Annexure-PFR - Environmental Clearances

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Annexure-PFR - Environmental Clearances
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
ii.
iii.
Location (map showing general location, Specific location, and project boundary 05
& project site layout)with coordinates
Profile of Project site
06
iv.
Site Layout Plan
v.
Details of alternate sites considered and the basis of selecting the proposed site, 10
particularly the environmental considerations gone into should be highlighted
Size or magnitude of operation
11
vi.
vii.
viii.
ix.
x.
05
08
Project description with process details (a schematic diagram/ flow chart 11
showing the project layout components of the project etc. should be given)
Raw material required along with estimated quantity, likely source, marketing 18
area of final products/s, mode of transport of raw Material and finished product
Resource optimization/ recycling and reuse envisaged in the project,
33
Availability of water its source, Energy/power requirement and source
33
xi.
4.
Quantity of waste to be generated (liquid and solid) and scheme for their 34
Management/disposal
xii.
Schematic representations of the feasibility drawing which give information of 41
EIA purpose
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.
Megafine Pharma(P)Ltd.
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 44
given):
8. Project Schedule & Cost Estimates…………………………………………………………………….............. 44
i.
Likely date of start of construction and likely date of completion
44
Estimated project cost along with analysis in terms of economic viability of the
ii.
44
project
9. Analysis of Proposal (Final Recommendations)…………………………………………………............. 45
i.
Financial and social benefits with special emphasis on the benefit to the local 45
people including tribal population, if any, in the area
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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 Project Activity:-5(f)per amendments
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 / [email protected] 26 MT/M
B. Milling Blending Activity:
Existing: 50 MT/Month
6.
Power Requirement
475 HP
7.
Utilities (D.G. Sets, Boilers, D.G. Set : Three(Capacity:250+25KVA(Existent) and 250 KVA
Thermopack, etc...)
(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
Measures
Synthetic
Organic
Chemicals,
Control All equipment and centrifuges are connected to scrubbers,
LDAR program implemented, Dust collector will be attached
to pulverizer.
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Megafine Pharma(P)Ltd.
11.
Water requirement & waste Water Consumption: 89.00 KL/day, Sourced from GIDC water
water generation with mode supply.
of disposal
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
Generation
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/ None
Sanctuary/Eco-sensitive zone.
waste Managed as per Hazardous Waste (Management, Handling
And Transboundary Movement) Rules-2008.
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Megafine Pharma(P)Ltd.
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, USFDA 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. B. Tech. (Chem.)
Soc., Bhulabhai Desai Road, Haji Ali, I.I.T.-Delhi having 39
Mumbai.
years of experience
2.
Mr. Hasmukh
Gandhi
P.
A/ 7&8, Ashoka Residency, B. Sc. having 35 years
Tilakwadi, B/H Rajiv Gandhi Bhavan of experience
Marg, Nasik - 422 002.
3.
Mr.
Shailesh
Sanghvi
J.
801-JoganiAppartment,
29-B B. Com. Having 25
Dongarsi
Road,
Walkeshwar, years of experience
Mumbai – 400 006.
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Prefeasibility Report
II.
Megafine Pharma(P)Ltd.
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 [email protected]
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, Gujarat396195. 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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Prefeasibility Report
III.
Megafine Pharma(P)Ltd.
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
10
Nearest Surface water Resource/Reservoir
11
Forest Patches
12
Location of Archaeologically /Historically
-important places
Expansion project-Synthetic Organic Chemicals
Daman (17KmsW)
Surat (125 Kms NW)
Arabian Sea (18 Km W)
DamangangaRiver (7 Km SW)
No patches of Reserve Forest within the study
area of project site.
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Prefeasibility Report
13
14
15
16
17
Megafine Pharma(P)Ltd.
National Park/Sanctuary or Ecologically Dadra& Nagar Haveli Wild Life Sanctuary
sensitive Area
Approx. 20 km E
Dadra & Nagar Haveli – 7 Km E
National or State Boundary
Daman – 15 km W
Dadra & Nagar Haveli – 7 Km E
Tourist Places
Daman – 15 km W
Proposed project is in the GIDC Notified
Selection of project Site and Detail of Industrial area having proper industrial
alternate Site.
infrastructure
hence
alternate
site
consideration is not envisaged.
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.
Megafine Pharma(P)Ltd.
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.
Megafine Pharma(P)Ltd.
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 –
•
Sr.
No.
LIST OF FINISHED PRODUCTS
Name of Product
Plant
Production
(MT/month)
Capacity
A. Manufacturing:
1
2
3
4
5
Intermediates
PiperazineDihydrochloride (PDH)
N-phenyl Piperazine (NPP)
1-methyl-3-phenylpiperazine (NM3PP)
1(2(2-Hydroxy ethoxy) ethyl) Piperazine (HEEP)
Existing
1-(3-Hydroxy Methyl Pyridyl-2)-2-Phenyl-4-Methyl Piperazine
(HMPPMP) OR [2-(4-methyl-2-phenylpiperazin-1-yl)pyridin-3yl]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)
8.71MT
11 3-(2-Chloroethyl)-6, 7, 8, 9-tetrahydro-9-hydroxy-2-methyl4H-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]-Nmethylmethanamine 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
Proposed
Total
16.29 MT
26MT
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(DTPD)
20
21
22
Dibenzo [b, f][1, 4]thiazepin-11(10H)-one (DTO)
5-(4-bromophenyl)-4,6-dichloropyrimidine (BDP)
1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile
(EFP)
Additional Proposed Products (Intermediates)
23 Disodium Pamoate (DSP)
24 Thiophene-2- Aldehyde (T2A)
(2S)-2-Hydroxy-3-methoxy-3,3-diphenylpropanoic acid (DPA
25
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)
(3aR,4S,7R,7aS)-hexahydro-4,7-methano-2H-isoindole-1,330
dione
( BHC)
31 (1R,2R)-Cyclohexane-1,2-diyldimethanol (HMC)
32 1-Benzyl piperidine-4-carbaldehyde (NBPCHO)
2-(1-benzyl-1,2,3,6-tetrahydro-pyridine-4yl)methylene33
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)
2-Ethoxy-5-(4-Methyl Piperazinyl Sulfonyl) Benzoic Acid
36
[Sil III]
4-amino-1-Methyl-3-n-propyl-5-pyrazolecarboxamide
37
hydrochloride
(MPC VI)
1-(2,4-Difluorophenyl)-2-(1H
1,2,4-triazol-1-yl)-1-ethanone
38
(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)
(+)-(2-chlorophenyl) (6,7-dihydro4H-thieno [3,4-C] pyridine 42 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)
1-(4-nitrophenyl)-3-morpholin-4-yl-5,6-dihydropyridin-2(1H)45
one (APV IV)
46
47
48
49
0.00
Ethyl 6-(4-nitrophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid ethyl
ester (APB VI)
3-acetamidophthalic anhydride (APA)
(S)-2-(3-Ethoxy-4-methoxyphenyl)-1-methyl sulphonyl)-eth2yl amine (EMS)
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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52
53
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55
56
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58
59
60
61
62
63
64
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68
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Trans-11-Chloro-2,3,3a, 12b-tetrahydro-2-methyl-1H-dibenz
[2,3:6,7] oxepino [4,5-c]pyrrol-1-one (TOP)
(R)-(+)-1-(1-Naphthyl) ethylamine HCl (RNA IV)
3-[3-(Trifluoromethyl) phenyl] propanol (TPP II)
Ethyl
3-(4-(methylamino)-3-nitro-N-(pyridin-2yl)benzamido)propanoate (DEM I)
3-[(3-Amino-4-methylaminobenzoyl)pyridin-2ylamino]propionic acid ethyl ester (DEM II)
3-[[[2-[[(4-Cyanophenyl)amino]methyl]-1-methyl-1Hbenzimidazol-5-yl]carbonyl]Pyridine-2-ylamino]propionic acid
ethyl ester (DEM III)
Ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1-methylN-(pyridin-2-yl)-1Hbenzo[d]imidazole-5carboxamido)propanoate HCl (DEM IV)
Dabigatran etexilate
(S)-2,2-Diphenyl-2-(pyrrolidin-3-yl)acetamide tartrate (Dar IV)
5,6-Dimethoxy-2-(pyridin-4-yl methylene)-indan-1-one (DOH
IV)
1-Benzyl-4-[(5,6-dimethoxy
indanon)-2-ylidenyl]
methylpiperidine (DON 1)
2-[(5-Chloropyridin-2-yl)-2-oxoacetic acid (CPO)
5-methyl-4,5,6,7-tetrahydro
thiazolo[5,4-c]
pyridine-2carbixylic Acid hydrochloride ( MTP)
Tert-Butyl(1R,2S,5S)-2-azido-5-[(dimethylamino)
carbonyl]
cyclohexylcarbamate (ADC)
1-[4-(3-Chloropropoxy)-3-methoxyphenyl]ethanone (CME)
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)
Prasugrel Free Base
Pamoic acid (PA)
1,2-Dimethyl-1,4,5,6-tetrahydropyrimidine (THP)
1-(2-fluorobenzyl)-1H-pyrazolo
[3,4-b]pyridine-3carboximidamide
( FPC)
[(E)- Phenyl Diazenyl] Malononitrile (RGT -II)
2-({(5S)-2-Oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3oxazolidin-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)
Ethyl-5-aminobenzofuran-2-carboxylate (EABC)
3-Aminoadamantan-1-ol (HAA)
(2S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile (CCP -II)
2,4 -dimethyl-benzenethiol ( DMT)
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2,4-dimethyl-1-[(2-nitrophenyl)thio]benzene ( VOR-I)
6-Chloro-5-(chloroacetyl)-1,3-dihydro-2H-indole-2-one
3-Piperazin-1-yl-1,2-benzisothiazole HCl (PBT HCL)
1-(1-benzothiophen-4-yl)piperazine
Trans-(4-amino-cyclohexyl) acetic Acid ethyl ester
N-[trans-4-(2-oxoethyl)cyclohexyl]-, 1,1-dimethylethyl ester
Benzyl
(5R)-5-methyl-1,4-diazepane-1-carboxylate
hydrochloride
4-Oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester
(ODC)
5-Amino-2,4-di-tert-butyl-phenol (ADP)
4-Isopropylamino butanol (4-IAV)
Bulk Drugs / API - Active Pharma Ingredients; Using Above
Intermediates
PyrantelPamoate;
4-[(3-Carboxy-2-hydroxynaphthalen-11
yl)methyl]-3-hydroxynaphthalene-2-carboxylic acid; 1-methyl2-[(E)-2-thiophen-2-ylethenyl]-5,6-dihydro-4H-pyrimidine
Morantel
Citrate;
1,4,5,6-Tetrahydro-1-methyl-2-(2-[32
methyl-2-thienyl]ethenyl)pyrimidine
3
OxantelPamoate;
3-[(E)-2-(1-Methyl-5,6-dihydro-4Hpyrimidin-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-[3methyl-2-thienyl]ethenyl)pyrimidine
6
Bosentan Monohydrate; 4-tert-butyl-N-[6-(2-hydroxyethoxy)5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4yl]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-2pyrimidinyl)oxy]-ethoxy]-4-pyrimidinyl]-N-propylsulfamide
9
Riociguat; methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1Hpyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate
10
Mirtazapine;
(±)-2-methyl-1,2,3,4,10,14bhexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine
11
Venlafaxine Hydrochloride; (RS)-1-[2-dimethylamino-1-(4methoxyphenyl)-ethyl]cyclohexanol
Desvenlafaxine
Succinate;
4-[2-dimethylamino-1-(1hydroxycyclohexyl)
ethyl]phenol
12
13
Duloxetine
Hydrochloride;(3S)-N-Methyl-3-(naphthalen-1yloxy)-3-(thiophen-2-yl)propan-1-amine Hydrochloride,
Expansion project-Synthetic Organic Chemicals
Page | 14
Prefeasibility Report
14
15
16
17
18
19
20
21
Megafine Pharma(P)Ltd.
Vilazodone
Hydrochloride;5-(4-(4-(5-cyano-1H-indol-3-yl)
butyl)
piperazin-1-yl)
benzofuran-2-carboxamide
Hydrochloride
Vorteoxetine;
1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]piperazine
Asenapine Maleate; (3aRS,12bRS)-rel-5-Chloro-2,3,3a,12btetrahydro2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole
Paliperidone;
(RS)-3-[2-[4-(6-fluoro-1,2-benzoxazol-3yl)piperidin-1-yl]ethyl]-9-hydroxy-2-methyl-6,7,8,9tetrahydropyrido[1,2-a]pyrimidin-4-one
Ziprasidone Hydrochloride; 5-[2-[4-(1,2-Benzisothiazol-3-yl)-1piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one
hydrochloride monohydrate,
Iloperidone;1-[4-[3-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin1-yl]propoxy]-3-methoxyphenyl]ethanone
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-1,3dione
Donepezil
Hydrochloride;
(RS)-2-[(1-benzyl-4piperidyl)methyl]- 5,6-dimethoxy-2,3-dihydroinden-1-one
22
Memantine
Hydrochloride;
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]thiazepin11-yl-1-piperazinyl)ethoxy]ethanol hemifumarate
24
DarifenacineHydrobromide;
(S)-2-[1-[2-(2,3dihydrobenzofuran-5-yl)ethyl] pyrrolidin-3-yl] -2,2-diphenylacetamide
25
Soilfenacine Succinate; 1-azabicyclo[2.2.2]oct-3-yl (1R)-1phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate
26
Mirabegron;2-(2-Amino-1,3-thiazole-4-yl)-N-[4-(2-{[(2R)-2hydroxy-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-2cyanopyrrolidine
29
Prasugrel
Hydrochloride;
(RS)-5-[2-Cyclopropyl-1-(2fluorophenyl)-2-oxoethyl]-4,5,6,7tetrahydrothieno[3,2c]pyridin-2-yl acetate
Expansion project-Synthetic Organic Chemicals
3,5-
Page | 15
Prefeasibility Report
30
31
32
Megafine Pharma(P)Ltd.
Dabigetran;Ethyl-3-{[(2-{[(4{N'hexyloxycarbonylcarbamimidoyl}phenyl)amino]methyl}-1methyl-1H-benzimidazol-5-yl)carbonyl]
(pyridin-2-ylamino)propanoate (Dabigatran etexilate)
Rivaroxaban;5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4yl)phenyl]-1,3-oxazolidin-5-yl}
methyl)thiophene-2carboxamide
Apixaban; 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3carboxamide
33
Ticagrelore;
(1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4Difluorophenyl)cyclopropylamino]-5-(propylthio)3H[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2hydroxyethoxy)cyclopentane-1,2-diol
34
Ivabradine;3-(3-{[((7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5trien-7-yl) methyl] methyl amino}propyl)-1,3,4,5-tetrahydro7,8-dimethoxy-2H-3-benzazepin-2-one hydrochloride
35
Brinzolamide;(R)-3,4-Dihydro-4-(ethylamino)-2-(3methoxypropyl)-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide1,1-dioxide
36
Teriflunomide;(Z)-2-Cyano-3-hydroxy-but-2-enoic
trifluoromethylphenyl)amide
37
Selexipag;
2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2yl)amino]butoxy}-N-(methanesulfonyl)acetamide
38
Brexpiprazole;
7-{4-[4-(1-benzothiophen-4-yl)piperazin-1yl]butoxy}quinolin-2(1H)-one
Ivacaftor;
N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4dihydroquinoline-3-carboxamide
Lumacaftor;3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)
cyclopropanecarboxamido)-3-methylpyridine-2-yl)benzoic
acid
39
40
41
42
43
44
45
acid-(4-
Paliperidone
Palmitate;
(9RS)-3-[2-[4(6-Fluoro-1,2benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9tetrahydro-4Hpyrido[1,2-a]pyrimadin-9-yl hexadecanoate.
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-2carbonyl)amino]cyclohexyl]oxamide
Suvorexant; [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2yl)phenyl]methanone
Cariprazine;N-[trans-4-[2-[4-(2,3-dichlorophenyl)-1piperazinyl]-ethyl]-cyclohexyl]N,N-dimethyl urea monohydrochloride
Blonanserin;
2-(4-ethylpiperazin-1-yl)-4-(4-fluorophenyl)5,6,7,8,9,10-hexahydrocycloocta[b]pyridine
Expansion project-Synthetic Organic Chemicals
Page | 16
Prefeasibility Report
46
47
48
49
B
C
Megafine Pharma(P)Ltd.
Netupitant; 2-[3,5-Bis(trifluoromethyl)phenyl]-N,2-dimethylN-[4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3pyridinyl]propanamide
Rolapitant;
(5S
,8S)-8-[[(1R)-1-[3
,5Bis(trifluoromethyl)phenyl] ethoxy] methyl]-8-phenyl-1,7diazaspiro[4.5]decan-2-one hydrochloride monohydrate.
Apremilast;N-{2-[(1S)-1-(3-Ethoxy-4-methoxyphenyl)-2(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4yl}acetamide
Neostigmine;3-{[(dimethylamino)carbonyl]oxy}-N,N,Ntrimethylbenzenaminium
Pilot Plant Capacity
0.00
1.00
1.00
8.71 MT
Total Quantity/ Month
Multimilling, Blending, Packing, Labelling of Bulk Drugs and
Intermediates like,:
17.29 MT
26MT
All types of Piperazine
derivatives like, Pharma 50.00
Intermediates and products like, Anthelmentic intermediates
and products like,
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:
Expansion project-Synthetic Organic Chemicals
Page | 17
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.
