Field of the Invention:
The invention relates to a novel process preparation of clopidogrel bisulfate (I) and base
catalyzed racemization of (R)- isomer of clopidogrel (I). The invention also relates to a novel
process for the preparation of clopidogrel bisulfate Form I.
Background of the Invention:
Clopidogrel bisul±ate (I) is a platelet aggregation inhibitor. The dextro isomer of clopidogrel
hydrogen sulfate possesses an excellent platelet aggregation inhibition activity. Clopidogrel
bisulfate is useful as a medicine for prophylaxis and treatment of thrombosis by acting a
platelet aggregation inhibitor. The S(+) isomer of (2-chlorophenyl)-6,7-dihydrothieno[3,2-c]
pyridine-5( 4H) acetic acid methyl ester of formula (II a) known as clopidogrel is an effective
antithrombotic agent, indicated especially for prevention of artherosclerotic events in patients
of infarction or stroke or suffering from ischemic disease of lower limbs.
O~OMe if00 (I) (II)
o OMe
6100 (II-a)
Various processes for the preparation of clopidogrel (I) are described in the literature. The
product patent US 4529596 describes the process for the preparation of clopidogrel as shown
below in scheme-I.
°
CI ..
° OMe
~~~CI~ \sAJ'cID
OMe
(III)
(IV)
(II)
SO'H!A
Resolution
CSA
61.
00.. OMe
CI
:~ ~~
~ ~sl
(II-a)
Aqueous NaHC03
DCM _so;A ..
(+) Clopidogrel free
base
Scheme I
The product patents describe process for the preparation of racemic clopidogrel (II) that
involves reaction of methyl alpha bromo (2-chloro) phenyl acetate (III) with 4,5,6,7-
tetrahydro thieno [3,2-c] pyridine (IV). Racemic clopidogrel (II) is resolved using camphor
sulphonie acid (CSA) and converted to (S) clopidogrel free base (II-a).
The specific product patent US 4847265 describes the process for the preparation of
clopidogrel bisulphate by treatment of (S) clopidogrel free base (II-a) with sulphuric acid.
The compound methyl alpha bromo (2-chloro) phenyl acetate (III) is one of the key
intermediate in the manufacture of clopidogrel bisulphate (I). There are various processes
reported in the literature for synthesis of methyl alpha bromo (2-chloro) phenyl acetate (III)
which are described below.
° 0 0
~OH
~ ~
OH
NBS, AIBN OMe
CI ~ CI ~ MeOH
CI ~ I~ Chloroform 1/:/ ..
Cone. H2SO4 1/:/
(VI)
(III) (VII)
Scheme-II
The patents liS 6048893 and US 5036156 describe the process for the preparation of alpha
bromo (2-chloro) phenyl acetic acid (VII) by the reaction of 2-chlorophenyl acetic acid (VI)
with N-bromosuccinimide in presence of azobisisobutyro nitrile (AIBN) in chloroform as
solvent. The bromoacid (VII) is esterified with methanol and concentrated sulphuric acid to
obtain methyl alpha bromo (2-chloro) phenyl acetate (II). The process is shown in scheme II.
Master et aL Indian Journal of Chemistry, Sec B, 2008, 97-105 describes the bromination of
2-chlorophenyl acetic acid (VI) with N-bromosuccinimide in carbon tetrachloride.
The prior art methods for the preparation of alpha bromo (2-chloro) phenyl acetic acid (VI)
suffer from the disadvantage that it employs use of chloroform, carbon tetrachloride etc.
which are carcinogenic and toxic solvents. Chloroform and carbon tetrachloride cause
irritation to skin and eyes and are prone to affect the central nervous system. These solvents
are known to cause digestive disorders, headache, drowziness etc.
The inventors of the present application have found a novel method that does not require
chloroform or carbontetrachloride for bromination of 2-chlorophenyl acetic acid (VI) and
avoids anhydrous environment and toxic reagents.
Most of the earlier methods for synthesis of (S)-isomer of clopidogrel consist of resolution of
the racemic clopidogrel with different chiral acids. Therefore, in such methods, it is
necessary to recycle unwanted (R) -isomer (II) in order to improve the cost. The recyclization
of (R) isomer is achieved by racemization of (R) -isomer to obtain racemic clopidogrel.
There are several methods reported in the literature for racemization of (R) -isomer, some of
them are discussed herein below:
Racemization of undesired (R) isomer using inorganic base such as sodium carbonate is
described in WO 00/59128. This process is accompanied with saponification of esters I and
II. hence. it becomes necessary to convert the alkali salts of clopidogrel acid that are formed
in racemization back to esters which increases the overall steps.
