appendix – ienvironmentclearance.nic.in/writereaddata/modification/amendment/... · 41 1...

ToR Amendment Tagoor Laboratories Private Limited

ANNEXURE – I

Details of Products as per Granted ToR and Amendment Required

S. No Product Name

Production Capacity Ton /Month Therapeutic

category As per granted ToR

Amendment Required

1 Abacavir sulfate 2.0 2.0 Anti HIV 2 Amitriptyline 5.0 10.0 Antidepressant 3 Atrovastatin Calcium 5.0 5.0 Hypercholesterolemia 4 Bupropion 5.0 5.0 Anti depressant 5 carisoprodol 2.0 2.0 Muscle Relaxant 6 Clopidogrelbisulfate 5.0 5.0 Antithrombotic 7 Cyclobenzaprine HCl 5.0 5.0 Muscle relaxant 8 Cyproheptadine HCl 5.0 10.0 Anti allergic 9 Desloratadine 5.0 5.0 Antihistamine 10 Domperidone 20.0 30.0 Anti emetic 11 Domperidone maleate 2.0 2.0 Anti emetic 12 Donepezil HCl 1.0 1.0 Alzheimer’s disease 13 Ebastine 5.0 5.0 Anti allergic 14 Esomeprazole Sodium 3.0 3.0 Anti ulcerative

15 Esomeprazole Magnesium trihydrate 3.0 3.0 Anti ulcerative

16 Fexofenadine Hydrochloride 6.0 15.0 Anti histamine 17 Haloperidol 2.0 2.0 Antipsychotic 18 Itopride Hydrochloride 2.0 2.0 Antispasmodics 19 Itraconazole 10.0 10.0 Antifungal 20 Ketrolac Tromethane 2.0 2.0 Anti Inflammatory 21 Lansoprazole 10.0 10.0 Ant ulcerative 22 Loperamide Hydrochloride 10.0 10.0 Anti diarrhea agent 23 Losartan Potassium 6.0 15.0 Anti Hypertensive 24 Nebivolol HCl 2.0 2.0 Anti Hypertensive 25 Nortriptyline HCl 2.0 2.0 Anti depressant 26 Omeprazole 40.0 40.0 Anti ulcerative 27 Omeprazole Sodium 2.0 2.0 Ant ulcerative

28 Omeprazole Magnesium Dihydrate 2.0 2.0 Ant ulcerative

29 Oxatomide 1.0 1.0 Antihistamine

30 Pantoprazole Sodium Sesqui Hydrate 10.0 20.0 Ant ulcerative

31 Pimozide 2.0 2.0 Antipsychotic 32 Pregabalin 2.0 2.0 Epileptic 33 Quetiapine Hemifumarate 2.0 2.0 Antipsychotic

Prepared By Rightsource Industrial Solutions Pvt. Ltd


S. No Product Name

Production Capacity Ton /Month Therapeutic

category As per granted ToR

Amendment Required

34 Rabeprazole Sodium 10.0 15.0 Ant ulcerative 35 Rupatadine fumarate 2.0 2.0 Antihistamine 36 Telmisartan 2.0 2.0 Anti Hypertensive 37 Terbinafine hydrochloride 8.0 15.0 Anti fungal 38 Valsartan 2.0 2.0 Anti Hypertensive 39 1-Benzy-4-piperidone 5.0 5.0 Drug Intermediate 40 1-Benzyl-4-chloropiperidine 5.0 5.0 Drug Intermediate 41 1-Benzylpiperidin-4-ol 5.0 5.0 Drug Intermediate 42 1-Methylpiperidin-4-amine 5.0 5.0 Drug Intermediate 43 4-Aminopiperidine 5.0 5.0 Drug Intermediate 44 4-Hydroxy piperidine 5.0 5.0 Drug Intermediate 45 4-Phenylpiperidine 1.0 1.0 Drug Intermediate 46 4-piperidinopiperidine 1.0 1.0 Drug Intermediate

47 N-tert-Butoxycarbonyl-4-hydroxy piperidine 5.0 5.0 Drug Intermediate

Total ( Worst Combination of any 12 Products at any given point of time)

140.0 200.0

Note:

The above Listed Products, we will manufacture either Finished Product or any Intermediate stage of finished Product as per given quantity by not increasing the

production capacity of 200 MT/Month.



List of By-Products for ToR Amendment

S. No. Product Name By product Quantity in

Kg /Day

1 Clopidogrel Bisulphate

Ammonium sulphate 3578.08 Omeprazole Domperidone

2 Domperidone

Sodium bromide 656 Cyclobenzaprinehydrochloride Itraconazole

3

Cyclobenzaprinehydrochloride

Magnesium Chloride 290 Cyproheptadine Hydrochloride Desloratadine

4 Desloratadine Potassium chloride 226 Ebastine

5 Ebastine Aluminium chloride solution (12%) 667

6 Itraconazole Potassium bromide 84 Telmisartan

7 Pantoprazole sodium sesquihydrate

Ammonium chloride 2216 Domperidone 8 Desloratadine


Ammonium acetate 234 Acetic acid 506 Ammonium phosphate 773.50 Sodium methyl sulphate 632

9

Pantoprazole sodium sesquihydrate

Sodium acetate 1244.45 Domperidone Rabeprazole sodium Omeprazole

10 Omeprazole Sodium nitrite 545 11 Domperidone Methanol 182 12 Losartan Potassium Trityl alcohol 326

Total 12160.03

Note:

The By-Products will be produced according to the combination of required products manufacturing.



ANNEXURE – II

Details of Water Consumption as per Granted ToR and Amendment Required

S.No Purpose Water consumptionIn KLD As per granted ToR Amendment Required

1 Process 40.0 152.5 2 Washings 5.0 6.0 3 Boiler make up 58.5 70.5 4 Cooling towers make up 72.5 119.0 5 Scrubbing system 8.0 18.0 6 Domestic 5.0 6.0 7 Gardening 5.0 5.0

Total 194.00 377.0

Total Water consumption is 377 KLD. 209 KLD of water will be recovered (from

Process: 90 KLD & Water Recycled from ZLD System: 119 KLD). Hence, Total

fresh water requirement is 377KLD -209 KLD = 168 KLD.

Source of water As per Granted ToR: Ground Water Amendment Required: Surface water Allotment from River /Ground Water

Details of Waste Water as per Granted ToR and Amendment Required

S. No Purpose Effluent In KLD

As per granted ToR

Amendment Required

1 Process 48.00 98.0 2 Washings 5.00 6.0 3 Boiler Blow down 8.50 10.0 4 Cooling towers Blow down 10.50 15.5 5 Scrubbing system 8.00 15.0 6 Domestic 4.00 5.5

Total 84.00 150.0



ANNEXURE -III

Details of Solid & Hazardous Waste Generation and Disposal as per Granted ToR and Amendment Required

S. No Details

Quantity Disposal Method As per

granted ToR Amendment

Required

1 Organic waste (Process Residue)

1743 Kg/Day

2211 Kg/Day

Sent to Cement Industries

2 Spent Carbon 167 Kg/Day

336 Kg/Day


3 Solvent Distillation Residue

1123 Kg/Day

2001 Kg/Day


4 Inorganic Waste 1216 Kg/Day

725 Kg/Day Sent to TSDF

5 Spent Mixed Solvents

2465 Kg/Day

4000 Kg/Day

Sent to authorized recyclers/Cement Industries

6 ETP Sludge 500 .00 Kg/Day

500 .00 Kg/Day Sent to TSDF

7 MEE Salts 4387 Kg/Day

8684 Kg/Day Sent to TSDF

8

Organic Evaporative Liquid ( from MEE Stripper)

0.82KLD 1560 Kg/Day Sent to Cement Industry

9 Used Oils 500L/Annum 500L/Annum SPCB Authorized Agencies for Reprocessing/Recycling

10

Detoxified Containers

600 No’s / Month 800 No’s / Month After Detoxification sent

to outside agencies.

11 Used Lead Acid Batteries 4 No’s/ Annum 4 No’s/ Annum

Send back to suppliers for buyback of New Batteries

12 Ash from boiler Ash from boiler

11550 Kg/Day 17100 Kg/Day Sent to Brick Manufacturers



ANNEXURE - IV

UTILITES AS PER GRANTED TOR

Boilers:

Existing: 6.0 TPH Coal fired/ Agro waste fired Boiler & 2,00,000 kcal/hr Thermo pack Boiler will be continued

Proposed: 4.0 TPH Coal fired/ Agro waste fired Boiler is proposed DG Sets:

250 KVA & 500KVA

DETAILS OF UTILITIES AS PER AMENDMENT REQUIRED

Boilers:

Existing: 6.0 TPH Coal fired/ Agro waste fired Boiler will be kept as Standby

The existing 2,00,000 kcal/hr. Thermo pack Boiler will be Continued

Proposed: 12.0 TPH Coal fired/ Agro waste fired Boiler DG Sets:

1000KVA X 2 no’s

STACK EMISSION DETAILS FOR 12 TPH COAL FIRED/ AGRO WASTE FIRED BOILER

Particulars Units 12.0 TPH Agro waste / Coal fired Boiler (Proposed)

Type of Fuel -- Agro waste /Indian Coal Coal Consumption TPD 48 Ash Content % 35 Sulphur Content % 0.4 No. of Stacks No 1 Height of stack M 32 Diameter of Stack M 0.6 Temperature of Flue Gas

oC 220

Velocity of Flue Gas m/s 15 Particulate Matter gm/sec 1.8 Sulphur dioxide emission

gm/sec 2.67

Oxides of Nitrogen emission

gm/sec 5.13

Pollution control equipment

- Cyclone separator followed by suitable pack of Bag filters

Note : 6.0 TPH Agro waste /Coal fired boiler (Stand by )



STACK EMISSION DETAILS FOR THERMO PACK BOILER

Particulars Units 2,00,000 kcal/hr. Thermo pack Boiler (Existing)

Thermo pack Boiler Capacity Kcal/hr. 2,00,000

Type of Fuel -- Agro waste/ Coal

Stack Temperature Before Air preheater

oC 250

Stack Temperature After Air preheater

oC 180

Stack Height m 9.0

Fuel Consumption per Day TPD 0.75

Diameter m 0.30

STACK EMISSION DETAILS FOR DG SETS

Capacity In KVA

Emission of SPM in mg/Nm3

Emission Of SO2 in mg/Nm3

Emission of NOx In mg/Nm3

Stack dia. in m

Flue Gas Temp. in OC

Stack Height in m

Flue gas Velocity in m/sec.

1000 KVA (Proposed)

80 50 60 0.2 300 10 16

1000 KVA (Proposed)

80 50 60 0.2 300 10 16



ANNEXURE -VII

Details of Process Emission as per Granted ToR and Amendment Required

S. No.

Name of the Gas

Quantity In Kg/Day

As per granted ToR

Amendment Required Treatment Method

1 Sulphur dioxide 697 1724 Scrubbed by using C.S.Lye Solution

2 Hydrogen chloride 330 1183 Scrubbed by using

chilled water media

3 Hydrogen Bromide 420 311 Scrubbed by using C. S.

Lye solution

4 Nitrogen 17 45 Dispersed into the atmosphere

5 Carbon dioxide 662 863 Dispersed into the atmosphere

6 Hydrogen 16 34 Diffused by using Nitrogen through Flame arrestor

7 Ammonia 68 104 Scrubbed by using chilled water media

8 Oxygen 136 794 Dispersed into the atmosphere

9 Chloro Methane 209 242 Scrubbed by using C.S.Lye Solution



ANNEXURE – X CONSOLIDATED STATEMENT- POLLUTION DETAILS ASPER TOR AMENDMENT


Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd)

Form-I

Form - 1

Appendix- I (See Paragraph-6)

(I) Basic Information S.

No. Item Details

1 Name of the Project/s

Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd)Expansion of Existing Bulk Drugs & Intermediates manufacturing unit

2 S.No. in the Schedule

5(f) Synthetic organic chemicals industry (dyes & dye intermediates; bulk drugs and intermediates excluding drug formulations; synthetic rubbers; basic organic chemicals, other synthetic organic chemicals and chemical intermediates)

3

Proposed capacity / area / length / tonnage to be handled /command area / lease area / number of wells to be drilled

Bulk Drugs & Intermediates – 200 Tons/Month (ToR Amendment)

4 New / Expansion / Modernization Expansion

5 Existing Capacity / Area etc. 10.00 TPM (As per EC vide F.No. J-11011/401/ 2014-IA-II (I) Dated : 01 Aug 2017)

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

7 Does it attract the general conditions? If yes, please specify

Not Applicable

8 Does it attract the Specific conditions? If yes, please specify.

Not Applicable

9

Location Latitude 17° 9'29.66"N Longitude 81°35'23.87"E

Plot / Survey / Khasra No Sy No. 29, Village Tupakulagudem (V) Mandal Tallapudi (M) District West Godavari (Dist.) State Andhra Pradesh

10 Nearest railway station / airport along with distance in km

Kovvuru Railway station – 22.0 KMs (SE) Rajahmundry Airport – 24.00 KMs (ESE)

11 Nearest town, city, district headquarters along with distance in km

Rajahmundry – 24 km (SE)

Prepared by Rightsource Industrial Solutions Pvt. Ltd. 1


Form-I

S.

No. Item Details

12 Village Panchayats, Zilla Parishad, Municipal Corporation, Local body (complete postal addresses with telephone nos. to be given)

Tupakulagudem (V) Tallapudi (M), West Godavari (Dist.), Andhra Pradesh

13 Name of the applicant P. Kasiviswanadha Raju

14 Registered Address Plot No 99 & 100, SV Cooperative Industrial Estate, IDA, Jeedimetla, Hyderabad, Telangana Sate

15

Address for Correspondence Duplex No: 29, Lakshmi Gayatri Enclave, Aditya Nagar, KPHB, Kukatpally, Hyderabad Telangana Sate

Name P. Kasiviswanadha Raju Designation (Owner/Partner/CEO) Director

Address Duplex No: 29, Lakshmi Gayatri Enclave, Aditya Nagar, KPHB, Kukatpally, Hyderabad Telangana Sate

Pincode 500072

E-mail [email protected], [email protected]

Telephone no. +91-9989311222 Fax no. -

16 Details of Alternate Sites examined, if any. Location of these sites should be shown on a toposheet.

Not Applicable

17 Interlinked Projects Not Applicable

18 Whether separate application of interlinked project has been submitted.

Not Applicable

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?

Not Applicable



Form-I

S.

No. Item Details

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

22 Whether there is any Government Order / Policy relevant / relating to the site

No, Government Order / Policy relevant / relating to the site are applicable.

23 Forest Land involved (hectares) No Forest land is involved in the project

24

Whether there is any litigation pending against the project and / or land in which the project is proposed to 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 litigations pending against the project.

(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.)

S. No.

Information / Checklist confirmation

Yes /No

Details thereof (with approximate quantities /rates, wherever possible)

with sources 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).

Yes

The expansion proposal is within the existing land. The total area of the unit is 11.80 Acres (47752.9 Sq.m) and Plant layout is Enclosed.

1.2 Clearance of existing land, vegetation and buildings?

No No major tree felling or clearance of buildings is envisaged.

1.3 Creation of new land uses? No None

1.4 Pre-construction investigations e.g. bore holes, soil testing?

No Not Applicable

1.5 Construction works? Yes

Construction of various blocks Production, Stores, QC, Boiler shed, DG set, Utility, Pollution treatment facility, Roads, solvent storage yard,



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S. No.


Yes /No


with sources of information data Green belt and others

1.6 Demolition works? No No major demolition work is envisaged

1.7 Temporary sites used for construction works or housing of construction works?

No

Majority of the labor will be hired from nearby villages so no housing or shelter facilities required for construction workers. However existing facilities are sufficient like drinking and sanitation facilities for workers during working hours.

1.8

Above ground buildings, structures or earthworks including linear structures, cut and fill or excavations

No Not Applicable

1.9 Underground works including mining or funneling?

No Not Applicable

1.10 Reclamation Works? No Not Applicable 1.11 Dredging? No Not Applicable 1.12 Offshore structures? No Not Applicable

1.13 Production and manufacturing processes? Yes

List of products, By-Products and capacities for TOR Amendment was Enclosed as in Additional Information and Manufacturing Process is Enclosed as Appendix - I

1.14 Facilities for storage of goods or materials? Yes

Common facility for storage of raw materials and finished products will be provided



Form-I

S. No.


Yes /No



1.15 Facilities for treatment or disposal of solid waste or liquid effluents?

Yes

Solid Waste: The Solid & hazardous waste generated in plant will be disposed as per rules. The Details of Solid/Hazardous Waste Details as per Amendment Required enclosed as Annexure in Additional Information File Liquid waste: Industrial effluent of 154 KL/ day is generated and will be treated in ZLD System.

1.16 Facilities for long term housing of operational workers?

No The workforce is recruited from nearby villages. No long term housing of operational workers

1.17 New road, rail or sea traffic during construction or operation?

No

Road traffic is likely to increase both during construction and operation stage for transportation of man and material. However, existing transport routes are adequate for the increase in traffic. No additional transport infrastructure is required due to the proposed project

1.18

New road, rail, air waterborne or other transport infrastructure including new or altered routes and stations, ports, airports etc?

No No, additional transport infrastructure is required due to the present proposal.

1.19

Closure or diversion of existing transport routes or infrastructure leading to changes in traffic movements?

No Not Required

1.20 New or diverted transmission lines or pipelines?

No Not Required

1.21 Impoundment, damming, culverting, realignment or other changes to the hydrology of watercourses or

No Not Required



Form-I

S. No.


Yes /No


with sources of information data aquifers?

1.22 Stream crossings? No None

1.23 Abstraction or transfers of water from ground or surface waters?

Yes

The total water requirement is 377 KL/day for the proposed project and Source of Water: Surface water Allotment from State Government /Ground Water

1.24 Changes in water bodies or the land surface affecting drainage or run-off?

No None (There will not be any changes in water bodies or the land surface affecting drainage or runoff)

1.25 Transport of personnel or materials for construction, operation or decommissioning?

No The raw materials and products will be transported during construction and operation phase

1.26 Long-term dismantling or decommissioning which could have an impact on the environment?

No Not Applicable

1.27 Ongoing activity during decommissioning which could have an impact on the environment?

No Not Applicable

1.28 Influx of people to an area in either temporarily or permanently?

Yes The Estimated employment generation for this proposed project is about 135 Direct employees.

1.29 Introduction of alien species? No No New species are introduced.

1.30 Loss of native species or genetic diversity?

No No Loss of native species or genetic diversity.

1.31 Any other actions? No None envisaged 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):

S. No.

Information /Checklist confirmation

Yes /No



2.1 Land especially undeveloped or agricultural land (ha)

No Total 11.80 Acres (47752.9 Sq.m) is of Industrial Land

2.2 Water (expected source & Yes The total water requirement is 377 KL/day



Form-I

competing users) Unit : KLD for the proposed project and Source of

Water: Surface water Allotment from River /Ground Water The Details as per Amendment Required are enclosed in Additional Information file

2.3 Minerals (MT) No Not Applicable

2.4 Construction material – stone, aggregates, and / soil (expected source- MT)

No Construction materials like stone, steel aggregates, sand & cement will be sourced locally.

2.5 Forests and timber (source-MT) No No Timber will be used.

2.6

Energy including electricity and fuels (source, competing users) Unit : fuel (MT), energy (MW)

Yes

Details as per Amendment Required The power requirement for the plant is 2000 KVA. Boilers: The existing 6.0 TPH Coal fired/ Agro

waste fired Boiler will be kept as standby

and 2,00,000 kcal/hr Thermo pack Boiler

will be Continued.

Proposed to install 12.0 TPH Coal fired/

Agro waste fired Boiler.

DG Sets: For emergency power supply industry is proposing two no’s DG sets of 1000 KVA and Existing:250 KVA will be dropped,

2.7 Any other natural resources (use appropriate standard units)

No None

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.

S. No.


Yes /No



3.1 Use of substance or materials, which are hazardous (as per MSIHC rules)

Yes The number of chemicals will be used for the production of Synthetic Drugs & Intermediates which have been



Form-I

to human health or the environment (flora, fauna and water supplies).

mentioned in the list of raw materials given in the Additional Information as Annexure.

3.2 Changes in occurrence of disease or affect disease vectors (e.g. insect or water borne diseases)

No No such occurrence is envisaged, since effluent generated will be treated properly.

3.3 Affect the welfare or people e.g. by changing living conditions?

Yes

The proposed expansion will generate direct and indirect employment opportunities during construction as well as operation phase for the local people based on their qualification and work experience.

3.4

Vulnerable groups of people who could be affected by the project e.g. hospital patient’s, children, the elderly etc.,

No None

3.5 Any other causes No None 4. Production of solid wastes during construction or operation or

decommissioning (MT/ month) S.

No. Information / Checklist

confirmation Yes /No

Details thereof (with approximate quantities /rates, wherever possible ) with sources of information data

4.1 Spoil, overburden or mine wastes No

Not Applicable

4.2 Municipal waste (domestic and or commercial wastes)

Yes

Commercial waste like empty cement bags, Iron scrap etc. will be sold to scrap buyers after the construction phase. Domestic waste like used paper, label, cartoons will be disposed to the scrap buyers. Organic waste from canteen will be disposed as per the local Panchayath / Municipal disposal mechanism.

4.3 Hazardous wastes (as per Hazardous Waste Management Rules)

Yes Hazardous wastes Details for ToR Amendment are Enclosed as Annexure in additional information

4.4 Other industrial process wastes Yes The detailed Solid & Hazardous wastes for ToR Amendment are Enclosed as Annexure in additional information



Form-I

S.

No. Information / Checklist

confirmation Yes /No


4.5 Surplus product No None

4.6 Sewage sludge or other sludge from effluent treatment

Yes ETP sludge is sent to TSDF

4.7 Construction or demolition wastes No

Minimal quantity of debris, scraps, excavated soil used cement bags, iron/steel scrap and cardboards waste could be generated during additional construction.

4.8 Redundant machinery or equipment

No None

4.9 Contaminated soils or other materials

No None

4.10 Agricultural wastes No None 4.11 Other solid wastes No None

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

S.No. Information /Checklist confirmation

Yes/ No



5.1

Emissions from combustion of fossil fuels from stationary or mobile sources

Yes

Gaseous emission like SO2, NOx, CO and particular matter shall be generated from Boilers and DG sets which will be maintained under prescribed limit. DG sets will be used during only power break down. Adequate stack height of Boilers and DG sets provided for effective dispersion of pollutants.

5.2 Emissions from production processes

Yes Proper control measures will be adopted to control emission as per prescribed Standard

5.3 Emissions from handling including storage and transport

Yes Fugitive emissions from material handling, loading /unloading and transport of material will be minimal due to closed loop system.

5.4 Emissions from construction activities

Yes This will be restricted to the construction phase and to the construction site only. It



Form-I


Yes/ No


with sources of information data including plant and equipment

will be minimized by sprinkling water.

5.5

Dust or odors from handling of materials including construction materials, sewage and waste.

Yes Dust will be generated from loading and unloading of raw material and finished products.

5.6 Emissions from incineration of waste

No No incinerator is proposed.

5.7

Emissions from burning of waste in open air (e.g. slash materials, construction debris)

No No waste will be burnt in open air.

5.8 Emissions from any other sources

Yes Dust Emissions from Ball Mill will be mitigated by providing Inbuilt bag filters.

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


Yes/ No

Details thereof (with approximate quantities /rates, wherever possible )


6.1 From operation of equipment e.g. engines, ventilation plant, crushers

Yes

Material transport shall be source of noise during construction, while transfer pumps, vacuum systems are the sources of noise during operation. The equipment in the plant are designed for noise levels not exceeding 90 dB (A). Proper encasement of noise generating sources is done to control the noise levels below 75 dB (A) at plant boundary. Maintenance of all equipment is carried out regularly to reduce noise. A proper green belt is developed which acts as a noise barrier.

6.2 From industrials or similar processes Yes

Pumps, motors, gearboxes etc will generate little bit of noise and will be mitigated with regular maintenance. Apart from all these a thick plantation of green belt will be developed along the periphery



Form-I


Yes/ No


with sources of information data of the compound wall to arrest the noise nuisance during the operation phase.

6.3 From construction or demolition Yes Temporary noise generation during construction activities

6.4 From blasting or piling No Not Applicable

6.5 From construction or operational traffic

Yes Noise due to movement of trucks during construction and operation phase

6.6 From lighting or cooling systems Yes Adequate Lighting shall be provided in unit and also local ventilation system shall be provided

6.7 From any other sources No Not Applicable 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

S. No.


Yes /No


7.1 From handling, storage, use or spillage of hazardous materials

Yes

Hazardous materials will be used and stored with due safety and care at site. All the norms under the Manufacture, Storage and Import Of Hazardous Chemicals (MSIHC) Rules and amendments thereafter will be complied.

7.2

From discharge of sewage or other effluents to water or the land (expected mode and place of discharge )

No ETP will be installed and will be designed for zero effluent discharge

7.3 By deposition of pollutants emitted to air into the land or into water

No

All possible air pollutants will be scrubbed/ filtered properly by various pollution control equipment before emitting into atmosphere. The norms will be maintained through regular monitoring and analysis of vent gases.

7.4 From any other sources No None 7.5 Is there a risk of long term build up No None



Form-I

of pollutants in the environment from these sources?

8. Risk of accidents during construction or operation of the Project, which could affect human or the environment


Yes/ No


8.1

From explosions, spillages, fires etc from storage, handling, use or production of hazardous substances

No

No explosions will occur during construction. During production operations, all inbuilt safety precautions will be adopted and there will not be any damage to environment or human health.

8.2 From any other causes No None

8.3

Could the project be affected by natural disasters causing environmental damage (e.g. floods, earthquakes, landslides, cloudburst etc)?

No

As the area is plain, there are no chances of landslides & there is no history of cloud burst. No natural disasters are envisaged, since site is in an area where such occurrences do not arise.

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 activates in the locality.


Yes /No



9.1

Lead to development of supporting. facilities, ancillary development or development stimulated by the project which could have impact on the environment e.g.: • Supporting infrastructure

(roads, power supply, waste

Yes

The proposed project will prove beneficiary for the localities as it provides: Additional direct and indirect employment



Form-I


Yes /No


with sources of information data or waste-water treatment etc.)

• Housing development

• Extractive industries

• Supply industries

• Other

9.2 Lead to after use of the site, which could have an impact on the environment

No None

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 None envisaged

(III) Environment Sensitivity

S. No. Areas Yes

/No

Aerial distances (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 values.

No -

2.

Areas which are important or sensitive for ecological reasons- Wetlands, water courses or other water bodies, coastal zone, biospheres. Mountains, forests

Yes

Reserve Forests • Fairly dense Jungle near

Gopavaram - 1.2 KMs (WNW) • Dense Mixed Jungle near

Hukumpet - 4.8 KMs (NNW) • Mixed Jungle near Rajampalem -

5.1KMs (NNW) • Vinjaram R.F. -9.1 KMs(NNW) • Karakapadu RF – 9.4 KMs (NW) • Polavaram RF- 9.6 KMs (N) Water bodies • Tadipudi lift canal – 1.50 KMs (S)



Form-I

S. No. Areas Yes

/No


boundary. • Tank near Bhimolu – 2.65 KMs

(SW) • River Godavari– 7.8 KMs (E) • Kovada kalva - 6.25 KMs (N) • Polavaram Right Canal - 3.5 KMs

(WNW) • Tank near Ramannapalem –

7.80KMs(N) • Pendrala kalva - 8.4 KMs (NW) • Kovvada Kalva Reservoir – 9.62

KMs (NW)

3.

Areas used by protected, important or sensitive species of flora or fauna for breeding, nesting, foraging, resting, over wintering, migration.

No None

4. Inland, coastal, marine or underground waters

No None

5. State, National boundaries No None

6. Routes or facilities used by the public for access to recreation or other tourist, pilgrim areas

No None

7. Defense installations No None

8. Densely populated or built-up area Yes Mandal head quarter Tallapudi is 8.50 kms

9.

Areas occupied by sensitive man-made land uses (hospitals, schools, places of worship, community facilities )

Yes Mandal head quarter Tallapudi is 8.50 kms

10.

Areas containing important, high quality or scarce resources (ground water resources, surface resources, forestry, agriculture, fisheries, tourism, minerals)

Yes

Reserve Forests • Fairly dense Jungle near

Gopavaram - 1.2 KMs (WNW) • Dense Mixed Jungle near

Hukumpet - 4.8 KMs (NNW) • Mixed Jungle near Rajampalem -

5.1KMs (NNW) • Vinjaram R.F. -9.1 KMs(NNW) • Karakapadu RF – 9.4 KMs (NW) • Polavaram RF- 9.6 KMs (N) Water bodies



Form-I

S. No. Areas Yes

/No


boundary. • Tadipudi lift canal – 1.50 KMs (S) • Tank near Bhimolu – 2.65 KMs

(SW) • River Godavari– 7.8 KMs (E) • Kovada kalva - 6.25 KMs (N) • Polavaram Right Canal - 3.5 KMs

(WNW) • Tank near Ramannapalem –

7.80KMs(N) • Pendrala kalva - 8.4 KMs (NW) • Kovvada Kalva Reservoir – 9.62

KMs (NW)

11.

Areas already subjected to pollution or environmental damage.(those where existing legal environmental standards are exceeded)

No None

12.0

Areas susceptible to natural hazard which could cause the project to present environmental problems (Earthquakes, subsidence, landslides, erosion, flooding or extreme or adverse climatic conditions)

No

The project is located in seismic zone II (Least Active) as per IS: 1893 (Part-1) 2002. Therefore, possibility of earthquake is not anticipated. So there will be no effect of natural hazards on the project.



APPENDIX-I

1-BENZYL-4-CHLOROPIPERIDINE

Process Description:

Stage-1:

Benzyl amine reacts with reacts with Acryclic acid methyl ester in presence of Methanol to give stage-1 product.

Stage-2:

Staeg-1 product reacts with Sodium Methoxide in presence of Hydrochloric acid and Toluene to give satge-2 product.

Stage-3:

Stage-2 product reacts with Hydrochloric acid and water in presence of Chloroform and Caustic Solution to give 1-Benzyl-4-Chloro-Piperidone.

Route of Synthesis:

Stage-1

NH2

Benzylamine

C7H9N107.15

+Acrylic acid methyl ester

O

O

C8H12O42X86.09=172.18

Methanol

3-[Benzyl-(2-methoxycarbonyl-ethyl)-amino]-propionic acid

methyl ester

OO

N

O

O

2

C15H21NO4

279.33

Prepared By Rightsource Industrial Solutions Pvt. Ltd Page 1


Stage-2


methyl ester

OO

N

O

O

C15H21NO4

279.33

+ CH3ONa

Sodium methoxide

54.02

Toluene

N

OCOOCH3

1-Benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester

C14H17NO3

247.29

+ HCl

36.46

+ 2 CH3OH

64.08

+ NaCl

58.44

Stage3

N

O

COOCH3


C14H17NO3

247.29

+ HCl

36.46

Chloroform,Caustic solution

N

Cl

1-Benzyl-4-chloropiperidone

+ CO2

44.01

C12H16ClN209.72

+ CH3OH

32.04+ H2O

18.02

+ 0.5 O216.00



Flowchart:

Stage-1

Stage-2


Benzylamine Acryclic acid methyl esterMethanol

Methanol RecoveryEffluent water

Toluene RecoveryEffluent water

Stage-1Sodium MethoxideHydrochloric acidToluene


Material Balance:

Material Balance of 1-Benzyl-4-Chloro-Piperidone Stage-1

Batch Size: 200.00 Kg Name of the input Quantity

in Kg Name of the out put Quantity

in Kg Benzylamine 140.00 Stage-1 330.00 Acryclic acid methyl ester 224.85 Methanol Recovery 285.00 Methanol 300.00 Methanol loss 10.00 Water 400.00 Effluent water 400.00 (Water-400) 0 Organic residue 39.85 Process residue – 34.85

Distillation residue-5 (Methanol-5)

Total 1064.85 Total 1064.85






in Kg Stage-1 330.00 Stage-2 263.00 Sodium Methoxide 63.70 Toluene Recovery 380.00 Hydrochloric acid 43.00 Toluene loss 12.00 Toluene 400.00 Effluent water 544.54 Water 400.00 (Water-400,Sodium Chloride-

68.97,Methanol-75.57) 0

Organic residue 37.16 Process residue-29.16

Distillation residue-8 (Toluene-8)

Total 1236.70 Total 1236.70




in Kg Stage-2 263.00 1-Benzyl-4-Chloro-Piperidone 200.00 Hydrochloric acid 38.65 Chloroform Recovery 475.00 Chloroform 500.00 Chloroform Loss 25.00 Caustic solution 50.00 Effluent water 383.93 Water 300.00 (Water-300,Water from Caustic

solution 50,Generated Methanol-33.93)

0

Process emission 63.38 (carbondioxide-46.55, oxygen-

16.83) 0

Organic residue 4.34 Process residue -4.34 Total 1151.65 Total 1151.65



1-BENZYL-4-PIPERIDONE


Stage-1:

Benzyl amine reacts with reacts with Acryclic acid methyl ester in presence of

Methanol to give stage-1 product.

Stage-2:

Staeg-1 product reacts with Sodium Methoxide in presence of Hydrochloric acid and

Toluene to give satge-2 product.

Stage-3:

Stage-2 product undergoes Hydrolysis with Sodium Hydroxide and Hydrochloric acid

in presence of Chloroform to give 1-Benzyl-4-Piperidone.