Raw Materials as per
Synthetic Organic
Chemical Reactions under
required conditions as
per requirement in a pilot
reactor (like acetylation,
nitration, hydrolysis,
bromination, reduction,
oxidation,
etc.)etchydrogenation,
Vent
If any process
gas emission
Unit Operations as per
requirement like Filtration,
Separation, Distillation,
Washing, Crystallisation
etc.
Drying as per required
conditions
To Scrubber
respective
Recovered liquid for
reuse/sale/disposed
off through ETP
Effluent to ETP
Spent Solvent- Distilled &
reuse/sale/ residue
disposal to incineration
I
Process Waste-Disposal to
TSDF / incineration
Packing & Dispatch
Expansion project-Synthetic Organic Chemicals
Page | 18
Prefeasibility Report
VIII.
Megafine Pharma(P)Ltd.
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.
Expansion project-Synthetic Organic Chemicals
Page | 19
Prefeasibility Report
•
Megafine Pharma(P)Ltd.
Transport and storage details of Raw materials :
Sr.
Name of Raw Material
Storage State of raw Mode of
No.
Cap. In MT material
Transport
Place of
storage
Source
RM Store
RM Store
RM Store
RM Store
RM Store
RM
Store/
isolated
place
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
1
2
3
4
5
6
Liquor ammonia solution
Adipic acid
Aniline
Activated carbon
Acetic acid (glacial)
Acetyl chloride
2
1
2
0.5
2
0.5
Liquid
Solid
Liquid
Solid
Liquid
Liquid
By Road
By Road
By Road
By Road
By Road
By Road
7
8
9
10
11
12
13
14
1
2
0.5
5
5
5
5
1
Liquid
Liquid
Liquid
Liquid
Liquid
Solid
Solid
Solid
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
15
16
17
18
19
20
21
22
23
24
25
26
Acetonitrile
Acetone
Benzyl chloride
Caustic lye 50%
Chloroform
2- chloro -3- cyano pyridine
Citric acid
Tetra butyl ammonium bromide
(cat-44)
Cyclohexane
Cyclohexanone
2-(2-chloro ethoxy) ethanol
Di iso propyl ether
Diethanol amine
N,N-dimethyl formamide(DMF)
Di methyl sulfoxide (DMSO)
2,5-dichloro nitro benzene
Dimethyl malonate
D-fructose
N,N-dimethyl aniline
Ethyl acetate
1
1
5
0.5
1
2
2
1
1
1
0.5
16
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Solid
Liquid
Solid
Liquid
Liquid
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
27
Ethyl chloroformate
1
Liquid
By Road
28
29
30
31
32
Ethyl chloro acetate
Hydrochloric acid
n-Hexane
Hyflowsupercel
Isopropylalcohol-Hydrochloric
acid (IPA.HCl)
Iso propyl alcohol
1
2
1
0.5
1
Liquid
Liquid
Liquid
Solid
Liquid
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
Underground
storage
RM
Store/
isolated
place
RM Store
RM Store
RM Store
RM Store
RM Store
2
Liquid
By Road
RM Store
33
Expansion project-Synthetic Organic Chemicals
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Page | 20
Prefeasibility Report
Sr.
No.
Name of Raw Material
Megafine Pharma(P)Ltd.
Storage State of raw Mode of
Cap. In MT material
Transport
34
35
Industrial solvent
Methanol
3
3
Liquid
Liquid
By Road
By Road
36
37
38
Methyl mono ethanol amine
Methylene chloride(MDC)
Mono ethylene glycol
1
3
21
Liquid
Liquid
Liquid
By Road
By Road
By Road
39
40
41
42
43
44
45
46
Chlorobenzene
4-methoxy phenyl acetonitrile
Ortho nitro chloro benzene
Phosphoric acid
Piperazine
Potassium fluoride
Poly phosphoric acid
Petroleum ether
3
1
1
1
5
2
1
1
Liquid
Liquid
Solid
Liquid
Solid
Solid
Thick Liquid
Liquid
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
47
48
Phenyl chloroformate
Phosphorus oxychloride
5
2
Liquid
Liquid
By Road
By Road
49
50
51
52
53
Sodium hydroxide ( caustic soda)
Sodium bi carbonate
Sodium sulphate
Styrene oxide
Sulphuric acid
5
1
1
2
1
Solid
Solid
Solid
Liquid
Liquid
By Road
By Road
By Road
By Road
By Road
54
55
56
1
1
0.5
Solid
Solid
Solid
By Road
By Road
By Road
57
Sodium chloride
Sodium carbonate ( soda ash)
Sodiummethoxide(sodium
methylate)
Thionyl chloride
3
Liquid
By Road
58
Toluene
16
Liquid
By Road
59
60
61
62
Tetra hydro furan
Triethylamine
Thiophenol
Tin metal
2
1
1
0.5
Liquid
Liquid
Liquid
Solid
By Road
By Road
By Road
By Road
Expansion project-Synthetic Organic Chemicals
Place of
storage
Source
RM Store
Methanol
Room/UG
storage
RM Store
RM Store
Underground
storage
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM
Store/
isolated
place
RM Store
RM
Store/
isolated
place
RM Store
RM Store
RM Store
RM Store
RM
Store/
isolated
place
RM Store
RM Store
RM Store
Indigenous
Indigenous
RM
Store/
isolated
place
RM
Store/
Underground
storage
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Page | 21
Prefeasibility Report
Sr.
No.
Name of Raw Material
63
Vitride /Synhydride /Sodium
bis(2-methoxy
phenoxy)aluminium hydride
Hexadecyl tri methyl ammonium
bromide/ Cetrimonium Bromide /
Centimide (CTAB)
Ammonium acetate
Potassium carbonate
Raney nickel catalyst
N-methyl -3-phenyl piperazine
1-[1-Cyano-1-(4methoxyphenyl)methyl]
cyclohexanol
Phenyl-2-(Phenylthio)-phenyl
Carbamate (DOA)
Dibenzo[b,f][1,4]thiazepin11(10H)-One
Guaiacol
2-(Bromomethyl)-1,3-dioxolane
Cysteamine hydrochloride
1-methyl-2-propanol (spicosol-m)
Potassium hydroxide
Dimethyl(4-chloro-2nitrophenyl)malonate (COA)
Dibenzo[b,f][1,4]thiazepin11(10H)-One (DOD)
1-[(2-(Amino)-1-(4-Methoxy
Phenyl ) Ethyl)] Cyclohexanol
acetate
2-amino diphenyl sulphide (DOB)
N-[Dibenzo-[B,F][1,4]-Thiazepine11-yl] Piperazine Hydrochloride
Salt (DP)
6-chloro-2-oxindole
1-(3-carboxy pyridyl-2)-2-phenyl4-methyl piperazine (HMA)
Diethyl malonate
Liquid bromine
Pyrimidine-2-carboximidamide
Hydrochloride (PCH)
P-toluene sulphonamide
Diethyl Bromo malonate (DMA)
2-Nitro-4-Chloro-phenyl
acetic
acid (COB)
2-Amino 3-Benzyloxy pyridine
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
Megafine Pharma(P)Ltd.
Storage State of raw Mode of
Cap. In MT material
Transport
Expansion project-Synthetic Organic Chemicals
Place of
storage
Source
8
Liquid
By Road
RM Store
Indigenous
0.1
Solid
By Road
RM Store
Indigenous
0.5
2
0.1
3
3
Solid
Solid
Solid
Solid
Solid
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
2
Solid
By Road
RM Store
Indigenous
3
Solid
By Road
RM Store
Indigenous
1
1
1
1
5
2
Liquid
Solid
Solid
Liquid
Solid
Solid
By Road
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
2
Solid
By Road
RM Store
Indigenous
3
Solid
By Road
RM Store
Indigenous
1
3
Solid
Solid
By Road
By Road
RM Store
RM Store
Indigenous
Indigenous
3
5
Solid
Solid
By Road
By Road
RM Store
RM Store
Indigenous
Indigenous
1
0.5
0.5
Liquid
Liquid
Solid
By Road
By Road
By Road
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
1
1
2
Solid
Liquid
Solid
By Road
By Road
By Road
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
1
Liquid
By Road
RM Store
Indigenous
Page | 22
Prefeasibility Report
Sr.
No.
Name of Raw Material
91
3-Acetyl-4,5-dihydro-2(3H)furanone(Butyrolactone)
10% Palladium on carbon
Iron powder
2-[2-chloro ethoxy] acetic acid
Boric acid
Ammonium formate
Ethylene Diamine tetra acetic
acid disodium salt
3-(2-Chloroethyl)-6,7,8,9tetrahydro-9- Hydroxy-2- methyl4H-Pyrido [1,2-a] Pyrimidin-4-one
(CHB)
Sodium dithionite (hydrous)
Phthalimide
S (+) epichlorohydrin
Potassium tertiary butoxide
1-[(2-(Amino)-1-(4-Methoxy
Phenyl ) Ethyl)] cyclohexanol
5-cyano indole
4-Chloro butanoyl chloride
Aluminum chloride
Megafine Pharma(P)Ltd.
Storage State of raw Mode of
Cap. In MT material
Transport
Place of
storage
Source
2
Liquid
By Road
RM Store
Indigenous
0.5
2
0.5
0.5
0.5
0.1
Solid
Solid
Liquid
Solid
Solid
Solid
By Road
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
5
Liquid
By Road
RM Store
Indigenous
0.01
0.5
1
1
3
Solid
Solid
Liquid
Solid
Liquid
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
0.5
0.5
0.5
Solid
Liquid
Solid
By Road
By Road
By Road
Indigenous
Indigenous
Indigenous
107 Sodium borohydride
0.5
Solid
By Road
108 Boron trifluorideetherate
0.5
Liquid
By Road
109 1-[2-(Amino)-1-(4-Methoxy
phenyl) ethyl]CyclohexanolHCl
5
Solid
By Road
RM Store
RM Store
RM
Store/
isolated
place
RM
Store/
isolated
place
RM
Store/
isolated
place
RM Store
110 6-chloro – 2- oxindole
111 1-[2(Amino)-1-(4-Methoxy
Phenyl)
ethyl]
Cyclohexanol
Acetate
112 Phenyl ethylamine
113 Nitric acid
5
5
Solid
Solid
By Road
By Road
RM Store
RM Store
Indigenous
Indigenous
1
0.5
Liquid
Liquid
By Road
By Road
Indigenous
Indigenous
0.5
Liquid
By Road
1
1
Liquid
Solid
By Road
By Road
RM Store
RM
Store/
isolated
place
RM
Store/
isolated
place
RM Store
RM Store
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
114 Mix acid (nitric acid + sulfuric
acid)
115 Ethyl-2- chloroaceto Acetate
116 P- anisidine
Expansion project-Synthetic Organic Chemicals
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Page | 23
Prefeasibility Report
Sr.
No.
Name of Raw Material
117
118
119
120
121
122
123
124
125
126
Sodium nitrite
Sodium acetate
Urea
2- anilino ethanol
Chloro acetyl chloride
Formic acid (98%)
4-bromophenyl acetic acid
Dimethyl carbonate
Formamide
N,N, Bis-(2-Chloro Ethyl) Amine
HCl
5-nitro salicylaldehyde
Ethyl cyano acetate
Dimethyl acroline
2-flourobenzyl hydrazine
3-(Dimethyl amino) acryldehyde
Malononitrile
m-xylene
Zinc dust
Sodium triacetoxy borohydride
Ammonium acetate
Trifluoro acetic acid
Trifluoro acetic anhydride
2- chloro benzoic acid
2-fluorobenzoic acid
2,4-ditert butyl phenol
Formalin
Thioacetamide
Tetra hydropyrimidine
Thiophene -2-aldehyde(T2A)
3-methyl thiophene
3-methyl thiophene-2-aldehyde
Phenol
Megafine Pharma(P)Ltd.
Storage State of raw Mode of
Cap. In MT material
Transport
Place of
storage
Source
1
1
0.5
0.5
2
1
1
0.5
0.5
0.5
Solid
Solid
Solid
Liquid
Liquid
Liquid
Liquid
Solid
Liquid
Solid
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
0.5
0.5
1.5
0.5
0.5
0.5
1
1
0.5
1
1
1
0.5
0.5
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
5
0.5
1
5
2
1
0.5
Solid
Liquid
Liquid
Solid
Liquid
Liquid
Liquid
Liquid
Solid
Solid
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Solid
Solid
Liquid
By Road
By Road
By Road
By Road
By Road
By Road
By Road
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
149 Iodine
0.5
Solid
By Road
150 Benzyl bromide
0.5
Liquid
By Road
151 Benzene sulphonic acid
152 Oxalyl chloride
1
0.5
Solid
Solid
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM
Store/
isolated
place
RM
Store/
isolated
place
RM
Store/
isolated
place
RM Store
RM Store
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
Expansion project-Synthetic Organic Chemicals
Indigenous
Indigenous
Indigenous
Indigenous
Page | 24
Prefeasibility Report
Sr.
No.
Name of Raw Material
Megafine Pharma(P)Ltd.
Storage State of raw Mode of
Cap. In MT material
Transport
153 Tri ethyl silane
154 N-methyl piperazine
155 Chlorosulphonic Acid
0.5
0.5
0.5
Liquid
Solid
Solid
By Road
By Road
By Road
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
2-ethoxy benzoic acid
Hydroxyl amine hydrochloride
3-tri fluro methyl cinnamic acid
Ethanolic hydrochloride
Paraformaldehyde
Camphor sulphonic acid
Di isopropyl amine
Ferric chloride anhydrous
(S)- 3 -hydroxypyrrolidone. HCl
Para toluene sulfonyl chloride
Diphenylacetonitrile
1-fluoronaphthalene
Lithium aluminium hydride
2,6 -lutidine
monomethyl amine solution
Para nitro phenol
Benzoyl chloride
Methane sulfonic acid
Pyridine
(+)
diisopinocampheylchloroborane
Solution in Hexane
176 N,N-diisopropyl ethyl amine
177 Morpholine
178 Phosphorus pentachloride
0.5
1
0.5
0.5
0.1
0.1
0.5
0.5
0.5
0.5
0.5
0.5
0.01
0.5
0.5
0.5
0.1
0.5
0.5
0.5
Liquid
Liquid
Solid
Solid
Solid
Solid
Liquid
Solid
Liquid
Liquid
Liquid
Solid
Solid
Solid
Liquid
Liquid
Liquid
Solid
Liquid
Liquid
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
0.5
0.5
0.5
Liquid
Liquid
Liquid
By Road
By Road
By Road
179
180
181
182
20%Palladiuhydroxide on Carbon
Isobutyl chloroformate
5-chlorovaleryl chloride
Phosphorus pentoxide
0.01
0.1
0.5
2
Solid
Liquid
Liquid
Solid
By Road
By Road
By Road
By Road
183
184
185
186
187
Para nitro aniline
Oxalic acid
Lithium chloride
Potassium borohydride
Sodium ethoxide
0.5
0.1
0.1
0.1
0.1
Solid
Liquid
Solid
Solid
Solid
By Road
By Road
By Road
By Road
By Road
Expansion project-Synthetic Organic Chemicals
Place of
storage
Source
RM Store
RM Store
RM
Store/
isolated
place
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
RM Store
RM Store
RM
Store/
isolated
place
RM Store
RM Store
RM Store
RM
Store/
isolated
place
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Page | 25
Prefeasibility Report
Sr.
No.
Name of Raw Material
188
189
190
191
192
193
194
195
196
197
198
199
200
Methane sulphonyl chloride
R (+) alpha methyl benzyl amine
Methyl amino propyl amine
Methyl formate
N-Butanol
Tert butanol
N-Heptane
1-3 dimethyladmantane
Polymeg 400 PM (PEG 400)
Tetramethyldisiloxane
Methyl ethyl ketone
Methyl tertiary butyl ether
4-Hydroxy-3-methoxyphenyl
ethanone
N-methyl Morpholine
Disodium pamoate
Potassium hydroxide
3-hydroxy-benzaldehyde
Tartaric acid
Maleic acid
5,6 dimethoxy-1-indanone
Fumaric acid
3-chloro benzothiozole (3CBT)
Sildenafil Citrate-II (2-Ethoxy-5(4methylpiperazynine
sulphonyl)
benzoic acid
1-(2,4-Difluorophenacyl)-4amino-4-H1,1,2,4triazoliumchloride (DFTA-1)
D-(-) mandelic acid
Potassium iodide
Bon acid
Sodium potassium tartrate
D-(-) tartaric acid
Zeolex
R-3 quiniclidinol
Bis-4-nitrophenyl carbonate
Succinic acid
N-methyl-2-pyrrolidone
Sodium metabisulphite
PTQ-III
(1-phenyl-1,2,3,4tetrahydroisoquinoline)
Benzaldehyde
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
Megafine Pharma(P)Ltd.
Storage State of raw Mode of
Cap. In MT material
Transport
Expansion project-Synthetic Organic Chemicals
Place of
storage
Source
0.1
0.1
1
1
1
0.5
1
1
1
0.5
0.5
1
0.1
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Solid
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
0.1
2
1
1
2
0.1
1
1
0.5
5
Liquid
Solid
Solid
Liquid
Solid
Solid
Solid
Solid
Liquid
Solid
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
5
Solid
By Road
RM Store
Indigenous
1
0.1
5
5
2
2
0.5
0.5
0.5
1
1
1
Solid
Solid
Solid
Solid
Solid
Solid
Solid
Solid
Solid
Liquid
Solid
Solid
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
1
Liquid
By Road
RM Store
Indigenous
Page | 26
Prefeasibility Report
Sr.
No.
Name of Raw Material
Megafine Pharma(P)Ltd.
