PLOT NO. 3609, NEAR FICOM CHOKDI, GIDC ESTATE ...environmentclearance.nic.in/writereaddata/Online/TOR/24...PROPOSED EXPANSION OF BULK DRUG INTERMEDIATES M/s. DARSHAN PHARMA PLOT NO

PROPOSED EXPANSION OF

BULK DRUG INTERMEDIATES

M/s. DARSHAN PHARMA

PLOT NO. 3609, NEAR FICOM CHOKDI,

ANKLESHWAR,

FORM-I

For

EXPANSION OF BULK DRUGS AND

BULK DRUG INTERMEDIATES IN

EXISTING UNIT

of

DARSHAN PHARMACHEM PVT. LTD.

NEAR FICOM CHOKDI, GIDC ESTATE,

R, DISTRICT: BHARUCH, GUJARAT

Consultant

AND

LTD.

GIDC ESTATE,

ARAT

APPENDIX I

FORM 1

(I) Basic Information

Sr.

No.

Item Details

1. Name of the Project/s M/s. Darshan Pharmachem Pvt. Ltd.

2. S. No. in the Schedule 5 (f)

3. Proposed

capacity/area/length/tonnage to be

handled/command area/lease

area/number of wells to be drilled

Proposed Capacity: 30 MT/Month

Existing Capacity: 27 MT/Month

Total Capacity: 57 MT/Month

List of Products with their capacity as Annexure: 2

4. New/Expansion/Modernization Expansion

5. Existing capacity/area etc. For detail Please refer Annexure: 2

6. Category of project i.e. ‘A’ or ‘B’ ‘A’

7. Does it attract the general condition?

If yes, please specify.

Yes. Located in critically polluted area

(Ankleshwar).

8. Does it attract the specific condition?

If yes, please specify.

N.A.

9. Location

Plot/Survey/Khasra No. 3609

Village GIDC Estate

Tehsil Ankleshwar

District Bharuch

State Gujarat

10. Nearest railway station/airport along

with distance in kms.

Nearest Railway Station: Ankleshwar: 3.3 km

Nearest Airport: Surat: 60 km

11. Nearest Town, city, District

Headquarters along with distance in

kms.

Nearest town: Ankleshwar: 1.9 km

12. Village Panchayats, zilla parishad,

Municipal corporation, Local body

(Complete postal addresses with

telephone nos. to be given)

Notified Area Authority, Ankleshwar

13. Name of the applicant M/s. Darshan Pharmachem Pvt. Ltd.

14. Registered address Plot No. 3609, Nr. Ficom Chokdi, GIDC Estate,

Ankleshwar-393002, District: Bharuch, Gujarat. 15. Address for correspondence:

Name Mr. Jitendra Dobaria

Designation (Owner/Partner/CEO) Partner

Address M/s. Darshan Pharmachem Pvt. Ltd.

Plot No. 3609, Nr. Ficom Chokdi, GIDC Estate,

Ankleshwar-393002, District: Bharuch, Gujarat.

Pin Code 393002

E-Mail [email protected]

Telephone No. +919924796811

Fax No. 91-2646-253392

16. Details of Alternative Sites examined,

if any location of these sites should be

shown on a topo sheet.

No

17. Interlinked Projects No

18. Whether separate application of

interlinked project has been

submitted?

No

19. If Yes, date of submission Not applicable

20. If no., reason Not applicable

21. Whether the proposal involves

approval/clearance under: If yes,

details of the same and their status to

be given.

(a) The Forest (Conservation) Act,

1980?

(b) The Wildlife (Protection) Act,

1972?

(c) The C.R.Z Notification, 1991?

No

22. Whether there is any Government

order/policy relevant/relating to the

site?

No

23. Forest land involved (hectares) No

24. Whether there is any litigation

pending against the project and/or

land in which the project is propose to

be set up?

(a) Name of the Court

(b) Case No.

(c) Orders/directions of the Court,

if any and its relevance with the

proposed project.

No

(II) Activity

1. Construction, operation or decommissioning of the Project involving actions, which will cause

physical changes in the locality (topography, land use, changes in water bodies, etc.)

Sr.

No.

Information/Checklist confirmation Yes

/No?

Details thereof (with approximate

quantities / rates, wherever possible) with

source of information data

1.1 Permanent or temporary change in

land use, land cover or topography

including increase in intensity of land

use (with respect to local land use

plan)

No Proposed expansion is within Existing

Premises.

1.2 Clearance of existing land, vegetation

and buildings?

Yes Minor site clearance activities shall be

carried out to clear shrubs and weed.

1.3 Creation of new land uses? No --

1.4 Pre-construction investigations e.g.

bore houses, soil testing?

No --

1.5 Construction works? Yes Approved plan for construction is attached

as Annexure: 1.

1.6 Demolition works? No --

1.7

Temporary sites used for construction

workers or housing of construction

workers?

No --

1.8 Above ground buildings, structures or

Earthworks including linear structures,

cut and fill or excavations

Yes Approved plan for construction is attached

as Annexure: 1.

1.9

Underground works including mining

or tunneling?

No --

1.10 Reclamation works? No --

1.11 Dredging? No --

1.12 Offshore structures? No --

1.13 Production and manufacturing Yes List of Products & their capacity is attached

as Annexure: 2 and manufacturing process

is attached as Annexure: 3.

1.14 Facilities for storage of goods or

materials?

Yes Dedicated storage area for storage of Raw

Materials and finished products, solvents,

etc. shall be provided.

1.15

Facilities for treatment or disposal of

solid waste or liquid effluents?

Yes Details of proposed Effluent Treatment

Plant are attached as Annexure: 5.

Details of Hazardous waste generation and

disposal is attached as Annexure: 6.

1.16

Facilities for long term housing of

operational workers?

No --

1.17 New road, rail or sea traffic during

construction or operation?

No --

1.18 New road, rail, air waterborne or No --

other airports etc?

1.19 Closure or diversion of existing

transport routes or infrastructure

leading to changes in traffic

movements?

No --

1.20 New or diverted transmission lines or

pipelines?

No --

1.21

Impoundment, damming, converting,

realignment or other changes to the

hydrology of watercourses or

aquifers?

No --

1.22 Stream crossings? No --

1.23

Abstraction or transfers or the water

form ground or surface waters?

No --

1.24

Changes in water bodies or the land

surface affecting drainage or run-off?

No --

1.25

Transport of personnel or materials for

construction, operation or

decommissioning?

Yes Transportation of personnel, raw material

and products will be primarily by road only.

1.26 Long-term dismantling or

decommissioning or restoration

works?

No --

1.27 Ongoing activity during

decommissioning which could have

an impact on the environment?

No --

1.28

Influx of people to an area in either

temporarily or permanently?

Yes Direct/Indirect people shall be employed for

proposed expansion operation.

1.29 Introduction of alien species? No --

1.30 Loss of native species of genetic

diversity?

No --

1.31 Any other actions? No --

2. Use of Natural resources for construction or operation of the Project (such as land, water,

materials or energy, especially any resources which are non-renewable or in short supply):

Sr.

No.

Information/checklist confirmation Yes/

No?

Details there of (with approximate

quantities/rates, wherever possible) with


2.1 Land especially undeveloped or

agriculture land (ha)

No --

2.2 Water (expected source & competing

users) unit: KLD

Yes Water requirement will meet through the

GIDC Water supply.

A detail of water balance is given as

Annexure – 4.

2.3 Minerals (MT) No --

2.4 Construction material -stone, Yes Company shall use Sand, stone, Cement and

aggregates, sand / soil (expected

source MT)

Structural Steel for Construction as

required.

2.5 Forests and timber (source - MT) No --

2.6

Energy including electricity and fuels

source, competing users Unit: fuel

(MT), energy (MW)

Yes Power Requirement:

Existing:

Power required from DGVCL is 150 KVA

1 DG Set = 250 KVA (for Emergency case

only)

Proposed:

Power required from DGVCL will be 500

KVA.

1 DG Set = 125 KVA (for Emergency case

only)

Fuel Requirement:

Existing:

Natural gas = 500 sm3/Day,

Diesel = 27 Lit/hr

Proposed:

Agrowaste = 15 MT/Day

Diesel = 10 Lit./hr (Only for emergency).

2.7 Any other natural resources (use

appropriates standard units)

No --

3. Use, storage, transport, handling or production of substances or materials, which could be harmful to

human health or the environment or raise concerns about actual or perceived risks to human health.

Sr.

No.

Information / Checklist confirmation Yes/

No?


quantities / rates wherever possible) with


3.1 Use of substances or materials, which

are hazardous (as per MSIHC rules) to

human health or the environment

(flora, fauna, and water supplies)

Yes

Please refer Annexure: 8

3.2 Changes in occurrence of disease or

affect disease vectors (e.g. insect or

water borne diseases)

No --

3.3 Affect the welfare of people e.g. by

changing living conditions?

No --

3.4

Vulnerable groups of people who

could be affected by the project e.g.

hospital patients, children, the elderly

etc.,

No --

3.5 Any other causes No --

4. Production of solid wastes during construction or operation or decommissioning (MT/month)

Sr.

No.

Information/Checklist confirmation Yes/

No?


quantities / rates, wherever possible)

with source of information data

4.1 Spoil, overburden or mine wastes No --

4.2

Municipal waste (domestic and or

commercial wastes) No --

4.3

Hazardous wastes (as per Hazardous

Waste Management Rules)

Yes Please refer Annexure: 6

4.4 Other industrial process wastes Yes Please refer Annexure: 6

4.5 Surplus product No --

4.6

Sewage sludge or other sludge from

effluent treatment


4.7 Construction or demolition wastes Yes Construction waste shall be utilized for

leveling, land filling in the premises.

4.8 Redundant machinery or equipment No --

4.9 Contaminated soils or other materials No --

4.10 Agricultural wastes No --

4.11 Other solid wastes Yes Please refer Annexure: 6

5. Release of pollutants or any hazardous, toxic or noxious substances to air (Kg/hr)

Sr.

No.


No


quantities/rates, wherever possible) with


5.1 Emissions from combustion of fossil

fuels from stationary or mobile sources


5.2 Emissions from production processes Yes Please refer Annexure: 7

5.3 Emissions from materials handling

storage or transport

Yes All liquid raw materials shall be procured

in tankers and shall be transferred through a

closed circuit pipe lines.

Solid raw materials shall be charged

through close pipeline into reactors and the

dust collection hopper shall be connected

to a bag filter and ID fan.

Also all hazardous chemicals storage tanks

will be provided with flame arrestors &

breather valves for safety.

5.4 Emissions from construction activities

including plant and equipment

Yes During construction work, only dust

contamination will be there & water

sprinklers shall be utilized whenever

necessary.

5.5 Dust or odours from handling of

materials including construction

materials, sewage and waste

Yes Dust from drying will be collected in to dust

collector through cyclone separator &

recovered powder will be recycled back to

process. Air Handling Unit will be provided

where ever applicable.

5.6 Emissions from incineration of waste No --

5.7 Emissions from burning of waste in

open air e.g. slash materials,

construction debris)

No

--

5.8 Emissions from any other sources Yes Please refer Annexure: 7

6. Generation of Noise and Vibration, and Emissions of Light and Heat:

Sr.

No.


No?


Quantities /rates, wherever possible) With

source of source of information data

6.1

From operation of equipment e.g.

engines, ventilation plant, crushers

Yes There are few activities due to which noise

would be generated. The equipments

resulting in noise generation are machinery

of plant and Diesel generator. Adequate

noise control measures will be provided

whenever required.

Proper and timely oiling, lubrication and

preventive maintenance will be carried out

for the machineries & equipments to reduce

noise generation.

Use of PPE like ear plugs and ear muffs will

be made compulsory near the high noise

generating machines.

Noise monitoring shall be done regularly in

plant area.

The D.G. Set will be installed in a closed

room and provided with acoustic enclosure.

The unit will increase the plantation species

in the proposed greenbelt within the

premises which will be preventing the noise

pollution in surrounding area.

6.2 From industrial or similar processes Yes All machinery / equipment shall be well

maintained, shall have proper foundation

with anti vibrating pads wherever applicable

to keep noise levels within permissible

limits.

Acoustic enclosures shall be provided for DG

set.

6.3 From construction or demolition No --

6.4 From blasting or piling No --

6.5 From construction or operational

traffic No

--

6.6 From lighting or cooling systems No --

6.7 From any other sources No --

7. Risks of contamination of land or water from releases of pollutants into the ground or into sewers,

surface waters, groundwater, coastal waters or the sea:

Sr.

No


No?




7.1

From handling, storage, use or

spillage of hazardous materials

Yes All the raw material shall be stored

separately in designated storage area and

safely. Bund walls shall be provided around

raw materials storage tanks for containing

any liquid spillage.

Please refer Annexure: 8.

7.2

From discharge of sewage or other

effluents to water or the land

(expected mode and place of

discharge)

Yes Sewage shall be treated in Septic Tank &

Soak Pit.

7.3

By deposition of pollutants emitted

to air into the land or into water

No --

7.4 From any other sources No --

7.5 Is there a risk of long term build up

of pollution in the environment from

these sources?

No --

8. Risks of accident during construction or operation of the Project, which could affect human

health or the environment:

Sr.

No.

Information/Checklist confirmation

Yes/

No?




8.1 From explosions, spillages, fires etc

from storage, handling, use or

production of hazardous substances


8.2 From any other causes No --

8.3 Could the project be affected by

natural disasters causing

environmental damage (e.g. floods,

earthquakes, landslides, cloudburst

etc)?

No --

9. Factors which should be considered (such as consequential development) which could lead to

environmental effects or the potential for cumulative impacts with other existing or planned

activities in the locality

Sr.

No.


No?




9.1 Lead to development of supporting.

laities, ancillary development or

development stimulated by the

project which could have impact on

the environment e.g.:

* Supporting infrastructure (roads,

power supply, waste or waste water

treatment, etc.)

• housing development

• extractive industries

• supply industries

• other

No Site is having the entire required

infrastructure.

Existing road infrastructure & power supply

are to be utilized.

Local people will be employed and no

housing is required.

Please refer Annexure: 9.

9.2

Lead to after-use of the site, which

could have an impact on the

environment

No

--

9.3 Set a precedent for later

developments No --

9.4 Have cumulative effects due to

proximity to Other existing or

planned projects with similar effects

No

--

(III) Environmental Sensitivity

Sr.

No.

Information/Checklist confirmation Name /

Identity

Aerial distance (within 15 km). Proposed

Project Location Boundary.

1 Areas protected under international

conventions national or local

legislation for their ecological,

landscape, cultural or other related

value

No Proposed expansion project site is within

the GIDC, Ankleshwar.

2 Areas which are important or sensitive

for Ecological reasons - Wetlands,

watercourses or other water bodies,

coastal zone, biospheres, mountains,

forests

No Proposed expansion project site is within

the GIDC, Ankleshwar.

3 Areas used by protected, important or

sensitive species of flora or fauna for

breeding, nesting, foraging, resting,

over wintering, migration

No --

4 Inland, coastal, marine or underground

waters

Yes River Narmada = 7.6 kms

5 State, National boundaries No --

6 Routes or facilities used by the public

for to recreation or other tourist,

pilgrim areas.

Yes Public transportation

7 Defense installations No --

8 Densely populated or built-up area Yes Ankleshwar City around 1.9 km from the

proposed expansion project site.

9 Areas occupied by sensitive man-made

land community facilities)

No --

10 Areas containing important, high

quality or scarce resources (ground

water resources, surface resources,

forestry, agriculture, fisheries, tourism,

tourism, minerals)

No

--

11 Areas already subjected to pollution or

environmental damage. (those where

existing legal environmental standards

are exceeded)

Yes Ankleshwar

12 Areas susceptible to natural hazard

which could cause the project to

present environmental problems

(earthquake s, subsidence ,landslides,

flooding erosion, or extreme or

adverse climatic conditions)

No --

IV). Proposed Terms of Reference for EIA studies: Please refer Annexure: 10.

ANNEXURES

1 PLANT LAYOUT

2 LIST OF PRODUCTS WITH PRODUCTION CAPACITY AND RAW MATERIALS

3 BRIEF MANUFACTRING PROCESS, CHEMICAL REACTION AND MASS BALANCE WITH

FLOW DIAGRAM

4 WATER CONSUMPTION AND EFFLUENT GENERATION

5 DETAILS OF PROPOSED EFFLUENT TREATMENT PLANT

6 DETAILS OF HAZARDOUS SOLID WASTE MANAGEMENT AND DISPOSAL

7 DETAILS OF STACK & VENTS

8 DETAILS HAZARDOUS CHEMICAL STORAGE FACILITY

9 SOCIO - ECONOMIC IMPACTS

10 PROPOSED TERMS OF REFERENCES

ANNEXURE: 1

PLANT LAYOUT

ANNEXURE: 2

LIST OF PRODUCTS WITH PRODUCTION CAPACITY

Sr

No Product Cas No.

Existing

Capacity

(MT/Month)

Additional

Capacity

(MT/Month)

Total

Capacity

(MT/Month)

Existing Products

1. 1-(4-Hydroxy Phenyl) Piperazine

Hydrochloride 0056621-48-8

10 -- 10

2. 2-Chloro Ethyl Amine


10 -- 10

3. N,N, Bis (2-Chloro Ethyl) Amine


7 -- 7

Total 27 -- 27

Proposed Products

1.

1-(3-Chlorophenyl)-4-(3-

chloropropyl) piperazine

hydrochloride

52605-52-4

-- 30 30

2.

N-methyl-N-benzyl-3-hydroxy

acetophenone suphate ( MAAP

Sulphate)

120410-24-4

3. N-Acetyl-Thiazolid-4-carboxylic

acid

5025-82-1

4. 1-Acetyl-4-(4’- Hydroxyphenyl)

Piperazine 67914-60-7

5. Dorepenem 148016-81-3

6. Candesartan & intermediates 139481-59-7

7. Celecoxib & intermediates 169590-42-5

8. Clopidogrel Besilate & intermediates

113665-84-2

9. Ketaconazole & intermediates 65277-42-1

10. Levo cetirizine dihydrochloride & intermediates

130018-87-0

11. Levetiracetam & intermediates 102767-28-2

12. Pantoprazole Magnesium & intermediates

102625-70-7

13. Phenylephrin Hydrochloride & intermediates

61-76-7

14. Prasugrel Hydrochloride &

intermediates 389574-19-0

15. Quetiapine fumarate &


16. Rabeprazole Sodium & intermediates

117976-90-6

17. Solifenacin & intermediates 242478-37-1

18. Tamsulosin Hydrochloride & intermediates

106463-17-6

19. Telmisartan & intermediates 144701-48-4

20. Bortezomib & intermediates 179324-69-7

21. Trimebutine Maleate& intermediates

34140-59-5

22. Caberogoline & intermediates 81409-90-7

23. Mycophenolat Mofetil &


24. Raloxifene Hydrochloride

& intermediates 82640-04-8

25. Febuxostat & intermediates 144060-53-7

26. Pregabline & intermediates 148553-50-8

27. Rosuvastatin Calcium

& intermediates 147098-20-2

28. Biperidine Hydrochloride &


29. Donepizil Hydrochloride&


30. Domperidone & intermediates 57808-66-9

31. Carisoprodole & intermediates 78-44-4

32. Topiramate & intermediates 97240-79-4

33. Valsartan & intermediates 137862-53-4

34. Moxifloxacin Hydrochloride &


35. Cinnarizine & intermediates 298-57-7

36. Cyano diol base 103146-25-4

37. Dextromethorphan

Hydrobromide & intermediates 125-69-9

38. 2-Amino-5- Methyl Thiazol 7305-71-7

Total

(Proposed Products)

-- 30 30

Total

(Existing + Proposed)

27 30 57

By-Products

1. 4-Nitro Toluene 99-99-0

--

13.8 13.8

2. 4-Nitrobenzyl Alcohol 619-73-8 3.8 3.8

3. Ammonium Sulphate 7783-20-2 7.17 7.17

4. Butane-1-thiol 4779-86-6 2.52 2.52

5. 2,3-Dichloro-5,6-Dicyano

benzoquinone 84-58-2

8.6 8.6

6. Triphenyl phosphine oxide 791-28-6 7.5 7.5

7. Tert-butyl fluoro dimethyl silane -- 3.4 3.4

8. Methoxy Ethanol 109-86-4 6.5 6.5

9. Dimethyl Sulfide 75-18-3 2.1 2.1

Total (By-Products) -- 55.4 55.4

List of Raw Material

Existing Products:

Sr.No. Raw Material Quantity (KG/KG)

1. 1-(4-Hydroxy Phenyl) Piperazine Hydrochloride

Bis HCL 1.88

PAP 1.18

NaOH 0.29

EDC 3.53

Acetic anhydride 1.13

Methanol 1.82

Toluene 0.59

2. 2-Chloro Ethyl Amine Hydrochloride

Monoethanolamine 0.63

Thionyl chloride 1.38

NaOH 0.16

EDC 1.88

3. N,N, Bis (2-Chloro Ethyl) Amine Hydrochloride

DiEthanolamine 0.63

Thionyl chloride 1.38

NaOH 0.16

EDC 1.88

Proposed Products:

Sr. No. Raw Materials Quantity

(KG/KG)

1. 1-(3-Chlorophenyl)-4-(3-chloropropyl) piperazine hydrochloride

MCA 2

Bis HCL 1.2

Toluene 20

Triethylamine 0.67

MDC 20

NaOH 0.27

Hydrochloric Acid (36%) 0.67

1-Bromo 3-chloro propane 1.17

Ethyl Acetate 33.33

Isopropyl Alcohol 23.33

Hexane 11.67

2. N-methyl-N-benzyl-3-hydroxy acetophenone suphate ( MAAP Sulphate)

M-Hydroxy Acetophenone 2.03

N-Methyle amine 0.47

Di isopropyl ethylamine 0.43

Toluene 10

Bromine 30

Palladium Carbon 2

n-Heptane 8

Hydrogen gas 0.03

Hydrochloric Acid 1.2

NaOH 1.33

Ethyl Acetate 110

3. N-Acetyl-Thiazolid-4-carboxylic acid

Bi cyclic ketone (BCK) Acetophenone 1.2

Amino Ethane thiol 0.28

Di-Isopropyl Amine

0.4


Acetonitrile 19

MDC 6

Formamidine 0.18

Para toluene sulfonyl chloride 0.36

Sodium Hydroxide 0.23

Hydrochloric Acid 0.22

Ethyl Acetate 18.74

Activated Carbon 0.1


Hydrogen 0.06

Methanol 17.34

Hexane

8.6

4. 1-Acetyl-4-(4’- Hydroxyphenyl) Piperazine

Bis-(2-Chloro ethyl)amine HCl 2.5

P-Amino phenol 1.55

Methanol 10

Sodium acetate trihydrate 3


Sodium hydroxide(47%) 7.13

5. Dorepenem

Methyl Vinyl Phosphate 1.5

Mercapto Pyrrolidine Chain 0.9

Acetonitrile

30

N-Ethyl Diispropyl Amine

0.5

DMF 15

NaOH 0.4

HCl (36%) 1

Palladium Carbon (10%)