Route of Synthesis:

Satge-1

NH2

Benzylamine

C7H9N107.15

+

Acrylic acid methyl ester

O

O

C8H12O42X86.09=172.18

Methanol


methyl ester

O

O

N

O

O

2

C15H21NO4

279.33



Stage-2


methyl ester

O

O

N

O

O

C15H21NO4

279.33

+ CH3ONa

Sodium methoxide

54.02

Toluene

N

O

COOCH3


C14H17NO3

247.29

+ HCl

36.46

+ 2 CH3OH

64.08

+ NaCl

58.44

Stage-3

N

O

COOCH3


C14H17NO3

247.29

+ HCl

36.46

Chloroform,Caustic solution

N

O

1-Benzyl-4-piperidone

+ NaOH

40.00C12H15NO

189.25

+ CH3OH32.04

+ + CO2

44.01NaCl

58.44



Flowchart:

Stage-1

Stage-2

1-BENZYL-4-PIPERIDONE

Benzylamine Acryclic acid methyl esterMethanol



Stage-1Sodium MethoxideHydrochloric acidToluene

Stage-2 Chloroform RecoveryEffluent water

Stage-2Hydrochloric acidChloroform Caustic solution Sodium Hydroxide

Material Balance:

Material Balance of 1-Benzyl-4- Piperidone Stage-1



in Kg Benzylamine 147.00 Stage-1 350.00 Acryclic acid methyl ester 236.00 Methanol Recovery 285.00 Methanol 300.00 Methanol loss 10.00 Water 400.00 Effluent water 400.00 (Water-400) 0 Organic residue 38.00 Process residue – 33


Total 1083.00 Total 1083.00






in Kg Stage-1 350.00 Stage-2 285.00 Sodium Methoxide 67.55 Toluene Recovery 380.00 Hydrochloric acid 45.50 Toluene loss 12.00 Toluene 400.00 Effluent water 553.30 Water 400.00 (Water-400,Sodium Chloride-

73.15,Methanol-80.15) 0



Total 1263.05 Total 1263.05




in Kg Stage-2 285.00 1-Benzyl-4- Piperidone 200.00 Hydrochloric acid 42.00 Chloroform Recovery 475.00 Chloroform 500.00 Chloroform Loss 25.00 Caustic solution 50.00 Effluent water 454.02 Sodium Hydroxide 45.88 (Water-300,Water from Caustic

solution 50,Generated Methanol-36.76,Sodium Chloride-67.26)

Water 300.00 Process emission 50.45 (carbondioxide-50.45) Organic residue 18.41 Process residue -18.41 Total 1222.88 Total 1222.88



1-BENZYL-PIPERIDIN-4-OL


Stage-1:

N-Benzyl-4-Piperidone undergoes Hydrogenation with Hydrogen in presence of Palladium Carbon and Methanol to give 1-Benzyl-piperidin-4-ol

Route of Synthesis:

Stage-1

N

O

N-Benzyl-4-piperidone

C12H15NO189.25

+ H2

2.02

Methanol,Pd/C

N

OH

C12H17NO

191.27

1-Benzyl-piperidin-4-ol

Flowchart:

Stage-1

1-BENZYL-PIPERIDIN-4-OL

N-Benzyl-4-PiperidoneHydrogen Methanol




Material Balance:

Material Balance of 1-Benzyl-Piperidin-4-ol .Stage-1



in Kg N-Benzyl-4-Piperidone 209.00 1-Benzyl-piperidin-4-ol 200.00 Hydrogen 2.20 Methanol Recovery 285.00 Methanol 300.00 Methanol loss 10.00 Water 400.00 Effluent water 400.00 (Water-400) 0 Organic residue 16.20 Process residue – 11.20


Total 911.20 Total 911.20

1-METHYLPIPERIDIN-4-AMINE


Stage-1:

1-methylpiperidin-4-one undergoes amination with Ammonia in presence of Methanol to give

1-Methylpiperidin-4-Amine

Route of Synthesis:

Stage-1:

1-methylpiperidin-4-one

N

O

CH3

C6H11NO113.16

Methanol,Methanolic ammonia

Raney Nickel,H2 gas

1-methylpiperidin-4-amine

N

NH2

CH3

C6H14N2

114.19

NH3

17.03

+ 0.5 O2

16.00

+



Flowchart:

Stage-1

1-METHYLPIPERIDIN-4-AMINE

1-methylpiperidin-4-oneAmmoniaMethanol Raney nickel Hydrogen gasMethanolic ammonia


Material balance:

Material Balance of 1-Methylpiperidin-4-Amine Stage-1

Batch Size: 200.00 Kg Name of the input Quantity in

Kg Name of the out put Quantity

in Kg 1-methylpiperidin-4-one 209.00 1-Methylpiperidin-4-Amine 200.00 Ammonia 31.35 Methanol Recovery 385.00 Methanol 400.00 Methanol Loss 10.00 Raney nickel 10.00 Effluent water 407.00 Hydrogen gas 2.00 (Water-400,Methanolic ammonia-

5,Hydrogen-2) 0

Methanolic ammonia 5.00 Raney nickel recovery 10.00 Water 400.00 Process emission 29.46 (oxygen-29.46) 0 Organic residue 15.89 Process residue -10.89


Total 1057.35 Total 1057.35



4-AMINO PIPERIDINE Process Description: Stage-1: N-carbethoxy-4-amino-Piperidine reacts with Sodium hydroxide and Hydrochloric acid in presence of water and Chloroform to give 4-Amino-Piperidine. Route of Synthesis: Stage-1

N

NH2

COOC2H5

N-Carbethoxy-4-amino piperidine

C8H16N2O2

172.22

+ NaOH

40.00

+ HCl

36.46

Water,Chloroform N

H

NH2

4-Amino piperidine

C5H12N2

100.16

+ C2H5OH

Ethanol46.07

+ NaCl58.44

+ CO2

44.01 Flowchart:

Stage-1

4-AMINO PIPERIDINE

N-Carbethoxy-4-amino piperidineSodium HydroxideHydrochloric acidChloroform

ChloroformRecoveryEffluent water

Material Balance of 4-Amino-Piperidine. Stage-1 Batch Size: 200.00 Kg

Name of the input Quantity in Kg

Name of the out put Quantity in Kg

N-Carbethoxy-4-amino piperidine 367.00 4-Amino-Piperidine 200.00 Sodium Hydroxide 85.15 Chloroform Recovery 285.00 Hydrochloric acid 77.45 Chloroform loss 15.00 Chloroform 300.00 Effluent water 622.39 Water 400.00 (Water-400, sodium chloride-

124.41,Ethanol-97.98) 0

Process emission 93.58 (Carbon dioxide-93.58) 0 Organic residue 13.63 Process residue – 13.63 Total 1229.60 Total 1229.60



4-HYDROXY PIPERIDINE

Process Description: Stage-1: N-Methyl-4-Piperidone reacts with Ethylchloroformate in presence of Toluene to give Satge-1 product. Stage-2: Stage-1 product undergoes Hydrogenation with Hydrogen gas in presence of Toluene and Raney nickel to give Stage-2 product. Stage-3: Stage-2 product undergoes hydrolysis with sodium hydroxide in presence of Toluene to give 4-Hydroxy piperidine. Route of Synthesis: Stage-1:

N

O

CH3

N-Methyl-4-Piperidone

C6H11NO

113.16

N

O

OO

CH3

ClO

OCH3

Ethylchloroformate

+

C3H5ClO2

108.52

4-Oxo-piperidine-1-carboxylic acid ethyl ester

C8H13NO3

171.19

+ CH3Cl

50.49

Chloromethane

Stage-2:

N

O

OO

CH3


C8H13NO3

171.19

N

OH

OO

CH3

4-Hydroxy-piperidine-1-carboxylic acid ethyl ester

C8H15NO3

173.21

+ H2

2.0



Stage-3:

N

OH

OO

CH3

4-Hydroxy-piperidine-1-carboxylic acid ethyl ester

C8H15NO3173.21

NH

OH

+ NaOH

80.00

C5H11NO101.15

4-Hydroxy Piperidine

2+ C2H5OH

46.07

+ Na2CO3

105.99

Flowchart:

Stage-1

4-HYDROXY PIPERIDINE

N-Methyl-4-PiperidoneEthylchloroformateTolueneAcetic acid C.S.Lye


Stage-2Stage-1HydrogenRaney NickelToluene


Stage-3Stage-2Sodium hydroxideToluene


Material Balance:

Material balance of 4-Hydroxy Piperidine Stage-1 Batch Size:100Kg



N-Methyl-4-Piperidone 130.00 Stage-1 188.00 Ethylchloroformate 124.55 Toluene Recovery 375.00 Toluene 400.00 Toluene Loss 15.00



Acetic acid 3.00 Effluent Water 359.09 C.S.Lye 2.00 (Water-350, Toluene-5,

Sodium acetate-4.09) 0

Water 350.00 Process Emission 57.98 (Chloromethane-57.98) 0 Organic Residue 14.48 Process residue-9.48


Total 1009.55 Total 1009.55

Material balance of 4-Hydroxy Piperidine Stage-2

Batch Size:100Kg Name of the input Quantity


in Kg Stage-1 188.00 Stage-2 180.00 Hydrogen 2.05 Toluene Recovery 332.00 Raney Nickel 10.00 Toluene Loss 15.00 Toluene 350.00 Raney Nickel reuse 10.00 Water 300.00 Effluent Water 302.00 (Water-300,Toluene-2) 0 Organic Residue 11.05 Process residue-10.05



Material balance of 4-Hydroxy Piperidine Stage-3



in Kg Stage-2 180.00 4-Hydroxy Piperidine 100.00 Sodium hydroxide 83.20 Toluene Recovery 285.00 Toluene 300.00 Toluene Loss 10.00 Water 300.00 Effluent Water 459.68 (Water-300,Ethanol-

47.7,Sodium carbonate-109.98,Toluene-2)

0

Organic Residue 8.52 Process residue-5.52





4-PHENYLPIPERIDINE


Stage-1:

4-Phenyl-piperidin-4-ol reacts with Sulphuric acid and Sodium Hydroxide in presence of Toluene to give 4-Phenyl Piperidine

Route of Synthesis:

Stage-1

NH

OH

4-Phenyl-piperidin-4-olC11H15NO

177.24

+ H2SO4

98.08

+ 2 NaOH

80.00

Toluene NH

4-Phenyl-piperidineC11H15N

161.24

+ Na2SO4

Sodium sulphate

142.04

+ 2 H2O

36.03

+ 0.5 O2

16.00

Flowchart:

Stage-1

4-PHENYLPIPERIDINE

4-Phenyl-piperidin-4-olSodium HydroxideSulphuric acidToluene




Material Balance: Material Balance of 4-Phenyl Piperidine.

Stage-1 Batch Size: 100.00 Kg Name of the input Quantity


in Kg

4-Phenyl-piperidin-4-ol 118.00 4-Phenyl Piperidine 100.00

Sodium Hydroxide 53.25 Toluene Recovery 285.00 Sulphuric acid 65.25 Toluene loss 10.00 Toluene 300.00 Effluent water 521.47 Water 400.00 (Water-400, sodium Sulphate-

94.52,Generated water-23.95,Toluene-3)

0

Process emission 10.62 (Oxygen-10.62) 0 Organic residue 9.41 Process residue – 7.41



4-PHENYLPIPERIDINE

Process Description: Stage-1: 4-Phenyl-piperidin-4-ol reacts with Sulphuric acid and Sodium Hydroxide in presence of Toluene to give 4-Phenyl Piperidine Route of Synthesis: Stage-1

NH

OH

4-Phenyl-piperidin-4-olC11H15NO

177.24

+ H2SO4

98.08

+ 2 NaOH

80.00

Toluene NH

4-Phenyl-piperidineC11H15N

161.24

+ Na2SO4

Sodium sulphate

142.04

+ 2 H2O

36.03

+ 0.5 O2

16.00



Flowchart:

Stage-1

4-PHENYLPIPERIDINE

4-Phenyl-piperidin-4-olSodium HydroxideSulphuric acidToluene


Material Balance:

Material Balance of 4-Phenyl Piperidine. Stage-1



in Kg

4-Phenyl-piperidin-4-ol 118.00 4-Phenyl Piperidine 100.00

Sodium Hydroxide 53.25 Toluene Recovery 285.00 Sulphuric acid 65.25 Toluene loss 10.00 Toluene 300.00 Effluent water 521.47 Water 400.00 (Water-400, sodium Sulphate-

94.52,Generated water-23.95,Toluene-3)

0




4-PIPERIDINOPIPERIDINE


Stage-1:

4-Oxo-piperidine-1-carboxylic acid ethyl ester reacts with Piperidine in presence of Hydrogen,Pd/c and Methanol to give Stage-1 product.

Staeg-2:

Staeg-1 Product undergoes Hydrolysis with Potassium Hydroxide and Hydrochloric acid in presence of IPA to give 4-Piperidinopiperidine



Route of Synthesis:

Stage-1

N

O

COOC2H5


C8H13NO3

171.19

+ NH

PiperidineC5H11N

85.15

+ H2

2.02

Pd/C,Methanol,

3-4Kg pressureN

N

COOC2H5

[1,4']Bipiperidinyl-1'-carboxylic acid ethyl ester

C13H24N2O2

240.34

+ H2O

18.02

Stage-2

N

N

COOC2H5

[1,4']Bipiperidinyl-1'-carboxylic acid ethyl ester

C13H24N2O2

240.34

+ KOH

Potassium hydroxide

56.11

+ HCl

36.46

IPA NH

N

4-Piperidinopiperidine

C10H20N2

168.28

+ C2H5OH

46.07Ethanol

+ KCl

74.55

+ CO2

44.01



Flowchart:

Stage-1

4-PIPERIDINOPIPERIDINE

4-Oxo-piperidine-1-carboxylic acid ethyl esterPiperidine Methanol Palladium carbonHydrogen


Stage-1Potassium HydroxideHydrochloric acidIPA

IPA recoveryEffluent waterStage-2

Material Balance: Material balance of 4-Piperidinopiperidine

Stage-1 Batch Size:100Kg Name of the input Quantity


in Kg 4-Oxo-piperidine-1-carboxylic acid ethyl ester

116.00 Stage-1 152.00

Piperidine 57.65 Methanol Recovery 385.00 Methanol 400.00 Methanol Loss 10.00 Palladium carbon 1.00 Effluent Water 362.18 Hydrogen 1.25 (Water-350, Generated

water-12.18) 0

Water 350.00 Organic Residue 16.72 Process residue-11.72



Material balance of 4-Piperidinopiperidine Stage-2 Batch Size:100Kg



Stage-1 152.00 4-Piperidinopiperidine 100.00 Potassium Hydroxide 35.42 IPA Recovery 385.00 Hydrochloric acid 22.95 IPA Loss 15.00 IPA 400.00 Effluent Water 426.15 Water 350.00 (Water-350, Ethanol-

9.03,Potassium chloride-47.12) 0

Process Emission 27.82 (Carbondioxide-27.82) 0 Organic Residue 6.40 Process residue-6.40 Total 960.37 Total 960.37



ABACAVIR SULFATE Process Description: Stage-1 ADT pyrimidine is reacted with ACM Tartrate and sodium carbonate in presence of

Toluene to give Stage-1 product. Stage-2 Stage-1 compound is treated with Cyclo propyl amine and sodium Hydroxide in

presence of IPA to give Stage-2 Product.

Stage-3 Stage-2 Product reacts with Sulfuric acid in presence of IPA to give Abacavir Sulfate.

Route of Synthesis:

Stage-1

N

N

ClHN

ClNH2

CHO

CO-OH

CH-OH

CH-OH

COOH

+ 11/2Na2CO3

11/2CO2 21/2H2O++NaCl ++

ADT PyrimidineACM Tartrate

Sodium Carbonate

N

NH2N

Cl

N

N

HOH2C COONa

CHOH

CHOH

COONa

C5H4Cl2N4O

207.2 C6H11NO113.16

C4H6O6150.09

Stage-1C11H12ClN5O

265.70

159.0

58.5C4H4Na2O6

194.05

66.0 45.0

CH2OHNH2

(4-Amino-cyclopent-2-enyl)-methanol

++

Disodium tartarate



Stage-2

N

NH2N

Cl

N

N

HOH2C

Stage-1

C11H12ClN5O

265.70

NH2

IPA

N

NH2N

NH

N

N

HOH2C

+ + NaOH

Cyclopropylamine

C3H7N

57.09

40.0 Stage-2

C14H18N6O

286.33

+ NaCl + H2O

58.5 18.0

Stage-3

N

NH2N

NH

N

N

HOH2C

Stage-2C14H18N6O286.33

IPA+ H2SO4

Sulphuric acid

H2SO4

98.0

N

NH2N

NH

N

N

HOH2C

Abacavir Sulphate

C14H20N6O5S

384.41



Flow Chart:

ADT PyrimidineACM Tartarate4-Amino-cyclopent-2-enyl)methanolToluene

Stage-1 Toluene Rec

Stage-2 IPA Rec

Stage-1CyclopropylamineTriethyl OrthoformateSodium HydroxideIsopropyl Alcohol

Stage-3 IPA RecAbacavir BaseSulfuric AcidIsopropyl Alcohol

ABACAVIR SULFATE

Material Balance:

Material Balance of Abacavir Sulfate Stage-1 Batch Size: 100Kg



ADT Pyrimidine 73.00 Stage-1 85.00 ACM Tartarate 53.00 Toluene Recovery 380.00 4-Amino-cyclopent-2-enyl)methanol

40.00 Toluene Loss 8.00

Sodium Carbonate 56.00 Effluent Water 210.92 Toluene 400.00 (Water-100,Gen water-15.8,Sodium

chloride-20.6, Sodium tartarate-68.52,Toluene-6)

0

Water 100.00 Process Emissions 23.24 (Carbon Dioxide) 0 Organic residue 14.84 Process residue – 8.84

Distillation residue – 6 (Toluene -6)




Material Balance of Abacavir Sulfate Stage-2 Batch Size: 100Kg



Stage-1 85.00 Stage-2 80.00 Cyclopropylamine 18.30 Triehtyl Orthoformate Recovery 257.00 Triethyl Orthoformate 270.00 Triethyl Orthoformate Loss 13.00 Sodium Hydroxide 12.80 Isopropyl Alcohol Recovery 475.00 Isopropyl Alcohol 500.00 Isopropyl Alcohol Loss

15.00 Water 100.00 Effluent Water 124.45 (Water-100,Gen water-5.75,Sodium

chloride-18.7)

Organic Residue 21.65 Process residue – 11.65

Distillation residue -10 (IPA- 10)

Total 986.10 Total 986.10 Material Balance of Abacavir Sulfate

Stage-3 Batch Size: 100Kg Name of the input Quantity


in Kg Stage-2 80.00 Abacavir Sulfate 100.00 Sulfuric Acid 30.00 Isopropyl Alcohol Recovery 285.00 Isopropyl Alcohol 300.00 Isopropyl Alcohol Loss 10.00 Organic Residue 15.00 Process residue -10

Distillation residue – 5 (IPA -5)




AMITRIPTYLINE HYDROCHLORIDE


Stage-1: Step-A: 1-bromo-3-chloropropane (BCP) reacts with Dimethylamine (DMA) the presence of

Toluene, water, C.S Lye, HCl, Potassium hydroxide and Sodium Sulphate to give

Step-A product.

Step-B: Step-A product reacts with Hydrochloric acid to give stage-1 Product.

Stage 2:

Step-A:

Isobenzofuran-1,3-dione reacts with Phenyl acetic acid in presence of Sodium

acetate and Potassium Hydroxide Solution to give Step-A Product.

Step-B:

Step-A Product undergoes Hydrogenation in presence of Raney nickel and Toluene

to give step-b product.

Step-C:

Step-B product undergoes dehydration with Phosphorous Pent oxide and

Phosphoric acid in presence of O-xylene to give Stage-2 product.

Stage-3:

Stage-2 product reacts with Stage-1 product in presence of Magnesium, Ammonium

Chloride, THF and Methanol to give stage-3 product.

Stage-4:

Stage-3 product undergoes Salt formation/Dehydration with Hydrochloric acid in

presence of Toluene, Carbon and Acetone to give Amitriptyline Hydrochloride



Route of Synthesis

Stage-1: Step-A

HNCH3CH3

N-methyl methanamineBr Cl

1-bromo-3-chloropropane

Cl N

3-chloro-N,N-dimethylpropan-1-amine

Toluene, water, HCL

KOH, Sodium sulphate

NaBr

Sodium bromide

NaOH

sodium Hydroxide

H2O

+

C2H7N45.08

C3H6BrCl157.44

40.00

C5H12ClN121.61

102.918.0

Step-B:

Cl N

CH3

CH3

3-chloro-N,N-dimethylpropan-1-amine Hydrochloride

C5H13Cl2N

+ HCl

36.46

. HCl

158.07

Cl N

CH3

CH3


C5H12ClN

121.61

Stage-2:

Step-A:

O

O

O

Isobenzofuran-1,3-dioneC8H4O3

148.12

+

O

OH

Phenyl-acetic acidC8H8O2

136.15

CH3COONaO

O

3-Benzylidene-3H-isobenzofuran-1-one

C15H10O2

222.24

+ CO2

44.0

+ H2O

18.02



Step-B:

Raney NiToluene

O

O

3-Benzylidene-3H-isobenzofuran-1-one

C15H10O2

222.24

O

OH

2-Phenethyl-benzoic acid

C15H14O2

226.27

+ 2 H2

4.00

Step-C:

XyleneO

OH

2-Phenethyl-benzoic acidC15H14O2

226.27

O

DibenzosuberoneC15H12O

208.26

+ H2O

18.0

P2O5 ,H3PO4,C.S.LYE

Stage-3:

O

Dibenzosuberone

C15H12O

208.26

+Cl N

CH3

CH3


C5H12ClN

121.61

+ Mg + NH4Cl

N

OH

24.31 53.49

5-(3-Dimethylamino-propyl)-10,11-dihydro-5H-dibenzo[a,d]

cyclohepten-5-olC20H25NO295.42

+ MgCl2 + NH3

95.21 17.03

THF/Methanol



Stage-4:

N

OH

5-(3-Dimethylamino-propyl)-10,11-dihydro-5H-dibenzo[a,d]

cyclohepten-5-olC20H25NO

295.42

+ HCl

36.46

N

HCl

Amitriptyline HydrochlorideC20H24ClN

313.86

Acetone

Carbon+ H2O

18.0

Flow Chart

Stage-1

Stage-2

1-Bromo-3-Chloro propaneDi methyl amineTolueneSodium HydroxideSodium sulfate.Hydrochloric Acid

Toluene recoveryEffluent water

Isobenzofuran-1,3-dionePhenyl-acetic acidPotassium hydroxideSodium acetateToluene Raney NickelHydrogenXylene CS Lye Flakes (10%)

Toluene RecoveryXylene RecoveryEffluent water

AMITRIPTYLINE HYDROCHLORIDE

Stage-3

Stage-4Toluene recoveryAcetone recoveryEffluent water

Toluene RecoveryMethanol RecoveryEffluent water

Stage-23-Chloro-N,N-dimethylpropan-1-amineAmmonium ChlorideMagnesiumTetra hydro furanTolueneMethanol

Stage-3Hydrochloric Acid TolueneAcetoneActivated Carbon



Material Balance:

Material Balance of Amitriptyline Hydrochloride

Stage-1 BatchSize:500 Kg Name of the input Quantity


in Kg 1-Bromo-3-Chloro propane 225.00 Stage-1 205.00 Di methyl amine 65.00 Toluene Recovery 475.00 Toluene 500.00 Toluene Loss 10.00 Sodium Hydroxide 57.00 Effluent Water 580.83 Sodium sulfate. 20.00 (water-400, Generated water-

25.83, Sodium Bromide-147, Toluene-8)

0

Hydrochloric Acid 50.00 Inorganic solid waste 20.00 Water 400.00 (Sodium sulfate) 0 Organic residue 26.17 Process residue-21.17


Total 1317.00 Total 1317.00

Material Balance of Amitriptyline Hydrochloride Stage-2 BatchSize:500 Kg



Isobenzofuran-1,3-dione 290.00 Stage-2 350.00 Phenyl-acetic acid 267.00 Xylene Recovery 385.00 Potassium hydroxide 50.00 Xylene Loss 10.00 Sodium acetate 10.00 Toluene Recovery 1140.00 Toluene 1200.00 Toluene Loss 40.00 Raney Nickel 20.00 Effluent Water 807.10 Hydrogen

7.50

(water-500, Generated water-67.10, Sodium acetate-10, Potassium Hydroxide-50, Phosphoric acid-50, Phosphorous Pent oxide-30, Water from CS Lye-90,Toluene-10)

0

Phosphorous Pent oxide 30.00 Process emission 86.14 Phosphoric acid 50.00 (carbondioxide-86.14) 0 Xylene 400.00 Organic residue 106.26 CS Lye Flakes (10%)

100.00 Process residue-91.26 Distillation residue-15 (Xylene-5,Toluene-10)

Water 500.00 Total 2924.50 Total 2924.50



Material Balance of Amitriptyline Hydrochloride Stage-3

BatchSize 500Kg Name of the input Quantity


in Kg Stage-2 350.00 Stage-3 480.00 3-Chloro-N,N-dimethylpropan-1-amine

205.00 Tetra hydro furan Recovery 238.00

Ammonium Chloride 90.00 Tetra hydro furan Loss 12.00 Magnesium 41.00 Toluene Recovery 95.00 Tetra hydro furan 250.00 Toluene Loss 3.00 Toluene 100.00 Methanol Recovery 190.00 Methanol 200.00 Methanol Loss 5.00 Water 500.00 Effluent Water 661.00 Water-500, Magnesium

Chloride-160,Toluene-1) 0

Process Emission 28.62 (Ammonia-28.62) 0 Organic Residue 23.38 Process residue-17.38

Distillation residue-6 (Toluene-1,Methanol-5)

Total 1736.00 Total 1736.00

Material Balance of Amitriptyline Hydrochloride Stage-4

BatchSize 500 Kg Name of the input Quantity


in Kg Stage-3 480.00 Amitriptyline Hydrochloride 500.00 Hydrochloric Acid 62.00 Toluene Recovery 570.00 Toluene 600.00 Toluene Loss 12.00 Acetone 250.00 Acetone Recovery 237.00 Activated Carbon 20.00 Acetone Loss 12.00 Water 400.00 Spent Carbon 20.00 Effluent water 433.28 (water-400,Generated water-

29.28,Toluene-4) 0

Organic Residue 27.72 Process residue-22.72,

Distillation residue-5 (Toluene-4,Acetone-1)

Total 1812.00 Total 1812.00



ATROVASTAIN CALCIUM


Stage-1

tert-Butyl-2-[(4R,6S)-6-(cyano methyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate

undergoes reduction with Hydrogen on Palladium Carbon in presence of Methanol to

give Stage-1 Product.

Stage-2

Aniline undergoes condensation with Dimethyl Carbonate and 2-Methyl-2-butanone

in presence of Methanol to give stage-2 product.

Stage-3

Stage-2 product reacts with Benzaldehyde in presence of potassium Carbonate,

Acetone and Toluene media to give stage-3 product.

Stage-4

Stage-3 Product reacts with stage-1 product and Fluorobenzaldehyde in presence of

Para Toulene Sulfonic acid, Isopropyl Alcohol and Toluene to give stage-4 product.

Stage-5

Stage- 4 product undergoes hydrolysis in presence of Sulfuric acid and Methanol to

give Stage-5 Product.

Stage-6

Stage-5 product undergoes salt formation with Calcium Acetate in presence of

Isopropyl Alcohol to give Atorvastatin Calcium.



Route of Synthesis:

Stage-1

CNO

CH3CH3

CH3

OOO

CH3H3C

+ 2 H2NH2 O

CH3CH3

CH3

OOO

CH3H3C

tert-Butyl-2[(4R,6S)-6-(cyano methyl)-2,2-dimethyl-1,3-dioxan-4yl] acetate

269.34

tert-Butyl-2[(4R,6S)-6-(amino ethyl)-2,2-dimethyl-1,3-dioxan-4yl] acetate

273.37

C14H23NO4

4.0

C14H27NO4

Methanol

Stage-2

NH2CH3H3C

H3C O

+ ++

Aniline

93.13

Dimethyl carbonate

90.08

2-Methyl-2-butanone

86.13

2 CH3OH

205.25

64.08

C6H7N C3H6O3

O

O

O

C5H10OC12H15NO2

4-Methyl-3-oxo-N-phenylpentanamide

CH3

O

HN

OCH3

Methanol

Stage-3

205.25

C12H15NO2

4-Methyl-3-oxo-N-phenylpentanamide

CH3

O

HN

O

CH3 H

O

Benzaldehyde

106.12

C7H6O

+ + K2CO3

138.20

C19H19NO2

293.36

+ 2KCl

149.10

+ CO2

44.01

2-Benzylidene-4-methyl-3-oxo-pentanoic acid phenylamide

CH3

O

NH

OH3C

+ 2 HCl

72.92

+ 2 H2O

36.04

Acetone, Toluene



Stage-4

C19H19NO2

293.36

+

2-Benzylidene-4-methyl-3-oxo-

pentanoic acid phenylamide

CH3

O

NH

OH3C

H

O

F

+NH2 O

CH3CH3CH3

OOO

CH3H3C

tert-Butyl-2[(4R,6S)-6-(amino ethyl)-2,2-dimethyl-1,3-dioxan-4yl] acetate

273.37

Fluorobenzaldehyde

124.03C14H27NO4

C7H5FO

2 H2O+

Atorvastatin Ester

654.81

NNH

O H3CCH3

F

O OH3C CH3

O

O CCH3

CH3CH3

C40H47FN2O5

36.04

IPA

Toluene

Stage-5

+

Atorvastatin Ester

654.81

NNH

O H3CCH3

F

O OH3C CH3

O

O CCH3

CH3CH3

C40H47FN2O5

2 H2O

CH3H3C

O

+ + C CH3

CH3

CH3

OH

Atorvastain

558.64

Acetone

58.08

tert-Butanol

74.12

36.0

NNH

O H3CCH3

F

OH OH O

OH

C33H35FN2O5

C3H6O C4H10O

Methanol



Stage-6

+

Atorvastain

1117.28

NNH

O H3CCH3

F

OH OH O

OH

C33H35FN2O5

CH3COOCa

Calcium Acetate

99.12

NNH

O H3CCH3

F

OH OH O

OH

Atorvastatin calcium

60.04

CH3COOH

C66H68CaF2N4O10

2

2

Ca2+

+

1155.36

Iso Propyl alcohol



Flow Chart: Tert-Butyl-2-[(4R,6S)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-yl]AcetatePalladium CarbonHydrogenMethanol

Stage-1Methanol RecoveryPalladoum carbon recovery

Stage-2Methanol RecoveryEffluent water

AnilineDimethyl Carbonate2-Methyl-2-ButanoneSulfuric AcidMethanol

Stage-3

Acetone RecoveryToluene RecoveryEffluent water

Stage-2BenzaldehydePotassium CarbonateHydrochloric acidAcetoneToluene

Stage-4Toluene RecoveryIsopropyl alcohol RecoveryEffluent water

Stage-3Stage-1FluorobenzaldehydeToluenePara Toluene Sulfonic AcidIsopropyl Alcohol


Stage-4Sulfuric AcidMethanol

Stage-6IPA RecoveryAcetic acid recovery

Calcium AcetateIsopropyl AlcoholActivated Carbon

ATORVASTATIN CALCIUM



Material Balance:

Material Balance of Atorvastatin Calcium Stage-1



in Kg Tert-Butyl-2-[(4R,6S)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-yl]Acetate

131.00 Stage-1 122.00

Palladium Carbon 1.00 Methanol Recovery 380.00 Hydrogen 1.85 Methanol Loss 15.00 Methanol 400.00 Palladium Carbon 1.00 Organic residue- 15.85 Process residue-10.85






in Kg Aniline 50.00 Stage-2 100.00 Dimethyl Carbonate 48.35 Methanol Recovery + generated

Methanol 177.40

2-Methyl-2-Butanone 46.00 Methanol Loss 4.00 Sulfuric Acid 0.80 Effluent Water 300.80 Methanol 150.00 (Water-300,Sulfuric acid-0.8) 0 Water 300.00 Organic Residue 12.95 Process residue-9.95








in Kg Stage-2 100.00 Stage-3 131.00 Benzaldehyde 51.50 Acetone Recovery 190.00 Potassium Carbonate 67.00 Acetone Loss 5.00 Hydrochloric acid 35.50 Toluene Recovery 285.00 Acetone 200.00 Toluene Loss 8.00 Toluene 300.00 Effluent Water 494.10 Water 400.00 (Water-400,Generated water-

17.50,Potassium Chloride-72.60, Toluene-4)

0

Process Emission 21.40 (Carbon dioxide- 21.40) 0 Organic residue 19.50 Process residue-11.50

Distillation residue-8 (Toluene-3, Acetone-5)

Total 1154.00 Total 1154.00




in Kg Stage-3 131.00 Stage-4 268.00 Stage-1 122.00 Isopropyl Alcohol Recovery 285.00 Fluorobenzaldehyde 55.00 Isopropyl Alcohol Loss 10.00 Toluene 500.00 Toluene Recovery 475.00 Para Toluene Sulfonic Acid 2.00 Toluene Loss 10.00 Isopropyl Alcohol 300.00 Effluent Water 425.98 Water 400.00 (Water-400,Generated water-

15.98, para Toluene Sulfonic acid-2, Toluene-8)


Distillation residue-12 (Toluene-7, Isopropyl alcohol-5)

Total 1510.00 Total 1510.00






in Kg Stage-4 268.00 Stage-5 210.00 Sulfuric Acid 2.50 Mixed Solvent Rceovery

(Methanol + Acetone-23.58,Tert-butanol-30.28)

433.86

Methanol 400.00 Methanol Loss 8.00 Water 300.00 Effluent Water 288.03 (Water-285.53,Sulfuric acid-2.5) 0 Organic residue 30.61 Process residue -18.61






in Kg Stage-5 210.00 Atorvastain Calcium 200.00 Calcium Acetate 18.48 Acetic acid Recovery 11.13 Isopropyl Alcohol 400.00 Isopropyl Alcohol Recovery 380.00 Activated Carbon 10.00 Isopropyl Alcohol Loss 20.00 Spent Carbon Recovery 10.00 Organic residue 17.35 Process residue-17.35 Total 638.48 Total 638.48



BUPROPION Route of synthesis: Stage-1 1-(3-Chloro-phenyl)-propan-1-one undergoes Bromination with in presence of MDC and Water to give Stage-1 Product. Stage-2 Stage-1 product undergoes condensation with tertiary-Butyl amine in presence of Toluene and Ethyl acetate to give Bupropion. Route of synthesis: Stage-1

ClO

CH3

1-(3-Chloro-phenyl)-propan-1-one

C9H9ClO168.62

+ Br2

159.81

MDCWater

Br

OCl

3-Bromo-1-(3-chloro-phenyl)-propan-1-one

C9H8BrClO247.52

+ HBr

80.91

Stage-2

Br

OCl

3-Bromo-1-(3-chloro-phenyl)-propan-1-one

C9H8BrClO247.52

+ HBr

80.91

+

Tertiary butylamine

NH2

H3C

CH3

CH3

C4H11N73.14

TolueneEthyl acetate

OH3C

NHCH3

CH3

H3CCl

C13H18ClNO239.74

BUPROPION

Flow Chart:

Stage-1

Stage-2

1-(3-Chloro-phenyl)-propan-1-oneLiquid BromineAcetic acidMDC

Acetic acid RecoveryMDC RecoveryEffluent water

Stage-1teritiary-Butyl amineTolueneEthyl acetate

Toluene RecoveryEthyl acetate RecoveryEffluent water

BUPROPION



Material Balance:

Material Balance of Bupropion Stage-1



in Kg 1-(3-Chloro-phenyl)-propan-1-one 175.000 Stage-1 230.000

Liquid Bromine 165.70 Acetic acid Recovery 285.00 Acetic acid 300.00 Acetic acid loss 10.00 MDC 250.00 MDC Recovery 238.00 Water 400.00 MDC loss 8.00 Effluent water 400.00 (Water-400) 0 Process emission 83.82 (Hydrogen bromide – 83.82) 0 Organic residue 35.88 Process residue – 26.88

Distillation residue-9 (Aceticacid-5,MDC-4)

Total 1290.70 Total 1290.70

Material Balance of Bupropion Stage-2



in Kg Stage-1 230.00 Bupropion 200.00 teritiary-Butyl amine 68.00 Toluene Recovery 190.00 Toluene 200.00 Toluene loss 5.00 Ethyl acetate 200.00 Ethyl acetate Recovery 190.00 Water 300.00 Ethyl acetate loss 5.00 Effluent water 306.00 (water-300, Toluene-3, ethyl

acetate-3) 0

Process emission 74.98 (Hydrogen bromide – 74.98) 0 Organic residue 27.02 Process residue -23.02

Distillation residue-4 (Ethyl acetate-2,Toluene-2)




CARISOPRODOL


Stage-1

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

the presence of Toluene and Sodium methoxide to give Stage-1 product.

Stage-2

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

Stage-3

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

chloroform to give Stage-3 product.

Stage-4

Stage-3 Product undergoes recystallisation by using methanol to give Carisoprodol

Route of synthesis:

Stage-1

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

H3C

H3COH

OH

132.20

C7H16O2

+

Dimethyl carbonate

O

O

OCH3H3C

C3H6O3

90.07

H3CO

O

H3C

O

+ 2 CH3OH

2X32.04=64.08

Methanol

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

C8H14O3

158.19

Toluene

NaOMe



Stage-2

H3CO

O

H3C

O

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

C8H14O3

158.19

+

Isopropyl amine

NH2

CH3H3C H3COH

O

H3C

HN

CH3

CH3O

Isopropyl-carbamic acid 2-hydroxymethyl-2-methyl-pentyl ester

C11H23NO3

217.30

C3H9N59.11

Stage-3

H3COH

O

H3C

HN

CH3

CH3O

Isopropyl-carbamic acid 2-hydroxymethyl-2-methyl-pentyl ester

C11H23NO3

217.30

+ NaOCN

Sodium cyanate

65.00

+ HCl

Hydrochloric acid

36.5

H3CO

O

H3C

HN

CH3

CH3O

O

NH2

Carisoprodol(Tech)

C12H24N2O4

260.32

+ NaCl

Sodium chloride

58.44

Toluene



Stage-4

H3CO

O

H3C

HN

CH3

CH3O

O

NH2

Carisoprodol(Tech)

C12H24N2O4

260.32

Methanol

H3CO

O

H3C

HN

CH3

CH3O

O

NH2

Carisoprodol(Pharma)

C12H24N2O4

260.32

Purification

Flow Chart:

2-Methyl-2-propyl-1,3-propane diolDimethyl carbonateToluene

Stage-1 Toluene Rec

Stage-2Stage-1Isopropylamine Isopropyl amine Rec

Stage-3

Stage-2Sodium cyanateChloroformToluene

Chlorofom RecToluene Rec

Stage-4Carisoprodol (Tech)MethanolActivated carbon

Methanol RecSpent carbon

CARSIPRODOL



Material Balance:

Material Balance of Carisoprodol Stage-1



in Kg 2-Methyl-2-propyl-1,3-propane diol

64.00 Stage-1 72.00

Dimethyl carbonate 43.50 Mixed Solvent

(Toluene Recovery + Generated methanol-30.97)

415.97

Toluene 400.00 Toluene Loss 10.00 Sodium methoxide 6.00 Organic Residue 15.53

Process residue-10.53 Organic impurities-4.53 (Sodium methoxide-6) Distillation residue-5 (Toluene-5)





in Kg Stage-1 72.00 Stage-2 93.00 Isopropylamine 147.00 Isopropylamine Recovery 114.00 Isopropylamine Loss 3.00 Organic Residue 9.00

Process residue -6

Distillation residue-3 (Isopropyl Amine-3)







in Kg Stage-2 93.00 Stage-3 105.00 Sodium cyanate 27.80 Chloroform Recovery 475.00 Chloroform 500.00 Chloroform Loss 20.00 Toluene 400.00 Toluene Recovery 385.00 Hydrochloric acid (35%) 45.00 Toluene Loss 10.00 Sulphuric acid 10.00 Effluent water 517.42 Water 450.00 (Water-450,Sodium chloride-

24.92, water from HCl-29.5,Sulfuric Acid-10,Toluene-3)

0

Organic Residue 13.38

Process residue-6.38

Distillation residue-7 (Chloroform-5,Toluene-2)

Total 1525.80 Total 1525.80


Batch Size: 100.0Kg Name of the input Quantity


in Kg Stage -3 105.00 Carisoprodol 100.00 Methanol 300.00 Methanol Recovery 285.00 Activated carbon 5.00 Methanol Loss 10.00 Water 400.00 Effluent water 400.00 (Water-400) 0 Spent carbon 5.00 Organic Residue 10.00

Process residue-5





CLOPIDOGREL BISULPHATE


Stage-1:

2-Amino-2-(2-chlorophenyl) acetic acid reacts with sulphuric acid and Methanol in presence of Ammonia and Toluene to give Stage-1 Product.

Stage-2:

Stage-1 Product undergoes resolution with L-(+) tartaric acid in presence of Methanol and Acetone to give Stage-2 Product.

Stage-3:

2-(thiophen-2-yl)ethanol reacts with Para Toluene Sulphonyl chloride in presence of Sodium hydrate and Toluene to give Stage-3 Product. Stage-4: Stage-3 Product reacts with Stage-2 product in presence of MDC, Ethyl acetate and Ammonia to give Stage-4 Product. Stage-5: Stage-4 Product reacts with Formaldehyde, sulphuric acid in presence of Acetone and Sodium bicarbonate to give Stage-5 Product. Stage-6: Stage-5 Product undergoes recrystalisation in presence of Acetone, Acetonitrile and Methanol to give Clopidogrel Bisulphate.



