WO2009122440A1 - PROCESS FOR THE PREPARATION OF 2-ACETOXY-5-(α -CYCLOPRPYLCARBONYL -2-FLUOROBENZYL)-4,5,6,7-TETRAHYDROTHIENO[3,2-C]PYRIDINE - Google Patents

PROCESS FOR THE PREPARATION OF 2-ACETOXY-5-(α -CYCLOPRPYLCARBONYL -2-FLUOROBENZYL)-4,5,6,7-TETRAHYDROTHIENO[3,2-C]PYRIDINE Download PDF

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WO2009122440A1
WO2009122440A1 PCT/IN2009/000209 IN2009000209W WO2009122440A1 WO 2009122440 A1 WO2009122440 A1 WO 2009122440A1 IN 2009000209 W IN2009000209 W IN 2009000209W WO 2009122440 A1 WO2009122440 A1 WO 2009122440A1
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compound
formula
salt
acid
preparation
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PCT/IN2009/000209
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French (fr)
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A.V.V. Srinivas Rao
Jalindar Jaware
Srinivas Goud
Gopinathan Pillai Bijukumar
Sunil Sadanand Nadkarni
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Torrent Pharmaceuticals Ltd.
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Publication of WO2009122440A1 publication Critical patent/WO2009122440A1/en

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

Definitions

  • the present invention relates to a process for the preparation of 2-Acetoxy-5-( ⁇ - cyclop ⁇ ylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine & pharmaceutically acceptable salt thereof using a 2-acetoxy-tetrahydrothienopyridine derivatives i.e. compound of formula (VI) & (VIII) or salt thereof or acid addition salt of 5-
  • the present invention also relates to the process for the preparation of 2- acetoxy-tetrahydrothienopyridine derivatives i.e. compound of formula (VI) & (VIII) or salt thereof and acid addition salt of compound of formula (II).
  • Prasugrel is a member of the thienopyridine class of ADP receptor inhibitors, like ticlopidine and clopidogrel (Plavix®). These agents are believed to reduce the aggregation ("clumping") of platelets by irreversibly binding to P2Y12 receptors.
  • Prasugrel is chemically known as 2-Acetoxy-5-( ⁇ -cycloprpylcarbonyl-2-fiuorobenzyl)- 4,5,6,7- tetrahydrothieno[3,2-c]pyridine having chemical structure of formula (I).
  • US Patent 5,288,726 is the basic product patent of prasugrel, which discloses and claims tetrahydrothienopyridine derivatives including 2-Acetoxy-5-( ⁇ -cycloprpylcarbonyl-2- fluorobenzyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine i.e. Prasugrel (I).
  • Prasugrel I
  • approaches known in the art for preparing prasugrel which can be described herein below.
  • step (d) acetylation of 2-oxo derivative (II) obtained in step (c) with acetic anhydride in the presence of sodium hydride in DMF provides prasugrel (I).
  • the acetylation of 2-oxo c derivative (II) obtained in step (c) required almost ⁇ 7 mole acetic anhydride per mole of 2-oxo derivative (II) obtained in step (c), which is quite higher amount.
  • ethyl acetate were added to the mixture, which was then washed four times with brine solution and organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give oil. This oil was crystallized from diisopropyl ether to obtain compound (I) as white crystal.
  • step (a) bromination of compound as obtained in step (a) can be carried out by using haloimide such as N-bromosuccinimide in the presence of radical initiator or bromine in inert solvent such as halogenated hydrocarbon. Furthermore, the purification of oily adduct as obtained in step (c) and ⁇ - bromo ketone as obtained in step (b) also required silica gel column chromatography as disclosed in US 6,693,115.
  • step (g) the compound obtained in step (f) is treated with TEA and DMAP and acetylated with acetic anhydride or the compound of step (f) is first hydrolyzed by using organic carboxylic acid and then acetylated with acetic anhydride.
  • US patent 6,693,1 15 B2 discloses and claims the hydrochloric acid and maleic acid salts of 2-Acetoxy-5-( ⁇ -cycloprpylcarbonyl-2-fluorobenzyl)-4,5,6,7- tetrahydrothieno[3,2- c]pyridine.
  • Drugs of Future 2001, 26(9): 385 disclose the process for the preparation of prasugrel as disclosed in US 5,288,726 and US 5,874,581.
  • WO 2007/114526 discloses the process for the preparation of highly pure prasugrel and its pharmaceutically acceptable salt by recrystallizing it from the specific solvent system.
  • pure hydrochloride salt of prasugrel can be prepared by slow addition of hydrochloric acid to the prasugrel.
