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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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Prefeasibility Report Megafine Pharma(P)Ltd.
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
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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
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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.
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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
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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
--
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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
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IV. Site Layout Plan: 1. Key plan
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2. Site Layout Plan of plot 911-912
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3. Site Layout Plan of plot 922
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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
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(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)
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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)
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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,
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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
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Prefeasibility Report Megafine Pharma(P)Ltd.
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
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Prefeasibility Report Megafine Pharma(P)Ltd.
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:
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Prefeasibility Report Megafine Pharma(P)Ltd.
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
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Prefeasibility Report Megafine Pharma(P)Ltd.
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.
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Prefeasibility Report Megafine Pharma(P)Ltd.
• 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
Expansion project-Synthetic Organic Chemicals Page | 20
Prefeasibility Report Megafine Pharma(P)Ltd.
Sr. No.
Name of Raw Material Storage Cap. In MT
State of raw material
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
Expansion project-Synthetic Organic Chemicals Page | 21
Prefeasibility Report Megafine Pharma(P)Ltd.
Sr. No.
Name of Raw Material Storage Cap. In MT
State of raw material
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)
2 Solid By Road RM Store Indigenous
71 Dibenzo[b,f][1,4]thiazepin-11(10H)-One
3 Solid By Road RM Store Indigenous
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)
2 Solid By Road RM Store Indigenous
79 1-[(2-(Amino)-1-(4-Methoxy Phenyl ) Ethyl)] Cyclohexanol acetate
3 Solid By Road RM Store Indigenous
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)
3 Solid By Road RM Store Indigenous
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
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Prefeasibility Report Megafine Pharma(P)Ltd.
Sr. No.
Name of Raw Material Storage Cap. In MT
State of raw material
Mode of Transport
Place of storage
Source
91 3-Acetyl-4,5-dihydro-2(3H)- furanone(Butyrolactone)
2 Liquid By Road RM Store Indigenous
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)
5 Liquid By Road RM Store Indigenous
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
5 Solid By Road RM Store Indigenous
110 6-chloro – 2- oxindole 5 Solid By Road RM Store Indigenous 111 1-[2- (Amino)-1-(4-Methoxy
Phenyl) ethyl] Cyclohexanol Acetate
5 Solid By Road RM Store Indigenous
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
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Prefeasibility Report Megafine Pharma(P)Ltd.
Sr. No.
Name of Raw Material Storage Cap. In MT
State of raw material
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
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Prefeasibility Report Megafine Pharma(P)Ltd.
Sr. No.
Name of Raw Material Storage Cap. In MT
State of raw material
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
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Prefeasibility Report Megafine Pharma(P)Ltd.
Sr. No.
Name of Raw Material Storage Cap. In MT
State of raw material
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
5 Solid By Road RM Store Indigenous
211 1-(2,4-Difluorophenacyl)-4-amino-4-H1,1,2,4-triazoliumchloride (DFTA-1)
5 Solid By Road RM Store Indigenous
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
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Prefeasibility Report Megafine Pharma(P)Ltd.
Sr. No.
Name of Raw Material Storage Cap. In MT
State of raw material
Mode of Transport
Place of storage
Source
225 1-benzylpiperidine-4-carbaldehyde
0.1 Liquid By Road RM Store Indigenous
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)
0.5 Solid By Road RM Store Indigenous
230 1-Methyl-4-nitro-3-n-propyl pyrazol-5-carboxamide (MPC-VI)
3 Solid By Road RM Store Indigenous
231 DMB(4,6 dichloro-5- (2-methoxy phenoxy)-2,2 bipyridine )
1 Solid By Road RM Store Indigenous
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
By Road RM Store Indigenous
235 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetonitrile.HBR(DAR-III)
1 Solid
By Road RM Store Indigenous
236 S-3-N-Methylamino-1-1thienyl-1-Propanol
1 Liquid By Road RM Store Indigenous
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)
0.5 Liquid By Road RM Store Indigenous
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)
0.5 Solid By Road RM Store Indigenous
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)
5 Solid By Road RM Store Indigenous
247 1,8-Diazabicyclo(5,4,0)undec-7-ene (DBU)
0.5 Liquid By Road RM Store Indigenous
248 2-bromo-1-cyclopropyl-2-(2-fluoro-phenyl-ethanone (BCE)
0.5 Solid By Road RM Store Indigenous
249 4-(4-Amino phenyl) morpholin-3-one (AMO)
0.5 Solid By Road RM Store Indigenous
250 S-(+)-N-(2,3-Epoxypropyl) phthalimide (OXI)
0.5 Solid By Road RM Store Indigenous
Expansion project-Synthetic Organic Chemicals Page | 27
Prefeasibility Report Megafine Pharma(P)Ltd.
