of -...

ON

THE PROPOSEDEXPANSION PROJECT

(BY ADDITION OF NEW PRODUCTS) (Manufacturing of Pharma Intermediates and APIs)

Under Activity: 5(f)

(Synthetic Organic Chemical Manufacturing Industry)

OF

Located at: Plot No. 911-912-922, Phase-III, GIDC Vapi,Tal-Vapi, Dist-Valsad

Pin- 396195, Gujarat-India

Prefeasibility Report Megafine Pharma(P)Ltd.

INDEX

1. Executive Summary……………………………………………………………………………………….……………… 01

2. Introduction……………………………………………………………………………………..………….………………. 03 i. Identification of the Project and Proponent. 03 ii. Brief Description of the project 04 iii. Need of the project and its importance to the country and or region 04 iv. Demand –Supply Gap 04 v. Imports vs. Indigenous production 04 vi. Export Possibility / Domestic / export Markets 04 vii. Employment Generation (Direct and Indirect) due to the project. 04

3. Project Description………………………………………………………………………………………………………… 05 i. Type of Project including interlinked and interdependent projects, If any 05 ii. Location (map showing general location, Specific location, and project boundary

& project site layout)with coordinates 05

iii. Profile of Project site 06 iv. Site Layout Plan 08 v. Details of alternate sites considered and the basis of selecting the proposed site,

particularly the environmental considerations gone into should be highlighted 10

vi. Size or magnitude of operation 11 vii. Project description with process details (a schematic diagram/ flow chart

showing the project layout components of the project etc. should be given) 11

viii. Raw material required along with estimated quantity, likely source, marketing area of final products/s, mode of transport of raw Material and finished product

18

ix. Resource optimization/ recycling and reuse envisaged in the project, 33 x. Availability of water its source, Energy/power requirement and source 33 xi. Quantity of waste to be generated (liquid and solid) and scheme for their

Management/disposal 34

xii. Schematic representations of the feasibility drawing which give information of EIA purpose

41

4. Site Analyses………………………………………………………………………………………………………………… 42 i. Connectivity 42 ii. Land Form, land Use and Land Ownership 42 iii. Existing Infrastructure/ land use pattern 42 iv. Soil Classification and Land Use Classification 42 v. Climate Data from secondary source 42 vi. Social Infrastructure 42

5. Planning Description……………………………………………………………………………………………………… 43 i. Planning Concept (Type of industries, facilities, transportation, etc.) 43 ii. Population Projection 43 iii. Land use planning (breakup along with green belt etc. 43 iv. Assessment of Infrastructure demand (Physical & Social) 43

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v. Amenities/ Facilities 43

6. Proposed Infrastructure ……………………………………………………………………………………………….. 44 i. Industrial Area (Processing Area) 44 ii. Residential Area (Non Processing Area). 44 iii. Green belt 44 iv. Connectivity 44 v. Drinking Water management (Source& Supply of water) 44 vi. Sewage System 44 vii. Industrial Waste Management 44

7. Rehabilitation and Resettlement (R&R) Plan…………………………………………………………………. 44

I. Policy to be adopted (Central/ State) in respect of the project affected persons

including home oustees, land oustees and landless laborers (a brief outline to be given):

44

8. Project Schedule & Cost Estimates…………………………………………………………………….............. 44

i. Likely date of start of construction and likely date of completion 44

ii. Estimated project cost along with analysis in terms of economic viability of the project 44

9. Analysis of Proposal (Final Recommendations)…………………………………………………............. 45 i. Financial and social benefits with special emphasis on the benefit to the local

people including tribal population, if any, in the area 45

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1. EXECUTIVE SUMMARY

1.0 About Project: M/s. Megafine Pharma(P)Ltd is an existing Company having its unit located at Plot no. 911-912, 922 G.I.D.C., Phase-III, Vapi,Dist.-Valsad,Gujarat-396195 manufacturing syntheticorganic compound as Advance Drug Intermediates and Bulk Drugs / APIs for Pharma Industry @ 8.71MT/Month.The unit is involved in Multimilling, Blending, Packing, Labeling of Bulk Drugs and Intermediates @ 50MT/Month.

Now, the Company propose to manufacture additional new products within its existing premises asAdvanceDrug Intermediates and Bulk Drugs / APIs @ 26MT/Month at Plot no. 911-912,922 G.I.D.C., Phase-III, Vapi,Dist.-Valsad,Gujarat-396195.

2.0 Highlights of the Project: Sr. No. Particulates Description

1. Project Location Megafine Pharma (P) Ltd. Plot no. 911, 912&922 G.I.D.C., Phase-III, Tal.-Vapi,Dist.-Valsad,Gujarat-396195

2. Project Activity, Category as per amendments

Project Activity:-5(f)- Synthetic Organic Chemicals, Category:-B

3. Project Cost Phase-I15.00Crores& Phase-II 9.00 Crores (Includes Modification, Modernization & Automation to comply better R&D, EHS & cGMP)

4. Total area of Project Abt. 4000 sq.mt

5. Products with capacity A. Manufacturing: Existing: Pharma Intermediates&Bulk Drugs/APIs: 8.71 MT /M Proposed: Pharma Intermediates & Bulk Drugs/APIs:17.29 MT /M Total after proposed : Pharma Intermediates &Bulk Drugs / APIs@ 26 MT/M B. Milling Blending Activity:

Existing: 50 MT/Month 6. Power Requirement 475 HP

7. Utilities (D.G. Sets, Boilers, Thermopack, etc...)

D.G. Set : Three(Capacity:250+25KVA(Existent) and 250 KVA (Proposed) Boiler IBR: 1120kgs/day, Thermopack: 4Lac Kcal/hr, Boiler Non-IBR: 800 kgs/day,Boiler IBR: 1120 kgs/day (proposed)

8. Fuel Requirements HSD : 60 Lit./hr.& Natural Gas: 1700 SCM/day, LDO- 75 Lit/hr

9. Man Power 150 persons 10. Air pollution Control

Measures All equipment and centrifuges are connected to scrubbers, LDAR program implemented, Dust collector will be attached to pulverizer.

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11. Water requirement & waste water generation with mode of disposal

Water Consumption: 89.00 KL/day, Sourced from GIDC water supply. Domestic waste water –12 KLD disposed off through adequate soak pit and septic tank. Industrial waste water- Will be segregated as diluted and concentrated streams. The diluted stream: 8.15 KL/day, being treated using existing adequate ETP to meet GPCB norms for further treatment by CETP through underground drainage of GIDC, Vapi The concentrated stream: Sent to CETP for CMEE, being approved member, through tankers with required manifest.

12. Solid / Hazardous waste Generation

Managed as per Hazardous Waste (Management, Handling And Transboundary Movement) Rules-2008.

13. Nearest Highway NH-8: 5.0 Km (Approx.)

14. Nearest Railway Station Vapi- 6.0 Km (Approx.)

15. Nearest Airport Daman 16 Km NW (Approx.) and Surat :125 Km NW (Approx.)

16. Nearest Forest/ Sanctuary/Eco-sensitive zone.

None



2. INTRODUCTION

I. Identification of Project and Proponent:

Name of the Project Proponent: M/s. Megafine Pharma(P)Ltd • Unit is established in 1980 as M/s Fine Chemicals then became Superfine Labs P. Ltd. and today it

is Megafine Pharma(P) Ltd. • Unit is manufacturing various synthetic organic compounds as pharma intermediates & bulk drugs

for pharma industries. • M/s Megafine Pharma(P) Ltd. achieved milestone in business journey.

o 1993 : Global pioneer in manufacturing advance macrolides. o 1994 : Visiting & Exhibiting in overseas market initiated o 2000 : Achieved almost 100% export oriented unit o 2006 : Gujarat State FDA approval for GMP as Schedule-M o 2008 : US-FDA Inspected without any Deficiency; This was First of its kind in Gujarat, US-

FDA approved Unit. o 2010 : ISO 9001:2008 Certification. o 2011 : SME Award of “Business Gaurav” as Best Performing Medium Scale Pharma Co. o 2012 – ISO 14001-18000 OHSAS Certification(Environment, Health & Safety) o 2013 –Audited by MNC for EHS&Surveillance audit by US-FDA

• Unit has obtained Consent to Establish and has obtained valid CCA of the board No.AWH-58429 dated 18-11-2013 valid up 30-09-2018 for manufacturing of existing products.

• The unit is member of CETP, Vapi Green Enviro Ltd.(VGEL) for discharge of treated waste water. And solid waste at TSDF site

• The unit is member of SEPPL through Vapi Green Enviro Ltd. (VGEL) for incineration of combustible residual waste. Member of Cement industries for co-processing of combustible waste

• The unit is member of FACCO and CMEE, Vapi Green Enviro Ltd. (VGEL) for segregated concentrated waste water treatment.

The company is a registered Private Limited company and is promoted by three Directors. Details related to them are given below:

Sr. No. Name of Directors Residential Address Background

1. Mr. Ashok K. Jhaveri 190-B, Heera Panna Co-op.Hsg. Soc., Bhulabhai Desai Road, Haji Ali, Mumbai.

B. Tech. (Chem.) I.I.T.-Delhi having 39 years of experience

2. Mr. Hasmukh P. Gandhi

A/ 7&8, Ashoka Residency, Tilakwadi, B/H Rajiv Gandhi Bhavan Marg, Nasik - 422 002.

B. Sc. having 35 years of experience

3. Mr. Shailesh J. Sanghvi

801-JoganiAppartment, 29-B Dongarsi Road, Walkeshwar, Mumbai – 400 006.

B. Com. Having 25 years of experience



II. Brief description of nature of the Project:

M/s. Megafine Pharma(P)Ltd is an existing Company having its unit located at Plot no. 911-912, 922 G.I.D.C., Phase-III,Vapi,Dist.-Valsad,Gujarat-396195 manufacturing synthetic organic compound as Advance Drug Intermediates and Bulk Drugs / APIs for Pharma Industry @ 8.71MT/Month. The unit is involved in Multimilling, Blending, Packing, Labelling of Bulk Drugs and Intermediates@ 50MT/Month.

Now, the Company propose to manufacture additional new products within its existing unit & proposed new block for PharmaIntermediates and bulk drugs/APIs @ 26 MT/Month which are synthetic organic chemicals, at Plot no., 911-912,922 G.I.D.C, Phase-III, Vapi, Dist.-Valsad, Gujarat-396195. For the proposed expansion project, the company propose to use in-house developed ready technology and intends to procure the available latest technology for manufacturing the proposed products.

The pharma / health industrial sector in the past many years has seen a consistent growth and also keeping in mind our strong presence in the local & globalmarket.Hence we have identified the demand for the proposed products which are meant for very new medicines meant for fast growing therapeutic segments like Cardiac, Neuro, Pulmonary, Diabetic, etc.with R&D developed our own process patents we can take a lead & produce commercially in bulk for domestic market as well as with strong presence in export markets.

As per the EIA notification- 2006 as amended the proposed new project involves the production of “Pharma Intermediates and APIs” which falls under item no. “5(f) – Synthetics Organic Chemical Industries“as per the EIA notification- 2006, hence required prior Environmental Clearance.

III. Need for the project and its importance to the country and or region: The proposed expansion project will provide a potential & required growth opportunity for the already running business of the company. The company is US FDA approved facility since 2008. Moreover company has strong presence with leading pharma cos. locally as-well-as internationally; mainly in regulated market. The company & the products are well approved & registered with the leading regulatory authorities & the pharma customers’ in local &international markets.

IV. Demand–Supply Gap: The products have very good demand & high potential asPharma Intermediates and bulk drugs/APIs

for PharmaceuticalIndustries.

V. Imports vs. Indigenous production: Proposed products manufacturing in the country will be very much viable &acceptable compare to importsdue to our grass-root technology, efficient productivity and EHS-GMP compliances. Our products approval & DMF filing for leading overseas customers gives tremendous boost to our export; whichearns valued forex revenue generation for our county.

VI. Export Possibility / Domestic / export Markets: There is a fast growing demand of the proposed products in the export & our local market. Our

products are widely used and are in huge demand in the domestic pharma/health industry.

VII. Employment Generation (Direct and Indirect) due to the project: There will be very good opportunity of employment generation of additional qualified staff

&unqualified workers directly for100 nos.and indirectly for 50 nos.) Due to proposed expansion project.



3. PROJECT DISCRIPTION

I. Type of Project including interlinked and interdependent projects, If any :

The proposed project is not interlinkedand interdependentproject of the company.

II. Location (map showing general location, specific location, and project boundary & project site layout) with coordinates:

The map showing general location, specific location and project boundary and project site layout of M/s. Megafine Pharma(P)Ltd unit located at Plot no. 911-912,922 G.I.D.C, Phase-III, Tal.-Vapi,Dist.-Valsad,Gujarat-396195.The latitude and longitude of the project site is20.21’58°N and72.56’43°E.

Fig. 3.1: Location map showing the Project site in Notified Industrial area of GIDC Vapi



III. Profile of Project Site:

Sr. No. Nearest Infrastructure Feature Distance from Project Site

1 Geographical Position 20°.21’58 N and 72°.56’43E.

2 Elevation above Sea Level 32 Meters (Approx.)

3 Nearest Village Chhiri- Chharwada (5.0 kmNE)

4 Nearest Town Vapi(5.0 km W)

5 Nearest National Highway NH 8 (5.0 Km W)

6 Nearest State Highway GJ SH 5 (5 Km SW)

8 Nearer RW Station Vapi (6 Km)

9 Nearest Airport Daman (17KmsW) Surat (125 Kms NW)

10 Nearest Surface water Resource/Reservoir Arabian Sea (18 Km W) DamangangaRiver (7 Km SW)

11 Forest Patches No patches of Reserve Forest within the study area of project site.

12 Location of Archaeologically /Historically important places

--



13 National Park/Sanctuary or Ecologically sensitive Area

Dadra& Nagar Haveli Wild Life Sanctuary Approx. 20 km E

14 National or State Boundary Dadra & Nagar Haveli – 7 Km E Daman – 15 km W

15 Tourist Places Dadra & Nagar Haveli – 7 Km E Daman – 15 km W

16 Selection of project Site and Detail of alternate Site.

Proposed project is in the GIDC Notified Industrial area having proper industrial infrastructure hence alternate site consideration is not envisaged.

17 Size or Magnitude of Operation Small Medium Scale (SME)

Plot site Area Statement:

Area Statement Area After Proposed Expansion (in m2)

Total Area 3992.00

Construction Area 2076.24

Open Land Area 1316.90

Greenbelt Area 598.80



IV. Site Layout Plan: 1. Key plan



2. Site Layout Plan of plot 911-912



3. Site Layout Plan of plot 922



V. Details of alternate sites considered and the basis of selecting the proposed site, particularly the environmental considerations gone into should be highlighted:

Existing unit is acquired for the proposed project in the GIDC Notified Industrial area having an excellent locational advantage & very good industrial infrastructure including CETP, COE, VIA, etc.hence alternate site consideration is not envisaged.

VI. Size or magnitude of operation: As per the proposed project cost the project is covered under Small Medium Scale category of manufacturing industries, it comes under SME segment of the industry

VII. Project description with process details (a schematic diagram/ flow chart showing the project layout components of the project etc. should be given):

Detailed project & product profile details –

• LIST OF FINISHED PRODUCTS Sr. No. Name of Product Plant Production Capacity

(MT/month)

A. Manufacturing: Intermediates Existing Proposed Total 1 PiperazineDihydrochloride (PDH)

8.71MT 16.29 MT 26MT

2 N-phenyl Piperazine (NPP) 3 1-methyl-3-phenylpiperazine (NM3PP) 4 1(2(2-Hydroxy ethoxy) ethyl) Piperazine (HEEP) 5 1-(3-Hydroxy Methyl Pyridyl-2)-2-Phenyl-4-Methyl Piperazine

(HMPPMP) OR [2-(4-methyl-2-phenylpiperazin-1-yl)pyridin-3-yl]methanol (HMPPMP)

6 N-ethoxy carbonyl Piperazine (NCP) 7 3-(4-chlorobutyl )indole 5-carbonitrile (CIC) 8 Ethyl 2-chloro-2 (4-methoxypthenylhydrazinylidene)

ethanoate (EMA) 9 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione (OXI) 10 6-chloro-2-oxindole (6CO) 11 3-(2-Chloroethyl)-6, 7, 8, 9-tetrahydro-9-hydroxy-2-methyl-

4H-Pyrido [1, 2-a] Pyrimidine-4-One (CHP) 12 1-[2-Amino-(4-Methoxy Phenyl) Ethyl] Cyclohexanol

Hydrochloride (AMCH) 13 4-(4-aminophenyl) morpholine-3-one (AMO) 14 Ethyl 5-piperazinyl-1-benzofuran-2-carboxylate (PBC) 15 4-nitro phenyl ethyl amine hydrochloride (NPA) 16 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (DMB) 17 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-

methylmethanamine Hydrochloride (MBC) 18 2,3,4,5-Bis-o-(1-methylethylidine)-B-D-Fructopyranose

(BMEF) 19 11-Piperazin-1-yldibenzo[b,f][1,4]thiazepine hydrochloride Expansion project-Synthetic Organic Chemicals Page | 11


(DTPD) 20 Dibenzo [b, f][1, 4]thiazepin-11(10H)-one (DTO) 21 5-(4-bromophenyl)-4,6-dichloropyrimidine (BDP) 22 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

(EFP)

Additional Proposed Products (Intermediates) 23 Disodium Pamoate (DSP)

0.00

24 Thiophene-2- Aldehyde (T2A)

25 (2S)-2-Hydroxy-3-methoxy-3,3-diphenylpropanoic acid (DPA IV)

26 Ammonium Benzene Sulphonate (ABS) 27 1-(3-Carboxy Pyridyl-2)-2-Phenyl-4-Methyl Piperazine (HMA) 28 6-Chloro-5-(chloroethyl)-1,3-dihydro-2H-indole-2-one (Zip II) 29 3-Piperazin-1-yl-1,2-benzisothiazole (PBT FB)

30 (3aR,4S,7R,7aS)-hexahydro-4,7-methano-2H-isoindole-1,3-dione ( BHC)

31 (1R,2R)-Cyclohexane-1,2-diyldimethanol (HMC) 32 1-Benzyl piperidine-4-carbaldehyde (NBPCHO)

33 2-(1-benzyl-1,2,3,6-tetrahydro-pyridine-4yl)methylene- 5,6-dimethoxy indan-1-one hydrochloride Diene Crystalised

34 (1S)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline ( PTQ IV) 35 1-(3-Bromopropyl)-3-( trifluoromethyl) benzene (TPP III)

36 2-Ethoxy-5-(4-Methyl Piperazinyl Sulfonyl) Benzoic Acid [Sil III]

37 4-amino-1-Methyl-3-n-propyl-5-pyrazolecarboxamide hydrochloride (MPC VI)

38 1-(2,4-Difluorophenyl)-2-(1H 1,2,4-triazol-1-yl)-1-ethanone (DFTA III)

39 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (GTR-3) 40 5-methylisoxazole-4-carboxylic acid (MIC) 41 3 methylthiophene -2- Aldehyde ( 3MT2A)

42 (+)-(2-chlorophenyl) (6,7-dihydro4H-thieno [3,4-C] pyridine -5yl) acetic acid methyl ester (-) camphor sulphonic acid salt (CL 7)

43 2-Hydroxy-3-methoxy-3,3-diphenylpropanoic acid (DPA III) 44 3, 3-dichloro-1-(4-nitrophenyl) piperdin-2-one ( APB III)

45 1-(4-nitrophenyl)-3-morpholin-4-yl-5,6-dihydropyridin-2(1H)-one (APV IV)

46 Ethyl 6-(4-nitrophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid ethyl ester (APB VI)

47 3-acetamidophthalic anhydride (APA)

48 (S)-2-(3-Ethoxy-4-methoxyphenyl)-1-methyl sulphonyl)-eth-2yl amine (EMS)

49 11-Chloro-2,3-dihydro-2-methyl-1H-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-1-one (DOP)



50 Trans-11-Chloro-2,3,3a, 12b-tetrahydro-2-methyl-1H-dibenz [2,3:6,7] oxepino [4,5-c]pyrrol-1-one (TOP)

51 (R)-(+)-1-(1-Naphthyl) ethylamine HCl (RNA IV) 52 3-[3-(Trifluoromethyl) phenyl] propanol (TPP II)

53 Ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-2-yl)benzamido)propanoate (DEM I)

54 3-[(3-Amino-4-methylaminobenzoyl)pyridin-2-ylamino]propionic acid ethyl ester (DEM II)

55 3-[[[2-[[(4-Cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]Pyridine-2-ylamino]propionic acid ethyl ester (DEM III)

56 Ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1Hbenzo[d]imidazole-5-carboxamido)propanoate HCl (DEM IV)

57 Dabigatran etexilate 58 (S)-2,2-Diphenyl-2-(pyrrolidin-3-yl)acetamide tartrate (Dar IV)

59 5,6-Dimethoxy-2-(pyridin-4-yl methylene)-indan-1-one (DOH IV)

60 1-Benzyl-4-[(5,6-dimethoxy indanon)-2-ylidenyl] methylpiperidine (DON 1)

61 2-[(5-Chloropyridin-2-yl)-2-oxoacetic acid (CPO)

62 5-methyl-4,5,6,7-tetrahydro thiazolo[5,4-c] pyridine-2-carbixylic Acid hydrochloride ( MTP)

63 Tert-Butyl(1R,2S,5S)-2-azido-5-[(dimethylamino) carbonyl] cyclohexylcarbamate (ADC)

64 1-[4-(3-Chloropropoxy)-3-methoxyphenyl]ethanone (CME)

65 R-2-Hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide (MBR I)

66 (R)-2-[2’-(4-Nitrophenyl)ethyl]amino]-1-phenylethanol HCl (MBR II)

R-2-[[2-(4-Aminophenyl)ethyl]-amino]-1-phenylethanol HCl (MBR III)

68 Prasugrel Free Base 69 Pamoic acid (PA) 70 1,2-Dimethyl-1,4,5,6-tetrahydropyrimidine (THP)

71 1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridine-3-carboximidamide ( FPC)

72 [(E)- Phenyl Diazenyl] Malononitrile (RGT -II)

73 2-({(5S)-2-Oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione ( RIV II

74 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl] phenyll}morpholin-3-one HCl (RIV III)

75 Ethyl-5-aminobenzofuran-2-carboxylate (EABC) 76 3-Aminoadamantan-1-ol (HAA) 77 (2S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile (CCP -II) 78 2,4 -dimethyl-benzenethiol ( DMT)



79 2,4-dimethyl-1-[(2-nitrophenyl)thio]benzene ( VOR-I) 80 6-Chloro-5-(chloroacetyl)-1,3-dihydro-2H-indole-2-one 81 3-Piperazin-1-yl-1,2-benzisothiazole HCl (PBT HCL) 82 1-(1-benzothiophen-4-yl)piperazine 83 Trans-(4-amino-cyclohexyl) acetic Acid ethyl ester 84 N-[trans-4-(2-oxoethyl)cyclohexyl]-, 1,1-dimethylethyl ester

85 Benzyl (5R)-5-methyl-1,4-diazepane-1-carboxylate hydrochloride

86 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (ODC)

87 5-Amino-2,4-di-tert-butyl-phenol (ADP) 88 4-Isopropylamino butanol (4-IAV) Bulk Drugs / API - Active Pharma Ingredients; Using Above Intermediates

1 PyrantelPamoate; 4-[(3-Carboxy-2-hydroxynaphthalen-1-yl)methyl]-3-hydroxynaphthalene-2-carboxylic acid; 1-methyl-2-[(E)-2-thiophen-2-ylethenyl]-5,6-dihydro-4H-pyrimidine

2 Morantel Citrate; 1,4,5,6-Tetrahydro-1-methyl-2-(2-[3-methyl-2-thienyl]ethenyl)pyrimidine

3 OxantelPamoate; 3-[(E)-2-(1-Methyl-5,6-dihydro-4H-pyrimidin-2-yl)ethenyl]phenol

4 Pyrantel Tartrate /Zeolex;1-Methyl-2-(2-[2-thienyl]ethenyl)-1,4,5,6-tetrahydropyrimidine

5 Morantel Tartrate;1,4,5,6-Tetrahydro-1-methyl-2-(2-[3-methyl-2-thienyl]ethenyl)pyrimidine

6 Bosentan Monohydrate; 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]benzene-1-sulfonamide

7 Ambrisentan; (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy] -3-methoxy-3,3-diphenylpropanoic acid

8 Macitentan;N-[5-(4-bromophenyl)-6-[2-[5-bromo-2-pyrimidinyl)oxy]-ethoxy]-4-pyrimidinyl]-N-propylsulfamide

9 Riociguat; methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate

10 Mirtazapine; (±)-2-methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine

11 Venlafaxine Hydrochloride; (RS)-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]cyclohexanol

12 Desvenlafaxine Succinate; 4-[2-dimethylamino-1-(1-hydroxycyclohexyl) ethyl]phenol

13 Duloxetine Hydrochloride;(3S)-N-Methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine Hydrochloride,



14 Vilazodone Hydrochloride;5-(4-(4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl) benzofuran-2-carboxamide Hydrochloride

15 Vorteoxetine; 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]piperazine

16 Asenapine Maleate; (3aRS,12bRS)-rel-5-Chloro-2,3,3a,12b-tetrahydro- 2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole

17 Paliperidone; (RS)-3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl]-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one

18 Ziprasidone Hydrochloride; 5-[2-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one hydrochloride monohydrate,

19 Iloperidone;1-[4-[3-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]propoxy]-3-methoxyphenyl]ethanone

20

Lurasidone Hydrochloride; (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione

21 Donepezil Hydrochloride; (RS)-2-[(1-benzyl-4-piperidyl)methyl]- 5,6-dimethoxy-2,3-dihydroinden-1-one

22 Memantine Hydrochloride; 3,5-dimethyltricyclo[3.3.1.13,7]decan-1amine or 3,5-dimethyladamantan-1-amine

23 Quetiapine Hemifumarate; 2-[2-(4-Dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]ethanol hemifumarate

24 DarifenacineHydrobromide; (S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl] pyrrolidin-3-yl] -2,2-diphenyl-acetamide

25 Soilfenacine Succinate; 1-azabicyclo[2.2.2]oct-3-yl (1R)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate

26 Mirabegron;2-(2-Amino-1,3-thiazole-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl] amino}ethyl) phenyl] acetamide

27 Cinacalcet Hydrochloride; (R)-N-[1-(1-naphthyl)ethyl]-3- [3-(trifluoromethyl)phenyl]propan-1-amine

28 Vildagliptine;(2S)-1-[(3-hydroxy-1-adamantyl) amino] acetyl-2-cyanopyrrolidine

29 Prasugrel Hydrochloride; (RS)-5-[2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl acetate



30

Dabigetran;Ethyl-3-{[(2-{[(4-{N'hexyloxycarbonylcarbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl] (pyridin-2-yl-amino)propanoate (Dabigatran etexilate)

31 Rivaroxaban;5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl} methyl)thiophene-2-carboxamide

32 Apixaban; 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

33

Ticagrelore; (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropylamino]-5-(propylthio)- 3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol

34 Ivabradine;3-(3-{[((7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl) methyl] methyl amino}propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one hydrochloride

35 Brinzolamide;(R)-3,4-Dihydro-4-(ethylamino)-2-(3-methoxypropyl)-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide-1,1-dioxide

36 Teriflunomide;(Z)-2-Cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)amide

37 Selexipag; 2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N-(methanesulfonyl)acetamide

38 Brexpiprazole; 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one

39 Ivacaftor; N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

40 Lumacaftor;3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridine-2-yl)benzoic acid

41 Paliperidone Palmitate; (9RS)-3-[2-[4(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4Hpyrido[1,2-a]pyrimadin-9-yl hexadecanoate.

