sak sep 2011
TRANSCRIPT
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Overview of Research WorkBy
Sandeep A. KotharkarPh.D.
Research Scientist
Emcure Pharmaceuticals Ltd.
Hinjawadi, Pune. (M.S.)
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INDEX
Introduction
Company research work
Ph. D. research work
Publications
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Experience
Total Experience ~ 5 years
1 Emcure Pharmaceutical. Ltd., Pune
Process development group as a Research Scientistfrom June 2007 to till date.
( ~ 4.3 years )
2. Biostadt Ltd Aurangabad India. :In R & D , Research Associate for the
tenure of six month
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Nature of Research work
Research and Development Department: -
Designing novel patentable synthetic route for
Active Pharmaceutical Ingredients (APIs). Synthesis of APIs with improved yield, purity and
lower cost.
Characterization of intermediates and compoundswith analytical tools like 1H NMR, 13CMR, Mass,
IR, HPLC etc.
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Melphalan HCl4-[bis(2-chloroethyl)amino]-L-
phenylalanine
OH
O
N
Cl
Cl NH2
HCl
Melphalan is the active L-isomer of the compound and was first synthesized in
1953 by Bergel and Stock; D-isomer, known as medphalan, is less active
against certain animal tumors
The racemic (DL-) form is known as merphalan or sarcolysin
Melphalan hydrochloride is well known as anti-cancer drugs.
Only few companies are manufacturing this drug on bulk scale
Patent :
1. An efficient process for preparation of Phenyl alanine mustard hydrochloride.
File No. :- 3062/MUN/2010 Date : 04/11/2010
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Synthetic route for Melphalan HCl
OH
O
NH2
OH
O
NH2
O2N
O
O
NH2
O2N
CH3OH/SOCl2
O
O
NHBOCO2N
RANEY Ni
CH3OH
O
O
NHBOCNH2
O
O
NHBOCN
OH
OH
O
CH3COOH
POCl3
CH3CN
O
O
NH2
N
Cl
Cl
OH
O
N
Cl
Cl NH2Conc. HCl
OH
O
N
Cl
Cl NH2
Nitration
HCl
Boc-anhydrideTEA/THF
HCl
MELPHALAN.HCl
MELPHALAN
HCl
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Escitalopram oxalateEscitalopram oxalate is designated S-(+)-
1[3-(dimethyl-amino)propyl]-1-(p-
fluorophenyl)-5-phthalancarbonitrile oxalate
Escitalopram is the pure S-enantiomer (single isomer) of
the racemic bicyclic phthalane derivative citalopram. Escitalopram oxalate is designated S-(+)-1[3-(dimethyl-
amino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile
oxalate
Escitalopram oxalate is mainly used as a antidepressant
drug.
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ON
NC
F
COOH
COOH
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Synthetic route for Escitalopram oxalate
NC
OH
OH
N
F
NC
OH
OH
N
F
DPTTA/IPA
DPTTA
NC
OH
OH
N
F
NH3 / Toluene
tosyl chloride / tolueneO
NNC
F
COOH
COOH2H2O O
NNC
F
COOH
COOH
Escitalopram oxalateEscitalopram
Acetone
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Promethazine hydrochlorideUsage : Antihistaminic, CNS depressant
S
NH
Cl
N
S
N
N
+
HCl
HCl
KOtBu/Toluene
IPA-HCl
Phenothiazine 2-chloro-N,N-dimethylpropylamine hydrochloride
Promethazine hydrochloride
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Customer demand molecules.