1.65

Tetrahydrofuran 15

6. Candesartan & intermediates

Trityl Candisartan 1.9

Dimethyl form amide 10.35

Potassium Carbonate 1.05

Cyclohexyl,1-Chloro ethyl carbonate

0.58

Ethyl Acetate 65.4

Sodium Chloride 1.05

Sodium Sulphate 1.08

Cyclo hexane 25

MDC 6.5

Methanol 10.4

Formic Acid 0.09

Sodium Bicarbonate 1.25

Isopropyl alcohol

4.3

7. Celecoxib & intermediates

Trifluro Acetic Acid 0.56

Methanol 3.5

Sulfuric Acid 0.02

4-Methyl Acetophenone 0.58

Sodium Methoxide 0.3


Toluene 15.95

4-Amino benzene Sulfonamide 1

Hydrochloric Acid (32%) 3

Sodium Nitrite 0.4


Sodium metabisulfite 1.2

Isopropyl Alcohol

2

Ethyl Acetate 1.5



2-Thophene Ethyl Amne 0.5

Formaldehyde 0.2

Sodum Sulphate 0.38

DMF 2

Hydrochlorc Acd (25%) 0.52

Toluene 9

Acetone 12.26

PA 3.2

Bromo Ester 0.9

Sulphurc Acd 0.28

Potassum carbonate 0.4

Methanol 7.05

L(-)Camphor sulphonc acd 0.66

Soda Ash 0.5

MDC 28.65

MBK 3.3

Ethyl Acetate 1.36

Sodum bcarbonate 0.25

Sodum bsulphate 0.18

Benzene sulfonc acd 0.38

MTB Ether 5.55

Hexane 2.27

Actvated Carbon 0.1

9. Ketaconazole & intermediates

Cs-2-(2,4-dchlorophenyl)2-(1H-mdazol-1-yl-methyl)-1,3-

doxolane-4-methanol 1.0

Para Toluene Sulfonyl Chlorde 0.58

Sodum Carbonate

0.2

Methanol 9.4

Methylene Dchlorde 7

Trethyl Amne 0.35

Hydrochlorc Acd (30%) 0.5

Ethyl Acetate 8.3

n-Hexane 5

Actvated Carbon 0.2

AHPP 0.55

Dmethyl Sulfoxde 2.96

SMO Powder 0.14

CS Flakes 0.15

Acetone 5

10. Levo cetirizine dihydrochloride

p-chloro benzo phenone 1.2

Ammonum formate 0.35

Hydrochlorc acd 0.25

Toluene 16

Actvated carbon 0.1

Sodum hydroxde 0.25

Tartarc acd 0.32

MDC 16.5

para toluene sulphonyl chlorde 0.52

n,n-bs( 2-chloro ethyl)amne 0.5

HCl 0

Sodum Hydroxde 0.25

Ethyl d sopropyl amne

0.28

Methanol 4

Hydro bromc acd 0.23

Acetc acd 0.15

Chloro ethanol

0.2

Trethyl amne 0.247

Sodum mono chloro acetate 0.27


D methyl formamde 1

Actvated Carbon 0.1

Acetone 1.0

11. Levetiracetam & intermediates

(S)-2-Amnobutanamde hydrochlorde 1.25

4-Chlorobutyryl chlorde 1.4

Sodum Sulphate 1.5

Potassum Hydroxde Powder 2.57

Tetrabutyl ammonum bromde 0.09

Ethyl acetate 6.07

Methylene Dchlorde 9.7

12. Pantoprazole Magnesium & intermediates

Maltol 0.85

Dmethyl sulphate 0.45


Acetone 10

Ammonum Carbonate 0.65

Toluene 3

Phosphorous oxy chlorde 0.35

Sodum Hydroxde 0.92

Methylenedchlorde 3

Hydrogen peroxde (30%) 0.5

Acetc acd 0.45

Methanol 8.75

MDC 7

Acetc Anhydrde 0.45

Chloroform

2

Thonyl chlorde 0.39

Methylenedchlorde 8.5

5-dFluoromethoxy-2-mercapto-benzmdazole 0.7

Sodum Hydroxde flakes 0.37

Toluene 5

Sodum hypochlorte (4%) 5.1

Methylenedchlorde 10

Actvated Carbon 0.1

Magnesum chlorde (5%) 3

13. Phenylephrin Hydrochloride

3-Hydroxy Acetophenone 1

Ethyl Acetate 6

Bromne 0.6

Aluminum Chlorde 0.02

Toluene 11

10% Sodum bcarbonate 1

Sodum Sulphate 0.1

N-Methyl Benzyl Amne 0.75

IPA-HCl 2

IPA 1

Methanol 10

10% Palladum Carbon 0.15

Hydrogen gas 0.03

Actvated Carbon 0.12

Lq.Ammona 3.7

L(+) Tartarc acd 2.44

PA 8

PA HCl 4

Acetone 3

14. Prasugrel Hydrochloride

2-Bromo-1-Cyclopropyl-2-(2-Fluorophenyl) Ethanone

0.88

5,6,7,7a-Tetrahydrotheno [3,2-c] Purdne-2(4H)-one 0.54

Potassum Hydroxde 0.22

Methanol 8.76

Acetc Anhydrde 0.32

Methyl Ethyl Ketone 2.94

Hydrogen Chlorde 0.12

Acetone 3.12

15. Quetiapine fumarate

2-Amnbphenylsulphate 0.63

Phenylchlorofumarate 0.54

Toluene 5.75

phosphorc acd 0.23

Acetone 2

Pperazne 0.205

Chloro ethoxy ethanol 0.30

Fumarc acd 0.28

Methanol. 2

16. Rabeprazole Sodium

2,3-Lutdne 0.46

Hydrogen Peroxde (50%) 0.33

Ntrc acd 0.3

Sulphurc acd 1.08

Acetc acd 0.46

3-Methoxy-1-Propanol 0.4

Sodum Hydroxde 0.67

Toluene 13.5

DMSO 2

Acetc anhydrde 1.5

Hydrochlorc acd 0.2

Thonyl Chlorde 0.53

MDC

13.5

Sodum Sulphate 0.1

2-Mercaptobenzmdazole 0.53

Sodum Hypochlorte (8%) 3.27

Acetone 1.5

Sodum hydro sulphate 0.12

MMA n Methanol 0.1

Isopropyl Alcohol 3

Actvated Carbon 0.1

17. Solifenacin

2-Phenyl ethyl amne 0.6

Benzoyl chlorde 0.7

Tr ethyl amne 0.75

Chloroform 6

N-Hexane 2.75

Phosphorus pentoxde 0.76

Phosphorus oxy chlorde 0.82

Toluene 5

MDC 17

NaOH flakes 1.26

Sodum boro hydrde 0.278

Methanol 6

D(-)-Tartarc acd 0.72

PA 8.4

Sodum Hydroxde 0.38

18. Tamsulosin Hydrochloride

(S)-5-(2-amnopropyl)-2- methoxybenzene sulfonamde 0.62

2-(O-Ethoxy phenoxy)ethyl bromde 0.91

Methanol 16.02

n-Hexane 3.73

50% lye soluton

0.4

Ethyl acetate 14.28

Ethanol 99% 7.45

Ethanol HCl 1.24

Absolute ethanol

5.58

19. Telmisartan

OTBN 0.45

Ethylene glycol 0.15

Potassum Hydroxde 0.37


D methyl sulphate 0.30

Potassum Carbonate 0.32

D bromo d methyl hydanton 0.67

Acetone 12.52

Cyclohexane 1.8

Actvated Carbon 0.35

MDC 10

2-n-Propyl-4-methyl-6-(1- methylbenzmdazole-2-

yl)benzmdazole 0.71

DMF 0.7

Methanol 6.8

20. Bortezomib

so Butyl Boronc Acd 0.8

N-Heptane 43.6

Pnanedol 1.8

Sodum Chlorde 0.12

Znc Chlorde 0.72

THF 26

N-Hexyl Lthum 9.5

D so Propyl Amne 0.54

MDC 73

Sulphurc acd

0.52

HMDS 0.8

DPE 2.7

Tr Fluoro Acetc Acd 0.46

Dsopropyl Ether 45

L-Phenyl Alanne 0.9

Thonyl Chlorde 0.7

Methanol 41.5

PA 4.5

Pyrazne Carboxylc acd 0.5

DMF 10

N-Hydroxy Succnamde 3

D Cyclohexyl Carbodmde 1

N-Methyl Morpholne 0.7

Ethyl Acetate 18

Acetone 4

Sodum Hydroxde 0.2

Hydrochlorc Acd 0.82

N-Hydroxysuccnamde 0.5

Dcyclohexyl dcarbodmde 0.8

D sopropyl ethylamne 0.9


Bortezomb base 1.5

sobutyl boronc Acd 0.3

21. Trimebutne Maleate

Methyl-2-(d methyl amno)-2-phenylbutyrate 0.55

70%Vtrde Toluene soluton 1.02

Toluene 9

Sodum hydroxde flake

0.1

Sodum sulphate 0.05

3,4,5-Trmethoxy benzoc acd 0.47

Trphosgene 0.67

DMF

0.01

Methanol 5

Trethyl Amne 0.23

Sodum sulphate 0.07

Malec acd 0.23

22. Cabergolne

Lysergol 1.4

Trethyl amne 0.56

Tert-butyldmethyl slyl chlorde 0.84

4-Dmethyl amno pyrdne 0.2

DMF 8

Palladum carbon 0.04

MDC 22

N-Heptane 4

Hydrogen gas 0.01

Ntrogen Gas 0.04

Chloro ethyl formate 0.4

Methanol 13


Sodum chlorde 0.2

Toluene 8

4-Dmethylamno pyrdne 0.4

D-tert-butyl dcarbonate 0.8

TBAF 0.2

Acetc acd 0.4

Acetontrle 8

THF 6

TEMPO 0.2

odobenzene dacetate 0.1

Sodum thosulphate 0.24

Thonyl chlorde 0.4

MDC 8

Allyl bromde 0.4

Sodum hydroxde 0.14

TEA 0.34


EDC Free base 0.42

Alumna 0.1

MTBE 6

Acetone 4

n-Heptane 2

Actvated carbon 0.2

23. Mycophenolate Mofetl

Mycophenolc acid 1

Methanol 6.4

Sulphuric acid 0.335

Morpholne ethanol 0.4

Znc oxde 0.048

Ethyl acetate 12

Sodum hydroxde 0.26


Phosphorc acd 0.012

Actvated carbon

0.2

24. Raloxfene Hydrochlorde

4[2-(1-pperdnoethoxy)]benzoc acd hydrochlorde

1

Thonyl chlorde 0.416

Toluene 8

Heptane 6

6-Methoxy-2-(4-methoxyphenyl)benzo(b)thophene 0.9

MDC 12

Ntrogen Gas 0.1

Alumnum chlorde 0.6

Ethane thol 0.2

Methanol 18

Hydrochlorc acd (10%) 1.4

DMF 2

Actvated carbon

0.2

25. Febuxostat

2-(4- hydroxyphenyl)-4-methyl-5- thazole carboxylc Acid ethyl

ester 1.4

Polyphosphouric acid 1.8

Hexamethyl tetramanine 0.2

Acetic Acid 0.32

DMF 11


sobutyl bromde 0.57

Hydorxyl amne Hydrochlorde 0.28

Formc acd 0.19

Sodum Formate 0.27

THF 25

Sodum hydroxde 0.16

Ethanol 15


Actvated carbon 0.1

26. Pregabalin

Isoveraldehyde 0.89

Diethyl malonate 1.68

Acetic acid 1.21

Di isopropyl amine 0.09

n-Hexane 1.64

Sodium cyanide 0.43

Ethanol 8.64

Toluene 4.55

Methanol 2

Potassium hydroxide 0.45

Raney nickel 0.27

IPA 3.18

Hydrogen gas 0.05

(S)-Mandelic acid 1.07

Isopropyl alcohol 8.73


4-Fluoro benzaldehyde 0.52

4-Methyl-3-oxo-pentanoic acid 0.663


Methyl Iodide 0.6

Methanol 5.5

S-Methyl iso thio urea 0.35

2,3-Dichloro-5,6-dicyano 0.85

HMPA 1

MDC 8

Meta chloro peroxy benzoic acid 1.19

Methyl amine 0.10

Ethanol 2.5

Methane sulfonyl chloride 0.35

Sodium hydride (60%) 0.01

Di methoxy ethane 3

Hydrogen 0.01

DIBAL-H 0.01

Toluene 8

Methyl(3R)-3-(tert butyl di methyl silyloxy)-5-oxo-6-triphenyl

phosphoranylidene hexanoate 1.45

Triethyl amine 0.15

N,N-Dimethyl formamide 3

Hydrogen fluoride 0.05

Ethyl acetate 10.5

Diethyl methoxy borane 0.2

Sodium boro hydride 0.01

THF 5

Calcium chloride 0.13

28. Biperiden Hydrochloride

Cyclo pentadiene 0.3

Methyl vinyl ketone 0.32

Sodium hydroxide 0.35

Methanol 5

Piperdine Hydrochloride 0.5

Para formaldehyde 0.15

Isopropyl alcohol 10

Phenyl magnesium chloride 0.5

Hydrochloric acid 0.2

THF 5

1,4-Dioxane 4


29. Donepezil Hydrochloride

Ethyl isonipecotate 0.75

Benzyl chloride 0.62

Toluene 14

Potassium carbonate 0.35

Vitride 0.86

Dimethyl sulfoxide 0.3

Hydrobromic Acid (48%) 0.3

5,6-Dimethoxy indanone 0.57

Methanol 8

Raney Nickel (catalyst) 0.1

Hydrogen 0.02

Isopropyl alcohol 3

Hydrogen chloride 0.2

30. Domperidone

N-Carbethoxy-4-piperidone 1.6

Ammonia gas 0.56

Methanol 16

Raney Nickel 0.6

Hydrogen 0.1

2,5-Dichloro Nitrobenzene 1.56

Sodium Carbonate 0.6

Hydrogen 0.1

Toluene 7

Urea 0.4

Sodium Hydroxide (48%) 1.5

1-(3-Chloropropyl)-1,3-dihydro- 0.8

2H-benzimedazole-2-one 0

Sodium Carbonate 0.4

Methyl Isobutyl Ketone 24

31. Carisoprodol

2-Methyl-2-propyl-1,3-propane diol 0.78

Dimethyl carbonate 1.1

Toluene 8.1

Sodium methoxide 0.06

Isopropylamine 1.64

Sodium cyanate 0.315

Chloroform 6.3

Hydrochloric acid (35%) 1

Sulphuric acid 0.5

Carisoprodol (Tech) 1.12

Methanol 3.35

Activated carbon

0.15

32. Topiramate

Fructose 1.15

Sulfuric Acid 0.31

Acetone 4.2


n-Hexane 0.1

Toluene 3.2

Pyridine 0.24

Ammonia gas 0.05

Sulfonyl Chloride 0.42

Sodium bicarbonate 0.01

n-Hexane 2.64

Sodium Chloride 0.01

Ethyl Acetate 3.22

Isopropyl Alcohol 2.83

33. Valsartan

L-Valine 0.45

Thionyl Chloride 0.457

Methanol 8

Toluene 25

4-Bromomethyl-biphenyl-2- carbonitrile 0.82


Valeryl Chloride 0.34

TEA 0.2

Sodium bicarbonate 0.25

Sodium Sulphate 0.1

Sodium Azide 0.16

Tri butyl tin chloride 0.8

Hydrogen 0.005


Xylene 2.4

MDC 5

Acetic Acid 0.4

N-Hexane 2


34. Moxifloxacin Hydrochloride

Moxifloxacin Q-Acid 0.9

2,8-Diazobicyclo(4.3.0)nonane 0.4

Triethylamine 0.32

Acetone 4

Dimethylformamide 2

Moxifloxacin Base 1.06


Methanol 10

EDTA 0.02


35. Cinnarizine

1-Benzhydryl piperazine 1.06

Cinnamyl chloride 0.93


Ethyl acetate 9.15

Methanol 1.9

Activated carbon 0.08

Hyflow 0.05

36. Cyano Diol Base

Para Bromo fluoro benzene 0.27

Magnesium turnings 0.10

Ethylene dibromide 0.04

THF 5.73

Dimethl amino propyl chloride 12.14



hydrochloric acid 1.4

Magnesium turnings 0.55

Iodine 0.17

5-Cyano phthalide 0.67

THF + Toluene 14.6

Uene 29.75

Acetic acid 3.4

37. Dextromethorphan Hydrobromide

PMPPA 4.94

CHEA 3.72

Phosphorous oxy chloride 4.57

Caustic lye 3.17

Toluene 25.89

Mandelic acid 0.61

Formic acid 0.15

Sodium methoxide powder 0.04

Phosphoric acid 16.28

Phosphorous pentoxide 0.59

Methanol 2.70

CS Lye 1.74

Formaldehyde 0.5

Acetone 1.79

Activated carbon 0.05

Hyflow 0.05

38. 2-Amino-5-Methyl Thiazol

Propionaldehyde 0.77

Sulphuryl Chloride 0.19

NaOH 0.02

Thiourea 0.42

ANNEXURE: 3

BRIEF MANUFACTRING PROCESS, CHEMICAL REACTION AND MASS BALANCE WITH FLOW

DIAGRAM

Existing Products: [1] 1-(4-Hydroxy Phenyl) Piperazine Hydrochloride

Manufacturing Process:

The mixture of Bis-(2-chloro ethylamine) hydrochloride para amino phenol ,Methanol was heated to

reflux (70-850C) & progress of the reaction was monitored by TLC.On completion the reaction mass

was cooled to 300C and further chilled to 0-5

oC when product crystallizes asoff white crystals this

product taken in reactor with water and methanol than slowly cooled 100C to 15

0C than slowly

addition acetc anhydride and progress of the reaction was monitored by TLC.On completion the

above solid was then dissolved in 30% sodium hydroxide sol. (100 ml) & warmed to 400C when a

clear sol. Was obtained.The sol. was then slowly cooled to 00C when product crystallizes as sodium

salt & thick slurry was obtained.The sodium salt of the product was isolated by filtration and washed

with chilled (00C,200ml) prior to drying at 70

0C under reduced pressure (10mm/Hg) for 12 hrs.

Chemical Reaction:

Mass balance:

INPUT QTY (kg) OUTPUT QTY (kg)

Bis HCL 160 Finish Product 85

PAP 100 Methanol Recovery 275

NaOH 25 Methanol Loss 25

EDC 300 Toluene Recover 45

Acetic anhydride 96 Toluene Loss 5

Methanol 155 Sodium Acetate 451

Toluene 50

TOTAL 886 TOTAL 886

[2] 2-Chloro Ethyl Amine Hydrochloride


In a dry GL fitted with a sealed mechanicals stirrer, an efficient reflux condenser, and addition flask

is placed of Thionyl Chloride and Ethylene Dichloride. Throughout, the entire period of operation,

as the reaction is very exothermic. Monoethanol amine is added through the flask and slow

addition.The cooled mass over a period of an hour, during which time there is a copious evolution

of sulfur dioxide. After all the Diethanol amine has been added, the cooling is stop and the reaction

mixture.

Chemical Reaction:

OH-CH2- CH2-NH2 + SOCl2 Cl-CH2- CH2-NH2.HCl + SO2

Monoethanolamine Thionyl Chloride 2-Chloro ethyl amine HCl Sulphur oxide

Or

Mass balance:

INPUT QTY (kg) OUTPUT QTY (kg)

Monoethanolamine 100 Finish Product 160

Thionyl chloride 220 EDC Recovery 275

NaOH 25 EDC Loss 25

EDC 300 NaSO4 40

HCl 25 % 145

TOTAL 645 TOTAL 645

EDC (Media)

[3] N,N, Bis (2-Chloro Ethyl) Amine Hydrochloride


In a dry GL fitted with a sealed mechanicals stirrer, an efficient reflux condenser, and addition flask

is placed of Thionyl Chloride and Ethylene Dichloride. Throughout the entire period of operation the

reaction is very exothermic. Diethanol amine is added through the flask and slow addition. The

cooled mass over a period of an hour, during which time there is a copious evolution of sulfur

dioxide after all the Diethanol amine has been added, the cooling is stop and the reaction mixture.

Chemical Reaction:

2(OH-CH2- CH2)NH2 + 2SOCl2 2(Cl- CH2- CH2)NH2 .HCl + SO2

Di Ethanol amine Thionyl Chloride Bis(2-Chloro ethyl)amine HCl Sulphur

oxide

Or

Mass Balance:

INPUT QTY (kg) OUTPUT QTY

(kg)

DiEthanolamine 100 Finish Product 160

Thionyl chloride 220 EDC Recovery 275

NaOH 25 EDC Loss 25

EDC 300 NaSO4 40

HCl 25 % 145

TOTAL 645 TOTAL 645

EDC (Media)

Proposed:

1. 1-(3-Chlorophenyl)-4-(3-chloropropyl) piperazine hydrochloride


Stage-1:

M-Chloroaniline is reacted with BIS HCl in presence of base in water to give crude T1. Pure T1 is

obtained after fractional distillation.

Stage-2:

Pure T1 is reacted with 1-bromo-3-chloropropane in presence of caustic lye in water and after

workup obtained 1-(3-chlorophenyl)-4-(3-Chloropropyl) Piperazine Hydrochloride (T2.HCl) by

adjusting pH with Con. HCl.

Chemical Reaction:

Flow Diagram:

Mass Balance:

1 (3-CHLORO PHENYL) PIPERAZINE Stage-1

Name of the input Quantity Name of the out put Quantity

in Kg in Kg

MCA 60.00 Product T1 60.00

Bis HCL 36.00 Toluene Recovery 560.00

Toluene 600.00 Toluene Loss 30.00

Triethylamine 20.00 MDC Recovery 570.00

MDC 600.00 MDC Loss 30.00

NaOH 8.00 Effluent water 1294.00Hydrochloric Acid (36%) 20.00 (Water-1200,gen.water-

26,Sodium chloride-

6, Toluene -10,Diphenyl

phosphoric acid-27,Triethyl

amine-25)

Water 1200.00

Total 2544.00 Total 2544.00

1-(3-Chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride

Stage-2


in Kg in Kg

Product T1 60.00 Product 30.00

1-Bromo 3-chloro propane 35.00 Ethyl Acetate Recovery 970.00

Ethyl Acetate 1000.00 Ethyl Acetate Loss 30.00

Isopropyl Alcohol 700.00 Isopropyl Alcohol Recovery 670.00

Hexane 350.00 Isopropyl Alcohol Loss 25.00

Water 950.00 n-Hexane Recovery 335.00

n-Hexane Loss 15.00

Effluent Water 952.00

(Water-947,Isopropyl Alcohol-5)

10% Palladium Carbon Reuse 34.50

Organic Residue 6.10

By Products

4-Nitro Toluene 27.40

Total 3095.00 Total 3095.00

2. N-methyl-N-benzyl-3-hydroxy acetophenone suphate ( MAAP Sulphate)


Stage-1:

Brief Description; M-hydroxy aceto phenone reacts with bromine in presence of aluminium

chloride to form M-hydroxyl bromo aceto phenone which will react with N-methyl benzyl amine

in presence of.

Chemical Reaction:

M-hydroxy aceto phenone N-methyl benzyl amine

Flow Diagram:

M-hydroxy Acetophenone

N-methyle amine

Toluene Rec Di isopropyl ethylamine

toluene Stage-1 HBr Rec

Bromine n-Heptane Rec Palladium Carbon n-

Heptane

N-methyl-N-benzyl-3-hydroxy acetophenone suphate( MAAP Sulphate)

Mass Balance:


in Kg in Kg

M-Hydroxy Acetophenone 60.95 Product 30.00

N-Methyle amine 14.20 Toluene Recovery 270.00

Di isopropyl ethylamine 13.00 Toluene Loss 25.00

Toluene 300.00 Bromine Recovery 880.00

Bromine 900.00 Bromine Loss 20.00

Palladium Carbon 60.00 n-Heptane Recovery 225.00

n-Heptane 240.00 n-Heptane Loss 15.00

Hydrogen gas 1.00 Ethyl Acetate Recovery 3250.00

Hydrochloric Acid 36.00 Ethyl Acetate Loss 50.00

NaOH 40.00 Effluent Water 4868.20

Ethyl Acetate 3300.00 (Water-4800,Acetonitrile-5,DIPA

HCl-16.7,gen.Water-20

,Diphenyl phosphoric acid

sodium-26.5)

DM Water 4800.00 Organic Residue 58.25

Palladium Carbon Re Use 60.00

By Products

Methylamine Re Use 13.70

Total 9765.15 Total 9765.15

3. N-Acetyl-Thiazolid-4-carboxylic acid


Stage-1:

Bi cyclic ketone Acetophenone reacts with amino ethane thiol in presence of Di isopropyl amine as

a solvent of Acetonitrile and MDC, After PH adjustment with Hydrochloric Acid get Stage-1.

Stage-2:

Stage -1 reacts with Formamidine in presence of Para toluene sulfonyl chloride .After filtration get

Stage-2

Stage-3:

Stage-2 reacts with Hydrogenation, Palladium carbon as a catalyst, Ethyl acetate using as a solvent.

After Filtration get Imipenem Product

Chemical Reaction:

N-Acetyl-Thiazolid-4-carboxylic acid

Mass Balance:

Stage-1 N-Acetyl-Thiazolid-4-carboxylic acid

Material Balance of N-Acetyl-Thiazolid-4-carboxylic acid

Stage-2 Name of the input Quantity Name of the out put Quantity

in Kg in Kg

Stage-1 700.00 Stage-2 (IMI) 774.63

Formamidine 9.15 Acetonitrile Recovery 315.00

Para toluene sulfonyl chloride 17.80 Acetonitrile Loss 25.00

Sodium Hydroxide 11.28 Ethyl Acetate Recovery 65.00

Hydrochloric Acid 11.16 Ethyl Acetate Loss 5.00

Acetonitrile 350.00 Effluent Water 950.22

Ethyl Acetate 70.00 (Water-900,Sodium Chloride-

16.5,Formic Acid-

7.12,Acetonitrile-10,Para

Toluene sulfonic acid-16.60)

Activated Carbon 5.00 Organic Residue 9.54

Water 900.00

Total 2074.39 Total 2074.39


in Kg in Kg

Bi cyclic ketone (BCK)

Acetophenone 60.00 Stage-1 (S-Alkyl BCK) 70.00

Amino Ethane thiol 14.00 Acetonitrile Recovery 560.00

Di-Isopropyl Amine 20.00 Acetonitrile Loss 30.00

Hydrochloric Acid (36%) 18.00 MDC Recovery 278.00

Acetonitrile 600.00 MDC Loss 22.00

MDC 300.00 Effluent Water 1252.00

DM Water 1200.00 (Water-1200,gen.Water-

4.0Acetonitrile-10,Di Isopropyl

Amine HCl-38)

Total 2212.00 Total 2212.00

Material Balance of N-Acetyl-Thiazolid-4-carboxylic acid Stage-3


in Kg in Kg

Stage-2 74.63 Stage-3 (IMI) 50.00

Acetic anhydride 173.00 Ethyl Acetate Recovery 823.00


Hydrogen 3.00 Methanol Recovery 815.00

Methanol 867.00 Methanol Loss 32.00

Hexane 430.00 n-Hexane Recovery 390.00

Water 1000.00 n-Hexane Loss 40.00


(Water-1000,Methanol-5)


Spent Palladium Carbon 173.53

By Product

(4-Nitro Toluene) 23.60

Process Emission 1.50

(Hydrogen)

Total 3414.63 Total 3414.63

4. 1-acetyl-4-(4-Hydroxy phenyl) Piperazine


Stage-1

Bis-(2-Chloro ethyl)amine HCl undergoes condensation with P-Amino phenol and further treatment

with Acetic anhydride in the presence of Methanol as a solvent media to give Stage-1 as product.

Stage-2

Stage-1 undergoes hydrolysis with aq.Sodium hydroxide in water media to give 1-(4-Hydroxy

phenyl)Piperazine as product.

Chemical Reaction:

Mass Balance:

Material Balance of 1-acetyl-4-(4-Hydroxy phenyl)Piperazine Stage-1


in Kg in Kg

Bis-(2-Chloro ethyl)amine HCl 250.00 Stage-1 135.00

P-Amino phenol 155.00 Methanol Recovery 946.00


Sodium acetate trihydrate 300.00 Effluent water 6246.72

Acetic anhydride 250.00 (Water-5000,Acetic acid-279.48,

Sodium chloride-292.58,

Generated water-169.51,Sodium

hydroxide-258.5,Water from

Sodium hydroxide-241.5,P-

Amino phenol-2.15,Methanol-3)

Sodium hydroxide(47%) 550.00 Organic Residue 127.28

Water 5000.00

(Organic impurities-

126.28,Methanol-1)

Total 7505.00 Total 7505.00

Material Balance of 1- acetyl-4-(4-Hydroxy phenyl)Piperazine Stage-2


in Kg in Kg

Stage-1 135.00 1-(4-Hydroxy phenyl)Piperazine 100.00

Sodium hydroxide(47%) 163.00 Effluent water 2888.74

(Water-2700,Water from Sodium

Water 2700.00 hydroxide-86.39,Sodium acetate

-50.25,Sodium hydroxide-52.10)


Total 2998.00 Total 2998.00

5. Dorepenem


Stage-1:

Methyl Vinyl Phosphate reacts with Mercapto pyrrolidine side chain, Sodium hydroxide in

presence of N-Ethyl diisopropyl amine as a Solvent of DMF. After PH adjustment with

Hydrochloric Acid get Stage-1.

