WO2009066326A2 - Improved process for the preparation of prasugrel and its pharmaceutically acceptable salts - Google Patents
Improved process for the preparation of prasugrel and its pharmaceutically acceptable salts Download PDFInfo
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- WO2009066326A2 WO2009066326A2 PCT/IN2008/000773 IN2008000773W WO2009066326A2 WO 2009066326 A2 WO2009066326 A2 WO 2009066326A2 IN 2008000773 W IN2008000773 W IN 2008000773W WO 2009066326 A2 WO2009066326 A2 WO 2009066326A2
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- 0 *N(CCC1S2)CC1=CC2=O Chemical compound *N(CCC1S2)CC1=CC2=O 0.000 description 2
- QOCGQCZGPLPEHC-UHFFFAOYSA-N CC(C(c(cccc1)c1F)Br)C1CC1 Chemical compound CC(C(c(cccc1)c1F)Br)C1CC1 QOCGQCZGPLPEHC-UHFFFAOYSA-N 0.000 description 1
- MFKSRGYMUVUYKG-UHFFFAOYSA-N O=C(C(C(C=CCC1)=C1F)N(CC1)Cc2c1[s]c(OC(C(C1CC1)=O)c(cccc1)c1F)c2)C1CC1 Chemical compound O=C(C(C(C=CCC1)=C1F)N(CC1)Cc2c1[s]c(OC(C(C1CC1)=O)c(cccc1)c1F)c2)C1CC1 MFKSRGYMUVUYKG-UHFFFAOYSA-N 0.000 description 1
- LMCZCCDXOZGIND-UHFFFAOYSA-N O=C(C(c(cccc1)c1F)Br)C1CC1 Chemical compound O=C(C(c(cccc1)c1F)Br)C1CC1 LMCZCCDXOZGIND-UHFFFAOYSA-N 0.000 description 1
- MJAMUSZUMAHFLH-UHFFFAOYSA-N O=C(C(c(cccc1)c1F)N(CCC1S2)CC1=CC2=O)C1CC1 Chemical compound O=C(C(c(cccc1)c1F)N(CCC1S2)CC1=CC2=O)C1CC1 MJAMUSZUMAHFLH-UHFFFAOYSA-N 0.000 description 1
- PYQVFGJHIWJNFS-UHFFFAOYSA-N O=C1SC(CCNC2)C2=C1 Chemical compound O=C1SC(CCNC2)C2=C1 PYQVFGJHIWJNFS-UHFFFAOYSA-N 0.000 description 1
Classifications
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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 an improved process for the preparation of prasugrel and its pharmaceutically acceptable salts.
- Prasugrel is chemically known as 2-acetoxy-5-( ⁇ -cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno [3,2-c] pyridine having structural formula-1,
- [3,2-c]pyridine derivatives have been initially disclosed in Japanese provisional patent publication No.130289/1991 & 41139/1994.
- Prasugrel and its pharmaceutically acceptable salts have been disclosed in US patent 5,288,726.
- the disclosed process for the preparation of prasugrel and its pharmaceutically acceptable salts involves the acetylation of 5-( ⁇ -cyclopropylcarbonyl-2-fluoro benzy)-2-oxo-2,4,5,6,7,7a-hexahydrothienq[3,2-c]pyridine in the presence of a strong base like sodium hydride. But use of strong base like sodium hydride is not advisable when the reaction is performed at an industrial scale.
- the present invention overcomes the problems associated with the prior art, and provides a process for the preparation of prasugrel and its pharmaceutically acceptable salts, with better yields and purity.
- the present invention relates to an improved process for the preparation of prasugrel.
- the first aspect of the present invention is to provide a process for the preparation of prasugrel and its pharmaceutically acceptable salts, which comprises of; a) protecting the amino functional group of 4,5,6,7-tetrahydrothieno[3,2-c] pyridine compound of formula-2 or its salts,
- the second aspect of the present invention is to provide a process for the purification of prasugrel compound of formula- 1.
- the third aspect of the present invention is to provide an improved process for the preparation of highly pure l-cyclopropyl-2-(2-fluorophenyl)ethanone.
- Figure-1 Illustrates the powder X-ray diffraction pattern of Prasugrel
- Figure-2 Illustrates the powder X-ray diffraction pattern of Prasugrel fumatrate
- Figure-3 Illustrates the powder X-ray diffraction pattern of Prasugrel hydrochloride
- Figure-4 Illustrates the powder X-ray diffraction pattern of Prasugrel maleate
- PG refers to protecting group which is selected from trityl, BOC (tert-butyloxy carbonyl) and benzoyl.
- the term "pharmaceutically acceptable salts” refers to the salt compound formed with a suitable acid selected from an inorganic acid addition salts such as hydrochloric acid, hydrobromic acid; or an organic acid such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p-toluenesulfonic acid and malic acid.
- a suitable acid selected from an inorganic acid addition salts such as hydrochloric acid, hydrobromic acid; or an organic acid such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p-toluenesulfonic acid and malic acid.
- highly pure prasugrel refers to prasugrel with the purity equal to 99.50 % or more by HPLC.
- the term "highly pure l-cyclopropyl-2-(2-fluorophenyl) ethanone” refers to l-cyclopropyl-2-(2-fluorophenyl)ethanone with the purity equal to 85.00 % or more by HPLC.
- the present invention relates to an improved process for the preparation of prasugrel.
- Prasugrel is chemically known as 2-acetoxy-5-( ⁇ -cyclopropylcarbonyl-2- fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine.
- the first aspect of the invention provides an improved process for the preparation of prasugrel compound of formula- 1 and its pharmaceutically acceptable salts, which comprises of; a) protecting the amino functional group of 4,5,6,7-tetrahydrothieno[3,2-c] pyridine compound of formula-2 or its salts, Formula-2 with suitable amino protecting agent selected from benzoyl chloride, BOC anhydride and triphenyl methyl chloride preferably triphenyl methyl chloride, in presence of a suitable base selected from a group of organic bases selected from triethylamine, tributylamine, pyridine, N-methyl morpholine or 4-dimethylamino pyridine preferably triethyl amine, in a suitable solvent selected from dichloromethane, dichloroethane, carbontetrachloride, dioxane, dimethyl acetamide and N-methyl pyrrolidine preferably methylene chloride, followed by crystallization from a suitable solvent
- Formula-6 in presence of suitable base selected from a group consisting of alkali metal carbonates like sodium carbonate, potassium carbonate; or an alkali metal hydroxide like sodium hydroxide, potassium hydroxide; or alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate; or an organic base like triethylamine, tributylamine, diisopropylethlyamine preferably sodium carbonate, in a suitable solvent selected from diisopropylether, tetrahydrofuran, dimethylformamide, dimethoxy ethane, diethyl ketone, propyl acetate, butyl acetate, acetonitrile and propionitrile preferably dimethylformamide, to provide compound of formula-7,
- a suitable acid selected from an inorganic acid such as hydrochloric acid, hydrobromic acid; or an organic acid such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p-tolunesulfonic acid and malic acid, in a suitable solvent selected from aliphatic hydrocarbons like hexane, cyclohexane, petroleum ether; or aromatic hydrocarbons like xylene, toluene; or halogenated hydrocarbons like dichloromethane, chloroform, 1,2-dichloroethane; or ethers like diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxy ethane; or ketones like acetone, methyl ethyl ketone, diethyl ketone; or acetates like e
- a suitable acid selected from an inorganic acid such as hydrochloric acid, hydrobro
- the second aspect of the present invention provides a process for the purification of prasugrel compound of formula-1, which comprises of the following steps; a) dissolving prasugrel in a suitable ester solvent like ethyl acetate, methyl acetate, isopropyl acetate by heating to reflux temperature, b) stirring the reaction mixture at reflux temperature, c) adding suitable anti-solvent selected from hydrocarbon solvent such as cyclohexane, heptane at 20-70 0 C, d) stirring the reaction mixture at reflux, e) cooling the reaction mixture to 0-5 0 C, f) filtering the solid and washing it with a suitable hydrocarbon solvent, g) drying the solid to provide highly pure prasugrel.
