plperazinyl)-1,2,-

benziso Thiazole HCl 0.63 12.6

6-chloro-5-(2-

chloroethyl oxidole) 0.51 10.2

Sodium carbonate 0.71 14.2


Con HCl 2 40

ANNEXURE-5

TOTAL 3.95 79

M/s. VIHITA CHEM (P) LTD.(UNIT

LIST OF PRODUCT WITH MANUFACTURE PROCESS

Product: 1

(1.) 2, 3, 4, 5-bis-o-[1-Methyl Ethyl idene] B

PROCESS:

Charge B-D-fructopyranose, Sulphuric Acid and Acetone, than start maintain & apply cooling,

filter, drying & Collect Product.

ITA CHEM (P) LTD.(UNIT-II)


Methyl Ethyl idene] B-D-Fructopyranose:

fructopyranose, Sulphuric Acid and Acetone, than start maintain & apply cooling,

duct.

ANNEXURE-6


Fructopyranose:

fructopyranose, Sulphuric Acid and Acetone, than start maintain & apply cooling,


FLOW CHART:

(02.) Di Methyl Formamide Di Methyl Acetal:Process:

Dimethyl formamide is reacted with sodium methoxide and dimethyl Sulphate. The solvent

and product are distilled and packed.

Input

B-D-Fructopyranose 390

Sulphric acid 211

Acetonne (Fresh) 50

Acetonne(Recovered) 950

Total 1601

Reaction mass 1601

Total 1601

Reaction mass 651

Water 500

Total 1151

Reaction mass 501

Toluene(Fresh) 20

Tolune (Recovered) 280

Total 801


(02.) Di Methyl Formamide Di Methyl Acetal:


and product are distilled and packed.

1601

1601

1601

1151

Purification ,Centifuge & Drying

Reactor

Maintain,Cooling&Filter

Centrifuge

ANNEXURE-6


Output

Reaction mass 1601

Total 1601

Recover Acetone

Reuse 950

Reaction mass 651

Total 1601

Effluent 650

Reaction mass 501

Total 1151

Tolune recovered 280

loss 21

Product 500

Total 801

ANNEXURE-6


MATERIAL BALANCE

(3.) 4-Methyl Catechol Di acetic acid Di methyl ester:

Stage - 1 Charge NaOH and Water Solution Add 4-Methyl catechol Stir it and Slowly

Add.Monochloro acetic acid and NaOH and Water solution Heat to 90-95� Maintain for 4

hours cool to reactor and Add Slowly Hydro chloric acid cool it to Reactor for 24 hours

Centrifuge it Wash with Water Dry it use for Next Stage.

Stage - 2 Charge Methanol and Stage 1 Acid and Sulfuric Acid Reflux for 3 hours distill

out Methanol and Toluene and Water Separate Toluene Layer & Water Layer distill out Toluene

and Purify in Methanol filter it Dry it.

Dimethyl formamide 330.0 reaction mass 1876.0

Dimethyl sulphate 570.0

sodium methoxide 25%

solution 976.0

Total 1876.0 Total 1876.0

reaction mass 1876.0 Methanol recovered 730.0

water 200.0 Effluent 846.0

Product 500.0

Total 2076.0 Total 2076.0

Distillation

Reactor

ANNEXURE-6


MATERIAL BALANCE


(04.) 4-Methyl catechol:

PROCESS:

Methyl Phenol and Hydro Bromic is reacted with peroxide under strictly controlled temp.

Pressure in presence of water the resultant product is further reacted with sodium hydroxide &

water. The formed product is purified & distillation & Packed.



in presence of water the resultant product is further reacted with sodium hydroxide &

water. The formed product is purified & distillation & Packed.

ANNEXURE-6


in presence of water the resultant product is further reacted with sodium hydroxide &

ANNEXURE-6


(5) ROS- Methylene dioxy phenol (SESAMOL):

4-Methyl catechol :

INPUT kg OUTPUT kg

Methyl Penhol 525

HBr 870 Product 500

H2O2

375 Sodium bromide solution 4250

Caustic soda 325 Recover of n-butanol

655

H2SO4 350 loss

35

N-butanol 700 Effluent 835

Water 3200 Residue 70

TOTAL 6345 6345

ANNEXURE-6


(5.) Methylene dioxy phenol (SESAMOL):

PROCESS:

Charge Methylene dioxybenzene at conform temp. Charge Zinc chloride & slowly add acetic

anhydride at critical temp. after complete addition charge formic acid. Now mass cool up to 25°

C & slowly add at Hydrogen peroxide. Maintain mass for fix temp. Cool up to RT. Charge

Caustic lye & filter the mass. Now adj. pH by addition Hydrochloric acid, Separate product by

CF.W /C.Purification in Methanol. Product dry & packed it.

ANNEXURE-6


FLOW CHART:

(06.) 4-Chloro -4’ HydroxyBenzophenone:

PROCESS:

- Charge 1,2 dichloro Benzene and Aluminium Chloride and Charge Phenol Slow addition Of

4- ChloroBenzotrichloride , Stirred for 4 hrs , Dumped in water and Filter the product and

Collect it

ANNEXURE-6


FLOW CHART:

ROUTE-2

4-CHLORO-4’-HYDROXY BENZOPHENONE

ROS:-

ANNEXURE-6


Cl

ClO

OH

+OH Cl

O

AlCl3

1,2 di chloro benzene

4-Chloro benzoyl Chloride

MOL FOR :- C6H4CoCL2

MOL WT :- 175

Phenol

MOL FOR :- C6H6O

MOL WT :- 94

4-Chloro-4'-hydroxy benzophenone

MOL FOR :- C13H9ClO2

MOL WT :- 232

+ HCL

Methanol

OH Cl

O

4-Chloro-4'-hydroxy benzophenone

MOL FOR :- C13H9ClO2

MOL WT :- 232

Manufacture Process :-

Charge in glass line reactor 1,2 di chloro benzene and charge AlCL3 at

10 0C and slow addition phenol in 3-hour at 10-15

0C than addition over now

addition start 4-chloro benzoyl chloride in 8-hour at 10-15 0C.than stirred and

dumping in ice and water , product filtration give hot water wash collet tech

product. Tech product Purification in methanol .

ANNEXURE-6


Flow diagram:-

Reactor

Product:-500 kg

4-chloro benzoyl chloride-400 kg

Packing

Total Effluent-765 kg

ALCL3:- 350 KG

WATER-1000KG

Reactor 20 %ALCL3 SOLUTION – 750 KG

Effluent- 710 kg

Recover 1,2 di chloro benzene-

975 KG

PHENOL– 215 kg 1, 2 di chloro benzene-1000 KG

Reactor

Tech 530KG

Methanol-1000 kg

Recover Methanol-975 KG

Effluent- 55kg

ANNEXURE-6


(7) 2-Bromo Veratryl Bromide:-

ROS:-

OCH3

OCH3

OCH3

OCH3

Br

OCH3

OCH3

Br

BrH2C

HBr

H2O2 (50%) HCHO

HBR in Acetic acid

TOLUENEMDC

Veratrol 4-Bromo veratrol 2-Bromo-veratryl bromide

MOL FOR : C8H10O2

MOL WT - 138.16 g/mol

MOL FOR : C8H9BRO2


MOL FOR : C9H10BR2O2


Acetic acid

Process:

Charge MDC in glass line reactor and charge Veratrol stirred than charge HBr and addition

H2O2(50%) at 20-25°C in 6-hour and stirred 1-hour after addition over .Separation done

.Aqueous layer MDC extraction & MDC layer water wash & distil out MDC . Collect crude

charge in Acetic acid and charge p-formaldehyde stirred and addition HBr in Acetic acid in 2-

4-CHLORO-4’ HYDROXY BENZOPHENONE INPUT kg OUTPUT kg

PHENOL 215 Dry Wt 500

4-chloro benzoyl chloride 400 Effluent 765

1,2 di chloro benzene 1000 20 %ALCL3 SOLUTION 750

ALCL3 350 Recover 1,2 di chloro benzene 975 Water 1000 Recover Methanol 975

Methanol 1000

TOTAL 3965 3965

ANNEXURE-6


hour at below 45°C and Maintain for 14-hour. Dumping in water product collect in Toluene and

distill out Toluene .

FLOW CHART:

(08) 7-ETHYLTYRPTOPHOL:-

ROS

CH3

NHNH2

2-ethylphenyl hydrazine. Hcl

Mol FOR :- C8H13N2CL

MOL Wt :- 172.66 gm/mol

7-ethyltyrptophol

HCL

CH3

NH

OH

dimethyl acetamide

Water

Con H2SO4

2,3-dihydrofuran Mol FOR :- C12H15NO


ANNEXURE-6


Process :-

Take 2-ETHYLPHENYLHYDRAZINE.HCL, Dimethyl Acetamide, Water in Reactor. Add

drop wise 2,3-dihydrofuran at RT . Add drop wise CON H2SO4 at 80 C. Maintain for

8-hrs at 80 C. Product extract in toluene and distilled solvent. Tech product

purified in toluene collect product and packing.

Flow diagram :-

ANNEXURE-6


ANNEXURE-6


MATERIAL BALANCE

ANNEXURE-6


(10) DI METHYL FORMAMIDE DI ISO PROPYL ACETAL:-

H3C OCH3H3C CH3

N-CH +2

H3C OCH3H3C CH3 OH

118 60

DMFDMA IPA

H3C OC3H7

N-CH + 2 CH3OH

H3C OC3H7

DMF DIPA Methanol

175

ANNEXURE-6


MATERIAL BALANCE

ANNEXURE-6


(11) 4-METHOXY BENZALDEHYDE DIMETHYL ACETAL:-

H3CO

+ H3CO CH +CH3OH HCOOCH3 + CH3OH

H3CO 60

OCH3

136 106 32 182

4-M Benzaldehyde TMOF Methanol4-Methoxy

Benzaldehyde

Dimethyl Acetal

HCOONa + 2CH3OH

CHO

OCH3

OCH3

H C

OCH3

NaOH

40

ANNEXURE-6


ANNEXURE-6


(12) BENZALDEHYDE DIMETHYL ACETAL:-

H3CO

+ H3CO CH +CH3OH +

3+CH3OH

H3CO

106 106 32 152 60

Benzaldehyde 40

Benzaldehyde TMOF MethanoldimethylAcetal

HCOONa +

2CH3OH

68

32

CHO

OCH3

H C OCH3

ANNEXURE-6


ANNEXURE-6


(13) 4-HYDROXY BENZYL ALCOHOL:-

4-Hydroxy Benzaldehyde 4-Hydroxy Benzyl

Alcohol

CHO CH2OH

Pd / C

H2

(18)

122 124

OH OH

ANNEXURE-6


ANNEXURE-6


(14) O-BENZYL HYDROXYL AMINE HYDROCHLORIDE

O- Benzyl Hydroxyl Amine HC (159.5)

ANNEXURE-6


ANNEXURE-6


(15) ALPHA-BROMO-ORTHO-CHLORO-PHENYL ACETIC ACID

METHYL ESTER

Ros :-

CH2CN

Cl

CH2COOH

ClCl

COOHBr

NaOH N-bromo succinimide

(2-chlorophenyl)acetonitrile

H2SO4

TOLUENE

chloro benzene

AIBN

Cl

COOCH3Br

H2SO4Methanol

Alpha bromo -2-chloro pheny acetic acid

MDC

Mol For :-C6H4CH2CNCL

Mol wt :-151.5Mol For :-C8H7CLO2

Alpha bromo -2-chloro pheny acetic acid

methyl ester

Mol For :-C9H8CL2BrO2

Mol wt :-263.52

Toluene

Mol wt :-170.59

2-chlorophenyl acetic acidMol For :-C8H7CLO2BR

Mol wt :-249.59

ANNEXURE-6


Flow chart :-

Reactor

Reactor

Reactor

2-Chlorophenyl)Acetonitrile-500 kg Water-1000 lit

NaoH-562 kg

Reactor

Reactor

Product -500 kg

N-bromosuccinimide-336 kg

Toluene-1000 lt

Water-1000 lit

50 % H2SO4 –1000 kg MDC-500 lit

50 %H2SO4- 500 kg Methanol-700 lit

Water-600 lit

Chloro benzene-1000 lit

Catalyst -10 kg

Toluene-1000 lit

Recover MDC- 450 lit

Recover chloro benzene-950 lit

Recover Methanol-650 lit Recover toluene- 1900 lit

Recover Water-2880 lit

effluent- 2178 kg

ANNEXURE-6


PROCESS :-

Charge Sodium hydroxide & Charge Water in Reactor at RT. Apply Heating at

100-110�. Maintain for 6 hrs at 100�.Apply cool to RT. Chilling to below 30

�.In aqueous layer MDC extraction Collect aqueous layer Set PH acidic (PH-2-

3)by adding 50 % H2SO4 at RT. Filter & give water wash. Charge ABCP ACID

(stage :-1) & Charge N-bromosuccnimide , catalyst &chloro benzene in Reactor

at RT. Apply Heating at 80-85�. Maintain for total 24 hrs at 80-85�.Apply

waterOrganic Layer distilled out. Purification in toluene. Charge ABCP (stage :-2)

& Charge Methanol in Reactor at RT. Chilled to 15-20�. Drop wise addition of

H2SO4 for 1-hrs at 15-20�.Charge Toluene in at 15-20�. Maintain for 24hrs at

15-20�.Organic Layer distilled out. collect product & packing

ANNEXURE-6


(16.1 ) 3-(1-Plperazinyl)-1,2-benzisothiazole:-

Ros :-

S

S

COOH

HOOC

S

S

COOCH3

H3COOC

NH

S

O

N

S

Cl

2,2'-dithio dibenzoic acid

Methanol

H2SO4

N

S

N

NH

.HCl

Acetamide

CH3ONa

Toluene

toluenePOCl3

H2O2NaHCO3

piperazine

Water

toluene

MOL FOR : C14H10O4S2

MOL WT - 306

Dimethyl 2,2'dithiodibenzoate


MOL WT - 334

1,2-Benzisothiazolin-3(2H)-one

MOL FOR : C7H5NSO

MOL WT - 151

HCL

Methanol

3-chloro-1,2-benzisothiazole

MOL FOR : C7H4NCLS

MOL WT - 169.5

3-(1-Plperazinyl)-1,2-benzisothiazole Hydrochlorida

MOL FOR : C11H14N3SCL

MOL WT - 255.5

N

S

N

NH

NaOH Soln

Toluene3-(1-Plperazinyl)-1,2-benzisothiazole

MOL FOR : C11H13N3S

MOL WT - 219

Hydrogen peroxide

Sodium methoxide

ANNEXURE-6


(16.1) 3-(1-Plperazinyl)-1,2-benzisothiazole :

Manufacturing process:- 3-(1-Plperazinyl)-1,2-benzisothiazole: Charge methanol and 2,2

di thio salicylic acid stir and addition of H2SO4 in Reactor than addition is over reflux few hour

than distill methanol and charge water make PH 7- by sodiumbicaronate than product is

filter and wash by water filter product collect in toluene addition of sodium methoxide than

addition over than addition of Acetamide in toluene layer than addition over reflux for 3-hour

Apply cooling up to Reactor charge water and separation of aqueous layer and addition of H2O2

than addition is over stir Reactor for 3-hour maintain time over addition of HCL when PH

2.0than product is filte and give water wash and dry it product charge in POCl3 stir and dumping

in water ,product collect in toluene and distill out solvent after distill technical product charge in

Toluene and addition of solution of piperazine in Toluene and maintain for 85 0C and dumping

in water than product extraction in toluene given water wash and distill out toluene crude product

collect in Methanol and filter it Dry it.

ANNEXURE-6


FLOW CHART :- 3-(1-Plperazinyl)-1,2-benzisothiazole

Reactor

Tech product

400 kg

GLR

Distill product

425 kg

Product

500 kg

2, 2'-Dithiosalicylic acid 900 kg NaHCO3 30 kg + Water 300 kg

Methanol 2700 kg

H2SO4 30 kg

NaOCH3 152 kg

Toluene 2700 kg

Acetamide 165 kg

POCl3 405 kg

Toluene 1215 kg

Piperazine 220 kg Toluene 1272 kg Methanol 848 kg

Methanol reuse (2650 kgs)

HCL 300 kg + Water 300 kg

Toluene Reuse (2640 kgs)

Toluene Reuse (1180


Methanol distill and Reuse (810 kgs)

Effluent 850 kg

Effluent 900 kg

Effluent 500 kg

ANNEXURE-6


(16.2 ) 3-(1-Plperazinyl)-1,2-benzisothiazole Hydrochloride :-

S

S

COOH

HOOC

S

S

COOCH3

H3COOC

NH

S

O

N

S

Cl

2,2'-dithio dibenzoic acid

Methanol

H2SO4

N

S

N

NH

.HCl

Acetamide

CH3ONa

Toluene

toluenePOCl3

H2O2NaHCO3

piperazine

Water

toluene


MOL WT - 306

Dimethyl 2,2'dithiodibenzoate


MOL WT - 334

MOL FOR : C7H5NSO

MOL WT - 151

HCL

Methanol

3-chloro-1,2-benzisothiazole

MOL FOR : C7H4NCLS

MOL WT - 169.5

3-(1-Plperazinyl)-1,2-benzisothiazole Hydrochloride


Hydrogen peroxide

Sodium methoxide

(16.2) 3-(1-Plperazinyl)-1,2-benzisothiazole Hydrochloride

Manufacturing process:- 3-(1-Plperazinyl)-1,2-benzisothiazole Hydrochloride

Charge methanol and 2,2 di thio salicylic acid stir and addition of H2SO4 inReactor than

addition is over reflux few hour than distill methanol and charge water makeph 7- by

sodiumbicaronate than product is filter and wash by water filter product collect in toluene

addition of sodium methoxide after addition over than addition of Acetamide in toluene layer

than addition over reflux for 3-hour Apply cooling up to 30 c ,in Reactor charge water and

separation of aqueous layer and addition of H2O2 than addition is over stir Reactor for 3-hour

than maintain time over addition of HCL when PH 2. Than product is filter and give water

wash and dry product charge in POCl3 stir and dumping in water product collect itoluene and

distill out solvent and technical product charge in Toluene and addition of solution of

piperazine in Toluene and maintain for 85 0C and dumping in water product extraction in toluene

given water wash and distill out toluene crude product collect in Methanol and addition of HCL

ANNEXURE-6


in RT than apply cooling and chilling mass temp 10 0C stir for 1-hour filter product and wash by

methanol and dry it.

FLOW CHART :-

Reactor

Tech product

400 kg

GLR

Distill product

425 kg

Product

500 kg

NaHCO3 30 kg + Water 300 kg

Methanol 2700 kg

H2SO4 30 kg

NaOCH3 152 kg

Toluene 2700 kg

Acetamide 165 kg

POCl3 405 kg

Toluene 1215 kg

Piperazine 220 kg Toluene 1272 kg

Methanol 848 kg

HCl 300 kg + Water 300 kg

Methanol Reuse (850 kg)

HCL 300 kg + Water 300 kg

Toluene Reuse (2640

kgs)

Toluene Reuse (1180 kgs )


Methanol distill and Reuse (810

kgs)

Effluent 850 kg

Effluent 900 kg

Total Effluent 850 + 900 + 1070 =2820 kg

Effluent 1070 kg

2, 2'-Dithiosalicylic acid 900 kg

ANNEXURE-6


3-(1-Plperazinyl)-1,2-benzisothiazole Hydrochloride

INPUT kg OUTPUT kg

2, 2'-Dithiosalicylic acid 900 Recover of Methanol

3460

Methanol 3548 Dry Wt 500

H2SO4 30 loss 255

NaOCH3 182 Recover of toluene

3820

HCL 600 Effluent 2820

Toluene 3915

Acetamide 165

WATER 900

POCL3 405

Piperazine 220

TOTAL 10865 10865

ANNEXURE-6


(17) 5-CHLOROETHYL-6-CHLORO-2-OXINDOLE:-

HCL

Fe

36.5

Fe+

6-Chloro Oxindole 167.5

ALCL3 CL CH2COCL 113

132

TriEthylsilane

116

ANNEXURE-6


(17) 5-chloroethyl-6-chloro-2-oxindole:

Process:

Charge in reactor di methyl sulphoxide and potassium carbonate and di methyl malonateadd 2,5

Di chloro nitro bezene stirred and distill di methyl sulphoxide crude in charge acetic acid

and Hydrochloric Acid reflux distil water crude and charge methanol and add iron and reflux

filter solvent distil crude and Zinc Chloride in Methylene Dichloride and add chloro acetyl

chloride stirred dumping in water distil solvent, crude stirred in tryethylsilane and ext water

collect product

Flow Chart:

ANNEXURE-6


(18) 2,4,6- TRI METHOXYBENZALDEHYDE :-

OCH3

OCH3H3CO

POCl3

DMF

OCH3H3CO

OCH3

CHO

1,3,5-Tri methoxy Benzene 2,4,6-Tri hydroxy Benzaldehyde

(18) 2,4,6-Trimethoxybenzaldehyde

Manufacturing process:-

Stage :- 1 Complex Preparation

Charge DMF in GLR Chill to 10�Add POCl3at 10� with in 1 hour stirr for 1 hour use for next

stage.

Stage:- 2

Charge DMF and 1,3,5-Tri Methoxy Benzene Heat to 100-110� Add stage 1 complex

at 100-110� with in 2 hour and dumping in Water and ice Adjust PH 8 by sodium carbonate

solution filter it dry it

Recrystallization :-

TackProduct in Methanol Heat & make cler solution cool it chill it Centrifuge Dry it pack it.

ANNEXURE-6


(19 ) 4-METHOXY-3-NITRO BENZYL SULFONYL ACETIC ACID:-

CH3

NO2

OCH3

NBS

N-Bromo succinimide

CH2Br

OCH3

NO2

SHCH2COOH

3-Nitro 4-Nethoxy toluene 3-Nitro 4-Methoxy Benzyl Bromide

Thioglycolic acid

CH2SCH2COOH

OCH3

NO2

H2O2

CH2 S CH2COOH

O

O

NO2

OCH3

4-Methoxy-3-Nitro Benzyl sulfonylacetic acid

2,4,6- TRI METHOXYBENZALDEHYDE INPUT kg OUTPUT kg

DMF 420 Recover of methanol

960

POCl3 400 Product 500

1,3,5-Tri methoxy Benzene

430 Loss 90

Methanol 1000 Effluent

2400

Na2co3 600

water 1100 TOTAL 3950 3950

ANNEXURE-6


(19. ) 4-Methoxy-3-Nitro Benzyl sulfonylacetic acid:

Manufacturing process:- Stage - 1 Charge ChloroBenzeneand 3-Nitro-4-Methoxy

Toluene and NBS Then Add Benzoyl peroxide(catalyst) Heat to 75-80� . Maintain 24 hours

cool to 20� filter it wash with Chloro Benzene

Cake is succinimide send to NBS give SBS wash to chloro Benzene Layer distill out chloro

Benzene use for Next Stage.

Stage - 2 Charge Methanol and NaOH stir it make clear solution cool to 25� and

Thioglycolic Acid at 25-30� Then and stage 1 Product Reflux for 4 hours dumping in ICE +

Water stir for 1 hours filter it dry it use for Next stage.

Stage - 3 Charge Acetic Acid and stage 2 Product stirr for 30 min and H2O2(30%)with in 30

min heat to 90� maintain form 2 hours dumping in ICE + Water stirr for 1 hours filter it Dry it

MP - 138-142� .

4-METHOXY-3-NITRO BENZYL SULFONYL ACETIC ACID INPUT kg OUTPUT kg

NBS 450 Recover of Chlorobenzene

1840

3-Nitro-4-Methoxy Toluene 380 Dry Wt 500

Chloro Benzene 1900

Benzoyl peroxide 5 Recover of Acetic acid 1350

Thioglycolic Acid 190 Recover of Methanol 1435

Methanol 1500 Effluent 2612

H2O2 630 NBS solution 800

WATER 2000

NaOH 82

Acetic acid 1400

TOTAL 8537 8537

ANNEXURE-6


(20) (1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane:-

O S CH3

O

O

O S CH3

O

O

COOH

COOH

OH

OH

(1R,2R)-1,2-Cyclohexane di carboxylic Acid

NaBH4

THF

NaOHMDC

(1R,2R)-1,2-Cyclohexane di methanol

MDC

TEAMSC

(1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane

Methane Sulfonyl Chloride

(20) (1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane:

Manufacturing process:-Stage :- 1

Charge THF and sodium borohydride chill to 0� .Add slowly (1R,2R)-1,2-Cyclohexane

di carboxylic Acid Add with in 3 hour stirr it for 24 hour at 0-5� temp Add NaOH

Watersolution make 10-11 PH distil out THF and Extract Product in MDC at 10� distil out

MDC Use Take Product in Next Stage .

Stage :- 2

Take MDC and stage 1 Product Add Triethyl Amine at 10� Add Slowly Methane sulfonyl

chloride with in 1 hour stirr for 3 hour at 10� increase Temp 35� stirr for 3 hour dumping

in Water sepn MDC Layer give Water Wash distil out MDC Product Pack it.

ANNEXURE-6


FLOW CHART :-

ANNEXURE-6


(21) 4 IsoPropyl Catechol:-

CHCH3CH3

NH2

+ NaNO2 + CuSO4.5H2O + H2SO4

CHCH3CH3

OH


p-Cumidine

MOL FOR - C9H13N

MOL WT - 69 g/mol MOL WT - 249 g/mol MOL WT - 98 g/mol

4-Isopropylphenol

+ H2O

MOL FOR - C9H12O


CHCH3CH3

OH

Br

CHCH3CH3

OH

OH

HBr

H2O2

NaOHCu

H2SO4

Bromo-4-Isopropylphenol

MOL FOR - C9H11OBr

MOL WT - 214 g/mol

4-Isopropyl Catechol

MOL FOR - C9H12O2

MOL WT - 152 g/mol

ANNEXURE-6


(21) 4-IsoPropyl Catechol


Stage 1

Charge.Ice and sulfuric acid, stir it heat to 50 c add p- cumidine stir for 2 hour chill to 0 c add

NaNo2 solution with in 4 hour. stir for 1 hour add in copper sulfate+water solution at 110c

add steam distil the product & use in next stage: Recover copper sulfate solution

Stage 2

Charge MDC add 4 iso propyl phenol chill to 5-10 c add HBr (48%) & addition

H2O2(50%) solution with in 6 hour stir for 6 hour seprate MDC layer wash it & distil out

MDC isolate the product use in next stage

Stage 3

Charge water and NaOH and make solu add copper powder &add stage 2 product reflux

for 4 hour filter it cool it adjust pH extract the product in n- Butanol distil out n-Butanol product

pack it

ANNEXURE-6


FLOW CHART: - 4-IsoPropyl Catechol

ANNEXURE-6


(22) 3-Methoxy Phenol :-

ROS

OH

OH

+ (CH3)2SO4 + NaoH

Toluene

50 % H2SO4

OH

O

CH3

Resorcinol

Dimethyl sulphate

Mol FOR :- C6H6O2

MOL Wt :- 110 gm/mol

Mol FOR :- C2H6SO4


3-Methoxy Phenol

Mol FOR :- C7H8O2


+ CH3OH Na2SO4+

Na2CO3

Process :-

Take Resorcinol, Soda Ash, Toluene in Reactor. Add diMethylsulphate drop wise

. Maintain PH by 50% H2SO4 and collect product and packing.

ANNEXURE-6


Flow diagram :-

Resorcinol-475 kg Na2CO3 :-550 kg

Toluene-1000 lit

Reactor Dimethyl sulfate- 550 kg

Reactor

Reactor

Maintaine-75-80 ° C Water -1000 lit

Recover water -1500 kg

reused

Reactor

Product -500kg

Recover Toluene- 950lit & Reused

50% NaoH sol

wash- 750 kg 50% H2SO4- 400 lit

High

vacuum

Effluent-1200 kg


SALT- 485 KG

Residue-50 kg

ANNEXURE-6


(23) Veratrol Alcohol

ROS :-

CHO

OH

OCH3

+

CHO

OCH3

OCH3

VANILLIN

MOL FOR:- C8H8O3

Mol wt :- 152.15 gm/mole

DMS

Mol wt :- 126 .13gm/mole

sodium carbonate

MOL FOR:- C9H10O3

Veratraldehyde


Toluene(CH3)2SO4

Water+ NaHCO3


+ +CO2 H2O

44 gm/mole

18 gm/mole

(CH3)SO4Na+134.087gm/mole

CH2OH

OCH3

OCH3

Veratrol Alcohol

MOL FOR:- C9H12O3


Sodium borohydrate

Methanol

ANNEXURE-6


Flow diagram :-

Reactor

Maintain &

Separation

Reactor

Vanillin-470 kg NaCO3 :-662 kg

Maintaine-85-90 ° C

Dimethyl sulphate-662 kg

Recover of water-5125 lit

Tolene-1880 lit

Water -5700 lit

Recover Toluene- 1800lit & Reused NaoH – 94 kg

Reactor


SALT- 580 kg

Methanol-1000 lit

NaBH4- 60 KG

Recover Methanol- 950lit & Reused MDC-500 lit

Water -500 lit

Product-500 kg

Recover MDC- 450lit & Reused

effluent-2073 kg

ANNEXURE-6


Process :-

Take Vanillin, Sodium carbonate, and Toluene in Reactor. Heating up to

45C.start DMS addition in 2 hrs at 45-50C.Reflux up to 85-90C fr 8 hrs. cool it at

room temp. then add 2ltr water.1hrs stir at 60-70C.seperation.collect aq. layer and

give toluene extraction. Give to organic layer extraction by caustic solution.

Collect organic layer and give water wash. Distilled toluene and collect product.

Take product, charge methanol & lot wise NaBH4 addition for 8 hrs at 25-30 c &

Maintain. Distilled methanol.Charge water & MDC. Layer separation & distilled

Solvent &collect product & packing.

(24) 3,4- Dihydroxy Benzoic Acid

ROS :-

COOH

OCH3

OCH3

MOL FOR:- C9H1004

Veratric acid

Mol wt :- 182 gm/mole

COOH

OH

OH

3,4-Dihydroxy benzoicacid

MOL FOR:- C7H6O4


Hbr (48 %)

Acetic acid

ANNEXURE-6


Flow diagram :-

Process :-

Take Veratric Acid, HBr (48 %), Acetic acid in reactor. Slowly Start heating to

reflux .maintain for 72 hrs at reflux temp. cool to RT. Filter and collect product.

Packing.

ANNEXURE-6


(25) 3, 4-Dihydroxy Benzaldehyde

ROS:-

CHO

OH

OCH3

CHO

OH

OH

VANILLIN

MOL FOR:- C8H8O3

Mol wt :- 152.15 gm/mole MOL FOR:- C7H6O3

3,4-hydroxy benzaldehyde

Mol wt :- 138 gm/mole

HBr(48%)

Acetic Acid

Flow diagram :-

ANNEXURE-6


Process:-

Take Vanillin, HBr (48 %), Acetic acid in reactor. Slowly Start heating to reflux

.maintain for 72 hrs at reflux temp. cool to RT. Filter and collect product. Packing.