42

Edoxaban; N'-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide

43 Suvorexant; [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone

44 Cariprazine;N-[trans-4-[2-[4-(2,3-dichlorophenyl)-1-piperazinyl]-ethyl]-cyclohexyl]- N,N-dimethyl urea monohydrochloride

45 Blonanserin; 2-(4-ethylpiperazin-1-yl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine



46 Netupitant; 2-[3,5-Bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinyl]propanamide

47 Rolapitant; (5S ,8S)-8-[[(1R)-1-[3 ,5- Bis(trifluoromethyl)phenyl] ethoxy] methyl]-8-phenyl-1,7- diazaspiro[4.5]decan-2-one hydrochloride monohydrate.

48 Apremilast;N-{2-[(1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide

49 Neostigmine;3-{[(dimethylamino)carbonyl]oxy}-N,N,N-trimethylbenzenaminium

B Pilot Plant Capacity 0.00 1.00 1.00

Total Quantity/ Month 8.71 MT 17.29 MT 26MT

C

Multimilling, Blending, Packing, Labelling of Bulk Drugs and Intermediates like,:

All types of Piperazine derivatives like, Pharma Intermediates and products like, Anthelmentic intermediates and products like,

50.00 00.00 50.00

Note:-Unit is manufacturing campaign based products as per market demand.Company will either

manufacture one product or all products listed inA. Manufacturing; but the Total quantity will be within 25 MT/Month.

• INFRASTRUCTURE, MACHINERIES, EQUIPMENT & TECHNOLOGIES: In-house technology, Installation of the plants, machineries and suitable manpower will be required

to manufacture the above additional products with proposed capacity To get the best results in terms of quality and quantity, the company will invests in the latest available

state-of-the-art plant - machinery and leverages of grass-root technologies duly supported by excellent marketing network will enable the project to get best of results.

• MANUFACTURING PROCESS: The company shall use the latest documented & developed green & eco-friendlynon-hazardous process technology for the production of all above products. This section includes the manufacturing process of the product, chemical reactions, flow diagrams and mass balance of each product.

1. Intermediates and API/Bulk drugs : The list of products has been divided into selected common groups based on their therapeutic category. Group-wise example of product has been shown. The detail of product- wise manufacturing process is attached as Annexure-I.

2. Details of Pilot Plant for Process Development & Scale-up study in the company:



We are manufacturing and exporting these drug intermediate for pharmaceutical industries. We strictly

follow the EHS & GMP policy.We are having well established in-house R&D center headed by very senior

PhD research scientist & supported by four group leaders (two PhDs & two M.Sc.) for eco-friendly process

development &improvements.We are incorporating pilot plant capacity for trial-runs& validation batches

of new products to establish up-gradation of process and to continuously supportreduction in

effluent/pollution load.

Products: Synthetic Organic Chemicals; which are developed & validated in the said pilot plant under various Reactions with requiredprocess conditions (like acetylation, nitration, hydrolysis, bromination, reduction, oxidation, hydrogenation, condensation, friedel craft reaction, Grignard reaction etc…)

Capacity: 1.00 MT/month Process Description: Raw Materials are charged into pilot reactors and subjected to unit processes as per requirements. Reaction mass is taken for unit operations as per requirement. This limited quantum of effluents are bifurcated (based on diluted and/or concentrated load) and are sent for required treatment (in-house and/or CMEE at CETP respectively). Product is then dried & packed.

Synthetic Organic Chemical Reactions under

required conditions as per requirement in a pilot reactor (like acetylation,

nitration, hydrolysis, bromination, reduction,

oxidation, etc.)etchydrogenation,

Raw Materials as per

If any process gas emission

To Scrubber respective

Recovered liquid for reuse/sale/disposed off through ETP

Unit Operations as per requirement like Filtration,

Separation, Distillation, Washing, Crystallisation

etc.

Drying as per required conditions

Packing & Dispatch

Effluent to ETP

Spent Solvent- Distilled & reuse/sale/ residue

disposal to incineration

I Process Waste-Disposal to

TSDF / incineration

Vent



VIII. Raw material required along with estimated quantity, likely source, marketing area of final product(s), mode of transport of raw material and finished product: Detailed raw material requirement along with estimated quantity, likely source, marketing area of final products, mode of transport of raw material and finish product

• Marketing area of final products: The products are used as drugintermediate and APIs in the pharmaceutical industries and the product has very good potential in local market as well as the overseas market for export of the same. The productis meant to be exported to the most regulated countries. Company has a very wide customer base; From MNC to large Generic cos.



• Transport and storage details of Raw materials :

Sr. No.

Name of Raw Material Storage Cap. In MT

State of raw material

Mode of Transport

Place of storage

Source

1 Liquor ammonia solution 2 Liquid By Road RM Store Indigenous 2 Adipic acid 1 Solid By Road RM Store Indigenous 3 Aniline 2 Liquid By Road RM Store Indigenous 4 Activated carbon 0.5 Solid By Road RM Store Indigenous 5 Acetic acid (glacial) 2 Liquid By Road RM Store Indigenous 6 Acetyl chloride 0.5 Liquid By Road RM Store/

isolated place

Indigenous

7 Acetonitrile 1 Liquid By Road RM Store Indigenous 8 Acetone 2 Liquid By Road RM Store Indigenous 9 Benzyl chloride 0.5 Liquid By Road RM Store Indigenous

10 Caustic lye 50% 5 Liquid By Road RM Store Indigenous 11 Chloroform 5 Liquid By Road RM Store Indigenous 12 2- chloro -3- cyano pyridine 5 Solid By Road RM Store Indigenous 13 Citric acid 5 Solid By Road RM Store Indigenous 14 Tetra butyl ammonium bromide

(cat-44) 1 Solid By Road RM Store Indigenous

15 Cyclohexane 1 Liquid By Road RM Store Indigenous 16 Cyclohexanone 1 Liquid By Road RM Store Indigenous 17 2-(2-chloro ethoxy) ethanol 5 Liquid By Road RM Store Indigenous 18 Di iso propyl ether 0.5 Liquid By Road RM Store Indigenous 19 Diethanol amine 1 Liquid By Road RM Store Indigenous 20 N,N-dimethyl formamide(DMF) 2 Liquid By Road RM Store Indigenous 21 Di methyl sulfoxide (DMSO) 2 Liquid By Road RM Store Indigenous 22 2,5-dichloro nitro benzene 1 Solid By Road RM Store Indigenous 23 Dimethyl malonate 1 Liquid By Road RM Store Indigenous 24 D-fructose 1 Solid By Road RM Store Indigenous 25 N,N-dimethyl aniline 0.5 Liquid By Road RM Store Indigenous 26 Ethyl acetate 16 Liquid By Road Under-

ground storage

Indigenous

27 Ethyl chloroformate 1 Liquid By Road RM Store/ isolated place

Indigenous

28 Ethyl chloro acetate 1 Liquid By Road RM Store Indigenous 29 Hydrochloric acid 2 Liquid By Road RM Store Indigenous 30 n-Hexane 1 Liquid By Road RM Store Indigenous 31 Hyflowsupercel 0.5 Solid By Road RM Store Indigenous 32 Isopropylalcohol-Hydrochloric

acid (IPA.HCl) 1 Liquid By Road RM Store Indigenous

33 Iso propyl alcohol 2 Liquid By Road RM Store Indigenous



Sr. No.



Mode of Transport

Place of storage

Source

34 Industrial solvent 3 Liquid By Road RM Store Indigenous 35 Methanol 3 Liquid By Road Methanol

Room/UG storage

Indigenous

36 Methyl mono ethanol amine 1 Liquid By Road RM Store Indigenous 37 Methylene chloride(MDC) 3 Liquid By Road RM Store Indigenous 38 Mono ethylene glycol 21 Liquid By Road Under-

ground storage

Indigenous

39 Chlorobenzene 3 Liquid By Road RM Store Indigenous 40 4-methoxy phenyl acetonitrile 1 Liquid By Road RM Store Indigenous 41 Ortho nitro chloro benzene 1 Solid By Road RM Store Indigenous 42 Phosphoric acid 1 Liquid By Road RM Store Indigenous 43 Piperazine 5 Solid By Road RM Store Indigenous 44 Potassium fluoride 2 Solid By Road RM Store Indigenous 45 Poly phosphoric acid 1 Thick Liquid By Road RM Store Indigenous 46 Petroleum ether 1 Liquid By Road RM Store/

isolated place

Indigenous

47 Phenyl chloroformate 5 Liquid By Road RM Store Indigenous 48 Phosphorus oxychloride 2 Liquid By Road RM Store/

isolated place

Indigenous

49 Sodium hydroxide ( caustic soda) 5 Solid By Road RM Store Indigenous 50 Sodium bi carbonate 1 Solid By Road RM Store Indigenous 51 Sodium sulphate 1 Solid By Road RM Store Indigenous 52 Styrene oxide 2 Liquid By Road RM Store Indigenous 53 Sulphuric acid 1 Liquid By Road RM Store/

isolated place

Indigenous

54 Sodium chloride 1 Solid By Road RM Store Indigenous 55 Sodium carbonate ( soda ash) 1 Solid By Road RM Store Indigenous 56 Sodiummethoxide(sodium

methylate) 0.5 Solid By Road RM Store Indigenous

57 Thionyl chloride 3 Liquid By Road RM Store/ isolated place

Indigenous

58 Toluene 16 Liquid By Road RM Store/ Underground storage

Indigenous

59 Tetra hydro furan 2 Liquid By Road RM Store Indigenous 60 Triethylamine 1 Liquid By Road RM Store Indigenous 61 Thiophenol 1 Liquid By Road RM Store Indigenous 62 Tin metal 0.5 Solid By Road RM Store Indigenous



Sr. No.



Mode of Transport

Place of storage

Source

63 Vitride /Synhydride /Sodium bis(2-methoxy phenoxy)aluminium hydride

8 Liquid By Road RM Store Indigenous

64 Hexadecyl tri methyl ammonium bromide/ Cetrimonium Bromide / Centimide (CTAB)

0.1 Solid By Road RM Store Indigenous

65 Ammonium acetate 0.5 Solid By Road RM Store Indigenous 66 Potassium carbonate 2 Solid By Road RM Store Indigenous 67 Raney nickel catalyst 0.1 Solid By Road RM Store Indigenous 68 N-methyl -3-phenyl piperazine 3 Solid By Road RM Store Indigenous 69 1-[1-Cyano-1-(4-

methoxyphenyl)methyl] cyclohexanol

3 Solid By Road RM Store Indigenous

70 Phenyl-2-(Phenylthio)-phenyl Carbamate (DOA)


71 Dibenzo[b,f][1,4]thiazepin-11(10H)-One


72 Guaiacol 1 Liquid By Road RM Store Indigenous 73 2-(Bromomethyl)-1,3-dioxolane 1 Solid By Road RM Store Indigenous 74 Cysteamine hydrochloride 1 Solid By Road RM Store Indigenous 75 1-methyl-2-propanol (spicosol-m) 1 Liquid By Road RM Store Indigenous 76 Potassium hydroxide 5 Solid By Road RM Store Indigenous 77 Dimethyl(4-chloro-2-

nitrophenyl)malonate (COA) 2 Solid By Road RM Store Indigenous

78 Dibenzo[b,f][1,4]thiazepin-11(10H)-One (DOD)


79 1-[(2-(Amino)-1-(4-Methoxy Phenyl ) Ethyl)] Cyclohexanol acetate


80 2-amino diphenyl sulphide (DOB) 1 Solid By Road RM Store Indigenous 81 N-[Dibenzo-[B,F][1,4]-Thiazepine-

11-yl] Piperazine Hydrochloride Salt (DP)


82 6-chloro-2-oxindole 3 Solid By Road RM Store Indigenous 83 1-(3-carboxy pyridyl-2)-2-phenyl-

4-methyl piperazine (HMA) 5 Solid By Road RM Store Indigenous

84 Diethyl malonate 1 Liquid By Road RM Store Indigenous 85 Liquid bromine 0.5 Liquid By Road RM Store Indigenous 86 Pyrimidine-2-carboximidamide

Hydrochloride (PCH) 0.5 Solid By Road RM Store Indigenous

87 P-toluene sulphonamide 1 Solid By Road RM Store Indigenous 88 Diethyl Bromo malonate (DMA) 1 Liquid By Road RM Store Indigenous 89 2-Nitro-4-Chloro-phenyl acetic

acid (COB) 2 Solid By Road RM Store Indigenous

90 2-Amino 3-Benzyloxy pyridine 1 Liquid By Road RM Store Indigenous



Sr. No.



Mode of Transport

Place of storage

Source

91 3-Acetyl-4,5-dihydro-2(3H)- furanone(Butyrolactone)


92 10% Palladium on carbon 0.5 Solid By Road RM Store Indigenous 93 Iron powder 2 Solid By Road RM Store Indigenous 94 2-[2-chloro ethoxy] acetic acid 0.5 Liquid By Road RM Store Indigenous 95 Boric acid 0.5 Solid By Road RM Store Indigenous 96 Ammonium formate 0.5 Solid By Road RM Store Indigenous 97 Ethylene Diamine tetra acetic

acid disodium salt 0.1 Solid By Road RM Store Indigenous

98 3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9- Hydroxy-2- methyl-4H-Pyrido [1,2-a] Pyrimidin-4-one (CHB)


99 Sodium dithionite (hydrous) 0.01 Solid By Road RM Store Indigenous 100 Phthalimide 0.5 Solid By Road RM Store Indigenous 101 S (+) epichlorohydrin 1 Liquid By Road RM Store Indigenous 102 Potassium tertiary butoxide 1 Solid By Road RM Store Indigenous 103 1-[(2-(Amino)-1-(4-Methoxy

Phenyl ) Ethyl)] cyclohexanol 3 Liquid By Road RM Store Indigenous

104 5-cyano indole 0.5 Solid By Road RM Store Indigenous 105 4-Chloro butanoyl chloride 0.5 Liquid By Road RM Store Indigenous 106 Aluminum chloride 0.5 Solid By Road RM Store/

isolated place

Indigenous

107 Sodium borohydride 0.5 Solid By Road RM Store/ isolated place

Indigenous

108 Boron trifluorideetherate 0.5 Liquid By Road RM Store/ isolated place

Indigenous

109 1-[2-(Amino)-1-(4-Methoxy phenyl) ethyl]CyclohexanolHCl


110 6-chloro – 2- oxindole 5 Solid By Road RM Store Indigenous 111 1-[2- (Amino)-1-(4-Methoxy

Phenyl) ethyl] Cyclohexanol Acetate


112 Phenyl ethylamine 1 Liquid By Road RM Store Indigenous 113 Nitric acid 0.5 Liquid By Road RM Store/

isolated place

Indigenous

114 Mix acid (nitric acid + sulfuric acid)

0.5 Liquid By Road RM Store/ isolated place

Indigenous

115 Ethyl-2- chloroaceto Acetate 1 Liquid By Road RM Store Indigenous 116 P- anisidine 1 Solid By Road RM Store Indigenous



Sr. No.



Mode of Transport

Place of storage

Source

117 Sodium nitrite 1 Solid By Road RM Store Indigenous 118 Sodium acetate 1 Solid By Road RM Store Indigenous 119 Urea 0.5 Solid By Road RM Store Indigenous 120 2- anilino ethanol 0.5 Liquid By Road RM Store Indigenous 121 Chloro acetyl chloride 2 Liquid By Road RM Store Indigenous 122 Formic acid (98%) 1 Liquid By Road RM Store Indigenous 123 4-bromophenyl acetic acid 1 Liquid By Road RM Store Indigenous 124 Dimethyl carbonate 0.5 Solid By Road RM Store Indigenous 125 Formamide 0.5 Liquid By Road RM Store Indigenous 126 N,N, Bis-(2-Chloro Ethyl) Amine

HCl 0.5 Solid By Road RM Store Indigenous

127 5-nitro salicylaldehyde 0.5 Solid By Road RM Store Indigenous 128 Ethyl cyano acetate 0.5 Liquid By Road RM Store Indigenous 129 Dimethyl acroline 1.5 Liquid By Road RM Store Indigenous 130 2-flourobenzyl hydrazine 0.5 Solid By Road RM Store Indigenous 131 3-(Dimethyl amino) acryldehyde 0.5 Liquid By Road RM Store Indigenous 132 Malononitrile 0.5 Liquid By Road RM Store Indigenous 133 m-xylene 1 Liquid By Road RM Store Indigenous 134 Zinc dust 1 Liquid By Road RM Store Indigenous 135 Sodium triacetoxy borohydride 0.5 Solid By Road RM Store Indigenous 136 Ammonium acetate 1 Solid By Road RM Store Indigenous 137 Trifluoro acetic acid 1 Liquid By Road RM Store Indigenous 138 Trifluoro acetic anhydride 1 Liquid By Road RM Store Indigenous 139 2- chloro benzoic acid 0.5 Liquid By Road RM Store Indigenous 140 2-fluorobenzoic acid 0.5 Liquid By Road RM Store Indigenous 141 2,4-ditert butyl phenol Liquid 142 Formalin 5 Liquid By Road RM Store Indigenous 143 Thioacetamide 0.5 Liquid By Road RM Store Indigenous 144 Tetra hydropyrimidine 1 Liquid By Road RM Store Indigenous 145 Thiophene -2-aldehyde(T2A) 5 Liquid By Road RM Store Indigenous 146 3-methyl thiophene 2 Solid By Road RM Store Indigenous 147 3-methyl thiophene-2-aldehyde 1 Solid By Road RM Store Indigenous 148 Phenol 0.5 Liquid By Road RM Store/

isolated place

Indigenous

149 Iodine 0.5 Solid By Road RM Store/ isolated place

Indigenous

150 Benzyl bromide 0.5 Liquid By Road RM Store/ isolated place

Indigenous

151 Benzene sulphonic acid 1 Solid By Road RM Store Indigenous 152 Oxalyl chloride 0.5 Solid By Road RM Store Indigenous



Sr. No.



Mode of Transport

Place of storage

Source

153 Tri ethyl silane 0.5 Liquid By Road RM Store Indigenous 154 N-methyl piperazine 0.5 Solid By Road RM Store Indigenous 155 Chlorosulphonic Acid 0.5 Solid By Road RM Store/

isolated place

Indigenous

156 2-ethoxy benzoic acid 0.5 Liquid By Road RM Store Indigenous 157 Hydroxyl amine hydrochloride 1 Liquid By Road RM Store Indigenous 158 3-tri fluro methyl cinnamic acid 0.5 Solid By Road RM Store Indigenous 159 Ethanolic hydrochloride 0.5 Solid By Road RM Store Indigenous 160 Paraformaldehyde 0.1 Solid By Road RM Store Indigenous 161 Camphor sulphonic acid 0.1 Solid By Road RM Store Indigenous 162 Di isopropyl amine 0.5 Liquid By Road RM Store Indigenous 163 Ferric chloride anhydrous 0.5 Solid By Road RM Store Indigenous 164 (S)- 3 -hydroxypyrrolidone. HCl 0.5 Liquid By Road RM Store Indigenous 165 Para toluene sulfonyl chloride 0.5 Liquid By Road RM Store Indigenous 166 Diphenylacetonitrile 0.5 Liquid By Road RM Store Indigenous 167 1-fluoronaphthalene 0.5 Solid By Road RM Store Indigenous 168 Lithium aluminium hydride 0.01 Solid By Road RM Store Indigenous 169 2,6 -lutidine 0.5 Solid By Road RM Store Indigenous 170 monomethyl amine solution 0.5 Liquid By Road RM Store Indigenous 171 Para nitro phenol 0.5 Liquid By Road RM Store Indigenous 172 Benzoyl chloride 0.1 Liquid By Road RM Store Indigenous 173 Methane sulfonic acid 0.5 Solid By Road RM Store Indigenous 174 Pyridine 0.5 Liquid By Road RM Store Indigenous 175 (+)

diisopinocampheylchloroborane Solution in Hexane

0.5 Liquid By Road RM Store Indigenous

176 N,N-diisopropyl ethyl amine 0.5 Liquid By Road RM Store Indigenous 177 Morpholine 0.5 Liquid By Road RM Store Indigenous 178 Phosphorus pentachloride 0.5 Liquid By Road RM Store/

isolated place

Indigenous

179 20%Palladiuhydroxide on Carbon 0.01 Solid By Road RM Store Indigenous 180 Isobutyl chloroformate 0.1 Liquid By Road RM Store Indigenous 181 5-chlorovaleryl chloride 0.5 Liquid By Road RM Store Indigenous 182 Phosphorus pentoxide 2 Solid By Road RM Store/

isolated place

Indigenous

183 Para nitro aniline 0.5 Solid By Road RM Store Indigenous 184 Oxalic acid 0.1 Liquid By Road RM Store Indigenous 185 Lithium chloride 0.1 Solid By Road RM Store Indigenous 186 Potassium borohydride 0.1 Solid By Road RM Store Indigenous 187 Sodium ethoxide 0.1 Solid By Road RM Store Indigenous



Sr. No.



