appendix i (see paragraph – 6) form 1 (i) basic...

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APPENDIX I (See paragraph – 6)

FORM 1

(I) Basic Information

S.

No. Item Details

1 Name of the Project/s M/s. Teck Bond Laboratories Pvt. Ltd., (APIs & API Intermediate Manufacturing Unit) Application for EC Validity extension

2 S.No. in the Schedule 5 (f) 3 Proposed capacity / area / length /

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

Production capacity : 240 TPA (Four products will be manufacture at a time on campaign basis out of 18 products)

4 New/ Expansion / Modernization Application for EC Validity extension 5 Existing Capacity / Area etc., Application for EC Validity extension

Area : 2.72 hectares 6 Category of Project ie., ‘A’ or ‘B’ Category ‘A’ 7 Does it attract the general Condition? If

Yes, Please specify No

8 Does it attract the specific condition? If Yes, Please specify

No

9 Location Plot/Survey/Khasra No. Sy. No. 168,170/A, 170/AA, 173/1, 173/1A. Village Anantharam Tehsil Jinnaram District Medak State Telangana

10. Nearest railway station / airport along with distance in km.

Dabilpur Railway Station – 10 km (SE) Shamshabad (Hyderabad) – 51 km (S) (aerial distance)

11. Nearest Town, City, District Headquarters along with distance in kms.

Jinnaram – 9 km (SW) Hyderabad ORR – 12km (S) Sangareddy – 32 km (SSW) District Headquarters – Medak – 39 km (NNW) (aerial distance)

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

Village Panchayat address (local body): Gram Panchayat Office, Anantaram Village, Jinnaram Mandal, Medak District, Telangana State

13 Name of the applicant M/s. Teck Bond Laboratories Pvt. Ltd., Mr. T. Bose Babu Managing Director

14 Registered Address M/s. Teck Bond Laboratories Pvt. Ltd., 96/C, LIGH, Vengala Rao Nagar, Hyderabad, Telangana – 500 038.

15. Address for correspondence: Name Mr. T. Bose Babu

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Designation(Owner/Partner/ CEO) Managing Director Address M/s. Teck Bond Laboratories Pvt. Ltd.,

96/C, LIGH, Vengala Rao Nagar, Hyderabad, Telangana – 500 038.

Pin Code 500038 E-mail [email protected] Telephone No. 040-23811864 Fax No. -

13 Details of Alternative Sites examined, if any, Location of these sites should be shown on a top sheet.

Not Applicable. Application for EC Validity extension.

14 Interlined projects Nil 15 Whether separate application of interlined

project has been submitted Not Applicable

16 If yes, date of submission Not Applicable 17 If no, reason Not Applicable 18 Whether the proposal involves

approval/clearance under: (a) The Forest (Conservation)Act, 1980 (b) The Wildlife (Protection) Act, 1972 (c) The C.R.Z Notification, Act, 1991

Not applicable

19 Forest land involved (hectares) Nil 20 Whether there is any litigation pending

against the project and / or land in which the project is propose to be set up

(a) Name of the Court (b) Case No. (c) Orders / directions of the Court, if

any and its relevance with the proposed project.

Nil

*Capacity corresponding to sectoral activity (such as production capacity for manufacturing, mining lease area and production capacity for mineral production, area for mineral exploration, length for linear transport infrastructure, generation capacity for power generation etc.,)

(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 source of information data

1.1 Permanent or temporary change in land use, land cover or topography including increase in intensity of land use (with respect to local land use plan)

Yes Application for EC Validity extension Area of the project is 2.72 Hectares. Plant layout is enclosed as Annexure – I.

1.2 Clearance of existing land, vegetation and buildings?

No Not envisaged.

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1.3 Creation of new land uses? No As per the Plant layout enclosed as Annexure-I.

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

Yes Application for EC Validity Extension.

1.5 Construction works? Yes As per the Plant layout enclosed as Annexure-I.

1.6 Demolition works? No Not envisaged. 1.7 Temporary sites used for construction

works or housing of construction workers?

No Construction workers are coming from the nearby villages. No accommodation for the construction workers.

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

Yes As per the Plant layout enclosed as Annexure-I.

1.9 Underground works including mining or tunneling?

No Not envisaged

1.10 Reclamation works? No Not envisaged 1.11 Dredging? No Not envisaged 1.12 Offshore structures? No Not envisaged 1.13 Production and manufacturing

processes? Yes Manufacturing process of the EC/CFE

permitted APIs is enclosed as Annexure-II.

1.14 Facilities for storage of goods or materials?

Yes Store room for all goods except for bulk solvents & high quantity liquid raw materials, which will be stored in above ground tanks.

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

Yes Schematic flow sheet for treatment and disposal of solid waste & liquid effluents is presented and enclosed as Annexure-III.

1.16 Facilities for long term housing of operational workers?

No Not envisaged.

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

No Not envisaged.

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

No Not envisaged.

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

No Not envisaged.

1.20 New or diverted transmission lines or pipelines?

No Not envisaged.

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

No Not envisaged.

1.22 Stream crossings? No Not envisaged. 1.23 Abstraction or transfers of water form

ground or surface waters? No Water requirement is met from the

Tankers / bore well (Ground water) 1.24 Changes in water bodies or the land

surface affecting drainage or run-off? No Not envisaged.

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

Yes The construction material will be obtained locally and will be transported through roads. The sources of raw materials and machinery for operation will vary based on market driven forces, which will be transported via roads.

1.26 Long-term dismantling or decommissioning or restoration works?

No Not envisaged.

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

No Not envisaged.

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

Yes Workers / employees will be increased and the working hours are in shifts / general.

1.29 Introduction of alien species? No Not envisaged. 1.30 Loss of native species or genetic

diversity? No Not envisaged.

1.31 Any other actions? No -

2. Use of Natural resources for construction or operation of the Project (such as land, water, materials or energy, especially any resources which are non-renewable or in short supply):

S. No.

Information/checklist confirmation Yes/No

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

2.1 Land especially undeveloped or agricultural land (ha)

No Application for EC Validity extension

2.2 Water (expected source & competing users) unit: KLD

Yes Water will be sourced from Ground water. Water Balance is enclosed as Annexure-IV.

2.3 Minerals (MT) No Not applicable 2.4 Construction material – stone,

aggregates, sand / soil (expected source – MT)

Yes Construction materials are procured from the local market and construction is based on the plant layout enclosed as Annexure – I.

2.5 Forests and timber (source – MT) No Not applicable 2.6 Energy including electricity and fuels

(source, competing users) Unit: fuel (MT), energy (MW)

Yes 1200 KVA power (electricity) will be required for the existing and proposed project. Coal : 40.0 TPD for 10.0 TPH and standby 3.0 & 1.0 TPH. Diesel: 175 liters/hr for 165 & 200 KVA, 500 KVA D.G. set (standby power).

2.7 Any other natural resources (use appropriate standard units)

No -

3. Use, storage, transport, handling or production of substances or materials,

which could be harmful to human health or the environment or raise concerns about actual or perceived risks to human health.

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S.No.

Information/Checklist confirmation

Yes/No

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

3.1 Use of substances or materials, which are hazardous (as per MSIHC rules) to human health or the environment (flora, fauna, and water supplies)

Yes List of hazardous chemicals used in the permitted products are enclosed in Annexure-V.

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

No Effluent will be segregate and treated for reuse within the plant premises (zero discharge). All solid waste will be stored in the covered platform with Leachate collection system and sent to TSDF. Process emissions will be scrubbed in the scrubbers.

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

Yes This is an existing permitted industry. The welfare of the people will have positive effects as the new proposed expansion project will give the additional employment to the locals and industry will continue in participating in the village welfare measures. Developing the greenbelt in and around the plant site and along the village’s roads.

3.4 Vulnerable groups of people who could be affected by the project e.g. hospital patients, children, the elderly etc.,

No Plant site is more than 1.5 km away from the nearest habitation.

3.5 Any other causes No -

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 source of information data

4.1 Spoil, overburden or mine wastes No Not envisaged. 4.2 Municipal waste (domestic and or

commercial wastes) No Commercial waste generated from the

administration building will be sold to scrap vendors.

4.3 Hazardous wastes (as per Hazardous Waste Management Rules)

Yes Hazardous wastes generated from the products are presented in Annexure-VI.

4.4 Other industrial process wastes Yes Other industrial process wastes from the products manufacturing are given in Annexure-VI.

4.5 Surplus product No Production capacity will be ensured for approved quantity. Hence there will not be any surplus production envisaged.

4.6 Sewage sludge or other sludge from Yes ETP sludge is being sent to

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effluent treatment TSDF/TSPCB Authorized vendors and continue the same

4.7 Construction or demolition wastes No Not envisaged 4.8 Redundant machinery or equipment No Not applicable 4.9 Contaminated soils or other materials No All precautionary measures will be

ensured to avoid the soil contamination.

4.10 Agricultural wastes No Nil 4.11 Other solid wastes No Please refer Annexure-VI for details of

other solid wastes from the permitted products

5. Release of pollutants or any hazardous, toxic or noxious substances to air

(Kg/hr)

S.No.


Yes/No


5.1 Emissions from combustion of fossil fuels from stationary or mobile sources

Yes Details of fuel used for Boiler, D.G.Sets enclosed in Annexure-VII.

5.2 Emissions from production processes Yes Emission from process reactions from the permitted products are given in Annexure-VIII.

5.3 Emissions from materials handling including storage or transport

Yes Pumps will be used for handling of liquid raw materials and trolleys will be used for Solid / Powder type raw materials. Vent condensers will be provided for all storage tanks.

5.4 Emissions from construction activities including plant and equipment

Yes Dust emissions during construction activities will be suppressed by water sprinkling system.

5.5 Dust or odours from handling of materials including construction materials, sewage and waste

Yes Dusting will be there due to construction work and due to transportation of goods and materials. It will be reduced by spraying of water.

5.6 Emissions from incineration of waste Yes Continue to send all Incinerable Hazardous waste to TSDF for incineration / Cement industries for used as alternate fuel.

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

No All construction debris will be used as filling material for roads and other waste materials are sold as scrap.

5.8 Emissions from any other sources No NIL

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

S.No. Information/Checklist confirmation

Yes/No Details thereof (with Approximate quantities/rates, wherever possible) with source of information data with source of information data

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

Yes Noise will be generated from the utilities section. Silencers are provided for D.G. Sets and other utilities equipment and these will be provided in separate room.

6.2 From industrial or similar processes

Yes Noise will be generated from the pumps, motors, centrifuges etc., which will be controlled by proper maintenance and procuring the sound proof equipments.

6.3 From construction or demolition

Yes Noise will be generated during construction phase, which will be temporary and for short time.

6.4 From blasting or piling No Not envisaged. 6.5 From construction or operational

traffic Yes Noise will be generated from the

transportation vehicles. 6.6 From lighting or cooling systems No NIL 6.7 From any other sources No NIL

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 Accidental spillages such as wastewater /solid wastes /raw materials are possible and the risk of this would be limited to within the premises of the manufacturing facility. Precautionary measures will be implemented for proposed industry for spillage control and to avoid contamination of land or water from the pollutants or raw materials. Suggestions from the safety consultants will be followed to avoid the risk and prevent accidents.

