pre - feasibility report -...
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PRE - FEASIBILITY REPORT
FOR
PROPOSED EXPANSION OF
AEROMATIC CHEMICALS, BULK DRUGS,
&BULK DRUG INTERMEDIATES
MANUFACTURING UNIT
BY
PLOT No. 187, PHASE-II, G.I.D.C ESTATE, VAPI-396 195,
DISTRICT: VALSAD, GUJARAT
OF
M/S. MANGALAM DRUGS & ORGANICS Ltd.
(UNIT-I)
SUMMARY
M/s. MANGALAM DRUGS & ORGANICS (UNIT-I)is planning for the expansion of their existing
Aeromatic Chemicals, Bulk Drugs & Bulk Drug Intermediates manufacturing unit at Plot No. 187, Phase-
II, G.I.D.C Estate, Vapi-396 195, District: Valsad, Gujarat
PROJECT COST
The total project cost for the proposed expansion project would be around Rs. 1 crore. Total capital cost of
pollution control measures will be Rs. 7 Lacs & recurring cost per annum will be 3 Lacs.
DETAILS OF PRODUCTS Details of existing and proposed products are given in following table.
LIST OF PRODUCTS
SR.
NO PRODUCT
PRODUCTION CAPACITY (MT/MONTH)
EXISTING PROPOSED TOTAL
(A) AROMATIC CHEMICALS
1. Phenyl Ethyl Methyl Ether 9.0 - 9.0
2. Phenyl Ethyl Chloride 3.0 - 3.0
(B) BULK DRUGS
Group 1
1 Nimesulide 17.0 63 80
2 Lumefantrine 18.0 62
3 Sulfadoxine - 80
Group 2
4 Furosemide 5.0 25
30
5 Hydroxy Chloroquine Sulphate (HCQS) 3.0 27
6 Allopurinol 5.0 25
7 Colesevelam Hydrochloride - 30
Group 3
8 Amodiaquine Hydrochloride (AMQ HCl) 9.0 21
30 9 Piperaquine Phosphate 5.0 25
Group 4
10 Tenofovir Disoproxil Fumarate 7.0 23
30 11 Efavirenz - 30
Group 5
12 Artemether 2.0 18 20 13 Artesunate 2.0 18
Group 6
14 Emtricitabine 1.0 9 10
15 Pyrimethamine - 10
16 Dihydroartemisinin - 10
17 Bisoprolol Fumarate - 10
Group 7
18 Pyronaridine 0.5 4.5 5
19 Atazanavir Sulfate - 5
20 Primaquine Phosphate - 5
21 Chloroquine Phosphate (CQP) 2.0 3
Group 8
22 Tenofovir Alafenamide Fumarate - 10 10
23 Tenofovir DipivoxilOrotate - 10
24 Sofosbuvir - 10
Group 9
25 Dolutegravir Sodium - 5 5
26 Velpatasvir - 5
27 AdefovirDipivoxil Fumarate - 5
28 Ledipasvir - 5
29 DaclatasvirDihydrochloride - 5
30 Tafenoquine Succinate - 5
Group 10
31 Ursodiol - 5 5
32 Terizidone - 5
33 Delamanid - 5
34 Tariquidar Analog - 5
35 Solifenacin Succinate - 5
36 Montelukast Sodium - 5
37 Silodosin - 5
38 Cinacalcet Hydrochloride - 5
39 Maraviroc - 5
40 Vilazodone Hydrochloride - 5
41 Metoprolol succinate
(C) BULK DRUGS INTERMEDIATES
1. Meta Chloro Aniline (MCA) 6.0 - 6.0
2. 2,7-Dichloro-9H-fluorene (DCF) 8.0 7.0 15.0
3. 2-(2,7-dichloro-9H-fluoren-4-yl)oxirane - 15.0 15.0
4. [2-Dibutylamino-1-(2-7-dichloro-9H-florine-
4-yl)] ethanol(DBA) 8.0 12.0 20.0
5. Dihydroartemisinin (DHA) 5.0 10.0 15.0
6. 4-cyanoethyl-2-methyl-phenol (MHPN) - 5.0 5.0
7. (R)-9-(2-phosphonylmethoxypropyl)-adenine
(PMPA) - 25.0 25.0
8. 4,7-Di ChloroQuinoline (4,7-DCQ) - 20.0 20
9. N-(2-phenoxyphenyl)-methanesuphonamide
(OPMSA) - 50.0 50
10. Meta Amino Acetanilide (MAA) - 5.0 5
11. N-{3-[(diethylamino)methyl]-4-
hydroxyphenyl}acetamide (Mannich Base) - 20.0 20.0
12. 4,6-dichloro-5-methoxypyrimidine - 25.0 25.0
13.
L-Menthyl-5-(2R,5S)-[4-amino-5-fluoro-2-
oxopyrimidin-1(2H)-yl]-1,3-oxathiolane-2-
carboxylate (FCME)
- 40.0 40.0
14.
(S)-2-(2-amino-5-chlorophenyl)-4-
cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol
(E-6)
- 24.0 24.0
15. Tenofovir Disoproxil Free Base (TD Base) - 10.0 10.0
BY-PRODUCT
1. Eutectic Oil - 6.0 6.0
2. Sodium ThioSulphate - 6.0 6.0
3. Hydrochloric Acid - 10.0 10.0
Note: Following products are discontinued from the existing product list.
1. Lopinavire (1 MT/M)
2. Praziquintal(2 MT/M)
3. Ritonavir (1 MT/M)
4. Ciprotloxacin Hydrochloride (5 MT/M)
5. M-1 &/Or M-2 &/Or M-3 &/Or M-4 &/Or M-5 &/Or M-6 &/Or M-7 &/Or M-13 &/Or M-
15 M-21 &/Or M-23 &/Or M-25 (50 MT/M)
6. 2(2-chloro-1-(2,7-dichloro-9H Fluorene-4-yl)ethanol (LF2) (8 MT/M)
REQUIREMENTS FOR THE PROJECT
LAND No new land will be acquired for the proposed expansion project. The proposed expansion project will get
established in existing premises by doing small modification and in available open space in existing
premises. Total plot area of the project is 8737.82 m2 from which around 2880 m2 (33% of total land area)
will be required for the development of green belt.
WATER
Total water requirement for the proposed expansion project would be estimated as 220 KLD, which will be
sourced from G.I.D.C
ELECTRICAL ENERGY Total power requirement for the proposed expansion project will be around 750 KVA and will be sourced
from DGVCL (Daxin Gujarat Vij Corporation Limited). During emergency purpose D. G. Set of 320 KVA
will be utilized.
MANPOWER For proposed expansion project total 430 (existing 350 and additional 80) personnel will be required.
SOURCES OF AIR POLLUTION AND CONTROL MEASURES
EMISSIONS FROM COMBUSTION OF FOSSIL FUELS FROM STATIONARY OR MOBILE
SOURCES
SR.
NO.
STACK ATTACHED
TO FUEL USED
STACK
HEIGHT
POLLUTION
CONTROL
SYSTEM
FINAL
CONCENTRATION
EXISTING
1 IBR Boiler Natural Gas
(193 m3/Hr)
30
meter
adequate stack
height is provided
SPM ≤ 150 mg/Nm3
SO2≤ 100 ppm
NOX≤ 50 ppm
2 Non IBR Boiler standby
facility
15
meter
3 D.G. Set (320 KVA) Diesel
(70 Lit/Hr)
11
meter
4 Thermic Fluid Heater
(4 Lac K cal)
LDO
(600 Lit/Day)
15
meter
PROPOSED
1. Gas Generator
(1 MW)
Natural Gas
5000 m3/Day
15
meter
adequate stack
height will be
provided
SPM ≤ 150 mg/Nm3
SO2≤ 100 ppm
NOX≤ 50 ppm
PROCESS EMISSION
SR.
NO.
STACK
ATTACHED TO
STACK
HEIGHT
POLLUTION
CONTROL
SYSTEM
Type of
Pollutants FINAL
CONCENTRATION
EXISTING
1. Chlorinator in Meta
Chloro Aniline Plant
11
Meter
A glass line water
scrubber followed by
ventury caustic
scrubber
Cl2
HCl
Cl2 ≤ 09 mg/Nm3
HCl ≤ 20 mg/Nm3
WASTE WATER GENERATION AND IT’S TREATMENT: Total wastewater i.e. 125 KLD will be generated from the proposed expansion project, which will be
treated in ETP consisting primary & secondary treatment. Treated effluent will be sent to CETP for further
treatment and final disposal
NOISE POLLUTION AND CONTROL MEASURES:
� From the proposed expansion manufacturing unit noise pollution will be generated which will be
controlled by adopting different types of noise pollution control measures. Main sources of the noise
pollution - machineries, electric motors, boiler, D. G. set and TFH, etc.
Following noise control measures to be adopted in the proposed expansion manufacturing project,
� Encasement of noise generating equipment.
� Greenbelt will be developed all around the plant boundary to act as noise attenuator.
� In addition, personnel, working near high noise level generating sources, will be provided with ear
muffs.
� Proper and suitable acoustic barrier will also be provided around, areas generating high noise.
� Effective preventive maintenance and vibration measurement of all rotating equipment will help in the
improvement of plant life and also noise reduction.
SOLID WASTE GENERATION AND ITS DISPOSAL METHOD The sources of solid wastes, generation and its management are as given in the following table.
SR.
NO.
NAME OF THE
WASTE
CAT
NO.
EXISTING
(MT/Year)
PROPOSED
(MT/Year)
TOTAL
(MT/Year)
METHOD OF
STORAGE AND
DISPOSAL
1 ETP Waste 34.2 72 228 350
Collection, storage,
Transportation,
disposal at TSDF-
VWEMCL
2 Distillation
Residue 20.3 43.2 1156.8 1200
Collection, storage and
disposed in incinerator
at Unit-II/ Sent to
Common incineration
facility 3 Process Residue 28.1 6 494 500
4 Spent Solvents 28.6 0 300 300 Recovered & reused/
Sent to end user.
5 Used Oil 5.1 0.06 0.06 0.12
Collection, storage and
reuse as lubricants in
the machineries within
the premises only or
send to authorized re-
processors.
6
Discarded
Containers/
Bags
33.1 2400
Nos./Year
3100
Nos./Year
5500
Nos./Year
Collection, storage and
send to authorized
recycler after
decontamination.
7 Iron Sludge 28.2 1800 200 2000
Collection, storage,
Transportation,
disposal at TSDF
8 Used/ Waste
filter clothes 35.1 0.05 0.10 0.15
Collection, storage,
Transportation,
disposal at TSDF
9 Sludge from wet
Scrubber 36.1 0.024 0.096 0.12
Collection, storage,
Transportation,
disposal at TSDF
10 Spent Carbon 28.2 78 222 300
Collection, storage and
disposed in incinerator
at Unit-II
GREEN BELT DEVELOPMENT
Company has proposed 33% of total land area for green belt development approx 2880 m2 land area.
INDEX
CHAPTER
NO. CONTENT
1 Introduction of the project
2 Project description
3 Site analysis
4 Planning brief
5 Proposed infrastructure
6 Rehabilitation and resettlement (R & R) plan
7 Project schedule & cost estimates
8 Analysis of proposal
1
CHAPTER-1
INTDOUCTION OF THE PROJECT
1.1 IDENTIFICATION OF PROJECT AND PROJECT PROPONENT
M/s. MANGALAM DRUGS & ORGANICS Ltd. (UNIT-I) is planning for the expansion of their existing
Aeromatic Chemicals, Bulk Drugs & Bulk Drug Intermediates manufacturing unit at Plot No. 187, Phase-II,
G.I.D.C Estate, Vapi-396 195, District: Valsad, Gujarat
1.2 PROMOTERS BACKGROUND
Details of project promoters are as below:
Mr. Govardhan M Dhoot Shri G.M.Dhoot has a commerce background and more than four decades of experience in the chemical and
pharma industry. He has been a driving force behind phenomenal expansion and diversification of the company
over last decade. His strategic interventions to inculcate strong regulatory focus have earned the company its
prestigious status among the top 5 companies approved by the Bill Clinton Foundation.
Mr. Brijmohan M Dhoot: Shri B. M. Dhoot has a commerce background and more than 40 years experience in chemical and pharma
industry.
Mr. Subhash C. Khattar Mr Subhash Khattar is a chartered accountant with above 50 years experience. He specialises in taxation and
auditing. He is on the statutory panel of bank audits and of other public sector undertakings and Private
Companies.
Mrs. Anuradha Sukhani Ms. Anuradha Sukhani has an arts background. She has been partner in Sourcing Solutions since 2002. It runs a
buying agency for leather goods. Product was souced from leather manufacturers all over India and exported to
niche markets in Northern Europe (Sweden, Finland, Germany, Amsterdam, Denmark)
1.3 BRIEF DESCRIPTION OF NATURE OF THE PROJECT
M/s. MANGALAM DRUGS & ORGANICS Ltd. (UNIT-I) is planning for the expansion of their existing
Aeromatic Chemicals, Bulk Drugs & Bulk Drug Intermediates manufacturing unit at Plot No. 187, Phase-II,
G.I.D.C Estate, Vapi-396 195, District: Valsad, Gujarat
LIST OF PRODUCTS
SR.
NO PRODUCT
PRODUCTION CAPACITY (MT/MONTH)
EXISTING PROPOSED TOTAL
(A) AROMATIC CHEMICALS
1. Phenyl Ethyl Methyl Ether 9.0 - 9.0
2. Phenyl Ethyl Chloride 3.0 - 3.0
(B) BULK DRUGS
Group 1
1 Nimesulide 17.0 63 80
2 Lumefantrine 18.0 62
3 Sulfadoxine - 80
Group 2
4 Furosemide 5.0 25
30
5 Hydroxy Chloroquine Sulphate (HCQS) 3.0 27
6 Allopurinol 5.0 25
7 Colesevelam Hydrochloride - 30
Group 3
2
8 Amodiaquine Hydrochloride (AMQ HCl) 9.0 21
30 9 Piperaquine Phosphate 5.0 25
Group 4
10 Tenofovir Disoproxil Fumarate 7.0 23
30 11 Efavirenz - 30
Group 5
12 Artemether 2.0 18 20 13 Artesunate 2.0 18
Group 6
14 Emtricitabine 1.0 9 10
15 Pyrimethamine - 10
16 Dihydroartemisinin - 10
17 Bisoprolol Fumarate - 10
Group 7
18 Pyronaridine 0.5 4.5 5
19 Atazanavir Sulfate - 5
20 Primaquine Phosphate - 5
21 Chloroquine Phosphate (CQP) 2.0 3
Group 8
22 Tenofovir Alafenamide Fumarate - 10 10
23 Tenofovir DipivoxilOrotate - 10
24 Sofosbuvir - 10
Group 9
25 Dolutegravir Sodium - 5 5
26 Velpatasvir - 5
27 AdefovirDipivoxil Fumarate - 5
28 Ledipasvir - 5
29 DaclatasvirDihydrochloride - 5
30 Tafenoquine Succinate - 5
Group 10
31 Ursodiol - 5 5
32 Terizidone - 5
33 Delamanid - 5
34 Tariquidar Analog - 5
35 Solifenacin Succinate - 5
36 Montelukast Sodium - 5
37 Silodosin - 5
38 Cinacalcet Hydrochloride - 5
39 Maraviroc - 5
40 Vilazodone Hydrochloride - 5
41 Metoprolol succinate
(C) BULK DRUGS INTERMEDIATES
1. Meta Chloro Aniline (MCA) 6.0 - 6.0
2. 2,7-Dichloro-9H-fluorene (DCF) 8.0 7.0 15.0
3. 2-(2,7-dichloro-9H-fluoren-4-yl)oxirane - 15.0 15.0
4. [2-Dibutylamino-1-(2-7-dichloro-9H-florine-
4-yl)] ethanol(DBA) 8.0 12.0 20.0
5. Dihydroartemisinin (DHA) 5.0 10.0 15.0
6. 4-cyanoethyl-2-methyl-phenol (MHPN) - 5.0 5.0
7. (R)-9-(2-phosphonylmethoxypropyl)-adenine
(PMPA) - 25.0 25.0
8. 4,7-Di ChloroQuinoline (4,7-DCQ) - 20.0 20
3
9. N-(2-phenoxyphenyl)-methanesuphonamide
(OPMSA) - 50.0 50
10. Meta Amino Acetanilide (MAA) - 5.0 5
11. N-{3-[(diethylamino)methyl]-4-
hydroxyphenyl}acetamide (Mannich Base) - 20.0 20.0
12. 4,6-dichloro-5-methoxypyrimidine - 25.0 25.0
13.
L-Menthyl-5-(2R,5S)-[4-amino-5-fluoro-2-
oxopyrimidin-1(2H)-yl]-1,3-oxathiolane-2-
carboxylate (FCME)
- 40.0 40.0
14.
(S)-2-(2-amino-5-chlorophenyl)-4-
cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol
(E-6)
- 24.0 24.0
15. Tenofovir Disoproxil Free Base (TD Base) - 10.0 10.0
BY-PRODUCT
1. Eutectic Oil - 6.0 6.0
2. Sodium ThioSulphate - 6.0 6.0
3. Hydrochloric Acid - 10.0 10.0
*Note: Following products are discontinued from the existing product list.
1. Lopinavire (1 MT/M)
2. Praziquintal(2 MT/M)
3. Ritonavir (1 MT/M)
4. Ciprotloxacin Hydrochloride (5 MT/M)
5. M-1 &/Or M-2 &/Or M-3 &/Or M-4 &/Or M-5 &/Or M-6 &/Or M-7 &/Or M-13 &/Or M-15 M-
21 &/Or M-23 &/Or M-25 (50 MT/M)
6. 2(2-chloro-1-(2,7-dichloro-9H Fluorene-4-yl)ethanol (LF2) (8 MT/M)
1.4 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
Company.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.
The Active Pharmaceutical Ingredient Industry is the organ by which active pharmaceutical ingredients are
manufactured from raw materials through both chemical and physical means. Depending on the complexity of
the molecule required, synthesis of APIs might need multi-step complex chemistry utilizing a range of
processing technologies.
1.5 DEMANDS-SUPPLY GAP
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 & global market. Hence we have identified the demand for the proposed
products which are meant for very new medicines meant for fast growing therapeutic segments with pilot plant
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.
1.6 EMPLOYMENT GENERATION
For proposed expansion project total 430 (existing 350 and additional 80) personnel will be required.
4
CHAPTER-2
PROJECT DESCRIPTION
2.1 TYPE OF PROJECT
M/s. Mangalam Drugs &Organics Ltd. (Unit-I) is planning for the expansion of their existing Aeromatic
Chemicals, Bulk Drugs & Bulk Drug Intermediates manufacturing unit at Plot No. 187, Phase-II, G.I.D.C
Estate, Vapi-396 195, District: Valsad, Gujarat
Industrial development in India has increased economic growth and improved living standards of people. These
growths are achieved through industrialization, infrastructure development. The industrialization has played a
major role in development of the country. This industrialization is also has many other benefits. Although the
industrial development leads to rapid consumption of natural resources, fuel etc.in day to day operational
activity. To control the pollutions from industrial activity, government has framed regulations which are
governed by Ministry of Environment, Forests and Climate Change in India.
2.2 LOCATION M/s. Mangalam Drugs &Organics (Unit-I)is planning for the expansion of their existing Aeromatic Chemicals,
Bulk Drugs & Bulk Drug Intermediates manufacturing unit at Plot No. 187, Phase-II, G.I.D.C Estate, Vapi-396
195, District: Valsad, Gujarat. Total plot area of the project is 8737.82 m2 from which around 2880 m2 (33% of
total land area) will be required for the development of green belt. A map showing project site is given in
following figure-1 & a detailed map of the project site & surrounding is showing in following figure.
Latitude - 20°22'6.14"N
Longitude - 72°55'47.97"E
LOCATION MAP
5
2.3 SIZE OR MAGNITUDE OF OPERATION M/s. Mangalam Drugs & Organics (Unit-I)is planning for the expansion of their existing Aeromatic
Chemicals, Bulk Drugs & Bulk Drug Intermediates manufacturing unit at Plot No. 187, Phase-II, G.I.D.C
Estate, Vapi-396 195, District: Valsad, Gujarat
2.4 PROCESS DESCRIPTION
MANUFACTURING PROCESSES
A. AEROMATIC CHEMICALS
1. Phenyl Ethyl Methyl Ether
Process Description: Phenyl Ethyl Alcohol and NaOH are taken in a reactor and dimethyl sulphate is added in a thin stream at 60oC
with Benzene. After completion of reaction temperature is maintained for another four hours. The semi-finished
crude Phenyl Ethyl Methyl Ether (PEME) is taken for vacuum distillation to get pure product Phenyl Ethyl
Methyl Ether
Flow Diagram:
2. Phenyl Ethyl Chloride
Process Description Charge Phenyl Methyl Alcohol and Thionyl chloride at room temperature, maintain it 50
o C for 2 hr. After
reaction distill out of Phenyl Ethyl Chloride and Process residue is sent to incinerator.
Flow Diagram
CHLORINATION
DISTILLATION
PE CHLORIDE
DISTILLATION RESIDUE
ALKALI
SCRUBBER
WATER
SCRUBBER
PEA
THIONYL
CHLORIDE
Cl2 Gas
METHYLATION
DMS
PEA
BENZENE
NaOH
DISTILLATION BENZENE, DMS RECYCLED &
RECOVERED
DISTILLATION
PEME
PROCESS RESIDUE
6
B. BULK DRUGS
GROUP 1
1. Nimesulide - COS
Process Description:
Stage - 1:
OPMSA is nitrated in presence of Acetic acid with Nitric Acid forms Nimesulide Crude which is Centrifuged
and Dried.
Stage - 2: Nimesulide crude dry is purified using methanol as a solvent to give Nimesulide Pure Wet Cake. Nimesulide
pure wet cake is dried, Milled, Jet milled, Sifted and packed in double LDPE bag; i.e. both are White
transparent, followed by HDPE/Fiber drum
FLOW DIAGRAM
Stage: I
Stage: II
CENTRIFUGE
NITRATION
OPMSA
ACETIC ACID
NEUTRALISATION
MCB & C. LYE
NIMESULIDE CRUDE
PROCESS RESIDUE
(HNO3)
ML MCB RECOVERED
DISTILLATION
RESIDUE
W.W. TO ETP
HNO3
WATER
CARBON
TREATMENT
METHANOL
CARBON
FILTRATION
CENTRIFUGE
DRYING
METHANOL ML RECOVERED &
RECYCLED
NIMESULIDE
ACETIC ACID
NIMESULIDE CRUDE
DISTILLATION RESIDUE
SPENT CARBON
PROCESS RESIDUE
7
2. Lumefantrine
Process Description:
Stage-1:
4 – Chlorobenzaldehyde is condensed with DBA in presence of Sodium Methoxide to get the Lumefantrine
crude using Methanol as a solvent.
Stage-2:
Lumefantrine crude is purified using Ethyl Acetate as solvent to get Lumefantrine pure. Lumefantrine pure is
dried, Milled (if required), Sifted and packed in double LDPE bag; i.e. Inner bag is white transparent & Outer
bag is black followed by HDPE drum
Flow Diagram
Stage: I
Stage: II
METHANOL
DBA
4 CHLORO
BENZYLDEHYDE
CONDENSATION
FILTRATION
ML FOR
RECOVERY
LUMEFANTRINE
CRUDE (STAGE-I)
SODIUM
METHOXIDE
METHANOL
RECOVERED & REUSED
DISTILLATION RESIDUE
LUMEFANTRINE
CRUDE (STAGE-I)
DISSOLUTION
FILTRATION
ETHYL ACETATE
RECOVERED & REUSED
DRYING
ETHYL ACETATE
DISTILLATION
LUMEFANTRINE
WATER
W.W. TO ETP
ACTIVATED CARBON
CENTRIFUGE HEXANES ML HEXANES RECOVERED &
REUSED
SPENT CARBON
DISTILLATION RESIDUE
8
3. Sulfadoxine
Process Description:
Stage-1:
� Charge sulfanilamide, NaOH and water at room temperature.