(26) 4 -Propyl Catechol:-

CH2

OH

CH3

4-propylphenol

MOL FOR - C9H12O


CH2

OH

Br

CH3

CH2

OH

OH

CH3

HBr

H2O2

NaOH

Cu

H2SO4

Bromo-4-propylphenol

MOL FOR - C9H11OBr

MOL WT - 214 g/mol

4-propyl Catechol

MOL FOR - C9H12O2

MOL WT - 152 g/mol

MDCn-butanol


Charge MDC add 4 propyl phenol chill to 5-10 c add HBr (48%) & addition H2O2(50%)

solution with in 6 hour stir for 6 hour separate MDC layer wash it & distil out MDC isolate

the product use in next stage.

Charge water and NaOH and make solution add copper powder &add stage 2 product

reflux for 4 hour filter it cool it adjust pH extract the product in n- Butanol distil out n-Butanol

product pack it

ANNEXURE-6


FLOW CHART :-

(27) Dimethyl AcetamideDimethylAcetal :-

ROS

+Methanol

Dimethyl acetamideDimethyl sulphate

Mol FOR :- C4H9NO

MOL Wt :- 87gm/mol

Mol FOR :- C2H6SO4

MOL Wt :- 126 gm/molMol FOR :- C6H15NO2


CH3oNa

O

CH3N

CH3

CH3

CH3

O

S

O

O

O

CH3

O

CH3N

CH3

CH3

CH3

O

CH3

Dimethyl acetamide dimethyl acetal

GLR

Distill & Product

Isolate 770 kg

S.S. Reactor

HDPE

Distill

Product

500kg

4-Propyl Phenol 500kg

MDC

1000kg

HBr(48%)

620kg H2O2(50%)+Water

250kg+250kg

Bromo Phenol

770kg

NaOH+Water

290kg+290kg Cu 10kg

H2SO4 +Water

360kg+360kg n-Butanol 1400 KGS

MDC Reuse 950 KGS

n-Butanol Reuse 1370

Aq. NaBr sale - 1100kg

Effluent510kg

Residue- 70kg

during High vacuamdist

Cu reuse 20

water Reuse 800 KGS

ANNEXURE-6



Take Dimethyl Sulfate and dimethyl Aceamide Heat to 80�.Maintain for 3 hour Cool it to RT

.Take Sodium Meth oxide solution .Chill to 0-5�and Complex Stage 1 with in 4 hour 0-5 �

.Stir for 1 hour Slowly increase temp to 20� . Stir for 1 hour.Then Heat to 60 � .Add Start

distillation of Methanol .charge methanol &distillation of MethanolCharge Methanol and above

product. Add do Fraction using Vigorous Column First Methanol Will distillation out at 64 – 80

�.ThenCollect product distilled & packing.

(28) Tert-butyl (4-bromophenyl) Methylcarbamate--

ROS :-

NHCH3

N-methyl Aniline

MOL FOR : C7H9N

MOL WT - 107 g/mol

MOL FOR : C9H8NBr

MOL WT - 185 g/mol

MOL FOR : C13H18BrNO2

MOL WT - 286g/mol

tert-butyl(4-bromomethyl)methyl carbamate4-Bromo N-methyl Aniline

NHCH3

Br

N-Bromo sucinimide

MDC

BOC

CH3

Br

NO

O

O

CH3

CH3

CH3

DMF

MDC

Di Methyl Acetamide Di Methyl Acetal INPUT kg OUTPUT kg

Dimethyl Aceamide 327 Recover of MeOH

850

dimethyl Sulphate 474 Product 500

sodium methoxide

976 EFFLUENT 927

Methanol 500

TOTAL 2277 2227

ANNEXURE-6


Flow diagram :-

PROCESS :-

Take N-methyl aniline, DMF in reactor. Chilled to in reactor at 20 C .drop wise addition of

N-bromosuccnimide (NBS)& dimethyl Formamide (DMF) solution for 6- hrs at 0C.Maintain

at 20C. water, Charged MDC & distillation product. Take product , water & NAOH in reactor

at RT. Drop wise addition of di-tert-butylpyrocarbonate(BOC) for 1 hrs at 0C. Maintain for 24-

hrs.cool to RT.MDC extraction at 20C. distillation product. Collect product & packing.

ANNEXURE-6


(29) 4-[(4-Methyl-1-piperazinyl)-methyl]-benzoyl chloride

dihydrochloride

ROS :-

Br

NC

Chlorofrom

4-cyano benzyl bromide

MOL FOR : C7H6BrN


MOL FOR : C13H17N3

MOL WT - 215 g/mol

MOL FOR : C13H18N2O2

MOL WT - 234g/mol

N

NH

CH3

NC

N

N

CH3

COOH

N

N

CH3

COCL

N

N

CH3

4-((4-Methyl-1- piperazinyl)-methyl benzoyl chloride .2HCL

MOL FOR : C13H19Cl3N2O


SOCl2

DMF

Con HCL

4-((4-Methyl-1- piperazinyl)-methyl benzoic acid

4-((4-Methyl-1- piperazinyl)-methyl benzonitrile

2 HCl

ANNEXURE-6


Flow diagram :-

4-cyano benzyl bromide-420 kg chloroforom -1000 LIT

Reactor

Maintain &

Separation

Maintaine-25 ° C

Reactor

Recover of water-1100 lit

Water -500 lit

Recover chloroform- 950 lit

Reactor


CON HCL-2000 lit

Recover SOCL2- 1950kg & Reused SOCL2-2000 kg

DMF- 50 lit

Product-500 kg

Recover MDC- 450lit & Reused

effluent-2000 kg

MDC-500 lit

N-methyl piperazine-590 kg

ANNEXURE-6


PROCESS :-

Take N-methyl piperazine in reactor. Charge 4-cyano benzyl bromide & chloroform in

reactor at 20 C .Maintain at 20C.water wash & distillation product. Take product & con. HCL in

reactor. Heating to reflux for 6-hrs.cool to RT. Filter the reaction mass. Dry it. Take product,

thionyl chloride & DMF. Heating to 65 c &Maintain for 6-hrs at 65.C. distillation product.

charge MDC in reaction mass. Chilled 10C. Filter reaction mass. Dry product .Packing.

30) (2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)methanol (Cas

no :-121660-11-5)

ROS:-

2-amino-4-fluoro benzophenone

MOL FOR : C13H10FNO


MOL FOR : C7H10O3

MOL WT - 142.15g/mol MOL FOR : C20H16FNO2

MOL WT - 321g/mol

MOL FOR : C19H19FNO

MOL WT - 293g/mol

DIBAL.H 25% sol in toluene

Toluene

Con H2SO4

methyl-2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxylate

3-cyclopropyl-3-oxo propionic acid methyl ester

NH2F

O

+ OCH 3

O O

Methanol

N

COOCH 3

F

N

CH 2OH

F

(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl) methanol

water

Na2CO3

HCL

10 % NaHCO3cyclohexane

ANNEXURE-6


Flow diagram :-

PROCESS :-

Take 2-amino-4-fluoro Benzophenone in methanol inreactor. Addition of 3-cyclopropyl-3-oxo

propionic acid methyl ester& con H2SO4 in reactor at 20 C .Maintain at 65C for 22 hrs.

distillation methanol product. Take product & water in reactor. Set Ph-6 by sodium carbonate.

cool to RT. Filter the reaction mass. Dry it. Take product, in toluene. chilled to 0 C & Addition

of DIBAL H 25 % solution in toluene .Maintain for 2-hrs at RT. Quenched by HCL. Set Ph by

sodium bicarbonate .distillation toluene product. Take product & charge cyclohexane in

reaction mass. Chilled 10C. Filter reaction mass. Dry product .Packing

ANNEXURE-6


(31) (-) ALCOHOL

ROS :-

MOL WT - 1664-FIUORO BENZALDEHYDE

MOL WT :- 124.11

MOL WT :- 140.06

PYRIDINE

P-fluro cinnamic acid

stage :-1

+ CH2(COOH)2 H2O

18

+

stage-2

SOCL2+thionyl chloride

MOL WT - 118

F

OHC

water

HCL

F

COOH

CO2+44

F

COOH

P-fluro cinnamic acid

MOL WT - 166

F

COCL

DMF methyl amine

31.6

F

NH

CH3

O

+ HCL

36.5

MOL WT - 179

stage-3F

NH

CH3

O

MOL WT - 179

+ CH2(COOET)2

diethyl malonate

MOL WT - 160

F

CO

NH CH3

(COOET)2

MOL WT - 339.36

P-t buoxide

F

NO

CH3

O

COOEt

MOL WT - 265

ester

+CH3CH2OH

MOL WT - 46

MOL WT - 183.5

malonic acid

ANNEXURE-6


stage :-4F

NO

CH3

O

COOEt

MOL WT - 265.29

ester

NaBH4

BF3 ETHRATE

F

NO

CH3

O

CH2OH

resolution

F

NO

CH3

O

OH

4-(4-fluorophenyl)-3-hydroxymethyl-1-methyl pyridin

MOL WT - 223.29 MOL WT - 223.29

(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethyl-1-methyl pyridin

ManufacturingProcess :-

Para –Fluoro –benzalaldehyde is reacted malonic acid in preseance of pyridine

solvent at 75C to gives Para –Fluoro –cinnamic acid .Which is reacted thionyl

chloride & than methyl amine to gives amine derive.Than reacted dimethyl

malonate & cyclized by sodium –t-buoxide to give ester derive. Which reacted

sodium borohydrate & BF3 ethrate.Which give(RS) alcohol(recamic mixture)

obtain.than resolution in preseance of Tartaric acid & IPA solvent to give (3S,4R)-4-(4-

fluorophenyl)-3-hydroxymethyl-1-methyl pyridine(-) alcohol.& (+) alcohol was converted to

racemic acid than racemic acid ester & further used.

(-) ALCOHOL INPUT OUTPUT

4-FIUORO BENZALDEHYDE 620 KG Recover water 1200 KG

malonic acid 700kg Recover pyridine 475 kg Pyridine 500 KG Recover thionyl chloride 475 kg Water 1000

KG

PRODUCT 500 KG

Con hcl 500 KG Effluent 2286

Thionyl chloride 500 kg Recover IPA 950 LIT

DMF 200 KG (+)alcohol in converted to

racemic acid & racemic ester -

500 kg

Diethyl malonate 700 KG Recover BF3 eharate 450 kg

Potassium t butoxide 516 KG Tartaric acid salt 560 kg

NaBH4 350 KG Recover DMF 190 KG

BF3ethrate 500 KG LOSS 150kg

ANNEXURE-6


32)3-METHOXY PROPIOPHENONE :- (CAS NO :-37951-

49-8)

ROS :-

CH3

OCH3

O

Br

Alcl3

Br2

DMF

CuCl

Propiophenone

MOL FOR :-C6H5COC2H5

MOL WT :-134.18

3-Bromo Propiophenone

MOL FOR :-C6H4COC2H5Br

MOL WT :-213.07

SMO (25 %)

HCLEDC

Toluene

OCH3

O

CH3

MOL FOR :-C10H12O2

MOL WT :- 164.21

3-Methoxy Propiophenone

Tartaric acid 500 KG

IPA 1000

LIT

Methyl amine 150 kg

TOTAL 7736KG 7736KG

ANNEXURE-6


Flow chart :-


Charge in EDC in Reactor and Cool up to 25-300C than Charge ALCL3 and

Addition of Propiophenone for 30 min at 25-350C and Sir for 3-hrs at25-35

0C

.Addition of Bromine for 6-hrs at 25-350C and Sir for 3-hrs at25-35

0C. Dumping

in water and Separate Solvent. Distil out solvent crude Obtain. Take crude &

Charge in sodium methoxide (SMO 25%) and Charge DMF and Charge CUCl

reflux for 20 hrs. and Product isolation in toluene and distill out solvent & crude

obtain.Take crude and charge HCl solution at RT .Stir for 2 hrs at RT.and Product

isolation in toluene and distill out solvent. Product distill out.

Reactor

Reactor

Propiophenone-408 KG EDC-1000 LIT

ALCL3- 610 KG Water-1000 lit

Reactor

DMF-300 lit

Product-500 kg

Recover EDC-950 lit

Recover water- 1500 lit

Effluent -1005 KG

Recover toluene- 950 lit

Recover Methanol -450 lit

Total Effluent -1005 KG

Bromine -487 KG

CUCL- 50 KG

25 % SMO – 750 kg

Toluene-500 lit

Toluene-500 lit

DilHCL-1000 lit

Hbr solution-500 lit

Recover DMF-250 lit

ALCL3 SOLUTION -500 lit

ANNEXURE-6


(33) ROS :- AFATINIB DIMALEATE

3-METHOXY PROPIOPHENONE INPUT OUTPUT

Propiophenone 408KG Recover of TOLUENE 950 LIT

EDC 1000 lit Dry Wt 500 KG

Water 1000 lit Recover of EDC 950 lit ALCL3 610 KG Recover of DMF 250 LIT

Bromine 487 KG Recover of methanol 450 lit

TOLUENE 1000 lit AlCL3 SOLUTION 500 lit

25 % SMO 750 KG Hbr solution 500 lit

DMF 300 LIT EFFLCENT 1005 kg CUCl 50 KG Recover of Water 1500 lit Dil HCL 1000

LIT

TOTAL 6605

KG

6605KG

O

NH

N

N

F

Cl

NH

O

ONMe2

O

NH

N

N

F

Cl

NH

O

ONMe2

Maleic acid , Ethanol

Afatinib

Afatinib dimaleate

(S,E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide

ANNEXURE-6


Manufacturing Process :-

To a Solution of Afatinib in Methanolis added maleic acid in Methanol slowly. The

Separated Solid is filtered and Washed with ethanol to get Afatinibdimaleate.

Flow diagram :-

(34) ROS :-Arbutin

AC O O H +O OAC

OAC

OACOAC

AC OO O OAC

OAC

OAC

AC O

AC O

O O OH

O H

OHOH

OH

M o n o a c e ty l h y d ro q u in o n eP e n ta a c e ty l-B -D -g lu c o s e

P e n ta a c e ty l a rb u tin e

B F 3

T E A

M D C

A rb u tin

M O L F O R : - C 7 H 8 O 2

M O L W T :- 1 2 4 .1 4 g /m o l M O L F O R :- C 1 6 H 2 2 O 1 1

M O L W T :- 3 9 0 .3 4 g /m o lM O L F O R : - C 2 2 H 2 6 O 1 2

M O L W T :- 4 8 2 g /m o l

M O L F O R :- C 1 2 H 1 6 O 7

M O L W T :- 2 7 2 .2 5 g /m o l

S o d iu m M e th o x id e

E th e ra te

ANNEXURE-6


Manufacturing process:-Arbutin

Take Pentaacetyl-B-D-glucose and Monoacetylhydroquinonein dried MDC stirr it make Clear solu Add

Triethyl amine Chill to 20� Add BF3etherateSoln Reflux for 24 hours chill to 20� Add Water Separate

Organic &Aq Layer give Water Wash to organic Layer Distill out MDC Recrystallise in Toluene mp –

145 – 148 �

Take This Product in Methanol Add Sodium Methoxide 25% Solu Reflux for 6 hours distill out

Methanol this is Tech Product Add Water and isolate the Product.

FLOW CHART :-Arbutin

(35) ROS :-AGOMELATINE

CH2CN

OMe

CH2-CH2-NH2

H3CO

CH2CH2NHCOCH3

OMe

Raney Ni CH3COCl

ANNEXURE-6



Catalytic hydrogenation of (7-Methoxy-1-naphthyl) acetonitrile using Methanol and Ammonia

gives 2-(7-Methoxy-1-naphthyl) ethanamine. Condensation of 2-(7-Methoxy-1-naphthyl)

ethanamine with acetyl chloride in presence of base gives crude Agolelatine. Which on

purification gives final Agomelatine API.

FLOW DIAGRAM

ANNEXURE-6


(36) ROS :- APIXABAN

N

O NN

N

O

OCH3

COOEt

N

O NN

N

O

OCH3

COOEt

Ethylene Glycol

NH3

H2O

Ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidine-1-yl)phenyl)-4,5,6,7 tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-Carboxylate

MOL FOR :- C27H28N4O5

MOL WT :- 488.53

Apixaban


MOL WT :- 459.71


Ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidine-1-yl)phenyl)-4,5,6,7 tetrahydro-1H-

pyrazolo[3,4-c]pyridine-3-Carboxylate reacts with Ammonia in Presence of Ethylene glycol to

give an intermediate which gets converted into Apixaban under ammonia Pressure.

ANNEXURE-6


Flow diagram :-

(37) ROS :-Aripiprazole

C l

C l

N

NO N

H

O

A r ip ip r a z o le - T e c h n ic a lC l

C l

N

NO N

H

O

E th y l a lc o h o l

A r ip ip r a z o le

C l

C l

N

NO N

H

O

A r ip ip r a z o le - T e c h n ic a l

C l

C l

N

NO N

H

O

A r ip ip r a z o le - C r u d e

C l

C l

N

NO N

H

O

A r ip ip r a z o le - C r u d e

NH

O Ol + N

NH C l

C l

HCL.

7 - ( 4 - io d o b to x y ) - 3 ,4 - d ih y d r o -2 ( 1 H ) q u in o l in o n e

1 - ( 2 , 3 - D ic h lo r o p h e n y l p i p e r a z in e h y d r o c h lo r id e

P o t o s s iu m

C a r b o n a te

D M F / P r o c e s s W a t e r

A c e t o n i t r i l e

M O L F O R : - C 1 3 H 1 6 lN O 2

M O L W T : - 3 4 5 . 1 8 M O L F O R : - C 1 0 H 1 3 C l 3 N 2

M O L W T : - 2 6 4 .5 8

M O L W T : - 4 4 8 .3 9

M O L F O R : - C 2 3 H 2 7 C l 2 N 3 O 2

M O L W T : - 4 4 8 .3 9M O L F O R : - C 2 3 H 2 7 C l 2 N 3 O 2

M O L W T : - 4 4 8 .3 9

M O L F O R : - C 2 3 H 2 7 C l 2 N 3 O 2

M O L W T : - 4 4 8 .3 9 M O L W T : - 4 4 8 .3 9

w a t e r

ANNEXURE-6



Stage :- 1 :- Preparation of Aripiprazole crude

7-(4-Chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone Condenses with 1-(2,3-

dichlorophenyl)piperazine hydrochloride in presence of potassium carbonate, N,N-

dimethylformamide and sodium iodide to yield Aripiprazole crude.

Stage :- 2 :- Preparation of Aripiprazole technical

Aripiprazole crude in heated with acetonitrile to yield pure Aripiprazole technical.

Stage :- 3 :- Purification of Aripiprazole

Aripiprazole technical obtained is purified with ethanol to yield pure Aripiprazole .

Flow diagram :- step:-1

ANNEXURE-6


Flow diagram :-step:-2

Flow diagram :- step:-3

Reactor

Centrifuge

Wet cake

Dry Wt

511 kg

Aripiprazole crude

step:-1

Acetonitrile

Potassiumcarbonate

170Kg

Recover of acetonitrile 1000kg

525Kg 1050 kg

Cool& chill

Residue 234kg

Reactor

Sparkler filter

Reactor

Centrifuge

Dry Wt

500 kg

Aripiprazole crude

step:-2

IPA

Heating

Recover of Ipa 1480kg

Hyflow

511Kg 1550kg

Residue 61 Kg

Charcol

50Kg

Wet cake

charcoal 70 Kg

ANNEXURE-6


(38) ROS :- ASENAPINE

O

Cl

N

HH

CH3

COOH

COOH

Trans-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole maleate(crude)

O

Cl

N

HH

CH3

COOH

COOH

Trans-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole maleate

n-Butyl alcohol

Activated Carbon

O

Cl

N

HH

CH3

COOH

COOH

Trans-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole maleate(crude)

O

Cl

N

HH

CH3

O

NH2

N

HH

CH3

Trans-2-methyl-5-amino-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole

O

O2N

N

HH

CH3

Trans-2-methyl-5-nitro-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole

Pd/(10%),H2

Methanol,Sodium hydroxide,Dichloro methane

NaNO2

Conc.HCL

Cuprous ChlorideEthyl acetate,Liq Ammoni gel,Cyclohexane,Ethyl acetate for Purification by ColummChromatography,n-Butyl alocohol

Activated carbon

Maleic acid

n-Butyl alcohol

+N2+NaCl+5H2O+Cu(OH)+NH4Cl

NitrogenSodium ChlorideWaterCupric hydroxideAmmonium Chloride


MOL WT :- 296.32


MOL WT :- 266.33

MOL FOR :- C17H16ClNO

MOL WT :- 285.76

MOL FOR :- C21H20ClNO5

MOL WT :- 401.84


MOL WT :- 401.84


MOL WT :- 401.84

Trans-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole


Stage :- 1 :- Preparation of Trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-

dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole maleate(Crude)

Trans-2-methyl-5-nitro-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole in

Methanol, is added 10% palladium charcoal (50% wet) and hydrogenated under hydrogen

pressure (8-10 kg/cm2

at 25-30� till the completion of reaction. The Catalyst is removed by

filtration through Hyflow and filtrate is distilled out under vacuum to give residue, which is

Partitioned between dichloromethane and dilute Sodium hydroxide. Distillation of organic layer

under vacuum yielded Trans -2-methyl-5-amino-2,3,3a,12b-tetrahydro-1H-

dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole as an oil. Dichloromethane is stripped out with Process

Water from the oil, the oil is taken in Conc. Hydrochloric acid and a Solution of Sodium nitrite

ANNEXURE-6


in Process Water is added to it at 0-5� (Diazonium Solution) Meanwhile a Solution of Cuprous

Chloride in Conc. Hydrochloric acid is Prepared and above diazonium Solution is added at 0-5�

Reaction mixture is allowed to stir at 20-25� till the Completion of reaction. Reaction is

quenched with simultaneous addition of ethyl acetate and liq. Ammonia to bring basic pH.

Organic layer is Separated, Stirred with activated Carbon and filtered through Hyflow bed

Distillation of organic layer under vacuum gave crude free base, which is purified by column

Chromatography using 35% ethyl acetate in Cyclohexane as an eluent. The pure free base

Preparation of Trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-

c]-pyrrole is obtained as an oil, which is unloaded in n-Butyl alcohol for the next reaction. The

oil in n-Butyl alcohol is heated to 60-65� after adding activated Carbon and filtered through

Hyflow bed. This Solution is added slowly to Previously prepared solution of Maleic acid in n-

Butyl alcohol at 40-45� After maintaining for 30 min. at same temperature, the reaction mixture

is cooled gradually to 25-35� within 3-4 hrs and followed by addition of seed crystal of

standard Asenapine maleate gave solid The obtained Asenapine maleate crude is filtered and

washed with n-Butyl alcohol and dried.

Stage :- 2 :- Preparation of Trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-

dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole maleate

Trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]-pyrrole

maleate is purified by taking it into n-Butyl alcohol and heated at 60-70� till clear or hazy

Solution. The activated Carbon is added and allowed to stir the reaction mixture at same

temperature. Carbon is removed by filtration though Hyflow bed and filtrated is allowed to stir at

25-30�. The obtained solid is filtered and Washed with n-Butyl alcohol and dried to give

Asenapine maleate.

Flow diagram :-

ANNEXURE-6


ANNEXURE-6


(39) ROS :- AXITINIB

ONH

CH3

S

N

NH

N

ONH

CH3

S

N

NH

N

DMSO / D M Water

Axitinib Solvate

MOL FOR :- C22H16N4OS

MOL WT :- 386.46 MOL FOR :- C22H16N4OS

Axitinib API

MOL WT :- 386.46


Dissolve Axitinib Solvate in DMSO and Precipitated D M Water to giveAxitinib (API)

Flow diagram :-

(40) ROS :- AZILSARTAN

ANNEXURE-6


N

N

OO

O

N

O

NH

CH3O

O

O

O

CH3

N

N

OO

O

N

O

N-K

+

CH3O

O

O

O

CH3

+Potassoium

Ethyl acetate CH3

CH3

O

OH

Azilsartan Medoxomil Mono Potassoium salt

2-ethylhex anoic acid

N

N

OO

O

N

O

NH

CH3O

O

O

O

CH3 Azilsartan Medoxomil

N

N

OO

O

N

O

NH

CH3O

O

O

O

CH3

Azilsartan Medoxomil(Technical)

Acetone

Water

N

N

OO

O

N

O

NH

CH3O

O

O

O

CH3

Azilsartan Medoxomil(Technical)

N

N

OOH

O

N

O

NH

CH3O

+O O

O

CH3

OH

p-TSCl

K2CO3

DMAcDMAP

Acetic acidEthyl acetate

MDC

+

+

+

KCl

CO2

p-TSA

+ CH3COO'K+


MOL WT :- 458.45

MOL FOR :- C9H6O4

MOL WT :- 130.10MOL FOR :- C30H24N4O8

MOL WT :- 568.53



MOL WT :- 568.53


MOL WT :- 568.53

MOL FOR :- C30H24KN4O8

MOL WT :- 606.62

MOL FOR :- C9H16O2

MOL WT :- 149.21

Azilsartan Medoxomil

ANNEXURE-6



Stage :- 1 :- AzilsartanMedoxomil

Azilsartan is reacted with 4-Hydroxymethyl-5-methyl-1,3-dioxol-2-one,p-TSCl and

DMAP,K2CO3 in DMAc as a solvent to give AzilsartanMedoxomil(Technical) after pouring in

the Process Water.

AzilsartanMedoxomil(Technical) is purified using mixture of acetone and water.

Stage :- 2 :- AzilsartanMedoxomilmonopotassium salt.

AzilsartanMedoxomil is treated with Potassium 2-ethyl hexanoate in presence of ethyl acetate as

a solvent to give potassium salt of AzilsartanMedoxomil.

Flow diagram :-

Reactor

Reactor

Technical 485Kg

Centrifuge

Azilsartan 410 Kg

Technical 485 Kg

Recover of MDC 750 kg

700Lit

Dry Wet 475Kg

Reactor

Reactor

K2CO3+di methyl acetal

390 Kg + 400kg

Recover Ethyl 750 kg

Chilled 0-10

500kg Acetone

Chilled 5-10C

4-Hydroxymethyl-5-

methyl-1,3-dioxol-2-one

110Kg

P-TSCl 260Kg

71 Kg Acetic acid

800 kgEthyl Acetate

800 kgMDC

75Kg KCL

P.TSA 400kg

Effluent 500kg

Residue 150Kg

500litWater

950 kg Recover of Acetone+ Water

Effluent :- 780 kg

190Kg potassium ethyl Hexanate

700Lit

AzilsartMedoxomil 475Kg

1000kg Ethyl Acetate

ANNEXURE-6


AZILSARTAN INPUT kg OUTPUT kg

Azilsartan 410 Recover Ethyl Acetate 750

4-Hydroxymethyl-5-Methyl-1,3-

Dioxol-2-One 110Kg

110 KCL 75

K2co3 390 Recover Of Mdc 750

P-Tscl 260 Recover Of Acetone+ Water 950

Acetic Acid 71 Residue 32

Ethyl Acetate 800 Recover Ethyl Acetate 950

MDC 800 2-Ethylhexanoic Acid 163

Acetone 500 Ptsa 400

Water 500 Effluent 780

Potassium Ethyl Hexanate 190 Product 500

Ethyl Acetate 1000 Loss 81

Di Methyl Acetal 400

TOTAL 5431 5431

Centrifuge

Dry Wet=500Kg

950kg Recover Ethyl Acetate

125Kg 2-ethylhexanoic acid

32Kg Residue

ANNEXURE-6


(41) ABCAVIR SULPHATE

ROS :-

IPA

Mol FOR :- C11H12N6O


N-(2-amino-4,6-dichloro-5-pyrimidiyl)formaide

Mol FOR :- C5H41ClN4O


+

(1S,2R)-4-amino-2-cyclopentene-1-methanol HCL


Mol FOR :- C6H11NO HCL

ABACAVIR SULPHATE

Mol FOR :- C14H18N6O. H2SO4


Cl

N

N

NH2

NH O

Cl OH

NH2

Na2CO3

triethyl ortho formate

Con HCl

OH

N

N

NH2

N

N

IPA

triethyl amine

cyclopropyl amine

con H2SO4Acetone

OH

N

N

NH

N

N

H2SO4

ANNEXURE-6


Flow chart :-

Reactor

Reactor

N-(2-amino-4,6-dichloro-5-pyrimidiyl)formaide-500 KG

1S,2R)-4-amino-2-cyclopentene-1-methanol HCL- 450 KG

-409 kg

Na2CO3-1000kg IPA-1000 kg

Triethylortho formate-2000 kg

Centrifuge

Product-500kg

Recover IPA- 2450 kg

Recover water- 1100 kg

Effluent -2850 KG

CON HCL-370 kg

Water :-1000 kg

Reactor

Reactor

IPA-1000 kg Cyclopropyl amine-300 KG

TEA-840 kg

Con H2SO4-144 kg

Acetone-200 kg

Recover triethylorthoformate- 1950 kg

75 % IPA-1000 kg

SALT-700 KG

Recover acetone- 150 kg


ANNEXURE-6



Charge of N-(2-amino-4,6-dichloro-5-pyrimidiyl)formaide, sodium

carbonate,(1S,2R)-4-amino-2-cyclopentene-1-methanol HCL & isopropyl alcohol

in reactor. Heating to reflux Maintain for 12 hrs at reflux temp. centrifuge&

distilled IPA. Dumping in water. Cool to RT & Child to 0 C centrifuge . dry. Take

product ,triethylorthoformate in reactor. Drop wise con Hcladdition at 0C For 2-

hrs. Maintain for 12 hrs at RT. centrifuge . dry. Take product, IPA

&triethylamine in reactor. Drop wise cyclpropylamineaddition at RT For 1- hrs.

Maintain for 15 hrs at reflux temp & distilled IPA. Charge acetone. Cool to RT &

Child to 0 C. centrifuge . Take product , 75 % IPA in reactor. Heating to 55-60 C.

Drop wise con H2SO4 for 55-60C.Maintain for 1 hrs to 55-60C. Cool to RT &

Child to 0 C for 1-hrs. centrifuge. Drying & packing.