- a suitable ester solvent like ethyl acetate, methyl acetate, isopropyl acetate by heating to reflux temperature
- suitable anti-solvent selected from hydrocarbon solvent such as cyclohexane, heptan
- Third aspect of the present invention is to provide an improved process for the preparation of l-cyclopropyl-2-(2-fluorophenyl)ethanone, which comprises of treating 2-fluorobenzyl bromide with magnesium metal in higher volumes of diethyl ether to provide 2-fluorobenzyl magnesium bromide, which is condensed in-situ with cyclopropyl cyanide in higher volumes of diethylether to provide highly pure l-cyclopropyl-2-(2-fluorophenyl)ethanone.
- the impurities observed and controlled by the present invention are 2-( ⁇ - cyclopropylcarbonyl-2-fluorobenzyloxy)-5H-4,5,6,7-tetrahydrothieno[3,2-c]pyridine designated as EVEP-I, 2-( ⁇ -cyclopropylcarbonyl-2-fluorobenzyloxy)-5-( ⁇ -cyclo propylcarbony-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine designated as IMP-2, 2-( ⁇ -cyclopropylcarbonyl-2-fluorobenzyloxy)-5-acetoxy-4,5,6,7-tetrahydro thieno[3,2-c]pyridine designated as IMP-3, 5-(5-chloro-l-(2-fluorophenyl)-2- oxopentyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl-acetate designated as IMP-4
- the invention controls and minimizes the formation of these impurities by using specific reagents and specific reaction conditions.
- the reaction conditions also prevented 'O' alkylation which controlled the formation of impurities viz. IMP-I and IMP-2 from being formed.
- the decrease in formation of impurity IMP-I is manifest in the decrease of N-acetylated impurity IMP-3 in the step involving acetylation of compound of formula-7 to yield prasugrel.
- strong base like sodium hydride was used along with acetic anhydride which may lead to the deacetylation of the prasugrel formed, to give back the starting material i.e. compound of formula-7 which might be the major reason for the decrease in the yields of prasugrel obtained.
- an organic base is used in this step i.e., triethylamine or diisopropylamine which controlled the deacetylation, and hence there was an increase in the yield of prasugrel formed as well as decrease in the quantity of compound of formula-7 as an impurity.
- the impurity designated as IMP-5 is formed due to the presence of isomer 4,5,6,7-tetrahydrothieno[2,3-c]pyridine in the starting material i.e. 4,5,6,7- tetrahydrothieno[3,2-c] pyridine(formula-2), which undergoes the same sequence of reactions to form IMP-5.
- the organic acid addition salts of prasugrel have been prepared which were found to be substantially free of the impurities mentioned above. Hence they can be used directly in the preparation of the medicament or can optionally be converted to its hydrochloride salt or maleate salt of high purity.
- a process for packing and storage of prasugrel hydrochloride comprises of the following steps: a) placing prasugrel salt in a clear polyethylene bag and tied with a thread, b) placing the primary packing containing prasugrel salt, inside a black color polyethylene bag and sealing it, c) placing the above double polyethylene bag inside a triple laminated bag, d) placing the sealed triple laminated bag inside a closed high density polyethylene (HDPE) container
- the oxygen busters can be used inside the black color polyethylene bag and a triple laminated bag.
- the process described in the present invention was 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-3 Preparation of 5-t-butyloxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c] pyridine.
- Example-4 Preparation of 5-triphenylmethyl-5,6,7,7a-tetrahydro-4H- thieno[3.2-c]2-pyridone.
- Example-5 Preparation of 5-benzoyl-5,6,7,7a-tetrahydro-4H-thieno[3.2-c]2- pyridone.
- Example-7 Preparation of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one benzene sulfonate.
- Example-8 Preparation of 5-( ⁇ -Cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo- 2,4,5,6,7,7a-hexahydrothieno[3, 2-c] pyridine.
- Example-10 Preparation of 2-Acetoxy-5-( ⁇ -cyclopropylcarbonyl-2-fluoro benzyl)-4,5,6,7-tetrahydrothieno[3, 2-c] pyridine fumarate. To a solution of 2-acetoxy-5-( ⁇ -cyclopropylcarbonyl-2-fluorobenzyl)-
- Example-U Preparation of prasugrel malate.
- the title compound is prepared analogues manner to example-10 using malic acid in place of fumaric acid. Yield: 3 grams
- Example-12 Preparation of prasugrel benzene sulfonate:
- Example-13 Preparation of prasugrel p-toluenesulfonic acid:
- Example-14 Preparation of 2-Acetoxy-5-( ⁇ -cyclopropyIcarbonyl-2- fluorobenzyl)-4,5,6,7-tetrahydrothieno[3, 2-c] pyridine hydrochloride.
- Triethylamine (181 ml) was added to a mixture of 4,5,6,7-tetrahydrothieno [3,2-c]pyridine hydrochloride (100 grams) and dichloromethane (220 ml) at 0-5 0 C.
- a solution of triphenyl methylchloride (151 grams) in dichloromethane (250 ml) was added drop-wise at 0-5 0 C over a period of 1 hour and then stirred for 9 hours.
- the reaction mixture was filtered and the solid washed with methylene chloride. The filtrate washed with water and the aqueous and organic layers were separated. The organic layer was dried over sodium sulphate and then distilled off the solvent.
- Example-16 Preparation of 5-triphenyImethyl-5,6,7,7a-tetrahydro-4H- thieno [3.2-c] 2-py ridone.
- Example-18 Preparation of 5-( ⁇ -cyclopropyIcarbonyl-2-fluorobenzyI)-2-oxo- 2,4,5,6,7,7a-hexahydrothieno[3, 2-c] pyridine.
- Example-20 Preparation of 5-( ⁇ -cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo- 2,4,5,6,7,7a-hexahydrothieno[3, 2-c] pyridine.
- the title compound is prepared analogues manner to example- 18 using potassium carbonate as a base and acetonitrile as a solvent in place of sodium carbonate and dimethylformamide. Yield: 1.5 grams
- Example-21 Preparation of 5-( ⁇ -cyclopropyIcarbonyl-2-fluorobenzyl)-2-oxo- 2,4,5,6,7,7a-hexahydrothieno[3, 2-c] pyridine.
- Triethylamine (53.5 grams) was added to a mixture of 5-( ⁇ -cyclopropyl carbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine (50 grams) and acetonitrile (350 ml) at 0-5 0 C.
- Acetic anhydride 50 ml was added drop-wise to the reaction mixture at 0-5 0 C and then stirred for 3 hours at 25-30 0 C.
- the reaction mixture was quenched with water and then extracted it with ethyl acetate. The ethyl acetate layer washed with sodium chloride followed by water.
- Example-23 Preparation of 5-( ⁇ -cyclopropylcarbonyl-2-fluorobenzyI)-2-oxo- 2,4,5,6,7,7a-hexahydrothieno[3, 2-c] pyridine.
- the ethyl acetate layer was washed successively with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfite, and then evaporated under reduced pressure.
- the residue was purified by chromatography on a silica gel column using toluene as the eluant to afford the desired product (23 g containing solvent) as a yellow liquid.
