WO2008004249A2 - An improved process for the preparation of clopidogrel and its pharmaceutically acceptable salts - Google Patents

An improved process for the preparation of clopidogrel and its pharmaceutically acceptable salts Download PDF

Info

Publication number
WO2008004249A2
WO2008004249A2 PCT/IN2007/000269 IN2007000269W WO2008004249A2 WO 2008004249 A2 WO2008004249 A2 WO 2008004249A2 IN 2007000269 W IN2007000269 W IN 2007000269W WO 2008004249 A2 WO2008004249 A2 WO 2008004249A2
Authority
WO
WIPO (PCT)
Prior art keywords
clopidogrel
formula
compound
hours
preparation
Prior art date
Application number
PCT/IN2007/000269
Other languages
French (fr)
Other versions
WO2008004249A3 (en
Inventor
Manne Satyanarayana Reddy
Muppa Kishore Kumar
Srinivasan Thirumalai Rajan
Karamala Rama Subba Reddy
Original Assignee
Msn Laboratories 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 Msn Laboratories Limited filed Critical Msn Laboratories Limited
Publication of WO2008004249A2 publication Critical patent/WO2008004249A2/en
Publication of WO2008004249A3 publication Critical patent/WO2008004249A3/en

Links

Classifications

    • 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 an improved process for the preparation of clopidogrel and its pharmaceutically acceptable salts, preferably hydrogen bromide compound of formula-3, hydrogen chloride compound of formula-4 and hydrogen sulfate form-I compound of formula-5.
  • Clopidogrel is chemically known as methyl (+)-(S)- ⁇ -(o- chlorophenyl)-6, 7-dihydrothieno-[3,2-c]pyridine-5(4H)-acetate compound of formula-1.
  • Clopidogrel and its pharmaceutically acceptable salts may be used, in particular, for inhibiting platelet aggregation or for treating, preventing or managing thrombosis, atherothrombosis, an atherothrombotic event, ischaemic stroke, myocardial infarction, non-Q-wave myocardial infarction, atherosclerosis, peripheral arterial disease, or unstable angina.
  • Clopidogrel is marketed under the brand name of PLAVIX® tablets containing about 98 mg of clopidogrel bisulfate, which is the equivalent of 75 mg clopidogrel base.
  • PLAVIX works by preventing platelets from sticking together to form clots that would strict blood flow.
  • the enantiomer (+)-clopidogrel is particularly preferred since it is the pharmaceutically active compound.
  • Clopidogrel and its pharmaceutically acceptable salts like hydrogen sulfate, hydrogen bromide and hydrogen chloride were first disclosed in US Patent 4847265. This patent also disclosed the process for the preparation of clopidogrel hydrogen sulfate, clopidogrel hydrogen bromide and clopidogrel hydrogen chloride.
  • US patent 5204469 discloses the process for the preparation of clopidogrel by reacting the (S)-methyl 2-(2-(thiophen-2-yl) ethylamino)-2-(2-chlorophenyl) acetate hydrochloride with formylating agent in presence of an acid, like a strong inorganic acid.
  • (2-(thiophen-2-yl)ethylamino)-2-(2-chloiOphenyl)acetate compound hydrolyzes into an acid in presence of an strong acid like hydrochloric acid and sulfuric acid which in turn leads to formation of contaminated clopidogrel.
  • the present invention provides an improved process for the preparation of clopidogrel and its pharmaceutically acceptable salts especially hydrogen sulfate, hydrogen bromide and hydrogen chloride. And the present invention also provides an improved process for the preparation of clopidogrel, clopidogrel hydrogen sulfate Form-I, hydrogen bromide and hydrogen chloride which is cost effective and easy to scale up.
  • clopidogrel base clopidogrel bisulfate
  • clopidogrel hydrogen chloride clopidogrel hydrogen bromide
  • (+) (S) clopidogrel base (+) (S) clopidogrel bisulfate
  • (+) (S) clopidogrel hydrogen chloride (+) (S) clopidogrel hydrogen bromide.
  • the present invention provides an improved process for the preparation of clopidogrel, clopidogrel hydrogen bromide, clopidogrel hydrogen chloride and clopidogrel bisulfate form-I which is simple, easily scalable and commercially viable.
  • an improved process is provided for the preparation of clopidogrel and its pharmaceutically acceptable salts, particularly hydrogen bromide, hydrogen chloride and hydrogen sulfate form-I.
  • the first aspect of the present invention is to provide an improved process for the preparation of clopidogrel compound of formula- 1 ,
  • the (S)-methyl 2-(2-(thiophen-2-yl) ethylamino)-2- (2-chlorophenyl) acetate compound of formula-2 can be prepared by the process disclosed in US 5204469 or by any other process known in the prior art.
  • the second aspect of the present invention is to provide an improved process for the preparation of clopidogrel hydrogen bromide compound of formula-3
  • .HBr which comprises of the following steps, a) Dissolving the clopidogrel in a suitable solvent or mixture of solvents, b) Treating with activated carbon, c) Adding aqueous hydrogen bromide solution to the filtrate, d) Stirring the reaction mixture for 1 to 15 hours, e) Isolating the product by filtration and drying the material gives clopidogrel hydrogen bromide compound of formula-3.