ABCAVIR SULPHATE INPUT OUTPUT

N-(2-amino-4,6-dichloro-5-

pyrimidiyl)formaide 500 KG Recover of IPA

2450 kg

Na2CO3 1000

KG

Dry Wt 500 KG

(1S,2R)-4-amino-2-cyclopentene-1-

methanol HCL 450 KG Recover of WATER 1100kg

IPA 2000 kg Recover of Triethylorthoformate 1950kg

Con HCL 370 kg Recover of Acetone 150kg

Triethylorthoformate 2000 kg salt 700 kg

Acetone 200 kg EFFLCENT 2850 KG

75 % IPA 1000 kg loss 104 kg

Con H2SO4 144 KG

Triethylamine 840 kg

Water 1000 kg

Cyclopropyl amine 300 kg

TOTAL 9804 kg 9804 KG

ANNEXURE-6


(42)ATROVASTATIN CALCIUM ROS :-

MOL WT :- 417

CH3

NHO

CH3O

O

F

diketo comp

+NH2

O

CH3 CH3

CH3

OOH O

CH3

CH3

CH3

ATR-1

MOL WT :- 273

+

CH3

CH3

CH3O

OH

pivalic acid

MOL WT :- 102

+ 3H2O CO2

18 44

+ +O

CH3

CH3

CH3

O- Na+

sodium pivalate

124

ATR-2

654

stage :-1

stage :-2

ATR-2

654

+ H2O

dil hcl IPA

O

CH3 CH3

CH3

OO O

CH3

CH3

CH3CH3

N

NH

O

F

O

CH3 CH3

CH3

OO O

CH3

CH3

CH3CH3

N

NH

O

F

O

CH3CH3

CH3

OHOH OCH3

CH3

N

NH

O

F

DIOL ESTER

614

+

CH3

CH3

O

58

ANNEXURE-6


stage :-3

O

CH3CH3

CH3

OHOH OCH3

CH3

N

NH

O

F

DIOL ESTER

614

+ NaoH 0.5(CH3COONa)2Ca

40158

calium acetate

H2O

18

+ +

O

CH3CH3

CH3

OHOH OCH3

CH3

N

NH

O

F

hh

2

0.5+

Ca+2

3H2O

O

CH3

O-

Na+

82

+

CH3

CH3

CH3

OH

74

0.5H2O

18

+

O

CH3CH3

CH3

OHOH OCH3

CH3

N

NH

O

F

hh

2

O

CH3CH3

CH3

OHOH OCH3

CH3

N

NH

O

F

hh

2

methyl ethyl ketone

methanol

atorvastain calium trihydrate

1209

1209

atorvastain calium trihydrate

3H2O

Ca+2

Ca+2

3H2O +

18

stage :-4

atorvastain calium

1155

ANNEXURE-6


Flow chart :-

Reactor

Reactor

Diketo compound-180 kg

Pivalic acid-44 kg

ATR-1-117 KG Water-500 lit

Stage-1-293 kg

Reactor

Water-500 lit

Centrifuge

Product-500 kg

Recover cyclohexane-475 kg

Recover water-490

Effluent -150 kg

NaoH-20 KG

Recover water-350 lit

cyclohexane-500 kg

Sodium bicarbonate-150 kg

Ethyl acetate-500kg

Recover ethyl acetate- 475 kg

IPA-500 kg

Dil HCL-500 kg

Recover water-850 kg

Recover IPA- 475 kg

Stage-2-270 kg

Water-250 lit

Calcium acetate- 70 kg

Methanol-250 kg+ t-

butyl ether-250 kg

Reactor

Dil HCL-250 kg

Stage-3-550 kg

Recover methanol- 230 kg

Recover t-butanol-150 kg

Sodium acetate- 80 kg

Methyl ethyl ketone -500 kg

Methanol -500 kg

Recover methanol-475 kg

Recover methyl ethylketone-475 kg

Effluent -100 KG

Sodium Pivalate - 151 kg

Effluent -450 KG

Recover ACETONE- 48 KG


ANNEXURE-6



Atr-1 is then condense with diketo comp in presence of pivalic acid &

cyclohexane, reaction mixture cool, ethyl acetate is added & it is washed with

sodium bicarbonate solution. organic layer after water wash is distilled out. The

residue mass is stripped off IPA & distilled out IPA. the mass taken in IPA. To the

DM water is added and stirred and filtered. the wet solid is washed with mixture

IPA & water. the solid is dried to give ATR-2.

ATR-2 is filtered with dilhcl in IPA to give diol ester. Neutralized the

reaction mass with liq-NH3 & than to the reaction mass of diol ester in IPA IS

distilled under reduce pressure.to the concentrated mass methanol is added &

mixture is heated to get clear solution. DM water is added for ppt& filtered off

washed by IPA & water. Dried.

Water solution of NaOH is added to the mixture of methanol,t-butyl methyl

ether &diol ester. Reaction mass is heated & maintain till complete of reaction.

after reaction is complete mass is cooled & washing of t-butyl methyl ether is

given. Ph is set by dil HCL. & reaction mass heated & add solution of calcium

acetate is added to above RXM with simultaneously to give atorvastatin calcium

trihydrate& dried U/VACCUM.

ATR-4 is dissolved in mix of methyl ethyl ketone & methanol followed by micron

filtration. The solution is evaporated using ATFD method. Collected product

dried.

ANNEXURE-6


(43)BUPROPION HCL

ATROVASTATIN CALCIUM INPUT kg OUTPUT kg

Diketo compound 180 Dry Wt 500

ATR-1 117 Recover of IPA 475

sodium bicarbonate 150 Recover of CYCLOHEXANE 475

IPA 500 Recover of ethyl acetate 475

Pivalic acid 44 Recover of methyl ethyl ketone 475

WATER 1250 Recover of t-butanol 150

cyclohexane 500 Recover of methanol 705 NaoH 20 Recover of water 1690 Calcium acetate 70 EFFLCENT 700

dil HCL 750 Sodium Pivalate salt 151 Ethyl acetate 500 Recover of acetone 48

Methanol 750

t-butyl ether 250

Methyl ethyl ketone 500

TOTAL 5844KG 5844KG

ANNEXURE-6


ROS :-

MOL FOR : C9H8BrClO

MOL WT - 247.5

3'-chloro propiophenone

MOL FOR : C9H9OCL

MOL WT :- 168

MDC

Br2(159)

CH3

O

Cl

CH3

O

Cl

Br+

Hbr

80

(CH3)3CNH2

Cl

CH3

O

NHC(CH 3)

HCL

Cl

CH3

O

NHC(CH 3)HCL

buoropion HCL

3'-chloro -2- bromopropiophenone

t-butyl amine

buoropion

IPA

MOL FOR : C13H18ClO

MOL WT - 239.74

MOL FOR : C13H19Cl2O

MOL WT - 276

ETHYL ACETATE

IPA

ANNEXURE-6


Flow chart :-

Reactor

Reactor

3'-chloropropiophenone-

320 KG

Bromine-300 KG

MDC-1000 kg

t-butyl amine-500 kg

Reactor

Ethyl acetate-500 kg

Centrifuge

Product-500 kg

Recover MDC -950 kg

HBr solution-150 kg

Effluent -600 KG

20 %HCL- 500kg

Recover ETHYL ACETATE- 475 kg

WATER-500 lit

Reactor IPA-500 kg

Recover T-BUTYL AMINE - 300 kg

Recover IPA- 475 kg



ANNEXURE-6



Charge 3'-chloropropiophenone was dissolved in MDC. bromine was added dropwise to this

solution at 0-5°C. The reaction mixture was stirred for 1 hour at 0-5°C.filterd reaction mass &

dry it..take 3'-chloro-2-bromopropiophenone and charge t-butyl amine. then refluxed for 4

hours. Excess of tert- butylamine was removed under reduced pressure. Obtained oily residue

was dissolved in of ethyl acetate and washed with 250 ml of water. chargeHCl was added to

ethyl acetate phase, stirred and separated. The water phase was washed with 250 ml of ethyl

acetate and separated. The water phase was concentrated at reduced pressure and the residue was

crystallised from isopropyl alcohol.

(44) ROS :- BAZEDOXIFENE

O

N

O

CH3

ON

5-(Benzyloxy)-2-[4-(benzyloxy)phenyl]-3-1-[4-(2-hexamethyleneimi

ne-1-yl-ethoxy0benzyl]-1H-indole

+ H2

OH

N

OH

CH3

ON

CH3COOH

+

CH3

1-(4-[Azepan-1-yl)ethoxyl]benzyl}-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol Acetate

BUPROPION HCL INPUT kg OUTPUT kg

3'-chloropropiophenone 320 Recover of IPA 472

Bromine 300 Dry Wt 500

MDC 1000 SOLVENT loss 63

IPA 500 Recover of water 760

WATER 500 EFFLCENT 600

10 % HCL 500 Recover of MDC 950

ETHYL ACETATE 500 Recover of ETHYL ACETATE 475

T-BUTYL AMINE 500 Recover of T-BUTYL AMINE 300

TOTAL 4120KG 4120 KG

ANNEXURE-6



Stage :- 1 :- Preparation of 1-{4-[2-(Azepan-1-yl)ethoxy]benzyl}-2-(4-hydroxyphenyl)-3-

methyl-1H-indol-5-ol Acetate

5-(Benzyloxy)-2-[4-(benzyloxy)phenyl-3-1-[4-(2-hexamethyleneimine-1-yl-ethoxy)benzyl]-1H-

indole (Benzyl Bazedoxifene) is hydrogenated over palladium on carbon and Hydrogen to give

Bazedoxifene free base. This free base treated with Acetic acid in Acetone to give Bazedoxifene

Acetate.

Flow diagram :-

ANNEXURE-6


(45) ROS :- CANAGLIFLOZIN

S

O

O

CH3 O

O

CH3O

O

CH3

O

OCH3

O

CH3

F

O

OH

OH

OHOH

CH3

F

Sodium methoxide

Methanol


1-(2,3,4,6-Tetra-O-propionyl-�-D-glucopyranosyl)-4-methyl-3-[5(4-fluorophenyl)-2-

thienylmethyl]benzene is depropionylated in methanol in Presence Sodium methoxide as Catalyst. After

Completion of reaction, work up with Water and Ethyl acetate and distill Organic layer to give

Canagliflozin further it will Crystallized from toluene and heptanes to give amorphous Product.

1-(�-D-glucopyranosyl)-4-methyl-3-[5(4-

fluorophenyl)-2-thienylmethyl]benzene 1-(2,3,4,6-Tetra-O-propionyl-�-D-

glucopyranosyl)-4-methyl-3-[5(4-

fluorophenyl)-2-thienylmethyl]benzene

ANNEXURE-6


Flow diagram :-

GLR

Reactor

Reactor

1-(2,3,4,6-Tetra-O-propionyl-�-D-

glucopyranosyl)-4-methyl-3-[5(4-fluorophenyl)-

2-thienylmethyl]benzene -661 kg

Sodium methoxide -35 kg

Water-1000 lit

Methanol -1200 kg

Ethyl Acetate -1200 kg

Toluene-500 kg+ Heptane - 500 kg

Recovery of Methanol -1150 kg

effluent -1250 kg

Technical DRY

WT -515 KG

Reactor

Centrifuge

Technical DRY WT -515 KG

Salt -50 kg

Recovery of Toluene+ Heptane -950 kg

Recovery of ethyl acetate -1150

DRY WT – 500 KG

ANNEXURE-6


CANAGLIFLOZIN

INPUT kg OUTPUT kg

1-(2,3,4,6-Tetra-O-Propionyl-�-D-

Glucopyranosyl)-4-Methyl-3-[5(4-

Fluorophenyl)-2-

Thienylmethyl]Benzene -

661 Recovery Of Methanol 1150

Sodium Methoxide 35 Recovery Of Ethyl Acetate 1150

Ethyl Acetate 1200 Effluent 1250

Water 1000 Salt 50

Toluene- 500 Recovery Of Toluene+ Heptane 950

Heptane 500 DRY WT – 500

Methanol 1200 Loss 46

TOTAL 5096 5096

(46) ROS:-CANDESARTAN CILEXETIL

N

N

COOCH3

O CH3

N

N N

N H

Dichloromethane

Trityl phenyl Chloride

Triethyl amineAcetonitrile

Triethyl amine hydrochloride

N

N

COOCH3

O CH3

N

N N

N C(Ph)3

2-Ethoxy-1[2'-{N-tri phenyl methyl tetrazole-5-yl}biphenyl-4yl)-methyl]benzimidazole-7carboxylic acid

Cyclohexyl 1-chloroethyl carbonate

Potassium Carbonate

Potassium iodide

Dimethyl sulphoxide

Acetonitrile

D.M.Water

Potassium Chloride

CO2

N

N

CO

O CH3

N

N N

N C(Ph)3

OOO

O

CH3

1-(CyclohexaloxyCarbonyloxy)ethyl-2-ethoxy-1[2'-{N-tri phenyl methyl tetrazole-5-yl biphenyl-4yl)-methyl]benzimidazole-7-carboxylate

N

N

CO

O CH3

N

N N

N H

OOO

O

CH3

Canadesatan Cilexitil

Conc.HCLMethanol

DichloromethaneSodium bicarbonate

D.M.WaterEthanol

Aceton

Tritanol

CO2

Sodium Chloride

Cyclohexane

2-Ethoxy-1[2'-{1h-tetrazole-5-yl}biphenyl-4yl)-methyl]benzimidazole-7carboxylic acid

ANNEXURE-6



Stage :- 1

Charge in DiChloromethane reacts with Sodium bicarbonate & then add methanolic

hydrochloric acid then Separate and add in ethanol for reaction mass Centrifugation.

Stage :- 2

Candesartan Cilexetil crude is Purified with mixture of Acetone and D M Water to get for

Purification for Candesartan Cilexetil Pure.

ANNEXURE-6


Flow diagram :-

Reactor

Reactor 590Kg

Reactor

Centrifuge

Dry Wet : 710Kg

KSM 1 400Kg

Step:2

Reactor

Reactor

Centrifuge

Dry Wet=510Kg

800kg MDC

Recover MDC 750 kg

=+

2-Ethoxy-1[2'-{1h-tetrazole-5-yl}biphenyl-4yl)-methyl]benzimidazole-7carboxylic acid

590Kg

710Kg 1500Lit MDC

RecoverMeOH 700kg

Reactor

Centrifuge

Dry Wet=500Kg

Recoveracetone+Water 950kg

Residue -40 Kg

Triethyl amine 90kg

249 Kg Trityl phenyl Chloride

Triethyl amine hydrochloride 120Kg

Residue -50Kg

Potassium Carbonate 30Kg

Cyclohexyl 1-chloroethyl carbonate 270Kg

DMSO 70Kg

Acetonitrile 1000 kg

RecoverAcetonitrile 950kg

200kg Effluent

Residue -60Kg

90 Kg Sodium bicarbonate

1000Lit MeOH.HCL

RecoverMDC 1450kg

600kg Effluent

Residue -30Kg

(salt)

1000kgacetone+Water Teacnical 510Kg

Chilled

ANNEXURE-6


CANDESARTAN CILEXETIL

INPUT kg OUTPUT kg

2-Ethoxy-1[2'-{1h-Tetrazole-5-

Yl}Biphenyl-4yl)-

Methyl]Benzimidazole-7-

Carboxylic Acid

400 Recover MDC 2200

Triethyl Amine 90 Triethyl Amine Hydrochloride 120

Trityl Phenyl Hychloride 249 Recover Acetonitrile 950

Dichlro Methane 2300 Effluent 800

Potassium Carbonate 30 Acetone+ Water 950

Dimethyl Sulfoxide 70 Methanol 700

Cyclohexyl 1-Chloroethyl

Carbonate

270 Residue 180

Acetonitrile 1000

Sodium Bicarbonate 90 Product 500 Methanol.HCL 1000 Loss 99

Acetone+ Water 1000

TOTAL 6499 6499

(47) ROS :-CELECOXIB

NHNH.HCL

SO 2 NH 2

C H 3

COCH 2 COCF 3

+

( 4 - S u l f a m o y l p h e n y l ) H y d r a z in e H y d r o c h lo r i d e

M O L F O R : - C 6 H 1 0 C l N 3 O 2 S

M O L W T : - 2 2 3 . 6

1 - ( 4 - m e t h y lp h e n y l ) 4 , 4 , 4 - T i f l u o r o b u t a n e , 3 - d i o n e

M O L F O R : - C 1 1 H 9 F 3 O 2

M O L W T : - 2 3 0 . 1 8

1 2 . 5 % a q u e o u s I P A

5 % a q u e o u s I P AN

NCF 3

CH 3

H 2 NO 2 S

M O L F O R : - C 1 1 H 1 4 F 3 N 3 O 2 S

M O L W T : - 3 8 1

NN

CF 3

CH 3

H 2 NO 2 S

C e le c o x i b - C r u d e

M O L F O R : - C 1 1 H 1 4 F 3 N 3 O 2 S

M O L W T : - 3 8 1

NN

CF 3

CH 3

H 2 NO 2 S

C e le c o x ib

M O L F O R : - C 1 1 H 1 4 F 3 N 3 O 2 S

M O L W T : - 3 8 1

3 0 % a q u e o u s i n I P A

R e f l u x

C e le c o x i b - C r u d e

ANNEXURE-6



Charge in 4-Sulfamoyl phenyl hydrazine hydrochloride in 12.5% Aqueous Isopropyl alcohol

followed maintaining of reaction mixture temp. The end point is monitored on GC and then the

reaction mass is cooled and precipitated by addition of Water. This Precipitated mass is then

Centrifuged. The wet cake is then further purified in Aqueous Isopropyl alcohol and chilled then

Centrifuged and dried and Packed.

Flow diagram :-

Reactor

(4-Sulfamoylphenyl)Hydrazine

Hydrochloride 310 kg

1-(4-methylphenyl) 4,4,4-Tifluorobutane,3-dione 320 kg

12.5% aqueous IPA 125 lit IPA + 875 lit Water

Reflux

Reactor

Cool

Reactor

400 lit Water

Centrifuge Effluent 1450 kg

60 kg Residue

Dry wt 510 kg

Reactor

30% IPA 300 lit + 700 lit Water Technical 510 kg

Centrifuge

Dry wt 500 kg

Effluent 980 kg

Total Effluent 1450 + 980 = 2430 kg

ANNEXURE-6


(48)ROS :- CLOPIDOGREL BISULFATE

N

S

CN

Cl

N

S

COOM

Cl

N

S

COOCH3

Cl

Kinetic Chiral Resolution

N

S

CO2CH3

Cl(S)-(+)-Clopidogrel


Charge in 2-Chlorophenylglycine with Thionyl Chloride & methanol at RT for 48 hrs gives

Hydrochloride salt of Methyl-�-amino(2-Chlorophenyl)acetate Which is then react with Sodium

bicarbonate & Ethyl acetate followed by Methanol & L-(+)-tartaric acid give L-(+)-Tartrate salt

of S- methyl-�-amino(2-Chlorophenyl)acetate Then Tartrate salt reacts with Sodium bicarbonate

& dichloromethane followed by Tosylate of 2-Thiophene ethano& K2HPO4 gives Methyl (2S)-

CELECOXIB

INPUT kg OUTPUT kg

4-Sulfamoyl Phenyl Hydrazine

Hydrochloride

310 Effluent 2430

- 1-(4- Methylphenyl4,4,4-Trifuloro

Butane,3-Dione)

320 Residue 60

Aqueous In IPA

125 Product 500

Water 1975 Loss 40

30% Ipa 300

TOTAL 3030 3030

ANNEXURE-6


(2-Chlorophenyl){[2-(2-thienyl)ethyl]amino}acetate. Reacts with (41%) formaldehyde Solution

followed by Conc. Sulphuric acid to give Clopidogrel bisulfate.

Flow diagram :-

Reactor

2-Chlorophenylglycine 300 kg Thionyl Chloride 125 kg

Methanol 1000 lit

Centrifuge

Dry wt 375 kg

900 kg Recover of Methanol

Reactor

110 kg NaHCO3 Hydrochloride salt of Methyl-�-

amino(2-Chlorophenyl)acetate-375 kg Ethyl acetate 700 lit

Reactor 238 kg L-tartaric acid + 500 lit Methanol


450 kg Recover of Methanol

Dry wt 550 kg

Reactor

190 kg K2HPH4

2-Thiophene ethano 230 kg

Tartrate salt of S- methyl-�-amino(2-

Chlorophenyl)acetate-550 kg

MDC 110 kg

Sodium bicarbonate 161 kg

Centrifuge

Dry wt 485 kg

Reactor

Methyl (2S)-(2-Chlorophenyl){[2-(2-

thienyl)ethyl]amino}acetate-485 kg

Formaldehyde 650 lit

Con . HCL 180 kg

Centrifuge

Dry wt 500 kg

ANNEXURE-6


CLOPIDOGREL BISULFATE INPUT kg OUTPUT kg

2-Chlorophenylglycine 300 Recover Of Methanol 1400

Thionyl Chloride 125 Effluent 2210

Methanol 1500 Product 500

Nahco3 110 Loss 84

Ethyl Acetate 700

L-Tartaric Acid 238

K2hph4 190

Dichloro Methane 110

Sodium Bicarbonate 161

Formaldehyde 350

Con Hydrochloric Acid 180

2-Thiophene Ethano 230

TOTAL 4194 4194

(49)ROS : - Dabigatran

CH3

NHCH3

N

N

O

O CH3

O

CDI / THF

AcOH

NC NH

O

OH

N

N

O

O CH3

O

NC NH

N

N

CH3

3-[(3-Amino-4-methylaminobenzoyl)pyridin-2-ylamino]propionic acid ethyl ester


MOL WT :- 342.39

N-(4-Cyanophenyl)glycine

MOL FOR :- C9H8N2O2

MOL WT :- 176.17

3-[[[2-[[(4-Cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]propionic acid ethyl ester


MOL WT :- 482.53

HCL / EtOH

(NH2)2CO3

N

N

O

O CH3

O

NH

N

N

CH3

NH

NH2

N

N

O

O CH3

O

NH

N

N

CH3

NH2

N

H13C5O

O

THF / H2O

ClCO2(CH2)5CH3

K2CO3

Dabigatran etexilate


MOL WT :- 627.73

3-{[(2-{[(4--{carbamimidoyl}phenyl)amino]methyl}-l-methyl-lH-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate

ANNEXURE-6


Manufacturing Process :-Dabigatran

3-[(3-Amino-4-methylaminobenzoyl)pyridin-2-ylamino]propionic acid ethyl ester

React with N-(4-Cyanophenyl)glycine in presence of N,N Carbonyldiimidazol + THF Using of

Acetic Acid to give 3-[[[2-[[(4-Cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-

yl]carbonyl]pyridin-2-ylamino]propionic acid ethyl ester This React with Ammonium

Carbonate using Methanol to give 3-{[(2-{[(4--{carbamimidoyl}phenyl)amino]methyl}-l-

methyl-lH-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate This react with

Potassium Carbonate Using THF and Centrifuge Which give Dabigatr.

Flow diagram :- Dabigatran

Reactor

Centrifuge

Dry wt 385 kg

Reactor

3-[(3-Amino-4-methylaminobenzoyl)pyridin-2-

ylamino]propionic acid ethyl ester- 290 kg

290 kg

N-(4-Cyanophenyl)glycine-150 kg

N,NCarbonyldiimidazol 136 kg

+ THF 150kg

Centrifuge

Dry wt- 400kg

Reactor

Centrifuge

HCL- 400 lit 3-[[[2-[[(4-Cyanophenyl)amino]methyl]-1-

methyl-1H-benzimidazol-5-

yl]carbonyl]pyridin-2-ylamino]propionic

acid ethyl ester 385 kg

3-{[(2-{[(4--

{carbamimidoyl}phenyl)amino]methyl}-l-

methyl-lH-benzimidazol-5-

yl)carbonyl](pyridin-2-

yl)amino}propanoate 400 KG

Effluent- 280 kg

THF 800 lit

Dry wt-500kg

Acetic Acid 600 kg

Recovery of solvent-650 lit &Reused

Methanol 800 lit

Ammonium Carbonate 96 kg

Potassium Carbonate 160 kg + Water 150

Effluent- 200 lit

Recovery of THF-800 lit &Reused

Recovery of Methanol-750

Effluent- 520 lit

ANNEXURE-6


(50) ROS :- DAPAGLIFLOZIN

O

COCH3

COCH3

COCH3O

CH3CO

Cl O

CH3

O

COCH3

COCH3

COCH3O

CH3CO

Cl O

CH3

Methanol / Water

Sodium hydroxide

4-Chloro-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazoline

Dapagliflozin

+ CH3COOH


4-Chloro-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazoline is treated with Sodium hydroxide

in Water and methanol to get the pure Dapagliflozin API.

Flow diagram :-

DAPAGLIFLOZIN

INPUT kg OUTPUT kg

4-Chloro-7-Methoxy-6-(3-

Morpholin-4-

Ylpropoxy)Quinazoline

525 Methanol 1050


Sodium Hydroxide 530 Product 500

Water 500 Loss 5

TOTAL 2655 2655

Reactor

Centrifuge

4-Chloro-7-methoxy-6-(3-

morpholin-4-ylpropoxy)quinazoline

525kg

Methanol -1100kg

NaOH +H2O

530Kg+500Lit

Recovery of methanol -1050 lit

effluent -1100Lit

DRY WT -500 KG Total effluent -1100Lit

ANNEXURE-6


(51) ROS :-DARIFENACIN

NH

Ph

Ph

CONH2

HOOC

COOHH

OH

OH

H +O

Br

3-(S)-(+)-(1-Carbamoyl-1,1-diphenylmethyl)pyrroloidine-L-(+)-tartarate


MOL WT :- 430.45

5-(2-Bromoethyl)-2,3-dihydrobenzofuran

MOL FOR :- C10H11BrO

MOL WT :- 227.09

O

N

Ph

Ph

CONH2

Darifenacin base

+ +KOOC

COOKH

OH

OH

H

KBr

+H2O

+CO2

dipotassium tartarate

Potassium bromide

Water

Carbon dioxide

O

N

Ph

Ph

CONH2

HBr

DMF

K2CO3

HBr

Darifenacin hydrobromide

MOL FOR :- C28H31BrN2O2

MOL WT :- 462

Acetone

Manufacturing Process:-

Charge in 3(S)-(+)-(1-Carbamoyl-1,1-diphenylmethyl) pyrrolidine L-(+)-tartrate reacts with)-

2,5-(2-Bromoethyl 3-dihydro-1-benzofuran in the Presence of potassium Carbonate in DMF to

give Darifenacin base which on treatment with aqueous HBr and Acetone to give

DarifenacinHydrobromide it is then Purified in absolute alcohol.

ANNEXURE-6


Flow diagram :-

Reactor

Darifenacinbas

e 422 kg

Reactor

3(S)-(+)-(1-Carbamoyl-1,1diphenylmethyl)

pyrrolidine L-(+)-tartrate 500 kg

5-(2-Bromoethyl)-2,3-dihydrobenzofuran 265 kg

Dimethylformamide 1000 KG

potassium Carbonate 370 kg

Acetone 1000 kg

Centrifuge

Reactor

Darifenacinbase 422

kg

Reactor

Recovery of DMF 960 lit

HBr 150 kg

Dipatassium Tartrate 270 kg

Effluent 300 kg Reside 30 kg

HBr 150 kg

Recovery of Acetone 950 kg

Effluent 100 kg

Dry 510 kg

MDC 1000 kg Technical 510 kg

Reactor

65-70�

Chilled

Reactor

Centrifuge Recovery of MDC 955 kg

Residue 4.0 kg

Dry wt -500 kg

ANNEXURE-6


DERIFENACIN INPUT kg OUTPUT kg

3(S)-(+)-(1-Carbamoyl-

1,1diphenylmethyl) Pyrrolidine

L-(+)-Tartrate

500 DMF 960

5-(2-Bromoethyl)-2,3-

Dihydrobenzofuran

265 Hbr 150

Dimethylformamide 1000 Dipatassium Tartrate 270

Potassium Carbonate 370 Effluent 400

Acetone 1000 Residue 34

Hydrobromine Acid 150 Recovery Of Acetone 950

Mdc 1000

Mdc 955

Product 500

Loss 66

TOTAL 4285 4285

(52) ROS :- DONEPEZIL

OH3CO

H3CO

N

Diene

MOL FOR :- C24H25NO3

MOL WT :- 375.46

Methanol/platinum oxide

Hydrogen gas/proces W ater

OH3CO

H3CO

N

Donepezil Base


MOL WT :- 379.49

OH3CO

H3CO

N

Donepezil Hydrochloride Crude

Conc.HCL/DichloromethaneN,N-Dimethylformamide/Acetone/NaCl/Proces W ater

.HCL

MOL FOR :- C24H29NO3.HCL

MOL WT :- 415.95

OH3CO

H3CO

N


.HCL


MOL WT :- 415.95

OH3CO

H3CO

N


.HCL


MOL WT :- 415.95

Ethanol/DM W ater

Di isopropyl ether/Activated charcoal Hyflo

ANNEXURE-6



Stage :- 1 :- Preparation of Donepezil Hydrochloride Crude

Donepezil Hydrochloride Di-ene is reduced using platinum oxide, hydrogen gas in

presence of methanol and water to give Donepezil base. The base is Converted to hydrochloride

salt with Concentrated Hydrochloric acid to yield Donepezil Hydrochloride Crude.

Stage :- 2 :- Purification of Donepezil Hydrochloride.

Donepezil Hydrochloride Crude is Purified using Ethanol, Diisopropyl ether and DM Water to

yield Donepezil Hydrochloride.

Flow diagram :-

Auto Clave

sparkler Filter

Reactor

Base-530Kg

Reactor

Diene 550Kg

methanol + water 50:50

H2 gas

Base-530Kg

Technical 510Kg

Reactor

1100kg

10Kg

platinum oxide 60Kg

Recover of Meoh+Water 1050 kg

1100kg MDC

Recover of MDC 1050kg

Effluent 80kg

Sparkler filter

Effluent -70kg

Catalyst Reuse -55 Kg

51 Kg Con. HCL

Centrifuge

Technical 510Kg

Residue 30Kg

Diisopropyl ether 1000kg

60Kg Charcoal

ANNEXURE-6


DONEPEZIL

INPUT kg OUTPUT kg

Diene 550 MDC 1050

Platinum Oxide 60 Effluent 210

Hydrogen Gas 10 Diisopropyl Ether 950

Methanol+Water 1100 Residue 80

Mdc 1100 Product 500

Diisopropyl Ether 1000 Catalyst 55

Charcoal 60 Methanol+Water 1050

Con Hcl 51 Product 500

Loss 36

TOTAL 3931 3931

Chilled 10°C

Centrifuge

Dry Wet 500Kg

Recover Diisopropyl ether 950kg

Residue 50Kg

Effluent 60kg

ANNEXURE-6


(53) ROS:- DRONEDARONE

O

O

O N

C4H9

C4H9

CH3

NH2

COOH

COOH

O

O

O N

C4H9

C4H9

CH3

NH2

Aqeous Ammonia solu

2-n-Butyl-3-[4-(3-di-n-butyl aminopropoxy)Benzoyl]-5-aminobenzofurn dioxalate


2

MOL WT :- 658.6

2-n-Butyl-3-[4-(3-di-n-butylaminopropoxy)Benzoyl]-5-aminobenzofurn


MOL WT :- 478.6

O

CH3

O N

C4H9

C4H9

CH3

H3CO2SHN

2-n-Butyl-3-[4-(3-di-n-butylaminopropoxy)Benzoyl]-5-methansulmide benzofurn


MOL WT :- 478.6

Pyridine

MDC

O

CH3

O N

C4H9

C4H9

CH3

H3CO2SHN

.HCL Ethyl Acetate

N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5-benzofuranyl]-,hydrochloride

MOL FOR :- C31H44N2O5S.HCL

MOL WT :- 593.22

O

CH3

O N

C4H9

C4H9

CH3

H3CO2SHN

.HCL



MOL WT :- 593.22

O

CH3

O N

C4H9

C4H9

CH3

H3CO2SHN

.HCL



MOL WT :- 593.22

Methanol

Ethyl acetate

Methansulmide

Ethyl Acetate HCL


Change 2-n-Butyl-3-[4-(3-di-n-butyl aminopropoxy)Benzoyl]-5-aminobenzofurn dioxalate

further on reduction and reaction with Methanesulphonyl Chloride obtained Dronedarone base

which is finally Converted into its hydrochloride.