- Example-24 Preparation of l-cyclopropyl-2-(2-fluorophenyl)ethanone: l-(bromomethyl)-2-fluorobenzene (100 grams) in diethylether (500 ml) was added to a suspension of magnesium metal (14 grams) in diethyl ether (500 ml) under nitrogen atmosphere 25-30 0 C. The reaction mixture was stirred for 30 minutes at 25-30 0 C and cyclopropyl cyanide (42 grams) in diethyl ether (500 ml) was added. The reaction mixture was heated to reflux temperature and stirred for 4 hours. The reaction mixture was quenched with ammonium chloride. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water followed by 10% sodium carbonate and then with sodium chloride solution. The ethyl acetate layer was distilled off completely under reduced pressure. Yield: 80 grams; Purity: 85% by GC
- the above obtained residue can be further purified by distillation under reduced pressure
- the related substance of prasugrel was analyzed by HPLC using the following conditions: Column: Hypersil BDS, 250 X 4.6 mm or equivalent; Flow rate: 0.8 ml/min; wavelength:240 nm ; Temperature: 40 0 C; Load: 20 ⁇ l; Run time:
Abstract
The present invention relates to an improved process for the preparation of prasugrel compound of formula- 1 and its pharmaceutically acceptable salts thereof.
Description
Improved Process for the Preparation of Prasugrel and its Pharmaceutically Acceptable Salts.
Related Applications:
This application claims the benefit of priority of our Indian provisional application number: 2689/CHE/2007, filed on 19th November 2007, which is incorporated herein by reference.
Field of the invention: The present invention relates to an improved process for the preparation of prasugrel and its pharmaceutically acceptable salts. Prasugrel is chemically known as 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno [3,2-c] pyridine having structural formula-1,
According to patent literature EP542411, 2-acetoxy-5-(α-cyclopropyl carbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and its derivatives thereof described as antagonists of receptors of adenosine diphosphate (ADP), exhibit excellent activity in inhibition of platelet aggregation and are useful as antithrombotic or antiembolic agents.. They are useful as medicaments (preferably useful as therapeutic or prophylactic agents) for thrombus formation-induced or embolization-induced diseases. They can be used to prevent thrombolytic cardiovascular complications in patients with recent ischemic stroke or with acute coronary syndromes. They may also be useful for reducing secondary complications, recurrent myocardial infraction, recurrent stroke and rehospitalization for severe angina. The acid addition salts of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluoro benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine i.e. prasugrel exhibit excellent oral absorption, metabolization into the active compound, low toxicity, and excellent storage and handling stability and hence useful in preparation of the medicaments which exhibit activity in inhibition of platelet aggregation.
Background of the Invention:
Analogues of prasugrel i.e., 2-acetyloxy-5-alkyl-4,5,6,7-tetrahydro thieno
[3,2-c]pyridine derivatives have been initially disclosed in Japanese provisional patent publication No.130289/1991 & 41139/1994. Prasugrel and its pharmaceutically acceptable salts have been disclosed in US patent 5,288,726. The disclosed process for the preparation of prasugrel and its pharmaceutically acceptable salts involves the acetylation of 5-(α-cyclopropylcarbonyl-2-fluoro benzy)-2-oxo-2,4,5,6,7,7a-hexahydrothienq[3,2-c]pyridine in the presence of a strong base like sodium hydride. But use of strong base like sodium hydride is not advisable when the reaction is performed at an industrial scale.
Hence there is a need to develop a process which can be performed at an industrial scale. The present invention overcomes the problems associated with the prior art, and provides a process for the preparation of prasugrel and its pharmaceutically acceptable salts, with better yields and purity.
Brief Description of Invention:
The present invention relates to an improved process for the preparation of prasugrel. The first aspect of the present invention is to provide a process for the preparation of prasugrel and its pharmaceutically acceptable salts, which comprises of; a) protecting the amino functional group of 4,5,6,7-tetrahydrothieno[3,2-c] pyridine compound of formula-2 or its salts,
Formula-2 with a suitable protecting group, followed by crystallization from a suitable hydrocarbon solvent to give a compound of general formula-3,
Formula -3 b) converting the compound of formula-3, by introducing a boronic group -B(OR')2 in second position to the thieno[3,2-c] pyridine skeleton through a lithium derivative, and treating it with an oxidizing agent, followed by crystallization
from a suitable hydrocarbon solvent to provide a 2-oxo-compound of general formula-4,
- FCormOula -4" c) removing the protecting group on nitrogen in formula-4 by treating with an suitable acid to provide corresponding 5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridine-2-one acid addition salt compound of general formula-5,
°=<SJO ACID Formula -5 d) reacting the acid addition salt of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2- one of general formula-5 or its free base with α-cyclopropylcarbonyl-2- fluorobenzyl bromide compound of formula-6,
Formula-6 in presence of a suitable base in a suitable solvent to provide a compound of formula-7,
e) acetylating the compound of formula-7 with a suitable acetylating agent in presence of a suitable base in a suitable solvent to provide prasugrel compound of formula- 1,
f) optionally converting the prasugrel into its acid addition salts by treating with a suitable acid in a suitable solvent.
The second aspect of the present invention is to provide a process for the purification of prasugrel compound of formula- 1.
The third aspect of the present invention is to provide an improved process for the preparation of highly pure l-cyclopropyl-2-(2-fluorophenyl)ethanone.
Brief Description of Drawings:
Figure-1: Illustrates the powder X-ray diffraction pattern of Prasugrel Figure-2: Illustrates the powder X-ray diffraction pattern of Prasugrel fumatrate Figure-3: Illustrates the powder X-ray diffraction pattern of Prasugrel hydrochloride Figure-4: Illustrates the powder X-ray diffraction pattern of Prasugrel maleate
Detailed description of the invention
As used herein, the term "PG" refers to protecting group which is selected from trityl, BOC (tert-butyloxy carbonyl) and benzoyl.
As used herein, the term "pharmaceutically acceptable salts" refers to the salt compound formed with a suitable acid selected from an inorganic acid addition salts such as hydrochloric acid, hydrobromic acid; or an organic acid such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p-toluenesulfonic acid and malic acid.
As used herein, the term "highly pure prasugrel" refers to prasugrel with the purity equal to 99.50 % or more by HPLC.
As used herein, the term "highly pure l-cyclopropyl-2-(2-fluorophenyl) ethanone" refers to l-cyclopropyl-2-(2-fluorophenyl)ethanone with the purity equal to 85.00 % or more by HPLC.
The present invention relates to an improved process for the preparation of prasugrel. Prasugrel is chemically known as 2-acetoxy-5-(α-cyclopropylcarbonyl-2- fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine.
