CHAPTER-4 AN EFFICIENT AND LARGE SACLE SYNTHESIS OF...

134 Chapter-4

CHAPTER-4

AN EFFICIENT AND LARGE SACLE SYNTHESIS

OF CLOPIDOGREL - AN ANTI PLATELET DRUG

135 Chapter-4

4.1 INTRODUCTION

Platelets are the one of the key component in blood, produced by

megakaryocyte (bone marrow cell) and these are small cell fragments

having average life time of about 5-9 days. Platelets provide proteins and

hormones that are essential for blood to coagulate. The average number

of platelets present in healthy human blood is about 0.15-0.45 millions

per millimeter of blood. Blood coagulation is an important phenomenon

that helps to prevent excessive blood loss when blood vessels are

injured. Platelets and proteins in plasma can help to prevent the blood

loss by forming a blood clot on the injured blood vessels. The blood clots

are dissolved naturally after the injury has cured. Sometimes, the blood

clots form on the inside of blood vessels without an injury and these

clots will not dissolve naturally. Blood clots can occur in both the veins

& arteries blood vessels. The blockage can develop larger and further

limit the blood flow. Blood coagulation in the coronary arteries leads to

heart attack and blockage in a cerebral artery may cause a stroke.

Though there are several antiplatelet drugs available in market,

the widely used drug for management of blood clots in coronary artery

disease, peripheral vascular disease, and cerebrovascular disease is

clopidogrel bisulfate1. Recent studies have shown that clopidogrel is

more effective in blocking platelet aggregation than aspirin and

ticlopidine even at much lower dosage2. This is ranked as one of the top

selling drugs (ranked as second top selling for few years) in the globe3.

136 Chapter-4

Clopidogrel bisulfate was developed by French pharmaceutical company,

Sanofi-aventis and marketed by Sanofi-aventis and Bristol Mayers Squib

(BMS). US FDA approved clopidogrel bisulfate in year 1997 in the form

of oral tablets having dosage of 75 mg and 300 mg and it is marketing

under the brand name of Plavix®4. Thereafter, clopidogrel bisulfate was

approved in more than 110 countries. The worldwide sales of clopidogrel

bisulfate is about USD 10,535 millions (~58,000 crores) with the

consumption of 517, 267 Kg.

The above discussed particulars of the clopidogrel bisulfate 3, an

antiplatelet agent motivated us to develop cost effective, efficient and

large scale synthesis of clopidogrel bisulfate.

4.1.1 PRODUCT PROFILE

1. Generic name : Clopidogrel bisulfate

2. Chemical structure :

S

N

COOCH3

Cl

. H2SO4

3. Chemical names:

Methyl (+)-(S)-α-(2-chlorophenyl)-

6,7-dihydrothieno[3,2-c]pyridine-

5(4H)acetate sulfate (1:1)

4. Molecular formula : C16H16ClNO2S.H2SO4

5. Molecular weight : 419.9

137 Chapter-4

6. CAS No : 120202-66-6

7. Therapeutic category : Anti platelet agent

8. Indication : For the reduction of atherosclerotic

events.

4.1.2 PHYSICAL CHARACTERISTICS

1. Description of API : white to off-white powder

2. Melting point : 147-149°C

3. Solubility of API : Methanol (FDA Label)

4.1.3 MARKET INFORMATION

1. Applicant : Sanofi Aventis US

2. Patentee : Sanofi Aventis US

3. Brand name : PLAVIX®

4. USFDA Approval date : November 17, 1995

4.2 LITERATURE REVIEW

The following synthetic path ways for the preparation of

clopidogrel bisulfate 3 was encountered during the literature survey.

Daniel Aubert et al5 have reported process for the preparation of racemic

clopidogrel bisulfate (±) 3, where reaction of hydrochloride salt of

tetrahydrothienopyridine compound 43 with chloro ester compound 97

in presence of K2CO3 and DMF afforded racemic clopidogrel, which upon

treated with H2SO4 in acetone to obtain racemic compound 3. Alain

Badore et al6 reported process for the preparation of compound 3 from

its racemic compound (±) 3. This involves the resolution of racemic

138 Chapter-4

compound (±) 3 using L-camphorsulfonic acid (CSA) as resolution agent

in acetone. The resulted CSA salt of clopidogrel 47 was recrystallized

from acetone to get the pure compound 47, which was converted into its

free base by treating compound 47 with sodium bicarbonate in mixture

of DCM and water, followed by reacted with H2SO4 in acetone to afford

compound 3. The key starting material thienopyridine 43 was prepared

by reacting thiophene-2-ethyl amine 98 with formaldehyde followed by

cyclization in acidic medium (Scheme 4.1).

S

NH.HCl

ClS

N

CO2CH3

Cl

DCM

Acetone, water

Acetone

IPA

. CSA

2. L-(-) CSA

Acetone

.H2SO4

1. K2CO3, DMF

1. Na2CO3

+

S

N

CO2CH3

Cl S

N

CO2CH3

Cl S

N

CO2CH3

Cl

.H2SO4. CSA 2. H2SO4

1. NaHCO3, DCM90 °C, 4 h

2. H2SO4

Cl

CO2CH3

30-35°C, 16-18 h

55 %

88 %

50 %

4397 (±) 3

47 47 3

54 %

S

HCHONH2

S

NH2C

DMF HCl

S

NH.HCl

4398

Scheme 4.1: Synthesis of Clopidogrel 3

Thereafter, similar processes were reported by following the

synthetic procedure as depicted in scheme 4.1 using bromo ester

compound 99 instead of chloro ester 97. Scientists from Enzytech Ltd

were reported7 process for the preparation of enantiomerically pure

bromo ester 99, as key starting material for the preparation of 3.

139 Chapter-4

Racemic compound 99 was subjected to enzymatic resolution using

hydrolases or hydrolase producing micro organisms to get the

enantiomerically pure isomer of bromo ester compound 99. Reaction of

optically pure compound 99 with tetrahydro thienopyridine compound

43 in presence of base afforded clopidogrel free base, which was

converted into bisulfate salt by treating with H2SO4. The major

modification of this process over the reported procedures is resolution of

key starting material 99 rather than the resolution of racemic

clopidogrel (±) 3 (Scheme 4.2).

NH.HCl

S

Cl

OCH3

O

Br

1)Base

2)H2SO4

Cl

OCH3

O

Br

Enzyme

(±) 99 99

S

N

CO2CH3

Cl

.H2SO4

3

43


Bobrova et al reported8 a different approach for synthesis of

clopidogrel 3, where reaction of o-chloro phenyl acetic acid 100 with

thionyl chloride to give acid chloride, which was chlorinated using

SO2Cl2 to afford dichloro compound 101. Reaction of 101 with

isopropanol amine derivative 102 in presence of NaHCO3 and THF

provided diastereomeric mixture of amine ester compounds 103(A) and

103(B), which upon condensation with tetrahydro thienopyridine

compound 43 in presence of LiHCO3 and DMF afforded mixture of

clopidogrel amine esters 104(A) and 104(B). The obtained amine esters

140 Chapter-4

were converted into clopidogrel 3 by transesterification of mixture of

104(A) and 104(B) with methanol in presence of zinc chloride (Scheme

4.3).

