WO2011010318A1 - Process for the preparation of clopidogrel polymorphous form 1 using seed chrystals - Google Patents

Process for the preparation of clopidogrel polymorphous form 1 using seed chrystals Download PDF

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Publication number
WO2011010318A1
WO2011010318A1 PCT/IN2009/000419 IN2009000419W WO2011010318A1 WO 2011010318 A1 WO2011010318 A1 WO 2011010318A1 IN 2009000419 W IN2009000419 W IN 2009000419W WO 2011010318 A1 WO2011010318 A1 WO 2011010318A1
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WO
WIPO (PCT)
Prior art keywords
clopidogrel
preparation
hydrogen sulfate
thienopyridyl
chlorophenyl
Prior art date
Application number
PCT/IN2009/000419
Other languages
French (fr)
Inventor
Hetul Mehta
Dr. Yogen Talia
Shailesh Parmar
Bhanudas Chaudhary
Dilip Burad
Original Assignee
Praveen Laboratories Private Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Praveen Laboratories Private Limited filed Critical Praveen Laboratories Private Limited
Priority to PCT/IN2009/000419 priority Critical patent/WO2011010318A1/en
Publication of WO2011010318A1 publication Critical patent/WO2011010318A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to the process for the preparation of hydrogen sulfate salt of dextro rotatory Methyl - ⁇ - 5 - (4,5,6,7- tetrahydro - (3,2-c ) thienopyridyl) - (2- chlorophenyl) acetate which is generally referred as clopidogrel hydrogen sulfate ( I ) in its crystalline form 1.
  • Clopidogrel is a compound, which has shown to have an activity with inhibitory properties towards platelet aggregation. It interferes with the mechanism of formation of arterial and venous thromboses. Clopidogrel is useful for the treatment and prevention of platelet disorders.
  • Clopidgrel hydrogen sulfate is a chiral product which can prepare by using (+) Methyl- ⁇ - 5-(4,5,6,7-tetrahydro-(3,2-c ) thienopyridyl)-(2-chlorophenyl) acetate (Clopidogrel base) and sulfuric acid in acetone.
  • US Patent no. 4529596 disclose the method for the preparation of racemic Methyl- ⁇ -5-(4,5,6,7-tetrahydro-(3,2-c ) thienopyridyl)- (2-chlorophenyl)acetate and its hydrochloride derivative.
  • US patent no. 4847265 disclose the resolution process of racemic Methyl- ⁇ -5-(4,5,6,7- tetrahydro-(3,2-c )thienopyridyl)-(2-chlorophenyl)acetate to obtain dexto and levo rotatory enantimers. These enantiomers were converted to their corresponding hydrogen sulfate salts by using H 2 SO 4 in acetone. This product was reported to have a melting point of 184 °C ( Form 1 ).
  • US patent no. 6429210 Bl ( WO 99/65915 ) disclosed a new polymorph of clopidogrel hydrogen sulfate. This form was reported to have a melting point of 176 ⁇ 3 °C. It also gave full description of both the forms ( Form 1 and 2 ).
  • the preparation method for polymorph 2 given by this patent was quite similar to that of US patent no. 4847265 that gave polymorph 1. It also states that form 2 is more stable than form 1. So, it can be understand that reproducibility of form 1 with that process must be very low. In such condition it is very difficult to achieve a clopidogrel form 1 substantially free from clopidogrel form 2.
  • This invention relates to a method for preparation of clopidogrel hydrogen sulfate polymorph 1 without detectable impurity of polymorh 2 with high ratio,, of reproducibility.

Abstract

The invention relates to the process for the preparation of hydrogen sulfate salt of dextro rotatory Methyl - α - 5 - (4,5,6,7- tetrahydro - (3,2-c ) thienopyridyl) - (2-chlorophenyl) acetate which is generally referred as clopidogrel hydrogen sulfate ( I ) in its crystalline form 1.