In accordance with the present invention, the first aspect of the invention provides an improved process for the preparation of prasugrel compound of formula- 1 and its pharmaceutically acceptable salts, which comprises of; a) protecting the amino functional group of 4,5,6,7-tetrahydrothieno[3,2-c] pyridine compound of formula-2 or its salts,
Formula-2 with suitable amino protecting agent selected from benzoyl chloride, BOC anhydride and triphenyl methyl chloride preferably triphenyl methyl chloride, in presence of a suitable base selected from a group of organic bases selected from triethylamine, tributylamine, pyridine, N-methyl morpholine or 4-dimethylamino pyridine preferably triethyl amine, in a suitable solvent selected from dichloromethane, dichloroethane, carbontetrachloride, dioxane, dimethyl acetamide and N-methyl pyrrolidine preferably methylene chloride, followed by crystallization from a suitable solvent selected from C5-C io aliphatic hydrocarbons like hexane, heptane; aromatic hydrocarbon solvents like toluene, xylene; and cyclohexane or mixtures thereof, to provide a compound of general formula-3,
Formula -3 wherein PG is a protecting group b) converting the compound of general formula-3 by introducing a boronic group -B(OR')2 using tri-n-butyl borate in second position of thieno[3,2-c] pyridine skeleton through a lithium derivative using n-butyl lithium in a suitable solvent like tetrahydrofuran, and then treating with an oxidizing agent like hydrogen peroxide, followed by crystallization from a suitable solvent selected from C5-C10 aliphatic hydrocarbons like hexane, heptane; aromatic hydrocarbon solvents like toluene, xylene; and cyclohexane or mixtures thereof, to provide a compound of general formula-4,
Formula -4 wherein PG is a protecting group; c) removing the protecting group on nitrogen compound of general formula-4 by treating it with a suitable acid selected from inorganic acids such as hydrobromic acid, phosphoric acid or an organic acid such as benzene sulfonic acid, p-toluene sulfonic acid, succinic acid, fumaric acid, maleic acid and oxalic acid preferably
p-toluene sulfonic acid, in a suitable solvent selected from dichloromethane, 1,2-dichloroethane, toluene, isopropyl alcohol, ethanol, acetone, methyl ethyl ketone, diethyl ketone, ethyl acetate, propyl acetate and acetonitile, to provide corresponding 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one acid addition salt compound of general formula-5,
o< V ACID
Formula -5 d) reacting the 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one acid addition salt compound of formula-5 or its free base with α-cyclopropylcarbonyl-2- fluorobenzyl bromide compound of formula-6,
Formula-6 in presence of suitable base selected from a group consisting of alkali metal carbonates like sodium carbonate, potassium carbonate; or an alkali metal hydroxide like sodium hydroxide, potassium hydroxide; or alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate; or an organic base like triethylamine, tributylamine, diisopropylethlyamine preferably sodium carbonate, in a suitable solvent selected from diisopropylether, tetrahydrofuran, dimethylformamide, dimethoxy ethane, diethyl ketone, propyl acetate, butyl acetate, acetonitrile and propionitrile preferably dimethylformamide, to provide compound of formula-7,
Formula-7 e) acetylating the compound of formula-7 with a suitable acetylating agent like acetic anhydride in a suitable solvent selected from diethylether, tetrahydrofuran, dioxane, acetone, methylethyl ketone, ethyl acetate, acetonitrile, dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide preferably acetonitrile, in
presence of a suitable organic base selected from triethyl amine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and diisopropylethyl amine preferably triethylamine, to provide the compound of formula- 1,
f) optionally converting the prasugrel into its acid addition salts by treating it with a suitable acid selected from an inorganic acid such as hydrochloric acid, hydrobromic acid; or an organic acid such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p-tolunesulfonic acid and malic acid, in a suitable solvent selected from aliphatic hydrocarbons like hexane, cyclohexane, petroleum ether; or aromatic hydrocarbons like xylene, toluene; or halogenated hydrocarbons like dichloromethane, chloroform, 1,2-dichloroethane; or ethers like diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxy ethane; or ketones like acetone, methyl ethyl ketone, diethyl ketone; or acetates like ethyl acetate, propyl acetate, butyl acetate; alcohol like isopropyl alcohol; or nitriles like acetonitrile and propionitrile or mixtures thereof to provide an acid addition salt of prasugrel.
The second aspect of the present invention provides a process for the purification of prasugrel compound of formula-1, which comprises of the following steps; a) dissolving prasugrel in a suitable ester solvent like ethyl acetate, methyl acetate, isopropyl acetate by heating to reflux temperature, b) stirring the reaction mixture at reflux temperature, c) adding suitable anti-solvent selected from hydrocarbon solvent such as cyclohexane, heptane at 20-700C, d) stirring the reaction mixture at reflux, e) cooling the reaction mixture to 0-50C, f) filtering the solid and washing it with a suitable hydrocarbon solvent, g) drying the solid to provide highly pure prasugrel.
Third aspect of the present invention is to provide an improved process for the preparation of l-cyclopropyl-2-(2-fluorophenyl)ethanone, which comprises of treating 2-fluorobenzyl bromide with magnesium metal in higher volumes of diethyl ether to provide 2-fluorobenzyl magnesium bromide, which is condensed in-situ with cyclopropyl cyanide in higher volumes of diethylether to provide highly pure l-cyclopropyl-2-(2-fluorophenyl)ethanone.
l-cyclopropyl-2-(2-fluorophenyl)ethanone, the key intermediate in the synthesis of prasugrel is prepared by the condensation of 2-fluorobenzyl bromide with cyclopropyl cyanide by Grignard reaction using magnesium metal in diethyl ether. This reaction has been disclosed as a reference example- 1 in US patent 6693115, but when experiments were conducted as per the above reference example, provided the product with 50% purity by Gas chromatography.
The major impurity formed in the above experiments was found to be the
2-flouorobenzyl dimer impurity having the following structural formula;
It was found that when the grignard reaction was carried out using higher dilutions of diethyl ether solvent with respect to the starting material i.e., 2-fluorobenyzlbromide, there was a substantial increase in the yields and quality of the product formed. It was observed that the concentration of the dimer impurity had decreased substantially. Therefore the increase in quality and yield of the product can be attributed to the decrease in the concentration of the dimer impurity. Optimum results were obtained when the reaction were carried out when the dilution was above 8 volume of diethylether with respect to starting material i.e., 2-fluoro benzyl bromide, preferably 10-15 volumes of diethyl ether.
Formula- Ia PRASUGREL HYDROCHLORIDE
Wherein PG =Benzoyl/BOC/trityl
Y= nucleophilic leaving group
5-(α-Cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno [3, 2-c] pyridine(formula-7) is in equilibrium with its enolic form which is represented below.
The impurities observed and controlled by the present invention are 2-(α- cyclopropylcarbonyl-2-fluorobenzyloxy)-5H-4,5,6,7-tetrahydrothieno[3,2-c]pyridine designated as EVEP-I, 2-(α-cyclopropylcarbonyl-2-fluorobenzyloxy)-5-(α-cyclo propylcarbony-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine designated as IMP-2, 2-(α-cyclopropylcarbonyl-2-fluorobenzyloxy)-5-acetoxy-4,5,6,7-tetrahydro thieno[3,2-c]pyridine designated as IMP-3, 5-(5-chloro-l-(2-fluorophenyl)-2- oxopentyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl-acetate designated as IMP-4, 6-(2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothieno[2,3-c] pyridin -2 -yl acetate designated as EVIP-5, 5-(5-chloro-l-(2-fluorophenyl)-2- oxopentyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one designated as IMP-6, have the following structures:
The formation of these impurities during the preparation of prasugrel and its acid addition salts have been depicted in Scheme-II and Scheme-Ill. Scheme-II:
The invention controls and minimizes the formation of these impurities by using specific reagents and specific reaction conditions.
The process disclosed in US Patent No 5,288,726 involves the coupling of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one hydrochloride with 2-fluoro-α- cyclopropyl carbonylbenzyl bromide yielding 32% of 5-(α-cyclopropylcarbonyl-2- fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine. When the reaction was carried out it was observed that debromination of 2-fluoro-α-cyclopropyl carbonylbenzyl bromide took place which led to the poor yield of the. coupling product.
Another process disclosed in US Patent No.5, 874,581 involves converting 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one to 'O' protected, 2-(trialkyl silyloxy)-5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridine salt and subsequently
condensing with 2-fluoro-α-cyclopropyl carbonylbenzyl bromide. The condensed product has to be deprotected and then acetylated to obtain prasugrel, which involves multiple steps and decrease in the yields.