Cl

COOH

N

S

OCH3O

Cl

NH.HCl

S

1)SOCl2

ClO

Cl

M. Wt: 223

Cl

2)SO2Cl2

N

OH

ClO

ON

H

H

ClO

ON

H

HCl Cl

100

101

THF

LiHCO3, DMF

N

S

OO

Cl

N

N

S

OO

Cl

N

103(A)103(B)

104(A) 104(B) 3

43 ZnCl2, Methanol

102


Shohei Yamamoto et al reported9 similar process for the

preparation of clopidogrel 3 by using 2(R)-1-oxo-1-pyrrolidinylpropane-

2-ol 105 as chiral auxiliary instead of isopropanol amine derivative 102

(Scheme 4.4).

COOH

NH.HCl

S

O

Cl

ON

OCl

Cl

O

N

ON

OCl

S

100

HO

N

O

1)SOCl2

2)SO2Cl2 ClO

Cl

Cl

N

S

OCH3O

Cl

3

105

101 106

107

TEA, THF, NaI

AlCl3

MeOH

43


141 Chapter-4

Lixin Wang et al10 described an alternative synthetic approach for

the preparation of clopidogrel 3 from 2-chlorobenzyl cyanide 108.

Bromination of 108 using bromine at elevated temperature afforded α-

bromo cyanide compound 109, which was condensed with tetrahydro

thieno pyridine compound 43 in presence of NaHCO3 to obtain cyano

compound 45. The obtained cyano compound 45 was converted into

racemic clopidogrel (±) 3 via amide intermediate 46. The requisite isomer

of clopidogrel was separated from the racemic compound using L-

camphorsulfonic acid as resolution agent, thus obtained CSA salt of 3

was treated with NaHCO3 followed by H2SO4 to afford clopidogrel 3

(Scheme 4.5).

S

N

CN

Cl

S

NH.HCl

S

N

CONH2

Cl S

N

CO2CH3

Cl

Methanol, water

TEBA, NaOH

Acetone

Toluene. CSA

L-(-) CSA

1. NaHCO3

S

N

CO2CH3

Cl

S

N

CO2CH3

Cl

.H2SO42. H2SO4

CN

Cl

Br2

100-110° C

CN

Cl

Br

NaHCO3, MeOH

Methanol, water

DMS, MeOH

108 10945

43

46 (±) 3 47

3


Scientists from Sanfi11 developed an alternative synthetic

approach for the preparation of 3 from 2-chloro phenyl glycine 110.

Esterfication of 110 using methanol in presence of thionyl chloride

followed by resulted HCl salt of ester 111 was treated with NaHCO3 to

142 Chapter-4

obtain racemic glycine ester 111. Thus obtained racemic glycine ester

111 was subjected to resolution using L-(+) tartaric acid as resolving

agent in presence of mixture of methanol, MIBK and acetonitrile.

Desaltification of desired glycine ester tartaric acid salt 41 using

NaHCO3 followed by reaction with thiophene 2-ethanol tosylate 40 in

presence of K2HPO4 and methyl acetate resulted compound 42 in the

form of free base, which upon treated with HCl to afford compound 42.

Reaction of 42 with aqueous formaldehyde followed by electrophylic

cyclization in acidic medium to give clopidogrel freebase, thus obtained

free base was treated with H2SO4 in acetone to afford clopidogrel

bisulfate 3 (Scheme 4.6).

+Diethyl ether

CO2H

NH2

Cl

CO2CH3

NH2

Cl

CO2CH3

NH2

Cl

L (+) -Tartaric acid

MeOH, MIBK

Acetonitrile

60 oC, 24 h

DCM. HCl N

Cl

CO2CH3

. H2SO4S

HN

Cl

CO2CH3

S

OTs

S

OH

S

1. Aq. HCHO

DMF HCl

2. H2SO4

Acetone

OH

OH O

OH

O

HO30 oC, 48 h

Isopropyl ether

SOCl2, MeOH

NaHCO3

1,2-dichloro ethane

CO2CH3

NH2

Cl

NaHCO3

SO2Cl

CH3

OTs

S

K2HPO4

Methyl acetate

Ethyl acetate

HCl

PTC

110 111 112

41

38 40

423

40


Bipin Pandey et al12 reported a new process for the preparation of

clopidogrel 3, where reaction of tetrahydro thieno pyridine compound 43

143 Chapter-4

with 2-chloro benzaldehyde 44 using sodium cyanide and sodium

bisulfite in water medium, employing Strecker synthesis conditions

resulted cyano compound 45. The resulted cyano compound 45 was

converted into amide intermediate 46 by treating 45 with potassium

hydroxide in presence of t-Butanol. Amide compound 46 was subjected

to resolution rather than the conversion of racemic clopidogrel.

Resolution of racemic amide compound using (S)-(+)-camphorsulfonic

acid as resolution agent to obtained camphorsulfonic acid salt of amide

compound 113, which was treated with NaHCO3 in ethyl acetate to

obtain enantimerically pure amide compound 114. Reaction of 114 with

dimethylsulfate in the presence of methanol and DMF to give clopidogrel

free base, thus obtained free base was treated with sulfuric acid to

obtain clopidogrel bisulfate 3 (Scheme 4.7).

S

N

CN

ClS

NH.HClOHC

Cl

S

N

CONH2

Cl

NaCN, NaHSO3

KOH, t-Butanol

Ethyl acetate

Cyclohexane

1. DMS, DMF

Methanol

Ethylacetate

+

45-50 °C, 6 h

92 %

48 %

water, Ethylacetate. CSA

(S)-(+)-CSA. H2O

S

N

CONH2

Cl36 %

S

N

CONH2

Cl

NaHCO3

Ethylacetate

.H2SO4S

N

COOCH3

Cl

H2SO4

Acetone

56 %S

N

COOCH3

Cl

43 44 45

46 113 114

3


144 Chapter-4

Stephen E.Horne et al13 reported process for the preparation of

clopidogrel 3 involves reaction of 2-bromoacetylthiophene 115 with

phenylglycine methyl ester 41 in presence of acid scavenger and DMF to

obtain 2-oxo-thiophene ethyl amine 116. Reduction of 116 using

sodiumborohydride afforded hydroxy compound 117, which was reacted

with formaldehyde in ethanol medium to obtain oxazoline compound

118. Rearrangement of oxazoline compound 118 in presence of HCl and

DMF followed by dehydroxylation using SnCl2 dihydrate in presence of

HCl furnished clopidogrel 3.

Cl

NH2

OCH3O

HN

S

OCH3O

Cl

Br

S

O O

HN

S

OCH3O

Cl

OH

NaBH4

N

OCH3O

S

O Cl

N

S

OCH3O

Cl

OH

N

S

OCH3O

Cl

.HCl

HCHO

HCl1)SnCl2/HCl

2)Base

N

S

OCH3O

Cl

TMSI

DMF

K2CO3

Methanol

Ethanol

DMF

41 115 116117

1181193

3


Robert P. Smyj et al14 reported an improved process for the

dehydroxylation step, which involves the usage of iodotrimethylsilane

145 Chapter-4

(TMSI) as reagent for dehydroxylation instead of HCl and SnCl2

dihydrtae (Scheme 4.8).

Hongping et al reported15 an alternative process for the

preparation of clopidogrel 3, where reaction of 2-chlorobenzaldehyde 44

and potassium cyanide in presence of methanol afforded cyanohydrin

compound 120. Asymmetric hydrolysis of cyanohydrin compound 120

utilizing an enzyme followed by esterification of optically active mandelic

acid 121 using methanol in presence of sulfuric acid to give mandelic

acid methyl ester 122. Reaction of 122 with benzenesulfonyl chloride in

presence of mixture of DMAP and TEA provided sulfonate compound

123, which was condensed with tetrahydrothieno pyridine 43 in

presence of base to obtain clopidogrel 3(Scheme 4.9).