CLOPIDOGREL BISULPHATE

Route of Synthesis:

Stage-1:

O

OH

Cl

NH2

O

OCH3

Cl

NH2

+ H2SO4

98.08

+ CH3OH

32.04

+

132.14

+

18.02

+

34.06

(NH4)2SO4 H2O

2-Amino-2-(2-chlorophenyl)acetic acid

Methyl 2-amino-2-(2-chlorophenyl)acetate

Ammonium sulphate

2NH3MDC,Toluene

C8H8ClNO2

185.61

C9H10ClNO2

199.63

Stage-2:

O

OCH3

Cl

NH2 + OH

OH O

OH

O

HO

150.09

O

OCH3

Cl

NH2

.OH

OH O

OH

O

HO

Methyl 2-amino-2-(2-chlorophenyl)acetate

L-(+) -Tartaric acid

(S)-Methyl 2-amino-2-(2-chlorophenyl)acetate (2S,3S)-2,3-dihydroxysuccinate

Methanol

C9H10ClNO2

199.63C13H16ClNO8

349.72

C4H6O6

Acetone



Stage-3:

S

OH + H3C

SO

O Cl

SO S

O

OCH3

+ NaOH

40.00

+ NaCl

58.44

+ H2O

18.02

2-(thiophen-2-yl)ethanol p-Toluene sulphonyl chloride

2-(Thiophen-2-yl)ethyl 4-methylbenzenesulfonate

Toluene

C6H8OS

128.19C7H7ClO2S

190.65

C13H14O3S2

282.38

Stage-4:

NH4+

NH4+

OH

OH O

O-

O

-O

+

HCl

36.46

NH3

34.06

2+

SO S

O

OCH3

+

SHN

OCH3O

Cl .HCl +

184.15

+ CH3

SO

O OK

K2HPO4

174.18

+

+ KH2PO4

136.09

210.29

2-(Thiophen-2-yl)ethyl 4-methylbenzenesulfonate

Dipotassoium ortho phosphate

(S)-Methyl 2-(2-chlorophenyl)-2-((2-(thiophen-2-

yl)ethyl)amino)acetate hydrochloride

Ammonium tartarate Potassium salt of p-toluene sulfonic acid

MDC, Ethyl acetate, IPA

Monopotassium phosphate

C13H14O3S2

282.38

C15H17Cl2NO2S

346.27

C4H12N2O6 C7H7KO3S

O

OCH3

Cl

NH2

.OH

OH O

OH

O

HO

(S)-Methyl 2-amino-2-(2-chlorophenyl)acetate Tartarate

C13H16ClNO8

349.72



Stage-5

SHN

OCH3O

Cl .HCl

30.03

+ H2SO4

98.08

S

N

O OCH3

Cl

H2SO4.

CH2O

+ 2H2O

36.03

+ + NaHCO3

84.01

+ NaCl

58.44

+ CO2

44.01

(S)-Methyl 2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)

acetate hydrochloride

Formaldehdye

(S)-Methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno

[3,2-c]pyridin-5(4H)-yl)acetate sulfate

Acetone, MDC

C15H17Cl2NO2S

346.27

C16H18ClNO6S2

419.90

Stage-6

S

N

O OCH3

Cl

H2SO4.

Clopidogrel bi sulphate(Crude)

S

N

O OCH3

Cl

H2SO4.

Clopidogrel bi sulphate(pure)

Acetonitrile,Methanol,Acetone

C16H18ClNO6S2

419.90C16H18ClNO6S2

419.90



Flow Chart:

Stage-1

Stage-2

2-Amino-2-(2-chlorophenyl)acetic acidSulphuric acidMethanolLiq. AmmoniaMDCTolueneSodium sulphate

MDC recoveryToluene recovery

Stage-1L-(+)-Tartaric acidMethanol Acetone

Methanol recoveryAcetone recovery

2-(thiophen-2-yl)ethanolPTSCSodium hydroxideSodium sulphateToluene

Stage-3 Toluene Recovery

Stage-2Stage-3(intermediate-1)Liq. AmmoniaHydrochloric acidMDCIPAEthyl acetateActivated carbonHyflowSodium sulfate

Stage-4IPA RecoveryMDC RecoveryEthyl acetate recovery

Stage-5

Stage-6

Stage-4FormaldehydeSulfuric acidSodium bi carbonateAcetoneMDCActivated carbonSodium sulfate

MDC recoveryAcetone recovery

Stage-5Acetone MethanolAcetonitrile

Methanol recoveryAcetone recoveryAcetonitrile Recovery

Clopidogrel Bisulphate



Material Balance: Material Balance of Clopidogrel Bisulphate



in Kg 2-Amino-2-(2-chlorophenyl)acetic

acid 149.00 Stage-1 150.00

Sulphuric acid 78.50 Methylene Dichloride Recovery 475.00 Methanol 25.50 Methylene Dichloride Loss 15.00 Liq. Ammonia 27.50 Toluene Recovery 285.00 Methylene Dichloride 500.00 Toluene loss 7.00 Toluene 300.00 Inorganic solid waste 125.94

Sodium sulphate 20.00 (Sodium sulfate-20, Ammonium sulphate-105.94 )

Water 400.00 Effluent water 418.47

(Water-400,Generated water-14.47,Toluene-4)


Process Residue-15.09

Distillation Residue-9 (MDC-5,Toluene-4)

Total 1500.50 Total 1500.50

Material Balance of Clopidogrel Bisulphate Stage-2 Batch Size: 200.0 Kg



Stage-1 150.00 Stage-2 247.00 L-(+)-Tartaric acid 112.65 Methanol Recovery 475.00 Methanol 500.00 Methanol loss 15.00 Acetone 150.00 Acetone Recovery 143.00 Acetone loss 5.00 Organic residue 27.65

Process residue-15.65,

Distillation residue-12 ( Methanol-10,Acetone-2)


Material Balance of Clopidogrel Bisulphate Stage-3 Batch Size: 200.0 Kg



2-(thiophen-2-yl)ethanol 97.00 Stage-3 199.00 ParaTolueneSulfonylChloride 144.50 Toluene Recovery 333.00 Sodium hydroxide 30.20 Toluene loss 7.00



Sodium sulphate 10.00 Effluent water 262.71

Toluene 350.00 (Water-200,Generated water-13.58, Sodium chloride-44.13, Toluene-5 )

0

Water 200.00 Inorganic residue 10.00 (Sodium sulfate) 0 Organic residue 19.99 Process Residue-14.99

Distillation Residue-5 (Toluene-5)


Material Balance of Clopidogrel Bisulphate Stage-4



in Kg Stage-3 199.00 Stage-4 185.00 Stage-2 247.00 MDC Recovery 380.00 Liq. Ammonia 23.80 MDC loss 8.00 Dipotassium ortho phosphate 122.50 IPA Recovery 333.00 Hydrochloric acid 25.68 IPA loss 7.00 MDC 400.00 Ethyl acetate Recovery 380.00 IPA 350.00 Ethyl acetate loss 8.00 Ethyl acetate 400.00 Effluent water 303.72

Activated carbon 2.50 (Water-200, Mono potassium

phosphate-95.72, Ethyl acetate-8)

0

Hyflow 0.50 Spent carbon & Hyflow 3.00 Sodium sulfate 10.00 Inorganic solid waste 10.00 Water 200.00 (Sodium sulfate) 0 Organic residue 363.26 Process Residue-

Organic impurities-59.47 (Ammonium tartarate-129.74, Potassium salt of para-toluene sulfonic acid-148.05, Distillation Residue-26 (MDC-12, IPA-10, Ethylacetate-4)

Total 1980.98 Total 1980.98






in Kg Stage-4 185.00 Stage-5 210.00 Formaldehyde 16.00 MDC Recovery 665.00 Sulfuric acid 53.00 MDC loss 15.00 Sodium bi carbonate 44.75 Acetone Recovery 570.00 Acetone 600.00 Acetone loss 12.00 MDC 700.00 Effluent water 350.32

Activated carbon 10.00 (Water-300, Generated water-19.24,Sodium chloride-31.08)

Sodium sulfate 20.00 Process emission 23.49 Water 300.00 (Carbon dioxide-23.49) Spent carbon 10.00 Inorganic solid waste 20.00 (Sodium sulfate) Organic residue 52.94 Process Residue-14.94,

Distillation Residue-38 ( MDC-20, Acetone-18 )

Total 1928.75 Total 1928.75




in Kg Stage-5 210.00 Clopidogrel Bisulphate 200.00 Acetone 250.00 Acetonitrile Recovery 190.00 Methanol 150.00 Acetonitrile Loss 5.00 Acetonitrile 200.00 Acetone Recovery 238.00 Acetone Loss 7.00 Methanol Recovery 143.00 Methanol Loss 5.00

Organic Residue 22.00 Process residue-10,

Distillation residue-12 (Acetonitrile-5,Acetone-5, Methanol-2)




CYCLOBENZAPRINE HYDROCHLORIDE


Stage-1: 1-bromo-3-chloropropane reacts with Dimethyl amine in presence of Sodium

Hydroxide,Toluene and water to give Steage-1 Product.

Stage-2:

Step-A:

Phenyl acetic acid reacts with Pthalic anhydride in prrsence of Methanol and sodium acetate to give stage-A product.

Step-B:

Stage-A Product reacts with Hydrogen in presence of sodium hydroxide and rabey-nickel to give Step-B Product.

Step-C:

Step-B product undergoes cyclisation in presence of Xylene, P2O5 and Phosphoric acid to give Stage-2 Product.

Stage-3:

Stage-2 Product reacts with Stage-1 Product in presence of Magnesium, THF,

Toluene and Methanol to give Stage-3 Product.

Stage-4:

Stage-3 Product undergoes Dehydration with Hydrochloric acid in presence of

Toluene and Acetone to give Cyclobenzaprine Hydrochloride



Route of Synthesis

Stage-1:

Dimethyl amine1-bromo-3-chloropropane


Toluene, water, HCl

KOH, Sodium sulphate

NaBr

NaOH

C3H6BrCl

157.44

40.00

C5H12ClN

121.61

102.9

N

CH3

CH3

Cl

HN

CH3H3CClBr + +

+ +

C2H7N

45.08

H2O

18.02

Stage-2:

Step-A:

COOH

Phenyl-acetic acidC8H8O2136.15

+

O

O

OPhthalic anhydride

C8H4O3

148.12

O

O3-Benzylidene-3H-

isobenzofuran-1-oneC15H10O2

222.24

+ H2O18.02

+ CO2

44.01



Step-B:

O

O3-Benzylidene-3H-


222.24

OH

O2-Styryl-benzoic acid

C15H12O2

224.25

+ H2

2.02

NaOH solution,HCl solution,Raney nickel

Step-C:

OH

O

2-Styryl-benzoic acidC15H12O2

224.25

O

DibenzosuberenoneC15H10O

206.24

P2O5,H3PO4

+ H2O

18.02Xylene



Stage-3:

3-chloro-N,N-Dimethylpropan-1-amine

+Mg+ NH4Cl

C5H12ClN

121.61

C15H10O

206.24

24.31 53.49

+ MgCl2 + NH3

95.21 17.03

THF/Methanol

5-(3-Dimethylamino-propyl)-5H-dibenzo[a,d]cyclohepten-5-ol

C20H23NO293.40

Dibenzosuberenone

N

CH3

CH3

Cl

O

+

OH

N

Stage-4:

+ HCl

36.46

Acetone

Carbon

+ H2O

18.025-(3-Dimethylamino-propyl)-5H-

dibenzo[a,d]cyclohepten-5-olC20H23NO

293.40

Cyclobenzaprine HydrochlorideC20H22ClN

311.85

OH

N

N

. HCl



Flow Chart

Stage-1

Stage-2

Stage-3

CYCLOBENZAPRINE HYDROCHLORIDE

1-Bromo-3-Chloro propaneDi methyl amineTolueneSodium HydroxideHydrochloric AcidPotassium hydroxideSodium sulfate.


Phenyl acetic acidPthalic anhydrideSodium acetate tri hydrateMethanolRaney NickelSodium Hydroxide SolutionHydrochloric acid SolutionTolueneHydrogen gasPhosphoric acidO-XylenePhosphorous penta oxide


Stage-2Stage-1Magnesium Ethyl BromideAmmonium ChlorideSodium Hydroxide (10%)Dil Hydrochloric Acid Tetra hydra furanTolueneMethanol


Stage-2Hydrochloric AcidActivated CarbonAcetoneTolueneIPA IPA HCl

IPA RecoveryAcetone RecoveryEffluent water

Stage-4



Material Balance

Material Balance of Cyclobenzaprine Hydrochloride Stage-1

BatchSize:200 Kg Name of the input Quantity


in Kg 1-Bromo-3-Chloro propane 123.00 Stage-1 90.00 Di methyl amine 35.20 Toluene Recovery 232.00 Toluene 250.00 Toluene Loss 12.00 Sodium Hydroxide 31.25 Effluent Water 600.34 Hydrochloric Acid 10.00 (water-500, Generated water-

14.02 ,Sodium Bromide-80.32, potassium hydroxide- 5, Toluene-1)

Potassium hydroxide 5.00 Inorganic solid waste 5.00 Sodium sulfate. 5.00 (Sodium sulfate) Water 500.00 Organic Residue 20.11 (Process residue-15.11,

Distillation residue -5 (Toluene-5)


Material balance of Cyclobenzaprine Hydrochloride Stage-2



in Kg Phenyl acetic acid 71.00 Stage-2 90.00

Pthalic anhydride 77.20 Methanol recovery 475.00

Sodium acetate tri hydrate 10.00 Methanol Loss 15.00

Methanol 500.00 Toluene recovery 475.00

Raney Nickel 5.00 Toluene Loss 10.00

Sodium Hydroxide Solution 100.00 O-Xylene Recovery 475.00

Hydrochloric acid Solution 50.00 O-Xylene Loss 25.00

Toluene 500.00 Raney Nickel Recovery 5.00

Hydrogen gas 1.00 Effluent water 875.69



Phosphoric acid 50.00 (Water-600,Generated water-17.69,Toluene-8,Sodium hydroxide Solution-100,HydroChloroc acid-50,Phosphaorous pentoxide-50,Phosphoric acid-50)

0

O-Xylene 500.00 Process emission 22.93

Phosphorous penta oxide 50.00 (Carbon dioxide-22.93) 0

Water 600.00 Organic residue 45.58

Process residue -28.58 Distillation residue-17 (Methanol-10,Toluene-7)

Total 2514.20 Total 2514.20


BatchSize:200 Kg Name of the input Quantity


in Kg Stage-2 150.00 Stage-2 200.00 Stage-1 90.00 Toluene Recovery 104.00 Magnesium 18.00 Toluene Loss 6.00 Ethyl Bromide 1.00 Methanol Recovery 187.00 Ammonium Chloride 40.00 Methanol Loss 10.00 Sodium Hydroxide (10%) 100.00 THF Recovery 283.00 Dil Hydrochloric Acid 9.00 THF Loss 15.00 Tetra hydra furan 300.00 Effluent Water 973.64 Toluene 120.00 (water-800,Magnesium Chloride-

69.24, Sodium chloride-14.4, water from NaOH-90)

0

Methanol 200.00 Process Emission 12.38 Water 800.00 (Ammonia-12.38) 0 Organic Residue 36.98 Process residue-21.98

Distillation residue-15 (Toluene-10,Methanol-3,THF-2)

Total 1828.00 Total 1828.00




BatchSize:200Kg Name of the input Quantity


in Kg Stage-2 200.00 Cyclobenzaprine Hydrochloride 200.00 Hydrochloric Acid 25.00 Toluene Recovery 698.00 Activated Carbon 20.00 Toluene Loss 37.00 Acetone 250.00 Acetone Recovery 237.00 Toluene 750.00 Acetone Loss 12.00 IPA 1200.00 IPA Recovery 1152.00 IPA HCl 10.00 IPA Loss 58.00 Water 800.00 Effluent Water 823.28 (Water-800,generated water-

18.28, Toluene-5)

Spent Carbon 20.00 Organic Residue 17.72 Process residue-6.72

Distillation residue -11 (Toluene-10,Acetone-1)

Total 3255.00 Total 3255.00

CYPROHEPTADINE HYDROCHLORIDE Process Description:

Stage-1:

Step-A:

Phenyl acetic acid reacts with Pthalic anhydride in prrsence of Methanol and sodium acetate to give stage-A product.

Step-B:

Stage-A Product reacts with Hydrogen in presence of sodium hydroxide and rabey-nickel to give Step-B Product.

Step-C:

Step-B product undergoes cyclisation in presence of Xylene, P2O5 and Phosphoric acid to give Stage-1 Product.

Stage-2:

Stage-1 Product undergoes Hydrogenation with hydrogen in presence of Methanol and Raney Nickel to give Stage-2 Product.



Stage-3:

Stage-2 Product undergoes Chlorination with Thionyl chloride in presence of Toluene, Chloform and Sodium Hydroxide to give stage-3 Product.

Stage-4:

Stage-3 product reacts with N-methyl-4-Chloro Piperidine in presnec of Magnesium, THF, Methanol, Toluene and Ammonia to give Staeg-4 product.

Stage-5:

Stage-4 product undergoes Dehydration in presence of Hydrochloric acid, Toluene,

IPA and water to give Cyproheptadine Hydrochloride

Route of Synthesis:

Stage-1

Step-A:

COOH

Phenyl-acetic acidC8H8O2136.15

+

O

O

OPhthalic anhydride

C8H4O3

148.12

O

O3-Benzylidene-3H-


222.24

+ H2O18.02

+ CO2

44.01



Step-B:

O

O3-Benzylidene-3H-


222.24

OH

O2-Styryl-benzoic acid

C15H12O2

224.25

+ H2

2.02

NaOH solution,HCl solution,Raney nickel

Step-C:

OH

O

2-Styryl-benzoic acidC15H12O2

224.25

O


206.24

P2O5,H3PO4

+ H2O

18.02Xylene

Stage-2:

N-Methyl4-piperidone

N

O

CH3

C6H11NO

113.16

+ H2

2.02

Methanol

N-Methyl 4-Hydroxy piperidine

N

OH

CH3

C6H13NO

115.17



Stage-3:

SOCl2+ + NaOH+ SO2NaCl +

N-Methyl-4-Hydroxy piperidine

N-Methyl-4-chloro piperidine

Na2CO3

TolueneChloroform

N

OH

CH3

C6H13NO

115.17

40.0118.97

N

Cl

CH3

C6H12ClN

133.62

58.564.06

+

18.0

H2O

Stage-4:

O


206.24

++ Mg + NH4Cl

24.31 53.49

+ MgCl2 + NH3

95.21 17.03

THF/Methanol

OH

C21H23NO305.41

N-Methyl-4-Chloro Piperidine

N

Cl

CH3

C6H12ClN

133.62

N

5-(1-Methyl-piperidin-4-yl)-5H-dibenzo[a,d]cyclohepten-5-ol



Stage-5:

Step-A:

OH

C21H23NO

305.41

N

5-(1-Methyl-piperidin-4-yl)-5H-dibenzo[a,d]cyclohepten-5-ol

+ HCl + 1 1/2H2O N

4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-methylpiperidine hydrochloride

Sesquihydrate

H

Cl

1 1/2H2O

36.46 27.0

C21H21N·HCl·1.5H2O350.86

+ H2O

18.02

Step-B:

N

4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-methylpiperidine hydrochloride

Sesquihydrate

H

Cl

1 1/2H2O

C21H21N·HCl·1.5H2O

350.86

N

Cyproheptadine HClsesquihydrate

H

Cl

1 1/2H2O

C21H21N·HCl·1.5H2O

350.86

IPA HCl



Flowchart:

Stage-1

Stage-2

Stage-3

Phenyl acetic acidPthalic anhydrideSodium acetate tri hydrateMethanolRaney NickelSodium Hydroxide SolutionHydrochloric acid SolutionTolueneHydrogen gasPhosphoric acidO-XylenePhosphorous penta oxide

Toluene recoveryMethanol recoveryEffluent water

N -Methyl-4-PiperidoneHydrogen Methanol

Methanol recoveryEffluent water

Stage-2Thionyl chlorideSodium HydroxideSodium bicarbonateToluene Chloroform

Toluene RecoveryChloroform RecoveryEffluent Water

Stage-1MagnesiumLithium bromideN-methyl-4-Chloro piperidineEthyl bromideAmmonium ChlorideTetrahydrafuranMethanolToluene


Stage-4IPAHCl(30%)

IPA RecoveryEffluent water

Stage-4

Stage-5

CYPROHEPTADINE HYDROCHLORIDE



Material Balance:

Material balance of Cyproheptadine Hydrochloride Stage-1



in Kg Phenyl acetic acid 260.00 Stage-1 332.00 Pthalic anhydride 283.00 Methanol recovery 475.00 Sodium acetate tri hydrate 10.00 Methanol Loss 15.00 Methanol 500.00 Toluene recovery 475.00 Raney Nickel 5.00 Toluene Loss 10.00 Sodium Hydroxide Solution 100.00 O-Xylene Recovery 475.00 Hydrochloric acid Solution 50.00 O-Xylene Loss 25.00 Toluene 500.00 Raney Nickel Recovery 5.00 Hydrogen gas 4.00 Effluent water 922.82 Phosphoric acid 50.00 (Water-600,Generated

water-64.82,Toluene-8,Sodium hydroxide Solution-100,HydroChloroc acid-50,Phosphaorous pentoxide-50,Phosphoric acid-50)

0

O-Xylene 500.00 Process emission 84.00 Phosphorous penta oxide 50.00 (Carbon dioxide-84) 0 Water 600.00 Organic residue 93.18 Process residue -76.18

Distillation residue-17 (Methanol-10,Toluene-7)

Total 2912 Total 2912.00



Material Balance of Cyproheptadine Hydrochloride Stage-2



in Kg N –Methyl-4-Piperidone 205.00 Stage-2 200.00 Hydrogen 4.00 Methanol Recovery 570.00 Methanol 600.00 Methanol Loss 12.00 Water 800.00 Effluent Water 800.00 (Water-800) 0 Organic residue 27.00 Process residue-9


Total 1609.00 Total 1609.00




in Kg Stage-2 200.00 Stage-3 216.00 Thionyl chloride 207.00 Toluene Recovery 570.00 Sodium Hydroxide 70.00 Toluene Loss 12.00 Sodium bicarbonate 20.00 Chloroform Recovery 475.00 Toluene 600.00 Chloroform Loss 25.00 Chloroform 500.00 Effluent Water 963.26 Water 800.00 (Water-800,Sodium chloride-

102,Generated water-31.26,Toluene-10,Sodium bicarbonate-20)

0

Process emission 111.24 (Sulphur dioxide-111.24) 0 Organic residue 24.50 Process residue-16.5


Total 2397.00 Total 2397.00






in Kg Stage-1 332.00 Stage-4 462.00 Magnesium 40.00 THF Recovery 331.00 Lithium bromide 5.00 THF Loss 17.00 N-methyl-4-Chloro piperidine 216.00 Methanol Recovery 190.00 Ethyl bromide 1.00 Methanol Loss 10.00 Ammonium Chloride 87.00 Toluene Recovery 774.00 Tetrahydrafuran 350.00 Toluene Loss 40.00 Methanol 200.00 Effluent Water 1662.26 Toluene 820.00 (Water-1500,Magnesium

Chloride-153.26,Lithium Bromide-5,Ethyl Bromide-1,Toluene-3)

0

Water 1500.00 Process Emission 27.41 (Ammonia-27.41) Organic Residue 37.33 Process residue-33.33

Distillation residue-4 ( Toluene-2,THF-2)

Total 3551.00 Total 3551.00




in Kg Stage-4 462.00 Cyproheptadine Hydrochloride 500.00 IPAHCl(30%) 786.00 IPA Recovery 570.00 Water 800.00 IPA Loss 12.00 Effluent Water 916.26 (Water-759,generated water-

27.26,water from HCl-130) 0


Distillation residue- (IPA-18)

Total 2048.00 Total 2048.00



DESLORATADINE


Stage-1

3-[2-(3-chlorophenyl)-ethyl] pyridine-2-carbonitrile reacts with Potassium hydroxide, Hydrochloric acid in presence of n-Butanol to give Stage-1 product.

Stage-2

Staeg-1 product undergoes cyclisation with Phosphorous penta chloride to give Stage-2 product.

Stage-3

Stage-2 product reacts with 4-Chloro-1-methyl piperdine, Magnesium, Hydrochloric acid in the presence of THF to give Stage-3 product.

Stage-4

Stage-3 Product undergoes dehydaration with Sulfuric acid and Sodium Hydroxide in presence of Ethyl acetate and n-Hexane to give Stage-4 product.

Stage-5

Stage-4 product reacts with ethyl chloro formate in the presence of Toluene and Cyclo hexane to give Stage-5 product.

Stage-6

Stage-5 product reacts with Sodium hydroxide, Hydrochloric acid in the presence of Methanol to give Desloratadine .



DESLORATADINE

Route of Synthesis:

Stage-1:

N CN

Cl

3-[2-(3-Chlorophenyl)-ethyl]-pyridine-2-carbonitrile

C14H11ClN2

242.70

+ KOH

56.11

+ H2O

18.0

+2HCl

N COOH

Cl

3-[2-(3-Chloro-phenyl)-ethyl]-pyridine-2-carboxylic acid

C14H12ClNO2

261.70

+ KCl

74.55

+ NH4Cl

53.49

72.00

Stage-2:

N COOH

Cl

3-[2-(3-Chloro-phenyl)-ethyl]-pyridine-2-carboxylic acid

C14H12ClNO2

261.70

PCl5 N

Cl

O+ H2O

8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one

C14H10ClNO

243.69

18.0



Stage-3:

N

Cl

O8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one

C14H10ClNO

243.69

+

4-Chloro-1-methyl-piperidine

N Cl

C6H12ClN

133.62

+ Mg

Magnesium

24.31

+ HCl

Hydrochloric acid36.5

N

Cl

N

CH3

OH

THF

8-Chloro-11(1-methyl-piperidine-4-yl)-6,11-dihydro-5H-benzo[5,6]cyclohepta

[1,2-b]pyriidn-11-olC20H23ClN2O

342.86

+ MgCl2

95.21



Stage-4:

N

Cl

N

CH3

OH


[1,2-b]pyriidn-11-olC20H23ClN2O

342.86

H2SO4

N

Cl

N

CH3


[1,2-b]pyridine

C20H21ClN2

324.85

+ 3 H2O

54.06

[N-Methyl Desloratadine]

+ + 2 NaOH

98.08 80.00

Ethyl acetate

n-Hexane

Na2SO4

142.04

+



Stage-5:

N

Cl

N

CH3

8-Chloro-11(1-methyl-piperidine-4-yl)-6,11-dihydro-5H-benzo

[5,6]cyclohepta[1,2-b]pyridine

C20H21ClN2

+

[N-Methyl Desloratadine]

Ethyl chloroformateC3H5ClO2

108.52

Toluene

N

Cl

N

COOC2H5

4-(8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)

-piperidine-1-carboxylic acid ethyl ester

C22H23ClN2O2

382.88

+ CH3Cl

50.49

O

O Cl

Chlormethane324.85

Stage-6:

N

Cl

N

COOC2H54-(8-Chloro-5,6-dihydro-benzo[5,6]

cyclohepta[1,2-b]pyridin-11-ylidene)-piperidine-1-carboxylic acid ethyl ester

C22H23ClN2O2

382.88

+ NaOH

40.0

+ HCl

36.46

10 % Aq.MeOH

N

Cl

N

H

+ C2H5OH

46.07

+ NaCl

58.5

+ CO2

44.0

Desloratadine

C19H19ClN2

310.82



Flow Chart:

3-[2-(3-Chloro phenyl)-ethyl]-pyridine-2-carbonitrilePotassium hydroxideHydrochloric acid

Stage-1 Ammonium chloride

Stage-2 DCM RecStage-1Phosphorous pentachlorideDCM

Stage-3 THF RecStage-24-Chloro-1-methyl-piperidineTHF

Stage-4 Generated waterStage-3Sulfuric acid

Stage-5 Toluene RecStage-4Ethyl chloroformateToluene

Stage-6 Methanol RecStage-5Sodium hydroxideMethanol

DESLORATADINE



Material Balance

Material Balance of Desloratadine Stage-1



in Kg 3-[2-(3-Chlorophenyl)-ethyl]-pyridine-2-carbonitrile 296.00 Stage-1 287.00

Potassium hydroxide 68.50 n-Butanol Recovery 90.00 n-Butanol 100.00 n-Butanol Loss 10.00 Hydrochloric acid 87.50 Effluent water 634.09 Water 500.00 (Water-478.10, Potassium

chloride-90.87, Ammonium chloride-65.12)

Organic Residue 30.91 Process residue -30.91 Total 1052.00 Total 1052.00




in Kg Stage-1 287.00 Stage-2 240.00 Methylene dichloride 200.00 Methylene dichloride Recovery 190.00 Phosphorous Pentachloride 228.00 Methylene dichloride Loss 10.00 Hydrochloric acid 30.00 Ethyl acetate Recovery 475.00 Ethyl acetate 500.00 Ethyl acetate Loss 10.00 Activated carbon 5.00 n-Hexane Recovery 90.00 Hyflow 5.00 n-Hexane Loss 5.00 n-Hexane 100.00 Spent carbon & Hyflow Recovery 10.00 Water 300.00 Effluent water 585.50

(Water-300, Generated water-19.50, Hydrochloric acid-30, Ethyl acetate-8, Phosphorous Pentachloride -228)

0


Process residue -27.50

Distillatiojn residue-12 (n-Hecxane-5, Ethyl acetate-7)

Total 1655.00 Total 1655.00 Material Balance of Desloratadine

Stage-3 Batch Size: 200.00Kg





Stage-2 240.00 Stage-3 304.00 4-chloro-1-methyl-piperidine 131.50 Tetrahydrofuran Recovery 475.00 Tetrahydrofuran 500.00 Tetrahydrofuran Loss 15.00 Magnesium metal 23.75 EthyleneDiBromide Recovery 90.00 EthyleneDiBromide 100.00 EthyleneDiBromide Loss 10.00 Ethyl acetate 500.00 Ethyl acetate Recovery 475.00 n-Hexane 100.00 Ethyl acetate Loss 10.00 Acetonitrile 150.00 Acetonitrile Recovery 143.00 Isopropyl alcohol 100.00 Acetonitrile Loss 7.00 Hydrochloric acid 35.75 Isopropyl alcohol Recovery 95.00 Water 500.00 Isopropyl alcohol Loss 5.00 n-Hexane Recovery 90.00 n-Hexane Loss 3.00 Effluent water 613.60

(Water-500,Magnesium chloride

-93.60,THF-10, Ethyl acetate-8, n-Hexane-2)



Distillation residue-12 (n-Hexane-5, Ethyl acetate-7)

Total 2381.00 Total 2381.00




in Kg Stage-3 304.00 Stage-4 259.00 Sulphuric acid 88.00 Ethyl acetate Recovery 475.00 Ethyl acetate 500.00 Ethyl acetate Loss 10.00 Sodium hydroxide 70.85 n-Hexane Recovery 475.00 n-Hexane 500.00 n-Hexane Loss 25.00 Hyflow 5.00 Effluent water 678.57

Activated carbon 2.00 (Water-500, generated water-47.72, Sodium sulfate-125.85,Ethyl acetate-5

0

Water 500.00 Spent carbon & Hyflow Recovery 7.00 Organic Residue 40.28


Distillation residue (Ethyl acetate-10)

Total 1969.85 Total 1969.85






in Kg Stage-4 259.00 Stage-5 274.00 Triethyl amine 80.00 Toluene Recovery 475.00 Ethyl chloro formate 86.50 Toluene Loss 10.00 Cyclo hexane 400.00 Cyclohexane Recovery 380.00 Toluene 500.00 Cyclohexane Loss 20.00 Water 400.00 Effluent water 488.00 (Water-400, Triethylamine-80,

,Toluene-8)

Process emission 40.14 (Chloro Methane-40.14) Organic Residue 38.36


Distillation residue – 7 (Toluene-7)

Total 1725.50 Total 1725.50




in Kg Stage-5 274.00 Desloratadine 200.00

Sodium hydroxide flakes 28.50 Methanol Recovery+ ethanol-32.88

270.88

Methanol 250.00 Methanol Loss 12.00 Toluene 300.00 Toluene Recovery 285.00 Cyclo hexane 400.00 Toluene Loss 10.00 Activated carbon 3.00 Cyclo hexane Recovery 380.00 Hydrochloric acid 26.00 Cyclo hexane Loss 20.00 Water 500.00 Effluent water 544.64

(Water-500,Toluene-3,Sodium Chloride-41.64)

0

Process Emissions 31.23 (Carbon dioxide-31.23) 0 Spent carbon 3.00 Organic Residue 24.75


Distillation residue- (Toluene-2)

Total 1781.50 Total 1781.50



DOMPERIDONE MALEATE

Process Description: Stage-1 5-Chloro-1-{1-[3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propyl]-piperidin-4-yl}-

1,3-dihydro-benzoimidazol-2-one(Domeperidone) Product reacts with Maleic

acid Product in presence of Methanol to give Domperidone Maleate

Route of synthesis: Stage-1:

NH

N ON

NH

N

O

Cl

425.91

(Domperidone)C22H24ClN5O2

Maleic acid

O

OH

O

OH

C4H4O4

116.07

+

5-Chloro-1-{1-[3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propyl]-piperidin-4-yl}-1,3-

dihydro-benzoimidazol-2-one

NH

NO

NNH

N

O

Cl

O

OH

O

OH

Domperidone Maleate

C26H28ClN5O6

541.98

Methanol



Flowchart:

Stage-10 Methanol Recovery

5-Chloro-1-{1-[3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one(Domeperidone)Maleic acidMethanol

DOMPERIDONE MALEATE

Material Balance:

Material balance of Domperidone Maleate

Stage-1 Batch Size:500Kg



5-Chloro-1-{1-[3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one(Domeperidone)

400.00 Domperidone Maleate 500.00

Maleic acid 110.00 Methanol Recovery 475.00 Methanol 500.00 Methanol Loss 15.00 Organic residue 20.00 Process residue-10

Distillation residue-10 (Methanol)

Total 1010.00 Total 1010.00

DOMPERIDONE Process description Stage-1 Methyl acrylate reacts with Methylamie in presence fo Methanol to give Stage-1

product

Stage-2 Step-A Stage-1 product reacts with Sodium methoxide in presence of water and

Chloroform to give Step-A product



Step-B Step-A product undergoes Hydrolysis with water in presence of Chloroform to

give Stage-2 Product

Stage-3 Stage-2 product reacts with Ethylchkloroformate in presence of Toluene to give

Stage-3 product

Stage-4 Step-A Stage-3 product undergoes Hydrogenation with Hydrogen gas in presence of

Raney Nickel and Methanol to give Step-A product

Step-B

Step-A product undergoes Amination with Ammonium and Sulphuric acid in

presence of Methanol to give Stage-4 product .