Mode of Transport

Place of storage

Source

188 Methane sulphonyl chloride 0.1 Liquid By Road RM Store Indigenous 189 R (+) alpha methyl benzyl amine 0.1 Liquid By Road RM Store Indigenous 190 Methyl amino propyl amine 1 Liquid By Road RM Store Indigenous 191 Methyl formate 1 Liquid By Road RM Store Indigenous 192 N-Butanol 1 Liquid By Road RM Store Indigenous 193 Tert butanol 0.5 Liquid By Road RM Store Indigenous 194 N-Heptane 1 Liquid By Road RM Store Indigenous 195 1-3 dimethyladmantane 1 Liquid By Road RM Store Indigenous 196 Polymeg 400 PM (PEG 400) 1 Liquid By Road RM Store Indigenous 197 Tetramethyldisiloxane 0.5 Liquid By Road RM Store Indigenous 198 Methyl ethyl ketone 0.5 Liquid By Road RM Store Indigenous 199 Methyl tertiary butyl ether 1 Liquid By Road RM Store Indigenous 200 4-Hydroxy-3-methoxyphenyl

ethanone 0.1 Solid By Road RM Store Indigenous

201 N-methyl Morpholine 0.1 Liquid By Road RM Store Indigenous 202 Disodium pamoate 2 Solid By Road RM Store Indigenous 203 Potassium hydroxide 1 Solid By Road RM Store Indigenous 204 3-hydroxy-benzaldehyde 1 Liquid By Road RM Store Indigenous 205 Tartaric acid 2 Solid By Road RM Store Indigenous 206 Maleic acid 0.1 Solid By Road RM Store Indigenous 207 5,6 dimethoxy-1-indanone 1 Solid By Road RM Store Indigenous 208 Fumaric acid 1 Solid By Road RM Store Indigenous 209 3-chloro benzothiozole (3CBT) 0.5 Liquid By Road RM Store Indigenous 210 Sildenafil Citrate-II (2-Ethoxy-5(4-

methylpiperazynine sulphonyl) benzoic acid


211 1-(2,4-Difluorophenacyl)-4-amino-4-H1,1,2,4-triazoliumchloride (DFTA-1)


212 D-(-) mandelic acid 1 Solid By Road RM Store Indigenous 213 Potassium iodide 0.1 Solid By Road RM Store Indigenous 214 Bon acid 5 Solid By Road RM Store Indigenous 215 Sodium potassium tartrate 5 Solid By Road RM Store Indigenous 216 D-(-) tartaric acid 2 Solid By Road RM Store Indigenous 217 Zeolex 2 Solid By Road RM Store Indigenous 218 R-3 quiniclidinol 0.5 Solid By Road RM Store Indigenous 219 Bis-4-nitrophenyl carbonate 0.5 Solid By Road RM Store Indigenous 220 Succinic acid 0.5 Solid By Road RM Store Indigenous 221 N-methyl-2-pyrrolidone 1 Liquid By Road RM Store Indigenous 222 Sodium metabisulphite 1 Solid By Road RM Store Indigenous 223 PTQ-III (1-phenyl-1,2,3,4-

tetrahydroisoquinoline) 1 Solid By Road RM Store Indigenous

224 Benzaldehyde 1 Liquid By Road RM Store Indigenous



Sr. No.



Mode of Transport

Place of storage

Source

225 1-benzylpiperidine-4-carbaldehyde


226 Paliperidone 0.5 Solid By Road RM Store Indigenous 227 6-fluoro-3-piperidin-4-yl-1,2-

benzisoxazole hcl (PBO HCl) 0.5 Solid By Road RM Store Indigenous

228 Sodium iodide 0.1 Solid By Road RM Store Indigenous 229 RNA-II(R-(+)-1(1-

naphthyl)ethanaminemandalate salt)


230 1-Methyl-4-nitro-3-n-propyl pyrazol-5-carboxamide (MPC-VI)


231 DMB(4,6 dichloro-5- (2-methoxy phenoxy)-2,2 bipyridine )


232 TBS(4-tert-butyl-benzene-suphanamide )

1 Solid

By Road RM Store Indigenous

234 BEB-II(5-(2-Bromoethyl)2, 3-dihydrobenzofuran)

1 Solid


235 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetonitrile.HBR(DAR-III)

1 Solid


236 S-3-N-Methylamino-1-1thienyl-1-Propanol


237 Amantadine HCl 0.5 Solid By Road RM Store Indigenous 238 L-prolinamide 0.5 Solid By Road RM Store Indigenous 239 Imidazole 0.1 Solid By Road RM Store Indigenous 240 Trans-11-Chloro-2,3,3a,12b-

tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxwpino[4,5-c]pyrrol-1-one(TOP)


241 Ammonium bicarbonate 1 Solid By Road RM Store Indigenous 242 11-chloro-2,3-dihydro-2-methyl-

1h-dibenz-[2,3:6,7] oxepino[4,5-c] pyrrol-1-one(DOP)


243 Magnesium metal turning 0.1 Solid By Road RM Store Indigenous 244 Silica gel 0.5 Solid By Road RM Store Indigenous 245 1-bromo-3-chloropropane 0.5 Liquid By Road RM Store Indigenous 246 (1-[(1RS)-2-(Dimethylamino)-1-(4-

methoxyphenyl)ethyl]cyclohexanol hydrochloride(VEN HCl)


247 1,8-Diazabicyclo(5,4,0)undec-7-ene (DBU)


248 2-bromo-1-cyclopropyl-2-(2-fluoro-phenyl-ethanone (BCE)


249 4-(4-Amino phenyl) morpholin-3-one (AMO)


250 S-(+)-N-(2,3-Epoxypropyl) phthalimide (OXI)




Sr. No.



Mode of Transport

Place of storage

Source

251 5-Chlorothiophene-2-carboxylic acid (CTA)


252 N,N-carbonyl diimidazole 0.5 Solid By Road RM Store Indigenous 253 Benzophenone 0.5 Solid By Road RM Store Indigenous 254 4,6-Dimethyl-2-

(methylsulphonyl)Pyrimidine 0.5 Solid By Road RM Store Indigenous

255 4-di methyl amino pyridine 0.5 Solid By Road RM Store Indigenous 256 N,N

dicyclohexylcarbodimide(DCC) 0.5 Solid By Road RM Store Indigenous

257 2,2-diphenyl-2-[(3S)-1-tosyl Pyrrolidin-3-yl]acetonitrile(DAR-II)


258 Sodium chlorite 0.1 Solid By Road RM Store Indigenous 259 Methyl-3-bromo-6-(cyclopropyl

Methyl)carbamoyl)picolinate (BCX-5913)

0.1 solid By Road RM Store Indigenous

260 5-hydroxy -4-methoxy-2-(4,45,5-tet ramethyl-1,3,2-dioxaboralan-2-yl)benaldehyde(BCX-6276)

0.1 By Road RM Store Indigenous

261 Smopex 234 0.1 Solid By Road RM Store Indigenous 262 Potassium bicarbonate 0.1 Solid By Road RM Store Indigenous 263 Hydroxylamine-o-sulphonic acid 0.1 Solid By Road RM Store Indigenous 264 Sodium azide 0.1 Solid By Road RM Store/

isolated place

Indigenous

265 Ditertbutyldicarbonate(BOC Anhydride)


266 (Benzotriazol-1-yloxy)tris(dimethylamino) phosphoniumhexafluorophosphate


267 4-aminobenzamidine dihydrochloride


268 1-Ethyl-3-(3-dimethylaminopropyl)carbodimide


269 Ambersep - 900 0.1 Solid By Road RM Store Indigenous 270 Indion 225h ion exchange resin 0.1 Solid By Road RM Store Indigenous 271 N-chlorosuccinimide 0.1 Solid By Road RM Store Indigenous 272 Megnesiumsulphate 0.1 Solid By Road RM Store Indigenous 273 5-Nitro-2-(Propylthio) Pyrimidine-

4,6-diol (GTR-03) 0.1 Solid By Road RM Store Indigenous

274 (1R,2S)-2-(3,4-difluorophenyl) cyclopropanaminium(2R)-2-hydroxy-2-phenylethanoate (GTR 01)




Sr. No.



Mode of Transport

Place of storage

Source

275 2-{[(3ar,4S,6R,6as)-6-amino-2,2-dimethyltetrahydro-3ah-cyclopenta[d][1,3]dioxol-4-yl]oxy}ethanol,L-tartaricacid(GTR02)


276 Sodium thiosulphate 0.5 Solid By Road RM Store Indigenous 277 7M ammonia solution in

methanol 0.5 Liquid By Road RM Store Indigenous

278 Cyclopropanecarboxaldehyde 0.1 Liquid By Road RM Store Indigenous 279 2-(4-nitrophenyl)ethanamine .HCl 0.5 Liquid By Road RM Store Indigenous 280 DCR-IV 1 Solid By Road RM Store Indigenous 281 (2-Amino-1,3-thiazol-yl) Acetic

Acid 0.5 Liquid By Road RM Store Indigenous

282 (3AR, 4S, 7R, 7AS)4,7-Methano-1H-indole-1,3(2H)-dione [BHC]


283 Cis-5-Norbornene-exo-2,3- Dicarboxylic anhydride (VDA)


284 Cis-1,2-cyclohexanedicarboxylic anhydride


285 (1R,2R)-1,2-cyclohexanedimethanol


286 Ethylisonipicotate 1 Liquid By Road RM Store Indigenous 287 Iso propyl acetate 2 Liquid By Road RM Store Indigenous 288 1-(2(2-Hydroxy ethoxy) ethyl)

Piperazine (HEEP) 5 Liquid By Road RM Store Indigenous

289 1-acetyl napthalene 1 Liquid By Road RM Store Indigenous 290 Propylene carbonate 1 Solid By Road RM Store Indigenous 291 Methyl isonicotinate 1 Liquid By Road RM Store Indigenous 292 Di ethylene glycol 5 Liquid By Road RM Store Indigenous 293 Dodecanethiol(Tert-dodecyl

mercaptan) 1 Liquid By Road RM Store Indigenous

294 2-phenyl ethyl amine 0.1 Liquid By Road RM Store Indigenous 295 2-methyl tetarhydrofuran 0.1 Liquid By Road RM Store Indigenous 296 Methyl chloro acetate 0.1 Liquid By Road RM Store Indigenous 297 (1s)phenylethanamine 0.1 Liquid By Road RM Store Indigenous 298 1,2 dimethoxy ethane 0.5 Liquid By Road RM Store Indigenous 299 1-bromo-3-methoxypropane 0.1 Liquid By Road RM Store Indigenous 300 Tri methyl ortho acetate 0.1 Liquid By Road RM Store Indigenous 301 Ethylenedichloride (EDC) 1 Liquid By Road RM Store Indigenous 302 Triethylorthoformate 1 Liquid By Road RM Store Indigenous 303 Trimethyl borate 0.5 Liquid By Road RM Store Indigenous 304 4-trifluoro methyl aniline 0.5 Liquid By Road RM Store Indigenous 305 Difluro benzene 0.1 Liquid By Road RM Store Indigenous 306 1,1 carbonyl diimidazole 0.1 Solid By Road RM Store Indigenous



Sr. No.



Mode of Transport

Place of storage

Source

307 1,3-diphenyl1h pyrazole-s amine 0.1 Solid By Road RM Store Indigenous 308 1-iodopropane (n-propyl iodide) 0.1 Liquid By Road RM Store Indigenous 309 Dichlorobenzene 0.1 Liquid By Road RM Store Indigenous 310 1-(2,3-Dichlorophenyl)piperazine 0.1 Solid By Road RM Store Indigenous 311 1,1 Dimethoxy ethane 0.1 Liquid By Road RM Store Indigenous 312 1,4 dioxane 0.1 Liquid By Road RM Store Indigenous 313 1,2,4-trizole 0.1 Solid By Road RM Store Indigenous 314 2,2-dimethoxy propane 0.1 Liquid By Road RM Store Indigenous 315 2-Amino-3-hydroxypyridine 0.1 Solid By Road RM Store Indigenous 316 2,4-dimethyl thiophenol 0.1 Liquid By Road RM Store Indigenous 317 2-[(5-Chloropyridin-2-yl)amino]-

2-Oxoacetic acid Lithium Salt 0.1 Solid By Road RM Store Indigenous

318 3-hydroxy-4-methoxy benzaldehyde (isovanillin)


319 3-trifluoro methyl benzaldehyde 0.1 Liquid By Road RM Store Indigenous 320 3-(2-chloroethyl)-9-hydroxy-2-

methyl-4H-pyrido[1,2-a]pyrimidin-4-one


321 3-amino-1-butanol 0.1 Liquid By Road RM Store Indigenous 322 3-dimethylamino phenol 0.1 Liquid By Road RM Store Indigenous 323 3-Morpholin-4-yl(4-nitrophenyl)-

5,6-dihydropyridin-2-(CHO-one) 0.1 Liquid By Road RM Store Indigenous

324 4-dimethylaminopyridine 0.1 Solid By Road RM Store Indigenous 325 4-(isopropylamino) butan-1-ol 0.1 Liquid By Road RM Store Indigenous 326 4-nitrophenyl acetic acid 0.1 Liquid By Road RM Store Indigenous 327 5-(2-bromoethyl)2,3-

dihydrobenzofuron 0.1 Solid By Road RM Store Indigenous

328 5,6,7,7a-Tetrahydro-4H-Thieno-[3,2-C]-2-Pyridine HCl


329 5-chloro-2-phenoxy acetophone 0.1 solid By Road RM Store Indigenous 330 5-chlorovaleryl chloride 0.1 Liquid By Road RM Store Indigenous 331 5-(4-bromophenyl)4,6-

dichlorpyrimidine 0.1 Solid By Road RM Store Indigenous

332 5-chloro-2,3-di-phenylpuyrazine 0.1 Solid By Road RM Store Indigenous 333 5-Methyl-4,5,6,7-

tetrahydrothiazolo[5c]Pyridine-2-carboxylic acid hydrochloride


334 Acrylonitrile 0.1 Liquid By Road RM Store Indigenous 335 Aluminium oxide 0.1 Solid By Road RM Store Indigenous 336 Ammonium

molybdatetetrahydrate 0.1 Solid By Road RM Store Indigenous

337 Ammonia gas cylinder 0.1 Liquid By Road RM Store Indigenous 338 Barium hydroxide 0.1 Solid By Road RM Store Indigenous 339 Benzophenone 0.1 Solid By Road RM Store Indigenous



Sr. No.



Mode of Transport

Place of storage

Source

340 Benzyl amine 0.1 Liquid By Road RM Store Indigenous 341 Bromocyclopropyl bromide 0.1 Liquid By Road RM Store Indigenous 342 Bis(dimethylamino)methyliumyl-

3H-benzotriazol-1-oxide hexafluorophosphate [HBTU]


343 Cuprous oxide red 0.1 Solid By Road RM Store Indigenous 344 Di-tert-butyl-pyrrocarbonate 0.1 Liquid By Road RM Store Indigenous 345 Dibenzoyl-l-tartaric acid

monohydrate 0.1 Solid By Road RM Store Indigenous

346 Dimethyl amine 0.1 Liquid By Road RM Store Indigenous 347 Dimethyl sulphate 0.1 Solid By Road RM Store Indigenous 348 Diethyl-2-

(ethoxymethylene)malonate 0.1 Liquid By Road RM Store Indigenous

349 Donepezil HCl 0.1 Solid By Road RM Store Indigenous 350 Ethyl-3-(dimethylamino)acrylate 0.1 Liquid By Road RM Store Indigenous 351 Hydrogen peroxide 0.1 Liquid By Road RM Store Indigenous 352 Imidodicarbonic acid bis(1,1-

dimethyl ethyl ester 0.1 By Road RM Store Indigenous

353 L-menthol 0.1 Solid By Road RM Store Indigenous 354 Maleic anhydride 0.1 Solid By Road RM Store Indigenous 355 Meta (3)-amino benzotrifluoride 0.1 Liquid By Road RM Store Indigenous 356 Methane sulphonyl chloride 0.1 Liquid By Road RM Store Indigenous 357 Methyl chloro acetate 0.1 Liquid By Road RM Store Indigenous 358 Malonic acid 0.1 Solid By Road RM Store Indigenous 359 N-Butyl Lithium Solution 1.6M in

Hexane 0.1 Liquid By Road RM Store Indigenous

360 N-methyl morpholine-n-oxide 0.1 Solid By Road RM Store Indigenous 361 N,N- Diisopropyl ethyl amine 0.1 Liquid By Road RM Store Indigenous 362 N,N- dimethyl carbamoyl chloride 0.1 Liquid By Road RM Store Indigenous 363 N-propanol 0.1 Liquid By Road RM Store Indigenous 364 N-chlorosuccinimide 0.1 Solid By Road RM Store Indigenous 365 Neostigmine methyl sulfate 0.1 Solid By Road RM Store Indigenous 366 Ortho-nitro fluoro benzene 0.1 Liquid By Road RM Store Indigenous 367 Ortho fluoro phenol 0.1 Liquid By Road RM Store Indigenous 368 Phosphorous acid 0.1 Liquid By Road RM Store Indigenous 369 Phosphorous trichloride 0.1 Liquid By Road RM Store Indigenous 370 Potassium bromate 0.1 Solid By Road RM Store Indigenous 371 Potassium phosphate tribasic 0.1 Solid By Road RM Store Indigenous 372 Peroxyacetic acid 0.1 Liquid By Road RM Store Indigenous 373 Pyridiniumchloro chromate 0.1 Solid By Road RM Store Indigenous 374 R(+) Phenyl ethyl Amine 0.1 Liquid By Road RM Store Indigenous 375 Sodium hydrogen sulphite 0.1 Solid By Road RM Store Indigenous 376 Sodium Metal in Liquid Paraffin 0.1 Solid By Road RM Store Indigenous



Sr. No.



Mode of Transport

Place of storage

Source

377 Sodium Sulfite anhydrous 0.1 Solid By Road RM Store Indigenous 378 S(-) phenyl ethyl amine 0.1 Liquid By Road RM Store Indigenous 379 Tert-Butyl(1R,2S,5S)-2-Oxido-5-

[(dimethylamino)carbonyl]cyclohexyl carbamate oxalic acid

0.1 By Road RM Store Indigenous

380 Tert butyl bromo Acetate 0.1 Liquid By Road RM Store Indigenous 381 Thiourea 0.1 Solid By Road RM Store Indigenous 382 Tert butyl dimethyl silyl chloride 0.1 Liquid By Road RM Store Indigenous 383 Tetrabutyl ammonium Iodide 0.1 Solid By Road RM Store Indigenous 384 Trimethylsulphonium Iodide 0.1 Solid By Road RM Store Indigenous 385 Trimethylsulphoxonium Iodide 0.1 Solid By Road RM Store Indigenous 386 2-phenylaminomethylene-

malonic acid diethyl ester [ODC-I] 0.5 Liquid By Road RM Store Indigenous

387 4-Hydroxyquiniline-3-carboxylic acid ethyl ester [ODC-II]


388 Benzyl chloroformat 0.5 Liquid By Road RM Store Indigenous 389 1-admantylamine hydrchloride 0.5 Liquid By Road RM Store Indigenous 390 R-mandelic acid 0.5 Liquid By Road RM Store Indigenous 391 3-tert-Butoxycarbonylamino-4-

hydroxy-cyclohexanecarboxylic acid ethyl ester

0.5 Semi Solid By Road RM Store Indigenous

392 1-Hydroxybenzotriazole 0.5 Liquid By Road RM Store Indigenous 393 Ethyl3-(pyridin-2-

ylamino)propanoate 0.5 Solid By Road RM Store Indigenous

394 Ethyl-3-[[4-(methylamino)-3-nitrobenzoyl](pyridin-2-yl)amino]propanoate (DEM-I)


395 3-[(3-amino-4-methylamino-benzoyl)-pyridin-2-yl-amino]propionic acid ethyl ester (DEM-II)


396 2-[(4-cyanophenyl)amino]acetic acid


397 Pivaloyl chloride 0.5 Liquid By Road RM Store Indigenous 398 Diisopropyl ethyl amine 0.5 Liquid By Road RM Store Indigenous 399 3-[[[2-[[(4-

Cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-yl amino]propionic acid ethyl ester


400 N-[[2-[[[4-(Aminoiminomethyl)phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-beta-alanine ethyl ester (DEM-IV)

0.5 Solid



http://www.liaoyuan.com.cn/product_detail_en/id/208







Sr. No.



Mode of Transport

Place of storage

Source

401 Hexyl-4-nitrophenyl carbonate 0.5 Liquid By Road RM Store Indigenous 402 3-(2-(4-chlorophenoxy)phenyl-1-

methyl-pyrrolidine-2,4-dione 0.5 Solid By Road RM Store Indigenous

403 11-chloro-2,3-dihydro-2-methyl-1H-dibenz-[2,3:6,7]oxepino[4,5-c] pyrrol-1-one (DOP)


404 5-Chloro-N-(4-Nitrophenyl) pentanamide (APB-I/NMD-I)


405 3,3-dichloro-1-(4-nitrophenyl)piperdin-2-one (APB-III)


406 Ethyl(2Z)-chloro[(4-methoxyphenyl)hydrazono]acetate


407 1-(4-nitrophenyl)-3-morpholine-4yl-5,6-dihydropyridin-2(1H)-one


408 Methyl-3,3-diphenyloxirane-2-carboxylate


409 Methyl-2-hydroxy 3-Methoxy 3,3-diphenylpropanoate


410 2-hydroxy-3-methoxy-3,3-diphenyl propanoic acid


411 (2S)-2-Hydroxy-3-methoxy-3,3-diphenylpropanoic acid


412 3-[3-(trifluoromethyl) phenyl]propan-1-ol


413 (3-bromopropyl)-3-(trifluoromethyl) benzene


414 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide


415 1-phenyl-1,2,3,4-tetrahydro isoquinoline


416 (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline


417 5,6- dimethoxyindanone 0.5 Liquid By Road RM Store Indigenous 418 Isonicotinic acid methyl ester 0.5 Solid By Road RM Store Indigenous 419 (2-chlorophenyl){[2-(2-

thienyl)ethyl]amino}acetate .HCl 0.5 Solid By Road RM Store Indigenous

420 L-camphor sulphonic acid 0.5 Solid By Road RM Store Indigenous 421 1-chloro-1,2-benzisothiazole 0.5 Liquid By Road RM Store Indigenous 423 6-(4-methyl-piperazin-1-yl)-4-O-

tolyl-pyridin-3-yl-amine 0.5 Solid By Road RM Store Indigenous

424 Trimethylorthoformate 0.5 Liquid By Road RM Store Indigenous 425 6-(4-methyl-piperazin-1-yl)-4-O-

tolyl-pyridin-3-yl]-amine 0.5 Solid By Road RM Store Indigenous

426 2-(3,5-bis-trifluoromethyl-phenyl)-2-




Sr. No.



Mode of Transport

Place of storage

Source

methylpropionylchloride 427 Rolapitantsulphone 0.5 By Road RM Store Indigenous 428 3-(4-fluorophenyl)-3-

oxopropanenitrile 0.5 Solid By Road RM Store Indigenous

429 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10 Hexahydrocycloocta[b]pyridine


430 Ethyl piperazine 0.5 Solid By Road RM Store Indigenous 431 Cyclooctanone 0.5 Liquid By Road RM Store Indigenous 432 Phenylphosphonic dichloride 0.5 Liquid By Road RM Store Indigenous 433 Potassium iodide 0.5 Solid By Road RM Store Indigenous 434 7-hydroxy-1H-quinolin 2-one 0.5 Solid By Road RM Store Indigenous 435 7-(4-chlorobutoxy)-1H-quinolin-2-

one 0.5 Solid By Road RM Store Indigenous

436 1-benzo[b]thiophen-4-yl-piperazine


437 5-methylisoxazole-4-carboxylic acid


438 Dimethoxyethane 0.5 Liquid By Road RM Store Indigenous 439 N-(4-trifluoromethyl)-5-

methylisoxazole-4-carboxamide 0.5 Solid By Road RM Store Indigenous

440 2-bromo-1-cyclopropyl-2-(2-fluoropheny l) ethanone (BCE)


441 5,6,7,7a-tetrahydrothieno-[3,2-c]pyridin-2(4H)-one hydrochloride


442 4-Bromo-1-benzothiophene 0.5 Liquid By Road RM Store Indigenous 443 Propane dinitrile 0.5 Liquid By Road RM Store Indigenous 444 2-chloroethoxy acetic acid(2-CEE) 0.5 Liquid By Road RM Store Indigenous 445 5-Chloropyridine-2-amine 0.5 Liquid By Road RM Store Indigenous 446 Di tertbutyl carbonate 0.5 Solid By Road RM Store Indigenous 447 Potassium-1-cyano,3-ethoxy,3-

oxoprop1-ene-2-olate 0.5 Liquid By Road RM Store Indigenous

448 2,3-dibenzoyl-d-tartaric acid 0.5 Solid By Road RM Store Indigenous 449 4-Hydroxy butan-2-one 0.5 Liquid By Road RM Store Indigenous 450 Benzyl carbamate 0.5 Liquid By Road RM Store Indigenous 451 3-Nitrophthalic acid 0.5 Solid By Road RM Store Indigenous 452 Ethyl alcohol 2.0 Liquid By Road RM Store-

Ethanol room

Indigenous

Unit is manufacturing campaign based products as per market demand.

IX. Resource optimization/ recycling and reuse envisaged in the project, if any, should briefly outlined:

The raw materials packed in drums and stored in the warehouse.



By adoption continuous improvement in technology and process the desired reduction in process waste generation will be achieved.

By proper and efficient handling of raw materials, wastages of raw materials will be reduced. By most efficient solvent recovery facilities established with additional high capacity hi-tech

distillation plant together with latest evolved box type condensers; we will reduce the solvent losses to bear minimum.

X. Availability of water its source, energy/power requirement and source should be given: Availability of water its source energy/power required and its source.

• Water Requirement:

Sr. No. Particulars Quantity KL /day Existing Proposed Total

1 Domestic 6.50 6.50 13.00 2 Industrial

Process & Washing 8.27 16.73 25.00 Boiler 10.00 20.00 30.00 Cooling 4.00 12.00 16.00 Sub-Total Industrial Use 22.27 48.73 71.00

3 Gardening& Misc. 1.00 4.00 5.00 Total Requirement 29.77 59.23 89.00

Source: Fresh water requirement will be catered from GIDC water supply dept., . • Energy Requirements and its source:

Sr. No.

