Vasudev Jadhav - Research Summary - 2021

Highlights of Research Work
Lead Researcher: Vasudev Jadhav, PhD

Highlights of the Projects Worked
1. Biotransformations and Biocatalysis: Chemo-Enzymatic
Synthesis and Resolution of Chiral Intermediates
2. Discovery Chemistry Research: Medicinal and Synthetic
Chemistry Research
3. Chemical Drug Development: Process Research and
Development of NCEs
4. API and Intermediate Development: Process Research
and Development, Contract Manufacturing, New Route
Scouting, Cost Reduction
5. Skills and Competences
12 September
2021
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CONFIDENTIAL

Biotransformations and Biocatalysis
Enantioselective Hydrolytic Reactions of Rice Bran Lipase (RBL):
1. Lipases of different origins are widely used in the Resolution of Racemic
mixtures of Chiral molecules
2. Lipases are from Yeast (Candida rugosa), Mold (Mucor sp.), Bacteria
(Pseudomonas sp.) and from Animal sources such as Pig pancreas
3. Wide Substrate Specificity, High Enantioselectivity, Good Stability, Low Cost
and Easy Availability
4. Rice Bran Lipase (RBL) is from Plant source (Rice Bran) which is available in
tonnage in India
5. Rice bran lipase was isolated by De-fatting the Rice Bran, Ammonium sulfate
Precipitation, Dialysis/Ultra-filtration and Freeze drying as reported in
literature with some modifications
6. Enzyme activity was determined by titration of butyric acid produced during
hydrolysis of Tributyrin and is expressed in International Units
7. Typically, Enzyme activity of 75 - 100 units/mg was obtained
12 September
2021
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CONFIDENTIAL

ENZYME Immobilization of Rice Bran Lipase (RBL):
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2021
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CONFIDENTIAL
RBL was immobilized in Gelatin, a technique of immobilization at low temperature
using CTAB, Cross-linked with Glutaraldehyde and shaped into circular membrane

Enzymatic Resolution of
Glycidate Esters with Rice Bran
Lipase (RBL):
1. Enzymatic resolution of racemic
Glycidate esters into Enantiomerically
pure forms is an important field of
research in production of
Pharmaceuticals
2. Synthesis of the Enantiomer Trans-
(2R, 3S) via Resolution of Racemic
Trans-MMPGA by RBL catalyzed
Enantioselective hydrolysis using an
Enzyme Membrane Reactor (EMR) in
Continuous flow mode is shown
3. Enantiomer Trans-(2R, 3S) was
converted further to Diltiazem in
multiple synthetic steps
12 September
2021
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CONFIDENTIAL

Enzymatic Resolution of Glycidate Esters using Enzyme Membrane Reactor (RBL):
12 September
2021
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CONFIDENTIAL
*Improved Process for Enzymatic Preparation of Optically Pure Glycidate Esters Useful as Drug Intermediates, Patent No.
573/DEL/99, CSIR; N. W. Fadnavis, V. Jadhav, A. Deshpande, S. K. Vadivel, K. Koteshwar

Enzymatic Resolution of Glycidate Esters using Enzyme Membrane Reactor (RBL):
1. Enzyme Membrane Reactor used as Model, was fabricated and indigenously made of 2 over-
lapping Stainless steel plates with grooves for fixing the Cross-linked Enzyme membrane and
Continuous flow of the Substrate solution
2. RBL was immobilized in Gelatin, a technique of immobilization at low temperature using CTAB,
cross-linked with Glutaraldehyde, shaped into circular membrane which was fixed between the
SS-plates (~4-inch diameter)
3. The Gelatin matrix provides a porous support; water content of the matrix can be controlled to a
level sufficient for Enzyme to be active (65% activity retained)
4. Trans-Racemic MMPGA solution (2 g, 5%) in Toluene was circulated through In-let of Reservoir
using the Dosing pump through the EMR in Continuous flow for 4 days
5. The Out-let of Reservoir was dipped in Aqueous solution of Sodium bisulphite (30%)
6. The reaction was monitored by HPLC (Chiral) by injecting the Organic layer
7. RBL hydrolyses the Enantiomer Trans-(2S, 3R) to corresponding Acid which converts to
2‐(4‐methoxyphenyl)acetaldehyde and is scavenged by Sodium bisulphite solution
8. The required Enantiomer Trans-(2R, 3S) is re-circulated to the organic layer with a yield of 40%
and Chiral purity (ee) of 99% after completion of reaction and separation
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2021
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CONFIDENTIAL