Stage-5 Stage-4 product undergoes Condensation with 1, 4-Dichloro-2-nitrobenzene in

presence of Water and Soda Ash to give Stgae-5 product

Stage-6 Stage-5 product undergoes Hydrogenation with Hydrogen in presence of Raney

Nickel and Methanol to give Stage-6 product

Stage-7 Step-A Stage-6 product reacts with Urea in presence of Water and Ammonium

hydroxide to give Step-A product

Step-B Step-A product undergoes Hydrolysis with Water and Soduium hydroxide in

presence of Water to give Stage-7 product

Stage-8 Orthophenylene diamie reacts with Methylacetoacetate in presence of O-

Xylene , Sodium hydroxide and water to give Stage-8 product

Stage-9 Stage-8 product reacts with 1-Bromo-3-Chloro-propane in presence of Sodium

hydroxide , TBAB & Water to give Stage-9 product



Stage-10 Stage-9 product reacts with Hydrochloric acid in presence of Methanol to give

Stage-10 product

Stage-11 Stage-7 product condensed with Stage-10 product in presence of Ammonium

hydroxide and MIBK to give Domperidone product

Route of synthesis: Stage-1

Methyl acrylateC4H6O2

2X86.09=172.18

CH3

NH2+

Methylamine31.06

CH3N

OO

CH3

OO

CH33-[(2-Methoxycarbonyl-ethyl)-methyl-amino]-

propionic acid methyl esterC9H17NO4

203.24

Methanol

OO

2

Stage-2 Step-A

CH3N

OO

CH3

OO

CH33-[(2-Methoxycarbonyl-ethyl)-methyl-

amino]-propionic acid methyl esterC9H17NO4

203.24

CH3N

OO

CH3

OCH3

O Na

Sodium 4-methoxy-3-(methoxycarbonyl)-1-methylpiperidin-

4-olateC9H16NNaO4

225.22

Sodium methoxide

CH3ONa+

54.02

+ CH3OH

32.04

Chloroform& water



Step-B:

CH3 N

OO

CH3

OCH3

ONa

Sodium 4-methoxy-3-(methoxycarbonyl)-1-methylpiperidin-

4-olateC9H16NNaO4

225.22

N

O

CH3

N-Methyl-piperidin-4-one

Chloroform

C6H11NO113.16

+ CH3COONa+

82.03

+ CH3OH

32.04

H2O

18.0

+ 1/2 O2

16.0

Distillation

Stage-3:

N-Methyl4-piperidoneC6H11NO

+Toluene

Ethyl chloroformate

O

O Cl

C3H5ClO2

108.52

N

O

O O CH3

4-Oxo-piperidine-1-carboxylic acid

ethyl esterC8H13NO3

171.19

N

O

CH3

113.16

CH3Cl+

50.49



Stage-4: Step-A

N

O

O O CH3

4-Oxo-piperidine-1-carboxylic acid

ethyl esterC8H13NO3

171.19

+ H2

C8H15NO3

173.21

2.02

Raney Nickel &Methanol

N

OH

O O CH3

4-Hydroxy-piperidine-1-carboxylic acid

ethyl ester

Step-B

C8H15NO3

173.21

Methanol

N

OH

O O CH3

4-Hydroxy-piperidine-1-carboxylic acid

ethyl ester

+ 3 NH3

51.09

N

NH2

O O CH3

4-Amino-piperidine-1-carboxylic acid

ethyl esterC8H16N2O2

172.22

+ H2O

18.02

+ H2SO4

98.08

+ (NH4)2SO4

132.14



Stage-5

+

Cl

Cl

NO2

C6H3Cl2NO2

192.00

4-(4-Chloro-2-nitro-phenylamino)-piperidine-1-carboxylic acid ethyl ester

+

C14H18ClN3O4

327.76

Soda AshWater

1,4-Dichloro-2-nitro-benzene

N

NH2

O O CH3

4-Amino-piperidine-1-carboxylic acid

ethyl ester

C8H16N2O2

172.22

N

NH

O O CH3

Cl

O2N

HCl

36.46

Stage-6

4-(4-Chloro-2-nitro-phenylamino)-piperidine-1-carboxylic acid ethyl ester

+

C14H18ClN3O4

327.76

H2

2.02

+

32.00

N

NH

O O CH3

Cl

O2N

O2

Raney NickelMethanol N

NH

O O CH3

Cl

H2N

4-(2-Amino-4-chloro-phenylamino)-piperidine-1-carboxylic acid ethyl ester

C14H20ClN3O2

297.78



Stage-7

Step-A

+

N

NH

O O CH3

Cl

H2N

4-(2-Amino-4-chloro-phenylamino)-piperidine-1-carboxylic acid ethyl ester

C14H20ClN3O2

297.78

Urea

NH2

OH2N

+

CH4N2O

60.06

NH4OH

35.05

+ HCl

36.46

Activated carbon Water

NO

O

CH3

NHN

O

C15H18ClN3O3

323.77

+ NH4Cl

53.49

+ H2O

18.02

+

34.06

2 NH3Cl4-(5-Chloro-2-oxo-2,3-dihydro-benzoimidazol-1

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



Step-B:

C15H18ClN3O3

323.77

4-(5-Chloro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid ethyl ester

Cl

N

HN O

N

O

O+ NaOH

40.00 5-Chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one

+ C2H5ONa

68.05

+ CO2

44.00

C12H14ClN3O251.71

NH

N

O

HN

Cl

Stage-8:

NH2

NH2

ortho phenylene di amine

C6H8N2

108.14

+H3C

O

O

CH3

O

Methyl aceto acetate

C5H8O3

116.12

NH

N

H3CCH2

O

1-Isopropenyl-1,3-dihydro-benzoimidazol-2-one

C10H10N2O

174.2

+ CO2

44.0

3 H2

6.0

O-XyleneWater

+ NaOH

40.00

+ HCl

36.46

NaCl

58.44

+ H2O

18.02

+ +



Stage-9

NH

N

H3CCH2

O

1-Isopropenyl-1,3-dihydro-benzoimidazol-2-one

C10H10N2O174.2

+ Br Cl

1-Bromo-3-chloro-propane157.44

N

N

H3CCH2

O

Cl1-(3-Chloro-propyl)-3-isopropenyl-1,3-dihydro-benzoimidazol-2-one

C13H15ClN2O

250.72

+ NaBr

102.89

TBAB,WATER+ NaOH

40.00

+ H2O

18.02

Stage-10

N

N

H3CCH2

O

Cl

1-(3-Chloro-propyl)-3-isopropenyl-1,3-dihydro-benzoimidazol-2-one

C13H15ClN2O250.72

N

HN

O

Cl

1-(3-Chloro-propyl)-1,3-dihydro-benzoimidazol-2-one

C10H11ClN2O

210.66

+ Methanol HCl

36.5

H3CCH2

Cl2-Chloro-propene

C3H5Cl

76.52

+



Stage-11

NH

N

HNCl

O

5-Chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one

C12H14ClN3O

251.71

+

1-(3-chloropropyl)-1,3-dihydro -2H-(Benzimidazole-2-one)

N

HN

O

Cl

C10H11ClN2O

210.66

+

+ NH4Cl

53.49

+

18.02

35.05

Ammonium chloride ,MIBK, Sodium hydroxide

& WaterNH4OH

H2ONHN

O

N

NHN

O

Cl

DomperidoneC22H24ClN5O2

425.91



Flow chart:

Methyl acrylate Mono methyl amine Methanol

Methanol lossOrganic residue

Stage -1Sodium methoxide Chloroform Water

Chloroform recovery Effluent water

Stage -2Ethylchloroformate Toluene

Toluene recovery

Stage -3Methanol Ammonia Sulphuric acid Raney Nickel Hydrogen

Generated water Methanol recovery

Stage -41,4-Dichloro-2-nitro-benzene (DCNB)Soda ash Water

Effluent water

Stage -5Methanol Raney nickel Hydrogen Toluene Water

Methanol recoveryToluene recovery

Stage-6Urea Ammonium hydroxide Hydrochloric acid Activated carbon Sodium hydroxideWater

Effluent water

Stage-1

Stage-2

Stage-3

Stage-4

Stage-5

Stage-6

Stage-7



Ortho phenylene diamine(OPDA)Methyl Aceto Acetate (MAA)Sodium hydroxide Hydrochloric acid (10%)O-XyleneWater

O -xylene recoveryeffluent waterStage-8

Stage-9

Stage-10

Stage-11

Stage-81-Bromo-3- chloro -propaneSodium hydroxideTBABWater

Effluent water

Stage-9Hydrochloric acid (12%)Methanol Water


Stage -7Stage-10Methyl iso butyl ketoneAmmonium hydroxide (30%)Sodium hydroxide Ammonium chloride Water

Effluent water

Domperidone

Material Balance:

Material Balance of Domperidone Stage-1

Batch Size: 840Kg Name of the input Quantity

in Kg Name of the output Quantity

in Kg Methyl acrylate 411.00 Stage -1 483.00 Mono methyl amine 76.00 Methanol loss 100.00 Methanol 100.00 Organic residue 4.00 Total 587 Total 587






in Kg Stage -1 483.00 Stage -2 211.00 Sodium methoxide 169.00 Chloroform recovery 6745.00 Chloroform 7100.00 Chloroform loss 355.00 Water 4830.00 Effluent water

(Water-4787) 4787.00

By products (Sodium acetate -195, Methanol-250.98)

445.98

Process emission (Oxygen)

38.02

Total 12582 Total 12582




in Kg Stage -2 211.00 Stage -3 275.00 Ethylchloroformate 259.25 Toluene recovery 1074.00 Toluene 1130.00 Toluene loss 56.00 Process emission

(Chloromethane) 94.14

Organic residue 101.11 Total 1600.25 Total 1600.25




in Kg Stage -3 275.00 Stage -4 258.00 Methanol 250.00 Spent raney nickel

recovery 5.00

Ammonia 56.20 By product (Ammonia sulphate)

95.00

Sulphuric acid 70.20 Generated water 29.00 Raney Nickel 5.00 Methanol recovery 238.00 Hydrogen 4.00 Methanol loss 12.00 Organic residue 23.40 Total 660.4 Total 660.4






in Kg Stage -4 258.00 Stage -5 544.00 1,4-Dichloro-2-nitro-benzene (DCNB)

310.00 Effluent water (Water-2300 Soda ash -103.5)

2403.50

Soda ash 103.50 Process emission (Hydrogen Chloride)

24.00

Water 2300.00 Total 2971.5 Total 2971.5




in Kg Stage -5 544.00 Stage-6 389.00 Methanol 820.00 Methanol recovery 779.00 Raney nickel 5.00 Methanol loss 17.00 Hydrogen 4.00 Toluene recovery 494.00 Toluene 520.00 Toluene loss 10.00 Water 300.00 Effluent water

(Water-300, Toluene-16) 316.00

Raney nickel recovery 5.00 Process emission

(Oxygen) 53.11

Organic residue Process residue-105.89 Distillation Residue-24 (Methanol-24)

129.89







in Kg Stage-6 389.00 Stage-7 550.00 Urea 138.00 Effluent water

(Water-2000, Generated Water-23.54 Sodium acetate-88.89)

2112.43

Ammonium hydroxide 444.00 By-product (Ammonium chloride- 565.50 )

565.50

Hydrochloric acid 306.00 Process emission (Ammonia-44.60, Carbon dioxide-57.47)

102.07

Activated carbon 35.00 Spent carbon 35.00 Sodium hydroxide 53.00 Water 2000.00 Total 3365 Total 3365



in Kg Name of the output Quantity in

Kg Ortho phenylene diamine(OPDA)

344.00 Stage-8 516.00

Methyl Aceto Acetate (MAA) 386.00 O –xylene recovery 2869.00 Sodium hydroxide 413.00 O –xylene loss 151.00 Hydrochloric acid (10%) 1270.00 Effluent water

(Water-5300, Generated Water-58, Water from hydrochloric acid -1143,excess sodium hydroxide-235, Sodium chloride-302)

7038.00

O-Xylene 3020.00 Process emission (Hydrogen-19.06, Carbon dioxide-139.94)

159.00

Water 5300.00 Total 10733 Total 10733



Material Balance of Domperidone Stage-9 Batch Size: 840Kg


Name of the output Quantity in Kg

Stage-8 516.00 Stage-9 608.00 1-Bromo-3- chloro -propane 471.00 Effluent water

(Water-3440 , Generated Water-54, TBAB-42)

3536.00

Sodium hydroxide 291.00 By-product (Sodium bromide )

604.00

TBAB 42.00 Organic residue 12.00 Water 3440.00 Total 4760 Total 4760




Stage-9 608.00 Stage-10 462.00 Hydrochloric acid (12%) 730.00 Methanol Recovery 475.00 Methanol 500.00 Methanol loss 25.00 Water 2645.00 Effluent water

(Water-2645,2-chloro propene- 186, water from Hydrochloric acid-642 )

3473.00

Organic residue 48.00 Total 4483 Total 4483




Stage -7 550.00 Domperidone 840.00 Stage-10 462.00 Effluent water

(Water-5000, Methyl iso butyl ketone-200, Sodium hydroxide-2000, Generated water-40, Water from Ammonium hydroxide 420)

7660.00

Methyl iso butyl ketone 200.00 By product (Ammonium chloride-1017)

1017.00

Ammonium hydroxide (30%) 600.00 Organic residue 195.00 Sodium hydroxide 2000.00 Ammonium chloride 900.00 Water 5000.00 Total 9712 Total 9712



DONEPEZIL HYDROCHLORIDE


Stage-1:

5,6 Dimethoxy-2-(Piperidin-4-yl) methyl)Indan-1-one reacts with Chloromethyl

Benzene in presence of Sodium bicarbonate , Iso propyl alcohol, Tetra butyl

ammonium bromide,Toluene, Methanol, IPA-HCl, Sodium hydroxide (NaOH),Con

HCl, Carbon and Water to give Stage–1 product

Stage-2:

Stage-1 product undergoes purification with Methylene dichloride, Acetone and

Carbon to give Donepezil HCl.

Route of Synthesis

Stage-1:

5,6-dimethoxy-2-(piperidin-4-yl-methyl)indan-1-one

O

O

NH

O

Cl

(chloromethyl)benzene

O

O

N

O

+

Methanol

TBAB/Toluene

C17H23NO3

289.37

C7H7Cl126.58

C24H29NO3

379.49

2-(1-Benzyl-piperidin-4-ylmethyl)-5,6-dimethoxy-indan-1-one

+ HCl

36.46



Stage-2:

O

O

N

O

C24H29NO3

379.49

2-(1-Benzyl-piperidin-4-ylmethyl)-5,6-dimethoxy-indan-1-one

+ HCl

36.46

O

O

N

O

HCl

C24H30ClNO3

415.95

MDC/Acetone

DONEPEZIL HCl

Flow Chart

Stage-1

Stage-2

DONEPEZIL HYDROCHLORIDE

5,6 Dimethoxy-2-(Piperidin-4-yl) methyl)Indan-1-one Chloromethyl BenzeneActivated CarbonSodium hydroxideTBABTolueneIsopropyl alcoholMethanol

Toluene RecoveryMethanol RecoveryIsopropyl alcohol RecoveryEffluent water

MDC RecoveryAcetone Recovery

Stage-1Activated CarbonMethylene DichlorideAcetoneHydrochloric Acid



Material Balance

Material Balance of Donepezil Hydrochloride Stage-1

BatchSize:100.00Kg Name of the input Quantity


in Kg 5,6 Dimethoxy-2-(Piperidin-4-yl) methyl)Indan-1-one

87.00 Stage-1 102.00

Chloromethyl Benzene 38.00 Toluene Recovery 285.00 Activated Carbon 10.00 Toluene Loss 10.00 Sodium hydroxide 15.00 Isopropyl alcohol Recovery 333.00 TBAB 2.00 Isopropyl alcohol Loss 18.00 Toluene 300.00 Methanol Recovery 190.00 Isopropyl alcohol 350.00 Methanol Loss 5.00 Methanol 200.00 Effluent Water 505.00 Water 500.00 (Water-500,Toluene-3,TBAB-2) 0.00 Process emission 10.88 (Hydrogen Chloride-10.88) 0 Spent Carbon 10.00 Organic Residue 33.12 (Process residue-17.12,

Distillation residue -16 (Toluene-2, Isopropyl alcohol-9,Methanol-5)

Total 1502.00 Total 1502.00

Material Balance of Donepezil Hydrochloride Stage-2

BatchSize:100.00 Kg Name of the input Quantity


in Kg Stage-1 102.00 Donepezil Hydrochloride 100.00 Activated Carbon 10.00 Methylene Dichloride Recovery 760.00 Methylene Dichloride 800.00 Methylene Dichloride Loss 16.00 Acetone 300.00 Acetone Recovery 285.00 Hydrochloric Acid 9.72 Acetone Loss 10.00 Spent Carbon 10.00 Organic Residue 40.72 Process residue-11.72

Distillation residue-29 (Acetone-5,MDC-24)

Total 1221.72 Total 1221.72



EBASTINE


Stage-1:

4-Benzhydryloxy-piperidine-1-carboxylic acid ethyl ester undergoes Hydrolysis with

Potassium Hydroxide in presence of IPA, Hydrochloric acid and Acetone to give

Stage-1 product.

Stage-2: Stage-1 Product undergoes salt formation with Hydrochloric acid in presence of

Toluene to give Stage-2 product.

Stage-3: Tert-Butyl-benzene reacts with 4-Chloro-Butyryl Chloride in presence of

Dichloromethane ,Aluminium chloride, Ice water and water to give stage-3 Product.

Stage-4:

Stage-3 Product reacts with stage-1 product in presence of Methanol, Toluene and

TBAB to give stage-4 Product.

Stage-5:

Stage-4 Product undergoes Purification in presence of Carbon to give Ebastine.



Route of Synthesis: Stage-1

O

N O

O

CH3

4-Benzhydryloxy-piperidine-1-carboxylic acid ethyl ester

C21H25NO3

339.43

+

KCl

74.55

+ 0.5 O2

16.00

KOH

56.11

+ HCl

36.46

Ethyl formate

O O +

C3H6O2

74.08

O

NH

4-Benzhydryloxy-piperidine

C18H21NO

267.37

+

Chloroform, Isopropylalcohol& Acetone

Stage-2:

+ HCl

36.46

O

NH


C18H21NO

267.37

O

NH

. HCl

303.83

C18H22ClNO

4-Benzhydryloxy-piperidine Hydrochloride



Stage-3

CH3H3C

CH3

tert-Butyl-benzene

C10H14

134.22

+

ClCl

O

4-Chloro-butyryl chlorideC4H6Cl2O

141.0

Dichloromethane, n-Hexane, Ice water & DM water

CH3

H3C

CH3

O

Cl

1-(4-tert-Butyl-phenyl)-4-chloro-butan-1-one

C14H19ClO

238.75

+ 4 HCl

+ AlCl3

133.34

+ Al(OH)3

78.00

+ 3 H2O

54.05

145.84

Stage-4:

CH3

H3C

CH3

O

Cl

1-(4-tert-Butyl-phenyl)-4-chloro-butan-1-one

C14H19ClO

238.75

O

NH


C18H21NO

267.37

+ + 0.5 K2CO3

69.10

Methanol, Toluene ,TBAB, Potassium iodide

O N

O

CH3

CH3

CH3

4-(4-Benzhydryloxy-piperidin-1-yl)-1-(4-tert-butyl-phenyl)-butan-1-one

C32H39NO2

469.66

+ KCl

74.55+ 0.5 CO2

22.00

+ 0.5 H2O

9.01



Stage-5:

O N

O

CH3

CH3

CH3

4-(4-Benzhydryloxy-piperidin-1-yl)-1-(4-tert-butyl-phenyl)-butan-1-one

C32H39NO2

469.66O N

O

CH3

CH3

CH3

EbastineC32H39NO2

469.66

Methanol

Activated Carbon



Flowchart:

Stage-1

Stage-2

4-Benzhydryloxy-piperidine-1-carboxylic acid ethyl esterPotassium HydroxideHydrochloric acidChloroform IPAAcetone

IPA RecoveryAcetone RecoveryEffluent water

Stage-1Hydrochloric acidToluene


Stage-3

Stage-4

Stage-24-Chloro-butyryl chlorideAluminum chlorideDichlorormethanen-Hexane

n-Hexane RecoveryDichloromethane RecoveryEffluent water

Stage-34-Benzyhydroloxy-piperidnePotassium carbonateMethanolTolueneTBABPotassium Iodide


Stage-5

Stage-4Methanol Activated carbonIPA

IPA Recovery

EBASTINE



Material Balance: Material Balance of Ebastine



in Kg 4-Benzhydryloxy-piperidine-1-carboxylic acid ethyl ester 420.00 Stage-1 314.00

Potassium Hydroxide 70.00 Acetone Recovery 385.00 Hydrochloric acid 45.00 Acetone Loss 10.0 Chloroform 400.00 Chloroform Recovery 385.00 IPA 400.00 Chloroform Loss 10.00 Acetone 400.00 IPA Recovery 385.00 Water 400.00 IPA Loss 10.00 Effluent water 584.24 (Water-400,Potassium chloride-

92.24,Ethyl formate-92) 0

Process emission 20.00 (Oxygen-20) 0 Organic residue 31.76 Process residue –16.76

Distillation residue-15 (Acetone-5,Chloroform-5,IPA-5)

Total 2135.00 Total 2135.00

Material Balance of Ebastine Stage-2 Batch Size: 500.00 Kg



Stage-1 314.00 Stage-2 340.00 Hydrochloric acid 43.00 Toluene Recovery 385.00 Toluene 400.00 Toluene Loss 10.0 Water 400.00 Effluent water 403.00 (Water-400,Toluene-3) 0 Organic residue 19.00 Process residue –17


Total 1157.00 Total 1157.00

Material Balance of Ebastine Stage-3 Batch Size: 500.00 Kg



Stage-2 165.00 Stage-3 280.00 4-Chloro-butyryl chloride 173.00 n-Hexane Recovery 385.00 Aluminum chloride 164.00 n-Hexane Loss 10.0



Dichlorormethane 400.00 Dichloromethane Recovery 385.00 n-Hexane 400.00 Dichloromethane Loss 10.00 Water 400.00 Effluent water 429.00 (Water-333,Aluminium

Hydroxide-96) 0

Process emission 179.00 (Hydrogenchloride-179) 0 Organic residue 24.00 Process residue –14

Distillation residue-10 (n-Hexane-5,Dichloromethane-5)

Total 1702 Total 1702.00

Material Balance of Ebastine Stage-4



in Kg Stage-3 280.00 Stage-4 525.00 4-Benzyhydroloxy-piperidne 314.00 Toluene Recovery 385.00 Potassium carbonate 81.00 Toluene Loss 10.00 Methanol 400.00 Methanol Recovery 385.00 Toluene 400.00 Methanol Loss 10.00 TBAB 5.00 Effluent water 515.99 Potassium Iodide 10.00 (Water-400,Generated water-

10.56,Potassium Chloride-87.43,Toluene-3,TBAB-5,Potassium Iodide-10)

0

Water 400.00 Process emission 26.00 (Carbon dioxide-26) 0 Organic residue 33.01 Process residue –26.01


Total 1890.00 Total 1890.00



Material Balance of Ebastine Stage-5



in Kg Stage-4 525.00 Ebastine 500.00 Methanol 400.00 Methanol Recovery 385.00 Activated carbon 5.00 Methanol Loss 10.00 IPA 400.00 IPA Recovery 385.00 IPA Loss 10.00 Spent carbon 5.00 Organic residue 35.00 Process residue –25

Distillation residue-10 (Methanol-5,IPA-5)

Total 1330.00 Total 1330.00



ESOMEPRAZOLE MAGNESIUM TRIHYDRATE Process Description: Stage-1 Omeprazole sulfide reacts with cumin hydro peroxide and magnesium chloride hexa

hydrate in the presence of Toluene to give Esomeprazole Magnesium

Route of Synthesis: Stage-1:

N

OCH3H3C CH3

CH2

SNH

N OCH3

5-Methoxy-2-[(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl Thio]-1H -Benzoimidazole

C17H19N3O2S

2X329.41=658.82

+

H3C OCH3

Cumin hydroperoxide

OH

C9H12O22X152.19=304.38

+ MgCl2. 6H2O

Magnesium chloride Hexahydrate

203.00

Toluene

+OHH3C

CH3

C9H12O

2X136.19=272.38

Cumin hydroxide

2

N

OCH3H3C CH3

CH2

SN

N OCH3O

2

Mg 3H2O

Esomeprazole Magnesium Tri Hydrate

C17H18N3O3S.Mg3H2O

767.15

2 + 2HCl

72.92

+ 3H2O

54.00

Flow Chart:

Stage-1

Omeprazole sulphideToluene D(-)-Diethyl tartrateN,N-DiisopropylethylamineMethanol

Methanol Rec

ESOMEPRAZOLE MAGNESIUM TRIHYDRATE



Material Balance:

Material balance of Esomeprazole Magnesium Trihydrate Stage-1



In Kg

Omeprazole sulphide 90.00 Esomeprazole Magnesium Tri hydrate

100.00

Toluene 400.00 Toluene Recovery 385.00 D(-)-Diethyl tartrate 12.00 Toluene Loss 15.00 Titanium tetra iso propoxide 7.50 Methanol Recovery 285.00 N,N-Di isopropyl ethylamine 5.00 Methanol Loss 15.00 Cumin hydro peroxide 42.00 Dichloromethane Recovery 385.00 Potassium hydroxide 44.00 Dichloromethane Loss 15.00 Methanol 300.00 Ethyl acetate Recovery 385.00 Dichloromethane 400.00 Ethyl acetate Loss 15.00 Acetic acid 15.00 Effluent water 1335.87 Sodium sulfate 10.00 (Water-1200,Generated water-

7.29,Potassium hydroxide-44, Acetic acid-15,Titanium tetra isopropoxide-7.5,N,N-Diisopropylethylamine-5,D(-) Diethyl tartarate-12,Cumin hydroxide-37.17,Hydrochloric acid-7.91)

0

MgCl2 6H2O 27.75 Inorganic Residue 10.00 Ethyl acetate 400.00 (Sodium sulphate-10) water 1200.00 Organic Residue 7.38 Process residue-7.38 Total 2953.25 Total 2953.25



ESOMEPRAZOLE SODIUM. Process Description Stage-1 5-Methoxy-2-[(4-Methoxy-3,5-Dimethyl-2-pyridinyl)MethylThio]-1H-Benzimidazole

reacts with Cumin hydro peroxide and Potassium hydroxide in the presence of

Toluene to give stage-1 product.

Stage-2 Stage-1 reacts with acetic acid and sodium hydroxide in the presence of MDC to

give Esomeprazole Sodium.

. Route of synthesis: Stage-1:

N

OCH3

H3C CH3

CH2

SNH

N OCH3

N

OCH3

H3C CH3

CH2

SN

N

5-Methoxy-2-[(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl Thio]-1H -Benzoimidazole

C17H19N3O2S

329.41

+

H3C O

CH3

Cumin hydroperoxide

OH

C9H12O2

152.19

+ KOH

Potassium hydroxide

56.10

Toluene

OCH3

K+

O

H2O +

OHH3C

CH3

C9H12O

136.19

Cumin hydroxide

C17H20KN3O4S

401.52

Esomeprazole potassium salt.Monohydrate



Stage-2:

N

OCH3

H3C CH3

CH2

SN

N OCH3

K+

O

H2O

C17H20KN3O4S

401.52

Esomeprazole potassium salt.Monohydrate

+

Acetic acid

60.05

+ NaOH

Sodium hydroxide

N

OCH3

H3C CH3

CH2

S

N

N OCH3O

H2O + CH3COOK

98.14

Potassium acetateEsomeprazole Sodium

385.41

H3C

O

OH

40.00

Na

C17H18N3NaO3S.H2O

+ H2O

18.00

MDC

Flowchart:

Stage-1

5-Methoxy-2-[(4-Methoxy-3,5-Dimethyl-2-pyridinyl)Methyl Thio]-1H-Benzimidazole Cumin hydroperoxide Potassium hydroxide Toluene

Toluene RecoveryCumin hydroxide

Stage-2

Stage-1Acetic acidMDCSodium hydroxide

MDC RecoveryPotassium acetate

ESOMEPRAZOLE SODIUM



Material Balance:

Material Balance Of Esomeprazole sodium Stage-1



in Kg Omeprazole sulfide 96.00 Stage-1 110.00 Cumin Hydroperoxide 44.35 Toluene Recovery 285.00 Potassium hydroxide 16.35 Toluene Loss 10.00 DET 11.30 Methanol Recovery 95.00 Ti(IV)Isopropoxide 2.50 Methanol Loss 3.00 NEDIPA 4.50 NEDIPA Loss 4.50 Toluene 300.00 Organic Residue 67.50 Methanol 100.00 Process residue-60.50

Organic impurities-7.06( Ti(IV)Isopropoxide-2.5, Cumin hydroxide-39.64,DET-11.3) Distillation residue-7 (Toluene-5,Methanol-2)


Material Balance Of Esomeprazole sodium Stage-2



in Kg Stage -1 110.00 Esomeprazole Sodium 100.00 Acetic acid 16.40 MDC Recovery 285.00 Sodium hydroxide 10.90 MDC Loss 10.00 MDC 300.00 Ethyl acetate Recovery 143.00 Ethyl acetate 150.00 Ethyl acetate Loss 2.00 Activated carbon 5.00 Effluent water 834.68 Water 800.00 (Water-800,Generated water

-4.84,Potassium acetate-26.84,Ethyl acetate-3)

0

Spent carbon 5.00 Organic residue 12.62 Process residue-5.62

Distillation residue-7 MDC-5,Ethyl acetate -2)

Total 1392.30 Total 1392.30



FEXOFENADINE HYDROCHLORIDE


Stage-1

2-[4-(4-Chloro-butyryl)-cyclohexyl]-2-methyl-propionic acid methyl ester on

undergoes condensation with Azacyclonol in presence of Sodium bicarbonate and

MIBK to give stage-1 product.

Stage-2

Stage-1 product undergoes reduction with, Sodiumborohydride and water in

presence of Methanol to give stage-2 product.

Stage-3

Stage-2 product undergoes salt formation with HCl in presence of IPA to give

Fexofenadine Hydrochloride




Route of Synthesis:

Stage-1

+ + NaHCO3

84.01

H3C

CH3

COOCH3

Cl

O

2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid methyl ester

HN

OH

Azacyclonol

H3C

CH3

COOCH3

ON

OH

MIBK

+ NaCl + CO2 + H2O

58.44 44.0 18.02

C15H19ClO3

282.10

C18H21NO

267.37

2-(4-{4-[4-(Hydroxy-diphenyl-methyl)-piperidin-1-yl]-butyryl}-phenyl)-2-methyl-

propionic acid methyl esterC33H39NO4

513.67



Stage-2

H3C

CH3

COOCH3

ON

OH

H3C

CH3

COOH

OHN

OH

+ NaBH4

37.83

+ 4 H2O

72.06

Methanol

+ H3BO3

61.83

+ CH3ONa

54.02

+

2-(4-{4-[4-(Hydroxy-diphenyl-methyl)-piperidin-1-yl]-butyryl}-phenyl)-2-methyl-propionic acid methyl ester

C33H39NO4

513.67

FexofenadineC32H39NO4

501.66

3 H2

6.00

Stage-3

H3C

CH3

COOH

OHN

OH + HClIPA

H3C

CH3

COOH

OHN

OH HCl

Fexofenadine hydrochloride

C32H40ClNO4

538.12

FexofenadineC32H39NO4

501.66

36.46




Flow Chart:

Dimethyl phenyl acetateSodium BicarbonateAzacyclonolMethyl isobutyl ketoneEthyl Acetate

Stage-1 Ethyl acetate Rec

Stage-2 Methanol Rec

Stage-1Sodium BorohydrideSodium HydroxideAcetic AcidMethanol

Stage-3 IPA RecStage-2Hydrochloric acidIsopropyl alcohol


Material Balance:

Material Balance of Fexofenadine Hydrochloride Stage-1



in Kg 2-[4-(4-Chloro-butyryl)-cyclohexyl]-2-methyl-propionic acid methyl ester

136.00 Stage-1 227.00

Sodium Bicarbonate 40.40 Ethyl Acetate recovery 665.00 Azacyclonol 129.00 Ethyl Acetate Loss 14.00 Methyl isobutyl ketone 200.00 Methyl Isobutyl Ketone Recovery 190.00 Ethyl Acetate 700.00 Methyl Isobutyl Ketone Loss 8.00 Water 600.00 Effluent water 641.71 (Water-600,Generated water-

8.56,Sodium chloride-28.15, Ethyl acetate-5)

Process Emission 21.08 (Carbon dioxide -21.08) Organic Residue 38.61 (Process Residue-20.61,

Distillation Residue-18, (Ethyl acetate-16,MIBK-2)

Total 1805.40 Total 1805.40






in Kg Stage-1 227.00 Stage-2 203.00 Sodium Borohydride 16.50 Methanol recovery 760.00 Activated carbon 10.00 Methanol Loss 16.00 Methanol 800.00 Effluent Water 519.30 Water 500.00 (Water-468.22, Boric acid-27.24,

Sodium methoxide-23.84) 0

Spent Carbon 10.00 Process Emissions 2.49 (Hydrogen-2.49) 0 Organic Residue 42.71 Process Residue-22.71

Organic Impurities-12.31 (Sodium methoxide-10.4) Distillation Residue-24 (Methanol-24)

Total 1553.50 Total 1553.50




in Kg Stage-2 203.00 Fexofenadine Hydrochloride 200.00 Hydrochloric acid 14.50 Isopropyl Alcohol Recovery 760.00 Isopropyl alcohol 800.00 Isopropyl Alcohol Loss 16.00 Organic Residue 41.50 Process Residue-17.50

Distillation Residue-24 (IPA-24)

Total 1017.50 Total 1017.50



HALOPERIDOL Process description: Stage-1: 1-4-Fluoro Phenyl-pentan-1-one reacts with 4-(Chloro phenyl)piperidine 4-ol in

presence of Potassiumcarbonate, Toluene , Cholofrom, Potassium Iodide &Water to

give Stage-1 Product Stage-2: Stage-1 Product undergoes purification in Methanol & activated carbon to give of

Haloperidol.


F

O

1-(4-Fluoro-phenyl)-pentan-1-one

C11H13FO180.22

+ NH

HO

Cl

4-(4-Chloro-phenyl)-piperidin-4-ol

C11H14ClNO211.69

Toluene,Chloroform,

Haloperidol(Crude)

C21H23ClFNO2

375.86

+ H2O

+ CH3OH

32.04

18.02

+

2.02

+K2CO3 2 HCl

138.21 72.92

+

Activated carbon,Potassium iodide,

2 KCl

149.10

H2CO3

62.02

+ H2+F

NO

OH

Cl



Stage-2

Haloperidol(Crude)

C21H23ClFNO2

375.86

F

NO

OH

Cl

Activated carbon,Methanol

Haloperidol(Pure)

C21H23ClFNO2375.86

F

NO

OH

Cl

Flowchart:

Stage-1

Haloperidol

Stage-2

1-4-Fluoro Phenyl-pentan-1-one4-(Chloro phenyl)piperidine 4-olPotassium carbonatePotassium IodideHydrochloric acidTolueneChloroform

Toluene RecoveryChlorofrom recoveryEffluent water

Stage-1Spent CarbonMethanol

Methanol RecoverySpent carbon Recovery

Material Balance:

Material Balance of Haloperidol Stage-1 Batch Size: 100 Kg



1-4-Fluoro Phenyl-pentan-1-one

57.00 Stage-I 110.00

4-(Chloro phenyl)piperidine 4-ol 67.00 Mixed solvent (Toluene Recovery + Generated Methanol )

390.08

Potassium carbonate 44.00 Toluene loss 8.00 Potassium Iodide 2.00 Chloroform Recovery 285.00 Hydrochloric acid 23.00 Chloroform loss 15.00 Toluene 400.00 Effluent water 567.10 Chloroform 300.00 (water -494.36, Potassium

Chloride-47.14, Carbonic acid-19.60, Toluene-6)

0

Water 500.00 Process emission 0.62



(Hydrogen-0.62) 0 Organic residue 17.20 Process residue-11.20


Total 1393.00 Total 1393.00

Material Balance of Haloperidol Stage-2 Batch Size: 100 Kg



Stage-1 110.00 Haloperidol 100.00 Spent Carbon 4.00 Methanol Recovery 570.00 Methanol 600.00 Methanol Loss 12.00 Spent carbon Recovery 4.00 Organic residue 28.00 Process residue- 10



ITOPRIDE HYDROCHLORIDE Process Description Stage-1 4-Hydroxy benzaldehyde reacts with (2-Chloroethyl)-dimethylamine hydrochloride

and Triethyl amine in presence of Chloroform to give stage-1 product.

Stage-2 Stage-1 product reacts with Hydroxyl amine sulfate and Hydrogen gas in presence of

Raney Nickel in presence of Methanol to give Stage-2 product.

Stage-3 Stage-2 product undergoes condensation with 3, 4-Dimethoxy benzoyl chloride in

presence of Toluene to give stage-3 product.

Stage-4 Stage-3 product undergoes purification in presence of Methanol and Isopropyl

alcohol to give Itopride Hydrochloride.



Route of Synthesis Stage-1:

H

OHO

4-Hydroxy-benzaldehyde

C7H6O2

122.12

+

NH3C

CH3

Cl

(2-Chloro-ethyl)-dimethyl-amine Hydrochoride

HCl

C4H11Cl2N

144.04

+

Triethyl-amine

Chloroform

202.00

H

O

O

NH3C

CH3

4-(2-Dimethylamino-ethoxy)-benzaldehyde

C11H15NO2

193.24

+

Triethyl amine Hydrochloride

275.30

N

N HCl.

2

2

C6H15N

C6H16ClN

Stage-2: H

O

O

NH3C

CH3

4-(2-Dimethylamino-ethoxy)-benzaldehyde

C11H15NO2

193.24

+ (NH2OH)H2SO4 +Raney Ni

Methanol

NH2

O

NH3C

CH3

[2-(4-Aminomethyl-phenoxy)-ethyl]-dimethyl-amine

C11H18N2O

194.27

+ H2SO4

Sulfuric acid

98.00

4.00

+

36.00

131.11

2 H2

2 H2O

Hydroxyl amine sulphate



Stage-3:

NH2

O

NH3C

CH3

[2-(4-Aminomethyl-phenoxy)-ethyl]-dimethyl-amine

C11H18N2O

194.27

+

Cl

O

H3CO

OCH3

3,4-Dimethoxy-benzoyl chloride

C9H9ClO3

200.62

Toluene

HN

ON

CH3

H3C O

OCH3

OCH3

HCl

C20H27ClN2O4

394.89

Itopride Hydrochloride (Crude)

Stage-4:

HNON

CH3

H3C O

OCH3

OCH3

HCl

C20H27ClN2O4

394.89

Itopride Hydrochloride (Crude)

Methanol HNON

CH3

H3C O

OCH3

OCH3

HCl

C20H27ClN2O4

394.89

Itopride Hydrochloride



Flow Chart:

4-Hydroxy benzaldehyde (2-Chloroethyl)-dimethylamine hydrochlorideTriethyl amine Chloroform

Chloroform Rec

Stage-1 Hydroxyl amine sulfate Raney Ni Methanol

Methanol Rec

Stage-2 3, 4-Dimethoxy benzoyl chlorideToluene

Toluene Rec

Stage-3 MethanolIsopropyl alcohol

Methanol RecIPA Rec

ITOPRIDE HYDROCHLORIDE

Stage-1

Stage-2

Stage-3

Stage-4

Material Balance:

Material Balance of Itopride Hydrochloride Stage-1



in Kg 4-Hydroxy benzaldehyde 37.00 Stage-1 56.00 (2-Chloro ethyl)-dimethyl hydrochloride 43.60 Chloroform Recovery 475.00

Triethylamine 61.20 Chloroform Loss 25.00 Chloroform 500.00 Effluent water 383.40

Water 300.00 (Water-300, Triethyl amine HCl-83.40)

0

Organic residue 2.40 Process residue-2.4 Total 941.80 Total 941.80



Material Balance of Itopride Hydrochloride Stage-2 Batch Size: 100.0Kg



Stage-1 56.00 Stage-2 54.00 Hydroxyl amine sulphate 38.00 Methanol Recovery 570.00 Methanol 600.00 Methanol Loss 12.00 Raney nickel 5.00 Effluent water 338.0

Hydrogen gas 1.12 (Water-300,Generated water-10.41,Sulfuric acid-28.39)

0

Water 300.00 Spent Raney Nickel Recovered 5.00 Organic residue 21.12

Process residue-3.12 Distillation residue-18 (Methanol-18)

Total 1000.12 Total 1000.12




Stage-2 54.00 Stage-3 105.00 3,4-Dimethoxy benzoyl chloride 55.50 Toluene Recovery 380.00 Toluene 400.00 Toluene Loss 12.00 Water 200.00 Effluent water 204.00 (Water-200,Toluene-4) 0 Organic Residue 8.50

Process residue-4.50 Distillation residue-4 (Toluene-4)



Name of the input Quantity in Kg Name of the out put Quantity in Kg Stage-3 105.00 Itopride Hydrochloride 100.00 Methanol 500.00 Methanol Recovery 475.00 Isopropyl alcohol 500.00 Methanol Loss 10.00

Activated carbon 3.50 Isopropyl alcohol Recovery

475.00

Water 200.00 Isopropyl alcohol Loss 10.00 Effluent water 200.00 (Water-200) 0 Spent carbon 3.50 Organic residue 35.00

Process residue-5 Distillation residue-30 (Methanol-15, Isopropyl alcohol-15)

Total 1308.5 Total 1308.50



ITRACONAZOLE

Process Description: Stage-1 1-(4-Methoxy-Phenyl)-piperazine reacts with 1-Bromo-4-nitro-benzene in presence of MDC and Methanol to give Stage-1 Product. Stage-2: Stage-1 Product reacts with Hydrogen in presence of Pd/c catalyst and DMF to give Stage-2 Product. Stage-3: Stage-2 product reacts with Phenyl Chloro formate in presence of Sodium bicarbonate and MDC to give Stage-3 product. Stage-4: Stage-3 product reacts with Hydrazine hydrate in presence of 1,4-Dioxane to give Stage-4 product. Stage-5: Stage-4 Product reacts with Formamidine in presence of Acetic acid and acetone to give Stage-5 product. Stage-6: Stage-5 product reacts with 2-Bromo-Butane in presence of Potassium carbonate and Methanol to give Stage-6 product. Stage-7: Stage-6 product reacts with Hydrobromic acid in presence of Sodium carbonate nd Methanol to give stage-7 Product. Stage-8: Step-A: 2,4Dichloroacetopheneone reacts with Glycerol and Bromine in presence of Toluene, PTSA and n-Butanol to give Step-A product. Step-B: Step-A product reacts with Benzyl Chloride in presence of Toluene and Methanol to give Stage-8 Product. Stage-9: Stage-8 Product reacts with 1,2,4-Triazole in presence of Potassium Carbonate , Sodium Hydroxide ,DMF and water to giveStage-9 Product. Stage-10: Stage-9 Product reacts with Methanol Sulfanyl Chloride in presence of TEA, MDC and water to give Stage-10 product. Stage-11: Stage-10 Product undergoes condensation with Stage-7 Product in presence of potassium hydroxide and Methanol to give Itraconazole.