Sr. No.
Name of Raw Material Storage Cap. In MT
State of raw material
Mode of Transport
Place of storage
Source
251 5-Chlorothiophene-2-carboxylic acid (CTA)
0.5 Solid By Road RM Store Indigenous
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)
1 Solid By Road RM Store Indigenous
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)
0.1 Liquid By Road RM Store Indigenous
266 (Benzotriazol-1-yloxy)tris(dimethylamino) phosphoniumhexafluorophosphate
0.1 Solid By Road RM Store Indigenous
267 4-aminobenzamidine dihydrochloride
0.1 Solid By Road RM Store Indigenous
268 1-Ethyl-3-(3-dimethylaminopropyl)carbodimide
0.5 Solid By Road RM Store Indigenous
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)
0.1 Solid By Road RM Store Indigenous
Expansion project-Synthetic Organic Chemicals Page | 28
Prefeasibility Report Megafine Pharma(P)Ltd.
Sr. No.
Name of Raw Material Storage Cap. In MT
State of raw material
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)
0.1 Liquid By Road RM Store Indigenous
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]
1 Solid By Road RM Store Indigenous
283 Cis-5-Norbornene-exo-2,3- Dicarboxylic anhydride (VDA)
1 Solid By Road RM Store Indigenous
284 Cis-1,2-cyclohexanedicarboxylic anhydride
0.5 Solid By Road RM Store Indigenous
285 (1R,2R)-1,2-cyclohexanedimethanol
0.5 Solid By Road RM Store Indigenous
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
Expansion project-Synthetic Organic Chemicals Page | 29
Prefeasibility Report Megafine Pharma(P)Ltd.
Sr. No.
Name of Raw Material Storage Cap. In MT
State of raw material
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)
0.1 Solid By Road RM Store Indigenous
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
0.1 Solid By Road RM Store Indigenous
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
0.1 Solid By Road RM Store Indigenous
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
0.1 Solid By Road RM Store Indigenous
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
Expansion project-Synthetic Organic Chemicals Page | 30
Prefeasibility Report Megafine Pharma(P)Ltd.
Sr. No.
Name of Raw Material Storage Cap. In MT
State of raw material
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]
0.1 Solid By Road RM Store Indigenous
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
Expansion project-Synthetic Organic Chemicals Page | 31
Prefeasibility Report Megafine Pharma(P)Ltd.
Sr. No.
Name of Raw Material Storage Cap. In MT
State of raw material
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]
0.5 Solid By Road RM Store Indigenous
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)
0.5 Solid By Road RM Store Indigenous
395 3-[(3-amino-4-methylamino-benzoyl)-pyridin-2-yl-amino]propionic acid ethyl ester (DEM-II)
0.5 Solid By Road RM Store Indigenous
396 2-[(4-cyanophenyl)amino]acetic acid
0.5 Solid By Road RM Store Indigenous
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
0.5 Solid By Road RM Store Indigenous
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
By Road RM Store Indigenous
Expansion project-Synthetic Organic Chemicals Page | 32
Prefeasibility Report Megafine Pharma(P)Ltd.
Sr. No.