� Heat the reaction mass to 75-80°C.
� Distilled out water under vacuum completely.
� Charge IPA and stir the reaction mass at 25-30°C.
� Filter it and wash with IPA.
� Dry it.
Stage-2:
� Charge DMF and sodium salt of sulfanilamide.
� Charge 4,6-DCMP under stirring.
� Maintain the reaction mass at 60-65°C for 3 hrs.
� Charge methanol and adjust pH with H3PO4.
� Slowly add water at chilled to 5-10°C.
� Filter it and wash with water.
� Dry it.
Stage-3:
� Charge 4,6-ACMS, sodium hydroxide and methanol .
� Maintain the reaction mass at 60-65°C for 10 hrs.
� Cool the reaction mass and slowly adds water.
� Charge carbon and filter it.
� Adjust pH with dilute hydrochloric acid.
� Chilled the reaction mass up to 20-25°C
� Filter it and wash with water.
Stage-4:
� Charge methanol and Sulfadoxine crude.
� Adjust pH with NaOH solution.
� Charge carbon and filter it.
� Adjust pH with dilute hydrochloric acid.
� Chilled the reaction mass up to 20-25°C
� Filter it and wash with water.
� Dry it.
9
Centrifuge
Flow Diagram:
Stage-I: Sodium salt of sulfanilamide.
Potable water
NaOH
Maintaining the reaction mass
Distillation out water
IPA
Wash the wet cake ML for IPA
Recovery
with IPA
For complete intermediate analysis
Reactor
Reactor
Fluid Bed Dryer
Sulfanilamide
Reactor
SStage-I
10
Centrifuge
Stage-II: 4-amino-N-(6-chloro-5-methoxy pyrimidin-4-yl) benzene sulfonamide (4,6-ACMS)
4, 6-DCMP
DMF
Check reaction completion by TLC
Methanol
H3PO4 + potable
water
Potable Water
Wash the wet cake ML for
Methanol/DMF
with potable water Recovery
For Complete Intermediate analysis
Reactor
Reactor
Fluid Bed Dryer
Stage-I
Reactor
Stage-II
11
Stage-III: 4-Amino-N-(5,6-dimethoxy pyrimidin-4-yl)benzene (Sulfadoxine crude)
Stage-II
Methanol
Heat to 50-55°C
NaOH Check TLC
Charge water
(Activated carbon + potable
water)
Filtration
HCl+ Potable
Water
Potable water ML for Methanol recovery
For complete Intermediate analysis
Reactor
Reactor
Reactor
Centrifuge
Stage-III
Check Clarity of Solution Sparkler Filter
Reactor
12
Stage-IV: 4-Amino-N-(5,6-dimethoxy pyrimidin-4-yl)benzene (Sulfadoxine Pure)
Stage-III
Methanol
NaOH soln
(Activated carbon + methanol)
Filtration
Purge N2 Gas
HCl + purified
water
Methanol washing ML for Methanol recovery
Check water content
If Required
If Required
For complete analysis
Reactor
Rotocon Vacuum Dryer
Reactor
Reactor
Centrifuge
Multi Mill
Jet Mill
Sifter
Packing
Check Clarity of Solution Sparkler Filter
Reactor
13
GROUP 2
4. Furosemide
Process Description:
Stage-1: 5-(aminosulfonyl)-2,4-dichlorobenzoic acid [Lasamide] is condensed with 1-(2-furyl) methanamine [Furfuryl
amine] at 117 to 119°C and then hydrolyzed with caustic soda to form sodium salt of Furosemide in presence
of isopropyl alcohol.
Stage-2: The Furosemide Sodium Salt is Purified with Water, neutralized with acetic acid, Re-crystallized and isolate to
form Pure Furosemide which is Centrifuged, Dried, Milled (If Required), Jet Milled (If Required), sifted and
finally packed.
Flow Diagram
Stage-I
Stage-II
WET CAKE CHARCOALING
Purified WATER
FILTRATION
PRECIPITATION
CENTRIFUGIN
G
W/W TOETP ACETIC ACID
Spent Carbon
WATER/ DNS FOR
DRYING
FUROSEMIDE
Activated Carbon
DNS
RECOVERE
D & REUSED
Distillation
Residue ML
W/W TOETP
LASAMIDE
CONDENSATION
FURFURYL AMINE
PH ADJUSTMENT
FILTRATION
WET CAKE
W/W TO ETP C.Flakes
WATER
IPA, FFARECOVERED
& REUSED IPA FOR WASHING
Distillation
Residue
ML
Process
Residue
14
5. HCQS - Hydroxy Chloroquine Sulphate
Process Description:
Stage-1: 4, 7-DCQ is condensed with HNDA to form Hydroxyl Chloroquine Base which reacts with H3PO4 to form
HCQP Crude
Stage-2: This Hydroxy Chloroquine Phosphate Crude purified in Water-Methanol mixture, is recrystallised and isolated
to form pure Hydroxy Chloroquine Phosphate
Stage-3: Pure Hydroxy Chloroquine Phosphate is neutralized to form Hydroxyl Chloroquine Base which reacts with
Sulphuric Acid to form HCQS and then it is recrystallised by IPA to get pure wet cake. This HCQS pure is
dried, pulverized, analyzed and packed in HDPE or fiber drums followed by two liners, primary white &
secondary black
Flow Diagram:
Stage: I
4, 7-DCQ
HNDA
CODENSATION
WASHING
MDC
K.I.
SODIUM
CARBONATE
WATER
AQ.
LAYER
MDC, METHANOL
RECOVERED & REUSED
H3PO4
DISTILLATION
CENTRIFUGE
ACTIVATED
CARBON
METHANOL
ML
DISTILLATION RESIDUE
W/W TO
ETP
PROCESS RESIDUE
SPENT CARBON
Stage-I
15
Stage: II
Stage: III
METHANOL
WATER
PURIFICATION
CENTRIFUGE
ML
ACTIVATED
CARBON
Stage-I
METHANOL RECOVERED &
REUSED
SPENT CARBON
DISTILLATION RESIDUE Stage-II
W/W TO ETP
Stage-II
Methanol, Hexane, IPA, MDC
Recovered & Reused
Filtration
DRYING
HYDROXY
CHLOROQUINE
SULPHATE
IPA, MDC
Activated Carbon
Methanol, H2SO4
Liq. Ammonia
Hexane, Water
Process Residue
Distillation Residue
Spent Carbon
ML
W/W to ETP
16
CYNOACETAMIDE
REACTOR(REFLUX)
IPA
STAGE-1 PRODUCT
MORPHOLINE
TRIETHYL
ORTHOFORMATE
CENTRIFUGE
W.W. TO ETP
DRYING
ML
MORPHOLINE, TEOF, IPA
RECOVERED & REUSED
DISTILLATION RESIDUE
WATER
HYDRAMINE
HYDRATE
H2SO4
STAGE-2
PRODUCT
STAGE-1
W.W. To ETP CENTRIFUGE WATER
Process Residue
REACTOR
(REFLUX)
6. Allopurinol
Process Description:
Stage-1:
2-Cyanoacetamide and Morpholine reacts in presence of Isopropyl alcohol and Triethyl orthoformate at reflux
temperature to yield 3-Morpholino-2-Cyanoacrylamide.
Stage-2:
3-MCA and hydrazine hydrate in presence of water undergoes cyclization which on further forms 3-Amino-4-
carboxamide pyrazolehemisulfate by the addition of Sulfuric acid in controlled manner at predetermined
temperature range.
Stage-3: Formamide and 3-Amino-4-carboxamide pyrazolehemisulfate undergoes cyclization in presence of liquor
Ammonia and Water to form Allopurinol crude. Allopurinol crude undergoes purification using water yields
Allopurinol pure which is centrifuged, dried, analyzed and packed
Flow Diagram
Stage-1:
Stage-2:
17
Stage-3:
7. Cloesevelam Hydrochloride
Process Discription
Stage-I
Allyl amine is polymerized using 2, 2’- Azobis (amidinopropane) dihydrochloride in presence of hydrochloric
acid in water. Product isolated from methanol.
Stage-2 COL-Polyallyl is cross-linked with epichlorohydrin in aqueous sodium hydroxide. Product is isolated after
aqueous workup.
Stage-3 COL-sevelamer is alkylated with 6-Bromohexyl trimethylammonium bromide and 1-Bromodecane in presence
of aqueous sodium hydroxide and hydrochloric acid in methanol. Product is isolated after aqueous workup.
STAGE-2
REACTOR
(REFLUX)
FILTRATION
CENTRIFUGATION
WATER
LIQ. AMMONIA
DRYING
ALLOPURINOL
FORMAMIDE
WATER
Spent Carbon A.Carbon, Hyflow
ML Formamide Recovered
and Reused
Process
Residue
W.W. TO ETP
18
Flow Diagram
Stage-I
Stir at 0-10°C
Reactor-II
Stir at 25-30°C
Reactor-I
Cool at 0-10°C
Conc. Hydrochloric acid
Allyl amine
Stir at 48-52°C till
completion of reaction
Methanol
Stir at 25-30°C
Filtration
Reaction mixture from
reactor-I
Methanol
Drying
COL-Polyallyl
Analysis as per specification
Distillation
2,2’-
Azobis(amidinopropane)
dihydrochloride
Water
ML Solvent
recovered
& recycled
Distilled
Residue
W.W. TO
ETPCOD812mg/Ltr
19
Stage-II
At 25-30°C till completion of
reaction
Drying
Reactor-I
Stir at 25-30°C
COL-Polyallyl
Water
Aq. sodium hydroxide
Epichlorohydrin
Filtration
COL-Sevelamer
Analysis as per specification
Stir at 25-30°C
Water
Isopropyl alcohol
W.W. TO ETP
COD 183mg/Ltr
ML
Distilled
Residue
Solvent
recovery&
recycled
20
Stage-III
At 25-30°C till completion of
reaction
Drying
Reactor-I
Stir at 25-30°C
Methanol
COL-Sevelamer
6-BHTAB
1-Bromodecane
Sodium hydroxide
Solution
Filtration
Colesevelam HCl
Analysis as per specification
Stir at 25-30°C
Concentrated HCl
Isopropyl Alcohol
ML Solvent recovery recycled
Distillation
Residue
W.W. TO ETP COD
19mg/Ltr
21
GROUP-3
8. Amodiaquine Hydrochloride
Process Description:
Stage-1: N-{3-[(diethylamino) methyl]-4-hydroxyphenyl} acetamide undergoes hydrolysis in presence of HCl which
further condenses with 4, 7-DCQ using toluene as a solvent to form crude Amodiaquine hydrochloride
Stage-2: Crude Amodiaquine hydrochloride is crystallized in a mixture of water and DNS to give Amodiaquine
hydrochloride. It is dried, milled, sifted, analyzed & packed
Flow Diagram:
Stage: I
CONDENSATION
M.BASE
WATER
HCl
DCQ
CRUDE AMQ-HCl WET
CAKE
DNS
FOR DNS RECOVERY
(DISTILLATION)
TOLUENE RECOVERED &
REUSED
LAYER SEPARATION FOR TOLUENE
RECOVERY
FILTRATION
DNS RECOVERED &
REUSED
TOLUENE
PROCESS RESIDUE
DISTILLATION RESIDUE
DISTILLATION RESIDUE
W.W. TO ETP
W.W. TO ETP
22
Stage: II
FILTRATION
CRYSTALLISER
CENTRIFUGE
DRYING
AMQ-HCl
AMQ-HCl CRUDE
WATER
ML DNS RECOVERED &
DNS
DNS
WASHING
HYFLO
HCl
DISTILLATION
RESIDUE
PROCESS RESIDUE
W/W to ETP
23
9. Piperaquine Phosphate
Process Description:
Stage-1: 4, 7-DCQ (G-I) and Piperazine anhydrous condenses using IPA as solvent and converted to 7-chloro-4-
piperazin-1-ylquinoline, which on in-situ reaction with 1, 3 dibromo propane in presence of caustic flakes gives
Piperaquine base.
Stage-2: Piperaquine base is converted to respective hydrochloride salt in presence of water and given carbon treatment
and again converted to Piperaquine free base using caustic solution which on further reaction with phosphoric
acid at lower temperature gives Piperaquine phosphate.
Flow Diagram
Stage-I
Stage-II
Piperaquine Base
PHOSPHATE
FORMALDEHYDE
WATER
PHOSPHORIC ACID
FILTRATION
DRYING
DNS
w/w TO ETP
PIPERAQUINE
HCl
Distillation Residue
Process Residue
DNS FORRECOVERY
Activated Carbon
C. Flakes
Spent
Carbon
CONDENSATION WATER
1,3 DI BROMO PROPANE
FILTRATION
Piperaquine
Base
DNS + CYCLOHEXANE
WASHING
MDC
CAUSTIC SOLUTION
w/w TO ETP
Distillation Residue
Process Residue
DNS, MDC, Cyclohexane, IPA forRECOVERY
4,7 - DCQ
PIPERAZIN ANHYDROUS
IPA
24
GROUP-4
10. Tenofovir Disoproxil Fumarate
Process Description:
Stage-1:
(R)-9-(2-phosphonylmethoxypropyl)-adenine [PMPA] and chloromethyl isopropyl carbonate [CMIC] on
condensation in presence of base using NMP as a solvent forms Tenofovir disoproxil base.
Stage-2: Tenofovir disoproxil base further reacts with fumaric acid using isopropyl alcohol at lower temperature to get
Tenofovir Disoproxil Fumarate. It is then centrifuged, analyzed, dried, milled, sifted and packed.
Flow Diagram:
Stage -1:
NMP
PMPA
TBAB
CMIC & TEA
Water
REACTOR
CENTRIFUGE
REACTOR
REACTOR
OUTPUT- TENOFOVIR
DISOPROXIL BASE
ML NMP recovered
& reused
Distillation
residue
W/W to ETP
25
Stage-2:
MDC
BASE WET CAKE
Water
Sodium Sulphate
Filtration
MDC
IPA
Fumaric Acid
Cyclohexane
11. Efavirenz
Process Description:
� Charge E-6 and toluene.
� Add solution of triphosgene in toluene at reaction mass at 25 – 30 oC.
� Maintain the reaction mass for 3.0 hour at 25 – 30 oC.
� Reaction mass of completely distilled out at 40 – 49 oC.
� Charge Methanol in to reaction mass and stir it.
� Stir and maintain the reaction mass for 1 hour.
� Filter the reaction mass and wash it with the Methanol.
Reactor
Reactor
Reactor
Filtration
Reactor
Centrifuge
Output - Tenofovir Disoproxil
Fumarate
Reactor
Reactor
ML
Ipa, Cyclohexane
Recovered & Reused
Distillation
residue
W/W to ETP
MDC recovered &
reused
Process residue
26
Flow Diagram
SSR
SSR
SSR
SSR
SSR
SSR
SSR
SSR
E-6 raw material
Sodium bicarbonateTriphosgene solution in toluene
Toluene
Methanol
Distillation
Centrifuge
Portable water
10% sodium hydroxide solution
Aqueous layer
Ammonia+sodium hydroxide solution
Aqueous layer
Portable water washingAqueous layer
1% acetic acid solutionAqueous layer
Portable water washingWater recovered & reused
Methanol azeotripic distillationToluene, Methanol recovered
& reused
Activated carbon
Sparkler filtration
Efavirenz Pharma
Portable water addition Methanol layer
Drying
ML
Distillation residue
ML Toluene, Methanol recovered
& reused
Distillation residueProcess residue
Spent carbon
27
Group-5
12. Artemether
Process Description:
Stage -1:
Dihydroartemisinin in presence of TMOA undergoes acetalation in methanol to form Artemether crude which
is centrifuged.
Stage-2: Artemether Crude is crystallized in methanol to obtain Artemether, which is centrifuged, dried, micronised (If
required), analyzed and packed.
Flow Diagram:
Stage – 1:
Stage – 2:
WASHING
DISTILLATION
DRYING
Methanolrecover
ed & reused
ARTEMETHER
TMOA
METHANOL& WATER
METHYLATION
Water + Methanol
Washing
HCl & TEA
DHA
W/W to ETP
Distillation
Residue
TMOA, Methanol
recovered & reused
Distillation residue
CENTRIFUGE Process Residue
ARTEMETHER
CRUDE
W/W to ETP
ARTEMETHER CRUDE
28
13. Artesunate
Process Description:
Stage-1:
Dihydroartemisinin reacts with Succinic Anhydride and TEA in presence of solvent Acetone produced
Artesunate crude.
Stage-2: Artesunate crude purified with methanol & it gives Artesunate pure.
Artesunate is dried, Mill & Sifted packed in HDPE or fiber drums along with two LDPE bag. Primary is white
& secondary is black
Flow Diagram
Stage -1:
Acetone
DHA
REACTION
WATER WASHING&
CRYSTALISATION Water
TEA
S.Anhydride
W/W to ETP Acetic Acid
Hyflow, A. Carbon Spent Carbon
Acetone Recovered
& reused
CENTRIFUGING ML
Distillation Residue ARTESUNATE
Crude
29
Group- 6
14. Emtricitabine
Process Description:
Stage-1: Emtricitabine Hydrochloride
A solution of dipotassium hydrogen phosphate in Water was stirred till clear solution obtained. DNS was added
and the mass was cooled to 0-5°C. (2S,5R)-5-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)-[1,3]-oxathiolane-2-
carboxylic acid, 2S-isopropyl-5R-methyl-1R-cyclohexyl ester (F-CME) was added at 0-5°C. A solution of
sodium borohydrate in NaOH was added at 0-5°C within 1.0 h. Raise the temperature of reaction mass to 5-
10°C and maintained the reaction mass till reaction complies. Emtricitabine was isolated as hydrochloride salt
(Emtricitabine HCl) using IPA.HCl (20.0-25.0%).
Stage-2: Emtricitabine Free base Emtricitabine HCl was dissolved in methanol. The mixture was stirred for 15 mins. Triethylamine was added to
the solution at 25-30°C. The solution was heated to 40-45°C for 30.0 mins. Methanol was distilled out
completely from reaction mass at 40-45°C under vacuum till dry solid obtain. MDC was charged to the dry
solid and maintained it for 1.0 h at 25-30°C under stirring. Solid was collected by filtration and leached with
MDC and washed with MDC. The solid was dried to get emtricitabine free base.
Stage-3: Emtricitabine Pharma
The technical grade free base emtricitabine was decolorized in IPA to get pharmaceutically accepted quality
product Emtricitabine.
30
Flow Diagram:
Stage-1:
DNS
NaOH
IPA
IPA
Purified water
Dipotassium hydrogen phosphate ReactorF-CME
Addition pot
Reactor
Purified waterSodium borohydride
DNS recovered & reused
Nutch filtration
Filtrate
DistillationPurified water
Toluene
Layers sepration
Nutch Hot filtration and
Distillation
Isolation
Reactor
Filtrate
Reactor
pH adjestment10% Sulphuric acid solution
Liq. ammonia
Layers sepration
Toluene layerReactor
20.0-25.0 % IPA.HCl
Centrifuge
Stage-1
Drying
ML
Distillation Residue
Methanol & Toluene
IPA recovered & reused
IPA recovered & reused
Distilation residue
W/W to ETP
Distillation Residue
Process residue
31
Stage-II
Triethyl amine
MDC
MDC
Stage-1
MethanolReactor
Reactor
methanol recovered & reused
ReactorMDC recovered & reused
Centrifuge
Stage-2
Reactor
Distillation
Distillation
Drying
Motherliquor
Distillation Residue
Process Residue (TEA)
Distillation Residue
32
Stage-3:
Activated carbon
IPA
Stage-2Reactor
Reflux
Distillation IPA recovered & reused
Layers sepration
Sparkler Hot filtration
Filtrate
Reactor
Mother liquor
CentrifugeIPA
washing
Stage-3
(Emtricitabine Pharma)
Drying
Hot filtrate
Isolation
Distillation residue
Spent carbon
IPA recovered & reused
Distillation residue
33
15. Pyrimethamine
Process Description:
Stage-1:
� Charge 4-chloro phenyl acetonitrile and ethyl propionate.
� Charge sodium Methoxide at room temperature.
� Maintain at 80-85°C for 4 hour.
� Distilled out ethyl propionate completely; charge water and MDC.
� Adjust pH with acetic acid.
� Separate layer and take organic layer. (three water washing)
� Distilled out MDC completely.
� Charge cyclo hexane and ethylene glycol at room temperature.
� Charge PTSA and heat the reaction mass u to reflux temp for 10-12 hrs.
� Chilled the reaction mass to 10-15°C; Charge sodium Methoxide and water.
� Separate layer and take organic layer. (three water washing)
� Distilled out cyclo hexane completely.
� Charge methanol and carbon in reaction mass.
� Filter it and slowly add water at room temperature.
� Chilled the reaction mass up to 5-10°C.
� Filter it and wash with water.
� Dry it.
Stage-2: � Charge guanidine hydrochloride and methanol.
� Charge sodium Methoxide and stir for 30 min.
� Filter the salt sodium chloride and wash with methanol.
� Charge 4-CPDA and methanol at room temperature.
� Charge carbon in reaction mass and filter it.
� Mix both filtrate ML and heat the reaction mass up to reflux temperature.
� Maintain it for 9 hrs and cool to room temperature.
� Filter it and wash with water and then with methanol.
� Dry it.
34
Flow Diagram:
Stage-I: 2-(4-Chlorophenyl)-2-(2-ethyl-1,3-dioxolan-2-yl)acetonitrile (4-CPDA):
4-CPA
Ethyl propionate (EP)
CH3ONa
Check TLC % of 4-CPA
Distilled out ethyl propionat
MDC + WATE
Layer separation
Distillation of MDC
Reactor
Reactor
Reactor
Reactor
Layer separate out Reactor
Reactor MDC + potable
Distillation of EP
Adjust pH 4.5-5.5
MDC
Potable water Layer separate out
Potable water Layer separate out
Reactor Potable water Layer separate out
Reactor Cyclo hexane
PTSA Remove water
azeotropic.
Reactor NaOCH3 Layer separate out
Reactor Potable water Layer separate out
35
Continue………
Distilled out cyclohexane
ML for Methanol
recovery
Stage-I for Complete analysis
Reactor
Potable water Layer separate out
Reactor
Potable water Layer separate out
Sparkler filter
Methanol
Reactor
Addition of
potable water
Centrifuge
Drying
36
Stage-II: 5-(4-Chlorophenyl)-6-ethylpyrimidine-2,4-diamine (Pyrimethamine):
Stage-I Guanidine HCl
Methanol CH3ONa
Methanol
Mainataining Filtration Check TLC
Wash with purified water
+Methanol ML for Methanol recovery
Check water content
If Required
If Required
Pyrimethamine for
Complete Analysis.
Reactor
Rotocon vacuum dryer
Sparkler
Centrifuge
Multi mill
Jet mill
Sifter
Packing
Reactor
37
Sparkler Filter
16. Dihydroartemisinin
Process Description:
Dihydroartemisinin is dissolved in Methanol followed by carbon treatment. Then water is added in to filtrate, to
get Dihydroartemisinin pure, which is dried milled (If required), Jet Milled (if required), sifted, Analyzed and
packed.
Flow Diagram:
Methanol
Dihydroartemisinin crude
Activated Carbon
Hyflow
Methanol
Clear Filtrate
Add
Water
Dihydroartemisinin Pure
Wet Cake
(If required)
(If required)
Reactor
Reactor
Centrifuge
RotoconVacuum Dryer
Multi mill
Jet mill
Dihydroartemisinin
Sifter
Reactor
Material transfer equipment
W/W to ETP
ML Methanol
recovered &
reused Process
residue
Spent Carbon
Distillation
residue
38
17. Bisoprolol Fumarate
Process Description:
Stage-1:
� Charge 2-Isopropoxy ethanol and 4-Hydroxy Benzyl alcohol.
� Charge Amberlyst-15 at room temperature.