  • the third aspect of the present invention is to provide an improved process for the preparation of clopidogrel hydrogen chloride compound of formula-4,
  • the fourth aspect of the present invention is to provide an improved process for the preparation of form-I of clopidogrel hydrogen sulfate compound of formula-5,
  • the fifth aspect of the present invention is to provide an improved process for the preparation of form-I of clopidogrel hydrogen sulfate compound of formula-5,
  • Figure-1 Illustrates clopidogrel hydrogenbromide having a plate-shaped morphology as seen through microscope.
  • an improved process is provided for the preparation of clopidogrel and its pharmaceutically acceptable salts, particularly hydrogen bromide compound of formula-3, hydrogen chloride compound of formula-4 and hydrogen sulfate form-I compound of formula-5.
  • the first aspect of the present invention is to provide an improved process for the preparation of clopidogrel compound of formula- 1
  • the second aspect of the present invention is to provide an improved process for the preparation of clopidogrel hydrogen bromide compound of formula-3,
  • the fourth aspect of the invention is to provide an improved process for the preparation of form-I of clopidogrel hydrogen sulfate compound of formula-5
  • the fifth aspect of the invention is to provide an improved process for the preparation of form- 1 of clopidogrel hydrogen sulfate compound of formula-5
  • the starting material, clopidogrel free base can be prepared by the process disclosed in patents US 4847265, EP 0281459 or by the first aspect of the present invention or by any other prior art references.
  • Clopidogrel free base can be prepared from clopidogrel hydrogen chloride and / or clopidogrel hydrogen bromide and / or clopidogrel hydrogen sulfate and / or from clopidogrel camphor sulphonic acid salt and / or the above salt mixtures thereof.
  • Clopidogrel hydrogen sulfate form-I can be prepared from clopidogrel free base obtained either from clopidogrel hydrogen sulfate form-II and / or clopidogrel hydrogen chloride and / or clopidogrel hydrogen bromide and / or from clopidogrel camphor sulphonic acid salt and / or the above salt mixtures thereof.
  • Clopidogrel hydrogen chloride can be prepared from clopidogrel free base obtained either from clopidogrel hydrogen sulfate form-II and / or clopidogrel hydrogen sulfate form-I and / or clopidogrel hydrogen bromide and / or from clopidogrel camphor sulphonic acid salt and / or the above salt mixtures thereof.
  • Clopidogrel hydrogen bromide can be prepared from clopidogrel free base obtained either from clopidogrel hydrogen sulfate form-II or clopidogrel hydrogen sulfate form-I and / or clopidogrel hydrogen chloride and / or from clopidogrel camphor sulphonic acid salt and / or the above salt mixtures thereof.
  • a Malvern master sizer 2000 instrument was used to characterize the particle size distribution of clopidogrel hydrogen sulfate.
  • a Mastersizer 2000 model equipped with an air dispersion with laser scattering particle size distribution analyzer was used. The measurement was done using dry method analysis. The sample about 2.0 g well mixed sample in to a micro volume sample tray which available in Scirocco 2000 accessory.
  • Hydro 2000 S (A) instrument was used to characterize the particle size distribution of clopidogrel hydrogen bromide.
  • Hydro 2000 S (A) model equipped with liquid paraffin dispersion was used. The sample about 100 mg well mixed sample in 25 ml measurable test tube. Add few drops of liquid paraffin make a uniform paste. Add 20 ml of liquid paraffin then mix well and sonicate for 3 minutes externally. Add sample slowly into Hydro 2000 S (A) accessory until the obscuration is with in the range, wait for a while and perform the measurements.
  • the process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention
  • Example-1 Preparation of clopidogrel compound of formula-1:
  • Particle size 5 ⁇ m to 300 ⁇ m, [D(4,3) is about 5 to 150 ⁇ m and D(v,0.9) is about 150 to
  • a solution of 65 grams of clopidogrel base compound of formula- 1, 1140 ml of 2-butanol was treated with carbon at 20-30 0 C. Filtered the reaction mixture through hyflow. Added 18.80 grams of sulphuric acid to the filtrate at 20-30°C. Seeded the reaction mixture with clopidogrel bisulfate form-1. Stirred the reaction mixture for 26 hours at 20-3 O 0 C temperature. Filtered the precipitated solid and washed with 2-butanol and optionally washed with cyclohexane. Dried the material at 30-40°C for 4 hours and followed by dried at 90°C under reduced pressure to get title compound formula-5.
  • Particle size 50 ⁇ m to 300 ⁇ m, [D(4,3) is about 50 to 150 ⁇ m and D(v,0.9) is about 100 to 300 ⁇ m]
  • Particle size 50 ⁇ m to 300 ⁇ m, [0(4,3) is about 50 to 150 ⁇ m and D(v,0.9) is about 100 to 300 ⁇ m]