N

S

OCH3O

Cl

NH.HCl

S

O

HCN

ClCl

OH

KCN

MeOH,

CH3COOH

Enzyme

Na2PO4

OH

Cl

COOH

OH

Cl

COOCH3

MeOH

H2S04

S

O

O

Cl

DMAP, TEA, DCM

OSO2Ph

Cl

COOCH3

K2CO3, DCM

43

44 120 121 122

123 3


Despite of the proven potential of the reported procedures for the

preparation of clopidogrel 3, there are certain drawbacks associated with

the reported processes. These processes involves the usage of (i) unsafe

and lachrymatory starting materials/intermediates such as α-haloester

146 Chapter-4

compounds 97 & 99, (ii) hazardous and carcinogenic reagents like

thionylchloride and bromine (iii) multiple solvent systems, (iv)

commercially less viable techniques such as column chromatography for

purification of crude compounds, and (v) expensive and partially

recoverable solvents such as methyl acetate, ethyl acetate,

tetrahydrofuran, acetonitrile. In addition to the above mentioned

disadvantages these processes involves the tedious workup processes,

longer reaction times. Racemisation was observed when optically active

compounds were used as starting materials or early intermediates.

4.3 PRESENT WORK

4.3.1 OBJECTIVE

Drawbacks associated with the reported processes motivated us to

develop efficient, cost effective, large scale processes for the preparation

of clopidogrel bisulfate 3. To study the complete impurity profile of

clopidogrel bisulfate including identification, root cause for their

formation, synthesis and characterization of all possible potential

impurities.

4.3.2 RESULTS AND DISCUSSION

Whilst there are many routes to Clopidogrel 3, we focused on two

which have potential for industrial manufacturing with some limitations

that can be addressed. We have designed two improved synthetic

approaches for the preparation of clopidogrel 3 and these two

approaches are advantageous over the reported processes.

147 Chapter-4

4.3.2.1 FIRST SYNTHETIC APPROACH FOR PREPARATION OF

CLOPIDOGREL BISULFATE 3

First synthetic approach involves the use of commercially available

and less expensive key starting materials like 2-chlorophenyl glycine and

thiophene-2-ethanol. Our new synthetic sequence commenced with

tosylation of thiophene-2-ethanol 38 using p-toluenesulfonyl chloride in

presence of triethylamine and toluene to give tosylate compound 40,

which upon in situ condensation with optically active 2-chlorophenyl

glycine methyl ester 41, followed by treatment with hydrochloric acid in

toluene to afford compound 42. Thereafter, the obtained compound 42

was treated with formalin followed by electrophilic cyclization in acidic

medium furnished clopidogrel free base, thus obtained free base was

treated with sulfuric acid in acetone medium to afforded clopidogrel

bisulfate 3 (Scheme 4.10).

+

3.0 vol. toluene

1.65 eq. TEA. HCl

N

Cl

CO2CH3

. H2SO4S

HN

Cl

CO2CH3

S

OTs

S

OH

S

SO2Cl

CH338 40 42

3

41

1.5 vol. toluene

3.0 eq. K2HPO4

100-110 oC, 18 h

HCl, 67%

1. HCHO

25-35 0 C, 22 h

DCM

2. Acetone

0.92 eq. H2SO4

H2N

Cl

CO2CH3

39

Scheme 4.10: Improved synthetic pathway for preparation of

Clopidogrel 3

148 Chapter-4

Based on the reaction mechanism and process chemistry knowledge, the

following three steps are identified as key steps for the synthesis of 3.

(i) Synthesis of enatiomerically pure o-chlorophenyl glycine methyl ester

41, key starting material for synthesis of 3.

(ii) Condensation of tosylate compound 40 and glycine methyl ester 41.

(iii) Synthesis of clopidogrel bisulfate 3 from compound 42.

4.3.2.1.1 SYNTHESIS OF (S)-METHYL 2-AMINO-2-(2-

CHLOROPHENYL) ACETATE 41

Synthesis of enantiomerically pure 2-chlorophenyl glycine methyl

ester 41 involves the esterification of 2-chlorophenyl glycine 119 using

methanol followed by resolution of the obtained racemic ester compound

111. Reported processes for the synthesis of ester 111 involve the usage

of carcinogenic and toxic reagent thionyl chloride in methanol medium.

Further, the resulted ester 111 was isolated as hydrochloride salt and

followed by treated with base for desaltification of hydrochloride salt. At

our end we have developed cost effective and simple process for the

preparation of ester compound 41 (with about 90% yield and more than

97% of purity) by reacting glycine 110 with methanol in presence of

sulfuric acid. Usage of carcinogenic reagent thionyl chloride (non-green

component) and isolation of hydrochloride salt 41 was avoided.

Patented processes 11 for the resolution of racemic ester compound

111 using L-(+)-tartaric acid involves the (i) use of binary solvent system

(acetonitrle and MIBK), (ii) elevated temperature (60 °C), (iii) longer

149 Chapter-4

duration for precipitation (24 hours) and (iv) purification in multiple

solvents (mixture of methanol and acetonitrile). To avoid the drawbacks

associated with the patented process and to develop robust resolution

process, key parameters like solvent, temperature and time was studied.

Various solvents (methanol, isopropyl alcohol, water, acetone,

acetonitrile, ethyl acetate, aqueous methanol and aqueous acetone) were

screened to check the impact of the solvent for the resolution of 111.

Experimental results indicated that methanol as solvent furnished

desired isomer with better yield and purity when compared with other

solvents. Temperature always play key role during the separation of

enantiomers from the racemic compound. In view of this, different

temperatures (-10 to -5 °C, 0-5 °C, 25-35 °C, 40-45 °C and 60-65 °C) are

studied to check the impact of the temperature. Experimental results

revealed that 0-5 °C is optimal temperature for resolution of 111.

Another major disadvantage of the patented process is longer duration

for precipitation of tartrate salt 112. By replacing the mixture of solvents

with methanol and reflux temperature with lower temperature (0-5 °C),

the precipitation time was significantly reduced to 2-3 hours from 24

hours. Thus obtained enantiomerically enriched isomer 112(a) was

further purified to reduce the contamination of undesired isomer. After

screening the various solvents and different temperatures, it was found

that slurry of crude compound 112a in methanol at ambient

150 Chapter-4

temperature afforded enantiomerically pure isomer (more than 99.5%)

112a.

We always think of implementing greener aspects in our

development thus our attempt to racemize undesired enantiomer 112b

facilitated us to develop an efficient process for the synthesis of 41. This

particular racemization by using thionyl chloride with laborious work up

process such as (i) conversion of tartrate salt 112b into its free base by

treating with NaHCO3, (ii) isolation of racemic compound as

hydrochloride salt and (ii) desaltification of hydrochloride salt of 111 is

reported by scientists from USV limited16. Strategically, we avoided the

use of thionyl chloride (non-green component) in our protocol of

racemization and developed simple racemiation process. We observed

complete racemisation by stirring the R- isomer enriched tartrate salt

112b in methanol at reflux temperature for about 14 hours. Thus

obtained tartratesalt of racemic glycine ester was treated with NaHCO3 to

afford 111.