� Maintain at room temperature for 3 hour.
� Filter the reaction mass and adjust pH with sodium bicarbonate.
� Distilled out solvent completely; charge water and MDC. (Repeat three times)
� Stir for 30 min.
� Separate layer and take organic layer.
� Distilled out MDC completely.
� Collect liquid as a product. (BS-1)
Stage-2:
� Charge Epichlorohydrin and BS-1.
� Charge K2CO3 and heat the reaction mass up to reflux temp for 12 hrs.
� Cool to RT and filter K2CO3.
� Distilled out Epichlorohydrin completely.
� Collect liquid as a product. (BS-2)
Stage-3:
� Charge methanol and BS-2.
� Charge mono isopropyl amine and heat the reaction mass up to reflux temp for 12 hrs.
� Cool to RT and distilled out methanol completely.
� Charge water and MDC. (Repeat three times)
� Stir for 30 min.
� Separate layer and take organic layer.
� Distilled out MDC completely.
� Collect liquid as a product. (BS-3)
Stage-4:
� Charge acetone and BS-3.
� Charge fumaric acid heat the reaction mass up to reflux temp for 30 min.
� Filter the reaction mass and cool to room temperature.
� Chilled up to 10 – 15 °C and maintain it for 3-4 hrs.
� Filter it and wash with acetone.
39
Flow Diagram:
Stage-I: 4-[(2-Isopropoxyethoxy)Methyl]Phenol [BS-1]
SS Reactor
Nutch Filter
SS Reactor
Nutch Filter / Sparkler Filter
2-IPE
4-HBA
Amberlyst-15
MIPA
2-Isopropoxy ethanol pad
washing
Check pH Sodium Bicarbonate + Water
SS Reactor Distill out
2-Isopropoxy
SS Reactor
SS Reactor
DM Water
MDC 1st Extraction
MDC 2nd & 3rd Extraction
SS Reactor
2-Isopropoxy ethanol pad
washing
Separate layer
Separate layer
Separate layer
Check TLC
All organics layers
DM water washing
SS Reactor
Collect liquid material [BS-1]
SS Reactor
Complete Analysis
DM water washing Separate layer
MDC Distillation Charge Organic layer
40
Stage-II : 2-[[4-(2-Isopropoxyethoxy)Methyl]-Phenoxymethyl]Oxirane [BS-2]
SS Reactor
Nutch Filter
SS Reactor
Collect Liquid
Epichlorohydrin
BS-1
Potassium carbonate
SS Reactor
Collect Liquid [BS-2]
Complete Analysis
Epichlorohydrin pad washing
Distill out
Epichlorohydrin
Complete Analysis
1st to 3
rd Fraction
41
Stage-III: Bisoprolol Base [BS-3]
SS Reactor
SS Reactor
SS Reactor
SS Reactor
Methanol
BS-2
NaBH4
MIPA
Check BS-2 Content
by GC
DM Water
MDC
Aq. Layer
Separated
Organic Layer
Separated
Organic Layer
Aq.LayEffluent Treatment Plant
Combined Organic Layer
Aq.Lay Effluent Treatment Plant
MDC
SS Reactor
Org.La
DM Water
DM Water Aq.LayEffluent Treatment Plant
Org.La
SS Reactor
Org.La Aq.LayEffluent Treatment Plant
SS Reactor
DM Water
Activated Carbon
MDC Wash
Sparkler Filter
Circulation
Clear Solution
Reactor PR-2 MDC Distillation
Bisoprolol Base [BS-3] Complete Analysis
Methanol Distillation
42
Stage – IV : Bisoprolol Fumarate [BS-4]
SS Reactor
Sparkler Filter
SS Reactor
Centrifuge
Acetone
Bisoprolol
Base
Bisoprolol Fumarate
Crude Wet Cake
SS Reactor
Chilled Acetone Washing
Sparkler Filter
SS Reactor
Centrifuge
Clear Solution
Acetone
Clear Solution
Chilled Acetone Washing
Rotocon Vacuum Dryer
Multi Mill
Jet Mill
Sifter
If Required
Check Moisture
Content
If Required
Packing
Complete Analysis
43
Group- 7
18. Pyronaridine Tetraphosphate:
Process Description:
Stage-1: o Charge Compound-A, Compound-B, ethanol and HCl.
o Stir at 40-45 0C for 24 hrs.
o Cool to 10-15 0C.
o Filter it.
o Dry It.
Stage-2:
o Charge stage-1
o Charge DMF
o Stir at 100-105 0C
o Clear sol. obtained
o Filter it
o Take filtrate.
o Adjust pH 5-5.6 with H3PO4
o Stir at RT for 24 hrs
o Cool to 15-20 0C & stir for 1 hrs
o Filter it
o Wash material with chill DMF
o Dry It
Flow Diagram:
Stage-1:
Ethanol recovered
& reused
Process Residue
45
19. Atazanavir
Manufacturing process:
Stage-I: Preparation of Atazanavir di-tert butyl analogue
1. Arrange dry and clean 1.0 lit. four necks round bottom flask equipped with stopper, thermo pocket and
water condenser.
2. Charge IPA into RB flask at 25-30°C under stirring.
3. Charge Boc hydrazine into RB flask at 25-30°C under stirring.
4. Charge Boc epoxy into RB flask at 25-30°C under stirring.
5. Raise the temperature of the reaction mass up to 65-70°C under stirring.
6. Maintain the reaction mass for 24.0 h at 65-70°C under stirring. [Observations: light to dark yellow
color thick semi solid reaction mass observe.]
7. Reaction was monitored by TLC. Send the reaction mass first sample to QC for reaction monitoring by
TLC.
8. If TLC complies, Charge potable water into reaction mass at 65-70°C under stirring.
9. Maintain reaction mass for 1.0 h at 65-70°C under stirring.
10. Cool reaction mass to 25-30°C under stirring.
11. Further cool reaction mass to 15-20°C under stirring.
12. Maintain the reaction mass for 1.0 h at 15-20°C under stirring.
13. Filter the solid from reaction mass at 15-20°C.
14. Wash the wet solid with IPA + Potable water.
15. Dry the material at 50-55°C for 12.0 h under vacuum.
Stage-II: Preparation of Atazanavir free base
(Part A)
1. Arrange dry and clean 1.0 lit. Four necks round bottom flask equipped with stopper, thermo pocket,
addition funnel and water condenser.
2. Charge MDC into RB flask at 30±2°C under stirring.
3. Charge stage-1 into RB flask at 30±2°C under stirring.
4. Slowly added conc. HCl into reaction mass within 30.0±5.0 min. at 30±2°C under stirring
5. Slowly raise the temperature of reaction mass to 35-40°C.
6. Maintain the reaction mass for 2.0 h at 35-40°C under stirring.
7. Send the sample of upper oily layer of reaction mass to QC for reaction monitoring of part A by TLC,
8. If TLC complies, Cool the reaction mass to 30±2°C under stirring.
9. Separate the layers of reaction mass at 30±2°C.
10. Collect the upper oily layer in RB Flask at 30±2°C.
11. Charge MDC into oily layer at 30±2°C under stirring.
12. Cool the reaction mass at 15-20°C under stirring.
13. Addition of tri ethyl amine (150.0 ml) into RB flask within 30.0±5.0 min. at 15-20°C under stirring.
Part-B: 1. Arrange dry and clean 2.0 lit. four necks round bottom flask equipped with stopper, thermo pocket,
addition funnel and water condenser.
2. Charge MDC lot 3 into RB flask at 30±2°C under stirring.
3. Charge N-methoxy carbonyl L-tert leucine into RB flask at 30±2°C under stirring.
4. Charge HOBT mono hydrate into RB flask at 30±2°C under stirring.
5. Charge EDC.HCl into reaction mass at 30±2°C under stirring.
6. Stir the reaction mass for 15.0 min. at 30±2°C.
7. Addition of Part A into reaction mass of Part-B within 30.0±5.0 min. at 30±2°C under stirring.
8. Maintain the reaction mass for 2.0 hrs at 30±2°C under stirring.
9. Send the sample of reaction mass to QC for reaction monitoring of Part B by TLC,
10. If TLC result complies then MDC layer given 3 potable water washings.
11. Distill off the MDC completely from reaction mass under vacuum at NMT 45°C.
12. Charge ethyl acetate into reaction mass at NMT 45°C under stirring.
13. Raise the temperature of reaction mass to 55-60°C under stirring.
14. Maintain the reaction mass for 1.0 h at 55-60°C under stirring.
15. Cool the reaction mass to 30±2°C under stirring.
46
16. Maintain the reaction mass for 3.0 h at 30±2°C under stirring.
17. Filter the solid from reaction mass at 30±2°C.
18. Dry the material at 50-55°C for 12.0 hrs ±5.0 min. under vacuum.
19. Charge methanol into RB flask at 30±2°C under stirring.
20. Charge dry stage-2 into RB flask at 30±2°C under stirring.
21. Stir and heat the reaction mass at 60-65°C.
22. Slowly addition of potable water into reaction mass with in 1.0 h at 60-65°C under stirring.
23. Maintain the reaction mass for 2.0 h at 60-65°C under stirring.
24. Cool the reaction mass to 30±2°C under stirring.
25. Maintain the reaction mass for 2.0 h at 30±2°C.
26. Filter the solid from reaction mass and wash with potable water + methanol.
27. Dry the material at 50-55°C for 12.0 hrs±5.0 min. under vacuum.
Stage-III: Preparation of Atazanavir sulphate:
1. Arrange dry and clean 2.0 lit. Four necks round bottom flask equipped with stopper, thermo pocket
addition funnel and water condenser.
2. Charge methanol into RB flask at 30±2°C under stirring.
3. Charge stage-2 into RB flask at 30±2°C under stirring.
4. Raise the temperature of reaction mass to 40-45°C under stirring.
5. Charge activated carbon into reaction mass at 40-45°C under stirring.
6. Maintain the reaction mass for 1.0 h at 40-45°C under stirring.
7. Hot filter the reaction massthrough hyflo bed and wash the bed with methanol.
8. Distill off the Methanol completely from reaction mass under vacuum at NMT 45°C under stirring.
9. Charge acetone into reaction mass and stir it for 15.0 min. at 40-45°C.
10. Distill off the methanol + acetone completely from reaction mass under vacuum (NLT 710 mm Hg) at
NMT 45°C under stirring.
11. Charge acetone into reaction mass at 40-45°C under stirring.
12. Charge con. H2SO4 into reaction mass at 40-45°C under stirring.
13. Maintain the reaction mass for 1.0 h at 30±2°C under stirring.
14. Filter the solid from reaction mass at 30±2°C
15. Wash the wet solid with acetone.
16. Check the weight of wet cake.
17. Dry the material at 50-55°C for 24.0 h under vacuum.
18. Check the weight of the dry solid at 30±2°C.
19. Send the dry sample to QC for Finished product complete analysis.
FLOW DIAGRAM:
Stage-I: Atazanavir di-tert butyl analogue
47
Stage-II:Atazanavir free base:
Stage-IReactor
(Part-A)
Reactor Organic Layer
MDC
Reactor
Conc. HCl
Reactor
Distillation
MDC
TEA
MDC
MOC L-tert leucine
HOBT.H2O
EDC.HCl
Potable water Aq. layer for
HOBT recovery
Solvent recovered
and Recycled
ReactorEthyl acetate
Reactor
(Part-B)
ReactorMethanol
Centrifuge
Centrifuge
Stage-2
MLSolvent recovered
and Recycled
Distillation
Residue
MLSolvent recovered
and Recycled
Distillation
Residue
49
20. PRIMAQUINE PHOSPHATE
Process Description:
Stage-1:
1,4-Dibromo pentane on reaction with potassium phthalimide at 50-55 °C in solvent acetone afford 4-bromo-1-
phthalimido pentane. After acetone recovery thick oily mass collected as stage-1 for further reaction.
Stage-2: Primaquine stage-1, 8-aminoquinoline and aq. solution of disodium hydrogen phosphate were added in to the
methanol and heated to 75-80°C. The reaction mass was maintained at 75-80°C for 45-50 hrs. After completion
of reaction cool the reaction mass to RT and MDC was added in to the reaction mass and stirred well. Separate
layer of the reaction mass and MDC layer was given a Conc. HCl washing. MDC layer was concentrated till
dryness and cooled to RT. Methanol and hydrazine hydrate were added in to the concentrated oily reaction mass
& was heated to reflux.Stirred the mass for 2 hrs at reflux to complete the reaction. Cool the reaction mass to
RT and filter the solid, washed with chilled methanol. Filtrate was taken for phosphate salt preparation by
adding 80% phosphoric acid in it. Reaction mass was heated to reflux and maintained for 1 hr. Cool the
reaction mass to RT and further cooled to 0-5°C. The isolated solid was filtered, washed with chilled methanol
and dried by suction. The solid was dried in hot air oven to obtain stage-2 of Primaquine phosphate.
Stage-3: Primaquine phosphate stage-2 was added into the Methanol at 25-30°C. Heat the reaction mass up to reflux to
obtain clear solution. Activated carbon was added into the clear reaction mass and stirred the mass for 30
minutes at reflux. Filter the reaction mass through hyflo bed and the carbon bed was washed with Methanol.
The reaction mixture was cooled to RT and further cooled to 0-5 °C. The isolated solid was stirred at 0-5 °C for
4 hrs then filtered,washed with chilled water and dried by suction. The solid was dried in hot air oven to obtain
stage-2P of Primaquine phosphate.
Flow Diagram:
Stage-1:
SSR
SSR
SSR
ML
1,4-DBP
Acetone
Distillation
SSR(Oily mass)
Potassium phthalimide
50-55°C
Centrifuge
Stage-1
Acetone/1,4 DBP recovered & reused
2-3 dihydrophthalazine-1,4-dione
[Salt (By product)]
50
Stage-2:
MDCSSR
SSR
SSR
SSR
SSR
8-AMQ, MDC & Methanol recovered & reused
8-AMQ
Na2HPO4 solution
Stage-1
Methanol
W/W to ETP
75-80°C
Distillation
Methanol
Hydrazine hydrate
Aq. HCl
Centrifuge
60-65°C
Phosphoric acid
Centrifuge
Drying
Stage-2
Mother liquor
60-65°C
Water
Conc. HCl
Process residue
Distillation residue
Hydrazine Hydrate recovered & reused
4, BPP
Distillation residue
Mother liquor
Methanol
Methanol recovered & reused
Distillation residue
51
Stage-3:
Stage-2
MethanolReactor
Sparkler
Distillation
Stage-3 (Primaquine Phosphate Pharma)
Drying
Methanol recovered & reused
Reactor
55-60°C
Activated carbon
W/W to ETPCentrifugeWater
Spent Carbon
Distillation residue
52
21. Chloroquine Phosphate
Process Description:
Stage-1: 4, 7-DCQ is condensed with NDA to obtain Chloroquine base, which is then taken in Solvents and reacted with
Phosphoric Acid to give Crude Chloroquine Phosphate (CQP).
Stage-2: Chloroquine Phosphate Crude is taken in Solvent and recrystallised to obtain pure Chloroquine Phosphate. This
Chloroquine Phosphate pure is dried, pulverized, analyses and packed in HDPE or fiber drums followed by two
liners, primary is black & secondary is white.
Flow Diagram:
Stage-1:
.
Caustic Lye
Activated Carbon
Phenol
Silica
Distillation Residue
Process Residue
Phenol
Recovered
Spent
Carbon
4,7 DCQ
NDA
Water
CONDENSATION
EXTRACTION Aq. Layer
WATER
EDTA
Toluene
W/W to ETP
DISTILLATION Methanol Toluene
recovery
Phosphate Formation
Phosphoric
acid Methanol Recovery
Crude CQP
53
Stage-2:
CARBON
TREATMENT
FILTRATION
CRYSTALISATION
CENTRIFUGING
DRYING
CQP
CQP CRUDE
WATER
CARBON
W/W to ETP
DNS
DNS Recovered
& Reused
H2O + DNS
WATER Washing
EDTA
Phosphoric acid
Hyflow
Silica
Process
Residue
Distillation
Residue
Spent Carbon
54
Group-8
22. Tenofovir Alafenamide Fumarate Manufacturing process
Stage-1:
1. Arrange dry and clean RBF with TP, stopper, water condenser, addition funnel and oil bath at
25-30°C.
2. Charge Acetonitrile into RBF at 25-30°C.
3. Charge PMPA into RBF under stirring at 25-30°C.
4. Charge Triphenyl phosphite into RBF under stirring at 25-30°C.
5. Add Triethylamine using addition pot within 30 mins at 25-30°C.
6. Charge DMAP to RBF.
7. Charge Toluene into RBF at 25-30°C.
8. Raise temperature up to 80-85°C.
9. Maintain reaction for 40-42 hrs at 80-85°C.
10. Check TLC after 40 Hrs. If TLC ok cool the reaction to 10-15°C.
11. Charge toluene in same RBF at 10-15°C.
12. Charge purified water in RBF at 10-15°C.
13. Stirrer reaction mass for 1 hr at 15-20°C.
14. Separate the layers, aqueous layer transferred to RBF at 15-20°C.
15. Adjust pH 2.0 to 3.0 slowly by using conc. HCl at 10-15°C.
16. Further cool reaction mass 0-5°C.
17. Maintain reaction mass 3-4 hrs at 0-5°C.
18. Filter the reaction mass at 0-5°C.
19. Wash the wet cake with chilled mixture of Acetonitrile and purified water at 0-5°C and suck
dry well.
20. Charge wet material in Toluene at 25-30°C.
21. Maintain for 4-8 hrs at 70-75°C.
22. Filter and suck dry well.
23. Unload w/c and dry at 60-65°C.
24. Unload dry material, Check weight of material.
Stage-2:
Part A: 1. Arrange dry and clean RBF with TP, stopper, water condenser, addition funnel and oil bath at
25-30°C.
2. Charge Toluene into RBF at 25-30°C.
3. Charge Mono phenyl PMPA into RBF under stirring at 25-30°C.
4. Add thionyl chloride using addition pot into RBF under stirring at 25-30°C.
5. Raise temp up to 85-100°C.
6. Maintain reaction mass under stirring for 60-65 hrs at 85-100°C.
7. Cool reaction mass at 60°C
8. Charge toluene at 60°C.
9. Distilled out reaction mass until about 4 vol up to 85-100°C.
10. Cool reaction mass to 25-30°C.
11. Charge MDC at 25-30°C.
12. Cool to 19-25 0C. Stir 1 hr at 19-25°C.
13. Further cool reaction mass below -10°C.
Part B: 14. Charge L-alanine isopropyl ester hydrochloride in another RBF.
15. Charge THF in RBF at 25-30°C
16. Cool reaction mass to 0-6°C.
17. Add slowly Triethyl amine using addition pot below 0-5°C
18. Maintain 1 hr at 0-5°C.
19. Filter the reaction mass, wash by chilled THF.
20. Collect filtrate in Clean RBF.
21. Cool reaction mass to 0-5°C
22. Further cool reaction mass below -10 to -20°C.
55
23. Add Part A reaction mass to Part B slowly below -10°C.
24. Maintain reaction for 1 hr at -10°C.
25. Raise temperature of reaction mass at 20-25°C.
26. Distilled out reaction mass until about 14 vol up to 45-50°C.
27. Cool reaction mass to 15-25°C.
28. Charge Acetonirile in RBF at 15-25°C.
29. Distilled out reaction mass until about 8 vol up to 45-50°C.
30. Cool reaction mass to 20-25°C.
31. Charge MDC in reaction mass at 20-25°C.
32. Charge sodium phosphate monobasic solution in reaction mass at 20-25°C.
33. Stir 30 mins at 20-25°C.
34. Settle & layer separated.
35. The product MDC layer is transferred to RBF at 20-25°C.
36. Charge purified water in reaction mass.
37. Stir 30 mins at 20-25°C.
38. Settle & layer separated.
39. The product MDC layer is transferred to RBF at 25-30°C.
40. Distilled out reaction, strip out by Acetone up to 40-45°C.
41. Charge Acetone in reaction mass, stir for 15 mins at 50-55°C.
42. Cool reaction mass to 20-25°C.
43. Filter the wet cake and suck dry well.
44. Unload w/c and dry at 55-60°C.
Stage-3: 1. Arrange dry and clean RBF with TP, stopper, water condenser, addition funnel and oil bath at
25-30°C.
2. Charge Stage-II in RBF at 25-30°C.
3. Charge Acetonitrile in RBF at 25-30°C.
4. Raise temp of reaction mass up to 65-70°C.
5. Charge fumaric acid in RBF at 65-70°C.
6. Stir for 45-60 min at 65-70°C.
7. Filter the Reaction mass at 65-70°C.
8. Filtrate further heat to 70-75°C.
9. Charge TAF (seed) into reaction mass 55-60°C.
10. Reactions mass gradually cool to 25-30°C.
11. Further cool the reaction mass upto 0-5°C.
12. Stir 1 hr at 0-5°C.
13. Filter the material and wash by clilled Acetonirtile.
14. Suck dry well.
15. Unload w/c and dry in VTD at 50-55°C.
16. Unload dry material, Check weight of material.
57
Stage-III:
23. Tenofovir DipivoxilOrotate Manufacturing process:
Stage-1: Tenofovir Disoproxil base: 1. Arrange dry and clean RBF.
2. Charge NMP into RB flask at 30 ± 5°C under stirring.
3. Charge PMPA into RB flask at 30 ± 5°C under stirring.
4. Charge TBAB into RB flask at 30 ± 5°C under stirring.
5. Raise the temperature of the reaction mass up to 49 ± 4°C under stirring.
6. Addition of CMIC + TEA mixture into reaction mass in 1.0 h ± 5 min at 49 ± 4°C.
7. Maintain the reaction mass for 2.0 h ± 5 min at 50 ± 2°C under stirring.
8. Chill the reaction mass to 0-5°C under stirring.
9. Add chilled water into reaction mass at in 1.0 h ± 10 min at 0-5°C.
10. Maintain the reaction mass for 16.0 h ± 15 min at 0-5°C under stirring.
11. Filter the solid from reaction mass at 0-5°C.
12. Charge MDC into RB flask at 0-5°C under stirring.
13. Charge wet cake into RB flask at 0-5°C under stirring.
14. MDC layer given chilled water washings at 0-5°C.
15. Combine aqueous layer given MDC extraction at 0-5°C.
16. Combine both MDC layers into RB flask and charge sodium sulphate at 0-5°C.
17. Stir the reaction mass for 30 ± 5 min at 0-5°C.
18. Filter the reaction mass and wash with MDC at 0-5°C.
19. Distill out MDC completely under vacuum at temperature below 35°C.
20. Cool the reaction mass at 20-25°C.
21. Charge ethyl acetate into reaction mass at 20-25°C.
22. Charge Cyclohexane into reaction mass at 30-35°C.
23. Maintain the reaction mass for 2.0 h ± 30 min at 25-30°C under stirring.
24. Filter the solid from reaction mass at 25-30°C.
58
25. Dry the material at 40-45°C for 4.0 h under vacuum.
Stage-2: Tenofovir Disoproxil Orotate
1. Arrange dry and clean RBF.
2. Charge Acetone into RB flask at 30 ± 2°C.
3. Charge Stage-1 into RB flask at 30 ± 2°C.
4. Charge Purified water into reaction mass at 30 ± 2°C.
5. Stir reaction mass for 15.0 min. at 30 ± 2°C.
6. Filter the reaction mass at 30 ± 2°C and wash with purified water.
7. Addition of orotic acid solution + DMSO solution in 1.0 hr ± 5 min. into reaction mass at 30 ±
2°C.
8. Charge Purified water into reaction mass at 30 ± 2°C.
9. Maintain reaction mass for 1.5 hr at 30 ± 2°C.
10. Filter the solid from reaction mass at 30 ± 2°C.
11. Dry the material at 40-45°C for 20.0 h under vacuum.
Flow Diagram Stage-1: Tenofovir Disoproxil base
59
Stage-2:
24. Sofosbuvir Manufacturing Process:
Preparation of Stage-1: 1. Arrange clean & dry RB flask equipped with addition funnel, thermo pocket and water condenser in
icebath.