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

Yes Possibility of contamination of land or water is there due to the discharge of trade effluent to water or land. However, all the effluents are stored in 1 meter above ground level RCC

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tanks. All the tanks of the effluent treatment plant will be above ground level. In phase 2 expansion after full fledge treatment all the treated effluent will be reused within the premises. Domestic waste water sent to ETP and treated water used back in Cooling Towers / Boilers.

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

Yes Possibility of deposition of pollutants emitted to air into the land or into water cannot be ruled out and the precautions taken by the industry to control such emissions by adopting the suitable controlling equipment like cyclone separators, scrubbers etc.,

7.4 From any other sources No NIL 7.5 Is there a risk of long term build up of

pollutants in the environment from these sources?

No Not envisaged.

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

affect human health or the environment

S.No.

Information/Checklist confirmation Yes/No


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

Yes All safety precautions will be taken by the industry to avoid such accidents.

8.2 From any other causes Yes Static Electricity 8.3 Could the project be affected by natural

disasters causing environmental damage (e.g. floods, earthquakes, landslides, cloudburst etc)?

Yes Not envisaged.

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

which could lead to environmental effects or the potential for cumulative impacts with other existing or planned activities in the locality

S. No.


Yes/No


9.1 Lead to development of supporting. lities, ancillary development or development stimulated by the project which could have

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impact on the environment e.g.: • Supporting infrastructure (roads, power supply, waste or waste water treatment, etc.) • housing development • extractive industries • supply industries • other

Yes NO Yes Yes

Supporting infrastructure such as Roads, Power supply, waste or wastewater treatment etc., may have impacts on the project activities. However the impact from such activities will be limited as this is existing industry and supporting infrastructure required for the industry is under construction. All employees will be coming from near by villages. Possibility of extractive industries cannot be ruled out. Supply industries will be supplying various raw material required for the operation of the industry. No.

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

No Not envisaged.

9.3 Set a precedent for later developments No Not envisaged. 9.4 Have cumulative effects due to

proximity to other existing or planned projects with similar effects

Yes Existing Industry

(III) Environmental Sensitivity

S.No.

Areas

Name/ Identity

Aerial distance (within 15 km.) Proposed project location boundary

1 Areas protected under international conventions, national or local legislation for their ecological, landscape, cultural or other related value

Yes Following Reserved forest blocks are present such as • Narsapur R.F (Dense Mixed Jungle)

>3.5 Km (W) • Nawabpet R.F (Fairly Dense Scrub)

>2Km (N) • Kunkunta R.F (Dense Scrub) >4.4

Km (NE) • Parikabanda RF (Dense Mixed

Jungle) >7 km (S) • Dabilpur RF (Dense scrub) > 8 km

(SE) 2 Areas which are important or sensitive

for ecological reasons - Wetlands, watercourses or other water bodies, coastal zone, biospheres, mountains, forests

No There are no wetlands near the plant site.

3 Areas used by protected, important or sensitive Species of flora or fauna for

No NIL

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breeding, nesting, foraging, resting, over wintering, migration

4 Inland, coastal, marine or underground waters

Yes No water bodies in less than 1.5 km. Gummadidala erra cheruvu – 1.8 km (SW) Erra Cheruvu – 2.5 km (NW)

5 State, National boundaries No NIL 6 Routes or facilities used by the public

for access to recreation or other tourist, pilgrim areas

No Industry is about 2 Km from State Highway (Hyderabad to Medak)

7 Defense installations No NIL 8 Densely populated or built-up area No Hyderabad (State capital) is at a

distance of 40 km from the industry. 9 Areas occupied by sensitive man-

made land uses (hospitals, schools, places of worship, communityfacilities)

No There is no habitation or sensitive man-made land used within 1.5 km distance.

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

No Not Applicable

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

NO Not Applicable

12 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 area is not known for these natural hazards. Seismically, this area is categorized under Zone II as per IS-1893 (Part-I)-2002.

(IV). Proposed Terms of Reference for EIA studies Application for EC validity Extension. EC copy is enclosed as Annexure-IX.

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I hereby given undertaking that the data and information given in the application and enclosures are true to the best of my knowledge and belief and I am aware that if any part of the data and information submitted is found to be false or misleading at any stage, the project will be rejected and clearance give, if any to the project will be revoked at our risk and cost. Date : 30-6-2016 Place : Hyderabad

Signature of the applicant With Name and Full Address

(Project Proponent / Authorized Signatory) NOTE: 1. The projects involving clearance under Coastal Regulation Zone Notification, 1991 shall

submit with the application a C.R.Z map duly demarcated by one of the authorized agencies, showing the project activities, w.r.t C.R.Z and the recommendations of the State Coastal Zone Management Authority. Simultaneous action shall also be taken to obtain the requisite clearance under the previous of the C.R.Z Notification, 1991 for the activities to be located in the C.R.Z.

2. The projects to be located within 10 km of the National Parks, Sanctuaries, Biosphere Reserves, Migratory Corridors of Wild Animals, the project proponent shall submit the map duly authenticated by Chief Wildlife Warden showing these features vix-a-vix the project location and the recommendations or comments of the chief Wildlife Warden thereon.

List of Annexures

I. Plant layout

II. Manufacturing process of the Proposed Products.

III. Effluent treatment plant

IV. Water balance

V. List of Hazardous Chemicals used in the proposed products

VI. Details of Hazardous solid waste and other waste.

VII. Fuel consumption and Emissions details of Boiler and D.G. Sets

VIII. Details of emissions from process reactions.

IX. EC Copy

Other Annexures X. Topomap

XI. CFE 2011

XII. CFO 2013

ANNEXURE - I

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Stage-1 : Pentafluorobenzoyl Chloride on condensation with Diethyl Malonate in the presence of MagnesiumMethoxide gives Diester derivative. Which on hydrolysis in the presence of Sulfuric Acid gives Beta Keto EsterDerivative.

Stage-2 : Beta Keto Ester on condensation with Triethyl orthoformate in the presence of Acetic acid givesEthoxy compound which on condensation with Cyclopropylamine gives Amino compound which on cyclisationgives Q-Ester Compound.

Stage-3 : Q-Ester on condensation with Benzylamine in presence of Triethylamine gives Benzyl Compound.

Stage-4 : Benzyl Compound on reduction with Hydrogen on Palladium Carbon gives Amino Compound.

Stage-5 : Amino Compound undergoes hydrolysis in presence of Sulfuric Acid gives Q-Acid.

Stage-6 : Q-Acid on condensation with Dimethyl Piperazine in presence of Potassium Carbonate givesSparfloxacin.

PRODUCT : Sparfloxacin

Description :

ANNEXURE - II

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Flow Chart

Pentafluorobenzoyl ChlorideMagnesium Methoxide Sol.RecoveryEthanol Evaporation LossDiethyl Malonate EffluentAcetone Organic ResidueSulfuric acid Inorgainc Solid WasteWater Process Emissions

Stage-1Triethyl Orthoformate Sol.RecoveryAcetic Acid Evaporation LossCyclopropylamine EffluentToluene Organic ResiduePotassium Carbonate Process EmissionsWater

Stage-2Benzylamine Sol.RecoveryPotassium Hydroxide Evaporation LossToluene EffluentWater Organic Residue

Stage-3 Sol.RecoveryCarbon Evaporation LossMethanol EffluentHydrogen Organic ResidueHyflo Spent CarbonWater Process Emissions

Stage-4Sulfuric Acid EffluentWater

Stage-5Dimethyl Piperazine Sol.RecoveryPotassium Carbonate Evaporation LossToluene EffluentMethanol Organic ResidueWater Process Emissions

Sparfloxacin

PRODUCT : Sparfloxacin

Stage I

Stage II

Stage III

Stage IV

Stage V

Stage VI

ANNEXURE - II

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Stage-1 : 1-Methyl-3-phenyl piperazine is condensed with 2-Chloro nicotinonitrile in Dimethylformamide inpresence of Sodium Hydroxide and Potassium Fluoride to obtain Mirtazapine Stage-I material.

Stage-2 : Hydrolysis of Mirtazapine Stage-I material with Sodium Hydroxide and Hydrochloric Acid in presence ofToluene, Methylene Dichloride and Ethanol solvent media gives the corresponding carboxylic acid (MirtazapineStage-II) material.

Stage-3 : Subsequent Mirtazapine Stage-II material reduction with Lithium Aluminum Hydride in refluxingTetrahydrofuran and Diisopropyl Ether provides Mirtazapine Stage-III material.

Stage-4 : Mirtazapine Stage-III material is cyclized in presence of Concentrated Sulfuric Acid in MethyleneDichloride and Diisopropyl Ehter media to produce Mirtazapine which is finally purified in Cyclohexane to givepure Mirtazapine.

PRODUCT : Mirtazapine

Description :

ANNEXURE - II

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Flow Chart

1-Methyl-3-phenyl piperazine2-Chloro nicotinonitrileDimethylformamide Sol.RecoveryEthyl Acetate Evaporation LossPotassium Fluoride EffluentSodium Hydroxide Organic ResidueSodium Chloride Inorgainc Solid WasteWater

Stage-1Toluene Sol.RecoveryMethylene Dichloride Evaporation LossEthanol EffluentSodium Hydroxide Organic ResidueHydrochloric Acid (35%) Process EmissionsWater

Stage-2Tetrahydrofuran Sol.RecoveryDiisopropyl Ether Evaporation LossLithium Aluminum Hydride EffluentSodium Hydroxide Organic ResidueWater Process Emissions

Stage-3Methylene Dichloride Sol.RecoveryDiisopropyl Ether Evaporation LossCyclohexane EffluentSulfuric Acid Organic ResidueSodium Hydroxide Inorgainc Solid WasteCarbon Spent CarbonWater

Mirtazapine

PRODUCT : Mirtazapine

Stage I

Stage II

Stage III

Stage IV

ANNEXURE - II

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Flow Chart

D-FructoseIsopropyl Alcohol By-ProductSulfuric Acid Sol.RecoveryAcetone Evaporation LossSodium Hydroxide Effluentn-Hexane Organic ResidueWater

Stage-1TolueneSulfuryl ChloridePyridine Sol.RecoveryAmmonia Solution (25%) Evaporation LossTetrahydrofuran EffluentIsopropyl Alcohol Organic Residuen-HexaneWater

Topiramate

Stage-1 : D-Fructose reacts with Acetone and Sulfuric acid at 0-5oC for 10 hrs. After reaction complies adjust thePH with Sodium Hydroxide and separate the inorganic salts. Distill out organic layer, isolate the material in IsopropylAlcohol and Hexane at 10-15oC to gives Stage-1 Compound.

Stage-2 : Stage-1 compound reacts with Sulfuryl Chloride and Pyridine in presence of Toluene at -15 to -10oC for 5hrs, after reaction complies. Take organic layer give water washings. Distill out Toluene. Add Tetrahydrofuran inabove residue. This layer reacts with Ammonia solution. After reaction complies, filter the by product and distill outTetrahydrofuran completely. After distillation add Isopropyl Alcohol and n-Hexane, cool to 0-5oC to gives finalTopiramate product.