Stage-2:

Protected Dorepenem Reacts with Hydrogen gas in presence of Palladium carbon as a

Catalyst.After Filtration get Dorepenem Product and get 4-Nitro benzyl alcohol By product.

Chemical Reaction:

Stage-I

OH

HS

O

H H

CH 3 O H

S NH 2

H3C N

O P OP h N O

N

OP h

O

O O

O

O

+

+ N-Ethyl diisopropyl amine.

DMF

NO 2

NO 2

(2S,4S)-1-p-nitrobenzyloxycarbonyl

Enolphosphate -2-sulfamylaminomethyl-4-mercapto

pyrrolidine.

C13

H18

N4

O6

S2

C

31

H32

N2

O9

P

Mol. Wt.: 390.44

Mol. Wt.: 607.57

NH 2

O

S

O

HN

O

CH 3

OH

OP h

H H

NH +

2 P

+ N-DIPEA.HCl+ NaCl

H3C

OP h

S

N

Di phenyl phosphoric acid

O

O

C13

H15

O4P

O

Mol. Wt.: 266.23

C

23

H33

N5

O7

S2

Mol. Wt.: 555.67 NO 2

PROTECTED DORIPENEM

Stage-II

O

NH2

S

O

NH2

HN

O

OHHH

CH3

S

O

NH

10%Pd/C /THF/Water HN

H3C OH

S

CH3

N HH

NH

O

O

H3C

S H

O

N

O OH

C23

H33

N5

O7

S2

O

C16H28N4O5S2

Mol. Wt.: 555.67 NO2

Mol. Wt.: 420.55

PROTECTED DORIPENEM DOREPENEM

Mass Balance:

Material balance of Dorepenem

Stage-1


in Kg in Kg

Methyl Vinyl Phosphate 30.00 Stage-1 27.70

Mercapto Pyrrolidine Chain 18.00 Acetonitrile Recovery 270.00

Acetonitrile 300.00 Acetonitrile Loss 20.00

N-Ethyl Diispropyl Amine 10.00 DMF Recovery 265.00

DMF 300.00 DMF Loss 30.00


HCl (36%) 10.00 (Water-600,Sodium Chloride-

5.85,n-DIPEA HCl-

12.8,Acetonitrile-10,DMF-

5,Diphenyl phosphoric acid-

13.15)

Water 600.00 Organic Residue 12.50

Total 1272.00 Total 1272.00

Material balance of

Dorepenem

Stage-2


in Kg in Kg

Protected Dorepenem (Stage-1) 27.70 Dorepenem 20.00

Palladium Carbon (10%) 33.00 Acetonitrile Recovery 270.00

Acetonitrile 300.00 Acetonitrile Loss 25.00

Tetrahydrofuran 300.00 THF Recovery 270.00

DM Water 1000.00 THF Loss 30.00


HCl (36%) 10.00 (Water-1000,Sodium Chloride-

5.85,gen.Water-

4.93,Acetonitrile-5)

Palladium Carbon Re Use 33.00

By Product

4-Nitrobenzyl Alcohol 7.63


Total 1674.70 Total 1674.70

6. Candesartan & intermediates


Stage-1

2-Ethoxy-3-((2'-(2-trityl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-3H-benzo[d]imidazole-4-

carboxylic acid is condensed with 1-Chloroethyl cyclo hexyl carbonate in presence of

potassium carbonate and Dimethyl formamide gives 1-(Cyclo hexyloxycarbonyloxy)ethyl 2-

ethoxy-3-((2'-(2-trityl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-3H-benzo[d]imidazole-4-

carboxylate.

Stage-2

1-(Cyclo hexyloxycarbonyloxy)ethyl 2-ethoxy-3-((2'-(2-trityl-2H-tetrazol-5-yl)biphenyl-4-

yl)methyl)-3H-benzo[d]imidazole-4-carboxylate reaction with formic acid gives

Candesartan Cilexetil.

Chemical Reaction:

Mass Balance:

Material Balance of Candesartan Stage-1


in Kg in Kg

Trityl Candisartan 38.00 Stage-1 35.00

Dimethyl form amide 207.00 Dimethyl form amide Recovery 192.00

Potassium Carbonate 21.00 Dimethyl form amide Loss 10.00

Cyclohexyl,1-Chloro ethyl 11.50 Cyclo hexane Recovery 152.00

carbonate

Ethyl Acetate 840.00 Cyclo hexane Loss 8.00

Sodium Chloride 21.00 Ethyl Acetate Recovery 798.00

Sodium Sulphate 21.57 Ethyl Acetate Loss 42.00

Cyclo hexane 160.00 Effluent Water 1390.53

Water 1320.00

(Water-1320,Sodium chloride-21,HCl-2.03, DMF-5

Potassium sulphate-26.4,

Sodium carbonate-16.1)

Organic Solid waste 12.54

Total 2640.07 Total 2640.07

Material Balance of Candesartan


in Kg in Kg

Stage-1 35.00 Candesartan 20.00

Ethyl Acetate 468.00 MDC Recovery 124.00

Cyclo hexane 340.00 MDC Loss 6.00

MDC 130.00 Cyclo hexane Recovery 323.00

Methanol 208.00 Cyclo hexane loss 17.00

Formic Acid 1.88 Isopropyl alcohol Recovery 80.00

Sodium Bicarbonate 25.00 Isopropyl alcohol Loss 4.00

Isopropyl alcohol 86.00 Ethyl Acetate Recovery 445.00

Water 920.00 Ethyl Acetate Loss 23.00

Methanol Recovery 193.00

Methanol Loss 10.00


(Water-919.27,Trityl alcohol-

10.68,Isopropyl alcohol-2,Methanol-

5,Sodium bicarbonate-25)


(Carbondioxide-1.79,Hydrogen-0.08)


Total 2213.88 Total 2213.88

7. Celecoxib & intermediates


Stage-1:

Trifluoro acetic Acid is esterification with Methanol to give Stage-1 Intermediate.

Stage-2:

Stage-1 Intermediate is reacts with 4-Methyl Acetophenone in the presence of Sodium

Methoxide and Hydrochloric acid in Toluene media to get Stage-2 Intermediate.

Stage-3:

Sulfanilamide is diazotized with Sodium Nitrite and reduced with Sodium Metbisulfate in

Isopropyl Alcohol Solvent media to give Stage-3 Intermediate.

Stage-4:

Stage-2 Intermediate is reacts with Stage-3 Intermediate is Ethyl Acetate Solvent media to

get Celecoxib Crude.

Stage-5:

Celecoxib Crude is purified in Toluene media to get Celecoxib Tech.

Stage-6:

Celecoxib Tech is purified in the presence of Carbon in Toluene Solvent media to get

Celecoxib Pure.

Chemical Reaction:

Stage-3

O O

S

H2N

+ NaNO2 + 2HCl + 2NaOH + Na S O 5

2 2

NH2

4-Aminobenzene sulfonamide Sodium Nitrite Hydrochloric Acid Sodium Hydroxide Sodium metabisulfite

(172) (69) (36.5) (40) (190)

O O

S

+

H2N

NH2.HCl + NaCl + H2O 2Na2SO4

NH

4-Sulfonamido Phenyl Hydrazine HCl Sodium Chloride Water Sodium Sulfate

(223.5) (58.5) (18) (142)

Stage-5

O O O O

H N S

H2N S

2

N

N Toluene N

N

CF CF3

3

H C H3C

3

Celecoxib Crude Celecoxib Tech

C

17

H14

F3

N3

O2

S

C17

H14

F3

N3

O2

S

381.37

381.37

Stage-6

O O O O

S

S

H2N

H2N

N N Toluene N

N

CF3

CF3

H3C H3C

Celecoxib Tech Celecoxib

C17

H14

F3

N3

O2

S

C17

H14

F3

N3

O2

S

381.37 381.37

Mass Balance:

Stage-1


in Kg in Kg

Trifluro Acetic Acid 56.00 Stage-1 55.00

Methanol 350.00 Methanol Recovery 314.30

Sulfuric Acid 2.00 Methanol Loss 17.00

Water 300.00 Effluent Water 313.84

(Water-300,generated water

8.84, Sulfuric Acid-2,Methanol-3)


Total 708.00 Total 708.00

Stage-2


in Kg in Kg

Stage-1 55.00 Stage-2 82.00

4-Methyl Acetophenone 57.50 Toluene Recovery 525.00

Sodium Methoxide 30.00 Toluene Loss 22.00

Hydrochloric Acid (35%) 65.00 Effluent Water 612.68

Toluene 550.00 (Water-500,Sodium Chloride-32.5,

HCl-2.48,Methanol-35.5,Water

from HCl-42.2)


(Organic Impurities-11.32,

Toluene-3)

Total 1256.00 Total 1256.00

Stage-3


in Kg In Kg

4-Amino benzene Sulfonamide 100.00 Stage-3 80.00

Hydrochloric Acid (32%) 300.00 Isopropyl Alcohol Recovery 188.00

Sodium Nitrite 40.00 Isopropyl Alcohol Loss 10.00

Ice Blocks 200.00 Effluent Water 811.90

Sodium Hydroxide 52.00 (Water-750,generated water-

10.4,Sodium chloride-34,Sodium

metabisulfite-10,IPA-2,Sodium

hydroxide-5.5)

Sodium metabisulfite 120.00 Spent Hydrochloric Acid 457.50

Isopropyl Alcohol 200.00 Inorganic Solid Waste 165.00

Water 750.00 (Sodium Sulfate)


Total 1762.00 Total 1762.00

Stage-4


in Kg in Kg

Stage-2 82.00 Celecoxib Crude 125.00

Stage-3 80.00 Ethyl Acetate Recovery 139.50



(Water-250,gen.Water-12.8,Ethyl

Acetate-1.5)


(Organic Impurities-11.2,Ethyl

Acetate-1.5)


(Hydrogen Chloride)


Stage-5


in Kg in Kg

Celecoxib Crude 125.00 Celecoxib Tech 106.00

Toluene 570.00 Toluene Recovery 540.00

Activated Carbon 12.50 Toluene Loss 23.00


(Water-625,Toluene-3,Organic

Impurites-9)

Spent Carbon 12.50


(Organic Impurites-10,Toluene-4)

Total 1332.50 Total 1332.50

Stage-6


in Kg in Kg

Celecoxib Tech 106.00 Celecoxib Pure 100.00


Activated Carbon 10.00 Toluene Loss 19.00


(Water-318,Toluene-1)


(Organic Impurities-6,Toluene-

8.0)

Spent Carbon 10.00




Stage-1

Step-A

Thiopene-2-Ethyl Amine reacted with formaldehyde in the presence of Toluene to get

CPG-I (A)

Step-B

CPG-I (A) reacted with Hydrochloride in the presence of Dimethyl formamide and

Toluene to get 4,5,6, 7-Tetrahydrothieno (3,2-C) Pyridine Hydrochloride.

Stage-2

Stage-1 is reacted- bromowith-2-chloroMethylphenylacetateα in the presence of

methanol to get RS-Clopidogrel Bisulphate

Stage-3

Stage-2 is reacted with L-Comphour sulphonic acid and purified in Acetone to get S(+)

Clopidogre Camphor Sulphonate.

Stage-4

Stage-3 is reacted with Sodium bicarbonate in the presence of Methylene chloride to get

Clopidogrel Base

Stage-5

Stage-4 reacted with Benzene sulphonic acid and further purified with MTB ether, Acetone

and Hexane to get Clopidogrel Besilate Crude

Stage-6

Stage-5 further purified with MTB ether, Acetone and Hexane to get pure

Clopidogerel Besilate

Chemical Reaction:

Mass Balance:

Materal balance of Clopdogrel Beslate Stage-1

Name of the Input Quantty Name of the out put Quantty

n Kg n Kg

2-Thophene Ethyl Amne 50.00 Stage-1 60.00

Formaldehyde 20.00 Toluene Recovery 473.00

Sodum Sulphate 5.00 Toluene Loss 25.00

DMF 200.00 DMF Recovery 190.00

Hydrochlorc Acd (25%) 52.00 DMF Loss 9.00

Toluene 500.00 PA Recovery 304.00

Acetone 120.00 PA Loss 16.00

PA 320.00 Acetone Recovery 114.00

Water 500.00 Acetone Loss 5.00


(Water-500,water from

Hydrochlorde-39,generated

water-7.0,Formaldehyde-

8.2,Hydrochlorc acd-0.1,DMF-1,

Acetone-1)

norganc Sold waste

Sodum sulphate 5.00

Organc Resdue 9.70

(Organc mpurtes-7.7,Toluene-

2)

Total 1767.00 Total 1767.00



n Kg n Kg

Stage-1 60.00 Stage-2 120.00

Bromo Ester 90.00 Methanol Recovery 452.00

Sulphurc Acd 28.00 Methanol Loss 20.00

Potassum carbonate 40.00 Toluene Recovery 380.00

Methanol 475.00 Toluene Loss 20.00

Toluene 400.00 Acetone Recovery 330.00

Acetone 350.00 Acetone Loss 17.00


(Water-600,generated water-

5.13,Potassum chlorde-21.24,

Potassum bromde-

33.83,Organc Compound-15,

Methanol-2,Acetone-1)

Organc Resdue 13.26

(Organc mpurtes-

10.26,Methanol-1, Acetone-2)

Process Emsson

Carbon doxde 12.54

Total 2043.00 Total 2043.00



n Kg n Kg

Stage-2 120.00 Stage-3 140.00

L(-)Camphor sulphonc acd 66.40 MDC Recovery 1348.00

Soda Ash 50.00 MDC Loss 50.00

Sodum Sulphate 15.00 MBK Recovery 315.00

MDC 1400.00 MBK Loss 15.00

MBK 330.00 Ethyl Acetate Recovery 130.00


Acetone 178.00 Acetone Recovery 169.00

Water 2250.00 Acetone Loss 8.00


(Water-2250,Soda ash-

50,Sulfurc Acd-28,Acetone-2)

norganc Sold waste

Sodum sulphate 15.00

Organc Resdue 19.40

(Organc mpurtes-16.4,MDC-

2,Acetone-1)

Total 4545.40 Total 4545.40

Materal balance of Clopdogrel Beslate

Stage-4


n Kg n Kg

Stage-3 140.00 Clopdogrel Base 77.00

MDC 1465.00 MDC Recovery 1392.00

Sodum bcarbonate 25.00 MDC Loss 70.00

Sodum bsulphate 17.50 Effluent Water 967.50

Sodum sulphate 17.50 (Water-925,Sodum bcarbonate-

25,Sodum bsulphate-17.5)

Water 925.00 L-Camphor Sulphonc Acd 58.70

norganc Sold waste

Sodum sulphate 17.50

Organc Resdue 7.30

(Organc mpurtes-4.3,MDC-3)

Total 2590 Total 2590.00


Stage-5


n Kg n Kg

Clopedogrel Base 77.00 Clopdogrel Beslate crude 105.00

Benzene sulfonc acd 37.90 Acetone Recovery 258.00


MTB Ether 340.00 MTB Ether Recovery 320.00

Hexane 100.00 MTB Ether Loss 17.00

Actvated Carbon 10.00 Hexane Recovery 95.00

Hexane Loss 5.00

Spent Carbon 10.00

Organc Resdue 14.90

(Organc mpurtes-9.9,Acetone-

2, MTBE-3)



Stage-6


n Kg n Kg

Clopdogrel beslate crude 105.00 Clopdogrel Beslte 100.00


MTB Ether 215.00 Acetone Loss 14.00

Hexane 127.00 MTB Ether Recovery 203.00

Methanol 230.00 MTB Loss 10.00

Hexane Recovery 122.00

Hexane Loss 5.00


Methanol Loss 11.00

Organc Resdue 10.00

(Organc mpurtes-5,MTB Ether-

2,Methanol-2, Acetone-1)


9. Ketaconazole & Intermediates:


Stage-1

Cis-imdazole Alcohol reacted wth p-Toluene Sulfonyl chlorde n the presence of sodum

carbonate and Methanol and MDC solvent meda to produce cs-Tosylate as a Stage-1

Stage-2

Cs-Tosylate reacted wth 1-Acetyl-4-(4-hydroxyphenyl) piperazne n the presence of sodum

methoxde and Sodum hydroxde, DMSO Solvent meda to get crude of Ketoconazole and

further undergoes purfcaton wth Actvated Carbon by usng Methanol and Ethyl Acetate

Solvent meda to produce pure Ketoconazole

Chemical Reaction:

Mass Balance:

Stage-1


n Kg n Kg

Cs-2-(2,4-dchlorophenyl)2- 100.00 Stage-1 120.00

(1H-mdazol-1-yl-methyl)-1,3-

doxolane-4-methanol

Para Toluene Sulfonyl Chlorde 58.00 Methanol Recovery 665.00

Sodum Carbonate 20.00 Methanol Loss 35.00

Methanol 700.00 Methylene Dchlorde Recovery 660.00

Methylene Dchlorde 700.00 Methylene Dchlorde Loss 40.00

Trethyl Amne 35.00 Ethyl Acetate Recovery 475.00

Hydrochlorc Acd (30%) 50.00 Ethyl Acetate Loss 25.00

Ethyl Acetate 500.00 n-Hexane Recovery 470.00

n-Hexane 500.00 n-Hexane Loss 30.00

Actvated Carbon 10.00 Effluent Water 2111.30

DM Water 2000.00 (Water-2000,generated water-2.7,

Sodum chlorde-17.8,Sodum

carbonate-3.8,TEA HCl-47.6,

water from HCl-35,HCl-2.4,

Methanol-2)

Spent Carbon 20.00

Organc Resdue 21.70

Total 4673.00 Total 4673.00

Stage-2


Kg Kg

Stage-1 120.00 Stage-2 100.00

AHPP 55.00 Acetone Recovery 475.00

Dmethyl Sulfoxde 296.00 Acetone Loss 25.00

SMO Powder 13.50 Methanol Recovery 230.00

CS Flakes 15.00 Methanol Loss 10.00

Acetone 500.00 Ethyl Acetate Recovery 320.00

Methanol 240.00 Ethyl Acetate Loss 10.00

Ethyl Acetate 330.00 DMSO Recovery 278.00

Actvated Carbon 10.00 DMSO Loss 16.00

DM Water 1500.00 Effluent Water 1550.40

(Water-1500,Sodum sulphate-

35.5, Methanol-7.9,Sodum

Hydroxde-5, DMSO-2)

Toluene generaton 22.60

Spent Carbon 10.00

Organc Resdue 32.50

Total 3079.50 Total 3079.50

10. LEVO CETRZNE DIHYDROCHLORDE


Stage-1 Step-A

P-Chlorobenzo phenone s condensed wth Ammonum formate to produce the C-(4-Chloro-

phenyl)-C-phenyl methylamne

Step-B C-(4-Chloro-phenyl)-C-phenyl methylamne reacts wth Hydrochlorc Acd n the presence of

Methanol solvent meda to get Stage-1 Compound.

Stage-2 Stage-1 reacts wth Sodum hydroxde n the presence of L-tartarc acd to get Stage-2

compound.

Stage-3 Stage-2 s treated wth p- Toluene sulphonyl chlorde and Sodum hydroxde n Methylene

dchlorde medum, the compound s obtaned

Stage-4 Stage-2 and Stage-3 Compound on condensaton n Methanol medum, the product s

obtaned.

Stage-5 Stage-4 s treated wth Hydrobromc Acd and Dlute Acetc acd, the compound s obtaned

Stage-6 Stage-5 reacts wth Chloro ethanol n the presence of Trethyl amne to get stage-6

Compound

Stage-7 Stage-6 s treated wth Sodum monochloro acetate n the presence of Hydrochlorc acd and

DMF solvent meda to get Levocetrzne dhydrochlorde

Chemical Reaction:

Stage-3

Stage-4

CH3

Cl

+

SO2 N Cl

1-Methanesulfonyl-4-methyl-benzene, (2-

chloro-ethyl)-chloromethyl-amne

C11H15Cl2NO2S

296.21

NH2

MeOH

Cl

(L)_(4-Chloro-phenyl)-C-phenyl -

methylamne-1-methane sulfonyl -4-

methyl-benzene(2-ethyl-methyl-amne

C13H12ClN

217.69

O

N N S CH3 +

2HCl

O

Cl 1-[(4-Chloro-phenyl)-phenyl-methyl]-4-(toluene-4-sulfonyl)-pperazneHydrochorc acd

C24H25ClN2O2S

2x58.5=117.0 440.50

Mass Balance:

Stage-1


n kg n Kg

p-chloro benzo phenone 120.00 Stage-1 140.00

Ammonum formate 35.00 Toluene Recovery 760.00

Hydrochlorc acd 25.00 Toluene Loss 40.00

Toluene 800.00 Effluent Water 915.50

Actvated carbon 10.00 (Water-900,generated water-

10,Hydrochlorc acd-

5,Toluene-0.5)

Water 900.00 Spent carbon 10.00

Process Emsson 24.50

(Carbon doxde)

Total 1890.00 Total 1890.00

Stage-2


n kg n Kg

Stage-1 140.00 L-Stage-2 60.00

Sodum hydroxde 25.00 MDC Recovery 665.00

Tartarc acd 32.00 MDC Loss 35.00


Water 800.00 (Water-800, generated water-

10,Sodum Chlorde-32,

Sodum hydroxde-3,

L-Tartarc Acd-32)

D-somer Recycle 60.00

Total 1697.00 Total 1697.00

Stage-3

Name of the nput Quantty Name of the out put Quantty

n kg n Kg

para toluene sulphonyl chlorde 52.00 Stage-3 80.00

n,n-bs( 2-chloro ethyl)amne 50.00 MDC Recovery 665.00

HCl

Sodum Hydroxde 25.00 MDC Loss 35.00


Water 800.00 (Water-800,generated water-

9.8,Sodum chlorde-31.9,Sodum

hydroxde-3.18,Organc

Compound-2.12)

Total 1627.00 Total 1627.00

Stage-4


n kg n Kg

Stage-3 80.00 Stage-4 110.00

Stage-2 60.00 Methanol Recovery 380.00

Ethyl d sopropyl amne 28.00 Methanol Loss 20.00

Methanol 400.00 Spent Hydrochlorc Acd 19.70

Ethy ld sopropyl amne Reuse 28.00

Organc Resdue 10.30


Stage-6

Stage-5


n Kg n kg

Stage-4 110.00 Stage-5 70.00

Hydro bromc acd 23.00 Toluene Recovery 372.00

Acetc acd 15.00 Toluene Loss 20.00


(Water-500,Bromoacetate-

34.65,Hydrobromc Acd-2.8,

Water 500.00 PTSA-38.96,Toluene-0.5)

Organc Resdue 9.09

(Organc mpurtes-7.59,

Toluene-1.5)

Total 1048.00 Total 1048.00


n kg n Kg

Stage-5 70.00 Stage-6 75.00

Chloro ethanol 20.00 Toluene Recovery 373.00

Trethyl amne 24.70 Toluene Loss 20.00


(Water-350,Trethyl amne

hydrochlorde-36.6,Chloro

Water 350.00 ethanol-0.35,Toluene-2)

Organc Resdue 7.75


Stage-7:Pharma


n kg n Kg

Stage-6 75.00 Levo Cetrzne d-Hydrochlorde 100.00

Sodum mono chloro acetate 27.00 MDC Recovery 238.00

Hydrochlorc acd 17.00 MDC Loss 12.00

D methyl formamde 100.00 Acetone Recovery 89.00

MDC 250.00 Acetone Loss 5.00

Actvated Carbon 10.00 DMF Recovery 89.00

Acetone 100.00 DMF Loss 5.00


(Water-200,Sodum chlorde-

13.26,Acetone-0.5,DMF-0.5)

Spent Carbon 10.00

Organc Resdue 16.74


Acetone-0.5,DMF-0.5)


88

11. Levetracetam & Intermediates


(S)-2-Amnobutanamde hydrochlorde s condenced wth 4-Chlorobutanoyl chlorde n presence of

potassum carbonate gves Levetracetam.

Chemical Reaction:

89

Mass Balance:

Materal Balance of Levetracetam

Stage-1


n Kg n Kg

(S)-2-Amnobutanamde 125.00 Levetracetam 100.00

hydrochlorde

4-Chlorobutyryl chlorde 140.00 Methylene Dchlorde Recovery 873.00

Sodum Sulphate 150.00 Methylene Dchlorde loss 97.00

Potassum Hydroxde Powder 257.00 Ethyl acetate Recovery 546.00

Tetrabutyl ammonum bromde 8.70 Ethyl acetate Loss 61.00

Ethyl acetate 607.00 Effluent Water 2863.50

Methylene Dchlorde 970.00 (Water-2500,generated water-

48.6,Potassum hydroxde-105,

Potassum chlorde-201.2,TBAB-

8.7)

Water 2500.00 norganc Sold Waste 150.00

(Sodum Sulphate)

Organc Resdue 67.20

Total 4757.70 Total 4757.70

90

12. Pantoprazole Magnesum


Stage-1 Maltol and D methyl sulphate condense n Acetone solvent medum. Excess D methyl sulphate s

removed by treatng the reacton mass wth Potassum Carbonate. Reacton takes place as per the

below equaton.

Stage-2 Stage-1 compound on treatng wth Lquor Ammona soluton stage-2 compound s formed.

Reacton proceeds as per the below equaton

Stage-3 Stage-2 compound on reacton wth Phosphorous oxy chlorde produces stage-3 compound.

Further reacton s stopped by treatng the reacton mass wth water. Fnal product s extracted wth

MDC and after dstllng out MDC compound s obtaned.

Below s the reacton scheme.

Stage-4 Stage-3 compound when reacts wth Hydrogen peroxde n presence of Acetc acd, stage-4

compound s obtaned. Methanol s the solvent employed.

Stage-5 Stage-4 compound on reacton wth Methanol n sodum hydroxde presence produces stage-5

compound. Execs Methanol s used. Below s the reacton

Stage-6 Above stage compound on reacton wth Acetc anhydrde produces an ntermedate.MDC used as

solvent. Product s precptated wth C.S. Flakes. Below s the reacton scheme.

Stage-7 Stage-6 compound when reacts wth Thonyl chlorde an ntermedate s formed.MDC s used as

solvent. Product s crystallzed n Methanol. Fnally product s purfed wth Acetone.