ANNEXURE-6


Flow diagram :-

Sparkler filter

Reactor

Reactor

Step-1 Wt-455Kg

Reactor

Base-530 Kg

2-n-Butyl-3-[4-(3-di-n-butyl

aminopropoxy)Benzoyl]-5-

aminobenzofurn dioxalate

660Kg

2-n-Butyl-3-[4-(3-di-n-butylaminopropoxy)Benzoyl]-5-methansulmide benzofurn-530 KG

Pyridine 55Kg

Reactor

Reactor

chilled 10To15°C

Reactor

chilled 10°C

Aqeous Ammonia solu(25%) 810kg

Carbon 50Kg

Effluent 850Kg

2-n-Butyl-3-[4-(3-di-n-butylaminopropoxy)Benzoyl]-5-aminobenzofurn

455Kg

Centrifuge Recover of Ethyl Acetate 1550kg

MDC 900Lit

Technical : 510Kg

Effluent 200Kg

Ethyl Acetate HCL 680kg

Centrifuge

Dry Wet=500Kg

RecoverEthyl Acetate950kg

Residue -50Kg

Residue -150Kg

Methansulmide 90Kg

RecoverMDC860kg

Effluent 110Kg

Ethyl Acetate 1100kg

Technical : 510Kg

Residue -50Kg

Ethyl Acetate 1000kg

Reactor

ANNEXURE-6


RONEDARONE

INPUT kg OUTPUT kg

2-N-Butyl-3-[4-(3-Di-N-Butyl

Aminopropoxy)Benzoyl]-5-

Aminobenzofurn Dioxalate

660

Aqeous Ammonia Solution (25%) 810 Effluent 1160

Methansulmide 90 Residue 250

Ethyl Acetate 2100

EthyalAcetate.HCL 680 MDC 860

Mdc 900 Ethyl Acetate 2500

Pyridine 55 Product 500

Loss 25

TOTAL 5295 5295

(54)DESVENLAFAXINE SUCCINATE MONOHYDRATE

ROS :-

V E N LA F A XIN E

M O L F O R : C 20 H 33 N O 7

M O L W T :- 2 77

th iop he no l

D M S O

N a oH + H 2 O

CH 3

OCH 3

N

C H 3O H

+ + +D M S O th iop he no l C H 3O H

CH 3

OCH 3

N

C H 3O H

a ce ton itri le

CH 3

OCH 3

N

C H 3O H

O H

O H

O

O

H 2O .

O H

O H

O

O

.H 2 O

de sve n la fax in e succ in a te m o no hyd ra te

M O L F O R : C 2 0H 3 3 N O 7

M O L W T :- 4 00

d esve n la fax in e

M O L F O R : C 16H 25 N o2

M O L W T :- 26 3 .38

ANNEXURE-6



Charge of Venlafaxine, DMSO, sodium hydroxide &thiophenol in reactor.

Heating to125C. Maintain for 12-hrs at 125C. filter reaction mass . charge

Water. Heating to 50C for 1hrs. .cool to RT& chilled 0-10C For 1-hrs maintain.

centrifuge& drying. Take product,Acetonitrile& succinate monohydrate in reactor.

Heating to 60-65C. Maintain for 2-hrs at 60-65C. cool to RT& chilled 0-10C For

1-hrs maintain. centrifuge& drying Packing.

DESVENLAFAXINE SUCCINATE MONOHYDRATE INPUT kg OUTPUT kg

Venlafaxine 384 Recover of DMSO 450

DMSO 500 Product 500

sodium hydroxide 138 Recover of Acetonitrile 950

Acetonitrile 1000 Recover of water 950

WATER 1000 Recover of Thiophenol 140

THIOPHENOL 153 EFFLCENT 335

succinate monohydrate 180 loss 30

TOTAL 3355 3355

ANNEXURE-6


55.DULOXETINE HYDROCHLORIDE

ROS :-

3-(dimethylamino)-1-(thiophen-2-ylpropan-1-one HCL

DTP.HCL

MOL WT :- 219.73

+HCL

CH3

S

N

CH3

O

NaBH4 3H2O+37.83 18

CH3

S

N

CH3

OH3-(dimethylamino)-1-(thiophen-2-yl)propan-1-ol

Methnol+Bi(OH)2+Nacl

58.4461.83

+ 3H2

2.0

Stage :-1

Stage :-2

DULOX-1

MOL WT :- 185.28

CH3

S

N

CH3

OH

3-(dimethylamino)-1-(thiophen-2-yl)propan-1-ol

DULOX-1

MOL WT :- 185.28

+

F

1-fluoronaphthalene

146.16

+

OOH

OHOH2O

H2O

oxalic acid

126.06

+ NaNH2

sadamide

39.0

DMSO

CH3

S

N

CH3

OO

OH

OHO

+ + +NaF NH3 2H2O

181741

DULOX-1

MOL WT :- 401.47

ANNEXURE-6


Stage :-3 A

S

N

CH3

O

CH3

OOH

OHO

DULOX-1

MOL WT :- 401.47

+ NH3

17

S

N

CH3

O

CH3

DBTA

+

OOH

OHO

NH3

NH3

N,N-dimethyl-3-(napthalen-1-ylox-y)-3-(thiophen-2-yl)propane-1-amine

MOL WT :- 311.4

ammonium oxalate

MOL WT :- 124.09

Stage :-3 B

S

N

CH3

O

CH3

N,N-dimethyl-3-(napthalen-1-ylox-y)-3-(thiophen-2-yl)propane-1-amine

MOL WT :- 311.4

+

O

O

OOH

OH

O

O

O H2O

dibenzoyl(l)tartaric acid

MOL WT :- 376.31

S

N

CH3

O

CH3

hh

1

O

O

OOH

OH

O

O

O

+H2O

18

N,N-dimethyl-3-(napthalen-1-ylox-y)-3-(thiophen-2-yl)propane-1-amine DBTA SALT

MOL WT :- 669.74

dulox-3

ANNEXURE-6


Stage :-4 A

S

N

CH3

O

CH3

hh

1

O

O

OOH

OH

O

O

O +NH3

17

N,N-dimethyl-3-(napthalen-1-ylox-y)-3-(thiophen-2-yl)propane-1-amine DBTA SALT

MOL WT :- 669.74

dulox-3

S

N

CH3

O

CH3

O

O

O

OH

O

O

O

O-

NH+

+

N,N-dimethyl-3-(naphthalen-3-(thiophen-2-yl-propane-1-amine

MOL WT :- 311.14

Ammonium salt of dbta

MOL WT :- 392.36

Stage :-4 B

S

N

CH3

O

CH3

N,N-dimethyl-3-(naphthalen-3-(thiophen-2-yl-propane-1-amine

MOL WT :- 311.14

+ +OCl

OCH3

CH3CH3

CH3

NH2

CH3

phenyl chloroformatediisopropylamine

MOL WT :- 156.56

O

S

N

O

CH3

O

+ CH3CLcarbomate comp

MOL WT :- 417.5MOL WT :- 50.48

ANNEXURE-6


Stage :-4 B

O

S

N

O

CH3

O

carbomate comp

MOL WT :- 417.5

+ NaoH

40

CH3

O

CH3

O

HCL+

124.5

O

O

NaO

S

NH

O

CH3

+ +

CH3

O

CH3

O

Dulox-4

MOL WT :- 337.87

sodium phenyl carbnmate

MOL WT :-160.

88.1

HCL

Stage :-5

S

NH

O

CH3

Dulox-4

MOL WT :- 337.87

acetone

Methanol

HCLS

NH

O

CH3

HCL

MOL WT :- 337.87

Duloxeline HCL.

ANNEXURE-6


Flow chart :-

NaBH4-60 kg

Reactor

Reactor

DTP.HCL-347 KG

Methanol-500 kg Water-500 kg

Stage-1-293

Reactor

Stage :-2 636 kg

Centrifuge

Product-500 kg

Recover Methanol -475kg

Recover water-475kg

Ammonium oxalate salt-243 kgKG

Liq-NH3-1400kg


Salt-64 kg

effluent -72 kg

sodamide-62.kg

DMSO-500.kg

Oxalic acid- 199 kg

1-fluronaphthalene-231 kg

Recover DMSO-475kg

NaF SALT-80kg

Effluent -94kg

Reactor

Stage :-3 493 kg DBIA -590KG

Ethyl acetate-500

Methanol-500kg

Reactor

Stage :-4 1061 kg

Recover ethyl acetate-475kg


Reactor

Liq-NH3-1500kg

Recover DBIAsalt-630 kg


Reactor

Stage :-5 493 kg

Phenyl chloro formate-265 kg DiIsopropyl amine- 500 kg

Stage :-6 661 kg Effluent -638kg

Effluent - 147 kg

Reactor

NaoH- 65 kg

ethyl acetate HCL-1000 KG

Recover ethyl acetate-750 KG

Stage :-7 528 kg

Acetone- 500 kg

Methanol-500KG

Recover acetone-475 KG

Recover CH3OH-475 KG

Phenylcarbonate sod salt-448 kg

Effluent -78kg

Total Effluent -1629kg

effluent - 500 kg

effluent - 100 kg

Recover DIPA-450 kg

ANNEXURE-6



DTP.HCL (3-(dimethylamino)-1-(thiophen-2-yl) propan-1-one

hydrochloride) is reduced with alkali metal sodium borohydride in methanol and

water as a solvent to give Dulox-1

Dulox-1 is further reacted with 1-naphthalene fluronaphthalene in presence

of sodamide, in DMSO solvent to give condensed product which is isolated using

oxalic acid dehydrate to get, Dulox-2

Dolox-2 is made salt free using aq ammonia, then resolving the compound with

Dibenzoyl-L-Tartaric acid monohydrate(DBTA) in ethyl acetate, methanol to give

Dulox-3.

Dulox-3 is made salt free using Aq. Ammonia, then it is reacted with phenyl

chloroformate in presence of DIPEA to give a oily carbomate compound which is

further hydrolysed using sodium hydroxide in DMSO and water to give crude

duloxetine (Dulox-4) which is isolated as a hydrochloride salt using Ethylacetate

HCL.

Purification of crude duloxetine HCL (Dulox-4) is carried out in acetone and

methanol mixture to give pure Duloxetine Hydrochloride.

DULOXETINE HYDROCHLORIDE INPUT OUTPUT

DTP.HCL 347 KG Dry Wt 500 KG

NaBH4 60kg Recover of Methanol 1425 kg

water 500 kg Recover of DMSO 475 kg

Methanol 1500 kg Recover of ethylacetate 1225 kg

1-fluronaphthalene 231 kg Recover of diisopropyl amine 475 kg

Oxalic acid 199 kg Recover of acetone 475 kg

sodamide 62 kg Recover of water 1985 kg

DMSO 500 kg Salt 144 kg Liq-NH3 2900 kg Ammonium oxalate salt 243 kg

Ethyl acetate 500 kg Recover DBIA salt 630 kg

DiIsopropyl amine 500 kg Phenylcarbonate sod salt 448 kg Phenyl chloroformate 265 kg EFFLCENT 1629KG

DBIA 590 kg

ethyl acetate HCL 1000 kg

Acetone 500 kg


ANNEXURE-6


(56) ROS :- ERLOTINIB

N

NOOH

OOH

Cl

MOL FOR :- C14H17ClN2O5

MOL WT :- 312.74

N

NOO

OO

NH

CH3

CH3

CH3


MOL WT :- 429.82

.HCL

3-Ethanylanline

Methanol, MDC


Which is condensed with 3-Ethylaniline in presence of methanol and methylene chloride

yields Erlotinib hydrochloride.

ANNEXURE-6


Flow diagram :-

ERLOTINIB

Input Kg Output Kg

Ksm 385 Mdc 750

3-Ethylaniline 145 Effluent 220

Mdc 800 Methanol 1300


Methanol. HCL 575 Loss 35

TOTAL 2805 2805

Reactor

Reactor

Base-460Kg

Reactor

KSM385Kg 3-Ethylaniline 145Kg

MDC 800Lit

Recover of MDC 750Lit

Effluent 100Lit

Methanol 900LIt Base 460Kg

MeOH .HCL 575Kg

Chiled 10°C

Centrifuge

Dry Wt- 500Kg

Recover of Methanol 1300Lit

Effluent 120Lit

ANNEXURE-6


(57) ROS :- ETORICOXIB

N

S

CH3

OO

O

CH3

+

NH2Cl

H

O

Ketosulfone3-amino-2-Chloroacrolein

Trifluro Acetic Acid

Etoricoxib Hydrochloride

N

S

CH3

OO

N

CH3

Cl

.HCL

Etoricoxib Hydrochloride

N

S

CH3

OO

N

CH3

Cl

.HCL

Etoricoxib

N

S

CH3

OO

N

CH3

ClAq. Ammonia

MOL FORN :- C15H15NO3S

MOL WT :- 289.34

MOL FORN :- C3H4ClNO

MOL WT :- 105.5

MOL FORN :- C15H15Cl2N2O2S

MOL WT :- 396.34

MOL FORN :- C15H15Cl2N2O2S

MOL WT :- 396.34MOL FORN :- C15H15ClN2O2S

MOL WT :- 358.84

IPA / Hexane

Toluene


Stage :- 1

Ketosulfone is reacted with CPT-Phosphate in Presence of Potassium tert-Butoxide in Tetra

hydrofurane to give Etoricoxib crude.

Stage :- 2

Etoricoxib crude recrystallized from IPA-Hexane to give Etoricoxib.

ANNEXURE-6


Flow diagram :-

Effluent – 150 kg

Reactor

Reactor

Dry Wt- 570Kg

Reactor

Ketosulfone 435Kg 3-amino-2-Chloroacrolein 160Kg

Trifluro Acetic Acid 190Kg

Recover of THF 850Lit

Effluent 400Lit

Aq. Ammonia 50kg

EtoricoxibHCl 570Kg

Toluene 1100Lit

Crude base 510Kg

Reactor

Heating

IPA+Hexane1000Lit (50:50)

Recover ofIpa+Hexane 950Lit

THF 900Lit

Potassium tert- Butoxide

170Kg

Centrifuge

Recover of Toluene 1050Lit

Crude base 510Kg

Centrifuge

Dry wt- 500 Kg

Residue 40Kg

ANNEXURE-6


ETORICOXIB Input Kg Output Kg

Ksm 435 THF 850

3-Amino-2-Chloroacrolein 160 Effluent 550

Trifluro Acetic Acid 190 Toluene 1050

Potassium tert- Butoxide 170 IPA Hexane 950

Tetrahydrofura 900 Residue 40

IPA+Hexane 1000 Product 500

Tolune 1100 Loss 65

Aq. Ammonia 50

TOTAL 4005 4005

(58) ETODLAC

ROS :-

ETODLAC METHYL ESTER

Methanol

con H2SO4

Mol FOR :- C18H23NO3


CH3

NH

OH

7-ethyltyrptophol

Mol FOR :- C12H15NO


+ CH3

O CH3

O O

methyl-3-oxopentanoate


Mol FOR :- C6H10O3

O

CH3

NH

O

CH3

O

CH3

O

CH3

NH

O

CH3

OH

ETODLAC

Mol FOR :- C17H21NO3


NaoH

water dil HCL

ANNEXURE-6


Flow chart :-


Charge of methanol in reactor. Child to 0 C & Drop wise con H2SO4

addition at 0C For 2- hrs. Drop wise 7-ethyl tryptophol addition at 0C For 1- hrs.

Drop wise Methyl-9-oxopentanoate addition at 0C For 1.Maintain for 3 hrs at

RT &. centrifuge .Take product , charge NaoH& Water. Heating to

reflux.Maintain for 14 hrs to reflux temp. set PH-Acidic by 10 %

HCL.CHILLED TO 0-5 C. centrifuge. Drying & packing.

Reactor

Reactor

7-ethyl tryptophol-500 Methyl-9-oxopentanoate-409 kg

Con H2SO4-136 kg

kg

Methanol-1000 kg

NAOH-145 kg

Centrifug

Product-500 kg

Recover Methanol- 950 kg

Recover water- 1800 lit Water-1000 lit

Effluent -900 KG

10% HCL-1000 kg

ANNEXURE-6


(59) ESEITALOPRAM OXALATE

ROS :-

MOL WT - 412.93MOL WT :- 306

NCOH

F

OHN

CH3

CH3

citalopram

NCOH

F

OHN

CH3

CH3

(+)DPTTA SALT

Methan sulfonyl chloride

NC

F

N

CH3

CH3

O

Escitaloram

NC

F

N

CH3

CH3

O

Escitaloram oxalate

MOL FOR :-324MOL FOR :-414

oxalic acid

(90)

COOH

HOOC

DPTTA

di-p-toluoyl-D-tartric acid

toluene

MDC25 % liq-NH3

TEAtoluene

IPA

ETODLAC INPUT kg OUTPUT

7-ethyl tryptophol 500 Recover of Methanol

950

Methyl-9-oxopentanoate 409 Dry Wt 500

Con H2SO4 136 Recover of WATER 1800

Methanol 1000 EFFLCENT 900

NAOH 145 loss 40

WATER 1000

Dil HCL 1000

TOTAL 4190 4190

ANNEXURE-6


Flow chart :-

cv

Recover of water-950

Reactor

Reactor

Citalopram—1020 kg di-p-toluoyl-D-tartaric acid -1500 kg

Methanol-1000 kg

water-1000kg

Reactor

MDC -750 kg

Reactor

Product-500 kg

Recover methanol -950 kg

Recover (- )DPTA SALT- 1260kg & REUSED

Effluent -1800KG

TEA -130 KG

Recover IPA- 950 kg

25 %liq- NH3- 300kg

toluene-500kg

methanesulfonyl chloride -140 KG

liq- NH3-150 kg

toluene-500kg

Centrifuge

IPA -1000 kg

Oxalic acid – 120 KG

Recover MDC- 700 kg

Recover Toluene- 950 kg

ANNEXURE-6



charge citalopram, charged di-p-toluoyl-D-tartaric acid & charge methanol in

rector. filtered reaction mass to obtain (+)DPTTA to form S-citalopram diol

(+)DPTTA salt as solid. & distilled methanol to obtain the citalopram diol

(−)DPTTA .(−)-4-(4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-

(hydroxymethyl)benzonitrile (+)-DPTTA salt in water; set pH= 9 by liq NH3. &

toluene extraction.Toluene distillation to obtain residue. Charge residue , charge

MDC, charge TEA in reactor. Chilled 0-5.Dropwise addition of methanesulfonyl

chloride for 3-hrs at 0-5.Maintain &distillation MDC solvent. Residue set ph= 9 by

liq NH3. toluene extraction. Toluene distillation toescitalopram obtain. Charge

escitalopram, charge IPA & charge oxalic acid in reactor. heated to about 50-60°

C.& stir for 30min.cool RT. Filtered. DRY &PACKING .

ESEITALOPRAM OXALATE INPUT kg OUTPUT

Citalopram 1020 Recover of IPA 950

di-p-toluoyl-D-tartaric acid 1500 Product 500

Methanol 1000 loss 50

water 1000 Recover of water 950

25 %liq- NH3 450 Recover of methanol 950

MDC 750 Recover of MDC 700

TOLUENE 1000 Recover of TOLUENE 950

TEA 130 Recover (- )DPTA SALT 1260

methane sulfonyl chloride 140 EFFLCENT 1 800

IPA 1000

Oxalic acid 120

TOTAL 8110 8110

ANNEXURE-6


(60) ROS :- FEBUXOSTATE

O

NC

CH3

CH3

S

N

CH3

O

OCH3

O

NC

CH3

CH3

S

N

CH3

O

OH

Ethyl2-[3-Cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazole Carboxylate

2-[3-Cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazole Carboxylic acid

MOL FOR :- C18H20N2O3S

MOL WT :- 344.42


MOL WT :- 316.37

Sodium Hydroxid

Conc. Hydrochloride acid

Denatured Ethanol

+ NaCl

Sodium Chloride

H2O

Water

+ + CH3OH

Ethanol

O

NC

CH3

CH3

S

N

CH3

O

OH



MOL WT :- 316.37

O

NC

CH3

CH3

S

N

CH3

O

OH



MOL WT :- 316.37

DM WaterActivated Carbon

Hyflo

Acetone


Ethyl-2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-Carboxylate is reacted with

hydroxylamine hydrochloride to form oxime which is dehydrated with sodium formate& formic

acid to form Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate which on

hydrolysis gives Febuxostate.

ANNEXURE-6


Flow diagram :-

Reactor

Reactor

Crude- 510Kg

Reactor

Ethyl2-[3-Cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazoleCarboxylate 585Kg

Hydroxylamine hydrochloride 190Kg

Sodium Hydroxide 170Kg

Con.HCL 170Kg

Acetone+ D.M water 1000kg Crude- 510Kg

Sparkler filter

Chiled 10°C

Reactor

Recover OfAcetone+ D.M water 950kg

Methanol 1200kg

Centrifuge

Centrifuge

Dry wt 500Kg

Residue 40Kg

Recover of Methanol 1150Kg

Effluent - 520kg

salt - 120Kg

ANNEXURE-6


(61) ROS :- FELODIPINE

Cl

Cl

OH

+ CH3O

CH3

O OCl

Cl

H

CH3O

Meo

O

NH2 OEt

CH3

O

N+

Cl

Cl

OEt

O

Meo

O

Me Me

Hl


2,3-dichloro Benzaldehyde is Condensed with Methylacetoacetate in Presence of Formic acid

and Piperidine at 60-65� to give Monomethyl ester is reacted with 3-amino Crotonic acid ethyl

ester at 80-85� to give Felodipine Crude. Felodipine Crude is Purified in the mixture of

Cyclohexane: Isopropyl alcohol to give Felodipine.

ANNEXURE-6


Flow diagram :-

Reactor

Centrifuge

Reactor

2,3-dichloro Benzaldehyde

250Kg

Methylacetoacetate 185Kg

Formic acid 50Kg

Effluent230Kg

3-amino Crotonicacid 165Kg Step1- 355Kg

Centrifuge

Dry wt 355Kg

Reactor

Recover of Cyclohexane: Isopropyl 950Lit

Piperidine121Kg

Dry wt 355Kg

Chilled

Centrifuge

Residue 50Kg

Cyclohexane: Isopropyl alcohol 1000Lit Teacnical 515Kg

Dry wt-500Kg

ANNEXURE-6


ELODIPINE Input Kg Output Kg

2,3-Dichloro Benzaldehyde 250 Effluent 230

Methylacetoacetate 185 Cyclohexane: Isopropyl 950

3-Amino Crotonic Acid 165 Residue 50

Cyclohexane 500 Product 500

Isopropyl Alcohol 500 Loss 41

Formic Acid 50

Piperidine 121

TOTAL 1771 1771

62. FLUCONAZOL

MOL WT -223MOL WT :- 114

2,4-difluoro-2-(1,4-1,2,4,trizole-1-yl)acetophenone (DFTA)

F

F

CLCH2COCL (112

FF

ClO

FF

O

N

N

N

4-amino-4H-1,2,4 trizole (84)

trimethyl sulfoxonium iodide (220)

FF

N

N

NO

methanol

N

N N

FF

OH

N

N

N

FLUCONAZOLE

MOL WT :- 306

EPOXY MESYLATE

MOL WT :- 333.31

S

O

O

OH CH3

N

N N

NH2

S+

CH3

CH3

CH3

O

1,3-difuoro benzene

ANNEXURE-6


Flow chart :-

Reactor

Reactor

1,3-difuoro benzene-196 kg Chloroacetyl chloride -200 kg

Ethyl acetate-500 LIT ALCL3-250 kg

Dil HCL-500 lit

Reactor

10 %K2CO3 SOLUTION -500

Centrifuge

Product-500 kg

NaNO2 +H2O- 100 kg+300 kg

Effluent -1100 KG

ETHYL ACETATE-500


Methanol -500 LIT

trimethylsulfoxonium iodide-380 kg

Reactor

Methanol -1000 LIT

Dil HCL-500 lit

Recover methanol -1450lit

Total Effluent 1100 KG

WATER-500 LIT

4H-amino-l,2,4- trizole-144 kg

KOH-50kg

Recover ethyl acetate-950lit

ALCL3 solution -500 lit

ANNEXURE-6



Charge Aluminumchloride&charge 1,3-difluorobenzenein reactor.drop wise addition

ofChloroacetylchloride at 20C for 2-hrs.Heating to 50-60C & Maintain for 5 hrs at 60C. cold to

RT & Charge to ethyl acetate . separation&distillation organic solvent. take product & charge

methanol in reactor. Drop wise addition4H-amino-l,2,4-triazole at RT for 3hrs. Heating to 70 C

& Maintain for 5 hrs at 70C.distillation methanol .takeresidue&charge dil. hydrochloric acid

&To the above solution sodium nitrite in water addition for4-hrs at 10 C. set ph natural by

potassium carbonate. Charge Ethylacetate.separation&distillation.the residue dissolved in water

and potassium hydroxide trimethylsulfoxonium iodide and lH-l,2,4-triazole were added. Stir

3hrs at 35 C.. The pH adjusted to neutral with dil. hydrochloric acid to give technical

Fluconazole. Purification in methanol.

FLUCONAZOL INPUT OUTPUT

1,3-difuoro benzene 196 KG Recover of ethyl acetate 950 LIT

Chloroacetyl chloride 200kg Dry Wt 500 KG

ALCL3 250 KG SOLVENT loss 20KG

Methanol 1500

LIT

Recover of water 1600 LIT

WATER 800 LIT Recover of METHANOL 1450 LIT

ETHYAL ACETATE 1000

LIT

ALCL3 solution 500 lit

Dilhcl 1000 lit EFFLCENT 1100KG 10 % K2CO3 500 LIT

NaNO2 100 KG

4H-amino-l,2,4- trizole 144 KG

trimethylsulfoxonium iodide 380 KG

KOH 50 KG

TOTAL 6120KG 6120KG

ANNEXURE-6


Flow chart :-

Reactor

Reactor

1,3-difuoro benzene-196 kg Chloroacetyl chloride -200 kg

Ethyl acetate-500 LIT ALCL3-250 kg

Dil HCL-500 lit

Reactor

10 %K2CO3 SOLUTION -500

Centrifuge

Product-500 kg

NaNO2 +H2O- 100 kg+300 kg

Effluent -1100 KG

ETHYL ACETATE-500


Methanol -500 LIT

trimethylsulfoxonium iodide-380 kg

Reactor

Methanol -1000 LIT

Dil HCL-500 lit

Recover methanol -1450lit

Total Effluent 1100 KG

WATER-500 LIT

4H-amino-l,2,4- trizole-144 kg

KOH-50kg

Recover ethyl acetate-950lit

ALCL3 solution -500 lit

ANNEXURE-6



Charge Aluminumchloride&charge 1,3-difluorobenzenein reactor.drop wise addition

ofChloroacetylchloride at 20C for 2-hrs.Heating to 50-60C & Maintain for 5 hrs at 60C. cold to

RT & Charge to ethyl acetate . separation&distillation organic solvent. take product & charge

methanol in reactor. Drop wise addition4H-amino-l,2,4-triazole at RT for 3hrs. Heating to 70 C

& Maintain for 5 hrs at 70C.distillation methanol .takeresidue&charge dil. hydrochloric acid

&To the above solution sodium nitrite in water addition for4-hrs at 10 C. set ph natural by

potassium carbonate. Charge Ethylacetate.separation&distillation.the residue dissolved in water

and potassium hydroxide trimethylsulfoxonium iodide and lH-l,2,4-triazole were added. Stir

3hrs at 35 C.. The pH adjusted to neutral with dil. hydrochloric acid to give technical

Fluconazole. Purification in methanol

FLUCONAZOL INPUT OUTPUT

1,3-difuoro benzene 196 KG Recover of ethyl acetate 950 LIT

Chloroacetyl chloride 200kg Dry Wt 500 KG

ALCL3 250 KG SOLVENT loss 20KG

Methanol 1500

LIT

Recover of water 1600 LIT

WATER 800 LIT Recover of METHANOL 1450 LIT

ETHYAL ACETATE 1000

LIT

ALCL3 solution 500 lit

Dilhcl 1000 lit EFFLCENT 1100KG 10 % K2CO3 500 LIT

NaNO2 100 KG

4H-amino-l,2,4- trizole 144 KG

trimethylsulfoxonium iodide 380 KG

KOH 50 KG

TOTAL 6120KG 6120KG

ANNEXURE-6


(63) Garnisetron HCL

ROS :-

+NCH3

NH2

MOL FOR:-C9H20N2CL2

MOL W T:-227.17

2HCL

HCL

GARNISETRON.HCL

Endo-9-methyl-9-azobicyclo[3,3,1] nonane 3-amine.2HCL

MOL FOR:-C18H24N4OHCL

MOL W T:-348.41

O

N

N

OH

CH3

N-methyl -indazole-3-Carboxylic acid

MOL FOR:-C9H8N2O2

MOL W T:-176.17

CH3

NCH3

NH

ON

N

thinoyl chloride

Chloroform

Dimethyl formide

MDC

NaoH

IPA

IPA.HCL

Flow chart:-

Reactor

Reactor

EMA.HCL-595kg MDC-1000 kg

NAOH-595 kg Water-1000 kg

ACID-392 kg DMF- 78 kg

Reactor

U/N2 10 C Water wash-500 kg

IPA-1000 kg

Centrifuge

Product-500 kg

Recover Thionyl chloride -700 kg

Recover MDC- 950 kg

Recover IPA-1300 kg

Thionyl chloride-784 kg


Effluent -2200 KG

TEA-285 KG

NaHCO3-500 KG

IPA.HCL-500 KG

ANNEXURE-6



Charge of endo-9-methyl-9-azabicyclo[3.3.1]nonylamine HCL, Water & sodium

hydroxide in reactor & charge MDC at 20 0C.Collect base in MDC& Charge

Triethyl amine. Take N-methyl -indazole-3-Carboxylic acid chloroform, charge DMF in

Reactor. Drop wise thionyl chloride addition for at RT. Heating to reflux.