In our process of the present invention involves coupling of organic salt of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one (formula-5) with 2-fluoro-α- cyclopropyl carbonylbenzyl bromide. The reaction was carried out using sodium carbonate in tetrahydrofuran or potassium carbonate in acetonitrile or potassium carbonate in dimethyl formamide, prevented debromination of 2-fluoro-α- cyclopropyl carbonylbenzyl bromide which increases the yield of condensed product.
The reaction conditions also prevented 'O' alkylation which controlled the formation of impurities viz. IMP-I and IMP-2 from being formed. The decrease in formation of impurity IMP-I is manifest in the decrease of N-acetylated impurity IMP-3 in the step involving acetylation of compound of formula-7 to yield prasugrel. In prior art the step involving acetylation of compound of formula-7 to obtain prasugrel, strong base like sodium hydride was used along with acetic anhydride which may lead to the deacetylation of the prasugrel formed, to give back the starting material i.e. compound of formula-7 which might be the major reason for the decrease in the yields of prasugrel obtained. In the present invention an organic base is used in this step i.e., triethylamine or diisopropylamine which controlled the deacetylation, and hence there was an increase in the yield of prasugrel formed as well as decrease in the quantity of compound of formula-7 as an impurity.
The impurity designated as IMP-5 is formed due to the presence of isomer 4,5,6,7-tetrahydrothieno[2,3-c]pyridine in the starting material i.e. 4,5,6,7- tetrahydrothieno[3,2-c] pyridine(formula-2), which undergoes the same sequence of reactions to form IMP-5.
In the present invention the organic acid addition salts of prasugrel have been prepared which were found to be substantially free of the impurities mentioned above. Hence they can be used directly in the preparation of the medicament or can optionally be converted to its hydrochloride salt or maleate salt of high purity.
The impurities can be synthesized in pure form by methods as illustrated in Scheme-IV.
Scheme-IV: ■ *" / i/Y u o / u o 0 7 7 3 '
It is observed that the salts of API's generally are hygroscopic and absorb moisture on storage for long periods. Hence to increase the stability and shelf life, special packing conditions were employed. A process for packing and storage of prasugrel hydrochloride comprises of the following steps: a) placing prasugrel salt in a clear polyethylene bag and tied with a thread, b) placing the primary packing containing prasugrel salt, inside a black color polyethylene bag and sealing it, c) placing the above double polyethylene bag inside a triple laminated bag, d) placing the sealed triple laminated bag inside a closed high density polyethylene (HDPE) container
The oxygen busters can be used inside the black color polyethylene bag and a triple laminated bag.
The process described in the present invention was 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 5-triphenylmethyl-4,5,6,7-tetrahydrothieno[3,2-c] pyridine:
To a solution of 4,5,6,7-tetrahydrothieno [3,2-c]pyridine (100 grams) in dichloromethane (200 ml) added triethylamine (80 ml). A solution of triphenylmethyl chloride (95.2 grams) in dichloromethane (100 ml) was added drop wise, at 0-50C over a period of 1 hr. The reaction medium was maintained at 0-50C for 16 hrs and then poured it into water (200 ml). The aqueous and the organic layers were separated; the organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. The compound was isolated using cyclohexane to obtain white crystalline solid.
Yield: 240 grams; M. R: 163-165° C
ExampIe-2: Preparation of 5-benzoyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.
To a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (10 grams) in dichloromethane (30 ml) added triethylamine (10 ml). A solution of benzoyl chloride (10 grams) in dichloromethane (20 ml) was added drop wise, at 0-50C over a period of 1 hr. The reaction medium was maintained at 0-50C for 16 hrs and then is poured into ice cold water (50 ml). The aqueous and the organic layers were separated, the organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. The compound was isolated using cyclohexane to obtain white crystalline solid. Yield: 14.0 grams
Example-3: Preparation of 5-t-butyloxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c] pyridine.
To a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (10 grams) in dichloromethane (30 ml) added triethylamine (10 ml). A solution of BOC anhydride
(16 grams) in dichloromethane (30 ml) was added drop wise at 0-50C over a period of 1 hr. The reaction medium was maintained at 0-50C for duration of 15 hrs and then is poured it into ice cold water (50 ml). The aqueous and the organic layers
were separated; the organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. The compound was isolated using cyclohexane to obtain white crystalline solid. Yield: 14.5 grams
Example-4: Preparation of 5-triphenylmethyl-5,6,7,7a-tetrahydro-4H- thieno[3.2-c]2-pyridone.
To a solution of 5-triphenylmethyl-4,5,6,7-tetrahydro thieno [3,2-c] pyridine (50 grams) in tetrahydrofuran (1000 ml), added a solution of butyl lithium (142.81 ml, 2.3 M solution in hexane) drop wise at 00C. The mixture was maintained at 10-15° C for lhr. The reaction mass was cooled to -200C and charged with tri-n-butyl borate. The reaction mass was maintained at this temperature for 1.5 hrs, further cooled to -400C and charged with aqueous hydrogen peroxide (45.0 ml, 30% (v/v)). The reaction mixture was stirred for 1 hour at room temperature and quenched with water. The reaction mixture was extracted with dichloromethane. The organic extraction phase was washed with water and dried over sodium sulfate. Evaporation of the solvent to dryness and isolation in cyclohexane provided the title compound. Yield: 36.0 grams
Example-5: Preparation of 5-benzoyl-5,6,7,7a-tetrahydro-4H-thieno[3.2-c]2- pyridone.
To a solution of 5-benzoyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(5 grams) in tetrahydrofuran (60 ml), added a solution of butyl lithium (10ml, 2.3 M solution in hexane) drop by drop at 00C. The mixture was maintained at 10-150C for lhr. The reaction mass was cooled to -200C and charged with tri-n-butyl borate. The reaction mass was maintained at this temperature for 1.5 hrs, further cooled to -400C and charged with aqueous hydrogen peroxide (45 ml, 30% (v/v)). The reaction mixture was stirred for 1 hour at room temperature and quenched with water. The reaction mixture was extracted with dichloromethane. The organic extraction phase was washed with water and dried over sodium sulfate. Evaporation of the solvent to dryness and isolation in cyclohexane provided the title compound. Yield: 3.0 grams
Example-6: Preparation of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one p- toluene sulfonate.
A mixture of 5-trityl-5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one (15.0 grams), p-toluenesulfonic acid monohydrate (7.4 grams) and tetrahydrofuran (200 ml) was stirred at 500C for 2 hours. The precipitated solid was filtered, washed with 30 ml of tetrahydrofuran and then dried to obtain 5,6,7,7a-tetrahydro-4H- thieno[3,2-c]-pyridin-2-one p-toluenesulfonate. Yield: 10.0 grams
Example-7: Preparation of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one benzene sulfonate.
A mixture of 5-benzoyl-5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridin-2-one (5.0 grams) in isopropyl alcohol added aqueous sodium hydroxide (3 grams dissolved in 40 ml of water) and heated to 800C for two hrs. Cooled the reaction mixture to 25°C and adjusted the pH to 6 using hydrochloric acid, extracted the reaction mixture with dichloromethane and concentrated. The residue obtained was dissolved in isopropyl alcohol (50 ml) and benzene sulfonic acid (3 grams) was added and stirred at 40-50° C for 2 hours. The precipitated solid was filtered, washed with isopropyl alcohol (10 ml) and then dried to obtain 5,6,7,7a-tetrahydro-4H- thieno[3,2-c]-pyridin-2-one benzene sulfonate. Yield: 4.0 grams
Example-8: Preparation of 5-(α-Cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo- 2,4,5,6,7,7a-hexahydrothieno[3, 2-c] pyridine. To a solution of 5,6,7, 7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2 -one benzene sulfonate (5.0 grams) in tetrahydrofuran (50 ml), added 2-fluoro-α-cyclopropyl carbonylbenzyl bromide (3.5 grams) and sodium carbonate (3.5 grams).The resulting mixture was stirred at 0-50C for 5 hours. The reaction mixture was quenched with water and ethyl acetate was added to the reaction mixture. Aqueous and organic layers were separated. The organic layer was dried over anhydrous sodium sulfate and the solvent evaporated to dryness. The title compound was obtained as brown oil. Yield: 1.4 grams
Example-9: Preparation of 2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyI) -4,5,6,7-tetrahydrothieno[3, 2-c] pyridine.