Chemo-Enzymatic Synthesis on Multi-Kilo Scale :
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2021
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CONFIDENTIAL
 Project Code: ABC-666
 Structure :
 Tech Pack : Scale up Tech Pack
 Key deliverables: 45 Kg under cGMP
 Specifications : 99.0% Chemical purity, Total impurities NMT 1.0%;
Chiral purity = 99.8% ee
Specified Impurities NMT 0.2% each, later changed to
0.1% each; Unspecified Impurities NMT 0.1% each
 No. Of FTE’s: 5
 Duration: 4 months (Process Improvements for 7 Steps
(4 Synthetic + 3 Recrystallization steps all under cGMP)

Chemo-Enzymatic Synthesis on Multi-Kilo Scale :
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2021
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CONFIDENTIAL
1. The Enzymatic step is the Heart of the process & very Critical in terms
of pH (narrow range of 8.80 to 8.85)
2. Slight changes in pH can hamper the chirality of the product as
Chemical hydrolysis will diminish the Enantiomeric Excess (ee)
3. Controlled addition of Sodium hydroxide maintaining pH at a very
narrow range of 8.80 to 8.85 was carried out
4. Step yield of 45% with Chemical purity of 99.5% and Chiral purity of
96.48% ee was achieved
5. Chiral purity was enhanced to 99.8% ee by Co-crystallization with a
Seed sample

Chemo-Enzymatic Synthesis on Multi-Kilo Scale:
12 September
2021
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CONFIDENTIAL
1. Delivery of 56 Kg of ABC-666 as against 45 Kg was achieved as per
Client specifications
2. Project rated as EEE by Client: Exceeded expectations on all fronts
including practice of Standard cGMP protocols
3. Excellent Team work across various departments, such as PR&D,
Analytical, QC, QA, Manufacturing was reason for this achievement
Stage Tech. Pack Lab Development Plant Scale up
1 84.8 80.7 86.3
2 43.65 40.6 45
3 97 93 93
4 67 68 76.84
Overall yield 24.05 20.72 27.75

Activation of Pig Liver Esterase in Organic Media with Organic Polymers:
Application to the Enantioselective Acylation of Racemic Functionalized Secondary Alcohols
12 September
2021
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CONFIDENTIAL
1. Pig Liver Esterase (PLE) is one of the most important enzymes for the
Enantioselective hydrolysis of Prochiral or Racemic esters in aqueous solution
2. Pig Liver Esterase (PLE) shows practically no activity in Acylation of alcohols with
Vinylic esters in organic solvents
3. Many factors have been found to affect the activity and enzyme stability in organic
solvents
4. One important factor is the Water Activity and the Nature of the Organic solvent.
Another one is the Formulation of the Enzyme.
5. However, addition of Methoxypoly(ethylene glycol) (MPEG), Bovine Serum
Albumin (BSA), TentaGelAmino resin (TGA), or Aminomethyl polystyrene (AMPS)
confers activity to PLE in Acylation of alcohols with vinyl propionate in organic
solvents of low water content
*Activation of Pig liver Esterase in Organic Media with Organic polymers. Application to the Enantioselective Acylation of Racemic
Functionalised Secondary Alcohols. J. Org. Chem. 2001, 66, 3384; H.-J. Gais, M. Jungen, V. Jadhav

Application to the Enantioselective Acylation of Racemic Functionalized Secondary Alcohols
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2021
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CONFIDENTIAL
1. The Colyophilisate (CLP) of PLE and MPEG/BSA was successfully applied to the
kinetic resolution of racemic functionalised sec-alcohols
2. Polymer activated PLE showed High Enantioselectivities (E > 100) in the Acylation of
racemic 1-alkoxy-, 1-ethylsulfanyl-, and 1-fluoro-3-aryl-2-propanols as well as
racemic 1-phenoxy-2-propanol and racemic 1-methoxy-2-phenoxy-2-propanol.
3. Alcohol (R)- and the Ester (S)- were formed with High selectivity (E> 100); further
scaled-up to Multi-gram level (PAM) with recycling of the Enzyme