2. Charge dry THF into RB flask at 25-30°C.
3. Charge Uridine into RB flask at 25-30°C under stirring.
4. Cool the reaction mixture up to 0 to 5°C under stirring.
5. Addition of t-BuMgCl into RB flask within at 0 to 5°C under stirring.
6. Charge Fluoro compound into the reaction mixture at 0 to 5° C under stirring.
7. Maintain the reaction mass at 0 to 5°C for 15 hrs under stirring.
8. After completion of reaction, add 2N HCl solution into the reaction mixture at 0 to 5°C under
stirring.
9. Charge MDC into the reaction mixture at 0 to 5°C under stirring.
10. Take the organic layer and give 5% aqueous Na2CO3 washing and brine washing respectively at 25-
30°C.
11. Take upper organic layer and give Na2SO4 treatment at 25-30°C and filter the mass.
12. Distill out MDC completely at 45-50°C under vacuum.
13. Cool the reaction mass to 25-30°C and charge MDC and Toluene in it at 25-30°C under stirring.
14. Cool the reaction mass at 0-5°C under stirring.
15. Filter the solid from reaction mass at 0-5° suck dry well and dry the mass in oven at 50-55 °C.
Preparation of Stage-2: 1. Arrange clean & dry RB flask equipped with thermo pocket and water condenser in waterbath.
2. Charge Methanol in it at 25-30°C
3. Charge stage-1 in it at 25-30°C under stirring.
4. Raise the temperature of reaction mass to 65-70°C under stirring.
5. Charge activated carbon into reaction mass.
6. Filter the hot reaction mass at 65-70°C through hyflo bed and wash the bed with Methanol.
7. Distill out methanol completely at 45-50°C under vacuum till oily mass obtained.
8. Cool the reaction mass at 25-30°C.
9. Charge MDC into RB flask at 25-30°C under stirring.
10. Further cool reaction mass to 0-5°C under stirring.
11. Filter the solid from reaction mass at 0-5°C under vacuum and suck dry well and dry the solid in
oven at 50-55°C.
Preparation of Stage-3 or Sofosbuvir: 1. Arrange clean & dry RB flask equipped with thermo pocket and water condenser in waterbath.
2. Charge purified water into RB flask at 25-30°C.
60
3. Charge stage-2 into RB flask at 25-30°C under stirring.
4. Raise the temperature of reaction mass to 50-55°C under stirring.
5. Maintain the reaction mass for 1.0 hrs at 50-55°C under stirring.
6. Cool the reaction mass at 25-30°C under stirring.
7. Filter the solid from reaction mass at 25-30°C under vacuum and suck dry well & dry the mass in
oven at 50-55°C.
Flow Diagram
Stage-1
Neutralisation
Centrifuge
Distillation
residue
Uridine CompdCondensation
5% Na2CO3
2N HCl
t-BuMgCl
Organic layer
THF
MDC
Brine soln
Waste Water
To ETP
Fluoro Compd
Organic layerAnhy. Na2SO4
Solvent recovered
and Recycled
Drying
Solid waste
Stage-1
DistillationSolvent recovered
and Recycled
SSRMDC
Toluene
Centrifuge ML
Waste Water
To ETP
62
GROUP-9
25. Dolutegravir Sodium Manufacturing process:
Preparation of Stage-I:
1. Arrange dry clean RBF with T.P., stopper and condenser in heating water bath at 25-30 °C.
2. Charge Acetonitrile in to the RBF at 25-30 °C.
3. Charge methoxy compound in it at 25-30 °C under stirring.
4. Heat the reaction mass up to 75-80°C under stirring.
5. Maintain the reaction mass at 75-80°C under stirring for 3.0-5.0 hrs or till TLC complies.
6. After completion of reaction cool the reaction mass to 25-30 °C under stirring.
7. Add 1N HCl using addition funnel within 15.0 min. at 25-30 °C under stirring.
8. After completion of addition heat the reaction mass up to 45-50 °C under stirring.
9. Distilled out acetonitrile completely from the reaction mass at 45-50 °C under vacuum.
10. Cool the reaction mass to 25-30 °C under stirring.
11. Charge methanol and stir the mass for 15.0 min. at 25-30 °C.
12. Add 30% HCl using addition funnel within 15.0 min. at 25-30 °C under stirring
13. After completion of addition add purified water in to the above reaction mass at 25-30 °C under
stirring.
14. Heat the reaction mass up to 60-65 °C under stirring.
15. Cool the reaction mass to 25-30 °C under stirring.
16. Further cool the reaction mass to 0-5 °C under stirring.
17. Filter the reaction mass at 0-5 °C.
18. Wash the solid with chilled methanol at 0-5 °C and suck dry well.
19. Transfer the solid and dry the solid in hot air oven at 50-55 °C.
Preparation of Stage-II or Dolutegravir Na:
1. Arrange dry clean RBF with T.P., stopper and condenser in heating water bath at 25-30 °C.
2. Charge Methanol in to the RBF at 25-30 °C.
3. Charge hydroxy compound in it at 25-30 °C under stirring.
4. Heat the reaction mass up to 60-65°C under stirring.
5. Add aq. NaOH solution using addition funnel within 15.0 min. at 25-30 °C under stirring.
6. Maintain the reaction mass at 60-65°C under stirring for 2.0 hrs.
7. Cool the reaction mass to 25-30 °C under stirring.
8. Further cool the reaction mass to 0-5 °C under stirring.
9. Filter the reaction mass at 0-5 °C.
10. Wash the solid with chilled methanol at 0-5 °C and suck dry well.
11. Transfer the solid and dry the solid in hot air oven at 50-55 °C.
63
Flow Diagram :
Stage-I
Neutralisation
Centrifuge
Drying
ML
Product of Stage-1
Solvent recovered and
Recycled
Distillation
residue
Acetonitrile
Methoxy compound
Demethoxylation
Acetonitrile
Methanol
1N HCl
30% HCl
LiBr
Solvent recovered and
Recycled
Neutralisation
Stage-II
64
26. Velpatasvir
Manufacturing process:
Preparation of Stage-1: 1. Arrange dry and clean four necks round bottom flask
2. Charge (2S,4S)-4-(Methoxymethyl)-1,2-pyrrolidinedicarboxylicacid2-[2-(9-bromo-8,9,10,11-
tetrahydro-8-oxo-5H-benzo[d]naphtho[2,3-b]pyran-3-yl)-2-oxoethyl]1-(1,1-dimethylethyl) ester into
RB flask at 25-30°C under stirring.
3. Charge (2S,5S)-1-((S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl pyrrolidine-2-
carboxylic acid into RB flask at 25-30°C under stirring.
4. Charge THF into RB flask at 25-30°C under stirring.
5. Charge Cesium carbonateinto RB flask at 25-30°C under stirring.
6. Stir and heat RM at 50-55°C and maintain for 20.0 h.
7. Distilled out RM completely at 50-55°C u/v and cool to RT.
8. Charge Ethyl acetate into the above concentrated mass.
9. Stir RM at 25-30°C for 1.0 h.
10. Filter and dry the solid.
Preparation of Stage-2:
1. Arrange dry and clean four necks round bottom flask
2. Charge Stage-1 into RB flask at 25-30°C under stirring.
3. Charge Sodium acetate into RB flask at 25-30°C under stirring.
4. Charge Toluene into RB flask at 25-30°C under stirring.
5. Stir and heat RM at 100-110°C and maintain for 5.0 h.
6. Distilled out RM completely at 50-55°C u/v and cool to RT.
7. Charge Methanol into the above concentrated mass.
8. Stir RM at 25-30°C for 4.0 h.
9. Filter and dry the solid.
Preparation of Stage-3:
1. Arrange dry and clean four necks round bottom flask
2. Charge Stage-2 into RB flask at 25-30°C under stirring.
3. Charge Manganese dioxide into RB flask at 25-30°C under stirring.
4. Charge MDC into RB flask at 25-30°C under stirring.
5. Maintain RM at 25-30°C for 13.0 h.
6. Charge Methanol at 25-30°C under stirring.
7. Stir RM at 25-30°C for 2.0 h.
8. Filter and dry the solid.
Preparation of Stage-4:
1. Arrange dry and clean four necks round bottom flask
2. Charge Stage-3 into RB flask at 25-30°C under stirring.
3. Charge MDC into RB flask at 25-30°C under stirring.
4. Charge Conc. HCl into RB flask at 25-30°C under stirring.
5. Maintain RM at 25-30°C for 1.0 h.
6. Charge (R)-2-((methoxycarbonyl) amino)-2-phenylacetic acid into RB flask at 25-30°C under stirring.
7. Charge COMU ( (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-
carbenium hexafluorophosphate) into RB flask at 25-30°C under stirring.
8. Charge DIPEA into RB flask at 25-30°C under stirring.
9. Maintain RM at 25-30°C for 2.0 h.
10. Distilled out RM completely at 40-45°C u/v and cool to RT.
11. Charge Ethyl acetate into the above concentrated mass.
12. Stir RM at 25-30°C for 1.0 h.
13. Filter and dry the solid.
67
27. AdefovirDipivoxil Fumarate Manufacturing process:
Stage-1: Adefovir Dipivoxil base
1. Arrange dry and clean RBF.
2. Charge NMP into RB flask at 25-30°C under stirring.
3. Charge Adefovir into RB flask at 25-30°C under stirring.
4. Raise the temperature of the reaction mass up to 45-50°C under stirring.
5. Addition of t-Butyl (chloromethyl) carbonate [t-BCMC] and TEA mixture into reaction mass in
1.0 h ± 5 min at 45-50°C.
6. Maintain the reaction mass for 2.0 h ± 5 min at 45-50°C under stirring.
7. Chill the reaction mass to 0-5°C under stirring.
8. Add chilled water into reaction mass at in 1.0 h ± 10 min at 0-5°C.
9. Maintain the reaction mass for 16.0 h ± 15 min at 0-5°C under stirring.
10. Filter the solid from reaction mass at 0-5°C.
11. Charge MDC into RB flask at 0-5°C under stirring.
12. Charge wet cake into RB flask at 0-5°C under stirring.
13. MDC layer separate and given chilled water washings at 0-5°C.
14. MDC layers into RB flask and charge sodium sulphate at 0-5°C.
15. Filter the reaction mass and wash with MDC at 0-5°C.
16. Distill out MDC completely under vacuum at temperature below 35°C.
17. Cool the reaction mass at 20-25°C.
18. Charge IPA into reaction mass at 20-25°C.
19. Maintain the reaction mass for 2.0 h ± 30 min at 25-30°C under stirring.
20. Filter the solid from reaction mass at 25-30°C.
21. Dry the material at 40-45°C for 4.0 h under vacuum.
Stage-2: Adefovir Dipivoxil Fumarate 1. Arrange dry and clean RBF.
2. Charge Acetone into RB flask at 30 ± 2°C.
3. Charge Stage-1 into RB flask at 30 ± 2°C.
4. Stir reaction mass for 15.0 min. at 50-55°C.
5. Charge fumaric acid into reaction mass at 50-55°C.
6. Filter the reaction mass at 50-55°C.
7. Maintain reaction mass for 30 min. at 50-55°C.
8. Stop heating and cool to room temp. then 0-5°C.
9. Maintain reaction mass for 2.0 hr at 0-5°C.
10. Filter the reaction mass at 0-5°C.
11. Dry the material at 45-50°C for 20.0 h under vacuum.
69
28.Ledipasvir Manufacturing process:
Preparation of Stage-I:
1. Arrange dry and clean four necks round bottom flask equipped with stopper, thermo pocket and water
condenser.
2. Charge (1R,3S,4S)-tert-butyl 3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1] heptane-2-
carboxylate into RB flask at 25-30°C under stirring.
3. Charge bis(pinacato)diboron into RB flask at 25-30°C under stirring.
4. Charge potassium propionate into RB flask at 25-30°C under stirring.
5. Charge Isopropyl acetate into RB flask at 25-30°C under stirring.
6. Stir and heat RM at 70-75°C and maintain for 4 h.
7. Cool RM to RT.
8. Charge 1M K3PO4 solution into RB flask at 25-30°C under stirring.
9. Charge N-acetyl-L-Cysteine into RB flask at 25-30°C under stirring.
10. Stir and heat RM at 35-40°C and maintain for 15.0 h.
11. Cool RM to RT and separate layer.
12. Take organic layer and distilled out IPAc completely at 50-55°C u/v and cool to RT.
13. Charge Acetonitrile and 1.5 N HCl solution into the above concentrated mass.
14. Stir and heat RM at 60-65°C and maintain for 2 h.
15. Cool RM upto 20°C and maintain for 2 h.
16. Filter and dry the solid.
Preparation of Stage-II: 1. Arrange dry and clean 1.0 lit. four necks round bottom flask equipped with stopper, thermo pocket and
water condenser.
2. Charge EDC.HCl into RB flask at 25-30°C under stirring.
3. Charge HOBT.H2O into RB flask at 25-30°C under stirring.
4. Charge MOC-Valine into RB flask at 25-30°C under stirring.
5. Charge DMF into RB flask at 25-30°C under stirring and further cool to 0-5°C
6. Charge Stage-1 and N-methyl morpholine at 0-5°C under stirring.
7. Raise temperature upto 25-30°C and maintain for 4 h.
8. Charge Ethyl acetate, stir for 15.0 min.and separate layer.
9. Distill out ETOAc completely at 50-55°C u/v and cool to RT.
10. Charge acetone into RB flask at 25-30°C under stirring.
11. Filter and dry the solid
Flow Diagram
Stage-1:
70
Stage-2:
29. Daclatasvir Dihydrochloride Manufacturing process:
Stage-I: 1. Arrange dry and clean RBF with TP, stopper, water condenser, addition funnel and oil bath at
25-30°C under nitrogen atmosphere.
2. Charge MDC into RBF at 25-30°C.
3. Charge 1,1'-(biphenyl-4,4'-diyl) diethanone into RBF under stirring at 25-30°C.
4. Add Bromine into RBF under stirring at 25-30°C.
5. Reaction mass stirrer for 20 hrs at 25-30°C under nitrogen atmosphere.
6. Charge MDC into RBF at 25-30°C.
7. Distill out solvent up to under vacuum at 35-40°C.
8. Stripping out solvent with THF up to under vacuum at 35-40°C.
9. Concentrated mass slowly cool to 20- 25°C.
10. Reaction mass stirrer for 1 hr at 20- 25°C.
11. Reaction mass filter and wash with MDC at 20- 25°C.
12. Material dry at 55-60°C.
Stage-II: 1. Arrange dry and clean RBF with TP, stopper, water condenser, addition funnel and oil bath at
25-30°C under nitrogen atmosphere.
2. Charge Acetonirtile into RBF at 25-30°C.
3. Charge Stage-Iinto RBF under stirring at 25-30°C.
4. Charge Boc L-Proline into RBF under stirring at 25-30°C.
5. Reaction mass cool to 15-20°C.
6. Add slowly DIPEA into RBF under stirring below 20°C.
7. Reaction mass stirrer for 3 hr at 25-30°C
8. After completion of maintaining, reaction mass wash with 13% Aq. NaCl solution.
9. Organic layer take into RBF and distill out Acetonitrile under vacuum by stripping with
Toluene
10. Charge Ammonium acetate at 25-30°C.
11. Reaction mass heat up to 95-100°C for 15 hrs.
12. After completion of reaction mass cool to 70-80°C.
13. Add Acetic acid, n-Butanol and (5 vol%) aqueous Acetic acid at 70-80°C.
71
14. Layer separate at 50-55°C.
15. Distill out solvent under vacuum at 60-65°C from organic layer and stripping out with Toluene
16. Charge Methanol to the above concentrated mass and heat to 70-75°C for 1 hr.
17. Reaction mass cool to 25-30°C, then stirrer for 1 hr.
18. Reaction mass filter and wash with Toluene: Methanol (10:3) mixed solvent at 25-30°C.
19. Material dry under vacuum under vacuum at 65-70°C.
Stage-III:
1. Arrange dry and clean RBF with TP, stopper, water condenser, addition funnel and oil bath at
25-30°C under nitrogen atmosphere.
2. Charge Methanol into RBF at 25-30°C.
3. Charge stage-IIinto RBF under stirring at 25-30°C.
4. Charge 6M aqueous HCl solution into RBF under stirring at 25-30°C.
5. Reaction mass heat to 50-55°C, for 5 hrs.
6. Reaction mass cool to 25-30°C, and stirrer for 18 hrs. at 20-25°C.
7. Reaction mass filter and wash with 90% Methanol/Water (w/v) and Methanol at 25-30°C.
8. Material dry under vacuum under vacuum at 50-55°C.
Stage-IV:
1. Arrange dry and clean RBF with TP, stopper, water condenser, addition funnel and oil bath
under nitrogen atmosphere at 25-30°C.
2. Charge Acetonirtile into RBF at 25-30°C.
3. Charge hydroxybenzotriazole hydrate into RBF under stirring at 25-30°C.
4. Charge N-(methoxycarbonyl)- L-valine into RBF under stirring at 25-30°C.
5. Charge l-(3-dimethyaminopropyl)-3- ethylcarbodiimide hydrochloride into RBF under stirring
at 25-30°C
6. Reaction mass cool to 20°C, for 1 hr.
7. Add Stage-III into RBF under stirring below 20°C.
8. Reaction mass cool to 0-5°C.
9. Add slowly DIPEA into RBF under stirring below 10°C.
10. Reaction mass slowly heat up to 15ᴼC, for 12 hrs.
11. After completion of maintaining, reaction mass wash charge to 13% Aq. NaCl solution.
12. Reaction mass heat up to 50ᴼC, for 1 hrs.
13. Reaction mass cool to 20°C, and add Isopropyl acetate.
14. Layer separation, organic layer wash with 0.5N NaOH solution containing 13% Aq. NaCl
solution.
15. Layer separation, organic layer wash with 13% Aq. NaCl solution.
16. Organic layer take into RBF and distill out Isopropyl acetate under vacuum at 50-55°C.and
stripping out by Ethanol.
17. Add 1.24M HCl in Ethanol at 50-55°C.
18. Reaction mass stirrer at 50-55ᴼC, for 3 hrs.
19. Reaction mass cool to 20ᴼC, and stirrer for 22 hrs.
20. Reaction mass filter and wash with (2:1) Acetone:Methanol at 20-25°C.
21. Material dry under vacuum under vacuum at 65-70°C.
74
30. Tafenoquine Succinate Manufacturing process :
Preparation of stage-1 1. Arrange dry clean four neck RB flask equipped with thermo pocket, water condenser, stopper and
addition pot and water bath.
2. Charge acetone into RB flask at 25-30°C.
3. Add slowly 1, 4-dibromo pentane using addition pot into reaction mass with in 15.0 min. at 25-
30°C under stirring.
4. Rinse addition pot with acetone at 25-30°C.
5. Charge potassium phthalimide into reaction mass at 25-30°C under stirring.
6. Heat the reaction mass up to 50-55°C under stirring.
7. Maintain the reaction mass for 24.0 hr at 50-55°C under stirring.
8. After completion of reaction; cool the reaction mass to R.T. then to 5-10°C under stirring.
9. Filter the reaction mass at 5-10°C & Wash the solid with chilled acetone.
10. Take filtrate for distillation and acetone completely distilled out from the reaction mass under
vacuum at 50-55°C till oily residue remain.
11. Cool the reaction mass to 25-30°C.
12. Collect the oily reaction mass as Stage-I.
Preparation of stage-11
1. Arrange dry and clean four neck RB flask equipped with thermo pocket, condenser, stopper and
addition pot.
2. Charge stage-I into the RB flask at 25-30°C.
3. Charge methanol by rinsing the container of stage-I at 25-30°C.
4. Charge 6-methoxy-8-amino quinoline at 25-30°C under stirring.
5. Heat the reaction mass up to 75-80°C under stirring.
6. Maintain the reaction mass for 40.0 hr at 75-80°C under stirring.
7. After completion of reaction distilled out MDC completely from the reaction mass at 40-45°C.
8. Charge methanol into RB flask at 40-45°C under stirring.
9. Charge hydrazine hydrate into the RB flask at 40-45°C under stirring.
10. Raise the temperature of reaction mass to 60-65°C under stirring.
11. Maintain the temperature of the reaction mass for 2.0 hrs at 60-65°C under stirring.
12. After completion of reaction cool the mass to 25-30°C.
13. Filter the reaction mass and wash the solid with methanol
14. Charge filtrate into RB flask at 25-30°C.
15. Add slowly succinic acid solution into reaction mass at 25-30°C.
16. After completion of addition heat the mass up to 50-55°C.
17. Cool the reaction mass to RT and further cool to 5-10°C.
18. Filter the solid and wash with methanol and dry the solid in oven to get final compound.
76
GROUP-10
31. Ursodiol Manufacturing process
Stage-1:Preparation of Ketolithocholic acid. KSM (Chenodeoxycholic acid) oxidized using N-Bromosuccinamide in Acetone Water as solvent at
room temperature to get 7-Ketolithocholic acid crude which is further purified in Ethyl acetate,
methanol, and water to get pure 7-Ketolithocholic acid (Stage-1).
Stage-2 : Preparation of Ursodiol Crude 7-Ketolithocholic acid (Stage-1) reduced in presence of Metal Alloy (Ra/ni) in presence of Base
Potassium tert. Butoxide in IPA to get Ursodiol crude
Stage-3: Preparation of Ursodiol Triethyl amine Salt.
Ursodiol crude, which is salting with Triethyl amine in Acetone, water to get URSO TEA salt. This TEA
salt is desalting with 10% HCl solution to get Ursodiol
Stage-4: Preparation of Ursodiol Extra Pure
Purification of Ursodiol Extra pure by Acetone+ water/IPA+Acetonitrile purification method.
Flow Diagram
Stage-I
Stir Reaction Mixture
Acetone
Water
N-Bromosuccinaamide
Maintained Reaction
Mixture
Water Maintained Reaction
Mixture
Filter
Stir Reaction Mixture Crude
Ethylacetate
Methanol
Water Maintained Reaction
Mixture
Filter the reaction mixture
Wet Cake
Drying
ML
Residue after distillation
Solvent Recovery
Acetone recovery
Stage-I
77
Stage-II
Maintained Reaction
Mixture
After Completion of
Reaction
Organic Layer
Distil the Organic Layer
Filter the reaction mixture
Oil Obtained Water
Ethyl acetate
Dil HCl
Maintain the reaction
mixture
Filter the reaction mix
Wet Cake
Drying
7-Ketolithocholic acid
IPA
Potassium Tert Butoxide
Ra/Ni
Stir Reaction Mixture
Stage-II
Aqueous layer ETP
Solvent recovery
Solvent recovery
ML
Residue distillation
Sludge
78
Stage- III
Maintained Reaction
Mixture
Filter the reaction mixture
Wet Cake
ML
Maintained Reaction
Mixture
Filter the reaction mixture
Drying
Stage-III
Solvent recovery
Stir Reaction Mixture Ursodiol TEA Salt
Water
Ethylacetate
HCl Solution
Ursodiol Crude Acetone
Water
Triethyl amine
Stir Reaction Mixture
Solvent Recovery
Residue Distillation
MLR
79
Stage- IV
Maintained Reaction
Mixture
Filter the reaction
mixture
Filtrate
Stir Reaction Mixture Ursodiol Pure
Acetone
Water
Water
Maintained Reaction
Mixture
Filter the reaction
mixture
Drying
Wet Cake
Product
MLR COD
Residue distillation
80
32. Terizidone
Manufacturing process:
Preparation of stage-1 1. D-Serine was dissolved in chloroform and dry HCl was added to the mixture for 10 min.
2. Then, the mixture was cooled to 0-8 °C and thionyl chloride was added drop wise into the mixture
within 1 hr.