PRODUCT : Topiramate

Description :

Stage I

Stage II

ANNEXURE - II

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Flow Chart

MalanonitrilePropionaldehyde Sol.RecoverySulfur Evaporation LossTriethylamine EffluentDimethylformamide Organic ResidueWater

Stage-1Ortho Fluoro Nitrobenzene Sol.RecoveryPotassium Hydroxide Evaporation LossAcetonitrile EffluentWater Organic Residue

Stage-2Isopropyl Alcohol By-ProductStannous Chloride Sol.RecoveryHydrochloric Acid (35%) Evaporation LossMethanol EffluentWater Organic Residue

Stage-3N-Methyl Piperazine Sol.RecoveryMethylene Dichloride Evaporation LossCarbon EffluentWater Spent Carbon

Olanzapine

Stage-1 : Malanonitrile reacts with Propionaldehyde and Sulfur in presence of Triethylamine andDimethylformamide at 0-5oC for 15 hrs. After reaction complies filter it to gives Stage-1 Compound.Stage-2 : Stage-1 Compound reacts with Ortho Fluoro Nitrobenzene in presence of Acetonitrile and PotassiumHydroxide at 20-40oC for 12 hrs to gives Stage-2 Compound.

Stage-3 : Stage-2 Compound reacts with Stannous Chloride and Hydrochloric acid in presence of IsopropylAlcohol reflux at 80-95oC for 20 hrs, after reaction complies filter it to gives Stage-3 Compound Crude material.The Crude Stage-3 Compound material purified in Methanol media to form Stage-3 Compound Pure.

Stage-4 : Stage-3 Compound reacts with N-Methyl Piperazine at 125 to 130oC for 10 hrs, after reactioncomplies, add water and filter it, to gives Olanzapine crude material. Take Olanzapine crude material addMethylene Dichloride and carbon, stir for 2 hrs filter it, distillout Methylene Dichloride to form final Olanzapinecompound.

PRODUCT : Olanzapine

Description :

Stage I

Stage II

Stage III

Stage IV

ANNEXURE - II

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Flow Chart

Phthalic Anhydride2-Amino ethanol EffluentWater

Stage-1Toluene Sol.Recovery4-Chloroethyl acetoacetate Evaporation LossSodium Hydride (40%) EffluentAcetic Acid Organic ResidueHydrochloric Acid (35%) Process EmissionsWater

Stage-22-Chloro Benzaldehyde CatalystMethyl Aceto Acetate Sol.RecoveryLiq.Ammonia (20%) Evaporation LossAcetic Acid Effluentn-Hexane Organic ResidueMonomethylamine (30%)Water

Amlodipine BaseBenzene Sulfonic acid Sol.RecoveryWater Evaporation LossMethanol EffluentActivated Carbon Organic ResidueEthyl Acetate Spent Carbon

Amlodipine Besylate

Description :

Stage-1 : Phthalic Anhydride is reacted with 2-Amino ethanol to get Phthalimido alcohol.

Stage-2 : Phthalic alfohol is reacted with 4-Chloro ethyl aceto acetate to obtain Ethyl-4-[2-(1,3-dioxo-1,3-dihydro-2 H- isonidol-2yl)ethoxy]-3-oxobutanoate.

Stage-3 : Ethyl-4-{[2-(1,3-dioxo-1,3-dihydro-2 H-isonidol-2yl)ethoxy]-3-oxobutanonate is condensed with 2-Chloro Benzaldehyde and the product obtained is reacted with Methyl Aceto Acetate and Ammonia to obtainMethyl ester which on condensation with Monomethyl amine gives Amlodipine Base.

Stage-4 : Amlodipine Base on condensation with Benzene Sulfonic acid gives Amlodipine Besylate.

PRODUCT : Amlodipine Besylate

Stage I

Stage II

Stage III

Stage IV

ANNEXURE - II

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Stage-7 : Methane Sulfonic acid-1-{3-[2-(7-Chloro-2-quinolinyl)vinyl]phenyl}-3-[2-(1-hydroxy-1-mehtylethyl)phenyl] Propyl ester is reacted with (1-Mercaptomethyl cyclopropyl) acetic acid in presence ofTetrahydrofuran and ethyl acetate to give Montelukast.Stage-8 : Montelukast is reacted with Dicyclohexylamine in presence of EthylAcetate and n-Hexane to giveMontelukast Dicyclohexylamine.

Stage-9 : Montelukast Dicyclohexylamine is reacted with Acetic acid to get Montelukast free acid. Montelukastfree acid then reacted with Sodium Hydroxide in presence of Toluene and n-Hexane to get Montelukast Sodium.

PRODUCT : Montelukast Sodium

Stage-3 : 1{3-[2-(7-Chloro-2-Quinolinyl) vinyl]Phenyl}prop-2-en-1-ol is reacted with Methyl iodobenzoate andPalladium acetate as a catalyst in presence of acetonitrile at 80-85oC further coool to 25-30oC to give 2-(3-{3-[2-(7-Chloro-2-quinolinyl) Vinyl] Phenyl}-3-oxo propyl) benzoic acid methyl ester.Stage-4 : 2-(3-{3-[2-(7-Chloro-2-Quinolinyl) vinyl] Phenyl}-3-Oxopropyl) benzoic acid methyl ester is reacted withDipchloride in presence of Tetrahydrofuran at -5oC to 0oC to give 2-(3-{3-[2-(7-Chloro-2-quinolinyl)vinyl] phenyl}-3-hydroxy propyl) benzoic acid methyl ester.

Stage-5 : 2-(3-{3-[2-(7-Chloro-2-Quinolinyl) vinyl] phenyl] 3-hydroxypropyl) benzoic acid methyl ester is reactedwith Methyl Magnesium Chloride and Hydrochloric Acid at -5oC to 0oC, further crystallized with Isopropyl Ether togive 1-{3-[2-(7-Chloro-2-quinolinyl)vinyl]phenyl}-3-[2-(1-Hydroxy-1-methyl ethyl) Phenyl] Propan-1-ol.

Stage-6 : 1-{3-[2-(7-Chloro-2-quinolinyl)vinyl]phenyl}-3-[2-(1-Hydroxy-1-methyl ethyl) Phenyl] Propan-1-ol isreacted with Methane Sulfonylchloride in presence of Diisopropylamine, Toluene and Acetonitirle as a solventmedia to give Methane Sulfonic acid -1-{3-[2-(7-Chloro-2-quinolinyl)vinyl]phenyl}-3-[2-(1-hydroxy-1-methyl ethyl)phenyl] propyl ester.

Stage-1 : 7-Chloro Quinaldehyde is reacted with Isopthalaldehyde in presence of Acetic Anhydride solvent asMethanol at 133-135oC further cool to 25-30oC to get 3-[2-(7-Chloro-2-Quinolinyl) Ethenyl] Benzaldehyde.Stage-2 : 3-[2-(7-Chloro-2-quinolinyl) ethenyl] benzaldehyde is reacted with Vinyl magnesium Bromide inTetrahydrofuran in presence of Toluene at 0-5oC to give 1-{3-[2-(7-Chloro-2-quinolinyl) vinyl]phenyl} prop-2-en-1-ol.

Description :

ANNEXURE - II

20

Flow Chart

7-Chloro quinaldehydeMethanol Sol.RecoveryIsophthaladehyde Evaporation LossAcetic Anhydride Organic Residue

Stage-1Toluene Sol.Recovery

Evaporation LossEffluent

Water Organic Residue

Stage-2Methyl Iodobenzoate Sol.RecoveryCatalyst Evaporation LossSodium Hydroxide EffluentAcetonitrile Organic ResidueWater

Stage-3 By-ProductDIP Chloride Sol.RecoveryTetrahydrofuran Evaporation LossWater Effluent

Organic ResidueProcess Emissions

Stage-4

Sol.Recoveryt-Butanol Evaporation LossIsopropyl ether EffluentHydrochloric Acid (35%) Organic ResidueWater


Vinyl Magnesium Bromide in Tetrahydrofuran (40%)

Methyl Magnesium Chloride in Tetrahydrofuran (25%)

Stage I

Stage II

Stage III

Stage IV

Stage V

ANNEXURE - II

21

Flow Chart

Stage-5Toluene Sol.RecoveryAcetonitrile Evaporation LossDiisopropylamine Organic ResidueMethane Sulfonyl Chloride

Stage-6Tetrahydrofuran

Sol.RecoveryEvaporation Loss

EffluentEthyl Acetate Organic ResidueSodium Chloride (10%)Tartaric acid (5%)

Stage-7Ethyl Acetate Sol.RecoveryDicyclohexylamine Evaporation Lossn-Hexane Organic Residue

Stage-8TolueneWater Sol.RecoveryAcetic Acid Evaporation Loss

EffluentOrganic Residue

n-Hexane

Montelukast Sodium

(1-Mercaptomethyl cyclo propyl) acetic acidn-Butyllithium in Cyclohexane (15%)


Sodium Hydroxide in Methanol (50%)

Stage VI

Stage VII

StageVIII

Stage IX

ANNEXURE - II

22

Stage-7 : Stage-6 intermediate reacts with Phosphorus Pentachloride in the presence of Toluene and MethyleneDichloride solvent media to get Stage-7 intermediate.

Stage-8 : Stage-7 intermediate reacts with N-Methyl chloro piperidine and Magnesium in presence of Water inToluene solvent media to get Stage-8 intermediate.

Stage-9 : Stage-8 intermediate under goes dehydrolysis in the presence of Sulfuric Acid in Toluene solvent mediato give Stage-9 intermediate.

Stage-10 : Stage-9 intermediate reacts with Ethyl chloroformate in presence of Triethylamine base inTetrahydrofuran solvent media to get Loratadine.

Stage-1 : Methyl Nicotinate reacts with m-Chlorobenzylcyanide in the presence of Sodium Methoxide in solventmedia to get Stage-1 intermediate.

Stage-2 : Stage-1 intermediate hydrolysis in the presence of Hydrochloric Acid in Toluene solvent media to getStage-2 intermediate.

Stage-3 : Stage-2 intermediate reacts with Hydrazine hydrate in the presence of Monoethylene glycol to get Stage-3 intermediate.

Stage-4 : Stage-3 intermediate reacts with Hydrogen Peroxide in presence of Chloroform solvent media to getStage-4 intermediate.

Stage-5 : Stage-4 intermediate reacts with Sodium cyanide in presence of Hydrochloric Acid in Chloroform solventmedia to get Stage-5 intermediate.

Stage-6 : Stage-5 intermediate reacts with Potassium Hydroxide in the presence of Hydrochloric Acid in Butanolsolvent media to get Stage-6 intermediate.