The patent US 6737411 and patent application US 20060074242 both describe the
racemization of R-isomer of cIopidogrel by using alcoholate preferably potassium tertiary
butanolate which requires an absolutely anhydrous environment.
Another patent application US 20080 182869 describes the racemization of R-clopidogrel by
using bases such as tetramethyl ammonium hydroxide or tetrabutyl ammonium hydroxide in
a suitablc alcoholic solvent. These bases are extremely toxic and can cause difficulty in
breathing.
The prior art methods for racemization of (R) clopidogrel discussed above suffer from the
following disadvantages:
a) use of hazardous reagents sueh as tetramethy1 ammonium hydroxide or tetrabutyl
ammonium hydroxide,
b) multiple reaction steps resulting in increased time cycle,
c) decreased yields and
d) maintaining anhydrous reaction conditions.
The patent EP 28 1459 specifically covers clopidogrel bisulfate and further state that
clopidogrel bisulfate salt is the most advantageous for pharmaceutical preparations. It has
no\\' been discovered that clopidogrel bisulfate exists in different polymorphic crystalline
forms which differ in their stability, physical properties, spectral characteristics and process
for preparation.
The later patent US 64292210 states that synthesis described in EP 281459 leads to the
formation of crystalline bisulfate and it is referred as crystalline clopidogrel Form I.
There are several patent documents related to various methods for preparation of clopidogrel
bisulfate Form I.
Summary of the Invention:
The present invention relates to:
i) a novel process tor the preparation of clopidogrel bisulfate (1) that comprises
preparation of alpha bromo (2-chloro) phenyl acetic acid (VII) by treatment of 2-
chloro phenyl acetic acid (VI) with N-bromo succinimide in the presence of a
radical initiator and using dialkyl carbonate as solvent;
ii) a novel process for racemization of (R) isomer of clopidogrel by using pyrrolidine
or sodamide in organic solvent and
iii) a novel process for the preparation of crystalline form I of clopidogrel bisulfate
that comprises of dissolving clopidogrel base in mixture of ethyl acetate and
cyclohexane followed by addition of sulphuric acid and isolation.
Description of the Drawings:
Figure 1: X-ray powder diffractogram (XRPD) for crystalline form I of clopidogrel bisulfate.
Figure 2: IR spectrum for crystalline form I of c1opidogrel bisulfate.
Detailed description of the invention:
The present invention provides novel process for the preparation of clopidogrel bisulphate (I)
as dcpictcd in schcmc-III.
tO
OH
CI ~
I~ tr °OH
CI """
I~
MeOH tr a
OMe
CI """
I~
NBS, AIBN
Dialkyl carbonate
(VI)
(VII) (III)
(JOHj DMF, K2C03
(IV)
Ic?Oe?l.!h R~" l (V) JS03 a
S03H a
Aqueous CSA
Na2C03
a OMe
~~:CI~ \S~'CI))
(II)
Sodamide or
Pyrrolidine
sulphuric acid
Clopidogrel bisulphate
Ethyl acetate-cyclohexane (I)
(+) Clopidogrel
free base Scheme-III
In the pre felTed embodiment, the present invention is related to a novel process for
preparation of intermediate alpha bromo (2-chloro) phenyl acetic acid (VII) which involves
reaction of 2-chlorophenyl acetic acid (VI) with N-bromosuccinimide in the presence of
radical initiator in dialkyl carbonate as solvent.
N-bromo sLlccinimide is used in the range of 0.1 to 2 moles, preferably 0.9 to 1.5 moles.
The radical initiator that can be used are azobisisobutyro nitrile (AlBN), 2'-azobis (2-
methylpropionamidine) dihydrochloride, 2,2'-azobis (2-methylpropionitrile) , 2,2'-azobis (2-
methylbutanenitrile) 4,4'-azobis(4-cyanovaleric acid), benzoyl peroxide etc. preferred radical
initiator is azobisisobutyro nitrile (AIBN). AIBN is used in the range of 0.01 to 0.1 moles.
The dialkyl carbonates used as solvents include dimethyl carbonate, diethyl carbonate,
dipropyl carbonate etc. The preferred solvent is dimethyl carbonate.
The reaction is carried at a temperature range of 30-ISOaC, preferably at the range of sol
:20°c.