Description

PROCESS FOR THE PREPARATION OF CLOPIDOGREL
POLYMORPHOUS FORM 1 USING SEED CHRYSTALS
Background of Invention.
The present invention relates to the process for the preparation of hydrogen sulfate salt of dextro rotatory Methyl - α - 5 - (4,5,6,7- tetrahydro - (3,2-c ) thienopyridyl) - (2- chlorophenyl) acetate which is generally referred as clopidogrel hydrogen sulfate ( I ) in its crystalline form 1.
Figure imgf000002_0001
( i )
Clopidogrel is a compound, which has shown to have an activity with inhibitory properties towards platelet aggregation. It interferes with the mechanism of formation of arterial and venous thromboses. Clopidogrel is useful for the treatment and prevention of platelet disorders.
Clopidgrel hydrogen sulfate is a chiral product which can prepare by using (+) Methyl-α- 5-(4,5,6,7-tetrahydro-(3,2-c ) thienopyridyl)-(2-chlorophenyl) acetate (Clopidogrel base) and sulfuric acid in acetone. US Patent no. 4529596 disclose the method for the preparation of racemic Methyl-α-5-(4,5,6,7-tetrahydro-(3,2-c ) thienopyridyl)- (2-chlorophenyl)acetate and its hydrochloride derivative.
US patent no. 4847265 disclose the resolution process of racemic Methyl-α-5-(4,5,6,7- tetrahydro-(3,2-c )thienopyridyl)-(2-chlorophenyl)acetate to obtain dexto and levo rotatory enantimers. These enantiomers were converted to their corresponding hydrogen sulfate salts by using H2SO4 in acetone. This product was reported to have a melting point of 184 °C ( Form 1 ).
US patent no. 6429210 Bl ( WO 99/65915 ) disclosed a new polymorph of clopidogrel hydrogen sulfate. This form was reported to have a melting point of 176±3 °C. It also gave full description of both the forms ( Form 1 and 2 ). The preparation method for polymorph 2 given by this patent was quite similar to that of US patent no. 4847265 that gave polymorph 1. It also states that form 2 is more stable than form 1. So, it can be understand that reproducibility of form 1 with that process must be very low. In such condition it is very difficult to achieve a clopidogrel form 1 substantially free from clopidogrel form 2.
Detail Description of invention
This invention relates to a method for preparation of clopidogrel hydrogen sulfate polymorph 1 without detectable impurity of polymorh 2 with high ratio,, of reproducibility.
It has been now found that the use of small amount of racemic Methyl-α-5-(4,5,6,7- tetrahydro-(3,2-c )thienopyridyl)-(2-chlorophenyl)acetate or (-) Methyl-α-5-(4,5,6,7- tetrahydro-(3,2-c )thienopyridyl)-(2-chlorophenyl)acetate is helpful for the preparation of form 1. It can be use in a ratio of 0.1 to 10.0% (of clopidogrel base used). 1 to 10 times ( of clopidogrel base ) acetone can be use as a solvent. 0.2 to 0.45 times ( of clopidogrel base ) of sulfuric acid can be use for the preparation of hydrogen sulfate salt. Surprisingly, when experiment have been carried out with the impure base which contain known quantity of enantiomeric impurity ( from 0.01% to 10% ) it was difficult to obtain form 1. But, when this known quantity of impurity has been added before sulfuric acid addition, it mostly gave form 1.
The quality of clopidogrel hydrogen sulfate polymorph 1 was checked by XRD , DSC, FTIR and HPLC. Experimental
Preparation of (-) Methyl-α-5- (4,5,6,7 - tetrahydro - (3,2-c ) thienopyridyl)- (2-chlorophenyl)acetate
200 gms of racemic Methyl-α-5-(4,5,6,7-tetrahydro-(3,2-c ) thienopyridyl)- (2- chlorophenyl)acetate was taken in 2 lit round bottom flask. 60 gms of (+) camphor sulfonic acid was added to it. Reaction mixture was stirred overnight at room temperature. Solid thus obtained was separated by filtration. It was dried and made slurry with acetone. It was filtered and dried to give 58 gm of white crystals. [M.R. - 165- 169°C, [α] D20- - 25.24° (c=1.79gm/100ml methanol)] These crystals were charged to 150 ml water and 200 ml of dichloromethane at 10°C. Saturated solution of sodium bicarbonate was added to it till alkaline pH. Organic layer was separated and it was dried on sodium sulfate. Solvent was removed under vacuum to give 30 gm oil. [[α] 020- -51.2° (c=1.58gm/100ml methanol)]. This oil was converted to corresponding hydrogen sulfate by using sulfuric acid in acetone.
M.P. 184-186°C.
[α]D 20- -54.94° ( c=1.89gm/100ml methanol )
Preparation of hydrogen sulfate of (+) Methyl-α-5-(4,5,6,7-tetrahydro-(3,2-c ) thienopyridyl)-(2-chlorophenyl)acetate Polymorph 1
Charge 25 gm of clopidogrel base in 250 ml RBF. Add (-) methyl-α-5-(4,5,6,7- tetrahydro-(3,2-c ) thienopyridyl)-(2-chlorophenyl)acetate with 75 ml acetone. Cool it to 0-5°C. Add drop wise H2SO4. After addition add seeding material of form 1 and raise temperature of reaction mass to 18-20°C and maintain it for 6 to 8 hours. Filter the product and wash with acetone. Dry it under vacuum at 50°C to get 28 gm of clopidogrel hydrogen sulfate polymorh 1. M.P. - 184-186° C.
[α]D 20- +53.78° ( c=1.89gm/100ml methanol )
XRD of product corresponds to form 1.