Formation of Side Products in PLE-Catalyzed Acylation of Alcohols with Vinyl Propionate
and Their Scavenging by Amino Group Bearing Polymers
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2021
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CONFIDENTIAL

Discovery Chemistry Research
Synthesis of Optically Active Prostaglandin-J2 and Δ12, 14-15 deoxy Prostaglandin-J2
12 September
2021
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CONFIDENTIAL
1. Prostaglandin-J2 (PGJ2) (1) and Δ12, 14-15 deoxy Prostaglandin J2 (2) have been shown
to be potent anti-viral agents
2. Molecule (2) has also attracted interest because of its action as an agonist on the PPAR-
gamma receptor, its anti-inflammatory activity and cytoprotective potential
*Synthesis of Optically Active Prostaglandin-J2 and 15-Deoxy-∆12, 14-prostaglandin-J2. Synlett. 2003, 8, 1170; J.F. Bickley, V. Jadhav, S.M.
Roberts, M.G. Santoro, A. Steiner, P.W. Sutton
Charterhouse Therapeutics (Liverpool, UK), a Spin-off Drug Discovery company from
University of Liverpool (Prof. Stanley Roberts; Medicinal & Synthetic Chemistry) and
University of Rome (Prof. Gabriela Santoro; Biology) worked on preparation of
Cyclopentanone and Cyclopentenone derivatives (NCEs) and their use in medicine and other
fields

Synthesis of Optically Active Prostaglandin-J2 and Δ12, 14-15 deoxy Prostaglandin-J2
12 September
2021
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CONFIDENTIAL
1. Synthesis involved the conversion of 7-chloronorbornadiene into the lithio compound
and reaction with trans-Oct-2-enal to give the Alcohol.
2. Alcohol was converted into the Silyl ether and subjected to the Oxidative Rearrangement
(Meinwald Rearrangement) and Hydrolysis to provide a 2:1 mixture of Hydroxy
aldehydes
3. Wittig reaction, Dess–Martin oxidation and concomitant desilylation/dehydration
furnished Δ12, 14-15 deoxy Prostaglandin-J2 (2)

Synthesis of 4-Aza-cyclopentenones:
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2021
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CONFIDENTIAL
1. Synthesis of 4-Aza-cyclopentenones were envisaged towards lead generation of
Cyclopentenone Prostaglandin based library (Prostanoids) with enhanced water solubility,
lipophilicity and/or therapeutic indices
2. 4-Hydroxycyclopent-2-enone could be converted on reacting with corresponding
Isocyanates into the Urethanes which itself were transformed into the 4-Anilino-
compound (with loss of CO2) on treatment with triethylamine
3. A focussed library of 4-Aza-cyclopentenones (1st Set of Lead Compounds) were
synthesized using Parallel synthesis/purification techniques and were tested
4. Further manipulated by reacting them with different set of Aldehydes in the presence of Ti
(VI) reagents and Triphenyl phopshine to give the 2nd Set of Lead Compounds

12 September
2021
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CONFIDENTIAL
1st Set of Lead Compounds:
2nd Set of Lead Compounds:
*Synthesis of 4-azacyclopent-2-enones and 5, 5-dialkyl- 4-
azacyclopent-2-enones. Tetrahedron 2004, 60(11), 2559; J.
Dauvergne, A.M. Happe, V. Jadhav, D. Justice, M.C. Matos,
P.J. McCormack, M.R. Pitts, S.M. Roberts., S.K. Singh, T.J.
Snape, J. Whittal
*Improvements in Pharmaceutically Useful Compounds,
Patent No. WO 2004013077 (A2), Charterhouse
Therapeutics Ltd.; Roberts, S. M., Santoro, G. M., Happe, A.
M., Dauvergne, J., Jadhav, V