25-35 0C, 14 h

90%

MeOH, 4 0C,

2 h, 80%

1.5 eq. H2SO4, MeOH

1.0 eq. L(+)-tartaricacid

H2N

Cl

CO2H

H2N

Cl

CO2Me

H2N

Cl

CO2Me

H2N

Cl

CO2Me

COOHHO

HO COOH

COOHHO

HO COOH

110 111

+

112a

112b

H2N

Cl

CO2Me

NaHCO3

H2N

Cl

CO2Me

COOHHO

HO COOH

NaHCO3

DCM

60 oC

15 hours

41Separated as solid

Remain in filterate

DCM

Racemisation

100%

Scheme 4.11: Improved synthetic approach for preparation of 41

151 Chapter-4

4.3.2.1.2 CONDENSATION OF TOSYLATE COMPOUND 40 AND

GLYCINE METHYL ESTER 41.

After developing an efficient process for the preparation of

enantiomerically pure isomer of glycine ester 41 (key intermediate for

synthesis of 3), our focus moved towards the condensation of tosylate

compound 40 and 41. Condensation of tosylate compound 40 and

optically active glycine ester 41 in presence of K2HPO4 using methyl

acetate, ethyl acetate and acetonitrile as solvent system is reported in

literature. Further, these reported processes having certain

disadvantages such as moderate yields, tedious workup processes,

racemisation during the reaction and multiple purifications for removal

of undesired isomer along with process related impurities. To avoid all

the drawbacks associated with the reported processes, key process

parameters such as solvent, dipotassium hydrogen phosphate mole

ratio, reaction temperature, HCl addition temperature during the

preparation of HCl salt and purification solvent were studied. At our end

we have developed an efficient and robust process for the preparation of

42 over the reported processes. Previously reported highly expensive and

partially recoverable solvents such as methyl acetate, t-butyl acetate,

acetonitrile and ethyl acetate solvents during the synthesis of 42 were

replaced with the non-hydrolytic, highly recoverable (more than 90%)

and less expensive solvent like toluene. Further, workup process was

simplified by opting toluene as solvent and tedious work up procedure

152 Chapter-4

(distillation & washings), multiple solvent system, formation of solvent

impurities (In aqueous HCl medium acids and alcohols of the

corresponding ester were observed) are avoided. In addition to this

toluene as solvent facilitated us to develop one pot process for the

preparation of 42 from the thiophene-2-ethanol 38 in a single solvent

system and isolation of tosylate intermediate 40 was avoided.

Time and temperature always plays a key role in chemical

reactions. In our protocol, we have observed that enrichment of

undesired isomer of 42 along with the maintenance time of the reaction.

By end of the reaction, undesired isomer of the compound 42 is reached

to 3.0-3.5% as described in Table 4.1.

Table 4.1: Impact of the time during the synthesis of 42.

Entry Maintenance Time (hours)

Undesired isomer of 42 (%)

Purity of 42 (%)

1 1 1.01 98.99

2 4 1.70 98.30

3 8 2.00 98.00

4 12 2.46 97.54

5 16 2.81 97.19

6 20 2.96 97.04

7 24 3.06 96.93

8 After workup 3.31 96.69

153 Chapter-4

To minimize the racemisation during the reaction various solvents

and different temperatures were studied but did not succeed.

Experimental results revealed that better results were obtained when

reaction was performed in toluene medium by maintaining the reaction

mass at 100-110 °C for 24±2 hours as compared with the other solvents

at different temperatures.

In crude compound 42, about 3-4% of undesired isomer was

observed. To check the impact of the undesired isomer in subsequent

stage, reactions were performed by using compound 42 having about

3.0%, 2.0%, 1.0% and 0.7% of undesired isomer. Experimental results

revealed that about 1.0% and 0.7% of undesired isomer having

compound 42 furnished desired compound 3 within the acceptable limit

of R-isomer (acceptable limit of R-isomer in final clopidogrel bisulfate 3

is less than 1.0%) where as 2.0% and 3.0% of undesired isomer having

compound 42 furnished compound 3 with more than 1.0% of R-isomer.

To reduce the R-isomer in clopidogrel bisulfate 3, various solvents and

purification techniques were screened but the results were not

impressive. In view of this, it was decided that to purify the crude

compound 42 rather than proceeded in to next stage. To develop robust

processes for the purification of crude compound 42, various solvents

such as dichloromethane, isopropyl alcohol, ethyl acetate, acetone,

mixture of dichloromethane: water (9:1), isopropyl alcohol: water (9:1),

ethylacetate:water (9:1), acetone:water (9:1) and acetone: aqueous HCl

154 Chapter-4

were screened. Mixture of acetone and aqueous HCl as solvent furnished

compound 42 with highest yield (90%) and purity (99.7%) when

compared to other solvents (Table 4.2).

Table 4.2: Solvents screening for the purification of 42.

Entry Name of the solvent Yield of 42 (%) Chiral purity of 42 (%)

1 Dichloromethane (DCM) 88 98.2

2 Isopropyl alcohol (IPA) 96 97.2

3 Ethyl acetate 95 97.1

4 Acetone 95 98.2

5 DCM:water (9:1) 87 98.7

6 IPA:water(9:1) 86 97.3

7 Ethyl acetate:water(9:1) 75 97.1

8 Acetone:water(9:1) 91 97.2

9 Acetone: 10% aq. HCl (9:1)

90 99.7

4.3.2.1.3 SYNTHESIS OF CLOPIDOGREL BISULFATE 3 FROM

COMPOUND 42

Formylation of compound 42 using formalin solution followed by

electrophilic cyclisation afforded clopidogrel freebase, which was treated

with H2SO4 furnished compound 3. During the synthesis of 3, two

unknown impurities were observed in crude clopidogrel bisulfate 3 at a

range of 0.2 to 1.0% along with the related compounds (compound A 48,

compound B 49 and compound C 50) reported in US pharmacopeia17.

155 Chapter-4

As per the ICH guidelines18 the limit of the any unknown impurity in

final compound 3 should be less than 0.10% and any known impurity

should be less than 0.15%. Based on the detailed investigation on

formylation trend and reports on molecular weight analysis by LC-MS,

we proposed the structures of the unknown impurities. These proposed

structures were confirmed by enrichment followed by synthesis and

structure elucidation.

S

N

Cl

CO2CH3

S N

Cl

CO2CH3

S

N

Cl

CO2CH3

HO

S

N

Cl

CO2H

48 5049

5152

Cl

N

S

H3CO O

Br

Figure 4.1: Chemical structures of impurities 48, 49, 50, 51 and 52

It was observed that removal of related compound 51 in

compound 3 was difficult by following the procedures reported in

literature. In view of this, various key process conditions like

temperature and solvent for isolation of compound 3 were thoroughly

studied. Temperature always plays a key role during the chemical

reactions. To check the impact of the temperature during the synthesis

of 3, reactions were performed at various temperatures. Experimental

156 Chapter-4

results indicated that formation of related compound 51 is high when

reactions were performed at higher temperature (Table 4.3). In similar

way, formation of related compound 51 was less when reaction was

performed at 25-35 °C (entry 1 Table 4.3).

Table 4.3: Synthesis of compound 3 in different temperatures.

Entry

Temperature

(0C)

Yield of 3

(%)

Purity of 3

(%)

Content of 51

(%)

1 25-35 74 99.7 0.21

2 35-45 84 99.3 0.40

3 50-55 81 98.8 0.58

4 70-80 57 4.02 49.6

After finalization of 25-35 °C as suitable temperature for the

synthesis of 3, various solvents were examined to found the suitable

solvent for isolation compound 3. Experimental results revealed that

aqueous acetone furnished compound 3 with the desired purity (more

than 99.7%) when compared with the other solvents. To check the

impact of the water content in acetone, reactions were carried out by

using 0.5, 1.0, 2.0, 3.0 and 4.0 % of water and without using water.