Claims

Claims:
We Claim,
1) A process which includes use of racemic Methyl-α-5-(4,5,6,7-tetrahydro-{3,2-c ) thienopyridyl)-(2-chlorophenyl)acetate and its hydrogen sulfate salt for the preparation of form 1.
2) A process as claimed in claim 1 wherein use of racemic Methyl-α-5-(4,5,6,7- tetrahydro-(3,2-c) thienopyridyl)-(2-chlorophenyl)acetateand its hydrogen sulfate salt in a ratio of 0.1% to 10.0% ( of clopidogrel base )
3) A process as claimed in 1 & 2 above which include use of (-) Methyl-α-5- (4,5,6,7-tetrahydro-(3,2-c ) thienopyridyl)-(2-chlorophenyl) acetate and its hydrogen sulfate salt for the preparation of form 1.
4) A process as claimed in claim 1 which includes use of (-) Methyl-α-5-(4,5,6,7- tetrahydro-{3,2-c ) thienopyridyl)-(2-chlorophenyl)acetateand its hydrogen sulfate salt in a ratio of 0.1% to 10.0% ( of clopidogrel base )
PCT/IN2009/000419 2009-07-23 2009-07-23 Process for the preparation of clopidogrel polymorphous form 1 using seed chrystals WO2011010318A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0281459A1 (en) * 1987-02-17 1988-09-07 Sanofi Dextrorotatory enantiomer of alpha-(4,5,6,7-tetrahydrothieno[3,2-c]pyrid-5-yl)(2-chlorophenyl)methyl acetate, process for its preparation and pharmaceutical compositions containing it
US6429210B1 (en) * 1998-06-15 2002-08-06 Sanofi-Synthelabo Polymorphic clopidogrel hydrogenesulphate form
WO2005003139A1 (en) * 2003-07-02 2005-01-13 EGIS Gyógyszergyár Rt. Process for the preparation of crystalline polymorph of a platelet aggregation inhibitor drug
WO2005016931A2 (en) * 2003-08-13 2005-02-24 Krka, Torvarna Zdravil, D.D., Novo Mesto Crystallisation of solid forms of clopidogrel addition salts

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0281459A1 (en) * 1987-02-17 1988-09-07 Sanofi Dextrorotatory enantiomer of alpha-(4,5,6,7-tetrahydrothieno[3,2-c]pyrid-5-yl)(2-chlorophenyl)methyl acetate, process for its preparation and pharmaceutical compositions containing it
US6429210B1 (en) * 1998-06-15 2002-08-06 Sanofi-Synthelabo Polymorphic clopidogrel hydrogenesulphate form
WO2005003139A1 (en) * 2003-07-02 2005-01-13 EGIS Gyógyszergyár Rt. Process for the preparation of crystalline polymorph of a platelet aggregation inhibitor drug
WO2005016931A2 (en) * 2003-08-13 2005-02-24 Krka, Torvarna Zdravil, D.D., Novo Mesto Crystallisation of solid forms of clopidogrel addition salts

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS, [online] 1 January 2007 (2007-01-01), MODY S ET AL: "Novel addition salts of thieno[3,2-c] pyridine-5-yl-acetic acid derivatives and pharmaceutical formulations thereof", XP007912559, retrieved from CAPLUS Database accession no. 2007:771953 *
DATABASE CAPLUS, [online] 1 January 2007 (2007-01-01), REDDY ET AL: "Preparation of the polymorphform -1 of clopidogrel hydrogen sulfate", XP007912558, retrieved from CAPLUS Database accession no. 2007:857503 *

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