Route of Synthesis Stage-1:

HN N OCH3

C11H16N2O

1-(4-Methoxy-phenyl)-piperazine

192.26

+ BrO2N

1-Bromo-4-nitro-benzeneC6H4BrNO2

202.01

NO2N N OCH3

1-(4-Methoxy-phenyl)-4-(4-nitro-phenyl)-piperazineC17H17N3O3

313.35

+ HBr

80.91

MDC

Methanol

Stage-2:

H3CO N N NO2

C17H19N3O3

313.35

+ 3H2 pd/Catalyst

H3CO N N NH2

C17H21N3O283.37

+ 2H2O

36.04

Hydrogen

6.05

DMF1-(4-Methoxy-phenyl)-4-(4-nitro-phenyl)-

piperazine

4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-phenylamine



Stage-3:

H3CO N N NH2

C17H21N3O

283.37

+OCl

O+ NaHCO3

Phenyl chloro formate

C7H5ClO2

156.57

84.01

H3CO N N NHCOOPh

C24H25N3O3

403.47

+ NaCl + CO2 + H2O

58.44 44.01 18.02

4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-phenylamine

{4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-phenyl}-carbamic acid phenyl ester

MDC

Stage-4:

H3CO N N NHCOOPh

C24H25N3O3

403.47

+ N2H4.H2O

Hydrazine hydrate

50.06

1,4-Dioxane

H3CO N N NHCONHNH2

C18H23N5O2

341.41

+

OH

PhenolC6H6O

94.11

+ H2O

18.02

{4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-phenyl}-carbamic acid phenyl ester

1,3-Dimethyl-7-{2-[(1-phenyl-2-propanyl)amino]ethyl}-3,7-dihydro-1H-purine-2,6-dione



Stage-5:

H3CO N N NHCONHNH2

C18H23N5O2

341.41

+ H2N NH + 2CH3COOH

FormamidineCH4N2

44.07

120.10

H3CO N N NN

NH

O

C19H21N5O2351.40

+

Ammonium acetate

2CH3COONH4

154.16

1,3-Dimethyl-7-{2-[(1-phenyl-2-propanyl)amino]ethyl}-3,7-dihydro-1H-purine-2,6-dione

2-{4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-phenyl}-2,4-dihydro-[1,2,4]triazol-3-one

Stage-6:

H3CO N N NN

NH

O

C19H21N5O2

351.40

+ +

C4H9Br

137.02

69.10

Methanol

C23H29N5O2

407.51

+ KBr + 1/2CO2 + 1/2 H2O

119.0 22.0 9.01

2-{4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-phenyl}-2,4-dihydro-[1,2,4]triazol-3-one

H3CCH3

Br

2-Bromo-butane

1/2 K2CO3

H3CO N N NN

N

O

CH3

CH3

4-Isobutyl-2-{4-[4-(4-methoxy-phenyl)-piperazin-1-yl]-phenyl}-2,4-dihydro-[1,2,4]triazol-3-one



Stage-7:

H3CO N N NN

N

O

CH3

CH3

C23H29N5O2

407.51

+ 2HBr + Na2CO3

Hydrobromic acid161.82

106.0

+ CH3OH + 2NaBr +

Methanol

C22H27N5O2

393.48

32.04 205.79 44.01

4-Isobutyl-2-{4-[4-(4-methoxy-phenyl)-piperazin-1-yl]-phenyl}-2,4-dihydro-[1,2,4]triazol-3-one

HO N N NN

N

O

CH3

CH3

2-{4-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-phenyl}-4-isobutyl-2,4-dihydro-[1,2,4]triazol-3-one

CO2

Stage-8: Step-A

Cl Cl

CH3

O

2,4-Dichloro acetophenone

+

Glycerol

HO OHOH

+ Br2

C8H6Cl2O189.04

C3H8O3

92.09

159.81

PTSA

n-Butanol

Cl Cl

O

O

Br

OH

C11H11BrCl2O3

342.01

+ +HBr

80.91

H2O

18.02[2-Bromomethyl-2-(2,4-dichloro-phenyl)-[1,3]dioxolan-4-

yl]-methanol

Step-B:

ClCl

O

O

Br

OOCC6H5

Cis-bromo benzoateC18H15BrCl2O4

446.12

Cl Cl

OO

Br

OH

[2-Bromomethyl-2-(2,4-dichloro-phenyl)]-[1,3]dioxolan

-4-yl]-methanol

C11H11BrCl2O3

342.01

+Benzoyl chloride

O

Cl

C7H5ClO140.57

+

Benzoic acid 2-bromomethyl-2-(2,4-dichloro-phenyl)-[1,3]dioxolan

-4-ylmethyl ester

HCl

36.46



Stage-9:

ClCl

O

O

Br

OOCC6H5

+ NN

HN

+ 1/2 K2CO3 + NaOH DMF

Water

Cis-bromo benzoateC18H15BrCl2O4

446.12

1,2,4-TriazoleC2H3N3

69.1

Potassium carbonate

69.0

Sodium hydroxide

40.0

+

C13H13Cl2N3O3

330.17

COONa

Sodium benzoate

144.10

+ KBr + 1/2 CO2 +

119.0 22.0 9.01

O

OHO

NN

N

Cl Cl

[2-(2,4-Dichloro-phenyl)-2-[1,2,4]triazol-1-ylmethyl-[1,3]dioxolan-4-yl]-methanol

C7H5NaO2

1/2 H2O

Stage-10:

ClCl

O

O

N

HO

N

N

C13H13Cl2N3O3

330.17

+ CH3SO2Cl + (C2H5)3NMDC

Water

C14H15Cl2N3O5S

408.26

+ (C2H5)3N.HCl

Methane sulfonyl chloride

114.55

Triethyl amine101.19

Triethyl amine hydrochloride

137.65

[2-(2,4-Dichloro-phenyl)-2-[1,2,4]triazol-1-ylmethyl-[1,3]dioxolan-4-yl]-methanol

ClCl

O

O

NO3SH3C

NN

1-[2-(2,4-Dichloro-phenyl)-4-ethyl-[1,3]dioxolan-2-ylmethyl]-1H-[1,2,4]triazole;



Stage-11:

ClCl

O

O

NO3SH3C

NN

C14H15Cl2N3O5S

408.26

C22H27N5O2

393.48

+ KOH

56.11

Methanol

CH3O2SOK + H2O

Methane sulfonate potassium

134.20

18.02

1-[2-(2,4-Dichloro-phenyl)-4-ethyl-[1,3]dioxolan

-2-ylmethyl]-1H-[1,2,4]triazole;(Stage-10)

+ HO N N NN

NO

CH3

CH3

2-{4-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-phenyl}-4-isobutyl-2,4-dihydro

-[1,2,4]triazol-3-one(Stage-7)

O N N NN

NO

CH3

CH3Cl Cl

OO

NN

N

+

C35H38Cl2N8O4705.63

ITRACONAZOLE



Flowchart:

Stage-1

Stage-2

1-(4-Methoxy-phenyl)-piperazine1-Bromo-4-Nitro-benzeneMDCMethanol

MDC recoveryMethanol recoveryEffluent water

Stage-1Palladium CarbonDMFHydrogen Gas

DMF RecoveryEffluent water

Stage-2Phenyl Chloro formateMethylene DichlorideSodium Bicarbonate

Stage-3Methylene Dichloride RecoveryEffluent water

Stage-3Hydrazine Hydrate1,4-Dioxane

Stage-41,4-Dioxane RecoveryEffluent water

Stage-4FormamidineDimethyl FormamideAcetic Acid

Dimethyl Formamide RecoveryEffluent water

Stage-52-Bromo ButanePotassium CarbonateMethanolDimethyl Formamide

Dimethyl Formamide RecoveryEffluent water

Stage-6Hydrogen BromideSodium CarbonateMethanol

Methanol recoveryEffluent water

Stage-5

Stage-6

Stage-7

Stage-8

2,4 -DichloroacetophenoneGlycerolLiq BromineBenzoyl chlorideToluene n-Butanolp-Toluenesulfonic acid

n-Butanol recoveryToluene RecoveryEffluent water



Stage-9

Stage-10

Stage-81,2,4-TriazoleSodium HydroxidePotassium CarbonateDimethyl Formamide

Dimethyl Formamide recoveryEffluent water

Stage-9Methane Sulfonyl ChlorideTriethylamineMethylene DichlorideIsopropyl Alcohol

Isopropyl alcohol RecoveryEffluent water

Stage-10Stage-7Potassium HydroxideActivated CarbonDimethyl FormamideMethanol

Stage-11Dimethyl formamide RecoveryMethanolRecoveryEffluent water

ITRACONAZOLE

Material Balance:

Material Balance of Itraconazole Stage-1 Batch Size:500.00Kg



1-(4-Methoxy-phenyl)-piperazine

208.00 Stage-1 322.00

1-Bromo-4-Nitro-benzene 219.00 Methanol Recovery 95.00 MDC 250.00 Methanol Loss 5.00 Methanol 100.00 MDC Recovery 238.00 Water 500.00 MDC Loss 5.00 Effluent Water 500.00 (Water-500) 0 Process Emissions 87.53 (Hydrogen Bromide-87.53) 0 Organic residue 24.47 Process residue -17.47

(Distillation Residue-7 (MDC-7)

Total 1277.00 Total 1277.00






Stage-1 322.00 Stage-2 277.00 Palladium Carbon 5.00 DMF Recovery 665.00 DMF 700.00 DMF Loss 15.00 Hydrogen Gas 6.30 Effluent Water 337.03 Water 300.00 (Water-300,Generated Water-

37.03)

Spent Catalyst (Palladium Carbon Reuse)

5.00

Organic Residue 34.27 Process residue- 14.27

Distillation Residue-20 (DMF-20)

Total 1333.30 Total 1333.30




Stage-2 277.00 Stage-3 375.00 Phenyl Chloro formate 154.00 MDC Recovery 475.00 Methylene Dichloride 500.00 MDC Loss 10.00 Sodium Bicarbonate 83.00 Effluent Water 424.73 Water 350.00 (Water-350,

GeneratedWater-17.60 Sodium chloride-57.13 )

Process Emissions 43.00 (Carbon Dioxide-43) Organic Residue 36.27 Process residue-21.27

Distillation Residue-15 ( MDC)

Total 1364.00 Total 1364.00



Name of the out put Quantity In Kg

Stage-3 375.00 Stage-4 300.00 Hydrazine Hydrate 47.00 1,4-Dioxane Recovery 475.00 1,4-Dioxane 500.00 1,4-Dioxane Loss 10.00 Water 500.00 Effluent Water 605.06 (Water-500, GeneratedWater-

17.60, Phenol-87.46)




Distillation Residue-15 (1,4-Dioxane-15)

Total 1422.00 Total 1422.00



Name of the out put Quantity In Kg

Stage-4 300.00 Stage-5 290.00 Formamidine 39.00 DMF Recovery 238.00 Dimethyl Formamide 250.00 DMF Loss 5.00 Acetic Acid 106.00 Effluent Water 635.46 Water 500.00 (Water-500,

Ammonium acetate-135.46) 0

Organic Residue 26.54 Process residue – 19.54


Total 1195.00 Total 1195.00




Stage-5 290.00 Stage-6 320.00 2-Bromo Butane 113.00 DMF Recovery 285.00 Potassium Carbonate 57.00 DMF Loss 10.00 Methanol 450.00 Methanol Recovery 427.00 Dimethyl Formamide 300.00 Methanol Loss 9.00 Water 300.00 Effluent Water 405.44 (Water-300, Generated Water-

7.44, Potassium bromide-98) 0

Process Emissions 18.15 (Carbon Dioxide-18.15) 0 Organic Residue 35.41 (Process residue-16.41,

Distillation Residue-19 (Methanol-14, DMF-5)

Total 1510.00 Total 1510.00




Stage-6 320.00 Stage-7 294.00 Hydrogen Bromide 128.00 Methanol Recovery+ Generated

Methanol 414.56

Sodium Carbonate 83.00 Methanol Loss 12.00 Methanol 400.00 Effluent Water 611.59 Water 450.00 (Water-450,

Sodium bromide-161.59) 0

Process emission 34.56 (Carbondioxide-34.56) 0 Organic residue 14.29 Process residue -6.29

Distillation Residue-8 (Methanol-8)

Total 1381.00 Total 1381.00


2,4 -Dichloroacetophenone 215.00 Stage-8 370.00 Glycerol 105.00 n-Butanol Recovery 475.00 Liq Bromine 182.00 n-Butanol Loss 15.00 Benzoyl chloride 152.00 Toluene recovery 380.00 Toluene 400.00 Toluene Loss 10.00 n-Butanol 500.00 Effluent water 630.49 p-Toluenesulfonic acid 5.00 (Effluent water-600, Generated

water-20.49,Toluene-5, Paratoluene Sulfonic acid-5)

0

Water 600.00 Process Emissions 145.30 (Hydrogen bromide-92,

Hydrogen Chloride-53.30) 0


Distillation Residue-15 (n-Butanol-10,Toluene-5)

Total 2159.00 Total 2159.00




Stage-8 370.00 Stage-9 260.00 1,2,4-Triazole 58.00 DMF Recovery 95.00 Sodium Hydroxide 34.00 DMF Loss 2.00 Potassium Carbonate 58.00 Effluent Water 725.66






Stage-9 260.00 Stage-10 305.00 Methane Sulfonyl Chloride 91.00 MDC Recovery 570.00 Triethylamine 80.00 MDC Loss 12.00 Methylene Dichloride 600.00 Isopropyl Alcohol Recovery 570.00 Isopropyl Alcohol 600.00 Isopropyl Alcohol Loss 12.00 Water 500.00 Effluent Water 608.40 (Water-500,Triethylamine

Hydrochloride-108.40) 0


Distillation Residue-36 (MDC-18,IPA-18)

Total 2131.00 Total 2131.00




Stage-10 305.00 Itraconazole 500.00 Stage-7 294.00 Dimethyl Formamide Recovery 285.00 Potassium Hydroxide 42.00 Dimethyl Formamide Loss 10.00 Activated Carbon 8.00 Methanol Recovery 380.00 Dimethyl Formamide 300.00 Methanol Loss 12.00 Methanol 400.00 Effluent Water 613.71 Water 500.00 (Water-500, Generated Water-

13.46 Potassium Methane Sulfonate-100.25)

Spent Carbon 8.00 Organic residue 40.29 Process residue-27.29

Distillation Residue-13 (Methanol-8, DMF-5)

Total 1849.00 Total 1849.00

Dimethyl Formamide 100.00 (Water-500, Generated Water-7.47 Potassium Bromide-98.69, Sodium Benzoate-119.50)

0

Water 500.00 Process Emission 18.24 (Carbon dioxide-18.24) 0 Organic residue 19.10 Process residue-16.1


Total 1120.00 Total 1120.00



KETOROLAC TROMETHAMINE Process Description Stage-1 5-chloro-2-benzoylpyrrole reacts with Methyl-gama-methoxy –butanoate in presence of Acetone to give Stage-1 product. Stage-2 Stage-1 Product undergoes condensation with Tromethamine in presence of Acetone to give Ketorolac Tromethamine. Route of synthesis Stage-1

HN Cl

O

5-Chloro-2-benzoyl pyrroleC11H8ClNO

205.64

+methyl-gama-methoxybutanoate

OCH3O

H3C

O

C6H12O3

132.16

+ NaOH

40.00

N

O

COOH

KetorolacC15H13NO3

255.27

+ NaCl

58.44

+ 2 CH3OH

64.08

Acetone

Stage-2

NO

COOH

KetorolacC15H13NO3

255.27

Tromethamine

NH2

HO OH

OH+

C4H11NO3

121.14

Acetone

NO

COOH

NH2

HO OH

OH

.

ketorolac tromethamineC19H24N2O6

376.40



Flow chart:

Stage-1AcetoneTromethamineCarbon & hyflow

Stage-2 Acetone Recovery

Ketorolac Tromethamine

Stage-1

5-chloro-2-benzoylpyrroleMethyl-gama-methoxy butanonateSodium hydroxideAcetone

Acetone Recovery

KETOROLAC TROMETHAMINE

Material Balance

Material Balance of Ketorolac Tromethamine Stage-1



in Kg 5-chloro-2-benzoylpyrrole 59.00 Stage-1 70.00 Methyl-gama-methoxy butanonate

37.85 Acetone Recovery 475.00

Sodium hydroxide 11.45 Acetone Loss 15.00 Acetone 500.00 Methanol Recovery 16.75 Water 500.00 Effluent water 516.75 (water-500,Sodium chloride-

16.75) 0


Distillation residue -10 ( Acetone-10)

Total 1108.30 Total 1108.30



Material Balance of Ketorolac Tromethamine Stage-2



in Kg Stage-1 70.00 Ketorolac Tromethamine 100.00 Acetone 300.00 Acetone Recovery 285.00 Tromethamine 34.00 Acetone Loss 7.00 Carbon & hyflow 10.00 Effluent water 400.00 Water 400.00 (water-400) 0 Spent carbon & hyflow 10.00 Organic residue 12.00 Process residue-4

Distillation residue – 8 (Acetone-8)


LANSOPRAZOLE

Process Description Stage-1 2, 3-Lutidine reacts with Hydrogen Peroxide and Nitric Acid in Presence of Acetic

acid to give stage-1 product.

Stage-2 Stage-1 Product reacts with 1, 1, 2- trifluoroethanol and Acetic Anhydride in

presence of Potassium Carbonate to give stage-2 product.

Stage-3 Stage-2 product undergoes chlorination with Thionyl Chloride in presence of Toluene to give stage-3 product. Stage-4 Stage-3 product undergoes condensation with 1H-Benzoimidazole-2-thiol in

presence of Sodium Hydroxide to give stage-4 product.

Stage-5 Stage-4 product undergoes oxidation with Hydrogen peroxide in presence of IPA to

give Lansoprazole.



LANSOPRAZOLE Route of Synthesis:

Stage-1

2,3-Lutidine

107.15

+

H2O2

34.00

+ HNO3

63.00

+ 2 H2O

C7H9N

36.044-Nitro-2,3-Dimethyl pyridine-N-Oxide

168.15

C7H8N2O3

N+

O-

H3C

H3C

NO2

NCH3

CH3

Hydrogen Peroxide

HO OH

Stage-2

+

4-Nitro-2,3-Dimethyl pyridine-N-Oxide

168.15

CF3CH2OH

+ K2CO3+

C4H6O3

+ + HCl

100.04 102.09

N

OCH2CF3

CH3

CH2OH

. HCl

257.64

+ KHCO3

100.12

+ KNO2

85.10

+CH3COONa

82.03

CH3COOH

C7H8N2O3

C9H11ClF3NO2

OO

OOHF

F

FN+

O-

H3C

H3C

NO2

1,1,2-Trifluoro-ethanol Acetic anhydride 138.21

NaOH

40.00 36.46

60.05

+

[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol



Stage-3

N

OCH2CF3

CH3

CH2OH

. HCl

257.64

+

C9H11ClF3NO2

[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol

+

SOCl2

Thionyl chloride

118.97

N

OCH2CF3

CH3

CH2Cl

. HCl

276.08

SO2

64.06

+ HCl

36.46

C9H10Cl2F3NO

S

O

Cl

Cl

2-Chloromethyl-3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridine Hydrochloride

Stage-4

N

OCH2CF3

CH3

CH2Cl

. HCl

276.08

C9H10Cl2F3NO

2-Chloromethyl-3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridine Hydrochloride

+N

HN

HS + 2 NaoH

80.00

150.20

N

OCH2CF3

CH3

CH2 SN

HN

+ 2 NaCl

116.88

+ 2 H2O

36.04

C7H6N2S

C16H14F3N3OS

353.36

1H-Benzoimidazole-2-thiol

2-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethylthio]-1H-benzo[d]imidazole



Stage-5

N

OCH2CF3

CH3

CH2 SN

HN

+

C16H14F3N3OS

353.36

2-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethylthio]-1H-benzo[d]imidazole

+

H2O2

Hydrogen peroxide

N

OCH2CF3

CH3

CH2 SN

HN

O

Lansoprazole

369.36

H2O

18.02C16H14F3N3O2S

HO OH

34.01

LANSOPRAZOLE



Flow Chart:

Stage-1

Stage-2

Stage-3

Stage-4

Stage-5

2,3-LutidineAcetic AcidHydrogen Peroxide (50%)Sulfuric AcidNitric Acid Effluent water

Stage-1Sodium HydroxidePotassium Carbonate1,1,2-Tri Fluoro EthanolMIBKAcetic AnhydrideTEBACTolueneHydrogen Chloride Activated Carbon

Stage-2Methylene DichlorideTolueneThionyl Chloride

Stage-3Sodium Hydroxide1H-Benzoimidazole-2thiol

Stage-4Isopropyl AlcoholHydrogen Peroxide (50%)CatalystChloroformAcetone

Isopropyl alcohol RecoveryAcetone recoveryEffluent water

Effluent water

Toluene recoveryMethylene Dichloride RecoveryEffluent water

MIBK RecoveryToluene RecoveryEffluent water

LANSOPRAZOLE

LANSOPRAZOLE



MATERIAL BALANCE:

Material Balance of Lansoprazole Stage-1



in Kg 2,3-Lutidine 188.00 Stage-1 280.00 Acetic Acid 46.00 Spent Sulfuric Acid 50.00 Hydrogen Peroxide (50%) 120.00 Effluent water 969.23 Sulfuric Acid 50.00 (Water-800, Generatedwater-

63.23,water from hydrogen peroxide-60, Acetic Acid - 46)

0

Nitric Acid 111.00 Organic Residue 15.77 Water 800.00 Process residue – 15.77 Total 1315.00 Total 1315.00

Material Balance of Lansoprazole Stage-2



in Kg Stage-1 280.00 Stage-2 405.00 Sodium Hydroxide 67.00 MIBK Recovery 140.00 Potassium Carbonate 230.00 MIBK Loss 5.00 1,1,2-Tri Fluoro Ethanol 167.00 Toluene Recovery 380.00 MIBK 150.00 Toluene Loss 10.00 Acetic Anhydride 170.00 Effluent Water 1041.59 TEBAC 1.00 (Water-800, Sodium Acetate-136.59,

Acetic Acid-100,Toluene-5) 0

Toluene 400.00 Inorganic solid waste 308.70 Hydrogen Chloride 61.00 (Potassium Nitrite-141.70, Potassium

Bicarbonate-167) 0

Activated Carbon 5.00 Spent Carbon 5.00 Water 800.00 Organic Residue 35.71 Process Residue-25.71

Distillation Residue-10 (MIBK-5,Toluene-5)

Total 2331.00 Total 2331.00



Material Balance of Lansoprazole Stage-3 Batch Size:500Kg



Stage-2 405.00 Stage-3 415.00 Methylene Dichloride 400.00 Toluene Recovery 475.00 Toluene 500.00 Toluene Loss 15 Thionyl Chloride 180.00 Methylene Dichloride Recovery 380.00 Methylene Dichloride Loss 12.00 Process Emissions 152.68 (Sulfur Dioxide-97.50,Hydrogen

Chloride-55.18) 0

Organic Residue 35.32 Process residue- 17.32

Distillation Residue-18 (Toluene-10, Methylene Dichloride -8)

Total 1485.00 Total 1485.00




Stage-3 415.00 Stage-4 505.00 Sodium Hydroxide 121.00 Effluent Water 829.88 1H-Benzoimidazole-2thiol 226.00 (Water-600, Generated Water-

54.18,Sodium Chloride-175.70) 0

Water 600.00 Organic Residue 27.12 (Process Residue-27.12) Total 1362.00 Total 1362.00




Stage-4 505.00 Lansoprazole 500.00 Isopropyl Alcohol 250.00 Isopropyl Alcohol Recovery 238.00 Hydrogen Peroxide (50%) 98.00 Isopropyl Alcohol Loss 5.00 Catalyst 1.00 Chloroform Recovery 384.00 Chloroform 400.00 Chloroform Loss 12.00 Acetone 150.00 Acetone Recovery 143.00 Water 600.00 Acetone Loss 3.00



Effluent Water 674.75 (Water-600, Generated Water-

25.75, Water from Hydrogen peroxide-49)

0

Catalyst Reuse 1.00 Organic Residue 43.25 Process residue-28.25

Distillation residue-15 (IPA-7, Chloroform-4,Acetone-4)

Total 2004.00 Total 2004.00

LOPERAMIDE HCL Process Description:

Stage-1: Diphenyl acetonitrile reacts with 1, 2-Dichloroethane in presence of TBAB, Toluene and Methanol to give Stage-1 Product.

Stage-2: Stage-1 product reacts with Sulphuric acid and water in presence of Acetic acid and IPA to give Staeg-2 product.

Stage-3: Stage-2 Product reacts with Hydrobromic acid in presence of Acetic acid to give Stage-3 Product.

Stage-4:

Stage-3 product reacts with Thionyl chloride in presence of Toluene to give Stage-4 product.

Stage-5:

Stage-4 Product reacts with Dimethyl amine in presence of Toluene, water to give Stage-5 product.

Stage-6:

Step-A:

4-Chloro Phenyl magnesium bromide reacts with 4-oxo-piperidine-1-carboxylic acid ethyl ester in presence of Toluene and Hydrobromic acid to give Step-A Product.



Step-B:

Step-A Product reacts with Sodium hydroxide in presence of Methanol, Toluene to give Stage-6 Product.

Stage-7:

Stage-5 reacts with stage-6 in presence of Potassium Carbonate, Potassium Iodide and acetone to give stage-7 Product.

Stage-8:

Stage-7 Product undergoes Salt formation with Hydrochloric acid in presence of Acetone to give Loperamide Hydrochloride.

Route of Synthesis.

Stage-1

N

ClCl

Diphenyl-acetonitrile

C14H11N

193.24

+

98.96

N

Cl

HCl+

C16H14ClN

255.74

TBAB

1,2-Dichloro-ethane 4-Chloro-2,2-diphenyl-butyronitrile

C2H4Cl2

36.46



Stage-2

NCl

C16H14ClN

255.74

+ H2SO4

Sulphuric acid98.08

O

O

NH4Cl +

3,3-Diphenyl-dihydro-furan-2-oneC16H14O2

238.28

53.49

+ SO2

64.06

Acetic acid

4-Chloro-2,2-diphenyl-butyronitrile

+ H2O

18.0

+ 1/2 O2

16.0

Stage-3

O

O

3,3-Diphenyl-dihydro-furan-2-one

C16H14O2

238.28

HO

O

Br

4-Bromo-2,2-diphenyl-butyric acid (Loperamide-III)

C16H15BrO2

319.19

+ HBr

80.91

CH3COOH



Stage-4: OH

O

Br

4-Bromo-2,2-diphenyl-butyric acid (Loperamide-III)

C16H15BrO2

319.19

+ SOCl2

Thionyl chloride

Toluene + SO2 + HCl

118.97

COCl

Br

4-Bromo-2,2-diphenyl-butyryl chloride

C16H14BrClO

337.64

36.4664.06

Stage-5:

COCl

Br

4-Bromo-2,2-diphenyl-butyryl chloride

C16H14BrClO

337.64

Dimethylamine

Toluene

Water

+HN

CH3H3C

C2H7N

45.08

N

O

BrCH3

H3C

346.26

4-Bromo-N,N-dimethyl-2,2-diphenyl-butyramide

C18H20BrNO

+ HCl

36.46(Dihydro-N,N-dimethyl-3,3-diphenyl

-2(3H)-furaniminium bromide)

or



Stage-6:

Step-A:

BrMg Cl

4-Chloro phenyl magnesium bromide

C6H4BrClMg

215.76

+ NO COOC2H5


C8H13NO3

171.19

Toluene,HCl solution

4-(4-Chloro-phenyl)-4-hydroxy-piperidine-1-

carboxylic acid ethyl ester

C14H18ClNO3

283.75

+ MgBr2

+ HBr

80.91

184.11

Cl N COOC2H5

HO

Step-B:

4-(4-Chloro-phenyl)-4-hydroxy-piperidine-1-

carboxylic acid ethyl ester

C14H18ClNO3

283.75

Cl N COOC2H5

HO

+ NaOH

40.00

+ HCl

36.46

Methanol,Toluene

4-(4-Chlorophenyl)-4-hydroxy piperidine

C11H14ClNO

211.69

+ C2H5OH

Ethanol46.07

+ CO2

44.01NaCl

58.44+Cl NH

HO



Stage-7:

N

O

BrCH3

H3C

346.26

C18H20BrNO

+ 4-(4-Chloro-phenyl)-piperidin-4-ol

K2CO,KI

AcetoneHN

OH

Cl

C11H14ClNO211.69

4-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-N,N-dimethyl-2,2-diphenyl-butyramide

ON

N

OH

Cl

C29H33ClN2O2

477.04

+ HBr

80.91

4-Bromo-N,N-dimethyl-2,2-diphenyl-butyramide

(Dihydro-N,N-dimethyl-3,3-diphenyl-2(3H)-

furaniminium bromide)or

Stage-8:

Loperamide Hydrochloride4-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-N,N-dimethyl-

2,2-diphenyl-butyramide

ON

N

OH

Cl

C29H34Cl2N2O2

513.50C29H33ClN2O2

477.04

+ HCl

36.46

ON

N

OH

Cl

HCl

Acetone

.



Flowchart:

Di phenyl acetonitrile1,2-Dichloro ethaneTBABC.S.LYEAcetic acidToluene Methanol

Stage-1Methanol RecoveryToluene RecoveryEffluent water

Stage-2 Isopropyl alcohol RecoveryEffluent water

Acetic AcidSulfuric acidSoda ash (10%)Isopropyl alcohol

Stage-3Toluene RecoveryEffluent water

HBr In Acetic acid (40%)Toluene


Thionyl chlorideToluene

Stage-5 Toluene RecoveryEffluent water

Sodium carbonateDimethylamineToluene

Stage-6Toluene RecoveryMethanol RecoveryEffluent water

4-Chloro Phenyl Magnesium BromideHydrobromic acidSodium HydroxideHydrochloric acidMethanolToluene

4-(4-Chloro-phenyl)-piperidin-4-olPotassium IodidePotassium carbonateActivated CarbonAcetone

Acetone recoveryEffluent water

Hydrochloric acidAcetone Acetone Recovery

Stage-7

Stage-8

LOPERAMIDE HCL

LOPERAMIDE HCL



Material Balance:

Material balance of Loperamide HCl Stage-1 Batch Size: 200.0 Kg



Di phenyl acetonitrile 114.00 Stage-1 142.00 1,2-Dichloro ethane 260.00 Dichloro ethane Recovery 190.00 TBAB 6.00 Dichloro ethane Loss 5.00 C.S.LYE 15.00 Toluene Recovery 285.00 Acetic acid 0.50 Toluene Loss 5.00 Toluene 300.00 Methanol recovery 190.00 Methanol 200.00 Methanol Loss 5.00 Water 500.00 Effluent water 526.50 (Water-500,Acetic acid-

0.5,C.S.lye-15, TBAB-6, Toluene-5)

Process emission 21.50 (Hydrogen Chloride-21.50) Organic Residue 25.50 Process residue-9.5,

Distillation residue-16 (Dichloro ethane -6,Toluene-5,Methanol-5)

Total 1395.50 Total 1395.50

Material balance of Material balance of Loperamide HCl Stage-2 Batch Size: 200.0 Kg



Stage-1 142.00 Stage-2 125.00 Acetic Acid 55.00 Effluent water 474.70 Sulfuric acid 55.00 (Water-290, Acetic acid-

55, soda ash solution-100, Ammonium chloride-29.70)

Soda ash (10%) 100.00 Isopropyl alcohol Recovery

143.00

Isopropyl alcohol 150.00 Isopropyl alcohol Loss 5.00 Water 300.00 Process Emission 44.44 (Sulphur dioxide-35.56,

Oxygen-8.88)


Distillation residue-2 (Isopropyl alcohol-2)




Material balance of Material balance of Loperamide HCl Stage-3 Batch Size: 200.0 Kg



Stage-2 125.00 Stage-3 160.00 HBr In Acetic acid (40%) 108.00 Toluene Recovery 238.00 Toluene 250.00 Toluene Loss 7.00 Water 300.00 Effluent water 369.80 (Water-300, Acetic acid-

64.8,Toluene-5)




Material Balance of Loperamide HCl Stage-4 Batch Size:200Kg



Stage-3 160.00 Stage-4 160.00 Thionyl chloride 60.00 Toluene recovery 190.00 Toluene 200.00 Toluene loss 5.00 Process Emission 50.38 (Sulphur dioxide-32.11,

Hydrogen Chloride-18.27







Stage-4 160.00 Stage-5 152.00 Sodium carbonate 40.00 Toluene Recovery 190.00 Dimethylamine 26.00 Toluene Loss 5.00 Toluene 200.00 Effluent Water 343.00 Water 300.00 (Water-300,Sodium

Carbonate-40,Toluene-3)

Process emission 17.27 (Hydrogen Chloride-17.27) Organic residue 18.73 Process residue-16.73








4-Chloro Phenyl Magnesium Bromide

106.00 Stage-6 94.00

4-Oxo-Piperidine-1-Carboxylic acid ethyl ester

85.00 Methanol Recovery 285.00

Hydrobromic acid 40.00 Methanol Loss 10.00 Sodium Hydroxide 19.00 (Mixed solvent)

Toluene Recovery + Generated Ethanol

211.59

Hydrochloric acid 18.00 Toluene Loss 5.00 Methanol 300.00 Effluent water 520.84 Toluene 200.00 (Water-400, Magnesium

Bromide-90.45,Sodium Chloride-27.39,Toluene-3)

Water 400.00 Process emission 20.62 (carbondioxide-20.62) Organic residue 20.95 Process residue-13.95


Total 1168.00 Total 1168.00

Material Balance of Loperamide HCl Stage-7: Batch Size:200Kg



Stage-6 152.00 Stage-7 200.00 4-(4-Chloro-phenyl)- piperidin-4-ol

94.00 Acetone recovery 190.00

Potassium Iodide 20.00 Acetone loss 5.00 Potassium carbonate 40.00 Effluent Water 460.00 Activated Carbon 10.00 (Water-400,Potassium

Iodide-20, Potassium Carbonate-40)

Acetone 200.00 Spent carbon 10.00 Water 400.00 Process emission 35.52 (Hydrogen Bromide-35.52 Organic Residue 15.48 Process residue-10.48

Distillation residue-5 (Acetone-5)




Material Balance of Loperamide HCl Stage-8:



in Kg Stage-7 200.00 Loperamide HCl 200.00 Hydrochloric acid 15.00 Acetone recovery 190.00 Acetone 200.00 Acetone loss 5.00 Organic residue 20.00 Process residue-15



LOSARTAN POTASSIUM Process Description Stage-1 Orthototylbenzonitrile and Sodium nitrate reacts with Sodium azide and sodium nitrite

in presence of Toluene and Hcl to give Stage-1 product.

Stage-2

Stage-1 product reacts with trityl chloride in presence of MDC to give Stage-2

product.

Stage-3

Stage-2 product undergoes bromination with N-Bromasuccinimiode in presence of

MDC and Ethyl acetate to give stage-3 product.