Abstract

The present invention provides an improved process for the preparation of clopidogrel and its pharmaceutically acceptable salts, especially hydrogen chloride and hydrogen bromide by dissolving clopidogrel base in a suitable single or mixture of solvents followed by adding suitable acid and isolating the corresponding acid addition salts of clopidogrel compound of formula-1. Also provides an improved process for the preparation of clopidogrel hydrogen sulfate form-1; Formula (I).

Description

An Improved Process For The Preparation Of Clopidogrel And Its Pharmaceutically Acceptable Salts
Related Applications:
This application claims the benefit of Indian patent application number 1812/CHE/2005; Indian patent application number 1158/CHE/2006 filed on July 4, 2006, all of which are incorporated herein by reference.
Field of the Invention:
The present invention relates to an improved process for the preparation of clopidogrel and its pharmaceutically acceptable salts, preferably hydrogen bromide compound of formula-3, hydrogen chloride compound of formula-4 and hydrogen sulfate form-I compound of formula-5. Clopidogrel is chemically known as methyl (+)-(S)-α-(o- chlorophenyl)-6, 7-dihydrothieno-[3,2-c]pyridine-5(4H)-acetate compound of formula-1.
Figure imgf000002_0001
Clopidogrel and its pharmaceutically acceptable salts may be used, in particular, for inhibiting platelet aggregation or for treating, preventing or managing thrombosis, atherothrombosis, an atherothrombotic event, ischaemic stroke, myocardial infarction, non-Q-wave myocardial infarction, atherosclerosis, peripheral arterial disease, or unstable angina.
Clopidogrel is marketed under the brand name of PLAVIX® tablets containing about 98 mg of clopidogrel bisulfate, which is the equivalent of 75 mg clopidogrel base. PLAVIX works by preventing platelets from sticking together to form clots that would strict blood flow. The enantiomer (+)-clopidogrel is particularly preferred since it is the pharmaceutically active compound.
Background of the Invention:
Clopidogrel and its pharmaceutically acceptable salts like hydrogen sulfate, hydrogen bromide and hydrogen chloride were first disclosed in US Patent 4847265. This patent also disclosed the process for the preparation of clopidogrel hydrogen sulfate, clopidogrel hydrogen bromide and clopidogrel hydrogen chloride.
US patent 5204469 discloses the process for the preparation of clopidogrel by reacting the (S)-methyl 2-(2-(thiophen-2-yl) ethylamino)-2-(2-chlorophenyl) acetate hydrochloride with formylating agent in presence of an acid, like a strong inorganic acid.
The main draw back of the said process is that the methyl ester of (S)-methyl 2-
(2-(thiophen-2-yl)ethylamino)-2-(2-chloiOphenyl)acetate compound hydrolyzes into an acid in presence of an strong acid like hydrochloric acid and sulfuric acid which in turn leads to formation of contaminated clopidogrel.
International publication WO 2004/081016 disclosed amorphous form of
(+)-clopidogrel bisulfate as well as composition of clopidogrel bisulfate form-I enriched with amorphous form of clopidogrel bisulfate and a composition of clopidogrel bisulfate form-II enriched with amorphous form of clopidogrel bisulfate.
International publication WO 2005/003139 disclosed process for the preparation of clopidogrel bisulfate form-I using ethers as a solvent medium specifically using diisopropyl ether as a solvent. The main drawback of this process is the usage of diisopropyl ether as a solvent, which is not recommendable for commercial scale up and its toxicology data is also not known. United states patent publication US 2003/0225129 disclosed process for the preparation of form-II of clopidogrel bisulfate using dichloromethane, 1,4-dioxane, toluene, chloroform, ethyl acetate, methyl ethyl ketone and tertiary butyl methyl ether.
International publication WO 03/051362 disclosed process for the preparation of clopidogrel bisulfate using 1-butanol as a solvent and also process for the preparation of clopidogrel bisulfate form-1 using methanol as a solvent for dissolution and using ether solvents as an anti solvent to precipitate the form-1 of clopidogrel bisulfate. The main drawback of this process is the usage of ether solvents, which are not recommendable for commercial scale up.
International publication WO 2004/020443 disclosed process for the preparation of clopidogrel bisulfate form-1 using primary, secondary or tertiary C1-C5 alcohols or their esters with C1-C4 carboxylic acids, or optionally of mixtures thereof and cooling the obtained solution to precipitate form-1 of clopidogrel bisulfate. Clopidogrel bisulfate precipitated out of a solution of Ci-C5 alcohol and 2-propanol.
The main draw back of this process is that the clopidogrel or its salts are freely soluble in methanol and ethanol. Clopidogrel bisulfate will not precipitate out even if we cool methanol or ethanol solution up to 00C. We studied the process using 2-propanol and 1-butanol as solvent medium and observed that these solvents are not consistently producing form-I of clopidogrel hydrogen sulfate. When we used 2-butanol as a solvent to prepare clopidogrel hydrogen sulfate form-I and we got consistent results, so 2-butanol is the suitable solvent to produce clopidogrel hydrogen sulfate form-I consistently. So the claim C1-C5 alcohol has no scientific meaning.
International publication WO 2005/026174 discloses polymorphic forms of clopidogrel hydrogen bromide and process for their preparation. The disclosed process involves the usage of mixture of solvents (2-propanol and diisopropyl ether) for the preparation of form-1 of clopidogrel hydrogen bromide. Mixtures of solvents are not suggestible for industrial scale up and the use of diisopropyl ether is also not recommendable for scale up.
International publication WO 2003/066637 discloses polymorphic forms of clopidogrel hydrogen chloride and process for their preparation. The disclosed the process of form-I and form-II by using solvents tetrahydrofuran, ethyl acetate, acetone and mixtures thereof.