The intem1ediate alpha bromo (2-chloro) phenyl acetic acid (VII) is treated with methanol
and concentrated sulphuric acid to obtain methyl alpha bromo (2-chloro) phenyl acetate (III)
which is fmiher reacted with 4,5,6,7 -tetrahydro thieno [3,2-c] pyridine (IV) to obtain racemic
clopidogrel (II). Racemic clopidogrel (II) is resolved using camphor sulphonic acid to obtain
(5) clopidogrel free base (II-a) which is converted to its bisulphate salt (I) by treating with
suiphuric acid.
In another preferred embodiment the present invention is related to a novel process for the
racemization of (R)-isomer of (2-chlorophenyl)-6, 7-dihydrothieno[3 ,2-c] pyridine-
)(4H)acetic acid methyl ester (II), i.e. R-(-) clopidogrel.
The raccmization of R-clopidogrel is carried out in the presence of organic or inorganic base
and a suitable solvent.
The inorganic bases are selected from a group comprising of carbonates such as sodium
bicarbonate, potassium bicarbonate; bicarbonates such as sodium bicarbonate, potassium
bicarbonate; hydroxides such as sodium hydroxide, potassium hydroxide, ammonium
hydroxide: alkali amides such as sodium amide, potassium amide etc; the preferred inorganic
base is sodamide.
The organic bases are selected from group comprising of tertiary cyclic or acyclic amines
such as trimethyl amine, tertiary butyl amine, triethyl amine, pyridine, pyrolidine, piperidine
etc; the preferred organic base is base is pyrrolidine.
The solvents used for racemization are selected from the group comprising of alcohols such
as methanol. ethanol. isopropanol; ketones such as diethyl ketone, dimethyl ketone, ethyl
methyl ketone. esters such as ethyl acetate, methyl acetate; ethers such dioxane.
hydrocarbons such as toluene, tetrahydrofuran and polar aprotic solvents such as
dimethylformamide. dimethyl sulfoxide. sulfolanes, 2-pyrrolidinonc etc; the most preferred
solvent is toluene.
When sodamide is used to carry out the racemization of R-clopidogrel the preferred solvent
is dimethyl sulfoxide and the reaction is carried out at a temperature range of 0-100°C,
preferably 20-40°C
When pyrrolidinc is used to carry out the racemization of R-clopidogrel the preferred solvent
is toluene and reaction is carried out at a temperature range of 0-200°C, preferably 100-
1500e
In an another embodiment, the present invention provides novel process for preparation of
crystalline Form I of clopidogrel bisulfate. The process comprises of dissolving clopidogrel
base in mixture of ethyl acetate and cyclohexane, addition of su1phuric acid followed by
isolation of crystalline Form 1.
The ratio of ethyl acetate to cyclohexane is in the range of 10: 1 to 20: 1, preferably ratio of
ethyl acetate to cyclohexane is in the range of 12: 1 to 16: 1.
The reaction is caITied out at a temperature range of -10 to 80°C. The preferred range is 0-
30°C, 1110stpreferred range is 0-1Ooe.
Fonn I of clopidogrel bisulfate is isolated by conventional techniques such as filtration,
concentration of solution or by evaporation.
The crystalline form of cloidogrel bisulfate Form I obtained by the process of the present
invention is characterized by XRPD pattern as shown in figure 1. The characteristic peaks in
XRPD of cloidogrel bisulfate Form I are shown in table 1.
Table 1: XRPD of crystalline form of Cloidogrel bisulfate Form I
------------
Degree 2 Theta Relative Intensity
9.18 31.02
10.86 26.23
10.99 15.38
11.53 22.11
14.35 13.27
14.81 18.27
14.84 18.33
!
15.48 I 21.99
I
18.96 16.22
20.55 i 28.56
I
21.84 10.51
23.16 100
23.83 16.36
25.48 25.83
28.89 10.61
The crystalline cloidogrel bisulfate Form I described herein is further identified by IR
spectrum as sho\\l1 in figure 2. The IR spectrum of crystalline c1opidogrel bisulfate Form I
described herein has significant bands at 3418,2985,2954,2719,2616,1752,1433,1360,
1324,1298,1221,1174,1068,1018,871,840,752, 766, 715, 624, and 584cm-1
The aforementioned process has the following advantages:
i) Use of less toxic and hazardous solvents such as dialkylcarbonates;
ii) Ecofriendly process;
i) Increased yields,
ii) Use ofless toxic reagents,
iii) Decrease in time cycle and,
iv) Simple reaction conditions
The principles. preferred embodiments, and modes of operation of the present invention have
been described in the foregoing examples. The invention, which is intended to be protected
herein, however. is not to be construed limited to the particular forms disclosed, since these
are to be regarded as illustrative rather than restrictive. Variations and changes may be made
by those skilled in the art, without departing from the scope of the invention.