  • the present invention provides a new and improved process for the preparation of prasugrel and its pharmaceutically acceptable salts which overcomes the aforementioned drawbacks, in particular for plant scale.
  • the first embodiment of the present invention is to provide a novel process for the preparation of prasugrel (I) or pharmaceutically acceptable salt thereof
  • Another embodiment of the present invention is to provide a novel process for the preparation of prasugrel (I) or pharmaceutically acceptable salt thereof
  • Yet another embodiment of the present invention is to provide a process for the preparation of compound of formula (VI) or salt thereof
  • Yet another embodiment of the present invention is to provide the compound of formula (VI) or salt thereof and (VIII) in isolated form.
  • Yet another embodiment of the present invention is to provide an improved process for the preparation of prasugrel (I) or pharmaceutically acceptable salt thereof
  • step (b) adding the reaction mixture obtained in step (a) into the water after completion of the acetylation; ;
  • Yet another embodiment of the present invention is to provide an improved process for the preparation of prasugrel (I) or pharmaceutically acceptable salt thereof comprising the following steps: (a) acetylating the hydrobromide salt of compound of formula (II) using an acetylating agent in presence of base and suitable solvent;
  • step (b) adding the reaction mixture obtained in step (a) into the water after completion of the acetylation;
  • Yet another embodiment of the present invention is to provide a process for the preparation of acid addition salt particularly hydrobromide salt of compound of formula (II) comprising the following steps:
  • Yet another embodiment of the present invention is to provide the hydrobromide salt of compound of formula (II) in an isolated form.
  • Yet another embodiment of the present invention is to provide the use of hydrobromide salt of compound of formula (II) for the preparation of prasugrel and its pharmaceutically acceptable salts.
  • Yet another embodiment of the present invention is to provide a process for the preparation of compound of formula (III),
  • DBDMH l,3-Dibromo-5,5-dimethylhydantoin
  • Yet another embodiment of the present invention is to provide a process for the preparation of compound of formula (III) _
  • Yet another embodiment of the present invention is to provide a process for the preparation of compound of formula (III),
  • Yet another embodiment of the present invention is to provide the pharmaceutical composition of Prasugrel (I) and its pharmaceutically acceptable salts obtained according to the present invention.
  • Prasugrel refers to 2-Acetoxy-5-( ⁇ -cycloprpylcarbonyl-2-fluorobenzyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine.
  • DBDMH refers to l,3-Dibromo-5,5-dimethylhydantoin.
  • NBS N-bromo succinimide
  • acid addition salt of compound of formula (II) refers to a halogen acid, sulfuric acid, phosphoric acid, carboxylic acid, phosphonic acid, sulfonic acid, or sulfamic acid such as perchlorate, hydrochloride, hydrobromide, sulphate, phosphate, oxalate, maleate, citrate, trifiuoroacetate, mesylate, besylate, p-toluenesulphonate, or 10-camphorsulphonate, etc.
  • Hydrobromide salt of compound of formula (II) refers to Hydrobromide salt of 5- ( ⁇ -cycloprpylcarbonyl-2-fluorobenzyl)-2-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of formula (II).
  • the first embodiment of the present invention is to provide a novel process for the preparation of prasugrel (I) or pharmaceutically acceptable salt thereof
  • Step a) of the above reaction the acetylation of the compound of formula (VII) can be done by using acetylating agent such as acetyl halide (like as acetyl chloride) or acetic anhydride.
  • acetylating agent such as acetyl halide (like as acetyl chloride) or acetic anhydride.
  • the amount of acetylating agent is not critical, but generally it can be from 3 to 5 times the equimolar amount with respect to the starting material of formula (VII). This reaction can be carried out in presence of suitable solvent and base.
  • the compound of formula (VII) i.e. 5-trityl-5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2- one can be prepared according the process described in US 4740150.
  • any base known for use in reactions of this type may equally be used here.
  • suitable bases include: organic amines, such as triethylamine or tributylamine; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; alkali bicarbonate such as sodium bicarbonate or potassium bicarbonate. Among them, the alkali bicarbonates are preferred.
  • Suitable solvents include: ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate; alcohols, such as methanol, ethanol, propanol, isopropanol or butanol; nitriles, such as acetonitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide; and sulphoxides, such as dimethyl sulphoxide.
  • the amides are preferred, preferably N,N-dimethylformamide.
  • the acetylation can take place at temperature from O 0 C to 50°C. In general, it is convenient to carry out the reaction at a room temperature.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, the preferred period for acetylation is from 1 to 5 hours.