Storage State of raw Mode of
Cap. In MT material
Transport
225 1-benzylpiperidine-4carbaldehyde
226 Paliperidone
227 6-fluoro-3-piperidin-4-yl-1,2benzisoxazole hcl (PBO HCl)
228 Sodium iodide
229 RNA-II(R-(+)-1(1naphthyl)ethanaminemandalate
salt)
230 1-Methyl-4-nitro-3-n-propyl
pyrazol-5-carboxamide (MPC-VI)
231 DMB(4,6 dichloro-5- (2-methoxy
phenoxy)-2,2 bipyridine )
232 TBS(4-tert-butyl-benzenesuphanamide )
234 BEB-II(5-(2-Bromoethyl)2,
3dihydrobenzofuran)
235 2,2-diphenyl-2-[(3S)-pyrrolidin-3yl]acetonitrile.HBR(DAR-III)
236 S-3-N-Methylamino-1-1thienyl-1Propanol
237 Amantadine HCl
238 L-prolinamide
239 Imidazole
240 Trans-11-Chloro-2,3,3a,12btetrahydro-2-methyl-1Hdibenz[2,3:6,7]oxwpino[4,5c]pyrrol-1-one(TOP)
241 Ammonium bicarbonate
242 11-chloro-2,3-dihydro-2-methyl1h-dibenz-[2,3:6,7] oxepino[4,5c] pyrrol-1-one(DOP)
243 Magnesium metal turning
244 Silica gel
245 1-bromo-3-chloropropane
246 (1-[(1RS)-2-(Dimethylamino)-1-(4methoxyphenyl)ethyl]cyclohexan
ol hydrochloride(VEN HCl)
247 1,8-Diazabicyclo(5,4,0)undec-7ene (DBU)
248 2-bromo-1-cyclopropyl-2-(2fluoro-phenyl-ethanone (BCE)
249 4-(4-Amino phenyl) morpholin-3one (AMO)
250 S-(+)-N-(2,3-Epoxypropyl)
phthalimide (OXI)
Expansion project-Synthetic Organic Chemicals
Place of
storage
Source
0.1
Liquid
By Road
RM Store
Indigenous
0.5
0.5
Solid
Solid
By Road
By Road
RM Store
RM Store
Indigenous
Indigenous
0.1
0.5
Solid
Solid
By Road
By Road
RM Store
RM Store
Indigenous
Indigenous
3
Solid
By Road
RM Store
Indigenous
1
Solid
By Road
RM Store
Indigenous
1
Solid
By Road
RM Store
Indigenous
1
Solid
By Road
RM Store
Indigenous
1
Solid
By Road
RM Store
Indigenous
1
Liquid
By Road
RM Store
Indigenous
0.5
0.5
0.1
0.5
Solid
Solid
Solid
Liquid
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
1
0.5
Solid
Solid
By Road
By Road
RM Store
RM Store
Indigenous
Indigenous
0.1
0.5
0.5
5
Solid
Solid
Liquid
Solid
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
0.5
Liquid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
Page | 27
Prefeasibility Report
Sr.
No.
Name of Raw Material
Megafine Pharma(P)Ltd.
Storage State of raw Mode of
Cap. In MT material
Transport
Place of
storage
Source
251 5-Chlorothiophene-2-carboxylic
acid (CTA)
252 N,N-carbonyl diimidazole
253 Benzophenone
254 4,6-Dimethyl-2(methylsulphonyl)Pyrimidine
255 4-di methyl amino pyridine
256 N,N
dicyclohexylcarbodimide(DCC)
257 2,2-diphenyl-2-[(3S)-1-tosyl
Pyrrolidin-3-yl]acetonitrile(DARII)
258 Sodium chlorite
259 Methyl-3-bromo-6-(cyclopropyl
Methyl)carbamoyl)picolinate
(BCX-5913)
260 5-hydroxy -4-methoxy-2-(4,45,5tet ramethyl-1,3,2-dioxaboralan2-yl)benaldehyde(BCX-6276)
261 Smopex 234
262 Potassium bicarbonate
263 Hydroxylamine-o-sulphonic acid
264 Sodium azide
0.5
Solid
By Road
RM Store
Indigenous
0.5
0.5
0.5
Solid
Solid
Solid
By Road
By Road
By Road
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
0.5
0.5
Solid
Solid
By Road
By Road
RM Store
RM Store
Indigenous
Indigenous
1
Solid
By Road
RM Store
Indigenous
0.1
0.1
Solid
solid
By Road
By Road
RM Store
RM Store
Indigenous
Indigenous
By Road
RM Store
Indigenous
0.1
0.1
0.1
0.1
Solid
Solid
Solid
Solid
By Road
By Road
By Road
By Road
Indigenous
Indigenous
Indigenous
Indigenous
265 Ditertbutyldicarbonate(BOC
Anhydride)
266 (Benzotriazol-1yloxy)tris(dimethylamino)
phosphoniumhexafluorophospha
te
267 4-aminobenzamidine
dihydrochloride
268 1-Ethyl-3-(3dimethylaminopropyl)carbodimid
e
269 Ambersep - 900
270 Indion 225h ion exchange resin
271 N-chlorosuccinimide
272 Megnesiumsulphate
273 5-Nitro-2-(Propylthio) Pyrimidine4,6-diol (GTR-03)
274 (1R,2S)-2-(3,4-difluorophenyl)
cyclopropanaminium(2R)-2hydroxy-2-phenylethanoate
(GTR 01)
0.1
Liquid
By Road
RM Store
RM Store
RM Store
RM
Store/
isolated
place
RM Store
0.1
Solid
By Road
RM Store
Indigenous
0.1
Solid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.1
0.1
0.1
0.1
0.1
Solid
Solid
Solid
Solid
Solid
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
0.1
Solid
By Road
RM Store
Indigenous
Expansion project-Synthetic Organic Chemicals
0.1
Indigenous
Page | 28
Prefeasibility Report
Sr.
No.
Name of Raw Material
Megafine Pharma(P)Ltd.
Storage State of raw Mode of
Cap. In MT material
Transport
275 2-{[(3ar,4S,6R,6as)-6-amino-2,2dimethyltetrahydro-3ahcyclopenta[d][1,3]dioxol-4yl]oxy}ethanol,Ltartaricacid(GTR02)
276 Sodium thiosulphate
277 7M
ammonia
solution
in
methanol
278 Cyclopropanecarboxaldehyde
279 2-(4-nitrophenyl)ethanamine .HCl
280 DCR-IV
281 (2-Amino-1,3-thiazol-yl)
Acetic
Acid
282 (3AR, 4S, 7R, 7AS)4,7-Methano1H-indole-1,3(2H)-dione [BHC]
283 Cis-5-Norbornene-exo-2,3Dicarboxylic anhydride (VDA)
284 Cis-1,2-cyclohexanedicarboxylic
anhydride
285 (1R,2R)-1,2cyclohexanedimethanol
286 Ethylisonipicotate
287 Iso propyl acetate
288 1-(2(2-Hydroxy ethoxy) ethyl)
Piperazine (HEEP)
289 1-acetyl napthalene
290 Propylene carbonate
291 Methyl isonicotinate
292 Di ethylene glycol
293 Dodecanethiol(Tert-dodecyl
mercaptan)
294 2-phenyl ethyl amine
295 2-methyl tetarhydrofuran
296 Methyl chloro acetate
297 (1s)phenylethanamine
298 1,2 dimethoxy ethane
299 1-bromo-3-methoxypropane
300 Tri methyl ortho acetate
301 Ethylenedichloride (EDC)
302 Triethylorthoformate
303 Trimethyl borate
304 4-trifluoro methyl aniline
305 Difluro benzene
306 1,1 carbonyl diimidazole
Expansion project-Synthetic Organic Chemicals
Place of
storage
Source
0.1
Liquid
By Road
RM Store
Indigenous
0.5
0.5
Solid
Liquid
By Road
By Road
RM Store
RM Store
Indigenous
Indigenous
0.1
0.5
1
0.5
Liquid
Liquid
Solid
Liquid
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
1
Solid
By Road
RM Store
Indigenous
1
Solid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
1
2
5
Liquid
Liquid
Liquid
By Road
By Road
By Road
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
1
1
1
5
1
Liquid
Solid
Liquid
Liquid
Liquid
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
0.1
0.1
0.1
0.1
0.5
0.1
0.1
1
1
0.5
0.5
0.1
0.1
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Solid
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Page | 29
Prefeasibility Report
Sr.
No.
Name of Raw Material
307
308
309
310
311
312
313
314
315
316
317
1,3-diphenyl1h pyrazole-s amine
1-iodopropane (n-propyl iodide)
Dichlorobenzene
1-(2,3-Dichlorophenyl)piperazine
1,1 Dimethoxy ethane
1,4 dioxane
1,2,4-trizole
2,2-dimethoxy propane
2-Amino-3-hydroxypyridine
2,4-dimethyl thiophenol
2-[(5-Chloropyridin-2-yl)amino]2-Oxoacetic acid Lithium Salt
3-hydroxy-4-methoxy
benzaldehyde (isovanillin)
3-trifluoro methyl benzaldehyde
3-(2-chloroethyl)-9-hydroxy-2methyl-4H-pyrido[1,2a]pyrimidin-4-one
3-amino-1-butanol
3-dimethylamino phenol
3-Morpholin-4-yl(4-nitrophenyl)5,6-dihydropyridin-2-(CHO-one)
4-dimethylaminopyridine
4-(isopropylamino) butan-1-ol
4-nitrophenyl acetic acid
5-(2-bromoethyl)2,3dihydrobenzofuron
5,6,7,7a-Tetrahydro-4H-Thieno[3,2-C]-2-Pyridine HCl
5-chloro-2-phenoxy acetophone
5-chlorovaleryl chloride
5-(4-bromophenyl)4,6dichlorpyrimidine
5-chloro-2,3-di-phenylpuyrazine
5-Methyl-4,5,6,7tetrahydrothiazolo[5c]Pyridine-2carboxylic acid hydrochloride
Acrylonitrile
Aluminium oxide
Ammonium
molybdatetetrahydrate
Ammonia gas cylinder
Barium hydroxide
Benzophenone
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
Megafine Pharma(P)Ltd.
Storage State of raw Mode of
Cap. In MT material
Transport
Expansion project-Synthetic Organic Chemicals
Place of
storage
Source
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
Solid
Liquid
Liquid
Solid
Liquid
Liquid
Solid
Liquid
Solid
Liquid
Solid
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
0.1
Solid
By Road
RM Store
Indigenous
0.1
0.1
Liquid
Solid
By Road
By Road
RM Store
RM Store
Indigenous
Indigenous
0.1
0.1
0.1
Liquid
Liquid
Liquid
By Road
By Road
By Road
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
0.1
0.1
0.1
0.1
Solid
Liquid
Liquid
Solid
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
0.1
Solid
By Road
RM Store
Indigenous
0.1
0.1
0.1
solid
Liquid
Solid
By Road
By Road
By Road
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
0.1
0.1
Solid
Solid
By Road
By Road
RM Store
RM Store
Indigenous
Indigenous
0.1
0.1
0.1
Liquid
Solid
Solid
By Road
By Road
By Road
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
0.1
0.1
0.1
Liquid
Solid
Solid
By Road
By Road
By Road
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Page | 30
Prefeasibility Report
Sr.
No.
Name of Raw Material
Megafine Pharma(P)Ltd.
Storage State of raw Mode of
Cap. In MT material
Transport
340 Benzyl amine
341 Bromocyclopropyl bromide
342 Bis(dimethylamino)methyliumyl3H-benzotriazol-1-oxide
hexafluorophosphate [HBTU]
343 Cuprous oxide red
344 Di-tert-butyl-pyrrocarbonate
345 Dibenzoyl-l-tartaric
acid
monohydrate
346 Dimethyl amine
347 Dimethyl sulphate
348 Diethyl-2(ethoxymethylene)malonate
349 Donepezil HCl
350 Ethyl-3-(dimethylamino)acrylate
351 Hydrogen peroxide
352 Imidodicarbonic acid bis(1,1dimethyl ethyl ester
353 L-menthol
354 Maleic anhydride
355 Meta (3)-amino benzotrifluoride
356 Methane sulphonyl chloride
357 Methyl chloro acetate
358 Malonic acid
359 N-Butyl Lithium Solution 1.6M in
Hexane
360 N-methyl morpholine-n-oxide
361 N,N- Diisopropyl ethyl amine
362 N,N- dimethyl carbamoyl chloride
363 N-propanol
364 N-chlorosuccinimide
365 Neostigmine methyl sulfate
366 Ortho-nitro fluoro benzene
367 Ortho fluoro phenol
368 Phosphorous acid
369 Phosphorous trichloride
370 Potassium bromate
371 Potassium phosphate tribasic
372 Peroxyacetic acid
373 Pyridiniumchloro chromate
374 R(+) Phenyl ethyl Amine
375 Sodium hydrogen sulphite
376 Sodium Metal in Liquid Paraffin
Expansion project-Synthetic Organic Chemicals
Place of
storage
Source
0.1
0.1
0.1
Liquid
Liquid
Solid
By Road
By Road
By Road
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
0.1
0.1
0.1
Solid
Liquid
Solid
By Road
By Road
By Road
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
0.1
0.1
0.1
Liquid
Solid
Liquid
By Road
By Road
By Road
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
0.1
0.1
0.1
0.1
Solid
Liquid
Liquid
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
0.1
0.1
0.1
0.1
0.1
0.1
0.1
Solid
Solid
Liquid
Liquid
Liquid
Solid
Liquid
By Road
By Road
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
Solid
Liquid
Liquid
Liquid
Solid
Solid
Liquid
Liquid
Liquid
Liquid
Solid
Solid
Liquid
Solid
Liquid
Solid
Solid
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Page | 31
Prefeasibility Report
Sr.
No.
Name of Raw Material
Megafine Pharma(P)Ltd.
Storage State of raw Mode of
Cap. In MT material
Transport
377 Sodium Sulfite anhydrous
378 S(-) phenyl ethyl amine
379 Tert-Butyl(1R,2S,5S)-2-Oxido-5[(dimethylamino)carbonyl]cycloh
exyl carbamate oxalic acid
380 Tert butyl bromo Acetate
381 Thiourea
382 Tert butyl dimethyl silyl chloride
383 Tetrabutyl ammonium Iodide
384 Trimethylsulphonium Iodide
385 Trimethylsulphoxonium Iodide
386 2-phenylaminomethylenemalonic acid diethyl ester [ODC-I]
387 4-Hydroxyquiniline-3-carboxylic
acid ethyl ester [ODC-II]
388 Benzyl chloroformat
389 1-admantylamine hydrchloride
390 R-mandelic acid
391 3-tert-Butoxycarbonylamino-4hydroxy-cyclohexanecarboxylic
acid ethyl ester
392 1-Hydroxybenzotriazole
393 Ethyl3-(pyridin-2ylamino)propanoate
394 Ethyl-3-[[4-(methylamino)-3nitrobenzoyl](pyridin-2yl)amino]propanoate (DEM-I)
395 3-[(3-amino-4-methylaminobenzoyl)-pyridin-2-ylamino]propionic acid ethyl ester
(DEM-II)
396 2-[(4-cyanophenyl)amino]acetic
acid
397 Pivaloyl chloride
398 Diisopropyl ethyl amine
399 3-[[[2-[[(4Cyanophenyl)amino]methyl]-1methyl-1H-benzimidazol-5yl]carbonyl]pyridin-2-yl
amino]propionic acid ethyl ester
400 N-[[2-[[[4(Aminoiminomethyl)phenyl]amin
o]methyl]-1-methyl-1Hbenzimidazol-5-yl]carbonyl]-N-2pyridinyl-beta-alanine ethyl ester
(DEM-IV)
Expansion project-Synthetic Organic Chemicals
Place of
storage
Source
0.1
0.1
0.1
Solid
Liquid
By Road
By Road
By Road
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
0.1
0.1
0.1
0.1
0.1
0.1
0.5
Liquid
Solid
Liquid
Solid
Solid
Solid
Liquid
By Road
By Road
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
0.5
0.5
0.5
Liquid
Liquid
Liquid
Semi Solid
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
0.5
0.5
Liquid
Solid
By Road
By Road
RM Store
RM Store
Indigenous
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
0.5
0.5
Liquid
Liquid
Solid
By Road
By Road
By Road
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
Page | 32
Prefeasibility Report
Sr.
No.
Name of Raw Material
Megafine Pharma(P)Ltd.