Particulars Existing Proposed Total

1 Heat Requirement 13 Lac Kcal/hr 7 Lac Kcal/hr 20 Lac Kcal/hr

• Power Requirements and its source: Sr. No. Particulars Existing Proposed Total Source

1 Power –Electricity requirement

300 HP 175 HP 475 HP DGVCL / DG set

XI. Quantity of waste to be generated (liquid and solid) and scheme for their Management/disposal:

• Quantity of Waste Water (liquid waste) generation and its management : Waste water generation:

Sr. No. Particulars Quantity KL /day

Existing Proposed Total 1 Domestic 6.00 6.00 12.00 2 Industrial

Process & Washing 7.95 13.9 21.85



Boiler 0.10 0.20 0.30 Cooling 0.10 0.20 0.30 Sub Total Industrial 8.15 14.10 22.45

3 Gardening 0.00 0.00 0.00 Total 14.15 20.10 34.45

• Domestic waste water - 12 KL/day disposed off through adequate soak pit and septic tank • Industrial waste waterwill be segregated as diluted and concentrated streams. • Diluted stream of 8.15 KL/day, which will be treated using adequate in-house ETP then, will be

disposed off through underground drainage to CETP, Vapi. • The concentrated streams will be sent to CETP for CMEE through tankers with required

manifest. • The company has obtained membership and NOC for common effluent treatment plant by

VGEL for CMEE, Vapi. • The company will discharge the additional treated waste water to CETP, when CETP permit

for additional waste water intake.

Design Criteria of ETP

• Source of Effluent: process, washing and utility etc. • Effluent Generation: 10 KL /Day Max. • Capacity of ETP: 10 KL /Day Max

Details of Effluent Treatment Plant:

SR NO. ITEM MOC CAPACITY NOS

1 Collection Tank RCC 10 KL 1

2 Collection Tank RCC 20 KL 1

3 Reaction Tank (Chemical Dosing Tank) RCC 06 KL 1

4 Neutralization Tank RCC 05 KL 2

5 Primary Settling Tank RCC 09 KL 1

6 Anaerobic reactor MS FRP 10 KL 1

7 Aeration Tank RCC 20 KL 1

8 Secondary Settling Tank RCC 09 KL 1

9 Treated Water Sump RCC 10 KL 1

10 Dual Media Filter MS 3 m3/hr 1

11 Activated Carbon Filter MS 3 m3/hr 1

12 Filter Press -- -- 1

13 Effluent Storage Tank for FACCO HDPE 10 KL 1

DETAILS OF ETP PROCESS AND FLOW DIAGRAM

Collection Tank:



Two different collection tanks are provided in the ETP.

CT-1: For collection of concentrated, higher COD effluent of products which contains traces of solvent and organic impurities.

CT-2: For collection of plant water washings of organic layers, equipment & floor washings along with the sewage water. This mixed stream will have lower COD around 1200; i.e. diluted stream.

Primary Treatment of CT-1 effluent:

The effluent from CT-1 will be taken for the –pH adjustment to the neutralization tank to send the material for CMEE treatment. -pH of the effluent will be adjusted to 6.5 to 8.5 using acid/alkali as per the designed criteria. The material will be filtered in PP press filter and collected in the HDPE storage tanks, analyzed for its COD and other specified parameters and sent to the CETP through tankers with manifest.

Primary & Secondary treatment (Anaerobic and Aerobic reactor) of CT-2 effluent:

The effluent from CT-2 will be taken for the –pH adjustment to the neutralization tank. –pH will be adjusted to 6.5 to 7.5 using acid/alkali. The hypochloride will be dosed for the oxidation as per requirement. Flocculent will be added to the settling tank. The effluent will be send to Anaerobic reactor; where pH and biomass is taken care.

After adequate hydraulic retention time the effluent will be taken for Aeration where the biomass is taken care of COD with required MLSS. The Dissolved Oxygen level is measured in the tank. The material will be taken in the secondary settling tank. Then it will be collected in the treated water sump. Analyzed for its quality as per the discharge norms of CETP.

If the effluent parameters are foundok then it is filtered through dual filter media and activated carbon bed filtration system and discharged through the on-line meter provided for discharge to the CETP underground line through the continuous discharge sampler tank.



Water Balance Diagram after proposed expansion:

Sr. No. Particular Water Consumption (KL/Day) Waste Water Generation (KL/Day) Final Disposal Existing Proposed Existing Proposed Recycle /Reuse Loss

1. Domestic 6.50 6.50 6.00 6.00 -- 1.00(usage loss) 12.00(To Soak pit/Septic tank)

2. Gardening 1.00 4.00 0.00 0.00 -- -- -- 3. Industrial Activity Process & Washing 8.27 16.73 7.95 15.90 1.15 will be

consumed in process

7.55(To ETP) 16.30(To CMEE)

Boiler 10.00 20.00 0.10 0.20 26.70 will be condensate back to process

3.00(Steam loss )

0.30 (To ETP)

Cooling 4.00 12.00 0.10 0.20 - 15.70(Evaporation Loss)

0.30 (To ETP)

Total 29.77 59.23 14.15 22.30 27.85 19.70



DETAILS OF AIR POLLUTION CONTROL MEASURES AFTER PROPOSED CHANGE:

Sr. No.

Stack Attached

Stack Height

in meter

Type of fuel and

consumption

Air Pollution Control Measures

Parameter

1.

Boilers Existing: IBR 1120 kgs/day Non-IBR 800 kgs/day Boiler Proposed: 1120 kgs/day(proposed )

11

PNG: 1700 SCM/Day

Adequate stack height and common stack monitoring facility is provided as air pollution control system to control particulate matter.

Particulate matter SOX NOX

2. Non IBR Thermopack Heater (4Lac Kcal)

11 LDO : 75 Lit/Hr.

3.

D.G. Set : Three Capacity:250 KVA + 25 KVA (Exi.) and 250 KVA (Proposed)

6 HSD : 60 Lit/Hr.

Adequate stack height and acoustic enclosure is provided and operated only during power break down.

Particulate matter SOX NOX

4. Process Reactor 15 -- Ventury followed by Alkali Scrubber

SO2 NOX HCl Cl2

5. Process Vent (Centrifuge) 11 -- -DO-

SO2 NOX HCl Cl2

Process Emission:

Sr. No.

Stack attached to Stack Ht. (in mtr) Probable pollutants & Limits

Air Pollution Control System

1 Pulverizer 9.00 PM<150 mg/Nm3 Dust Collector

Hazardous Waste Management:

During our proposed production activities hazardous wastes will be generated as per HW (M, H & TM) Rules 2008 and will be managed as follows.

Sr. No.

Name of the Waste

Source

HW Sch. Category

Quantity Existing

Total Quantity after proposed

change

Method of Disposal

1. ETP Waste

Effluent Treatment Plant

34.3 15

MT/Month

15

MT/Month Collection, Storage, Transportation, Disposal at TSDF, Vapi



2. Used Oil

Machinery 5.1 120

Lit/Year

300

Lit/Year

Collection, Storage, Transportation, disposal by selling to registered recyclers.

3. Discharged Container/Bags /Liners

Raw Materials

33.3 1800 Nos./Year

6000

Nos./Year Collection, Storage, Decontamination, Disposal on sale to actual users.

4. Used Filter Cloth

Mfg. Process

35.1 0.06

MT/Year

0.25

MT/Year Collection, Storage, transportation, Disposal at TSDF-VGEL, Vapi.

5. Spent Solvent

Mfg. Process

28.5 15

MT/Month

50

MT/Month Receptions, recover, storage, reuse in premises orsale to registered distillation facilities

6. Distillation Residue

Mfg. Process

28.1 18 MT/Year

60 MT/Year Collection, storage, transportation, disposal at SEPPL-Kutch and disposal by selling to registered end users.

7. Spent Carbon Mfg. Process

28.2 2 MT/Year 6 MT/Year Collection, storage, transportation, disposal at SEPPL-Kutch and disposal by selling to registered end users.



XII. Schematic representations of the feasibility drawing which give information of EIA purpose:

A schematic representation of the feasibility drawing

Resource requirements • Raw Material: Sourced from Manufacturer / Traders of the same. • Land: Acquired land for proposed project, at existing land • Water: Will be sourced through GIDC water supply. • Power: Power will be sourced through Dakshin Gujarat Vij Co.

Ltd. • Fuel : Local dealer, PNG gas: GSPC • PNG

Env. Mgt. Plan (EMP) • Air Pollution Control Measures: Air Pollution control system will be

provided. • Greenbelt area 12% of the total area is within company premises • Health & Safety measures will be followed properly

• Soak pit/ Septic Tank and ETP for Industrial waste water. • Flue Gas emissions: Adequate chimney height will be

provided. • Fugitive emission: There is no generation of fugitive

emissions.

Type of Industry Proposed mfg. unit of “Synthetic Organic

Chemicals” Pharma Intermediates and APIs

Site Location: Plot No. 911, 912, 922, Phase-III,

GIDCVapi

Public consultation: Not required as the project is

located in notified

Submission of Form-1 and Pre-Feasibility Report & Draft TOR

Proposed Activity: The proposed expansion project

involves the production of "Synthetic Organic Compounds"

Type of category as per EIA notification:Synthetic Organic Chemicals

(Activity -5(f)- Category-B)

Presentation before the EAC for TOR



4. SITE ANALYSIS

4.0 Site Analysis I. Connectivity:

The project is located in notified Industrial Estate of Vapi, Gujarat which is very well connected to National Highway no.8 and Western Railways. And the nearest Mumbai airport and port are 180 KM away from the project site by road.

II. Land Form, Land use and Land ownership: The land is in the form of industrial shed owned by Gujarat Industrial Development Corporation. The total plot area (3225sq.m.) is belonging to M/s Megafine Pharma (P) Ltd. The existing land is located in the notified industrial area of GIDC,Vapi (Notification no.GHU/75-45,GID:1974/4084/(10), dated : 6th May 1975)

III. Existing Infrastructure/ land use pattern Proposed project will be located within the GIDC notified industrial area of Vapi which has available infrastructure like water, electricity, roads, rail, transportation and drainage system, CETP and TSDF Site. Surrounding area is consisting with agriculture, other industrial units.

IV. Soilclassification and Land use classification: General soil classification of the area is as under: The area, being of basaltic formation, falls under the broad soil group of red loams and black clay soils. The transmission of water through similar parent material seems to have influenced the development of different physiographic characteristics of the soils in the area. The area in between the hills with sloping lands contains dark yellowish brown to very dark grayish brown gravelly clay loam to clayey soils of shallow to moderate thickness. The dissected hill and steep slopes suffer from severe erosion hazards. The steep hill slopes are almost devoid of soil.

V. Climate data from secondary sources: Rainfall Data: The climate here is tropical. The winter months are much rainier than the summer months in Valsad. This climate is considered to be as according to the Köppen-Geiger climate classification. The temperature here averages 26.9 °C. Rain fall about 1500 mm approximately of precipitation falls annually during 2015.

VI. Social Infrastructure available: M/s Megafine Pharma(P)Ltd. Infrastructure owes itself largely to the initiatives of G.I.D.C., in building the Industrial infrastructure and in attracting young entrepreneurs from Gujarat and other neighboring states. Equally, the growth of the social infrastructure - School, Colleges, Hospital, vocational training - stems from the bold initiatives of the Gyandham School, Ashadham School, etc. Haria Hospital, other private hospitals. .National Highway No. 8 passes through Vapi. It is connected to all major cities. Vapi railway stations on the Mumbai-Ahmedabad rail link of Western Railway (India) has become the direct beneficiary in terms of revenues due to daily commuters. The Union territories as well as Vapi town, Bhilad, Umbergaon, and Pardi, only 5–40 km from Vapi, There are good residential and commercial areas. Daman and Silvassa (the capital of Dadra and Nagar Haveli) attract both Indian and international tourists.



5. Planning Description

5.0 Planning Brief. I. Planning Concept (Type of industries, facilities, transportation etc) Town and Country Planning

/Development authority Classification: There is a cluster of numerous large-scale, medium-scale and small-scale industries, engaged in

manufacture of variety of products in the Gujarat Industrial Development Corporation (GIDC) notified area of Vapi. GIDC notified industrial area of Vapihas the entire available infrastructure like water, electricity, roads, rail, and transportation, availability of raw material, CETP, TSDF Site and drainage system.

II. Population Projection: Not applicable

III. Land use planning (breakup along with green belt etc.): The project is located within the Notified Industrial Area by Government of Gujarat and due to the proposed project there will not be any change in the land use pattern of the region. Plot Area Statement:

Area Statement Area After Proposed Expansion (in m2)

Total Area 3992.00

Construction Area 2076.24

Open Land Area 1316.90

Greenbelt Area 598.80

IV. Assessment of Infrastructure demand (Physical & Social):

The proposed infrastructure to manufacture products will be built with standard engineering design considering all the relevant parameters related to environment, health and safety. Facilities like road and communication are good. Banks, ATM's and medical facilitiesare also adequate.

V. Amenities/ Facilities: Education- schools including middle, secondary and higher secondary schools, Colleges, social welfare hostels. Medical and Health- Community Health Centre, & Primary Health center are available nearby area. 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 State Highway no. 8, Western railways.



6. Infrastructure Details

6.0 Proposed Infrastructure: I. Industrial Area (Processing Area):

Basic infrastructure developed already and the required additional plant and machineries will be installed after getting statutory clearance.

II. Residential Area (Non Processing Area): No residential area is involved in the proposed project. The employs are accommodated in nearby Residential areas

III. Green Belt: Green belt area will be provided and maintain at the tune of 15 % of the total land area as the project site is within the developed industrial area.

IV. Connectivity (Traffic and Transportation Road/ Rail/ Metro/ Water ways etc): The project site is very well connected by road through National Highway no. 8 and western

railways. V. Drinking Water management (Source& Supply of water):

Water requirement will be fulfilled through GIDC water supply. VI. Sewerage System:

Sewerage water is disposed off to soak pit through septic tank.

VII. Industrial Waste Management: Industrial waste water 22.45 KL/daygenerated mainly from the washing, process, Boiler & Cooling.Generated waste water will be treated by adequate effluent treatment plant and treated waterwill be send to CETP and CMEE, Vapi.

7. Rehabilitation and Resettlement (R&R) Plan: II. Policy to be adopted (Central/ State) in respect of the project affected persons including home

oustees, land oustees and landless laborers (a brief outline to be given): The proposed Industry does not envisage any disturbance to local community or the village since the land is acquired and fully owned by GIDC –Vapi Notified industrial Area. The proposed project will not affect the home oustees, land oustees and landless laborers. Hence there is no R & R plan required.

8. Project Schedule & Cost Estimates:

I. Likely date of start of construction and likely date of completion (Time schedule for the project to be given):

After obtaining Environmental clearance and Consent to Establish from GPCB, the company shall start the proposed construction and commissioning of the project.

II. Estimated project cost along with analysis in terms of economic viability of the project: Estimated project cost along with the analysis in terms of economic viability of the project



Plant & Machinery, Pipeline & Fittings, Electrical Installation, Safety systems, etc. are the major heads considered in the Capital Cost Projection for the proposed expansion project. Environment Protection has also been considered in planning the Cost Projection, which will include Green belt development, safety systems, etc. Capital Cost Projection

Sr. No.

Purpose Cost

(Rs. in coroes) Existing

Cost (Rs. in coroes)

Proposed

Cost (Rs. in coroes)

Total after expansion

1. Land 1.60 0.00 1.60

2. Building and Civil Works 8.80 1.00 9.80

3. Plant & Machinery and other fittings

4.00 4.50 8.50

4. Environmental protection measures

0.75 0.50 1.25

TOTAL : 15.15 6.00 21.15

The company will provide budgetary provision for the recurring expenses for environmental issues while planning the allocation of funds during the annual budgetary planning. Recurring Cost per annum

Sr. No.

Component Proposed (Rs. in Lacs/annum)

1. Environment & Safety Management System

23.00

2. Greenbelt Maintenance 2.00

3. Enterprise social contribution 5.00

Total 30.00

9. Analysis of Proposal (Final Recommendations):

I. Financial and social benefits with special emphasis on the befit to the local people including tribal population, if any, in the area:

Proposed expansion activity will provide benefits to the local people in terms of financial and social welfare.

• 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.


A. Anti-coagulant: API Intermediates

Apixaban

Ethyl chloro [(4-methoxyphenyl)hydrazono]acetate (EMA) 3, 3-dichloro-1-(4-nitrophenyl) piperdin-2-one ( APBIII) 1-(4-nitrophenyl)-3-morpholin-4-yl-5,6-dihydropyridin-2(1H)-one (APV IV Ethyl 6-(4-nitrophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid ethyl ester (APB VI)

Dabigatran Etexilate Mesylate

Ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-2-yl)benzamido)propanoate (DEM I) 3-[(3-Amino-4-methylaminobenzoyl)pyridin-2-ylamino]propionic acid ethyl ester (DEM II) 3-[[[2-[[(4-Cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]Pyridine-2-ylamino]propionic acid ethyl ester (DEM III) Ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1Hbenzo[d]imidazole-5-carboxamido)propanoate HCl (DEM IV) Dabigatran etexilate

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

oxazolidin-5-yl} methyl)thiophene-2-carboxamide

4-(4-Aminophenyl)-3-morpholinone (AMO) 2-({(5S)-2-Oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione ( RIV II 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl] phenyll}morpholin-3-one HCl (RIV III) 2-[(S)-2-Oxiranylmethyl]-1H-isoindole-1,3-(2H)-dione (OXI)

Edoxaban

2-[(5-Chloropyridin-2-yl)-2-oxoacetic acid (CPO) 5-methyl-4,5,6,7-tetrahydro thiazolo[5,4-c] pyridine-2-carbixylic Acid hydrochloride ( MTP) Tert-Butyl(1R,2S,5S)-2-azido-5-[(dimethylamino) carbonyl] cyclohexylcarbamate (ADC)

01 Product Name: Ethyl 2-chloro-2(4-methoxypthenylhydrazinylidene)ethanoate (EMA) Capacity : Application/Use of Product : Pharma Intermediate

A. Route of synthesis

NH2

OCH3

N

OCH3

N

Cl

+

O

O

Cl

CH3

O

CH3

NH

OCH3

N

ClO

O

CH3

NaNo2,HCl

-5-0 oC

4-methoxyaniline (E)-1-chloro-2-(4-methoxyphenyl)diazene

ethyl (2Z)-chloro[2-(4-methoxyphenyl)hydrazinylidene]ethanoate

Molecular Formula = C7H9NO Molecular Formula = C7H7ClN2O

Molecular Formula = C11H13ClN2O3

Formula Weight = 123.15246 Formula Weight = 170.59628

Formula Weight = 256.68552

ethyl 2-chloro-3-oxobutanoate

Molecular Formula = C6H9ClO3


Chloroform, CH3COONa

B. Process: -

The reactor was charge with DM water followed by p-anisidine, completed under stirring,

charge HCl under stirring, the reaction mass was stir at below 45 °C for 30 minutes, cool the

reaction mass at below 0°C, Sodium nitrite solution was added to it, stir the reaction mass for

1 hr, decomposed excess sodium nitrite by urea addition followed by sodium acetate solution

with require time, charge ethyl2-chloro aceto acetate followed by chloroform, temperature

raise up to 30°C, stir the reaction mass for require time & monitor the reaction by HPLC,

After completion of reaction separate the layer & aq. layer extract with chloroform, all

organic layer mixed together wash with water, Distilled out solvent & recrystalized by IPA ,

wash the material with IPA, dry the material at 50-55°C till LOD less than 0.5%. Pack the

material in polythene bag

C. Flow Chart:-

Filtration

p-Anisidine

Reactor

Sodium acetate solution

DM water HCl

Separation

Neutralization

5% NaHCO3

Organic Layer

NaNO2 Solution

Aqueous Layer Organic Layer

Organic Layer

Aq. send to ETP

Crude

Crystallization

Drying

Product

Urea Solution

Ethy2-chloro aceto acetate

Chloroform

IPA

D. Material Balance

Material Balance for Ethyl 2-chloro-2(4-methoxypthenylhydrazinylidene)ethanoate

Sr. no Input Raw Material Name Quantity

Kg Mole.

Weight Out put Quantity

Kg Remarks

1 p-anisidine 0.69 123

2 HCl 3.40 36.5

3 Sodium Nitrite 0.48 69

Aqueous Effluent 21.50 4 Urea 0.34 60

5 Sodium Acetate 1.92 86

6 Ethyl2-chloro aceto acetate 1.00 164.5

Recover Chloroform

13.00 Reuse 7 Chloroform 13.70 --- Chloroform Vapour loss

during distillation

0.70 Scrubber 8 Isopropyl Alcohol 3.50 ---

Recover IPA 3.30 Reuse

IPA Vapour loss during distillation 0.20 Scrubber

9 D.M. Water 20.0

Product:- Ethyl 2-chloro-2 (4-methoxypthenyl hydrazinylidene)

1.00 Desire product

Organic Residue 0.76

Hazardous Waste storage.

Total Quantity input 40.46

Total Quantity output

40.46

A. Therapeutic category : Anti-Depressant

API Intermediates Desvenlafaxine

Succinate

Mirtazapine

N-Methyl-3-phenyl piperazine (NM3 PP)

1-(3-Carboxy Pyridyl-2)-2-Phenyl-4-Methyl Piperazine (HMA)

1-(3-Hydroxymethyl pyridyl-2)-2-phenyl-4-methylpiperazine (HMPPMP)

Venlafaxine HCl 1-[2-(Amino)-1-(4-methoxyphenyl ethyl)] cyclohexanol HCl (AMCH) 1-[2-(Amino)-1-(4-methoxyphenyl ethyl)] cyclohexanol acetate(AMCA)

Vilazodone HCl Ethyl-5-aminobenzofuran-2-carboxylate (EABC) 3-(4-Chlorobutyl)-1H-indole-5-carbonitrile (CIC) Ethyl 5-piperazin-1-yl-1-benzofuran-2-carboxylate (PBC)

Vorteoxetine HBr 2,4-dimethyl-1-[(2-nitrophenyl)thio]benzene ( VOR-I)

2,4 -dimethyl-benzenethiol ( DMT)

Duloxetine Hydrochloride

Brexpiprazole 1-(1-benzothiophen-4-yl)piperazine

VILAZODONE HYDROCHLORIDE

1. Brief Process:

1.1. Preparation of Vilazodone stage-I (VIL-I)

Condensation of ethyl 5-piperazin-1-yl-1-benzofuran-2-carboxylate hydrochloride with 3-(4-

chlorobutyl)-1H-indole-5-carbonitrile in presence of acetonitrile added triethyl amine and potassium

iodide. The resulting reaction mixture was refluxed and maintained till completion of reaction; after

completion of reaction, cooled the content and quenched over ice water. Obtained solid was

filtered, dried to yield an ethyl 5-(4-(4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl) benzofuran-2-

carboxylate [VIL-I] as a yellowish crystalline solid.

1.2. Preparation of Vilazodone stage-II (VIL-II)

Amidation of obtained Ethyl 5-(4-(4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl) benzofuran-2-

carboxylate with ammonia gas in methanol at elevated temparature give 5-(4-(4-(5-cyano-1H-

indol-3-yl) butyl) piperazin-1-yl) benzofuran-2-carboxamide [VIL-II] as yellowish crystalline solid.

1.3. Preparation of Vilazodone stage-III (VIL-III)

5-(4-(4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl) benzofuran-2-carboxamide was suspended in

isopropyl alcohol to these added hydrochloric acid in isopropyl alcohol provide Vilazodone

hydrochloride[VIL-III] as white crystalline solid.

2. Route of synthesis:

NH

NCCl

NH

CNN N

OO

O

NNH OO

O

+

NH

CNN N

ONH2

O

VIL-II

CIC PBCE

NH

CNN N

ONH2

O

VIL-III

Vilazodone hydrochloride

VIL-I

.HCL

ACN, KI, TEA

MeOH, NH3(g)

ACN, ACOH

IPA, IPA.HCl

Process flow chart:

1. PREP ARATION OF VIL-I 2. PREP ARATION OF VIL-II

PREP ARATION OF VIL-III

Round bottom Flask

Methanol NH3(g)

VIL-I

Maintenance at 25-30°C

Filtration

Crude VIL-II

Purification ACN, ACOH

Filtration

Pure VIL-II

ML

ML

Round bottom Flask

Heating and Maintenance

Cooling

Acetonitril

e

PBC.ester CIC

TEA, KI

Quenching

Water

Filtration

Crude VIL-I

ML

Purification

Pure VIL-I

ML

ACN

Round bottom Flask

IPA

Maintenance at 55-60°C

Filtration

Vilazodone. HCl

ML

IPA.HCl

Material Balance:

Batch Size : 5.00 kg.

INPUT Kg. OUTPUT Kg. Reactants : Product : Stage-II 5.56 Vilazodone -III (wet) 5.26 HCl 1.39 By product : 0.00 Solvent Recovered : Solvents : Acetonitrile 128.70 Acetonitrile 135.47 Distillation losses 6.77

Liquid Effluent : 1.69

Total Input 142.42 Total Output 142.42

Therapeutic Category: C: Anti Alzimer :

MEMANTINE HYDROCHLORIDE:

1. Brief Process;

MEM-I & MEM-II

1,3-dimethyladmantane treated with bromine at 30-35°C gives 1-bromo-3,5-dimethyl

adamantane. This is treated with acetonitrile in the presence of sulphuric acid and extracted

with dichloromethane and isolated N-(3,5-dimethyl-1-adamantyl)acetamide in

diisopropylether.