OHNH
O
N
NH
O
N
O
F
Quinoline derivative
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OHNH
O
N
NH
O
N
O
F
Part A Part B
Retro-synthesis
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Synthesis of part A
OH
MeO COOMe
OTf
MeO COOMe
BOH OH
COOMeMeO
MeO COOHCOOMeMeO
a b
c
Reagents and Chemicals: a) Triflic anhydride, TEA, Toluene; b) Pd(PPh3)4,sodium carbonate, water; c) Methanolic NaOH, Toluene
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Synthesis of part B
Reagents and Chemicals: a) CDMT, NMM, EtOAc,85oC
N
COOK
NH2
ClH H2N
N
O
F
NNH2
N
O
F
NH
O
+
a
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Coupling of A and B and de-
methylation to get final product
NNH2
N
O
F
NH
O
MeO COOH
MeONH
O
N
N
O
FO
OHNH
O
N
N
O
FO
+
a
b
Reagents and Chemicals: a) TBTU, DIPEA, Toluene; b) AlCl3, 1-
decane thiol, DCM14
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CRO
N
N NH
Cl
OH
N
OK+
O
N H2
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O O
O
OH OH
10 % Pd
CH3COOH
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OEt
OEtO
ONC
COOEtEtO
OEt CN
NH2
NH2
S
NaOt , EtOH
N
N
OH
NH2
SH
OEt
OEtN
N
OH
NH2
OEt
OEt
NH
N
N
OH
NH
N
N
Cl
+
Raney NiNH4OH
HCl
POCl3
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N
OH
O
N
O
OBz
N
O
OBz
O
NH4Cl / TEA
N
O
OBz
NH2 N
O
OK
NH2
CDI
Benzyl alcohol
TsClKOH
UHP
Phthalic anhydridie
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APIs
NS
N
N
NH2
OH
HCl
Thiamine HCl
S
N
N
Promethazine HCl
HCl
N
Benzphetamine HCl
HCl
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Research Work
A Search for Pharmacologically Active NitrogenHeterocycles
Research Guide
Dr. Devanand B. shinde
Prof. and Head, University Department
of Chemical Technology,
Aurangabad - 431210.
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Nit t i i h t li
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Nitrogen containing heterocyclic
compound
N
N
N
N
N
N
X
H
H
N
Quinoxaline Pyrazine
Dihydropyrimidine Pyridine
Nitrogen containing heterocycles widely occur in thenature as the constituents of plant and animal cells in theform of alkaloids, vitamins, pigments etc. and known toposses significant pharmacological activity.
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QUINOXALINE
N
N Anticancer
Antimicrobial
Antidepressant
Anti-inflammatory
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S th i f b tit t d
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Synthesis of substitutedquinoxalines
NH2
NH2
N
N
O
OH+
R
(1) (2)
(3)
R
EtOH
R2
R1
R2
R1
HgI2
REPORTED WORK Manganese dioxide
Usually 10 equivalent
Longer reaction time(2-4 hrs)
Yields are poor (35 to 65 %)
PRESENT WORK
Mercuric iodide
2 equivalent
Lower reaction time (45-65min.)
Higher yield (60- 85 %)23
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Synthetic route for Quinoxalines
Two different methods are developed usingdifferent catalysts to improve the yields inshorter reaction time
(1) Lead Oxide (PbO) Mediated Synthesis of Quinoxaline
Sandeep A. Kotharkar and Devanand B. Shinde
Journal of the Iranian Chemical Society, 2006, 3, 267.
(2) Mercuric Iodide (HgI2) as an Oxidizing Agent for theSynthesis Quinoxaline
Sandeep A. Kotharkar and Devanand B. Shinde
Bull. Korean Chem. Soc. 2006, 27, (9),1465.
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Synthesis of antimicrobial active
novel compounds containingquinoxalines
Literature survey reveals the quanoxalinemoiety containing compounds posses
antimicrobial activity.
Novel Chemical Entities (NCEs)containing quanoxaline were synthesized
Evaluated the antimicrobial activity.