Storage State of raw Mode of
Cap. In MT material
Transport
401 Hexyl-4-nitrophenyl carbonate
402 3-(2-(4-chlorophenoxy)phenyl-1methyl-pyrrolidine-2,4-dione
403 11-chloro-2,3-dihydro-2-methyl1H-dibenz-[2,3:6,7]oxepino[4,5-c]
pyrrol-1-one (DOP)
404 5-Chloro-N-(4-Nitrophenyl)
pentanamide (APB-I/NMD-I)
405 3,3-dichloro-1-(4nitrophenyl)piperdin-2-one (APBIII)
406 Ethyl(2Z)-chloro[(4methoxyphenyl)hydrazono]acetat
e
407 1-(4-nitrophenyl)-3-morpholine4yl-5,6-dihydropyridin-2(1H)-one
408 Methyl-3,3-diphenyloxirane-2carboxylate
409 Methyl-2-hydroxy 3-Methoxy 3,3diphenylpropanoate
410 2-hydroxy-3-methoxy-3,3diphenyl propanoic acid
411 (2S)-2-Hydroxy-3-methoxy-3,3diphenylpropanoic acid
412 3-[3-(trifluoromethyl)
phenyl]propan-1-ol
413 (3-bromopropyl)-3(trifluoromethyl) benzene
414 1-methyl-4-nitro-3-propyl-1Hpyrazole-5-carboxamide
415 1-phenyl-1,2,3,4-tetrahydro
isoquinoline
416 (1S)-1-phenyl-1,2,3,4tetrahydroisoquinoline
417 5,6- dimethoxyindanone
418 Isonicotinic acid methyl ester
419 (2-chlorophenyl){[2-(2thienyl)ethyl]amino}acetate .HCl
420 L-camphor sulphonic acid
421 1-chloro-1,2-benzisothiazole
423 6-(4-methyl-piperazin-1-yl)-4-Otolyl-pyridin-3-yl-amine
424 Trimethylorthoformate
425 6-(4-methyl-piperazin-1-yl)-4-Otolyl-pyridin-3-yl]-amine
426 2-(3,5-bis-trifluoromethylphenyl)-2Expansion project-Synthetic Organic Chemicals
Place of
storage
Source
0.5
0.5
Liquid
Solid
By Road
By Road
RM Store
RM Store
Indigenous
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
Liquid
By Road
RM Store
Indigenous
0.5
Liquid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
Liquid
By Road
RM Store
Indigenous
0.5
Liquid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
0.5
0.5
Liquid
Solid
Solid
By Road
By Road
By Road
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
0.5
0.5
0.5
Solid
Liquid
Solid
By Road
By Road
By Road
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
0.5
0.5
Liquid
Solid
By Road
By Road
RM Store
RM Store
Indigenous
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
Page | 33
Prefeasibility Report
Sr.
No.
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
Name of Raw Material
Megafine Pharma(P)Ltd.
Storage State of raw Mode of
Cap. In MT material
Transport
methylpropionylchloride
Rolapitantsulphone
3-(4-fluorophenyl)-3oxopropanenitrile
2-chloro-4-(4-fluorophenyl)5,6,7,8,9,10
Hexahydrocycloocta[b]pyridine
Ethyl piperazine
Cyclooctanone
Phenylphosphonic dichloride
Potassium iodide
7-hydroxy-1H-quinolin 2-one
7-(4-chlorobutoxy)-1H-quinolin-2one
1-benzo[b]thiophen-4-ylpiperazine
5-methylisoxazole-4-carboxylic
acid
Dimethoxyethane
N-(4-trifluoromethyl)-5methylisoxazole-4-carboxamide
2-bromo-1-cyclopropyl-2-(2fluoropheny l) ethanone (BCE)
5,6,7,7a-tetrahydrothieno-[3,2c]pyridin-2(4H)-one
hydrochloride
4-Bromo-1-benzothiophene
Propane dinitrile
2-chloroethoxy acetic acid(2-CEE)
5-Chloropyridine-2-amine
Di tertbutyl carbonate
Potassium-1-cyano,3-ethoxy,3oxoprop1-ene-2-olate
2,3-dibenzoyl-d-tartaric acid
4-Hydroxy butan-2-one
Benzyl carbamate
3-Nitrophthalic acid
Ethyl alcohol
0.5
0.5
Source
Solid
By Road
By Road
RM Store
RM Store
Indigenous
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
0.5
0.5
0.5
0.5
0.5
Solid
Liquid
Liquid
Solid
Solid
Solid
By Road
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
Liquid
By Road
RM Store
Indigenous
0.5
0.5
Liquid
Solid
By Road
By Road
RM Store
RM Store
Indigenous
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
Solid
By Road
RM Store
Indigenous
0.5
0.5
0.5
0.5
0.5
0.5
Liquid
Liquid
Liquid
Liquid
Solid
Liquid
By Road
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM Store
RM Store
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
0.5
0.5
0.5
0.5
2.0
Solid
Liquid
Liquid
Solid
Liquid
By Road
By Road
By Road
By Road
By Road
RM Store
RM Store
RM Store
RM Store
RM
StoreEthanol
room
Indigenous
Indigenous
Indigenous
Indigenous
Indigenous
Unit is manufacturing campaign based products as per market demand.
IX.
Place of
storage
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.
Expansion project-Synthetic Organic Chemicals
Page | 34
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
1
2
Quantity KL /day
Existing
6.50
Proposed
6.50
Total
13.00
Domestic
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
Power
–Electricity
1
300 HP
requirement
XI.
Proposed
Total
Source
175 HP
475 HP
DGVCL / DG set
Quantity of waste to be generated (liquid and solid) and
Management/disposal:
• Quantity of Waste Water (liquid waste) generation and its management :
Waste water generation:
Sr. No.
Particulars
1
2
Domestic
Industrial
Process & Washing
Expansion project-Synthetic Organic Chemicals
Existing
6.00
7.95
Quantity KL /day
Proposed
6.00
13.9
scheme
for
Total
12.00
21.85
Page | 35
their
Prefeasibility Report
Boiler
Cooling
Sub Total Industrial
Gardening
Total
3
•
•
•
•
•
•
Megafine Pharma(P)Ltd.
0.10
0.10
8.15
0.00
14.15
0.20
0.20
14.10
0.00
20.10
0.30
0.30
22.45
0.00
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:
ITEM
SR NO.
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:
Expansion project-Synthetic Organic Chemicals
Page | 36
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.
Expansion project-Synthetic Organic Chemicals
Page | 37
Prefeasibility Report
Expansion project-Synthetic Organic Chemicals
Megafine Pharma(P)Ltd.
Page | 38
Prefeasibility Report
Megafine Pharma(P)Ltd.
Water Balance Diagram after proposed expansion:
Sr. No.
Particular
Water Consumption (KL/Day)
Existing
Proposed
6.50
6.50
Existing
6.00
Waste Water Generation (KL/Day)
Proposed
Recycle /Reuse
Loss
6.00
-1.00(usage loss)
1.
Domestic
2.
3.
Gardening
Industrial Activity
Process & Washing
1.00
4.00
0.00
0.00
--
8.27
16.73
7.95
15.90
Boiler
10.00
20.00
0.10
0.20
Cooling
4.00
12.00
0.10
0.20
Total
29.77
59.23
14.15
22.30
1.15
will
be
consumed
in
process
26.70 will be 3.00(Steam loss )
condensate back
to process
15.70(Evaporation
Loss)
27.85
19.70
Expansion project-Synthetic Organic Chemicals
Page | 39
--
Final Disposal
12.00(To
Soak
pit/Septic tank)
-7.55(To ETP)
16.30(To CMEE)
0.30 (To ETP)
0.30 (To ETP)
Prefeasibility Report
Expansion project-Synthetic Organic Chemicals
Megafine Pharma(P)Ltd.
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
Boilers Existing:
IBR 1120 kgs/day
Non-IBR 800 kgs/day
Boiler Proposed:
1120 kgs/day(proposed )
1.
11
Non
IBR
Thermopack
11
Heater (4Lac Kcal)
2.
D.G. Set :
Three Capacity:250 KVA +
6
25 KVA (Exi.) and
250 KVA (Proposed)
3.
4.
5.
Type of fuel
and
consumption
PNG:
SCM/Day
1700
LDO : 75 Lit/Hr.
HSD : 60 Lit/Hr.
Process Reactor
15
--
Process Vent (Centrifuge)
11
--
Air Pollution
Control Measures
Parameter
Adequate stack height
and common stack
monitoring facility is
provided
as
air
pollution
control
system to control
particulate matter.
Particulate
matter
SOX
NOX
Adequate stack height
and acoustic enclosure
is
provided
and
operated only during
power break down.
Particulate
matter
SOX
NOX
SO2
Ventury followed by NOX
HCl
Alkali Scrubber
Cl2
SO2
NOX
-DOHCl
Cl2
Process Emission:
Sr. Stack attached to
No.
1
Pulverizer
Stack Ht. (in mtr)
9.00
Probable pollutants Air Pollution Control
& Limits
System
3
PM<150 mg/Nm
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.
1.
Name of the
Waste
ETP Waste
Source
Effluent
Treatment
Plant
HW Sch.
Category
34.3
Expansion project-Synthetic Organic Chemicals
Quantity
Existing
Total Quantity
after proposed
change
15
15
MT/Month
MT/Month
Method of Disposal
Collection,
Storage,
Transportation,
Disposal at TSDF, Vapi
Page | 41
Prefeasibility Report
2.
3.
4.
5.
Used Oil
Machinery
Discharged
Container/Bags
/Liners
Used
Cloth
Megafine Pharma(P)Ltd.
Raw
Materials
Filter Mfg.
Process
Spent Solvent
5.1
33.3
35.1
Mfg.
Process
28.5
120
300
Lit/Year
Lit/Year
1800
Nos./Year
6000
0.06
0.25
MT/Year
MT/Year
15
50
MT/Month
MT/Month
Nos./Year
Collection,
Storage,
Transportation,
disposal by selling to
registered recyclers.
Collection,
Storage,
Decontamination,
Disposal on sale to
actual users.
Collection,
Storage,
transportation,
Disposal at TSDF-VGEL,
Vapi.
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
XII.
Megafine Pharma(P)Ltd.
Schematic representations of the feasibility drawing which give information of EIA purpose:
A schematic representation of the feasibility drawing
Type of Industry
Proposed mfg. unit of “Synthetic Organic
Chemicals” Pharma Intermediates and APIs
Type of category as per EIA
notification:Synthetic Organic Chemicals
(Activity -5(f)- Category-B)
Proposed Activity:
The proposed expansion project
involves the production of
"Synthetic Organic Compounds"
Site Location:
Plot No. 911, 912, 922, Phase-III,
GIDCVapi
Submission of Form-1 and PreFeasibility Report & Draft TOR
Public consultation: Not
required as the project is
located in notified
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
Presentation before the
EAC for TOR
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.
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/7545,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.
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.
V.
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.
Expansion project-Synthetic Organic Chemicals
Page | 44
Prefeasibility Report
Megafine Pharma(P)Ltd.
5. Planning Description
5.0
I.
II.
Planning Brief.
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.
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:
IV.
Area Statement
Area
After
Expansion (in m2)
Total Area
3992.00
Construction Area
2076.24
Open Land Area
1316.90
Greenbelt Area
598.80
Proposed
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
I.
Proposed Infrastructure:
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.
II.
Rehabilitation and Resettlement (R&R) Plan:
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.
I.
Project Schedule & Cost Estimates:
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
1.
Land
1.60
0.00
Cost
(Rs. in coroes)
Total after
expansion
1.60
2.
Building and Civil Works
8.80
1.00
9.80
Plant & Machinery and
other fittings
Environmental protection
measures
4.00
4.50
8.50
TOTAL :
15.15
Sr.
No.
3.
4.
Purpose
Cost
(Rs. in coroes)
Existing
Cost
(Rs. in coroes)
Proposed
0.75
0.50
6.00
1.25
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
System
2.
Greenbelt Maintenance
2.00
3.
Enterprise social contribution
5.00
Total
30.00
&
Safety
Management
23.00
9.
I.
Analysis of Proposal (Final Recommendations):
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
Apixaban
Intermediates
Ethyl chloro [(4-methoxyphenyl)hydrazono]acetate
(EMA)
3, 3-dichloro-1-(4-nitrophenyl) piperdin-2-one (
APBIII)
1-(4-nitrophenyl)-3-morpholin-4-yl-5,6dihydropyridin-2(1H)-one (APV IV
Ethyl 6-(4-nitrophenyl)-1-(4-methoxyphenyl)-7-oxo4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3carboxylicacid ethyl ester (APB VI)
Ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-2yl)benzamido)propanoate (DEM I)
3-[(3-Amino-4-methylaminobenzoyl)pyridin-2ylamino]propionic acid ethyl ester (DEM II)
Dabigatran Etexilate Mesylate
3-[[[2-[[(4-Cyanophenyl)amino]methyl]-1-methyl-1Hbenzimidazol-5-yl]carbonyl]Pyridine-2ylamino]propionic acid ethyl ester (DEM III)
Ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1methyl-N-(pyridin-2-yl)-1Hbenzo[d]imidazole-5carboxamido)propanoate HCl (DEM IV)
Dabigatran etexilate
4-(4-Aminophenyl)-3-morpholinone (AMO)
Rivaroxaban, 5-chloro-N-({(5S)-2-oxo-3-[4(3-oxomorpholin-4-yl)phenyl]-1,3oxazolidin-5-yl} methyl)thiophene-2carboxamide
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-3yl] phenyll}morpholin-3-one HCl (RIV III)
2-[(S)-2-Oxiranylmethyl]-1H-isoindole-1,3-(2H)-dione
(OXI)
2-[(5-Chloropyridin-2-yl)-2-oxoacetic acid (CPO)
Edoxaban
01
5-methyl-4,5,6,7-tetrahydro thiazolo[5,4-c] pyridine2-carbixylic Acid hydrochloride ( MTP)
Tert-Butyl(1R,2S,5S)-2-azido-5-[(dimethylamino)
carbonyl] cyclohexylcarbamate (ADC)
Product Name: Ethyl 2-chloro-2(4-methoxypthenylhydrazinylidene)ethanoate (EMA)
Capacity :
Application/Use of Product : Pharma Intermediate
A. Route of synthesis
Cl
H3C
N
N
NH2
O
NaNo2,HCl
+
o
-5-0 C
H3C
4-methoxyaniline
Molecular Formula = C7H9NO
Formula Weight
= 123.15246
O
O
H3C
ethyl 2-chloro-3-oxobutanoate
O
O
H3C
Cl
Molecular Formula = C6H9ClO3
(E)-1-chloro-2-(4-methoxyphenyl)diazene
Formula Weight
= 164.58686
Molecular Formula = C7H7ClN2O
Formula Weight
= 170.59628
Chloroform, CH3COONa
O
Cl
O
N
HN
CH3
O
H3C
ethyl (2Z)-chloro[2-(4-methoxyphenyl)hydrazinylidene]ethanoate
Molecular Formula = C11H13ClN2O3
Formula Weight
= 256.68552
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:p-Anisidine
DM water
HCl
Urea Solution
NaNO2 Solution
Reactor
Sodium acetate
solution
Ethy2-chloro aceto acetate
Chloroform
Separation
Aq. send
to ETP
Aqueous Layer
Organic Layer
Organic Layer
Neutralization
5% NaHCO3
Organic Layer
Crude
Crystallization
Filtration
Drying
Product
IPA
D. Material Balance
Material Balance for Ethyl 2-chloro-2(4-methoxypthenylhydrazinylidene)ethanoate
Sr.
no
Input Raw Material Name
Quantity
Kg
Mole.
Weight
2 HCl
3.40
36.5
3 Sodium Nitrite
0.48
69
4 Urea
0.34
60
5 Sodium Acetate
1.92
86
6 Ethyl2-chloro aceto acetate
1.00
164.5
1 p-anisidine
7 Chloroform
8 Isopropyl Alcohol
9 D.M. Water
0.69
13.70
3.50
20.0
Out put
Quantity
Kg
Aqueous Effluent
21.50
123
Recover Chloroform
--- Chloroform Vapour loss
during distillation
--Recover IPA
IPA Vapour loss during
distillation
Product:Ethyl 2-chloro-2
(4-methoxypthenyl
hydrazinylidene)
Organic Residue
Total Quantity input
40.46
Remarks
Total Quantity output
13.00
Reuse
0.70
Scrubber
3.30
Reuse
0.20
Scrubber
1.00
Desire
product
Hazardous
Waste
0.76 storage.
40.46
A. Therapeutic category : Anti-Depressant
API
Desvenlafaxine
Succinate
Intermediates
N-Methyl-3-phenyl piperazine (NM3 PP)
Mirtazapine
Venlafaxine HCl
Vilazodone HCl
Vorteoxetine HBr
1-(3-Carboxy Pyridyl-2)-2-Phenyl-4-Methyl Piperazine (HMA)
1-(3-Hydroxymethyl pyridyl-2)-2-phenyl-4-methylpiperazine (HMPPMP)
1-[2-(Amino)-1-(4-methoxyphenyl ethyl)] cyclohexanol HCl (AMCH)
1-[2-(Amino)-1-(4-methoxyphenyl ethyl)] cyclohexanol acetate(AMCA)
Ethyl-5-aminobenzofuran-2-carboxylate (EABC)
3-(4-Chlorobutyl)-1H-indole-5-carbonitrile (CIC)
Ethyl 5-piperazin-1-yl-1-benzofuran-2-carboxylate (PBC)
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-(4chlorobutyl)-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-2carboxylate [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-2carboxylate with ammonia gas in methanol at elevated temparature give 5-(4-(4-(5-cyano-1Hindol-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:
NC
O
Cl
O
+
N
H
HN
O
N
PBCE
CIC
NH
ACN, KI, TEA
O
N
N
CN
O
O
VIL-I
MeOH, NH3(g)
NH
ACN, ACOH
O
N
N
CN
NH2
O
VIL-II
IPA, IPA.HCl
NH
CN
N
O
.HCL
N
O
VIL-III
Vilazodone hydrochloride
NH2
Process flow chart:
1. PREP ARATION OF VIL-I
PBC.ester
2.
PREP ARATION OF VIL-II
CIC
Acetonitril
TEA, KI
NH3(g)
Methanol
e
Round bottom Flask
VIL-I
Round bottom Flask
Heating and Maintenance
Maintenance at 25-30°C
Cooling
Filtration
Water
ML
Quenching
Crude VIL-II
Filtration
ML
ACN, ACOH
Purification
Crude VIL-I
Filtration
Purification
ACN
ML
Pure VIL-II
Pure VIL-I
IPA
IPA.HCl
Round bottom Flask
Maintenance at 55-60°C
Filtration
Vilazodone. HCl
ML
PREP ARATION OF VIL-III
ML
Material Balance:
Batch Size :
5.00 kg.
INPUT
Kg.