Synthesis of -SR derivatives of 4-Hydroxy Cyclopent-2-enone as “Pro-Drugs”
12 September
2021
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CONFIDENTIAL
1. Cyclopentenone compounds are known to undergo Michael addition reactions with
Glutathione (a Thiol peptide) in the cells an in-built Defence mechanism
2. To overcome this issue, synthesis of Thiol-Adducts of Cyclopentenone derivatives were
envisaged as “Pro-Drugs” which could convert into the Active compound by Reverse
Michael reaction (in vivo)
3. A focussed library of –SR adducts of Cyclopentenones were synthesized using Parallel
synthesis/purification techniques and were tested
4. Commercially available (S)-4-OTBDMS-Cyclopent-2-enone and 4-Aza-Cyclopentenones
(Synthesized in-house) were reacted with various Thiols in presence of TEA in Chloroform
to give corresponding Thiol Ether derivatives

12 September
2021
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CONFIDENTIAL
Lead compounds within the Pro-drug concept:
*Improvements in Pharmaceutical Compositions, Patent No. WO 03082813 (A2), Charterhouse Therapeutics Ltd.;
Roberts, S. M., Ross, N. C., Jadhav, V., Evans, P., Snape, T. J., Happe, A. M., Santoro, G. M

12 September
2021
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CONFIDENTIAL
Lead compounds within the Pro-drug concept:

Chemical Drug Development
Process Research & Development of NCEs: Early Stage Development
12 September
2021
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CONFIDENTIAL
 Project code: XYZ-111
 Structure:
 Tech Pack: Med Chem type (5-10 g Scale; 9 Synthetic steps + Pd
Scavenging)
 Key deliverables: 1) Delivery of 250 g target compound (>98% purity,
Single Maximum Impurity: <1% & Pd content: <10 ppm)
2) Optimization of Existing process
 No. of FTE’s: 5
 Duration: 6 months

Process Research & Development of NCEs: Optimization of Stage-1 reaction
12 September
2021
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CONFIDENTIAL
1. The feasibility studies were carried out with various bases and solvents
Reaction Conditions: SM (1.0
eq), Ethyl cyanoacetate (2.0 eq),
Sulfur (1.0 eq), Morpholine (1.0
eq), Solvent, Heat, 24 Hrs
S No Input
(g)
Base (1.0 eq) Solvent Temp
(oC)
Purity %
HPLC
Output (g) Yield
(%)
1 1 Morpholine Ethanol (2 V)
60 89 0.98 51.5
2 1 Morpholine DMF (2 V)
60 94 0.88 46
3 1 Morpholine Water (2 V)
90 89.7 1 52.6
90 92 0.95 50
90 88 0.67 35

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CONFIDENTIAL
Reaction Conditions: SM (1.0 eq), Ethyl cyanoacetate (2.0 eq), Sulfur (1.0 eq),
TEA (1.0 eq), Solvent, Heat, 24 Hrs
S. No Input
(g)
(oC)
Purity %
(HPLC)
Output (g) Yield
(%)
1 1 Et3N Ethanol (2 V)
60 91.5 1.0 52.6
2 1 Et3N DMF (2 V)
60 95 1.2 63
3 1 Et3N Water (2 V)
90 88 0.85 44
90 92 1.2 63
90 79 0.48 25

12 September
2021
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CONFIDENTIAL
Reaction Conditions: SM (1.0 eq), Ethyl cyanoacetate (2.0 eq), Sulfur (1.0 eq),
DABCO (1.0 eq), Solvent, Heat, 24 Hrs
1. DABCO/Water system showed good result
2. Process optimized to improve yield from ~40% to 74%; Gewald reaction
demonstrated on 1 Kg scale in Water (1 V) and DABCO (1 Eq.) as base
S. No Input
(g)
(oC)
Purity %
(HPLC)
Output (g) Yield
(%)
1 1.0 DABCO Water (2 V) 60 90.1 0.88 46
2 1.0 DABCO DMF (5 V) 60 90 0.52 27
3 1.0 DABCO Water (10V) 90 87.5 0.27 14
4 1.0 DABCO Water (1 V) 60 87 1.5 79
5 5.0 DABCO Water (2 V) 60 87.5 7.2 75
6 5.0 DABCO Water (3 V) 60 88 6.78 71
7 5.0 DABCO Water (1 V) 65 91.5 7.34 77
8 50.0 DABCO Water (1 V) 65 92 76 80
9 100.0 DABCO Water (1 V) 65 89.9 155 81
10 1000.0 DABCO Water (1 V) 65 92.7 1045 74