Stage-8 When 2-Chloromethyl-3, 4-dmethoxy-pyrdne Hydrochlorde reacts wth 5-dFluoro methoxy-2-

mercapto-benzmdazole, n presence of Sodum hydroxde, product s formed. Mythylene dchlorde

s the solvent.

Stage-9 Stage-8 s treated wth Sodum hypochlorte n presence of Sodum hydroxde, to produce the

Pantoprazole sodum .Ths s purfed n Acetone. Methylene dchlorde s used as solvent.

91

Stage-10

Pantoprazole sodum reacts wth Magnesum chlorde n the presence of water to gve

Pantoprazole Magnesum as product.

.

Chemical Reaction:

92

93

94

95

Mass Balance:

Stage-1

Name of the Input Quantty Name of the output Quantty

n Kg n Kg

Maltol 85.00 Stage-1 85.00

Dmethyl sulphate 45.00 Acetone Recovery 378.00

Potassum carbonate 47.00 Acetone Loss 20.00

Acetone 400.00 Generated water 6.00

norganc Sold Waste 40.20

(Potassum Sulphate)

Organc Resdue 32.80


Acetone-2)


(Carbon doxde)


96

Stage-2


n Kg n Kg

Stage-1 85.00 Stage-2 75.00

Ammonum Carbonate 65.00 Toluene Recovery 280.00



(Water-700,Ammonum

hydroxde-21.2,Ammonum

carbonate-6.7,generated

water-10.9,Toluene-2)

Organc Resdue 12.48


Toluene-3)


(Carbon doxde)

Total 1150.00 Total 1150.00

Stage-3


n Kg n Kg

Stage-2 75.00 Stage-3 70.00

Phosphorous oxy chlorde 35.00 MDC Recovery 280.00

Sodum Hydroxde 30.00 MDC Loss 15.00

Methylenedchlorde 300.00 Effluent Water 780.00

Water 725.00 (Water-725,Phosphorc

acd-18,Phosphorus

oxychlorde-7,Sodum

hydroxde-30)

Organc Resdue 20.00

(Organc mpurtes-

15,MDC-5)

Total 1165.00 Total 1165.00

97

Stage-4


n Kg n Kg

Stage-3 70.00 Stage-4 65.00

Hydrogen peroxde (30%) 50.00 MDC Recovery 668.00

Acetc acd 35.00 MDC Loss 30.00


Sodum Hydroxde 20.00 Methanol Loss 12.50


Water 700.00 (Water-700,Sodum

Acetate-41,Acetc Acd-

5,generated water-

17.6,water from hydrogen

peroxde-35, Methanol-2.5)

Organc Sold Waste 15.40

(Organc mpurtes-

11.4,MDC-2,Methanol-2)

Total 1825.00 Total 1825.00

Stage-5


n Kg n Kg

Stage-4 65.00 Stage-5 60.00


Sodum Hydroxde 22.00 Methanol Loss 20.00

Acetc Acd 10.00 Effluent Water 749.00

Water 700.00 (Water-700,gen.water-9.85,

Sodum Chlorde-22,Sodum

Acetate-13.6,Methanol-3,

Organc Compound-0.55)

Total 1294.00 Total 1294.00

98

Stage-6


n Kg n Kg

Stage-5 60.00 Stage-6 55.00

Acetc Anhydrde 45.00 Chloroform + Acetc 198.80

Anhydrde Recovery

Chloroform 200.00 Chloroform Loss 10.00

Sodum hydroxde 20.00 Effluent Water 561.20

Water 500.00 (Water-500,Acetc Acd-

21.3, Sodum hydroxde-

7,Sodum Acetate-26.7

,Organc Compound-6.2)


Stage-7


n Kg n Kg

Stage-6 55.00 Stage-7 65.00

Thonyl chlorde 39.00 MDC Recovery 810.00

Methylenedchlorde 850.00 MDC Loss 40.00


Acetone 200.00 Methanol Loss 25.00

Acetone Recovery 189.00

Acetone Loss 10.00


(Sulphur Dioxde)

Organc Resdue 10.00

(Organc mpurtes-8,

Methanol-1,Acetone-1)

Total 1269.00 Total 1269.00

99

Stage-8


n Kg n Kg

Stage-7 65.00 Stage-8 100.00

5-dFluoromethoxy-2- 70.00 Toluene Recovery 472.00

mercapto-

benzmdazole

Sodum Hydroxde flakes 25.00 Toluene Loss 25.00



Chlorde-34,gen.Water-

10.4, Sodum hydroxde-

1.8, Toluene-1.5)

Organc Resdue 15.30


Toluene-1.5)

Total 1360.00 Total 1360.00

Stage-9


n Kg n Kg

Stage-8 100.00 Stage-9 105.00

Sodum hypochlorte (4%) 510.00 MDC Recovery 950.00

Sodum Hydroxde flakes 12.00 MDC Loss 50.00

Methylenedchlorde 1000.00 Acetone Recovery 378.00

Actvated Carbon 10.00 Acetone Loss 20.00

Acetone 400.00 Effluent Water 1819.00

Water 1300.00 (Water-1300,gen.water-

4.9, water from Sodum

hypochlorte-489.6,Sodum

chlorde-15.9, Acetone-

2,Organc Compound -6.6)

Spent carbon 10.00

Total 3332.00 Total 3332.00

100

Stage-10


n Kg n Kg

Stage-9 105.00 Pantoprazole Magnesum 100.00

Magnesum chlorde (5%) 300.00 Effluent water 805.00

DM Water 500.00 (Water-500,Sodum

chlorde-15,water from

Magnesum chlorde-

285,Magnesum chlorde-

3,Organc Compounds-2)


101

13. Phenylepherne Hydrochloride


Stage-1

3-Hydroxy Acetophenone reacts wth Bromine n the presence of Aluminum chloride and Ethyl

Acetate to get Stage-1 Compound

Stage-2

Stage-1 compound reacts wth N-Methyl Benzyl Amine n the presence of PA-HCl to get Stage-2

Stage-3

Stage-2 reacts wth 10% Palladum carbon n the presence of Hydrogen gas and Methanol as a

solvent meda to get Stage-3

Stage-4

Stage-3 reacts wth L(+) Tartarc Acd n the presence of isopropyl alcohol and Liq.Ammonia to get

Stage-4

Stage-5

Stage-5 Compound reacts wth Lq.Ammona and Sulfuric Acid n the presence of Acetc Anhydride

to get Stage-5

Stage-6

Stage-5 Compound reacts wth Hydrochlorde n the presence of isopropyl Alcohol to get

Phenylephrine Hydrochlorde

Chemical Reaction:

Stage-1

OH OH

H3C

Br2

AlCl3 BrH2C

HBr

+

+

Ethyl Acetate O

O

3-Hydroxy Acetophenone 159.8 2-Bromo-1-(3-hydroxy-phenyl)-ethanone 80.9

C8H8O2 C H BrO

136.15

8 7 2

215.04

102

103

104

Mass Balance:

Stage-1


n Kg n Kg

3-Hydroxy Acetophenone 100.00 Stage-1n Toluene 1130.00

Ethyl Acetate 500.00 Ethyl Acetate Recovery 475.00

Bromne 60.00 Ethyl Acetate Loss 25.00

Aluminum Chlorde 2.00 Effluent water 1132.00

Toluene 1000.00 (Water-1000,Sodum

10% Sodum bcarbonate 100.00 bicarbonate-10,water from

Sodum Sulphate 10.00 sodum bcarbonate-90,

Hydro bromc acd-30,

Alumnum chloride-2)

Inorganic Sold Waste 10.00

(Sodium sulphate)

Water 1000.00

Total 2772.00 Total 2772.00

Stage-2


n Kg n Kg

Stage-1n Toluene 1130.00 Stage-2 150.00

N-Methyl Benzyl Amne 75.00 Ethyl Acetate Recovery 95.00

IPA-HCl 200.00 Ethyl Acetate Loss 5.00

Ethyl Acetate 100.00 Toluene Recovery 1043.00


IPA 100.00 IPA+ HCl Recovery 283.00

Water 632.00 IPA Loss 15.00


(Organici mpurtes-6.1,

Toluene-2,PA-2)

Spent Hydro bromc Acd 680.90

Total 2337.00 Total 2337.00

105

Stage-3


n Kg n Kg

Stage-2 150.00 Stage-3 92.00


10% Palladum Carbon 15.00 Methanol Loss 37.00

Hydrogen gas 3.00 Toluene Recovery 50.00

Actvated Carbon 2.00 Effluent Water 476.13

Lq.Ammona 70.00 (Water-400,Toluene-

4.13,Ammonium

hydroxde-7,water from Lq

Ammonia-63,Methnaol-2)

Water 400.00 Palladum Carbon Recycle 18.00


(Organic impurities-5.27,

Methanol-1)

Hydrogen gas 0.60

Total 1390.00 Total 1390.00

Stage-4


n Kg n Kg

Stage-3 92.00 Stage-4 172.00

L(+) Tartarc acd 81.30 PA Recovery 378.00

PA 400.00 PA Loss 20.00

Lq Ammona 150.00 Effluent Water 553.30

Water 400.00 (Water-400,Ammonum

hydroxide-30,water from

Lq.Ammona-120,PA-

2,Organic impurities-1.3)

Total 1123.30 Total 1123.30

106

Stage-5


n Kg n Kg

Stage-4 172.00 Stage-5 90.00

L(+) Tartarc acd 81.30 Acetc Anhydrde 143.00

Recovery

PA 400.00 Acetc Anhydrde Loss 7.00

Lq Ammona 150.00 PA Recovery 283.00

L(+) Tartarc acd 81.30 PA Loss 15.00


(Water-750,generated

water-19.5,Sulfurc Acd-5,

PA-2,Ammonum

hydroxde-2, Organc

Compound-2.5)


(L-Tartarc Acd)

By-Product 71.70

(Ammonum Sulphate)

Spent Carbon 10.00

Total 1482.00 Total 1482.00

Stage-6


n Kg n Kg

Stage-5 90.00 Phenylepherne HCl 100.00

PA HCl 400.00 PA Recovery 360.00

Acetone 300.00 PA Loss 20.00

Methanol 250.00 Acetone Recovery 283.00

Actvated Carbon 10.00 Acetone Loss 15.00


Methanol Loss 12.00

Spent Carbon 10.00

Organc Resdue 13.00

(Organc mpurtes-10,

Acetone-2,Methanol-1)

Total 1050.00 Total 1050.00

107

14. Prasugrel Hydrochlorde


Stage-1

2-Bromo-1-cyclopropyl-2-(2-fluorophenyl) ethanone s reacted wth 5, 6, 7,7a-tetrahydrotheno

[3,2-c] pyrdne-2(4H)-one n the presence of potassum hydroxde and methanol to gve the ttle

compound.

Stage-2

Stage – s heated wth acetc anhydrde n the presence of ethyl methyl ketone to gve prasugrel.

Stage-3

Hydrogen chlorde gas s passed through prasugrel n methanol to gve Prasugrel

Hydrochlorde (crude).

Stage-4

Presugrel hydrochlorde (Crude) purfed from acetone and methanol to gve Prasugrel

Hydrochlorde (pure).

Chemical Reaction:

5-(2-Cyclopropyl-1-(2-fluorophenyl)- Potassum bromide water

2-oxoethyl)-5,6,7,7a-tetrahydrotheno- [3,2-c]pyrdn-2-(4H)-one

331 119 18

108

Stage-2

Stage-3

109

Mass Balance:

Stage-1


n Kg n Kg

2-Bromo-1-Cyclopropyl-2-(2- 44.00 Stage-1 49.00

Fluorophenyl) Ethanone

5,6,7,7a-Tetrahydrotheno [3,2-c] 27.00 Methanol Recovery 126.00

Purdne-2(4H)-one

Potassum Hydroxde 11.00 Methanol Loss 6.00

Methanol 132.00 Effluent Water 527.00

Water 500.00 (Water-500,Potassum

bromde-23.4,Organc

mpurtes-3.6)

Organc Resdue 6.00


Stage-2


n Kg n Kg

Stage-1 49.00 Stage-2 50.00

Acetc Anhydrde 16.00 Methyl Ethyl Ketone 140.00

Recovery

Methyl Ethyl Ketone 147.00 Methyl Ethyl Ketone Loss 7.00

Organc Resdue 15.00

(Organc mpurtes-15)


110

Stage-3


n Kg n Kg

Stage-2 50.00 Prasugrel Hydrochlorde 52.00

Crude

Hydrogen Chlorde 6.00 Methanol Recovery 143.00


Organc Resdue 3.00

(Organc mpurtes-3)

Process Emssons 1.00

(Hydrogen Chlorde)


Stage-4


n Kg n Kg

Prasugrel Hydrochlorde Crude 52.00 Prasugrel Hydrochlorde 50.00

Pure


Methanol 156.00 Acetone Loss 7.00


Methanol Loss 7.00

Organc Resdue 2.00


111

15. Mono methyl Urea


Stage-1

2-Amnbphenylsulphate when reacts wth Phenylchlorofumarate, the compound s formed.

Toluene s the solvent .Toluene layer s washed wth water to remove acdc salts that form durng

the reacton.

Stage-2

Stage-1 compound s hydrolyzed n presence of Phosphorc acd to obtan the stage-2 compound.

Acetone wash s gven to remove water traces.

Stage-3

Stage-2 compound made to react wth Pperazne n Toluene medum to produce the stage -3

compounds.

Stage-4

Stage-3 s converted to pharma by treatng wth Chloro ethoxy ethanol and Fumarc acd n Toluene

medum. Toluene layer s washed wth water to remove water soluble mpurtes. Fnally the

pharma s re-crystallzed n Methanol.

Chemical Reaction:

112

113

Mass Balance:

Stage-1


n Kg n Kg

2-Amnbphenylsulphate 126.50 Stage-1 153.20

Phenylchlorofumarate 107.10 Toluene Recovery 380.00



(Water-700,Organc mpurtes-

1.4, Chloro-oxo- ethane

peroxoc acd-58)


(Carbon doxde)

Total 1333.60 Total 1333.60

Stage-2


n Kg n Kg

Stage-1 153.30 Stage-2 133.20

phosphorc acd 46.70 Acetone Recovery 372.00


Water 250.00 Phosphorc acd Reuse 40.00


(Water-250,Acetc Acd-

20.1,Acetone-8,Phosphorc

Acd-6.7)


114

Stage-3


n Kg n Kg

Stage-2 133.20 Stage-3 165.70

Pperazne 41.00 Toluene Recovery 332.50


Gen. Water 8.50


Stage-4


n Kg n Kg

Stage-3 165.70 Quetapne fumarate 200.00

Chloro ethoxy ethanol 59.40 Toluene Recovery 380.00

Fumarc acd 55.30 Toluene Loss 20.00

Methanol. 400.00 Methanol Recovery 370.00

Toluene 400.00 Methanol Loss 20.00


(Water-800,gen.water-

8.6,Methanol-10,Chloro

fumarc acd-71.8)

Total 1880.40 Total 1880.40

115

16. Rabeprazole Sodium


Stage-1

2, 3-Lutdne s reacted wth Hydrogen Peroxde n presence of Acetc Acd to gve N-Oxde t further

reacts wth Ntraton mxture (Ntrc Acd + Sulfurc Acd) to gve Stage-1

Stage-2

Stage-1 s reacted wth 3-Methoxy-1-Propanol and Sodum Hydroxde to get Stage-2Compound

Stage-3

Stage-2 Compound s reacted wth Acetc Anhydrde, Sodum Hydroxde and Hydrochlorc Acd to get

Stage-3 Compound

Stage-4

Stage-3 Compound s reacted wth Thonyl Chlorde n the presence of MDC Solvent meda to get

Stage-4 compound

Stage-5

Stage-4 Compound s reacted wth 2-Mercapto Benzmdazole, Sodum hydroxde n the presence of

Toluene Solvent Meda to get Stage-5 Compound

Stage-6

Stage-5 Compound s reacted wth Sodum Hypochlorte to get Rabeprazole Base

Stage-7

Rabeprazole Base s reacted wth Sodum hydroxde to get Rabeprazole Sodium

116

Chemical Reaction

117

118

Stage -7

119

Mass Balance:

Stage-1


n Kg n Kg

2,3-Lutdne 46.00 Stage-1 65.00

Hydrogen Peroxde (50%) 33.00 Spent Acds for sale 140.00

Ntrc acd 30.00 (Sulfurc Acd-100,Acetc

Acd-40)

Sulphurc acd 108.00 Effluent Water 408.00

Acetc acd 46.00 (Water-350,Sulfurc Acd-

8,Acetc Acd-6,Hydrogen

Peroxde-1.9,Ntrc Acd-

2.9, mpurtes-7.2,gen.

water-15.5,Water from

Hydrogen peroxde-16.5)

Water 350.00


Stage-2


n Kg n Kg

Stage-1 65.00 Stage-2 80.00

3-Methoxy-1-Propanol 40.00 Toluene Recovery 235.00

Sodum Hydroxde 18.50 Toluene Loss 12.00

Toluene 250.00 DMSO Recovery 188.00

DMSO 200.00 DMSO Loss 10.00

Generated water 7.00


(Sodum Ntrte-

26.7,Sodum hydroxde-

3)



Toluene-3,DMSO-2)


120

Stage-3


n Kg n Kg

Stage-2 80.00 Stage-3 90.00

Acetc anhydrde 150.00 Toluene Recovery 660.00

Sodum Hydroxde 20.00 Toluene Loss 35.00

Hydrochlorc acd 20.00 Acetc Anhydrde 107.00

Recovery

Toluene 700.00 Acetc Anhydrde Loss 4.00


(Water-400,Sodum

Acetate-31,Acetc Acd-

22.7, Toluene-2,Sodum

hydroxde-4.8)

Organc Resdue 13.50

(Organc mpurtes-

10.5,Toluene-3)

Total 1370.00 Total 1370.00

Stage-4


n Kg n Kg

Stage-3 90.00 Stage-4 80.00

Thonyl Chlorde 53.00 MDC Recovery 710.00


Sodum Sulphate 10.00 Effluent Water 526.50

Water 500.00 (Water-500,Hydrochlorc

acd-26.5)


(Sodum Sulphate)

Organc Resdue 16.30

(Organc mpurtes-

13.3,MDC-3)


(sulfur doxde)

Total 1403.00 Total 1403.00

121

Stage-5


n Kg n Kg

Stage-3 80.00 Stage-4 100.00

2-Mercaptobenzmdazole 53.00 Toluene Recovery 375.00

Sodum hydroxde 15.00 Toluene Loss 20.00



chlorde-20.4,generated

water-6.3,Toluene-2,

Sodum hydroxde-1)

Organc Resdue 23.30

(Organc mpurtes-

20.3, Toluene-3)


Stage-6


n Kg n Kg

Stage-4 100.00 Stage-5 100.00

Sodum Hypochlorte (8%) 327.00 MDC Recovery 570.00



Sodum hydro sulphate 12.00 Acetone Loss 10.00

MMA n Methanol 10.00 Effluent Water 1544.30


Chlorde-17,water from

sodum hypochlorte-

300,Sodum

Hypochlorte-5.3,MMA-

10, Sodum

hydrosulphate-12)



Acetone-3)

Total 2399.00 Total 2399.00

122

Stage-7


n Kg n Kg

Stage-5 100.00 Rabeprazole Sodum 100.00

Sodum Hydroxde 13.00 PA Recovery 280.00

sopropyl Alcohol 300.00 PA Loss 15.00

Actvated Carbon 10.00 Generated water 5.00

Spent carbon 10.00

Organc Resdue 13.00

(Organc mpurtes-

8,PA-5)


123

17. Solfnacn


Stage-1

2-Phenyl ethyl amne condensed wth benzoyl chlorde in the presence of Tri ethyl amne and

chloroform as a solvent meda to give N-(2-phenyl ethyl) benzamide

Stage-2

N-(2-Phenyl ethyl) Benz amde reacts wth Phosphorous pent oxde and Phosphorous oxy chloride

in the presence of sodum hydroxde by using Toluene as solvent meda to give 1-Phenyl 1,2-

dihydrosoqunolne.

Stage-3

1-Phenyl-1, 2-dihydro soqunolne undergoes reduction with sodium boro hydrde n methanol as

a solvent to gve 1-Phenyl-1, 2, 3, 4-tetra so qunolne

Stage-4

1-Phenyl-1, 2, 3, 4-tetra hydro so qunolne undergoes resoluton wth D-(-)-tartarc acd n PA as a

solvent to gve (S)-phenyl-1, 2, 3, 4-tetra hydro so qunolne tartarate salt

Stage-5

(S)-Phenyl-1, 2, 3, 4-tetra hydro soqunolne tartarate salt undergoes base hydrolyss n MDC as a

solvent to gve (S)-phenyl-1, 2, 3, 4-tetra hydro so qunolne (Solfnacn) as a product.

Chemical Reaction:

Stage-1

Stage-2

124

Stage-3

Stage-4

Stage-5

125

Mass Balance:

Stage-1


n Kg n Kg

2-Phenyl ethyl amne 30.00 Stage-1 54.00

Benzoyl chlorde 35.00 Chloroform Recovery 285.00

Tr ethyl amne 37.50 Chloroform Loss 15.00

Chloroform 300.00 n-Hexane Recovery 130.00

N-Hexane 137.50 n-Hexane Loss 7.50


(Water-350,Trethyl Amne

HCl-34)

Organc resdue 14.50


Stage-2


n Kg n Kg

Stage-1 54.00 Stage-2 50.00

Phosphorus pentoxde 38.00 Toluene Recovery 235.00

Phosphorus oxy chlorde 41.00 Toluene Loss 10.00

Toluene 250.00 MDC Recovery 475.00


NaOH flakes 63.00 Effluent Water 872.70

Water 787.00 (Water-787,Meta

phosphorc Acd-

17.7,NaOH-63,Toluene-5)

Organc resdue 12.04

Process emsson

HCl gas 9.76

norganc Sold Waste

Phosphorc Acd 43.50

Total 1733.00 Total 1733.00

126

Stage-3


n Kg n Kg

Stage-2 50.00 Stage-3 50.00

Sodum boro hydrde 13.90 Methanol Recovery 280.00


Water 195.00 Effluent water 206.70

(water-177,Methanol-

10,Sodum hydroxde-

14.7,Borane-5)

Organc resdue 12.20


Stage-4


n Kg n Kg

Stage-3 50.00 Stage-4 85.00

D(-)-Tartarc acd 36.00 PA Recovery 390.00

PA 420.00 PA Loss 20.00


(Water-175,PA-10,Tartarc

acd-16)

Organc resdue 15.00


Stage-5


n Kg n Kg

Stage-4 85.00 (s)-phenyl-1,2,3,4-tetra 50.00

hydro so qunolne

Sodum Hydroxde 19.00 MDC Recovery 330.00



(Water-550,sodm salt of

Tartarc acd-27,gen.water-5)

Organc resdue 22.00

Total 1004.00 Total 1004.00

127

18 Tamsulosn Hydrochlorde


Stage-1

(S)-5-(2-Amnopropyl)-2-methoxybenzenesulfonamide s reacted wth 2-(O-Ethoxyphenoxy) ethyl

bromde in presence of 50% sodium hydroxde solution and further Hydrochlorde salt formaton

with Ethanolc HCl gives Tamsulosn HCl.

Stage-2

Product is purfed using Methanol and Ethanol.

Chemical Reaction:

128

Mass Balance:

Stage-1


n Kg n Kg

(S)-5-(2-amnopropyl)-2- Stage- 113.00

methoxybenzene sulfonamde 62.00

2-(O-Ethoxy phenoxy)ethyl Methanol Recovery 1177.00

bromde 91.00


n-Hexane 373.00 n-Hexane Recovery 354.00

50% lye soluton 40.00 n-Hexane Loss 19.00

Ethyl acetate 1428.00 Ethyl acetate Recovery 1356.00

Ethanol 99% 745.00 Ethyl acetate Loss 71.00

Ethanolc HCl 124.00 Ethanol Recovery 814.00

DM Water 2652.00 Ethanol Loss 37.00


(Water-2652,Water from NaOH-

20,NaOH-20,Organc mpurtes-

31.8,Methanol-15,Ethanol-12)

Organc Resdue 15.20

Total 6757.00 Total 6757.00

Stage-2


n Kg n Kg

Stage-1 113.00 Tamsulosn HCl 100.00


Absolute ethanol 558.00 Methanol Loss 18.00

Ethanol Recovery 530.00

Ethanol Loss 28.00

Organc Resdue 13.00

Total 1031.00 Total 1031.00

129

19. Telmsartan


Stage-1 OTBN on hydrolysis with Potassium Hydroxide in presence of Ethylene glycol gives stage-1.

Product is preciptated wth Hydrochloric acid.

Stage-2 Stage-1 when reacts wth Dimethyl sulphate , Potassium carbonate and Di bromo Dimethyl

Hydanton in Acetone solvent medum ,stage -2 product s obtaned. Product is solated wth MDC

and purified with Carbon. Cyclohexane is the solvent used in the purfcaton.

Stage-3 Stage-2 undergoes couplng reacton wth Stage-1 in presence of Potassum Hydroxde soluton.

Acetone is the solvent used.

Stage-4 Stage-4 product, on hydrolyss with Potassum Hydroxde produces Pharma. Methanol is

used in the process. Product is solated wth MDC and purfed and precptated with Acetic

acid.