Optimum results were obtained when 2.0% aqueous acetone was used

as solvent for isolation of compound 3 (Table 4.4). By implementing all

optimal conditions desired compound 3 was prepared with good yield

and purity. This improved process is advantageous over the reported

processes.

157 Chapter-4

Table 4.4: Isolation of compound 3 in different ratios of aqueous

acetone

Entry

Amount of

water (%)

Yield of 3

(%)

Purity of 3

(%)

Content of 51

(%)

1 Nil 76 98.9 0.84

2 0.5 75 99.4 0.14

3 1.0 75 99.7 0.11

4 2.0 73 99.7 0.07

5 3.0 58 99.7 0.07

6 4.0 45 99.7 0.06

4.3.2.2 SECOND SYNTHETIC APPROACH FOR PREPARATION OF

CLOPIDOGREL BISULFATE 3

The second synthetic approach starts with the commercially

available key starting materials such as 2-chloro benzaldehyde 44 and

thieno pyridine compound 43. Reaction of 43 with 44 by using NaCN in

water medium, employing Strecker synthesis conditions afforded cyano

compound 45 which was converted into amide 46 using potassium

hydroxide in t-butanol. Reported process12 for the synthesis of amide

compound 46 involves the use of multiple solvents and laborious work

up procedure such as layer separations, extractions, washings,

distillation of solvent and isolation of crude compound and purifications.

At our end multiple solvents were replaced with single solvent (t-

butanol), laborious workup process was avoided and product was

158 Chapter-4

isolated from the reaction mass by adding water to the reaction mixture.

In addition to this one pot process was developed for the preparation of

amide compound 46.

S

N

CN

Cl

S

NH.HClOHC

Cl

S

N

CONH2

Cl

1.0 eq.NaCN

Water

3.0 eq. KOH,

t-Butanol

DMS, H2SO4

Methanol

+

60-65 °C, 2 h

100%

67%

water, Acetone. CSA

(S)-(+)-CSA. H2O

S

N

COOCH3

Cl

NaHCO3

DCM

H2SO4

2-Butanol

.H2SO4

S

N

COOCH3

Cl

43 44 45

46 47(±) 3

80-85 °C, 3h

92%

Acetone

.H2SO4S

N

COOCH3

Cl

3

Scheme 4.12: Improved synthetic approach for preparation of 3

Reaction of amide compound 46 with dimethyl sulfate in presence

of H2SO4 in methanol medium provided racemic clopidogrel free base,

which was treated with H2SO4 to obtain racemic clopidogrel bisulfate (±)

3. This step was previously reported with 48% yield where as in our

improved reaction conditions yield was increased to about 68%.

Resolution of racemic compound 3 using L-(+)-camphorsulfonic acid

monohydrate as resolution agent in mixture of water and acetone

afforded CSA salt of requisite (S)-isomer 47, the resulted CSA salt 47

recrystallized from mixture of acetone and water followed by treated with

NaHCO3 to obtain clopidogrel free base. Thus obtained clopidogrel free

base was treated with sulfuric acid to afford compound 3.

159 Chapter-4

R-isomer enriched CSA salt of clopidogrel (obtained by

concentrating the filtrate after isolation of compound 47) was converted

in to racemic clopidogrel bisulfate (±) 3 by treating R-isomer enriched

CSA salt of clopidogrel with sulfuric acid in acetone. Improved synthetic

process (Scheme 4.12) for the preparation of clopidogrel bisulfate 3 is

superior process over the earlier reported process.

4.4 CONCLUSION

In conclusion, an efficient, cost effective and commercially viable

processes for the preparation of Clopidogrel bisulfate 3 was developed.

The possible potential impurities in clopidogrel bisulfate 3 was

synthesized, root cause for thier formation was identified and controlled

to below acceptable limit in final Clopidogrel bisulfate 3.

4.5 EXPERIMENTAL SECTION

4.5.1 Process description

4.5.1.1 Methyl 2-amino-2-(2-chlorophenyl)acetate (111)

H2N

Cl

CO2Me

To a pre cooled (10 °C) stirring suspension of 2-chloro phenyl

glycine 110 (180 kg, 970 moles) and methanol (900 L), sulfuric acid

(145.3 kg, 1483 moles) was slowly added at below 35 ° C and the

resulted reaction mixture was heated to 65 °C. After stirring the reaction

mixture at 65 °C for 15 hours, solvent was distilled at below 65 °C under

160 Chapter-4

reduced pressure. Water (540 L) and DCM (360 L) was added to the

reaction mixture at ambient temperature and stirred for 15 minutes.

Reaction mass pH was adjusted to 6.5-7.5 at below 25 °C using 30%

aqueous Na2CO3 solution (360 L) and stirred for 30 minutes. Layers

were separated, the aqueous layer was extracted with DCM (2 X 90 L),

and the combined organic layers were washed with water (360 L). The

organic layer was distilled completely at below 70 °C under reduced

pressure to afford 174 kg (90%) title compound 111 as brownish oil with

99.2% of purity.

IR (KBr, cm–1): 2952 (CH, Ali), 1751 (C=O, ester), 1248 & 1136 (C-O,

ester).

1H NMR (400 MHz, DMSO–d6): δH 7.8 (m, 2H, NH), 7.2-7.7 (m, 4H, Ar-

H), 5.0 (s, 1H, CH), 3.7 (s, 3H, CH3).

M/S (m/z): 200.0 (M+ + H).

4.5.1.2 (+)-Tartarate salt of α-amino-2-chloro phenyl acetic acid

methyl ester (112a).

H2N

Cl

CO2Me

COOHHO

HO COOH

To a stirring solution of compound 111 (260 kg, 1302 moles) and

methanol (540 L), L (+)-tartaric acid (192 kg, 1279 moles) was added at

28 °C and stirred for 10 minutes. (+)-tartarate of α-amino-2-chloro

phenyl acetic acid methyl ester 112a (1.92 kg, 5.490 moles) seed was

161 Chapter-4

added to the reaction mass at 28 °C and cooled to 3 °C. After stirring

the reaction mixture at 3 °C for 2 hours, the separated solid was filtered

and washed with methanol (130 L). The resulted wet compound and

methanol (360 L) were stirred at 28 °C for 30 min and followed by stirred

at 3 °C for 1 hour. The suspended solid was filtered, washed with

methanol (65 L) and dried at 70 °C under vacuum to give 180 kg (79%)

of title compound as white solid with 99.2% HPLC purity.


ester).


H), 5.0 (s, 1H, CH), 3.7 (s, 3H, CH3).

M/S (m/z): 200.0 (M+ + H).

SOR: [α]20D: +92 ° (C=1% methanol)

4.5.1.3 Racemisation of R-(-)-isomer (112b) of α-amino-2-chloro

phenyl aceticacid methyl ester tartarate

H2N

Cl

CO2Me

COOHHO

HO COOH

21b

65 oC

16 hours

Racemisation H2N

Cl

CO2Me

COOHHO

HO COOH

NaHCO3

DCMH2N

Cl

CO2Me

20

Filtrate obtained after isolation of compound 112a (with input 111

batch size of 260 kg) was stirred at 65 ˚C for 16 hours followed by total

solvent was distilled at same temperature under vacuum to afford

tartrate salt of compound 111. To the resultant crude compound water

162 Chapter-4

(360 L) and DCM (360 L) was added at ambient temperature and

reaction mass pH was adjusted to 6.5-7.5 using 30% aqueous Na2CO3

solution at 20 ˚C. After stirring the reaction mixture for 15 minutes,

organic and aqueous layers are separated, aqueous layer extracted with

DCM (2 X 180 L) and the total organic layer was washed with water (180

L). The obtained organic phase was concentrated at below 50 ˚C under

reduced pressure to afford 76 kg of compound 111 with more than 99%

of chemical purity.


ester).