Examples
Example 1: Preparation of alpha bromo (2-chloro) phenyl acetic acid (VII)
2-chloro phenyl acetic acid (100 g, 0.29 moles) was added to dimethyl carbonate (500 ml).
N-bromo succinimide (146,0.41 moles) and. azobisisobutyro nitrile (9.6 g, 0.029 moles) was
added to the reaction mixture. The reaction mixture was stirred for 1-3 hours at 80-90°C and
then concentrated under reduced pressure. Toluene (250 ml) was added, stirred and filtered.
Toluene filtrate was washed with water and concentrated under reduced pressure.
Cyclohexane (100 ml) was added to the concentrate and stirred. The reaction mixture was
cooled to 15-20°C. The reaction mixture is stirred for an hour at 15-20 °C and solid was
tiltered.
'{icld: 132 gm (90 %)
Example 2: Preparation of methyl alpha bromo (2-chloro) phenyl acetate (III)
To the solution of alpha bromo (2-chloro) phenyl acetic acid (130 gm, 0.20 moles) m
methanol (1300 ml) was added concentrated sulphuric acid (98%) (10.4 gm, 0.08 moles).
The reaction mixture was stirred for 3-5 hours at 60-65uC and concentrated under reduced
pressure. Ethyl acetate (250 ml) was added to the mass and stirred. Ethyl acetate layer was
washed twice with sodium bicarbonate solution (250 ml) followed by water (250 ml). The
ethyl acetate layer was concentrated under reduced pressure.
Yield: 125 gm (91 %)
Example 3: Preparation of racemic clopidogrel (II)
-U.6.7-tetrahydro thieno[32-c] pyridine hydrochloride salt (60 gm, 0.284 moles) was added
to dimethyl formamide (240 ml). Potassium carbonate powder (141.6 gm, 0.855 moles) was
added to the reaction mixture and stirred. Methyl alpha bromo (2-chloro) phenyl acetate (108
gm, 0.342 moles) was added to the reaction mass and was stirred for 1-3 hours at 65-70°C.
The reaction mass was poured in water (800 ml) and extracted with dichloromethane (250
ml). The organic layer was washed with water (250 ml X 5) and concentrated under reduced
pressure to obtain oily residue. Acetone (200 ml) was added to the oily mass and stirred.
Concentrated sulphuric acid (37.6 gm) was added to the slurry and stirred for one hour. The
solid was filtered, \vashed with acetone and dried under reduced pressure to obtain racemic
dopidogrel hydrogen sulfate. The racemic clopidogrel hydrogen sulphate salt (125 gm) was
added in dichloromethane (937 ml) and water (450 ml). To the mixture aqueous ammonia
(187 ml) ,vas added. The mixture was stirred and the organic layer was separated. The
organic layer was concentrated and dried under reduced pressure to give oily mass.
Example 4: Resolution of racemic clopidogrel (II)
etone (700 ml) was added to racemic cLopidogrel obtained in example 3. To the solution
camphor sulphonic acid (69.68 gm, 0.239 moles) and mixture was stirred at 25-30°C. The
reaction mixture was seeded with (S)-(+)-cLopidogrel CSA salt and stirred for 18 hours at 25-
30'C. The solid was filtered and washed with acetone (50 ml). The wet cake was added to
acetone (150 ml) and the mixture was stirred. The solid was filtered. washed and dried under
reduced pressure.
Yield: 54.5 gm (75%)
Example 5: Preparation of (8) clopidogrel (II-a)
(S)-clopidogrel camphor sulphonate salt (50 gm, 0.180 moles) was added to dichloromethane
(400 ml) and water (250 ml). To the reaction mixture was added 20 % sodium carbonate
solution (100 ml) and stirred. Organic layer was separated. The aqueous layer was extracted
with dichloromethane (2 X 100 ml). The dichloromethane layers were combined and washed
with water ( 3 X 100 ml). Activated carbon (2.5 gm) was added to the organic layer and
stirred. The mass was filtered and washed with dichloromethane (100 ml). Combined filtrate
\\<1S concentrated under reduced pressure to give an oily product.