The present invention provides an improved process for the preparation of clopidogrel and its pharmaceutically acceptable salts especially hydrogen sulfate, hydrogen bromide and hydrogen chloride. And the present invention also provides an improved process for the preparation of clopidogrel, clopidogrel hydrogen sulfate Form-I, hydrogen bromide and hydrogen chloride which is cost effective and easy to scale up. In this specification we mentioned clopidogrel base, clopidogrel bisulfate, clopidogrel hydrogen chloride and clopidogrel hydrogen bromide, which means (+) (S) clopidogrel base, (+) (S) clopidogrel bisulfate, (+) (S) clopidogrel hydrogen chloride and (+) (S) clopidogrel hydrogen bromide.
The present invention provides an improved process for the preparation of clopidogrel, clopidogrel hydrogen bromide, clopidogrel hydrogen chloride and clopidogrel bisulfate form-I which is simple, easily scalable and commercially viable.
Brief description of the Invention:
In accordance with the present invention an improved process is provided for the preparation of clopidogrel and its pharmaceutically acceptable salts, particularly hydrogen bromide, hydrogen chloride and hydrogen sulfate form-I.
The first aspect of the present invention is to provide an improved process for the preparation of clopidogrel compound of formula- 1 ,
Figure imgf000006_0001
which comprises of reacting free base of (S)-methyl 2-(2-(thiophen-2-yl)ethylamino)-2- (2-chlorophenyl)acetate compound of formula-2
Figure imgf000006_0002
with formalin solution in presence of an organic acid or lewis acid or resins in a suitable solvent gives clopidogrel compound of formula- 1.
The (S)-methyl 2-(2-(thiophen-2-yl) ethylamino)-2- (2-chlorophenyl) acetate compound of formula-2 can be prepared by the process disclosed in US 5204469 or by any other process known in the prior art.
The second aspect of the present invention is to provide an improved process for the preparation of clopidogrel hydrogen bromide compound of formula-3
.HBr
Figure imgf000006_0003
Which comprises of the following steps, a) Dissolving the clopidogrel in a suitable solvent or mixture of solvents, b) Treating with activated carbon, c) Adding aqueous hydrogen bromide solution to the filtrate, d) Stirring the reaction mixture for 1 to 15 hours, e) Isolating the product by filtration and drying the material gives clopidogrel hydrogen bromide compound of formula-3.
The third aspect of the present invention is to provide an improved process for the preparation of clopidogrel hydrogen chloride compound of formula-4,
Figure imgf000007_0001
Formula-4
Which comprises of the following steps, a) Dissolving the clopidogrel in a suitable solvent, b) Passing hydrochloric acid gas or adding isopropyl alcohol containing hydrochloric acid to the above solution, c) Stirring the reaction mixture for about 10 to 20 hours, d) Isolating the product by filtration and drying the material gives clopidogrel hydrogen chloride compound of formula-4, e) Optionally slurrying the above obtained clopidogrel hydrogen chloride in 2-propanol gives coarse material of clopidogrel hydrogen chloride.
The fourth aspect of the present invention is to provide an improved process for the preparation of form-I of clopidogrel hydrogen sulfate compound of formula-5,
Figure imgf000008_0001
Which comprises of the following steps, a) Dissolving the clopidogrel in a suitable solvent, b) Treating the above solution with activated carbon, c) Adding sulphuric acid to the filtrate, d) Stirring the reaction mixture for 15-25 hours, e) Isolating the product by filtration and drying the material gives clopidogrel bisulfate form-1 compound of fonnula-5.
The fifth aspect of the present invention is to provide an improved process for the preparation of form-I of clopidogrel hydrogen sulfate compound of formula-5,
Figure imgf000008_0002
Which comprises of the following steps, a) Dissolving the clopidogrel in a suitable solvent, b) Treating the above solution with activated carbon, c) Adding diluted sulphuric acid to the filtrate, d) Stirring the reaction mixture for 10-15 hours, e) Isolating the product by filtration and drying the material gives clopidogrel bisulfate form-1 compound of formula-5. Brief Description of the Drawings:
Figure-1: Illustrates clopidogrel hydrogenbromide having a plate-shaped morphology as seen through microscope.
Detailed description of the Invention:
In accordance with the present invention an improved process is provided for the preparation of clopidogrel and its pharmaceutically acceptable salts, particularly hydrogen bromide compound of formula-3, hydrogen chloride compound of formula-4 and hydrogen sulfate form-I compound of formula-5.
The first aspect of the present invention is to provide an improved process for the preparation of clopidogrel compound of formula- 1
Figure imgf000009_0001
which comprises of reacting (S)-methyl 2-(2-(thiophen-2-yl)ethylamino)-2-(2- chlorophenyl)acetate compound of formula-2
Figure imgf000009_0002
with formalin solution in presence of an organic acid like para toluene sulfonic acid or lewis acid like zinc chloride or resins in a suitable solvents like methanol, ethanol, 2-propanol, methylene chloride, or mixtures thereof, to give the compound of formula- 1. The first aspect of the present invention is schematically represented as follows
Figure imgf000010_0001
Formula-2 Formula- 1
The second aspect of the present invention is to provide an improved process for the preparation of clopidogrel hydrogen bromide compound of formula-3,
Figure imgf000010_0002
Which comprises of the following steps, a) Dissolving the clopidogrel in a suitable solvent selected from cyclohexane, hexanes, 2-propanol or mixtures thereof at a temperature ranges from 10-50°C, preferably at a temperature of about 25-350C, b) Treating the above obtained solution with carbon at 25-35°C, c) Adding aqueous hydrogen bromide solution to the above obtained filtrate at a temperature ranges from 15-30°C, preferably at a temperature of about 10-20°C and most preferably at 10-15°C, d) Stirring the reaction mixture for 10 to 20 hours, preferably for 10-14 hours at a temperature ranges from 15-45°C, preferably at 25-35°C, e) Isolating the solid by filtration and washing the material with suitable solvent selected from cyclohexane, hexanes, 2-propanol or mixtures thereof, f) Drying the product at 40-80°C under reduced pressure gives clopidogrel hydrogen bromide compound of formula-3. The third aspect of the invention is to provide an improved process for the preparation of clopidogrel hydrogen chloride compound of formula-4,