Stage-4

Stage-3 product undergoes condensation eith Butyl Chloroformyl imidazole in

presence of Sodium hydroxide and Methanol to give Stage-4 product..

Stage-5

Stage-4 product undergoes salt formation with POTASSIUM Hydroxide in presence of

Methanol to give Losartan potassium.




Ortho tolylbenzonitrile

CN

CH3

+

Sodium Azide

NaN3 + NaNO2 + 2 HCl

CH3

N N

NHN

5-(4'-Methyl-biphenyl-2-yl)-2H-tetrazole

Sodium nitrite Hydrochloric Acid

C14H11N

193.24

65.0 69.0 2X36.46=72.92 C14H12N4

236.27

+ 2 NaCl + H2O + N2

2X58.44=116.89 18.0 28.0 Stage-2

CH3

N N

NHN

5-(4'-Methyl-biphenyl-2-yl)-2H-tetrazole

C14H12N4

236.27

+

trityl chloride

Cl + HCl

5-(4'-Methyl-biphenyl-2-yl)-2-trityl-2H-tetrazole

36.46

CH3

N N

NN

C19H15Cl

278.78

C33H26N4

478.59



Stage-3

5-(4'-Methyl-biphenyl-2-yl)-2-trityl-2H-tetrazole

CH3

N N

NN

C33H26N4478.59

+

N-Bromosuccinimide

OO N

Br

CH2Br

N N

NN

5-(4'-Bromomethyl-biphenyl-2-yl)-2-trityl-2H-tetrazole

C4H4BrNO2177.98

C33H25BrN4 557.48

OOHN

+

Succinimide

C4H5NO299.09



Stage-4 CH2Br

N N

NN

5-(4'-Bromomethyl-biphenyl-2-yl)-2-trityl-2H-tetrazole

C33H25BrN4 557.48

NH

N

ClCH3

HO+

HO

N

NHN

N N

N

Cl

+ NaOH

Sodium hydroxide

+

trityl alcohol

OH

Losartan Base

+ NaBr

Sodium bromide

C22H23ClN6O 422.91

C19H16O260.33

102.89

40.0C8H13ClN2O

188.65

Butylchloroformyl imidazole

Stage-5

HO

N

NHN

N NN

Cl

Losartan BaseC22H23ClN6O

422.91

+ KOH

HO

N

NKN

N NN

Cl

C22H22ClKN6O 461.00

Losartan PotassiumPotassium hydroxide56.11

+ H2O

18.0

Flow Chart:



Stage-1

Stage-2

Stage-3

Ortho tolylbenzonitrileSodium AzideHydrochloric acidSodium nitriteToluene


Stage-1Trityl chlorideTEAMDCMethanol

MDC RecoveryMethanol RecoveryEffluent water

Stage-2N-Bromosuccinimide (NBS)Sodium meta bisulphateMethylenedichlorideEthyl Acetate

Methylene dichlorie RecoveryEthyl acetate RecoveryEffluent water

LOSARTAN POTASSIUM

Stage-4

Stage-3Butyl chloro formyl imidazole TBABMethanolSodium hydroxide



Stage-4Potassium hydroxideMethanolActivated Carbon

LOSARTAN POTASSIUM

Material Balance:

Material Balance Of Losartan Potassium

Stage-1 Batch Size:100kg



Ortho tolylbenzonitrile 62.00 Stage-1 70.00

Sodium Azide 20.85 Toluene Recovery 380.00 Hydrochloric acid 23.50 Toluene Loss 8.00 Sodium nitrite 22.15 Effluent water 645.21 Toluene 400.00 (Water-600,

Generated water-5.76, Sodium chloride-37.45,

0



Toluene-2) Water 600.00 Process Emission 8.92 (Nitrogen-8.92) 0 Organic Residue 16.37 Process residue-6.37

Distillation Residue-10 (Toluene-10)

Total 1128.50 Total 1128.50

Material Balance Of Losartan Potassium Stage-2

Batch Size:100kg Name of the input Quantity


in Kg Stage-1 70.00 Stage-2 130.00 Trityl chloride 82.50 MDC Recovery 475.00 TEA 30.00 MDC Loss 10.00 MDC 500.00 Methanol Recovery 475.00 Methanol 500.00 Methanol Loss 10.00 Water 500.00 Effluent Water 530.00 (Water-500,TEA-30) 0 Process emission 10.78 (Hydrogen chloride-10.78) 0 Organic Residue 41.72 Process residue-11.72

Distillation Residue-30 (Methanol-15,MDC-15)

Total 1682.50 Total 1682.50




in Kg Stage-2 130.00 Stage-3 140.00 N-Bromosuccinimide (NBS) 48.25 Methylenedichloride

Recovery 380.00

Sodium meta bisulphate 10.00 Methylenedichloride Loss 8.00 Methylenedichloride 400.00 Ethyl Acetate Recovery 190.00 Ethyl Acetate 200.00 Ethyl Acetate Loss 4.00 Water 600.00 Effluent Water 613.00 (Water-600,

Sodium meta bisulphate-10, Ethyl acetate-3,)

0




Process residue-38.25 (Organic impurities-11.34 succinimide-26.91) Distillation Residue-15 (Ethyl acetate-3,MDC-12)

Total 1388.25 Total 1388.25




in Kg Stage-3 140.00 Stage-4 99.00 Butyl chloro formyl imidazole (BCFI)

47.35 Methanol Recovery 760.00

TBAB 5.00 Methanol Loss 20.00 Methanol 800.00 Effluent Water 730.76 Sodium hydroxide 9.95 (Water-700,

Sodium bromide-25.76, TBAB-5)

0

Water 700.00 By-Product 65.24 (trityl alcohol-65.24) 0 Organic Residue 7.30 Process residue- 7.30

Distillation Residue-20 (Methanol-20)

Total 1702.3 Total 1695

Material Balance Of Losartan Potassium Stage-5:



in Kg Stage-4 99.00 Losartan Potassium 100.00 Potassium hydroxide 13.05 Methanol Recovery 380.00 Methanol 400.00 Methanol Loss 10.00 Activated Carbon 15.00 Effluent Water 406.15 Water 400.00 (Water-400,

Generated water-4.15) 0

Spent Carbon 15.00 Organic Residue 15.90 Process residue-5.90





NEBIVOLOL HYDROCHLORIDE Process Description: Stage-1:

(R)-2-(benzyl amino)-1-(6-fluro-3, 4-dihydro-2H-chromen-2-yl) ethanol react with 6-Fluro-3, 4-dihydro-2-(oxiran-2- yl)-2H chromene in presence of diisopropylethylamine, Methanol,HCl to form NBL/Stage-1. Stage-2: NBL/Stage-I reacts with Pd/C in presence of methanol and treated with IPA HCL to form Nebivolol hydrochloride Pharma (Stage-2). Route of synthesis Stage-1

O

F

O

F

N O

F

MethanolO

F

NH

OH

(R)-2-(benzylamino)-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol

OH

OH

O

6-fluoro-3,4-dihydro-2-((R)-oxiran-2-yl)-2H-chromene

HCl

HCl+ HCl

36.5

2-{Benzyl-[2-(6-fluoro-chroman-2-yl)-2-hydroxy-ethyl]-amino}-

1-(6-fluoro-chroman-2-yl)-ethanol Hydrochloride

C18H20FNO2

301.36

C11H11FO2194.2

C29H32ClF2NO4

532.02Stage-2

O

F

HN O

FPd/C, MeoHIPA HCl

Nebivolol Hydrochloride

C22H25F2NO4 HCL

CH3

Toluene

HCl OH

OHO

F

N O

F

OH

OHHCl

2-{Benzyl-[2-(6-fluoro-chroman-2-yl)-2-hydroxy-ethyl]-amino}-

1-(6-fluoro-chroman-2-yl)-ethanol Hydrochloride

+ H2

2.00

C29H32ClF2NO4

532.02

C7H8

92.14

442.03



Flow Chart

Stage-1

Stage-2

NEBIVOLOL HYDROCHLORIDE

(R)-2-(benzyl amino)-1-(6-fluro-3,4-dihydro-2H-chromen-2-yl) ethanol6-Fluro-3,4-dihydro-2-(oxiran-2- yl)-2HchromeneDiiso propyl etherMethanol

Methanol Rec

Stage-1MethanolPd/carbon

Methanol Rec

Material Balance

Material Balance of Nebivolol Hydrochloride Stage-1 BatchSize:200.0Kg



(R)-2-(benzyl amino)-1-(6-fluro-3,4-dihydro-2H-chromen-2-yl) ethanol

169.00 Stage-1 268.00

6-Fluro-3,4-dihydro-2-(oxiran-2- yl)-2Hchromene

108.85 Methanol Recovery

550.00 Diiso propyl ether 400.00 Methanol Loss 30.00 Methanol 600.00 Diiso propyl ether

Recovery 380.00

Hydrochloric acid 20.45 Diiso propyl ether Loss 20.00 Organic Residue 50.30 Process residue -30.3,

Distillation residue -20 Methanol-20)

Total 1298.30 Total 1298.30

Material Balance of Nebivolol Hydrochloride Stage-2 BatchSize:200.0Kg



Stage-1 268.00

Nebivolol Hydrochloride 200.00



Methanol 800.00 Mixed solvent (Methanol Recovery + Toluene Recovery)

806.36

Pd/carbon 2.00 Methanol Loss 20.00 Hydrogen 0.80 Pd/carbon 2.00 IPA HCl 80.00 IPA Recovery 50.00 IPA Loss 30.00 Organic residue 42.44 Process residue -22.44


Total 1150.80 Total 1150.80

NORTRIPTYLINE HYDROCHLORIDE


Stage-1:

[3-(10,11-Dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-dimethyl-amine Hydrochloride reacts with ethyl chloro formate in presence of Sodium Hydroxide and toluene to give Stage-1 product.

Stage-2:

Stage-1 Product undergoes Hydrolysis with Potassium Hydroxide in presence of Isopropyl alcohol an Hydrochloric acid to give Stage-2 product.

Stage-3:

Stage-2 product undergoes Salt formation in presence of IPA.HCl and Acetone to give Nortriptyline Hydrochloride.



Route of Synthesis

Satge-1:

NCH3

CH3

. HCl

[3-(10,11-Dihydro-dibenzo[a,d]cyclohepten-5-ylidene)

-propyl]-dimethyl-aminehydrochloride

C20H24ClN

313.86

Ethyl chloroformate

O

O Cl+

C3H5ClO2

108.52

+ NaOH40.00

+

Sodium Sulphate, Toluene , DM water

NaCl58.44

+ HCl36.46

NCH3

OO

CH3

[3-(10,11-Dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-methyl-carbamic acid

ethyl esterC22H25NO2

335.44

+ CH3OH32.04

Stage-2

NCH3

O

O

CH3

[3-(10,11-Dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-methyl-carbamic acid

ethyl esterC22H25NO2

335.44

Chloroform+ KOH

56.11

+ HCl

36.46

NH

CH3

[3-(10,11-Dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-

methyl-amineC19H21N263.38

+Methyl formate

OOH3C

C2H4O260.05

+ KCl74.55

+ CH3OH

32.04

+

H2O+

18.02

0.5 O2

16.00

Isopropylalcohol



Stage-3

Acetone, Activated carbon

NH

CH3

[3-(10,11-Dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-

methyl-amineC19H21N

263.38

NH

CH3

. HCl

Nortriptyline HCl

C19H22ClN

299.84

+ HCl

36.46

Flowchart:

Stage-1

Stage-2

[3-(10,11-Dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-dimethyl-amine HydrochlorideEthyl chloroformateSodium hydroxideSodium sulphateToluene


Stage-1Potassium HydroxideHydrochloric acidChloroform IPA

IPA RecoveryEffluent water

Stage-3

Stage-2Hydrochloric AcidAcetone Activated carbon

Acetone RecoveryEffluent water

NORTRIPTYLINE HYDROCHLORIDE



Material Balance:

Material Balance of Nortriptyline Hydrochloride Stage-1 Batch Size: 200.00 Kg



[3-(10,11-Dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-dimethyl-amine Hydrochloride

240.00

Stage-1 245.00

Ethyl chloroformate 83.00 Toluene Recovery 385.00 Sodium hydroxide 31.00 Toluene Loss 10.00 Sodium sulphate 20.00 Effluent water 472.50 Toluene 400.00 (water-400,Sodium chloride-

45,Methanol-24.5,Toluene-3) 0

Water 400.00 Inorganic solid waste 20.00 (Sodium sulphate-20) 0 Process emission 28.00 (Hydrogen Chloride-28) 0 Organic residue 13.50 Process residue -11.5


Total 1174.00 Total 1174.00




Stage-1 245.00 Stage-2 183.00 Potassium Hydroxide 41.00 Chloroform Recovery 385.00 Hydrochloric acid 27.00 Chloroform Loss 15.00 Chloroform 400.00 IPA Recovery 385.00 IPA 400.00 IPA Loss 10.00 Water 400.00 Effluent water 507.85 (water-386,Potassium chloride-

54.45,Methyl formate-44,Methanol-23.40)

0

Process emission 12.00 (Oxygen-12) 0 Organic residue 15.15 Process residue -10.15

Distillation residue-5 (IPA-5)

Total 1513.00 Total 1513.00






Stage-2 183.00 Nortriptyline Hydrochloride 200.00 Hydrochloric Acid 26.00 Acetone Recovery 190.00 Acetone 200.00 Acetone Loss 5.00 Activated carbon 5.00 Effluent water 300.00 Water 300.00 (water-300) Spent carbon recovery 5.00 Organic residue 14.00 Process residue -9



N-TERT-BUTOXYCARBONYL-4-HYDROXY PIPERIDINE


Stage-1:

N-Carbethoxy-4-Piperidone reacts with Di-tert butyl dicarbonate in presence of water Toluene to give N-Tert-Butoxycarbonyl-4-Hydroxy Piperidine.

Route of Synthesis:

Stage-1

O

O

O

O

O CH3

H3C CH3

H3C

H3C CH3

+

N-Carbethoxy-4-piperidone

NOO

O

N-tert butoxy carbonyl-4-hydroxy piperidine

NHOO

O

CH3

CH3

CH3

C8H13NO3171.19

Di-tert butyl dicarbonateC10H18O5

218.25

C10H19NO3201.26

+ O

O

O

O

HO CH3

H3C CH3

C6H10O5

162.14

+ C2H5OH

Ethanol46.07

+ 2 H2O

36.03

+ 0.5 O2

16.00

Water

Tert butyl pyrocarbonate



Flowchart:

Stage-1

N-TERT-BUTOXYCARBONYL-4-HYDROXY PIPERIDINE

N-Carbethoxy-4-amino piperidinedi-tert butyl dicarbonateToluene


Material Balance:

Material Balance of N-Tert-Butoxycarbonyl-4-Hydroxy Piperidine. Stage-1 Batch Size: 100.00 Kg



N-Carbethoxy-4-amino piperidine 90.00 N-Tert-Butoxycarbonyl-4-Hydroxy Piperidine.

100.00

di-tert butyl dicarbonate 114.66 Toluene Recovery 385.00 Toluene 400.00 Toluene Loss 10.00 Water 400.00 Effluent water 493.53 (Water-381.10, Ethanol-

24.20,Toluene-3, Tert butyl pyrocarbonate-85.23)

0



Total 1004.66 Total 1004.66



OMEPRAZOLE MAGNESIUM DIHYDRATE Process Description: Stage-1: Omeprazole reacts with Ammonium hydroxide and Magnesium sulfates to give Omeprazole Magnesium dihydrate. Route of Synthesis: Stage-1:

N

OCH3

H3C CH3

SNH

N OCH3O

OmeprazoleC17H19N3O3S

2X345.41=690.82

2 + NH4OH

35.04

+ MgSO4

120.36

N

OCH3

H3C CH3

SN-

N OCH3OMg+2 2H2O

2

+ (NH4)2SO4

132.13Ammonium sulfate

749.12

Omeprazole Magnesium Dihydrate

C17H18N3O3S.Mg+2.2H2O

Ammonium hydroxide Magnesium sulphate

Flowchart:

Stage-1

Omeprazole Ammonium hydroxide (20%)Magnesium sulfateActivated carbon

OMEPRAZOLE MAGNESIUM DIHYDRATE

Effluent water



Material Balance: Material Balance Of Omeprazole Magnesium Dihydrate

Stage-1 Batch Size: 100.0Kgs Name of the input Quantity


in Kg Omeprazole 103.00 Omeprazole Magnesium

Dihydrate 100.00

Ammonium hydroxide (20%) 25.75 Effluent water 540.27 Magnesium sulfate 17.90 (Water-500,Water from

ammonium hydroxide-20.60, Ammonium sulfate-19.67)

Activated carbon 5.00 Spent carbon 5.00 Water 500.00 Organic Residue 6.38 (Process residue-6.38) Total 651.65 Total 651.65

OMEPRAZOLE SODIUM

Process Description

5-Methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethanesulfinyl)-1H-benzoimidazole (Omeprazole) Product reacts with sodium hydroxide in the presence of Methanol to give Omeprazole sodium.

OMEPRAZOLE SODIUM

Stage-1:

HN

NS

ON

O

O

(Omeprazole)C17H19N3O3S

345.42

+ NaOH

40.00

N

OCH3H3C CH3

SN

N OCH3O

Na

H2O

Methanol

Omeprazole SodiumC17H19N3NaO3S.H2O

385.41

5-Methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethanesulfinyl)-

1H-benzoimidazole



Flow Chart:

OMEPRAZOLE SODIUM

Stage-1

5-Methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethanesulfinyl)-1H-benzoimidazole (Omeprazole)Sodium hydroxideMethanol

Methanol Recovery

OMEPRAZOLE SODIUM

Material Balance:

Material Balance of Omeprazole Sodium Stage-1 Batch Size: 500.00Kg



5-Methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethanesulfinyl)-1H-benzoimidazole (Omeprazole)

462.00 Omeprazole Sodium 500.00

Sodium hydroxide 54.00 Methanol Recovery 380.00 Methanol 400.00 Methanol Loss 10.00 Organic Residue 26.00 Process residue-16



OMEPRAZOLE

Process description:

Stage-1

3,5-Dimethyl-pyridine undergoes Oxidation with Hydrogen peroxide in presence of Acetic acid to give Stage-1 product

Stage-2

Stage-1 product undergoes Nitration with Nitric acid in presence of Sulphuric acid & Methanol to give Stage-2 product

Stage-3



Stage-2 product reacts with Dimethylsulphate in presence of Chloroform & Methanol to give Stage-3 product

Stage-4

Stage-3 product reacts with Ammonium persulphate and Ammonium sulphate in presence of Toluene & Methanol to give Stage-4 product

Stage-5

Stage-4 product undergoes Chlorination with Thionyl chloride in presence of Toluene , IPA & Acetone to give Stage-5 product

Stage-6

Stage-5 product undergoes Condensation with 2-Mercapto-5-methoxy benzimidazole in presence of Toluene, Sodium hydroxide & Water to give Stage-6 product

Stage-7

Stage-6 product undergoes Oxidation with Hydrogen peroxide in presence of Acetic acid & Dichloromethane to give Omeprazole product

Route of Synthesis:

Stage-1

N

3,5-Dimethyl-pyridineC7H9N

107.15

+ H2O2

34.01

Acetic acidN+

+O-

3,5-Dimethyl-pyridine 1-oxideC7H9NO

123.15

H2O18.02



Stage-2

MethanolN+

+O-

3,5-Dimethyl-pyridine 1-oxideC7H9NO

123.15

H2O18.02

+ 2 NH3

34.06

H2SO4

98.08

+ HNO3

63.01

N+

O-

NO2

3,5-Dimethyl-4-nitro-pyridine 1-oxide

C7H8N2O3

168.15

+

Ammonium sulphate

NH4+

NH4+

S

O

O-O O-

(NH4)2SO4

132.14

+

Stage-3

Methanol, Chloroform

N+

O-

NO2


C7H8N2O3

168.15

Dimethylsulphate

SO

O

OO

+

C2H6O4S

126.13

+ 2 NaOH

80.00

+ CH3COOH

60.05

CH3OH+

32.04

N+

O

OMe

CH3SO4-

C10H17NO6S

279.31

+ CH3COONa

82.03

+ NaNO2

69.00

+ 2 H2O

36.03Methyl sulphate salt formation of 1,4-Dimethoxy-3,5-dimethyl-pyridinium



Stage-4

N+

O

OMe

CH3SO4-

C10H17NO6S279.31 Ammonium Sulphate,

Toluene & mehanol

Ammonium perSulphate,

NH4+

NH4+

O-SO

OOOS O

O

-O

+

1,4-Dimethoxy-3,5-dimethyl-pyridinium

methyl sulphateH8N2O8S2

228.20

N

OMe

OH

(4-Methoxy-3,5-dimethyl-pyridin-2-yl)-methanol

C9H13NO2

167.21

+

Ammonium Sulphate,

NH4+

NH4+

S

O

O-O O-

H8N2O4S

132.14X2=264.28

+ 2 NH4OH

35.04X2=70.08

2

+ H2O2

34.02

+ CH3OH

32.02

+ 2 H2O

36.03 64.06

+ SO2 + 1.5 O2

48

Stage-5

N

O

+

C9H13NO2

167.21

OH

2-Hydroxy methyl-3,5-dimethyl-4-

methoxypyridine

N

O

ClHCl.

C9H13Cl2NO

222.11

2-Chloromethyl-4-methoxy-3,5-dimethyl-pyridine Hydrochloride

Isopropyl alcoholToluene ,ice , Acetone ,

Sodium sulphate Activated carbon & Hyflow

SOCl2

118.97

+ SO2

64.06



Stage-6

C9H13Cl2NO222.11

N

O

Cl+

2-Chloromethyl-4-methoxy-3,5-dimethyl pyridine

Hydrochloride

HCl.

2-Mercapto-5-methoxy benzimidazole

N

HN

OHS

C8H8N2OS

180.23

+ 2 NaOH

80.00

Toluene & Water

N

NH

OS

NCH3

H3C OCH3

5-Methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethylthio)-1H-benzo[d]imidazole

C17H19N3O2S329.42

+ 2 NaCl

116.89

+ 2 H2O

36.04

Stage-7

N

NH

OS

NCH3

H3C OCH3

5-Methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethylthio)-1H-

benzo[d]imidazole

C17H19N3O2S

329.42

+

34.01

EDTA, CS Flakes , Acetic acid , Hydrose , Activated carbon, Dichloromethane

HN

NS

O

N

O

O

Omeprazole

C17H19N3O3S

345.42

+ H2O

18.01

HO OH



Flow chart:

3,5- Lutidine Hydrogen peroxide Acetic acid Sodium tungstate

Water from hydrogen peroxide+ Acetic acid Sodium tungstate Recovery

Stage-1Sulphuric acid Nitric acid (72%)Ammonia gas Methanol Water

Effluent Water

Stage-2Dimethylsulphate Sodium hydroxid flakesMethanol Acetic acidChloroform Water

Chloroform Recovery Methanol recoveryEffluent Water

Stage-3Ammonium persulphateAmmonium sulphateHydrogen peroxideMethanol Toluene Ammonium hydroxide HyflowCarbon Water

Toluene Recovery Methanol recoveryEffluent Water

Iso propyl alcohol recoveryAcetone recovery Effluent Water

Stage-4Thionyl chloride Isopropylalcohol Toluene Acetone Sodium sulphate HyflowCarbon Hydrochloric acid Liq Ammonia (15 %)Ice

Toluene RecoveryEffluent Water

Stage-1

Stage-2

Stage-3

Stage-4

Stage-5

Stage-6

Stage-52-Mercapto-5-methoxy benzimidazoleCaustic lye Toluene Water



Stage-6Hydrogen peroxide Sodium Hydroxide flakesAmmonia Acetic acid Dichloromethane HydroseActivated carbon EDTATriethylamine Water

Dichloromethane RecoveryEffluent WaterStage-7

Omeprazole

OMEPRAZOLE

Material Balance

Material Balance of Omeprazole Stage-1



in Kg 3,5- Lutidine 765.00 Stage-1 878.00 Hydrogen peroxide 691.00 Water from hydrogen

peroxide+ Acetic acid 723.00

Acetic acid 145.00 Sodium tungstate Recovery

5.00

Sodium tungstate 5.00 Total 1606 Total 1606




in Kg Stage-1 878.00 Stage-2 915.00 Sulphuric acid 3059.00 Effluent Water 1339.00 Nitric acid (72%) 1535.00 (Water-730.5Generated

water-128.5, Water from Nitric acid-430, Methanol-50)

0

Ammonia gas 1275.00 By product (Ammonium sulphate)

942.00

Methanol 50.00 Water Recovery 21000.00 Water 18000.00 Water evaporation loss 600.00 Total 24796 Total 24796






in Kg Stage-2 915.00 Stage-3 2385.00 Dimethylsulphate 637.00 Chloroform Recovery 21000.00 Sodium hydroxid flakes 266.00 Chloroform loss 1000.00 Methanol 7000.00 Methanol recovery 6485.00 Acetic acid 80.00 Methanol loss 341.00 Chloroform 22000.00 Effluent Water 264.00 Water 4200.00 (Water-68, Generated

water-196) 0

Water recovery 2800.00 By product

(Sodium nitrite-376, Sodium acetate-447 ))

823.00





in Kg Stage-3 2385.00 Stage-4 742.00 Ammonium persulphate 160.00 Toluene Recovery 1763.00 Ammonium sulphate 1193.00 Toluene loss 37.00 Hydrogen peroxide 581.00 Methanol recovery 6798.00 Methanol 7155.00 Methanol loss 143.00 Toluene 1855.00 Effluent Water 1543.84 Ammonium hydroxide 614.00 ( Generated water-307.65,

Methanol-273.41,Toluene-55, Water from hydrogen peroxide-907.78)

0

Hyflow 2.00 Water recovery 11500.00 Carbon 25.00 Evaporation loss 867.00 Water 12000.00 Spent Carbon & hyflow 27.00 By products

(Ammonium sulphate) 1378.30

Process emissions (sulphur dioxide-547, Oxygen-409.86)

956.86

Organic Residue Distillation Residue-214 (Methanol-214)

214.00







in Kg Stage-4 742.00 Stage-5 715.00 Thionyl chloride 742.00 Toluene Loss 200.00 Isopropylalcohol 265.00 Iso propyl alcohol

recovery 265.00

Toluene 200.00 Acetone recovery 250.00 Acetone 250.00 Effluent Water 589.80 Sodium sulphate 50.00 (Ice-196.6,

Water from Ammonia-190, Water from Hydrochloric acid-203.2)

0

Hyflow 3.00 Water recovery 3700.00 Carbon 15.00 Spent Carbon & hyflow 18.00 Hydrochloric acid 1975.00 Inorganic solid waste

(Sodium sulphate) 50.00

Liq Ammonia (15 %) 1325.00 Process emissions (sulphur dioxide-284.30, Hydrogen chloride-494.9)

779.20

Ice 1000.00 Total 6567 Total 6567




in Kg Stage-5 715.00 Stage-6 1000.00 2-Mercapto-5-methoxy benzimidazole

615.00 Toluene Recovery 3800.00

Caustic lye 630.00 Toluene Loss 80.00 Toluene 4000.00 Effluent Water 1431.00 Water 5000.00 (Water-500,

Generated water-116 Sodium chloride-377, Toluene-60, Water form Caustic lye-378)

0

Water recovery 4589.00 Organic Residue 60.00 Distillation Residue-60

(Toluene )







in Kg Stage-6 1000.00 Omeprazole 920.00 Hydrogen peroxide 230.00 Dichloromethane

Recovery 2375.00

Sodium Hydroxide flakes 150.00 Dichloromethane Loss 50.00 Ammonia 4.00 Effluent Water 831.00 Acetic acid 250.00 (Water-200,

Generated water-55 Sodium hydroxide flakes-150,Ammonia-4, Acetic acid -250, Hydrose-10, Triethylamine-30, EDTA-5, Water from hydrogen peroxide-127)

0

Dichloromethane 2500.00 Water recovery 5900.00 Hydrose 10.00 Spent carbon 5.00 Activated carbon 5.00 Organic Residue 103.00 EDTA 5.00 Process residue-28

Distillation Residue-75 (Dichloromethane )

Triethylamine 30.00 Water 6000.00 Total 10184 Total 10184



OXATOMIDE

Description: Stage-1: 1- (diphenyl methyl) piperazine reacts with 1-(3-chloropropyl)1,3-dihydro-2H-benzimidazol-2-one, in presence of Methyl Iso butyl ketone ,Soda ash, Water, sodium hydroxide, Con HCl, to give Staeg-1 product. Stage-2:

Stage-1 Product undergoes purification with Methanol and Carbon to give Oxatomide.

Route of Synthesis

Stage-1:

N

NH

N

HN

O

Cl

1-(3-Chloro-propyl)-1,3-dihydro-benzoimidazol-2-one

NN N

NH

O

1- (diphenyl methyl) piperazine

+

1-[3-(4-Benzhydryl-piperazin-1-yl)-propyl]-1,3-dihydro-benzoimidazol-2-one

+ NaCl

C27H30N4O

426.55

58.44

+ 1/2 Na2CO3

C17H20N2

252.35C10H11ClN2O

210.66

53.0

+ 1/2 CO2

22.0

MIBK/Sodium hydroxide

HCl

+ 1/2 H2O

9.0



Stage-2:

N NN

NH

O


C27H30N4O

426.55

N N N

NH

O


C27H30N4O

426.55

Methanol

Flow Chart

Stage-1

Stage-2

1-(diphenyl methyl) piperazine1-(3-chloropropyl)1,3-dihydro-2H-benzimidazol-2-oneSodium carbonateDil. Hydrochloride MIBK

MIBK RecoveryEffluent water

Stage-1Activated CarbonMethanol

OXTOMIDE

Methanol RecoverySpent carbon

Material Balance

Material Balance of Oxtomide Stage-1 BatchSize:100 Kg



1-(diphenyl methyl) piperazine 65.00 Stage-1 105.00 1-(3-chloropropyl)1,3-dihydro-2H-benzimidazol-2-one

54.25 MIBK Recovery 283.00

Sodium carbonate 13.65 MIBK Loss 15.00 Dil. Hydrochloride 10.00 Effluent Water 627.32 MIBK 300.00 (Water-600,Generated wtaer-

2.28, Sodium chloride-15.04, Water from HCl-10

0

Water 600.00 Process Emission 5.65 (Carbon dioxide-5.65) 0



Organic Residue 6.93 (Process residue -4.93,

Distillation residue -2 (MIBK-2)

Total 1042.90 Total 1042.90

Material Balance of Oxtomide Stage-2 BatchSize:100 Kg



Stage-1 105.00 Oxtomide 100.00 Activated Carbon 10.00 Methanol Recovery 475.00 Methanol 500.00 Methanol Loss 10.00 Spent Carbon 10.00 Organic Residue 20.00 Process residue-5



PANTOPRAZOLE SODIUM SESQUIHYDRATE

Process description:

Stage-1

Maltol reacts with Dimethylsulphate and Sodium hydroxide in presence of Water and

Chloroform to give Stage-1 product

Stage-2

Stage-1 product reacts with Ammonium hydroxide in presence of Water to give

Stage-2 product

Stage-3

Stage-2 product reacts with Phosphorous oxychloride in presence of Ammonium

hydroxide & Water to give Stage-3 product

Stage-4

Stage-3 product reacts with Hydrogen peroxide in presence of Acetic acid,

Chloroform & Ammonium hydroxide to give Stage-4 product



Stage-5

Stage-4 product reacts with Sodium hydroxide, Methanol & Acetic anhydride in

presence of Methanol, Toluene & Chloroform to give Stage-5 product

Stage-6

Stage-5 product reacts with Sodium hydroxide in presence of Water &

Chloroform to give Stage-6 product

Stage-7

Stage-6 product undergoes Chlorination with Thionyl chloride in presence of

Methanol & Acetone to give Stage-7 product

Stage-8

Stage-7 product reacts with 5-Difluoromethoxy-2-mercapto-1H-benzimidazole in

presence of Water , Sodium hydroxide & Dichloromethane to give Stage-8 product

Stage-9

Step-A

Stage-8 product reacts with Sodium oxy chloride in presence of Acetone & Ethyl

acetate to give Step-A product

Step-B

Step-A product reacts with Sodium hydroxide in presence of Acetone & Ethyl

acetate to give Step-B product

Step-C

Step-B product reacts with Water in presence of Acetone & Ethyl acetate to give Pantoprazole Sodium Sesquihydrate product



Route of Synthesis:

Stage-1

Na+

SO

O

O

-O

O

O

OH

CH3

MaltolC6H6O3

126.11

Dimethyl sulphate

(CH3)2SO4

126.13

2 NaOH

80.00

O

O

OCH3

CH3

C7H8O3

140.14

++

+

+ HCl36.46

Chloroform & water

3-Methoxy-2-methyl-pyran-4-one

+ NaCl

58.44

2 H2O+

36.03Sodium methyl sulphateCH3NaSO4

134.09

Stage-2:

O

O

OCH3

CH3

C7H8O3

140.14

+

3-Methoxy-2-methyl-pyran-4-one

NH4OH

35.05

NH

O

OCH3

CH3

3-Methoxy-2-methyl-1H-pyridin-4-one

C7H9NO2

139.15

+ 2 H2O

36.03



Stage-3

NH

O

OCH3

CH3

C7H9NO2

+ POCl3

Phosphorous oxychloride

153.33

N

Cl

OCH3

CH3

C7H8ClNO

+

3-Methoxy-2-methyl-1H-pyridin-4-one

+ 4NH4OH

4-Chloro-3-methoxy-2-methyl-pyridine

(NH4)3PO4

149

+ HCl

36.46

+

53.49

4X35.04=140.16

+ 2H2O

157.60

NH4Cl

2X18.01=36.02

139.15

Ammonium phosphate

Water

Ammonium chloride

Stage-4:

N

Cl

OCH3

CH3

C7H8ClNO

157.60

+ H2O2

Hydrogen peroxide

34.01

Chloroform , Sodium tungstate

& Methnol

N+

Cl

OCH3

CH3

O-

3-methoxy-2-methyl-4-chloro pyridine-N-oxide

C7H8ClNO173.60

+ 2 H2O

36.03

4-Chloro-3-methoxy-2-methyl-pyridine

NH4OH+

35.05

+ CH3COOH

60.05

+

Ammonium acetate

NH4+

O

-O

C2H7NO2

77.08



Stage-5:

N+

Cl

OCH3

CH3

O-

3-methoxy-2-methyl-4-chloro pyridine-N-oxide

C7H8ClNO2

173.60

NaOH

40.00

+

methanol , Chloroform , Toluene & Acetic acid+

Aceticanhydride

OO

O

C4H6O3

102.09

N

OCH3

OCH3

CH2

O

CH3

O

Acetic acid 3,4-dimethoxy-2-methylene-2H-pyridin-1-yl ester

C10H13NO4

211.21

+ CH3COOH

60.05

+ NaCl

58.44

+ CH3OH

32.04

+ H2O

18.02



STAGE-6

Activated carbon , Chloroform , Sodium sulphate & Water

+ NaOH

40.00

N

OCH3

OCH3

CH2

O

CH3

O

Acetic acid 3,4-dimethoxy-2-methylene-2H-pyridin-1-yl ester

C10H13NO4

211.21

N

OCH3

OCH3

OH

(3,4-Dimethoxy-pyridin-2-yl)-methanol

C8H11NO3

169.18

+ CH3COONa

82.03



Stage-7:

Methanol & AcetoneN

OCH3

OCH3

OH

(3,4-Dimethoxy-pyridin-2-yl)-methanol

C8H11NO3

169.18

+ SO2

64.06

+ SOCl2

118.97

N

OCH3

OCH3

Cl . HCl

2-Chloromethyl-3,4-dimethoxy-pyridine; Hydrochloride

C8H11Cl2NO2

224.08



Stage-8:

Dichloromethane & water

+N

OCH3

OCH3

Cl .HCl

2-Chloromethyl-3,4-dimethoxy-pyridine; Hydrochloride

C8H11Cl2NO2

224.08

NO

HN

F F

SH

5-Difluoromethoxy-2-mercapto-1H-benzimidazole

+

C8H6F2N2OS

216.21

2 NaOH

80.00

N

OCH3

OCH3

CH2 S

N

HN

O

F

F5-Difluoromethoxy-2-(3,4-dimethoxy-pyridin-

2-ylmethylsulfanyl)-1H-benzoimidazole

C16H15F2N3O3S

367.37

+ 2 NaCl

116.89

+ 2 H2O

36.03



Stage-9:

Step-A

Hypo , Acetone & Ethyl acetate

N

OCH3

OCH3

CH2 S

N

HN

O

F

F5-Difluoromethoxy-2-(3,4-dimethoxy-pyridin-

2-ylmethylsulfanyl)-1H-benzoimidazole

C16H15F2N3O3S

367.37

+

74.44

+ NaCl

58.44

NaOCl

N

OCH3

OCH3

CH2 S

N

HN

O

F

F

O

5-Difluoromethoxy-2-(3,4-dimethoxy-pyridin-2-ylmethanesulfinyl)-1H-benzoimidazole

C16H15F2N3O4S

383.37



Step-B

Hypo , Acetone & Ethyl acetate

+

40.00

+ H2O

18.02

NaOH

N

OCH3

OCH3

CH2 SN

HN

OF

F

O

5-Difluoromethoxy-2-(3,4-dimethoxy-pyridin-2-ylmethanesulfinyl)-1H-benzoimidazole

C16H15F2N3O4S

383.37

N

OCH3

OCH3

CH2 S

N

N

O

F

F

O

Na

Pantoprazole Sodium

C16H14F2N3NaO4S

405.35



Step-C

N

OCH3

OCH3

CH2 SN

N

OF

F

O

+

Na

H2O

Pantoprazole sodium

C16H14F2N3NaO4S

405.35

27.00

Pantoprazole Sodium Sesqui Hydrate

.