Reactants :
Stage-II
HCl
5.56
1.39
OUTPUT
Solvents :
Acetonitrile
135.47
Product :
Vilazodone -III (wet)
By product :
Solvent Recovered :
Acetonitrile
Distillation losses
Total Input
142.42
Liquid Effluent :
Total Output
Kg.
5.26
0.00
128.70
6.77
1.69
142.42
Therapeutic Category: C: Anti Alzimer :
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-5,6dimethoxy indan-1-onehydrochloride
(Diene
Crystallised)
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.
Route of synthesis;
MEM-I & MEM-II
Br
Br2
CH3
H3C
H3C
1,3-dimethyladamantane
Mole. wt.- 164. 28
CH3
1-bromo-3,5-dimethyladamantane
Mole. wt.- 243. 18
H2SO4
Acetonitrile
MDC
DIPE
O
HN
H3C
CH3
CH3
N-(3,5-dimethyl-1-adamantyl)acetamide
Mole. wt.- 221. 33
MEM-III
O
NH2
HN
CH3
.HCl
Diethylene glycol,NaOH
MDC/Ethanol/ DIPE/IPA.HCl
H3C
H3C
CH3
CH3
Memantine hydrochloride
Mole. wt.= 215. 8
2. Process flow chart:
MEM-I & MEM-II:
1-3-dimethyladantane
Br2 Liq.
REACTION
MAINTENANCE
DISTILLATION
Memantine Hydrochloride Stage-I
MEM-I & MEM-II:
Acetonitrile
H2SO4
REACTION
MAINTAIN
Dichloromethane
WORK-UP
Water
Diisopropyl ether
FILTRATION
DRYING
Memantine Hydrochloride Stage-II
MEM-III:
MEM-II
REACTION
NaOH
MAINTENANCE
Water
Dichloromethane
WORK-UP
DISTILLATION
Ethanol
CHARCOLISATION
IPA.HCl
Diisopropyl
SALT FORMATION
DRYING
MEMANTINE HYDROCHLORIDE
INPUT
Reactants :
1,3dimethyladamanten
Bromine
Acetonitrile
Sulphuric acid
Solvents :
Water
Di chloro methane
Di-isopropyl ehter
Kg.
13.33
53.32
62.38
31.45
OUTPUT
Product :
Memantine step-I
(wet)
16.00
By product :
Solvent Recovered :
Di chloro methane
Di-isopropyl ehter
483.90
180.22
37.32
Kg.
175.00
32.00
Liquid Effluent :
605.00
Salt for washing
NaCl
Sodium hydroxide
3.46
26.66
Solid Waste
NaCl, NaOH, NaBr
64.04
Gaseous
Emmissions
Total Input
892.04
PRODUCT : Memantine Step -II
INPUT
Kg.
Reactants :
Diethylene glycol
Step-I
Sodium hydroxide
169.60
11.31
34.71
Total Output
OUTPUT
Product :
Memantine step-I
I(oil)
Kg.
11.31
By product :
Solvent Recovered :
Dichloro methane
Solvents :
Water
Dichloro methane
892.04
140.00
621.60
146.93
Liquid Effluent :
832.84
Salt for washing
Sodium chloride
Total Input
5.65
989.80
Solid Waste
NaCl, Sod. Acatate
Total Output
5.65
989.80
Therapeutic Category: D: Antianginal
API
Intermediates
Ivabradine HCl
(S)-N-{(3, 4-Dimethoxybenzocyclobut-1-yl)}-N(methyl)]-N-(methyl) amine HCl - MBC.HCl
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, distillout
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-3benzazepin 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
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:
O
O
Sodium iodide,
THF
O
N
O
N
O
Cl
O
Water
I
IVA-I
CDB
Stage – II:
O
I
O
O
O
O
O
Potassium carbonate,
Acetone
N
+
O
IPA/ Pd-C
Toluene
N
Conc. HCl/ACN
N
.HCl
.HCl
O
NH
N
IVA-I
O
MBC.HCl
Intermediate - A
IVA-II
N
O
O
O
O
O
O
Stage – III:
O
O
O
EtOH/ MTBE
O
N
O
N
.HCl
N
.HCl
O
N
O
IVA-II
O
Crude IVA.HCl
O
O
Delta form of IVA-HCl
3. Flow chart of Mfg. process:
Stage-I: Process flow chart of Ivabradine IVA-I:
THF
CDB
NaI
Reactor
Stir and Heat
60±2°C
Maintain 60±2°C
Distill-out THF
THF
Cool RM
Water
Thick mass
Stirred RM
Filtered solid
Dry solid
IVA
Stage-I
ML
Stage-II: Process flow chart of Ivabradine (IVA-II):
Acetone
K2CO3
IVA-I
Reactor
MBC.HCl
Stir reaction mass
Maintain for 24-30 h
Distill-out Acetone
Acetone
Water
Toluene
Residue
Separated layers
Water
Aq. Layer
Toluene layer
Separated layers
Aq. Layer
Toluene layer
Distill-out toluene
Syrup
Aq. Layer
IPA
Heat to 55 ± 2°C
Solution transfer to
Auto-clave
Pd/c
H2
RM in autoclave
Heat RM to 60-65°C
Maintain 60-65°C
Cool RM to RT
Distillation
Acetonitrile
Conc. HCl
IPA
Syrup
Reaction mass
Filtered
Drying
IVA
Stage-II
ML
Stage-III: Process flow chart of Ivabradine (Ivabradine hydrochloride API):
Ethanol
IVA-II
Reactor
Heat RM
Clear solution
Filter
MTBE
Filtrate
Filter
Drying
IVA.HCl
API
ML
Material balance:
INPUT
Reactants :
CDB
NaI
Solvents :
Water
THF
Total Input
INPUT
Kg.
1.00
1.00
Water
Toluene
Acetone
Total Input
Kg.
A ) Product
A1 Product
1.25
B ) Solvent recovered
B1 - THF
4.30
C )Effluent
Aqueous Effluent
11.83
Organic residue
0.25
11.00
4.43
17.43
Kg.
Reactants :
Step-I
Potassium
carbonate
MBC.HCl
OUTPUT
17.43
OUTPUT
Kg.
A ) Product
A1 Product
1.37
B ) Solvent recovered
B1 - Acetone
B2- Toluene
4.60
7.82
C )Effluent
Aqueous Effluent
8.11
Organic residue
0.27
1.25
0.89
0.75
6.25
8.12
4.91
22.17
22.17
OUTPUT
INPUT
Reactants :
Step-II
Pd-C
Conc. HCl
Hydrogen
IPA
Water
Acetonitrile
Kg.
1.37
0.20
0.50
1.00
6.30
5.30
11.79
Salt for washing
Hyflo
Total Input
Kg.
A ) Product
A1 Product
1.00
B ) Solvent recovered
Acetonitrile
IPA
11.00
6.00
C )Effluent
Aqueous Effluent
8.09
Organic residue
0.17
C5 - Rec. Catalyst (Pd/c)
C3 - Spent solid (Hyflo,)
0.20
0.50
0.50
26.96
26.96
E: Anti hypertension:
Intermediates
API
16
2-Hydroxy-3-methoxy-3,3-diphenylpropanoic acid (DPA III) ,2S)-2-Hydroxy-3methoxy-3,3-diphenylpropanoic acid (DPA IV), 4,6-Dichloro-5-(2methoxyphenoxy)-2,2’-bipyrimidine ( DMB) , 5-(4-bromophenyl)-4,6dichloropyrimidine (BDP), 1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridine-3carboximidamide (FPC), [(E)-Phenyl diazenyl]Malononitrile(RGT-II), 4Isopropylamino butanol (4-IAV), Ammonium benzene sulfonate, 2-Ethoxy-5-(4Methyl Piperazinyl Sulfonyl) Benzoic Acid (SIL-III) , 4-amino-1-Methyl-3-n-propyl-5pyrazolecarboxamide hydrochloride(MPC-VII)
Product Name: 5 - (4-bromophenyl)-4,6-dichloropyrimidine. (BDP)
Capacity :
Application/Use of Product : Pharma Intermediate
A. Route of synthesis
Stage: - I
O
OH
CH3
Methanol, MDC
O
Br
(4-bromophenyl)acetic acid
O
Sulphuric Acid
Br
methyl (4-bromophenyl)acetate
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.
C.
Flow Chart:-
Methanol
4-Bromophenyl acetic
Reactor
Sulfuric Acid
Solvent recovery
MDC
Separation
Water
MDC recovery
Product
A. Route of synthesis
Stage: - II
O
O
CH3
O
CH3
THF,
CH3ONa
O
CH3
O
Br
Dimethyl Carbonate
methyl (4-bromophenyl)acetate
IPA,
O
Br
dimethyl (4-bromophenyl)propanedioate
BDP -I
BDP -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 NaOCH 3 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.
The product crystallizes. The crystals are collected, washed with IPA and dried to give 2-(4bromophenyl)-malonic acid dimethyl ester as light yellow crystals.
C. Flow Chart:-
BDP-I
NaOCH3
DMC
THF
Reactor
Water
Separation
Washing
Solvent recovery
IPA
Crystallization
Centrifuge
A. Route of synthesis
Product
Stage: - III
O
O
HO
CH3
O
CH3
+
HCONH2
CH3ONa , Methanol
N
O
Br
N
OH
Br
dimethyl (4-bromophenyl)propanedioate
BDP -II
5-(4-bromophenyl)pyrimidine-4,6-diol
BDP -III
B. Process: At room temperature sodium methoxidee) was added to a solution of dimethyl-(omethoxyphenoxy) 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
precipitate formed. The precipitate was collected, washed with water and dried to give 5-(omethoxyphenoxy)-4, 6-dihydroxy-pyrimidine as a white powder.
C. Flow Chart:-
BDP-II
Methanol
Formamide
Sodium methoxide
Reactor
Ammonium formate
Distillation
Acidification
Filtration
Water wash
Drying
Product
A. Route of synthesis
Stage: - IV
O
O
HO
CH3
O
CH3
+
HCONH2
CH3ONa , Methanol
N
O
Br
N
OH
Br
dimethyl (4-bromophenyl)propanedioate
BDP -II
5-(4-bromophenyl)pyrimidine-4,6-diol
BDP -III
B. Process: To a solution of 5-(4-phenyl)-4,6-dihydroxy-pyrimidine in POCl 3 . 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-(omethoxyphenoxy)-pyrimidine as a white powder repurification in methanol..
C. Flow Chart:-
BDP-III
POCl3
Reactor
Quenching
Filtration
Purification
Water + ICE
Water wash
Methanol
Drying
Product
D. Material Balance
Sr.
no
Input Raw Material
Name
Quantity
Kg
1
4-Bromophenyl acetic
acid
2
Sulfuric acid
0.45
3
Methanol
7.00
4
5
Dichloromethane (MDC)
Sodium hydrogen
Out put
Quantity
Kg
Remarks
1.50
6.00
0.50
Recover sulfuric acid 70%
0.65 By product
Recover Methanol
Methanol Vapour loss
during distillation
6.50
Recover MDC
MDC Vapour loss during
distillation
0.50 Scrubber
5.80
0.20 Scrubber
carbonate
5
Tetrahydrofuran(THF)
5.00
Sodium methoxide
1.10
Hydrochloric acid
3.00
IPA
6.00
7
Sodium sulfate
0.07
8
POCl 3
3.00
9
DM Water
6
10.00
Recover THF
THF Vapour loss during
distillation
4.90
Recover IPA
IPA Vapour loss during
distillation
5.80
Inorganic salt
0.10
Recover phosphoric acid
Aqueous Effluent
Product:-BDP
Organic Residue
Total Quantity input
43.62
Total Quantity output
0.10 Scrubber
0.20 Scrubber
10.00 By product
7.50
1.00
Desire product.
Hazardous
0.37 Waste storage.
43.62
F. Therapeutic category
Schizophrenia
API
Asenapine Maleate
Iloperidone
Intermediates
11-Chloro-2,3-dihydro-2-methyl-1H-dibenz[2,3:6,7] oxepino[4,5c]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)
1-[4-(3-Chloropropoxy)-3-methoxyphenyl]ethanone (CME)
(1R,2R)-Cyclohexane-1,2-diyldimethanol (HMC)
Lurasidone HCl
Paliperidone
3-Piperazin-1-yl-1,2-benzisothiazole (PBT FB)
(3aR,4S,7R,7aS)-hexahydro-4,7-methano-2H-isoindole-1,3-dione (
BHC)
3-(2-Chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (CHP)
Dibenzo-[b,f][1,4]-thiazepine-11(10H)-one (DTO)
Quetiapine
Hemifumarate
N-[Dibenzo-[b,f][1,4]-thiazepine-11-yl] piperazine di-HCl (DTPD)
1-(2-(2-Hydroxyethoxy)-ethyl) piperazine (HEEP)
6-Chloro-2-oxindole (6CO)
Ziprasidone HCl
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
-Trans-(4-amino-cyclohexyl)-acetic Acid ethyl ester
Cariprazine
N-[trans-4-(2-oxoethyl)cyclohexyl]-, 1,1-dimethylethyl ester
Trans-(4-amino-cyclohexyl)-acetic Acid
Boc-trans-4-aminocyclohexane acetic acid
Tioperidone
Paliperidone Palmitate
N-Ethoxycarbonyl piperazine ( NCP)
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 (POCl 3 ) 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
N,N-Dimethyl Aniline
S
S
Phosphorous Oxychloride
Toluene
N
N
H
Cl
O
Mole wt.= 245. 72
DTCl
Mole wt.= 227. 3
DTO
O
OH
N
Toluene
HN
HEEP
Conc.HCl,Sodium carbonate,MDC
water,sodium hydroxide
S
S
N
N
N
HOOC
N
ethanol,fumaric Acid
water
N
COOH
O
OH
Mole wt.= 883. 1
Quetiapine Hemifumarate
.2
N
O
OH
Mole wt.= 383. 5
Quetiapine free base
3. Process flow chart:
N- N-Dibenzo[b, f][1, 4]
thiazepine-11(10-H)-one
[DTO]
N,N-Dimethyl aniline
Phosphorus oxychloride
Toluene
CHLORINATION
Hydroxy ethoxy ethyl
piperazine [HEEP]
Toluene
Conc. Hydrochloric acid
Sodium carbonate
Dichloromethane
Water
Sodium Hydroxide
CONDENSATION
Ethanol
Fumaric acid
water
SALT FORMATION
QUETIAPINE
HEMIFUMARATE
Material Balance:
INPUT
Kg.
Reactants :
OUTPUT
Kg.
Remarks
A ) Product
BDP
6.75
n-propyl sulfonamide
4.59
Pottasium. Tert. Butoxide
4.72
A1 Product
5.00
B ) Solvent
recovered
Solvents :
DMSO
25.00
Ethyl acetate
35.00
methanol
30.00
Conc. HCl
3.71
B1-methanol
28.00
Reuse
B2-Ethyl acetate
33.00
Reuse
B3-DMSO
23.75
Reuse
C )Effluent
Total Input
INPUT
Aqueous Effluent
13.75
Organic residue
1.27
Inorganic salt
5.00
109.77
Kg.
Reactants :
MCT-stage-I
8.50
Ethylene glycol
24.00
Pottasium tert. butoxide
5.00
Citric acid
5.00
OUTPUT
109.77
0.00
Kg.
Remarks
A ) Product
A1 Product
5.00
B ) Solvent
recovered
Solvents :
Dimethoxy ethane
34.00
Ethyl acetate
20.00
Methanol
35.00
B1-Ethyl acetate
19.00
Reuse
B2-Methanol
32.50
Reuse
B3-Dimethoxy ethane
32.50
Reuse
B4-Ethylene glycol
22.50
Reuse
C )Effluent
Total Input
131.50
Aqueous Effluent
6.50
Organic residue
1.75
Inorganic salt
11.75
131.50
INPUT
Reactants :
MCT-stage-II
5-bromo-2chloropyrimidine
Kg.
OUTPUT
Kg.