3. The mixture was stirred at room temperature for 2 hr and then under reflux for 4 hr.
4. The reaction mixture was cooled subsequently and the solid was removed by filtration.
5. The solid was washed with chloroform and dried in vacuo to get a white powder Yield: 90%; m. p.:
128–1308C;
Preparation of stage-2
1. To a cooled solution of hydroxylamine hydrochloride in absolute ethanol of 0.91 N sodium
methoxide in methanol were added.
2. The mixture was cooled to 0-8 °C, the sodium chloride was filtered, and a solution of intermediate
stage-1 in absolute ethanol was added to the filtrate.
3. This solution was cooled to 0-8°C and 0.91 N sodium methoxide was added slowly.
4. The solution was concentrated in vacuo at room temperature to about 45 mL.
5. The water was added to the solution and 0.46 N hydrochloric acid was added drop wise and the
product was crystallized.
6. The product was filtered and dried in vacuo. Yield: 84%; m. p.: 191–1938C;
Preparation of stage-3 1. A solution of intermediate 2 in water was stirred and cooled.
2. The mixture’s pH was adjusted to 11 by an aqueous sodium hydroxide solution (30% wt).
3. The mixture was stirred at 25 °C for 2 h.
4. Then mixture of 1:1 ethanol/isopropyl alcohol was added.
5. The precipitated salts were filtered and the filtrate was cooled to 5°C.
6. To the cold well-stirred solution sufficient glacial acetic acid was added drop wise over a 35-40 min
period to bring the alcoholic solution to pH 6.0.
7. The crystalline precipitate was filtered, washed twice with l:l ethanol/isopropyl alcohol and twice
with ether.
8. Colorless crystals of D-4-amino-3-isoxazolidone were obtained. Yield: 50%; m. p.: 153–155 C;
Preparation of stage-4 or Terizidone 1. Terephthalaldehyde was dissolved in methanol and the solution is heated to boiling.
2. Highly purified D-4-amino-3-isoxazolidone was suspended in methanol and added to the aldehyde
solution with rapid agitation.
3. The isoxazolidone is employed in excess and the mixture was kept at boiling temperature for about 2
minutes and then rapidly chilled to about 0 °C.
4. Stir the mass at 0 °C for 2 hr. and the separated solid was filtered through suction.
5. The solid was washed with cold methanol and with cold water and suck dry well.
9. The washed solid again washed with boiling methanol and dried in vacuum oven at about 40 ºC.
Yield: 94%; m. p.: 204-205 °C
83
33. Delamanid Manufacturing process:
Preparation of stage-1
1. To a solution of (R)-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-methylpropane-1,2-diol in pyridine
was added methanesulfonyl chloride at below 15 °C drop wise over 30 min.
2. After addition the solution was stirred for 2 h, 6 M hydrochloric acid was added to the reaction
mixture at below 30 °C.
3. The resulting mixture was extracted with ethyl acetate, and the combined organic layer was
concentrated under reduced pressure, and to the residue was added toluene.
4. The resulting precipitates were collected by filtration to afford crude R)-3-(2-chloro-4-nitro-1H-
imidazol-1-yl)-2-hydroxy-2-methylpropyl methanesulfonate
5. To a solution of this crude in ethyl acetate was added 1,8-diazabicyclo [5.4.0]-7-undecene and the
mixture was stirred at room temperature for 2 h.
6. The reaction mass was concentrated under reduced pressure.
7. The residue was purified ethyl acetate/hexane (1/1) to give Stage-1 as colorless needles.
Preparation of stage-2 1. To a mixture of (R)-2-Chloro-1-(2-methyl-2,3-epoxypropyl)-4-nitroimidazoleand 4-[4-(4-
trifluoromethoxyphenoxy)piperidin-1-yl]phenol in N,N-dimethylformamide (1600 mL) was added
60% sodium hydride at 0 °C portion wise.
2. After the mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere, the reaction mixture was
cooled in an ice bath and carefully quenched with ethyl acetate and ice water.
3. Thus-obtained mixture was poured into water and stirred for 30 min.
4. The resulting precipitates were collected by filtration, washed with water, and dried at 60 °C
overnight.
5. The residue was recrystallized from ethyl acetate-isopropyl alcohol to afford final compound as a
pale yellow crystalline powder. Mp 195-196 °C.
Flow Diagram
Stage-I
84
Stage-II
34. Tariquidar Analog Manufacturing process:
Preparation of stage-1 1. A solution of compound 4,5-dimethoxy-2-nitrobenzoic acid in toluene at 25-30 ᵒC was added
thionyl chloride through addition funnel within 30 min. & slowly heated to 100 ᵒC.
2. Catalytic amount of DMF was added in to the reaction mass and stirred for 2 hrs at 100 ᵒC till clear
solution obtained.
3. After completion of reaction the mass was cooled to RT and concentrated.
4. The above acid chloride was dissolved in MDC and to this the compound 4-(2-(6,7-dimethoxy-3,4-
dihydroisoquinolin-2(1H)-yl)ethyl)aniline in pyridine and MDC was added drop wise manner at 0
ᵒC.
5. After completion of addition, the mass was slowly warmed to RT and stirred for 2 hrs.
6. The reaction mass then quenched with Saturated NaHCO3 solution and concentrated.
7. The obtained solid was filtered.
8. This solid was again dissolved in MDC and dried with Na2SO4 and filtered and concentrated.
9. The crude compound was triturated with 10% Acetone in ethyl acetate and filtered and dried and
collected as yellow solid.
Preparation of stage-2
1. A solution of N-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)phenyl) -4,5-
dimethoxy-2-nitrobenzamide in 1:1 mixture of Methanol+THF was added, 10% Pd/C wet in parr
shaker vessel at 25-30 ᵒC.
2. The reaction mass was hydrogenated for 24 hr. under H2 pressure.
3. After completion of reaction the mass was filtered through celite bed washed with (1:1) mixture of
Methanol+THF.
85
4. The combined filtrate was concentrated and the solid was filtered, washed with ethyl acetate and
with methanol and dried as white solid.
Preparation of stage-3 1. A solution of compound Quinoline-3-carbonyl chloride in dry MDC at ᵒC was added in to the
solution of compound 2-amino-N-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-
yl)ethyl)phenyl)-4,5-dimethoxybenzamide in pyridine through addition funnel.
2. The reaction mass was stirred for 24 hrs at 25-30 ᵒC.
3. The reaction mass then quenched with Saturated NaHCO3 solution.
4. The layers were separated and the aq. layer was extracted twice with MDC.
5. The combined organic layer was washed with brine, dried with Na2SO4 and filtered and
concentrated.
6. The obtained compound was triturated with methanol, filtered and dried to obtain the final
compound.
Flow Diagram
Stage-I
86
Stage-II
Stage-III
Centrifuge
Drying
ML
API
Solvent recovered
and Recycled
Distillation
residue
MDC
Quinoline-3-Carbonyl
chloride
Condensation
Stage-2
MDC
Sat.NaHCO3 solu.
Solvent recovered and
Recycled
Quenching
Pyridine
Organic Layer
Aq.Layer to ETP
Brine solu.
87
35. Solifenacin Succinate
Manufacturing Process:
Stage-1 : Preparation of N-(2-phenyl ethyl) benzamide [SOL-Benzamide] 2-Phenyl ethyl amine (KSM-1) reacts with benzoyl chloride in presence of base like Sodium
Hydroxide to Produce N-2 Phenethylbenzamide (Stage-1).
Stage-2 : Preparation of 1-phenyl-1, 2, 3, 4-tetrahydroisoquinolin[SOL-Isoquinoline]
N-2 phenethylbenzamide cyclized in presence of POCl3 and P2O5 to produce 3, 4-dihydro-1-
phenylisoquinoline (Stage-02 A) which reduce in-situ by sodium borohydride in alcoholic
solvent like methanol to get 1-Phenyl-1, 2, 3, 4-tetrahydroisoquinoline..
Stage-3 :Preparation of (S)-1-Phenyl-1, 2, 3, 4-tetrahydro isoquinoline tartrate [SOL-
Tartrate]
Resolution of 1-phenyl-1,2,3,4-tetrahydroquinoline carried out by reaction with D-(-) Tartaric acid
in solvent like isopropyl alcohol, water mixture to get (S)-1-Phenyl-1,2.3,4-tetrahydroisoquinoline
tartrate [Stage-3]
Stage-4 : Preparation of (S)-1-Phenyl-1, 2, 3, 4-tetrahydro isoquinoline [SOL (S)
Isoquinoline]
Desalting of pure (S)-1-phenyl-1,2,3,4-tetrahydroisoquinioline tartrate by base like sodium
hydroxide to produce (S)-1-phenyl-1,2,34, -tetrahydroisoquinoline,
Stage-5: Preparation of (1S, 3'R)-3'-quinuclidinyl-1-phenyl-1,2,3,4-tetrahydro-2-
isoquinolinecarboxylate succinate [Solifenacin succinate crude]
(S)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline (Stage-04) react ethyl chloroformate using solvent like
toluene: water and base like sodium carbonate to get (1S)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2-
isoquinoline carboxylate (Stage-5A), which in-situ further react with R-(-)-(3)-Quinuclidinol
(KSM-2) in presence of base like sodium hydride in solvent toluene to get (1S, 3'R)-3'-
quinuclidinyl-1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate (Stage-5B) which is further
convert to salt reacting with Succinic acid in solvent like acetone to (1S, 3'R)-3'-quinuclidinyl-1-
phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate succinate [Solifenacin succinate crude]
Stage-6: Preparation of Solifenacin succinate [SOL]
Purification of 1S, 3'R)-3'-quinuclidinyl-1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate
succinate [Solifenacin succinate crude] carried out in solvent like acetone to get pure Solifenacin
Succinate.
88
Flow Diagram
Stage I
Charge Water & Sodium
hydroxide in Reactor Water
Sodium Hydroxide
2-Phenylethylamine Charge 2-Phenylethylamine
in Reactor
Benzoyl Chloride Charge Benzoyl Chloride
Addition in Reactor
Maintain till completion of
reaction then filter
Wet-Cake Filtrate for ETP Sodium
bicarbonateWash
Dry in Tray Dryer
Stage-1
89
Stage: II
Charge Stage I, POCl3,
P2O5 in a Reactor
Maintain till completion of
reaction
Distillation
Wet Cake
Dry in Tray Dryer
Stir Reaction Mixture&
Filter
Crushed ice & Water ice
Stir the reaction mixture &
Separate the layer
Quenching Part-I
Quenching Part-II
Toluene., NaOH
Stage-I
Phosphorous Oxychloride
Phosphorous Pentaoxide
Methanol
Sodium Borohydride
Methanol Recovery
Stage-2
Aqueous layer ETP
COD 4.8602
Toluene Recovery
90
Stage-III
Charge Stage-III, IPA &
Water a Reactor
Stir Reaction Mixture
clear solution observed
Isopropyl alcohol
Slurry Wash
Cool Reaction Mixture &
Filter
Wet Cake
Dry in Tray Dryer
Heat RM 60° to 65°C
Charge Crude in Reactor at
25°C to 30°C
Filter
Wet Cake
Dry in Tray Dryer
Stage-II
Isopropyl Alcohol
Water
Isopropyl Alcohol
Water
IPA Recovery
D-(-) Tartaric Acid
Stage-3
ML
91
Stage- IV
Charge Stage-III, & Water in
a Reactor
Stir Reaction Mixture
Filter
Wet Cake
Dry in Tray Dryer
Water Slurry Wash
Stage-III
Purified Water
50% NaOH solution
WW for ETP Wet Cake Purified Water
WW for ETP
Wet Cake Water Wash
Stage-4
92
Stage: V (A)
Stage: V (B)
Charge Stage-IV, Water,
K2CO3, & Toluene in a
Reactor
Stir Reaction Mixture and
Cool
Stir Reaction Mixture &
Separate the layer
Organic Layer Distillation
Stage-5 A
Sodium Sulphate
Water
Stage-IV
Potassium Carbonate
Water
Toluene
Ethylchloroformate
Toluene Recovery
Aqueous layer ETP
Charge Stage-5A, & Toluene
in a Reactor
Charge R-Quinuclidinol,
DMF & NaH in a Reactor
Heat Reaction Mixture
Stir Settled and Separate
the layers Toluene
15% Brine Solution
Stage-5A
Toluene
R-Quinuclidinol
Dimethyl Sulphoxide
Sodium Hydride
Stir Reaction Mixture at
till completion of reaction
Distillation
Stage-5 B
Toluene Recovery
Methanol
Sodium Carbonate
HCl
Aqueous layer ETP
93
Stage: V (B)
Charge Acetone & Stage
5B in a Reactor
Charge Succinic acid in a
Reactor
Heat Reaction Mixture
Dry in tray Dryer
Stage-5B
Acetone
Succinic Acid
Filter the Reaction Mixture
Acetone recovery
Wet Cake
Acetone wash Acetone Recovery
Maintain Reaction Mixture
for 2.0 h
Stage-5
94
Stage: VI
36. Montelukast Sodium
Process Description:
Stage-1 (S)-1-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propan-1-ol [MON-Diol ]reacts with Methane sulphonyl chloride in presence of base like N,N-Diisopropyl ethyl amine to Produce MON-Mesyl which is then substituted with MON-Mercapto acid to get MON-Acid Salting of MON-Acid with tert. Butyl amine to get Tert-butylamine 2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-(2-hydroxypropan-2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetic (MON-TBA salt) Stage-2
Tert-butylamine 2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-(2-hydroxypropan-2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetic (MON-TBA salt crude) purified in Toluene to give pure Tert-butylamine 2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-(2-hydroxypropan-2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetic acid
Charge Acetone & Stage 5
in a Reactor
Heat reaction mixture
Filter the reaction mixture
Dry in tray Dryer
Stage-5
Acetone
Activated Charcoal
Acetone
Hyflo
Filter the Reaction Mixture
Acetone Recovery
Wet Cake
Acetone Acetone Recovery
Cool reaction mixture
Stage-6 (PRODUCT)
95
Stage-3
Tert-butylamine 2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-(2-hydroxypropan-2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetic acid desalted to 2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-(2-hydroxypropan-2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetic acid using 5% acetic acid in MDC, further sodium salt made using sodium hydroxide in Methanol and isolated in N-Heptane to give [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl) ethenyl]-3-[2-(1-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid, monosodium salt.
Flow diagram
Stage-1 Part A
Stage-1 Part-B
Dichloromethane
MON-Diol
Diisopropyethylamine
Stir Reaction Mixture
Methane Sulphonyl
Chloride
Maintained Reaction
Mixture
Stir Reaction Mixture
Hexanes
Filter the reaction mixture
Stage-I (Part A)
Mon-Mesyl
ML
Solvent Recovery
ETP
Maintained Reaction
Mixture
After Completion of
Reaction
Organic Layer, Cool
Stir and Allow Layer to
Separate
Sodium Methoxide
Mon-Mesyl Compound
Filter
Wet-CakeWet Cake
Dimethyl Sulphoxide
Mon-Mercaptoacid
Stir Reaction Mixture
ML
Solvent Recovery
Distillation Residue
Sodium Hydroxide
Acetic acid
n-Heptane
Toluene
Aqueous layer
ETP
96
Stage-1 Part-C
Stage-2
Maintained Reaction
Mixture
Cool the reaction mixture
Wet Cake
Drying
Filter the reaction mixture
Stage-I (Part C)
TBA
Mon-Acid
Acetone
Acetonitrile
Stir Reaction Mixture
ML
Solvent Recovery
Distillation Residue
Cool the reaction
mixture
Wet Cake
Drying
Filter the reaction
mixture
Stage-II
Maintained Reaction
Mixture
Toluene
MON-TBA
Stir the Reaction
Mixture
ML
Solvent Recovery
Distillation Residue
97
Stage-3
Stir Reaction Mixture MON-TBA
Dichloromethane
Stir the Reaction Mixture Acetic Acid
Organic Layer
Distill the Organic Layer
Stir and Allow Layer to
Separate
Drying
Cool the reaction mixture
Filter the reaction
mixture
Wet-Cake
Stage-III
MON-Na
Sodium hydroxide
Methanol
Distillation N-Heptane
Distillation Residue
MLCOD 91.5 mg/Ltr
&71.45 mg/Ltr
Solvent Recovery
Solvent Recovery
Aqueous layer for
ETPCOD 380 mg/Ltr
98
37. Silodosin
Process Discription
Stage-1 3-[5-((2R)-2-Aminopropyl)-7-cyano-2, 3-dihydro-1H-indol-1-yl] propyl benzoate (2R, 3R)-monotartrate
neutralized with aqueous Sodium carbonate in Toluene at room temperature to produce 3-[5-((2R)-2-
Aminopropyl)-7-cyano-2, 3-dihydro-1H-indol-1-yl] propyl benzoate as an oil. 3-[5-((2R)-2-Aminopropyl)-7-
cyano-2, 3-dihydro-1H-indol-1-yl] propyl benzoate alkylated with 2-[2-(2, 2, 2-Trifluoroethoxy) phenoxy] ethyl
methane sulfonate in presence of Sodium carbonate in t-Butanol to get 3-{7-Cyano-5-[(2R)-2-({2-[2-(2, 2, 2-
trifluoroethoxy) phenoxy] ethyl} amino) propyl)-2, 3-dihydro-1H-indol-1-yl)-propyl benzoate further purify
with salt formation of L-(+)-Tartaric acid in Ethyl acetate to get pure compound 3-{7-Cyano-5-[(2R)-2-({2-[2-
(2, 2, 2-trifluoroethoxy) phenoxy] ethyl} amino) propyl)-2, 3-dihydro-1H-indol-1-yl)-propyl benzoate (2R, 3R)
monotartrate.
Stage-2 A solution of Potassium hydroxide in purified water was added to 3-{7-Cyano-5{(2R)-2-({2-[2-(2, 2, 2-
trifluoroethoxy) phenoxy] ethyl} amino) propyl)-2, 3-dihydro-1H-indol-1-yl)-propyl benzoate (2R, 3R)
monotartarate and Methanol at 25-30°C to get 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2, 2, 2-trifluoroethoxy)
phenoxy] ethyl} amino) propyl]-2, 3-dihydro-1H-indole-7-carbonitrile as oil.
Stage-3 A solution of Sodium hydroxide in water was added to mixture of SIO-Nitrile (Stage-2) and Dimethyl sulfoxide
at 25-30°C. 30% Hydrogen peroxide solution was added to reaction mass at 20-25°C to get 1-(3-
hydroxypropyl)-5-[(2R)-2-({2-[2-(2, 2, 2-trifluoroethoxy) phenoxy] ethyl} amino) propyl]-2, 3-dihydro-1H-
indole-7-carboxamide. Crystallization using Ethyl acetate as solvent to get 1-(3-hydroxypropyl)-5-[(2R)-2-({2-
[2-(2, 2, 2-trifluoroethoxy) phenoxy] ethyl} amino) propyl]-2, 3-dihydro-1H-indole-7-carboxamide.
Stage-4
Silodosin crude crystals was added to Ethyl acetate and mixture was heated to dissolve. After insoluble
materials were filtered off, the filtrate was allowed to stand at room temperature. The resulting crystals were
collected by filtration and dried under vacuum to get Silodosin.
99
Flow Diagram
Stage-I
Stage- 2
Reactor -I (Under nitrogen)
Cool to 20-25°C
Heat the reaction mass
Stage-I
Dry in Vacuum Tray Dryer
Maintain till completion of
reaction
Settled and separate layers
Distillation
Ethyl acetate & Filter
2-[2-(2, 2, 2-
Trifluoroethoxy)
phenoxy] ethyl methane
sulfonate
t-Butanol
Toluene
Sodium chloride
Sodium sulphate
(Anhydrous)
L-(+)-Tartaric acid
3-[5-((2R)-2-
Aminopropyl) -7-cyano-
2, 3-dihydro-1H-indol-1-
yl] propyl benzoate (2R,
3R)-monotartrate
Purified water
Sodium Carbonate
Ethyl acetate
recovery
Toluene for
recovery& Solid
waste
Aqueous layer for
ETP
Reactor -I (Under Nitrogen)
Cool to 25-30°C
Maintain till completion of
reaction
Settled and separate layers
Distillation Toluene
Sodium bicarbonate
Sodium Sulphite
Stage-I
Methanol
Purified water
Potassium hydroxide
Stage-II
Toluene for
recovery& Solid
waste
Aqueous layer for
ETP
Organic Layer Distillation
100
Stage-3
Reactor-1 (Under Nitrogen)
Stir at 25-30°C
Stir at 25-30°C
Stage-III
Dry in Vacuum Tray Dryer
Maintain till completion of
reaction
Settle and separate layers
Distillation
Ethyl acetate & Filter
Sodium hydroxide
Purified Water
30% Hydrogen
peroxide
Sodium sulphite
Dichloromethane
Conc. Hydrochloric
acid
Sodium Bicarbonate
SIO-Nitrile
Dimethyl sulfoxide
Ethyl acetate
recovery
Dichloromethane
for recovery&
Solid waste
Aqueous Layer ETP
COD 250.0 mg/Ltr
101
Stage-4
Reactor-1
Stir at 70-75°C
Stir at 70-75°C
Silodosin
Dry in Vacuum Tray Dryer
Filtration through hyflow
supercell and
crystallization
Filtration
Ethyl acetate & Filter
Activated Charcoal
Ethyl acetate
SIO-Crude
Ethyl acetate
Filtrate for ETP
Ethyl acetate for
recovery
102
38. Cinacalcet Hydrochloride
Process Discription Stage-1
3-(3-(trifluoromethyl) phenyl) propan-1-ol [CIN-Alcohol] using methane sulfonyl chloride[Mesylchloride]
in Dichloromethane [MDC] and Triethylamine [TEA] at 5-15 C to give3-[3-(trifluoromethyl) phenyl]
propyl methane sulfonate [CIN-Mesyl].
Stage-2
3-[3-(trifluoromethyl) phenyl] propyl methane sulfonate [CIN-Mesyl] react with (R)-1-(naphthalene-1-yl)ethanamine [CIN-Amine] in presence of N, N-Dimethyl formamide [DMF] and Diisopropyl amine at 80-85° C give 3-(3-(trifluoromethyl) phenyl)-N-((R)-1-(naphthalen-5-yl) ethyl) propan-1- amine [CIN-Base]Which is further salting with IPA.HCl gives Cinacalcet Hydrochloride crude. Stage-3 Purified Crude Cinacalcet hydrochloride first with methanol then with acetonitrile to give Pure Cinacalcet hydrochloride.
Flow Diagram
Stage-1
Maintained Reaction
Mixture
After Completion of
Reaction
Organic Layer
Distil the Organic Layer
Stir and Allow Layer to
Separate
Mesyl Chloride
Stage-I
CIN-Mesyl
Dichloromethane 3-(3-
(trifluoromethyl)
phenyl) propan-1-ol Tri
Ethylamine
Stir Reaction Mixture
MDC Recovery
Aqueous Layer for
ETPCOD804 mg/Ltr
103
Stage- II
Maintained Reaction
Mixture
After Completion of
Reaction
Distil the Organic Layer
CIN-Mesyl (Stage-I)
Stage-II
CIN-Base
Oil Obtained DichloromethaneSodiu
m Bicarbonate Solution
Stir and Allow Layer to
Separate
Organic Layer
Distil the Organic Layer
Stage-II
CIN-Hydrochloride
Diisopropyl ether
IPA HCl.