C16H17F2N3NaO6S

432.37

N

OCH3

OCH3

CH2 SN

N

OF

F

O

Na

Acetone

1.5

1.5 H2O



Flow chart:

Maltol Sodium hydroxide Dimethyl sulphate Chloroform Hydrochloric acid Water

Chloroform recovery Effluent water

Stage-1Ammonium hydroxide Effluent Water

Stage-2Phosphorous oxy chloride Ammonium hydroxide Water

Effluent Water

Stage-3Hydrogen peroxide Methanol Acetic acid Ammonium hydroxideChloroform Sodium tungstate

Chloroform recovery Methanol recoveryEffluent Water

Chloroform recovery Methanol recoveryToluene recovery

Stage-4Sodium hydroxide Acetic anhydride Acetic acid Chloroform Methanol Toluene

Chloroform recovery Effluent Water

Stage-1

Stage-2

Stage-3

Stage-4

Stage-5

Stage-6

Stage-5Caustic lye Activated carbon Chloroform Sodium sulphateWater



Stage-6Thionyl chloride MethanolAcetone

Methanol Recovery Acetone recoveryStage-7

Stage-8

Stage-9

Stage-75-Difluoromethoxy-2-mercapto-1H-benzimidazoleSodium hydroxide Dichloromethane Water

Dichloromethane Recovery Effluent Water

Stage-8Sodium hypochlorite Sodium Hydroxide flakesEthyl acetate AcetoneWater

Ethyl acetate RecoveryAcetone RecoveryEffluent Water

Pantoprazole Sodium Sesquihydrtae

PANTOPRAZOLE SODIUM SESQUIHYDRATE

Material balance

Material Balance of Pantoprazole Sodium Sesquihydrtae Stage-1



in Kg Maltol 557.00 Stage-1 557.00 Sodium hydroxide 483.00 Chloroform recovery 2660.00 Dimethyl sulphate 669.00 Chloroform loss 140.00 Chloroform 2800.00 Effluent water

(Water -268 generated water-163, Sodium chloride-258.1)

689.10

Hydrochloric acid 33.00 Water recovery 2182.00 Water 2450.00 By product

(Sodium methyl sulphate-711)

711.00

Organic residue 52.90 Total 6992 Total 6992



Material Balance of Pantoprazole Sodium Sesquihydrtae Stage-2 Batch Size: 750Kg



Stage-1 557.00 Stage-2 557.00 Ammonium hydroxide 836.00 Effluent water

(generated water-143.20Watre from ammonium hydroxide-692.8)

836.00





Stage-2 557.00 Stage-3 537.00 Phosphorous oxy chloride 896.00 Effluent water

(generated water-144.18,Water from Ammonium hydroxide-530.68)

674.86

Ammonium hydroxide 1592.00 Water recovery 3840.00 Water 3342.00 By product

(Ammonium Phosphate-870 Ammonium chloride -312.20)

1189.20

Process emission (Hydrogen chloride)

145.94





Stage-3 537.00 Stage-4 557.00 Hydrogen peroxide 583.00 Chloroform recovery 2645.00 Methanol 567.00 Chloroform loss 140.00 Acetic acid 58.00 Methanol recovery 539.00 Ammonium hydroxide 179.00 Methanol loss 11.00 Chloroform 2785.00 Effluent water

(generated water-123, Sodium tungstate-18, Water from hydrogen peroxide-414)

555.00

Sodium tungstate 18.00 By product (Ammonium acetate )

263.00



Organic residue Distillation Residue-17 (Methanol)

17.00





Stage-4 557.00 Stage-5 557.00 Sodium hydroxide 140.00 Chloroform recovery 346.00 Acetic anhydride 335.00 Chloroform loss 18.00 Acetic acid 220.00 Methanol recovery 1226.00 Chloroform 364.00 Methanol loss 28.00 Methanol 1393.00 Toluene recovery 133.00 Toluene 140.00 Toluene loss 7.00 By product

(Acetic acid -569,) 569.00

Effluent water (Generated water -57.81, Sodium chloride-145)

202.81

Organic residue Process residue-26.19 Distillation Residue-36 (Methanol)

62.19





Stage-5 557.00 Stage-6 429.00 Caustic lye 995.00 Chloroform recovery 3838.00 Activated carbon 15.00 Chloroform loss 202.00 Chloroform 4040.00 Effluent water

(Water from Sodium hydroxide-875)

875.00

Sodium sulphate 30.00 Water recovery 3180.00 Water 3180.00 By product

(Sodium acetate) 248.00

Spent carbon 15.00 Inorganic solid waste

(Sodium sulphate) 30.00







Stage-6 429.00 Stage-7 500.00 Thionyl chloride 378.00 Methanol Recovery 713.00 Methanol 750.00 Methanol loss 15.00 Acetone 1275.00 Acetone recovery 1211.00 Acetone loss 26.00 Process emission

(sulphur dioxide-162.44) 162.44


Distillation Residue-60 (Methanol-22, Acetone-38)





Stage-7 500.00 Stage-8 825.00 5-Difluoromethoxy-2-mercapto-1H-benzimidazole

500.00 Dichloromethane Recovery

4750.00

Sodium hydroxide 225.00 Dichloromethane loss 100.00 Dichloromethane 5000.00 Effluent Water 5400.00 Water 5000.00 (Water-5000

Generated water-80.39 , Sodium chloride-319.61)

0

Organic Residue 150.00 Distillation Residue-150

(Dichloromethane)





Stage-8 825.00 Pantoprazole Sodium Sesquihydrtae

750.00

Sodium hypochlorite 7500.00 Ethyl acetate Recovery 1900.00 Sodium Hydroxide flakes 80.00 Ethyl acetate Loss 40.00 Ethyl acetate 2000.00 Acetone Recovery 3800.00 Acetone 4000.00 Acetone Loss 80.00 Water 5000.00 Effluent Water 1715.00 (Water-1169, Generated 0



water-40.46 , Ethyl acetate-60, Sodium chloride-445.54)

Water recovery 11000.00 Organic Residue 120.00 Distillation Residue-120

(Acetone-120)


PIMOZIDE

Process Description: Stage-1: 4-chloro-1, 1-bis (4-fluorophenyl) butane (PIM-III) react with 1-(piperidin-4-yl) 1H-

benza imidazole-2(3H)-one (Keto-9) in presence of sodium carbonate, tetrabutyl

ammonium bromide, MIBK to give Stage-1 product

Stage-2: Stage-1 Product undergoes Purification with Methanol and carbon to form Pimozide.

Route of synthesis Stage-1

F

F

N

HN

O

NH

F

F

NHN

ON

Cl

4-chloro-1,1-bis(4-fluorophenyl)butane

1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

1-(1-(4,4-bis(4-fluorophenyl)butyl)piperidin-4-yl)-1H-

benzo[d]imidazol-2(3H)-one

+ + 1/2 Na2CO3

MIBK

TBAB

53.0

+ NaCl + 1/2 H2O + 1/2 CO2

58.44 9.0 22.0

C16H15ClF2

280.74C12H15N3O

217.27

C28H29F2N3O

461.55



Stage-2

F

F

NHN

ON

1-(1-(4,4-bis(4-fluorophenyl)butyl)piperidin-4-yl)-1H-benzo

[d]imidazol-2(3H)-one

F

F

NHN

ON

Pimozide

(Pimozide Crude)

Methanol

Activated Carbon

C28H29F2N3O

461.55

C28H29F2N3O

461.55

Flow Chart

Stage-1

Stage-2

PIMOZIDE

4-chloro-1, 1-bis (4-fluorophenyl) butane (PIM-III) 1-(piperidin-4-yl) 1H-benza imidazole-2(3H)-one (Keto-9)Sodium carbonate (25%)Potassium IodideTetra butyl ammonium bromideMIBK

MIBKl RecoveryEffluent water

Stage-1Activated CarbonMethanol

Methanol recoverySpent carbon

Material Balance



Material Balance of Pimozide Stage-1

BatchSize:100 Kg Name of the input Quantity in


in Kg 4-chloro-1, 1-bis (4-fluorophenyl) butane (PIM-III)

67.00 Stage-1 105.00

1-(piperidin-4-yl) 1H-benza imidazole-2(3H)-one (Keto-9)

52.00 MIBK Recovery 285.00

Sodium carbonate (25%) 50.00 MIBK Loss 12.00 Potassium Iodide 1.00 Effluent Water 457.09 Tetra butyl ammonium bromide 2.50 (Water-400,Generated water-

2.14,water form Sodium carbonate-37.5,Sodium Chloride-13.95, Potassium Iodide-1,TBAB-2.5)

MIBK 300.00 Process Emission 5.22 Water 400.00 (Carbon dioxide-5.22) Organic Residue 8.19 (Process residue -5.19,

Distillation residue-3 MIBK-3)


Material Balance of Pimozide Stage-2

BatchSize:100 Kg Name of the input Quantity in


in Kg Stage-1 105.00 Pimozide 100.00 Activated Carbon 5.00 Methanol Recovery 285.00 Methanol 300.00 Methanol Loss 10.00 Spent Carbon 5.00 Organic Residue 10.00 Process residue-5

Distillation residue -5 Methanol-5




PREGABALIN

Process Description: Stage-1 2-(1-Cyano-3-methyl-butyl)-malonic acid diethyl ester reacts with Hydrogen in

presence of Raney Nickel, Potassium hydroxide, Acetic acid and Water to give

Stage-1 product.

Stage-2 Stage-1 product reacts with Mandelic acid in presence of IPA to give Stage-2

product.

Stage-3 Stage-2 product reacts with Sodium hydroxide in presence of THF to give Pregabalin

product.



PREGABALIN Route of Synthesis: Stage –1

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

C13H21NO4

255.31

CH3C

CH3

N

O

OC2H5

C

O

OC2H5

KOH + CH3COOH

CH3COOK CO22 C2H5OH

+

+++

56.11 60.05

C8H17NO2

159.23

98.14 44.003-Aminomethyl 5 -methyl

hexanoic acid

H2O

18.00

Raney Nickel

+ 2H2

2X2=4.0

+

H3C

H3C

NH2

COOH

2 X46.07=92.14

Methanol

Stage –2

C8H17NO2

2 x 159.23 = 318.46

3-Aminomethyl 5 -methylhexanoic acid

H3C

H3CNH2

COOH

+ COOH

OH

Mandelic acidC8H8O3

152.15

IPA

-OOC

HO

C16H25NO5

S(+)Pregabalin mandalate salt

H3C

H3CNH3

+

COOH

+ (R)-Isomer

159.23

2

311.37



Stage –3

-OOC

HO

C16H25NO5

311.37

S(+)Pregabalin mandalate salt

H3C

H3C

NH3+

COOH

COOH

OH

Mandelic acid

C8H8O3

152.14

C8H17NO2

159.23

S(+)Pregabalin

THF

H3C

H3C

NH2

COOH

+NaOH

Flow Chart:

2-(1-Cyano-3-methyl-butyl)-malonic acid diethyl esterEthanolPotassium hydroxideAcetic acidRaney nickelIPAHydrogen gas

Ethanol Recovery IPA Recovery

stage-1

IPA Recoverystage-2

THF Recovery IPA Recovery

stage-3

Stage-1(S)-Mandelic acidIsopropyl alcohol

Stage -2TetrahydrofuranIsopropyl alcohol

Pregabalin



PREGABALIN Material Balance:

Material Balance Of Pregabalin Stage-1

Batch Size: 200.0Kgs Name of the input Quantity


in Kg 2-(1-Cyano-3-methyl-butyl)-malonic acid diethyl ester

753.00 Stage-1 445.00

Ethanol 200.00 Ethanol Recovery 461.08 Potassium hydroxide 165.00 Ethanol loss 10.00 Acetic acid 176.95 IPA Recovery 333.00 Raney nickel 5.00 IPA Loss 12.00 IPA 350.00 Raney Nickel Reuse 5.00 Hydrogen gas 11.30 Effluent water 836.44 Water 600.00 (Water-547.29,Poatassium

acetate-289.15)

Process emission 129.52 (Carbon dioxide-129.52) 0 Organic residue 29.21 Process residue-24.21

Distillation residue-5 (IPA-5)

Total 2261.25 Total 2261.25




in Kg Stage-1 445.00 Stage -2 413.00 (S)-Mandelic acid 213.00 IPA Recovery 475.00 Isopropyl alcohol 500.00 IPA Loss 10.00 Water 300.00 Effluent water 300.00 (Water-300) Organic residue 260.00 Process residue-

245,organic impurities-22.5 (R-Isomer Recycle-222.5) Distillation residue-15 (IPA-15)

Total 1458.00 Total 1458.00




Batch Size:200.0Kg Name of the input Quantity


in Kg Stage -2 413.00 Pregabalin 200.00 Tetrahydrofuran 300.00 THF Recovery 285.00 Isopropyl alcohol 400.00 THF Loss 15.00 Sodium Hydroxide 5.00 IPA Recovery 385.00 Water 500.00 IPA Loss 15.00 Effluent water 505.00 (Water-500,Sodium

hydroxide-5) 0

Organic residue 213.00 Process residue-213

(Organic impurities-11.46 Mandelic acid recovery-201.54) Distillation residue-5 (IPA-5)

Total 1618.00 Total 1618.00

QUETIAPINE FUMARATE


Stage-1:

11-Piperazin-1-yl-4a,11a-dihydro-dibenzo[b,f] [1,4]thiazepine Di hydrochloride reacts with 2-Chloroethoxy ethanol in presence of Sodium carbonate, Toluene and water to give Stage-1 product.

Stage-2:

Stage-1 product reacts with Fumaric acid in presence of Acetone to give Quetiapine Fumarate.



Route of Synthesis:

Stage-1

S

NN

NH . 2 HCl

11-Piperazin-1-yl-4a,11a-dihydro-dibenzo[b,f][1,4]thiazepine Di hydrochloride

C17H21Cl2N3S

370.34

+

2-Chloroethoxy ethanol

HOO

Cl

C4H9ClO2

124.57

+ Na2CO3

105.99

S

NN

NO

OH

2-{2-[1-(4a,11a-Dihydro-dibenzo[b,f][1,4]thiazepin-11-yl)-piperidin-4-yl]-ethoxy}-ethanol(Quetiapine)

C21H27N3O2S

385.52

+ 2 NaCl

116.89

+ CO2

44.01

+ H2O

18.02

+ HCl

36.46

Toluene

Stage-2

S

NN

NO

OH

2-{2-[1-(4a,11a-Dihydro-dibenzo[b,f][1,4]thiazepin-11-yl)-piperidin-4-yl]-ethoxy}-

ethanol(Quetiapine)C21H27N3O2S

771.00

+

Fumaric acid

O

OHO

HO

C4H4O4116.07

S

NN

N O OH

2.

OOH

OHO

Quetiapine FumarateC46H58N6O8S2

887.12

Acetone2



Flowchart:

Stage-1

Stage-2

11-Piperazin-1-yl-4a,11a-dihydro-dibenzo[b,f][1,4]thiazepine Dihydrochloride2-Chloroethoxy ethanolSodium carbonateToluene

Toluene recoveryEffluent water

Stage-1Fumaric acidAcetone


QUETIAPINE FUMARATE

Material Balance:

Material Balance of Quetiapine Fumarate. Stage-1



in Kg 11-Piperazin-1-yl-4a,11a-dihydro-dibenzo[b,f] [1,4]thiazepine Di hydrochloride

90.00 Stage-1 90.00

2-Chloroethoxy ethanol 30.25 Toluene Recovery 285.00 Sodium carbonate 25.75 Toluene loss 10.00 Toluene 300.00 Effluent water 434.59 Water 400.00 (Water-400, Generated water –

4.32, Sodium chloride-27.27,Toluene-3)

Process emission 19.44 (Hydrogen Chloride– 8.82,

Carbon dioxide-10.62)

Organic residue 6.97 Process residue – 4.97

Distillation residue-2 ((Toluene-2)

Total 846.00 Total 846.00 Material Balance of Quetiapine Fumarate.

Stage-2 Batch Size: 100.00 Kg





Stage-1 90.00 Quetiapine Fumarate. 100.00 Fumaric acid 13.50 Acetone Recovery 285.00 Acetone 300.00 Acetone loss 10.00 Water 400.00 Effluent water 400.00 (Water-400) 0 Organic residue 8.50 Process residue – 3.50



RABEPRAZOLE SODIUM

Process Description

Stage-1

2, 3-Lutidine reacts with Hydrogen Peroxide and Nitric acid in presence of Sulfuric Acid and water to give Stage-1Product.

Stage-2

Stage-1 Product reacts with 3-Methoxy-1-Propanol and Sodium Hydroxide in presence of Toluene and DMSO to give Stage-2 Product.

Stage-3

Stage-2 Product reacts with Acetic Anhydride in presence of Sodium Hydroxide, Toluene and Hydrochloric Acid to give Stage-3 Product.

Stage-4

Stage-3 Product reacts with Thionyl Chloride in the presence of Toluene,Methanol and MDC to giveStage-4 Product.

Stage-5

Stage-4 Product reacts with 2-Mercapto Benzimidazole, in presence of Toluene, methanol to give Stage-5 Product.

Stage-6

Stage-5 Product reacts with Sodium Hypochlorite in presence of MDC and Toluene to give Stage-6 product.

Stage-7



Stage-6 product reacts with Sodium hydroxide in presence of Acetone to get Rabeprazole Sodium

Route of Synthesis:

Stage-1

N

CH3

CH3

2,3-LutidineC7H9N107.15

+ H2O2

34.01

+ HNO3

63.0

H2SO4+ 2H2O

36.0

C7H8N2O3

168.15

N+

O-

H3C

H3C

NO2


Stage-2

C7H8N2O3168.15

4-Nitro-2,3-Dimethyl pyridine-N-oxide

3-Methoxy-1-Propanol

HO O + NaOH+

C4H10O2

90.12 C11H17NO3211.26

+ NaNO2 + H2O

Sodium Nitrite

69.0

18.0

40.0

N+

O-

H3C

H3C

NO2

N+

H3C

O O

O-

H3C

4-(3-Methoxy-propoxy)-2,3-dimethyl-pyridine 1-oxide

TolueneDMSO



Stage-3

C11H17NO3

211.26

N+

H3C

O O

O-

H3C

4-(3-Methoxy-propoxy)-2,3-dimethyl-pyridine 1-oxide

OO

O

+

Acetic anhydride

NaOH

4(3-methoxy propoxy)-2-hydroxy methyl -3-methyl pyridine hydrochloride

+

CH3COONa+ CH3COOH

82.0 60.0

40.0

C11H17NO3 HCl

247.72

+ HCl

36.5C4H6O3

102.09

HClN

OH

OO

.+

Toluene

Methanol

Stage-4

Toluene

Methanol

4(3-methoxy propoxy)-2-hydroxy methyl -3-methyl pyridine hydrochloride

+

C11H17NO3 HCl

247.72

HClN

OH

OO

. SOCl2

118.97

Thionyl Chloride 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine hydrochloride

HClN

Cl

OO

.

C11H17Cl2NO2

266.16

SO2+ HCl

64.0 36.46

+



Stage-5

Toluene

Methanol

2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine hydrochloride

HClN

Cl

OO

.

C11H17Cl2NO2

266.16

2-Mercapto benzimidazole

N

HN

HS +

80.00

2 NaOH

C7H6N2S

150.25

+

2-[4-(3-Methoxy-propoxy)-3-methyl-pyridin-2-ylmethylthio]-1H-benzo[d]imidazole

NCH2

O O

N

NH

S

C18H21N3O2S

343.44

+ + 2 H2O

36.03

2 NaCl

116.89

Stage-6

2-[4-(3-Methoxy-propoxy)-3-methyl-pyridin-2-ylmethylthio]-1H-benzo[d]imidazole

NCH2

O O

N

NH

S

C18H21N3O2S343.44

+ NaOCl

NCH2

O O

N

NH

S

O

2-[4-(3-Methoxy-propoxy)-3-methyl-pyridin-2-ylmethanesulfinyl]-1H-benzoimidazole

C18H21N3O3S

359.44

+ NaCl

58.5

74.44

Sodium Hypochlorite

Toluene

MDC



Stage-7

NCH2

O O

N

NH

S

O

2-[4-(3-Methoxy-propoxy)-3-methyl-pyridin-2-ylmethanesulfinyl]-1H-benzoimidazole

C18H21N3O3S

359.44

+ NaOH NCH

O O

N

NH

S

O

Na

Rabeprazole Sodium40.0 + H2O

18.0C18H20N3NaO3S

381.42

Acetone



RABEPRAZOLE SODIUM

Flow Chart:

Stage-1

Stage-2

Stage-3

Stage-4

Stage-5

Stage-6

Stage-7

2,3-LutidineHydrogen Peroxide (50%)Nitric acidSulphuric acidAcetic acid

Effluent water

Stage-13-Methoxy-1-PropanolSodium HydroxideTolueneDMSO

Toluene RecoveryDMSO RecoveryGenerated water

Stage-2Acetic anhydrideSodium HydroxideHydrochloric acidTolueneMethanol

Toluene RecoveryMthanol RecoveryEffluent water

Stage-3Thionyl ChlorideMDCSodium SulphateToluene Methanol

Methanol RecoveryMDC RecoveryEffluent water

Stage-42-MercaptobenzimidazoleSodium hydroxideTolueneMethanol


Stage-5Sodium Hypochlorite (8%)MDCToluene Sodium hydro sulphateMMA in Methanol

MDC RecoveryEffluent water

Stage-6Sodium HydroxideAcetone Activated Carbon

Acetone Recovery Generated water

RABEPRAZOLE SODIUM



RABEPRAZOLE SODIUM

Material Balance:

Material balance of Rabeprazole Sodium Stage-1



in Kg 2,3-Lutidine 210.00 Stage-1 310.00 Hydrogen Peroxide (50%) 135.00 Spent Acids for sale 140.00 Nitric acid 124.00 (Sulfuric Acid-100,Acetic

Acid-40)

Sulphuric acid 108.00 Effluent Water 552.55 Acetic acid 46.00 (Water-400,Sulfuric Acid-

8,Acetic Acid-6,Generated water-70.55,Water from Hydrogen peroxide-68)

Water 400.00 Organic Residue 20.45 Process resiue-20.45 Total 1023.00 Total 1023.00




in Kg Stage-1 310.00 Stage-2 370.00 3-Methoxy-1-Propanol 167.00 Toluene Recovery 235.00 Sodium Hydroxide 74.00 Toluene Loss 12.00 Toluene 250.00 DMSO Recovery 188.00 DMSO 200.00 DMSO Loss 10.00 Generated water 33.18 Inorganic Solid Waste 127.20 (Sodium Nitrite-127.20) 0 Organic residue 25.62

Process residue-20.62 Distillation residue-5 (Toluene-3,DMSO-2)

Total 1001.00 Total 1001.00






in Kg Stage-2 370.00 Stage-3 412.00 Acetic anhydride 179.00 Toluene Recovery 380.00 Sodium Hydroxide 70.00 Toluene Loss 10.00 Hydrochloric acid 64.00 Methanol Recovery 475.00 Toluene 400.00 Methanol Loss 15.00 Methanol 500.00 Effluent Water 653.61 Water 400.00 (Water-400,Sodium

Acetate-143.61,Acetic Acid-105, Toluene-5)

0.00


Distillation residue-15 (Toluene-5,Methanol-10)

Total 1983.00 Total 1983.00




in Kg Stage-3 412.00 Stage-4 420.00 Thionyl Chloride 198.00 MDC Recovery 710.00 MDC 750.00 MDC Loss 37.00 Sodium Sulphate 10.00 Toluene Recovery 475.00 Toluene 500.00 Toluene Loss 10.00 Methanol 500.00 Methanol Recovery 475.00 Water 500.00 Methanol Loss 15.00 Effluent Water 508.00 (Water-500,Toluene-8) 0 Inorganic Solid Waste 10.00 (Sodium Sulphate) 0 Process Emission 167.08 (sulfur dioxide-106.44,

Hydrogen chloride-60.64)

0

Organic Residue 42.92 Process residue -22.92

Distillation residue-20 (Methanol-10, Toluene-7, MDC-3)

Total 2870.00 Total 2870.00






in Kg Stage-4 420.00 Stage-5 510.00 2-Mercaptobenzimidazole 240.00 Toluene Recovery 380.00 Sodium hydroxide 127.00 Toluene Loss 10.00 Toluene 400.00 Methanol Recovery 380.00 Methanol 400.00 Methanol Loss 10.00 Water 400.00 Effluent Water 646.31 (Water-400,Sodium

chloride-184.45,Generated water-56.86,Toluene-5)

0


Distillation residue-15 (Toluene-5, Methanol-10)

Total 1987.00 Total 1987.00




in Kg Stage-5 510.00 Stage-6 500.00 Sodium Hypochlorite (8%) 1388.00 MDC Recovery 570.00 MDC 600.00 MDC Loss 30.00 Toluene 150.00 Toluene Recovery 143.00 Sodium hydro sulphate 12.00 Toluene Loss 5.00 MMA in Methanol 10.00 Effluent Water 1775.87 Water 400.00 (Water-400,Sodium

Chloride-86.87,water from sodium hypochlorite-1277, ,MMA-10, Toluene-2)

Organic Solid Waste 46.13 Process residue-43.13


Total 3070.00 Total 3070.00






in Kg Stage-6 500.00 Rabeprazole Sodium 500.00 Sodium Hydroxide 56.00 Acetone Recovery 280.00 Acetone 300.00 Acetone Loss 15.00 Activated Carbon 10.00 Generated water 25.00 Spent carbon 10.00 Organic Residue 36.00 (Process residue-31,



RUPATADINE FUMERATE


Stage-1:

8-chloro-6,11-dihydro-11-(4-piperdinylidene)-5H-benzo(5,6)cyclohepta(1,2-b)pyridine react with 3-chloromethyl-5-methylpyridine in presence of sodium hydroxide, water, TBAB, Ethyl acetate to give stage-1 product.

Stage-2 :

Stage-1 product reacts with But-2-enedioic acid in presence of Methanol, Acetone to give Rupatadine Fumerate

Route of synthesis

Stage-1

N

NH

Cl

N

Cl

N

N

Cl

N

3-(chloromethyl)-5-methylpyridine

8-chloro-6,11-dihydro-11-(4-piperdinylidene)- 5H-benzo

[5,6]cyclohepta[1,2-b]pyridine

Sodium hydroxide,TBAB

8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

Ethyl acetate+

C19H19ClN2310.82

C7H8ClN141.6 C26H26Cl

N3415.96



Stage-2

N

N

Cl

N

8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine N

N

Cl

N

8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-

5H-benzo[5,6]cyclohepta[1,2-b]pyridine fumeric acid

COOHH

HOOC H

Methanol,AcetoneCOOHH

HOOC H

+

But-2-enedioic acid

C4H4O4

116.07C26H26ClN3

415.96

C30H30ClN3O4

532.03

Flow Chart

Stage-1

Stage-2

8-chloro-6,11-dihydro-11-(4-piperdinylidene)-5H-benzo(5,6)cyclohepta(1,2-b)pyridine3-chloromethyl-5-methylpyridineEthyl acetateSodium hydroxideTBAB

Ethyl acetate RecoveryEffluent water

Stage-1But-2-enedioic acidMethanolAcetoneActivated carbon

Methanol recoveryAcetone recovery

RUPATADINE FUMERATE



RUPATADINE FUMERATE

Material Balance

Material Balance of Rupatadine Fumerate Stage-1

BatchSize:100.0Kg Name of the input Quantity in

Kg Name of the out put Quantity in

Kg 8-chloro-6,11-dihydro-11-(4-piperdinylidene)-5H-benzo(5,6)cyclohepta(1,2-b)pyridine(DLRD)

62.00 Stage-1 80.00

3-chloromethyl-5-methylpyridine 28.20 Ethyl acetate Recovery 190.00

Ethyl acetate 200.00 Ethyl acetate Loss 5.00 Sodium hydroxide 20.00 Effluent water 625.00 TBAB 2.00 (Water-600,TBAB-2,

Sodium hydroxide-20, Ethyl acetate-3)

0

Water 600.00 Organic Residue 12.20 Process residue-10.20

Distillation residue-2 (Ethyl acetate-2)


Material Balance of Rupatadine Fumerate Stage-2

BatchSize:100.0Kg Name of the input Quantity

in Kg Name of the out put Quantity in

Kg Stage-1 80.00 Rupatadine Fumerate 100.0 But-2-enedioic acid 22.30 Acetone Recovery 93.00 Methanol 150.00 Acetone Loss 5.00 Acetone 100.00 Methanol Recovery 143.00 Activated carbon 5.00 Methanol Loss 4.00 Spent carbon 5.00 Organic residue 7.30

Process residue-2.30 Distillation residue-5 ( Acetone-2,Methanol-3)




TELMISARTAN

Process Description

Stage-1

4-Methyl-biphenyl-2-carbonitrile undergoes hydrolysis with Potassium Hydroxide

inpresence of Ethylene glycol and HCl to give Stage-1 product. Stage-2

Step-A

Stage-1product undergoes methylation with Dimethyl sulphate in presence of

Potassium carbonate and MDC to give step-A product.

Step-B Step-A product undergoes Bromination with DDH in presence of Acetone and Cyclo

hexane to give Stage-2 product.

Stage-3

Stage-2 product undergoes condensation with 1,7’-Dimethyl-2’-propyl-

3’a,4’,5’,6’,7’,7’,a-hexahydro-1H,3’H-[2,5’]bibenzoimidazolyl in presence of

potassium hydroxide and acetone to give stage-3 product..

Stage-4

Stage-3 product undergoes hydrolysis with Potassium Hydroxide in presence of

water and Acetic acid to give Telmisartan.



Route of Synthesis:

Stage-1

+ HO OHEthylene glycol

CH3

CN

4'-Methyl-biphenyl-2-carbonitrile

+KOH

CH3

COOH

+ + NH3

56.11

+ HCl

KCl +

C14H11N

193.24

C2H6O2

62.07

36.46

4'-Methyl-biphenyl-2-carboxylic acid

C14H12O2

212.24

74.55 17.03

+ H2O

18.02

CH3COOH

60.05+ H2

2.02

Stage-2

Step-A

CH3

COOH

4'-Methyl-biphenyl-2-carboxylic acid

C14H12O2

212.24

+

Dimethyl sulphate

126.13

+ K2CO3

138.21

CH3

COOCH3

+ CH3OH + K2SO4 + CO2

44.00

C2H6SO4

4'-Methyl-biphenyl-2-carboxylic acid methyl ester

C15H14O2

226.27

32.04 174.26



Step-B

CH3

COOCH3

4'-Methyl-biphenyl-2-carboxylic acid methyl ester

C15H14O2

226.27

NON

OCH3CH3

Br

Br

DibromodimethylHydantoin

H2C

COOCH3

Br

+NO

N

O

CH3

CH3

Br

H

1-Bromo-5,5-dimethyl-imidazolidine-2,4-dione

+

C5H6Br2N2O2

285.92

C15H13O2Br

305.17

4'-Bromomethyl-biphenyl-2-carboxylic acid methyl ester

C5H7BrN2O2

207.03



Stage-3:

H2C

COOCH3

Br

+

C15H13O2Br

305.17

4'-Bromomethyl-biphenyl-2-carboxylic acid methyl ester

+ KOH

COOCH3N N

H3C N

N

CH3

CH3

+

Telmisartan Ester

N N

H3C NNH

CH3

CH3

310.44

C19H26N4

1,7'-Dimethyl-2'-propyl-3'a,4',5',6',7',7'a-hexahydro-1H,

3'H-[2,5']bibenzoimidazolyl

56.11

C34H32N4O2

534.69

KBr H2O+

119 18.02

Stage-4

COOCH3N N

H3C NN

CH3

CH3

+

Telmisartan EsterC34H32N4O2

534.69

+ KOH + CH3COOHWaterMDC

COOHN N

H3C NN

CH3

CH3

Telmisartan

CH3OH + CH3COOK

56.11 60.05

520.66C33H36N4O2

32.04 Potassium Acetate98.14



Flow Chart:

Stage-1

Stage-2

Stage-3

Stage-4

TELMISARTAN

4-methyl-biphenyl-2-carbonitrileEthylene glycolPotassium HydroxideHydrochloric acid

Effluent water

Stage-1Di methyl sulphateDibromodimethyl HydantoinPotassium CarbonateAcetoneCyclohexaneActivated CarbonMDC

Acetone RecoveryMDC recoveryEffluent water

Stage-21,7'-Dimethyl-2'-propyl-3'a,4',5',6',7',7'a-hexahydro-1H,3'H-[2,5']bibenzoimidazolylPotassium HydroxideAcetone


Stage-3Potassium HydroxideAcetic acidDMFMethanolMDCActivated Carbon

MDC RecoveryMethanol RecoveryEffluent water



Material Balance: Material, balance of Telmisartan

Stage-1 Batch Size:100kg



4-methyl-biphenyl-2-carbonitrile

52.00 Stage-1 53.00

Ethylene glycol 16.70 Effluent Water 631.31 Potassium Hydroxide 15.08 (Water-595.17,

Potassium chloride-20.02, Acetic acid-16.12)

0

Hydrochloric acid 9.77 Process Emission 5.09 Water 600.00 (Ammonia-4.57,Hydrogen-

0.52)

Organic Residue 4.15 Process Residue-4.15 Total 693.55 Total 693.55

Material, balance of Telmisartan Stage-2



in Kg Stage-1 53.00 Stage-2 67.00 Di methyl sulphate 31.50 MDC Recovery 570.00 Dibromodimethyl Hydantoin 66.95 MDC Loss 12.00 Potassium Carbonate 34.50 Acetone Recovery+

Methanol 387.95

Acetone 400.00 Acetone Loss 10.00 Cyclohexane 200.00 Cyclohexane Recovery 190.00 Activated Carbon 5.00 Cyclohexane Loss 5.00 MDC 600.00 Effluent Water 843.50 Water 800.00 (Water-800,Potassium

sulphate-43.50) 0

Spent Carbon 5.00 Process Emission 10.98 (Carbon dioxide-10.98) 0 Organic Residue 89.52 Process Residue-56.52

Organic impurities-8.08 (1-Bromo-5,5-dimethyl-imidazolidine-2,4-dione-48.44) Distillation Residue-33 (Acetone-10,Cyclo hexane-5,MDC-18)

Total 2190.95 Total 2190.95






in Kg Stage-2 67.00 Stage-3 110.00 1,7'-Dimethyl-2'-propyl-3' a,4',5',6',7',7'a-hexahydro-1H, 3'H-[2,5']bibenzoimidazolyl

68.15 Acetone recovery 475.00

Potassium Hydroxide 12.25 Acetone loss 15.00 Acetone 500.00 Effluent water 430.00 Water 400.00 (Water-400,

Generated water-3.95, Potassium bromide-26.05)

0

Organic Residue 17.40 Process Residue-7.40

Distillation Residue-10 (Acetone-10)

Total 1047.40 Total 1047.40




in Kg Stage-3 110.00 Telmisartan 100.00 Potassium Hydroxide 11.45 Methanol Recovery+

Generated Methanol 386.49

Acetic acid 12.32 Methanol Loss 12.00 DMF 100.00 MDC Recovery 380.00 Methanol 400.00 MDC Loss 8.00 MDC 400.00 DMF Recovery 95.00 Activated Carbon 5.00 DMF Loss 2.00 Water 600.00 Effluent water 620.13 (Water-600, Potassium

Acetate-20.13)

Spent Carbon 5.00 Organic Residue 30.15 Process Residue-7.15

Distillation Residue-23 (MDC-12,Methanol-8,DMF-3)

Total 1638.77 Total 1638.77



TERBINAFINE HYDROCHLORIDE

Process Description: Stage-1 Napthyl methyl chloride reacts with Methyl amine in the presence of to give stage-1 product. Stage-2 Pinacolone undergoes Alkylation in the presence of Potassium carbonate, Acetone and Hydrochloric acid to give stage-2 product. Stage-3 Stage-2 Product reacts with acrolein in the presence of DIPE to give stage-3 product. Stage-4 Step-A: Stage-3 Product reacts with Isopropyl alcohol in presence of Aluminium Isopropoxide to give Step-A Product. Step-B: Step-A product reacts with Hydrochloric acid in presence of Toluene and Methanol to give stage-4 Product. Stage-5 Stage-4 Product reacts with Stage-1 in presence of Potassium Carbonate, Methanol, Toluene and Ethyl acetate to give Terbinafine Hydochloride

TERBINAFINE HYDROCHLORIDE

Route of synthesis:

Stage-1:

Methyl amine

H2N CH3

31.06

HCl

Napthyl methyl chloride

Cl

+

C11H9Cl

176.64 C12H14ClN207.70

Methanol .

N-Methyl-1-napthalene methylamine HCl

NH3C CH3



Stage-2:

Pinacolone

CH3

OH3C

H3CH3C

C6H12O

100.15

H3C

H3C

H3C

CH

C6H10

82.14

3,3-Dimethyl-but-1-yne

+ K2CO3 +

138.20

Acetone+ 2 HCl

72.92

2 KCl

149.10

+ + CO22 H2O

36.04 44.01Stage-3:

H3C

H3CH3C

CH

C6H10

82.14

3,3-Dimethyl-but-1-yne

+

Acrolein

OH2C

C3H4O

56.06

H3CH3C

H3C

CHO

6,6-Dimethyl-hept-2-en-4-ynal

+

C9H12O136.19

DIPE

H2

2.00

Stage-4:

Step-A

H3CH3C

H3C

CHO

6,6-Dimethyl-hept-2-en-4-ynal

C9H12O

136.19

+

Isopropyl alcohol

CH3H3C

OH

C3H8O

60.09

H3CH3C

H3COH

6,6-Dimethyl-hept-2-en-4-yn-1-ol

C9H14O138.20

Aluminium isopropoxide

+

Acetone

H3C

O

CH3

C3H6O

58.07



Step-B

H3CH3C

H3COH

6,6-Dimethyl-hept-2-en-4-yn-1-ol

C9H14O

138.20

+

36.5

HCl

H3C

H3C

H3C

Cl

1-Chloro-6,6-dimethyl-hept-2-en-4-yne

C9H13Cl

156.65

H2O+

18.0

Stage-5:

Toluene

1-Chloro-6,6-Dimethyl Hept-2-ene-4-yne

H3C

H3C CH3

Cl

C9H13Cl156.65

+

N

CH3H3CCH3

CH3

Terbinafine HydrochlorideC21H26ClN

327.89

+ KCl

+ 1/2K2CO3

69.10

74.55

+ 1/2CO2

22.0

+ 1/2H2O

9.0

. HCl

HCl

C12H14ClN

207.70

.