  • the compound of formula (VIII) can be obtained from the reaction mixture by conventional means.
  • a suitable recovery procedure comprises: adding water with any water-immiscible organic solvent such as ether like tert- butyl methyl ether; separating the layers and drying the organic layer; and distilling the solvent off.
  • the product thus obtained can be further purified by conventional means, such as recrystallization from the organic solvent or it can be taken as it is for hydrolysis.
  • step b) the hydrolysis of compound of formula (VIII) can be carried out in presence of acid, for example, an organic carboxylic acid such as acetic acid, etc., an organic sulfonic acid such as p-toluenesulfonic acid, etc., an inorganic acid such as hydrochloric acid.
  • acid for example, an organic carboxylic acid such as acetic acid, etc., an organic sulfonic acid such as p-toluenesulfonic acid, etc., an inorganic acid such as hydrochloric acid.
  • the preferred acid is p-toluenesulfonic acid.
  • the hydrolysis is easily finished within 2 hour to 5 hour.
  • the hydrolysis proceeds at a reaction temperature of about room temperature (25°C), and heating is not particularly required.
  • the suitable organic solvent to be used for the hydrolysis is not particularly limited, examples of suitable solvents include: ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate; alcohols, such as methanol, ethanol, propanol, isopropanol or butanol; nitriles, such as acetonitrile; amides, such as N,N-dimethylformamide, N 5 N- dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide; and sulphoxides, such as dimethyl sulphoxide, an ether type solvent such as tetrahydrofuran is preferred.
  • ethers such as diethyl ether, tetrahydrofuran or dioxane
  • ketones such as acetone or methyl e
  • the compound of formula (VI), obtainable after hydrolysis is obtained generally ' ' as a salt of the acid used in hydrolysis.
  • the compound of formula (VI) can be obtained from the reaction mixture by conventional means; generally it is obtained as solid, which can be separated simply by filtration.
  • the obtained compound of formula (VI) can be further dried at 40°C-60°C for sufficient time.
  • Step c) of the above reaction the compound of formula (VI) or a salt thereof is condensed with the compound (III) to give the compound of formula (I).
  • This reaction is carried out in presence of suitable solvent and base.
  • any base known for use in reactions of this type may equally be used here.
  • suitable bases include: organic amines, such as triethylamine or tributylamine; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; alkali bicarbonate such as sodium bicarbonate or potassium bicarbonate. Among them, the alkali bicarbonates are preferred.
  • the amount of base employed is not critical, but generally it can be from an equimolar amount to 4 times the equimolar amount with respect to the starting material of formula (VI).
  • a suitable solvent there is no particular restriction on the nature of the suitable solvent to be employed, provided that it has no adverse effect on the reaction, at least to some extent.
  • suitable solvents include: ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate; alcohols, such as methanol, ethanol, propanol, isopropanol or butanol; nitriles, such as acetonitrile; amides, such as N 5 N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide; and sulphoxides, such as dimethyl sulphoxide.
  • the amides are preferred, preferably N,N-dimethylformamide.
  • the condensation reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it is convenient to carry out the reaction at a temperature from 0°C to 45°C/The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed, however the preferred time required for condensation can be of a period from 1 to 5 hours, which will usually suffice.
  • the reaction mixture can be added with some little amount of acetic anhydride after some time, which will convert the deacetylated intermediate (if formed) to prasugrel (I) as precautionary measure.
  • step (d) after completion of the condensation reaction, the desired compound of formula (I) can be isolated from the reaction mixture by conventional means.
  • suitable solvent such as mentioned in step (c).
  • a suitable recovery procedure comprises: adding water with any water-immiscible organic solvent such as ether like tert-butyl methyl ether; separating the layers and drying the organic layer; and distilling the solvent off.
  • the product thus obtained can be further purified by conventional means, such as recrystallization from the organic solvent such as alcohol, preferably ethanol.
  • the obtained compound of formula (I) can be further dried at 40°C-60°C for sufficient time.
  • Another embodiment of the present invention is to provide an improved process for the preparation of prasugrel (I) or pharmaceutically acceptable salt thereof
  • step (b) adding the reaction mixture obtained in step (a) into the water after completion of the acetylation;
  • the present invention provides an improved process for the preparation of prasugrel (I) or pharmaceutically acceptable salt thereof comprising the following steps:
  • step (b) adding the reaction mixture obtained in step (a) into the water after completion of the acetylation;
  • the acetylation of acid addition salt of compound of formula (II) can be carried out by using acetylating agent such as acetyl halide (like as acetyl chloride) or acetic anhydride.