PRODUCT : Loratadine

Description :

ANNEXURE - II

23

Flow Chart

Methyl Nicotinatem-Chlorobenzyl cyanide Sol.RecoverySodium Methoxide Evaporation LossMethanol EffluentIce water

Stage-1Hydrochloric Acid (35%) Sol.RecoveryAmmonia (25%) Solution Evaporation LossToluene EffluentWater Process Emissions

Stage-2Hydrazine hydrate (80%) EffluentSodium Hydroxide Organic ResidueMonoethylene glycol Process Emissions

Stage-3MethanolAcetic AcidHydrogen Peroxide (50%) Sol.RecoveryAmmonia (25%) Solution Evaporation LossChloroform EffluentSodium TungstateWater

Stage-4Chloroform Sol.RecoverySodium Cyanide Evaporation LossHydrochloric Acid (35%) EffluentIsopropyl Alcohol Organic ResidueWater


Stage I

Stage II

Stage III

Stage IV

Stage V

ANNEXURE - II

24

Flow Chart

Stage-5Potassium Hydroxide Sol.RecoveryButanol Evaporation LossHydrochloric Acid (35%) EffluentWater Process Emissions

Stage-6Methylene DichloridePhosphorus Pentachloride Sol.RecoveryAluminum Chloride Evaporation Loss

EffluentOrganic Residue

Toluene Process EmissionsHydrochloric Acid (35%)Water

Stage-7N-Methyl chloro piperidineMagnesium Sol.RecoveryTetrahydrofuran Evaporation LossLithium Bromide EffluentAmmonium Chloride Organic ResidueToluene Inorgainc Solid WasteWater

Stage-8Sulfuric AcidAmmonia (25%) Solution Sol.RecoveryToluene Evaporation LossSodium Sulfate EffluentWater

Stage-9Ethyl Chloroformate Sol.RecoveryTriethylamine Evaporation LossTetrahydrofuran EffluentWater Process Emissions

Loratadine


Sodium Hydroxide (40%) Solution

Stage VI

Stage VII

StageVIII

Stage IX

Stage X

ANNEXURE - II

25

Flow Chart


Potassium Carbonate EffluentAcetonitrile Organic ResidueHydrogen Process EmissionsWater

Stage-1Valeryl Chloride Sol.RecoveryTriethylamine Evaporation LossToluene EffluentWater Organic Residue

Stage-2Tributyl tinazideAcetone Sol.RecoverySulfuric Acid Evaporation LossSodium Hydroxide EffluentAmmonium Sulfate Organic ResidueEthyl AcetateWater

2-Cyano biphenyel-4-carboxaldehydeMethyl-L-Valinate Hydrochloride

PRODUCT : Valsartan

Description :

Valsartan

Stage-1 : 2-Cyano biphenyl-4-carboxaldehyde on reacting with Methyl-L-Valinate Hydrochloride in presence ofPotassium Carbonate as a base and Acetonitrile solvent media and it is further on reductive amination withHydrogen gives Methyl-N-[(2-Cyano biphenyl-4-yl) methyl]-L-valinate.

Stage-2 : Methyl-N-[(2-Cyano biphenyl-4-yl) methyl]-L-valinate on treatment with Valeryl chloride in presence ofTriethylamine base and Toluene solvent media gives Methyl-N-Valeryl-N-[(2-Cyano biphenyl-4- yl) methyl]-L-valinate.

Stage-3 : Methyl-N-Valeryl-N-[(2-Cyano biphenyl-4-yl) methyl]-L-valinate on treatment with Tributyl tinazide inpresence of Acetone and Ethyl Acetate solvent media gives Valsartan.

Stage I

Stage II

Stage III

ANNEXURE - II

26

Stage-7 : Take Acetone lot-1 in reactor, add Clopidogrel base and cool to below 10oC. Feed Sulfuric Acid below10oC. Maintain for 1 to 1.5 hrs below 10oC. Raise temperature and maintain at room temperature for 20-24 hrs.Filter the Clopidogrel Hydrogensulfate product and wash with Acetone lot-2. Dry the Clopidogrel Hydrogensulfateproduct below 40oC for 6-8 hrs.

Stage-1 : Take Methanol, add 2-Chlorophenyl Glycine and feed Sulfuric acid below 15oC. Heat to 60-65oC andmaintaine for 20 hrs. Distill off solvent completely and add Toluene and distill off Toluene to remove theMethanol traces. Cool to residue to room temp. and add water. Stir to dissolve and add Methylene Dichloride.Adjust pH (neutral) with aq. Ammonia and separate layers. Distill of Methylene Dichloride complelty to get crudeStage-1 product.

Stage-2 : Take Methanol, add Stage-1 and add L-Tartaric acid. Stir for 20 hrs at room temp. Centrifuge thematerial. Dry the product at 50-60oC. Take Methanol Mls and distill off solvent completely. Add water to theresidue and adjust pH with Aq. Ammonia (to neutral pH). Extract with Methylene Dichloride. Distill off solventcompletely to get recovered Stage-2.

Stage-3 : Take water and add Sodium Hydroxide flakes. Stir to dissolve and cool to room temp. Add 2-Thiophene Ethanol and Toluene lot-1 mixture. Cool to below 10oC. Feed mixture of P-Toluene Sulfonyl Chlorideand Toluene lot-2 below 10oC and maintian for 1 hr. Separate layers and wash organic layer with water lot-2 and3. Distill off solvent to get Stage-3 product.

Stage-4 : Take water lot-1 and add Stage-2. Add Toluene and adjust pH with Aq. Ammonia to neutral. Separatelayers. Distill off Toluene completely. Add Stage-3 and Potassium Bicarbonate. Heat and maintaine at 80-85o for 48 hrs. Cool to room temperature and add water lot-2 stir to dissolve. Add Ethyl Acetate separate layers.Wash organic layer with water lot-3 add Hydrochloric Acid to organic layer below 15oC. Centrifuge the materialand dry the Stage-4 product at 50-60oC.

Stage-5 : Take Toluene and add Stage-4 Crude. Heat to 50-55oC and maintaine for 1hrs. Cool to roomtemperature and centrifuge the material. Dry the Stage-5 pure product at 60-65oC. Collect Mls and distill offToluene to get reccovered Toluene.Stage-6 : Take water lot-1, Stage-5 in reactor. Add Formalin solution at room temperature. Heat and maintain at50-55oC till reaction completion. Cool to room temperature and charge water lot-2 and Toluene lot-1. AddSodium Hydroxide separate Toluene layer. Extract aq.layer with Toluene lot-2. Combine Toluene layers anddistill off solvent to get Clopidogrel base.

PRODUCT : Clopidogrel Hydrogensulfate

Description :

ANNEXURE - II

27

Flow Chart

2-Chlorophenyl GlycineMethanolSulfuric Acid Sol.RecoveryToluene Evaporation LossMethylene Dichloride EffluentAmmonia (25%) solution Organic ResidueWater

Stage-1Methanol Sol.RecoveryL-Tartaric Acid Evaporation LossMethylene Dichloride EffluentAmmonia (25%) solution Organic ResidueWater

2-Thiophene EthanolP-Toluene Sulfonyl ChlorideSodium Hydroxide Sol.RecoveryToluene Evaporation LossHydrochloric Acid (35%) EffluentWater Organic Residue

Stage-2Ammonia (25%) solutionStage-3 Sol.RecoveryPotassium Bicarbonate Evaporation LossToluene EffluentEthyl Acetate Organic ResidueHydrochloric Acid (35%) Process EmissionsWater

Stage-4 (Crude) Sol.RecoveryToluene Evaporation Loss

Organic Residue


Stage I

Stage II

Stage III

Stage IV

Stage V

ANNEXURE - II

28

Flow Chart

Stage-5 (Pure)Formalin (37%) Sol.RecoverySodium Hydroxide Evaporation LossToluene EffluentWater Organic Residue

Clopidogrel Base Sol.RecoveryAcetone Evaporation LossSulfuric Acid Organic Residue

Clopidogrel Hydrogensulfate


Stage VI

Stage VII

ANNEXURE - II

29

Flow Chart

1,1-Cyclohexane diacetic acid Sol.RecoveryAcetic Anhydride Evaporation Loss

Effluent

Stage-1Hydroxylamine Hydrochloride EffluentSodium Carbonate Process EmissionsWater

Stage-2Sodium Carbonate (10%) EffluentBenzene Sulfonyl Chloride Process EmissionsWater

Stage-3 Sol.RecoverySodium Hydroxide (10%) Evaporation LossHydrochloric Acid (35%) EffluentEthanol Process Emissions

Stage-1 : This stage invloves the reaction of 1,1-Cyclohexane diacetic acid with Acetic Anhydride to give 1,1-Cyclohexane diacetic acid anhydride.

Stage-2 : 1,1-Cyclohexane diacetic acid anhydride obtained in stage-1 is treated with HydroxylamineHydrochloride in presence of Sodium Carbonate to get 1,1-Cyclohexane diacetic acid N-Hydroxyimide.

Stage-3 : This stage invloves the reaction of 1,1-Cyclohexane diacetic acid N-Hdyroxyimide with BenzeneSulfonyl Chloride in presence of Sodium Carbonate to give N-Benzene sulfonyloxy-1,1-Cyclohexane diacetic acidimide.

Stage-4 : The N-Benzene sulfonyloxy-1,1-Cyclohexane diacetic acid imide derivative obtained in Stage-3 issubjected to Lossen rearrangement by boiling in 10% Sodium Hydroxide solution, followed by pH adjustment withHydrochloric Acid in presence of Ethanol to give the Gabapentin product.

Gabapentin

PRODUCT : Gabapentin

Description :

Stage I

Stage II

Stage III

Stage IV

ANNEXURE - II

30

Stage-3 : Q-Ester on condensation with Benzylamine in presence of Triethylamine gives Benzyl Compound.

Stage-4 : Benzyl Compound on reduction with Hydrogen on Palladium Carbon gives 5-Amino-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester.

PRODUCT : 5-Amino-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester

Description :

Stage-1 : Pentafluorobenzoyl Chloride on condensation with Diethyl Malonate in the presence of MagnesiumMethoxide gives Diester derivative. Which on hydrolysis in the presence of Sulfuric Acid gives Beta Keto EsterDerivative.

Stage-2 : Beta Keto Ester on condensation with Triethyl orthoformate in the presence of Acetic acid givesEthoxy compound which on condensation with Cyclopropylamine gives Amino compound which on cyclisationgives Q-Ester Compound.

ANNEXURE - II

31

Flow Chart

Pentafluorobenzoyl ChlorideMagnesium Methoxide Sol.RecoveryEthanol Evaporation LossDiethyl Malonate EffluentAcetone Organic ResidueSulfuric acid Inorgainc Solid WasteWater Process Emissions

Stage-1Triethyl Orthoformate Sol.RecoveryAcetic Acid Evaporation LossCyclopropylamine EffluentToluene Organic ResiduePotassium Carbonate Process EmissionsWater

Stage-2Benzylamine Sol.RecoveryPotassium Hydroxide Evaporation LossToluene EffluentWater Organic Residue

Stage-3 Sol.RecoveryCarbon Evaporation LossMethanol EffluentHydrogen Organic ResidueHyflo Spent CarbonWater Process Emissions

5-Amino-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester

PRODUCT : 5-Amino-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester

Stage I

Stage II

Stage III

Stage IV

ANNEXURE - II

32

Flow Chart

1-Methyl-3-phenyl piperazine2-Chloro nicotinonitrileDimethylformamide Sol.RecoveryEthyl Acetate Evaporation LossPotassium Fluoride EffluentSodium Hydroxide Organic ResidueSodium Chloride Inorgainc Solid WasteWater

Stage-1Toluene Sol.RecoveryMethylene Dichloride Evaporation LossEthanol EffluentSodium Hydroxide Organic ResidueHydrochloric Acid (35%) Process EmissionsWater

2-(4-Methyl-2-phenyl piperazin-1-yl) pyridine-3-carboxylic acid

PRODUCT : 2-(4-Methyl-2-phenyl piperazin-1-yl) pyridine-3-carboxylic acid

Description :

Stage-1 : 1-Methyl-3-phenyl piperazine is condensed with 2-Chloro nicotinonitrile in Dimethylformamide inpresence of Sodium Hydroxide and Potassium Fluoride to obtain Mirtazapine Stage-I material.

Stage-2 : Hydrolysis of Mirtazapine Stage-I material with Sodium Hydroxide and Hydrochloric Acid in presence ofToluene, Methylene Dichloride and Ethanol solvent media gives 2-(4-Methyl-2-phenyl piperazin-1-yl) pyridine-3-carboxylic acid.