Maintain for 4-hrs at reflux temp. distilled chloroform. Take product and charge

base in reactor at 15C U/N2. Maintain for 14-hrs at 15-20 C. Sodium bicarbonate

wash. MDC layer distilled out. Take base in charge IPA & IPA HCL at RT.

centrifuge .drying &Packing

Garnisetron HCL

INPUT kg OUTPUT kg

EMA-HCL 595 Recover of MDC 950

water 1500 Product 500

NaoH 595 loss 129

MDC 1000 Recover of Thinoyl chloride 700

ACID 392 Recover of IPA 1300

Thinoyl chloride 784 Recover of WATER 1450

DMF 78 EFFLUENT 2200

TEA 285

NaHCO3 500

IPA 1000

IPA HCL (25 %) 500

TOTAL 7229 7229 KG

ANNEXURE-6


(64) ROS :- GEFITINIB

N

N

Cl

O

O

N

O

CH3

F

ClNH2N

N

NH

O

O

N

O

CH3

F

Cl

Conc. HCL

Isopropyl alcohol

N

N

NH

O

O

N

O

CH3

F

Cl

N

N

NH

O

O

N

O

CH3

F

Cl

n-Propanol


3-Chloro-4-fluoroaniline in Presence of isopropyl alcohol yields Gefitinib which is

further purified with n-Propanol gets pure Gefitinib.

ANNEXURE-6


Flow diagram :-

Gefitinib

Input Kg Output Kg

Ksm 410 IPA 750

3-Chloro-4-Fluoroaniline 175 Effluent 200

Con Hydrochloric Acid 150 N-Propanol 950

Isopropyl Alcohol 800 Residue 90

N-Propanol 1000 Product 500

loss 45

TOTAL 2535 2535

Reactor

Centrifuge

Reactor

Centrifuge

Dry Wt-500Kg

KSM 410Kg 3-Chloro-4-fluoroaniline 175Kg

Conc. HCL 150Kg

Technical 515Kg

isopropyl alcohol 800kg

Technical 515Kg

N-Propanol 1000 kg

Recover of Ipa 750 kg

Effluent 200 kg Residue 50Kg

Recover of N-Propanol 950 kg

Residue 90Kg

ANNEXURE-6


(65) GABAPENTIN

ROS :-

MOL FOR : C9H17NO4

MOL WT - 171

Gabapentin lactum

MOL FOR : C9H15NO

MOL WT :- 153

GABAPENTIN

O

NH

aq-HBr

HOOCNH2

HBr

HOOCNH2

GABAPENTIN HBR SALT

MOL FOR : C9H17NO4 HBR

MOL WT - 251

IPA

+CH3CH2Br

+ CH3CH2NH2

Acetone Methanol

diethylamine109

45.0873.14

Flow chart:-

Reactor

Reactor

gabapentin lactam-480

kg

Acetone-500 KG

50 %HBr- 1000 KG Water-500 lit

Diethylamine-230 kg

Reactor

IPA-500 KG

Centrifuge

Product-500 kg

Recover acetone -450 KG


Effluent -700 KG

Recover IPA- 475 KG

Methanol-500 KG

Recover Methanol -475 KG

Recover methylamine-160 kg


ANNEXURE-6



charged with of gabapentin lactam , charged water and charged hydrobromic acid 49.02% IN

reactor U/N2.heated to -108-114° C and stirred for 6 hours at reflux temperature. cooled to -0-5°

C and stirred for 15-16 hours at this temperature. The filtrate ml heated to108-114° C and stirred

6hrs to reflux (-108-114° C) . cooled to -10-20° C and stirred at this temperature for 15 hours.

Precipitation began following seeding with a small portion of the gabapentin HBr obtained in the

previous step. After stirring 3 hours at this temperature, the product was filtered and dried by

suction to yield of moist gabapentin HBr. The first and second yields were then combined (321

& charge acetone reactor &cool to 0-5. filtered and washed with acetone. Charged with

gabapentin HBr and charge methanol .heated to -40-45° C and neutralized by of diethylamine

added at -35-40° C over 50 minutes. Check pH to between 7.5 and 8.0.&reflux for 1-hrs. and

charge isopropyl alcohol was added over 10-15 min. The suspension was then cooled to -0-5° C

over 25 minutes, stirred for 2 hours and filtered. The resulting solid was washed twice with 30

mL of cold isopropyl alcohol and dried under suction to give moist gabapentin .

GABAPENTIN INPUT Kg OUTPUT kg

gabapentin lactam 480 Recover of IPA 475

50 %HBr 1000 Product 500

Water 500 Recover of acetone 450


Acetone 500 EFFLUENT 700

Diethylamine 230 Recover of methanol 475

Methanol 500 Methyl amine 160


ANNEXURE-6


(66) ROS :- ILOPERIDONE

HO3S OR

1H

Ar-

R2

OR

3

HO3C

LS

O

R4

O

OH

H3OC

R4 =H,OH , CH3


Reaction of 1-(4-hydroxy-3-methoxyphenyl) ethanone with 1-bromo-3-Chloropropane in

Presence of Potassium Carbonate gives 1-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone.

Condensation of 1-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone with 6-fluoro-3(4-

piperidinyl)-1,2-benzisoxazole hydrochloride in Presence of Potassium Carbonate gives Crude

Iloperidone. Iloperidone Crude is the treated with Tartaric acid to Product Tartarate salt of

IloperidoneWhich on basification with ammonia to furnish pure Iloperidone.

ILOPERIDONE INPUT kg OUTPUT kg

1-(4-Hydroxy-3-Methoxyphenyl)

Ethanone

200 Effluent 820

1-Bromo-3-Chloropropane 190 Residue 130

Potassium Carbonate 90 Salt 150

6-Fluoro-3(4-Piperidinyl)-1,2-

Benzisoxazole Hydrochloride

310 Product 500

Potassium Carbonate 90 Loss 60

Tartaric Acid 180

AmmoniaSolution (25%) 600

TOTAL 1660 1660

ANNEXURE-6


Flow diagram :-

Reactor

Centrifuge

Reactor

1-(4-hydroxy-3-methoxyphenyl)

ethanone 200Kg

1-bromo-3-Chloropropane 190Kg


6-fluoro-3(4-piperidinyl)-1,2-

benzisoxazole hydrochloride 310Kg

1-[4-(3-chloropropoxy)-3-

methoxyphenyl] ethanone -345 kg


Centrifuge

Reactor

Residue 130 kg

Effluent 880 kg

DryWt: 345Kg

Crude – 495 Kg

Technical:660Kg

Reactor

Crude – 495 Kg

Tartaric acid 180Kg

Centrifuge

Ammonia 600KG Technical: 660Kg

Centrifuge

Dry Wt:500Kg

Salt : 150Kg

ANNEXURE-6


(67) ROS :- IRBESARTAN

N

N

O

COOH

CN

N

N

O

COOH

NH

N

N

N

2-(n-butyl)-3-(2'-cynobiphenyl-4-ylmethyl)-4-oxo-1,3-diazaspiro [4.4]non-1ene

Irbesartan

Tributyltin ChlorideDM Water

NaOHHCL

Water

Charcoal95% Ethanol

Methyl-t.Butyl ether

Sodiumazide

Manufacturing Process :

2-(n-butyl)-3-(2’-Cynobiphenyl-4-ylmethyl)-4-oxo-1,3-diazaspiro [4.4] non-1ene which on

treatment with tributyltin Chloride and Sodium azide in refluxing xylene to form Irbesartan

which is isolated and purified in alcohol.

ANNEXURE-6


Flow diagram :-

Reactor

2-(n-butyl)-3-(2’-Cynobiphenyl-4-

ylmethyl)-4-oxo-1,3-diazaspiro [4.4]

non-1ene-496 kg

tributyltin Chloride 325 kg

Sodiumazide 270 kg

Xylene 1000 KG

Reflux

Reactor

NaOH 424 kg HCL 346 KG

Reactor Effluent 1400 kg

Recovery of Xylene 950 KG

Reactor

Methyl-t-butyl ether 1000 KG Charcoal- 50kg

Centrifuge Recovery of Methyl-t-butyl ether 950 KG

Recovery of Residue 70 kg

Technical Dry

515 kg

Reactor

Technical 515 kg IPA 1000 KG

Chill to 10�

Reactor

Centrifuge Recovery of IPA 950 KG

Residue 40 kg

Dry wt 500 kg

ANNEXURE-6


IRBESARTAN

INPUT kg OUTPUT kg

2-(N-Butyl)-3-(2’-

Cynobiphenyl-4-Ylmethyl)-4-

Oxo-1,3-Diazaspiro [4.4] Non-

1ene

496 Effluent 1400

Tributyltin Chloride 325 Xylene 950

Sodiumazide 270 IPA 950

Xylene 1000 Residue 110

Sodium Hydroxide 424 Methyl-T-Butyl Ether 950

Hydrochloric Acid 346 Product 500

Methyl-T-Butyl Ether 1000 Loss 51

Charcoal 50

Isopropyl Alcohol 1000

TOTAL 4911 4911

(68)ITOPRIDE HYROCHLORIDE

ANNEXURE-6


ROS :-

M O L W T - 358

(2-(4-am inom ethyl) phenoxy) N ,N dim ethyl ethanam ine)

M O L W T :- 194.27

+

M O L W T :- 200

3,4-dim ethoxy benzoyl chloride(Vertroyl chloride)

K2CO 3

ITO PRIDE BASE

NH 2

O

NCH 3 CH 3

O

CH 3

O

CH3

O

Cl

NH

O

NCH3 CH3

O

CH 3

O

CH 3

O +HCL

36.5

NH

O

NCH 3 CH 3

O

CH 3

O

CH3

O ITO PRIDE BASE

MO L W T - 358

1.5HCL

36.5

+

acetone

NH

O

NCH 3 CH 3

O

CH 3

O

CH3

O

MO L W T - 394.5

ITO PRIDE HCL

HCL

0.5 HCL+

36.5

to luene

ANNEXURE-6


Flow chart :-


2-(4-aminomethyl) phenoxy) N,N dimethyl ethanamine)- is reacted with Vertroyl chloride in

toluene in presence of anhydrous potassium carbonate. The crude is isolated by removal of the

solvent(Itopride base). Crude product is treated with carbon in hot acetone .After removal of

carbon, addition of presence of HCL leads to formation of the Itopride HCL.

ITOPRIDE HYROCHLORIDE INPUT kg OUTPUT kg

Vertroyl chloride 270 Recover of toluene 975

2-(4-aminomethyl) phenoxy) N,N

dimethyl ethanamine)- 260 Product 500

K2CO3 340 Recover of Acetone 975 Toluene 1000 Recover of water 300

Acetone 1000 EFFLCENT 670

CON HCL 550

TOTAL 3420 3420 KG

Reactor

Reactor

Vertroyl chloride-270 kg 2-(4-aminomethyl) phenoxy) N,N dimethyl ethanamine)-260 kg

K2CO3-340kg Toluene-1000 KG

base-450 kg

Reactor

Centrifuge

Product-500 kg

Recover toluene -975KG

Effluent -225 KG

HCL-550 KG

Recover water- 300 KG

Acetone-1000 KG

Effluent -445 KG

Recover Acetone -975KG


ANNEXURE-6


(69) ROS :- LAPATINIB

OOHC N

N

NHCl

O

F

CH3

S

OHOO

O N

N

NHCl

O

F

NHS

OO

CH3

CH3

S

OHOO 2 .H2O

NH2S

OO

CH3

2-(methylsulfonyl)ethylamine hydrochloride

NaB(OAC)3H

THF / ACOH

DIPEAPTSA /H2O

Lepatinib ditosylate monohydrate Crude

O N

N

NHCl

O

F

NHS

OO

CH3

Lepatinib ditosylate monohydrate Crude

CH3S OH

O

O2 .H2O

Purification

THF : Water

N-[3-Chloro-4-(3-fluorobenzyloxy)phenyl]-6-iodoquinazolin-4-amine

MOL FOR :- C26H17ClN3O3 (C7H8O3S)2

2.

MOL WT :- 646.08

MOL FOR :- C3H10ClN2S

MOL WT :- 159.63

N-(3-Chloro-4-{[(3-fluophenyl)oxy}phenyl)-6-[5-({[2-(methylsulfonyl)amino}methyl)-2-furanyl]-4-quinazolinaminebis(4-methylbenzenesulfonate)monohydrate

MOL FOR :- C26H17ClN3O3 (C7H8O3S)2

MOL WT :- 943.46

.HCL


Condensation of N-[3-Chloro-4-(3-fluorobenzyloxy)phenyl]-6-iodoquinazolin-4-amine with 2-

(methylsulfonyl)ethanamine hydrochloride in Presence of Sodium triacetoxyborohydride and

Diisopropyl ethylamine in methanol and tetrahydrofuran than react with p-toluene sulfonic acid

to give Lapatinibditosylate monohydrate crude after purification in tetrahydrofuran and D M

Water to ger pure Lapatinibditosylate monohydrate.

ANNEXURE-6


Flow diagram :-

GLR

Centrifuge

Technical DRY

WT -510 KG

N-[3-Chloro-4-(3-fluorobenzyloxy)phenyl]-

6-iodoquinazolin-4-amine -370 kg

2-(methylsulfonyl)ethanamine HCL – 91 kg

Sodiumetriacetoxyborohydride – 166 kg

Diisopropyl ethylamine-200

+Methanol -200 kg P-toluene sulfonic acid -575

+Tetrahydrofuran -500 kg

effluent -1100 kg

Reactor

Centrifuge

DRY WT -500 KG


Total effluent -1600 kg

Recovery of Tetrahydrofuran – 470 kg

tt4501050 lit

Tetrahydrofuran -500 kg +

Water -500 kg

Recovery of Tetrahydrofuran – 470 kg

tt4501050 liteffluent -500 kg

ANNEXURE-6


LAPATINIB

INPUT kg OUTPUT kg

N-[3-Chloro-4-(3-

Fluorobenzyloxy)Phenyl]-6-

Iodoquinazolin-4-Amine

370 Tetrahydrofuran 940

2-(Methylsulfonyl)Ethanamine

HCL

91 Effluent 1600

SodiumeTriacetoxyBorohydride 166 Product 500

Diisopropyl Ethylamine 200 loss 62

Methanol 200

P-Toluene Sulfonic Acid 575

Tetrahydrofuran 1000

Water 500

TOTAL 3102 3102

(70) lurasidone HCL

ROS :-

M O L FO R : C 19H40O N3S

M O L W T - 348

M O L W T :- 529

N

S

N

NH

3-(1-P lperazinyl)-1,2-benziso

thiazole

M O L FO R : C 11H 13N 3S

M O L W T :- 219

+O HOH

M O L FO R : C8H 18o2

M O L W T :- 146

IPAC a(O H)2

Acetone

n-hexane

NS

NN

O H

K2CO 3

to luene

IPAH C L

NH

O

O

H

H

N

O

O

H

H

NS

NN

H

H

LU RASIDR O N HC L

M ol FO R :- C 28H 37C LN 4O 2S

H CL

(1R ,2R)-1.2,Cyclohexane

dim ethanol

ANNEXURE-6


Flow chart :-


Charge of 3-(1-Plperazinyl)-1,2-benzisothiazole, Isopropyl alcohol

Calcium hydroxide & (1R,2R)-1.2,Cyclohexanedimethanol in reactor & Heating

to reflux. Maintain for 14-hrs at reflux temp. filter reaction mass &distilled IPA.

Take product and charge acetone & n-hexane chilled. centrifuge& drying. Take

product,Bicyclo[2,2,1] hep-tane-2,3-exodicarboximide,toluene & potassium

carbonate in reactor. Heating to reflux. Maintain for 14-hrs at reflux temp. filter

reaction mass &distilled toluene. & Take product ,charge IPA. Heating to

reflux.drop wise con HCL for 1-hrs at reflux temp.cool to RT & chilled to 10C for

1-hrs . centrifuge .drying &Packing

Reactor

Reactor

3-(1-Plperazinyl)-1,2-benziso

thiazole -295 kg

1R,2R)-1.2,Cyclohexane

Dimethanol -393 kg

Ca(OH)2-316 kg IPA-1000 kg

Acetone-200 kg n-hexane- 200 kg

Reactor

Toluene-1000 kg

Bicyclo[2,2,1] hep-tane-2,3-exodicarboximide :-211 kg

Centrifuge

Product-500 kg

Recover IPA -950 kg

Recover n-hexane- 180 kg

Recover IPA-450 kg


Recover toluene -950 kg

Effluent -1280 KG

K2CO3-232 KG

HCL-300 kg

IPA-500 kg

ANNEXURE-6


(71) ROS :- LOSARTAN POTASSIUM

N

N

N

N

C Ph

Ph

Ph

BrC2H

NC4H9

N

HC2OH

Cl

.NN

NKN


Then Subjected to salt formation by treating it with Potassium hydroxide Solution to attain

alkaline pH. After the pH adjustment is over it is Charcoalised filtered and Precipitated by

distilling off excess of Methanol and Centrifuging the Precipitated mass. The wet cake is further

dried and packed. This is Losartan Potassium.

lurasidone HCL INPUT kg OUTPUT kg


thiazole

295 Recover of IPA 1400

1R,2R)-1.2,Cyclohexane

Dimethanol

393 Product 500

Ca(OH)2 316 loss 157

IPA 1500 Recover of TOLUENE 950

Acetone 200 Recover of ACETONE 180

n-hexane 200 Recover of N-HEXANE 180

Bicyclo[2,2,1] hep-tane-2,3-

exodicarboximide

211 EFFLUENT 1280

K2CO3 232

TOLUENE 1000

HCL 300

TOTAL 4647 4647

ANNEXURE-6


Flow diagram :-

LOSARTAN POTASSIUM

INPUT kg OUTPUT kg

Ksm 605 Methanol 1150

Potassium Hydroxide 110 Effluent 800



Charcoal 60 Loss 25

TOTAL 2575 2575

(72) ROS :- MEM CHLORIDE

HCHO

Paraformaldehyde

+ CH3OC2H4OH

Methyl Cellosolve

+ SOCl2

Thionyl Chloride

CH3OC2H4OCH2Cl+HCL+SO2

Methoxy Ethoxy Methyl Chloride

Reactor

Reactor

Centrifuge

Dry wt 500 kg

KSM 605 kg Potassium hydroxide 110 kg + Water 600 lit

Methanol 1200 lit

Charcoal 60 kg

Sparkler Filter

Recovery of Methanol 1150 lit

Effluent 800 kg

Residue 100 kg

ANNEXURE-6



Hydrogen Chloride gas is generated and reacted with the reaction mixture of

Paraformaldehyde/1,3,5Trioxane and Methyl Cellulose to give Methoxymethyl Chloride.

MEM CHLORIDE

INPUT kg OUTPUT kg

Paraformaldehyde 125 Effluent 350

Methyl Cellulose 315 Recovery Of 1,3,5 Trioxane 450

1,3,5 Trioxane 500 Residue 100

Thionyl Chloride 495 Product 500

Loss 35

TOTAL 1435 1435

Reactor

Paraformaldehyde 125 kg Methyl Cellulose 315 kg

1,3,5Trioxane 500 lit

Thionyl Chloride 495 kg

Reactor


Recovery of 1,3,5Trioxane 450 lit

Residue- 100 kg

Total -Effluent -350 kg

Dry wt 500 kg

ANNEXURE-6


(73) Ros:-MINODRONIC ACID

O

N

N

OH

.HCL

O

OH

N

N

POH

OH

O

POH

OH

.H2O

+ HCL + H3PO3

O

OH

N

N

POH

OH

O

POH

OH

.H2O

O

OH

N

N

POH

OH

O

POH

OH

.H2O

Dliute HCL Solution

Phousphorous Acid

Phosphorous trichloride

Tetramethylurea

Dliute HCL Solution


Phosphorous acid and Phosphorous trichloride. The resultant Product is hydrolyzed with

aqueous HCL solution to give 1-Hydroxy-2-(Imidazo[1,2-a]pyridine-3-yl)ethane-1,1-

bis(phosphonic acid )monohydrate(Crude Minodronic acid). This is Purified with dil HCL

Solution which gives pure Minodronic acid.

ANNEXURE-6


Flow Diagram :-

MINODRONIC ACID

INPUT kg OUTPUT

Ksm 315 Effluent 1400

Phosphorous Acid 98 Salt 130

Phosphorous Trichloride 870 Product 500

Dliute Hydrochloric Acid 60 Loss 88

Tetramethylurea 115

DilHcl Solution 660

TOTAL 2118 2118

Reactor

KSM 315 kg Phosphorous acid 98 kg

Phosphorous trichloride 870 kg

Tetramethylurea 115 kg

Reactor

Centrifuge

Technical Dry

wt 510 kg

Effluent 800 kg

Salt 130 kg

Dil. HCL 60 lit

Reactor

Dil. HCL Solu 660 lit Technical 510 kg

Centrifuge Effluent 600 lit

Dry wt 500 kg Total Effluent-

ANNEXURE-6


(74) ROS :- MOCLOBEMIDE

Cl

CO-NH-CH2-CH2-N- O

Toluene

Sodium Carbonate

Water

Cl

CO-NH-CH2-CH2-N- O

Cl

CO-NH-CH2-CH2-N- O

Cl

CO-NH-CH2-CH2-N- O

Isopropanol

Moclobemide


Stage :- 1

Charging of Toluene followed by Moclobemide.Dissolution of the material by heating then

Sodium Carbonate Solution addition & two Water washing.Distillation of the Toluene & finally

gradual Cooling Centrifugation drying & packing of the material.

Stage :- 2

Charging of Isopropyl followed by dissolution Charcoalisation of the material Distillation of the

Isopropyl alcohol gradual Cooling Centrifugation of the material. Finally material is dried in

FBD followed by milling sifting blending again micronizarion sifting & finally Packing of the

material.

ANNEXURE-6


Flow diagram :-

Reactor

Reactor

Reactor

Centrifuge

Dry wt-510kg

KSM 535 kg

Sodium Carbonate

Toluene 1000 KG

Water 500 KG

Reactor

Sparker Filter

Reactor

Centrifugation

Dry wt-500kg

Charcoal-50kg

530 KG

Water-500 kg

Effluent-1400 kg

IPA-1000kg

RecoverToluene- 950 kg

Technical-510 kg

Carbon-50kg

Recovery of IPA-950 kg

Residue-200kg

Total Efflucent-1450 kg

ANNEXURE-6


MOCLOBEMIDE INPUT kg OUTPUT kg

Ksm 535 Effluent 1450

Toluene 1000 Residue 250

Sodium Carbonate 530 Toluene 950

Charcoal 50 IPA 950

Isopropyl Alcohol 1000 Product 500

Water 1000 Loss 65

TOTAL 4115 4115

(75) ROS :- MODAFINIL

OH

Benzhydrol

ThloureaS

OH

O

Diphenyl Methyl Thioacetic acid

Ammonia

SNH2

O

Diphenyl Methyl Thioacetamide

Glaclal acetic acid

Hydrogen Peroxide

SNH2

OO

Modafinil


Thio Urea and Benzhydrol are reacted in Presence of Hydrobromic acid. Then the mass is treated

with Ammonia gas and Sulfuric acid. Finally the treatment is done with Acetic acid and

Hydrogen peroxide to give Modafinil.

ANNEXURE-6


Flow diagram :-

MODAFINIL

INPUT kg OUTPUT kg

Benzhydrol 400 Efflucent 1900

Thio Urea 144 Salt 200

Hydrobromic Acid 1200 Recovery Of Acetic Acid 950

Ammonia Solution (25%) 730 Product 500

Sulfuric Acid 145 Loss 114

Acetic Acid 1000

Hydrogn Peroxide. 45

TOTAL 3664 3664

Reactor

Chilled

Benzhydrol 400 kg Thiourea 144 kg

HBr 1200 kg

Centrifuge Efflucent-950kg

Salt 200 kg

Dry wt 535 kg

Reactor

Ammonia 730 kg

Sulfuric acid 145 kg

Diphenyl-Methyl

ThioaceticAcid 535 kg

Centrifuge

Dry wt 510 kg

Reactor

Centrifuge

Dry wt 500 kg

Efflucent-870 kg

Technical 510 kg Acetic Acid 1000 kg

H2O2 45 kg

Recovery of Acetic Acid 950 kg

Efflucent-80 kg

Total Efflucent- 1900 KG

ANNEXURE-6


(76) METOPROLOL TARTRATE

ROS :-

M O L W T - 2 0 8 .9 3

4 -(2 -M E T H O X Y E T H Y L P H E N O L

M O L W T : - 1 5 2 .1 9

+

M O L W T : - 9 2 .5 2

e p ic h lo ro h y d r in

w a te r

to lu e n e

4 -(2 -m e th h o xy e th y l)p h e n o x y m e th y l o x ira n e

O

CH 3

O H

O

C l

O

O

CH 3

O

H C L+

is o p ro p y la m in e

O

CH 3

O N H C H 3

C H 3

O Hm e to p ro lo l

O

CH 3

O N H C H 3

C H 3

O H

M O L W T - 2 6 7

M O L W T - 4 1 7

m e to p ro lo l ta r tra te

OH

COOH

OHCOOH

OH

COOH

OHCOOH

ta r t ra l ic a c id

1 5 0

a c e to n e

N a O H

to lu e n e

ANNEXURE-6


Flow chart :-

Reactor

Reactor

4-(2-methoxyethyl)phenol-

186 kg

Epichlorohydrin-199 kg

TOLUENE-500kg Water-500 kg

isopropyl amine -100 kg

Reactor

WATER-500 kg

Centrifuge

Product-500 kg

Recover toluene-975 kg

Effluent - 315KG

toluene- 500 kg


NaoH- 50 kg

Acetone- 500 kg tartaric acid -180 kg


ANNEXURE-6



charge 4-(2-methoxyethyl)phenol , charge water and charge epichlorohydrin, in reactor. Charge

sodium hydroxide. Heating to40° to 45° for 5 hrs. charge toluene & set PH- 7to 8 by

washing.organic layer azeotropic distillation under vacuum below 55° C. to obtain oxiranedervi.

Take oxiranedervi, charge isopropyl amine, charge water in reactor. stir for 6-hrs at RT. cool to

0-5 & quenching in water.& toluene extraction.& toluene layer distilled out under vacuum below

55° C &metoprolol base obtain. Take metoprolol base, charge acetone & charge tartaric acid in

reactor. heating to 45 C. cool to RT & SET PH-6.0 to 6.2.chilled to 10C.filtered reaction mass.

dry& packing.

METOPROLOL TARTRATE INPUT kg OUTPUT kg

4-(2-methoxyethyl)phenol 186 Recover of acetone 450

Epichlorohydrin 199 Dry Wt 500

Sodium Hydroxide 50 Recover of toluene 975

Toluene 1000 Recover of water 975

WATER 1000 EFFLUENT 315

Acetone 500

isopropyl amine 100

tartaric acid 180

TOTAL 3215 3215

ANNEXURE-6


(77) ROS :- NISOLDIPINE

H

OCH3

NO2

O

O

CH3

CH3

+H

OCH3

NO2

O

O

CH3

CH3

CH3 O

CH3

ONH2

MOL FOR :- C5H9NO2

MOL WT :- 115.13

Toluene

Di Sodium hydrogenPhosphateAcetonitrile

N-methyl-2-pyrrolldinone

NO2

NH

O

O

CH3

CH3

O

CH3

O

CH3 CH3

2-nitrobenzylidine acetoaceticacid isobutyl ester

Z-Isomer E-Isomer


MOL WT :- 291.29

Nisoldipine Crude

MOL WT :- 388.41


NO2

NH

O

O

CH3

CH3

O

CH3

O

CH3 CH3

Nisoldipine Crude


NO2

NH

O

O

CH3

CH3

O

CH3

O

CH3 CH3

Nisoldipine Crude

MOL WT :- 388.41


Acetonitrile

Methylene dichloride


2-nitro benzaldeyde is Condensed with Isobutylacetoacetate in presence of formic acid and

Piperidine at 40-45� to give Monoisobutyl ester. Monoisobutyl ester is reacted with 3-amino

crotonic acid methyl eater in Presence of 4-Dimethyl amino pyridine at 80-85� to give

Nisoldipine Crude. Nisoldipine Crude is Purified in the mixture of Acetone: Water to give

Nisoldipine.

ANNEXURE-6


Flow diagram :-

NISOLDIPINE INPUT kg OUTPUT kg

2-Nitrobenzylidine Acetoaceticacid

Isobutyl Ester

405 Efflucent- 390

3-Amino Crotonic Acid Methyl

Eater

160 Toluene 750

Di Sodium Hydiogen Phosphate 195 Salt 60

Di Methyl Aminopyridine 170 Acetone 475

Toluene 800 Water 475

Acetone 500 Residue 40

Water 500 Loss 40

Product 500

TOTAL 2730 2730

Reactor

2-nitrobenzylidine acetoaceticacid isobutyl ester 405 kg

Di methyl aminopyridine 170 kg

3-amino crotonic acid methyl eater 160 kg

Toluene 800 lit

Di Sodium hydiogen Phosphate 195 kg

Reactor

Centrifuge

Technical Dry

wt 515 kg

Efflucent-390 kg

Recovery of Toluene 750 kg

Salt 60 kg

Reactor

Acetone 500 kg + Water 500 Technical 515 kg

Centrifuge Recovery of Acetone & Water 950 kg

Residue 40 kg

Dry wt 500 kg Tota Efflucent-390 KG

ANNEXURE-6


(78) OMEPRAZOLE

ROS :-

MOL WT - 3292-chloromethyl-3,5-dimethyl-4-methoxy pyridine hcl

MOL WT :- 222

+

MOL WT :- 180

2-mercapto-5-methoxy benzimidazole

water

NaOH

methanol sulfide comp

CH3

N

CH3

Cl

O CH3

N

NH

SH

O

CH3

CH3

N

CH3

O CH3

N

NH

S

O

CH3

+ +2NaCL H2O

58.8 18

Stage:-1

Stage:-2

CH3

N

CH3

O CH3

N

NH

S

O

CH3

sulfide comp

MOL WT - 329

+ H2O2

34

ammonium molybadate tetrahydrate CH3

N

CH3

O CH3

N

NH

S

O

CH3

O

MOL WT - 345 H2O

18

+

Stage:-3

CH3

N

CH3

O CH3

N

NH

S

O

CH3

O

omeprazole crude

MOL WT - 345

+NaoH

40

+CH3COONH2

sodium acetate

77

water

acetone

CH3

N

CH3

O CH3

N

NH

S

O

CH3

O

MOL WT - 345

omeprazole pure

+ + +H2O

18

CH3COONa

82

NH3

17

HCL

omeprazole crude

ANNEXURE-6


Flow chart :-

Reactor

Reactor

CHLORO COMP-340 kg

Macrapto como-275 kg

NaOH-122kg Water-500 kg

Stage-1-503 kg-

Reactor

Stage-2-527 kg

Centrifuge

Product-500 kg

Recover water -450 kg

NaCl salt-134 kg

Effluent -130 KG

NaOH- 67 kg


methnol-500 kg

H2O2-51 kg

Ammonium molybdate tetrahydrate-100 kg

Sodium acetate -117 kg

Water-500kg Recover catalyst -110 kg

acetone-500 kg

Recover methanol -450kg


Effluent -200KG


Ammonium acetate salt -131 KG


ANNEXURE-6



Charge of 2-chloromethyl-3,5-dimethyl-4-methoxy pyridine hcl (chloro

compound) is condensed with 2-mercapto-5-methoxy benzimidazole in (mercapto comp)

presence of sodium hydroxide as a base in aqueous in methanol to get sulfide comp.

sulfide comp is oxidized with hydrogen peroxide in the presence of ammonium molybadate tetra

hydrate as a catalyst to get omeprazole crude.

omeprazole crude is taken in water & sodium hydroxide solution is added to get omeprazole

sodium as clear solution. this solution is wash with MDC & filtered to remove insoluble solid .to

this filtrate , aqueous ammonium acetate solution is added drop wise to isolated omeprazole pure

obtain.