  • acetylating agent such as acetyl halide (like as acetyl chloride) or acetic anhydride.
  • the amount of acetylating agent is not critical, but generally it can be from 1 to 5 times the equimolar amount with respect to the acid addition salt of compound of formula (II). This reaction is carried out in presence of suitable solvent and base.
  • the acetylating agent can be also added in step wise manner.
  • the “acid addition salt of compound of formula (II)” is selected from the group comprising of halogen acid, sulfuric acid, phosphoric acid, carboxylic acid, phosphonic acid, sulfonic acid, or sulfamic acid such as perchlorate, hydrochloride, hydrobromide, sulphate, phosphate, oxalate, maleate, citrate, trifluoroacetate, mesylate, besylate, p-toluenesulphonate, or 10- camphorsulphonate, etc. More preferred acid addition salt is halogen acid.
  • any base known for use in reactions of this type may equally be used here.
  • suitable bases include: organic amines, such as triethylamine or tributylamine; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; alkali bicarbonate such as sodium bicarbonate or potassium bicarbonate. Among them, the alkali metal carbonates are preferred.
  • the amount of base employed is not critical, but generally it can be from an equimolar amount to 3 times the equimolar amount with respect to the acid addition salt of compound of formula (II).
  • Suitable solvents include: ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate; alcohols, such as methanol, ethanol, propanol, isopropanol or butanol; nitriles, such as acetonitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide; and sulphoxides, such as dimethyl sulphoxide.
  • the amides are preferred, preferably N,N-dimethylformamide.
  • the acetylation can take place at temperature from -10 0 C to 50°C. In general, it is convenient to carry out the reaction at -10°C to 10 0 C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, the preferred period for acetylation is from 1 to 5 hours.
  • the completeness of acetylation can be checked by using any known analytical method i.e. TLC or HPLC.
  • step (b) after the completion of acetylation of compound of formula (II), the obtained reaction mixture is added into the water.
  • the addition of the reaction mixture obtained in step (a) into the water is carried out at 0 0 C to 10 0 C over a period of 30 minutes to 1 hour.
  • step (c) the isolation of compound of formula (I) is simply carried out by maintaining the reaction mixture obtained in step (b) at 0 0 C to 10 0 C with stirring till the precipitation is complete. Generally, the isolation of compound of formula (I) is completed in less than 1 hour.
  • the obtained compound of formula (I) is then isolated by technique known in the art such as filtration followed by washing with suitable solvent or prasugrel base can be optionally re-crystallized by using one or more suitable solvent like water, alcohol, ester or etc. at ambient temperature.
  • the obtained compound of formula (I) i.e. Prasugrel base is further dried under vacuum for 2-12 hrs to obtain dry product at 35-65°C.
  • the compound of formula (I) i.e. prasugrel base obtained according to the present invention can be optionally converted into its pharmaceutically acceptable salt such as hydrochloride and hydrobromide by method known in the art.
  • Another embodiment of the present invention provides a process for the preparation of acid addition salt particularly hydrobromide salt of compound of formula (II) comprising the following steps:
  • Suitable solvents in step (i) include, but are not limited to ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate; alcohols, such as methanol, ethanol, propanol, isopropanol or butanol; nitriles, such as acetonitrile; amides, such as N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide; and sulphoxides, such as dimethyl sulphoxide. More preferably the solvent is selected from the group consisting of water, ketones, ethers, ester and alcohol. Most preferably the solvent is acetone.
  • Acidifying the mixture can be either with aqueous Hydrobromic acid or solution of hydrobromic acid in glacial acetic acid, preferably 30-33% solution of hydrobromic acid in glacial acetic acid.
  • the hydrobromic acid is in an amount sufficient to react with substantially entire amount of the compound of formula (II), more preferably an amount from about 1 to about 2 moles per mole of compound of formula (II).
  • the solution of hydrobromic acid may be added drop wise at 0°C to 10°C over a period of 1 hour to 2 hour.
  • reaction mixture obtained after the addition of hydrobromic acid solution is stirred for about 30 minutes to about 20 hours at 0°C to 10 0 C.
  • Hydrobromide salt of compound of formula (II) may be recovered by any method known in the art, such as by filtering, washing, preferably with the solvent used, and drying. Drying is preferably performed until a constant weight is obtained, preferably at a temperature of from about 35 0 C to about 65°C under reduced pressure.