Stir reaction mass at RT
Filter
Acetonitrile
(R)-1-(naphthalene-1-
yl)ethanamine
Diisopropylethylamine
Stir Reaction Mixture
ACN Recovery
MDC Recovery
W.W. TO ETP
ML
Solvent recovered&
recycled
Aqueous layer for ETP
104
Stage- III
39. Maraviroc
Process Discription
Stage-1
Step-1
Thionyl chloride add to solution of (S)-3-Amino-3-phenylpropanoic acid, DMF and Ethanol at Heat to
reflux temperature and stir for 1 h at reflux temperature. Distill out Ethanol and excess Thionyl chloride
a. Charge water to dissolve residue
Step-2 Thionyl chloride add to solution of 4, 4-Difluoro cyclohexane carboxylic acid and Toluene at 2 Heat
reaction mass to reflux temperature. Stir for 1 h at reflux temperature. Distill out excess Thionyl
chloride and Toluene under vacuum, Toluene add to the reaction mass
Step-3 Condensation of step-1 and step-2 by using Sodium carbonate and MDC Stir for 3 h , Water add to
reaction mass, Separate layers. Aqueous layer extract with MDC. Combine both layers and wash with 1
m NaOH. Distill out solvents under vacuum. Toluene and Heptane add to residue and cool. Stir for
Filter solid product and wash with Heptane. Dry product under vacuum to get compound (S)-ethyl 3-(4,
4-difluorocyclohexanecarboxamido)-3-phenylpropanoate.
Stage-2 Charge lot wise Sodium borohydride to (S)-Ethyl-3-(4, 4-difluorocyclohexanecarboxamido)-3-
phenylpropanoate and Tetrahydrofuran. Heat to 50°C. Add very slowly Methanol to reaction mass at.
Temperature raised to reflux and stir for 2 h .Add slowly Acetone to reaction mass and charge Cyclohexane.
Isolate the material by using Tetrahydrofuran and Cyclohexane to get 4, 4-Difluoro-N-((S)-3-hydroxy-1-
phenylpropyl) cyclohexanecarboxamide.
Maintained Reaction
Mixture
Filter the reaction mixture
Filter Water Wash
Drying
Maintain the Reaction
Mixture
Stage-III
CIN-HCl
Acetonitrile
Methanol
CIN-HCl
Water
Stir Reaction Mixture
ML
Solvent
recovered
& recycled
W.W. TO ETP
105
Stage-3 Potassium bromide and TEMPO take in MDC at 25-30°C. (1S)-4, 4-Difluoro-N-(3-hydroxy-1-phenylpropyl)
cyclohexane Carboxamide charge to reaction mass at 25-30°C. Sodium hypochlorite solution (pH-8 to 9
adjusted with NaHCO3 addition. Stir for 3 h at 10-15°C. Sodium thio sulphate solution in water add to reaction
mass, Separate layers and extract with MDC. Combine organic layers and distill out solvent under vacuum and
isolation using Toluene and Heptane to get compound (1S)-4, 4-Difluoro-N-(3-oxo-1-phenylpropyl)
cyclohexane Carboxamide.
Stage-4 8-benzyl-3-(3-isopropyl-5-methyl-4H-1, 2, 4-triazol-4-yl)-8-aza-bicyclo [3.2.1] octane and Ammonium formate
charge to Ethanol at 25-30°C under nitrogen atmosphere. Pd/C (10%) add to reaction mass at 25-30°C. Slowly
heat the reaction mass to reflux temperature. Stir for 3 h at reflux temperature. Ammonia solution (25%) add to
reaction mass. Stir for 1 h at reflux temperature. Cool to 25-30°C. Filter through Hyflo bed and wash with
Ethanol. Distill out solvents from filtrate under vacuum at 50-55°C to get solid residue. Ethyl acetate add to
residue. Heat to reflux temperature. Stir for 1 h at reflux temperature. Cool to 25-30°C. Stir for 30 min at 25-
30°C. Filter and wash with Ethyl Acetate. Dry under vacuum at 25-30°C to get compound 3-(3-Isopropyl-5-
methyl-4H-1, 2, 4-triazol-4-yl)-exo-8-azabicyclo [3.2.1] octane.
Stage-5
3-(3-Isopropyl-5-methyl-4H-1, 2, 4-triazol-4-yl)-exo-8-azabicyclo [3.2.1] octane phosphate salt and MDC stir
at 25-30°C under Nitrogen atmosphere. (1S) - 4, 4-Difluoro-N-(3-oxo-1-phenylpropyl) cyclohexane
carboxamide in MDC add at 25-30°C. Sodium triacetoxy borohydride add lot wise to reaction mass at 25-30°C.
Stir for 5 h at 25-30°C. Water add after completion of reaction at 25-30°C. Settle and separate layers. Aqueous
layer extract with MDC. Combine both organic layers and wash with 1M KOH solution at 25-30°C. Organic
layer wash with water. Organic layer wash with brine solution. Solution of o-Phosphoric acid in water add to
organic layer at 20-25°C. (pH 5 to 6). Separate layers. Aq. layer wash with MDC. Solution of Sodium carbonate
in water add to the aqueous layer at 20-25°C. (pH 7 to 7.5) MDC add to extract the product at 25-30°C.
Separate layers. Aqueous layer extract with MDC. Combine MDC layers and dry over anhydrous Sodium
sulphate. Distill out solvents under vacuum to get Maraviroc.
Flow Diagram Stag-1
Stir the Reaction Mixture 3-amino-3- phenyl
propionic acid Ethanol
DMF
Thionyl Chloride
Solvent Recovery
Maintain the reaction
Mixture
Sodium Carbonate
MDC
Acid Chloride
Distillation of Reaction
Mixture
Maintain till completion of
reaction then filter
Stir and Separate the layer
Aqueous layer ETP
Cyclohexane
n-Heptane
Distillation
Filtration
Stage-I
Solvent Recovery
106
Stage-2
Stir the reaction mixture
Maintain till completion of
reaction
Distillation
Wet Cake
Dry in Tray Dryer
Filter the reaction
mixture
Stir the reaction mixture &
Separate the layer
Acetone
Cyclohexane
Sodium Hydroxide Solution
MAR-Amide
Tetrahydrofuran
Sodium Borohydride
Methanol
Tetrahydrofuraan
Cyclohexane
Sodium Borohydride Solvent Recovery
Stage-2
Aqueous layer ETP
Solvent Recovery
107
Stage-3
Stir the reaction mixture
Maintain the reaction
mixture
Wet Cake
Dry in Tray Dryer
Filter the reaction mixture
Stir the reaction mixture
and separate layer
Distillation
Stir the reaction mixture
MAR-Amide Hydroxy
Dichloromethane
TEMPO
Potassium Bromide
Water
Toluenen-Heptane
Solvent Recovery
Sodium hypochlorite
solution
Solvent Recovery
Stage-3
Aqueous layer ETP
108
Stage- 4
Reactor-I (Under Nitrogen)
Reactor-I
Stage-4
Dry in Tray Dryer
Maintain till completion of
reaction at reflux
temperature.
Filter
Pd/C (10%) (50% wet)
Ammonium formate
Solid waste
Ammonium solution
Distillation
Crystallization & Filter
Ethanol for
recovery
Ethyl acetate MLR
recovery Ethyl acetate
8-benzyl-3-(3-
isopropyl-5-methyl-
4H-1, 2, 4-triazol-4-yl)-
8-aza-bicyclo [3.2.1]
octane
Ethanol
109
Stage-5
Reactor-I
Reactor-I
Stage-5
Dry in Vacuum Tray Dryer
Maintain till completion of
reaction
Filter
(1S)-4, 4-Difluoro-N-(3-
oxo-1-phenylpropyl)
cyclohexane
carboxamide
Solid waste
Sodium triacetoxy
borohydride
Distillation
Filter
Solvent recovery
3-(3-Isopropyl-5-
methyl-4H-1, 2, 4-
triazol-4-yl)-exo-8-
azabicyclo [3.2.1]
octane
Dichloromethane
110
40. Vilazodone Hydrochloride
Process Discription
Stage-I VIL-Piprazine-Esterinpresence of solvent methanol and Ammonia to get VIL-Piperazine Caboxamide.
Stage-2 Compound (VIL- Piperazine Carboxamide) in presence of Chloroindole and triethylamine to get VIL-Base
Stage-3
Compound (VIL-Base) in presence of solvent IPA and aqueous HCl to get Vilazodone hydrochloride.
Flow Diagram
Stage-I
Methanol
VIL-Piperazine Ester
Stir Reaction Mixture
Ammonia gas Maintained Reaction
Mixture
Water After Completion of
Reaction
Filter the reaction mixture
Wet Cake
Stage-IA
Stage-IA
DMF
Sodium Hydroxide
Solution
Stir the reaction mixture
Maintained Reaction
Mixture
Filter the Reaction
Mixture
Wet Cake & Drying
Stage-I
ML
WW for ETP
Solvent Recovery
Solvent Recovery
WW for ETP
ML
111
Stage-II
Maintained Reaction
Mixture
After Completion of
Reaction
Filter
Filtrate
Wet Cake
VIL-Base
Dimethylformamide Stir the reaction mixture
Maintain the reaction
mixture
Filter the reaction mixture
Stage-II
Sodium Bicarbonate
Solution
Filter
Wet Cake & Drying
MLR for ETP COD
102.6 mg/Ltr
MLR COD 1062
mg /Ltr
Water
Triethyl amine
VIL-Piperazineamide
Chloroindole
Stir Reaction Mixture
112
Stage- III
Maintained Reaction
Mixture
Filter the reaction mixture
Filter
Drying
Filtrate
Stage-III
VIL-HCl
IPA.HCl
Wet Cake
IPA
VIL-Base
Water
Stir Reaction Mixture
MLR
IPA Recovery
WW for ETP
Distilled residue
113
41. Metoprolol succinate
Process Discription
Stage-1 Condensation of 4-(2-methoxyethyl) phenol with Epichlorohydrin in water, in presence of NaOH at 35-40°C.
After reaction completion quenched the reaction mass with water, then Extracted with Toluene .Toluene layer
washed with water. Toluene layer distilled at 40°C to 45°C under vacuum to get Step-I (2-((4-(2-
methoxyethyl)phenoxy)methyl)oxirane) MET-Epoxide
Stage-2 2-((4-(2-methoxyethyl)phenoxy)methyl)oxirane (MET-Epoxide) suspended in water at 5°C to 10°C then
Isopropyl amine added slowly at 5°C to 10°C. After reaction completion add water then extracted with Toluene.
Toluene layer washed with water & brine. Toluene layer is distilled at 45°C to 50°C under vacuum to get1-(4-
(2-methoxyethyl)phenoxy)-3-(isopropylamino)propan-2-ol. MET-Base
1-(4-(2-methoxyethyl)phenoxy)-3-(isopropylamino)propan-2-ol (MET-Base) is dissolve in acetone at 25°C to
30°C. Then Succinic acid dissolved in Acetone added to the reaction mixture at 25°C to30°C within 01 hr. then
raised temperature up to reflux, maintain for 02 hr. at same temperature. Cool reaction mixture at 25°C to
30°C.Solid filtered and washed with Chilled acetone to get Step-II Metoprolol succinate crude (MET-Crude)
Stage-3 Metoprolol Crude dissolved in Methanol at 50°C to 60°C, then cool to 0°C to 5°C and stir for 1hr. filter solid
wash with chilled methanol we get Metoprolol Succinate
114
Stage-1 : Preparation of 2-((4-(2-methoxyethyl)phenoxy)methyl)oxirane (MET-
Epoxide)
Maintained Reaction
Mixture
After Completion of
Reaction
Organic Layer
Distil the Organic Layer
Stir and Allow Layer to
Separate
Stage-I MET-Epoxide
Purified Water
Sodium Hydroxide
2-((4-(2-
methoxyethyl)phenoxy)
methyl)oxirane
Epichlorohydrin
Stir Reaction Mixture
Toluene Recovery
Aqueous Layer for
ETPCOD404 mg/Ltr
115
Stage-2 :Preparation of MET-Crude
Maintained Reaction
Mixture
After Completion of
Reaction
Distil the Organic Layer
Stage-II CIN-Base
Oil Obtained
Stir and Allow Layer to
Separate
Organic Layer
Distil the Organic Layer
Stage-II MET-Crude
Acetone
Succinic acid
Maintain the reaction
Cool and Filter
Purified Water
Isopropyl amine
Stage-I
Stir Reaction Mixture
Iso propyl amine
Recovery
Toluene Recovery
COD 331.0 mg/Ltr
ML
Solvent (Acetone) recovered
Aqueous layer for ETP
COD 280.1 mg/Ltr
116
Stage-3 : Purification of MET-Crude
Maintained Reaction
Mixture
Filter the reaction
mixture
FilterMethanol Wash
Drying
Stage-III Metoprolol Succinate
Activated Charcoal
Methanol
Stage-2 (MET-Crude)
Stir Reaction Mixture
Solvent recovered &
recycled
Maintained Reaction
Mixture
Solid Waste
117
(C) BULK DRUG INTERMEDIATES
1. MCA
Process Description:
Dehydrated Nitrobenzene is partially chlorinated in presence of Iodine which give acidic crude material
containing unreacted Nitrobenzene + MCNB + PNCB + OCNB.
Acidic crude material is washed and neutralized to get pH or crude material (at V301)
At V501, above neutral crude is fractionated to recover unreacted Nitro benzene and pure MCNB.
At V601 pure MCNB is reduced to crude Meta Chloro Aniline with caustic + sulphur or NaHS and finally
washed.
The above product is a mixture of two products like MCA and Eutactic oil. The same is separated in to two
products namely MCA and Eutactic oil which is sellout in the open market
Flow Diagram
118
2. 2, 7 Dichloro - 9 H - Fluorene (LF1 / DCF)
Process Description: Charge acetonitrile, fluorine and N-chlorosuccinimide, after completion of reaction, add HCl, stir at 600 C then
filter solids is separated & Mother liquor is taken for recovery
Flow Diagram:
DMF
Fluorine
Chlorine
CONDENSATION
FILTRATION
ML
L-1/ DCF
FeCl3
DMF recovered
& reused
Process residue
119
3. 2-(2,7-dichloro-9H-fluoren-4-yl)oxirane Process Description:
Stage:
� Charge ADCF and methanol at room temperature.
� Chilled the reaction mass up to 0-5°C.
� Slowly add NaBH4 and maintain at 0-5°C.
� Filter it and wash with methanol.
� Dry it.
Flow Diagram:
LF-2/ ADCF
Sodium boro hydride
Methanol
Recovered &
reused
Distillation
residue
Process
residue
CONDENSATION
Methanol
FILTRATION
ML
Oxirane
120
4. [2-Dibutyl amino-1-(2, 7- Dichloro-9H-fluorene-4-yl)ethanol] (LF3/DBA)
Process Discription
� Charge ADCF and methanol at room temperature.
� Chilled the reaction mass up to 0-5°C.
� Slowly add NaBH4 and maintain at 0-5°C.
� Charge N,N-dibutyl amine and heat up to reflux temp.
� Cool to RT and distilled out solvent.
� Charge ethyl acetate and cool to RT
� Chilled the reaction mass and filter it and wash with methanol.
� Dry it.
Flow Diagram:
Methanol/Ethyl acetate
LF-2/ ADCF
Sodium boro
hydride
CONDENSATION
FILTRATION
ML
LF-3/ DBA
Methanol
Recovered &
reused
Distillation
residue
N,N- dibutyl amine
Process
residue
121
Centrifuge
5. Dihydroartemisinin
Process Description: Artemisinin react with Sodium Borohydride in presence of Methanol, gives Dihydroartemisinin crude
which is centrifuged and dried.
Flow Diagram:
Artemisinin
Sodium Borohydride
Acetic Acid
Adjust pH 6 to 7
Water
Wash the wet cake
with water
Reactor
Reactor
Fluid Bed Dryer
Methanol
Reactor
Dihydroartemisinin
Crude
W/W to ETP
ML Methanol
recovered &
reused Process
residue
Distillation
residue
122
6. 4-Cyanoethyl-2-methyl –phenol: (MHPN)
Process Description
� Charge o-cresol at 25-30°C.
� Charge Acrylonitrile and Hydroquione under N2 gas.
� Heat up to 60-65°C Charge AlCl3.
� Maintain reaction mass at 60-65°C for 2.0 hrs.
� Cool to RT.
� Charge water and stir for 1.0 hrs.
� Separate Aq. Layer and Org. layer.
� Collect Org. layer in drum
Flow Chart:
AlCl3 Acrylonitrile Hydroquione
Reactor
Heating
O-cresol
Separation
Cooling
Water
Aq. Layer
Org. Layer
123
7. (R)-9-(2-phosphonylmethoxypropyl)-adenine: (PMPA)
Process Description:
Stage-1: � Charge DMF and Adenine.
� Charge R-Propylene at room temperature.
� Charge NaOH at room temperature.
� Heat up to 124 – 130 oC and maintain it for 12 hour.
� Cool to rum temperature.
� Slowly add Toluene at room temperature.
� Stir for 1.0 hour.
� Filter it and wash with methanol
Stage-2: � Charge stage 1 and DMF
� Charge DESMP and MTS stir for 30 min at room temperature.
� Heat up to 85 to 90 oC and maintain it for 6 hour.
� Cool to rum temperature and slowly add acetic acid.
� Distilled out DMF u/v completely. ( Recovery 85 to 90% )
� Charge water, methylene chloride and 48% HBL.
� Separate layer and take aqueous layer and heat up to 85 to 90 oC.
� Maintain it for 15 hour.
� Cool to rum temperature and adjust pH with NaOH.
� Chilled up to 0 – 5 oC and maintain it for 5 hrs.
� Filter it and wash with water.
Flow Diagram:
Stage-1:
Crystallization
Filtration
Reactor
Dimethyl formamide
R-1,2-Propylene carbonate
Adenine
NaOH
Reactor Methanol,
Toluene
Centrifuge
Mother liquor
(R)-9-(2-Hydroxypropyl) adenine[HPA]
Methanol, Toluene
Recovered and reused
R-propylene carbonate
Recovered and reused
124
Stage- 2:
Isolation
Filtration
Extraction
Filtration
Reactor
DMF
HPA
DESMP
MTB
Reactor
Acetic acid
Reactor Hydrobromic acid
Separation
Reactor
Centrifuge Mother liquor
MDC, NaOH
Wash with Water
PMPA
DMF, DESMP
recovered and
reused
MDC recovered
and reused
Distillation
residue
W/W to ETP
Process residue
125
8. 4, 7-Dichloro Quinoline: (4, 7- DCQ)
Process Description:
Stage-1:
� Charge Toluene and 4-hydroxy and heat reaction mass up to 85-112°C.
� Maintain at to 85-112°C for 12 hour.
� Cool the reaction mass 30 + 5°C.
� Slowly add POCl3 and heat up to 90 + 5 °C
� Maintain at to 90 + 5 °C for 4 hour.
� Cool the reaction mass and charge water, than adjust pH 6.5 to 7.5 using caustic lye.
� Stop stirring and settle for 1.0 hrs. (three water washing)
� Distilled out toluene completely and collect product after flaking.
Stage-2:
� Charge methanol 4, 7-DCQ and heat reaction mass up to 65 + 2°C.
� Charge activated carbon, hyflow and EDTA at 65 + 2°C.
� Maintain reaction mass at 65 + 2°C for 1.0 hrs.
� Filter it and wash with methanol.
� Cool the reaction mass up to 40 to 35°C
� Chilled up to 15 + 3°C and maintain for 1.0 hrs.
� Maintain at 15 + 3°C for 1.0 hrs.
� Filter it and dry it.
Flow Diagram:
Stage-1 4,7-DCQ Crude
4-Hydroxy
Toluene
POCl3
Chlorination
Layer
Separation
Water
Distillation
Caustic lye
Flaker
Waste water to ETP
4,7-DCQ
(Crude)
Toluene
Recovered and Reused
126
Stage-2 4,7-DCQ Pure
Heat 65+ 2 °C
4,7-DCQ Crude
Methanol
EDTA/ Hyflow
Reactor
Sparkler filter
Filtrate ML
Process residue
Activated Carbon
Cool 15 + 3°C
Centrifuge ML
Methanol wash
4,7-DCQ
(Pure)
127
9. N-(2-phenoxyphenyl) methane sulfonamide (OPMSA)
Process Description:
Stage:
� Charge OPA and DMA at room temperature.
� Slowly add MSC below 62°C in 5.0 hrs.
� Maintain the reaction mass at 62 + 2°C for 3.0 hrs.
� Charge water and adjust pH with hydrochloric acid.
� Cool the reaction mass up to 30°C.
� Filter it and wash with water.
Flow Diagram:
Ortho Phenoxy Aniline (OPA)
Rector
Rector
DMA recovered
& reused
OPMSA
ML
Process residue
Dimethyl aniline (DMA)
Methan Sulfonyl Chloride
(MSC)
Water
HCl
Waste water to ETP
Centrifuge
128
10. Meta Amino Acetanilide:(MAA)
Process Description:
Stage-1: � Charge MNA and Acetic anhydride and heat reaction mass up to 130-140°C.
� Maintain at to 130-140°C for 2 hour.
� Distilled out acetic acid under vacuum.
� Charge water and cool to 30 + 5°C.
� Filter it.
Stage-2: � Charge water and cast iron powder and heat reaction mass up to 60°C.
� Charge acetic acid and Acetyl MNA at 80 to 100°C.
� Maintain reaction mass till TLC complies.
� Adjust pH 7.5 to 8.0 with hydrate Lime and charge Activated carbon.
� Filter it and add sodium hydrosulphite in filtrate ML.
� Cool the reaction mass up to 30 to 35°C
� Chilled up to 22 +2°C and maintain for 1.0 hrs.
� Slowly add common salt in 4.0 to 5.0 hrs.
� Maintain at 22 +2°C for 1.0 hrs.
� Filter it and dry it.
Flow Diagram:
Stage-1 Acetyl MNA
m-Nitro Aniline
Acetic anhydride
Water
Acetylation
FILTRATION
ML
Acetyl MNA
Distillation
residue
129
Stage-2 Meta Amino Acetanilide
Heat 90-100°C
11. N-{3-[(diethylamino)methyl]-4-hydroxyphenyl}acetamide:(Mannich Base) Process Description
� Charge methanol and paracetamole.
� Start stirring and charge formaldehyde at room temperature.
� Slowly add diethyl amine at 35 + 5°C in 4.0 hrs.
� Heat the reaction mass up to 65-70°C.
� Maintain the reaction mass for 12. Hrs.
� Chilled up to 15-20°C.
� Filter it.
� Again charge wet cake and water for slurry preparation.
� Heat up to 30-35°C and maintain reaction mass at 30-35°C for 1.0 hrs.
� Filter it.
Acetyl MNA
Acetic Acid
Water
Acetylation
Reaction mass
Filtrate ML
Process residue
Cast Iron
Hydrate Lime
Carbon
Sodium hydro
sulphite
Cool 22 + 2°C
Centrifuge ML
Common salt
Product
130
Flow Diagram:
Heat 65-70°C
12. 4,6-Dichloro-5-methoxy pyrimidine: (4,6-DCMP)
Process Description:
Stage-1: � Charge Methyl methoxy acetate and methanol.
� Charge Dimethyl malonate at room temperature.
� Slowly add sodium Methoxide at 25-30°C.
� Heat the reaction mass up to reflux temperature.
� Maintain at reflux temperature for 8 hour.
� Distilled out methanol completely under vacuum and rise temp up to 180-190°C.
� Cool the reaction mass and collect oily mass as product. (Stage-1)
Stage-2: � Charge stage-1 and toluene with stirring.
� Charge formamide at room temperature.
� Slowly add sodium Methoxide at 25-30°C.
� Heat the reaction mass up to reflux temperature.
� Maintain at reflux temperature for 15 hour.
� Cool the reaction up to 25-30°C and slowly add POCl3.
� Maintain it for 5-6 hrs.
� Charge water in reaction mass and stir for 30 min.
� Separate aqueous layer and toluene layer.
� Chilled the reaction mass up to 0-5°C.
Paracetamole
Formaldehyde
Methanol
Recovered &
reused
Distillation
residue
DEA
CONDENSATION
Methanol
Centrifuge
ML
Slurry
preparation Water
Centrifuge
ML Waste water to ETP
Mannich Base
131
� Filter it and wash it with chilled toluene.
� Dry it.
Flow Diagram:
Stage-1
Heat up to reflux temp.
Heat up to 180-190°C.
Stage-2
Heat up to reflux temp.
Heat up to 110-112°C.