(79) ROS :- O DES VENLAFEXINE

N

OH

CH3

CH3

H3CO

HCL

Venlafaxine hydrochloride


MOL WT :- 313.86

DMF

NaH/C2H9SH

Acetic acid

N

OH

CH3

CH3

NaO

Sodium salt of O desmethyl Venlafaxine in-situ intermediate

MOL FOR :- C16H24NNaO2

HCL

Toluene

NaOH

N

OH

CH3

CH3

OH

O Desrnethylvenlafaxine


MOL WT :- 263.37

OMEPRAZOLE INPUT kg OUTPUT kg

CHLORO COMP 340 Recover of METHNOL 450

Macraptocomo 275 Product 500 NaOH 189 NaCL salt 134

Water 1000 Recover of water 942

Methanol 500 EFFLUENT 330

Ammonium

molybdatetetrahydrate

100 Ammonium acetate salt 131

H2O2 51 Recover of ACETONE 475

Sodium acetate 117 Recover catalyst 110

acetone 500

TOTAL 3072 3072

ANNEXURE-6



Stage :- 1

Venlafaxine hydrochloride is reaction in mixture of DMF with Sodium hydroxide and MTL with

Acetic acid then Separation filtration and the precipitated mass. The wet cake is furthert dried

and packed.

Stage :- 2

O Desmethyl Venlafaxine is dissolved in methanol and stirred to reflux and filter through

Hyflow. The methanol is distilled at atmospheric Pressure. The reaction mixture is Chilled

Crystallized and filtered. The wet cake obtained is dried.

ANNEXURE-6


Flow diagram :-

Reactor

Reactor

Centrifuge

Dry wt 551 kg

Venlafaxine HCL 640 kg

Ethanthial 50 kg + Acetic acid 100 kg

DMF 650 kg

Reactor

Centrifuge

Technical Dry wt

510 kg

Salt of 551 kg Toluene 1100 kg

Stage - l

Sodium hydroxide 44 kg

Recovery of DMF-600 kg

Efflucent-180 KG

Salt 150 kg

HCL 740 kg

Recovery of Toluene-1050 kg

Efflucent-800 KG

Reactor

Technical 510 kg Methanol 1000 kg

Heating

Reactor

Chilled

Centrifuge

Dry wt 500 kg

Recovery of Methanol-950 kg

Residue-50 kg

ANNEXURE-6


(80) ROS :- OLMESARTAN

O DES VENLAFEXINE

INPUT kg OUTPUT kg

Venlafaxine HCL 640 DMF 600

Ethanthial 50 Effluent 980

Acetic acid 100 Methanol 950

Sodium hydroxide 44 Salt 150

Dimethylformamide 650 Toluene 1050

Toluene 1100 Residue 50

Hydrochloric Acid 740 Product 500


TOTAL 4324 4324

ANNEXURE-6


O

CH3O

O

O

N

N

O

CH3

NH

N

N

N

CH3

OHCH3

+ O

CH3

+OH

Olmesartan medoxomil(Technical)


MOL WT :- 558.58

Triphenyl methyl ether

MOL FOR :- C20H18O

MOL WT :- 274.35

Tritanol

MOL FOR :- C19H16O

MOL WT :- 260.32

O

CH3O

O

O

N

N

O

CH3

NH

N

N

N

CH3

OHCH3

Olmesartan medoxomil


MOL WT :- 558.58


Stage :- 1

Detritylation of using methanol& hydrochloride acid gives OlmesartanMedoxomil(Technical).

Stage :- 2

Crystallization of OlmesartanMedoxomil(Technical) in acetone gives

OlmesartanMedoxomil.

ANNEXURE-6


Flow diagram :-

GLR

Centrifuge

Technical DRY

WT -510 KG

Olmesartan Medoxomil-540 kg

Triphenyl methyl ether-265 kg

Tritanol 260

Methanol -1000 kg

HCL-510

lit

Acetone-1000 kg

Recovry of Methanol -950 kg

efflucent -1000 kg

Reactor

Centrifuge

DRY WT -500 KG


Salt -100 kg

Salt -50 kg

Recovery of Acetone-950 kg

ANNEXURE-6


OLMESARTAN

INPUT kg OUTPUT kg

OlmesartanMedoxomil 540 Recovery of Methanol 950

Triphenyl methyl ether 265 effluent 1000

Tritanol 260 Salt 150

Methanol 1000 Recovery of Acetone 950

Hydrochloric Acid 510 PRODUCT 500

Acetone 1000 LOSS 25

TOTAL 3575 3575

(81) ROS :-Pitavastatin calcium

N

p

F

Ph

PhPh

.Br +CHO O

O O

CH3CH3

O

CH3

CH3

CH3

O

O O

CH3CH3

O

CH3

CH3

CH3N

CH3

CH3

F

O

O H OH O

CH3

CH3

CH3N

F

DMSO

Potassiume carbonate

Methanoloxalic Acid

Toluene

Sodiume carbonate

dichloro methane

NaoH

HCL

Calciume chloride

triphenyl(2-cyclopropyl-4-(fluophenyl)quinaoline-3-yl-m ethyl)phosphonium)br salt

MOL FOR :-C37H30NFBr

MOL W T :-585 gm /m ol

t-butyl-2-(4R,4S)-6-form yl-2-2-d imethyl-1-3-dioxan-4yl)acetate

MOL W T :-285.31 gm/mol

MOL FOR :-C13H22NO 5

Pitavastatin -t-butyl ester

MOL FOR :-C29H32NFO 4

MOL W T :-585 gm/mol

Pitavastatin calicum

MOL FOR :-C50H46CaN2F2O 8

FF

O

O H OH O

N

CaO HO HO

N

MOL W T :- 880.98 gm/mol

ANNEXURE-6


Flow diagram :-Pitavastatin calcium

Manufacturing Process :-Pitavastatin calcium

Triphenyl (2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-phosphonium bromide in DMSO added a

solution of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate in DMSO (. Heated the

Potassium carbonate -235 kg

Effluent-700 KG

Recovery of DMSO-950 kg & Reused

Oxalic ACID-354 KG +water-400 kg Step-I - 595 kg

sodium Carbonate -280 kg +

water-300 kg

Reactor

Centrifuge

Dry wt-541 kg

Toluene 500 kg

Pitavastatin tertiary butyl ester 541 kg

triphenyl(2-cyclopropyl-4-(4-fluorophenyl)quinoline-

3-yl)-phosphonium bromide -700 kg

tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-

1,3-dioxan-4-yl)acetate-310 kg

Dimethyl sulfoxide-1000 kg

Reactor

Centrifuge

Dry wt- 595kg

Reactor

Centrifuge

Reactor

Methanol-1100 k

Recovery of Methanol-1050 kg &

Reused Effluent-1450 kg

MDC 1000 kg

10 % HCL- 200 kg 10 %NaOH– 260 kg

Reactor

Centrifuge

Recovery of Toluene-450 kg & Reused

Dry wt-500 kg

Calcium chloride-150 KG+

Water-150 kg t-butyl ACETATE-500 kg

Recovery of MDC-950 kg& Reused

Recovery of solvent-450 kg& Reused

Effluent-900 kg

ANNEXURE-6


reaction mixture to 75° C. and added potassium carbonate to it. Stirred the reaction mixture for 7 hrs at

75° C. Cooled the reaction mixture to 25° C., added water and stirred for 90 min. Filter the solid

precipitated . To the solution of (4R,6S)-(E)-6-{2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-

2,2-dimethyl-[1,3]-dioxan-4-yl-acetic acid tertiary butyl ester in methanol added a solution of oxalic acid

in water . Stirred the reaction mixture for 6 hrs at 35° C. . Adjusted the pH to 7.0 by using sodium

carbonate solution . Filtered the solid and washed with water. Filtered the reaction mixture. To the wet

solid added toluene ( and stirred for 30 minutes at 75° C. Cooled the reaction mixture to 0° C. and stirred

for 3 hrs at same temperature. Filtered the solid and dry wt. pitavastatintert-butyl ester compound was

dissolved in of methanol and added aqueous sodium hydroxide solution . Stirred the reaction mixture for

90 minutes at 0° C. Distilled off the solvent completely from reaction mixture. To the obtained residue

added water. and washed it by using tert-butyl acetate. Added 160 ml of water to the reaction mixture and

adjusted the pH to 9.0 by using 10% NaOH solution. Then treated the reaction mixture with aqueous

calcium chloride solution . Then cooled the reaction mixture to 10°-15° C. and stirred overnight at the

same temperature. Filtered the solid precipitated, washed with water and dried the compound.

Pitavastatin calcium

INPUT kg OUTPUT kg

triphenyl(2-cyclopropyl-4-(4-

fluorophenyl)quinoline-3-yl)-

phosphonium bromide -

700 Effluent 3050

tert-butyl 2-((4R,6S)-6-formyl-2,2-

dimethyl-1,3-dioxan-4-yl)acetate- 310 Recovery of DMSO-950 950

Potassium carbonate 235 Recovery of Methanol-1050 1050

Dimethyl sulfoxide- 1000 Recovery of Toluene-450 450

Methanol- 1100 Recovery of MDC-950 950

Oxalic ACID 354 Recovery of solvent-450 450

sodium Carbonate 280 PRODUCT 500

water 850 LOSS 39

Toluene 500

MDC 1000

10 % HCL- 200

10 %NaOH 260

Calcium chloride 150

t-butyl ACETATE 500

TOTAL 7439 7439

ANNEXURE-6


(82) ROS :-Pinylperoic acid

COCH3

O

O

NaOCl

Sodium Hypochlorite

1,2-methylene dioxy Acetophenone

COOH

O

O

Pinylperoic acid


Charge Sodium Hypochlorite solution (8-9%) charge 1,2-methylene dioxyAcetophenone

at Room temp slowly temp increase up to 90-92� it is exothermic reaction maintain for 3 hour at to

90-92� cool to -20� adjust PH 3.0 with dil.HCL Centrifuge dry it.

FLOW CHART :-

ANNEXURE-6


INPUT kg OUTPUT kg

Sodium Hypochlorite (NaOCl) 5000 Distill water 3500

1,2-methylene dioxyAcetophenone 550 Effluent 2500

HCL 500 PRODUCT 500

Water 500 LOSS 50

TOTAL 6550 6550

(83) ROS :- PRAMIPEXOLE DIHYDROCHLORIDE

MONOHYDRATE

N

SNHCH3

NH2

methanol HCL . H2O

(6S)-N6-Propyl-4,5,6,7-tetrahydro

-1,3-benzothiazole-2,6-diamine

N

SNHCH3

NH2



2HCL . H2O

N

SNHCH3

NH2



2HCL . H 2O

dihydrochloride monohydrate

dihydrochloride monohydrate


Stage :- 1

Pramipexole (6S)-N6-Propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine is dissolved in

methanol and Charcoalized with Activated Charcoal. Reaction mass then filtered through hyflo

bed. pH of the reaction mass adjusted With Ethanolic HCL and maintained for crystallization.

Reaction mass is then filtered to get wet cake and this wet Cake is dried to get

PramipexoleDihydrochloride Monohydrate (6S)-N6-Propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-

2,6-diamine dihydrochloride monohydrate

Stage :- 2

ANNEXURE-6


PramipexoleDihydrochlorideMonohydrate(6S)-N6-Propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-

2,6-diamine dihydrochloride monohydrate is Purified in ethanol to get

PramipexoleDihydrochloride Monohydrate APl.

Flow diagram :-

PRAMIPEXOLE DIHYDROHLORIDE MONOHYDRATE

INPUT kg OUTPUT kg

(6S)-N6-Propyl-4,5,6,7-tetrahydro-

1,3-benzothiazole-2,6-diamine

370 Effluent 500

Methanol 2450 Recover of meoh 2350

Charcoal 40 Residue 90

HCL 250 PRODUCT 500

water 370 LOSS 40

Total 3480 3480

Reactor

Sparkler filter

Reactor

Centrifuge

(6S)-N6-Propyl-4,5,6,7-tetrahydro-1,3-

benzothiazole-2,6-diamine 370Kg

Methanol 700kg

Charcoal 40Kg

Methanol. HCL 1000kg

Dry Wt-510Kg

Reactor

Methanol 1000kg

Centrifuge

Dry wt- 500Kg

H2O 370kg

Recover of meoh 1400kg

Residue 50Kg Effluent500kg

Technical 510Kg

Recover Of Methanol 950kg

Residue 40Kg

ANNEXURE-6


(84) ROS :- PRASUGREL HYDROCHLORIDEManufacturing

Process :-

The hydrochloride is Prepared by dissolving 2-acetoxy-5-(�-cyclopropylcarbony1-2-

fluorobenzyl)-4,5,6,7-tetrahydro thieno[3,2-c]pyridine prasugrel in ethyl methyl ketone at 35-

40� followed by addition of IPA.HCL The solid obtained is filtered to yield 2-Acetoxy-5-(�-

cyclopropylcarbony1-2-fluorobenzyl)-4,5,6,7-tetrahydro thieno[3,2-c]pyridine hydrochloride

(Prasugrel hydrochloride) (APl).

Flow diagram :-

PRASUGREL HYDROCHLORIDE INPUT kg OUTPUT kg

2-acetoxy-5-(�-

cyclopropylcarbony1-2-

fluorobenzyl)-4,5,6,7-tetrahydro

thieno[3,2-c]pyridine

480 Recovery Of ethyl methyl ketone 950

Ethyl methyl ketone 1000 Recovery Of Ipa 950

IPA.HCL 1000 Salt 60

Product 500

loss 20

TOTAL 2480 2480

Reactor

Chilled 10°C

Centrifuge

2-acetoxy-5-(�-cyclopropylcarbony1-

2-fluorobenzyl)-4,5,6,7-tetrahydro

thieno[3,2-c]pyridine 480Kg

Ethyl methyl ketone 1000kg

IPA.HCL 1000kg

Recovery Of ethyl methyl ketone 950kg

Recovery OfIpa 950kg

Salt 60 kg

Reactor

Dry wt-500Kg

ANNEXURE-6


(85)Paroxitine HCL ROS :-

(-)trans carbinol

Mol FOR :- C13H18FNO


+


Mol FOR :- C6H11NO HCL

N

CH2OH

F

CH3

OH

OO

SO2CL2

NaoH

O

OO

N

F

CH3

O

OO

N

F

OPH

O

O

OO

NH

F

toluene

HCL

Paroxetine.HCL

Mol for :-C19H20FNO3.HCl

Mol wt:-365.5 gm/mole

Paroxetine.HCL

Mol for :-C19H20FNO3

Mol wt:-329.5 gm/mole

KOH

toluene

toluene

dimethylethylamine

DMFsodiume methoxide

sesamole

Mol FOR :- C19H16FNO3


Mol FOR :- C26H24FNO5


O

OO

NH

F

toluene

phenylchloroformate

ANNEXURE-6


Flow chart :-

Reactor

Reactor

(-)trans carbinol-355 KG

Benzenesulfphonyl chloride-250 KG

Dimethylethylamine -250kg

Toluene-500 kg

DMF- 500 lit

Centrifuge

Product-500kg

Recover DMF- 450 lit

Effluent -1044 KG

Sesamole-238 kg

Reactor

Reactor

toluene-500 kg Phenylchloroformate :-230kg

KOH-540kg

Con HCL-180kg

Toluene-500 kg

Recover Toluene- 1450 kg

SMO-1.0 kg


ANNEXURE-6



chargedToluene charged to a clean, dry and charge trans-(-)-4-(4'-fluorophenyl)-3-

hydroxymethyl-1 -methylpiperidine in Reactor. The vessel contents are cooled to 5 °C and

dimethylethylamine is added, and then a nitrogen purge is attached and the vessel contents

further cooled to 0UC. A mixture of benzenesulphonyl chloride and toluene added at 0C

.Charge N,N'-dimethylformamide is added. Charge solution of sesamol and sodium methoxide

in N,N'-dimethylformamide added over. Water wash &The combined toluene solutions are

distilled to give an anhydrous toluene solution of (-) trans 4-(4'-fluorophenyl)-3-(3',4'-

methylenedioxyphenoxymethyl)-l- methylpiperidine.Take product dissolved in toluene &chare a

solution of phenyl chloroformate in toluene s added dropwise with stirring under nitrogen, over

25 to 30 minutes. Water wash & distilled toluene to give an anhydrous toluene solution of (-)

trans 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy phenoxymethyl)-l-

phenoxycarbonylpiperidine.Charge potassium hydroxide & take product a solution in toluene

and the well stirred mixture is refluxed for 2 hours. &water wash. distilled toluene.& free base

obtain.Charge free base in toluene in Reactor and drop wise concentrated hydrochloric acid

addition in2-hrs.stirred for 2 hours at RT &centrifuge. Dry & packing

Paroxitine HCL INPUT kg OUTPUT kg

(-)trans carbinol 355 Recover of DMF

450

Dimethylethylamine 250 Dry Wt 500 Benzenesulfphonyl chloride 250 Recover of WATER 500 DMF 500 Recover of toluene 1450 Sodium methoxide (smo) 1.0 EFFLUENT 1044 Sesamole 238 loss 100

Phenylchloroformate 230

KOH 540

Con HCL 180

Toluene 1500

TOTAL 4044 4044

ANNEXURE-6


86) Pinavarium Bromide

ROS :-

MOL FOR : C17H310O2N

MOL WT - 281.43

MOL WT :- 529

DIHYDRONEPOL

MOL FOR : C9H16

MOL WT :- 124

+

MOL FOR : C6H12CLNO

MOL WT :- 186

IPANa2CO3

Acetone

Pinavarium bormide

Mol FOR :- C28H37CLN4O2S

4-(2-chloroethyl)morpholine

CH3

CH3 N

O

Cl

ONCH3

CH3 O

Br

ON+

CH3

CH3 O

OCH3OCH3

Br

Br

Br

H3CO OCH3

2-bromo veratyl bromide

ANNEXURE-6


Flow chart :-


Charge of dihydronepol, Isopropyl alcohol Sodium carbonate &4-(2-

chlroethyl)morpholinein reactor &. Heating to reflux. Maintain for 14-hrs at reflux

temp. filter reaction mass & distilled IPA. centrifuge& drying. Take product,2-

bromo-veratyl bromide& Acetone in reactor. Heating to reflux. Maintain for 14-hrs

at reflux temp. cool to RT & Chilled to 5-10 C for 1-hrs . centrifuge .drying &

Packing .

Reactor

Reactor

dihydronepol-124 kg

4-(2-chlroethyl)morpholine -186 kg

Na2CO3-340 kg IPA-1000 KG

Acetone-1000 KG

Reactor

Centrifuge

Product-500 kg

Recover IPA -950 KG

Recover Acetone-950 KG

2-bromo-veratyl bromide-

310 kg

Effluent -500 KG

ANNEXURE-6


(87)PIOGLITAZONE HYDROCHLORIDE

ROS :-

Pinavarium Bromide INPUT kg OUTPUT kg

dihydronepol 124 Recover of IPA 950

4-(2-chlroethyl)morpholine 186 Dry Wt 500

Na2co3 340 LOSS 60

IPA 1000 Recover of ACETONE 950

Acetone 1000 EFFLUENT 500

2-bromo-veratyl bromide 310

TOTAL 2960 2960

ANNEXURE-6


PG L-1

M O L W T - 242 .3

5-e thy l-2 -(2-(4-n itrophenox y)e thyl)py rid ine

E PN B

M O L W T :- 272 .3

hyd ro g en g as

M O L W T :- 2 .0

pa llad ium carbon

4-(2-(5-e thylpyrid in -2-y l)ethox yan illine

N

CH 3

O

NO 2

stage :-1

+ 3 H 2

N H 2

N

CH 3

O

2H 2 O

18+

sta ge-2N H 2

N

CH 3

O

4-(2-(5-e thylpy rid in-2-y l)e thox yan illine

P G L -1

M O L W T - 242 .3

N aN O 2 2H B r+ + +

O

CH 2

C H 3

Oso d ium n itra te

h ydrobrom ic a c idm ethy l acry la te

M O L W T - 69

M O L W T - 81

M O L W T - 86 .08

copp er oxide

N

CH 3

O

O

C H 3

O

B r

N aB rN 2 2 H 2 O

+ + +

so d ium n itra te W A T E RN itogen

m ethyl-2 -brom o-3-(4-(2-(5ethy lpy rid in-2-y l)e thox y)phenyl) p ropanoate

M O L W T - 392 .28

PG L-2

M O L W T - 1 03 M O L W T - 28 M O L W T - 18

C H 4

ANNEXURE-6


N

CH3

O

O

CH3

O

Br

methyl-2-bromo-3-(4-(2-(5ethylpyridin-2-yl)ethoxy)phenyl) propanoate

MOL WT - 392.28

PGL-2

Stage 3

+

S

NH2 NH2

+

ONaCH3

Othioureasodium acetate

MOL WT - 76.1 MOL WT - 82.03

N

CH3

O

S

NH

NH

O

NaBr CH3COOH CH3OH+ + +

Sodium bromide Acetic Acid methanol5-{4-{-(6-ethylpyridin-2-yl)ethoxy)ben zyl}-2-amino-13-thinzolidin-4-one

MOL WT - 355.4 MOLWT -103 MOL WT - 60 MOL WT - 32

PGL-3

N

CH3

O

S

NH

NH

O+

5-{4-{-(6-ethylpyridin-2-yl)ethoxy)ben zyl}-2-amino-13-thinzolidin-4-one

MOL WT - 355.4

PGL-3

2HCL + H20 + KHCO

MOLWT-36.46 MOLWT -18 MOLWT -100.11

N

CH3

O

S

NH

O

O


MOL WT - 355.4

NH4CL KCL

CO2

H2O+ + +

+

MOLWT -53.5 MOLWT -74.5 MOLWT -18

MOLWT -44PGL-4

Stage 4

ANNEXURE-6


Stage 4

N

CH3

O

S

NH

O

O


MOL WT - 356.4 PGL-4

DMF

N

CH3

O

S

NH

O

O


MOL WT - 356.4 PGL-5Stage 5

N

CH3

O

S

NH

O

O


MOL WT - 356.4

HCL+36.5

N

CH3

O

S

NH

O

O

HCL

MOL WT - 392.89

Pioglitazone hydrochloride

ANNEXURE-6


Flow chart :-

Reactor

Reactor

EPNB-347 KG palladium carbon-10 KG

-10 kg

Hydrogen gas- 6 kg

Stage-1-310 kg

Reactor

Stage-2 500kg

Reactor

Product-500 kg

Recover catalyst-13 kg

Effluent -40kg

Ammonium chloride -110

thiourea-97 kg

KCL-130 kg

Sodium nitrate-88 KG

-10 kg HBr-207 kg

Methyl acrylate-110

NaBr salt-131 KG

Effluent-84 KG

Sodium acetate-150 KG

-10 kg


Stage-3452kg

Con hcl-91 kg

KHCO3-127 kg

water-500 KG

Reactor

Stage-4454kg

Effluent 26 KG

DMF- 500 kg

Recover DMF- 475 kg Reactor

Stage-5445kg

Con HCL-1000kg

NaBr-131 KG RecoverAceticacid-114kg KG

Recover CH3OH-450kg KG

CENTRIFUGE Recover water-832 kg

Effluent 363 KG

Effluen-84 KG

TOTAL Effluent-697 KG

50% ethanol- 500 kg

Recover ethanol-250 kg

WATER- 500 kg

Recover water 450 kg

methano-500 kg Recover cuo salt-50 KG

CuO-50 kg

Effluent100 KG

ANNEXURE-6



5-ethyl-2-(2(4-nitrophenoxy)ethyl)pyridine (EPNB) is hydrogenated in presence of

palladium catalyst to produce PGL-1, which is further diazotized using sodium

nitrite solution in waterto get diazotized PGL-1. It is further reacted with HBR

&methyl acrylate in presence of copper oxide to get PGL-2.

PGL-2 is cyclized using thiourea& sodium acetate in methanol to give PGL-3(5-{4-

{-(6-ethylpyridin-2-yl)ethoxy)ben zyl}-2-amino-13-thinzolidin-4-one)

PGL-3 is reacted with HCL in water to give PGL-4 (5-{4-{-(6-ethylpyridin-2-

yl)ethoxy)ben zyl}-2-amino-13-thinzolidin-4-one).

PGL-4 is purified in DMF & water mixture to get PURE PIOGLITAZONE. PGL-5

PGL-5 is isolatetd as a HCL salt using con HCL IN ethanol & water mixture as a

solvent to give PIOGLITAZONE HYDROCHLORIDE .

PIOGLITAZONE HYDROCHLORIDE INPUT OUTPUT

EPNB 347 KG Recover catalyst 13 KG

Hydrogen gas 6 kg NaBr salt 262 kg

palladium carbon 10 KG Recover Acetic acid 114 kg

HBr 207 KG Recover CH3OH 450 kg

Methyl acrylate 110 KG Ammonium chloride salt 110 kg

Sodium nitrate 88 KG KCL SALT 130 kg

thiourea 97 KG Recover DMF 475 KG

Sodium acetate 150 KG Recover water 1732 KG

Con hcl 91 KG Effluent 697 KHCO3 127 PRODUCT 500 KG

water 1000

KG

Recover ethanol 250 kg

DMF 500 KG Recover copper oxide 50 kg

Con hcl 1000

KG

loss 10 kg

50 % ETHANOL 500 KG

methanol 500 kg

copper oxide 50 kg


ANNEXURE-6


(88) Quetiapine Fumarate

ROS :-

MOL WT - 247.74

Ketone deri.

MOL WT :- 227.28

pocl3

K2CO3

S

NH

O

S

NH

Cl

chloro compound

NH

NH

S

N

N

NH

piperzine dervi

MOL WT -349.50

OH

O Cl

Na2CO3

2-chloro ethoxy ethanol

OH

O

S

N

N

N

MOL WT - 385.99

quetiapine

OH

O

S

N

N

N

ETHANOL

furaric acid

O OH

OHO

quetiapine fumarate

MOL WT - 883.09

2

(153.33)

(172.71)

(124.57)

(115.11)

ANNEXURE-6


Flow chart :-

Reactor

Reactor

KETONE -150 kg

POCL3-110 kg

K2CO3-100kg

TOLUENE-500 KG

Piperazine -217 kg

kg

Reactor

2-chloroethoxyethanol-74 kg

Centrifuge

Product-500 kg

Con HCL –100 kg

Effluent -440 KG

Na2co3-90 kg

Recover ethanol- 450 kg

water-500 KG

DMSO- 25kg

toluene -500kg

ethanol – 250kg water -500 lit

water- 500kg

toluene -500 kg

Reactor

ethanol- 250kg Furamic acid- 70kg

Distilled POCL3-90 kg

Distilled toluene& reused-1400 kg

Distilled dmso-230kg

Recover piperazine - 100kg



ANNEXURE-6



Charge Dibenzo[Z\/][l,4]thiazepine-l l-(10H)one (keto compound), charge phosphorus

oxychloride& charge potassium carbonate at RT and heated to reflux at 1000C ± 5°C for 6 hours.

and the phosphorus oxychloride completely distilled. Charge Toluene& charge water layer

separation and toluene layer distilled out.& filter reaction mass. Toluene wash. dry it.

chargedDimethylsulfoxide , charged piperazine&charged toluene at RT under nitrogen and the

heated to 500C to 60

0C.. To it a solution of 11- chloro-dibenzo[Z\/]l,4]thiazepine (chloro

compound) in toluene at RT. and stirred for 3 hours at RT.& charge water . & toluene layer

separation. toluene layer distilled out. Take oil & charge Ethanol at RT Con HCL addition

&chilled 0-5 C. filter reaction mass. dry it.

Charge l-piperazinyl-dibenzo[Z\/][l,4]thiazepinedihydrochloride (piperazinedervi), Charge

sodium bicarbonate, Charge water , Charge 2-chloroethoxyethanol, Charge toluene . and heated

to reflux at 950C to 100

0C. After completion of the reaction & set ph-5.4 to5.5 bidilHCL .toluene

layer distilled out.

charge Ethanol & charged into the residue at RT. heated to 45°C to 500C. chargedFumaric

mixture. heated to reflux 800C and for 1-hrs. cool to RT & chilled 0-5 filter reaction mass. dry

it.

Quetiapine Fumarate INPUT kg OUTPUT kg

KETONE 150 Recover of TOLUENE 1400

POCL3 110 Dry Wt 500

Potassium carbonate 100 loss 51

TOLUENE 1500 Recover of water 1400

WATER 1500 Recover of Piperazine 100

Piperazine 217 Recover of DMSO 230

DMSO 250 Recover of Pocl3 90

Con HCL 100 Recover of ethanol 450 2-chloroethoxyethanol 74 EFFLUENT 440

Na2co3 90

Furamic acid 70

ethanol 500

TOTAL 4661 4661

ANNEXURE-6


(89) ROS :- RABEPRAZOLE SODIUM

N

O

OCH3

S

CH3

O N

NH

2-[{4-(3-methoxypropoxy)-3-methyl-pyridine-2-yl}methylsulfinyl]-1H-benzimidazole


MOL WT :- 359.4

N

O

OCH3

S

CH3

O N

NH

2-[{4-(3-methoxypropoxy)-3-methyl-pyridine-2-yl}methylsulfinyl]-1H-benzimidazole-1H-Sodium salt

MOL FOR :- C18H20N3O3SNa

MOL WT :- 381.4

NaOH

Sodium hydroxide

Methanol

Toluene

Ethyl acetate

Methy 1-butyl ether

+ H2O


Rabeprazolesulphoxide is reacted with sodium hydroxide in methanol to form rabeprazole

Sodium.