H), 5.0 (s, 1H, CH), 3.7 (s, 3H, CH3).

M/S (m/z): 200.0 (M+ + H).

4.5.1.4 (S)-methyl 2-(2-(thiophen-2-yl)ethylamino)-2-(2-

chlorophenyl) acetate hydrochloride (42).

. HClHN

Cl

CO2CH3

S

To a stirring suspension of thiophene-2-ethanol (25 kg, 195 mol),

p-toluene sulfonyl chloride (40.8 kg, 214 mol) and toluene (100 L),

triethylamine (32.5 kg, 321 mol) was slowly added at below 5 °C and

stirred for 8 hours at ambient temperature. Precipitated byproduct (TEA

HCl salt) was filtered, washed with toluene (25 L) and filtrate was

163 Chapter-4

washed with water (50 L). About 50% of the filtrate was distilled at below

60 ˚C under reduced pressure. To the resultant reaction mass, K2HPO4

(84.2 kg, 483 mol), (S)-(+)-isomer of amino-(2-chlorophenyl)-acetic acid

methyl ester (32.5 kg, 163 mol) was added at 28 ˚C and stirred for 30

hours at 100°C. Toluene (95 L) and water (280 L) was added to the

reaction mixture at 28 ˚C and stirred for 20 minutes. Organic and

aqueous layers were separated, aqueous layer extracted with toluene (25

L), and the total organic layer washed with water (62.5 L). Aqueous HCl

(14 L) was slowly added to the organic layer at 10 °C and stirred for 1

hour at same temperature. Precipitated solid was filtered and washed

with toluene (25 L). Suspension of resulted wet compound, aqueous HCl

(14.2L) and acetone (250 L) were heated to 55 °C and stirred at 55 ˚C for

20 minutes followed by cooled to 15 ˚C. Resulted solid was filtered,

washed with acetone (25 L) and dried at 55 °C for 5 hours under

reduced pressure to afford 37.8 kg (67%) of title compound with 99.9%

of chemical purity and 99.6% of chiral purity.

IR (KBr, cm–1): 3465 (NH, Amine), 2923 (CH, Ali), 1740 (C=O, ester),

1219&1036 (C-0, ester);

1H NMR (200 MHz,CDCl3) δ: 10.7 (s, 1H, NH), 6.8-8.2 (m, 7H, Ar-H),

5.6 (s, 1H, CH), 3.8 (s, 3H, CH3), 3.0-3.2 (m, 2H, CH2), 3.4-3.6 (m, 2H,

CH2).

MS (m/z): 310.4 (M+);

SOR: [α]20D=116° (c=1.0 % methanol);

164 Chapter-4

4.5.1.5 (+)-Methyl-(2-chlorophenyl)-(6,7-dihydro)-4H-thieno(3,2-

c)pyrid-5-yl)acetate bisulfate salt (3)

.H2SO4S

N

COOCH3

Cl

Suspension of formalin (125 L) and compound 42 (25 kg, 72.2

moles) was stirred at ambient temperature for 23 hours and the resulted

reaction mixture was filtered. To the filtrate, DCM (75 L) was added and

the resulted reaction mixture pH adjusted to 6.5-7.5 using 10% aqueous

Na2CO3 solution. After stirring reaction mixture at 28 ˚C for 20 minutes,

organic and aqueous phases are separated, aqueous phase extracted

with DCM (2 X 62.5 L) and the total organic phase was washed with

water (50 L). The obtained organic phase was distilled completely at

below 40 ˚C under reduced pressure to afford clopidogrel free base as

syrup. To the syrup, acetone (245 L) and water (5 L) was added and

stirred for 15 minutes. Sulfuric acid (98%, 6.5 kg, 66.2 moles) was

slowly added to the reaction mixture at 12 °C followed by Clopidogrel

bisulfate (0.25 kg) seed was added. After stirring the reaction mixture at

12 °C for 4 hours, precipitated solid was filtered, washed with acetone

(25 L) and dried at 65 °C under vacuum to afford 24 kg (76%) of title

compound with 99.8% of chemical purity by HPLC.

165 Chapter-4

IR (KBr cm-1): 3121 & 3080 (CH, Aromatic), 2956 (CH, Ali), 2852 &

2509 (NH, Pyridyl), 1753 (C=O, Ester), 1188 (CN, Pyridyl), 1244 (C-O,

Ester);

1H NMR (200 MHz,CDCl3) δ: 7.5-7.8 (m, 4H, Ar-H), 7.4 (d, 1H, J = 5.2

Hz, Ar-H), 6.9 (d, 1H, J = 5.2 Hz, Ar-H), 5.6 (s, 1H, CH), 4.2 (br, s, 2H,

CH2), 3.8 (br, s, 3H, CH3), 3.4 (br, s, 2H, CH2), 3.1 (br, s, 2H, CH2);

13C NMR (200 MHz,CDCl3) δ: 22.4, 38.2, 38.7, 39.1, 39.5, 39.9, 40.3,

40.7, 49.1, 50.4, 53.7, 65.6, 125.1, 125.5, 127.9, 128.5, 130.2, 130.65,

131.7, 132.3, 134.3 and 167.4.

MS (m/z): 322 (M++1);

SOR: [α]25D= 53.8° (c=1.0 % methanol);

4.5.1.6 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-

5(4H)-yl)acetamide (46)

S

N

CONH2

Cl

Solution of 6,7-dihydro-4H-thieno (3,2-c) pyridine hydrochloride

43 (50 kg, 284 mol) in water and 2-chlorobenzaldehyde 44 (40 kg, 284

mol) was simultaneously added to the reaction mixture containing NaCN

(14 kg, 284 mol) and water (70 L) at about 28 °C and the resulted

reaction mixture was heated to 60°C. After stirring reaction mass at 60

°C for 3 hours cooled to 28°C, DCM (200 L) was added to the traction

mixture at 28 °C. Organic and aqueous layers were separated, aqueous

166 Chapter-4

layer extracted with DCM (100 L) and total organic phase washed with

water (100 L). The resulted organic layer was distilled completely under

reduced pressure at below 40 °C to afford compound 45. KOH (46.4 kg,

828 mol), t-butanol (400 L) and water (24 L) was added to the compound

45 and the resulted reaction mixture was heated to 80 °C. After stirring

the reaction mixture at 80 °C for 3 hours, water (800 L) was added at 27

°C and stirred for 30 minutes. The resulted solid was collected by

filtration, washed with water (80 L) and dried at 65 °C under reduced

pressure for 4 hours to afford title compound 46 (84.04 Kg) in 92% yield

and >98.9 % purity.

IR (KBr, cm–1): 2334 (NH), 1656 (C=O, Amide)

1H NMR (400 MHz, DMSO–d6): δH 7.4-7.5 (m, 4H, Ar-H), 7.2 (d, 1H, Ar-

H), 7.0 (d, 1H, Ar-H), 6.7 (d, 1H, CH), 6.0 (d, 1H, CH), 4.9 (s, 1H, CH),

3.6 (s, 2H, CH2), 2.9 (m, 2H, CH2).

M/S (m/z): 307.2 (M+ + H).