  • Another embodiment of the present invention is to provide a process for the preparation of compound of formula (III)
  • a compound of formula (III) is prepared by reacting a compound of formula (IV) with a l,3-Dibromo-5,5-dimethylhydantoin (DBDMH) in presence of a radical initiator, such as benzoyl peroxide or azo-bis-isobutyronitrile (AIBN), in cyclic hydrocarbon such as benzene, cyclohexane, toluene, more preferred is cyclohexane.
  • a radical initiator such as benzoyl peroxide or azo-bis-isobutyronitrile (AIBN)
  • AIBN azo-bis-isobutyronitrile
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it is convenient to carry out the reaction at a reflux temperature. The time required for the reaction may also vary widely, however it is generally completed within 2 to 3 hours.
  • the compound of formula (III) can be obtained from the reaction mixture by any conventional means; alternatively, a suitable recovery procedure comprises: cooling the reaction mass, filtering the unwanted solid mass, washing the organic layer with sodium metabisulphite; and distilling the solvent off.
  • a suitable recovery procedure comprises: cooling the reaction mass, filtering the unwanted solid mass, washing the organic layer with sodium metabisulphite; and distilling the solvent off.
  • the product thus obtained can be further purified by any conventional means.
  • Another embodiment of the present invention provides a process for the preparation of compound of formula (III)
  • a compound of formula (III) is prepared by reacting a compound of formula (IV) with NBS in presence of a radical initiator, such as benzoyl peroxide or azo-bis-isobutyronitrile (AIBN), in cyclohexane.
  • a radical initiator such as benzoyl peroxide or azo-bis-isobutyronitrile (AIBN)
  • AIBN azo-bis-isobutyronitrile
  • present invention provides a process for the preparation of compound of formula (III)
  • a compound of formula (III) is prepared by reacting a compound of formula (IV) with an NBS in presence of a radical initiator p-toluenesulfonic acid in a suitable solvent.
  • suitable solvents include, but are not limited to ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate; alcohols, such as methanol, ethanol, propanol, isopropanol or butanol; nitriles, such as acetonitrile; amides, such as N 5 N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide; and sulphoxides, such as dimethyl sulphoxide; cyclic hydrocarbon such as benzene,
  • the solvent is selected from the group comprising of methanol, cyclohexane, dimethyl sulphoxide, acetonitrile, dimethylformamide, methylene dichloride and mixture of methylene dichloride and N, N-dimethylformamide .
  • the amount of PTSA can be 0.1 - 1.5 mole equivalent to starting raw material i.e. compound of formula (IV). More preferably the amount of PTSA is 0.1-0.2 mole equivalent to compound of formula (IV).
  • reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it is convenient to carry out the reaction at a reflux temperature. The time required for the reaction may also vary widely, however it is generally completed within 2 to 6 hours.
  • the compound of formula (III) can be obtained from the reaction mixture by any conventional means; alternatively, a suitable recovery procedure comprises: cooling the reaction mass, quenching with organic solvent, washing the organic layer with sodium metabi sulphite; and distilling the solvent off.
  • a suitable recovery procedure comprises: cooling the reaction mass, quenching with organic solvent, washing the organic layer with sodium metabi sulphite; and distilling the solvent off.
  • the product thus obtained can be further purified by any conventional means.
  • inventors of present invention have also observed when bromination of compound of formula (IV) is carried out with NBS particularly in presence of P- toluenesulfonic acid in suitable solvent to prepare the compound of formula (III), doesn't the require column chromatography for the purification of compound of formula (III) and yield is also improved .
  • prasugrel (I) and its pharmaceutically acceptable salts obtained according to the present invention can be administered alone or as a mixture with pharmaceutically acceptable excipients, diluents and the like, in suitable dosage forms such as tablets, capsules, granules, powders, syrups or the like for oral administration; and injections, suppositories or the like for parenteral administration.
  • formulations can be prepared by well-known methods using additives for the formulation such as diluents, lubricants, binders, disintegrants, emulsifiers, stabilizers, organoleptic agent.
  • diluents include lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, cellulose derivatives such as crystalline cellulose; calcium hydrogenphosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, and the like.
  • lubricants include stearic acid; metal stearate derivatives such as calcium stearate or magnesium stearate; talc; DL-Leucine; lauryl sulfate derivatives such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acid derivatives such as silicic anhydride or silicic acid hydrate; and starch derivatives, sodium stearyl fumarate.
  • binders include cellulose derivative such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol and gums.
  • disintegrants include cellulose derivatives such as lower-substituted hydroxypropylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose or internally cross-linked sodium carboxymethylcellulose; chemically modified starch or cellulose derivatives such as carboxymethylstarch or sodium carboxymethylstarch; cross- linked polyvinylpyrrolidine; and starch derivatives.