Flow diagram :-

Reactor

Centrifuge

Reactor

Rabeprazolesulphoxide 500Kg 405KgNaOH+600lit Water

Methanol 1000kg

Recovery OfMeoh 950kg

Toluene1000kg Technical 510Kg

Dry wt-510Kg

Centrifuge

Effluent 1030kg

Dry wt-500Kg

Recovery Of Toluene 950kg

ANNEXURE-6


RABEPRAZOLE SODIUM

INPUT kg OUTPUT kg

Rabeprazolesulphoxide 500 Recovery Of Meoh 950

NaOH 405 Effluent 1030

Water 600 Recovery Of Toluene 950


Toluene 1000 loss 75

TOTAL 3505 3505

(90)ROS :- RIVAROXABAN

O

N

O

O

NH2

O

N

O

HCL

4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one.HCL

MOL FOR :- C14H18N3O4Cl

MOL WT :- 327.8

SClO

OH

5-Chlorothiophene-2-Cacoxylic acid

Sodium Acetate

O

N

O

O

N

O

NHS

O

Cl

5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene-Carboxamide

MOL FOR :- C19H18ClN3O5S

MOL WT :- 435.8

+ CO2+ HCL

+ +NaCl CH3COOH

O

N

O

O

N

O

NHS

O

Cl

5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene-Carboxamide


MOL WT :- 435.8

O

N

O

O

N

O

NHS

O

Cl

Rivaroxaban


MOL WT :- 435.8

Acetic acid


Stage :- 1

5-Chlorothiophene-2-Carboxylchloride which is further reacted with 4-{4-[(5S)-5-

(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one.HCL in Presence of Sodium

acetate in Process Water / sulfolane to give 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-

morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene-Carboxamide

ANNEXURE-6


Stage :-2

5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-

thiophene-Carboxamide is Crystallized from Acetic acid to give Rivaroxaban.

Flow diagram :-

RIVAROXABAN

INPUT kg OUTPUT kg

4-{4-[(5S)-5-(aminomethyl)-2-

oxo-1,3-oxazolidin-3-

yl]phenyl}morpholin-3-one.HCL

405 Efflucent 1300


Carboxylchloride

225 Salt 200

Sodium Acetate 600 Acetic Acid 950


Acetic Acid 1000 Product 500

loss 50

TOTAL 3030 3030

Reactor

Centrifuge

Technical DRY

WT-515KG

Reactor

4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-

oxazolidin-3-yl]phenyl}morpholin-3-

one.HCL 405 kg


Carboxylchloride 225 kg

Sodium Acetate 600 Kg + Water 800 lit

Centrifuge

DRY wt-500kg

Residue-30kg

Acetic Acid-1000 kg

Technical wt: 515kg

Efflucent-1300 kg

Salt-200kg

Recovery ofAcetic Acid-950kg

ANNEXURE-6


(91) ROS :-ROPINIROLE HYDROCHLORIDE


(2-nitro-6-(N,N-di-n-prethyl)phenyl)acitic acid HCL in presence of 10%palladium on cabon

using D solvent givesRopinirole HCL tech acid base purifaction of ropinirole HCL tech using

ethylacetate/sodiumbicarbonte/ethanolic HCL gives RopiniroleHaydrochloride

CH 3

N

CH 3

NO 2

O

O H

HCL

CH 3

N

CH 3

NH

O

HCL10% pd/c, M ethanol

E thanol H 2

M ethylene chloride

Triethylam im e

Ethanolic HCL

Ethyl-2-nitro-6-(N ,N-di-n-propylam ino)ethylphenyl)acetic acid hydrochloride

M O L FO R :- C16H 24N2O 4 H CL

M O L W T :- 344.84

M O L W T :-296.84

Ropinirole hydrohchloride

M O L FO R :- C16H24N2O .H CL

CH 3

N

CH 3

NH

O

HCL

M O L W T :-296.84


M O L FO R :- C 16H24N 2O .H CL

CH3

N

CH3

NH

O

HCL

M O L W T :-296.84


M O L FO R :- C 16H24N 2O .H C L

Purif ication

M ix ture of E thyl Acetate & Ethanol* E thanolic HCL,E thyl acetate

ANNEXURE-6


Flow diagram :-

Reactor

Sparkler filter

Reactor

Reactor

Ethyl-2-nitro-6-(N,N-di-n-

propylaminoethylphenyl)acetic acid.HCL-625kg

Methanol 1250kg

10% Pdc-65kg

Centrifuge

Technical Dry

wt-510kg

Efflucent-300kg

Reactor

Centrifuge

Residue-60kg

Recovery of Methanol 1200kg

Triethyl amine-185 KG MDC-1000 kg

Technical 510Kg

Recover Of Ethyl acetate 950kg

Residue 40Kg

10% Pdc-60kg Reused

Recovery Of MDC- 950kg

Ethyl acetate- 1000kg

Dry wt-500kg

ANNEXURE-6


ROPINIROLE HYDROCHLORIDE INPUT kg OUTPUT kg

Ethyl-2-nitro-6-(N,N-di-n-

propylaminoethylphenyl)acetic

acid.HCL

625 10% Pdc-60kg Reused

60

Methanol 1250 Recovery of Methanol 1200

10% Pdc 65 Residue 100

MDC 1000 MDC 950

Triethyl amine 185 Effluent 300

Ethyl acetate 1000 Ethyl acetate 950

Product 500

loss 65

TOTAL 4125 4125

(92) Resperidone

ROS :-

MOL WT - 410

6-fluoro-3-(4-piperidinyl 1,2 benzisooxazole

MOL WT :- 220 MOL WT :- 226

NH

N O

F

+ N

N

OCl

CH3N

N

O

CH3

N

N O

F

RISPERIDONE

K2CO3

DMF3-(2-chloroethyl-6,7,8,9-tetrahydro-2-methyl-4h-pyrido(1,2.a)pyridimidine 4-one

ANNEXURE-6


Flow chart :-


Charge of 6-fluoro-3-(4-piperidinyl1,2 benzisooxazole,DMF, potassium

carbonate &3-(2-chloroethyl-6,7,8,9-tetrahydro-2-methyl-4h-pyrido(1,2.a)pyridimidine 4-one

in reactor. Heating to reflux. Maintain for 12-hrs at reflux temp. filter reaction

mass . Tak cool to RT& chilled 0-10C For 1-hrs maintain. centrifuge& drying..

Resperidone INPUT kg OUTPUT kg

6-fluoro-3-(4-piperidinyl1,2

benzisooxazole

268 Recover of DMF 975

3-(2-chloroethyl-6,7,8,9-tetrahydro-2-

methyl-4h-pyrido(1,2.a)pyridimidine

4-one

275 Product 500

potassium carbonate 358 EFFLUENT 426

DMF 1000

TOTAL 1901 1901

Reactor

6-fluoro-3-(4-piperidinyl1,2 benzisooxazole-268 KG

3-(2-chloroethyl-6,7,8,9-tetrahydro-2-methyl-4h-pyrido(1,2.a)pyridimidine 4-one-275

K2CO3-358kg DMF-1000 kg

Centrifuge

Product-500 kg

Recover DMF -975 kg

Effluent -426 KG

Reactor

ANNEXURE-6


(93) Sertraline Hydrochloride

ROS :-

MOL WT - 320MOL WT :- 291

O

ClCl

+ CH3NH2

N

ClCl

CH3

Pd/Baso4

NHCH3

ClCl

NHCH3

ClCl

H OH

COOH

NaoH

NHCH3

ClCl

H

NHCH3

ClCl

H

HCLHCL

sertraline HCLcis (+)sertraline base

(+/-)sertraline base

MOL WT :- 306

MOL WT :- 306

MOL WT :- 342

cis(+) sertraline mandelate

MOL WT :- 458

sertralone ketamine

MOL WT :- 31

ANNEXURE-6


Flow chart :-

Reactor

Reactor

Setralone-425 kg mono methylamine -50 kg

Pb/BaSO4-50 KG

Water-500 kg

Methanol-500kg

Reactor

ethyl acetate-500 kg

Centrifuge

Product-500 kg

RecoverPb/BaSO4 – 60 kg


Effluent - 500KG

10 % NAOH-500 kg

Recover ethyl acetate- 475kg

Hyrogen -4 kg

D-(-)-Mandelic acid -225 kg

Reactor HCL-100 kg

Acetonitrile- 1000 kg


Recover acetonitrile- 950 kg

ANNEXURE-6



setralone, aqueous mono methylamine solution in reactor. The mixture is heated to 75-900C

under stirring for 40 hours,cooled to 20-250C, filtered, washed with water to ketamine obtain.

Charge ketamine in methanol is hydrogenated in the presence of catalyst Pd/BaSO4 at rt and at

a pressure of 4 kg for 8 hours. filtration through bed, washed thee with methanol. Distilled

methanol to sertraline base obtain.sertraline base reacted The ethyl acetate solution is treated

with D-(-)-Mandelicacid .cool to RT & filtrate mass to obtain cis (+)sertraline mandelate salt

obtain. cismandelate salt in ethyl acetate & charge 10% NaOH solution &ethyl acetate distilled

out to obtain cis(+) sertraline free base. The cis (+) sertraline free base & charge acetonitrile

.HCL gas purging at 20-25C and hydrogen chloride is bubbled through the solution at 25-27°C.

During the addition of HCl, the temperature of the reaction mixture raises form 25 to 250C.

chilled to 10C.filtrate. dry& packing.

Sertraline Hydrochloride INPUT kg OUTPUT kg

Setralone 425 Recover of ETHYL ACETATE 475

mono methylamine 50 Product 500

Water 500 Recover of Methnol 475

ETHYL ACETATE 500 Recover of water 850

Methanol 500 EFFlUENT 500

Hyrogen 4.0 Recover of acetonirile 950 Pb/BaSO4 50 Recover Pb/Baso4 60

D-(-)-Mandelic acid 225 Loss 44 10 % NAOH 500 Acetonitrile 1000 HCL 100

TOTAL 3854 3854

ANNEXURE-6


(94) 1-[3-(benzyloxy)propyl]-5-formylindoline-7-Carbonitrile

ROS :-

N

O

C6H5

CHO

Br

1-[3-(benzyloxy)propyl]-7-bromoindoline-5-Carbaldehyde

MF:-C19H20BrNO2

FW:-374.271

CuCN

dimetylformamide

N

O

C6H5

CHO

CN

+ CuBr

MF:-C20H20N2O2

FW:-320.385

1-[3-(benzyloxy)propyl]-5-formylindoline-7-Carbonitrile


Reaction of 1-[3-(benzyloxy)propyl]-7-bromoindoline-5-Carbaldehyde(brom.indo) with

copper(I)cyanide in dimetylformamide ,further upon work up will give crude 1-[3-

(benzyloxy)propyl]-5-formylindoline-5-Carbonitrile (cyano aldehyde). Finally purification of

crude will give pure 1-[3-(benzyloxy)propyl]-5-formylindoline-7-Carbonitrile (cyano aldehyde)

ANNEXURE-6


Flow diagram :-

1-[3-(benzyloxy)propyl]-5-formylindoline-7-Carbonitrile

INPUT kg OUTPUT kg

1-[3-(benzyloxy)propyl]-7-

bromoindoline-5-Carbaldehyde

625 Effluent 300

DMF 1000 Recovery of DMF 950

Coppercyanide 150

Methanol 1000 Recovery of Methanol 950

Residue 40

Product 500

loss 35

TOTAL 2775 2775

Reactor

Centrifuge

Technical Dry wt

510 kg

1-[3-(benzyloxy)propyl]-7-

bromoindoline-5-Carbaldehyde 625 kg

DMF 1000 kg

Reactor

Centrifuge

Technical 510 kg Methanol 1000 kg

Copper cyanide 150 kg

Recovery of DMF-950 kg

Effluent-300 kg


Residue 40 kg

Dry wt 500 kg

ANNEXURE-6


(95 )ROS :- SOLIFENACIN SUCCINATE

N

CN

O

H5C6

NH

CH3

O

O

CF3

(1-[3-(Benzyloxy)propyl]-5-{(2R)-2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl]indoline-7-Carbonitrile Oxalate

OHO

OHO

N

CN

O

H5C6

NH

CH3

O

O

CF3

(1-[3-(Benzyloxy)propyl]-5-{(2R)-2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl]indoline-7-Carbonitrile

+

ONaO

ONaO

+ +CO2H2O

MOL FOR :- C34H38F3N3O7

MOL WT :- 657.67


MOL WT :- 567.64

Na2CO3

MOL FOR :- C2HNa2O4

MOL WT :- 134

MOL FOR :- CO2

MOL WT :- 44MOL FOR :- H2O

MOL WT :- 18

N

CN

O

H5C6

NH

CH3

O

O

CF3

+ H2ON

CONH2

O

H5C6

NH

CH3

O

O

CF3

+ O2 + 2H2O

(1-[3-(Benzyloxy)propyl]-5-{(2R)-2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl]indoline-7-Carbonitrile


MOL WT :- 567.64

1-[3-(benzyloxy)propyl]-5-{(2R)-2-({2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl]indoline-7-Carboxamide)

Benzyl silodosin


MOL WT :- 585.65

2H2O2.DMSO

NaOH


(1-[3-(Benzyloxy)propyl]-5-{(2R)-2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl]indoline-7-

Carbonitrile Oxalate is Converted to Free base, Which Oxidized to 1-[3-(benzyloxy)propyl]-5-{(2R)-2-

({2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl]indoline-7-Carboxamide) (Benzyl Silodosin) in

Presence of Hydrogen Peroxide and Dimethylsulphoxide.

ANNEXURE-6


Flow diagram :-

SOLIFENACIN SUCCINATE INPUT kg OUTPUT kg

(1-[3-(Benzyloxy)propyl]-5-{(2R)-

2-[2-(2,2,2-

trifluoroethoxy)phenoxy]ethyl}amin

o)propyl]indoline-7-Carbonitrile

Oxalate

595 Effluent 1000

Sodium bicarbonate 106 DMSO 950

Hydrogen Peroxide 582 Product 500

Dimethyl sulfoxide 1000 loss 33

water 200

TOTAL 2483 2483

Reactor

Centrifuge

Free Base -485 kg

(1-[3-(Benzyloxy)propyl]-5-{(2R)-2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyl]indoline-7-Carbonitrile Oxalate -595 kg

Sodium bicarbonate 106 kg

+ Water -200 lit

Dimethyl sulfoxide-1000 kg

Effluent- 400 kg

Reactor

Hydrogen peroxide – 582 kg Free Base 485 kg

Centrifuge

Dry wt 500 kg

Recovery of DMSO - 950 kg

Effluent- 600 kg

Total Effluent- 1000kg

ANNEXURE-6


(96) ROS :-dimethyl formamide di-tert- butyl Acetal

CH3

N

CH3

CHO + CH3 O S

O

O

O

CH3N, N Di-methyl formamide

MOL FOR :- C3H7NO

MOL WT :- 73 gm/mole

Dimethyl sulfate

MOL FOR :- C2H6O4S

MOL WT :- 126 gm/mol

CH3

N

CH3

CHO CH3 O S

O

O

O

CH3

.

DMF.DMS Complex

MOL FOR :- C2H6O4S


Step :-1

CH3

N

CH3

CHO CH3 O S

O

O

O

CH3

.

DMF.DMS Complex

MOL FOR :- C2H6O4S


+

CH3CH3

CH3

OK

Potassium-tert -butoxide

MOL FOR :- C4H9OK

MOL WT :- 112.21 gm/mole

tert-Butanol

CH3

CH3

CH3

O O

CH3

CH3

CH3

N

CH3CH3

dimethyl formamide di-tert- butyl Acetal

MOL FOR :- C11H25O2 N

MOL WT :- 203.52 gm/mole

Step :-2


Take DMF in Rector and drop wise addition DMS for 3-hrs at RT. Heating to 85 ˚C.

Maintaining for 3 hours at 85 ˚C.Cool to RT.

Take t-butanol and Potassium tert- buoxide U/N 2 .Heating to 65-70 ˚C for 30 min.

drop wise addition DMF-DMS complex for 3-hrs at 30-35 ˚C for 3 hours U/N 2.stirr for 30 min.

Heating to reflux 80-85 ˚C. Maintaining for 40 hours at 80-85 ˚C.cool to RT.Filter the rxm . bed

wash with t-butanol. Fractional distillation.t-butanol reused.

ANNEXURE-6


Flow diagram :-

dimethyl formamide di-tert- butyl Acetal

INPUT kg OUTPUT kg

N,N Dimethtylformimade 203 Recover Of t-butanol 1450

Dimethyl sulfate 350 Residue 20

t-butanol 1500 SALT 400

Potassium tert- buoxide 320 Product 500

loss 3

TOTAL 2373 2373

N,NDimethtyl formimade-203 KG Dimethyl sulfate-350 kg

Reactor

Reactor

DMF- DMS

Complex- 553 kg

Reactor

Reactor

Centrifuge

SALT-400kg

Reactor

Product- 500kg

DMF-DMS Complex-553 kg t-butanol-1500 kg

Recover Of t-butanol- 1450 kg reused

Residue 20Kg

Potassium tert-

buoxide- 320 kg

ANNEXURE-6


(97)ROS :- TADALAFIL

N

NH

OCH3

O

O

O

Cl

O

+ CH3 NH2

N

NH

NCH3

O

O

O

OMethanol/Hyflo

(1R,3R)-methyl-1,2,3,4-tetrahydro-2-chloroacetyl-1-(3,4-metylenedioxyphenyl)-9H-pyrido[Chloroacetyl intermediate]


MOL WT :- 426.85

Methylamine

MOL FOR :- CH5N

MOL WT :- 31.06

Tadalafil Crude


MOL WT :- 389.40

N

NH

NCH3

O

O

O

O

Tadalafil Crude


MOL WT :- 389.40

N

NH

NCH3

O

O

O

O

Tadalafil Crude


MOL WT :- 389.40

Methanol / Dichloromethane

Isopropanol / Activated carbon / Hyflo


Stage :- 1 :- Preparation of Tadalafil Crude

CisCarboline reacts with Chloroacetyl Chloride Presence of Sodium bicarbonate and

dichloromethane to form Corresponding ChloroacetylCarboline derivative, Which reacts with

methylamine and Undergoes Cyclisation reaction in methanol medium to yield Tadalafil Crude.

Stage :- 2 :- Purification of Tadalafil

Tadalafil Crude is dissolved in a mixture of Methanol and Dichloromethane and further purified

in Isopropyl alcohol to yield pure Tadalafil.

ANNEXURE-6


Flow diagram :-

Reactor

Sparkler Filter

Reactor

CentrifugeCentr

KSM 590 kg

Methanol 1200 kg

Methyl Amine 45 kg

Reactor

Sparkler Filter

Technical 510 kg IPA 1000 kg

Carbon 50 kg

Recovery of IPA-950 kg

Carbon 80 kg

Technical 510 kg


Efflucent- 160 kg

Centrifuge

Reactor

Chilled

Dry wt 500 kg

ANNEXURE-6


TADALAFIL

INPUT kg OUTPUT kg

KSM 590 Methanol 1150


Methyl Amine 45 IPA 1000

IPA 1000 Carbon 80

Carbon 50 Product 500

loss 5

TOTAL 2885 2885

(98) ROS :- TICAGRELOR

NO

N

N

N

N

S

CH3

O O

CH3

CH3

OHNH

F

F

Conc.HCL

Methanol

Ethylacetate

Cyclohexane

NO

N

N

N

N

S

CH3

OH OH

OHNH

F

F

Ticagrelor


This is reacted with Conc. HCL and methanol to get the title Compound Ticagrelor.

ANNEXURE-6


Flow diagram :-

TICAGRELOR

INPUT kg OUTPUT kg

KSM 495 Methanol 950


Con. HCL 470 Cyclohexane 950

Cyclohexane 1000 Product 500

loss 15

TOTAL 2965 2965

Reactor

Centrifuge

Technical

Drywt 510 kg

KSM 495 kg

Methanol 1000 kg

Con. HCL 470 kg

Reactor

Technical 510 kg Cyclohexane 1000 lit

Recovery of Cyclohexane -950 lit

Effluent-50 kg


Effluent- 500 kg

Centrifuge

Dry wt 500 kg

ANNEXURE-6


(99) Topiramate

ROS :-

O O

CH 2OH

O

O

O

CH3

CH3

CH3CH3

2,3:4,5-bis-o-(1-methyl ethyl idene)

B-D-fructopyranose(pure)

MOL F:- C12H20O6

MOL W t:- 260.28 gm/mole

Topiramate(Technical)

MOL F:- C12H21NO8S

MOL W t:- 339.36gm/mole

SO

ONH2

O O

O

O

O

CH3

CH3

CH3CH3

O

O-Xylene

Sulfuryl chloride

Pyridine

Ammonia

Tetrahydrofuran

n-Hexane

Flow chart :-

Reactor

Reactor

BME-DFP-500kg O-Xylene-1000 kg

Pyridine-214 kg

kg

Sulfuryl chloride-348 kg

Terahydrofuran-1000 kg Ammonia gas- 50 kg

Reactor

Disitillation Terahydrofuran-500 kg

n-Hexane-3000

lit

Centrifuge

Product-500 kg

Recover o-xylene- 950 kg

Recover THF- 1450 kg

Recover n-hexane-2850 kg

Water-1000 kg


Effluent -850 KG

ANNEXURE-6



Charge of o-xylene in reactor & charge sulfuryl chloride at 20 0C. Chill

below -10 to -5 0C, slow addition of solution A (2,3:4,5-BIS-O-[1-Methyl Ethyl

idene]B-D-Fructopyranose+ O-Xylene + Pyridine )for 3-4 hours at -10 to -5 0C.

stir for 2 hours .Check TLC .TLC O.K Water wash. Take Organic mass charged in

Reactor & charged Tetrahydrofuran . Ammonia gas pass and set Ph-9 to10. Stir

for 3-hrs at 35-400C. Check TLC .TLC O.K Water wash. Distilled out

Terahydrofuran& O-xylene .Charge Terahydrofuran and Charge n-hexane the

products obtain &. Chilled 5-10 0C and centrifuge .drying.

Topiramate INPUT kg OUTPUT kg

BME-DFP

500 Recover of O-XYLENE

950

O-xylene 1000 Dry Wt 500

sulfuryl chloride 348 loss 62

Pyridine 214 Recover of THF

1450

THF 1500 Recover of N-HEXANE

2850

WATER 1000 Recover of WATER

950

Ammonia gas 50 EFFLUENT 850

n-hexane 3000

TOTAL 7612 7612

ANNEXURE-6


(100) ROS :- VILAZODONE HYDROCHLORIDE

NH

CN

N

N

O

NH2

O

+ Conc.HCL Formic acid


MOL WT :- 441.52

NH

CN

N

N

O

NH2

O


MOL WT :- 477.98

HCL


The hydrochloride formation and amorphous form Conversion done in formic acid and

Conc. HCL using spray dryer.

Flow diagram :-

VILAZODONE HYDROCHLORIDE

INPUT kg OUTPUT kg

KSM 485 Efflucent 750

Con. HCL 45 Salt 70

Formic Acid 800 Product 500

loss 10

TOTAL 1330 1330

Reactor

Centrifuge

Dry wt 500 kg

KSM 485 kg

Con. HCL 45 kg

Salt 70 kg

Effluent- 750 kg

Formic Acid 800 kg

ANNEXURE-6


(101) ROS :- VALSARTAN

NH

N

N

N

N

CH3

CH3

CH3

O

OHO

Ca++

NH

N

N

N

N

CH3

CH3

CH3

O

OHO

HCL, Ethyl Acetate

DIPE

Calcium Valsartan Valsartan


Valsartan Calcium salt is treated with hydrochloric acid in ethyl acetate and Water. The ethyl

acetate layer is treated with diisopropyl ether to obtain the pure Valsartan.

Flow diagram :-

Reactor

Centrifuge

Technical

Drywt 510 kg

Calcium Valsartan 580 kg

HCL 710 lit

Reactor

Technical 510 kg Di isopropyl ether 1000 kg

Recovery of Di isopropyl ether -950 kg

Salt 40 kg

Recovery of Ethyl Acetate -1150 kg

Efflucent- 830 kg

Centrifuge

Dry wt 500 kg

Ethyl Acetate 1200 kg

ANNEXURE-6


VALSARTAN

INPUT kg OUTPUT kg

Calcium Valsartan 580 Ethyl Acetate 1150

HCL 710 Effluent 830

Ethyl Acetate 1200 Di isopropyl ether 950

Di isopropyl ether 1000 Salt 40

Product 500

loss 20

TOTAL 3490 3490

(102) ROS :- VORTIOXETINE HYDROBROMIDE

N

N

OO

BOC

S

CH3

CH3

Borane DMS

THF

HCL

tert-butyl-4-{2-[(2,4-dimethylphenyl)sulfanyl]phenyl}-3,5-dioxopiperazine-1-Carboxylate.

N

NH

S

CH3

CH3

HBr

N

NH

S

CH3

CH3

.HBr

Vortioxetine Base


The resulting aniline derivative is convert in 3,5diketopiperazine using N-

butyloxycarbonyliminodiacetic acid. The 3,5-diketopiperazine derivative reduce with borane to

gives Corresponding BOC Protected Piperazine ,which was deprotected to piperazine in situ then

salt formed with hydrobromic acid and gives VortioxetineHydrobromide.

ANNEXURE-6


Flow diagram :-

VORTIOXETINE HYDROBROMIDE

INPUT kg OUTPUT kg

Tert-butyl-4-{2-[(2,4-

dimethylphenyl)sulfanyl]phenyl}-

3,5-dioxopiperazine-1-

Carboxylate

735 THF 950

Borane DMS 925 Effluent 3200

THF 1000 Salt 270

HCL 1500 Product 500

HBr

800 loss 40

TOTAL 4960 4960

Reactor

Centrifuge

Base Dry wt 410 kg

Tert-butyl-4-{2-[(2,4-

dimethylphenyl)sulfanyl]phenyl

}-3,5-dioxopiperazine-1-

Carboxylate 735 kg

Borane DMS 925 kg

Recover of THF 950 kg

THF 1000 kg

HCL 1500 kg

Effluent- 2500 kg

Salt 270 kg

Reactor

HBr 800 kg Vortioxetine Base 410 kg

Centrifuge

Dry wt 500 kg

Effluent- 700 kg

ANNEXURE-6


(103) ROS :- VEMURAFINIB

N NH

Br

O

NH

F

F

SO

O

CH3

N-{3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)Carbonyl]-2,4-diflorophenyl}propane-1-Sulfonamide

Acetonitrile

Pd(PPh3)4, K2CO3

N NH

O

NH

F

F

SO

O

CH3

Cl

Cl

B

OH

OH

Vemurafenib


VemurafenibN-{3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)Carbonyl]-2,4-

diflorophenyl}propane-1-Sulfonamide is reacted with 4-Chlorophenylboronic acid in Presence of

Potassium Carbonate and Tetrakistriphenylphosphine palladium in acetonitrile gives pure

Vemurafenib.

Flow diagram :-

GLR

Sparkler Filter

Centrifuge

N-{3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-

yl)Carbonyl]-2,4-diflorophenyl}propane-1-

Sulfonamide - 490 kg

4-Chlorophenylboronic acid – 170 kg

Tetrakistriphenylphosphinep

alladium - 230 kg

Acetonitrile-1000 kg

Recovery of Acetonitrile -950 kg

Effluen 215kg

DRY WT -500 KG

Catalyst -200 kg reused

Total effluent - 250 kg

ANNEXURE-6


(104) ROS :-Warfarin Sodium Clatharte

O

OH

O

CH3

O

IPA

Water / NaOH

Warfarin Acid

MOL FOR :- C19H16O4

MOL WT :- 308.33

O

O

O

CH3

ONa+

Warfarin Sodium Clatharte

MOL FOR :- (C19H15NaO4)2.C3H8O

MOL WT :- 720.72

OH

CH3

CH3

+ H2O


Warfarin Sodium is formed by reaction with Sodium hydroxide in a mix of methanol and

isopropyl alcohol at 20-25� .

VEMURAFINIB

INPUT kg OUTPUT kg

N-{3-[(5-Bromo-1H-

Pyrrolo[2,3-B]Pyridin-3-

Yl)Carbonyl]-2,4-

Diflorophenyl}Propane-1-

Sulfonamide

490 Catalyst 200

4-Chlorophenylboronic Acid 170 Acetonitrile 950

TetrakisTriphenylphosphine

Palladium

230 Effluent 215

Acetonitrile 1000 Product 500

Loss 25

Total 1890 1890

ANNEXURE-6


Flow diagram :-

Warfarin

INPUT kg OUTPUT kg

Warfarin Acid 220 effluent 300

IPA 60 Product 500


Water 300

TOTAL 820 820

(105) ZIPRASIDONE HCl

ROS :-

MOL FOR : C21H21CLN4OS

MOL WT - 412.93

N

S

N

NH


thiazole hydrochloride


MOL WT :- 255.5

+

MOL FOR : C19H9cl2NO

MOL WT :- 230

6-chloro-5-(2-chloroethyl)

oxidole

HCLNH

O

Cl

Clwater

Na2CO3

IPA

con HCL

O

NS

NN

Cl

NH

HCL

ZIPRASIDRON HCL

Reactor

Centrifuge

Dry wt 500 kg

Warfarin Acid 220 kg

IPA 60 KG

Effluent- 300 kg

Methanol 240 kg+ Water 300 lit

ANNEXURE-6


Flow chart :-


Charge of 3-(1-Plperazinyl)-1,2-benzisothiazolehydrochloride, Water

sodium carbonate &6-Chloro-5-(2-chloroethyl) oxidole in reactor. Heating to

reflux. Maintain for 28-hrs at reflux temp. filter reaction mass . Take product and

charge IPA Heating to 50C for 1hrs. cool to RT& chilled 0-10C For 1-hrs

maintain. centrifuge& drying. Take product,,water& con HCL in reactor. Heating

to 60-65C. Maintain for 14-hrs at 60-65C. cool to RT& chilled 0-10C For 1-hrs

maintain. centrifuge& drying Packing.

Reactor

Reactor


Thiazole HCL -315 kg

6-Chloro-5-(2-chloroethyl) oxidole-256 kg

Na2CO3-358kg Water-1000 KG

IPA-500kg

Reactor

WATER-500 kg

Centrifuge

Product-500 kg

Recover IPA -450 kg


Effluent -970 KG

HCL-1000 kg


ANNEXURE-6


ZIPRASIDONE HCL INPUT kg OUTPUT kg


Thiazole HCL

315 Recover of IPA 450

6-Chloro-5-(2-chloroethyl)

oxidole

256 Dry Wt 500

sodium carbonate 358 SOLVENT loss 59


WATER 1500 EFFLCENT 970

CON HCL 1000


ANNEXURE-7


EXISTING DETAIL OF EFFLUENT TREATMENT PLANT

Existing ETP Description –

Raw water from the plant has been collected in settling tank and then collected in

collection tank-. This collected effluent is then neutralizing by dil.H2SO4 0r Caustic

Lye in neutralization tank. Than we are providing chemical treatment in the

neutralization tank where neutralized effluent will be treated with Hydrogen Peroxide

and sodium hypo chloride after this primary treatment treated effluent pumped to

storage tank. From there it is sent to CETP of ETL for further treatment and final

disposal.