Chilled up to 0-5°C
Methyl methoxy
acetate
Dimethyl malonate
Sodium Methoxide
CONDENSATION
Methanol
Distillation
Methanolreused
Oily mass
(stage-1)
Stage-1
Formamide
Sodium Methoxide
Cyclazation
Toluene
Chlorination
Aqueous layer to ETP
Reactor
POCl3
Layer
separation Water
Centrifuge Toluene
Recovered & reused
ML
Distillation
residue
Product
132
13. L-Menthyl-5-(2R,5S)-[4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl]-1,3-oxathiolane-2-carboxylate
(FCME)
Manufacturing process:
Chlorination reaction
14. Arrange dry and clean 3.0 lit. four necks RBF
15. Charge DMF into RB flask at 25-30°C.
16. Charge MDC into RB flask at 25-30°C.
17. Cool the reaction mass to 15-20°C.
18. Add thionyl chloride in 30.0 min. into reaction mass at 15-20°C
19. Maintain the reaction mass at 15-20°C for 1 h
20. Cool the reaction mass to 5-10°C
21. Add HME + MDC solution into reaction mass in 1.0 h at 5-10°Cand maintain for 3 h.
22. Raise temperature of reaction mass to 40-45 °C (reflux) and maintain for 3 h.
23. MDC layer given 3 water washings.
24. Combine all aqueous layer given MDC extraction and sodium sulphate treatment.
25. Combine all lower Organic layer given sodium sulphate treatment
26. Stir reaction mass for 15 min.
27. Distill out MDC completely U/V at 40-45°C
28. Charge MDC into residue [CHLORO COMPOUND].
Silylation 1. Arrange dry and clean 2.0 lit. four RBF.
2. Charge HMDS at 25-30°C.
3. Charge 5-Fluoro Cytosine at 25-30°C.
4. Charge Ammonium Sulphate at 25-30°C.
5. Heat reaction mass at 125-130°C and maintain for 4 h.
6. Cool reaction mass at RT.
7. Charge MDC at 25-30°C.
8. Stir reaction mass for 15 min.
9. Addition of TEA in reaction mass in 30 min. at 25-30°C
10. Stir reaction mass for 30 min. at 25-30°C.
11. Raise temperature of reaction mass upto 40-45°C.
12. Addition of Chloro compound in reaction mass at 40-45°C in 1 h.
13. Maintain reaction mass at 40-45°C for 18 h.
14. Cool reaction mass at RT.
15. MDC layer given water washing.
16. MDC layer given HCl solution washing.
17. MDC layer given10% NaCl solution water washing.
18. Combine all aqueous layer given MDC extraction.
19. Distill out MDC completely U/V at 40-45°C till residue.
20. Charge Ethyl acetate at 25-30°C.
21. Raise temperature of RM to 50-55°C and maintain for 1.0 h.
22. Cool reaction mass to RT and maintain for 12 h.
23. Cool reaction mass at 0-5°C and maintain for 1 h.
24. Filter it and dry the solid.
134
14. (S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol (E-6)
Manufacturing process:
Part-A: 26. Arrange dry and clean 3.0 lit. four necks RBF.
27. Charge water into RB flask at 30 ± 5°C under stirring.
28. Charge 4-chloro-2-trifluoro acetyl aniline hydrochloride hydrate into RB flask at 30 ± 5°C.
29. Cool RM at 10-15°C.
30. Adjust pH 7.0-10.0 using sodium hydroxide solution.
31. Stir RM at 10-15°C for 1.0 h.
32. Filter it and wash with water.
33. Arrange dry and clean 3.0 lit. four necks RBF.
34. Charge Toluene into RB flask at 30 ± 5°C under stirring.
35. Charge Wet cake into RB flask at 30 ± 5°C under stirring.
36. Stir and heat RM at 110 ± 5°C under stirring.
37. Maintain RM at 110 ± 5°C for 2.0 h.
38. Distill out toluene completely u/v at 55-60°C.
39. Cool RM to RT.
40. Charge THF
Part-B:
41. Arrange dry and clean 3.0 lit. four necks RBF.
42. Charge THF into RB flask at 30 ± 5°C under stirring.
43. Cool RM at 0-5°C.
44. Charge cyclopropyl acetylene at 0-5°C.
45. Addition of n-butyl magnesium chloride at 0-5°Cin 6.0 h.
46. Stir RM for 30.0 min.
Part-C: 47. Arrange dry and clean 3.0 lit. four necks RBF.
48. Charge NPN into RB flask at 30 ± 5°C under stirring.
49. Charge Toluene at 30 ± 5°C under stirring.
50. Charge 2,2,2-trifluoro ethanol at 30 ± 5°C under stirring.
51. Cool RM at 0-5°C.
52. Addition of Diethyl zinc solution at 0-5°C in 6.0 h.
53. Raise the temperature of RM to 30 ± 5°C and maintain for 30.0 min.
54. Cool RM at 0-5°C.
55. Addition of Part-A into RM at 0-5°C in 6.0 h.
56. Addition of Part-B into RM at 0-5°C in 4.0 h.
57. Raise the temperature of RM to 30 ± 5°C and maintain for 4.0 h.
58. Send sample to Q.C for TLC
59. Cool RM at 10-15°C.
60. Addition of Citric acid solution into RM at 10-15°C in 4.0 h.
61. Layer separation of RM
62. Distill out Toluene completely under vacuum at temperature below 60°C.
63. Cool RM at 30 ± 5°C.
64. Charge Toluene at 30 ± 5°C.
65. Cool RM at 0-5°C and maintain for 2.0 h
66. Filter and dry the solid.
136
15. Tenofovir Disoproxil Free Base (TD Base)
Manufacturing process:
1. Arrange dry and clean four necks RBF.
2. Charge NMP into RB flask at 30 ± 5°C under stirring.
3. Charge PMPA into RB flask at 30 ± 5°C under stirring.
4. Charge TBAB into RB flask at 30 ± 5°C under stirring.
5. Raise the temperature of the reaction mass up to 49 ± 4°C under stirring.
6. Addition of CMIC + TEA mixture into reaction mass in 1.0 h ± 5 min at 49 ± 4°C.
7. Maintain the reaction mass for 2.0 h ± 5 min at 50 ± 2°C under stirring.
8. Chill the reaction mass to 0-5°C under stirring.
9. Add chilled purified water into reaction mass at in 1.0 h ± 10 min at 0-5°C.
10. Maintain the reaction mass for 16.0 h ± 15 min at 0-5°C under stirring.
11. Filter the solid from reaction mass at 0-5°C.
12. Charge MDC into RB flask at 0-5°C under stirring.
13. Charge wet cake into RB flask at 0-5°C under stirring.
14. MDC layer given chilled water washings at 0-5°C.
15. Combine aqueous layer given MDC extraction at 0-5°C.
16. Combine both MDC layers into RB flask and charge sodium sulphate at 0-5°C.
17. Stir the reaction mass for 30 ± 5 min at 0-5°C.
18. Filter the reaction mass and wash with MDC at 0-5°C.
19. Distill out MDC completely under vacuum at temperature below 35°C.
20. Cool the reaction mass at 20-25°C.
21. Charge ethyl acetate into reaction mass at 20-25°C.
22. Charge Cyclohexane into reaction mass at 30-35°C.
23. Maintain the reaction mass for 2.0 h ± 30 min at 25-30°C under stirring.
24. Filter the solid from reaction mass at 25-30°C.
25. Wash the wet solid with Cyclohexane.
26. Dry the material at 40-45°C for 4.0 h under vacuum.
138
2.5 RAW MATERIALS REQUIREMENT WITH THEIR SOURCE AND TRANSPORATATION
Details of Raw material consumption and Mode of Transportation are given in following table.
LIST OF RAW MATERIALS
SR.NO NAME OF RAW MATERIAL MT/MT MODE OF
TRANSPORT
A. AROMATIC CHEMICALS
1. Phenyl Ethyl Methyl Ether
1. Phenyl Ethyl Alcohol 0.84
By Road 2. DMS 0.10 3. NaOH 0.23 4. Benzene 0.21
2. Phenyl Ethyl Chloride
1. Phenyl Ethyl Alcohol 1 By Road
2. Thionyl Chloride 0.2
B. BULK DRUGS
Group 1
1. Nimesulide
1. OPMSA 1.04
By Road
2. Acetic Acid 0.29
3. Nitric Acid 0.45
4. MCB 3.13
5. Caustic Lye 0.03
6. Methanol 19.48
7. Activated Carbon 0.06
8. Hyflow 0.01
2. Lumefantrine
1. DBA 0.89
By Road
2. Methanol 4.97
3. 4-Chlorobenzaldehyde 0.34
4. Sodium Methoxide 0.14
5. Ethyl Acetate 4.08
6. Activated Carbon 0.04
7. Hexane 0.34
3.Sulfadoxine
1. Sulfanilamide 1.74
By Road
2. NaOH 1.14
3. IPA 5.56
4. 4,6-DCMP 0.69
5. Dilute hydrochloric Acid 1.79
6. DMF 3.17
7. Methanol 11.28
8. Phosphoric Acid 0.45
9. Activated Carbon 0.04
10. Hyflow 0.01
11. Sodium hydroxide 0.17
Group-2
4. Furosemide
1. Lasamide 1.33
By Road
2. Furfuryl Amine 2.40
3. Caustic Flakes 0.39
4. IPA 4.99
5. Activated Carbon 0.04
6. Acetic Acid 0.36
139
7. De-natured Spirit (DNS) 0.04
8. Hydrose 0.001
9. EDTA 0.001
10. Citric Acid Anhydrous 0.001
5. Hydroxy Chloroquine Sulphate (HCQS)
1. 4,7-DCQ (crude) 0.70
By Road
2. HNDA 0.93
3. Sodium Hydroxide 0.14
4. Acetic Anhydride 0.07
5. Sodium Sulphate 0.14
6. MDC 13
7. Methanol 8.04
8. Phosphoric acid 0.77
9. Hyflow 0.03
10. Activated carbon 0.19
11. Ammonia 1.44
12. Ethyl Acetate 7
13. IPA 6.06
14. Sulphuric acid 0.27
6. Allopurinol
1. 2-Cyanoacetamide 1.14
By Road
2. Morpholine 1.53
3. TEOF 2.45
4. IPA 0.57
5. Hydrazine Hydrate 0.70
6. Sulphuric Acid 1.15
7. Formamide 4.34
8. Liquor Ammonia Solution 1.06
9. Activated Carbon 0.08
10. Hyflow 0.01
7. Colesevelam Hydrochloride
1. Allyl amine 0.51
By Road
2. Hydrochloric acid 1.93
3. Azobis catalyst 0.08
4. Methanol 28.99
5. Sodium hydroxide 0.21
6. Epichlorohydrin 0.04
7. Isopropyl alcohol 19.32
8. 6-BHTMAB 0.77
9. 1-bromodecane 0.53
10. Sodium hydroxide 0.22
11. Sodium chloride 6.71
12. Allyl amine 0.51
Group-3
8. Amodiaquine Hydrochloride (AMQ HCl)
1. 4,7-DCQ 0.51
By Road
2. Mannich base 0.64
3. Toluene 1.34
4. De-natured Spirit (DNS) 0.57
5. HCl 0.73
6. Hyflow 0.00
7. De-natured Spirit (DNS) 3.68
9. Piperaquine Phosphate
1. 4,7-DCQ 0.78 By Road
2. Piperazine Anhydrous 1.01
140
3. 1,3-Dibromopropane 0.43
4. Caustic Flakes 0.44
5. Isopropyl Alcohol (IPA) 1.82
6. Methylene Dichloride (MDC) 5.37
7. Phosphoric Acid 0.57
8. Denatured Spirit (DNS) 6.87
9. Cyclohexane 0.09
10. Acetic Acid 0.26
11. HCl 0.52
12. Activated Carbon 0.03
13. Caustic Flakes 0.15
Group-4
10. Tenofovir Disoproxil Fumarate
1. PMPA 0.67
By Road
2. Chloromethyl isopropyl carbonate [CMIC] 1.60
3. TEA 0.56
4. N-methyl-2-pyrrolidone [NMP] 1.41
5. Tetra butyl ammonium bromide
[TBAB] 0.73
6. MDC 7.09
7. Sodium sulphate 0.13
8. IPA 4.19
9. Fumaric acid 0.27
10. Cyclohexane 10.53
11. Efavirenz
1.
(S)-5-Chloro-α-Cyclopropylethynyl-2-
amino-α-(trifluoromethyl) benzene
methanol (Short name: E-6) 1
By Road
2. Triphosgene 0.44
3. Sodium bicarbonate 0.87
4. Acetic acid 0.001
5. Ammonia 0.08
6. Sodium hydroxide 0.26
7. Toluene 6.09
8. Hyflo supercell 0.01
9. Activated carbon 0.02
10. Methanol 4.73
Group- 5
12. Artemether
1. Dihydroartemisinin 1.06
By Road
2. HCl 0.02
3. Tri methyl ortho acetate (TMOA) 1.51
4. Triethyl Amine (TEA) 0.06
5. Methanol 7.24
13. Artesunate
1. Dihydroartemisinin 0.84
By Road
2. Acetone 1.98
3. Succinic Anhydride 0.42
4. Triethyl Amine (TEA) 0.42
5. Acetic Acid 1.59
6. Activated Carbon 0.07
7. Hyflow 0.02
8. Cyclohexane 7.55
9. Methanol 2.53
Group- 6
141
14. Emtricitabine
1.
(2S,5R)-5-(4-amino-5-fluoro-2-oxo-2H-
pyrimidin-1-yl)-[1,3]-oxathiolane-2-
carboxylic acid, 2S-isopropyl-5R-methyl-
1R-cyclohexyl ester (Short name: F-CME) 2.14
By Road
2. Di potassium hydrogen phosphate 2.94
3. Denatured spirit (DNS) 17.14
4. Sodium borohydride 0.43
5. Sodium hydroxide 0.01
6. Con. sulphuric acid 0.08
7. Liq. ammonia 0.11
8. Toluene 6.43
9. Isopropanol 49.01
10. 20.0-25.0 % IPA.HCl solution 2.14
11. Methanol 5.46
12. Triethylamine 0.83
13. MDC 29.39
14. Activated carbon 0.12
15. Hyflo supercell 0.02
15. Pyrimethamine
1. 4-Chloro Phenyl Acetonitrile 0.91
By Road
2. Ethyl propionate 2.73
3. Sodium Methoxide 0.95
4. Acetic acid 0.73
5. MDC 4.84
6. Cyclo hexane 6.18
7. p-toluene sulfonic acid 0.53
8. Ethylene glycol 0.88
9. Methanol 1.89
10. Activated carbon 0.03
11. Hyflow 0.01
12. 4-Chloro Phenyl Acetonitrile 0.91
13. Ethyl propionate 2.73
16. Dihydroartemisinin
1. Artemisinin 1.05
By Road 2. Methanol 2.53
3. Sodium Borohydride 0.17
4. Acetic Acid 0.37
17. Bisoprolol Funarate
1. 4-Hydroxy Benzyl Alcohol 0.66
By Road
2. 2-Isopropoxy ethanol 6.6
3. Amberlyst -15 (Dry) 0.33
4. Sodium carbonate 0.008
5. MDC 7.23
6. Epichlorohydrin 62.7
7. Potassium carbonate 7.7
By Road
8. Methanol 1.33
9. Mono isopropyl amine 0.958
10. Sodium borohydride 0.006
11. Activated Carbon 0.04
12. Hyflow 0.008
Group-7
18. Pyronaridine
1. 1,4 Di bromo pentane 1.63 By Road
2. Potassium phthalimide 1.64
142
3. Acetone 11.51
4. 6 methoxy 8 amino quinoline 1.16
5. 4 bromo 1 phthalimide pentane 1.97
6. MDC 43.26
7. Methanol 71.88
8. Hydrazine hydrate 1.16
9. Phosphoric acid 1.16
10. Disodium hydrogen phosphate 0.98
11. Con. HCl (35.0%) 1.12
12. Hyflow 0.12
13. Activated carbon 0.12
19. Atazanavir Sulfate
1. Boc Hydrazine 0.78
By Road
2. Boc Epoxy 0.75
3. IPA 3.69
4. N-methoxy carbonyl L-tert leucine (MOC-
L-tert Leucine) 1.05
5. 1- hydroxy benzotriazole mono hydrate
(HOBT mono hydrate) 0.82
6.
1-(3-imethylaminopropyl)-3-
ethylcarbodiimide hydrochloride
(EDC.HCl) 1.37
7. Conc. HCl 1.14
8. Triethyl amine 1.85
9. MDC 18.28
10. Methanol 19.5
11. Ethyl acetate 29.62
12. Sulphuric acid 0.13
13. Acetone 19.75
14. Activated carbon 0.2
15. Hyflo 0.2
20. Primaquine Phosphate
1. 1,4 Di bromo pentane 1.63
By Road
2. Potassium phthalimide 1.64
3. Acetone 11.51
4. 6 methoxy 8 amino quinoline 1.16
5. 4 bromo 1 phthalimide pentane 1.97
6. MDC 43.26
7. Methanol 71.88
8. Hydrazine hydrate 1.16
9. Phosphoric acid 1.16
10. Disodium hydrogen phosphate 0.98
11. Con. HCl (35.0%) 1.12
12. Hyflow 0.12
13. Activated carbon 0.12
21. Chloroquine Phosphate (CQP)
1. 4,7-DCQ (crude) 0.41
By Road
2. NDA 0.35
3. Phenol 0.20
4. Caustic lye 0.17
5. Toluene 1.29
6. Activated carbon 0.01
7. Methanol 2.12
8. Silica 0.00
9. EDTA 0.00
143
10. Phosphoric acid 0.48
11. DNS 2.66
12. Activated carbon 0.02
13. Hyflow 0.001
14. Silica 0.0002
15. Phosphoric Acid 0.001
Group-8
22. Tenofovir Alafenamide Hemifumarate
1. PMPA 1.67
By Road
2. Acetonitrile 8.01
3. Triphenyl phosphite 2.72
4. Toluene 20.99
5. Dimethyl aminopyridine 0.72
6. Triethyl amine 3.17
7. Conc. HCl 0.83
8. Toluene 97.45
9. Thionyl chloride 1.36
10. L-Alanine isopropyl ester HCl 9.54
11. MDC 64.28
12. THF 31.12
13. Sodium phosphate monobasic 4.33
14. Acetone 15.82
15. Fumeric acid 0.15
16. Acetonitrile 12.77
23. Tenofovir Disoproxil Orotate
1.
R)-(((1-(6-amino-9H-purin-9-yl)propan-2-
yl)oxy)methyl) phosphonic acid (PMPA
monohydrate)
1.05
By Road
2. N-methyl pyrrolidone (NMP) 2.22
3. Tetra butyl ammonium bromide (TBAB) 1.15
4. Triethylamine (TEA) 0.87
5. Chloromethyl isopropyl carbonate (CMIC) 2.52
6. MDC 9.77
7. Ethyl acetate 0.81
8. Cyclohexane 8.19
9. Sodium sulphate 2
10. Orotic acid 0.49
11. Acetone 5.47
12. Dimethyl sulphoxide 4.15
24. Sofosbuvir
1. (Uridine compd.) 0.78
By Road
2. Fluoro compd 2.03
3. THF 10.4
4. Tertiary butyl magnesium chloride 3.49
5. Conc. HCl (30%) 6.04
6. Na2CO3 (Anhydrous) 1.56
7. NaCl 2.34
8. Na2SO4 0.78
9. MDC 46.68
10. Toluene 8.11
Group-9
25. Dolutegravir Sodium
1. Acetonitrile 19.04
By Road 2. Lithiumbromide (LiBr) 0.524
3. 1N HCl 0.619
144
4. 30% HCl 0.476
5. Methanol 23.47
6. Methoxy Compound 1.19
7. Aq. NaOH 1.547
26. Velpatasvir
1. THF 14.5
By Road
2. Cesium carbonate 0.95
3. Ethyl acetate 10.76
4. Toluene 13.22
5. Sodium acetate 26.74
6. Methanol 64.34
7. MDC 80.79
8. Manganese dioxide 14.19
9. Conc. HCl 34
10. (R)-2-((methoxycarbonyl) amino)-2-
phenylacetic acid 0.36
11. DMF 29.62
12. DIPEA 2.78
13. Ethyl acetate 6.82
27. Adefovir Dipivoxil Fumarate
1.
((2-(6-amino-9H-purin-9-yl)
ethoxy)methyl)phosphonic acid (Adefovir
monohydrate)
1.3
By Road
2. N-methyl pyrrolidone (NMP) 4.5
3. Triethylamine (TEA) 1.37
4. MDC 9.7
5. IPA 8
6. Sodium sulphate 2
7. Fumaric acid 0.31
8. Acetone 5.54
28. Ledipasvir
1.