Process Research & Development of NCEs: Palladium Scavenging & Purification
12 September
2021
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CONFIDENTIAL
S. No Batch No Scale (Kg) Conditions HPLC purity
(%)
Out put
(Kg)
Yield w/w
(%)
Residual
Palladium
(ppm)
Before After
1 Batch-1 0.388
DMF (25v),
Thiourea (20%
w/w), 80°C, 24 h
95.58
SMI: 2.47
0.361 93 125.9 60
2 Batch-2 0.361
DMF (25v),
Thiourea (20%
w/w), 80°C, 24 h
96.61
SMI: 1.73
0.335 93 60 30.42
3 Batch-3 0.335
DMF (4v), Thiourea
(20% w/w), 50°C,
Slurring, 18 h
96.89
SMI: 1.70
0.294 87.7 30.42 15.5
4
Batch-4
0.294
DMF (2v), Thiourea
(10% w/w), 50°C,
Slurring, 18 h
97.5
SMI: 1.39
0.285 97 15.5 8.8
5 Batch-5 0.285
DMF (3v), 50°C,
Slurring, 18 h
97.99
SMI: 1.15
0.274 96 -- --
6
Batch-6
0.274
12% DMF in EA
(8.0 V), slurring,
75oC, 1 h
98.00
SMI: 0.71
0.257 94 -- --
1. 2 Back-to-Back Suzuki reactions lead to High content of Residual Pd in the Final
Stage of the Process

API and Intermediate Development
Process Research & Development, Contract Manufacturing
12 September
2021
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CONFIDENTIAL
 Project code: API-210
 Name: Ropinirole
 Therapeutic Area: Parkinson's disease (PD) and Restless
Legs Syndrome (RLS)
 Approvals: 1997 in USA, Generic Medication
 Structure:
 Tech Pack : Scale up Tech Pack (Synthetic steps: 3)
 Key deliverables: Lab Familiarization & Process Improvements,
Consistency Batches, Tech transfer, Validation
batches, Contract manufacturing; Analytical
Development
 No. of FTE’s: 5 (3 CR&D + 2 AR&D)

12 September
2021
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CONFIDENTIAL

12 September
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CONFIDENTIAL
 Name: Valganciclovir
 Therapeutic Area: Anti-Viral to treat CytoMegaloVirus (CMV), HIV/AIDS
 Approvals: 2001 in USA, Generic Medication in 2017
 Structure:
Consistency Batches, Tech transfer, Validation
batches, Contract manufacturing; Analytical
Development

12 September
2021
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CONFIDENTIAL

Process Research & Development, Analytical development
12 September
2021
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CONFIDENTIAL
 Name: Saxagliptin
 Therapeutic Area: Anti-diabetic drug
 Approvals: 2016 in USA
 Structure:
 Tech Pack : Base Patent, MedChem Tech Pack (Synthetic steps: 5)
 Key deliverables: Process Development, Consistency Batches, Tech
transfer, Validation batches, Contract manufacturing;
Analytical Development

Process Research & Development, Analytical Development
12 September
2021
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CONFIDENTIAL

Process Research & Development, KSM Development & Manufacturing
12 September
2021
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CONFIDENTIAL
 Name: Febuxostat
 Therapeutic Area: To treat Gout due to High Uric acid levels
 Approvals: 2008 in EU, 2009 in USA; Generic Medication in 2019
 Structure:
Consistency Batches, New Route Scouting, Key
Intermediate Development and Supply; Analytical
Development
*An Industrial Process for The Preparation of 5-Bromo-2-Fluorobenzonitrile, Patent No. 747/DEL/2014, Ind-Swift Labs Ltd.;
Rajesh V. Naik, Vasudev Jadhav, Mahendar Velisoju