4.5.1.7 Racemic clopidogrel (±3)

.H2SO4S

N

COOCH3

Cl

Dimethyl sulfate (31 L, 326 mol) was slowly added to the reaction

mixture containing methanol (180 L) and sulfuric acid (52 L, 976 mol) at

10°C, the resulted reaction mass was heated to 70 °C and stirred at

same temperature for 11/2 hour. Amide compound 46 (50 kg, 162 mol)

167 Chapter-4

was charged in to reaction mixture at 28 °C and heated to 70 °C. After

stirring the reaction mixture at 70 °C for 35 hr, DCM (250 L) and water

(500 L) was added at 27 °C. Aqueous and organic phases were

separated, aqueous phase was extracted with DCM (3 x 100 L) and total

organic phase was washed with 5% NaHCO3 solution (2 x 200 L)

followed by water (250 L). The resulted organic layer solvent was

evaporated completely at below 40 °C under reduced pressure to obtain

crude compound. Acetone (200 L) was added to the crude compound

and stirred for clear solution. Sulfuric acid (5.0 L) was slowly added to

the reaction mixture at 10°C and stirred for 11/2 hour. To the resulted

reaction mass, water (5.0 L) was added at 25 °C and heated to 55 °C.

After stirring at 55 °C for 30 minutes further cooled to 10 °C and stirred

for 11/2 hour. The resulted solid was filtered, washed with acetone (50 L)

and dried at 65 °C under reduced pressure for 4 hours to afford title

compound (±) 3 (46.0 Kg) in 67.2% yield and more than 99.0% purity.

IR (KBr, cm–1): 2953 (CH, Ali), 1755 (C=O, ester), 1574&1479 (C=C,

Aromatic), 1064 (C-O, ester).

1H NMR (400 MHz, DMSO–d6): δH 7.2-7.8 (m, 4H, Ar-H), 7.0 (d, 1H,

CH), 6.8, (d, 1H, CH), 5.7 (s, 1H, CH), 3.8 (s, 3H, CH3), 4.2 (s, 2H, CH2)

3.5 (s, 2H, CH2), 3.4 (t, 2H, CH2).

M/S (m/z): 321.9 (M+ + H).

4.5.1.8 Crystalline form-1 of Clopidogrel bisulfate (3)

168 Chapter-4

.H2SO4S

N

COOCH3

Cl

To a stirring solution of racemic clopidogrel bisulfate (50 Kg, 119

mol) and DCM (200 L), NaHCO3 solution (27 kg of in 130 L of water) was

slowly added at 3 °C and stirred for 15 minutes. Organic and aqueous

phases are separated, aqueous phase extracted with DCM (2x50 L) and

total organic phase was washed with water (2x 45 L). The resulted

organic phase was distilled completely at below 60 °C under reduced

pressure to afford racemic clopidogrel free base as residue. Acetone (210

L) was added to the residue at 30 °C and stirred for 15 minutes followed

by water (2 L) and L-(-)-camphor sulfonic acid (CSA) monohydrate (28.6

kg, 123 mol) was added and stirred for 30 minutes. The resulted

reaction mixture was seeded with (+)-Clopidogrel CSA salt (0.2 kg) at 28

°C. After stirring reaction mass at 28 °C for 18 hours, precipitated solid

was filtered. The resulted wet compound was recrystallized from 5.0

volume of acetone to afford pure (+)-Clopidogrel CSA salt (21.5 kg) in

65% yield with chiral purity 99.75%. 10% NaHCO3 solution (20 L) was

slowly added to the reaction mixture containing (+)-Clopidogrel CSA salt

(20 kg) and DCM (80 L) at 3 °C and stirred for 15 minutes. Organic ans

aqueous phases were separated, aqueous phase was extracted with

DCM (2 x 30 L) and total organic phase was washed with water (2 x 30

L). Organic phase was distilled completely at below 50 °C under reduced

169 Chapter-4

pressure. Traces of DCM in crude compound was removed by chasing

the residue with 2-butanol (20 L) at below 60 °C under reduced

pressure. To the resultant residue, 2-butanol (200 L) was added to the

reaction mixture at 35 °C and stirred for 10 minutes. Sulfuric acid (1.8

liters of 98%) was added slowly at 24 °C followed by seeded with 112.5 g

of crystalline (+)-Clopidogrel bisulfate form-1 and stirred for 15 hours.

The precipitated solid was filtered, washed with of 2-butanol (20 L)

followed by cyclohexane (10 L) and dried at 100 °C under reduced

pressure for 22 hours to afford title compound (8.7 kg) in 57% yield.

IR (KBr, cm–1): 2956 (CH, Ali), 1753 (C=O, ester), 1573&1497 (C=C,

Aromatic).

1H NMR (400 MHz, CDCl3–d6): δH 7.5-7.8 (m, 4H, Ar-H), 7.4 (d, 1H, J =

5.2 Hz, CH), 6.9, (d, 1H, J = 5.2 Hz ,CH), 5.6 (s, 1H, CH), 4.21 (s, 2H,

CH3), 3.8 (s, 3H, CH3) 3.4 (s, 2H, CH2), 3.1 (t, 2H, CH2).

M/S (m/z): 322.0 (M+ + H).

4.5.1.9 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-

yl)acetic acid (48)

S

N

Cl

CO2H

To a stirring solution of clopidogrel bisulfate 3 (25 g, 59.5 mmol)

and water (75 mL), aqueous NaOH solution (12 g in 50 mL of water) was

slowly added at ambient temperature and the obtained reaction mass

170 Chapter-4

was heated to 80 °C. After stirring reaction mass at 80 °C for 4 hours,

reaction mass pH was adjusted to 2.0-3.0 with hydrochloric acid. To the

resulted reaction mass, DCM (50 mL) was added and stirred for 20

minutes. Organic and aqueous phases are separated, aqueous layer

washed with DCM (2x25 mL) and total organic layer was distilled at

below 50 °C under vacuum to afford 18 g of the title compound with

99.0% of chemical purity.

1H NMR (400 MHz, CDCl3–d6): δH 7.3-7.8 (m, 4H, Ar-H), 7.3 (d, 1H, J =

4.8 Hz, CH), 6.8, (d, 1H, J = 4.8 Hz ,CH), 4.7 (s, 1H, CH), 3.8 (s, 2H,

CH3), 3.6 (s, 2H, CH2), 2.8 (t, 2H, CH2).

M/S (m/z): 307.9 (M+ + H).

4.5.1.10 (±)-methyl 2-(2-chlorophenyl)-2-(4,5-dihydrothieno[2,3-

c]pyridin-6(7H)-yl)acetate (49)

S N

Cl

CO2CH3

Mixture of (±)-α-{(2-Thien-2-yl)-ethyl amino}-α-(2-chloro

phenyl)methyl acetate hydrochloride (15 g, 0.0484 mol) and formalin

(37%, 120 mL, 1.3875 mol) was stirred for 7 hours at ambient

temperature. The precipitated solid was filtered, washed with acetone

(15 mL) and dried at 65 °C under vacuum to afford 15 g (86%) of title

compound with 99.2% chemical purity.