Chemical Reaction:

Stage-

CH3 CH3

+ KOH + HCl

O

CN + HO COOH + H C CH3 + KCl

+

NH

OH 3

4'-Methyl-bphenyl-

Ethylene glycolPot.Hydroxde Hydrochloc Stage-1 Acetaldehyde Pot Ammona

2-carbontrle C H O

acd C H O +

Chlorde

C H N

C2H4O

14 11 2 6 2 14 12 2

Mol. Wt.: 193.2 Mol. Wt.: 62.1

Mol. Wt.: 56 Mol. Wt.:36.5 Mol. Wt.: 212.2 Mol. Wt.: 44.1 Mol. Wt.: 74.5 17

130

131

132

Mass Balance: Stage-1

Name of the nput Quantty Name of the output Quantty

n Kg n Kg

OTBN 45.25 Stage-1 49.70

Ethylene glycol 15.00 Effluent Water 1228.17

Potassum Hydroxde 13.00 (Water-1200,Potassum

chlorde-17.3,Acetaldehyde-

10.7,org.mpurtes-0.17)

Hydrochlorc acd 8.60 Process Emsson 3.98

Water 1200.00 (Ammona)

Total 1281.85 Total 1281.85

Stage-2


n Kg n Kg

Stage-1 49.70 Stage-2 71.50

D methyl sulphate 29.50 MDC Recovery 570.00

Potassum Carbonate 32.32 MDC Loss 30.00

D bromo d methyl hydanton 67.00 Acetone Recovery 530.00


Cyclohexane 180.00 Cyclohexane Recovery 170.00

Actvated Carbon 10.00 Cyclohexane Loss 10.00


Water 1200.00 (Water-1200,Methanol-

7.5,Acetone-10,Potassum

Sulphate-40.7)

Spent Carbon 10.00

Process Emssion 10.30

(Carbon dioxde)

Organic Sold Waste 48.52

(1-Bromo-5,5-dmethyl-

mdazoldne-2,4-done)

Total 2728.52 Total 2728.52

133

Stage-3


n Kg n Kg

Stage-2 71.50 Stage-3 103.00

2-n-Propyl-4-methyl-6-(1- 71.30 Acetone recovery 650.00

methylbenzmdazole-2-

yl)benzmdazole

Potassum Hydroxde 13.00 Acetone loss 20.00

Acetone 680.00 Effluent water 611.80

Water 570.00 (Water-570,gen.water-

4.2,Potassum bromde-

27.6,Acetone-10)

Organc Resdue 21.00

Total 1405.80 Total 1405.80 Stage-4


n Kg n Kg

Stage-3 103.00 Telmsartan 100.00

Potassum Hydroxde 10.90 Methanol Recovery 650.00

Acetc acd 12.00 Methanol Loss 20.00

DMF 70.00 MDC Recovery 380.00

Methanol 680.00 MDC Loss 20.00

MDC 400.00 DMF Recovery 67.00

Actvated Carbon 25.00 DMF Loss 3.00


(Water-800,Methanol-6.23,

Potassum Acetate-19.6)

Spent Carbon 25.00

Organc Resdue 10.07

Total 2100.90 Total 2100.90

134

20. Bortezomb


Stage-1 so butyl Boronc acd reacted wth Ppanedol n the presence of n-Heptane and to

get 2,(2 methyl propyl) 3aS4S,6S,7aR),hexahydro3a,5,5tr methyl-4,6-methano-

1,3,2- Benzodoxaborde.

Stage-2 Stage End Product reacted wth Znc Chlorde n the presence of THF, D Phenyl

amne & MDC, n- Hexyl Lthum are the solvents and to get 1-Chloro-3-methyl

butyl 3aS, 4S, 6S,7aR)Hexa hydro-3-a5,5 Tr methyl-4-6-methano 1,3,2 benzodoxabord.

Stage-3 Stage end product reacted wth HMDS n presence of N-Hexyl lthum and THF

to get N, N- Bs (Trmethylslyl(1R)1-(3aS,4S,6S,7aR)hexahydro-3a,5,5-

trmethyl4,6 methanol1,3,2 benzodoxoborol-2-yl]3-methyl butyl amne.

Stage-4 Stage end product reacted wth Tr fluoro Acetc acd n presence of D so propyl ether and 4,6 methane 1,3 2 benzo doxoborole 2- methanamne hexamne hexahydro-3a,5,5 tr methyl- α (2 methyl-(αR,3aS,6S,7aR)propyl) tr flu

Stage-5 L-Phenyl alanne reacted wth Thonyl chlorde n presence of Methanol & PA to get L-Phenyl alanne Methyl Ester HCl.

Stage-6 Stage 5 end product reacted wth Pyrazne Carboxylc acd & N-Hydroxy

succanamde n presence of DMF as a solvent to get N-(Pyraznyl Carboxyl)L-

phenyl Alanne Methyl Ester, and reacted wth NaOH & Acetone and to get N –

(Pyraznyl Carbonyl) L-phenyl Alanne .Methyl Ester.

135

Stage-7 Stage-4 & Stage-6 reacts wth N-hydroxy Succnamde and MDC as a solvent and to get (N-[(1S)-

2[(3a, 4S, 6S, 7aR)-hexahydro-3a, 5S, Trmethyl-4-6 methano-1,3,2 benzodoxoboral2-yl]3-

methyl butyl amno]2-oxo-1-(phenyl-methyl)ethyl]Pyrazne Carboxamde.

Stage-8 Stage-7 reacts wth sobutyl boronc acd n the presence of Methanol to gve Bortezomb

Pharma Product

Chemical Reaction:

136

Stage-3

Stage-4

137

Stage-5

Stage-6

138

Stage-7

Stage-8

139

Mass Balance:

Stage-1

Name of the nput Quantty Name of the Out Put Quantty

n Kg n Kg

so Butyl Boronc Acd 0.40 Stage-1 0.60

N-Heptane 3.00 N-Heptane Recovery 2.90

Pnanedol 0.90 N-Heptane Loss 0.10

Sodum Chlorde 0.06 Effluent Water 0.80

Water 0.60 (Water-0.6,generated water-

0.14,Sodum chlorde-0.06)

Organc resdue 0.56


Stage-2


n Kg n Kg

Stage-1 0.60 Stage-2 0.60

Znc Chlorde 0.36 THF Recovery 9.40

THF 10.00 THF Loss 0.50

N-Hexyl Lthum 1.25 MDC Recovery 11.88

D so Propyl Amne 0.27 MDC Loss 0.62


Sulphurc acd 0.26 (Water-18.76,Znc sulphate-

0.42,Ammonum chlorde-

0.14,THF-0.1,N-Hexyl

Lthum-1.25)

Water 18.76 Pentane Recovery 0.19

Organc Resdue 0.14


140

Stage-3


n Kg n Kg


HMDS 0.40 THF Recovery 2.85

THF 3.00 THF Loss 0.15

N-Hexyl Lthum 3.50 DPE Recovery 1.29

DPE 1.35 DPE Loss 0.06

N-Hexyl Lthum Reuse 3.50

Organc Resdue 0.12

Process Emsson 0.08

(Hydrogen chlorde)


Stage-4


n Kg n Kg


Tr Fluoro Acetc Acd 0.23 Dsopropyl ether Recovery 21.28

Dsopropyl Ether 22.50 Dsopropyl ether Loss 1.12

DM Water 27.80 Effluent Water 28.23

(Water-27.8,Hexamethyl

dslane-0.29,DPE-

0.1,Organc mpurtes-0.04)


141

Stage-5


n Kg n Kg

L-Phenyl Alanne 0.45 Stage-5 0.50

Thonyl Chlorde 0.35 Methanol Recovery 2.15


PA 2.25 PA Recovery 2.15

PA Loss 0.10

Process Emsson 0.26

(Hydrogen chlorde-0.09,

Sulfurdoxde-0.17)

Organc Resdue 0.04


Stage-6


n Kg n Kg


Pyrazne Carboxylc acd 0.25 DMF Recovery 4.75

DMF 5.00 DMF Loss 0.25

N-Hydroxy Succnamde 1.50 Ethyl Acetate Recovery 8.55

D Cyclohexyl Carbodmde 0.50 Ethyl Acetate Loss 0.45

N-Methyl Morpholne 0.35 N-Heptane Recovery 1.71

Ethyl Acetate 9.00 N-Heptane Loss 0.09

n-Heptane 1.80 Acetone Recovery 1.90


Sodum Hydroxde 0.10 Effluent Water 29.84

Hydrochlorc Acd 0.10 (Water-27.5,generated water-

0.04,Sodum chlorde-0.13,

Methanol-0.07,HCl-0.1, DCC-

0.5,N-Hydroxy Succnamde-

1.5)

DM Water 27.50 Organc Sold Waste 0.46


142

Stage-7


n Kg n Kg

Stage-4 0.70 Bortezomb Base 0.75

Stage-6 0.50 MDC Recovery 6.65

N-Hydroxysuccnamde 0.25 MDC Loss 0.35

MDC 7.00 Methanol Recovery 3.30

Dcyclohexyl dcarbodmde 0.40 Methanol Loss 0.17


D sopropyl ethylamne 0.45 (Water-7,generated water-

0.03,Trfluoro acetc acd-

0.21,Sodum bcarbonate-

0.2,HCl-0.25,DPA-0.45)

Hydrochlorc Acd 0.25 Organc Resdue 0.89

Sodum bcarbonate 0.20 (Organc mpurtes-0.86,

Methanol-0.03)

DM Water 7.00


Stage-8


n Kg n Kg

Bortezomb base 0.75 Bortezomb Pharma 0.50


N-Heptane 17.00 Methanol Loss 0.70

sobutyl boronc Acd 0.15 MDC Recovery 16.20


Sodum bcarbonate 0.19 N-Heptane Recovery 16.50

Hydrochlorc Acd 0.06 N-Heptane Loss 0.50


(Water-2.5,Sodum

bcarbonate-0.19,HCl-0.06,

Methanol-0.1,Organc

mpurtes-0.40)


143

21. Trmebutne Maleate

MANUFACTURING PROCESS:

Stage-1 Methyl-2-(d methyl amno)-2-phenylbutyrate reacts wth Sodum hydroxde and water n the

presence of Sodum bs (2-methoxyethoxy) alumnum hydrde gves Stage-1 as product. Stage-2 Step-A 3, 4, 5-Trmethoxybenzoc acd reacts wth tr phosgene and water n the presence of Toluene and DMF as solvent meda to gve Stage-2A as product. Step-B

3, 4, 5-Trmethoxybenzoyl chlorde reacts wth 2-dmethylamno-2-phenylbutan-1-ol n the

presence of Toluene and methanol as solvent Meda to gve Stage-2B as product. Stage-3 3,4,5-trmethoxy-benzoc acd -2-dmethylamno-2phenylbutylester reacts wth Malec acd n the

presence of water to gve Tr mebutne Maleate as product.

Chemical Reaction:

Stage-1

Sodumbs

N

(2-methoxyethoxy)

N

alumnum hydrde O

+ NaOH +

H2O

O

OH

Methyl-2-(dmethylamno) Sodum hydroxde Water

2-D Methylamno-2

-2-phenylbutyrate

40.0 18.0 -phenylbutan-1-ol

C13

H19

NO2

C12H19NO

221.30

193.29

+

NaHCO3 +

H2

84.01 2.0

Stage-2

144

Stage-2

O

H3CO

Cl O Cl

OH Cl Cl

Toluene

+

O O +

2H2O

DMF

H3CO Cl Cl

OCH3

3,4,5-Trmethoxy benzoc acd Trphosgene Water

C3Cl6O3

C10

H12

O5

2X18=36

296.75 212.20

O

H3CO

Cl

+ 5HCl + 3CO2

H3CO

OCH3

3,4,5-Trmethoxy benzoyl chlorde 5X36.5=182.5 3X44=132.0 C10H11ClO4

230.64

145

146

Mass Balance:

Stage-1


n Kg n Kg

Methyl-2-(d methyl amno)-2- 55.00 Stage-1 42.00

phenylbutyrate

70%Vtrde Toluene soluton 102.00 Toluene + Vtrde 290.00

Recovery


Sodum hydroxde flakes 10.00 Effluent water 223.00

Sodum sulphate 5.00 (Water-200,Sodum

bcarbonate-21, Toluene-2)

Water 200.00 norganc Sold Waste 5.00

(Sodum Sulphate)

Organc Resdue 2.00


Stage-2


n Kg n Kg

3,4,5-Trmethoxy benzoc acd 47.00 Stage-2 50.00

Trphosgene 67.00 Toluene Recovery 190.00


DMF 0.70 Spent Hydrochlorc Acd 134.90

Water 100.00 Process Emsson 29.80

(Carbon doxde)


147

Stage-3


n Kg n Kg

Stage-2 50.00 Stage-3 80.00

Stage-1 42.00 Toluene Recovery 473.00



Trethyl Amne 23.00 Methanol Loss 10.00

Sodum sulphate 7.00 Effluent Water 532.82

Water 500.00 (Water-500,Trethyl Amne

hydrochlorde-29.82, TEA-

1,Methanol-2)

Organc Resdue 14.18


Toluene-2, Methanol-1)

Total 1322.00 Total 1322.00

Stage-4


n Kg n Kg

Stage-3 80.00 Tr mebutne Maleate 100.00

Malec acd 23.00 Methanol Recovery 280.00



(Water-200, Methanol-3)

Organc Resdue 5.00

(Organc mpurtes-3,

Methanol-2)


148

22. Cabergolne


Stage-1 Lysergol reacts wth TBDMS chlorde n the presence of DMFas solvent meda to gve Stage-1 as

product. Stage-2 Stage-1 product reacts wth Hydrogen n the presence of palladum catalyst to gve stage-2 as

product. Stage-3 Stage-2 product reacts n the presence of Methanol as solvent meda undergoes Demethylaton to gve Stage-4 as product. Stage-4 Stage-3 product reacts wth Tert butyoxy carbonyl n the presence of THF as solvent meda to

gve Stage-5 as product. Stage-5 Stage-4 product reacts wth Water n the presence of MDC as solvent meda to gve Stage-5 as product. Stage-6 Stage-5 product reacts wth Thonyl chlorde and allyl bromde n the presence of methanol

as solvent meda to gve stage-6 as product. Stage-7 Stage-6 product reacts wth EDC free base n the presence of MDC, Acetone as solvent

meda to gve stage-7 as product.

149

Chemical Reaction:

Stage-2

Stage-1

OH CH3 CH3

S C

O CH3

CH CH3

3

N CH3 S Cl DMF

+ DMAP N CH3 + HCl

HN

HN

(7-Methyl-4,6,6a,7,8,9-hexahydro

Hydrochlorc acd -ndolo[4,3-fg]qunoln-9-yl)-methanol TBDMS-Chlorde Stage-1

C

16H

18N

2O

150.72 C22H32N2OS

368.59 36.5 254.33

CH3

CH3

CH3CH3

S C CH3

O

O S C CH3

CH CH

3

3 pd/c CH3

CH3

DMF

MDC

Heptane

H

N CH3

+ H

2

N CH3

H

HN

HN

Stage-1 Hydrogen

Stage-2

C22H32N2OS 2.0 C22H34N2OS

368.59

370.6

150

Stage-3

CH

CH3

3

CH

CH3

3

O S C CH3

O S C CH3

CHCH

3

3 CHCH3

3

H C3H5ClO2

N CH3 H

+ CH3OH

NH+ C2H5OH

H

H

32.0

HN

HN

Stage-2 Stage-3 Ethyl Alcohol

C22H34N2OS C H N OS

21 32 2

370.6 356.58 46.0

Stage-4

CH3

CH3

S C

O CH3

CH3

CH3

H •

NH C

+ 2 O O

H

tert butyloxy carbonyl

HN

C5

H9

O2

2X101.12=202.24

Stage-3

C21H32N2OS

356.58 TBAF/THF

OH

CH3

H

N C O C CH3 •

S

H O

CH3 +

CH3

N C O C

H3C

O

CH3

Stage-4

TBDMS

C25

H34

N2O

5

115.27 442.55

151

Stage-5

OH

H CH3 O OH

N C O C CH3

H O CH3

CH3

MDC

H

CH3 + H2O N C O C CH3

H3C

C

O

C N

H

O CH

3

CH O CH3 2H

2

3

H C

C

O

C

N

+

3

Stage-4 CH3 O

C

25H

34N

2O

5 Water

Stage-5 Hydrogen

442.55

18.0

C25

H32

N2O

6

4.0

456.53

Stage-6

Step-A

OH

O

CH3

H

N C O C CH3

+ CH3OH + SOCl2

H O CH3

CH3 Methanol Thonyl chlorde

H3C C O C N 32.0 118.97

CH3 O

Stage-5

C25

H32

N2O

6

456.53

COOCH3

H

CH

3

NH + 2

C O C CH + SO2 +HCl

H HCl 3

O

CH

3

HN

Sulphur doxde Hydrochlorc acd

Tert butyloxy carbonyl

C16H18N2O2.HCl

306.83 2x101.12 64.0 36.5

152

Step-B

COOCH3

H

NH

Br Et3N/MeOH

H HCl

+ NaOH

aq.HCl

HN

Allyl bromde Sodum hydroxde

C16H18N2O2.HCl

306.83 C3H5Br 40.0

120.98

COOH

H

N

+ NaBr+ CH3OH + HCl

H

HN

Stage-6 Sodum Methanol Hydrochlorc acd

bromde

C18

H20

N2O

2

296.36 102.89 32.0 36.5

Stage-7

H

O N COOH

N

N

O

H

N MDC/MTBE

+

H NN N Acetone

H

N

HN

EDC Free Base H Stage-6

C18

H20

N2O

2 C

8H

17N

3

296.36 155.24 HN

Stage-7 C

26H

37N

5O

2

451.6

153

Mass Balance:

Stage-1


n Kg n Kg

Lysergol 70.00 Stage-2 85.00

Trethyl amne 28.00 DMF Recovery 370.00

Tert-butyldmethyl slyl chlorde 42.00 DMF Loss 20.00

4-Dmethyl amno pyrdne 10.00 Effluent Water 458.00

DMF 400.00 (Water-400,DMF-10,TEA

HCl-38,DMAP-10)

Water 400.00 Organc Resdue 17.00


Stage-2


n Kg n Kg

Stage-2 85.00 Stage-3 80.00

Palladum carbon 2.00 MDC Recovery 285.00


N-Heptane 200.00 N-Heptane Recovery 190.00

Hydrogen gas 0.50 N-Heptane Loss 10.00

Ntrogen Gas 2.00 Palladum carbon 2.00

Organc Resdue 5.50

Process Emsson 2.00

(Ntrogen)


154

Stage-3


n Kg n Kg

Stage-3 80.00 Stage-4 70.00

Chloro ethyl formate 20.00 Methanol Recovery 180.00


Sodum bcarbonate 30.00 Toluene Recovery 380.00

Sodum chlorde 10.00 Toluene Loss 20.00


Water 400.00 (Water-400,Sodum chlorde-

10,Sodum bcarbonate-

30,Ethanol-10,Methanol-3)

Chloro ethyl formate Reuse 20.00

Organc Resdue 7.00

Total 1140.00 Total 1140.00

Stage-4


n Kg n Kg

Stage-4 70.00 Stage-5 80.00

4-Dmethylamno pyrdne 20.00 THF Recovery 280.00

D-tert-butyl dcarbonate 40.00 THF Loss 15.00

TBAF 10.00 Acetontrle Recovery 380.00

Acetc acd 20.00 Acetontrle Loss 20.00

Acetontrle 400.00 Effluent Water 455.00

THF 300.00 (Water-400,DMAP-20,TBAF-

10,THF-5,Acetc Acd-20)

Water 400.00 Tert-butyl dmethyl slyl 22.63

Organc Resdue 7.37

Total 1260.00 Total 1260.00

155

Stage-5


n Kg n Kg

Stage-4 80.00 Stage-5 75.00

TEMPO 10.00 MDC Recovery 380.00

odobenzene dacetate 5.00 MDC Loss 20.00

Sodum thosulphate 12.00 Effluent water 313.80

MDC 400.00 (Water-296.8,Sodum

thosulphate-

12,odobenzene dacetate-5)

Water 300.00 TEMPO Reuse 10.00

Process Emsson 0.72

(Hydrogen)

Organc Resdue 7.48


Stage-6A


n Kg n Kg

Stage-5 75.00 Stage-6A 50.00

Thonyl chlorde 20.00 Methanol Recovery 35.00

Methanol 50.00 MDC Recovery 380.00



(Water-300,HCl-

6.1,Methanol-10)

Tert butyl oxy carbonyl 33.20

Process Emsson

(sulfur doxde) 10.70


156

Stage-6B


n Kg n Kg

Stage-6B 50.00 Stage-7 40.00

Allyl bromde 20.00 Methanol Recovery 380.00

Sodum hydroxde 7.00 Methanol Loss 20.00

TEA 17.00 Effluent Water 551.20

Methanol 400.00 (Water-500,Sodum

bromde-17,Methaol-

5.2,HCl-6,TEA HCl-23)

Hydrochlorc Acd 6.00 Organc Resdue 8.80

Water 500.00

Total 1000.00 Total 1000.00

Stage-7


n Kg n Kg

Stage-7 40.00 Cabergolne 50.00

EDC Free base 21.00 MDC Recovery 380.00

Alumna 5.00 MDC Loss 20.00

MDC 400.00 MTBE Recovery 285.00

MTBE 300.00 MTBE Loss 15.00


n-Heptane 100.00 Acetone Loss 10.00

Actvated carbon 10.00 n-Heptane Recovery 95.00

n-Heptane Loss 5.00

Spent carbon 10.00

Alumna Recycle 5.00

Organc Resdue 11.00

Total 1076.00 Total 1076.00

157

23. Mycophenolate Mofetl


Mycophenolate methyl ester and Morpholno Ethanol s heated at 1250c for 20 hours, cooled

and water added, acdfed wth phosphorc acd and extracted wth Ethyl acetate. Aqueous layer s

upon basfcaton wth 50% sodum hydroxde and extracted wth Ethyl acetate. Ethyl acetate layer s

charcolsed fltered through celte &concentrated to gve Mycophenolate mofetl n good yeld.

Chemical Reaction:

Stage-1

CH3

O H3CO

H2SO4

O

+ CH3OH

HO

CH3

OH O

Mycophenolc acd Methanol

C

17H

20O

6 32.0

320.35

CH3

O

H3

CO

O +

H2

O

H3C

O

CH3

OH O

Mycophenolc acd ester Water

C18

H22

O6 18.0

334.35

158

Stage-2

CH3

O H3CO HO

O

N O

+

H3C

O

CH3

OH O

2-Morpholno ethanol Mycophenolc acd ester

C6H

13NO

2

C18

H22

O6 131.17

334.35

ZnO

125-128O

C

CH3

O O H3CO

N

O+ CH3OH

O

CH3 OH O

Methanol Mycophenolate mofetl

32.0

C23

H31

NO7

433.49

159

Mass Balance:

Stage-1


n Kg n Kg

Mycophenolc acd 50.00 Stage-1 48.00


Sulphurc acd 1.75 Methanol Loss 16.00

Water (Washngs) 300.00 Effluent Water 303.75

(Water-300,Sulphurc Acd-

1.75,Methanol-2)

Organc resdue 22.00


Stage-2


n Kg n Kg

Stage-1 48.00 Mycophenolate mofetl 50.00

Morpholne ethanol 20.00 Ethyl Acetate Recovery 570.00

Znc oxde 2.40 Ethyl Acetate Loss 30.00

Ethyl acetate 600.00 Effluent water 540.20

Sulphurc acd 15.00 (Water-500,Sulphurc Acd-12,Znc

sulphate-4.7,Sodum hydroxde-

13,Sodum bcarbonate-

5,Phosphorc acd-0.6,Methanol-4.9)

Sodum hydroxde 13.00 Spent Carbon 10.00

Sodum bcarbonate 5.00 Organc Resdue 13.80

Phosphorc acd 0.60

Actvated carbon 10.00

Water 500.00

Total 1214.00 Total 1214.00

160

24. Raloxfene Hydrochlorde


4[2-(1-pperdnoethoxy)] benzoc acd hydrochlorde s converted to the acd chlorde by usng thonyl

chlorde. Upon reacton completon, Toluene s added and the excess thonyl chlorde s dstlled off

to the mnmum volume usng hgh vacuum and the same s repeated to remove the thonyl

chlorde. Fnally heptane s added and cooled to 25-30Oc and the product s fltered and suck dred

to gve the damp acd chlorde.

The damp acd chlorde taken n MDC whch s further reacted wth6-methoxy-2-(4-

methoxyphenyl)benzo[b]tho phene through a Fredal crafts acylaton reacton usng alumnum

chlorde as catalyst to gve dmethoxy Raloxfene.The Raloxfene s not solated and subsequently

demethylated wth ethane thol to gve the Raloxfene free Base. The free Base s not solated and

converted to hydrochlorde salt usng Aq.Hydrochlorc acd. The damp Raloxfene s pulped wth

water, fltered and dred to gve ([6-Hydroxy-2-(4-hydroxyphenyl0benzo[b]then-3-yl][4-[2-(1-

pperdnyl)ethoxy]phenyl]-methanone,hydrochlorde).

Raloxfene hydrochlorde s subjected to purfcaton usng methanol-dmethyl form amde and

methanol water to gve Raloxfene Hydrochlorde.