Figure imgf000011_0001
Which comprises of the following steps, a) Dissolving the clopidogrel in a suitable solvent selected from organic solvents like cyclohexane, isopropyl alcohol, toluene preferably cyclohexane at a temperature range from 10-50°C, preferably at 25-35°C5 b) Introducing hydrochloric acid by means of passing hydrogen chloride gas or adding hydrochloric acid in isopropyl alcohol slowly to the above obtained solution at a temperature range from -10 to 50°C, preferably at 25-35°C, c) Stirring the reaction mixture for 1 to 20 hours, preferably for 15 to 20 hours at a temperature range from 10 to 50°C, preferably at 25 to 35°C, d) Isolating the product by filtration and washing the material with suitable solvent selected from organic solvents like cyclohexane, isopropyl alcohol, toluene preferably mixture of cyclohexane and isopropyl alcohol, e) Drying the product at 30-60°C under reduced pressure gives clopidogrel hydrogen chloride compound of formula-4, f) Optionally slurrying the above obtained clopidogrel hydrogen chloride in 2-propanol at 25-35°C gives coarse material of clopidogrel hydrogen chloride.
The fourth aspect of the invention is to provide an improved process for the preparation of form-I of clopidogrel hydrogen sulfate compound of formula-5
Figure imgf000012_0001
Which comprises of the following steps; a) Dissolving the Clopidogrel in a suitable solvent like 2-butanol, b) Treating the above obtained solution with carbon at 20-300C, c) Adding sulphuric acid to the above obtained filtrate at a temperature ranges from 5-3O0C, preferably at 20-30°C, d) Stirring the reaction mixture for 10 to 28 hours, preferably for 18-20 hours at a temperature ranges from 15-45°C, preferably at 20-300C, e) Isolating the solid by filtration and wash the material with 2-butanol, optionally wash with cyclohexane solvent also, f) Drying the material at 20-500C for 2-5 hours and finally drying at 70-1000C under reduced pressure gives clopidogrel hydrogen sulfate Form-I.
The fifth aspect of the invention is to provide an improved process for the preparation of form- 1 of clopidogrel hydrogen sulfate compound of formula-5
Figure imgf000012_0002
Which comprises of the following steps; a) Dissolving the clopidogrel in a suitable solvent such as ester solvent like ethyl acetate, methyl acetate, isopropyl acetate, ketone solvent like acetone or mixtures thereof preferably a mixture of ethyl acetate and acetone, b) Treating the above obtained solution with carbon at 20-300C3 c) Adding diluted sulphuric acid to the above obtained filtrate at a temperature range from 0-300C5 preferably at 0-20°C, d) Stirring the reaction mixture for 5 to 18 hours, preferably for 8-14 hours at a temperature range from 15-45°C, preferably at 18-200C, e) Isolating the product by filtration and wash the material with a mixture of ethyl acetate and acetone, f) Drying the product at 20-500C for 2-5 hours and followed by drying at 70-100°C under reduced pressure gives clopidogrel hydrogen sulfate form-I compound of formula-5.
The starting material, clopidogrel free base can be prepared by the process disclosed in patents US 4847265, EP 0281459 or by the first aspect of the present invention or by any other prior art references.
Clopidogrel free base can be prepared from clopidogrel hydrogen chloride and / or clopidogrel hydrogen bromide and / or clopidogrel hydrogen sulfate and / or from clopidogrel camphor sulphonic acid salt and / or the above salt mixtures thereof.
Clopidogrel hydrogen sulfate form-I can be prepared from clopidogrel free base obtained either from clopidogrel hydrogen sulfate form-II and / or clopidogrel hydrogen chloride and / or clopidogrel hydrogen bromide and / or from clopidogrel camphor sulphonic acid salt and / or the above salt mixtures thereof.
Clopidogrel hydrogen chloride can be prepared from clopidogrel free base obtained either from clopidogrel hydrogen sulfate form-II and / or clopidogrel hydrogen sulfate form-I and / or clopidogrel hydrogen bromide and / or from clopidogrel camphor sulphonic acid salt and / or the above salt mixtures thereof.
Clopidogrel hydrogen bromide can be prepared from clopidogrel free base obtained either from clopidogrel hydrogen sulfate form-II or clopidogrel hydrogen sulfate form-I and / or clopidogrel hydrogen chloride and / or from clopidogrel camphor sulphonic acid salt and / or the above salt mixtures thereof.
Particle size determination: Clopidogrel hydrogen sulfate samples PSD measurement by Malvern particle size analyzer "Master sizer 2000"
A Malvern master sizer 2000 instrument was used to characterize the particle size distribution of clopidogrel hydrogen sulfate. A Mastersizer 2000 model equipped with an air dispersion with laser scattering particle size distribution analyzer was used. The measurement was done using dry method analysis. The sample about 2.0 g well mixed sample in to a micro volume sample tray which available in Scirocco 2000 accessory.
Start SOP and then take 4 measurements.
Clopidogrel hydrogen bromide samples PSD measurement by particle size analyzer "Hydro 2000 S (A)"
Handling unit Hydro2000S(A) Dispersant Liquid paraffin Dispersant RI 1.468 Sensitivity Normal
Particle shape Irregular Obscuration Range 10-20%
A Hydro 2000 S (A) instrument was used to characterize the particle size distribution of clopidogrel hydrogen bromide. Hydro 2000 S (A) model equipped with liquid paraffin dispersion was used. The sample about 100 mg well mixed sample in 25 ml measurable test tube. Add few drops of liquid paraffin make a uniform paste. Add 20 ml of liquid paraffin then mix well and sonicate for 3 minutes externally. Add sample slowly into Hydro 2000 S (A) accessory until the obscuration is with in the range, wait for a while and perform the measurements. The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention
Examples: Example-1: Preparation of clopidogrel compound of formula-1:
Added 7 grams of paratoluene sulfonic acid to a solution of 100 grams of (S)-methyl 2-(2-(thiophen-2-yl)ethylamino)-2-(2-chlorophenyl)acetate compound of formula-2, 800ml of formalin solution and 200 ml of methanol at 20-25 °C. Heated the reaction mixture to 50-55°C. Stirred the reaction mixture at 50-55°C for 28 hours. Cooled the reaction mixture to 20-25°C. Quenched the reaction mixture with water. Adjusted the pH of the reaction mixture to 7.9 with 10% sodium bicarbonate solution. Extracted the reaction mixture with methylene chloride. Separated the organic and aqueous layer. Washed the organic layer with water then dried the organic layer over sodium sulphate. Distilled the solvent completely under reduced pressure to get the title compound of formula-1 as a residue. Yield : 120 grams
Example-2:
Preparation of clopidogrel compound of formula-1:
Added 50 grams of Zinc chloride to a solution of 100 grams of (S)-methyl 2-(2- (thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate compound of formula-2, 800 ml of formalin solution and 200 ml of methanol at 20-25°C. Heated the reaction mixture to 50-55°C. Stirred the reaction mixture at 50-550C for 28 hours. Cooled the reaction mixture to 20-250C. Quenched the reaction mixture with water. Adjusted the pH of the reaction mixture to 7.9 with 10% sodium bicarbonate solution. Extracted the reaction mixture with methylene chloride. Separated the organic and aqueous layer. Washed the organic layer with water then dried the organic layer over sodium sulphate. Distilled the solvent completely under reduced pressure to get the title compound of formula- 1 as a residue.
Yield : 70 grams
Example-3:
Preparation of clopidogrel hydrogen bromide compound of formula-3:
Dissolved 30 grams of clopidogrel base compound of formula-1 in 240 ml of cyclohexane at 25-35°C. Added 8 ml of aqueous hydrogen bromide solution slowly at
10-15°C. Stirred the reaction mixture for 14 hours at 25-35°C. Filtered the precipitated solid and washed with cylcohexane. Dried the material at 50-60°C to get title compound of formula-3.
Yield: 32 grams
Water content: 4.0%
Melting Range: 101 to 1100C (shrinking from 70 to 900C) Particle size: 5 μm to 400 μm, [D(4,3) is about 5 to 200 μm and D(v,0.9) is about 200 to
400 μm]
Example-4:
Preparation of clopidogrel hydrogen bromide compound of formula-3: A solution of 150 grams of clopidogrel base compound of formula-1, 750 ml of cylcohexane and 300 ml of isopropyl alcohol was treated with carbon at 25-35°C. Filtered the reaction mixture through hyflow. Added 60 ml of aqueous hydrogen bromide solution slowly to the filtrate at 10-150C. Stirred the reaction mixture for 14 hours at 25-35°C. Filtered the precipitated solid and washed with mixture of cylcohexane and isopropyl alcohol. Dried the material at 50-60°C to get title compound of formula-3. Yield: 170 gram Water content: 3.7%
Melting Range: 101 to 110°C (shrinking from 70 to 90°C) Particle size: 5 μm to 400 μm, [D(4,3) is about 5 to 200 μm and D(v,0.9) is about 200 to 400 μm] ExampIe-5:
Preparation of clopidogrel hydrogen chloride compound of formula-4:
Dissolved 30 grams of clopidogrel base compound of formula- 1 in mixture of 60 ml of cyclohexane and 18 ml of isopropyl alcohol at 25-35°C. Added 12 ml of isopropyl alcohol containing hydrochloric acid to above solution at 25-35°C. Stirred the reaction mixture at 25-35°C for 15-20 hours. Filtered the precipitated solid and washed with the mixture of cyclohexane and isopropyl alcohol solvents in the ratio of 1 : 2. Dried the material at 40-50°C under reduced pressure to get title compound of formula-4. Yield: 60 grams Particle size: 5 μm to 300 μm, [D(4,3) is about 5 to 150 μm and D(v,0.9) is about 150 to 300 μm]
Example-6:
Preparation of clopidogrel hydrogen chloride compound of formula-4: Added 58 ml of isopropyl alcohol containing hydrochloric acid gas to a solution
145 grams of clopidogrel base compound of formula-1, 430ml of cyclohexane at 0-10°C.
Stirred the reaction mixture for 3 hours at 10-15°C. Allowed the reaction mixture to attain the temperature of about 25-35°C. Stirred the reaction mixture at 25-35°C for
8 hours. Cooled the reaction mixture to 0-5°C and stirred for 2 hours at 0-5°C. Filtered the precipitated solid and washed with cyclohexane. Dried the material at 40-500C under reduced pressure to get title compound of formula-4.
Yield: 89 grams
Particle size: 5 μm to 300 μm, [D(4,3) is about 5 to 150 μm and D(v,0.9) is about 150 to
300 μm] A mixture of 65 grams of clopidogrel hydrogen chloride and 108 ml of isopropyl alcohol stirred for 60 minutes at 25-35°C. Filtered the solid. Dried the material at
40-50°C to get coarse material of Clopidogrel hydrogen chloride.
Yield: 43 grams Example-7:
Preparation clopidogrel hydrogen sulfate form-1 compound of formula-5:
A solution of 65 grams of clopidogrel base compound of formula- 1, 1140 ml of 2-butanol was treated with carbon at 20-300C. Filtered the reaction mixture through hyflow. Added 18.80 grams of sulphuric acid to the filtrate at 20-30°C. Seeded the reaction mixture with clopidogrel bisulfate form-1. Stirred the reaction mixture for 26 hours at 20-3 O0C temperature. Filtered the precipitated solid and washed with 2-butanol and optionally washed with cyclohexane. Dried the material at 30-40°C for 4 hours and followed by dried at 90°C under reduced pressure to get title compound formula-5.
Yield: 32 grams
Particle size: 50 μm to 300 μm, [D(4,3) is about 50 to 150 μm and D(v,0.9) is about 100 to 300 μm]
Example-8:
Preparation of Clopidogrel hydrogen sulphate form-I compound of formula-5:
Dissolved 60 Kgs. of clopidogrel base compound of formula- 1 in a mixture of 386 liters of ethyl acetate and 60 liters of acetone at 25-30°C. Stirred the reaction mixture for 30 minutes at 25-30°C. Cooled the reaction mixture to 0-50C. Added 9.32 Kgs. of sulfuric acid in 220 liters of ethyl acetate at 0-50C for 4 hours. Stirred the reaction mixture at 0-50C for 3 hours. Slowly raised the reaction mixture temperature to 190C. Stirred the reaction mixture at 19°C for 11 hours. Filtered the solid and washed with a mixture of ethyl acetate and acetone. Dried the material at 30-400C for 4 hours followed by at 90°C under reduced pressure to get the title compound of formula-5. Yield: 30 Kgs.
Particle size: 50 μm to 300 μm, [0(4,3) is about 50 to 150 μm and D(v,0.9) is about 100 to 300 μm]