  • emulsifiers include colloidal clay such as bentonite or veegum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as benzalkonium chloride; non-ionic surfactants such as polyoxyethylene alkyl ether, polyoxyethyene sorbitan esters of fatty acids or sucrose esters of fatty acids.
  • colloidal clay such as bentonite or veegum
  • metal hydroxides such as magnesium hydroxide or aluminum hydroxide
  • anionic surfactants such as sodium lauryl sulfate or calcium stearate
  • cationic surfactants such as benzalkonium chloride
  • non-ionic surfactants such as polyoxyethylene alkyl ether, polyoxyethyene sorbitan esters of fatty acids or sucrose esters of fatty acids.
  • stabilizers include para-hydroxybenzoic acid ester derivatives such as methylparaben or propylparaben; alcohol derivatives such as chlorobutanol, benzyl alcohol or phenethyl alcohol; benzalkonium chloride; phenol derivatives such as phenol or cresol; thimerosal; dehydroacetic acid or sorbic acid.
  • organoleptic agent examples include sweeteners, souring agents, flavorings or the like which are conventionally used.
  • Prasugrel or its pharmaceutically acceptable salt such as hydrochloride exhibits defined' micrometric properties such as particle size distribution.
  • a particle size distribution where 90 volume percent of the particles have specified size is referred to as "dgo”.
  • Prasugrel or it's pharmaceutically acceptable salt such as hydrochloride exhibits d 9 o less than about 50 ⁇ m or about 30 ⁇ m.
  • Prasugrel and its salts such as hydrochloride with desired d 90 can directly be obtained from a synthesis process, or alternatively, any known particle size reduction processes can be employed, such as but not limited to sifting, milling, micronization, fluid energy milling, ball milling, and the like to obtain the material with desired d 90 .
  • Example- 1 The processes described in the present invention were 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 The processes described in the present invention were 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 Example- 1:
  • reaction mass was then cooled to 25°C-30°C and was added with cyclohexane (1000 ml) and sodium metabisulphate (10% solution, 2000 ml.) and stirred the reaction mixture for 15-20 minutes.
  • the separated organic layer was added with sodium bicarbonate solution (2000 ml) and stirred for 15-20 minutes and separated organic layer.
  • the obtained organic layer was washed with 2x2000 ml of RO water and dried over 25 gm of sodium sulphate. Finally organic layer was distilled off under reduced pressure to afford 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone (287 g m) as an oil.
  • the mixture was added to the pre-cooled (5 ⁇ 3°C) water at 5 ⁇ 3°C over a period of 30-45 minutes and stirred for 1 hrs. at the same temperature, filtered the obtained solid and washed with 3x20 ml of pre-chilled water and suck dried well.

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The present invention relates to a process for the preparation of 2-Acetoxy-5-(α-cycloprpylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine & pharmaceutically acceptable salt thereof using a 2-acetoxy-tetrahydrothienopyridine derivatives i.e. compound of formula (VI) & (VIII) or salt thereof or acid addition salt of 5-(α-cycloprpylcarbonyl-2-fluorobenzyl)-2-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of formula (II). The present invention also relates to the process for the preparation of 2-acetoxy-tetrahydrothienopyridine derivatives i.e. compound of formula (VI) & (VIII) or salt thereof and acid addition salt of compound of formula (II).

Description

PROCESS FOR THE PREPARATION OF 2-ACETOXY-5-( α -
CYCLOPRPYLCARBONYL -2-FLUOROBENZYL)-4,5,6,7-
TETRAHYDROTHIENO[3,2-C1PYRIDINE
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 2-Acetoxy-5-(α- cyclopφylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine & pharmaceutically acceptable salt thereof using a 2-acetoxy-tetrahydrothienopyridine derivatives i.e. compound of formula (VI) & (VIII) or salt thereof or acid addition salt of 5-
(α-cycloprpylcarbonyl-2-fluorobenzyl)-2-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of formula (II). The present invention also relates to the process for the preparation of 2- acetoxy-tetrahydrothienopyridine derivatives i.e. compound of formula (VI) & (VIII) or salt thereof and acid addition salt of compound of formula (II).
BACKGROUND OF THE INVENTION
Prasugrel is a member of the thienopyridine class of ADP receptor inhibitors, like ticlopidine and clopidogrel (Plavix®). These agents are believed to reduce the aggregation ("clumping") of platelets by irreversibly binding to P2Y12 receptors.