(1R,3S,4S)-tert-butyl 3-(6-bromo-1H-
benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]
heptane-2-carboxylate 0.82
By Road
2. bis(pinacolato)diboron 0.63
3. Potassium propionate 0.7
4. 1M K3PO4 solution 7.37
5. N-Acetyl-L-Cysteine 0.2
6. Acetonitrile 3.92
7. 1.5N HCl 6.15
8. EDC.HCl 1.09
9. HOBT.H2O 0.51
10. MOC-Valine 1
11. DMF 12.5
12. N-methyl morpholine 1.25
13. Ethyl acetate 13.82
14. Acetone 11.72
29. Daclatasvir Dihydrochloride (API)
1. 1,1’-(Biphenyl-4,4’-diyl) diethanone 0.936
By Road
2. Bromine 1.269
3. MDC 33.453
4. THF 8.234
5. Boc-L-Proline 1.461
6. Acetonitrile 10.075
145
7. DIPEA 0.865
8. Toluene 55.681
9. Ammonium acetate 0.5
10. Acetic acid 3.294
11. n-Butanol 3.114
12. Methanol 5.569
13. NaCl 2.89
14. Methanol 23.1
15. Conc. HCl 0.49
16. (P)-L-Valine 0.68
17. Acetonitrile 7.096
18. DIPEA 0.834
19. EDC HCl 0.743
20. HOBT 0.618
21. Isopropyl acetate 3.294
22. Ethanol 3.114
23. NaOH 0.433
24. Acetone 2.357
30. . Tafenoquine succinate
1. 1,4-DBP 0.672
By Road
2. Potassium phthalimide 0.541
3. Acetone 4.247
4. 2,6-dimethoxy-4-methyl-5-(3-
(trifluoromethyl) phenoxy)quinolin-8-amine 1.065
5. MDC 1.11
6. Methanol 3.871
7. Hydrazine hydrate 1.065
8. Succinic acid 0.206
Group 10
31. Ursodiol
1. Chenodeoxycholic acid 2.75
By Road
2. Acetone 72
3. NBS 2.24
4. Potassium tert butoxide 2.44
5. Raney Nickel 0.96
6. Ethyl acetate 1.92
7. Isopropanol 34.2
8. Conc HCl 2.1
9. Triethylamine 0.55
10. Acetone 18.7
11. Ethyl acetate 6.16
12. Ursodiol Crude 1.7
13. Ursodiol pure 1.27
32. Terizidone
1. (S)-2-amino-3-hydroxypropanoic acid or D-
Serine 2.02
By Road
2. Chloroform 57.31
3. Dry HCl 0.7
4. Thionyl chloride 5.81
5. Ethanol (Absolute) 42.1
6. Hydroxyl amine hydrochloride 1.805
7. 0.91 N Sodium methoxide 29.87
8. Hydrochloric acid (30%) 1.94
9. 30% Aq. NaOH 2.539
10. Isopropyl alcohol 14.29
146
11. Glacial acetic acid 0.88
12. Ether 1.78
13. Methanol 24.82
14. Terephthalaldehyde 0.468
33. Delamanid
1. (R)-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-
2-methylpropane-1,2-diol 1.545
By Road
2. Pyridine 3.028
3. Methane sulphonyl chloride 1.126
4. Conc. HCl 5.88
5. Ethyl acetate 47.2
6. Toluene 10.07
7. 1,8-diazabicyclo[5.4.0]-7-undecane 1.096
8. 4-(4-(4-(trifluoromethoxy)
phenoxy)piperidin-1-yl) phenol 1.391
9. DMF 12.62
10. NaH (60%) 0.189
11. IPA 0.982
34. Tariquidar
1. 4-(2-(6,7-dimethoxy-3,4-
dihydroisoquinolin-2(1H)-yl)ethyl)aniline 3.339
By Road
2. 4,5-dimethoxy-2-nitrobenzoic acid 2.66
3. Toluene 28.65
4. Thionyl chloride 1.4
5. DMF 0.5
6. MDC 700
7. Pyridine 0.845
8. NaHCO3 (Sat. Solution) 7.2
9. Na2SO4 0.01
10. Acetone 2.63
11. Ethyl acetate 90
12. Methanol 101
By Road
13. THF 87.97
14. 10% Pd/C wet (50% w/w) 1.333
15. Quinoline-3-carbonyl chloride 2
16. Pyridine 1.64
17. NaHCO3 2.664
18. NaCl 11.66
19. Na2SO4 0.2
20. Methanol 31.59
21. NaCl 11.66
22. Na2SO4 0.2
35. Solfinacin Succinate
1. 2-Phenylethylamine 1.76
By Road
2. Sodium Hydroxide 1.2
3. Benzoyl Chloride 2.654
4. 5% Sodium Bicarbonate Solution 9.02
5. 2-Phenylethylamine 1.76
6. Phosphorous Pentaoxide 0.756
7. Phosphorous oxychloride 3.6
8. Ethylchloroformate 0.535
9. Toluene 70
10. NaOH Flakes 9
11. Sodium Sulphate 0.35
12. Methanol 15.3
147
13. Sodium Borohydride 0.467
14. IPA 28.27
15. D(-)-tartaric acid 1.792
16. Potassium Carbonate 0.544
17. R-Quinuclidinol 0.86
18. DMF 0.602
19. Sodium Hydride 0.155
20. Methanol 0.155
21. Sodium Chloride 0.645
22. HCl 0.568
36. Montelukast Sodium
1. MON-Diol 1.736
By Road
2. Methane sulphonyl chloride 0.478
3. Diisopropylethylamine 0.782
4. Dichloromethane 11.544
5. MON-Mercaptoacid 0.72
6. Sodium methoxide solution (25%) (d-0.945) 2.224
7. Hexanes 6.822
8. Dimethyl Sulfoxide 7.638
9. Sodium Hydroxide 0.832
10. n-Heptane 1.186
11. Toluene 76
12. Acetic acid (12.8%) 1.888
13. MON-Acid 1.388
14. Tert-butylamine 0.19
15. Acetone 4.708
16. Acetonitrile 9.448
17. MON-TBA 1.25
18. Sodium hydroxide (97%) 0.078
19. Dichloromethane 12.062
20. Sodium sulphate 0.124
21. Acetic acid (5%) 10.152
22. n-Heptane 9.412
23. Methanol 5.944
24. Activated charcoal 0.064
25. Hyflo 0.128
37. Silodosin
1. SIO-Tartrate 2.75
By Road
2. Sodium Carbonate 1.125
3. Toluene 155
4. Anhydrous Sodium Sulphate 2.75
5. SIO-Mesylate 1.675
6. Sodium Carbonate 0.385
7. Ethyl acetate 125
8. L-(+)-Tartaric acid 0.88
9. Methanol 10.4
10. Potassium Hydroxide 1.22
11. Sodium bicarbonate 0.6
12. Sodium Sulphite 1.3
13. SIO-Cyano 1.7
14. DMSO 21.25
15. NaOH 0.255
16. Hydrogen Peroxide 0.885
17. MDC 61.25
18. Sodium bicarbonate 1.19
148
19. Conc HCl 0.85
20. Sodium Sulphite 0.74
21. Sodium Sulphate 0.85
22. Ethyl acetate 31
38. Cincalcet HCl
1. 3-(Trifluoromethyl) benzene propanol 1
By Road
2. Mesyl Chloride 0.744
3. Dichloromethane 8
4. Triethyl amine 0.744
5. Sodium Sulphate 0.2
6. Concentrated HCl 2.4
7. (R)-1-(1-Naphthalenyl) ethylamine 1.516
8. Diisopropylethyl amine 0.86
9. Acetonitrile 4.874
10. Dichloromethane 16.624
11. Sodium Bicarbonate 1
12. Sodium Sulphate 0.12
13. Diisopropyl ether 9.954
14. IPA HCl 0.436
15. Activated Charcoal 0.1
16. Methanol 4.35
17. Hyflo Supercel 0.07
18. Acetonitrile 9.28
39. Maraviroc
1. (S)-3-Amino-3-phenyl propanoic acid 1.11
2. 4,4 Difluorocyclohexane carboxylic acid 1.32
3. Thionyl chloride 2.40
4. Sodium Hydroxide 1.98
By Road
5. Sodium Carbonate 3.56
6. Toluene 26.67
7. Ethanol 5.56
8. MDC 34.44
9. Heptane 20.00
10. Sodium Sulphate 0.56
11. THF 18.72
12. Methanol 1.20
13. Acetone 2.00
14. Cyclohexane 29.72
15. Sodium borohydride 0.44
16. Sodium Sulphate 1.80
17. Sodium chloride 2.44
18. MDC 34.44
19. Toluene 7.58
20. Heptane 10.33
21. Potassium bromide 0.02
22. 2,2,6,6-Tetramethyl-1-piperidinyloxy, free
radical, 2,2,6,6-Tetramethylpiperidine 1-
oxyl 0.01
23. Sodium bicarbonate 1.03
24. Sodium thiosulphate 1.32
25. Sodium hypochlorite 9.71
26. Ammonium formate 3.79
27. Pd/C 0.49
28. Ammonia 1.17
29. Ethyl acetate 9.78
149
30. (1S)-4, 4-Difluoro-N-(3-oxo-1-
phenylpropyl) cyclohexane carboxamide 0.98
31. Potassium hydroxide 0.27
32. Methylene chloride 50.84
33. Sodium carbonate 0.49
34. Sodium sulphate 0.98
35. Charcoal 0.05
36. water 67.86
37. Hyflo 0.10
40. Vilazodone HCl
1. VIL-Piperazine Ester HCl 2.35
By Road
2. Methanol 15.83
3. N,N Dimethyl formamide 19.32
4. Sodium Hydroxide 0.15
5. VIL-Carboxamide 1.34
6. VIL-Chloroindole 1.27
7. NaHCO3 4.30
8. Methanol 5.31
9. Hyflow 0.30
10. Activated Carbon 0.13
11. Na2S2O5 Solution (5%) 2.75
12. IPA 53.59
13. IPA HCl 0.78
41. Metoprolol succinate
1. MET-Phenol 0.73
By Road
2. Epichlorohydrin 1.33
3. Sodium Hydroxide 0.27
4. Toluene 8.1
5. MET-Epoxide 0.99
6. Isopropyl amine 1.48
7. Succinic acid 2.29
8. Acetone 6.21
9. MET-Crude 1.23
10. Methanol 5.37
11. Activated charcoal 0.02
12. Hyflo 0.12
(C) BULK DRUGS INTERMEDIATES
1. Meta Chloro Aniline (MCA)
1 Nitrobenzene 1.00
By Road
2 Cl2 gas 0.39
3 FeCl3 0.02
4 NaHS 0.02
5 Na2CO3 0.00
2. 2,7-Dichloro-9H-fluorene (DCF)
1 DMF 3.28
By Road
2 Fluorine 1.11
3 Chlorine gas 0.94
4 FeCl3 0.04
5 Methanol 3.67
3. 2-(2,7-dichloro-9H-fluoren-4-yl)oxirane
1 LF-2/ ADCF 1.14
By Road 2 Methanol 9.14
3 Sodium boro hydride 0.06
4. [2-Dibutylamino-1-(2-7-dichloro-9H-florine-4-yl)] ethanol(DBA)
1 LF-2/ ADCF 0.98 By Road
150
2 Methanol 7.03
3 Sodium boro hydride 0.05
4 N,N- Dibutyl amine 2.05
5 Ethyl acetate 1.54
5. Dihydroartemisinin (DHA)
1 Artemisinin 1.05
By Road 2 Methanol 2.53
3 Sodium Borohydride 0.17
4 Acetic Acid 0.37
6. 4-Cyanoethyl-2-methyl –phenol: (MHPN)
1 o-cresol 0.72
By Road 2 Acrylonitrile 0.46
3 AlCl3 0.18
4 Hydroquione 0.0004
7. (R)-9-(2-phosphonylmethoxypropyl)-adenine: (PMPA)
1 Adenine 20.0
By Road
2 R-Propylene carbonate 17.9
3 Dimethyl formamide 9.5
4 NaOH 1.1
5 Toluene 15.6
6 Methanol 1.6
8. 4, 7-Dichloro Quinoline :( 4, 7- DCQ)
1. 4-hydroxy 1.419
By Road
2. Toluene 3.527
3. POCl3 1.195
4. Caustic lye 2.392
5. Methanol 4.822
6. Activated carbon 0.076
7. EDTA 0.000
8. Hyflow 0.001
9. N-(2-phenoxyphenyl) methane sulfonamide (OPMSA) 1. Ortho Phenoxy Aniline 0.71
By Road 2. Dimethyl Aniline (DMA) 0.60
3. Methane Sulfonyl chloride (MSC) 0.46
4. Caustic Lye 0.15
10. Meta Amino Acetanilide:(MAA)
1. MNA 1.43
By Road
2. Acetic Anhydride 1.00
3. Acetyl MNA 1.43
4. Cast Iron powder 1.10
5. Acetic Acid 0.01
6. Hydrate Lime 0.04
7. Sodium hydrosulphite 0.01
8. Common salt 1.37
9. Activated carbon 0.01
11. N-{3-[(diethylamino)methyl]-4-hydroxyphenyl}acetamide:(Mannich Base)
1. Mannich base 0.84
By Road 2. Formaldehyde 0.51
3. Diethyl amine 0.49
4. Methanol 0.88
12. 4,6-Dichloro-5-methoxy pyrimidine: (4,6-DCMP)
1. Methyl methoxy acetate 0.67
By Road 2. Dimethyl malonate 1.00
3 Sodium Methoxide 0.50
151
4. Methanol 2.67
5. Formamide 0.33
6. Toluene 3.60
7. POCl3 0.33
13. 13. L-Menthyl-5-(2R,5S)-[4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl]-1,3-
oxathiolane-2-carboxylate (FCME)
1.
(2R,5R)-5-hydroxy-1,3-oxathiolane-2-
carboxylic acid (1R,2S,5R)-5-methyl -2-(1-
methylethyl) cyclohexyl ester (HME) 1.25
By Road
2. 5-Fluoro Cytosine (5-FC) 0.41
3. Methane sulphonic acid (MSA) 0.005
4. Thionyl chloride (TC) 1.03
5. N,N-Dimethyl formamide (DMF) 0.63
6. Hexamethyldisilazane (HMDS) 0.63
7. Triethyl amine 0.43
8. Ammonium sulfate 0.02
9. Conc. HCl 0.002
10. MDC 18.28
11. Ethyl acetate 0.98
12. Sodium chloride 0.12
13. Sodium sulphate 2
14. (S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol
(E-6)
1. 4-chloro-2-trifluoroacetyl aniline
hydrochloride hydrate 31.92
By Road
2. Diethyl Zinc (15% in Toluene) 79.68
3. 2,2,2-Trifluoro ethanol 6.72
4. Cyclo propyl acetylene 8.88
5. (1R,2S)-N-Pyrolidinyl Nerophredine (NPN) 35.04
6. n-Butyl Magnesium chloride (NBC) 13.2
7. Citric acid monohydrate 40.8
8. Tetrahydrofuran (THF) 21.12
9. Toluene 110.88
10. Sodium hydroxide (NaOH) 0.55
11. n-Butyl Magnesium chloride (NBC) 13.2
12. Citric acid monohydrate 40.8
13. Tetrahydrofuran (THF) 21.12
15. Tenofovir Disoproxil Free Base (TD Base)
1.
R)-(((1-(6-amino-9H-purin-9-yl)propan-2-
yl)oxy)methyl) phosphonic acid (PMPA
monohydrate)
8.3
By Road
2. N-methyl pyrrolidone (NMP) 17.5
3. Tetra butyl ammonium bromide (TBAB) 9.1
4. Triethylamine (TEA) 6.8
5. Chloromethyl isopropyl carbonate (CMIC) 19.9
6. MDC 77.2
7. Ethyl acetate 6.4
8. Cyclohexane 65.5
9. Sodium sulphate 20
2.6 RESOURCE OPTIMIZATION / RECYCLING AND REUSE IN THE PROJECT
The materials are packed in drums and stored in a very organized way, segregated as Solid and Liquid area in
warehouse. We have good practices in place like good house-keeping, good Manufacturing practices, best
Environment control, safety and health practices. By adoption of continuous improvement in technology and
152
processes 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.
2.7 AVAILABILITY OF WATER ITS SOURCE, ENERGY / POWER REQUIREMENT AND
SOURCE
WATER
Total water requirement for the proposed expansion project would be estimated as 220 KLD, which would be
sourced from G.I.D.C
POWER
Total power requirement for the proposed expansion project will be 750 KVA.During emergency purpose
D.G. Set of 320 KVA will be utilized. .Power supply shall be full-filled by DGVCL (Daxin Gujarat Vij
Corporation Limited).
2.7.1 WATER REQUIREMENT AND WASTE WATER GENERATION
Total wastewater i.e. 125 KLD will be generated from the proposed expansion project, which will be treated in
ETP consisting primary & secondary treatment. Treated effluent will be sent to CETP for further treatment and
final disposal
2.7.2 FUEL REQUIREMENT
Sr. No. Fuel
Daily Fuel Consumption
Existing Proposed Total
1. Natural Gas 193 m3/Hr 208 m3/Hr 401 m3/Hr
2. LDO 600 Lit/Day -- 600 Lit/Day
2. Diesel 70 Lit/Hr -- 70 Lit/Hr
153
2.7.3 AIR POLLUTION
EMISSIONS FROM COMBUSTION OF FOSSIL FUELS FROM STATIONARY OR MOBILE SOURCES
SR.
NO.
STACK ATTACHED
TO FUEL USED
STACK
HEIGHT
POLLUTION
CONTROL
SYSTEM
FINAL
CONCENTRATION
EXISTING
1 IBR Boiler Natural Gas
(193 m3/Hr)
30
meter
adequate stack
height is provided
SPM ≤ 150 mg/Nm3
SO2≤ 100 ppm
NOX≤ 50 ppm
2 Non IBR Boiler standby
facility
15
meter
3
D.G. Set (320 KVA)
Diesel
(70 Lit/Hr)
11
meter
4 Thermic Fluid Heater
(4 Lac K cal)
LDO
(600 Lit/Day)
15
meter
PROPOSED
1. Gas Generator
(1 MW)
Natural Gas
5000 m3/Day
15
meter
adequate stack
height will be
provided
SPM ≤ 150 mg/Nm3
SO2≤ 100 ppm
NOX≤ 50 ppm
PROCESS EMISSION
SR.
NO.
STACK
ATTACHED TO
STACK
HEIGHT
POLLUTION
CONTROL
SYSTEM
Type of
Pollutants FINAL
CONCENTRATION
EXISTING
1. Chlorinator in Meta
Chloro Aniline Plant
11
Meter
A glass line water
scrubber followed by
ventury caustic
scrubber
Cl2
HCl
Cl2 ≤ 09 mg/Nm3
HCl ≤ 20 mg/Nm3
154
2.7.5 SOLID WASTE GENERATION AND ITS MANAGEMENT The sourcesof solid wastes, generation and its management are as given in the following table.
SR.
NO.
NAME OF THE
WASTE
CAT
NO.
EXISTING
(MT/Year)
PROPOSED
(MT/Year)
TOTAL
(MT/Year)
METHOD OF
STORAGE AND
DISPOSAL
1 ETP Waste 34.2 72 228 350
Collection, storage,
Transportation,
disposal at TSDF-
VWEMCL
2 Distillation
Residue 20.3 43.2 1156.8 1200
Collection, storage and
disposed in incinerator
at Unit-II/ Sent to
Common incineration
facility 3 Process Residue 28.1 6 494 500
4 Spent Solvents 28.6 0 300 300 Recovered & reused/
Sent to end user.
5 Used Oil 5.1 0.06 0.06 0.12
Collection, storage and
reuse as lubricants in
the machineries within
the premises only or
send to authorized re-
processors.
6
Discarded
Containers/
Bags
33.1 2400
Nos./Year
3100
Nos./Year
5500
Nos./Year
Collection, storage and
send to authorized
recycler after
decontamination.
7 Iron Sludge 28.2 1800 200 2000
Collection, storage,
Transportation,
disposal at TSDF
8 Used/ Waste
filter clothes 35.1 0.05 0.10 0.15
Collection, storage,
Transportation,
disposal at TSDF
9 Sludge from wet
Scrubber 36.1 0.024 0.096 0.12
Collection, storage,
Transportation,
disposal at TSDF
10 Spent Carbon 28.2 78 222 300
Collection, storage and
disposed in incinerator
at Unit-II
155
CHAPTER-3
SITE ANALYSIS
3.1 CONNECTIVITY
3.1.1 RAIL
The nearest railway station is Vapi Station, which is around 2.28 km in North West direction from the project
site.
3.1.2 ROAD
The site is well connected by road network to all the key places. The major highway passing near the project
site isNH-8which is around 0.75 km West direction from the project site.
3.1.3 AIR
The nearest airport from the project site is Daman Airport. The distance of airport from project site is around 12
km in North West direction.
3.1.4 COMMUNICATION
Proposed project site is within existing company premises which is already well connected with telephone, tele
fax etc. all the communications facilities are well developed in the area.
3.2 TOPOGRAPHY
Topography of the land is plane.
3.3 EXISTING LAND USE PATTERN
There is no Forest, National park; Wild life sanctuary within a radius of 10 km. Details of existing land use is
given in the following table:
DETAILS OF EXISTING LAND USE
SR.NO. PARTICULAR NAME & ITS DISTANCE
1. Nearest National Highway NH-8 which is around 0.75 km west direction
2. Nearest city Vapi City is around 2.5 km in west direction
3. Nearest River Damanganaga at 3.8 km in south west direction
4. Nearest Railway station Vapi Station at around 2.5 km in west direction
5. National park/Reserve Forest,
Biosphere, etc. None within 15 km
3.4 EXISTING SOCIAL STRUCTURE
Project site is located at Vapi, G.I.D.C. All the infrastructures are available within city like Schools, Hospitals
& community facilities even nearby area of the project site is also developed.
156
CHAPTER – 4
PLANNING BRIEF
4.1 PLANNING CONCEPT
Type of industries:
The Active Pharmaceutical Ingredient industry is the organ by which active pharmaceutical ingredients are
manufactured from raw materials through both chemical and physical means. Depending on the complexity of
the molecule required, synthesis of APIs might need multi-step complex chemistry utilizing a range of
processing technologies.
4.2 LAND USE PLANNING
The plant general Layout has been planned considering production facilities, auxiliary and ancillary facilities
and plant utilities & services.Total plot area of the project is 8737.82 m2 from which around 2880 m2 (33% of
total land area) will be required for the development of green belt. Land use shall be as build up area of
buildings, storage facility, roads, greenbelt, open land etc.,
4.3 AMENTIES / FACILITIES
Adequate storage facility for chemicals, machinery spares and consumables shall be provided. A small
mechanical and electrical/ instrument workshop facilities for repairs and maintenance shall be provided. Time
and security offices shall be provided in the plant. To avoid fire hazard, internal fire hydrants system in all
major plant unit will be provided.
157
CHAPTER – 5
PROPOSED INFRASTRUCTURE
5.1 INDUSTRIAL AREA
The company has already acquired land area of 8737.82 m2 in which company will expand their production
capacity.
5.2 GREEN BELT
The main objective of the green belt is to provide a barrier between the source of pollution and the surrounding
areas. The green belt helps to capture the fugitive emission and to attenuate the noise generated apart from
improving the aesthetics. Development of green belt and other forms of greenery shall also prevent soil erosion
and washing away of topsoil besides helping in stabilizing the functional ecosystem and further to make the
climate more conducive and to restore water balance. The company will develop green belt area with Lawn,
plants and flowers spread across about 33% of the total area i.e. 2880 m2.
Green belt shall be developed at plant boundary, road side, around offices & buildings and Stretch of open land.
The selection of tree species suitable for plantation at the industry are governed by guiding factors as stated
below:
• The trees should be tolerant to air pollutants present in the area
• The trees should be able to grow and thrive on soil of the area, be evergreen, inhabitant, having
minimum of leaf fall.
• The trees should be tall in peripheral curtain plantation and with large and spreading canopy in primary
and secondary attenuation zone.
• The trees should posses extensive foliar area to provide maximum impinging surface for continued
efficient adsorption and absorption of pollutants.
• The trees should be fast growing and indigenous and should maintain ecological, land and hydrological
balance of the region.
• It is also recommended to plant few trees, which are sensitive to air pollution, as air pollution indicator.
• It is also recommended to carry out extensive plantation within premises.
Keeping in view the climatic conditions, status of soils and vegetation types in and around the project area the
species shall be selected for proposed green belt development.
5.3 SOCIAL INFRASTRUCTURE
Drinking water facility, Canteen, proper sanitation, etc. will be provided to the workers working in plant.
5.4 CONNECTIVITY
As discussed earlier, proposed location of the plant is already well connected with the network of road & rail.
So there is no need to construct any new road or rail for the transportation.
5.5 WASTE WATER MANAGEMENT
Total wastewater i.e. 125 KLD will be generated from the proposed expansion project, which will be treated in
ETP consisting primary & secondary treatment. Treated effluent will be sent to CETP for further treatment and
final disposal
5.7 INDUSTRIAL SOLID WASTE MANAGEMENT
From the proposed expansion project activity there shall be mainlySpent/Used Oil, ETP Sludge, Process
Residue, Distillation rsidue, Spent Carbon, Discarded containers, Iron sludge, used/waste filter clothes &
Sludge from wet scrubber.
158
CHAPTER – 6
REHABILITATION AND RESETTLEMENT (R & R) PLAN
The project is located on private land, which is already acquired and there is no habitat. So the project proposal
does not involve any Rehabilitation & Resettlement.
159
CHAPTER – 7
PROJECT SCHEDULE & COST ESTIMATES
7.1 TIME SCHEDULE FOR THE PROJECT
The implementation of the project will involve major activities like preparation of specification / drawings,
issue of tenders, receipt of quotations, scrutiny of tenders, placing of orders, civil & structural construction,
delivery & erection of equipment, test trial runs of various items of equipment and commissioning of the plant
& equipment and completion of the project will take about 6 months after the necessary clearances are
available, and the funding for the project has been tied up.
7.2 ESTIMATED PROJECT COST
The total project cost for the proposedexpansion project would be around Rs. 1 crore. Total capital cost of
pollution control measures will be Rs. 7 Lacs & recurring cost per annum will be 3 Lacs.
7.3 BUDGETORY PROVISIONS FOR EMP
Adequate budgetary provisions have been made by the management for execution of environmental
management plans. The details of capital and recurring (per annum) budget earmarked for pollution control /
monitoring equipment; operation and maintenance of pollution control facilities, for greenbelt development and
maintenance.
COST OF ENVIRONMENTAL PROTECTION MEASURES
SR.
NO. PARTICULATES RS. IN LACS
1. Capital Expenditure 7
2. Recurring expenditure on environmental management cell and on
pollution control systems per annum. 3
160
CHAPTER – 8
ANALYSIS OF PROPOSAL
8.1 FINANCIAL AND SOCIAL BENEFITS
The total cost of the proposed expansion project is estimated at about Rs. 1 crore.
For the coming of this project surrounding area will get developed due to this project and through the
Corporate Social Responsibility (CSR) activities, socio-economic status of the region will also get
developed.