Claims

We Claim:
1. An improved process for the preparation of clopidogrel compound of formula- 1
Figure imgf000019_0001
Formula- 1
which comprises of reacting (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2- chlorophenyl)acetate compound of formula-2
Figure imgf000019_0002
Formula-2
with formalin solution in presence of an organic acid like para toluene sulfonic acid or lewis acid like zinc chloride or resins in a suitable solvents like methanol, ethanol, 2-propanol, methylene chloride, or mixtures thereof, gives the compound of formula- 1.
2. The process according to claim 1, wherein the organic acid or lewis acid used is paratoluene sulfonic acid and zinc chloride.
3. An improved process for the preparation of clopidogrel hydrogen bromide compound offormula-3,
Figure imgf000020_0001
which comprises of the following steps, a) Dissolving the clopidogrel in a suitable solvent selected from cyclohexane, hexanes, 2-propanol or mixtures thereof, b) Treating the above solution with carbon at 25-35°C, c) Adding aqueous hydrogen bromide solution to the filtrate at a temperature ranges from 15-300C, preferably at a temperature of about 10-20°C and most preferably at 10-150C, d) Stirring the reaction mixture for 10 to 20 hours, preferably for 10-14 hours at a temperature ranges from 15-45°C, preferably at 25-35°C, e) Isolating the solid by filtration and wash the material with suitable solvent selected from cyclohexane, hexanes, 2-propanol or mixtures thereof gives clopidogrel hydrogen bromide.
4. The process according to claim 3a, wherein the solvent is selected from cyclohexane, 2-propanol or mixtures thereof.
5. An improved process for the preparation of Clopidogrel hydrogen chloride compound offormula-4,
Figure imgf000020_0002
which comprises of the following steps, a) Dissolving the clopidogrel in a suitable organic solvent selected from like cyclohexane, isopropyl alcohol, toluene preferably mixture of cyclohexane and isopropyl alcohol, b) Adding isopropyl alcohol containing hydrochloric acid slowly to the above solution at ambient temperature, preferably at 25-35 °C, c) Stirring the reaction mixture for 20 hours, preferably at 25-35°C, d) Isolating the solid by filtration and wash the material with suitable solvent selected from organic solvents like cyclohexane, isopropyl alcohol, toluene preferably the mixture of cyclohexane and isopropyl alcohol gives clopidogrel hydrogen chloride, e) Optionally slurrying the clopidogrel hydrogen chloride in 2-propanol gives coarse material of clopidogrel hydrogen chloride.
6. The process according to claim 5a, wherein the solvent selected from cyclohexane, toluene, 2-propanol or mixtures thereof.
7. An improved process for the preparation of form-I of clopidogrel hydrogen sulfate compound of formula-5,
Figure imgf000021_0001
which comprising of the following steps; a) Dissolving the clopidogrel in a suitable solvent like 2-butanol, b) Treating the above obtained solution with carbon at 20-30°C, c) Adding sulphuric acid to the above obtained filtrate at a temperature ranges from 5-350C, preferably at 20-300C, d) Stilting the reaction mixture for 10 to 28 hours, preferably for 18-20 hours at a temperature ranges from 15-450C3 preferably at 20-300C, e) Isolating the solid by filtration and wash the material with a mixture of 2-butanol, f) Drying the material at tray drier at 20-500C and followed by continuous drying in the rotary cone vacuum drier at 70-100°C gives clopidogrel hydrogen sulfate form-I.
8. An improved process for the preparation of form-I of clopidogrel hydrogen sulfate compound of formula-5,
Figure imgf000022_0001
Which comprises of the following steps; a) Dissolving the clopidogrel in a suitable solvent such as ester solvent like ethyl acetate, methyl acetate, isopropyl acetate, ketone solvent like acetone or mixtures thereof preferably a mixture of ethyl acetate and acetone, b) Treating the above obtained solution with carbon at 20-300C, c) Adding diluted sulphuric acid to the above obtained filtrate at a temperature range from 0-30°C, preferably at 0-200C, d) Stirring the reaction mixture for 5 to 18 hours, preferably for 8-14 hours at a temperature range from 15-35°C, preferably at 18-200C, e) Isolating the product by filtration and wash the material with a mixture of ethyl acetate and acetone, f) Drying the product at 20-500C for 2-5 hours and followed by drying at 70- 1000C under reduced pressure gives clopidogrel hydrogen sulfate form-I compound of formula-5.
9. The process according to claim 8a, wherein the solvent used is a mixture of ethyl acetate and acetone.
10. Clopidogrel hydrogenbromide having a plate morphology as shown in figure- 1.
PCT/IN2007/000269 2006-07-04 2007-07-03 An improved process for the preparation of clopidogrel and its pharmaceutically acceptable salts WO2008004249A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1158/CHE/2006 2006-07-04
IN1158CH2006 2006-07-04

Publications (2)

Publication Number Publication Date
WO2008004249A2 true WO2008004249A2 (en) 2008-01-10
WO2008004249A3 WO2008004249A3 (en) 2008-04-10