171 Chapter-4

IR (KBr, cm–1): 3284 (CH, Aromatic) 2953 (CH, Ali), 1689 (C=O, Ester),

1541&1496 (C=C, Aromatic), 1245&1162 (C-O, Ester);

1H NMR (400 MHz, CDCl3): δ 7.8 (m, 1H, Ar-H), 7.4 (m, 1H, Ar-H), 7.4–

7.3 (m, 2H, Ar-H), 7.1 (d, J ═ 4.8 Hz, 1H, Ar-H), 6.80 (d, J ═ 5.6 Hz, 1H,

Ar-H), 5.10 (s, 1H, CH), 4.0 (s, 2H, CH2), 3.7 (s, 3H, CH3), 3.1 (t, 2H,

CH2), 2.8 (t, 2H, CH2);

MS (m/z): 322 [M+ + H];

4.5.1.11 (R)-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-

c]pyridin-5(4H)-yl)acetate (50)

S

N

Cl

CO2CH3

Suspension of formalin (500 mL) and (R)-methyl 2-(2-(thiophen-2-

yl)ethylamino)-2-(2-chlorophenyl)acetate (100g, 288 mmole) was stirred

at ambient temperature for 23 hours and the resulted reaction mixture

was filtered. To the filtrate, DCM (500 mL) was added and the resulted

reaction mixture pH adjusted to 6.5-7.5 using 10% aqueous Na2CO3

solution. After stirring reaction mixture at 28 ˚C for 20 minutes, organic

and aqueous phases are separated, aqueous phase extracted with DCM

(2 X 250 mL) and the total organic phase was washed with water (300

mL). The obtained organic phase was distilled completely at below 40 ˚C

under reduced pressure to afford free base as syrup. To the syrup,

acetone (980 mL) and water (20 mL) was added and stirred for 15

172 Chapter-4

minutes. Sulfuric acid (14 mL) was slowly added to the reaction mixture

at 3 °C. After stirring the reaction mixture at 3 °C for 4 hours,

precipitated solid was filtered, washed with acetone (100 mL) and dried

at 45 °C under vacuum to afford 70 g (58.3%) of title compound with

99% of chemical purity by HPLC.

1H NMR (200 MHz,CDCl3) δ: 7.5-7.7 (m, 4H, Ar-H), 7.4 (d, 1H, J = 4.8

Hz, Ar-H), 6.9 (d, 1H, J = 5.2 Hz, Ar-H), 5.5 (s, 1H, CH), 4.1 (br, s, 2H,

CH2), 3.7 (br, s, 3H, CH3), 3.3 (br, s, 2H, CH2), 3.0 (br, s, 2H, CH2);

MS (m/z): 322.1 (M++1);

4.5.1.12 5-[(2-Chlorophenyl)methoxycarbonyl-methyl]-6,7-

dihydrothieno[3,2-c]pyridin-5-ium bromide (52)

Cl

N

S

H3CO O

Br

To a stirring solution of clopidogrel (32 g, 99.5 mmol) and DCM

(600 mL), N-bromosuccinimide (18 g, 99.6 mmol) was slowly added at 2

°C. After stirring at ambient temperature for 12 hours, solvent was

distilled at below 55 °C under vacuum. To the resultant crude, acetone

(320 mL) was added and stirred for 2 hours at 28 °C. The separated solid

was filtered, washed with acetone (32 mL) and dried at 65 °C under

vacuum to afford 15 g (70%) of the title compound with 99.5% chemical

purity by HPLC.

173 Chapter-4

IR (KBr, cm–1): 3039 (CH, Aromatic), 2903 (CH, Ali), 1738 (C=O, ester),

1621 (C=N, imine), 1225 (C-O, ester);

1H NMR (400 MHz, CDCl3): δ 10.2 (s, 1H, CH), 7.92 (d, J ═ 8.8 Hz, 1H),

7.6 (d, J ═ 4.8 Hz, 1H, Ar-H), 7.5–7.4 (m, 3H, Ar-H), 7.3 (d, J ═ 5.2 Hz,

1H, Ar-H), 4.5–4.4 (m, 1H, CH), 3.8 (s, 3H, CH3), 3.8–3.7 (m, 2H, CH2),

3.6–3.5 (m, 1H, CH2);

MS (m/z): 321 [M+ +1];

4.5.1.13 Methyl 2-(2-chlorophenyl)-2-(6,7-dihydro-2-

(hydroxymethyl) thieno[3,2-c]pyridin-5(4H)-yl)acetate (51)

S

N

Cl

CO2CH3

HO

Suspension of formalin (125 mL) and compound 42 (25 g, 72.2

mmole) was stirred at 70 °C for 45 hours. To the resultant reaction

mixture, DCM (75 mL) was added at 28 °C and reaction mixture pH

adjusted to 6.5-7.5 using 10% aqueous Na2CO3 solution. After stirring

reaction mixture at 28 ˚C for 20 minutes, organic and aqueous phases

are separated, aqueous phase extracted with DCM (2 X 50 mL) and the

total organic phase was washed with water (50 mL). The obtained

organic phase was distilled completely at below 40 ˚C under reduced

pressure. Thus obtained crude compound was purified using column

chromatography to afford 17 g of title compound with 97% of chemical

purity.

174 Chapter-4

1H NMR (400 MHz, CDCl3): δ 10.2 (s, 1H, CH), 7.92 (J ═ 8.8 Hz, 1H),

7.6 (d, J ═ 4.8 Hz, 1H, Ar-H), 7.5–7.4 (m, 3H, Ar-H), 7.3 (d, J ═ 5.2 Hz,

1H, Ar-H), 5.2 (s, 1H, OH), 4.8 (s, 2H, CH2), 4.7–4.6 (m, 1H, CH), 3.7 (s,

3H, CH3), 3.1 (t, 2H, CH2), 2.8 (t, 2H, CH2);

MS (m/z): 352.6 [M+ +1];

4.6 REFERENCES

1. (a) Gurbel, P. A.; O’Connor, C. M.; Cummings, C. C.; Serebruany, V.

L. Clopidogrel: the future choice for preventing platelet activation

during coronary stenting?, Pharmacol. Res. 40, 1999, 107–111. (b)

Yang, L. H.; Hoppensteadt, D.; Fareed, J. Modulation of

vasoconstriction by clopidogrel and ticlopidine, Thromb. Res. 92,

1998, 83–89.

2. (a) Coukell, A. J.; Markham, A. Clopidogrel, Drugs 54, 1997, 745–

751. (b) Boneu, B.; Destelle, G. Platelet anti-aggregating activity and

tolerance of clopidogrel in atherosclerotic patients, Thromb.

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3. "New products and markets fuel growth in 2005". IMS Health.

4. United states food and drug administration;

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/

5. Aubert, D.; Ferrand, C.; Maffrand, P.J. U. S. Patent 4,529,596

(1985).

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9. Yamamoto, S.; Fujii, A.; Mitsuda, M. U. S. Patent application

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Org .Process Res. Dev. 2007, 11, 3, 487-489.

11. Marcel, D.; Joel, R. U. S. Patent 5,204,469 (1993).

12. Pandey, B.; Lohray, V. B.; Lorhray. B. B. U. S. Patent application

2002/0177712 A1 (2002).

13. Horne, E.S.; Weeratunga, G.; Comanita, M. B.; Nagireddy, R. J.;

McConachie, K. L. U. S. Patent 6,495,691 (2002).

14. Smyj, P. R.; Weeratunga, G. U. S. Patent 7,060,831 (2006).

15. Hongping, Y.; Meng, S.; Zuolin, Z.; PCT Application WO2006/086921

(2006).

16. Maheswari, K. K.; Sarma, K. R.; Joshi, V. S.; Barde, R. A.; Sutar, P.

R.; Ranade, V. P. U. S. Patent 6,812,363 (2004).

17. United States Pharmacopoeia 30, pp. 1802–1803.

18. ICH harmonized tripartite guideline, Impurities in New Drug

Substances Q3A (R2), current step 4 version dated 25 October

2006.

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