Example 6: Preparation of (8) c1opidogrel bisulfate (I)
Ethyl acetate (845 ml) was added to (S) clopidogrel free base obtained in example 5 and
stirred. To the solution cyclohexane (60 ml) was added. Concentrated sulphuric acid (9 gm,
0.18 moles) was added to the solution. The reaction mixture was stirred for 1 hour at 0-5oe.
The reaction temperature was raised to 25-30°C. The solid was filtered and washed with ethyl
acetate. The product was dried under reduced pressure.
'{ield: 33.5 gm (89 %)
Racemization of R-c1opidogrel using pyrrolidine
Example 7: R-clopidogrel free base (50 gm) was charged to 500 ml toluene and 25 ml
pyrrolidine. The reaction mixture was heated to 11O-115°C for 15-16 hours. The toluene was
distilled off. Dichloromethane was added to residue and washed with water. The organic
layer was concentrated. Residue was stirred in acetone (200 ml ). The solid obtained was
filtered and dried under vacuum.
Yield: 54 gm.
Example 2: Racemization of R-c1opidogrel using sod amide
R-clopidogrel free base (50 gm) was added to 100 ml dimethyl sulfoxide. Sodamide (3.75
gm) was added and stirred at 25-35°C for 3-4 hours. The reaction mixture was added to water
(500 ml) and the product was extracted with dichloromethane (2x 250 ml). The
dichloromethane layer was concentrated and acetone was added to the reaction mass
followed by addition of concentrated hydrochloric acid. The solid was filtered and washed
with acetone followed by drying.
Yield: 52 gm.
We Claim:
1) A process for preparation of clopidogrel bisulfate (I) that comprises preparation of
alpha bromo (2-chloro) phenyl acetic acid (VII) by treatment of 2-chloro phenyl
acetic acid (VI) with N-bromo succinimide in the presence of a radical initiator and
using dialkyl carbonate as solvent.
2) The process of claim 1 wherein, the radical initiator is selected from group
comprising of azobisisobutyro nitrile (AIBN), 2'-azobis (2-methylpropionamidine)
dihydrochloride. 2,2'-azobis (2-methylpropionitrile), 2,2'-azobis (2-
methylbutanenitrile) 4A'-azobis(4-cyanovaleric acid), and benzoyl peroxide.
3) The process of claim 2 wherein. the radical initiator is azobisisobutyro nitrile.
4) Thc process of claim 1 wherein the dialkyl carbonates are selected from a group
comprising of dimethyl carbonate, diethyl carbonate, dipropyl carbonate.
5) The process of claim 4 wherein the solvent is dimethyl carbonate.
6) A process for racemization of (R) isomer of clopidogrel in presence of alkali amides
such as sodium amide. potassium amide.
7) The process of claim 6 wherein the alkali amide is sodamide.
8) The process of claim 6 wherein the solvent is selected from group comprising of
alcohols such as methanol, ethanol, isopropanol; ketones such as diethyl ketone,
dimethyl ketone, ethyl methyl ketone, esters such as ethyl acetate, methyl acetate;
ethers such dioxane, hydrocarbons such as toluene, tetrahydrofuran and polar aprotic
solvents such as dimethylfonnamide, dimethyl sulfoxide, sulfolanes, 2-pyrrolidinone.
9) The process of claim 8 wherein the solvent is dimethyl sulfoxide.
10)A process for racemization of (R) isomer of clopidogrel in the presence of organic
base selected from group comprising of tertiary cyclic or acyclic amines such as
tertiary butyl amine, triethyl amine, pyridine, pyro1idine, piperidine.
11) The process of claim 10 wherein the organic base is pyrro1idine.
12) The process of claim 8 wherein the solvent is selected from group comprising of
alcohols such as methanol, ethanol, isopropanol; ketones such as diethyl ketone,
dimethyl ketone, ethyl methyl ketone, esters such as ethyl acetate, methyl acetate;
ethers such dioxane, hydrocarbons such as toluene, tetrahydrofuran and polar aprotic
solvents such as dimethylformamide, dimethyl sulfoxide, sulfolanes, 2-pyrrolidinone.
13) The process of claim 12 wherein the solvent is toluene.
14) The process for the preparation of Clopidogrel bisulfate form Icomprising dissolving
clopidogrel free base in a mixture of ethyl acetate- cyc10hexane followed by addition
of sulphuric acid.
15) The process of claim 11 wherein the ratio of ethyl acetate : cyclohexane is in the
range of 10: 1 to 20: 1, preferably 12: 1 to 16: 1.