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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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