Process Research & Development, KSM Development & Manufacturing
12 September
2021
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CONFIDENTIAL
F
CN
F
CN
Br
H2SO4/ DMW
NBS
C7H3BrFN
Mol. Wt.: 200.01
C7H4FN
Mol. Wt.: 121.11
*An Industrial Process for The Preparation of 5-Bromo-2-Fluorobenzonitrile, Patent No.
747/DEL/2014, Ind-Swift Labs Ltd.; Rajesh V. Naik, Vasudev Jadhav, Mahendar Velisoju

Process Research & Development, Cost Reduction
12 September
2021
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CONFIDENTIAL
 Name: Cinacalcet
 Therapeutic Area: To treat Secondary Hyperparathyroidism, Parathyroid
Carcinoma, and Primary Hyperparathyroidism
 Approvals: 2004 in EU, 2004 in USA
 Structure:
 Key deliverables: Cost-reduction, Process Development,
Consistency Batches, New Reagent Scouting, Key
Intermediates Development and Supply; Analytical
Development
*An Industrial Process for The Preparation of Phenyl Propanol Derivative, Patent No. 3834/DEL/2013, Ind-Swift Labs Ltd.;
Rajesh V. Naik, Vasudev Jadhav, Sandeep Vyas, Sandeep Kumar

Process Research & Development, Cost Reduction
12 September
2021
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CONFIDENTIAL
H2N
H CH3 S
O2N
O
O
Cl
Na2CO3, H2O. DCM
+
HN
H CH3
S
NO2
O
O
M. F: C18H16N2O4S
M. Wt: 356.40
N
Cl
M. F: C12H13N
M. Wt: 171.24
M. F: C6H4ClNO4S
M. Wt: 221.62
N
H
H CH3
CF3
OH
CF3
O
Pd/C (10%)
H2, toluene
OH
CF3
O BH3-DMS
toluene, MeOH
OH
CF3
p-TsCl
TEA, DMAP
DCM
O
CF3
S
O
O
M. F: C10H7F3O2
M. Wt: 216.16
TCA03
M. F: C10H9F3O2
M. Wt: 218.17
TPM01
M. F: C10H11F3O
M. Wt: 204.19
TPM02
M. F: C17H17F3O3S
M. Wt: 358.38
TPT01
RNEA
RNN01
O
CF3
S
O
O
HN
H CH3
S
NO2
O
O
K2CO3, TEBA. toluene
KMno4
N
H CH3
CF3
S
NO2
O
O
M. F: C28H25F3N2O4S
M. Wt: 542.57
CNN01
HCl
Cinacalcet Hydrochloride
1) Thiophenol, K2CO3
TEBA, DMSO
2) IPE, HCl
TPT01
RNN01
*An Industrial Process for The Preparation of Phenyl Propanol Derivative, Patent No.
3834/DEL/2013, Ind-Swift Labs Ltd.; Rajesh V. Naik, Vasudev Jadhav, Sandeep Vyas,
Sandeep Kumar

New Route Scouting, Process Research & Development, Cost Reduction
12 September
2021
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CONFIDENTIAL
 Name: Roxadustat
 Therapeutic Area: To treat Anaemia caused by Chronic Kidney
Disease (CKD)
 Approvals: 2018 in China, 2019 in Japan
 Structure:
 Tech Pack : Chinese Patent (Synthetic steps: 7-8)
 Key deliverables: New Route/Reagent Scouting, Key Intermediates
Development, Process Development, Cost Reduction,
Consistency Batches,; Analytical Development

12 September
2021
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CONFIDENTIAL

Skills and Competences
12 September
2021
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CONFIDENTIAL
Goal oriented
Critical thinking
Strategy
Leadership
Technical expertise
Business acumen
Customer Relationship Management
Time Management
Project Management
People Management
Verbal and written communication
Score 1 2 3 4 5
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Vasudev Jadhav - Research Summary - 2021

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Vasudev Jadhav - Research Summary - 2021