Remarks
A ) Product
11.10
A1 Product
5.00
8.00
Sodium Hydride
3.80
Citric acid
2.80
B ) Solvent
recovered
Solvents :
Tetrahydrofuran
DMF
22.20
11.10
Ethylacetate
6.00
Methanol
10.00
Water
5.00
B1-Tetrahydrofuran
21.00
Reuse
B2-DMF
10.50
Reuse
B3-Ethyl acetate
5.60
Reuse
B4-Methanol
9.40
Reuse
B5-Process loss
2.80
Scrubber
C ) Effluent
Total Input
80.00
Aqueous Effluent
20.00
Organic residue
1.70
Inorganic salt
4.00
80.00
G. Therapeutic
category
Product Name
Overactive Bladder
Intermediates
2-(4-Nitrophenyl) ethanamine HCl (NPA. HCL)
Mirabegron
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 (MBRI):
OH
NH2
OH
. HCl
O
NO2
R(-) Mandelic acid
Mole.Formula: C8H8O3
Mol. Wt.: 152.15
NPA.HCl
2-(4-Nitro-phenyl)- ethylamine HCl
Mole. Formula: C8H11 ClN2O2
Mol. Wt.: 202.64
N,N-Diisopropylethyl amine Acetonitrile, Ethyl acetate
Trimethyl borate, HCl
Toluene
Sodium hydroxide
Sodium chloride
OH
NH
O
NO2
MBR-I
(R)-2-Hydroxy-N-[2-(4-nitro-phenyl)-ethyl]-2-phenyl-acetamide
Mole. Formula: C16H16N2O4
Mol. Wt.: 300.31
Stage II: Preparation of (R)-2-[[2-(4-Nitrophenyl)-ethyl]-amino]-1-phenyl-ethanol hydrochloride
(MBR-II)
OH
H
N
O
NO2
MBR-I
(2R)-2-Hydroxy-N-[2-(4-nitrophenyl)-ethyl]-2-phenyl-acetamide
Mole. Formula: C16H16N2O4
Mol. Wt.: 300.31
Methylene dichloride
Isopropyl alcohol HCl
Sodium chloride
Methanol
Isopropyl alcohol
OH
Sodium borohydride
Tetrahydrofuran,
Conc.HCl
Sodium Thiosulphate Pentahydrate
Iodine
Liquid ammonia
H .HCl
N
NO2
MBR-II
(R)-2-{[2-(4-nitro-phenyl)-ethyl]amino}-1-phenyl-ethanol hydrochloride
Mole. Formula: C16H19ClN2 O3
Mol. Wt.: 322.79
Stage III: Preparation of (R)-2-[[2-(4-aminophenyl)-ethyl]-amino]-1-phenyl-ethanol hydrochloride
(MBR-III)
OH
H
N
.HCl
NO2
MBR-II
(1R)-2-{[2-(4-nitro-phenyl)-ethyl]amino}1-phenylethanol hydrochloride
Mole. Formula: C16H19ClN2O3
Mol. Wt.: 322.79
Isopropyl alcohol Raney nickel
Methanol
Toluene
Hydrogen gas
OH
H .HCl
N
NH2
MBR-III
(R)-2-[[2-(4-amino-phenyl)-ethyl]amino]-1-phenylethanol hydrochloride
Mole. Formula: C16 H21ClN2O
Mol. Wt.: 292.80
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)
OH
H
N
. HCl
S
O
NH2
NH2
N
HO
MBR-III
ATA
(R)-2-[[2-(4-amino-phenyl)-ethyl]amino]1-phenylethanol hydrochloride
Mole. Formula: C16H21ClN2 O
Mol. Wt.: 292.80
Conc. HCl
Liq. ammonia
Ethyl acetate
n-Butanol
Toluene
Isopropyl alcohol
Sodium Chloride
OH
2-[2-Amino-thiazole-4-yl] acetic acid
Mole. Formula: C5H6N2O2 S
Mol. Wt.: 158.18
N .HCl
N
N
[1-(3-dimethylaminopropyl)3-ethylcarbodiimide monohydrochloride]
(EDC.HCl)
H
N
O
S
NH2
N
H
N
MBR-IV
2-(2-Amino-1,3 thiazole-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2phenylethyl]amino}ethyl) phenyl] acetamide
Mole.Formula:C21H24 N4O2S
Mol. Wt.: 396.51
3. Process flow chart;
Stage I: (R)-2-hydroxy-N-[2-(4-nitrophenyl) ethyl]-2-phenylacetamide (MBR-I)
R (-) Mandelic acid + NPA. HCl
Acetonitrile
Trimethyl borate
N, N-Di isopropyl ethyl amine
Ethyl acetate
Sodium Hydroxide
Dil. HCl
10 % Brine solution
Sodium Chloride
Toluene
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
Tetrahydrofuran
Sodium Borohydrate
Iodine solution (THF+ Iodine)
Methanol
Sodium Thiosulphate
Pentahydrate
Methylene dichloride
Isopropyl alcohol
Purified water
10 % Brine solution
Conc. HCl
Aq. Ammonia solution
IPA. HCl
MBR-II
Stage III: (R)-2-[[2-(4-aminophenyl)-ethyl]-amino]-1-phenyl-ethanol hydrochloride (MBR-III)
MBR-II
Methanol
Hydrogen
Isopropyl alcohol
Toluene
Activated raney nickel
MBR-III
Stage IV: 2-(2-Amino-1,3 thiazole-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)
phenyl] acetamide (MBR-IV)
MBR-III
Ethyl acetate
n-butanol
Liq. ammonia
ATA
EDC. HCl
Conc. HCl
Sodium chloride
Purified water
Toluene
Isopropyl alcohol
Activated carbon Norit CN1
MBR-IV
ATA: 2-[2-Amino-thiazole-4-yl]acetic acid
EDC. HCl: 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide mono hydrochloride
INPUT
Reactants :
NPA
R (-) Mandelic acid
Trimethyl borate
DIPEA
Solvents :
Kg.
15.00
16.89
11.54
14.34
OUTPUT
Kg.
A ) Product
A1Product
18.90
B ) Solvent
recovered
B1 - Acetonitrile
B2- Toluene
B3 - Ethyl Acetate
43.00
70.00
43.00
Remarks
Reuse
Reuse
Reuse
Ethyl acetate
Toluene
Water
Salt for washing
NaCl
Total Input
INPUT
Reactants :
MBR Step-I
THF
Sodium
borohydrate
Iodine
45.00
75.00
50.00
5.00
Kg.
15.00
66.00
6.61
25.35
8.20
10.80
Solvents :
Methanol
Water
MDC
5.55
60.00
90.00
Salt for washing
Nacl
6.00
INPUT
Reactants :
MBR Step II
Raney Nickel
79.00
Organic residue
5.87
Inorganic salt
settle solid
16.00
232.77
Conc.HCl
NaOH
Total Input
C )Effluent
Aqueous Effluent
293.51
Kg.
15.00
3.00
275.77
OUTPUT
Kg.
A ) Product
A1 -Product
12.09
B ) Solvent
recovered
B1 -THF
B2- MDC
B3- Methanol
63.00
86.00
5.20
C )Effluent
Aqueous Effluent
Organic residue
111.35
3.87
Inorganic salt
OUTPUT
Remarks
Reuse
Reuse
Reuse
12.00
293.51
Kg.
A ) Product
A1 Product
11.57
B ) Solvent
recovered
B1 -Methanol
142.00
Remarks
Reuse
Solvents :
Ethyl Acetate
Methanol
Hyflo
Carbon (charcoal)
Total Input
INPUT
Reactants :
MBR step III
ATA
EDC.HCl
Conc. HCl
60.00
150.00
1.00
1.5
230.50
Kg.
15.00
8.18
11.88
5.40
Solvents :
Water
Ethyl Acetate
n-heptane
75.00
75.00
60.00
Total Input
250.46
B2- Ethyl acetate
57.00
C )Effluent
Organic residue
Aqueous Effluent
3.43
11.00
Rec. Catalyst
Spent solid
(Carbon ,Hyflo,)
OUTPUT
3.00
2.50
Reuse
230.50
Kg.
A ) Product
A1 Dry Product
14.22
B ) Solvent
recovered
B1 - Ethyl Acetate
B2 - n-heptane
B3 - EDC
71.00
58.00
9.00
C )Effluent
Aqueous Effluent
Organic residue
Reuse
95.50
2.74
250.46
Remarks
Reuse
Reuse
Reuse
H:
Therapeutic category
API
Multiple sclerosis
Intermediates
5-methylisoxazole-4-carboxylic acid
(MIC)
Teriflunomide
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 4trifluoromethyl
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):
O
O
N
O
CH3
NH2
Cl
OH
SOCl2
F
+
Dimethaoxyethane
N
O
F
CH3
F
TFMA
MIC
Dimethaoxyethane
Water
Toluene
O
F
N
O
F
NH
F
CH3
Leflunomide
Stage-II: (Z)-2-Cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl) amide
(Teriflunomide):
N
O
N
O
F
F
NH
CH3
Leflunomide
F
Methanol
NaOH
Conc.HCl/ Water
Acetone
H3C
NH
OH
F
O
F
Teriflunomide
F
3. Process Flow chart:
Stage-I: Preparation of N-(4-trifluoromethyl)-5-methylisoxazole-4-carboxamide (TFN-I/
Leflunomide):
DME
Reactor
MIC
Reactor
Heat
Thionyl chloride
Reaction mass
Stir 3-4 hrs. at 70-80°C.
Reaction mass
Distilled out DME u/v at below 50°C
Distilled DME
DME
Residue
Distillation
DME
Distilled DME
Residue
Slowly added at below at 25°C
DME
TFMA
Reactor
Cool to 0-5°C
Reaction mixture
Stir for 45-60 min at 20-25°C
Filtration
Filtrate
Recovered TFMA HCl salt
Distilled out DME U/V at below 50°C
Water
Residue
Distilled DME
Cool to 25-30°C
Stir for 45-60 min at 25-30°C
Reaction mixture
Water
Filtration
Stir
Wet material
MLs
Drying
Leflunomide
Stage-II: Preparation of (Z)-2-Cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)
amide:
1. Methanol
2. Leflunomide
Reactor
NaOH solution
(NaOH dissolved in Purified water)
Charcoal
Methanol
Conc. HCl
Reaction mixture
Stir for 30 min at 25-30°C
Celite bed
Reaction mixture
Stir for 60 min.at 25-30°C
Filtrate
Methanol MLs
Purified water
Wet solid
Water MLs
Purified water
Wet solid
Heat to 45-50°C
Stir for 60 min at 45-50°C
Filtration
Acetone & water
Wet solid (Teriflunomide)
Heat to 50-55°C for 60 min
Crystallization mixture
Cool to 25-30°C & stir for 60 min
Crystallization mixture
Water
Centrifuge
Drying
Teriflunomide
I.
Therapeutic category:
API
Ticagrelor
Acute coronary syndrome
Intermediates
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 NO 2 (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 (Na 2 CO 3 +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
heptane.
n-
2. Route of synthesis:
Stage-I: Preparation of TGR-I:
Cl
.Tartarate
O
H2N
NH2
HO
Cl
O
NH2
N
N
O
GTR-03- V
CH3
S
Cl
HO
N
Monoethylene glycol/N,N-Diisopropyl ethylamine
DBU/Ethyl acetate/n-Heptane
O
NH
O
O
H3C
CH3
N
S
NaCl /Purified water
H3C
CH3
CH3
TGR-I
GTR-02
Molecular Formula
= C10H19NO4 C4H6O6
Formula Weight
= 367.34
= C17H27ClN4O4S
Molecular Formula
Formula Weight
= 418.93
Stage-II: Preparation of TGR-II:
N
NH2
NH
O
Cl
HO
N
O
O
H3C
CH3
N
Purified water+ Sodium Nitrite
+ Amersep -900(OH) Form
=Resin NO2
N
Cl
HO
N
O
PTSA, Acetonitrile
Sodium Bicarbonate, sodium Chloride
MDC
S
N
O
N
O
H3C
S
CH3
TGR-II
TGR-I
CH3
CH3
Formula Weight
= C17H24ClN5O4S
Molecular Formula
= C17H27ClN4O4S
Molecular Formula
Formula Weight
= 418.93
= 429.92
Stage-III: Preparation of TGR-III:
N
N
F
N
N
N
Cl
HO
F
H2N
O
H3C
N
N
.mandalate
S
NH
HO
GTR-01
O
O
CH3
N
O
O
K2CO3,Purified water,Acetonitrile
MDC,Conc. HCl,NaCl
H3C
N
N
O
CH3
S
F
TGR-II
CH3
Molecular Formula = C17H24ClN5O4S
Formula Weight
= 429.92
TGR-III
CH3
Molecular Formula = C26H32F2N6O4S
Formula Weight
= 562.63
F
Stage-IV: Preparation of TGR-IV:
N
N
N
N
N
NH
HO
O
H3C
N
O
O
N
NH
HO
Conc HCl,Purified Water,
NaOH
N
HO
N
OH
N
O
Ethyl acetate, NaCl,
Na2CO3, Acetonitrile
S
CH3
S
F
F
TGR-III
CH3
TGR-IV
F
F
Molecular Formula = C23H28F2N6O4S
Formula Weight
= 522.56
Molecular Formula = C26H32F2N6O4S
Formula Weight
CH3
= 562.63
STAGE-V: PREPARATION OF TGR-V
N
O
O
N
HO
HO
N
N
OH
NH
N
HO
Ethyl acetate, n-heptane
N
HO
OH
NH
N
N
S
S
F
TGR-IV
N
N
CH3
F
Molecular Formula = C23H28F2N6O4S
Formula Weight
= 522.56
F
TGR-V
Ticagrelor
CH3
F
Molecular Formula = C23H28F2N6O4S
Formula Weight
= 522.56
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-4yl]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}-2,2dimethyl 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:
GTR-03-V
GTR-02
Monoethylene glycol
1,8-Diazabicyclo (5,4,0) Undec-7-ene
(DBU) (LR Grade)
N,N-diisopropyl ethyl amine
Purified water
Ethyl acetate
n-Heptane
Sodium chloride
TGR-I
Stage-II: TGR-II:
TGR-I
Sodium nitrite
Purified water
Amersep-900 (OH) form
Para-toluene sulphonic acid
Acetonitrile
Methylene Dichloride
Sodium chloride
Sodium bicarbonate
TGR-II
Stage-III: TGR-III:
TGR-II
GTR-01
Acetonitrile
K2CO3
Purified water
Conc. Hydrochloric acid
Methylene dichloride
Sodium Chloride
Acetonitrile
TGR-III
Stage-IV: TGR-IV:
TGR-III
Conc. Hydrochloric acid
Purified water
Sodium Hydroxide
Ethyl acetate
Sodium Chloride
Sodium Bicarbonate
Acetonitrile
TGR-IV
Stage-V: TGR-V:
TGR-IV
N-Heptane
Ethyl acetate
TGR-V
PRODUCT
:
INPUT
Ticagrelor Stage -I
Kg.
OUTPUT
Reactants :
Kg.
Remarks
A ) Product
GTR-03
5.00
GTR-02
N,N-diisopropyl ethyl
amine
8.50
12.50
DBU
0.25
Solvents :
A1 - Dry Product
0.00
B ) Solvent
recovered
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
Sodium chloride
7.50
Charcoal
0.70
Hyflow
1.00
Aqueous Effluent
102.00
Organic residue
1.75
Spent solid
1.70
(Carbon, Hyflo)
Total Input
200.45
200.45
PRODUCT
:
INPUT
Ticagrelor Stage -II
Kg.
OUTPUT
Reactants :
Kg.
Remarks
A ) Product
TGR-I
7.00
PTSA
4.78
Ambersep-900 OH
15.00
Sodium nitrite
9.03
A1 - Brinzolamide
stage-II (Syrup)
0.00
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
PRODUCT
188.48
:
INPUT
188.48
Ticagrelor Stage -III
Kg.
OUTPUT
Reactants :
TGR-II
7.10
GTR-01
5.00
Potasium carbonate
4.55
A ) Product
A1 - Dry Product
Kg.
Remarks
0.00
B ) Solvent
recovered
Solvents :
Purified water
97.06
Ethyl acetate
90.00
B1-Ethyl acetate
86.00
Reuse
B2-Process loss
4.00
Scrubber
C ) Effluent
Total Input
203.71
Aqueous Effluent
106.00
Organic residue
2.71
Inorganic salt
5.00
203.71
PRODUCT
:
INPUT
Ticagrelor Stage -IV
Kg.
OUTPUT
Reactants :
TGR-III
8.94
Conc. HCL
44.72
A ) Product
A1 - Dry Product
Kg.
Remarks
5.90
B ) Solvent
recovered
Solvents :
B1 - Ethyl acetate
53.00
Reuse
Reuse
MDC
45.00
B2 - MDC
43.00
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
2.36
Activated carbon
1.18
Spent solid
Hyflo
1.18
(Carbon, Hyflo)
Total Input
PRODUCT
182.50
:
INPUT
182.50
Ticagrelor Stage -V
Kg.
OUTPUT
Reactants :
TGR-IV
5.90
Solvents :
A ) Product
A1 - Dry Product
B ) Solvent
recovered
Kg.
Remarks
5.00
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
Therapeutic category Psoriatic Arthritis
J
API
Intermediates
3-acetamidophthalic anhydride(APA)
(S)-2-(3-Ethoxy-4-methoxyphenyl)-1-methyl sulphonyl)-eth-2yl
amine (EMS)
Apremilast
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):
O
O
O
CH3
CH3
O
O
H3C
NH
O
S
H2N
3.
Mass Balance:
N
O
1.3
Kg.
Reactants :
O
OUTPUT
Apremilast
Kg.
A ) Product
EMSA
1.00
APA
sodium
bicarbonate
1.30
0.75
A1 Product
B )Solvent
recovered
0.35
Dimethoxyethane
7.70
Dichloromethane
12.85
Solvents :
O
CH3
NH
H 3C
EMSA
Batch Size : Kg.
INPUT
S
O
MDC/ NaHCO3
Acetone/ Methanol
O
O
APA
CH3
H
O
Dimethoxyethane
Acetic acid
+
O
CH3
O
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
CH3
Flow chart of Mfg. process:
1. APA
2. EMSA
3. Acetic acid
Dimethoxyethane
Heat 80-85°C
Reaction Mixture
Maintaining at 80-85°C
Reaction Mixture
Distillation
Dimethoxyethane Distillation
Residue
Cool 25-30°C
Purifier water
Dichloromethane
Reaction Mixture
Organic layer
Dichloromethane
7% NaHCO 3 washing
Aqueous layer
Aqueous layer
Organic Layer
Aqueous layer
Organic Layer
Distillation
Acetone
Methanol
Residue
Distilled MDC
Reaction mixture
Stir at 50-55°C
Reaction mixture
Cool 0-5°C
Reaction mixture
Stir at 0-5°C
Methanol washing
Filtration
MLs
Drying
Apremilast
K
Therapeutic category
Product Name
Ivacaftor
Cystic fibrosis
Intermediates
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 4Oxo-1, 4-dihydro-quinoline-3-carboxylic acid [ODC] (44.9 g, 237 mmol), Diisopropyl 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 6366 °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:
OH
O
OH
O
OH
N
H
+
H2N
ODC
ADP
MW: 189. 17
MW: 221. 34
1. DMF
2. DIPEA
3. BOP
4. Ethyl Acetate
5. Aq. Ammonia
6. Methanol
7. Acetone
O
O
NH
N
H
Ivacaftor
MW: 392. 49
3. Flow chart of Mfg. process:
N, N-Dimethylformamide
ODC
DIPEA
DIPEA
BOP
ADP
DM water
Stirring at 25-30 °C
Stirring at 25-30 °C
for 20 h
At 20-30 °C
Ethyl acetate
Layer separation
Aq. layer
Dilute aq. ammonia
Organic layer
Layer separation
Aq. layer
5 % Brine solution
Organic layer
Layer separation
Aq. layer
Concentration of
Organic layer
Methanol
Recovered
Ethyl acetate
Heating to 63-66 °C
Cooling to 25-30 °C
Filtration
Drying at 55-60 °C
Ivacaftor
PRODUCT : Ivacaftor
Batch Size : Kg.