Stage I

Stage II

ANNEXURE - II

33

Flow Chart

D-FructoseIsopropyl Alcohol By-ProductSulfuric Acid Sol.RecoveryAcetone Evaporation LossSodium Hydroxide Effluentn-Hexane Organic ResidueWater

2,3:4,5-Bis-O-(1-Methyl ethylidene)-b-Fructopyranose

PRODUCT : 2,3:4,5-Bis-O-(1-Methyl ethylidene)-b-Fructopyranose

Description :

Stage-1 : D-Fructose reacts with Acetone and Sulfuric acid at 0-5oC for 10 hrs. After reaction complies adjust thePH with Sodium Hydroxide and separate the inorganic salts. Distill out organic layer, isolate the material in IsopropylAlcohol and Hexane at 10-15oC to gives 2,3:4,5-Bis-O-(1-Methyl ethylidene)-b-Fructopyranose.

Stage I

ANNEXURE - II

34

Flow Chart

MalanonitrilePropionaldehyde Sol.RecoverySulfur Evaporation LossTriethylamine EffluentDimethylformamide Organic ResidueWater

Stage-1Ortho Fluoro Nitrobenzene Sol.RecoveryPotassium Hydroxide Evaporation LossAcetonitrile EffluentWater Organic Residue

Stage-2Isopropyl Alcohol By-ProductStannous Chloride Sol.RecoveryHydrochloric Acid (35%) Evaporation LossMethanol EffluentWater Organic Residue

Stage-1 : Malanonitrile reacts with Propionaldehyde and Sulfur in presence of Triethylamine andDimethylformamide at 0-5oC for 15 hrs. After reaction complies filter it to gives Stage-1 Compound.Stage-2 : Stage-1 Compound reacts with Ortho Fluoro Nitrobenzene in presence of Acetonitrile and PotassiumHydroxide at 20-40oC for 12 hrs to gives Stage-2 Compound.Stage-3 : Stage-2 Compound reacts with Stannous Chloride and Hydrochloric acid in presence of IsopropylAlcohol reflux at 80-95oC for 20 hrs, after reaction complies filter it to gives Stage-3 Compound Crude material.The Crude Stage-3 Compound material purified in Methanol media to form 2-Methyl-4-amino-10H-thieno [2,3-b][1,5] benzodiazepine Hydrochloride.

2-Methyl-4-amino-10H-thieno[2,3-b][1,5] benzodiazepine Hydrochloride

PRODUCT : 2-Methyl-4-amino-10H-thieno[2,3-b][1,5] benzodiazepine Hydrochloride

Description :

Stage I

Stage II

Stage III

ANNEXURE - II

35

Flow Chart

Phthalic Anhydride2-Amino ethanol EffluentWater

Stage-1Toluene Sol.Recovery4-Chloroethyl acetoacetate Evaporation LossSodium Hydride (40%) EffluentAcetic Acid Organic ResidueHydrochloric Acid (35%) Process EmissionsWater

Stage-2 : Phthalic alfohol is reacted with 4-Chloro ethyl aceto acetate to obtain Ethyl-4-[2-(1,3-dioxo-1,3-dihydro-2 H- isonidol-2yl)ethoxy]-3-oxobutanoate.

PRODUCT : Ethyl-4-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-ethoxy]-3-oxobutanoate

Ethyl-4-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-ethoxy]-3-oxobutanoate

Description :

Stage-1 : Phthalic Anhydride is reacted with 2-Amino ethanol to get Phthalimido alcohol.

Stage I

Stage II

ANNEXURE - II

36

Flow Chart

7-Chloro quinaldehydeMethanol Sol.RecoveryIsophthaladehyde Evaporation LossAcetic Anhydride Organic Residue

Stage-1Toluene Sol.Recovery


Water Organic Residue

Stage-2Methyl Iodobenzoate Sol.RecoveryCatalyst Evaporation LossSodium Hydroxide EffluentAcetonitrile Organic ResidueWater

Stage-1 : 7-Chloro Quinaldehyde is reacted with Isopthalaldehyde in presence of Acetic Anhydride solvent asMethanol at 133-135oC further cool to 25-30oC to get 3-[2-(7-Chloro-2-Quinolinyl) Ethenyl] Benzaldehyde.

(E)-2-(3-{3-[2-(7-Chloro-2-quinolinyl) vinyl] phenyl}-3-oxo propyl) benzoic acid methyl ester

Vinyl Magnesium Bromide in Tetrahydrofuran (40%)

Stage-2 : 3-[2-(7-Chloro-2-quinolinyl) ethenyl] benzaldehyde is reacted with Vinyl magnesium Bromide inTetrahydrofuran in presence of Toluene at 0-5oC to give 1-{3-[2-(7-Chloro-2-quinolinyl) vinyl]phenyl} prop-2-en-1-ol.Stage-3 : 1{3-[2-(7-Chloro-2-Quinolinyl) vinyl]Phenyl}prop-2-en-1-ol is reacted with Methyl iodobenzoate andPalladium acetate as a catalyst in presence of acetonitrile at 80-85oC further coool to 25-30oC to give 2-(3-{3-[2-(7-Chloro-2-quinolinyl) Vinyl] Phenyl}-3-oxo propyl) benzoic acid methyl ester.

PRODUCT : (E)-2-(3-{3-[2-(7-Chloro-2-quinolinyl) vinyl] phenyl}-3-oxo propyl) benzoic acid methyl ester

Description :

Stage I

Stage II

Stage III

ANNEXURE - II

37

Flow Chart


Potassium Carbonate EffluentAcetonitrile Organic ResidueHydrogen Process EmissionsWater

Stage-1 : 2-Cyano biphenyl-4-carboxaldehyde on reacting with Methyl-L-Valinate Hydrochloride in presence ofPotassium Carbonate as a base and Acetonitrile solvent media and it is further on reductive amination withHydrogen gives N-[(2-Cyano-(1,1'-biphenyl)-4-yl) methyl] valine methyl ester.

2-Cyano biphenyel-4-carboxaldehyde

PRODUCT : N-[(2-Cyano-(1,1'-biphenyl)-4-yl) methyl] valine methyl ester

Methyl-L-Valinate Hydrochloride

N-[(2-Cyano-(1,1'-biphenyl)-4-yl) methyl] valine methyl ester

Description :

Stage I

ANNEXURE - II

38

Stage-1 : Take Methanol, add 2-Chlorophenyl Glycine and feed Sulfuric acid below 15oC. Heat to 60-65oC andmaintaine for 20 hrs. Distill off solvent completely and add Toluene and distill off Toluene to remove theMethanol traces. Cool to residue to room temp. and add water. Stir to dissolve and add Methylene Dichloride.Adjust pH (neutral) with aq. Ammonia and separate layers. Distill of Methylene Dichloride complelty to get crudeStage-1 product.

Stage-2 : Take Methanol, add Stage-1 and add L-Tartaric acid. Stir for 20 hrs at room temp. Centrifuge thematerial. Dry the product at 50-60oC. Take Methanol Mls and distill off solvent completely. Add water to theresidue and adjust pH with Aq. Ammonia (to neutral pH). Extract with Methylene Dichloride. Distill off solventcompletely to get recovered Stage-2.

Stage-3 : Take water and add Sodium Hydroxide flakes. Stir to dissolve and cool to room temp. Add 2-Thiophene Ethanol and Toluene lot-1 mixture. Cool to below 10oC. Feed mixture of P-Toluene Sulfonyl Chlorideand Toluene lot-2 below 10oC and maintian for 1 hr. Separate layers and wash organic layer with water lot-2 and3. Distill off solvent to get Stage-3 product.

Stage-4 : Take water lot-1 and add Stage-2. Add Toluene and adjust pH with Aq. Ammonia to neutral. Separatelayers. Distill off Toluene completely. Add Stage-3 and Potassium Bicarbonate. Heat and maintaine at 80-85o for 48 hrs. Cool to room temperature and add water lot-2 stir to dissolve. Add Ethyl Acetate separate layers.Wash organic layer with water lot-3 add Hydrochloric Acid to organic layer below 15oC. Centrifuge the materialand dry the Stage-4 product at 50-60oC.

PRODUCT : (+)-2-(2-Chlorophenyl)-N-(2-thienyl) ethyl) glycine methyl ester hydrochloride

Description :

Stage-5 : Take Toluene and add (+)-2-(2-Chlorophenyl)-N-(2-thienyl) ethyl) glycine methyl ester hydrochloridecrude. Heat to 50-55oC and maintaine for 1hrs. Cool to room temperature and centrifuge the material. Dry the(+)-2-(2-Chlorophenyl)-N-(2-thienyl) ethyl) glycine methyl ester hydrochloride product at 60-65oC. Collect ML'sand distill off Toluene to get reccovered Toluene.

ANNEXURE - II

39

Flow Chart

2-Chlorophenyl GlycineMethanolSulfuric Acid Sol.RecoveryToluene Evaporation LossMethylene Dichloride EffluentAmmonia (25%) solution Organic ResidueWater

Stage-1Methanol Sol.RecoveryL-Tartaric Acid Evaporation LossMethylene Dichloride EffluentAmmonia (25%) solution Organic ResidueWater

2-Thiophene EthanolP-Toluene Sulfonyl ChlorideSodium Hydroxide Sol.RecoveryToluene Evaporation LossHydrochloric Acid (35%) EffluentWater Organic Residue

Stage-2Ammonia (25%) solutionStage-3 Sol.RecoveryPotassium Bicarbonate Evaporation LossToluene EffluentEthyl Acetate Organic ResidueHydrochloric Acid (35%) Process EmissionsWater


Toluene Organic Residue

(+)-2-(2-Chlorophenyl)-N-(2-thienyl) ethyl) glycine methyl ester hydrochloride

PRODUCT : (+)-2-(2-Chlorophenyl)-N-(2-thienyl) ethyl) glycine methyl ester hydrochloride

(+)-2-(2-Chlorophenyl)-N-(2-thienyl) ethyl) glycine methyl ester hydrochloride (Crude)

Stage I

Stage II

Stage III

Stage IV

Stage V

ANNEXURE - II

40

Stage-8 : Stage-7 Product reacts with Hexyl Cabonochloridate in presence of Methanesulfonic acid andTriethylamine in Chloroform and Ethyl Acetate solvent media to form Dabigatran Etexilate Mesylate.

PRODUCT : Dabigatran Etexilate Mesylate

Description :

Stage-1 : 4-Chloro-3-Nitrobenzoic acid reacts with Methylamine in presence of Acetic acid in Isopropyl Alcoholsolvent medium to get Stage-1 Compound.

Stage-2 : 2-Aminopyridine on reaction with Ethyl Propionate in presence of Hydrochloric acid and Ammonia inChloroform and n-Hexane solvent media to give Stage-2 Intermediate.

Stage-3 : 4-Aminobenzonitrile reacts with Bromoacetic acid in presence of Sodium Hydroxide in Ethyl Acetatesovent medium to form Stage-3 Compound.

Stage-4 : Stage-1 Compound on reaction with Stage-2 Intermediate in presence of Oxalyl Chloride, SodiumHydroxide and Triethylamine in Toluene and Ethanol solvent media to get Stage-4 Product.

Stage-5 : Stage-4 Product on reduction with Hydrogen in presence of Ammonia in Ethyl Acetate solventmedium to get Stage-5 Compound.