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Synthesis of antimicrobial 2,9,10-trisubstituted-6-
oxo-7,12-dihydro-chromeno[3,4-b]quinoxalines
Bioorganic and Medicinal Chemistry Letters, 2006, 16, 6181.Sandeep A. Kotharkar and Devanand B. Shinde
O
NH
NH
O
R1
R1
R
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Synthetic Route
O
OHR
C2H
5O OC
2H
5
O
O O
OH
R
O O
OH
R Br2
O O
OH
R Br
CHCl3
O
NH
NH
O
R1
R1
R
NH2
NH2
R1
R1
Coumarins
Na, 4 hr
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Synthesis of (3-phenyl substituted -quinoxalin-2-yl)acetic acid ester
N
NR1
R1
O
OMe
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Synthetic Routes
OH
O
O
O
O
OM e
AlCl3
O OO
Br2
O
O
Br
OMe
CHCl3
R1
R1
NH2
NH2
N
NR1
R1
O
OMe
MeOH
SOCl2
Piperidine, EtOH
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Synthesis of 6-Chloro-7-(2,3-dichloro-
phenoxy)-2,3-disubstituted-quinoxaline
(CNQX), (DNQX)
O
Cl
Cl
Cl
N
N R
R
O
Cl
Cl
Cl
NH
NH
O
O
OR
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Synthetic Route (A)
O
Cl NH2
NH2
Cl
Cl
+R
R
O
O
EtOH
O
Cl
Cl
Cl
N
N R
R
(3)
(1) (2)
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Synthetic Route (B)
O
Cl NH2
NH2
Cl
Cl Cl
Cl
O
O
O
Cl
Cl
Cl
NH
NH
O
O
+
EtOH
(3)
(1) (2)
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Dihydropyrimidines
derivatives as a antimicrobial
compounds
Biginelli Reaction Antihypertensive
Calcium channel blockers
Antibacterial Antitumour
Anti-inflammatory
N
N
X
O
H
HO
R
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Synthetic RouteREPORTED WORK
Acid Lewis acid
Stoichiometric amount ofcatalyst
Long reaction time (1 hr to 6
hr) Unsatisfactory yield (60 %)
Difficult product isolationprocedure
Only aromatic aldehyde
PRESENT WORK Lower reaction time(40 to 75
minute)
Higher yield (88%-94%)
Alphatic and aromatic
aldehyde showing excellentyield
R H
O
+
OR'
OO
+
NH2
NH2
X
Catalyst
NH
NH
RO
R'O
X
EtOH
X = O
X = S
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Synthetic route for DHPMs
Three new catalysts were used for the synthesis ofDHPMs to improve the yields in shorter reaction time
- Sulphamic acidLetters in Organic Chemistry, 2005, 2, 398 - 403
- Chlorosulfonic acidUkranica Bioorganica Acta, 2006, 2, 17-21
- Zirconium oxychloride
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Pyrazines
Antifungal
Antibacteriral
Antiviral
N
NR
N
NR
Dihydrpyrazine
Pyrazine
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Synthetic route for Pyrazines
REPORTED WORK
Manganese dioxide
Usually 10equivalent
Aromatizations
Longer reaction time
(20 hr.) Yields are very poor
(33%)
RO
OH+ NH
2
NH2
N
NR
N
NR
KOH
MnO2
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P W k
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Present Work
Chinese Journal of Chemistry, 2007,25, (1), 105-107.
Sandeep A. Kotharkar and Devanand B. Shinde
OH
O
R2
R1
+ NH2
NH2
N
NR1
R2
Pb(NO3)2 70
oC
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Synthesis of (3-phenyl substituted- 5,6- dihydro-
pyrazin-2-yl) acetic acid ester
CHCl3
EtOH / piperidine
NH2
NH2
O
O
OR
R1
R2
O
O
OR
Br
R1
R2
N
N
O
OR
R1
R2
Br2
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Synthesis of fused pyrazine derivatives
O
OH
O
R
CHCl3
NH2
NH2
O
OH
O
R
Br
R1
R2
N
NO
O
R
R1
R2
Br2
R1
R2
Ethanol
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Dihydropyridine
containing compounds
Microwave assisted Synthesis of 1,4-Dihydropyridines.Sandeep A. Kotharkar and Devanand B. Shinde
Ukranica Bioorganica Acta, 2006, 1, 3.