161

Chemical Reaction:

Stage-1

Stage-2

Cl

H

O

HO Toluene/Heptane

+ SOCl2

N

O

Thonyl chlorde

4-(2-Pperdn-1-yl-ethoxy)

118.97

-benzoc acd; hydrochlorde

C14H20ClNO3

285.77

Cl

H O

Cl + SO2 + HCl

N

O

Stage-1 Sulphur doxde Hydrochlorc acd

C14H19Cl2NO2 64.06 36.5

304.20

Cl

H

O

Cl

O

N

O

S O

Stage-1

6-Methoxy-2-(4-methoxyphenyl)benzo(b)thophene

C14H19Cl2NO2

304.20

C16

H14

O2

S

270.35

DCM

N

O

+ 2 HCl

H3C O

O

S

O CH3

Stage-3

Hydrochlorc acd

C30

H31

NO4S

73.0 501.64

162

Stage-3

Stage-4

N

O

H3C O

O

+ HS + HCl S

O CH3

Stage-3 Ethane thol Hydrochlorc acd

C30H31NO4S C H S Aqueous HCl

2 6

501.64 62.13

36.5

N

O

HCl + HS

HO

N N

O O

Methanol-DMF

HCl HCl

HO Methanol-Water HO

O O

S S

OH OH

Stage-3 Stage-4

C28H28ClNO4S

510.04 C28H28ClNO4S

510.04

163

Mass Balance:

Stage-1


n Kg n Kg

4[2-(1-pperdnoethoxy)] 50.00 Stage-1 50.00

benzoc acd hydrochlorde

Thonyl chlorde 20.80 Toluene Recovery 375.00


Heptane 300.00 Heptane Recovery 285.00

Water 200.00 Heptane Loss 15.00

Effluent water 214.60

(Water-200,HCl-6.3,Toluene-

5,Organc mpurtes-3.3)


(Sulfur doxde)


Stage-2


n Kg n Kg

Stage-1 50.00 Stage-2 70.00

6-Methoxy-2-(4- 45.00 MDC Recovery 570.00

methoxyphenyl)benzo(b)thophene


Ntrogen Gas 5.00 Effluent Water 1042.30

Alumnum chlorde 30.00 (Water-988,Alumnum hydroxde-

17.6,HCl-36.7)

Water 1000.00 Organc Resdue 17.70

Total 1730.00 Total 1730.00

164

Stage-3


n Kg n Kg

Stage-2 70.00 Stage-3 60.00

Ethane thol 10.00 Methanol Recovery 283.00


Hydrochlorc acd (10%) 70.00 Effluent water 367.00

Water 300.00 (Water-300,HCl-2,water from HCl-

63,Methanol-2)

By-Product 12.60

(Butane-1-thol)

Organc Resdue 12.40


Stage-4


n Kg n Kg

Stage-3 60.00 Stage-4 50.00


DMF 100.00 Methanol Loss 30.00

Actvated carbon 10.00 DMF Recovery 93.00

DM Water 400.00 DMF Loss 5.00


(Water-400,Methanol-10,DMF-2)

Spent carbon 10.00

Organc Resdue 10.00

Total 1170.00 Total 1170.00

165

25. Febuxostat


2-(4-hydroxyphenyl)-4-methyl-5-thazole carboxylc acd ethyl ester was formylated usng

polyphosphorc acd and hexamethyltetramne to yeld 2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-

thazole carboxylc acd ethyl ester.2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thazole carboxylc

acd ethyl ester was O-alkyalted usng sobutyl bromde to get 2-(3-formyl-4-sobutyloxy phenyl)-4-

methyl-5-thazole carboxylc acd ethyl ester. The formyl group of 2-(3-formyl-4-sobutyloxy

phenyl)-4-methyl-5-thazole carboxylc acd ethyl ester was converted to ntrle usng formc acd,

hydroxylamne hydrochlorde to yeld 2-(3-cyano 4-sobutyloxy phenyl)-4-methyl-5-thazole

carboxylc acd ethyl ester. 2-(3-cyano 4-sobutyloxy phenyl)-4-methyl-5-thazole carboxylc acd

ethyl ester was hydrolyzed usng sodum hydroxde n ethanol whch on further crystallzaton

afforded FEBUXOSTAT.

Chemical Reaction:

166

Stage-2

HO

H

N

CH3

O

O S K2CO3

+ Br DMF H N

OC2H5 CH3 + HBr

O O S

Stage-1 sobutyl bromde OC2H5

C14H13NO4S Stage-2 O

C4H9Br C H NO S Hydro

18 21 4

291.33 137.02

bromc acd

347.44 81.0

Stage-3

O

H N

CH3 HCOONa

+ NH2OH.HCl + HCOOH O S

OC2H5

Stage-2 O Hydroxyl amne Formc acd

C18H21NO4S hydrochlorde

46.0 347.44 69.49

O

N

NC

+

+ 2 H O

+ H2

CH3 + HCl

CO2 2

S

OC2H5

O

Stage-3 Hydrochlorc Carbon Water Hydrogen

acd doxde

C18

H20

N2

O3

S

2.0

344.44 36.5 44.0 36.0

167

Stage-4

O

N

O

NC

CH3

S + NaOH NC N + C2H5ONa

C2H5OH-THF CH3

OC2H5 S

THF

O

OH

Stage-3 O

C

18H

20N

2O

3S

Sodum Stage-4 Sodum

hydroxde C

16H

16N

2O

3S ethoxde

344.44

40.0 316.3 68.05

Stage-5

O

O

N NC

CH3 EtoH-Water

NC N

S CH3

S

OH

O OH

Stage-4 O

C

16H

16N

2O

3S

Stage-5

316.3 C

16H

16N

2O

3S

316.3

168

Mass Balance:

Stage-1


n Kg n Kg

2-(4-hydroxyphenyl)-4-methyl-5- 140.00 Stage-1 120.00

thazole carboxylc acd ethyl

ester

Polyphosphorc acd 180.00 Dlute Phosphorc acd Reuse 2225.00

Hexamethyl tetramne 20.00 (Water-2000,Phosphorc acd-

208,Methanol-17)

Acetc acd 32.00 Organc Resdue 27.00

Water 2000.00

Total 2372.00 Total 2372.00

Stage-2


n Kg nKg

Stage-1 120.00 Stage-2 140.00

DMF 1100.00 DMF Recovery 1055.00

Potassum carbonate 57.00 DMF Loss 45.00

sobutyl bromde 56.50 Effluent water 1562.70


3.7,Potassum bromde-49,DMF-10)


(Carbon doxde)

Organc Resdue 12.80

Total 2833.50 Total 2833.50

169

Stage-3


n Kg n Kg

Stage-2 140.00 Stage-3 135.00

Hydorxyl amne Hydrochlorde 28.00 THF Recovery 950.00

Formc acd 18.53 THF Loss 50.00

Sodum Formate 27.40 Effluent Water 356.50

THF 1000.00 (Water-300,Sodum chlorde-

23.5,Formc Acd-18.5,generated

water-14.5)

odne 5.00 Process Emssons 18.50

Water 300 (Carbondoxde-17.7,Hydrogen-

0.8) 8.93

Organc Resdue

Total 1518.93 Total 1518.93

Stage-4


n Kg n Kg

Stage-3 135.00 Stage-4 120.00

Sodum hydroxde 16.00 Ethanol Recovery 950.00

Ethanol 1000.00 Ethanol Loss 50.00

THF 1500.00 THF Recovery 1420.00

Hydrochlorc Acd 14.30 THF Loss 75.00


(Water-500,Sodum chlorde-23,

Ethanol-18,THF-5)

Organc Resdue 21.00

Total 3182.00 Total 3182.00

170

Stage-5


n Kg n Kg

Stage-4 120.00 Febuxostat 100.00

Ethanol 1000.00 Ethanol Recovery 940.00

Actvated carbon 10.00 Ethanol Loss 50.00


(Water-500,Ethanol-10,Organc

mpurtes-20)

Spent carbon 10.00

Total 1630.00 Total 1630.00

171

26. Pregabalin


Stage-1 Isoveraldehyde reacts with diethyl malonate in the presence of n-hexane as solvent media to

give stage–1 as product.

Stage-2 Stage-1 reacts with sodium cyanide and acetic acid in the presence of ethanol as solvent

media to give stage–2 as product.

Stage-3 Stage –2 reacts with potassium hydroxide, water and acetic acid by passing hydrogen gas in

the presence of raney nickel acting as catalyst to give stage –3 as product.

Stage-4 Stage –3 reacts with mandelic acid in the presence of isopropyl alcohol as solvent media to

give Stage –4 as product.

Stage-5 Stage –4 undergoes hydrolysis with tetrahydrofuran to give pregabalin as product.

172

Chemical Reaction:

Stage –1

O

H 3

C

O

C

OC2H5

H3C

C

OC H CH

CH2

CH

C

2 5 n-Hexane

CH2

C

O C H

CH CH CHO +

2 5

2

H 3

C

C

OC2H 5

H 3C O

O

2-(3-M ethyl-butylidene)-malonic

Isoveraldehyde Diethyl malonate acid diethyl ester

C5H10O C

7H

12O

4 C

12H

20O

4

86.13 160.17

228. 28

+ H2O

18.00

Stage – 2

O

H3C

C OC2H5

Ethanol

CH CH2 CH C + NaCN + CH3COOH

C OC2H5

H3C

O

2-(3-Methyl-butylidene)-malonic Sodium Acetic acid

acid diethyl ester cyanide

60.05

C12

H20

O4

49.00

228.28

N

CH3

O

C OC2H5

H3C + CH COONa

3

C

2-(1-Cyano-3-methyl-butyl)-malonic acid Sodium acetate

diethyl ester

82.03

C

13

H21

NO4

Page 4

173

Stage – 3

N

CH3

O

C OC2H5

H3C +

C OC2H5

O

2-(1-Cyano-3-methyl-butyl)-malonic acid

diethyl ester C

13

H21

NO4

255.31

H3C

NH2

H3C

+ CH3COOK

COOH

3-Aminomethyl 5 -methyl 98.14

hexanoic acid

C8H17NO2

159.23

2H2 + KOH + CH3COOH + H2O

Hydrogen Potassium Acetic aid 18.00

hydroxide 60.05

2X2=4.0

56.11

Raney Nickel

+ 2 C2H5OH + CO

2

2 X46.07=92.14 44.00

174

Stage-5

Mass Balance:

Stage –1


in Kg in Kg

Isoveraldehyde 98.00 Stage –1 221.00

Diethyl malonate 185.00 n-Hexane Recovery 171.00

Acetic acid 13.00 n-Hexane Loss 9.00

Stage –4

H3C H C

3

NH2

OH

NH +

3

HO

H3C IPA

+

COOH

1/2

H3

C

-OOC

COOH COOH

3-Aminomethyl 5 -methyl Mandelic acid

S(+)Pregabalin mandalate salt

hexanoic acid

C H NO C8H8O3

C16

H25

NO5

8 17 2

152.14 159.23 1/2X311.37=155.68

+ 1/2 (R)-Isomer

1/2X311.37=155.68

H3C

NH +

3 H3C

OH

HO

H3C

THF

NH2

COOH

-OOC

H3C

+

COOH

COOH

S(+)Pregabalin mandalate salt

S(+)Pregabalin Mandelic acid

C16

H25

NO5

311.37 C8H17NO2

C8

H8

O3

159.23 152.14

175

Di isopropyl amine 10.00 Effluent Water 781.18

n-Hexane 180.00 (Water-735,generated

water-20.5,Diisopropyl

Amine-10,Acetic Acid-

13,Diethyl Malonate-2.68)


(Organic Impurities)

Total 1221.00 Total 1221.00


in Kg in Kg

Stage –1 221.00 Stage-2 225.00

Sodium cyanide 47.50 Toluene Recovery 470.00

Ethanol 900.00 Toluene Loss 25.00

Toluene 500.00 Ethanol Recovery 855.00

Acetic acid 60.00 Ethanol Loss 45.00


(Water-1000,Sodium

Acetate-79.5,Acetic Acid-

1.8,Toluene-3)



Toluene-2)

Total 2728.50 Total 2728.50


in Kg in Kg

Stage-2 225.00 Stage-3 120.00

176


Potassium hydroxide 50.00 Methanol loss 11.00

Acetic acid 60.00 IPA Recovery 333.00

Raney nickel 30.00 IPA Loss 17.00

Ethanol 50.00 Ethanol Recovery 123.00

IPA 350.00 Raney Nickel Reuse 30.00

Hydrogen gas 5.00 Effluent water 1885.90

Water 1800.00 (Water-1784,Potassium

Acetate-86.7,Ethanol-6.2,

Acetic Acid-7,IPA-2)



(Carbon dioxide-38.7,

Hydrogen-1.48)

Total 2790.00 Total 2790.00

177


in Kg in Kg

Stage-3 120.00 Stage -4 110.00

(S)-Mandelic acid 118.00 IPA Recovery 908.00

Isopropyl alcohol 960.00 IPA Loss 48.00


(Water-300,Mandelic acid-

3.28,IPA-2)

R-Isomer Recycle 110.00



IPA-2)

Total 1498.00 Total 1498.00

178



Stage-1 4-Fluoro-Benzadehyde reacts with 4-Methyl-3-oxo-pentanoic acid ethyl ester in presence of

Base to give Stage-1 as product. Stage-2 Stage-1 product reacts with S-Methyl iso thio urea and 2, 3Dichloro-5, 6-dicyano benzo quinone

in presence of HMPA to give stage-2 as product. Stage-3 Stage-2 product reacts with meta-chloro peroxy benzoic acid to give Stage-4 as product and

Meta chloro benzoic acid as by-product. Stage-4 Stage-3 product reacts with methyl amine in presence of Ethanol s solvent media to give Stage-

4 as product. Stage-5 Stage-4 product reacts with Methane sulfonyl chloride in presence of Sodium hydride as

catalyst to give Stage-5 as product. Stage-6 Stage-5 product undergoes reduction and oxidation in presence of Hydrogen gas to give Stage-

6 as product. Stage-7 Stage-6 product reacts with methyl (3R)-3-(ert-butyldimethylsilyloxy)-5-oxo-6-

triphenylphosphoranylidene hexanoate. Stage-8 Stage-7 product reacts with Hydrogen fluoride in presence of Acetonitrile as solvent media to

give Stage-8 as product. Stage-9 Stage-8 product reacts with Sodium Boro hydride undergoes hydrogenation to give Sage-9 as

product.

179

Stage-10 Stage-9 product reacts with Calcium chloride undergoes saponification to give Rosuvastatin

Calcium as product.

Chemical Reaction:

Stage-1

F

O

H3C MeOH

+ CH C CH COOC H + KOH + CH3I

2 2 5

CHO H3C

4-Fluoro-benzaldehyde 4-Methyl-3-oxo-pentanoic Potassium

Methyl Iodide

acid ethyl ester hydroxide

C7H5F0 C

8

H14

O3

124.11 158.19 56.11 141.94

F

COOC2H5 CH3

+ KI + CH3OH + H2O

CH3

O

2-(4-Fluoro-benzylidene)-4-methyl 166.0 32.0 18.0

-3-oxo-pentanoic acid ethyl ester

C15

H17

FO3

264.29

180

Stage-2

O

F NH

COOC2H5 NC

Cl

CH3 +

CH3 +

CH3 H2N

S NC Cl

O

O

2-(4-Fluoro-benzylidene)-4-methyl S-methylisothiourea 2,3-Dichloro-5,6-dicyano-p-benzoquinone -3-oxo-pentanoic acid ethyl ester

C15

H17

FO3

264.29

F COOC

2

H5 CH3

CH3

N N

SCH3

4-(4-Fluoro-phenyl)-6-isopropyl-

2 -methylsulfanyl-pyrimidine -

5-carboxylic acid ethyl ester

C17H19FN2O2S

334.41

C2H6N2S C8Cl2N2O2

90.15

227.0

HMPA

MDC

OH

NC

Cl

+

+ H2O

NC

Cl

OH

2,3-Dichloro-5,6-dicyano 18.0 -p-

benzoquinol

C8H2Cl2N2O2

229.02

181

Stage-3

F

COOC2H5 CH Cl

3

O

CH3 + 2 MDC

N

N

O

OH

SCH3

4-(4-Fluoro-phenyl)-6-isopropyl-2 meta-Chloroperoxybenzoic acid

-methylsulfanyl-pyrimidine

-5-carboxylic acid ethyl ester

C H FN O S C7H5ClO3

17 19 2 2

2x172.57=345.14

334.41

F Cl

COOC2H5 CH 3 O

+ 2

CH3

HO

N N

SO2CH3

4-(4-Fluoro-phenyl)-6-isopropyl-2- meta-Chlorobenzoic acid

methanesulfonyl-pyrimidine-5

-carboxylic acid ethyl ester

C7H5ClO2

C17H19FN2O4S

366.41 2x156.57=313.14

182

Stage-5

Stage-4

F

F

COOC2

H5 CH3 COOC H

Ethanol

2 5CH

3

+

H2N CH

3

MeOH

CH3 CH3

N N N N

NHCH3

SO2CH3

4-(4-Fluoro-phenyl)-6-isopropyl-2- Methylamine

methanesulfonyl-pyrimidine-5

-carboxylic acid ethyl ester

C17H19FN2O4S CH5N

366.41

31.06

4-(4-Fluoro-phenyl)-6-isopropyl-

2-methylamino-pyrimidine-5-

carboxylic acid ethyl ester

C17

H20

FN3

O2

317.36

+ O S OH

CH3

F

COOC2H5

CH 3

F

Cl

COOC

2

H5 CH3 NaH(60%) CH3

+ O S O

N N

CH3 CH3 Dimethoxy + HCl

ethane

N

N

N CH3

NHCH3

SO CH

2 3

4-(4-Fluoro-phenyl)-6-isopropyl-2- Methane sulfonyl chloride 4-(4-Fluoro-phenyl)-6-isopropyl 36.5

methylamino-pyrimidine-5- -2-(methanesulfonyl-methyl

carboxylic acid ethyl ester -amino)-pyrimidine-5-


C17

H20

FN3

O2 CH3ClO2S C18H22FN3O4S

317.36 114.55 395.45

183

Stage-6

Stage-7

F

F

COOC2

H5 CH3 CHO CH3

Reduction

CH3 + H2

CH3 + C H OH

2 5

Oxidation

N N N N

Toluene/

DIBAL-H

N CH3 N CH3

SO CH SO2CH3

2 3

4-(4-Fluoro-phenyl)-6-isopropyl Hydrogen N-[4-(4-Fluoro-phenyl)-5-formyl-6- 46.07

-2-(methanesulfonyl-methyl isopropyl-pyrimidin-2-yl]-N-methyl

-amino)-pyrimidine-5- -methanesulfonamide


C16

H18

FN3

O3

S

C18H22FN3O4S

395.45 2.0 351.40

F CHO

CH3

CH3

N N

N CH3

SO2CH3

N-[4-(4-Fluoro-phenyl)-5-formyl-6-

isopropyl-pyrimidin-2-yl]-N-methyl -

methanesulfonamide C

16

H18

FN3

O3

S

351.40

O CH3

O

O

+

CH3O

H3C

Si CH P

3

H3

CH3C

Methyl (3R)-3-(tert-butyldimethylsilyloxy)-5 -

oxo-6-triphenylphosphoranylidenehexanoate

TEA C31H39O4PSi

N,N-DMF 534.70

KI

184

Stage-8

F

O

N

N N CH3

H3CO2S

CH3 CH3

CH3 CH

3

Si CH3

O

CH CH3 + O P

3

COOCH3

3-(tert-Butyl-dimethyl-silanyloxy)-7-[4-(4-fluoro-phenyl)-6- Triphenylphosphine oxide

isopropyl-2-(methanesulfonyl-methyl-amino)

-pyrimidin-5-yl]-5-oxo-hept-6-enoic acid methyl ester

C18

H15

OP

C29H42FN3O6SSi

278.28 607.81

185

F

CH3 CH

3

Si CH3

O O

CH3 CH3 THF/Ethyl acetate

COOCH3 + HF N

N N CH3

H3CO2S

CH3

CH3

3-(tert-Butyl-dimethyl-silanyloxy)-7-[4-(4-fluoro-phenyl)-6- Hydrogen fluoride

isopropyl-2-(methanesulfonyl-methyl-amino)

-pyrimidin-5-yl]-5-oxo-hept-6-enoic acid methyl ester

C29H42FN3O6SSi

20.01

607.81

F

CH3 CH

O OH

3

+ F Si CH3

N COOCH3

CH3 CH3

N N CH3

H3CO2S

CH3 CH3

7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl tert-Butyl-fluoro-dimethyl-silane

-methyl-amino)-pyrimidin-5-yl]-3-hydroxy

-5-oxo-hept-6-enoic acid methyl ester

C23H28FN3O6S C6H15FSi

134.27

493.55

186

7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-

amino)-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoic acid methyl ester

C23H30FN3O6S

495.56

Stage-9

F

O OH

Diethylmethoxyborane

COOCH3 N

NN CH3

H3CO2S

CH3 CH3

+ H

2

NaBH4 Ethyl acetate

7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-

(methanesulfonyl -methyl-amino)-

pyrimidin-5-yl]-3-hydroxy -5-oxo-hept-6-

enoic acid methyl ester C

23

H28

FN3

O6

S

493.55

F

N

N N H3CO2S

CH3

Hydrogen

2.0

OH OH

COOCH3

CH3

CH3

187

Stage-10

F

OH OH

Water 2

COOCH3 + CaCl

N

2

Toluene,Ethyl acetate

N

N CH3

H3CO2S

CH3 CH3

7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl- Calcium chloride

methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-

hept-6-enoic acid methyl ester

C23

H30

FN3

O6

S

2x495.56=991.12 110.98

F

OHOH

COO- Ca

2+ +

2

N

2 CH3Cl

N N CH3

H3CO2S

CH3 CH3

Methyl chloride

Rosuvastatin calcium

C2H6Cl2 (C22H27FN3O6S)Ca

100.98

1001.14

188

Mass Balance:

Stage-1

Name of the input Quantity Name of the out put Quantity in Kg in Kg

4-Fluoro benzaldehyde 52.00 Stage-1 100.004-Methyl-3-oxo-pentanoic acid 66.30 Methanol Recovery 237.00

ethyl ester

Potassium hydroxide 23.50 Methanol Loss 12.00

Methyl Iodide 60.00 Effluent water 590.56

Methanol 250.00 (Water-500,Potassium Iodide-

69.5,Methanol-13.52,gen

water-7.54)



Methanol-1)


Stage-2


in Kg in Kg

Stage-1 100.00 Stage-2 115.00

S-Methyl iso thio urea 35.00 MDC Recovery 474.00

2,3-Dichloro-5,6-dicyano 85.00 MDC Loss 25.00

benzoquinon

e

HMPA 100.00 HMPA Recovery 94.50

MDC 500.00 HMPA Loss 5.00


(Water-300,gen water-

6.81,MDC-0.5,HMPA-0.5)

By-Product 85.75

(2,3-Dichloro-5,6-Dicyano-

benzoquinol)


(Organic Impurities-

11.94,MDC-0.5)

Total 1120.00 Total 1120.00

189

Stage-3

Stage-4


in Kg in Kg

Stage-2 115.00 Stage-3 120.00

Meta chloro peroxy benzoic 118.68 MDC Recovery 284.50

acid MDC 300.00 MDC Loss 15.00

500.00 Effluent water 506.51

(Water-500,MDC-0.5,Organic

Impurities-6.01)

Meta chloro benzoic acid 107.67

Reuse Total 1033.68 Total 1033.68


in Kg in Kg

Stage-3 120.00 Stage-4 96.00

Methyl amine 10.20 Ethanol Recovery 238.00

Ethanol 250.00 Ethanol Loss 12.00


Water 300.00 Methanol Loss 15.00


(Water-300,Methane sulfonic

acid-26.23,Ethanol-1)



6.97,Methanol-0.5) Total 980.20 Total 980.20

190

Stage-5


in Kg in Kg

Stage-4 96.00 Stage-5 112.00

Methane sulfonyl chloride 35.00 Di methoxy ethane Recovery 285.00

Sodium hydride (60%) 1.00 Di methoxy ethane Loss 15.00

Di methoxy ethane 300.00 Hydrochloric acid 11.15



Stage-6


Stage-5 112.00 Stage-6 95.00

Hydrogen 0.56 Toluene Recovery 284.00

DIBAL-H 1.00 Toluene Loss 15.00

Toluene 300.00 Ethanol Recovery 13.04



Toluene-1)


191

Stage-7


in Kg in Kg

Stage-6 95.00 Stage-7 155.00

Methyl(3R)-3-(tert butyl di 144.55 N,N-Dimethyl formamide 280.00

methyl silyloxy)-5-oxo-6- Recovery triphenyl

phosphoranylidene hexanoate

Triethyl amine 15.00

N,N-Dimethyl formamide

Loss 15.00

N,N-Dimethyl formamide 300.00 Effluent water 320.00

Water 300.00 (Water-300,Triethyl amine-

15,N,N-DMF-5)


By-Product 75.22

(Triphenyl phosphine oxide) Total 854.55 Total 854.55

Stage-8


in Kg in Kg

Stage-7 155.00 Stage-8 120.00

Hydrogen fluoride 5.10 THF Recovery 237.00

250.00 THF Loss 12.00


Ethyl acetate Loss 15.00

By-Product 34.24

(Tert-butyl-fluoro-dimethyl

silane


(Organic Impurities-5.86,THF-

1) Total 710.10 Total 710.10

192

Stage-9


in Kg in Kg

Stage-8 120.00 Stage-9 115.00

Hydrogen 0.48 Ethyl acetate Recovery 237.50

Diethyl methoxy borane 20.00 Ethyl acetate Loss 12.00

Sodium boro hydride 1.00 THF Recovery 474.50

Ethyl acetate 250.00 THF Loss 25.00

THF 500.00 Sodium Boro hydride Reuse 1.00


(Organic Impurities-25.48,THF-

0.5,Ethyl acetate-0.5)


Stage-10


Stage-9 115.00 Rosuvastatin Calcium 100.00

Calcium chloride 13.00 Toluene Recovery 473.50



Water 250.00 Ethyl acetate Loss 25.00


(Water-250,Methyl chloride-

11.82, Toluene-1)



16.18,Toluene-0.5)

Total 1378.00 Total 1378.00

193

28. Biperiden Hydrochloride


Stage-1 Cyclo pentadiene reacts with Methyl vinyl ketone in the presence of Sodium methoxide by

using Methanol as solvent media to give Stage-1 as product. Stage-2 Stage-1 product reacts with piperdine Hydrochloride and para formaldehdye in the presence of

sodium hydroxide by using IPA as solvent media to give Stage-2 as product. Stage-3 Stage-2 product reacts with phenyl magnesium chloride ND Hydrochloric acid in the presence

of THF as solvent media to give Biperiden as product. Stage-4 Biperiden reacts with hydrochloric acid Hydrochloric acid in the presence of Isopropyl alcohol

as solvent media to give Biperiden Hydrochloride as product.