To a solution of 5-(α.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6, 7,7a-hexahydrothieno[3,2-c]pyridine (0.5 grams) dissolved in a mixture of acetonitrile (10 ml) and acetic anhydride(3 ml), added diisopropylethyl amine (3ml). The mixture was then stirred for 20 minutes at 10-150C temperature, after which it was stirred for further 3 hours at 25-300C temperature. Ethyl acetate (20 ml) was added to the mixture, which was then washed four times, each time with 10 ml of a saturated aqueous solution of sodium chloride. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure to give yellow oil. This oil was crystallized from diisopropyl ether, to obtain the title compound as white crystals, melting at 120-123° C. 1 H NMR (CDCl3) δppm: 0.81-0.94 (2H, m), 1.03-1.08 (2H, m), 2.21-2.34 (4H, m), 2.79-2.94 (4H, m), 3.52-3.56 (2H, m), 4.88 (IH, s), 6.26 (IH, s), 7.10-7.49 (4H, m) Mass (CI, m/z): 374 (M+ +1), 331, 206, 177; Yield: 0.31grams
Example-10: Preparation of 2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluoro benzyl)-4,5,6,7-tetrahydrothieno[3, 2-c] pyridine fumarate. To a solution of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-
4,5,6,7-tetrahydrothieno[3, 2-c] pyridine (5 grams) in isopropyl alcohol(50ml) added drop wise a solution of fumaric acid (1.5 grams) in isopropyl alcohol (20ml) with constant stirring at 25° C. The reaction mixture was heated to 60-650C and stirred for 2 hours. The reaction mixture was cooled to 20-250C. The crystals obtained were filtered, washed with isopropyl alcohol (10 ml) and dried to obtain the title compound as crystalline solid. M. R: 218-220° C. Yield: 5.5 grams
Example-U: Preparation of prasugrel malate. The title compound is prepared analogues manner to example-10 using malic acid in place of fumaric acid. Yield: 3 grams
Example-12: Preparation of prasugrel benzene sulfonate:
The title compound is prepared analogues manner to example- 10 using benzene sulfonic acid in place of fumaric acid. Yield: 3.2 grams
Example-13: Preparation of prasugrel p-toluenesulfonic acid:
The title compound is prepared analogues manner to example- 10 using p-toluene sulfonic acid in place of fumaric acid. Yield: 2.8 grams
Example-14: Preparation of 2-Acetoxy-5-(α-cyclopropyIcarbonyl-2- fluorobenzyl)-4,5,6,7-tetrahydrothieno[3, 2-c] pyridine hydrochloride.
To a solution of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7-tetrahydrothieno[3,2-c] pyridine fumarate (5 grams) in water (50 ml) added sodium carbonate (3.5 grams) and stirred the solution for one hour. At the end of this time, ethyl acetate was added to the mixture. Aqueous and organic layers were separated. To the organic layer added drop wise a solution of hydrochloric acid (36 %, 1.5 grams)in ethyl acetate, with constant stirring at 200C over a period of one hour and after the addition completion of addition the mixture was further stirred for one hour at the same temperature. The crystals obtained were filtered, washed with ethyl acetate (20 ml) and dried to obtain the title compound as white crystalline solid. Yield: 6.5 grams
Example-15: Preparation of 5-triphenylmethyl 4,5,6,7-tetrahydro thieno[3,2-c] pyridine:
Triethylamine (181 ml) was added to a mixture of 4,5,6,7-tetrahydrothieno [3,2-c]pyridine hydrochloride (100 grams) and dichloromethane (220 ml) at 0-50C. A solution of triphenyl methylchloride (151 grams) in dichloromethane (250 ml) was added drop-wise at 0-50C over a period of 1 hour and then stirred for 9 hours. The reaction mixture was filtered and the solid washed with methylene chloride. The filtrate washed with water and the aqueous and organic layers were separated. The organic layer was dried over sodium sulphate and then distilled off the solvent. Cyclohexane (75 ml) was added to the obtained residue and cooled to 0-50C then
stirred for 1 hour. The separated solid was filtered, washed with cyclohexane and then dried to get the title compound. Yield: 172 grams; M.R: 162-1640C
Example-16: Preparation of 5-triphenyImethyl-5,6,7,7a-tetrahydro-4H- thieno [3.2-c] 2-py ridone.
A solution of butyl lithium (139 ml, 1.6 M solution in hexane) was added to a solution of 5-triphenylmethyl-4,5,6,7-tetrahydrothieno[3, 2-c] pyridine (50 grams) in tetrahydrofuran (1000 ml) was added drop-wise at 0-50C under nitrogen atmosphere and stirred for an hour at 10-15° C. The reaction mixture was cooled to 0-50C and tri-n-butyl borate (90 grams) in tetrahydrofuran (75 ml) was added then stirred for 2 hours. Aqueous hydrogen peroxide (45.0 ml, 30% (v/v)) was added and then stirred for 2 hours at 25-300C. The reaction mixture was quenched with water and then extracted with methylene chloride. The methylene chloride layer was distilled under reduced pressure. Cyclohexane (30 ml) was added to the obtained residue and stirred for 30 minutes. The separated solid was filtered, washed with cyclohexane and then dried at 500C to get the title compound. Yield: 38 grams
Example-17: Preparation of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one p-toluene sulfonate:
A mixture of 5-trityl-5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridin-2-one (110 grams), p-toluenesulfonic acid (52.6 grams) and tetrahydrofuran (1 100 ml) was heated to 60-650C and stirred for 3 hours. Then the reaction mixture was cooled to 0-50C and stirred for 30 minutes. The precipitated solid was filtered, washed with tetrahydrofuran and then dried to get the title compound. Yield: 86 grams; M.R: 195-196°C
Example-18: Preparation of 5-(α-cyclopropyIcarbonyl-2-fluorobenzyI)-2-oxo- 2,4,5,6,7,7a-hexahydrothieno[3, 2-c] pyridine.
2-fluoro-α-cyclopropyl carbonyl benzyl bromide (3.5 grams) was added to a mixture of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one p-touenesulfonate (5.0 grams) and sodium carbonate (3.5 grams) in dimethylformamide (80 ml) at 0-50C and stirred for 3 hours. The reaction mixture was quenched with water and then extracted it with methylene chloride. The methylene chloride washed with
water and organic and aqueous layers were separated. The methylene chloride from the organic layers was distilled off completely and the obtained residue purified using cyclohexane and ethyl acetate to provide the title compound. Yield: 1.4 grams
Example-19: Preparation of 5-(α-cyclopropylcarbonyI-2-fluorobenzyI)-2-oxo-
2,4,5,6,7,7a-hexahydrothieno[3, 2-c] pyridine.
The title compound is prepared analogues manner to example- 18 using the 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one hydrochloride in place of 5,6,7, 7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2 -one p-touenesulfonate. Yield: 1.25 grams
Example-20: Preparation of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo- 2,4,5,6,7,7a-hexahydrothieno[3, 2-c] pyridine. The title compound is prepared analogues manner to example- 18 using potassium carbonate as a base and acetonitrile as a solvent in place of sodium carbonate and dimethylformamide. Yield: 1.5 grams
Example-21: Preparation of 5-(α-cyclopropyIcarbonyl-2-fluorobenzyl)-2-oxo- 2,4,5,6,7,7a-hexahydrothieno[3, 2-c] pyridine.