Memantine Hydrochloride

N-(3,5-dimethyl-1-adamantyl)acetamide is hydrolyzed with sodium hydroxide in the presence

of Diethylene glycol gives 3,5-dimethyladamantan-1-amine,Which is further dissolved in

ethanol and acidified with IPA.HCl and precipitated with diisopropylether gives Memantine

hydrochloride.

API Intermediates 5,6-Dimethoxy-2-(pyridin-4-yl methylene)-indan-1-one (DOH

IV), 1-Benzyl piperidine-4-carbaldehyde (NBPCHO) Donepezil HCl Form I, Memamtine HCl

1-Benzyl-4-[(5,6-dimethoxy indanon)-2-ylidenyl] methylpiperidine (DON 1)

2-(1-benzyl-1,2,3,6-tetrahydro-pyridine-4yl) methylene-5,6-dimethoxy indan-1-onehydrochloride (Diene Crystallised)

Route of synthesis;

CH3

CH3

1,3-dimethyladamantane

CH3CH3

Br

CH3CH3

NH CH3

O

CH3CH3

NH2

.HCl

Mole. wt.= 215. 8

Br2

MEM-I & MEM-II

MDC/Ethanol/ DIPE/IPA.HCl

Diethylene glycol,NaOH

CH3CH3

NH CH3

OMEM-III

Mole. wt.- 243. 18Mole. wt.- 164. 28

N-(3,5-dimethyl-1-adamantyl)acetamideMole. wt.- 221. 33

Memantine hydrochloride

H2SO4Acetonitrile

1-bromo-3,5-dimethyladamantane

MDCDIPE

2. Process flow chart: MEM-I & MEM-II:

REACTION

MAINTENANCE

DISTILLATION

Memantine Hydrochloride Stage-I

1-3-dimethyladantane

Br2 Liq.

MEM-I & MEM-II:

REACTION

MAINTAIN

WORK-UP

FILTRATION

DRYING

Memantine Hydrochloride Stage-II

Dichloromethane

Water

Acetonitrile

H2SO4

Diisopropyl ether

MEM-III:

REACTION

MEM-II

NaOH

MAINTENANCE

WORK-UP

DISTILLATION

CHARCOLISATION

SALT FORMATION

DRYING

MEMANTINE HYDROCHLORIDE

Water

Dichloromethane

Ethanol

IPA.HCl

Diisopropyl

INPUT Kg. OUTPUT Kg. Reactants : Product : 1,3-dimethyladamanten 13.33

Memantine step-I (wet) 16.00

Bromine 53.32 Acetonitrile 62.38 By product : Sulphuric acid 31.45

Solvent Recovered :

Di chloro methane 175.00

Solvents : Di-isopropyl ehter 32.00 Water 483.90 Di chloro methane 180.22 Di-isopropyl ehter 37.32 Liquid Effluent : 605.00 Salt for washing Solid Waste NaCl 3.46 NaCl, NaOH, NaBr 64.04 Sodium hydroxide 26.66

Gaseous Emmissions

Total Input 892.04 Total Output 892.04 PRODUCT : Memantine Step -II

INPUT Kg. OUTPUT Kg.

Reactants : Product :

Diethylene glycol 169.60 Memantine step-I I(oil) 11.31

Step-I 11.31 Sodium hydroxide 34.71 By product : Solvent Recovered :

Dichloro methane 140.00 Solvents : Water 621.60 Dichloro methane 146.93 Liquid Effluent : 832.84 Salt for washing Solid Waste Sodium chloride 5.65 NaCl, Sod. Acatate 5.65 Total Input 989.80 Total Output 989.80

Therapeutic Category: D: Antianginal

Product Name: Ivabradine,3-(3-{[((7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl) methyl] methyl amino}propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one hydrochloride

IVABRADINE HYDROCHLORIDE

1. Brief Process:

Synthesis of ivabradine hydrochloride involves 3 stages

Stage – I: 3-(3-chloropropyl)-7, 8-dimethoxy-1, 3-dihydro-2H-3-benzazepin-2-one

(CDB) reacted with Sodium iodide in tetrahydrofuran at elevated temperature. After

completion of reaction, distilled-out the tetrahydrofuran up to thick slurry, reaction mass

slurry cooled to room temperature, stirred the reaction mass at room temperature, filtered

the precipitated solid, and washed with water to obtain off-white solid.

Stage – II: 3-(3-iodopropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (IVA-I)

is reacted with 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-

methylmethanamine hydrochloride in presence of potassium carbonate in acetone at

room temperature. After completion of reaction, acetone was distilled out to obtain thick

slurry, water and toluene was charged and product was extracted in toluene layer, distill-

out the toluene under vacuum to get (S)-7, 8-dimethoxy-3-{-N-[(4, 5-

Dimethoxybenzocyclobut-l-yl) methyl] -N- (methyl) amino) propyl)-1, 3-dihydro-2H-3-

benzazepin 2-one as a thick syrup. The obtained syrup subjected for reduction reaction in

autoclave by using palladium on carbon in IPA at elevated temperature under hydrogen

pressure. After completion of reaction, filtered the reaction mass through celite bed,

concentrate to get syrup. The obtained syrup dissolved in acetonitrile at elevated

API Intermediates Ivabradine HCl

(S)-N-{(3, 4-Dimethoxybenzocyclobut-1-yl)}-N-(methyl)]-N-(methyl) amine HCl - MBC.HCl

temperature to obtain clear solution, cooled the solution to RT, and conc. HCl was added

to precipitated the solid, filtered the solid, washed with acetonitrile and dried to get white

crystalline solid of ivabradine hydrochloride.

Stage – III: Crude 3-(3-{[((7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)

methyl] methyl amino}propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one

hydrochloride (ivabradine hydrochloride) dissolved in ethanol at elevated temperature to

obtained clear solution, methyl tertiary butyl ether (MTBE) was added as anti-solvent,

precipitated solid filtered, washed and dried under vacuum to obtain delta form of

Ivabradine hydrochloride.

2. Route of Synthesis:

Stage – I:

NO

OO

Cl

NO

OO

I

CDB IVA-I

Sodium iodide,THF

Water

Stage – II:

N

OO

O

I

IVA-IN

O

O

O

N

O

O

+

NH

O OPotassium carbonate,

Acetone

Toluene

.HCl

N

O

O

O

N

O

O

MBC.HCl

.HCl

Intermediate - A IVA-II

IPA/ Pd-C

Conc. HCl/ACN

Stage – III:

NO

OO

N

O

O

.HClNO

OO

N

O

O

Crude IVA.HClDelta form of IVA-HCl

.HCl

EtOH/ MTBE

IVA-II

3. Flow chart of Mfg. process:

Stage-I: Process flow chart of Ivabradine IVA-I:

THF

NaI

Water

CDB

IVA Stage-I

Reactor

Stir and Heat 60±2°C

Maintain 60±2°C

Distill-out THF

Cool RM

Thick mass

Stirred RM

THF

Filtered solid

ML

Dry solid

Stage-II: Process flow chart of Ivabradine (IVA-II):

Acetone

K2CO3

MBC.HCl

Acetone

Water

Aq. Layer

IVA-I

Syrup

Reactor

Stir reaction mass

Maintain for 24-30 h

Distill-out Acetone

Residue

Separated layers

Toluene layer

Separated layers

Toluene layer

Water

Toluene

Aq. Layer

Distill-out toluene

Aq. Layer

Heat to 55 ± 2°C

IPA

RM in autoclave

Solution transfer to Auto-clave

Heat RM to 60-65°C

H2

Pd/c

Maintain 60-65°C

Cool RM to RT

Distillation

Syrup

Reaction mass

Acetonitrile

Filtered

Drying

ML

IPA

IVA Stage-II

Conc. HCl

Stage-III: Process flow chart of Ivabradine (Ivabradine hydrochloride API):

Ethanol

ML

IVA-II

Reactor

Heat RM

Clear solution

Filter

Filtrate

Filter

Drying

MTBE

IVA.HCl API

Material balance:

OUTPUT

Kg. INPUT Kg.

Reactants : A ) Product CDB 1.00 A1 Product 1.25 NaI 1.00 B ) Solvent recovered B1 - THF 4.30 Solvents :

Water 11.00 THF 4.43 C )Effluent Aqueous Effluent 11.83 Organic residue 0.25 Total Input 17.43 17.43

OUTPUT

Kg. INPUT Kg.

Reactants : A ) Product A1 Product 1.37 Step-I 1.25 Potassium carbonate 0.89 MBC.HCl 0.75 B ) Solvent recovered B1 - Acetone 4.60

B2- Toluene 7.82 Water 6.25 Toluene 8.12 Acetone 4.91 C )Effluent Aqueous Effluent 8.11 Organic residue 0.27 Total Input 22.17 22.17

OUTPUT

Kg.

INPUT Kg. Reactants : A ) Product Step-II 1.37 A1 Product 1.00 Pd-C 0.20 Conc. HCl 0.50 Hydrogen 1.00 B ) Solvent recovered Acetonitrile 11.00

IPA 6.00 IPA 6.30

Water 5.30 Acetonitrile 11.79 C )Effluent Aqueous Effluent 8.09 Salt for washing Organic residue 0.17 Hyflo 0.50 C5 - Rec. Catalyst (Pd/c) 0.20 C3 - Spent solid (Hyflo,) 0.50 Total Input 26.96 26.96

E: Anti hypertension:

API

Intermediates

2-Hydroxy-3-methoxy-3,3-diphenylpropanoic acid (DPA III) ,2S)-2-Hydroxy-3-methoxy-3,3-diphenylpropanoic acid (DPA IV), 4,6-Dichloro-5-(2-

methoxyphenoxy)-2,2’-bipyrimidine ( DMB) , 5-(4-bromophenyl)-4,6-dichloropyrimidine (BDP), 1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridine-3-

carboximidamide (FPC), [(E)-Phenyl diazenyl]Malononitrile(RGT-II), 4-Isopropylamino butanol (4-IAV), Ammonium benzene sulfonate, 2-Ethoxy-5-(4-

Methyl Piperazinyl Sulfonyl) Benzoic Acid (SIL-III) , 4-amino-1-Methyl-3-n-propyl-5-pyrazolecarboxamide hydrochloride(MPC-VII)


Stage: - I

Br

OH

O

(4-bromophenyl)acetic acid

Br

O

O

CH3

methyl (4-bromophenyl)acetate

Sulphuric Acid

Methanol, MDC

B. Process: -

At room temperature 4-bromophenylacetic acid is carefully charged in methanol with stirring.

Carefully sulphuric acid was added; heat the reaction mass to reflux till reaction complies. Distilled

methanol under vacuum, charge MDC & water, stir the mass followed by settling & separation,

distilled MDC layer, the crude product light yellowish brown colour.

16 Product Name: 5 - (4-bromophenyl)-4,6-dichloropyrimidine. (BDP) Capacity : Application/Use of Product : Pharma Intermediate

C. Flow Chart:-


Stage: - II

Br

O

O

CH3

methyl (4-bromophenyl)acetate Br

O

O

CH3

OOCH3

dimethyl (4-bromophenyl)propanedioate

THF,

IPA,

CH3ONa

Dimethyl Carbonate

BDP -IBDP -II

B. Process: -

At room temperature a solution of 4-bromophenylacetic acid methyl ester (BDP-I) in THF (100 mL)

is carefully added to a suspension of NaOCH3 in dry THF. Dimethylcarbonate (DMC) is added drop

wise while the temperature of the mixture is maintained at 0°C. Stirring is continued till reaction

complies. The mixture is neutralized to pH 6-7 with aq. HCl before bulk of the THF is removed in

vacuum. The residue is dissolved in MDC, washed with brine; distill off MDC before IPA is added.

4-Bromophenyl acetic

Reactor

Methanol

Sulfuric Acid

Separation

Product

MDC recovery

MDC

Solvent recovery

Water

The product crystallizes. The crystals are collected, washed with IPA and dried to give 2-(4-

bromophenyl)-malonic acid dimethyl ester as light yellow crystals.

C. Flow Chart:-

Washing


Stage: - III

Br

O

O

CH3

OOCH3


Br

N

N

OH

OH

5-(4-bromophenyl)pyrimidine-4,6-diol

+ HCONH2

BDP -II BDP -III

CH3ONa , Methanol

B. Process: - At room temperature sodium methoxidee) was added to a solution of dimethyl-(o-

methoxyphenoxy) malonate in methanol. Upon completion of the addition stirring was

continued at r.t. for 30 min followed by the addition of formamide. The mixture was stirred at

reflux temperature till reaction complies. Eventually, the solvent was removed under reduced

pressure and the remaining residue was suspended in water & acidify with HCl.. A white

Reactor

Water

DMC THF

Separation

Solvent recovery

Crystallization

NaOCH3

Centrifuge

Product

BDP-I

IPA

precipitate formed. The precipitate was collected, washed with water and dried to give 5-(o-

methoxyphenoxy)-4, 6-dihydroxy-pyrimidine as a white powder.

C. Flow Chart:-


Stage: - IV

Br

O

O

CH3

OOCH3


Br

N

N

OH

OH

5-(4-bromophenyl)pyrimidine-4,6-diol

+ HCONH2

BDP -II BDP -III

CH3ONa , Methanol

B. Process: - To a solution of 5-(4-phenyl)-4,6-dihydroxy-pyrimidine in POCl3 . The mixture was heated to

80 to 90 ° C. and stirred till reaction complies. Cool the reaction mass to room temperature;

quench the reaction mass in water: ice mixture. The precipitate filter and wash with water

The remaining solid was washed with methanol and dried. This gave 4, 6-dichloro-5-(o-

methoxyphenoxy)-pyrimidine as a white powder repurification in methanol..

C. Flow Chart:-

Reactor

Methanol

Filtration

Drying

BDP-II

Product

Water wash

Sodium methoxide

Ammonium formate Formamide

Distillation

Acidification

D. Material Balance

Sr. no

Input Raw Material Name Quantity

Kg Out put Quantity

Kg Remarks

1 4-Bromophenyl acetic acid

1.50

2 Sulfuric acid 0.45 Recover sulfuric acid 70% 0.65 By product

3 Methanol 7.00 Recover Methanol 6.50

Methanol Vapour loss during distillation 0.50 Scrubber

4 Dichloromethane (MDC) 6.00 Recover MDC 5.80

MDC Vapour loss during distillation 0.20 Scrubber

5 Sodium hydrogen

0.50

Reactor

Filtration

Drying

BDP-III

Product

Water wash

Purification

Water + ICE

POCl3

Quenching

Methanol

carbonate

5 Tetrahydrofuran(THF) 5.00 Recover THF 4.90

THF Vapour loss during distillation 0.10 Scrubber

Sodium methoxide 1.10

6 Hydrochloric acid 3.00

IPA 6.00 Recover IPA 5.80

IPA Vapour loss during distillation 0.20 Scrubber

7 Sodium sulfate 0.07 Inorganic salt 0.10

8 POCl3 3.00 Recover phosphoric acid 10.00 By product

9 DM Water 10.00 Aqueous Effluent 7.50

Product:-BDP 1.00

Desire product.




Total Quantity output

43.62

F. Therapeutic category Schizophrenia

API Intermediates

Asenapine Maleate

11-Chloro-2,3-dihydro-2-methyl-1H-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-1-one (DOP) Trans-11-Chloro-2,3,3a, 12b-tetrahydro-2-methyl-1H-dibenz [2, 3:6, 7] oxepino [4,5-c]pyrrol-1-one (TOP)

Iloperidone 1-[4-(3-Chloropropoxy)-3-methoxyphenyl]ethanone (CME)

Lurasidone HCl

(1R,2R)-Cyclohexane-1,2-diyldimethanol (HMC) 3-Piperazin-1-yl-1,2-benzisothiazole (PBT FB) (3aR,4S,7R,7aS)-hexahydro-4,7-methano-2H-isoindole-1,3-dione ( BHC)

Paliperidone 3-(2-Chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one (CHP)

Quetiapine Hemifumarate

Dibenzo-[b,f][1,4]-thiazepine-11(10H)-one (DTO)

N-[Dibenzo-[b,f][1,4]-thiazepine-11-yl] piperazine di-HCl (DTPD) 1-(2-(2-Hydroxyethoxy)-ethyl) piperazine (HEEP)

Ziprasidone HCl

6-Chloro-2-oxindole (6CO) 6-Chloro-5-(chloroacetyl)-1,3-dihydro-2H-indole-2-one 6-Chloro-5-(chloroethyl)-1,3-dihydro-2H-indole-2-one (Zip II) 3-Piperazin-1-yl-1,2-benzisothiazole HCl (PBT HCL)

Blonanserin --

Cariprazine

Trans-(4-amino-cyclohexyl)-acetic Acid ethyl ester N-[trans-4-(2-oxoethyl)cyclohexyl]-, 1,1-dimethylethyl ester Trans-(4-amino-cyclohexyl)-acetic Acid Boc-trans-4-aminocyclohexane acetic acid

Tioperidone N-Ethoxycarbonyl piperazine ( NCP)

Paliperidone Palmitate 3-(2-Chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one (CHP)

QUETIAPINE HEMIFUMARATE:

1. Brief process:

Preparation of Quetiapine Hemifumarate involves chlorination of N-Dibenzo[b,f]

[1,4]thiazepine-11(10-H)-one (DTO) with phosphorous oxychloride (POCl3) in the presence

of N,N-dimethyl aniline. The chloro compound obtained is extracted in toluene layer and

further treated with Hydroxy ethyl ethoxy piperazine (HEEP) to obtain free base which is

then treated with Fumaric acid in ethanol to get Quetiapine Hemifumarate.


Synthetic Scheme of Quetiapine Hemifumarate

NH

S

ON

S

Cl

N

S

N

N

O

OH

HOOC

COOH

N,N-Dimethyl AnilinePhosphorous Oxychloride

Toluene

Quetiapine Hemifumarate

ethanol,fumaric Acid

N

NH

OOH

N

S

N

N

O

OH

Conc.HCl,Sodium carbonate,MDC

Mole wt.= 883. 1 Mole wt.= 383. 5

Mole wt.= 245. 72Mole wt.= 227. 3DTO DTCl

HEEP

Quetiapine free base

.2

Toluene

water,sodium hydroxide

water

3. Process flow chart:

CHLORINATION

N- N-Dibenzo[b, f][1, 4] thiazepine-11(10-H)-one [DTO] N,N-Dimethyl aniline Phosphorus oxychloride Toluene

CONDENSATION

Hydroxy ethoxy ethyl piperazine [HEEP] Toluene Conc. Hydrochloric acid Sodium carbonate Dichloromethane Water Sodium Hydroxide

SALT FORMATION

Ethanol Fumaric acid water

QUETIAPINE HEMIFUMARATE

Material Balance:

INPUT Kg. OUTPUT Kg. Remarks

Reactants : A ) Product BDP 6.75 A1 Product 5.00 n-propyl sulfonamide 4.59 Pottasium. Tert. Butoxide 4.72

B ) Solvent recovered

B1-methanol 28.00 Reuse B2-Ethyl acetate 33.00 Reuse

Solvents : B3-DMSO 23.75 Reuse DMSO 25.00 Ethyl acetate 35.00 methanol 30.00 Conc. HCl 3.71 C )Effluent Aqueous Effluent 13.75 Organic residue 1.27 Inorganic salt 5.00 Total Input 109.77 109.77 0.00


Reactants : A ) Product MCT-stage-I 8.50 A1 Product 5.00 Ethylene glycol 24.00

Pottasium tert. butoxide 5.00 Citric acid 5.00


B1-Ethyl acetate 19.00 Reuse B2-Methanol 32.50 Reuse

Solvents : B3-Dimethoxy ethane 32.50 Reuse Dimethoxy ethane 34.00 B4-Ethylene glycol 22.50 Reuse Ethyl acetate 20.00 Methanol 35.00 C )Effluent Aqueous Effluent 6.50 Organic residue 1.75 Inorganic salt 11.75 Total Input 131.50 131.50


Reactants : A ) Product MCT-stage-II 11.10 A1 Product 5.00 5-bromo-2-chloropyrimidine 8.00

Sodium Hydride 3.80 Citric acid 2.80


B1-Tetrahydrofuran 21.00 Reuse B2-DMF 10.50 Reuse

Solvents : B3-Ethyl acetate 5.60 Reuse Tetrahydrofuran 22.20 B4-Methanol 9.40 Reuse DMF 11.10 B5-Process loss 2.80 Scrubber Ethylacetate 6.00 Methanol 10.00 Water 5.00 C ) Effluent Aqueous Effluent 20.00 Organic residue 1.70 Inorganic salt 4.00 Total Input 80.00 80.00

G. Therapeutic category Overactive Bladder

Product Name Intermediates

Mirabegron

2-(4-Nitrophenyl) ethanamine HCl (NPA. HCL)

R-2-Hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide (MBR I)

(R)-2-[2’-(4-Nitrophenyl)ethyl]amino]-1-phenylethanol HCl (MBR II)

R-2-[[2-(4-Aminophenyl)ethyl]-amino]-1-phenylethanol HCl ( MBR III)

Solifenacin Succinate (1S)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline ( PTQ IV)

Darifenacine HBR (S)-2,2-Diphenyl-2-(pyrrolidin-3-yl)acetamide tartrate (DAR-IV)

MIRABEGRON:

1. Brief process:

Stage I: MBR-I

2-(4-Nitrophenyl) ethanamine hydrochloride (NPA. HCl) and R-Mandelic acid (R-MA) were coupled

in presence of trimethyl borate and di-isopropyl ethyl amine (DIPEA) in acetonitrile as a solvent.

Upon completion of reaction acetonitrile was partially distillated out, product was extracted in

ethyl acetate, and ethyl acetate layer was washed successively by 1N HCl solution, 5% NaOH

solution and brine solution. Ethyl acetate was removed by distillation, toluene was added to furnish

recrystallization, precipitated solid was filtered and dried to obtain MBR-I.

Stage II: MBR-II Amide group of MBR-I was reduced using Sodium Borohydride and iodine in THF at reflux

temperature. Upon conversion of MBR-I to MBR-II to desired extent, reaction mass was quenched

with methanol and then with conc. HCl, product was extracted in DCM on basifying with aqueous

ammonia solution. DCM layer further acidified with IPA. HCl to precipitate out product, obtained

solid was filtered, washed and dried to obtain MBR-II.

Stage III: MBR-III Nitro group of MBR-II was reduced using Raney nickel and hydrogen gas at room temperature.

After completion of reaction, reaction mixture filtered through celite to recover Raney nickel,

filtrate was concentrated, and product was isolated from IPA-toluene combination, washed and

dried to obtain MBR-III.

Stage IV: Mirabegron (MBR-IV) R-2-[[2-(4-Aminophenyl) ethyl]-amino]-1-phenylethanol hydrochloride (MBR-III) was coupled with

[2-Amino-1, 3-thiazole-4-yl] acetic acid (ATA) in presence of EDC. HCl and hydrochloric acid in water

as a solvent. Upon completion of reaction product was extracted in n-butanol on basifying reaction

mass with aqueous ammonia solution. Organic layer was separated and washed with aqueous

ammonia and excess of water. The separated organic layer partially distilled out and toluene was

added at elevated temperature, product was precipitated by lowering the temperature.

Precipitated solid filtered, washed with toluene and dried to obtain crude MBR-IV, crude MBR-IV

was purified in IPA-toluene to obtain pure Mirabegron (MBR-IV).