Stage-6 : Stage-5 Compound gets reacted with Stage-3 Compound in presence of Carbonyldiimidazole, Aceticacid and Ammonia in Methylene Dichloride, Ethyl Acetate, Dimethylformamide and Acetone solvent media toform Stage-6 Intermediate.

Stage-7 : Stage-6 Intermediate on reaction with Ammonium Carbonate in presence of Hydrochloric acid andSulfuric acid in Ethanol and Ethyl Acetate solvent media to form Stage-7 Product.

ANNEXURE - II

41

Flow Chart

4-Chloro-3-Nitrobenzoic acidMethylamine (40%) Sol.RecoveryIsopropyl Alcohol Evaporation LossAcetic acid EffluentWater

2-AminopyridineEthyl Propionate Sol.RecoveryHydrochloric acid (35%) Evaporation LossChloroform EffluentAmmonia (25%) Solution Organic Residuen-Hexane Process EmissionsWater

4-AminobenzonitrileBromoacetic acid Sol.RecoveryEthyl Acetate Evaporation LossSodium Hydroxide EffluentWater

Stage-1Stage-2Oxalyl Chloride Sol.RecoveryToluene Evaporation LossTriethylamine EffluentEthanol Organic ResidueSodium HydroxideWater

Stage-4Ammonia (25%) Solution Sol.RecoveryEthyl Acetate Evaporation LossRaney Nickel EffluentHydrogen Organic ResidueWater Process Emissions


Stage I

Stage II

Stage III

Stage IV

Stage V

ANNEXURE - II

42

Flow Chart

Stage-5Methylene DichlorideEthyl AcetateDimethylformamide Sol.RecoveryStage-3 Evaporation LossCarbonyldiimidazole EffluentAcetic acid Organic ResidueAcetone Process EmissionsAmmonia (25%) SolutionWater

Stage-6 Sol.RecoveryEthanol Evaporation LossEthyl Acetate EffluentAmmonium Carbonate Organic ResidueHydrochloric acid (35%) Inorgainc Solid WasteSulfuric acid Process Emissions

Stage-7Hexyl CabonochloridateChloroform Sol.RecoveryTriethylamine Evaporation LossEthyl Acetate EffluentMethanesulfonic acid Organic ResidueWater

Dabigatran Etexilate Mesylate


Stage VI

Stage VII

StageVIII

ANNEXURE - II

43

Stage-3 : Stage-2 Intermediate on hydrolysis in presence of Chloroform solvent medium give Stage-3 Compound.

PRODUCT : Domperidone

Stage-1 : Monomethylamine reacts with Methyl Acrylate in Methanol solvent medium to form Stage-1 Compound.

Stage-2 : Stage-1 Compound on reaction with Sodium Methoxide in aqueous medium to get Stage-2 Intermediate.

Stage-4 : Stage-3 Compound on reaction with Ethyl Chloroformate in presence of Sodium Hydroxide in Toluenesolvent medium to get Stage-4 Intermediate. .

Stage-5 : Stage-4 Intermediate on hydrolysis in presence of Ammonia in Methanol solvent medium to form Stage-5Compound.

Description :

Stage-6 : Stage-5 Compound gets reacted with 2,5-Dichloronitrobenzene in presence of Sodium Hydroxide andPotassium Iodide in aqueous medium to give Stage-6 Product.

Stage-7 : Stage-6 Product on hydrolysis in presence of Toluene and Methanol solvent media to get Stage-7Intermediate.

Stage-8 : Stage-7 Intermediate is on reaction with Urea in presence of Hydrochloric acid and Ammonia in aqueousmedium and gets purified with Carbon to form Stage-8 Compound.

Stage-9 : o-Phenyldiamine gets reacted with Methyl Acetoacetate in presence of Sodium Hydroxide andHydrochloric acid in o-Xylene solvent medium to give Stage-9 Intermediate.

Stage-10 : Stage-9 Intermediate is on reaction with 1-Bromo-3-Chloropropane in presence of Sodium Hydroxideand Tetrabutylammonium Bromide in aqueous medium to get Stage-10 Compound.

Stage-11 : Stage-10 Compound on hydrolysis in presence of Ammonia and Hydrochloric acid in Methanol solventmedium to form Stage-11 Intermediate.

Stage-12 : Stage-9 Intermediate on condensation with Stage-11 Intermediate in presence of Sodium Hydroxide,Ammonium Chloride, Acetic acid and Ammonia in Methanol sovlent medium and gets purified with Carbon to obtainDomperidone.

ANNEXURE - II

44

Flow Chart

Monomethylamine Sol.RecoveryMethyl Acrylate Evaporation LossMethanol Organic Residue

Stage-1 Sol.RecoverySodium Methoxide Evaporation LossWater Organic Residue

Inorganic Solid WasteProcess Emissions

Stage-2 Sol.RecoveryChloroform Evaporation LossWater Effluent

Stage-3Toluene Sol.RecoveryEthyl Chloroformate Evaporation LossSodium Hydroxide (40%) EffluentWater Organic Residue

Stage-4 Sol.RecoveryMethanol Evaporation LossAmmonia EffluentHydrogen Organic ResidueRaney Nickel Process Emissions

Stage-52,5-DichloronitrobenzeneSodium Hydroxide (40%) EffluentPotassium IodideWater

Stage-6 Sol.RecoveryHydrogen Evaporation LossToluene EffluentMethanol Organic ResidueRaney Nickel Process Emissions


Stage I

Stage II

Stage III

Stage IV

Stage V

Stage VI

Stage VII

ANNEXURE - II

45

Flow Chart

Stage-7UreaHydrochloric acid (35%) EffluentCarbon Spent CarbonAmmonia (15%) SolutionWater

o-PhenyldiamineMethyl Acetoacetateo-Xylene Sol.RecoverySodium Hydroxide (40%) Evaporation LossHydrochloric acid (35%) EffluentWater

Stage-91-Bromo-3-ChloropropaneSodium Hydroxide (40%) EffluentTetrabutylammonium BromideWater

Stage-10 Sol.RecoveryMethanol Evaporation LossAmmonia (10%) Solution EffluentHydrochloric acid (15%) Organic Residue

Stage-8Stage-11Sodium Hydroxide (40%) Sol.RecoveryAmmonium Chloride Evaporation LossAcetic acid EffluentMethanol Organic ResidueAmmonia (25%) Solution Spent CarbonCarbonWater

Domperidone


StageVIII

Stage IX

Stage X

Stage XI

Stage XII

ANNEXURE - II

46

Stage-3 : Stage-2 Intermediate on reaction with Hydrogen Chloride which is purged in Isobutanol in presence ofIsopropyl Alcohol solvent medium to form Stage-3 Compound.

PRODUCT : Irbesartan

Stage-4 : 2-Cyano-4-methyl byphenyl on reaction with N-Bromo Succinimide in presence of Azoisobutironitrile inMethylene Dichloride solvent medium to get Stage-4 Product.

Stage-5 : Stage-4 Product on condensation with Stage-2 Intermediate in presence of Potassium Hydroxide andTetrabutylammonium Bromide in Methylene Dichloride solvent medium to form Stage-5 Compound.

Stage-6 : Stage-5 Compound on reaction with Sodium Azide in presence of Tributytin Azide and SodiumHydroxide in o-Xylene and Ethyl Acetate solvent media to obtain Irbesartan.

Description :

Stage-1 : Cyclopentanone on reaction with Sodium Cyanide in presence of Ammonium Chloride and Ammonia inMethanol and Methylene Dichloride solvent media to get Stage-1 Compound.

Stage-2 : Stage-1 Compound on reaction with Valeryl Chloride in presence of Sodium Bicarbonate in MethyleneDichloride solvent medium to form Stage-2 Intermediate.

ANNEXURE - II

47

Flow Chart

Cyclopentanone Sodium Cyanide Ammonium Chloride Sol.RecoveryMethanol Evaporation LossAmmonia (25%) Solution EffluentMethylene Dichloride Organic ResidueWater

Stage-l Sol.RecoverySodium Bicarbonate Evaporation LossValeryl Chloride EffluentMethylene Dichloride Organic ResidueWater Process Emissions

Stage-2Isobutanol Sol.RecoveryIsobutanol Hydrochloride (5%) Evaporation LossIsopropyl Alcohol Organic Residue

2-Cyano-4-methyl byphenyl Methylene Dichloride Sol.RecoveryAzoisobutironitrile Evaporation LossN-Bromo Succinimide EffluentWater Organic Residue

Stage-4Stage-2 Sol.RecoveryMethylene Dichloride Evaporation LossPotassium Hydroxide EffluentTetrabutylammonium Bromide Organic ResidueWater

Stage-5o-XyleneSodium Azide Sol.RecoveryTributytin Azide Evaporation LossSodium Hydroxide EffluentEthyl Acetate Organic ResidueWater

PRODUCT : Irbesartan

Irbesartan

Stage I

Stage II

Stage III

Stage IV

Stage V

Stage VI

ANNEXURE - II

48

PRODUCT : Losartan Potassium

Description :

Stage-1 : 2-Cyano-4-methyl byphenyl reacts with N-Bromo Succinimide in presence of Azoisobutironitrile inMethylene Dichloride solvent medium to get Stage-1 Compound.

Stage-2 : Valeronitrile gets reacted with Methanol in presence of Hydrochloric acid, Sodium Hydroxide and Sulfuricacid in Toluene solvent medium to give Stage-2 Intermediate.

Stage-3 : Stage-2 Intermediate is react with Aminoacetic acid in presence of Toluene and Methanol solvent mediato form Stage-3 Compound.

Stage-4 : Stage-3 Compound on reaction with Phosphorous Oxychloride in presence of Sodium Hydroxide, Aceticacid and Dimethylformamide in Methanol and Toluene solvent media and gets purified with Carbon to get Stage-4Product.

Stage-5 : Stage-4 Product reacts with Stage-1 Compound in presence of Sodium Borohydride, Sodium Hydroxide,and Tetrabutylammonium Bromide in Toluene solvent medium to form Stage-5 Compound.

Stage-6 : Stage-5 Compound on reaction with Sodium Azide in presence of Potassium Hydroxide, SodiumMatabisulfate, Triethylamine Hydrochloride and Hydrochloric acid in Toluene, Ethyl Acetate and Isopropyl Alcoholsolvent media to obtain Losartan Potassium.

ANNEXURE - II

49

Flow Chart

2-Cyano-4-methyl byphenylMethylene Dichloride Sol.RecoveryAzoisobutironitrile Evaporation LossN-Bromo Succinimide EffluentWater Organic Residue

ValeronitrileMethanolHydrochloric acid (35%) Sol.RecoverySulfuric acid Evaporation LossToluene EffluentSodium Hydroxide (40%) Organic ResidueWater

Stage-2Toluene Sol.RecoveryAminoacetic acid Evaporation LossMethanol EffluentWater Organic Residue

Stage-3Phosphorous OxychlorideDimethylformamide Sol.RecoverySodium Hydroxide (40%) Evaporation LossMethanol EffluentToluene Organic ResidueCarbon Spent Carbon#REF!Water

Stage-4 Stage-1 Sol.RecoveryToluene Evaporation LossSodium Hydroxide EffluentTetrabutylammonium Bromide Organic ResidueSodium Borohydride Process EmissionsWater


Stage I

Stage II

Stage III

Stage IV

Stage V

ANNEXURE - II

50

Flow Chart

Stage-5TolueneTriethylamine HydrochlorideSodium Azide Sol.RecoverySodium Matabisulfate Evaporation LossPotassium Hydroxide EffluentCarbon Organic ResidueHydrochloric acid (35%) Spent CarbonEthyl AcetateIsopropyl AlcoholWater

Losartan Potassium


Stage VI

ANNEXURE - II

51

PRODUCT : Olmesartan Medoxomil

Description :

Stage-4 : Diethyl taratrate on rection with Ammonium Acetate in presence of Butyraldehyde, Acetic acid, SodiumHydroxide, N-Bromo Succinimide and Azoisobutyronitrile in Tetrahydrofuran solvent medium to get Stage-4Intermediate.