Prasugrel is chemically known as 2-Acetoxy-5-(α-cycloprpylcarbonyl-2-fiuorobenzyl)- 4,5,6,7- tetrahydrothieno[3,2-c]pyridine having chemical structure of formula (I).
Figure imgf000002_0001
(I)
US Patent 5,288,726 is the basic product patent of prasugrel, which discloses and claims tetrahydrothienopyridine derivatives including 2-Acetoxy-5-(α-cycloprpylcarbonyl-2- fluorobenzyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine i.e. Prasugrel (I). There are several approaches known in the art for preparing prasugrel, which can be described herein below.
US 5,288,726 disclose the process for the preparation of prasugrel comprising the following steps:
(a) reaction of the Grignard reagent prepared from 2-flurobenzyl bromide (V) and Mg in ether with cyclopropanecarbonitrile in ether gives l-cyclopropyl-2-(2-fluorophenyl) ethanone (IV),
(b) bromination of l-cyclopropyl-2-(2-fluorophenyl) ethanone (IV) with Br2 in CCl4 yield the α- bromo ketone derivative (III),
(c) condensation of α- bromo ketone derivative (III) with 2,3,4,5,6,7-hexahydrothieno
[3,2-C]pyridine-2-one hydrochloride in the presence of base and DMF affords the 2- oxo derivative (II),
(d) acetylation of 2-oxo derivative (II) obtained in step (c) with acetic anhydride in the presence of sodium hydride in DMF provides prasugrel (I).
The schematic representation of above process for the preparation of prasugrel as disclosed in US 5,288,726 is given as below.
Scheme- 1;
Figure imgf000004_0001
(I) (II)
According to scheme-I, the acetylation of 2-oxocderivative (II) obtained in step (c) required almost ~ 7 mole acetic anhydride per mole of 2-oxo derivative (II) obtained in step (c), which is quite higher amount. At the end of the acetylation reaction ethyl acetate were added to the mixture, which was then washed four times with brine solution and organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give oil. This oil was crystallized from diisopropyl ether to obtain compound (I) as white crystal.
US 5,288,726 suggested that bromination of compound as obtained in step (a) can be carried out by using haloimide such as N-bromosuccinimide in the presence of radical initiator or bromine in inert solvent such as halogenated hydrocarbon. Furthermore, the purification of oily adduct as obtained in step (c) and α- bromo ketone as obtained in step (b) also required silica gel column chromatography as disclosed in US 6,693,115.
Furthermore US 5,874,581 discloses that process for the preparation of compound (I) as suggested in US 5,288,726 is not an industrially satisfactory process because the 5-alkyl- 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one derivative i.e. 2-oxo derivative (II) as obtained in step (c) of scheme- 1 is unstable under reaction condition.
US 5,874,581 discloses the alternative process for the preparation of Prasugrel suggests the use of novel 2-silyoxy-tetrahydrothienopyridine intermediate. The said process can be schematically represented as below in scheme-2.
Scheme- 2:
Figure imgf000005_0001
(e) reaction of 2,3,4,5,6,7-hexahydrothieno[3,2-c]pyridine-2one PTSA with TBDMS-Cl and TEA in suitable solvent gives the silylated enol ether, (f) condensation of silylated enol ether obtained in step (a) with l-cyclopropyl-2-chloro- 2-(2-fluorophenyl)ethanone in the presence of TEA in suitable solvent,
(g) the compound obtained in step (f) is treated with TEA and DMAP and acetylated with acetic anhydride or the compound of step (f) is first hydrolyzed by using organic carboxylic acid and then acetylated with acetic anhydride.
The process as disclosed in above patent i.e. US 5,874,581 is lengthy process because it involves TBDMS protection before condensation and de-protection step before acetylation, which makes it somewhat expensive and industrially unfavorable.
US patent 6,693,1 15 B2 discloses and claims the hydrochloric acid and maleic acid salts of 2-Acetoxy-5-(α -cycloprpylcarbonyl-2-fluorobenzyl)-4,5,6,7- tetrahydrothieno[3,2- c]pyridine.
Drugs of Future 2001, 26(9): 385 disclose the process for the preparation of prasugrel as disclosed in US 5,288,726 and US 5,874,581.
WO 2007/114526 discloses the process for the preparation of highly pure prasugrel and its pharmaceutically acceptable salt by recrystallizing it from the specific solvent system. The same application also discloses that pure hydrochloride salt of prasugrel can be prepared by slow addition of hydrochloric acid to the prasugrel.