2. Route of synthesis; The manufacturing process of Mirabegron is consisted of four synthetic Steps. Stage I: Preparation of (R)-2-hydroxy-N-[2-(4-nitrophenyl) ethyl]-2-phenylacetamide (MBR-I):

OH

O

OH

R(-) Mandelic acidMole.Formula: C8H8O3Mol. Wt.: 152.15

NO2

Mole. Formula: C8H11ClN2O2Mol. Wt.: 202.64

NPA.HCl

NH2

. HCl

Acetonitrile, Ethyl acetateTrimethyl borate, HClSodium hydroxide

N,N-Diisopropylethyl amine TolueneSodium chloride

NH

NO2O

OH

Mole. Formula: C16H16N2O4Mol. Wt.: 300.31

MBR-I

2-(4-Nitro-phenyl)- ethylamine HCl

(R)-2-Hydroxy-N-[2-(4-nitro-phenyl)-ethyl]-2-phenyl-acetamide

Stage II: Preparation of (R)-2-[[2-(4-Nitrophenyl)-ethyl]-amino]-1-phenyl-ethanol hydrochloride

(MBR-II)

HN

NO2O

OH

(2R)-2-Hydroxy-N-[2-(4-nitro-phenyl)-ethyl]-2-phenyl-acetamideMole. Formula: C16H16N2O4Mol. Wt.: 300.31

MBR-I

Sodium borohydrideTetrahydrofuran, Conc.HClSodium Thiosulphate PentahydrateIodineLiquid ammonia

Methylene dichlorideIsopropyl alcohol HClSodium chlorideMethanolIsopropyl alcohol

HN

NO2

OH

(R)-2-{[2-(4-nitro-phenyl)-ethyl]amino}-1-phenyl-ethanol hydrochlorideMole. Formula: C16H19ClN2O3Mol. Wt.: 322.79

MBR-II

.HCl

Stage III: Preparation of (R)-2-[[2-(4-aminophenyl)-ethyl]-amino]-1-phenyl-ethanol hydrochloride

(MBR-III)

HN

NO2

OH

(1R)-2-{[2-(4-nitro-phenyl)-ethyl]amino}-1-phenylethanol hydrochlorideMole. Formula: C16H19ClN2O3Mol. Wt.: 322.79

MBR-II

.HCl

Raney nickelMethanolHydrogen gas

Isopropyl alcoholToluene

HN

NH2

OH

Mole. Formula: C16H21ClN2OMol. Wt.: 292.80

MBR-III

.HCl

(R)-2-[[2-(4-amino-phenyl)-ethyl]amino]-1-phenylethanol hydrochloride

Stage IV: Preparation of 2-(2-Amino-1,3-thiazole-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]

amino}ethyl) phenyl] acetamide (MBR-IV)

HN

NH2

OH

Mole. Formula: C16H21ClN2OMol. Wt.: 292.80

MBR-III

. HCl

(R)-2-[[2-(4-amino-phenyl)-ethyl]amino]-1-phenylethanol hydrochloride

[1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride] (EDC.HCl)

Conc. HClLiq. ammoniaEthyl acetaten-ButanolTolueneIsopropyl alcoholSodium Chloride

HN

NH

O

OH

N

SNH2

N

S

HO

O NH2

ATA2-[2-Amino-thiazole-4-yl] acetic acidMole. Formula: C5H6N2O2SMol. Wt.: 158.18

MBR-IV

Mole.Formula:C21H24N4O2SMol. Wt.: 396.51

2-(2-Amino-1,3 thiazole-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl) phenyl] acetamide

N N N .HCl

3. Process flow chart;

Stage I: (R)-2-hydroxy-N-[2-(4-nitrophenyl) ethyl]-2-phenylacetamide (MBR-I)

NPA. HCl: 2-(4-nitro-phenyl)-ethylamine hydrochloride

Stage II: (R)-2-[[2-(4-Nitrophenyl)-ethyl]-amino]-1-phenyl-ethanol hydrochloride (MBR-II)

MBR-I

R (-) Mandelic acid + NPA. HCl

Acetonitrile Trimethyl borate

Ethyl acetate

Dil. HCl

Sodium Hydroxide

10 % Brine solution

Toluene

Sodium Chloride

N, N-Di isopropyl ethyl amine

Stage III: (R)-2-[[2-(4-aminophenyl)-ethyl]-amino]-1-phenyl-ethanol hydrochloride (MBR-III)

MBR-I

MBR-II

Tetrahydrofuran Sodium Borohydrate

Iodine solution (THF+ Iodine) Methanol

Conc. HCl

Purified water

Methylene dichloride

Aq. Ammonia solution

Sodium Thiosulphate Pentahydrate

10 % Brine solution

Isopropyl alcohol

IPA. HCl

MBR-II

MBR-III

Methanol

Activated raney nickel

Hydrogen

Isopropyl alcohol

Toluene

Stage IV: 2-(2-Amino-1,3 thiazole-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl) phenyl] acetamide (MBR-IV)

ATA: 2-[2-Amino-thiazole-4-yl]acetic acid EDC. HCl: 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide mono hydrochloride

OUTPUT

Remarks INPUT Kg. Kg. Reactants : A ) Product NPA 15.00 A1Product 18.90 R (-) Mandelic acid 16.89 Trimethyl borate 11.54 DIPEA 14.34


B1 - Acetonitrile 43.00 Reuse

B2- Toluene 70.00 Reuse

Solvents : B3 - Ethyl Acetate 43.00 Reuse

MBR-III

ATA

EDC. HCl Conc. HCl

n-butanol

Liq. ammonia

Purified water Sodium chloride

Toluene

Isopropyl alcohol

Activated carbon Norit CN1

Ethyl acetate

MBR-IV

Ethyl acetate 45.00

Toluene 75.00 C )Effluent Water 50.00 Aqueous Effluent 79.00 Salt for washing Organic residue 5.87 NaCl 5.00 Inorganic salt 16.00 settle solid Total Input 232.77 275.77

OUTPUT

Remarks INPUT Kg. Kg. Reactants : A ) Product MBR Step-I 15.00 A1 -Product 12.09 THF 66.00 Sodium borohydrate 6.61 Iodine 25.35

Conc.HCl 8.20 B ) Solvent recovered

NaOH 10.80 B1 -THF 63.00 Reuse

B2- MDC 86.00 Reuse

Solvents : B3- Methanol 5.20 Reuse Methanol 5.55

Water 60.00 MDC 90.00 C )Effluent Aqueous Effluent 111.35 Salt for washing Organic residue 3.87 Nacl 6.00 Inorganic salt 12.00 Total Input 293.51 293.51

OUTPUT

Remarks INPUT Kg. Kg. Reactants : A ) Product MBR Step II 15.00 A1 Product 11.57 Raney Nickel 3.00


B1 -Methanol 142.00 Reuse

B2- Ethyl acetate 57.00 Reuse Solvents :

Ethyl Acetate 60.00 Methanol 150.00 C )Effluent Organic residue 3.43 Hyflo 1.00 Aqueous Effluent 11.00 Carbon (charcoal) 1.5

Rec. Catalyst 3.00 Reuse

Spent solid 2.50 (Carbon ,Hyflo,) Total Input 230.50 230.50

OUTPUT

Remarks INPUT Kg. Kg. Reactants : A ) Product MBR step III 15.00 A1 Dry Product 14.22 ATA 8.18 EDC.HCl 11.88 Conc. HCl 5.40


B1 - Ethyl Acetate 71.00 Reuse

B2 - n-heptane 58.00 Reuse

Solvents : B3 - EDC 9.00 Reuse Water 75.00

Ethyl Acetate 75.00 n-heptane 60.00 C )Effluent Aqueous Effluent 95.50 Organic residue 2.74 Total Input 250.46 250.46

H: Therapeutic category Multiple sclerosis

API Intermediates

Teriflunomide

5-methylisoxazole-4-carboxylic acid (MIC)

TERIFLUNOMIDE:

1. Brief Process:

Stage-I: N-(4-trifluoromethyl)-5-methylisoxazole-4-carboxamide (TFN-I/ Leflunomide):

5-methylisoxazole-4-carboxylic acid is reacted with thionyl chloride in dimethoxyethane as

solvent to obtain corresponding 5-methylisoxazole-4-carboxylic acid chloride. The

obtained 5-methylisoxazole-4-carboxylic acid chloride is further condensed with 4-

trifluoromethyl aniline in dimethoxyethane to obtain N-(4-trifluoromethyl)-5-

methylisoxazole-4-carboxamide (Leflunomide) was isolated in water.

Stage – II: (Z)-2-Cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)amide

(Teriflunomide):

N-(4-trifluoromethyl)-5-methylisoxazole-4-carboxamide (Leflunomide) is reacted with

aqueous sodium hydroxide solution in methanol and then acidified with concentrated

hydrochloric acid to obtain (Z)-2-Cyano-3-hydroxy-but-2-enoic acid-(4-

trifluoromethylphenyl)amide (teriflunomide). The obtained product is purified in mixture

of acetone and water.

2. Route of Synthesis (ROS):

Stage-I: N-(4-trifluoromethyl)-5-methylisoxazole-4-carboxamide (TFN-I/ Leflunomide):

NH2

FF

F

ON

OH

O

CH3O

N

Cl

O

CH3

NHF

F

FO

NO

CH3

SOCl2

Dimethaoxyethane+

DimethaoxyethaneWaterToluene

MIC

TFMA

Leflunomide Stage-II: (Z)-2-Cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl) amide

(Teriflunomide):

NHF

F

FO

NO

CH3

NH

F

F F

OH

N

O

CH3

Leflunomide Teriflunomide

MethanolNaOHConc.HCl/ WaterAcetone

3. Process Flow chart:

Stage-I: Preparation of N-(4-trifluoromethyl)-5-methylisoxazole-4-carboxamide (TFN-I/

Leflunomide):

DME MIC Heat Thionyl chloride Stir 3-4 hrs. at 70-80°C.

Distilled out DME u/v at below 50°C Distilled DME DME Distillation Distilled DME DME Slowly added at below at 25°C DME TFMA Cool to 0-5°C Stir for 45-60 min at 20-25°C Filtration

Reactor

Reactor

Reaction mass

Reaction mass

Residue

Residue

Reactor

Reaction mixture

Filtrate

Recovered TFMA HCl salt Distilled out DME U/V at below 50°C

Distilled DME Water Cool to 25-30°C Stir for 45-60 min at 25-30°C

Filtration Stir

Water MLs

Residue

Reaction mixture

Wet material

Drying

Leflunomide

Stage-II: Preparation of (Z)-2-Cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)

amide:

1. Methanol 2. Leflunomide

NaOH solution

(NaOH dissolved in Purified water)

Charcoal Stir for 30 min at 25-30°C

Methanol

Conc. HCl

Stir for 60 min.at 25-30°C

Methanol MLs

Purified water

Water MLs

Purified water

Heat to 45-50°C

Stir for 60 min at 45-50°C

Reactor

Reaction mixture

Filtrate

Wet solid

Wet solid

Reaction mixture

Filtration

Celite bed

Acetone & water

Heat to 50-55°C for 60 min

Cool to 25-30°C & stir for 60 min

Water

Wet solid (Teriflunomide)

Crystallization mixture

Crystallization mixture

Centrifuge

Drying

Teriflunomide

I. Therapeutic category: Acute coronary syndrome

API Intermediates

Ticagrelor 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine (GTR-03)

TICAGRELOR:

1. Brief process:

Stage-I: Preparation of TGR-I

GTR-03-V is condensed with GTR-02 using monoethylene glycol in presence of DBU and N,N-diisopropyl

ethylamine. Product is extracted in ethyl acetate and washed with brine solution (NaCl + Purified water).

TGR-I is isolated in n-heptane as a crystalline solid.

Stage-II: Preparation of TGR-II

TGR-I is diazotized using resin NO2 (Prepared using purified water, sodium nitrite and Amersep-900

(OH) form) and paratoluene sulphonic acid in presence of acetonitrile. After completion of reaction, resin is

filtered and extracted the product in methylene dichloride and washed the organic layer with purified water

sodium bicarbonate solution (Na2CO3 +Purified water) and brine solution (NaCl +Purified water) and

concentrated to get TGR-II as oil.

Stage-III: Preparation of TGR-III

TGR-II is condensed with GTR-01 in presence of purified water and anhydrous potassium carbonate. After

completion of reaction, product was extracted in methylene dichloride and washed with purified water,

acidic wash and brine solution. Methylene Dichloride is distilled out and after complete distillation, reaction

mass is stripped out using the acetonitrile. Then reaction mass is dissolved in the Methylene Dichloride and

the residue is unloaded into the drum.

Stage-IV: Preparation of TGR-IV (Ticagrelor crude)

Residual mass of TGR-III is deprotonated using Conc. hydrochloric acid. After completion reaction, pH of the

reaction mass is adjusted using the sodium hydroxide solution

(NaOH+ purified water) and product is extracted using Ethyl acetate and wash the organic layer with brine

solution and 2% HCl solution (Conc. HCl + Purified water) and sodium carbonate solution. Obtained reaction

mass is filtered and crude Ticagrelor is isolated using the acetonitrile.

Stage-V: Preparation of TGR-V (Ticagrelor pure)

Pure Ticagrelor is isolated as crystalline solid from Ticagrelor crude using ethyl acetate and n-

heptane.

2. Route of synthesis: Stage-I: Preparation of TGR-I:

N

N SCH3

Cl

NH2

Cl

Monoethylene glycol/N,N-Diisopropyl ethylamine DBU/Ethyl acetate/n-Heptane

.Tartarate

GTR-02

GTR-03- V

Molecular Formula = C10H19NO4 C4H6O6

Formula Weight = 367.34 Formula Weight = 418.93

Molecular Formula = C17H27ClN4O4S

TGR-I

NaCl /Purified water

NH2

O

O

O

OH

CH3 CH3

OH

NN

NH2NH

S

CH3

O

O

Cl

O

CH3 CH3

Stage-II: Preparation of TGR-II:

TGR-I TGR-II

PTSA, Acetonitrile

Molecular Formula = C17H27ClN4O4SMolecular Formula = C17H24ClN5O4S

Formula Weight = 429.92Formula Weight = 418.93

Purified water+ Sodium Nitrite+ Amersep -900(OH) Form

=Resin NO2

Sodium Bicarbonate, sodium Chloride MDC

OH

NN

NH2NH

S

CH3

O

O

Cl

O

CH3 CH3

OH

NN

N

N

S

CH3

O

OCl

O

CH3 CH3

N

Stage-III: Preparation of TGR-III:

TGR-II

NH2

F

F

TGR-III

GTR-01.mandalate

Molecular Formula = C17H24ClN5O4SFormula Weight = 429.92

Molecular Formula = C26H32F2N6O4SFormula Weight = 562.63

K2CO3,Purified water,Acetonitrile MDC,Conc. HCl,NaCl

OH

NN

N

N

S

CH3

O

OCl

O

CH3 CH3

N

NH

F

F

OH

NN

N

N

S

CH3

O

O

O

CH3 CH3

N

Stage-IV: Preparation of TGR-IV:

TGR-III TGR-IV



Conc HCl,Purified Water, NaOH

Ethyl acetate, NaCl,Na2CO3, Acetonitrile

NH

F

F

OH

NN

N

N

S

CH3

O

O

O

CH3 CH3

N

NH

F

F

OH

NN

N

N

S

CH3

OH

O

OH

N

STAGE-V: PREPARATION OF TGR-V

TGR-IV TGR-VTicagrelor

OH

NN

NN

N

S

CH3

ONH

F

F

OH OH

OH

NN

NN

N

S

CH3

ONH

F

F

OH OH



Ethyl acetate, n-heptane

Expansion for the abbreviation:

Abbreviation Expansion for the abbreviation

GTR-02 2-{[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta [d][1,3]dioxol-4-

yl]oxy} ethanol,L-tartaric acid

GTR-03-V 4,6-dichloro-2-(propylthio)pyrimidin-5-amine

GTR-01 2-{[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyl tetrahydro-3aH-cyclopenta [d][1,3] dioxol-4-

yl]oxy} ethanol

DBU 1, 8-bicyclo [5.4.0] undec-7-ene

PTSA paratoluene sulphonic acid

TGR-I

2-[(3aR,4S,6R,6aS)-6-{[5-mino-6-chloro-2-(propylsulfanyl)-4-pyrimidinyl]amino}-2,2-

dimethyl tetrahydro-3aH-cyclopenta [d] [1,3]dioxal-4-yl]oxy]-1-ethanol)

TGR-II 2-({(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylsulfanyl)-3H-[1,2,3] triazolo [4,5-d]pyrimidin-3-yl]-

2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxal-4-yl]oxy}-1-ethanol)

TGR-III 2-({(3aR,4S,6R,6aS)-6-[7-{[(1R,2S)-2-(3,4-diflurophenyl) cyclopropyl]amino}-5-(propylsul

fanyl)-3H-[1,2,3]triazolo[4,5-d] pyrimidin-3-yl]- 2,2-dimethyl tetrahydro-3aH-cyclopenta[d]

[1,3] dioxal-4-yl]oxy}-1-ethanol)

TGR-IV Ticagrelor crude

TGR-V Ticagrelor pure


Stage-I: TGR-I:

Stage-II: TGR-II:

Stage-III: TGR-III:

Stage-IV: TGR-IV:

GTR-03-V

TGR-I

Monoethylene glycol GTR-02

n-Heptane

Purified water Ethyl acetate

Sodium chloride

TGR-I

TGR-II

1,8-Diazabicyclo (5,4,0) Undec-7-ene (DBU) (LR Grade)

Purified water

Sodium bicarbonate Sodium chloride

TGR-II

TGR-III

Acetonitrile GTR-01

Acetonitrile

Conc. Hydrochloric acid

Purified water

Methylene dichloride

K2CO3

N,N-diisopropyl ethyl amine

Sodium nitrite

Para-toluene sulphonic acid Amersep-900 (OH) form

Acetonitrile Methylene Dichloride

Sodium Chloride

Stage-V: TGR-V:

PRODUCT : Ticagrelor Stage -I

INPUT Kg. OUTPUT

Remarks Kg.

Reactants : A ) Product GTR-03 5.00 A1 - Dry Product 0.00 GTR-02 8.50 N,N-diisopropyl ethyl amine 12.50

DBU 0.25 B ) Solvent recovered

Solvents : B1-Ethyl acetate 28.00 Reuse Water 70.00 B2-n-heptane 37.00 Reuse Ehtlylene glycol 25.00 B3 Ehtlylene glycol 23.50 Reuse Ethyl acetate 30.00 B4-Process loss 6.50 Scrubber n-heptane 40.00

C )Effluent

Aqueous Effluent 102.00 Sodium chloride 7.50 Organic residue 1.75 Charcoal 0.70 Hyflow 1.00 Spent solid 1.70 (Carbon, Hyflo) Total Input 200.45 200.45

TGR-III

TGR-IV

Purified water

Sodium Hydroxide

Conc. Hydrochloric acid

Ethyl acetate

Sodium Chloride

TGR-IV

TGR-V

N-Heptane Ethyl acetate

Sodium Bicarbonate

Acetonitrile

PRODUCT : Ticagrelor Stage -II

INPUT Kg. OUTPUT

Remarks Kg.

Reactants : A ) Product

TGR-I 7.00 A1 - Brinzolamide stage-II (Syrup) 0.00

PTSA 4.78

Ambersep-900 OH 15.00 Sodium nitrite 9.03


B1-Ethyl acetate 33.00 Reuse B2-Process losses 2.77 Scrubber

Solvents :

Water 116.90 C )Effluent Ethyl acetate 35.77 Aqueous Effluent 151.00 Organic residue 1.71 Total Input 188.48 188.48

PRODUCT : Ticagrelor Stage -III

INPUT Kg. OUTPUT

Remarks Kg.

Reactants : A ) Product TGR-II 7.10 A1 - Dry Product 0.00 GTR-01 5.00

Potasium carbonate 4.55


Solvents : B1-Ethyl acetate 86.00 Reuse Purified water 97.06 B2-Process loss 4.00 Scrubber Ethyl acetate 90.00 C ) Effluent Aqueous Effluent 106.00 Organic residue 2.71 Inorganic salt 5.00 Total Input 203.71 203.71

PRODUCT : Ticagrelor Stage -IV

INPUT Kg. OUTPUT

Remarks Kg.

Reactants : A ) Product TGR-III 8.94 A1 - Dry Product 5.90 Conc. HCL 44.72


Solvents : B1 - Ethyl acetate 53.00 Reuse MDC 45.00 B2 - MDC 43.00 Reuse Ethyl acetate 55.22 B3 - n-heptane 25.00 Reuse n-heptane 26.26 B4- Process loss 5.48 Scrubber

C ) Effluent

Aqueous Effluent 47.00

Organic residue 0.76

Activated carbon 1.18 Spent solid 2.36

Hyflo 1.18 (Carbon, Hyflo)

Total Input 182.50 182.50

PRODUCT : Ticagrelor Stage -V

INPUT Kg. OUTPUT

Remarks Kg.

Reactants : A ) Product TGR-IV 5.90 A1 - Dry Product 5.00

Solvents : B ) Solvent recovered

Ethyl acetate 140.14 B1 Ethyl acetate 135.00 Reuse n-heptane 62.93 B2 n-heptane 60.00 Reuse B3 Process loss 8.07 Scrubber Salt for washing C )Effluent

Activated carbon 0.59

Hyflo 0.59 Organic residue 0.90

Spent solid 1.18 (Carbon, Hyflo) Total Input 210.15 210.15

J Therapeutic category Psoriatic Arthritis

API Intermediates

Apremilast 3-acetamidophthalic anhydride(APA)

(S)-2-(3-Ethoxy-4-methoxyphenyl)-1-methyl sulphonyl)-eth-2yl amine (EMS)

1. Manufacturing process:

(S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine (EMSA) was reacting

with 3-acetamidophthalic anhydride (APA) in mixture of dimethoxyethane and acetic acid to

furnish apremilast. The obtained apremilast was purified from mixture of acetone and

methanol furnishes pure apremilast.

2. Route of Synthesis (ROS):

OCH3

O

CH3

NH2S

O

OCH3

N

O

O

OCH3

O CH3

S

O

O

CH3

H

NH

CH3

O

O

O

NH

O

CH3

O

+

EMSAAPAApremilast

DimethoxyethaneAcetic acid

MDC/ NaHCO3

Acetone/ Methanol

3. Mass Balance:

Batch Size : Kg. 1.3 INPUT Kg. OUTPUT Kg.

Reactants : A ) Product EMSA 1.00 A1 Product 1.30

APA 0.75 B )Solvent recovered

sodium bicarbonate 0.35 Dimethoxyethane 7.70 Solvents : Dichloromethane 12.85 Water 15.00 Acetone 1.25 Dimethoxyethane 8.00 Methanol 5.80 Acetic acid 0.50 C ) Effluent Dichloromethane 13.50 Aqueous Effluent 17.50 Acetone 1.35 Methanol 6.00 Organic residue 0.05 Total 46.45 Total 46.45

Flow chart of Mfg. process:

1. APA 2. EMSA 3. Acetic acid Heat 80-85°C

Maintaining at 80-85°C Distillation Dimethoxyethane Distillation Cool 25-30°C Purifier water Dichloromethane

Organic layer Dichloromethane Aqueous layer

7% NaHCO3 washing Aqueous layer Distillation Distilled MDC Acetone Methanol

Dimethoxyethane

Reaction Mixture

Reaction Mixture

Aqueous layer

Organic Layer

Residue

Reaction Mixture

Residue

Organic Layer

Stir at 50-55°C Cool 0-5°C Stir at 0-5°C Methanol washing MLs

Reaction mixture

Reaction mixture

Filtration

Drying

Apremilast

Reaction mixture

K Therapeutic category Cystic fibrosis

Product Name Intermediates

Ivacaftor 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (ODC)

5-Amino-2,4-di-tert-butyl-phenol (ADP)

Lumacaftor --

IVACAFTOR

1. Brief Process:

In a clean and dry RBF, charged N, N-dimethylformamide (500 mL) followed by 4-Oxo-1, 4-dihydro-quinoline-3-carboxylic acid [ODC] (44.9 g, 237 mmol), Di-isopropyl ethylamine [DIPEA] (58.4 g, 452 mmol) and (Benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexaflurophosphate [BOP] (149.6 g, 339mmol) at 25-30 °C. Reaction mass was stirred for 15 min at same temperature. After the addition of 5-Amino-2, 4-di-tert-butyl-phenol [ADP] (50 g, 226 mmol), the reaction mass was stirred for 20 h at 25-30 °C. DM water (750 mL) and ethyl acetate (1000 mL) were charged in to the reaction mass. Aqueous and organic layers were separated. Organic layer washed by dilute aq. ammonia (2 x 1000 mL) followed by 5 % brine solution (3 x 750 mL). Organic layer then concentrated under vacuum at below 60 °C. To the obtained residue, charged methanol (250 mL) and heated to 63-66 °C, stirred for 1 h at same temp, cooled slowly to 25-30 °C, filtered the solid and dried under vacuum at 55-60 °C to get Ivacaftor (78.0 g).


NH

O

OH

O

+

OH

NH2 NH

O

NH

O

OH1. DMF2. DIPEA3. BOP

4. Ethyl Acetate5. Aq. Ammonia6. Methanol7. AcetoneODC ADP Ivacaftor

MW: 189. 17 MW: 221. 34 MW: 392. 49

3. Flow chart of Mfg. process:

DIPEA

Stirring at 25-30 °C

Stirring at 25-30 °C for 20 h

At 20-30 °C

Organic layer

Organic layer

Concentration of Organic layer

Heating to 63-66 °C

ODC DIPEA

BOP

N, N-Dimethylformamide

ADP

DM water Ethyl acetate

Layer separation Aq. layer

Dilute aq. ammonia


5 % Brine solution


Recovered Ethyl acetate

Methanol

Cooling to 25-30 °C Filtration

PRODUCT : Ivacaftor

Batch Size : Kg. 0.078

OUTPUT

INPUT Kg. Kg. Reactants : A ) Product

ADP 0.05 A1 Product 0.08 ODC 0.04

DIPEA 0.06

BOP 0.15 B ) Solvent recovered

Ethyl acetate 0.85

Methanol 0.19 Solvents : DMF 0.45

Water 6.00 Process loss 0.08

DMF 0.47 Ethyl acetate 0.90 C )Effluent

Methanol 0.20 Aqueous Effluent 6.21 Organic residue 0.01 Total Input 7.87 7.87

Drying at 55-60 °C

Ivacaftor

L Therapeutic category Insomnia

API Intermediates

Suvorexant Benzyl (5R)-5-methyl-1,4-diazepane-1-carboxylate hydrochloride (MDA)

SUVOREXANT API

1. Brief Process:

Step-I: Preparation of benzyl (5R)-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane-1-carboxylate (SRT-I):

To a 1 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer,

and condenser was charged SUV-II (100 g, 0.40 mol), MTB (81.8 g, 0.40 mol), EDC (76.4

g, 0.40 mol), HOBt (54 g, 0.40 mol), TEA (80.8 g, 0.80 mol) and DMF (200 mL). The

reaction mixture was stirred for 3 hours, water (500 mL) was added to saturate the DMF,

extract the product in ethyl acetate (500 mL). Concentrated the ethyl acetate to get colorless

oil of (5R)-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane-1-carboxylate

(SUV-III).