Stage-1 : 2-Cyano-4-methyl biphenyl on reaction with Sodium Azide in presence of Sulfuric acid, Sodium Nitrateand Triethylamine Hydrochloride in Toluene solvent medium to form Stage-1 Compound.

Stage-2 : Stage-1 Compound reacts with Trityl Chloride in presence of Triethylamine in Methylene Dichlorideand Methanol solvent media to get Stage-2 Intermediate.

Stage-3 : Stage-2 Intermediate is react with N-Bromo Succinimide in presence of Sodium Metabisulfate andAzobisisobutyronitrile in Methylene Dichloride and Ethyl Acetate solvent media to give Stage-3 Compound.

Stage-6 : Stage-5 Product on condensation with Stage-3 Compound in presence of TetrabutylammoniumBromide and Sodium Hydroxide in Acetone and Methanol solvent media to get Stage-6 Compound.

Stage-5 : Stage-4 Intermediate on reaction with Methyl Magesium Chloride in presence of Hydrochloric acid andSodium Chloride in Toluene and Tetrahydrofuran solvent media to form Stage-5 Product.

Stage-7 : Stage-6 Compound reacts with 4-(Chloromethyl)-5-methyl-1,3-dioxol-2-one in presence ofTriethylamine in Dimethylacetimide and Methanol solvent media to obtain Stage-7 Intermediate.

Stage-8 : Stage-7 Intermediate on hydrolysis in presence of Acetic acid and Isopropyl Alcohol solvent media toform Olemisartan Medoxomil.

ANNEXURE - II

52

Flow Chart

2-Cyano-4-methyl biphenylTolueneSodium Azide Sol.RecoveryTriethylamine Hydrochloride Evaporation LossSulfuric acid EffluentSodium Nitrate Organic ResidueWater

Stage-1Methylene DichlorideTrityl Chloride Sol.RecoveryTriethylamine Evaporation LossMethanol EffluentWater Organic Residue

Stage-2Methylene Dichloride Azobisisobutyronitrile Sol.RecoveryN-Bromo Succinimide Evaporation LossEthyl Acetate EffluentSodium Metabisulfate Organic ResidueWater

Diethyl TaratrateN-Bromo SuccinimideAzoisobutyronitrile Sol.RecoveryTetrahydrofuran Evaporation LossButyraldehyde EffluentAmmonium Acetate Organic ResidueAcetic acid Process EmissionsSodium HydroxideWater

Stage-4TolueneTetrahydrofuran Sol.Recovery


Hydrochloric acid (35%) Organic ResidueSodium Chloride Water

Methyl Magesium Chloride (22%) in Tetrahydrofuran


Stage I

Stage II

Stage III

Stage IV

Stage V

ANNEXURE - II

53

Flow Chart

Stage-3Stage-5Acetone Sol.RecoverySodium Hydroxide Evaporation LossTetrabutylammonium Bromide EffluentMethanol Organic ResidueWater

Stage-6

Sol.RecoveryTriethylamine Evaporation LossDimethylacetimide EffluentMethanol Organic ResidueWater

Stage-7 Sol.RecoveryAcetic acid Evaporation LossIsopropyl Alcohol EffluentWater Organic Residue

4-(Chloromethyl)-5-methyl-1,3-dioxol-2-one

Olmesartan Medoxomil


Stage VI

Stage VII

StageVIII

ANNEXURE - II

54

Stage-2 : Stage-1 Compound is on reaction with Urea in presence of Sodium Hydroxide in Toluene solventmedium to give Stage-2 Intermadiate.

Stage-3 : Stage-2 Intermadiate gets resolution with (R)-(+)-Phenylethylamine in presence of Chloroform andEthanol solvent media to form Stage-3 Compound.

Stage-4 : Stage-3 Compound is on reaction with Hydrochloric acid in presence of Chloroform solvent medium togive Stage-4 Intermadiate.

Stage-5 : Stage-4 Intermadiate on hydrolysis in presence of Bromine, Sodium Hydroxide and Hydrochloric acid inIsopropyl Alcohol solvent medium to obtain Pregabalin.

PRODUCT : Pregabalin

Description :

Stage-1 : Isovalaraldehyde on reaction with Ethyl Cyanoacetate in presence of Di-n-Propylamine, Diethylmalonate and Hydrochloric acid in n-Hexane solvent medium to get Stage-1 Compound.

ANNEXURE - II

55

Flow Chart

Isovalaraldehyde Ethyl Cyanoacetate Sol.RecoveryDi-n-Propylamine Evaporation LossDiethyl malonate Effluentn-Hexane Organic ResidueHydrochloric acid (35%) Process EmissionsWater

Stage-1 Sol.RecoveryUrea Evaporation LossSodium Hydroxide EffluentToluene Organic ResidueWater

Stage-2(R)-(+)-Phenylethylamine Sol.RecoveryChloroform Evaporation LossEthanol Organic Residue

Stage-3 Sol.RecoveryHydrochloric acid (35%) Evaporation LossChloroform EffluentSodium Hydroxide Organic ResidueWater

Stage-4Bromine Sol.RecoverySodium Hydroxide Evaporation LossHydrochloric acid (35%) EffluentIsopropyl Alcohol Organic ResidueWater

PRODUCT : Pregabalin

Pregabalin

Stage I

Stage II

Stage III

Stage IV

Stage V

ANNEXURE - II

56

PRODUCT : Quetiapine Hemifumarate

Description :

Stage-1 : Benzene thiol is on reaction with 1-Chloro-2-Nitrobenzene in presence of Isopropyl Alcohol solventmedium to form Stage-1 Compound.

Stage-2 : Stage-1 Compound on reduction in presence of Raney Nickel catalyst in Methanol solvent medium toget Stage-2 Intermediate.

Stage-3 : Stage-2 Intermediate on reaction with Phenyl Chloroformate in presence of Potassium Carbonate inToluene and Methanol solvent media to give Stage-3 Compound.

Stage-4 : Stage-3 Compound in presence of Polyphosphoric acid in Dimethylformamide and Acetone solventmedia to form Stage-4 Intermediate.

Stage-5 : 2-(2-Chloroethoxy)ethanol on reaction with Piperizine in presence of Hydrochloric acid and SodiumHydroxide in aqueous medium to get Stage-5 Compound.

Stage-6 : Stage-4 Intermediate on reaction with Stage-5 Compound in presence of Sodum Hydroxide andHydrochloric acid in Methylene Dichloride solvent medium to obtain Quitapine Hemifumarate.

ANNEXURE - II

57

Flow Chart

Benzene thiol Sol.Recovery1-Chloro-2-Nitrobenzene Evaporation LossIsopropyl Alcohol EffluentWater Organic Residue

Process Emissions

Stage-1 Sol.RecoveryMethanol Evaporation LossRaney Nickel EffluentHydrogen Organic Residue

Process Emissions

Stage-2Phenyl Chloroformate Sol.RecoveryToluene Evaporation LossPotassium Carbonate EffluentMethanol Organic ResidueWater Process Emissions

Stage-3Polyphosphoric acid Sol.RecoveryDimethylformamide Evaporation LossAcetone EffluentWater Organic Residue

2-(2-Chloroethoxy)ethanolPiperizine Hydrochloric acid ( 35% ) EffluentSodium Hydroxide ( 40% )Water

Stage-4Stage-5 Sol.RecoveryHydrochloric acid (35%) Evaporation LossMethylene Dichloride EffluentSodum Hydroxide Organic ResidueWater

Quetiapine Hemifumarate

PRODUCT : Quetiapine Hemifumarate

Stage I

Stage II

Stage III

Stage IV

Stage V

Stage VI

ANNEXURE - II

58

PRODUCT : Raloxifene Hydrochloride

Description :

Stage-1 : 1-(4-Methoxyphenyl)ethanone on reaction with Bromine in presence of Sodium Hydroxide in Methanolsolvent medium to form Stage-1 Compound.

Stage-2 : Stage-1 Compound gets reacted with 3-Methoxy Benzenethiol in presence of Potassium Hydroxide inMethanol solvent medium to get Stage-2 Intermediate.

Stage-3 : Stage-2 Intermediate in presence of Polyphosphoric acid and Sodium Sulfate in Acetone and EthylAcetate solvent media to give Stage-3 Compound.

Stage-4 : Methylparaben reacts with 2-Chloroethyl Piperidine Hydrochloride in presence of PotassiumCarbonate in Acetone and Methanol solvent media to form Stage-4 Intermediate.

Stage-5 : Stage-3 Compound on condensation with Stage-4 Intermediate in presence of PhophorousPentachloride, Sodium Hydroxide, N-Phenylmercapton and Sodium Sulfate in Methylene Dichloride solventmedium to obtain Raloxifene Hydrochloride.

ANNEXURE - II

59

Flow Chart

1-(4-Methoxyphenyl)ethanoneBromine Sol.RecoveryMethanol Evaporation LossSodium Hydroxide EffluentWater

Stage-13-Methoxy Benzenethiol Sol.RecoveryPotassium Hydroxide Evaporation LossMethanol EffluentWater Organic Residue

Stage-2Polyphosphoric acid Sol.RecoveryAcetone Evaporation LossEthyl Acetate EffluentSodium Sulfate Organic ResidueWater Inorganic Solid Waste

MethylparabenAcetone Sol.Recovery


Potassium Carbonate Organic ResidueMethanol Process EmissionsWater

Stage-3Stage-4Phophorous Pentachloride Sol.RecoverySodium Hydroxide Evaporation LossMethylene Dichloride EffluentN-Phenylmercapton Organic ResidueSodium Sulfate Inorganic Solid WasteWater

Raloxifene Hydrochloride

2-Chloroethyl Piperidine Hydrochloride

PRODUCT : Raloxifene Hydrochloride

Stage I

Stage II

Stage III

Stage IV

Stage V

ANNEXURE - II

60

Stage-6 : Stage-4 Product on reaction with Stage-5 Compound in presence of Potassium Hydroxide in Acetone,Methanol and Monoethylene Glycol solvent media to obtain Telmisartan.

PRODUCT : Telmisartan

Description :

Stage-1 : Methyl-3-nitro-4-(butanoyl amine)-5-methylbenzoate on reduction with Hydrogen in presence ofMethanol solvent medium to form Stage-1 Compound.

Stage-2 : Stage-1 Compound in presence of Acetic acid and Methylene Dichloride solvent media to get Stage-2Intermediate.

Stage-3 : Stage-2 Intermediate on reaction with Sodium Hydroxide in presence of Methanol solvent medium togive Stage-3 Compound.

Stage-4 : Stage-3 Compound on reaction with N-Methyl-1,2-benzenediamine dihydrochloride in presence ofPolyphosphoric acid and Sodium Hydroxide in Toluene and Methanol solvent medium to get Stage-4 Product.