The title compound is prepared analogues manner to example- 18 using potassium carbonate in place of sodium carbonate Yield: 1.9 grams
Example-22: Preparation of Prasugrel:
Triethylamine (53.5 grams) was added to a mixture of 5-(α-cyclopropyl carbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine (50 grams) and acetonitrile (350 ml) at 0-50C. Acetic anhydride (50 ml) was added drop-wise to the reaction mixture at 0-50C and then stirred for 3 hours at 25-300C. The reaction mixture was quenched with water and then extracted it with ethyl acetate. The ethyl acetate layer washed with sodium chloride followed by water. The ethyl acetate layer dried over sodium sulphate and then distilled off the solvent completely. Cyclohexane and ethyl acetate was added to the obtained crude and
cooled to 0-50C. The reaction mixture was stirred for 90 minutes at 0-50C. The solid was filtered, washed with cyclohexane and then dried to get the title compound. Yield: 28.7 grams: Purity: 96.5% HPLC
Example-23: Preparation of 5-(α-cyclopropylcarbonyl-2-fluorobenzyI)-2-oxo- 2,4,5,6,7,7a-hexahydrothieno[3, 2-c] pyridine.
2-fluoro-α-cyclopropyl carbonyl benzyl bromide (3.5 grams) was added to a mixture of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one(5.0 grams) and triethylamine (2.0 grams) in tetrahydrofuran (80 ml) at 0-50C and stirred for 3 hours. The reaction mixture was quenched with water and then extracted it with methylene chloride. The methylene chloride washed with water and organic and aqueous layers were separated. The methylene chloride from the organic layers was distilled off completely and the obtained residue purified using cyclohexane and ethyl acetate to provide the title compound. Yield: 3.5 grams
Reference Example: Preparation of l-cyclopropyl-2-(2-fluorophenyl)ethanone
To a suspension of magnesium powder (7.2 g) in anhydrous diethyl ether (60 ml) was added a solution of 2-fluorobenzylbromide (30 ml) in diethyl ether (30 ml), then the mixture was stirred at room temperature for 1 hour. The reaction mixture was added dropwise to a solution of cyclopropyl cyanide (18.2 ml) in diethylether (120 ml) over 100 minutes. After stirring for 30 minutes at room temperature the stirred mixture was heated under reflux for 1 hour. After the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The ethyl acetate layer was washed successively with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfite, and then evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene as the eluant to afford the desired product (23 g containing solvent) as a yellow liquid.
Example-24: Preparation of l-cyclopropyl-2-(2-fluorophenyl)ethanone: l-(bromomethyl)-2-fluorobenzene (100 grams) in diethylether (500 ml) was added to a suspension of magnesium metal (14 grams) in diethyl ether (500 ml) under nitrogen atmosphere 25-300C. The reaction mixture was stirred for 30 minutes
at 25-300C and cyclopropyl cyanide (42 grams) in diethyl ether (500 ml) was added. The reaction mixture was heated to reflux temperature and stirred for 4 hours. The reaction mixture was quenched with ammonium chloride. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water followed by 10% sodium carbonate and then with sodium chloride solution. The ethyl acetate layer was distilled off completely under reduced pressure. Yield: 80 grams; Purity: 85% by GC
The above obtained residue can be further purified by distillation under reduced pressure
Example-25: Preparation of 2-fluoro- α-cyclopropyl carbonyl benzyl bromide
A mixture of l-cyclopropyl-2-(2-fluorophenyl)ethanone (40 grams), chloroform (400 ml), N-bromo succinamide (50 grams) and benzoylperoxide (0.6 gram) was heated to reflux temperature and stirred for 6 hours. The reaction mixture was cooled to 25-300C and then filtered and the solid washed with ,. chloroform. The filtrate washed with water and then distilled off the filtrate under reduced pressure. The residue was cooled to 25-300C and extracted the product with cyclohexane. The extracted layer was distilled under reduced pressure to get the title compound. Yield: 45 grams;
Example-26: Purification of Prasugrel:
A mixture of prasugrel (52 grams) and ethyl acetate (75 ml) was heated to 60-650C to get a clear solution. The reaction mixture was stirred for an hour at 60-650C. cyclohexane (75 ml) was added to the reaction mixture at 60-650C and stirred for an hour. The reaction mixture was cooled to 0-50C and stirred for an hour. The solid obtained is filtered, washed with cyclohexane and then dried to get high pure prasugrel. Yield: 35 grams; Purity: 99.90% by HPLC
Example-27: Purification of Prasugrel:
A mixture of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7- tetrahydrothieno[3,2-c] pyridine fumarate (5 grams) and ethyl acetate and aqueous sodium carbonate was stirred for 30 minutes. The aqueous and organic layers were separated. The combined organic layer was washed with water and distilled the
organic layer completely under reduced pressure and isolated pure prasugrel as a solid prasugrel.
Yield: 2 grams; Purity: 99.89% by HPLC
HPLC and GC method of analysis:
The related substance of prasugrel was analyzed by HPLC using the following conditions: Column: Hypersil BDS, 250 X 4.6 mm or equivalent; Flow rate: 0.8 ml/min; wavelength:240 nm ; Temperature: 400C; Load: 20 μl; Run time:
3 times of the main peak; diluent: acetonitrile; mobile phase: 40:60 v/v of buffer and acetonitrile.
The related substance of l-cyclopropyl-2-(2-fluorophenyl)ethanone was analyzed by Gas chromatography using the following conditions: Column: DB-I or equivalent; Length: 30mts. ID:0.53mm; Film thickness: 1.Oμm; carrier gas: Helium; Flow rate: 3.0Psi; Injector mode: Split ratio 1 :50; Injector temperature: 2200C; Detector temp.: 2600C and Injection volume: 0.2μ.
Claims
1. An improved process for the preparation of prasugrel compound of formula- 1 ,
and its pharmaceutically acceptable salts thereof; Which comprises of: a) protecting the amino functional group of 4,5,6,7-tetrahydrothieno[3,2-c] pyridine compound of formula-2 or its salts,
with a suitable amino protecting agent in a suitable solvent, followed by crystallization from a suitable hydrocarbon solvent to provide a compound of general formula-3, Formula -3 b) converting the compound of general formula-3 into 2-oxo compound of general formula-4, by introducing a boronic group -B(OR')2 with suitable borate compound in second position of the thieno[3,2-c] pyridine skeleton through a suitable lithium derivative in a suitable solvent, and then treating it with an oxidizing agent followed by crystallization from a suitable hydrocarbon solvent,
- Fcormoula -4" c) removing the protecting group on nitrogen in compound of general formula-4 by treating it with suitable acid in a suitable solvent to provide the corresponding 5,6,7, 7a-tetrahydro-4H-thieno[3,2-c]pyridine-2 -one acid addition salt compound of general formula-5, Formula -5 d) reacting the 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one acid addition salt compound of general formula-5 with α-cyclopropylcarbonyl-2-fluoro benzyl bromide compound of formula-6
Formula-6 in presence of a suitable base in a suitable solvent to provide condensed compound of formula-7,
Formula-7 e) acetylating the compound of formula-7 with a suitable acetylating agent in presence of a suitable base in a suitable solvent to provide prasugrel compound of formula- 1, f) treating the prasugrel with suitable acid in a suitable solvent to provide an acid addition salt of prasugrel.