Step-II: Preparation of Suvorexant (SRT-II):

10% Pd/C (10 g), SUV-III (100 g, 0.23 mol) and methanol (1.0 L) were charged to a 3.5 L

Parr hydrogenator, under a nitrogen atmosphere. Hydrogen was charged to the reaction

vessel for up to 55 psi. The mixture was shaken for 5 hours, maintaining hydrogen pressure

between 50 and 55 psi. Hydrogen was released and the mixture was purged with nitrogen 3

times. The suspension was filtered through a celite bed and rinsed with methanol (100 mL).

The filtrate was concentrated under vacuum to get white foam. In the resulting white foam

DMF (200 mL), TEA (46.5 g, 0.46 mol) and DCB (43.3 g, 0.23 mol) was charged at 25-30

°C, mixture was stirred for 2-3 hrs, Water (500 mL) was charged to the mixture and stirred

for 3 h to precipitate out the solid, filtered the solid, washed with water (100 mL) and dried

to get off white to white solid of suvorexant

2. Route of Synthesis: Synthesis of SRT-I (Step-1):

O N

O

NH

+

NN

NO

OHO

NO

N

N NN

OEDC/HOBt/ DMF/TEA/water

MTBMDA SRT - I

Synthesis of SRT-II (Step-2):

+O

NO

N

N NN

O N

O

ClCl

NN

NN

NON

O

Cl

DCB

Pd/H2/Methanol/DMF/TEA/water

SuvorexantSRT - I SRT - II

3. Process Flow chart:

Step-I: Preparation of SUV-III

DMF

MDA

Aq. layer

TEA

SRT-I

Reactor

Stir reaction mass

Quenching of reaction mass

Distillout of ethyl acetate

MTB

EDC HOBt

Water Ethyl acetate

Layer separation

Ethyl acetate

Step-II: Preparation of Suvorexant

SRT-I

H2 gas

Catalyst

Methanol

SRT-II (Suvorexant)

Hydrogenator

Filtration

Concentration of filtrate

White solid

Methanol

DMF

TEA

Reaction mass

DCB

Water

Maintaining

Filtration

Ml

Drying

PROCESS MASS BALANCE PRODUCT :Suvorexant; SRT-I (Step -I)


INPUT Kg. OUTPUT

Kg. Remarks

Reactants : A ) Product MDA 0.10 A1 - Product 0.15 TEA 0.08 0.00 EDC 0.08 B ) Solvent recovered HOBt 0.05 Ethyl acetate 0.47 Reuse MTB 0.08 DMF 0.19 Reuse Solvents : Process loss 0.04 Scrubber DMF 0.20 C )Effluent

water 0.50 Aqueous Effluent 0.70 Ethyl acetate 0.50


Total 1.59 1.59

Step -II


INPUT

Kg. OUTPUT

Kg. Remarks

Reactants : A ) Product SRT-I 0.10 A1 - Product 0.10 10 % Pd/C 0.01 B ) Solvent recovered TEA 0.05 Methanol 0.84 Reuse DCB 0.05 DMF 0.18 Reuse Solvents : Process loss 0.05 Scrubber Methanol 0.88 C )Effluent

DMF 0.19 Aqueous Effluent 0.70 Water 0.60


Hyflo 0.01 Spent solid 0.01 (Carbon ,Hyflo,) Total 1.89 1.89

M Therapeutic category Antiemetic

API Intermediates

Netupitant

Rolapitant

NETUPITANT

1. Brief process:

1.1 Preparation of Methyl-[6-(4-methyl-piperazin-1-yl)-4-O-tolyl-pyridin-3-yl]-

amine

Compound 6-(4-methyl-piperazin-1-yl)-4-O-tolyl-pyridin-3-yl-amine treated with

trimethyl ortho formate and trifluoroacetic acid in Tetrahydrofuran in presence of

strong base lithium aluminium hydride at elevated temperature offered Methyl-[6-

(4-methyl-piperazin-1-yl)-4-O-tolyl-pyridin-3-yl]-amine[Netupitant-I].

1.2 Preparation of Netupitant

Condensation of Methyl-[6-(4-methyl-piperazin-1-yl)-4-O-tolyl-pyridin-3-yl]-

amine with 2-(3,5-bis-trifluoromethyl-phenyl)-2-methylpropionylchloride in

presence of diisopropyl ethylamine in dichloromethane at elevated

temperature provide Netupitant.

Page 1 of 5



amine:-

N

NH2

NN

N

NH

NN

HC(OMe)3,LiAlH4

Netupitant-IAmine compound

2.2 Preparation of Netupitant:-

N

NH

NN

F3C

CF3O

Cl+

N

N

NN

CF3

CF3

O

DIPEA

MDC

II (Netupitant)

Netupitant-I Acyl compound

Page 2 of 5

3. Process flow chart :-


amine

Round bottom Flask

Reaction maintenance 130°C, 3h

Distillation

Residue

Maintenance at 30°C, 1h

Trimethyl ortho formate 6-(4-methyl-piperazin-1-

yl)-4-O-tolyl-pyridin-3-

yl-amine Trifluoroacetic acid

HCl/NaOH

THF, LAH

Acidic and Basic work up

Distillation

Syrup [Netupitant-I]

Recover trimethyl ortho formate

Recover THF

Page 3 of 5

3.2 Preparation of Netupitant

Round bottom Flask

Reaction maintenance reflux, 3h

Work up

Distillation

Syrup

Stage-I/DIPEA 2-(3,5-bis-trifluoromethyl-

phenyl)-2-methyl

propionylchloride MDC

NaHCO3 sol

Netupitant

Recover MDC

Aq. Layer

Page 4 of 5

PRODUCT : Netupitant-I

Batch Size : 1.00

INPUT Kg.

OUTPUT

Remarks Kg. Reactants : A ) Product 6-(4-methyl-piperazin-1-yl)-4-O-tolyl-pyridin-3-yl-amine 1.60 A1 Product 1.00

Trimethyl ortho formate 12.34 B ) Solvent recovered Trifluoroacetic acid 0.09 B1-THF 4.41 Reuse

LAH 0.43 B2-Trimethyl ortho formate 11.96 Reuse

sodium hydroxide 2.00 B3-Process loss 0.47 Scrubber Solvents : C )Effluent

THF 4.50 Aqueous Effluent 10.50 Conc. HCl 1.50 Organic residue 0.12 Water 6.00


PRODUCT :

Netupitant-II

Batch Size : 1.00

INPUT Kg.

OUTPUT

Remarks Kg. Reactants : A ) Product Netupitant-I 0.70 A1 Product 1.00 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl propionylchloride

0.84 B ) Solvent recovered

DIPEA 5.50 B1-MDC 2.40 Reuse Sodium bicarbonate 0.35 B2-DIPEA 5.40 Reuse B3-Process loss 0.20 Scrubber Solvents :

MDC 2.50 water 9.00 C )Effluent Aqueous Effluent 9.80 Organic residue 0.09 Total Input 18.89 18.89

Page 5 of 5

N Therapeutic

category Antidiabetic

API Intermediates

Vildagliptine 3-Aminoadamantan-1-ol (HAA)

(2S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile (CCP -II)

VILDAGLIPTIN:

1. Brief process:

3-aminoadamantan-1-ol (HAA) VLD-I:

A mixture of conc. H2SO4 and conc. HNO3 was cooled and 1-admantylamine hydrochloride was

added slowly under stirring. After completion of reaction, reaction mass was quenched into cold

water. The solution was stirred followed by addition of aqueous NaOH solution (50%) to adjust the

pH. The product is extracted with a mixture of toluene and n-butanol. The extract was concentrated

and isolated in a mixture of n-heptane and methanol to give 3-aminoadamantan-1-ol as solid and

dried the solid.

(2S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile (CCP) (VLD-II):

To a solution of L-prolinamide in methylene dichloride, a solution of chloro acetyl chloride in

methylene dichloride was added drop-wise. The reaction mass was stirred and cooled, to this cooled

solution trifluoro acetic anhydride (TFAA) were added. Once the reaction was completed, the

reaction mass was cooled and added ammonium bicarbonate and purified water. Organic layer is

separated and washed with 6% HCl solution followed by 5% sodium bicarbonate solution and

aqueous layer is washed with dichloromethane. Finally organic layer is washed by purified water.

The organic layer was then concentrated to obtained syrup which was stripped out with isopropyl

alcohol and n-heptane. The precipitated solid was cooled, filtered and dried.

(2S)-1-[(3-hydroxy-1-adamantyl) amino] acetyl-2-cyanopyrrolidine (VLD-III):

3-aminoadamantan-1-ol (VLD-I) was reacted with (2S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile

(VLD-II) in presence of potassium iodide as a catalyst and potassium carbonate as a base in acetone.

After completion of the reaction, the reaction mass was distilled and adjusted the pH with acetic

acid then it washed with methylene dichloride. Then basified the aqueous layer with liq. NH3, the

product is extracted into methylene dichloride. In the extract, water was added and adjusted the pH

with tartaric acid then the aqueous layer was washed with methylene dichloride. Then basified the

aqueous layer with liq.NH3, the product is extracted into methylene dichloride. The extract was

concentrated and the resulting oily product or semi-solid was dissolved in methyl ethyl ketone. The

reaction mass is heated, stirred, cooled, filtered and dried.

Route of synthesis:

1. 3-aminoadamantan-1-ol (HAA) VLD-I:

NH2

ClH

NH2

OHAdamantan-1-amine

hydrochloride3-Aminoadamantan-1-ol

NaOHToluene/ n-Butanoln - heptane / Methanol

H2SO4/HNO3Water

Mol. Wt = 187. 71Mol. F. = C10H18ClN Mol. F. = C10H17NO

Mol. Wt = 167 . 24

2. (2S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile (CCP) (VLD-II):

NCN

O

Cl

NH NH2

O

(2S)-1-(chloroacetyl)pyrrolidine-2-carbonitrile

(2S)-Pyrrolidine-2-carboxamide

Chloroacetyl chloride, MDC

2, 6-lutidine/ TFAAaq. HCl / NH4CO3 / NaHCO3

IPA/ n - Heptane

Mol. F. = C7H9ClN2OMol. Wt = 172 . 61

Mol F = C5H10N2O

Mol. Wt = 114. 15

3. Vildagliptin (VLD-III):

N

CNO

NHOHNH2OH

N CN

O

Cl

+

3-Aminoadamantan-1-ol (2S)-1-(chloroacetyl)pyrrolidine-2-carbonitrile

(2S)-1-{[(3-hydroxy-1-adamantyl)amino]acetyl}pyrrolidine-2-carbonitrile

Acetone/KI /K2CO3

Aceticacid/Tartaric acid/Liq. NH3MDC/ MEK

Mol. F. = C10H17NO

Mol. Wt = 167 . 24

Mol. F. = C7H9ClN2OMol. Wt = 172 . 61

Mol. F. = C17H25N3O2

Mol. Wt = 303 . 40


1. 3-aminoadamantan-1-ol (HAA) VLD-I:

Reactor

Quenching

Conc. H2SO4 Conc. HNO3 1-adamantyl amine HCl

50% NaOH solution

Separation

Separation

30% brine solution

Distillation

Reaction mass

Centrifugation

Drying

Methanol n-heptane

VLD-I

n-butanol + toluene

Aqueous layer

Aqueous layer

n-heptane

Organic layer

Organic layer

2. (2S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile (CCP) (VLD-II):

Reactor

Cooling and stirring

Dichloromethane L-prolinamide 2,6 lutidine Chloroacetyl chloride

Trifluoro acetic anhydride Ammonium carbonate Purified water

Separation

Separation

Aq. HCl washing

Separation

Filtration

Distillation

Reaction Mass

Dichloromethane washing

Aqueous layer

Aqueous layer

Aq. Sodium bicarbonate washing

Dichloromethane

Centrifugation

Drying

VLD-II

Isopropyl alcohol n-heptane

n-heptane

Organic layer

Organic layer

3. Synthetic scheme of vildagliptin (VLD-III):

Condensation

Distillation

Acetone VLD-I VLD-II Potassium iodide Potassium carbonate

Reaction Mass

Separation

Separation

Filtration

Distillation

Reaction Mass

Purified water Acetic acid Dichloromethane

Organic layer keep aside

Aq. NH3 Dichloromethane

Dichloromethane

Centrifugation

Drying and sifting

VLD-III

Methyl ethyl ketone

Methyl ethyl ketone

Aqueous layer

Distillation

Methyl ethyl ketone

Separation

Purified water Tartaric acid solution

Aqueous layer

Acetone

Organic layer

Organic layer

Organic layer

Material Balance

INPUT

Kg. OUTPUT

Kg. Remarks

Reactants : A ) Product 1-admantyl amine hydrochloride 7.94 A1 Product 5.00 Conc. Sulphuric acid 43.83 B ) Solvent recovered Conc. Nitric acid 11.12 B1 - methanol 14.00 Reuse Potassium hydroxide 65.70 B2- n- hepatane 24.00 Reuse Solvents : B3- Toluene 29.00 Reuse Water 60.00 B4- n-butanol 49.00 Reuse n-butanol 50.00 C )Effluent

Toluene 30.00 Aqueous Effluent 74.00 methanol 15.00 Organic residue 0.59 n-hepatane 25.00 Spent Acid 70.00

Inorganic salt 43.00

Total Input 308.59 308.59 PRODUCT : Vildagliptin (CCP-I)

INPUT

Kg. OUTPUT

Kg. Remarks Reactants : A ) Product L- prolinamide 9.14 A1 Product 7.95 Chloroacetyl chloride 9.96 B ) Solvent recovered Potassium carbonate 11.06 B1 -Chloroform 87.00 Solvents : B2- Ethyl acetate 31.00 Chloroform 90.00 C ) Effluent Ethyl acetate 32.90 Aqueous Effluent 4.90 Inorganic salt 21.50

Organic residue 0.71 Total Input 153.06 153.06 PRODUCT : Vildagliptin (CCP-II)

INPUT

Kg. OUTPUT

Kg. Remarks

Reactants : A ) Product CCP-I 7.95 A1 Product 5.17 Trifloro acetic anhydride 17.61 B ) Solvent recovered Amonnium bicarbonate 24.72 B1 -Tetrahydrofuran 68.00 Solvents : B2- n-hepatane 58.00 Water 39.75 B3- Toluene 120.00 Tetrahydrofuran 70.76 C ) Effluent Toluene 124.50 Aqueous Effluent 49.60 n-hepatane 60.34 Organic residue 0.86

C3 - settle solid 44.00

(Ammonium Trifluro acetate

& Bicarbonate) Total Input 345.63 345.63 PRODUCT : Vildagliptin

INPUT

Kg. OUTPUT

Kg. Remarks

Reactants : A ) Product HAA 5.00 A1 Product 5.00 CCP-2 5.17 B ) Solvent recovered Potassium carbonate 4.13 B1 -Tetrahydrofuran 46.00 Acetic acid 2.23 B2- Dichloromethane 108.00 tartaric acid 1.67 B3- Methylethylketone 28.50 Liq. Ammonia 8.44 C ) Effluent Potassium iodide 0.25 Aqueous Effluent 61.50

Organic residue 0.88 Solvents : settle solid 17.00

Water 50.00 (Ammonium Trifluro acetate

Tttrahydrofuran 48.00

Dichloromethane 112.00

Methylethylketone 30


BRINZOLAMIDE

1. Brief process:

Stage-I: 3-(2-Bromoacetyl)-5-chlorothiophene-2-sulfonamide undergoes asymmetric reduction with (+) DIP Chloride at (-40)°C temperature to give (S)-3-(2-Bromo-1-hydroxyethyl)-5-chlorothiophene-2-sulfonamide which further cyclized using NaOH to provide Stage-I.

Stage-II: Condensation between Stage-I and 1-Bromo-3-methoxy porpane in presence of Potassium carbonate affords Stage-II. Stage-III: Stage-II sequentially reacts with n-BuLi and SO2 gas at (-65)°C temperature under inert atmosphere to give Sulphonyl Lithium intermediate which reacts Hydroxylamine-O-sulphonic acid in aqueous medium to yield Stage-III. Stage-IV: Reaction of Stage-III with Trimethylorthoaceate, p-Tosyl chloride and aqueous Ethylamine build Brinzolamide. Crystallization of Brinzolamide gives required quality and morphology.


Stage-I: (S)-6-Chloro-3,4-dihydro-4-hydroxy-2H-thieno[3,2-e][1,2]thiazine-1,1-dioxide

S

Cl

OBr

SO2NH2

3-(2-Bromoacetyl)-5-chlorothiophene-2-sulfonamide CAS: 160982-11-6,

MF: C6H5BrClNO3S2, MW: 318.60

S

Cl

SNH

O O

OH

(+)-DIP Chloride*CAS: 112246-73-8

S

Cl

OHBr

SO2NH2

(S)-6-Chloro-3,4-dihydro-4-hydroxy-2H -thieno[3,2-e][1,2]thiazine-1,1-dioxideStage-I, CAS: 160982-16-1, MF: C6H6ClNO3S2, MW: 239.70

(S)-3-(2-Bromo-1-hydroxyethyl)-5-chlorothiophene-2-sulfonamide

MF: C6H7BrClNO3S2, MW: 320.61

NaOH

(+)-DIP Chloride* = (+)-Diisopinocampheylchloroborane

O Therapeutic category Anti ocular Hypertensive.

API Intermediates

Brinzolamide

Stage-II: (S)-6-Chloro-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e][1,2]thiazine-1,1-dioxide

S

Cl

SNH

O O

OH

S

Cl

SN

O O

OH

Br OMeOMe

+

Stage-I1-Bromo-3-methoxypropaneMF: C4H9BrO, MW: 153.02

CAS: 36865-41-5

(S)-6-Chloro-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H -thieno[3,2-e][1,2]thiazine-1,1-dioxide

Stage-II, MF: C10H14ClNO4S2, MW: 311.81

K2CO3

Stage-III: (S)-3,4-Dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide-1,1-dioxide

S

Cl

SN

O O

OH

OMe S

H2NO2S

SN

O O

OH

OMe

Stage-II / (S)-HCM (S)-3,4-Dihydro-4-hydroxy-2-(3-methoxypropyl)-2H -thieno[3,2-e][1,2]thiazine-6-sulfonamide-1,1-dioxide

Stage-III, CAS: 154127-42-1MF: C10H16N2O6S3, MW: 356.44

1) n-BuLi

2) SO2 gas3) NH2OSO3H

Stage-IV: Brinzolamide (API)

1.

S

H2NO2S

SN

O O

OH

OMe

BrinzolamideMF: C12H21N3O5S3, MW: 383.51

CAS: 138890-62-7

S SN

O O

HN

OMe

Stage-III

1) CH3C(OMe)3 H2NO2S

2) p-TsCl3) EtNH2

4. List of raw materials :

S.N. Name of raw material

01 3-(2-Bromoacetyl)-5-chlorothiophene-2-sulfonamide [KSM]

02 (+)-DIP chloride 03 Methyl tert-Butyl ether 04 Toluene 05 Sodium hydroxide 06 Hydrochloric acid 07 1-Bromo-3-methoxypropane 08 Dimethyl sulfoxide 09 Potassium carbonate 10 Ethyl acetate 11 Sodium chloride 12 Sodium hypochlorite solution 13 n-Butyl lithium (1.6 M solution in hexane)*# 14 Hydroxyl amine-O-sulfonic acid (HOSA)# 15 Tetrahydrofuran 16 Sulfur dioxide gas* 17 Sodium acetate 18 Sodium bicarbonate 19 Dichloromethane 20 Acetonitrile 21 Trimethylorthoacetate 22 p-Toluene sulfonyl chloride 23 Ethyl amine (70% aqueous solution) 24 Triethylamine 25 Methanol 26 Isopropanol 27 Activated carbon (Norit CN1) 28 Activated carbon (Norit SX plus) 29 Celite 30 Process Water


Flow diagram for (S)-6-Chloro-3,4-dihydro-4-hydroxy-2H-thieno[3,2-e][1,2]thiazine-1,1-dioxide (Stage I)

Gas Liquid Solid

Methyl tert-Butyl ether (1400 ml)

KSM* (100 g)

10 L 4 neck RBF

Cool to (-50) - (-45)°C

(+)-DIP Chloride** (309.8-335.6 g)

Reaction mass

Raise to (-35) - (-30)°C and stir for 60 minutes

Reaction mass

Raise to (-25) - (-20)°C and stir for 150 minutes

Sodium hydroxide(64 g) Process water (1600 ml)

RBF Reaction mass

In process-1: KSM (Impurity-2*): NMT 3.0% Cool to 25-30°C (Refer Specification No. IP-0023)

Addition of Sodium hydroxide solution (1200 ml) below 10°C

Reaction mass

Raise to 25 -30°C and stir for 120 minutes In process-2: pH : 10-12 (Refer Specification No. IP-0023) Addition of Sodium hydroxide solution (X ml) below 10°C (If required) Reaction mass

Continue on next page…..

KSM*= 3-(2-Bromoacetyl)-5-chlorothiophene-2-sulfonamide; (+)-DIP Chloride**= (+)-Diisopinocampheyl chloroborane in heptane / hexane (60-65% w/w)

Continue from previous page…..

Stir the reaction mass for 240 minutes

Reaction mass

In process-3: HCB (Impurity-1*): NMT 2.0% (Refer Specification No. IP-0023)

Reaction mass

Layer separation

Organic layer

Aqueous layer

Methyl tert-Butyl ether (300 ml)

Layer separation

Organic layer

Aqueous layer

Sodium hydroxide solution (200 ml) Combined organic layer

Layer separation

Sodium hydroxide solution (200 ml-Xml) Organic layer Aqueous layer


HCB*- (S)-3-(2-Bromo-1-hydroxyethyl)-5-chlorothiophene-2-sulfonamide


Layer separation

Solvent recovery Organic layer

Aqueous layer

Methyl tert-Butyl ether (600 ml) Hydrochloric acid (LR grade) (50-65 ml)

Combined aqueous layer

Stir the reaction mass for 5-10 minutes In process-4: pH : 1-2

(Refer Specification No. IP-0023)

Layer separation

Methyl tert-Butyl ether (400 ml) Aqueous layer

Organic layer

Layer separation

Methyl tert-Butyl ether (400 ml) Aqueous layer

Organic layer

Layer separation

ETP Aqueous layer Organic layer

Activated carbon (Norit CN1) (10 g) Combined Organic layer



Heat to 45-50°C and stir for 30-45 minutes and filtration

Methyl tert-Butyl ether (100ml) Hyflo bed Filtrate

ETP Hyflo bed

Filtrate

Combined the filtrate

Under vacuum distillation below 55°C till ~70-100 ml volume

Reaction mass ( slight thick slurry)

Solvent recovery

Cool the reaction mass to 25-30°C

Brinzolamide Stage-I*(0.1 g) for seeding (if required)

Reaction mass ( slight thick slurry)

Stir for 30-45 minute at 25-30°C

Reaction mass (solid suspension slurry)

Under vacuum distillation below 55°C.