Commonly Hantzsch synthesis
method used
Biological activity
Developed new methodology
using microwave assisted
reaction for facile synthesis of
DHP
O O
OR' R H
O
NH3
NH
RO O
OR'R'O
+
EtOH
DHPs
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Pb(NO3)2 : A Versatile Oxidizing Agent for Aromatization
of Hantzsch 1,4-Dihydropyridines
NH
RO O
OR'R'O
N
RO O
OR'R'OAcetic acid
Lead nitrate
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Synthesis of some new coumarin condensed 1,4-
dihydropyridine derivative
O O
OH
RR1
O
OO
O R1
NH2
O
OH
P2O5
OO
O R1O
NH
R
R
RR
CH3COONH4
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Coumarin containing compounds
OH
R
OO
OEt
O O
R
+
Coumarins
PREVIOUS WORK
Lewis acids
Excess of catalyst
Longer reaction time
Yields are poor
PRESENT WORK
Zirconyl oxy chloride,
chlorosulphonic acid
2 equivalent
Lower reaction time
Higher yield44
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Pechmann condensations
Two different methods are developed using differentcatalysts to improve the yields in shorter reaction time
(1) Chlorosulfonic acid
Sandeep A. Kotharkar, Sushilkumar S. Bahekar andDevanand B. Shinde
Mendeleev Commun, 2006, 4, 241-242.
(2) Zirconyl(IV)ChlorideSandeep A. Kotharkar and Devanand B. ShindeOrganic Chemistry : An Indian Journal 2006, 9,17.
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Synthesis of various chalcone using water as
solvent
O
x1
X
O
x1
X
R
+ R-CHO30% NaOH,
Water
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Claisen-Schmidt condensation reaction in
aqueous media
O O
OH O
R
+ R1CHO
O O
OH O
R
R1
30 % aq. NaOH
O O
OH O
R
R1
30 % aq. NaOH
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ACTIVITY
Bacteria :(Streptomycin)
1. Staphyllococus aureus
2. Bacillus subtilis 3. E coli
4. Pseudomonas aeruginosa
Fungi : (Nystatin)
1. Aspergillus flavus
2. Fusarium oxysporum
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The chronology of susceptibility of variousmicrobes to different synthesized derivatives
in decreasing order was as follows 2,9,10-trisubstituted-6-oxo-7,12-dihydro-
chromeno[3,4-b]quinoxalines
Substituted fused pyrazine derivatives
6-Chloro-7-(2,3-dichloro-phenoxy)-2,3-
disubstituted-quinoxaline
(3-phenyl substituted -quinoxalin-2-yl)acetic
acid ester (3-phenyl substituted- 5,6- dihydro-pyrazin-2-yl)
acetic acid ester
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Thank you
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N
OH
O
N
O
OBz
N
O
OBz
O
NH4Cl / TEA
N
O
OBz
NH2 N
O
OK
NH2
CDI
Benzyl alcohol
TsClKOH
UHP
Phthalic anhydridie
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TBTU - O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate
CDMT - 2-Chloro-4,6-dimethoxy-1,3,5-triazine
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CRO
N
N NH
Cl
OH
N
OK+
O
N H2
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O O
O
OH OH
10 % Pd
CH3COOH
AlCl3/180oC
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OEt
OEtO
O
NCCOOEtEtO
OEt CN
NH2
NH2
S
NaOt , EtOH
N
N
OH
NH2
SH
OEt
OEt
N
N
OH
NH2
OEt
OEt
NH
N
N
OH
NH
N
N
Cl
+
Raney Ni
NH4OHHCl
POCl3
NaH
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APIs
NS
N
N
NH2
OH
H
Cl
Thiamine HCl
S
N
N
Promethazine HCl
HCl
N
Benzphetamine HCl
HCl
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While referring, literature survey revels thatheterocyclic compounds are the backbones ofpharmacologically active organic nuclei. But thereremains a considerable gap in the range of drugsavailable to treat the diseases of the immunologicalsystem and their disorders to various body systems.
Today, a number of scientists have tried to find outsome relation between chemical structure andphysiological or biological properties. It is now well-established fact that the activity of a compounddepends upon the heterocyclic moiety, nature of
substituents and their position Nitrogen containing heterocycles widely occur in the
nature as the constituents of plant and animal cells inthe form of alkaloids, vitamins, pigments etc. andknown to posses significant pharmacological activity.
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Present Work The present work entitled as A Search
for Pharmacologically active NitrogenHeterocycles The work is focused on
i) Synthesis of biological activeheterocycles like Quinoxaline,Pyrimidine and Pyrazine compounds.
ii)Modification of the synthetic
sequence of the compounds to achieve abetter yield.
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