Name of Raw Material Storage Cap. In MT
State of raw material
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)
0.5 Solid By Road RM Store Indigenous
404 5-Chloro-N-(4-Nitrophenyl) pentanamide (APB-I/NMD-I)
0.5 Solid By Road RM Store Indigenous
405 3,3-dichloro-1-(4-nitrophenyl)piperdin-2-one (APB-III)
0.5 Solid By Road RM Store Indigenous
406 Ethyl(2Z)-chloro[(4-methoxyphenyl)hydrazono]acetate
0.5 Solid By Road RM Store Indigenous
407 1-(4-nitrophenyl)-3-morpholine-4yl-5,6-dihydropyridin-2(1H)-one
0.5 Solid By Road RM Store Indigenous
408 Methyl-3,3-diphenyloxirane-2-carboxylate
0.5 Liquid By Road RM Store Indigenous
409 Methyl-2-hydroxy 3-Methoxy 3,3-diphenylpropanoate
0.5 Liquid By Road RM Store Indigenous
410 2-hydroxy-3-methoxy-3,3-diphenyl propanoic acid
0.5 Solid By Road RM Store Indigenous
411 (2S)-2-Hydroxy-3-methoxy-3,3-diphenylpropanoic acid
0.5 Liquid By Road RM Store Indigenous
412 3-[3-(trifluoromethyl) phenyl]propan-1-ol
0.5 Liquid By Road RM Store Indigenous
413 (3-bromopropyl)-3-(trifluoromethyl) benzene
0.5 Solid By Road RM Store Indigenous
414 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide
0.5 Solid By Road RM Store Indigenous
415 1-phenyl-1,2,3,4-tetrahydro isoquinoline
0.5 Solid By Road RM Store Indigenous
416 (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline
0.5 Solid By Road RM Store Indigenous
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-
0.5 Solid By Road RM Store Indigenous
Expansion project-Synthetic Organic Chemicals Page | 33
Prefeasibility Report Megafine Pharma(P)Ltd.
Sr. No.
Name of Raw Material Storage Cap. In MT
State of raw material
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
0.5 Solid By Road RM Store Indigenous
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
0.5 Solid By Road RM Store Indigenous
437 5-methylisoxazole-4-carboxylic acid
0.5 Liquid By Road RM Store Indigenous
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)
0.5 Solid By Road RM Store Indigenous
441 5,6,7,7a-tetrahydrothieno-[3,2-c]pyridin-2(4H)-one hydrochloride
0.5 Solid By Road RM Store Indigenous
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.
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Prefeasibility Report Megafine Pharma(P)Ltd.
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
Expansion project-Synthetic Organic Chemicals Page | 35
Prefeasibility Report Megafine Pharma(P)Ltd.
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 water- will 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:
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Prefeasibility Report Megafine Pharma(P)Ltd.
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.
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Prefeasibility Report Megafine Pharma(P)Ltd.
Expansion project-Synthetic Organic Chemicals Page | 38
Prefeasibility Report Megafine Pharma(P)Ltd.
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
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Prefeasibility Report Megafine Pharma(P)Ltd.
Expansion project-Synthetic Organic Chemicals Page | 40
Prefeasibility Report Megafine Pharma(P)Ltd.
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
Expansion project-Synthetic Organic Chemicals Page | 41
Prefeasibility Report Megafine Pharma(P)Ltd.
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.
Expansion project-Synthetic Organic Chemicals Page | 42
Prefeasibility Report Megafine Pharma(P)Ltd.
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
Expansion project-Synthetic Organic Chemicals Page | 43
Prefeasibility Report Megafine Pharma(P)Ltd.
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.
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Prefeasibility Report Megafine Pharma(P)Ltd.
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.
Expansion project-Synthetic Organic Chemicals Page | 45
Prefeasibility Report Megafine Pharma(P)Ltd.
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
Expansion project-Synthetic Organic Chemicals Page | 46
Prefeasibility Report Megafine Pharma(P)Ltd.
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.
Expansion project-Synthetic Organic Chemicals Page | 47
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
Formula Weight = 164.58686
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)
A. Route of synthesis
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:-
A. Route of synthesis
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
A. Route of synthesis
Stage: - III
Br
O
O
CH3
OOCH3
dimethyl (4-bromophenyl)propanedioate
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:-
A. Route of synthesis
Stage: - IV
Br
O
O
CH3
OOCH3
dimethyl (4-bromophenyl)propanedioate
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.
Organic Residue 0.37
Hazardous Waste storage.
Total Quantity input 43.62
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.