0.078
INPUT
Kg.
Reactants :
OUTPUT
Kg.
A ) Product
ADP
0.05
ODC
0.04
DIPEA
0.06
BOP
0.15
A1 Product
0.08
B ) Solvent recovered
Solvents :
Ethyl acetate
0.85
Methanol
0.19
DMF
0.45
Process loss
0.08
Water
6.00
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
Therapeutic category
API
L
Suvorexant
Insomnia
Intermediates
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]-1,4diazepane-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
NH
O
+
N
N
N
N
N
EDC/HOBt/ DMF/
TEA/water
HO
O
O
O
N
N
N
N
O
MDA
MTB
SRT - I
Synthesis of SRT-II (Step-2):
N
O
O
O
N
N
SRT - I
N
N
Cl
+
N
Cl
Pd/H2/Methanol/
DMF/TEA/water Cl
O
N
N
O
DCB
N
O
SRT - II
Suvorexant
N
N
N
3. Process Flow chart:
Step-I: Preparation of SUV-III
MDA
DMF
MTB
TEA
EDC
Reactor
HOBt
Stir reaction mass
Water
Ethyl acetate
Quenching of
reaction mass
Layer separation
Aq. layer
Distillout of ethyl
acetate
Ethyl acetate
SRT-I
Step-II: Preparation of Suvorexant
SRT-I
Methanol
H2 gas
Hydrogenator
Filtration
Catalyst
Concentration of
filtrate
DMF
Methanol
White solid
TEA
DCB
Reaction mass
Water
Maintaining
Filtration
Drying
SRT-II
(Suvorexant)
Ml
PROCESS MASS BALANCE
PRODUCT
:Suvorexant; SRT-I (Step -I)
Batch Size : Kg.
INPUT
0.15
OUTPUT
Kg.
Reactants :
Kg.
Remarks
A ) Product
MDA
0.10
TEA
0.08
EDC
0.08
B ) Solvent recovered
HOBt
0.05
Ethyl acetate
0.47
Reuse
MTB
0.08
DMF
0.19
Reuse
Process loss
0.04
Scrubber
Solvents :
A1 - Product
0.15
0.00
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.
INPUT
0.095
OUTPUT
Kg.
Reactants :
Kg.
Remarks
A ) Product
SRT-I
0.10
A1 - Product
10 % Pd/C
0.01
B ) Solvent recovered
TEA
0.05
Methanol
0.84
Reuse
DCB
0.05
DMF
0.18
Reuse
Process loss
0.05
Scrubber
Solvents :
0.10
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
API
Netupitant
Rolapitant
Antiemetic
Intermediates
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
temperature provide Netupitant.
Page 1 of 5
at elevated
2. Route of synthesis:
2.1 Preparation of Methyl-[6-(4-methyl-piperazin-1-yl)-4-O-tolyl-pyridin-3-yl]amine:-
N
N
N
N
N
HC(OMe)3,LiAlH4
N
NH2
NH
Amine compound
Netupitant-I
2.2 Preparation of Netupitant:-
N
N
O
NH
Netupitant-I
N
F 3C
N
+
N
CF 3
MDC
Cl
N
DIPEA
Acyl compound
N
O
CF 3
CF 3
II (Netupitant)
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
6-(4-methyl-piperazin-1-
Trimethyl ortho formate
yl)-4-O-tolyl-pyridin-3-
Trifluoroacetic acid
yl-amine
Round bottom Flask
Reaction maintenance 130°C, 3h
Distillation
Recover trimethyl ortho
formate
THF, LAH
Residue
Maintenance at 30°C, 1h
HCl/NaOH
Acidic and Basic work up
Distillation
Syrup [Netupitant-I]
Page 3 of 5
Recover THF
3.2 Preparation of Netupitant
2-(3,5-bis-trifluoromethyl-
Stage-I/DIPEA
phenyl)-2-methyl
MDC
propionylchloride
Round bottom Flask
Reaction maintenance reflux, 3h
NaHCO3 sol
Work up
Distillation
Syrup
Netupitant
Page 4 of 5
Aq. Layer
Recover MDC
PRODUCT :
Batch Size :
INPUT
NetupitantI
1.00
Kg.
OUTPUT
Reactants :
6-(4-methyl-piperazin-1-yl)4-O-tolyl-pyridin-3-yl-amine
Trimethyl ortho formate
Trifluoroacetic acid
1.60
A1 Product
12.34
0.09
LAH
sodium hydroxide
Solvents :
THF
0.43
2.00
4.50
Conc. HCl
1.50
Organic residue
Water
Total Input
6.00
28.46
INPUT
Reactants :
Netupitant-I
2-(3,5-bis-trifluoromethylphenyl)-2-methyl
propionylchloride
DIPEA
Sodium bicarbonate
Solvents :
MDC
water
1.00
4.41
Reuse
11.96
0.47
Reuse
Scrubber
10.50
0.12
28.46
NetupitantII
1.00
Kg.
0.70
OUTPUT
A ) Product
A1 Product
0.84
B ) Solvent recovered
5.50
0.35
B1-MDC
B2-DIPEA
B3-Process loss
Kg.
18.89
Page 5 of 5
Remarks
1.00
2.40
5.40
0.20
2.50
9.00
C )Effluent
Aqueous Effluent
Organic residue
Total Input
Remarks
A ) Product
B ) Solvent recovered
B1-THF
B2-Trimethyl ortho
formate
B3-Process loss
C )Effluent
Aqueous Effluent
PRODUCT :
Batch Size :
Kg.
9.80
0.09
18.89
Reuse
Reuse
Scrubber
N
Therapeutic
category
API
Vildagliptine
Antidiabetic
Intermediates
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. H 2 SO 4 and conc. HNO 3 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. NH 3 , 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.NH 3 , 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
NH2
H2SO4/HNO3
Water
HCl
NaOH
Toluene/ n-Butanol
n - heptane / Methanol
Adamantan-1-amine
hydrochloride
OH
3-Aminoadamantan-1-ol
Mol. F. = C10H17NO
Mol. F. = C10H18ClN
Mol. Wt = 187. 71
Mol. Wt = 167 . 24
2. (2S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile (CCP) (VLD-II):
O
N
H
CN
Chloroacetyl chloride,
MDC
N
2, 6-lutidine/ TFAA
aq. HCl / NH4CO3 / NaHCO3
IPA/ n - Heptane
NH2
O
Cl
(2S)-1-(chloroacetyl)pyrrolidine2-carbonitrile
(2S)-Pyrrolidine-2-carboxamide
Mol F = C5H10N2O
Mol. F. = C7H9ClN2O
Mol. Wt = 114. 15
Mol. Wt = 172 . 61
3. Vildagliptin (VLD-III):
HO
CN
N
+
Acetone/KI /K2CO3
N
NH2
O
Aceticacid/Tartaric acid/Liq. NH3
MDC/ MEK
Cl
3-Aminoadamantan-1-ol
(2S)-1-(chloroacetyl)pyrrolidine2-carbonitrile
Mol. F. = C10H17NO Mol. F. = C H ClN O
7 9
2
Mol. Wt = 167 . 24
Mol. Wt = 172 . 61
HO
NH
O
CN
(2S)-1-{[(3-hydroxy-1-adamantyl)amino]
acetyl}pyrrolidine-2-carbonitrile
Mol. F. = C17H25N3O 2
Mol. Wt = 303 . 40
4. Process flow chart:
1. 3-aminoadamantan-1-ol (HAA) VLD-I:
Conc. H2SO4
Conc. HNO3
1-adamantyl amine HCl
50% NaOH solution
n-butanol + toluene
Reactor
Quenching
Separation
Aqueous layer
Organic layer
30% brine solution
Separation
Aqueous layer
Organic layer
Distillation
Methanol
n-heptane
n-heptane
Reaction mass
Centrifugation
Drying
VLD-I
2. (2S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile (CCP) (VLD-II):
Dichloromethane
L-prolinamide
2,6 lutidine
Chloroacetyl chloride
Trifluoro acetic anhydride
Ammonium carbonate
Purified water
Dichloromethane
washing
Reactor
Cooling and stirring
Separation
Aqueous layer
Organic layer
Aq. HCl washing
Separation
Aqueous layer
Organic layer
Aq. Sodium bicarbonate
washing
Separation
Filtration
Distillation
Isopropyl alcohol
n-heptane
Reaction Mass
n-heptane
Centrifugation
Drying
VLD-II
Dichloromethane
3. Synthetic scheme of vildagliptin (VLD-III):
Acetone
VLD-I
VLD-II
Potassium iodide
Potassium carbonate
Condensation
Distillation
Purified water
Acetic acid
Dichloromethane
Acetone
Reaction Mass
Separation
Organic layer keep aside
Aqueous layer
Aq. NH3
Dichloromethane
Separation
Organic layer
Purified water
Tartaric acid solution
Separation
Aqueous layer
Organic layer
Filtration
Organic layer
Distillation
Methyl ethyl ketone
Reaction Mass
Distillation
Methyl ethyl ketone
Dichloromethane
Methyl ethyl ketone
Centrifugation
Drying and sifting
VLD-III
Material Balance
INPUT
Reactants :
1-admantyl amine hydrochloride
Conc. Sulphuric acid
Conc. Nitric acid
Potassium hydroxide
Solvents :
Water
n-butanol
Toluene
methanol
n-hepatane
Total Input
Kg.
7.94
43.83
11.12
65.70
60.00
50.00
30.00
15.00
25.00
308.59
OUTPUT
A ) Product
A1 Product
B ) Solvent recovered
B1 - methanol
B2- n- hepatane
B3- Toluene
B4- n-butanol
C )Effluent
Aqueous Effluent
Organic residue
Spent Acid
Inorganic salt
Kg.
Remarks
5.00
14.00
24.00
29.00
49.00
Reuse
Reuse
Reuse
Reuse
74.00
0.59
70.00
43.00
308.59
PRODUCT : Vildagliptin (CCP-I)
INPUT
Reactants :
L- prolinamide
Chloroacetyl chloride
Potassium carbonate
Solvents :
Chloroform
Ethyl acetate
Total Input
Kg.
9.14
9.96
11.06
90.00
32.90
153.06
OUTPUT
A ) Product
A1 Product
B ) Solvent recovered
B1 -Chloroform
B2- Ethyl acetate
C ) Effluent
Aqueous Effluent
Inorganic salt
Organic residue
Kg.
Remarks
7.95
87.00
31.00
4.90
21.50
0.71
153.06
PRODUCT : Vildagliptin (CCP-II)
INPUT
Reactants :
CCP-I
Trifloro acetic anhydride
Amonnium bicarbonate
Solvents :
Water
Tetrahydrofuran
Toluene
n-hepatane
Kg.
OUTPUT
A ) Product
A1 Product
B ) Solvent recovered
B1 -Tetrahydrofuran
B2- n-hepatane
39.75 B3- Toluene
70.76 C ) Effluent
124.50 Aqueous Effluent
60.34 Organic residue
7.95
17.61
24.72
Kg.
5.17
68.00
58.00
120.00
49.60
0.86
Remarks
Total Input
345.63
C3 - settle solid
(Ammonium Trifluro
acetate
& Bicarbonate)
44.00
345.63
PRODUCT : Vildagliptin
INPUT
Reactants :
HAA
CCP-2
Potassium carbonate
Acetic acid
tartaric acid
Liq. Ammonia
Potassium iodide
Kg.
5.00
5.17
4.13
2.23
1.67
8.44
0.25
Solvents :
Water
Tttrahydrofuran
Dichloromethane
Methylethylketone
Total Input
50.00
48.00
112.00
30
266.88
OUTPUT
A ) Product
A1 Product
B ) Solvent recovered
B1 -Tetrahydrofuran
B2- Dichloromethane
B3- Methylethylketone
C ) Effluent
Aqueous Effluent
Organic residue
settle solid
(Ammonium Trifluro
acetate
Kg.
5.00
46.00
108.00
28.50
61.50
0.88
17.00
266.88
Remarks
Therapeutic category
API
Brinzolamide
O
Anti ocular Hypertensive.
Intermediates
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)-5chlorothiophene-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 SO 2 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
O
Br
OH
(+)-DIP Chloride*
CAS: 112246-73-8
Br
Cl
Cl
S
S
SO2NH2
SO2NH2
(S )-3-(2-Bromo-1-hydroxyethyl)-5chlorothiophene-2-sulf onamide
MF: C6H7BrClNO3S2, MW: 320.61
3-(2-Bromoacetyl)-5-chlorothiophene-2-sulf onamide
CAS: 160982-11-6,
MF: C6H5BrClNO3S2, MW: 318.60
NaOH
OH
Cl
NH
S
S
O
O
(S )-6-Chloro-3,4-dihydro-4-hydroxy-2H -thieno[3,2-e][1,2]thiazine-1,1-dioxide
Stage-I, CAS: 160982-16-1, MF: C6H6ClNO3S2, MW: 239.70
(+)-DIP Chloride* = (+)-Diisopinocampheylchloroborane
Stage-II: (S)-6-Chloro-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e][1,2]thiazine-1,1dioxide
OH
OH
K2CO3
+
Br
Cl
OMe
Cl
NH
S
S
O
O
Stage-I
O
O
1-Bromo-3-methoxypropane
MF: C4H9BrO, MW: 153.02
CAS: 36865-41-5
OMe
N
S
S
(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
Stage-III: (S)-3,4-Dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e][1,2]thiazine-6sulfonamide-1,1-dioxide
OH
OH
Cl
OMe
N
S
1) n-BuLi
2) SO2 gas
3) NH2OSO3H
H2NO2S
S
S
O
O
O
OMe
N
S
O
(S )-3,4-Dihydro-4-hydroxy-2-(3-methoxypropyl)-2H thieno[3,2-e][1,2]thiazine-6-sulf onamide-1,1-dioxide
Stage-III, CAS: 154127-42-1
MF: C10H16N2O6S3, MW: 356.44
Stage-II / (S)-HCM
Stage-IV: Brinzolamide (API)
HN
OH
1) CH3C(OMe)3
H2NO2S
N
S
S
O
Stage-III
1.
OMe
2) p-TsCl
3) EtNH2
H2NO2S
N
S
S
O
O
O
Brinzolamide
MF: C12H21N3O5S3, MW: 383.51
CAS: 138890-62-7
OMe
4. List of raw materials :
S.N.
01
02
03
04
05
06
07
08
09
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Name of raw material
3-(2-Bromoacetyl)-5-chlorothiophene-2-sulfonamide
[KSM]
(+)-DIP chloride
Methyl tert-Butyl ether
Toluene
Sodium hydroxide
Hydrochloric acid
1-Bromo-3-methoxypropane
Dimethyl sulfoxide
Potassium carbonate
Ethyl acetate
Sodium chloride
Sodium hypochlorite solution
n-Butyl lithium (1.6 M solution in hexane)*#
Hydroxyl amine-O-sulfonic acid (HOSA)#
Tetrahydrofuran
Sulfur dioxide gas*
Sodium acetate
Sodium bicarbonate
Dichloromethane
Acetonitrile
Trimethylorthoacetate
p-Toluene sulfonyl chloride
Ethyl amine (70% aqueous solution)
Triethylamine
Methanol
Isopropanol
Activated carbon (Norit CN1)
Activated carbon (Norit SX plus)
Celite
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** (309.8335.6 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
Cool to 25-30°C
Addition of Sodium hydroxide
solution (1200 ml) below 10°C
Addition of Sodium hydroxide solution
(X ml) below 10°C
(If required)
Reaction mass
In process-1: KSM (Impurity-2*): NMT 3.0%
(Refer Specification No. IP-0023)
Reaction mass
Raise to 25 -30°C and stir for 120 minutes
In process-2: pH : 10-12
(Refer Specification No. IP-0023)
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
Sodium hydroxide solution (200 ml)
Aqueous layer
Combined organic layer
Layer separation
Sodium hydroxide solution
(200 ml-Xml)
Organic layer
Aqueous layer
Continue on next page…..
HCB*- (S)-3-(2-Bromo-1-hydroxyethyl)-5-chlorothiophene-2-sulfonamide
Continue from previous page…..
Layer separation
Solvent recovery
Organic layer
Aqueous layer
Methyl tert-Butyl ether (600 ml)
Combined aqueous layer
Hydrochloric acid (LR grade)
(50-65 ml)
Methyl tert-Butyl ether
(400 ml)
Stir the reaction mass for 5-10 minutes
In process-4: pH : 1-2
(Refer Specification No. IP-0023)
Layer separation
Aqueous layer
Organic layer
Layer separation
Methyl tert-Butyl ether
(400 ml)
Aqueous layer
Organic layer
Layer separation
ETP
Aqueous layer
Activated carbon (Norit CN1)
(10 g)
Organic layer
Combined Organic layer
Continue on next page…..