Family

ID=38895004

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2007/000269 WO2008004249A2 (en) 2006-07-04 2007-07-03 An improved process for the preparation of clopidogrel and its pharmaceutically acceptable salts

Country Status (1)

Country Link
WO (1) WO2008004249A2 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008118030A1 (en) * 2007-03-23 2008-10-02 Tomasz Kozluk Process for preparation of pure polymorphic form 1 of clopidogrel hydrogensulfate
WO2009060712A1 (en) 2007-11-09 2009-05-14 Toyota Jidosha Kabushiki Kaisha Screw fastening device
WO2011055378A1 (en) * 2009-11-09 2011-05-12 Pharmazell Gmbh Improved process for preparation of clopiodogrel bisulfate crystalline form-1
WO2011042804A3 (en) * 2009-10-08 2011-07-21 Jubliant Life Sciences Limited An improved process for the preparation of clopidogrel hydrogen sulfate form i

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003066637A1 (en) * 2002-02-06 2003-08-14 EGIS Gyógyszergyár Rt. Polymorphs of clopidogrel hydrochloride and their use as antithrombic compounds
US20040260110A1 (en) * 1997-10-06 2004-12-23 Andre Bousquet Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates
WO2005104663A2 (en) * 2004-03-05 2005-11-10 Ipca Laboratories Limited Industrial process for preparation of clopidogrel hydrogen sulphate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040260110A1 (en) * 1997-10-06 2004-12-23 Andre Bousquet Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates
WO2003066637A1 (en) * 2002-02-06 2003-08-14 EGIS Gyógyszergyár Rt. Polymorphs of clopidogrel hydrochloride and their use as antithrombic compounds
WO2005104663A2 (en) * 2004-03-05 2005-11-10 Ipca Laboratories Limited Industrial process for preparation of clopidogrel hydrogen sulphate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: 'Synthesis of the stable polymorph I of Clopidogrel hydrobromide' RESEARCH DISCLOSURE (MASON PUBLICATIONS) vol. 490, no. 4, 01 February 2005, HAMPSHIRE, GB, XP007134723 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008118030A1 (en) * 2007-03-23 2008-10-02 Tomasz Kozluk Process for preparation of pure polymorphic form 1 of clopidogrel hydrogensulfate
WO2009060712A1 (en) 2007-11-09 2009-05-14 Toyota Jidosha Kabushiki Kaisha Screw fastening device
WO2011042804A3 (en) * 2009-10-08 2011-07-21 Jubliant Life Sciences Limited An improved process for the preparation of clopidogrel hydrogen sulfate form i
WO2011055378A1 (en) * 2009-11-09 2011-05-12 Pharmazell Gmbh Improved process for preparation of clopiodogrel bisulfate crystalline form-1

Also Published As

Publication number Publication date
WO2008004249A3 (en) 2008-04-10

Similar Documents

Publication Publication Date Title
US20080051581A1 (en) Novel process for the manufacture of (+)-(S)-clopidogrel bisulfate form-1
WO2008004249A2 (en) An improved process for the preparation of clopidogrel and its pharmaceutically acceptable salts
EP1680430B1 (en) Processes for preparing form i of (s)-(+)- clopidogrel bisulfate
EP1927595A2 (en) Salts of clopidogrel and process for preparation
US20060074242A1 (en) Rapid resolution process of clopidogrel base and a process for preparation of clopidogrel bisulfate polymorph-form I
US20090247569A1 (en) Process for Preparing Clopidogrel Bisulphate
US20120232274A1 (en) Process for preparation of clopiodogrel bisulfate form-1
WO2008068569A2 (en) Processes for the preparation of clopidogrel hydrochloride
KR20110047068A (en) Process for preparing crystalline Form ?Clopidogrel bisulfate
US20080182869A1 (en) Method of Racemization of the R(-) Isomer of the (2-Chlorophenyl)-6,7-Dihydrothieno[3,2-C]Pyridine-5(4H)-Acetic Acid Methyl Ester
CA2530449A1 (en) Process for the preparation of crystalline polymorph of a platelet aggregation inhibitor drug
WO2007102037A3 (en) A PROCESS FOR THE PREPARATION OF POLYMORPH FORM I OF (S)-(+)-METHYL-α-(2-CHLOROPHENYL)-6,7-DYHIDRO-THIENO-[3,2-c]PYRIDINE-5(4H)-ACETATE HYDROGEN SULFATE
WO2011083955A2 (en) Method for manufacturing crystalline form (i) of clopidogrel hydrogen sulphate
WO2006117614A1 (en) Process for the preparation of pramipexole and new anhydrous forms of its dihydrochloride
EP2107061A1 (en) Process for the preparation of optically enriched clopidogrel
US20110118467A1 (en) Process for the preparation of clopidogrel hydrogen sulfate crystalline form i
WO2004081015A1 (en) Amorphous clopidogrel hydrogen sulfate
US20080319189A1 (en) Processes for the synthesis of olanzapine
US20110190502A1 (en) Process for the preparation of s-clopidogrel
MX2008007340A (en) Process for the preparation of s-(+)-clopidogrel by optical resolution.
US7960550B2 (en) Process for preparing (S)-(+)-clopidogrel base and its salts
WO2009080469A1 (en) Process for the preparation of clopidogrel bisulphate form i
WO2008146249A1 (en) Processes for the preparation of clopidogrel
SK50112006A3 (en) Process for preparation of amorphous form of platelet aggregation inhibitor drug
WO2007144895A1 (en) Process for the preparation of (s) - (+)-clopidogrel

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07827509

Country of ref document: EP

Kind code of ref document: A2

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase in:

Ref country code: DE

NENP Non-entry into the national phase in:

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 07827509

Country of ref document: EP

Kind code of ref document: A2