Toluene (100 ml) Residual mass (Solid) Solvent recovery

Under vacuum distillation below 55°C



Toluene (100 ml) Residual mass (Solid) Solvent recovery


Toluene (200 ml) Residual mass (Solid)

Heat to 50-55°C for 60-75 minutes

Reaction mass (Suspension)

Cool to 25-30°C and stir for 60-90 minutes


Filtration

Toluene (100ml x 2) Wet cake Mother liquor

Wet cake Washing Mother liquor Solvent recovery

Drying at 55-60°C in hot air oven In process-5: LOD: NMT 1.0%

(Refer Specification No. IP-0023)

(S)-6-Chloro-3,4-dihydro-4-hydroxy-2H-thieno[3,2-e][1,2]thiazine-1,1-dioxide (Stage-I)

Output: 56-69 g

Flow diagram for (S)-6-Chloro-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e] [1,2]thiazine-1,1-dioxide (Stage II)

Gas Liquid Solid

Dimethyl sulfoxide (400 ml) Stage-I* (100 g) Potassium carbonate (173 g)

1 L 4 neck RBF

1-Bromo-3-methoxypropane (77g) Heat to 30 - 35°C


Stir at 30-35°C for 5 hours In process-1: Stage-I: NMT 1.0% (Refer Specification No. IP-0024)

Cool to 25-30°C Reaction mass

Reaction mass

5 L 4 neck RBF

Ethyl aceatate (600 ml) Process water (3000 ml)

Cool to 15-20°C

below 30°C Mixture of solvent

Stir for 15-20 minute and layer separation

Organic layer

Aqueous layer

Ethyl acetate (400 ml)

Organic layer

Aqueous layer



Stage-I*=(S)-6-Chloro-3,4-dihydro-4-hydroxy-2H-thieno[3,2-e][1,2] thiazine-1,1-dioxide


Layer separation

Organic layer

Aqueous layer

ETP

Combined Oragnic layer

Cool to 20-25°C

Reaction mass

Soution of Sodium hydroxide (40 g) in Process water (1000 ml)

Layer separation

Solution of Sodium hypochlorite(20 ml) in process water(180ml)

Organic layer

Aqueous layer ETP

Layer separation

Solution of Sodium chloride(90 g) in process water (300ml)

Organic layer

Aqueous layer ETP

Layer separation

Organic layer

Aqueous layer ETP


Solvent recovery

Oily mass

In process-2: Ethyl acetate content by GC NMT 1.0%

Degas the oily mass under vacuum below 10 mm of Hg at 50-55°C In process-3: BMP and DMSO content by HPLC BMP NMT 1.5% and DMSO NMT 0.5 % (Refer Specification No. IP-0024)

(S)-6-Chloro-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e][1,2]thiazine-1,1-

dioxide (Stage-II) Output: 115-132 g

Flow diagram for (S)-3,4-Dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide-1,1-dioxide (Stage III)

Gas Liquid Solid

Hydroxyl amine-O-Sulfonic acid (HOSA) In-process-1: Assay of HOSA should be NLT 75% (Refer Specification No. IP-0025)

Tetrahydrofuran (2200 ml)

5 L 3 neck RBF Nitrogen atmosphere

Stir for 5 miutes In process-2: Water content of Tetrahydrofuran: NMT 0.1% (Refer Specification No. IP-0025)

Stage-II* (100 g) Tetrahydrofuran (500 ml)

Tetrahydrofuran

Cool to (-75) – (-70)°C

n-Butyl lithium (1.6 M in hexane) (501 ml) Reaction mass

(Clear solution)

Stir for 90 minutes at (-70) – (-58)°C In process-3: Stage-II: NMT 20 % (Refer Specification No. IP-0025)

Reaction mass (Clear solution)

Sulphur dioxide gas below (-50°C) In process-4: pH: 2.8 – 4.0 (Refer Specification No. IP-0025)

Stir for 30 minutes at (-65) – (-50)°C


Raise to 25-30°C in 30-60 minutes



Stage-II*=(S)-6-Chloro-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e][1,2]thiazine-1,1-dioxide


Stir for 45 minutes In process-5: HLiM: Limit- NMT 8.0% (Refer Specification No. IP-0025)

Reaction mass

Under vacuum distillation below 35°C till solid precipitation

starts

Process water (500 ml) Reaction mass

Under vacuum distillation below 35°C till water droplet

comes

Reaction mass (Almost clear solution)

Cool to 25-30°C

Dichloromethane (500 ml) Reaction mass

Stir for 5-10 minute and layer separation

MDC (250 ml) Aqueous layer Organic layer

Aqueous layer Organic layer

Solvent recovery



Process water (700 ml)

Sodium acetate (158 g)

5 L 3 neck RBF

Cool to 0-5°C

Hydroxyl amine-O-Sulfonic acid (145 g)

Reaction mass

Below 20°C Reaction mass (Suspension)

Stir for 30 minute below 20°C

Reaction mass

Raise to 25-30°C stir for 8 hours

In process-6: HSO2LiM: Limit- NMT 3.0% (Refer Specification No. IP-0025)

Ethyl acetate (400 ml) Reaction mass

Layer separation

Organic layer Aqueous layer




Layer separation

Organic layer Aqueous layer Ethyl acetate (400 ml)

Layer separation

Organic layer Aqueous layer ETP

Sodium bicarbonate solution (64 g in 800 ml water) Combine Organic layer

Layer separation

Sodium bicarbonate solution (64 g in 800 ml water) Organic layer Aqueous layer

ETP

Layer separation

Sodium chloride solution (90 g in 300 ml water) Organic layer Aqueous layer

ETP

Layer separation

Activated carbon (Norit CN1) (5.0 g) Organic layer Aqueous layer

ETP

Heat to 50-55°C and stir for 45 minutes and filtration

Ethyl acetate (100ml) Hyflo bed Filtrate



ETP Hyflo bed Filtrate

Combined the filtrate


Dichloromethane (100 ml) Residual mass Solvent recovery


Dichloromethane (600 ml) Residual mass

Cool to 25-30°C

Brinzolamide Stage-III* (0.1 g) for seeding Reaction mass

Stir for 30-45 minute at 25-30°C

Reaction mass

Heat to 40-45°C for 60 minutes

Reaction mass

Cool to 10-15°C


Brinzolamide Stage-III *= (S)-3,4-Dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide-1,1-dioxide


Reaction mass

Fltration

MDC (100 ml x 2) Wet cake Mother liquor

Wet cake Washing Mother

liquor

Solvent recovery

Drying at 50-55°C in hot air oven In process-7:LOD: Limit -NMT 1.0% (Refer Specification No. IP-0025)

(S)-3,4-Dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide-1,1-dioxide (Stage-III)

Output: 60-80 g

Flow diagram for (R)-3,4-Dihydro-4-(ethylamino)-2-(3-methoxypropyl)-2H-thieno[3,2-e][1,2]thiazine-6-

sulfonamide-1,1-dioxide (Brinzolamide) (Stage IV) Gas Liquid Solid

Acetonitrile (1000 ml) 5 L 4 neck RBF

Nitrogen atmosphere

In process-1: Moisture content NMT 0.1% (Refer Specification No. IP-0026)

Stage-III* (100 g) Trimethylorthoacetate (87.70 g)

Acetonitrile

Heat to 78-83°C and reflux for 8 hours In process-2: Stage-III: NMT 1.5 %) (Refer Specification No. IP-0026)

If reaction does not comply after 16-17 hours then charge Trimethylorthoacetate. A = Input stage-III x 0.017 x % unreacted stage-III


Cool to 40-45°C Under vacuum distialltion below 45°C

Tetrahydrofuran (THF) (600 ml) Residual mass

In process-3: Moisture content NMT 0.2% Cool to 25-30°C (Refer Specification No. IP-0026 )

Residual mass

Cool to (-10) to (-5)°C

Triethylamine (62.5 g) p-Toluene Sulfonyl chloride (107 g) Reaction mass

Stir for 2 hours at (-10) to (-5)°C In process-4: HPSM: NMT 1.0 % (Refer Specification No. IP-0026) Ethylamine (70 % w/w solution) addition (1446 g) Reaction mass

Raise to 25-30°C and stir for 10 hours

Continue on next page….. Stage-III* = (S)-3,4-Dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide-1,1-dioxide

Continue from previous page….. In process-5: TPSM: NMT 1.0 % (Refer Specification No. IP-0026)

Reaction mass

Cool to 0-5°C

Hydrochloric acid (LR grade) (1650 – 2000 ml) below 50°C Reaction mass

In process-6: pH: Between 0.4 – 0.6 (Refer Specification No. IP-0026)

Reaction mass

Cool to 25-30°C

Dichloromethane (700 ml)

Reaction mass

Layer separation

Dichloromethane (700 ml)


Layer separation




Mixture of Hydrochloric acid (LR grade) (50ml) in Process water (150 ml)

Combined organic layer

Layer separation

Aqueous layer Organic layer Solvent recocery

Sodium bicarbonate (150-165 g)

Combined Aqueous layer

Stir for 1 hour at 25-30°C In process-7: pH: between 6.5 – 8.0 (Refer Specification No. IP-0026)

Ethyl acetate (1200 ml) Reaction mass

Layer separation

Ethyl acetate (400 ml) Aqueous layer Organic layer

Layer separation

Ethyl acetate (400 ml) Aqueous layer Organic layer

Layer separation

ETP Aqueous layer Organic layer



Solution of Sodium chloride (40 g) in Process water (200 ml)

Combined Organic layer

Layer separation

Activated carbon (Norit SX plus) (10 g) Organic layer Aqueous layer

ETP

Heat at 50-55°C and stir for 30-45 minutes

Reaction mass

Hot Filtration


Hyflo bed Filtrate

ETP

Hyflo bed Filtrate

Combined filtrate

Under vacuum distillation below 55°C Methanol (100 ml)

Residual mass

Solvent recovery




Methanol (200 ml)

Residual solid

Heat to 62-70°C Process water addition (400 ml) Reaction mass (Clear

solution)

Stir for 15 minutes at 62-80°C

Reaction mass


Reaction mass

Fltration Mixture of Methanol (67 ml) & Process water (133 ml) (100 ml x 2)

Wet cake

Mother liquor

Wet cake

Washing Mother

liquor

Solvent recovery

Suck dry Wet cake

3 neck RBF

Methanol (120 ml)

Heat to 62-70°C Process water (240 ml)





Reaction mass


Reaction mass

Filtration Mixture of Methanol (40 ml) & Process water (80 ml)

(60 ml x 2)

Wet cake

Mother liquor

Wet cake Washing Mother liquor Solvent recovery

Drying at 50-55°C in hot air oven In process-8: LOD: NMT 1.0 %

Dry solid material (50-65 g)

In process-9: Impurity at RRT 0.51 & RRT 1.08 Limit: NMT 0.08%

Complies If not complies (Part-B) Methanol (200 ml)

Dry solid material (100 g)

Heat to 62-70°C

Process water (400 ml)





Reaction mass


Reaction mass

Fltration

Mixture of Methanol (67 ml) & Process water (133 ml) (100 ml x 2)

Wet cake

Mother liquor

Wet cake Washing Mother liquor

Solvent recovery

Drying at 50-55°C in hot air oven In process-8: LOD: Limit: NMT 1.0%

Dry solid material Output : 85-95 g

In process-9: Impurity at RRT 0.51 & RRT 1.08 Limit: NMT 0.08%

Complies If not complies (Part-C) Dry solid material (100

g)

Isopropanol (800 ml)

Heat to 78-82°C

Activated carbon (Norit SX plus) (10 g) Reaction mass



Stir for 30-45 minutes at 78-82°C

Reaction mass

Hot filtration

Isopropanol (100 ml)

Hyflo bed

Filtrate

ETP

Hyflo bed

Filtrate

Combined filtrate


Reaction mass

Fltration

Isopropanol (100 ml x 2)

Wet cake Mother liquor

Fltration

Wet cake Washing Mother liquor

Solvent recovery



Drying at 50-55°C in air oven In process-10: LOD: Limit: NMT 0.5% (R)-3,4-Dihydro-4-(ethylamino)-2-(3-methoxypropyl)-2H-

thieno[3,2-e][1,2]thiazine-6-sulfonamide-1,1-dioxide Brinzolamide (Stage-IV) Output (Part C) : 80-95 g

Oveall yield from stage-III :45 – 60 g

Material balance:


Reactants : A ) Product Stage-III 22.00 A1 Product 11.00

Trimethylorthoacetate 18.21 B ) Solvent recovered

Triethylamine 9.98 B1 - Acetonitrile 169.00 p-Toluene sulfonyl chloride 23.54 B2 - THF

114.00

Ethylamine (70% w/w solution 25.70

B3 - MDC 39.00

Conc. HCl 53.20 B4 - Ethyl acetate 40.00

B5 - Isopropanol 188.00 Solvents : C ) Effluent

Acetonitrile 173.80 Aqueous Effluent 303.00

THF 117.48 Organic residue 1.85 MDC 40.56 Spent solid 7.00

Ethyl acetate 41.80 (Carbon, Hyflo)

Isopropanol 191.18

Purified water 150.00

Activated carbon 4.40

Hyflo 1.00 Total Input 872.85 872.85

P Therapeutic category Cough Supressant

API Intermediates

Droproprizine N-phenyl piperazine (NPP)


NH

OH

OH

+ S

O

Cl

Cl2MCB

RefluxeNH

Cl

Cl

thionyl dichloride N,N-bis(2-chloroethyl)amine2-[(2-hydroxyethyl)amino]ethanol

Formula Weight = 105.136 Formula Weight = 118.971 Formula Weight = 142.026

+ S

O

O

+ ClH

NH

Cl

Cl

N,N-bis(2-chloroethyl)amine


+

NH2

aniline


Refluxe

NH

N

1-phenylpiperazine


Product Name: N-phenyl Piperazine (NPP) Capacity : Application/Use of Product : Pharma Intermediate

B. Process: -

MCB and Diethanol amine charge to the reactor. Thionyl chloride was added at required

temperature. Reaction was maintained for required time and temperature. After the

reaction completion aniline was charged and refluxed for required time. After the reaction

completed water and caustic was added to decompose the Thionyl chloride. The layer was

separated at required temperature and the aqueous layer was sent to ETP. The organic

was layer was distilled off to recover MCB and Aniline.

C. Flow Chart:-

Reactor

Aniline

Distillation Recover MCB + Aniline

Thionyl chloride

MCB DEA

Fractional distillation

Product

Separation

Organic layer

A. Material Balance

Sr. no Input Raw Material Name Quantity

Kg Out put Quantity

Kg Remarks

1 Monochloro Benzene(MCB) 4.70 Recover MCB +Aniline 4.60

MCB +Aniline Vapour loss during distillation 0.50 Scrubber

2 NPA 1.00

3 Thionyl Chloride 2.40 SO2 + HCl gas 1.0 Scrubber

4 Caustic Soda Flakes 3.00 Aqueous Effluent 9.00

5 Aniline 3.20

6 Water 4.00

Product:- N- phenyl Piperazine

1.00 Desire product.




Total Quantity output 18.30

Q Therapeutic category Antifungal

API Intermediates

Fluconazole 1-(2,4-Difluorophenyl)-2-(1H 1,2,4-triazol-1-yl)-1-ethanone (DFTA-III)

1-(2, 4-DIFLUOROPHENYL)-2-(1H-1, 2, 4-TRIAZOL-1-YL) ETHANONE (DFT-III)

1. Brief Process :

Step-1: Preparation of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone.

Step- I is dissolved in water and conc.hydrochloric acid at 25-30°C temp. Cool the content 15-

20°C and treated with aqueous solution of sodium nitrite solution at 15-20° C in 2 hrs.

Maintained the reaction mixture at 20-25°C till completion of reaction. Liq. ammonia is then

added until the pH is in the range 8-9. Cool the reaction mixture to 0-5°C and maintain for 60-90

min. The resulting solid was filtered, washed with water and dried under vacuum at 50°C to

offered step-2.

Step-3: Preparation of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl) ethanone (DFT-III)

Slep-2 is dissolved in ethyl acetate at 65-70°C and maintained for 30 min. Slowly cool the

reaction mass to 25-30°C. Chill the reaction mixture to -5±3°C and maintained for 60 min. The

resulting solid was filtered. Washed with prechilled ethyl acetate and dried under vacuum at

50°C to offered step-3.


NaNO2/HCl/NH4OH F

F

N NN

O

WaterF

F

N+ N

N

ONH2 Cl-

Ethylacetate

F

F

N NN

O

4-amino-1-[2-(2,4-difluorophenyl)-2-oxoethyl]-4H-1,2,4-triazol-1-ium salt

1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanoneStep-2Step-1

1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone Step-3


Step-I: Preparation of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (DFT-II) Crude

Step-II: Preparation of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (DFT-III) pure

4- amino-1-[2 difluorophenyl)- 2-oxoethyl)-4H-1,2,4-triazol-1-ium salt

(DFT-I)

1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (DFT-II)

HCl

NH4OH

NaNO2

1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (DFT-II)

1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (DFT-III)

Ethyl acetate

Water

Material Balance:

PRODUCT : DFTA -I

INPUT

Kg. OUTPUT

Kg.

Reactants : A ) Product 1,3- Difluorobenzene 250.00 A1 DFT - I 500.00 Aluminium Chloride 322.00 B ) Recovered Solvent Chloroacetyl chloride 250.00 B1 -MDC 1770.00 4-Amino 1,2,4- Trizole 233.00 B2 - IPA 1520.00 Solvents : C )Effluent MDC 1815.00 Aqueous Effluent 1570.00 IPA 1567.00 Organic residue 14.00 Water 1125.00 Settle Solid 188.00

(Al(OH)3,

Total Input 5562.00 5562.00 PRODUCT : DFTA - II

INPUT

Kg. OUTPUT

Kg.

Reactants : A ) Product Step - I 500.00 A1 DFT - II 330.00 Activated carbon 5.00 B ) Recovered Solvent Hyflo 4.00 B1 -Ethyl Acetate 420.00 Sodium Nitrite 145.00 C )Effluent Liq. Ammonia 225.00 Aqueous Effluent 1795.00 Solvents : Organic residue 6.00 Water 1250.00 Spent Carbon&hyflo 10.00 Ethyl Acetate 432.00

Total Input 2561.00 2561.00

PRODUCT : DFTA - III

INPUT

Kg. OUTPUT

Kg. Reactants : A ) Product Step - III 298.00 A1 -DFT - III 285.00 Solvents : B ) Recovered Solvent Ethyl Acetate 432.00 B1- Ethyl Acetate 420.00 Organic residue 13.00 Total Input 730.00 730.00

S Therapeutic category Antihyperparathyroidism

Cinacalcet HCl

R)-(+)-1-(1-Naphthyl) ethylamine HCl -RNA(IV)

3-[3-(Trifluoromethyl) phenyl] propanol-TPP-II

1-(3-Bromopropyl)-3-( trifluoromethyl) benzene-TPP-III

CINACALCET HYDROCHLORIDE

1. Brief process:

Process for the preparation of Cinacalcet hydrochloride involves in three stages.

Third step involves the hydrolysis of (1R)-1-(1-naphthyl) ethanamine mandelate salt to give

(1R)-1-(1-naphthyl) ethanamine free base. Which is treated with benzaldehyde to provide a

Schiff'’s base, which is then dissolved in N-methyl-2-pyrrolidinone and reacted with 3-

bromopropyl)-3-(trifluoromethyl) benzene in the same pot. After the completion of reaction,

water was added to the reaction mass, basified with aqueous ammonia, and extracted with

toluene. The toluene layer was washed with 10% sodium metabisulphite solution followed by

conc hydrochloric acid solution and then distilled off to get the thick residue. The residue was

diluted with diisopropylether, stirred and filtered off the cinacalcet hydrochloride, which is

then slurried with ethyl acetate to get the crude cinacalcet hydrochloride.

Cinacalcet hydrochloride was then purified by dissolving the crude in the mixture of

acetonitrile and water at 65-70°C and decolorized with activated carbon. The filtrate was

cooled to 15-20°C precipitate obtained was filtered, and dried under vacuum to give pure

Cinacalcet hydrochloride as white crystalline solid.

3. Synthetic route: Synthesis of Cinacalcet Hydrochloride involves in three steps process mentioned below.

(1R)-1-(1-naphthyl) ethanamine Mol. F.: C12H13NMol.Wt.: 171.24

. Mandelate

DichloromethaneWater

Aqueous ammonia

Benzaldehyde

(1R)-1-(1-naphthyl) ethanamine mandelateMol. F.: C20H21NO3Mol.Wt.: 323.15

(1R)-1-(1-naphthyl)-N-[(1E)-phenylmethy-lene]ethanamineMol. F.: C19H17NMol.Wt.: 259.34(Schiff's Base)

N-methyl-2-pyrolidinone

(TPP-III)

N+

CH3

F3C

Br-

Aqueous AmmoniaTolueneCon. Hydrochloric acidSodium metabisulphite

Diisopropyl etherEthyl acetateAcetonitrileWater

HN

CH3

F3C

.HCl

N-[(1R)-1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl] propan-1-amine. HydrochlorideMol. F.: C22H22F3N. HClMol.Wt.: 393.91(Cinacalcet Hydrochloride)

H3C NH2 H3C NH2

RNA-II

4. Process flow chart: Preparation of Cinacalcet hydrochloride

10% Sodium metabisulphite Solution

MDC

EXTRACTION

Methylene Dichloride + water

(1R)-1-(1-naphthyl) Ethanamine mandelate

Aqueous Ammonia

DISTILLATION

Aqueous Layer

MAINTENANCE

N-methylpyrrolidinone

1-(3-bromopropyl)- 3-(trifluoromethyl) benzene

EXTRACTION

Purified water + Aqueous ammonia

Conc. Hydrochloric acid + Purified water

Aqueous layer

Toluene

DISTILLATION

Diisopropyl ether

Toluene

MAINTENANCE Benzaldehyde

MAINTENANCE

FILTRATION

Diisopropyl ether MLs

WET CINACALCET HCL

Ethyl acetate

FILTRATION Ethyl acetate MLs

CRUDE CINACALCET HCL

Acetonitrile + Purified water

Activated charcoal

Charcoal

FILTRATION

Acetonitrile + Water MLs

DRYING

CINACALCET HYDROCHLORIDE

MAINTENANCE

FILTRATION

PRODUCT : Cinicalcet Step -I

INPUT

Kg. OUTPUT

Kg. Reactants : A ) Product RNA-III 15.00 A1 Product 13.32 TPA 11.10 B ) Solvent recovered Liq.ammonia 6.30 B1 - Toluene 75.00 Boric Acid 0.20 B2- n-Heptane 65.00 HCl 8.20 C )Effluent Solvents : Aqueous Effluent 85.00 Water 52.50 Organic residue 0.38 Toluene 77.40

n-Heptane 68.00 Total Input 238.70 238.70 PRODUCT : Cinicalcet Step –II

INPUT

Kg. OUTPUT

Kg.

Reactants : A ) Product THF 172.50 A1 Product 15.00 Step-I 13.00 B ) Solvent recovered Sodium borohydrate 10.30 B1 - THF 162.00 Boron trifloride etharate 44.40 B2- n-Heptane 169.00 HCl 41.40 B3 - Toluene 159.00 Liq.ammonia 41.40 C )Effluent

Aqueous Effluent 440.00 Solvents : Organic residue 1.00 Water 280.00 C3 - Spent solid 1.60 Toluene 165.00 (Carbon ,Hyflo,) n-Heptane 178.00

Salt for washing Carbon 0.60

Hyflo 1.00 Total Input 947.60 947.60

PRODUCT : Cinicalcet Step -III

INPUT

Kg. OUTPUT

Kg. Reactants : A ) Product Acetonitrile 28.88 A1 Product 11.38 Step-II 13.50 B ) Solvent recovered Acetonitrile 27.00 Solvents : C )Effluent Water 115.20 Aqueous Effluent 119.00 Salt for washing Organic residue 0.20 Carbon 0.50 Spent solid 1.00 Hyflo 0.50 (Carbon ,Hyflo,) Total Input 158.58 158.58

T Therapeutic category Anthelmentic

API Intermediates

Morantel Citrate

3 Methyl Thiophene -2- Aldehyde ( 3MT2A)

Morantel Tartrate

Oxantel Pamoate

Pyrantel Pamoate / Embonate

Disodium pamoate (DSP)

Pamoic acid (PA)

Thiophene -2- Aldehyde (T2A)

1,2-Dimethyl-1,4,5,6-tetrahydropyrimidine (THP)

Pyrantel Tartrate /Zeolex

Piperazine Di HCl

MORANTEL CITRATE

1. Brief Process:

1,2-Dimethyl-1,4,5,6-tetrahydropyrimidine is reacted with 3-Methylthiophene-2-

carbaldehyde (3-MT2A) in presence of methyl formate to form Morantel base. Morantel base is

treated with citric acid to obtain Morantel Citrate which is purified in Methanol and purified

water.


S CHO

CH3

+N

N

CH3

CH3

1,2-dimethyl-1,4,5,6-tetrahydropyrimidine

methylformate

Water/Methanol

Morantel Citrate

OH

CH2COOH

COOHCH2COOH OH

CH2COOH

COOHCH2COOH

3-methylthiophene-2-carbaldehyde

(Morantel Base)

N

NS

CH3

CH3

N

NS

CH3

CH3

1-methyl-2-[(E)-2-(3-methylthiophen-2-yl)ethenyl]-1,4,5,6-tetrahydropyrimidine


Methyl Formate

Reaction

Temp. Maintaining

Morantel base

Drying

Milling

1,2-Dimethyl-1,4,5,6-tetrahydropyrimidine

Packing

3-Methylthiophene-

2-carbaldehyde

Methanol

Purified water

Citric acid

Dissolution

Filtration

Reaction

Temp. Maintaining

Centrifugation

Cooling

Chilling Purified water Methanol

PRODUCT: Morantel Citrate

INPUT

Kg

OUTPUT Kgs.

Reactants Tetrahydro Pyrimidine 285 A) Wet Product 3 Methyl Thiophene 2 Aldehyde 200 A1 Dry Product 510.00 Methyl Formate 128 B) Solvent Recover

Citric Acid 351 B1- Methanol 375.00 Solvents C )Effluent Water 1240 Aqueous Effluent 1700.00 Methanol 389 Organic residue 8 Total Input 2593 2593

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