194

Chemical Reaction:

Stage-1

O O

Methanol

+

Cyclopentadiene Methyl vinyl ketone 1-Bicyclo[2.2.1]hept-5-en-2-yl ethanone

C5H6 C4H6O C9H12O

66.10 70.09

136.19

Stage-2

O

+

Cl + HCHO +

NaOH

N H

H

1-Bicyclo[2.2.1]hept-5-en-2-yl

Piperdine Hydrochloride

Paraformaldehyde Sodium Hydroxide

ethanone

C5H12ClN CH2O 40.0

C9H12O

136.19 121.61 30.03

IPA

N + NaCl + 2H2O

O

58.44 36.0

1-Bicyclo[2.2.1]hept-5-en-2-yl -3-piperidin-1-yl-propan-1-one

C15H23NO

233.35

195

Stage-3

N

THF

+ + HCl

Mg

O

Cl

1-Bicyclo[2.2.1]hept-5-en-2-yl Phenyl magnesium Hydrochloric acid

-3-piperidin-1-yl-propan-1-one Chloride

36.5

C H NO C6H5ClMg

15 23

136.86 233.35

+ MgCl2 N

OH

Biperden Magnesium chloride

C21H29NO 95.21

311.46

Stage-4

N

IPA

N

+ HCl

OH OH

Cl

H

Biperden

Hydrochloric acid

Biperdin Hydrochloride

C21H29NO 36.5

C21H30ClNO

311.46

347.96

196

Mass Balance:

Stage-1

Name of the Input Quantity Name of the Output Quantity

in kg in kg

Cyclo pentadiene 30.00 Stage-1 50.00

Methyl vinyl ketone 32.00 Methanol Recovery 470.00

Sodium hydroxide 15.00 Methanol Loss 25.00

Methanol 500.00 Effluent water 417.00

Water 400.00 (Water-400,Sodium

hydroxide-15,Methanol-2)


(Organic Impurities-12,

Methanol-3)


Stage-2


in kg in kg

Stage-1 50.00 Stage-2 85.00

Piperdine Hydrochloride 50.00 Isopropyl alcohol Recovery 473.00

Para formaldehyde 15.00 Isopropyl alcohol Loss 25.00

Sodium Hydroxide 20.00 Effluent water 452.00

Isopropyl alcohol 500.00 (Water-400,generated

water-13.2,Sodium

chloride-21.5,para

formaldehyde-4,Sodium

hydroxide-5.3, IPA-2,

Piperidine HCl-5.3,Organic

Compound-0.7)

Water 400.00

Total 1035.00 Total 1035.00

197

Stage-3


in kg in kg

Stage-2 85.00 Stage-3 100.00

Phenyl magnesium chloride 50.00 THF Recovery 470.00

Hydrochloric acid 20.00 THF Loss 25.00

THF 500.00 1,4-Dioxane Recovery 380.00

1,4-Dioxane 400.00 1,4-Dioxane Loss 20.00


(Water-500,Magnesium

chloride-34.8,HCl-6.7,THF-

2)


(Organic Compound-13.5,

THF-3)

Total 1555.00 Total 1555.00

Stage-4

Name of the Input Quantity Name of the Output Quantity in kg in kg

Stage-3 100.00 Biperiden Hydrochloride 100.00

Hydrochloric acid 15.00 IPA Recovery 470.00



(Water-500,Hydrochloric

Acid-3.3,IPA-2)



IPA-3)

Total 1115.00 Total 1115.00

198

29. Donepezil Hydrochloride


Stage-1 Ethyl iso nipecotate reacts with Benzyl chloride and potassium carbonate in the presence of

Toluene as solvent media to give Stage-1 as product.

Stage-2 Stage-1 product reacts with vitride solution by using Toluene as solvent media to give Stage-2

as product.

Stage-3 Stage-2 product reacts with Dimethyl sulfoxide undergoes oxidation in the presence of

Hydrobromic acid by using Toluene as solvent media to give Stage-3 as product.

Stage-4 Stage-3 product reacts with 5, 6-Dimethoxy indanone in the presence of Methanol as solvent

media to give Stage-4 as product.

Stage-5 Stage-4 product undergoes hydrogenation by using Raney Nickel as catalyst yields Donepezil

base which is converted to hydrochloride by treating with isopropyl alcohol hydrochloride to

give Donepezil hydrochloride as product.

Chemical Reaction:

Stage-1

O

O

O

N

O Toluene

2

+ 2 + K2CO3 HN

Cl

2

Piperdine-4-carboxylic

Benzyl chloride Potassium 1-Benzyl-piperidine-4-

acid ethyl ester

carbonate carboxylic acid ethyl ester

C H NO

C7H7Cl

8 15 2

138.21

2X126.58=253.16

C15

H21

NO2

2X157.21=314.42

2X247.33=494.66

+ 2KCl + CO2

+ H2O

149.1 44.0 18.0

Stage-2

199

Stage-2

O

O

N

Toluene

2

+ 2 NaAlH2(OCH2CH2OCH3)2 +

6 H2O

1-Benzyl-piperidine-4-

Vitride

Water carboxylic acid ethyl ester

C

15H

21NO

2 C6H16NaAlO4 6X18=108.0

2X202.16=404.32

2X247.33=494.66

OH

N

O

+

+ 2C2H5ONa 2 Al(OH)3 + 4 HO

2

(1-Benzyl-piperidin-4-yl)-methanol Sodium ethoxide Aluminium Methoxy Ethanol

Hydroxide

C H

NO

2X68.05=136.10

C3H8O2

13 19 2X78.0=156.0

4X76.09=304.36 2X205.30=410.60

200

201

Mass Balance:

Stage-1

Name of the Input Quantiy Name of the Output Quantity

in kg in kg

Ethyl isonipecotate 75.00 Stage-1 105.00

Benzyl chloride 62.00 Toluene Recovery 470.00


Potassium carbonate 35.00 Effluent water 544.79

Water 500.00 (Water-500,generated

water-4.29,Potassium

chloride-35.5,Potassium

carbonate-2,Toluene-3)

Process Emission(Carbon dioxide) 10.49



Toluene-2)

Total 1172.00 Total 1172.00

Stage-5

O

N

H3CO

+ H2 + HCl

H3CO

2-(1-Benzyl-piperidin-4-ylmethylene)-5,6-dimethoxy-indan-1-one Hydrogen Hydrochloric acid

C

24

H27

NO3 2.0 36.5

377.48

Raney Nickel

Methanol

O

N Cl

H3CO

H

H3CO

Donepezil Hydrochloride

C24H30ClNO3

415.99

202

203

Stage-2


in kg in kg

Stage-1 105.00 Stage-2 70.00

Vitride 86.00 Toluene Recovery 470.00



(Water-727,Sodium

ethoxide-28.9,Aluminium

hydroxide-33,Toluene-2)

By-Product 64.73

(Methoxy Ethanol)



Toluene-3)

Total 1441.00 Total 1441.00

Stage-3


Stage-2 70.00 Stage-3 60.00

Dimethyl sulfoxide 30.00 Toluene Recovery 375.00


Hydrobromic Acid (48%) 30.00 Effluent water 538.13

Water 500.00 (Water-500,generated

water-6.13,Hydrobromic

Acid-15.6,water from HBr-

14.4,Toluene-2)

By-Product 21.17

(Dimethyl Sulfide)



Toluene-3)

Total 1030.00 Total 1030.00

204

Stage-4


Stage-3 60.00 Stage-3 100.00

5,6-Dimethoxy indanone 57.00 Methanol Recovery 375.00



(Water-500,generated

water-5.3,Methanol-3)



Methanol-2)

Total 1017.00 Total 1017.00

Stage-5


Stage-4 100.00 Donepezil Hydrochloride 100.00


Raney Nickel (catalyst) 10.00 Methanol Loss 20.00

Hydrogen 2.00 IPA Recovery 285.00


Hydrogen chloride 20.00 Raney Nickel Reuse 10.00


(Water-300,HCl-10.3,IPA-

2,Organic Compound-

8.23)


(Hydrogen)

Total 1132.00 Total 1132.00

205

30. Domperidone


Stage-1: N-carbethoxy-4-piperidone is reacted with Hydrogen and Ammonia in the presence of Raney

nickel as catalyst and Methanol as solvent media to give stage-1 as product.

Stage-2: Stage-1 reacts with 2, 5-Dichloro nitrobenzene & Sodium Carbonate in presence of Methanol as

a solvent media to give Stage-2 as product. Stage-3: Stage-2 reacts with Hydrogen in presence of Raney Nickel as catalyst and Toluene as solvent

media to give Stage-3 as product.

Stage-4: Stage-3 reacts with Urea in the presence of Sodium Hydroxide as a solvent media to give Stage-

4 as product. Stage-5: Stage-4 undergoes hydrolysis with Sodium Hydroxide to give Stage-5 as product.

Stage-6: Stage-5 reacts with 1-(3-chloropropyl)-1, 3-dihydro-2H-benzimedazole-2-one and Sodium

Carbonate in the presence of Methyl Isobutyl Ketone as solvent media to give Domperidone as

product.

Chemical Reaction:

Stage-1:

O NH2

Raney Nickel

+

+ H2 + NH3 H2O

N N

O O

CH3 O

O

CH3

18.00 N-Carbethoxy-4-piperidone

Hydrogen Ammonia

4-Amino-piperidine-1-


17.03

C8

H13

NO3 2.00

C8

H16

N2

O2

171.19

172.22

206

Stage-2:

Cl

NH2

HN

Cl NO2

NO2

Methanol

+

+

1/

Na CO

N 2 2 3

N

Cl

O O CH3

O O CH3

4-Amino-piperidine-1- 2,5-Dichloro Sodium 4-(4-Chloro-2-nitro-phenylamino)

carboxylic acid ethyl ester Nitrobenzene carbonate -piperidine-1-carboxylic acid ethyl ester

C H N O 1/ X105.98=52.99 C H ClN O

8 16 2 2 C H Cl NO 2 14 18 3 4

6 3 2 2

172.22 192.00 327.76

+ NaCl + 1/2 CO2 + 1

/2 H2O

Sodium chloride Carbon dioxide 1

/2X18=9.00

58.44 1/2X44=22.00

207

Stage-3:

Cl

Cl

HN

HN

NH2

NO2 Raney Nickel

+ 3 H2

Toluene N

N

O O CH3

O O CH3

4-(4-Chloro-2-nitro-phenylamino) Hydrogen 4-(2-Amino-4-chloro-phenylamino)

-piperidine-1-carboxylic acid ethyl ester -piperidine-1-carboxylic acid ethyl ester

3X2=6.00

C H ClN O C14H20ClN3O2

14 18 3 4

297.78

327.76

+ 2H2O

2X18=36.00

Stage-4:

H

Cl Cl N

O

N

HN

NH2 O

NaOH

+ N

N H2N NH2

O O CH3

O O CH3

4-(5-Chloro-2-oxo-2,3-dihydro- 4-(2-Amino-4-chloro-phenylamino) Urea

enzoimidazol-1-yl)-piperidine-1- -piperidine-1-carboxylic acid ethyl ester

CH4 N2O carboxylic acid ethyl ester

C14

H20

ClN3

O2

60.05

C15H18ClN3O3

297.78

323.77

+ 2NH3

Ammonia

2X17.03=34.06

208

Stage-5:

H

Cl N

H

Cl

O N

N

O

N

+ NaOH

N

N

H

O

O

CH3

4-(5-Chloro-2-oxo-2,3-dihydro-benzoimidazol Sodium hydroxide 5-Chloro-1-piperidin-4-yl-1,3

-1-yl)-piperidine-1-carboxylic acid ethyl ester -dihydro-benzoimidazol-2-one

40.00

C

15

H18

ClN3

O3 C12H14ClN3O

323.77 251.71

+ C H ONa + CO2

2 5

Sodium ethoxide Carbon dioxide

68.05 44.00

Stage-6:

H

Cl N

O H

N N MIBK

O +

1/2Na2CO3

+

N

Cl

N

H

5-Chloro-1-piperidin-4-yl-1,3 1-(3-chloropropyl)-1,3-dihydro Sodium carbonate

-dihydro-benzoimidazol-2-one -2H-(Benzimidazole-2-one) 1

/2X105.98=52.99

C12H14ClN3O C10H11ClN2O

251.71

210.66

N

N

O

N

+

NaCl

+

1/

H

O +

1/2 CO2

N

2 2

H

O Cl

N

H

Domperidone Sodium chloride Water Carbon dioxide

C H ClN O 58.44 1/X18=9.00 1

/2X44=22.00

22 24 5 2 2

425.91

209

Mass Balance:

Stage-1


in Kg in Kg

N-Carbethoxy-4-piperidone 80.00 Stage-1 70.00

Ammonia gas 28.00 Methanol Recovery 283.00


Raney Nickel 20.00 Raney Nickel Reuse 20.00

Hydrogen 5.00 Generated water 8.40


(Organic Impurities-10.6,Methanol-

2)


(Ammonia-20,Hydrogen-4)


Stage-2


in Kg in Kg

Stage-1 70.00 Stage-2 95.00

2,5-Dichloro Nitrobenzene 78.00 Methanol Recovery 470.00

Sodium Carbonate 30.00 Methanol Loss 25.00



3.65,Sodium chloride-

23.7,Sodium

carbonate-8.5,Methanol-3)


(Carbon dioxide)


(Organic Impurities-38.22,Methanol-

2)

Total 1328.00 Total 1328.00

210

Stage-3


in Kg in Kg

Stage-2 95.00 Stage-3 75.00

Hydrogen 5.00 Toluene Recovery 330.00

Raney Nickel 10.00 Toluene Loss 17.00

Toluene 350.00 Raney Nickel Reuse 10.00



10.43,Toluene-1,Organic

Impurities-

1.5)


(Hydrogen)


(Organic Impurities-9.8,Toluene-2)

Total 1060.00 Total 1060.00

Stage-4


in Kg in Kg

Stage-3 75.00 Stage-4 67.00

Urea 20.00 Effluent Water 1029.43

Sodium Hydroxide (48%) 60.00 (Water-950,Urea-4.9,Sodium

hydroxide-28.8,water from

sodium

hydroxide-31.2,Organic

compound-

14.53)

Water 950.00 Process Emission 8.57

(Ammonia)

Total 1105.00 Total 1105.00

211

Stage-5


Stage-4 67.00 Stage-5 45.00

Sodium Hydroxide 15.00 Effluent Water 527.90

Water 500.00 (Water-500,Sodium hydroxide-

6.7,Sodium ethoxide-14,Organic

Compound-7.2)

Process Emission

(Carbon dioxide) 9.10


Stage-6


in Kg in Kg

Stage-5 45.00 Domperidone 50.001-(3-Chloropropyl)-1,3-dihydro- 40.00 Methyl Isobutyl Ketone Recovery 1135.00

2H-benzimedazole-2-one

Sodium Carbonate 20.00 Methyl Isobutyl Ketone Loss 60.00

Methyl Isobutyl Ketone 1200.00 Effluent Water 524.50


1.6,Sodium chloride-10.4,Sodium

carbonate-10.5,MIBK-2)


(Carbon Dioxide)


(Organic Impurities-28.57,MIBK-3)

Total 1805.00 Total 1805.00

212

31. Carisoprodol


Stage-1 2-Methyl-2-propyl-1,3-propane diol undergo cyclisation with Dimethyl carbonate in the

presence of Toluene as a solvent media and Sodium methoxide as catalyst to give Stage-1 as

product.

Stage-2 Stage-1 undergo condensation with Isopropylamine to give stage-2 as product.

Stage-3 Stage-2 reacts with sodium cyanate and Hydrochloric acid in the presence of chloroform

as a solvent media to give carisoprodol (Tech) as product.

Stage-4 Carisoprodol (Tech) undergo recystallisation by using methanol to give carioprodol (Pharma )

as product.

213

Chemical Reaction:

Stage-1: O O

OH O

H C Toluene H3C

3 OH + H3C CH3 O

H3C O O NaOMe H3C

2-Methyl-2-Propyl-1,3-Propane diol Dimethyl carbonate

5-Methyl-5-propyl-[1,3]dioxan-2-one

C7H

16O

2 C3H6O3

90.07

C8

H14

O3

132.20

158.19

+ 2 CH3OH

Methanol

2X32.04=64.08

Stage-2: H

O N CH 3

O O O NH2 CH3

H3C + H3C

OH

O H3C CH3 H3C

H3C

5-Methyl-5-propyl-[1,3]dioxan-2-one Isopropyl amine Isopropyl-carbamic acid 2-hydroxymethyl

-2-methyl-pentyl ester

C8

H14

O3

C3H9N

158.19 59.11 C

11

H23

NO3

217.30

214

Stage-3:

H

O N CH3

O CH3

Toluene

H3C + NaOCN + HCl

OH

H3C

Isopropyl-carbamic acid 2-hydroxymethyl

Sodium

cyanate Hydrochloric acid

-2-methyl-pentyl ester

65.00 36.5 C

11

H23

NO3

217.30

H

ON CH3

O CH3

H3C

O NH2

H3C

O

Carisoprodol(Tech)

C12

H24

N2

O4

260.32

Stage-4:

H

O N CH3

O CH3

H3C O NH2

H3C

O

Carisoprodol(Tech)

C12

H24

N2

O4

260.32

B) NaCl

Sodium chloride

58.44

H

ON CH3

O CH3

Methanol H3C

O

NH2

Purificatio

n H3C

O

Carisoprodol(Pharma) C

12

H24

N2

O4

260.32

215

Mass Balance:

Stage-1


in Kg in Kg 2-Methyl-2-propyl-1,3-propane 78.00 Stage-1 82.00

diol

Dimethyl carbonate 110.00 Toluene Recovery 370.00


Sodium methoxide 6.00 Dimethyl carbonate Recovery 52.00

Dimethyl carbonate Loss 3.00

Methanol generation 37.82



Toluene-3,Sodium methoxide-

6)


Stage-2


in Kg in Kg

Stage-1 82.00 Stage-2 105.00

Isopropylamine 164.00 Isopropylamine Recovery 123.00

Isopropylamine Loss 8.00



Isopropyl Amine-2.38)


216

Stage-3


in Kg in Kg

Stage-2 105.00 Carisoprodol (Tech) 112.00

Sodium cyanate 31.50 Chloroform Recovery 593.50

Chloroform 630.00 Chloroform Loss 31.50


Hydrochloric acid (35%) 100.00 Toluene Loss 17.00

Sulphuric acid 50.00 Effluent water 898.69

Water 735.00 (Water-735,Sodium chloride-

28.32,Hydrochloric Acid-

17.37,

water from HCl-65,Sulfuric

Acid-

50,Toluene-3)



Chloroform-5,Toluene-2)

Total 2071.5 Total 2071.50

Stage-4


in Kg in Kg

Carisoprodol (Tech) 112.00 Carisoprodol (Pharma) 100.00


Activated carbon 15.00 Methanol Loss 16.00


(Water-230,Methanol-3)

Spent carbon 15.00



Methanol-2)


217

32. Topiramate


Stage-1 Fructose reacts with sulphuric acid in the presence of sodium hydroxide and Acetone, n-Hexane

solvent media to produce 2, 3:4, 5-Bis-O-(1-MethylEthylidene)-B-D-fructo pyranose Stage-2 Step-A Stage-1 reacts with sulfonyl chloride in the presence of Pyridine and Toluene solvent media to

produce 2, 3:4, 5-bis-O-(1-methyl ethylidence) beta-d fructopyranose sulfonyl chlorides. Step-B 2,3:4,5-bis-O-(1-methyl ethylidene)-beta-d-fructo pyranose sulfonyl chloride further reacts with

Ammonia gas in the presence of n-Hexane, IPA and Ethyl Acetate Solvent media to produce

Topiramate.

Chemical Reaction:

Stage-1

HO O

O OH HO

Acetone O

+ H2 SO4 + 2 NaOH

O

2

HO O

O

HO OH

Fructose Sulfuric Acid Sodium Hydroxide2,3:4,5-bis-O-(1-Methyl Ethylidene)

-B-D-fructopyranose

C

6H

12O

6 98.0 2 X40=80.0 C H O

12 20 6

2X180.16=360.32

260.28

+ Na2SO4 + 4 H2O +2 O2

142.04 4X18=72.0 2X32=64.0

218

Stage-2 Step-A

HO O

O

O O N Toluene

+ Cl S Cl +

O

O

O

2,3:4,5-bis-O-(1- Methyl Ethylidene) Sulfonyl Chloride Pyridine

-B-D-fructopyr anose

Cl O S C 5H5N

2 2

C12

H20

O6

7 9.1

134.97

260.28

Cl O

S

O

O O

N

O

O +

Cl

H

O

O

2,3:4,5-bis-O-(1-methylethylidene)-beta Pyridine Hydrochloride

-d-fructopyranose sulfonyl chloride

C12H21NO8S C5H6ClN

358.79 115.56

Step-B

Cl O H2N O

S S O

O

O O O O O

O

O O

+ NH3

O

O

O O

2,3:4,5-bis-O-(1-methylethylidene)-beta Ammonia 2,3:4,5-bis-O-(1-methylethylidene)-beta

-d-fructopyranose sulfonyl chloride -d-fructopyranose sulfamate

17.03

C12H21NO8S C

12

H21

NO8

S

358.79 339.36

+ HCl

36.46

219

Mass Balance:

Stage-1


in Kg in Kg

Fructose 575.00 Stage-1 400.00

Sulfuric Acid 157.00 Acetone Recovery 1995.00


Sodium Hydroxide 131.00 n-Hexane Recovery 48.00

n-Hexane 50.00 n-Hexane Loss 2.00



114.8,Sodium hydroxide-3.4,

Acetone-2)

Sodium sulphate (Inorganic ) 226.60



(Oxygen)

Total 3873.00 Total 3873.00

Stage-2


in Kg in Kg

Stage-1 400.00 Topiramate 500.00


Pyridine 122.00 Toluene Loss 80.00

Ammonia gas 26.50 n-Hexane Recovery 1254.00

Sulfonyl Chloride 208.00 n-Hexane Loss 66.00Sodium bicarbonate 5.00 Ethyl Acetate Recovery 1530.00

n-Hexane 1320.00 Ethyl Acetate Loss 80.00

Sodium Chloride 5.00 IPA Recovery 1345.00

Ethyl Acetate 1610.00 IPA Loss 70.00

Isopropyl Alcohol 1415.00 Effluent Water 668.00

Water 600.00 (Water-600,Sodium bicarbonate-

5,Sodium chloride-5,Hydrochloric

Acid-56, Tolune-2)

Pyridine Hydrochloride (By- 178.2

Product)

220


Total 7311.50 Total 7311.50

33. Valsartan


Stage-1 L-Valine reacts with Methanol in presence of Methanol as solvent media to give Stage-1 as

product. Stage-2 Stage-1 product reacts with 4-Bromomethyl-biphenyl-2-carbonitrile in presence of Methanol as

solvent media to give Stage-2 as product. Stage-3 Stage-2 product reacts with Valeryl chloride in presence of Methanol as solvent media to give

Stage-3 as product. Stage-4 Stage-3 product reacts with Sodium azide; Tri butyl tin chloride undergoes Hydrogenation in

presence of Methanol as solvent media t give Valsartan as product.

Chemical Reaction:

Stage-1

Step-A

NH2

NH2

H3C Cl H3 C

OH

+ SOCl Cl + SO2

2

CH3 O H

CH3 O

L-Valine

Thionyl Chloride 2-Amino-3-methyl-butyryl chloride 64.06

hydrochloride

C5H11NO2 118.97

C5H11Cl2NO

117.15

172.05

221

Stage-B

Stage-2

NH2 NH2

H3C OCH3

H3C

Cl

HCl

Cl + CH3OH Cl +

H

CH3 O H CH3 O

2-Amino-3-methyl-butyryl chloride 32.04 2-Amino-3-methyl-butyric Acid 36.46

hydrochloride

methyl ester hydrochloride

C5H11Cl2NO C6 H14NO2Cl

172.05

167.63

222

Stage-3

N

NH2

H3C OCH3 Toluene

Cl + + K2CO3

CH3 O H

Br

2-Amino-3-methyl-butyric Acid 4-Bromomethyl-biphenyl- Potassium Carbonate

methyl ester hydrochloride 2-carbonitrile

C6 H14NO2Cl C H BrN 138.21

14 10

167.63 272.14

N

+ KBr + KCl + CO2 + H2O

NH

O

O

18.0 2-[(2-Cyano-biphenyl-4-ylmethyl)-amino]- 119.0 74.55 44.0

3-methyl-butyric acid methyl ester

C

20

H22

N2

O2

322.40

223

N

O

NH TEA

+ + NaHCO3

Cl

O

O

[(2-Cyano-biphenyl-4-ylmethyl)-amino]- Valeryl Chloride Sodium bicarbonate


C

20

H22

N2

O2 C5H9 ClO 84.0

322.40 120.58

N

O

O

N

+ NaCl + CO2 +

H2O

O

[(2-Cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]- 58.44 44.0 18.0


C25

H30

N2

O3

224

C24

H29

N5

O3 C13H30Sn

435.5 305.0

Stage-4

N

O

O Cl

N +H2 +NaN3+ Sn

O

2-[(2-Cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]- Hydrogen Sodium Tributyl tin chloride

3-methyl-butyric acid methyl ester Azide

C12H27ClSn

C25

H30

N2

O3

2.0 65.0

325.5

406.52

N

HN N

N

H3C

N + + NaCl

Sn

O

OH

O

Valsartan Tributyl methyl stannane 58.46

225

Mass Balance:

Stage-1


in Kg in Kg

L-Valine 45.00 Stage-1 50.00

Thionyl Chloride 45.70 Methanol Recovery 758.00



Toluene Loss 25.00


(Organic Impurities-5.33, Methanol-

2, Toluene-1)


(Hydrogen chloride-10.8, Sulfur

dioxide-24.57)

Total 1390.70 Total 1390.70

Stage-2


Stage-1 50.00 Stage-2 90.00

4-Bromomethyl-biphenyl-2- 82.00 Toluene Recovery 565.00

carbonitrile

Potassium carbonate 45.00 Toluene Loss 30.00



5.3,Potassium chloride-

22.2,Potassium Bromide-

35.5,Potassium carbonate-

3.78,Toluene-3)


(Organic Impurities-7.22, Toluene-2


(Carbon dioxide)

Total 1577.00 Total 1577.00

226

Stage-3


in Kg in Kg

Stage-2 90.00 Stage-3 100.00

Valeryl Chloride 34.00 Toluene Recovery 660.00


TEA 20.00 Effluent Water 744.80

Sodium bicarbonate 25.00 (Water-700,generated water-5,

Sodium chloride-16.3, Sodium

bicarbonate-1.5,TEA-20,Toluene-2)

Sodium Sulphate 10.00 Inorganic Solid Waste 10.00

Water 700.00 (Sodium Sulphate)


(Organic Impurities-13.93, Toluene-3)

Process Emission (Carbon dioxide) 12.27

Total 1579.00 Total 1579.00

Stage-4


in Kg in Kg

Stage-3 100.00 Valsartan 100.00

Sodium Azide 16.00 Toluene Recovery 660.00

Tri butyl tin chloride 80.00 Toluene Loss 35.00

Hydrogen 0.50 MDC Recovery 475.00

Sodium hydroxide 20.00 MDC Loss 25.00

Xylene 240.00 Xylene Recovery 228.00

Toluene 700.00 Xylene Loss 12.00

MDC 500.00 N-Hexane Recovery 190.00

Acetic Acid 40.00 N-Hexane Loss 10.00

N-Hexane 200.00 Effluent Water 877.30

Activated Carbon 10.00 (Water-800,generated water-

9,Sodium Chloride-14.3,Toluene-

3, Sodium Acetate-41,Acetic Acid-10)

Water 800.00 Spent Carbon 10.00

Tri butyl-methyl –stannane for sale 74.98


(Organic Impurities-7.22, Toluene-2)

Total 2706.50 Total 2706.50

227

34. Moxifloxacin Hydrochloride


Stage-1 Moxifloxacin Q-acid is reacted with 2, 8-Diazobicycloc (4.3.0) nonane in presence of

Triethylamine in Acetone and Dimethylformamide solvent media to get Moxifloxacin Base.