Stage-5 : 2-Cyano-4-methyl byphenyl on reaction with N-Bromo Succinimide in presence of Azoisobutiro nitrile inMethylene Dichloride solvent medium to form Stage-5 Compound.

ANNEXURE - II

61

Flow Chart

Sol.RecoveryPalladium Carbon Evaporation LossMethanol EffluentHydrogen Organic Residue

Stage-1 Sol.RecoveryAcetic acid Evaporation LossMethylene Dichloride Effluent

Organic Residue

Stage-2 Sol.RecoveryMethanol Evaporation LossSodium Hydroxide Organic Residue

Stage-3Sol.Recovery

Evaporation LossToluene EffluentPolyphosphoric acid Organic ResidueSodium Hydroxide (47%) Inorgainc Solid WasteMethanol Spent CarbonCarbon

2-Cyano-4-methyl byphenyl Methylene Dichloride Sol.RecoveryAzoisobutironitrile Evaporation LossN-Bromo Succinimide EffluentWater Organic Residue

Stage-4Stage-5 Sol.RecoveryPotassium Hydroxide Evaporation LossAcetone EffluentMonoethylene Glycol Organic ResidueMethanol Spent CarbonCarbon Process EmissionsWater

Telmisartan

PRODUCT : Telmisartan

Methyl-3-nitro-4-(butanoyl amine)-5-methylbenzoate

N-Methyl-1,2-benzenediamine dihydrochloride

Stage I

Stage II

Stage III

Stage IV

Stage V

Stage VI

ANNEXURE - II

62

Stage-4 : Stage-3 Compound on reduction with Sodium Borohydride in presence of Dipotassium HydrogenOrthophosphate, Sodium Hydroxide and Hydrochloric acid in Isopropyl Alchol, Toluene and Ethanol solventmedia to obtain Emtricitabine.

PRODUCT : Emtricitabine

Description :

Stage-2 : Stage-1 Compound on reaction with 2,5-Dihydroxy-1,4-Dithiane in presence of Acetic acid andTriethylamine in Toluene and Hexane solvent media to give Stage-2 Intermediate.

Stage-3 : Stage-2 Intermediate reacts with 5-Fluorocytosine in presence of Thionyl Chloride, Triethylamine and Hexamethyldisilazane in Methylene Dichloride and Methanol solvent media to form Stage-3 Compound.

Stage-1 : L-Menthol on reaction with Glyoxalic acid in presence of Sodium Bisulfate, Formaldehyde andSulfuric acid in Cyclohexane solvent medium to get Stage-1 Compound.

ANNEXURE - II

63

Flow Chart

L-MentholGlyoxalic acidCyclohexane Sol.RecoverySodium Bisulfate Evaporation LossSulfuric acid EffluentFormaldehyde (40%) Organic ResidueWater

Stage-1Acetic acid Sol.RecoveryToluene Evaporation LossTriethylamine Organic Residue2,5-Dihydroxy-1,4-Dithiane Process EmissionsHexane

Stage-2Methylene Dichloride Oxalyl Chloride Sol.Recovery5-Fluorocytosine Evaporation LossHexamethyldisilazane EffluentMethanol Organic ResidueTriethylamineWater

Stage-3Isopropyl Alchol

Sodium Hydroxide Sol.RecoverySodium Borohydride Evaporation LossHydrochloric acid (35%) EffluentToluene Organic ResidueEthanol Spent Carbon

Process Emissions

CarbonWater

Emtricitabine

PRODUCT : Emtricitabine

Dipotassium Hydrogen Orthophosphate

Isopropyl Alchol Hydrochloride (20%)

Stage I

Stage II

Stage III

Stage IV

ANNEXURE - II

64

PRODUCT : Lamivudine Salicylate

Description :

Stage-1 : L-Menthol on reaction with Glyoxalic acid in presence of Sodium Bisulfate, Formaldehyde and Sulfuricacid in Cyclohexane solvent medium to get Stage-1 Compound.

Stage-2 : Stage-1 Compound on reaction with 2,5-Dihydroxy-1,4-Dithiane in presence of Acetic acid andTriethylamine in Toluene and Hexane solvent media to give Stage-2 Intermediate.

Stage-3 : Stage-2 Intermediate reacts with Cytosine in presence of Thionyl Chloride, Triethylamine andHexamethyldisilazane in Methylene Dichloride and Toluene, Isopropyl Alochol and Dimethylformamide solventmedia to form Stage-3 Compound.

Stage-4 : Stage-3 Compound on reduction with Sodium Borohydride in presence of Dipotassium HydrogenOrthophosphate, Sodium Hydroxide, Salicylic acid and Hydrochloric acid in Isopropyl Alchol, Toluene and Ethanolsolvent media to obtain Lamivudine Salicylate.

ANNEXURE - II

65

Flow Chart

L-MentholGlyoxalic acidCyclohexane Sol.RecoverySodium Bisulfate Evaporation LossSulfuric acid EffluentFormaldehyde (40%) Organic ResidueWater

Stage-1Acetic acidToluene Sol.RecoveryTriethylamine Evaporation Loss2,5-Dihydroxy-1,4-Dithiane Organic ResidueHexane Process Emissions

Stage-2Methylene Dichloride Oxalyl ChlorideCytosine Sol.RecoveryHexamethyldisilazane Evaporation LossToluene EffluentTriethylamine Organic ResidueIsopropyl AlocholDimethylformamideWater

Stage-3Isopropyl Alchol

Sol.RecoverySodium Hydroxide Evaporation LossSodium Borohydride EffluentHydrochloric acid (35%) Organic ResidueToluene Spent CarbonEthanol Process EmissionsSalicylic acidCarbonWater

Lamivudine Salicylate

PRODUCT : Lamivudine Salicylate

Dipotassium Hydrogen Orthophosphate

Stage I

Stage II

Stage III

Stage IV

ANNEXURE - II

66

ANNEXURE - III

67

WATER BALANCE

Item Water

Requirement

in KLD

Waste Water

Generation

in KLD

Treatment Method

Process 24.4 30.6* Forced evaporation and the condensate sent to

Effluent Treatment Plant for reuse

Floor & Reactor

washings 3.0 3.0

Full Fledge ETP & treated water reused for Cooling towers / Boilers

Boiler & Cooling

Tower 120.0 10.0

D.M. Regeneration 1.0 1.0

Scrubber, Q.C &

R&D 6.5 2.0

Domestic 10.5 10.0 Sent to Sewage

Treatment plant and treated used for

Gardening Total 165.4 56.6

Note:

* 30.6 KLD consists of 3458 Kg of inorganics and 987 kg of organics and 29.26 KLD

water.

ANNEXURE - IV

68

List of Hazardous Chemicals

Raw Material

2-Chloro Benzaldehyde AcetonitrileAmmonia Solution (25%)Benzene Sulfonic acidBenzylamineDiethyl MalonateDimethylformamideEthanolHydrochloric Acid (35%)Methylene DichlorideMonomethyl amine (30%)n-HexanePhthalic AnhydridePropionaldehydePyridineSodium Hydride (40%)Sulfuric AcidSulfuryl ChlorideTetrahydrofuranTolueneTriethylamine

ANNEXURE - V

69

SOLID WASTE GENERATION FORM THE PLANT

Sl. No.

Source TPD* Handling Method

Disposal

1. Organic residue 1.51 HDPE Drums

Sent to TSDF 2. Inorganic &

Evaporation Salt 3.72 HDPE Bags

3. Spent Carbon 0.62 HDPE Drums 4. ETP Sludge 0.2 HDPE Bags 5. Boiler Ash 16.0 Stored in

covered area Sold to Brick Manufactures

Total 22.05

* Solid waste quantities on worst combination (any four products at a time)

ANNEXURE - VI

70

STACK EMISSION DETAILS

Source Stack Height (m)

Diameter (m)

Temperature in oK

Flue Gas Flow rate (m3/Hr)

Exit Gas Velocity in m/sec

SPM SO2 NOx

Kg/hr

10.0 TPH Coal fired

Boiler 30 0.7 423 21950 15.8 1.38 10.8 5.4

ANNEXURE - VII

71

PROCESS EMISSION DETAILS

HCl, Ammonia, CO2, N2 and H2 emissions are liberated from the process. HCl (25.87 Kg/day)

and Ammonia (16.49 Kg/day) will be scrubbed in the scrubber and dilute HCl and Liquid

Ammonia will be used for Neutralisation. N2 (6.85Kg/day) and CO2 (258.99 Kg/day) will be

routed to atmosphere through vents and H2 (27.11 Kg/day) will be diffused with flame arrestor.

Product wise gaseous emissions and its treatment method details are given below.

Sl. No. Product

Name of the

Process Emission

Quantity Kg/day Treatment Method

Propose Bulk Drugs – Campaign products (4 products at a time)

1. Sparfloxacin CO2 H2

53.67 7.5

Dispersed into atmosphere Diffused with flame arrestor

2. Mirtazapine NH3 H2

3.59 0.89

Scrubbed with water Diffused with flame arrestor

3. Topiramate Nil --- --- 4. Olanzapine Nil --- --- 5. Amlodipine Besylate H2 2.07 Diffused with flame arrestor

6. Montelukast Sodium HCl H2

12.0 1.0

Scrubbed with water Diffused with flame arrestor

Sl. No. Product

Name of the

Process Emission

Quantity Kg/day Treatment Method

7. Loratadine

NH3 CO2 N2 HCl

7.81 28.05 6.85

13.87

Scrubbed with water Dispersed into atmosphere Dispersed into atmosphere

Scrubbed with water

8. Valsartan CO2 H2

15.6 8.57


9. Clopidogrel Hydrogensulfate CO2 58.7 Dispersed into atmosphere

10. Gabapentin CO2 118.57 Dispersed into atmosphere

11.

5-Amino-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester

CO2 H2

24.35 4.17


12. 2-(4-Methyl-2-phenyl piperazin-1-yl) pyridine-3-carboxylic acid

NH3 5.09 Scrubbed with water

13. 2,3:4,5-Bis-O-(1-Methyl ethylidene)-b-Fructopyranose

Nil --- ---

14. 2-Methyl-4-amino-10H-thieno[2,3-b][1,5] Nil --- ---

ANNEXURE -VIII

72

benzodiazepine Hydrochloride

15.

Ethyl-4-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-ethoxy]-3-oxobutanoate

H2 1.38 Diffused with flame arrestor

16.

(E)-2-(3-{3-[2-(7-Chloro-2-quinolinyl) vinyl] phenyl}-3-oxo propyl) benzoic acid methyl ester

Nil --- ---

17. N-[(2-Cyano-(1,1'-biphenyl)-4-yl) methyl] valine methyl ester

CO2 H2

12.51 6.87


18.

(+)-2-(2-Chlorophenyl)-N-(2-thienyl) ethyl) glycine methyl ester hydrochloride

CO2 27.16 Dispersed into atmosphere

ANNEXURE -VIII

ANNEXURE - IX

73

ANNEXURE - IX

74

ANNEXURE - IX

75

ANNEXURE - IX

76

ANNEXURE - IX

77

ANNEXURE - IX

78

ANNEXURE - IX

79

ANNEXURE -I

ANNEXURE - X

80

kecpl3

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ANNEXURE - XI

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appendix i (see paragraph – 6) form 1 (i) basic...

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