2. A process of claim 1, comprise of any one of the following steps; i) a step a) wherein the suitable protecting agent is selected from benzoylchloride, BOC anhydride and triphenyl methyl chloride; and the base is organic base selected from triethylamine, tributylamine, pyridine, N-methyl morpholine and 4-dimethylamino pyridine; and a suitable solvent is inert solvent selected from dichloromethane, dichloroethane, carbon tetrachloride, dioxane, dimethyl acetamide and N-methyl pyrrolidine; a suitable hydrocarbon solvent selected from Cs-Ci0 aliphatic hydrocarbons like hexane, heptane; aromatic hydrocarbon solvents like toluene, xylene; and cyclohexane or mixtures thereof; ii) a step b) wherein the boronic group is tri-n-butyl borate; and the lithium derivative is n-BuLi; and the suitable solvent is tetrahydrofuran; and a suitable oxidizing agent is hydrogen peroxide; suitable hydrocarbon solvent selected from C5-C10 aliphatic hydrocarbons like hexane, heptane; aromatic hydrocarbon solvents like toluene, xylene; and cyclohexane or mixtures thereof; iii) a step c) wherein the suitable acid is selected from an inorganic acid like hydrobromic acid and phosphoric acid; an organic acid such as benzene sulfonic acid, p-toluenesulfonic acid, succinic acid, fumaric acid, maleic acid and oxalic acid; and the suitable solvent is selected from the group comprising of dichloromethane,l,2-dichloroethane, toluene, isopropyl alcohol, ethanol, acetone, methyl ethyl ketone, diethyl ketone, ethyl acetate, propyl acetate and acetonitile or mixtures thereof; iv) a step d) wherein the suitable base is selected from alkali metal carbonates such as sodium carbonate, potassium carbonate; or a alkali metal hydroxide such as sodium hydroxide, potassium hydroxide; or alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; or an organic base such as triethylamine, tributylamine and diisopropylethlyamine; and the suitable solvent is selected from diisopropylether, tetrahydrofuran, dimethyl formamide, dimethoxy ethane, diethyl ketone, propyl acetate, butyl acetate, acetonitrile and propionitrile or mixtures thereof; v) a step e) wherein the suitable acetylating agent is acetic anhydride; and the suitable base is an organic base selected from triethyl amine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and diisopropyl ethylamine; and the suitable solvent is selected from diethyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide or mixtures thereof; vi) a step f) where in the suitable acid addition salt is selected from an inorganic acid such as hydrochloric acid, hydrobromic acid; or an organic acid such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, malic acid, p-toluene sulfonic acid and succinic acid; and the suitable solvent is selected from diethyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide or mixtures thereof;
3. An improved process for the preparation of prasugrel hydrochloride compound of formula- Ia, which comprises of; a) protecting the amino functional group of 4,5,6,7-tetrahydrothieno[3,2-c] pyridine hydrochloride compound of formula-2a,
Formula-2a with triphenylmethyl chloride in presence of triethylamine in methylene chloride, followed by crystallization using cyclohexane to provide a compound of formula-3a,
Formula -3a b) reacting the compound of formula-3a with tri-n-butyl borate in presence of n-butyl lithium in tetrahydrofuran followed by treatment with hydrogen peroxide and then crystallized using cyclohexane to provide the 2-oxo compound of formula-4a,
Formula -4a c) deprotecting the trityl protecting group by treating it with p-toluene sulfonic acid in tetrahydrofuran to provide p-toluene sulfonic acid salt compound of formula-5a,
°=CGNKPTSA Formula -5a d) reacting the p-toluene sulfonic acid salt compound of formula-5a with α-cyclopropylcarbonyl-2-flurobenzyl bromide compound of formula-6 in presence of sodium carbonate in dimethylformamide to provide a condensed compound of formula-7,
4. A process for the preparation of prasugrel compound of formula- 1, which comprises of acetylating the 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo- 2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine compound of formula-7 with suitable acetylating agent in presence of an organic base and in a suitable solvent.
5. A process of claim 4, where in suitable acetylating agent is selected from either acetic anhydride or acetyl chloride; and a suitable organic base is selected from triethyl amine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methyl morpholine and diisopropylethyl amine; and a suitable solvent is selected from diethyl ether, tetrahydrofϊiran, dioxane, acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide or mixtures thereof.
6. A process for the preparation of highly pure prasugrel having total impurities less than 0.5% by HPLC, which comprises of treating the acid addition salts of prasugrel with a suitable base in a suitable solvent.
7. The process according to claim 6, wherein highly pure prasugrel having known and unknown impurities less than 0.1% by HPLC.
8. A process according to claim 6, wherein acid addition salt is selected from an inorganic acid such as hydrochloric acid, hydrobromic acid; or an organic acid such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p-toluene sulfonic acid and malic acid; and a suitable base is selected from alkali metal carbonates such as sodium carbonate, potassium carbonate; or a alkali metal hydroxide such as sodium hydroxide, potassium hydroxide; or alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and a suitable solvent is selected from ester solvent like ethyl acetate, methyl acetate, isopropylacetate; chloro solvents like methylene chloride; hydrocarbon solvents like cyclohexane, heptane or mixtures thereof.
9. A process for the preparation of compound of formula-7,
which comprises of reacting 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one p-toluene sulfonate salt compound of formula-7a with α-cyclopropyl carbonyl-
2-fluorobenzyl bromide compound of formula-6 in the presence of potassium carbonate in acetonitrile to provide the compound of formula-7.
10. A process for the preparation of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2- oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine compound of formula-7, which comprises of reacting 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one free base with α-cyclopropyl carbonyl-2-fluorobenzyl bromide compound of formula-6 in the presence of a suitable base in a suitable solvent to provide the compound of formula-7.
11. The process according to claim 9, wherein the suitable base is selected from an organic base such as triethylamine, tributylamine and diisopropylethlyamine; alkali metal carbonates such as sodium carbonate, potassium carbonate; or a alkali metal hydroxide such as sodium hydroxide, potassium hydroxide; or alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; and a suitable solvent is selected from diisopropylether, tetrahydrofuran, dimethyl formamide, dimethoxy ethane, diethyl ketone, ethyl acetate, propyl acetate, butyl acetate, acetonitrile and propionitrile or mixtures thereof.
12. The process for the preparation of pure l-cyclopropyl-2-(2-fluoro phenyl)ethanone, which comprises of; a) reacting the 2-fluorobenzyl bromide with magnesium metal in higher volumes of ether solvent to provide 2-fluorobenzyl magnesium bromide, b) treating the above obtained magnesium bromide compound with cyclopropyl cyanide in higher volumes of ether solvent to provide highly pure l-cyclopropyl-2-(2-fluorophenyl)ethanone.
13. A process of claim 12, which comprises of any one of the following; i) a step a) wherein the volume of ether is more than or equal to 10 times with respect to 2-fluorobenzyl bromide, ii) a step b) wherein the volume of ether is more than or equal to 5 volumes with respect to 2-fluorobenzyl bromide.
14. A process of claim 12, wherein in step a) 2-fluorobenzyl bromide is taken in 5 or more volumes of ether, and magnesium metal is taken in 5 or more volumes of ether.
15. A process for the purification of prasugrel compound of formula- 1, which comprises of the following steps; a) dissolving prasugrel in a suitable ester solvent like ethyl acetate by heating to reflux temperature, b) stirring the reaction mixture at reflux, c) adding suitable anti-solvent like cyclohexane at 55-600C, d) stirring the reaction mixture at reflux, e) cooling the reaction mixture to 0-50C, f) filtering the solid and washing it with cyclohexane, g) drying the solid to provide highly pure prasugrel.
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