Stage-2 Moxifloxacin base is reacted with Hydrochloric acid in presence of Methanol and water to get

Moxifloxacin Hydrochloride Monohydrate.

Chemical Reaction:

Stage-1

OCH3

H

F N

Acetone

+ NH + (C2H5)3N

F COOH N

H

H

O

Moxifloxacin Q-acid 2,8-Diazobicyclo(4.3.0)nonane Triethylamine

C14

H11

F2

NO4

C7

H14

N2 101.19

295.24 126.20

H

OCH3

N N

N + (C2H5)3N.HF

H H

F COOH

O

Moxifloxacin Base Triethyl amine Hydrofluoride

C21

H24

FN3

O4 121.20

401.43

228

Stage-2

H

OCH3

N N

Methanol N

+

H H HCl + H2O

F COOH

O

Moxifloxacin Base

Hydrochloric acid Water

C

21

H24

FN3

O4 36.5 18.0

401.43

H

OCH3

N N

Cl

N

H H H H2O

F COOH

O

Moxifloxacin Hydrochloride Monohydrate

C21H27FClN3O5

455.93

229

Mass Balance:

Stage-1


in Kg in Kg

Moxifloxacin Q-Acid 45.00 Stage-1 53.00

2,8-Diazobicyclo(4.3.0)nonane 20.00 Acetone Recovery 189.00

Triethylamine 16.00 Acetone Loss 10.00

Acetone 200.00 Dimethylformamide Recovery 95.00

Dimethylformamide 100.00 Dimethylformamide Loss 5.00

Inorganic Solid Waste

(Tri ethyl amine hydro fluoride) 19.16


(Organic Impurities-8.84,Acetone-

1)


Stage-2


in Kg in Kg

Moxifloxacin Base 53.00 Moxifloxacin Hydrochloride 50.00

Monohydrate

Hydrochloric acid 10.00 Methanol Recovery 471.00


EDTA 1.00 Effluent Water 709.19

Activated Carbon 5.00 (Water-700,EDTA-1,Methanol-

3,HCl-5.19)



7.81,Methanol-1)

Spent Carbon 5.00

Total 1269.00 Total 1269.00

230

35. Cinnarizine


Stage-1

1-Benzhydryl piperazine reacts with Cinnamyl chloride in the presence of Ethylacetate and

Methanol as solvent media to give Cinnarizine as product.

Chemical Reaction:

Stage-1:

NH

N

Ethylacetate

+

Methanol

Cl

Cinnamyl chloride

1-Benzhydryl piperazine

C9H9Cl

C17

H20

N2

152.62

252.35

N N

+ HCl

Hydrochloric acidCinnarizine Pharma

36.5 C26

H28

N2

368.51

231

Mass Balance:

Stage-1 Name of the Quantity in Name of the out put Quantity in

input Kg Kg

1-Benzhydryl 106.00 Cinnarizine 100.00

piperazine

Cinnamyl chloride 93.00 Ethyl acetate Recovery 869.25

Potassium 63.50 Ethyl acetate Loss 45.75

carbonate

Ethyl acetate 915.00 Methanol Recovery 177.50


Activated carbon 8.40 Effluent water 277.74

Hyflow

5.30 (Water-190,Hydrochloric acid

-22.24,Potassium carbonate-

63.5,Methanol-2)

Water

190.00 Spent carbon & Hyflow 13.70

Unreacted Cinnamyl chloride 28.90

Recovered for Reuse

Organic Residue

48.86

(Organic impurities-47.86,

Methanol-1)

Total 1571.20 Total 1571.20

232

36. Cyano Diol Base


Stage-1

Parabromo-4-fluoro benzene reacts with Magnesium turnings in the presence of

Ethylene dibromide and THF as solvent media to give Grignard-A as product.

Stage-2

Grignard-A reacts with Potassium hydroxide and Hydrochloric acid in the presence of Sodium

hydroxide as base to give Stage-2 as product.

Stage-3

Dimethyl amino propyl chloride reacts with Magnesium turnings in the presence of

Iodine and THF as solvent media to give Grignard-B as product.

Stage-4

Grignard-A reacts with 5-Cyano pthalide in the presence of THF as solvent media and further it

reacts with Grignard-B followed by hydrolysis in the presence of Toluene and THF as solvent

medias to give Cyano Diol base as product.

Chemical Reaction:

Stage-1

233

Stage-2

Stage-3

234

235

Step-C:

OMgBr

NC

C OMgCl

CH2CH2CH2N(CH3)2

+

F

Stage-4(B)

C15H9BrFMgNO2.C5H12MgClN

504.36

OH

NC

C OH

CH2CH2CH2N(CH3)2

+

F 4-[4-Dimethylamino-1-

(4-fluoro-phenyl)-

1-hydroxy-butyl]-3-hydroxymethyl-

benzonitrile (Diol base) C

20

H23

FN2

O2

342.41

2H2O

2X18=36.0

MgBrOH + MgClOH

121.22

76.77

236

Mass Balance:

Stage-1

Stage-1 Batch size:100.0Kg


in Kg in Kg

Para Bromo fluoro benzene 27.00 Stage-1(Grignard A+ THF) 214.00

Magnesium turnings 10.05 THF Loss 10.75

Ethylene dibromide 1.70 Ethylene dibromide 1.70

Recovery

THF 213.00 Organic Residue 25.30


Stage-2



in Kg in Kg

Dimethl amino propyl chloride 934.00 Stage-2 280.00

Potassium hydroxide 140.00 Effluent water 1719.47

Sodium hydroxide 234.00 (Water-1167,Sodium

chloride-341.87,Generated

water-210.6)

drochloric acid 140.00 Dimethl amino propyl chloride 339.00

Recovered for Reuse

Water 1167.00 Inorganic Solid waste 186.00


Total 2615.00 Total 2615.00

Stage-3



in Kg in Kg

Dimethyl amino propyl chloride 280.00 Stage-3(Grignard B) 335.00

Magnesium turnings 55.00 THF Recovery 342.00

Iodine 16.75 THF Loss 18.00

Ethylene dibromide 2.70 Iodine Recovery 16.75

THF 360.00 Ethylene dibromide 2.70

Recovery


237

Stage-4


Name of the input Quantity Name of the out put Quantity in

in Kg Kg

Stage-1(Grignard A) 214.00 Cyano Diol Base 100.00

5-Cyano phthalide 67.00 THF + Toluene Recovery 1387.00

THF + Toluene 1460.00 THF + Toluene Loss 73.00

uene 2975.00 Toluene Recovery 2821.25

Stage -3(Grignard B) 335.00 Toluene Loss 148.75

Acetic acid 340.00 Effluent Water 1992.32

Water 1600.00 (Water-1589.5,Magnesium

hydroxyl bromide-

35.4,Magnesium hydroxyl

Chloride-22.42, Acetic acid-

340,Toluene-5)

THF Recovery 202.25

Unreacted stage-3 Recovered for 266.43

Reuse

Total 6991.00 Total 6991.00

238

37. Dextromethorphan Hydrobromide


Stage-1

2-Cyclohex-1-en-1-yl ethamine reacts with 4-Methoxy phenyl acetic acid and Phosphorous oxy

chloride in presence of Toluene as a solvent media to give Stage-1 as a product. Stage-2

Stage-1 reacts with hydroxy phenyl acetic acid in presence of Toluene as a solvent media to give

Stage-2 as a product. Stage-3

Stage-2 reacts with Sodium Hydroxide in presence of toluene as a solvent media to give Stage-3

as a product. Stage-4

Stage-3 reacts with Formic acid in presence of Toluene as a solvent media to give Stage-4 as a

product. Stage-5

Stage-4 reacts with Methanol and Sodium Hydroxide in presence of Toluene as a solvent media

to give Stage-5 as a product. Stage-6

Stage-5 reacts with Formaldehyde in presence of Toluene as a solvent media to give Stage-6 as

a product. Stage-7

Stage-6 reacts with Hydrobromic acid in presence of Acetone as a solvent media to give

Dextromethorphan Hydrobromide.

239

Chemical Reaction:

240

241

242

243

244

245

Mass Balance:

Stage-1


in Kg In Kg

PMPPA 449.00 Stage-1 695.00

CHEA 338.34 Toluene Recovery 475.00

Phosphorous oxy chloride 415.00 Toluene Loss 25.00

Caustic lye 218.00 Effluent water 1302.03

Toluene 500.00 (Water-473.9,Generated

water-48.63,Hydrochloric

acid-296.3,Phosphoric acid-

265.2, Caustic lye-218)

Water 620.00 Process Emission 43.31

(Oxygen)

Total 2540.34 Total 2540.34

Stage-2


in Kg In Kg

Stage-1 695.00 Stage-2 231.50


Mandelic acid 55.00 Toluene Loss 46.00



Toluene-2)


246

Stage-3


in Kg In Kg

Stage-2 231.50 Stage-3 134.27


CS Lye 70.00 Toluene Loss 26.00


(Water-278,Generated water-

31.5,Sodium mandalate-98.4,

Toluene-1)



Toluene-1)

Total 1099.50 Total 1099.50

Stage-4


in Kg In Kg

Stage-3 134.27 Stage-4 150.43


Formic acid 13.88 Toluene Loss 15.00

Sodium methoxide powder 3.41 Generated water 5.42

Phosphoric acid 1480.00 Phosphoric acid Reuse 1480.00

Phosphorous pentoxide 54.00 Inorganic solid waste 4.29

(Sodium formate-4.29) 0




Toluene-1)

Total 2004.56 Total 2004.56

247

Stage-5


in Kg In Kg

Stage-4 150.43 Stage-5 127.45

Methanol 245.00 Toluene Recovery 431.00

CS Lye 128.03 Toluene Loss 22.00

Toluene 453.00 Methanol Recovery 215.20

Water 570.00 Methanol Loss 12.00


(Water-570,CS Lye-105,

Generated water-19.8,

Sodium acetate-43.01, Methanol-1)

Total 1546.46 Total 1546.46

Stage-6


in Kg In Kg

Stage-5 127.45 Stage-6 90.90

Formaldehyde 45.45 Toluene Recovery 378.00



CS Lye 30.00 Acetone Loss 8.00

Activated carbon 4.50 Effluent water 275.71

Hyflow 4.50 (Water-228,CS Lye-30,

Formaldehyde-15.71, Acetone-2)

Water 228.00 Spent carbon & Hyflow 9.00


(Carbon dioxide-21.78, Hydrogen-0.99)



Toluene-1)

Total 1000.90 Total 1000.90

248

Stage-7


in Kg In Kg

Stage-6 90.90 Dextromethorphan 100.00

Hydrobromide


Hydrobromic acid 9.10 Acetone Loss 12.00


249

38. 2-Amino-5-Methyl Thiazol


Propionaldehyde treated with Sulphuryl Chloride & Stir for 2 hrs and added Thiourea Basified

with NaOH after Cool to 25-30 °C to get filter and finished Product and pack it.

Chemical Reaction:

CH3

O

SC

NaOH

CH3

O

Cl

SC

THIOUREA

2-chloropropanal

N

SCH3

NH2

2-AMINO-5

-METYL THIAZOL

PROPIONALDEHYDE

Mass Balance:

INPUT QTY kg OUTPUT QTY (kg)

Propionaldehyde 100 Finish Product 130

Sulphuryl Chloride 24.40 NaSO4 5

NaOH 2.5 Effluent 296.9

Thiourea 55

Water 250

TOTAL 431.9 431.9

250

ANNEXURE: 4

WATER CONSUMPTION AND WASTEWATER GENERATION

WATER CONSUMPTION

WASTEWATER GENERATION

Sr.

No.

Category Wastewater Generation (KL/day)

Existing Proposed Total

1. Industrial

Process Nil 22.8 22.8

Boiler Nil 0.3 0.3

Cooling Tower Nil 0.4 0.4

Washing Nil 0.5 0.5

Total (Industrial) Nil 24.0 24.0

2. Gardening -- -- --

3. Domestic 0.5 0.5 1.0

Total 0.5 24.5 25.0

Sr.

No.

Category Water Consumption (KL/day)

Existing Proposed Total

1. Industrial

Process 4.0 23.0 27.0

Boiler 2.0 3.0 5.0

Cooling Tower 2.0 3.0 5.0

Washing 0.5 0.5 1.0

Total (Industrial) 8.5 29.5 38

2. Gardening -- 0.5 0.5

3 Domestic 2.0 2.0 4.0

Total 10.5 32.0 42.5

251

WATER BALANCE DIAGRAM (EXISTING)

All figures are in KL/Day.

Raw Water: 10.5

Domestic:

2.0

Process:

4.0

Boiler:

2.0

Cooling

Tower:

2.0

Gardening:

Nil

Septic Tank

& Soak Pit:

0.5

Nil Nil

Washing:

0.5

Nil Nil

252

WATER BALANCE DIAGRAM (TOTAL)

All figures are in KL/Day.

Raw Water: 42.5

Domestic:

4.0

Process:

27.0

Boiler:

5.0

Cooling

Tower:

5.0

Gardening:

0.5

Septic Tank

& Soak Pit:

1.0

0.3 0.4

ETP: 20.00

Low TDS & low

COD stream-II

Washing:

1.0

0.5

CETP (M/s. ETL)

for further

treatment

22.8

ETP: 4.00

High TDS & High

COD stream-I

COMMON

MEE,

Ankleshwar

for further

253

ANNEXURE: 5

DETAILS OF EFFLUENT TREATMENT PLANT (ETP)

M/s. Darshan Pharmachem Pvt. Ltd. shall have an Effluent treatment plant consisting of

primary unit. The effluent confirming to inlet standards of CETP of M/s ETL. The details of ETP

are as follows.

First all non-toxic and biodegradable stream-II (low COD & low TDS) of wastewater shall be

collected in Equalization cum Neutralization tank (ENT-01) where the continuous addition and

stirring of Caustic solution is done to maintain neutral pH of wastewater from Caustic Dosing

Tank (CDT-01) as per requirement by gravity. Mixer is provided in the ENT-01 to keep all

suspended solids in suspension and for proper mixing.

Then, neutralized wastewater shall be pumped to Primary Settling Tank (PST-1). Alum and

Polyelectrolyte shall be dosed from Alum Dosing Tank (ADT-01) and Polyelectrolyte Dosing Tank

(PEDT-01) respectively by gravity into PST-01 to carry out coagulation by using a Mixer. Then

Mixer is stopped and effluent is allowed to settle in Primary Settling Tank (PST-01). After

Primary treatment, Clear supernatant from PST-01 shall be collected in Treated Effluent Sump

(TES-01) before sent to CETP of M/s. ETL for further treatment.

Sludge settled in PST-01 shall be collected in Sludge Drying Beds (SDBs-01-A/B) where,

dewatering shall be carried out before storage in HWSA and ultimate disposal to TSDF.

EXPECTED CHARACTERISTICS OF WASTEWATER BEFORE & AFTER TREATMENT

Sr.

No.

Parameter

Characteristics (mg/L) CETP Inlet Norms

(mg/L) Untreated

High TDS &

High COD

stream-I

Untreated

Low TDS &

low COD

stream-II

Treated

1. pH 4.0-5.0 4.0-5.0 5-9 6.5-8.5

2. COD 10000 8000 < 6000 3000

3. BOD3 2500 3000 < 2000 1200

4. TDS 200 100 < 50 100

254

Effluent Treatment Plant (Dimension):

S.N. Name of unit Size (m x m x m) No. MOC/ Remark

Low COD Stream Flow 20.0 KLD

1

Equalization cum

Neutralization Tank

(ENT-01)

3.0 m x 3.0 m x

(2.5 m+0.5 FB) 1

MOC = RCC

M30+A/A Bk. Lining

2 Primary Settling Tank

(PST-01)

3.0 m x 1.5 m x

(2.0 m + 0.5 HB + 0.3 FB) 1 RCC M30

3 Treated Effluent Sump

(TES-01)

4.0 m x 3.0 m x

(3.0 m+0.5 FB) 1 RCC M30

4 Sludge Drying Beds

(SDBs-01-A/B) 4.0 m x 3.0 m 2

Bk. Maso. With RCC

Bedding

High COD Stream Flow 4.0 KLD

5. MEE Feed Tank(MFT-01) 10 KLD 1 RCC M30

RCC M30 = REINFORCED CEMENT CONCRETE (M 30 GRADE)

BK.MAS. = BRICK MASONARY

255

Flow Diagram:

256

ANNEXURE: 6

DETAILS OF HAZARDOUS SOLID WASTE MANAGEMENT AND DISPOSAL

Sr.

No

Category

No.

Type of

waste Existing Proposed Total

Disposal Method

1 33.1

Discarded

Containers

6

MT/ year

4

MT/ year

10

MT/ year

Collection, Storage,

Transportation & Disposal by

selling to registered recycler

2 5.1

Used/

Spent Oil

0.01

MT/ year

0.01

MT/ year

0.02

MT/ year


Transportation & Disposal by

selling to registered recycler

3 35.3 ETP sludge -- 10

MT/ year

10

MT/year

Collection, storage,

transportation and dispose

common TSDF site.

4 B36 Salts of

Per-Acids

420

MT/year --

420

MT/year

(Collection, storage,

transportation and disposal)

Sodium Sulphide (30% Sol):

Disposal by sell out to

authorized users who is having

valid CCA and Rule 9

permission to receive this

waste.

5 28.1 Organic

Residue --

20

MT/year

20

MT/year


Transportation & send to

cement industries for co-

processing or incineration in

CHWIF.

6 28.3 Spent

Carbon --

5

MT/year

5

MT/year


Transportation and sent for co-

processing in cement industries

or Disposal at common

incineration site.

7 --

Inorganic

Solid

Waste

-- 13

MT/year

13

MT/year


transportation and dispose

common TSDF site.

8 26.3 Spent Acid -- 84.7

MT/year

84.7

MT/year


transportation &

sale to authorize vendor.

257

ANNEXURE: 7

Details of Stack & Vents

EXISTING:

1. Details of Flue Gas Stack

2. Details of Process Vent

Sr.

No.

Stack attached

to

Stack

Height

Air Pollution

Control System

Parameter & Permissible

Limit

1 Reaction vessel vessel 10 m Alkali Scrubber &

Water Scrubber

SO2 < 40 mg/Nm3

Chlorine < 9 mg/Nm3

Particulars Fuel Stack height Emission Norms

Boiler

(Capacity = 1.5 TPH)

Natural gas =

500 sm3/Day,

30 m

SPM < 150 mg/Nm

3

SO2 < 100 ppm

NOx < 50 ppm

DG Sets

(Capacity = 250 KVA)

Standby

Diesel =

27 Lit/hr

9 m

SPM < 150 mg/Nm3

SO2 < 100 ppm

NOx < 50 ppm

258

PROPOSED:

1. Details of Flue Gas Stack

2. Details of Process Vent

Sr.

No.

Stack attached

to

Stack

Height

Air Pollution

Control System

Parameter Permissible

Limit

1 Process Vent - 1 11 m Two Stage Scrubber HCl 20 mg/Nm3

2 Process Vent - 2 11 m Two Stage Scrubber SO2 40 mg/Nm3

3 Process Vent - 3 11 m Two Stage Scrubber NH3 175 mg/Nm3

Particulars Fuel Stack

height

Emission Norms APCM

Boiler

(Capacity = 3.0 MT/Hr)

Agrowaste =

10 MT /Day

30 m

SPM < 150 mg/Nm

3

SO2 < 100 ppm

NOx < 50 ppm

Multicyclone Separator

and Bag Filter

Thermic Fluid Heater

(Capacity = 3 lakh

kcal/Hr)

Agrowaste =

5 MT /Day

30 m SPM < 150 mg/Nm3

SO2 < 100 ppm

NOx < 50 ppm

Multicyclone Separator

and Bag Filter

DG Sets

(Capacity = 125 KVA)

Standby

Diesel=

10 Lit/hr

11 m

SPM < 150 mg/Nm3

SO2 < 100 ppm

NOx < 50 ppm

--

259

ANNEXURE: 8

DETAILS HAZARDOUS CHEMICAL STORAGE FACILITY

Sr.

No.

Name of the

Hazardous Chemicals

Type of

Hazard

Type of

Storage &

MOC

No. of

Vessel

Vessel

Capacity

(MT)

Maximum

Storage

(MT/day)

1. Toluene Toxic Tank 4 20 80

2. Ethyl Acetate Toxic/Flammable Tank 5 20 100

3. HCl Corrosive Tank 1 10 10

4. Isopropyl Alcohol Toxic/Flammable Tank 2 10 20

5. Hexane Toxic Tank 2 10 20

6. MDC Toxic Tank 2 20 40

7. Bromine Toxic Bottle 100 3 kg 0.3

8. Hydrogen gas Flammable Cylinder -- -- --

9. Ammonia gas Corrosive/Toxic Cylinder -- -- --

10. Acetonitrile Flammable Drums 5 200 lit 1

11. Methanol Flammable Tank 4 20 80

12. Acetic anhydride Flammable Drums 5 200 lit 1

13. Dimethyl Formamide

(DMF)

Toxic/Flammable Tank 2 10 20

14. Tetrahydrofurane

(THF)

Flammable Tank 2 10 20

15. Formic Acid Toxic/Flammable Drums 5 200 lit 1

16. Sulphuric Acid Corrosive Drums 5 200 lit 1

17. Acetone Toxic/Flammable Tank 2 10 20

18. Hydrobromic Acid Corrosive Carboy 4 50 kg 0.2

19. Acetic acid Corrosive Drums 5 200 lit 1

20. Thionyl Chloride Toxic Drums 5 200 lit 1

21. Liq. Ammonia Toxic Drums 5 200 lit 1

260

ANNEXURE: 9

SOCIO - ECONOMIC IMPACTS

1) EMPLOYMENT OPPORTUNITIES

The manpower requirement for the proposed project is expected to generate some permanent

jobs and secondary jobs for the operation and maintenance of plant. This will increase direct /

indirect employment opportunities and ancillary business development to some extent for the

local population. This phase is expected to create a beneficial impact on the local socio-economic

environment.

2) INDUSTRIES

Required raw materials and skilled and unskilled laborers will be utilized maximum from the local

area. The increasing industrial activity will boost the commercial and economical status of the

locality, to some extent.

3) PUBLIC HEALTH

The company regularly examines, inspects and tests its emission from sources to make sure that

the emission is below the permissible limit. Hence, there will not be any significant change in the

status of sanitation and the community health of the area, as sufficient measures have been

taken and proposed under the EMP.

4) TRANSPORTATION AND COMMUNICATION

Since the existing factory is having proper linkage for the transport and communication, the

development of this project will not cause any additional impact.

In brief, as a result of the proposed project there will be no adverse impact on sanitation,

communication and community health, as sufficient measures have been proposed to be taken

under the EMP. The proposed project is not expected to make any significant change in the

existing status of the socio - economic environment of this region.

261

ANNEXURE: 10

PROPOSED DRAFT TERMS OF REFERENCE

1. Project Description

• Justification of project.

• Promoters and their back ground

• Project site location along with site map of 5 km area and site details providing various industries,

surface water bodies, forests etc.

• Project cost

• Project location and Plant layout.

• Water source and utilization including proposed water balance.

• Product spectrum (proposed products along with production capacity) and process

• List of hazardous chemicals.

• Mass balance of each product

• Storage and Transportation of raw materials and products.

2. Description of the Environment and Baseline Data Collection

• Micrometeorological data for wind speed, direction, temperature, humidity and rainfall in 5 km

area.

• Existing environmental status Vis a Vis air, water, noise, soil in 5 km area from the project site.

For SPM, RSPM, SO2, NOx.

• Ground water quality at 5 locations within 5 km.

• Complete water balance

3. Socio Economic Data

• Existing socio-economic status, land use pattern and infrastructure facilities available in the study

area were surveyed.

4. Impacts Identification And Mitigatory Measures

• Identification of impacting activities from the proposed project during construction and

operational phase.

• Impact on air and mitigation measures including green belt

• Impact on water environment and mitigation measures

• Soil pollution source and mitigation measures

• Noise generation and control.

• Solid waste quantification and disposal.

5. Environmental Management Plan

• Details of pollution control measures

• Environment management team

• Proposed schedule for environmental monitoring including post project

262

6. Risk Assessment

• Objectives and methodology of risk assessment

• Details on storage facilities

• Process safety, transportation, fire fighting systems, safety features and emergency capabilities to

be adopted.

• Identification of hazards

• Consequence analysis through occurrence & evaluation of incidents

• Disaster Management Plan.

7. Information for Control of Fugitive Emissions

8. Post Project Monitoring Plan for Air, Water, Soil and Noise.

9. Information on Rain Water Harvesting

10. Green Belt Development plan

Annexure-11

________________________________________

GIDC Plot Allotment Letter

______________________________________________________

263

______________

GIDC Plot Allotment Letter

264

Annexure-12

________________________________________

GIDC Water Supply Letter

______________________________________________________

265

______________

Annexure-13

________________________________________

ETL Membership Letter

__________________________ _____________________

266

___________________________

Annexure-13

________________________________________

ETL Membership Letter

__________________________ _____________________

267

___________________________

268

Annexure-14

______________________________________________ ____________________________

Common MEE Membership Letter

Annexure-15

________________________________________

TSDF & CHWIF membership

______________________________________________________

269

______________

270

Annexure-16

__________________________________________________________________________

Toposheet

Documents

PLOT NO. 3609, NEAR FICOM CHOKDI, GIDC ESTATE ...environmentclearance.nic.in/writereaddata/Online/TOR/24...PROPOSED EXPANSION OF BULK DRUG INTERMEDIATES M/s. DARSHAN PHARMA PLOT NO