EQUIPMENT LIST OF ETP

Sr.

No.

Name of unit Qty. Capacity MOC

1. Collection Tank 1 330 cm *140 cm *147 cm ACID PROOF BRICK

2. Neutralization Tank 1 237 cm *216 cm *214 cm ACID PROOF BRICK

3. Storage Tank 1 15 Kl MS

EXISTING ETP DIAGRAM

TO ETL

Storage Tank

Settling Tank

Collection Tank

Neutralization

Tank

Raw

Effluent

From Plant

ANNEXURE-7


PROPOSED ETP DESCRPTION

Raw water from Plant-C & D has been collected in collection tank-1 through Settling

trap then it is transfer throw pump to collection tank-2 for Neutralization with

Caustic Soda/Sulphuric acid after neutralization it is transfer to final tank or for

chemical treatment tank throw filter where Stage –I chemical treatment is given for

bringing down the organic load by sodium Hypo Chloride and then transferred to

tank -4 where Second Stage Chemical Treatment given by Hydrogen Peroxide &

Ferrous Sulphate after second stage chemical treatment it is transfer to final treated

effluent tank throw filter & this final treated Effluent send to CETP of ETL and

ACPTCL for Further Treatment and final disposal.

EQUIPMENT LIST OF ETP

Sr.

No.

Name of unit Qty. Capacity MOC

1. Primary collection tank 1 6.OKL ACID PROOF BRICK

2. Neutralization tank 1 15 KL ACID PROOF BRICK

3. Final tank 1 15 KL MS

4. Common mee tank 1 12KL PPFRP

5. Chemical treatment tank-I 1 12 KL HDPE

6. Chemical treatment tank-II 1 12 KL HDPE

ANNEXURE-7


ANNEXURE-8


DETAILS OF WATER CONSUMPTION

Sr.

No

Particulars Existing Water

Consumption

CCA-H-84112

(KL/Day)

Proposed Water

Consumption KL/Day

(As per proposed

expansion)

Total

Water Consumption

KL/Day

1. Domestic 2 3 5

2. Gardening / Other use -- 11.5 11.5

INDUSTRIAL WATER CONSUMPTION

3. Process 4 16 20

4. Boiler 1 1.5 2.5

5. Cooling 1 14 15

6. Equip. & Floor Washing -- 1 1

Total (Industrial) 6 32.5 38.5

TOTAL

(Domestic + Industrial

+Gardening)

8 47 55

DETAILS OF WASTE WATER GENERATION

Sr.

No.

Particulars Existing Waste

Water Generation

CCA-H-84112

KL/Day

Proposed Waste

water

Generation

KL/Day

Total Waste Water

Generation after

expansion KL/Day

1. Domestic 2 3 5

2. Industrial

Process 3.75 8.25 12

Boiler 0.15 1.85 2

Cooling 0.1 0.9 1

Equip. & Floor

Washing

0 1 1

Total Industrial 4* 12** 16

TOTAL (Domestic +

Industrial)

6 15 21

*Existing discharge 4 Kl/Day will be sent to ETL.

** Proposed discharge 12 KL/Day will be sent to ACPTCL. Hence, unit will follow Zero Liquid

Discharge for additional quantity.

ANNEXURE-8


TOTAL WATER CONSUMPTION

(55 KL/Day)

DOMESTIC

(5 KL/Day)

PROCESS

(20 KL/Day)

FLOOR

WASHING

(1 KL/Day)

GARDENING

(11.5 KL/Day)

BOILER

(2.5 KL/Day)

COOLING

(15 KL/Day)

Soak Pit

(5 KL/Day)

Floor Washing

(1 KL/Day)

Boiler Blow-

Down

(2 KL/Day)

Cooling

Blow-Down (1 KL/Day)

Loss

(14

KL/Day)

Effluent

(12 KL/Day)

Effluent Treatment Plant

(16KL/Day)

Loss

(0.5 KL/Day)

Discharge at ETL

(4KL/Day)

ACPTCL (ZLD

PLANT) (12KL/Day)


ANNEXURE 9

FUEL CONSUMPTION

POWER CONSUMPTION

SR.

NO

FUEL QUANTITY As per

Existing

(CCA-H-84112)

QUANTITY

(As per proposed

expansion)

TOTAL

1. Diesel 10 Lit/Hr 120 lit/Hr 130 Lit/Hr

2. Natural gas 600 SCM/Day 5400 SCM/Day 6000 SCM/Day

SR.

NO

POWER QUANTITY

QUANTITY

(As per proposed

expansion)

TOTAL

QUANTITY

1. Electricity 225 KVA 425 KVA 650 KVA


ANNEXURE-10

HAZARDOUS WASTE GENERATION

Sr.

No.

Waste Categor

y

Quantity/

Year

Quantity/

Year

(As per Proposed

Expansion)

Total Facility

1. Process Solid

Waste

28.1 18 736 754 Process waste-

Disposal by send it

to TSDF-

BEIL,Ankleshwar

2. Spent solvent 28.6 36 264 300 Disposal by Reuse

OR sell out to

authorized users

who is having

authorization with

valid CCA and rule

9 permission to

receive this waste.

3. Distillation

residue

28.1 12 163 175 Disposal by

incineration in

common

incineration of

BEIL,Ankleshwar

4. Formic acid

solution(50

to 60% soln);

28.1 144 476 620 Disposal by sell out

to authorized users

who is having

authorization with

valid CCA and rule

9 permission to

receive this waste.

5. Zinc chloride

Solution (20

to 22% soln);


to authorized users

who is having

authorization with

valid CCA and rule

9 permission to

receive this waste.

6. Succinimide

solution:


to authorized users

who is having

authorization with

valid CCA and rule

9 permission to

receive this waste.


7. Sodium

Bromide

Solution (10

to 12% soln);


to authorized users

who is having

authorization with

valid CCA and rule

9 permission to

receive this waste.

8. Aluminium

Chloride

Solution,

28.1 --- 720 720 Disposal by sell out

to authorized users

who is having

authorization with

valid CCA and rule

9 permission to

receive this waste.

9. Hydrochloric

acid


to authorized users

who is having

authorization with

valid CCA and rule

9 permission to

receive this waste.

10. Acetic Acid 28.1 --- 980 980 Disposal by sell out

to authorized users

who is having

authorization with

valid CCA and rule

9 permission to

receive this waste.

11. Hydrobromic

acid


to authorized users

who is having

authorization with

valid CCA and rule

9 permission to

receive this waste.

12. Empty

barrels/contai

ners/liners

contaminate

with

hazardous

chemicals/wa

stes

33.1 34.560 35.44 70 Disposal by send it

to authorized

decontamination

facility/recycler or

reuse or send back

to supplier

13. Chemical

sludge from

waste water

treatment

35.3 18 62 80 Disposal by send it

to TSDF-

BEIL,Ankleshwar

14. Used or 5.1 0.200 4.8 5 Disposal by reuse in


Spent oil plant & machineries

as lubrication or sell

it to authorized re-

refiners/recycler.

15. Spent Carbon 28.3 0 3.2 3.2 Collection, Storage,

Transportation,

Disposal at BEIL


ANNEXURE-11

FLUE GAS EMISSION

Sr.

No.

Stack Attached

To

Stack

Height

(m)

Fuel Consumption APCM

Type

of

Emission

Permissible

Limit

AS PER Existing CCA No:-H-84112

1. Boiler (1 TPH)

15 Natural gas

---

PM

Sox

Nox

150 mg/Nm3

100 ppm

50 ppm 2.

TFH

(2 lac Kcal/hr)

3. D.G.Set * 9 Diesel

PM

Sox

Nox

150 mg/Nm3

100 ppm

50 ppm

AS PER PROPOSED EXPANSION

4. Steam

Boiler(2 TPH)

15 Natural gas ---

PM

Sox

Nox

150 mg/Nm3

100 ppm

50 ppm

5. Steam Boiler

(5TPH)

6.

Thermic fluid

Heater

(2 lac kcal/hr)

7.

Diesel Generator

1) 500 KVA

2) 750 KVA

11 Diesel

Adequate stack

height

PM

Sox

Nox

150 mg/Nm3

100 ppm

50 ppm

• *Unit will dismantle Existing D.G.Set and install new D.G.Sets.(500 KVA and 750

KVA).D.G.Set will be used by the unit only in case of emergency.


ANNEXURE-12

PROCESS GAS EMISSION

As per Existing CCA No.: H-84112

Sr.

No.

APCM attached to Stack

Height

APCM Pollutant Remarks

There is no process gas emission.

For Proposed Expansion

1 Reaction vessel 12 Water

Scrubber/Acid

scrubber

NH3

VOC

150

mg/Nm3

2 Reaction vessel

12 Alkali

Scrubber

HCl/HBr

Cl2 / Br2

VOC

20 mg/Nm3

09 mg/Nm3

---


ANNEXURE-13

DETAILS OF SOLVENT RECOVERY

A solvent recovery system comprises of two stage heat exchangers. Cooling tower water will be

circulated in primary heat exchanger and in secondary heat exchanger chilled water circulation is

done. The uncondensed solvent after the secondary heat exchanger will be diverted to water

scrubber the traces of solvent will get dissolved in water. On getting saturation, the solvent mix

water will be subjected for recovery of solvent (if feasible) and/or water will be diverted to ETP

plant for further treatment the process will ensure no VOC emission from solvent recovery

system.

The scrubbing system consists of a scrubber (packed column absorber), an exhaust blower and

scrubbing media circulation via pumps followed by carbon adsorption tower. The vapors coming

from the process vents and raw material storage area enters the primary scrubber where they are

absorbed in water. Thus, the air leaving from the scrubber is clean, which is again feed into the

secondary tower consists of carbon to trap any remaining VOC. The figure of scrubber system is

given below as figure.


FLOW DIAGRAM OF SOLVENT RECOVERY SYSTEM

Vent

Carbon

Adsorption tower

Reactor

Primary

Condenser

Cooling Tower Line

Secondary

Condenser

Chilled Water

Circulation Spray

Water Tank

Receiver

Un

scrubbed

VOCs

VOC

DT : 10/02/2017

In exercise of the power conferred under Section-25 of the Water (Prevention andControl of Pollution) Act - 1974, under Section - 21 of the Air ( Prevention and Control of Pollution) Act - 1981 and Authorization under rule 6(2) of the Hazardous & Other Wastes (Management and Transboundary Movement) Rules-2016, framed under the E(P)Act-1986.

And whereas Board has received consolidated application dated 09/11/2016 and inward no.110698 for the consolidated consent and authorization ( CC & A) of this Boardunder the provisions / rules of the aforesaid Acts , Consolidated Consent & Authorization is hereby granted as under.

CONSOLIDATED CONSENT AND AUTHORISATION:(Under the provisions / rules of the aforesaid Environmental Acts)

TO,

M/s. Vihita Chem (P) Ltd. (Unit-2) ( Formerly - Pankaj Organics Pvt. Ltd).

PLOT NO: 3709/1&2

GIDC ESTATE:Ankleshwar

DIST- Bharuch - 393002,Gujarat,India

1. Consent Order No.: H-84112 date of Issue 10/02/2017.

2. The consent under Water Act - 1974 for conveying the industrial effluent to the CETP of M/s. ETL for the treatment and disposal of treated effluent, The consent under Air Act-1981 & Authorization under Environment (Protection) Act, 1986 shall be valid up to 01/05/2020 to operate industrial plant to manufacture following products:

NO: GPCB / ANK / CCA- 513(2)/ ID- 15459/ -403707

TALUKA: Ankleshwar

Sr. Products Quantity Unit Per Month

CAS No. Remarks

1 4-METHYL CATECHOL AND/OR

7.000 Metric Tonne

Total production of sr. no. 1 to 8 shall not exceed 7 MT/Month in

any case.

2 HYDROXY UREA AND/OR

7.000 Metric Tonne


any case.

3 4-HYDROXY BENZYL ALCOHOL

AND/OR

7.000 Metric Tonne


any case.

4 BENZALDEHYDE DIMETHYL ACETAL

AND/OR

7.000 Metric Tonne


any case.

By R.P.A.D

CONSOLIDATED CONSENT AND AUTHORIZATION (CC & A) CCA NO:H-84112

Page No-1 of 10

Clean Gujarat Green GujaratISO-9001-2008 & ISO - 14001 - 2004 Cerfified Organisation

Computer generated Order thru XGN, does NOT require Physical Signature

GUJARAT POLLUTION CONTROL BOARDParyavaran Bhavan, Sector-10/A,

Gandhinagar - 382010

Phone: (079)23226295

Fax: (079)23232156

Websit: WWW.gpcb.gov.in

GPCB

Sr. Products Quantity Unit Per Month

CAS No. Remarks

5 4-METHOXY BENZALDEHYDE

DIMETHYL ACETAL AND/OR

7.000 Metric Tonne


any case.

6 DI METHYL FORMAMIDE DI ISO

PROPYL ACETAL AND/OR

7.000 Metric Tonne


any case.

7 2 -BROMO 2’,5’ – DIMETHOXY

ACETOPHENONE AND/OR

7.000 Metric Tonne


any case.

8 METHYLENE DIOXY PHENOL

7.000 Metric Tonne


any case.

9 DI METHYL FORMAMIDE DI

METHYL ACETAL AND/OR

13.000 Metric Tonne


any case.

10 4-CHLORO-4’ HYDROXY

BENZOPHENONE AND/ OR

13.000 Metric Tonne


any case.

11 2,3,4,5 –BIS-O-[1-METHYL ETHYL

IDENE] B-D-FRUCTOPYRANOSE

AND/OR

13.000 Metric Tonne


any case.

12 ALPHA –BROMO -2-CHLORO PHENYL

ACETIC ACID AND/OR

13.000 Metric Tonne


any case.

13 ALPHA –BROMO -2-CHLORO PHENYL

ACETIC ACID METHYL ESTER

AND/OR

13.000 Metric Tonne


any case.

14 O-BENZYL HYDROXYL AMINE HYDROCHLORIDE

AND/OR

13.000 Metric Tonne


any case.

15 O-BENZYL HYDROXYL AMINE

METHANE SULPHONIC ACID

13.000 Metric Tonne


any case.

SPECIFIC CONDITIONS

Page No-2 of 10





Phone: (079)23226295

Fax: (079)23232156


GPCB

1. Previous Consent order issued vide CCA no. AWH – 71568, letter no. GPCB/ ANK / CCA – 513(2)/ ID-15459/ 332163 dated 06/11/15 shall be considered as null & void i.e. shall be treated as cancelled.2. Either individual or total production of all products mentioned in sr. no. 1 to 8 shall not exceed 7 MT/Month in any case. 3. Either individual or total production of all products mentioned in sr. no. 9 to 15 shall not exceed 13 MT/Month in any case.

OTHER CONDITIONS

1.All the efforts shall be made to send hazardous waste to cement industry for Co- processing first & there after it shall be disposed through other options.

2.Unit shall follow spent solvent management guideline framed by the Board and shall make MoU with outside distillation units, if any. Also submit the prescribed forms as per guideline.

3. CONDITION UNDER THE WATER ACT:

3.1 The quantity of total water consumption shall not exceed 8.000 KL/Day as per below break up as mentioned in form D submitted for consent application under the Water Act- 1974.

a) Industrial: 6.000 KL/Day b) Domestic: 2.000 KL/Day

3.2 The quantity of total waste water generation shall not exceed 6.000 KL / Day as per below break up as mentioned in form D submitted for consent application under the Water Act- 1974.

a) Industrial: 4.000 KL/Day b) Domestic: 2.000 KL/Day

3.3 Sewage shall be disposed off through septic tank/soak pit system or shall be treated separately in Sewage Treatment Plant (STP) to conform the following standards and treated sewage shall be utilized on land for irrigation / plantation.

Sr. No. PARAMETERS PERMISSIBLE LIMIT

1 Biochemical Oxygen Demand, BOD3, 27⁰ C Less than 20 mg/L

2 Total Suspended Solids Less than 30 mg/L

3 Total Residual Chlorine Minimum 0.5 ppm

Or Sewage shall be treated in ETP along with Industrial effluent and disposed to CETP of ETL through designated road tankers for further treatment & disposal.

3.4 The quality of industrial effluent shall conform to the following standards(as per GPCB norms, whichever is applicable)

Page No-3 of 10





Phone: (079)23226295

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GPCB

Sr. No.

PARAMETERS PERMISSIBLE LIMIT

1 Biochemical Oxygen Demand, BOD3, 27⁰ C 3600 mg/L

2 Chemical Oxygen Demand (COD) 11000 mg/L

3 Phenolic Compounds 1 mg/L

4 Ammonia 100 mg/L

5 Free Acidity 55000 ppm

6 Cyanide (as CN) 0.2 mg/L

7 Pesticides Absent

8 Hexavalent Chromium (as Cr+6) 0.1 mg/L

9 Total Chromium (as Cr) 2 mg/L10 Copper (as Cu) 3 mg/L11 Nickel (as Ni) 3 mg/L12 Zinc (as Zn) 5 mg/L

13 Mercury (as Hg) 0.01 mg/L

14 Lead (as Pb) 0.1 mg/L

15 Arsenic (as As) 0.2 mg/L

16 Cadmium (as Cd) 1 mg/L

17 Selenium (as Se) 0.05 mg/L

3.5 The effluent conforming to the above standards shall be disposed to CETP of ETL through designated road tankers for further treatment & disposal.

3.6 Unit shall be required to make storage facilities to store the effluent for at least 72 hours by providing acid proof brick lined impervious tanks/HDPE tanks.

3.7 In case of shut-down of plant for more than three (3) days for any reason, the ETL unit member shall intimate to ETL authority & GPCB well in advance for the better operation & management of CETP.

3.8 Unit shall make fixed arrangement for loading the effluent from their collection tanks to the designated tanker of ETL. Unit shall not keep any by-pass line or system or loose or flexible pipeline for loading the effluent into the designated tanker of ETL.

3.9 Magnetic flow meters shall be installed at the inlet & outlet of effluent collection tanks / ETP to measure the quantity of effluent send to ETL.

3.10 Unit shall affix of water meters as per Section 4 (1) of the water (Prevention and Control ofPollution) Cess Act –1977 for the purpose of measuring and recording the quantity of water consumed at such places as may be required, within 15 days and it shall be presumed that thequantity indicated by the meter has been consumed by the unit until the contrary is proved.

3.11 The underground drainage connection given by the GIDC for discharge of industrial effluent shall be disconnected & the outlet shall be sealed, if unit have.

Page No-4 of 10





Phone: (079)23226295

Fax: (079)23232156


GPCB

3.12 The entire quantity of industrial effluent shall have to be send to ETL for further treatment& disposal. In no circumstances the effluent either treated or untreated shall be discharged into underground drainage pipeline of GIDC, storm water drain or anywhere else. 3.13 Unit shall provide adequate / safe effluent sampling facility for the effluent being stored in finalcollection /discharge tank of ETP or being discharged into CETP.

3.14 Unit shall be responsible for loading its effluent into the tankers of the ETL for transporting theeffluent. Due care shall be taken to avoid any leakage or spillage of effluent during loading the tanker.

3.15 Unit shall put up at the entrance a board displaying the name of unit, particulars of the products/ process, the name of proprietor / partners / directors of the unit, ETL membership number & date of joining of ETL, the electricity consumer number as on the record of DGVCL.

3.16 Unit shall have to display on - line data outside the main factory gate with regard to and nature of hazardous chemicals being handled in the plant, including waste water and air emission and solid hazardous waste generated within the factory premises.

3.17 Unit shall either stop or curtail its production activities if the effluent is not adequately treated by the ETL to conform to the standards specified by GPCB.

3.18 The authorized representative of ETL shall have right of entry at any time for the purpose of inspection and monitoring the effluent collection facilities/ETP (if required) of Unit.

3.19 Unit shall have to keep accurate records of quality & quantity of effluent discharged to ETLon day-to-day basis. Separate logbook shall be maintained for recording the data & shall be madeavailable for inspection as & when asked.

3.20 Unit shall keep accurate records of quantity of production of each product, quantity of water consumption, quantity of effluent generated and consumption of electricity on day to day basis and required to submit the complied record of each month to GPCB on or before fifth day of the succeeding month.

3.21 In case of incinerators or MEE, the flow measuring devices for mother liquor / toxic effluent / Non-biodegradable effluent, light diesel oil, Furnace oil, etc. i.e. fuel used for combustion, air used for combustion shall be separately provided. Incinerator temperature recording devices as well as gaseous flow measuring devices for scrubber shall also be provided. These data of temperature & flow should be recorded every day & submitted to GPCB on monthly basis.

3.22 Disposal system for storm water shall be provided separately. In no circumstances storm water shall be mixed with the industrial effluent.

3.23 Leachate from the hazardous solid waste, if any shall also be connected into a collection tank through leachate collection facilities and shall be treated along with industrial effluent and final treated effluent shall be discharged to the CETP of ETL.

3.24 If the ETL authority terminates the membership of CETP, the ETL member unit shall have to close down the manufacturing activities / industrial operation of the process plant immediately

Page No-5 of 10





Phone: (079)23226295

Fax: (079)23232156


GPCB

until the ETL membership is resumed.

3.25 The Environmental Management Unit / Cell shall be setup to ensure implementation on and monitoring of environment safeguards and other conditions stipulated by statutory authorities.The Environmental Management Cell / Unit shall directly report to the Chief Executive of the organization and shall work as a focal point for internalizing environmental issued.These Cells also coordinate the exercise of environmental audit and preparation of environmental statements.

3.26 The Environmental audit shall be carryout yearly, if applicable.The environmental statements pertaining to the previous year shall be submitting to this State Board latest by 30th September every year.

3.27 Adequate plantation shall be carried out all along the periphery of the industrial premises in such a way that the density of plantation is at least 1000 trees per acre of land and a green belt of 5 meters width is developed.

3.28 In case of change of ownership / management the name and address of the new ownership / partners / directors / proprietor should immediately be intimate to the Board. Also any changein equipment or working conditions as mentioned in the consents form / order should immediately be intimated to this Board.

3.29 The Board reserves the right to review and/ or revoke the consent and /or make modifications in the conditions which it seems fit in accordance with provisions of Water Act-1974.

4.CONDITIONS UNDER THE AIR ACT:

4.1 Unit shall use fuel as specified in this consent and the flue gas emission through stack shall conform to the following standards:

Sr. No.

PCB ID of

Stack

Stack attached

to

Capacity /

Remarks

Name of

Fuel

Quantity of

Fuel

Air Pollution Control Measure (APCM)

Stack Height in

Meter (From G.L.)

Parameter Permissible limit

Unit

1 60565 D.G. Sets

Cap. 75 KVA

Diesel 10 Lit/Hr

Not provide

d

9 PMSO2

NOX

15010050

mg/Nm³ppmppm

2 9981 Boiler+T.F.H

Boiler cap. 1

TPH & TFH

Cap. 2 lacKcal/

hr (common stack)

Natural Gas

600 SCM/D

ay (Total)

Not Applica

ble

15 PMSO2

NOX

15010050

mg/Nm³ppmppm

4.2 There shall be no process gas emission from the manufacturing process and any other ancillary industrial operation through various stacks/ vent of reactors, process, vessel from plant premises.

Page No-6 of 10





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GPCB

4.3 The concentration of the following parameters in the ambient air within the premises of the unit shall not exceed the limits specified hereunder.

Sr. No. Parameters Permissible Limit (microgram /m3)

Annual 24 Hours Average1. Particulate Matter (PM10 ) 60 100

2. Particulate Matter (PM2.5 ) 40 60

3. Oxides of Sulphur (SOx) 50 80

4. Oxides of Nitrogen (NOx) 40 80

a. Annual arithmetic mean of minimum 104 measurements in a year at a particular site taken twice a week 24 hourly at uniform intervals.

b. 24 hourly or 08 hourly or 01 hourly monitored values, as applicable, shall be complied with 98% of the time in a year. 2% of the time, they may exceed thelimits but not on two consecutive days of monitoring.

4.4 Unit shall operate industrial plant / air pollution control equipment very efficiently and continuously so that the gaseous emission always conforms to the standards specified as above.

4.5 The consent to operate the industrial plant shall lapse if at any time the parameters of the gaseous emission are not within the tolerance limits specified as above.

4.6 Unit shall provide portholes, ladder, platform etc at chimney(s) for monitoring the air emissions and the same shall be open for inspection to / and for use of Board’s staff. The chimney(s) vents attached to various sources of emission shall be designed by numbers such as S-1, S-2 , etc. and these shall be painted / displayed to facilitate identification.

4.7 Unit shall take adequate measures for control of noise levels from its own sources within the premises so as to maintain ambient air quality standards in respect of noise to less than 75 dB(a) during day time and 70 dB (A) during night time. Daytime is reckoned in between 6 a.m. and 10 p.m. and nighttime is reckoned between 10 p.m. and 6 a.m.

4.8 All efforts shall be made to control VOC emissions and odor problem, if any.

5. AUTHORISATION FOR THE MANAGEMENT & HANDLING OF HAZARDOUS WASTES Form-2 (See rule 6(2))

Page No-7 of 10





Phone: (079)23226295

Fax: (079)23232156


GPCB

SPECIFIC CONDITION

1. Unit shall sell By-product / Hazardous waste to authorized users who is having authorization with valid CCA and rule 9 permission to receive this waste.

5.1 Number of authorization: H-84112 date of Issue 10/02/2017 .

5.2 M/s. Vihita Chem (P) Ltd. (Unit-2) ( Formerly - Pankaj Organics Pvt. Ltd). is granted an authorization to operate facility for following hazardous wastes on the situated at PLOT NO: 3709/1&2 GIDC ESTATE Ankleshwar DIST: Bharuch.

Sr Name of Hazardous

Waste

Sch Catg. Qty MT/Year

Facility Mode of Disposal & Remarks

1 Spent Catalyst I 18.1 18.000 Collection,Disposal,Treatment,Storage,Transportatio

n

Process Waste - Disposal by send it to TSDF- BEIL, Ankleshwar

2 Spent Solvents I 20.2 36.000 Collection,Disposal,Reuse,Storage,

Transportation

Disposal by Reuse OR sell out to authorized users who is having authorization with valid CCA and rule 9 permission to receive this

waste.

3 Distillation Residues

I 20.3 12.000 Collection,Incineration,Disposal,Storage,Transportat

ion

Disposal by incineration in common incinerator of BEIL, Ankleshwar

4 Process Residue and wastes

I 28.1 144.000

Collection,Disposal,Reuse,Recovery,Storage,Transp

ortation

Formic Acid Solution (50 to 60 % Soln.): Disposal by sell out to authorized users who is having authorization with valid CCA and

rule 9 permission to receive this waste.


I 28.1 432.000


ortation

Zinc Chloride Solution (20 to 22 % Soln.): Disposal by sell out to authorized users who is having authorization with valid CCA and



I 28.1 48.000 Collection,Disposal,Reuse,Recovery,Storage,Transp

ortation

Succinimide Solution: Disposal by sell out to authorized users who is having authorization

with valid CCA and rule 9 permission to receive this waste.


I 28.1 720.000


ortation

Sodium Bromide Solution (10 to 12 % Soln.): Disposal by sell out to authorized users who is having authorization with valid CCA and


8 Empty barrels/containers

/liners contaminated

with hazardous chemicals

/wastes

I 33.1 34.560 Collection,Decontamination,Disposal,Reuse,Storage,Transportation

Disposal by send it to authorized decontamination facility / recycler or reuse or

send back to supplier

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Fax: (079)23232156


GPCB

Sr Name of Hazardous

Waste

Sch Catg. Qty MT/Year

Facility Mode of Disposal & Remarks

9 Chemical sludge from waste water

treatment

I 35.3 18.000 Collection,Disposal,Treatment,Storage,Transportatio

n

Disposal by send it to TSDF- BEIL, Ankleshwar

10 Used or Spent Oil

I 5.1 0.200 Collection,Disposal,Reuse,Recovery,Storage,Transp

ortation

Disposal by Reuse in plant & machinery as lubricant or sell it to authorized re-refiners /

recycler.

5.3 The authorization is granted to operate a facility as above.

5.4 The authorization shall be in force for a period up to 01/05/2020.

5.5 The authorization is subject to the conditions stated below and such other conditions as may be specified in the rules from time to time under the Environment (Protection) Act - 1986.

6 TERMS AND CONDITIONS OF AUTHORISATION:6.1 The authorised person shall comply with the provisions of the Environment (Protection) Act,1986,and the rules made there under.

6.2 The authorisation or its renewal shall be produced for inspection at the request of an officer authorised by the Gujarat Pollution Control Board.

6.3 The person authorised shall not rent, lend, sell, transfer or otherwise transport the hazardous and other wastes except what is permitted through this authorisation.

6.4 Any unauthorised change in personnel, equipment or working conditions as mentioned in the application by the person authorised shall constitute a breach of his authorisation.

6.5 The person authorised shall implement Emergency Response Procedure (ERP) for which this authorisation is being granted considering all site specific possible scenarios such as spillages, leakages, fire etc. and their possible impacts and also carry out mock drill in this regard at regular interval of time.6.6 The person authorised shall comply with the provisions outlined in the Central Pollution Control Board guidelines on “Implementing Liabilities for Environmental Damages due to Handling and Disposal of Hazardous Waste and Penalty”6.7 It is the duty of the authorised person to take prior permission of the Gujarat Pollution Control Board to close down the facility.

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Fax: (079)23232156


GPCB

6.8 The imported hazardous and other wastes shall be fully insured for transit as well as for any accidental occurrence and its clean - up operation.

6.9 The record of consumption and fate of the imported hazardous and other wastes shall be maintained.

6.10 The hazardous and other waste which gets generated during recycling or reuse orrecovery or pre - processing or utilisation of imported hazardous or other wastes shall be treated and disposed of as per specific conditions of authorisation.

6.11 The importer or exporter shall bear the cost of import or export and mitigation of damages if, any.

6.12 An application for the renewal of an authorisation shall be made as laid down under Hazardous & Other Wastes (Management and Transboundary Movement) Rules - 2016.

6.13 Any other conditions for compliance as per the Guidelines issued by the Ministry of Environment, Forest and Climate Change or Central Pollution Control Board from time to time.

6.14 Annual return shall be filed by June 30th for the period ensuring 31st March of the year.

6.15 Unit shall have to display the relevant information with regard to hazardous waste as indicated in the Court’s order in W.P. No. 657 of 1995 dated 14th October 2003.

For and on behalf of GUJARAT POLLUTION CONTROL BOARD

D. M. Thaker, Unit Head

Page No-10 of 10





Phone: (079)23226295

Fax: (079)23232156


GPCB

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