N-Methyl-1-napthalene methylamine HCl

NH3C CH3



Flow Chart

Stage-1

Stage-2

Stage-3

Stage-4

Stage-5

TERBINAFINE HYDOCHLORIDE

Napthyl methyl chlorideMono methyl amineTolueneMDC

Toluene RecoveryMDC RecoveryEffluent water

Pinacolone Potassium carboanteHydrochloric acidAcetone


Stage-2Acrolein DIPE

DIPE RecoveryEffluent water

Stage-3Isopropyl alcoholHydrochloric acidToluene Methanol Aluminium Isopropoxide

Isopropyl alcohol RecoveryToluene RecoveryEffluent water

Stage-1Stage-4ToluenePotassium carbonateMethanol Ethyl acetate

Toluene RecoveryMetahnol RecoveryEffluent water



Material Balance:

Material Balance of Terbinafine Hydrochloride Stage-1



in Kg Napthyl methyl chloride 150.00 Stage-1 166.00 Mono methyl amine 27.00 Toluene Recovery 285.00 Toluene 300.00 Toluene Loss 10.00 MDC 500.00 MDC Recovery 475.00 Water 450.00 MDC Loss 15.00 Effluent water 453.00 (Water-450, Toluene-3) 0 Organic Residue 23.00 Process residue-11

Distillation residue-12 (Toluene-2, MDC-10)

Total 1427.00 Total 1427.00




in Kg Pinacolone 100.00 Stage-3 77.00 Potassium carboante 138.00 Acetone Recovery 190.00 Hydrochloric acid 73.00 Acetone Loss 5.00 Acetone 200.00 Effluent water 584.85 Water 400.00 (Water-400,Generated water-35.98,

Potassium chloride-148.87)

Process emission 43.94 (Carbondioxide-43.94) Organic Residue 10.21 Process residue-5.21








in Kg Stage-2 77.00 Stage-2 122.00 Acrolein 52.55 DIPE Recovery 475.00 DIPE 500.00 DIPE Loss 25.00 Water 400.00 Effluent water 400.00 (Water-400) Process emission 1.88 (Hydrogen -1.88) Organic Residue 5.67 Process residue-5.67 Total 1029.55 Total 1029.55




in Kg Stage-3 122.00 Stge-4 126.00 Isopropyl alcohol 250.00 Isopropyl alcohol Recovery 190.00 Hydrochloric acid 31.00 Isopropyl alcohol Loss 5.00 Toluene 400.00 (Mixed Solvent)

Toluene recovery + Generated Acetone

432.00

Methanol 400.00 Toluene Loss 12.00 Aluminium Isopropoxide 20.00 Methanol Recovery 380.00 Water 500.00 Methanol Loss 10.00 Effluent water 538.23 (Water-500, Generated water-

15.23,Toluene-3,Aluminium isopropoxide-20)

0


Distillation residue-16 (Toluene-5, Methanol-10,Isopropylalcohol-1)

Total 1723.00 Total 1723.00






in Kg Stage-1 166.00 Terbinafine Hydrochloride 250.00 Stage-4 126.00 Toluene Recovery 475.00 Toluene 500.00 Toluene Loss 15.00 Potassium carbonate 56.00 Methanol recovery 380.00 Methanol 400.00 Methanol Loss 10.00 Ethyl acetate 500.00 Ethyl acetate Recovery 475.00 Water 450.00 Ethyl acetate Loss 15.00 Inorganic solid waste 59.58 (Potassium chloride-59.58) Effluent water 467.19 (Water-450, Generated water-7.19,

Toluene-5, Ethyl acetae-5)

Process Emission 17.58 (Carbon dioxide-17.58) Organic Residue 33.65 Process residue-13.65

Distillation residue-20 (Toluene-5, Ethyl acetate -5, Methanol-10)

Total 2198.00 Total 2198.00

VALSARTAN Process Description:

Stage-1

Step-A:

L-Valine reacts with Thionyl chloride in presence of Toluene to give Step-A product.

Step-B:

Step-A Product reacts with Methanol in presence of water to give Stage-1 Product.

Stage-2:

Stage-1 product reacts with 4-Bromomethyl-biphenyl-2-carbonitrile in presence of Toluene to give Stage-2 product.

Stage-3



Stage-2 product reacts with Valeryl chloride in presence of Toluene to give Stage-3 product.

Stage-4

Stage-3 product reacts with Sodium azide, Tri butyl tin chloride undergoes Hydrogenation in presence of Toluene, MDC and n-Hexane t give Valsartan.

Route of Synthesis:

Stage-1

Step-A

L-Valine

C5H11NO2

117.15

NH2

CH3

H3C OH

O

+ SOCl2

NH2

CH3

H3C Cl

O+ SO2

HCl

Thionyl Chloride

118.972-Amino-3-methyl-butyryl chloride

hydrochlorideC5H11Cl2NO

172.05

64.06

Toluene

Step-B

NH2

CH3

H3C Cl

O

+H

Cl

2-Amino-3-methyl-butyryl chloride

hydrochlorideC5H11Cl2NO

CH3OH

NH2

CH3

H3C OCH3

O HCl + HCl

32.04 2-Amino-3-methyl-butyric Acid methyl ester hydrochloride

36.46

C6H14NO2Cl

167.63

Methanol

172.05



Stage-2

NH2

CH3

H3C OCH3

O HCl

2-Amino-3-methyl-butyric Acid methyl ester hydrochloride

C6H14NO2Cl

167.63

4-Bromomethyl-biphenyl-2-carbonitrile

N

Br

+

N

O

O

NH

2-[(2-Cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid methyl ester

C14H10BrN

272.14

+

Potassium Carbonate

138.21

Toluene

C20H22N2O2

322.40

+ KBr +

K2CO3

KCl + CO2 + H2O

119.0 74.55 44.0 18.0



Stage-3

N

O

O

NH

2-[(2-Cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid methyl ester

C20H22N2O2

322.40

Valeryl Chloride

O

Cl+ + NaHCO3

Sodium bicarbonate

Toluene

C5H9ClO

120.58

84.0

OO

N

N

O

2-[(2-Cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric acid methyl ester

C25H30N2O3

406.52

+ NaCl + CO2 + H2O

58.44 44.0 18.0



Stage-4

O

O

N

N

O

2-[(2-Cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric acid methyl ester

C25H30N2O3

406.52

O

OH

N

O

NN

HN

N

+ NaN3 +

Tributyl tin chloride

SnCl

+ H2

Hydrogen Sodium Azide

2.0 65.0 C12H27ClSn

325.5

Valsartan

C24H29N5O3

435.5

+ SnH3C

+ NaCl

Tributyl methyl stannane

C13H30Sn

305.0

58.46

TolueneMDC



Flow-Chart

Stage-1

Stage-2

L-ValineThionyl ChlorideMethanolToluene

Methanol RecoveryToluene Recovery

Stage-14-Bromomethyl-biphenyl-2-carbonitrilePotassium carbonateToluene


Stage-2Valeryl ChlorideTolueneTEASodium bicarbonateSodium Sulphate


Stage-3Sodium AzideTri butyl tin chlorideHydrogen Sodium hydroxideXyleneTolueneMDCN-HexaneActivated Carbon

Stage-4

Xylene RecoveryMDC RecoveryToluene RecoveryEffluent watetr

VALSARTAN



VALSARTAN

Material Balance:

Material Balance of Valsartan Stage-1



in Kg L-Valine 45.00 Stgae-1 51.00 Thionyl Chloride 45.67 Methanol Recovery 380.00 Methanol 409.00 Methanol Loss 12.00 Toluene 400.00 Toluene Recovery 380.00 Toluene Loss 12.00 Process Emission 34.06 (Sulfur dioxide-24.57, Hydrogen

Chloride-9.49) 0

Organic Residue 30.61 Process residue -14.61,

Distillation residue -16 (Methanol-8, Toluene-8)





in Kg Stage-1 51.00 Stage-2 87.00 4-Bromomethyl-biphenyl-2-carbonitrile

82.77 Toluene Recovery 570.0

Potassium carbonate 42.02 Toluene Loss 20.00 Toluene 600.00 Effluent Water 569.04 Water 500.00 (Water-500,Generated water-5.45,

Potassium chloride-22.44, Potassium Bromide-36.15, Toluene-5)

0

Process Emission 13.36 (Carbon dioxide-13.36) 0 Organic Residue 16.39 Process residue -11.39


Total 1275.79 Total 1275.79






in Kg Stage-2 87.00 Stage-3 104.00 Valeryl Chloride 32.53 Toluene Recovery 665.00 Toluene 700.00 Toluene Loss 20.00 TEA 20.00 Effluent Water 448.52 Sodium bicarbonate 22.62 (Water-400,Generated water-

4.78, Sodium chloride-15.74, TEA-20,Toluene-8)

Sodium Sulphate 10.00 Inorganic Solid Waste 10.00 Water 400.00 (Sodium Sulphate) Process Emission 11.83 (Carbon dioxide-11.83) Organic Residue 12.80 Process residue -5.8,


Total 1272.15 Total 1272.15




in Kg Stage-3 104.00 Valsartan Pharma 100.00 Sodium Azide 16.55 Toluene Recovery 665.00 Tri butyl tin chloride 83.20 Toluene Loss 20.00 Hydrogen 0.42 MDC Recovery 475.00 Sodium hydroxide 20.00 MDC Loss 15.00 Xylene 240.00 Xylene Recovery 228.00 Toluene 700.00 Xylene Loss 12.00 MDC 500.00 N-Hexane Recovery 190.00 N-Hexane 200.00 N-Hexane Loss 10.00 Activated Carbon 10.00 Effluent Water 832.87 Water 800.00 (Water-800, Sodium Chloride-

14.87,Toluene-8, Acetic Acid-10) 0

Spent Carbon 10.00 Organic Residue 116.30 Process residue –99.3

Organic Impurities-21.3, (Tri butyl-methyl –stannane-78) Distillation residue- 17 (Toluene-7, MDC-10)

Total 2674.17 Total 2674.17


ToR AMENDMENT

PRE - FEASIBILITY REPORT For

EXPANSION OF EXISTING BULK DRUGS & INTERMEDIATES MANUFACTURING UNIT

at

Survey No: 29, Tupakulagudem (Village), Tallapudi (Mandal), West Godavari (Dist.), Andhra Pradesh

By


Office address:

Duplex No: 29, Lakshmi Gayatri Enclave, Aditya Nagar, KPHB, Kukatpally, Hyderabad

MAY - 2018

Contents

S. No. Description Page no. 1.0 Executive Summary 1 2.0 Introduction of the Proposed Project 2 2.1 Project Proponent 2 2.2 Brief description of the project 3

2.3 Need for the project and its importance to the country and or region 3-4

2.4 Demand-Supply Gap. 4-5

2.5 Employment Generation(Direct and Indirect) due to the project 5

3.0 Project description 5 3.1 Product and Production Capacity 8 3.2 Raw materials required and Quantities 11 3.3 Manufacturing Process 11 3.4 Resource – Utilize and Recycling 12

3.4.1 Water 12

3.4.2 Power Requirement 12 3.4.3 Fuel Requirement 12 3.5 Quantity of wastes generated 12

3.5.1 Waste Water Generation and utilization 12 - 13 3.5.2 Solid waste generation and Disposal 13

3.6 Schematic representations of the feasibility drawing which give information of EIA purpose 14

4.0 Site Analysis 15 4.1 Connectivity 15 4.2 Land Form, Land use and Land ownership. 15 4.3 Existing Infrastructure 15 4.4 Soil classification 15 4.5 Climatic data from secondary sources 15 4.6 Social Infrastructure available 16 5.0 Planning in brief 16 6.0 Proposed infrastructure 16 6.1 Industrial Area 16 6.2 Residential Area 16 6.3 Green Belt 16 6.4 Social Infrastructure 16 - 17 6.5 Water management 17 6.6 Sewerage System 17 6.7 Industrial Waste Management 17 7.0 Rehabilitation and Resettlement (R&R) Plan 17

8.0 Project Schedule and Cost estimate 17 9.0 Analysis of project 17

LIST OF TABLES

Table No Description Page no. 3.1 Proposed Products and Existing Products and their

Production Capacities 8 - 10

3.2 List of By-Products 10 - 11 3.3 Water Requirement Details 13 3.4 Wastewater generation and Treatment Method 13 3.5 Solid and hazardous waste generation and Disposal 13 -14

LIST OF FIGURES

Figure No Description Page no. 1.1 Location Map 6 1.2 Google Earth Map Showing Tagoor Laboratories Private

Limited 7

LIST OF FLOW CHART

Flow Chart No Description Page no.

3.1 Generalized Flow Chart for Bulk Drug Manufacturing 11

Tagoor Laboratories Private Limited Pre Feasibility Report

1.0 EXECUTIVE SUMMARY

Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt

Ltd) is a partnership firm and it is registered office at Duplex No: 29, Lakshmi Gayatri

Enclave, Aditya Nagar, KPHB, Kukatpally, Hyderabad Telangana State.

S. No Parameter Description

1 Project Location Survey No: 29, Tupakulagudem (V) Tallapudi (M), West Godavari (Dist.), Andhra Pradesh

2 Category of Project as per EIA Notification & Amendments

5(f) “A”

3 Project cost As per Granted ToR: 42 Cores

Amendment Required : 45 Cores

4 Plot area 11.80 Acres (47752.9 Sq.m)

5 Proposed Products Proposed Products List is mentioned in section 3.1

Resources

6 (I)Electricity Requirement

2000 KVA

7 Source of electricity Andhra Pradesh Southern Power Distribution Company Limited (APSPDCL)

D. G. Sets

As per Granted ToR Existing: 250 KVA (Continued) Proposed: 500 KVA

Amendment Required : Existing: 250 KVA (Dropped) Proposed: 1000 KVAX 2 No’S

(II) Water consumption

As per Granted ToR: 194.0 KL/day

Amendment Required : 377.0 KL/day

(Water Recovered from Process is 90 KLD & Water Recycled from ZLD System is 119 KLD)

Fresh Water Requirement: 168 KLD

8 Source of water

As per Granted ToR: Ground Water

Amendment Required : Surface water Allotment from State Government /Ground Water

Waste water generation As per Granted ToR: 84.0 KL/day

Page 1


Amendment Required : 150.0 KL/day

(III)Boiler

As per Granted ToR:

Existing: 6.0 TPH Coal fired/ Agro waste fired Boiler, 2,00,000 kcal/hr. Thermo pack Boiler (Continued);

Proposed: 4.0 TPH Coal fired/ Agro waste fired Boiler Amendment Required : Existing: 6.0 TPH Coal fired/ Agro waste fired Boiler will be kept as Standby

The existing 2,00,000 kcal/hr. Thermo pack Boiler will be Continued

Proposed: 12.0 TPH Coal fired/ Agro waste fired Boiler

9 (IV)Fuel Coal Requirement As per Granted ToR: 33.00 TPD Amendment Required : 48.75 TPD

10 Mode of disposal Zero Liquid Discharge System 11 Solid waste generation Mentioned in Para 3.5.2 of report

12 Nearest Highway National Highway NH - 16: 26 KMs (SE) (Rajahmundry – Anakapalle)

13 Nearest Railway Station Kovvuru Railway station – 22.0 KMs (SE)

14 Nearest Airport Rajahmundry Airport – 24.00 KMs (ESE)

2.0 INTRODUCTION OF THE PROJECT

The objective of this pre- feasibility study is to provide information on proposed to

Expansion of Existing Bulk Drug & Intermediate manufacturing unit of Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd)

located at Survey No: 29, Tupakulagudem (V) Tallapudi (M), West Godavari (Dist.),

Andhra Pradesh.

2.1 Project Proponent

Mr. Penmetsa Subramanyam Raju, Managing partner of the company is young

and energetic personality with vast experience in pharmaceutical industry

Mr. Subramanya Raju has work experience of more than 18 years in bulk drugs

industry. He has worked in senior position as Director-manufacturing in Vasudha

group of industries and helped to emerge as one of the leading group in bulk drug

Page 2


industry. During his tenure in Vasudha Pharma Chem Limited, he had managed 3

units situated in jeedimetla, kazipally, and Visakhapatnam looking after production,

research and development, packing, dispatch of the finished intermediates and APIs

at right time, conforming to the specifications. Added to this, he is actively involved in

discussing with the customers for extracting business by increasing the yields and

reducing production cost to meet the demand of the customers. He has visited many

countries in Europe & Asia for exhibiting the bulk drug products. Mr. Subramanyam

Raju is also Managing Partner of Sri Venkateswara Industries which manufactures

the intermediates & bulk drugs, situated in Hyderabad. Considering his skills and

abilities, M/s Shree Jaya Laboratories Pvt Ltd., have offered him the post of Director

during February 2012 and he assumed charge of the Director during February 2012

and has taken charge as Chairman during April 2013 looking after the entire

production, research and development activities of the organization. He has

improved the turnover of the company from 28 crores to 120 crores within a short

span of one year.

Mr. Subramanyam Raju is experienced in manufacturing, process development,

project management, scale up to operations, quality systems and the aqua culturing

technically.

Mr. Subramanyam Raju was also awarded Hon. Doctorate by the international

university in Colombo during November 2013. He has also acquired more than

20acres of land in west Godavari district of Tallapudi Mandal for establishment of

Vensar and Vensub laboratories for manufacturing APIs. All the relevant licenses for

commencement of the units were obtained and the land is made ready for

construction works.

Dr. Pericherla Kasiviswanadharaju, the partner of the company is technically

qualified person, having rich experience in organic synthesis. He recently finished his

Ph. D from prestigious institute BITS Pilani, Rajasthan and his technical background

is an additional asset to the industry. Presently, he is involved in purchase,

marketing and research and development departments.

Page 3


2.2 Brief description of the project Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt

Ltd) is proposed to expansion of Existing Bulk Drug & Intermediate manufacturing

unit at Survey No: 29, Tupakulagudem (V) Tallapudi (M), West Godavari (Dist.),

Andhra Pradesh.

2.3 Need for the project and its importance to the country and region


Ltd) is proposed to expansion of existing Bulk Drug & Intermediate manufacturing

unit at Survey No: 29, Tupakulagudem (V) Tallapudi (M), West Godavari (Dist.),

Andhra Pradesh.

• Availability of the well-connected road and railway network for easy

transportation of the construction equipments and materials, Raw materials

and finished products.

• Easy availability of skilled and unskilled labor for construction of Plant and its

operation.

The Indian pharmaceutical industry currently tops the chart amongst India's science-

based industries with wide ranging capabilities in the complex field of drug

manufacture and technology. A highly organized sector, the Indian pharmaceutical

industry is estimated to be worth $ 4.5 billion, growing at about 8 to 9 percent

annually. It ranks very high amongst all the third world countries, in terms of

technology, quality and the vast range of medicines that are manufactured. It ranges

from simple headache pills to sophisticated antibiotics and complex cardiac

compounds; almost every type of medicine is now made in the Indian

pharmaceutical industry.

The Indian pharmaceutical sector is highly fragmented with more than 20,000

registered units. It has expanded drastically in the last two decades. The

Pharmaceutical and Chemical industry in India is an extremely fragmented market

with severe price competition and government price control The Pharmaceutical

industry in India meets around 70% of the country's demand for bulk drugs, drug

intermediates, pharmaceutical formulations, chemicals, tablets, capsules, orals, and

injectibles. There are approximately 250 large units and about 8000 Small Scale

Units, which form the core of the pharmaceutical industry in India (including 5 Central

Public Sector Units).

Page 4


The Indian pharma industry, which is expected to grow over 16 per cent per annum

between 2017 and 2020, will outperform the global pharma industry, which is set to

grow at an annual rate of 5 per cent between the same period!. The market is

expected to grow to US$ 55 billion by 2020, thereby emerging as the sixth largest

pharmaceutical market globally by absolute size, as stated Indian Ambassador to the

US. Branded generics dominate the pharmaceuticals market, constituting nearly 80

per cent of the market share (in terms of revenues).

India has also maintained its lead over China in pharmaceutical exports with a year-

on-year growth of 11.44 per cent to US$ 12.91 billion in FY 2015-16, according to

data from the Ministry of Commerce and Industry. Imports of pharmaceutical

products rose marginally by 0.80 per cent year-on-year to US$ 1,641.15 million.

Overall drug approvals given by the US Food and Drug Administration (USFDA) to

Indian companies have nearly doubled to 201 in FY 2015-16 from 109 in FY 2014-

15. The country accounts for around 30 per cent (by volume) and about 10 per cent

(value) in the US$ 70-80 billion US generics market.

2.4 Demand-Supply Gap.

There is a quite considerable gap between supply and demand for, fine chemicals,

bulk drugs and intermediates. Very few players are in the market who can offer

continuous supply. The company wants to bridge this gap between demand and

supply by expanding the production capacity and thereby, making good business.

Company's marketing edge comes from its direct and close contact with the

customers. Their products are major strength of their customers. Each stage of their

product is been monitored /checked for their quality to ensure quality product

reaches their customer. They plan to launch new products every year to satisfy the

need of their customers as per the market demand.

2.5 Employment Generation (Direct and Indirect) due to the project

Approximate employment generation due to proposed unit is 135. Apart from this

there will be significant non estimated employment generation at the supplier firms

and service industry providing services to the company. Company shall be giving

preference to people from economically weaker sections for employment in various

semi-skilled/unskilled jobs thereby contributing to their upliftment.

Page 5


3.0 Project Description


Ltd) is proposing the Expansion of existing Bulk Drug and Intermediates

Manufacturing Unit with production capacity of 200.0TPM

The Location map is shown at Figure - 3.1 and Google earth map showing Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt Ltd)

plant is shown at Figure - 3.2.

The site central GPS - coordinates are Latitude: 17009’30.20” North

Longitude: 81035’23.36” East.

The project site does not offer any negative impact on the local area, but rather it has

a positive impact on socio economic conditions of the habitants around it because of

employment to locals.

The Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories

Pvt Ltd) is 26 kms away from National Highway NH – 16 and 22 kms from

Kovvuru Railway station.

Page 6


FIGURE 1.1: LOCATION MAP

Project Site

Page 6


FIGURE 1.2: GOOGLE EARTH MAP SHOWING TAGOOR LABORATORIES PRIVATE LIMITED

Page 7


3.1 Proposed Products and Existing Products and their Production Capacities


Ltd) is proposing to Expansion of existing Bulk Drug and Intermediates

Manufacturing Unit Capacity of 200.0 TPM and the list of proposed products and

Existing Products are shown in Table 3.1 & 3.2.

Table 3.1: Proposed Products and Quantities as per Required TOR Amendment

S. No. Product Name

Production Capacity

Ton / Month

CAS No. Therapeutic category

1 Abacavir sulfate 2.00 188062-50-2 Anti HIV 2 Amitriptyline 10.00 549-18-8 Antidepressant 3 Atrovastatin Calcium 5.00 134523-03-8 Hypercholesterolemia 4 Bupropion 5.00 34841-39-9 Anti depressant 5 carisoprodol 2.00 78-44-4 Muscle Relaxant 6 Clopidogrelbisulfate 5.00 135046-48-9 Antithrombotic 7 Cyclobenzaprine HCl 5.00 6202-23-9 Muscle relaxant 8 Cyproheptadine HCl 10.00 41354-29-4 Anti allergic 9 Desloratadine 5.00 100649-74-8 Antihistamine 10 Domperidone 30.00 57808-69-9 Anti emetic 11 Domperidone maleate 2.00 99497-03-7 Anti emetic 12 Donepezil HCl 1.00 12004-70-3 Alzheimer’s disease 13 Ebastine 5.00 90729-43-4 Anti allergic 14 Esomeprazole Sodium 3.00 161796-78-7 Anti ulcerative

15 Esomeprazole Magnesium trihydrate 3.00 217087-09-7 Anti ulcerative

16 Fexofenadine Hydrochloride 15.00 143439-40-8 Anti histamine 17 Haloperidol 2.00 52-86-8 Antipsychotic 18 Itopride Hydrochloride 2.00 122892-31-3 Antispasmodics 19 Itraconazole 10.00 84625-61-6 Antifungal 20 Ketrolac Tromethane 2.00 74103-07-4 Anti Inflammatory 21 Lansoprazole 10.00 103577-45-3 Ant ulcerative 22 Loperamide Hydrochloride 10.00 34552-83-5 Anti diarrhea agent 23 Losartan Potassium 15.00 124750-99-8 Anti Hypertensive 24 Nebivolol HCl 2.00 99200-09-6 Anti Hypertensive 25 Nortriptyline HCl 2.00 894-71-3 Anti depressant 26 Omeprazole 40.00 73590-58-6 Anti ulcerative 27 Omeprazole Sodium 2.00 95510-70-6 Ant ulcerative 28 Omeprazole Magnesium 2.00 95382-33-5 Ant ulcerative

Page 8


S. No. Product Name

Production Capacity

Ton / Month

CAS No. Therapeutic category

Dihydrate 29 Oxatomide 1.00 60607-34-3 Antihistamine

30 Pantoprazole Sodium Sesqui Hydrate 20.00 164579-32-2 Ant ulcerative

31 Pimozide 2.00 2062-78-4 Antipsychotic 32 Pregabalin 2.00 148553-50-8 Epileptic 33 Quetiapine Hemifumarate 2.00 111974-72-2 Antipsychotic 34 Rabeprazole Sodium 15.00 117976-90-6 Ant ulcerative 35 Rupatadine fumarate 2.00 182349-12-8 Antihistamine 36 Telmisartan 2.00 144701-48-4 Anti Hypertensive 37 Terbinafine hydrochloride 15.00 78628-80-5 Anti fungal 38 Valsartan 2.00 137862-59-4 Anti Hypertensive 39 1-Benzy-4-piperidone 5.00 3612-20-2 Drug Intermediate 40 1-Benzyl-4-chloropiperidine 5.00 67848-71-9 Drug Intermediate 41 1-Benzylpiperidin-4-ol 5.00 4727-72-4 Drug Intermediate 42 1-Methylpiperidin-4-amine 5.00 41838-46-4 Drug Intermediate 43 4-Aminopiperidine 5.00 13035-19-3 Drug Intermediate 44 4-Hydroxy piperidine 5.00 5382-16-1 Drug Intermediate 45 4-Phenylpiperidine 1.00 771-99-3 Drug Intermediate 46 4-piperidinopiperidine 1.00 4897-50-1 Drug Intermediate

47 N-tert-Butoxycarbonyl-4-hydroxy piperidine 5.00 109384-19-2 Drug Intermediate

Total ( Worst Combination of any 12 Products at any given point of time)

200.00

Note:

The above Listed Products, we will manufacture either Finished Product or any Intermediate stage of finished Product as per given quantity by not increasing the

production capacity of 200 MT/Month.

Page 9


Table – 3.2. List of By-Products

S. No. Product Name By product Quantity in

Kg /Day

1 Clopidogrel Bisulphate

Ammonium sulphate 3578.08 Omeprazole Domperidone

2 Domperidone

Sodium bromide 656 Cyclobenzaprinehydrochloride Itraconazole

3

Cyclobenzaprinehydrochloride

Magnesium Chloride 290 Cyproheptadine Hydrochloride Desloratadine

4 Desloratadine Potassium chloride 226 Ebastine

5 Ebastine Aluminium chloride solution (12%) 667

6 Itraconazole Potassium bromide 84 Telmisartan


Ammonium chloride 2216 Domperidone 8 Desloratadine


Ammonium acetate 234 Acetic acid 506 Ammonium phosphate 773.50 Sodium methyl sulphate 632

9

Pantoprazole sodium sesquihydrate

Sodium acetate 1244.45 Domperidone Rabeprazole sodium Omeprazole

10 Omeprazole Sodium nitrite 545 11 Domperidone Methanol 182 12 Losartan Potassium Trityl alcohol 326

Total 12160.03

Note:

The By-Products will be produced according to the combination of required products manufacturing.

Page 10


3.2 Raw materials required and Quantities

All the raw materials required for manufacturing of above products will be sourced

from local market.

3.3 Manufacturing Process

The manufacturing process of bulk drugs and Intermediates consists of chemical

synthesis extending to stages of processing involving different type of chemical

reactions. The generalized Flow chart for bulk drug manufacturing is shown in Flow chart 3.1.

Flow Chart 3.1: Generalized Flow Chart for Bulk Drug Manufacturing

3.4 Resource – Utilize & Recycling 3.4.1 Water Water requirement of the project for domestic and industrial activity during operation

phase will be 377 KLD. The water requirement will be met through Surface water

Allotment from State Government / Ground water sources. The detailed water

requirement shown in below Table 3.3

Page 11


Table 3.3: WATER CONSUMPTION DETAILS

S.No Purpose Water consumption In KLD

1 Process 152.5 2 Washings 6.0 3 Boiler make up 70.5 4 Cooling towers make up 119.0 5 Scrubbing system 18.0 6 Domestic 6.0 7 Gardening 5.0

Total 377.0 Total Water consumption of 377 KLD. 209 KLD of water will be recovered (from

Process: 90 KLD & Water Recycled from ZLD System: 119 KLD). Hence, Total

fresh water requirement is 377KLD -209 KLD = 168 KLD.

3.4.2 Power Requirement Power requirement of proposed project will be made available through Andhra

Pradesh Southern Power Distribution Company Limited (APSPDCL). The

total power requirement for the unit is 2000 KVA respectively

D.G. sets of Existing 250 KVA will be dropped and Proposed to install 1000 KVA DG

Set 2 no’s to meet the emergency power requirement of the plant.

3.4.3 Fuel Requirement The existing 6.0 TPH Coal fired/ Agro waste fired Boiler will be kept as standby and

2,00,000 kcal/hr Thermo pack Boiler will be Continued.

Proposed to install 12.0 TPH Coal fired/ Agro waste fired Boiler and total fuel

requirement of coal will be around 48.75 MT /Day and it will be procured from local

sources.

3.5 Quantity of wastes to be generated

3.5.1 Waste Water Generation and utilization

Total effluent will generate in the project is 150.0 KLD. The treated water will be

reused for plant operations.

Page 12


The HTDS waste water from Process after neutralization taken for treatment in

stripper followed by MEE and ATFD, vapor condensate collected and transferred to

Biological Treatment. LTDS waste water including domestic sewage, floor Washes,

Utilities waste water taken along with Vapour Condensate from MEE & ATFD for

Biological Treatment. Treated effluent from BTP sent to RO, RO permeate collected

and RO rejects are sent to MEE followed by ATFD for evaporation and separation of

salts. Evaporation salts collected and sent to TSDF. MEE & ATFD vapour

condensates collected & reused along with RO permeate in plant operations.

Table 3.4: Waste water generation and Treatment Method

Unit HTDS KLD

LTDS KLD

Effluent Generation

in KLD

Treatment Method

Process 63 35 98 HTDS effluent sent to ETP with MEE System LTDS effluents treated in ETP – RO Plant / RO Rejects to MEE System and RO permeate to reuse, Condensate from MEE to reuse and MEE residue to ATFD.

Washings 0 6 6

Boiler Blow down 0 10 10

Cooling towers Blow down 0 15.5 15.5

Scrubbing system 15 0 15 Domestic 0 5.5 5.5

Total 78 72 150

3.5.2 Proposed Solid and Hazardous waste generation and Disposal The types of Solid and Hazardous wastes generated from the project, method of

disposal is shown in below table 3.5.

Table 3.5: Proposed Solid / Hazardous waste generation and Disposal S. No Name of the

Hazardous Waste Quantity

Disposal Method

1 Organic waste (Process Residue)

2211 Kg/Day Sent to Cement Industries

2 Spent Carbon 336 Kg/Day Sent to Cement Industries

3 Solvent Distillation Residue 2001 Kg/Day Sent to Cement Industries

4 Inorganic Waste 725 Kg/Day Sent to TSDF

5 Spent Mixed Solvents 4000 Sent to authorized

Page 13


S. No Name of the Hazardous Waste

Quantity Disposal Method

Kg/Day recyclers/Cement Industries

6 ETP Sludge 500 .00 Kg/Day Sent to TSDF

7 MEE Salts 8684 Kg/Day Sent to TSDF

8 Organic Evaporative Liquid ( from MEE Stripper) 1560 Kg/Day Sent to Cement Industry

9 Used Oils 500L/Annum SPCB Authorized Agencies for Reprocessing/Recycling

10 Detoxified Containers 800 No’s /

Month After Detoxification sent to outside agencies.

11 Used Lead Acid Batteries 4 No’s/ Annum

Send back to suppliers for buyback of New Batteries

Solid waste generation and Disposal

12 Ash from boilers 17100 Kg/Day

Sent to Brick Manufacturers

3.6 Schematic representations of the feasibility drawing which give

information of EIA purpose.

The applicability of the S.O.1533 for the proposed project was explored by

considering different possibilities & provision made in the said notification.

Considering the products & project location of the proposed project it is noticed that

the proposed project falls under Category 5 (f) “A” of the Schedule-I of EIA

Notification S.O.1533.

As per the provision of the SO 1533, it is necessary to get Environmental Clearance

by applying to MoEF&CC along with the Environmental Impacts Assessment Study

Report for the proposed project prior to commissioning of the project activities.

Therefore the EIA is required to conduct to comply with provisions of SO 1533 made

for Category 5 (f) “A” of schedule –I of the notification.

4.0. Site Analysis 4.1 Connectivity Tagoor Laboratories Private Limited (Formerly known as Vensub Laboratories Pvt

Ltd) located at Survey No: 29, Tupakulagudem (V) Tallapudi (M), West Godavari

(Dist.), Andhra Pradesh.

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• Gopavaram village is at a distance of 1.43 KMs in N Direction from the site.

• Kovvur is a Town; it is at a distance of 20 KMs in SE side from the project site.

• Site is at a distance of 24 KMs from Rajahmundry in SE direction.

• Nearest State Highway from the site is SH-42 (Koyyalagudem- Nallajerla) at a

distance of 17 KMs in W side from the project site.

• Nearest National Highway from the site is NH-5 (Rajahmundry - Anakapalle) at a

distance of 26 KMs in SE side from the project site.

4.2 Land Form, Land use and Land ownership. The land use of the Area of 11.8 Acres (47752.9 Sq.m) will be permanently changed

to industrial purpose.

4.3 Existing Infrastructure.

The Proposed project proposed to Expansion of existing Bulk Drug and

Intermediates Manufacturing Unit which is 26 kms away from NH-17 and Mandal

head quarter Tallapudi is 8.50 kms (ESE) from the project site.

4.4 Soil classification

The predominant soils in the district are Sandy loams, black cotton soils and coastal

sands.

4.5 Climatic data from secondary sources. Annual Max Temp is 36.80C

Annual Min Temp is 19.50C

Normal Annual Rainfall is 1078 mm

4.6 Social Infrastructure available.

Well developed social infrastructure facilities are available at nearby Habitations.

5.0 Planning Brief

Proposed plant activities will be started after getting statutory clearance form related

authorities. The project will be completed within two years. Further project

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management will take care of all the rules and regulation of statutory authority and

provide all necessary control measures

6.0 Proposed Infrastructure

6.1 Industrial Area The infrastructure and other facilities are already well developed in Tallapudi, which

is a Mandal head quarter.

6.2 Residential Area The employees who will work in the industry are from nearby villages and hence no

proposal for residential area for employees.

6.3 Green Belt: 16461.5 SQM (34.50 %) of Green Belt will be developed and maintained. 6.4 Social Infrastructure: Facilities like roads, communication, Banks, ATM's and medical facilities are

available.

Amenities: Education Schools including middle, secondary and higher secondary schools, social welfare hostels Medical and Health Community Health Centre & Primary Health center are

available in Tallapudi which is 8.50 kms ESE of proposed project site.

Power and water- All the villages are electrified and drinking water facilities are

extended to all villages.

Rail and Road- The project site is very well connected by road through National

Highway No. 16 and nearest railway station is Kovvur.

6.5 Water management Water requirement will be met through ground water.

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6.6 Sewerage System: There will be no discharge of industrial effluent as company proposing Zero Liquid

Discharge (ZLD) system. The treated effluent will be reused.

6.7 Industrial Waste Management: Due to proposed project, the effluent from cooling and Plant/Equipment washing will

be generated and treated in the well designed Effluent Treatment Plant. The treated

effluent will be reused.

7.0 Rehabilitation and Resettlement (R & R) Plan Rehabilitation & Resettlement (R & R) plan is not applicable to this proposed project.

8.0 Project Schedule & Cost Estimates Proposed project activities will be started after getting statutory clearance form

related authorities. The project will be completed within two years.

The project cost for proposed Project is 4500 Lakhs (45 Crores) will be used for

constructing additional building, Equipments & misc.

9.0 Analysis of Benefits to proposal Local people will get direct financial benefit by way of employment.

Local people will get some contracts of supply and services to get indirect

income.

Company will contribute in improving education and health facilities in nearby

area.

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appendix – ienvironmentclearance.nic.in/writereaddata/modification/amendment/... · 41 1...

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