2. Route of synthesis:
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
INPUT Kg. OUTPUT Kg. Remarks
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
B ) Solvent recovered
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
INPUT Kg. OUTPUT Kg. Remarks
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
B ) Solvent recovered
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
B ) Solvent recovered
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
B ) Solvent recovered
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
B ) Solvent recovered
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
Molecular Formula = C26H32F2N6O4SFormula Weight = 562.63
Molecular Formula = C23H28F2N6O4SFormula Weight = 522.56
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
Molecular Formula = C23H28F2N6O4SFormula Weight = 522.56
Molecular Formula = C23H28F2N6O4SFormula Weight = 522.56
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
3. Process flow chart:
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
B ) Solvent recovered
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
B ) Solvent recovered
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
B ) Solvent recovered
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).
2. Route of Synthesis:
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
Layer separation Aq. layer
5 % Brine solution
Layer separation Aq. layer
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)
Batch Size : Kg. 0.15
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
Organic residue 0.04
Total 1.59 1.59
Step -II
Batch Size : Kg. 0.095
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
Organic residue 0.01
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
2. Route of synthesis:
2.1 Preparation of Methyl-[6-(4-methyl-piperazin-1-yl)-4-O-tolyl-pyridin-3-yl]-
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 :-
3.1 Preparation of Methyl-[6-(4-methyl-piperazin-1-yl)-4-O-tolyl-pyridin-3-yl]-
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
Total Input 28.46 28.46
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
4. Process flow chart:
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
Total Input 266.88 266.88
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.
2. Route of Synthesis:
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
5. Process flow chart:
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
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HCB*- (S)-3-(2-Bromo-1-hydroxyethyl)-5-chlorothiophene-2-sulfonamide
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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
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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
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Toluene (100 ml) Residual mass (Solid) Solvent recovery
Under vacuum distillation below 55°C
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
Reaction mass (Suspension)
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
Reaction mass (Suspension)
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
Ethyl acetate (400 ml)
Continue on next page…..
Stage-I*=(S)-6-Chloro-3,4-dihydro-4-hydroxy-2H-thieno[3,2-e][1,2] thiazine-1,1-dioxide
Continue from previous page…..
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
Under vacuum distillation below 55°C
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
Reaction mass (Suspension)
Raise to 25-30°C in 30-60 minutes
Reaction mass (Suspension)
Continue on next page…..
Stage-II*=(S)-6-Chloro-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e][1,2]thiazine-1,1-dioxide
Continue from previous page…..
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
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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
Ethyl acetate (400 ml)
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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
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ETP Hyflo bed Filtrate
Combined the filtrate
Under vacuum distillation below 55°C
Dichloromethane (100 ml) Residual mass Solvent recovery
Under vacuum distillation below 55°C
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
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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
Continue from previous page…..
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
Reaction mass (Clear solution)
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)
Aqueous layer Organic layer
Layer separation
Aqueous layer Organic layer
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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
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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
Ethyl acetate (100 ml)
Hyflo bed Filtrate
ETP
Hyflo bed Filtrate
Combined filtrate
Under vacuum distillation below 55°C Methanol (100 ml)
Residual mass
Solvent recovery
Under vacuum distillation below 55°C
Continue on next page…..
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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
Cool to 30-35°C and stir for 60-90 minutes
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 (Clear solution)
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Stir for 15 minutes at 62-80°C
Reaction mass
Cool to 30-35°C and stir for 60-90 minutes
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 (Clear solution)
Continue on next page…..
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Stir for 15 minutes at 62-80°C
Reaction mass
Cool to 30-35°C and stir for 60-90 minutes
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
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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
Cool to 10-15°C and stir for 60-90 minutes
Reaction mass
Fltration
Isopropanol (100 ml x 2)
Wet cake Mother liquor
Fltration
Wet cake Washing Mother liquor
Solvent recovery
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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:
INPUT Kg. OUTPUT Kg. Remarks
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)
A. Route of synthesis
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
Formula Weight = 142.026
+
NH2
aniline
Formula Weight = 93.127
Refluxe
NH
N
1-phenylpiperazine
Formula Weight = 162.232
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.
Organic Residue 2.20
Hazardous Waste storage.
Total Quantity input 18.30
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.
2. Route of synthesis:
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
3. Process flow chart:
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.
2. Route of synthesis:
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
3. Process flow chart:
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