Continue from previous page…..
Heat to 45-50°C and stir for 30-45 minutes and filtration
Methyl tert-Butyl ether
(100ml)
ETP
Hyflo bed
Filtrate
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)
seeding (if required)
for
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
Continue on next page…..
Continue from previous page…..
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
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[3,2e][1,2]thiazine-1,1-dioxide (Stage-I)
Output: 56-69 g
Solvent
recovery
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)
1 L 4 neck RBF
Potassium carbonate (173 g)
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
Ethyl aceatate (600 ml)
Process water (3000 ml)
5 L 4 neck RBF
Cool to 15-20°C
below 30°C
Mixture of solvent
Stir for 15-20 minute and layer separation
Organic layer
Aqueous layer
Organic layer
Aqueous layer
Ethyl acetate (400 ml)
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
Soution of Sodium hydroxide (40 g) in
Process water (1000 ml)
Reaction mass
Layer separation
Solution of Sodium
hypochlorite(20 ml) in
process water(180ml)
Organic layer
Solution of Sodium
chloride(90 g) in
process water (300ml)
Organic layer
Aqueous layer
ETP
Layer separation
Aqueous layer
ETP
Layer separation
Organic layer
Aqueous layer
ETP
Under vacuum distillation below 55°C
Solvent recovery
Oily mass
Degas the oily mass under vacuum below 10 mm of
In process-2: Ethyl acetate content by GC
Hg at 50-55°C
NMT 1.0%
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-(3methoxypropyl)-2H-thieno[3,2-e][1,2]thiazine-1,1dioxide (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-6sulfonamide-1,1-dioxide (Stage III)
Gas
Liquid
Solid
In-process-1: Assay of HOSA should be NLT 75%
Hydroxyl amine-O-Sulfonic acid (HOSA)
(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)
Sulphur dioxide gas
Reaction mass
below (-50°C)
(Clear solution)
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-1,1dioxide
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
Continue on next page…..
Solvent recovery
Continue from previous page…..
Process water (700 ml)
Sodium acetate (158 g)
5 L 3 neck RBF
Cool to 0-5°C
Hydroxyl amine-OSulfonic acid (145 g)
Below 20°C
Reaction mass
Reaction mass
(Suspension)
Stir for 30 minute below 20°C
Reaction mass
Raise to 25-30°C stir for 8 hours
In process-6: HSO 2 LiM: Limit- NMT 3.0%
(Refer Specification No. IP-0025)
Ethyl acetate (400 ml)
Reaction mass
Layer separation
Organic layer
Aqueous layer
Continue on next page…..
Ethyl acetate (400 ml)
Continue from previous page…..
Layer separation
Organic layer
Aqueous layer
Ethyl acetate (400 ml)
Layer separation
Organic layer
Sodium bicarbonate solution
(64 g in 800 ml water)
Aqueous layer
ETP
Combine Organic layer
Layer separation
Sodium bicarbonate solution
(64 g in 800 ml water)
Organic layer
Aqueous layer
ETP
Layer separation
Sodium chloride solution
g in 300 ml water)
(90
Organic layer
Aqueous layer
ETP
Layer separation
Activated carbon (Norit CN1)
g)
(5.0
Organic layer
Aqueous layer
ETP
Heat to 50-55°C and stir for 45 minutes and filtration
Ethyl acetate (100ml)
Hyflo bed
Continue on next page…..
Filtrate
Continue from previous page…..
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
Continue on next page…..
Brinzolamide Stage-III *= (S)-3,4-Dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e][1,2]thiazine6-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
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[3,2e][1,2]thiazine-6-sulfonamide-1,1-dioxide (Stage-III)
Output: 60-80 g
Solvent recovery
Flow diagram for (R)-3,4-Dihydro-4-(ethylamino)-2-(3-methoxypropyl)-2H-thieno[3,2-e][1,2]thiazine-6sulfonamide-1,1-dioxide (Brinzolamide) (Stage IV)
Gas
Liquid
Solid
Acetonitrile (1000 ml)
Nitrogen atmosphere
5 L 4 neck RBF
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 stageIII
Reaction mass
(Clear solution)
Cool to 40-45°C
Under vacuum distialltion below 45°C
Tetrahydrofuran
(THF) (600 ml)
In process-3: Moisture content NMT 0.2%
(Refer Specification No. IP-0026 )
Residual mass
Cool to 25-30°C
Residual mass
Cool to (-10) to (-5)°C
Triethylamine (62.5 g)
p-Toluene Sulfonyl chloride (107 g)
Ethylamine (70 % w/w solution)
addition (1446 g)
Reaction mass
Stir for 2 hours at (-10) to (-5)°C
In process-4: HPSM: NMT 1.0 %
(Refer Specification No. IP-0026)
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-6sulfonamide-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
Continue on next page…..
Continue from previous page…..
Mixture of Hydrochloric acid (LR
grade) (50ml) in Process water
(150 ml)
Combined organic layer
Layer separation
Aqueous layer
Sodium bicarbonate
(150-165 g)
Organic layer
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
Continue on next page…..
Continue from previous page…..
Solvent recocery
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
ETP
Aqueous layer
Heat at 50-55°C and stir for 30-45 minutes
Reaction mass
Hot Filtration
Ethyl acetate (100 ml)
ETP
Hyflo bed
Filtrate
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…..
Continue from previous page…..
Methanol (200 ml)
Residual solid
Heat to 62-70°C
Process water addition
(400 ml)
Reaction mass
solution)
(Clear
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
solution)
(Clear
Continue on next page…..
Continue from previous page…..
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%
If not complies (Part-B)
Complies
Methanol (200 ml)
Dry solid material
g)
(100
Heat to 62-70°C
Process water (400 ml)
Reaction mass
solution)
(Clear
Continue on next page…..
Continue from previous page…..
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
(Part-C)
If not complies
Dry solid material
g)
(100
Heat to 78-82°C
Activated carbon (Norit SX plus)
(10 g)
Reaction mass
Continue on next page…..
Isopropanol (800 ml)
Continue from previous page…..
Stir for 30-45 minutes at 78-82°C
Reaction mass
Hot filtration
Isopropanol (100 ml)
ETP
Hyflo bed
Filtrate
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
Continue on next page…..
Solvent recovery
Continue from previous page…..
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)-2Hthieno[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.
Reactants :
OUTPUT
A ) Product
Stage-III
22.00
A1 Product
Trimethylorthoacetate
18.21
B ) Solvent recovered
Triethylamine
9.98
B1 - Acetonitrile
23.54
B2 - THF
p-Toluene sulfonyl
chloride
Ethylamine (70% w/w
solution
Conc. HCl
Kg.
25.70
53.20
Solvents :
B3 - MDC
11.00
169.00
114.00
39.00
B4 - Ethyl acetate
40.00
B5 - Isopropanol
188.00
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
Remarks
Therapeutic category
API
Droproprizine
P
Cough Supressant
Intermediates
N-phenyl piperazine (NPP)
Product Name: N-phenyl Piperazine (NPP)
Capacity :
Application/Use of Product : Pharma Intermediate
A. Route of synthesis
Cl
OH
Cl
+
HN
O
MCB
2
S
+
HN
Cl
Refluxe
O
S
+
O
Cl
OH
2-[(2-hydroxyethyl)amino]ethanol
Formula Weight
= 105.136
N,N-bis(2-chloroethyl)amine
thionyl dichloride
Formula Weight
= 118.971
Formula Weight
= 142.026
H
N
Cl
NH2
+
HN
Refluxe
N
Cl
N,N-bis(2-chloroethyl)amine
Formula Weight
= 142.026
aniline
Formula Weight
= 93.127
1-phenylpiperazine
Formula Weight
= 162.232
HCl
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:MCB
DEA
Thionyl chloride
Aniline
Reactor
Separation
Organic layer
Recover MCB +
Aniline
Distillation
Fractional distillation
Product
A. Material Balance
Sr.
no
Input Raw Material Name
1
Monochloro Benzene(MCB)
2
NPA
3
Thionyl Chloride
4
Caustic Soda Flakes
5
Aniline
6
Water
Quantity
Kg
Out put
4.70 Recover MCB +Aniline
MCB +Aniline Vapour loss
during distillation
Remarks
4.60
0.50 Scrubber
1.00
2.40 SO 2 + HCl gas
3.00 Aqueous Effluent
1.0 Scrubber
9.00
3.20
4.00
Product:- N- phenyl
Piperazine
Organic Residue
Total Quantity input
Quantity
Kg
18.30
Total Quantity output
1.00
Desire product.
Hazardous Waste
2.20 storage.
18.30
Therapeutic category
API
Q
Fluconazole
Antifungal
Intermediates
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 1520°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:
O
O
F
+
N
N
N
N
NH2 Cl-
F
NaNO 2/HCl/NH4OH
N
N
Water
F
4-amino-1-[2-(2,4-difluorophenyl)-2-oxoethyl]-4H1,2,4-triazol-1-ium salt
Step-1
F
1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)
ethanone
Step-2
Ethylacetate
O
N
F
N
N
F
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
4- amino-1-[2 difluorophenyl)- 2oxoethyl)-4H-1,2,4-triazol-1-ium salt
(DFT-I)
NaNO2
NH4OH
HCl
Water
1-(2,4-difluorophenyl)-2-(1H-1,2,4triazol-1-yl)ethanone (DFT-II)
Step-II: Preparation of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (DFT-III) pure
1-(2,4-difluorophenyl)-2-(1H-1,2,4triazol-1-yl)ethanone (DFT-II)
Ethyl acetate
1-(2,4-difluorophenyl)-2-(1H-1,2,4triazol-1-yl)ethanone (DFT-III)
Material Balance:
PRODUCT : DFTA -I
INPUT
Kg.
Reactants :
1,3- Difluorobenzene
Aluminium Chloride
Chloroacetyl chloride
4-Amino 1,2,4- Trizole
Solvents :
MDC
IPA
Water
1815.00
1567.00
1125.00
Total Input
5562.00
250.00
322.00
250.00
233.00
OUTPUT
A ) Product
A1 DFT - I
B ) Recovered Solvent
B1 -MDC
B2 - IPA
C )Effluent
Aqueous Effluent
Organic residue
Settle Solid
(Al(OH)3,
Kg.
500.00
1770.00
1520.00
1570.00
14.00
188.00
5562.00
PRODUCT : DFTA - II
INPUT
Kg.
Reactants :
Step - I
Activated carbon
Hyflo
Sodium Nitrite
Liq. Ammonia
Solvents :
Water
Ethyl Acetate
1250.00
432.00
Total Input
2561.00
500.00
5.00
4.00
145.00
225.00
OUTPUT
A ) Product
A1 DFT - II
B ) Recovered Solvent
B1 -Ethyl Acetate
C )Effluent
Aqueous Effluent
Organic residue
Spent Carbon&hyflo
Kg.
330.00
420.00
1795.00
6.00
10.00
2561.00
PRODUCT : DFTA - III
INPUT
Reactants :
Step - III
Solvents :
Ethyl Acetate
Total Input
Kg.
298.00
432.00
730.00
OUTPUT
A ) Product
A1 -DFT - III
B ) Recovered Solvent
B1- Ethyl Acetate
Organic residue
Kg.
285.00
420.00
13.00
730.00
S
Therapeutic category
Antihyperparathyroidism
R)-(+)-1-(1-Naphthyl) ethylamine HCl -RNA(IV)
Cinacalcet HCl
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 3bromopropyl)-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.
H3C
. Mandelate
NH2
H3C
Dichloromethane
Water
NH2
Benzaldehyde
Aqueous ammonia
(1R)-1-(1-naphthyl)-N-[(1E)phenylmethy-lene]ethanamine
Mol. F.: C19 H17 N
Mol.Wt.: 259.34
(Schiff's Base)
(1R)-1-(1-naphthyl)
ethanamine
Mol. F.: C12H13 N
Mol.Wt.: 171.24
(1R)-1-(1-naphthyl)
ethanamine mandelate
Mol. F.: C20 H21 NO3
Mol.Wt.: 323.15
RNA-II
N-methyl-2pyrolidinone
(TPP-III)
F3C
F 3C
Aqueous Ammonia
Toluene
Con. Hydrochloric acid
Sodium metabisulphite
HN
CH3
.HCl
Diisopropyl ether
Ethyl acetate
Acetonitrile
Water
N-[(1R)-1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]
propan-1-amine. Hydrochloride
Mol. F.: C22H22 F3N. HCl
Mol.Wt.: 393.91
(Cinacalcet Hydrochloride)
N+
CH3
Br-
4. Process flow chart:
Preparation of Cinacalcet hydrochloride
Methylene Dichloride
+ water
(1R)-1-(1-naphthyl)
Ethanamine mandelate
EXTRACTION
Aqueous Layer
DISTILLATION
MDC
Aqueous Ammonia
Benzaldehyde
MAINTENANCE
N-methylpyrrolidinone
1-(3-bromopropyl)3-(trifluoromethyl)
benzene
Purified water +
Aqueous ammonia
MAINTENANCE
Toluene
Conc. Hydrochloric
acid + Purified water
Aqueous layer
EXTRACTION
10% Sodium
metabisulphite
Solution
DISTILLATION
Diisopropyl ether
MAINTENANCE
Toluene
FILTRATION
Ethyl acetate
WET CINACALCET
HCL
FILTRATION
Acetonitrile +
Purified water
Activated charcoal
Diisopropyl ether
MLs
Ethyl acetate MLs
CRUDE
CINACALCET HCL
FILTRATION
Charcoal
MAINTENANCE
FILTRATION
DRYING
CINACALCET
HYDROCHLORIDE
Acetonitrile +
Water MLs
PRODUCT : Cinicalcet Step -I
INPUT
Reactants :
RNA-III
TPA
Liq.ammonia
Boric Acid
HCl
Solvents :
Water
Toluene
n-Heptane
Total Input
Kg.
15.00
11.10
6.30
0.20
8.20
52.50
77.40
68.00
238.70
OUTPUT
A ) Product
A1 Product
B ) Solvent recovered
B1 - Toluene
B2- n-Heptane
C )Effluent
Aqueous Effluent
Organic residue
Kg.
13.32
75.00
65.00
85.00
0.38
238.70
PRODUCT : Cinicalcet Step –II
INPUT
Reactants :
THF
Step-I
Sodium borohydrate
Boron trifloride etharate
HCl
Liq.ammonia
Solvents :
Water
Toluene
n-Heptane
Salt for washing
Carbon
Hyflo
Total Input
Kg.
OUTPUT
A ) Product
172.50 A1 Product
13.00 B ) Solvent recovered
10.30 B1 - THF
44.40 B2- n-Heptane
41.40 B3 - Toluene
41.40 C )Effluent
Aqueous Effluent
Organic residue
280.00 C3 - Spent solid
165.00 (Carbon ,Hyflo,)
178.00
0.60
1.00
947.60
Kg.
15.00
162.00
169.00
159.00
440.00
1.00
1.60
947.60
PRODUCT : Cinicalcet Step -III
INPUT
Reactants :
Acetonitrile
Step-II
Solvents :
Water
Salt for washing
Carbon
Hyflo
Total Input
Kg.
OUTPUT
A ) Product
A1 Product
B ) Solvent recovered
Acetonitrile
C )Effluent
115.20 Aqueous Effluent
Organic residue
0.50 Spent solid
0.50 (Carbon ,Hyflo,)
158.58
28.88
13.50
Kg.
11.38
27.00
119.00
0.20
1.00
158.58
Therapeutic category
API
Morantel Citrate
Morantel Tartrate
Oxantel Pamoate
T
Anthelmentic
Intermediates
3 Methyl Thiophene -2- Aldehyde
( 3MT2A)
Disodium pamoate (DSP)
Pamoic acid
(PA)
Thiophene -2- Aldehyde (T2A)
1,2-Dimethyl-1,4,5,6-tetrahydropyrimidine (THP)
Pyrantel Pamoate / Embonate
Pyrantel Tartrate /Zeolex
Piperazine Di HCl
MORANTEL CITRATE
1.
Brief Process:
1,2-Dimethyl-1,4,5,6-tetrahydropyrimidine is reacted with 3-Methylthiophene-2carbaldehyde (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:
H3C
CH3
S
CHO
H3C
+
CH3
3-methylthiophene
-2-carbaldehyde
N
N
S
methylformate
N
N
CH3
1,2-dimethyl-1,4,5,6-tetra
hydropyrimidine
1-methyl-2-[(E)-2-(3-methylthiophen-2-yl)ethenyl]1,4,5,6-tetrahydropyrimidine
(Morantel Base)
H3C
CH2COOH
HO
COOH
CH2COOH
CH2COOH
N
S
N
Water/Methanol
HO
COOH
CH2COOH
CH3
Morantel Citrate
3. Process flow chart:
1,2-Dimethyl-1,4,5,6-tetrahydropyrimidine
3-Methylthiophene2-carbaldehyde
Purified water
Methyl Formate
Methanol
Reaction
Citric acid
Temp. Maintaining
Dissolution
Morantel base
Filtration
Reaction
Temp. Maintaining
Cooling
Purified water
Methanol
Chilling
Centrifugation
Drying
Milling
Packing
PRODUCT: Morantel Citrate
INPUT
Reactants
Tetrahydro Pyrimidine
3 Methyl Thiophene 2 Aldehyde
Methyl Formate
Citric Acid
Solvents
Water
Methanol
Total Input
Kg
285
200
128
351
1240
389
2593
OUTPUT
A) Wet Product
A1 Dry Product
B) Solvent Recover
B1- Methanol
C )Effluent
Aqueous Effluent
Organic residue
Kgs.
510.00
375.00
1700.00
8
2593

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