Chinese publications like CN 101250193, CN 101250192, CN 1245073, CN 1245072 discloses the process for the preparation of prasugrel comprising the reaction of 2-methoxy- 4,5,6,7-tetrahydrothieno [3,2-C] pyridine hydrochloride with α-halo-fluorobenzyl cyclopropyl ketone to provide 2-methoxy 5- (α- cyclopropyl carbonyl-2- Fluorobenzyl)- 4,5,6,7-Tetrahydrothieno[3,2-c] pyridine hydrochloride, which is converted into the hydrochloride salt of compound of formula (II), and the obtained hydrochloride salt of compound of formula (II) is transferred into base form of compound of formula (II) with the appropriate alkali base and then acetylated with acetic anhydride followed by tedious extraction process to obtain compound of formula (I).
However, the prior art process as disclosed in above Chinese publications is lengthy & not feasible at plant scale as it involves more number of steps, protection and deprotection at intermediates level, and tedious extraction process.
Thus, the known processes for the preparation of prasugrel and its pharmaceutically acceptable salts are not satisfactory, in particular for plant scale production, as they are lengthy and economically not viable. Thus, there still exists a need of process which is feasible for plant scale manufacturing.
In accordance with the foregoing, the present invention provides a new and improved process for the preparation of prasugrel and its pharmaceutically acceptable salts which overcomes the aforementioned drawbacks, in particular for plant scale.
SUMMARY OF THE INVENTION The first embodiment of the present invention is to provide a novel process for the preparation of prasugrel (I) or pharmaceutically acceptable salt thereof
Figure imgf000007_0001
(0 comprising the following steps: a) acetylating the compound of formula (VII) in presence of base and suitable solvent
Figure imgf000008_0001
(VII) to obtain the compound of formula (VIII);
Figure imgf000008_0002
(VIII)
b) hydrolyzing the compound of formula (VIII) in presence of acid in suitable solvent to obtain the compound of formula (VI) or salt thereof;
Figure imgf000008_0003
(Vl) c) condensing the compound of formula (VI) or a salt thereof with the compound of formula (III) in presence of base and suitable solvent; and
Figure imgf000008_0004
(III) d) isolating the compound of formula (I).
Another embodiment of the present invention is to provide a novel process for the preparation of prasugrel (I) or pharmaceutically acceptable salt thereof
Figure imgf000009_0001
(I) comprising the following -steps:
(a) condensing the compound of formula (VI) or a salt thereof with the compound of formula (III) in presence of base and suitable solvent; and
Figure imgf000009_0002
(b) isolating the compound of formula (I).
Yet another embodiment of the present invention is to provide a process for the preparation of compound of formula (VI) or salt thereof
Figure imgf000010_0001
(Vl) comprising the following steps:
(a) acetylating the compound of formula (VII) in presence of base and suitable solvent
Figure imgf000010_0002
to obtain the compound of formula (VIII); and
Figure imgf000010_0003
(VIII)
(b) hydrolyzing the compound of formula (VIII) in presence of acid in suitable solvent to obtain the compound of formula (VI) or salt thereof.
Yet another embodiment of the present invention is to provide the compound of formula (VI) or salt thereof and (VIII) in isolated form.
Yet another embodiment of the present invention is to provide the use of compound of formula (VI) or salt thereof for the preparation of prasugrel and its pharmaceutically acceptable salts. Yet another embodiment of the present invention is to provide the use of compound of formula (VIII) for the preparation of prasugrel and its pharmaceutically acceptable salts.
Yet another embodiment of the present invention is to provide an improved process for the preparation of prasugrel (I) or pharmaceutically acceptable salt thereof
Figure imgf000011_0001
(I) comprising the following steps:
(a) acetylating the acid addition salt of compound of formula (II) using an acetylating agent in presence of base and suitable solvent;
Figure imgf000011_0002
(H)
(b) adding the reaction mixture obtained in step (a) into the water after completion of the acetylation; ; and
(c) isolating the compound of formula (I).
Yet another embodiment of the present invention is to provide an improved process for the preparation of prasugrel (I) or pharmaceutically acceptable salt thereof comprising the following steps: (a) acetylating the hydrobromide salt of compound of formula (II) using an acetylating agent in presence of base and suitable solvent;
(b) adding the reaction mixture obtained in step (a) into the water after completion of the acetylation; and
(c) isolating the compound of formula (I).
Yet another embodiment of the present invention is to provide a process for the preparation of acid addition salt particularly hydrobromide salt of compound of formula (II) comprising the following steps:
(i) providing the solution of compound of formula (II) in a suitable solvent;
(ii) acidifying the solution of compound of formula (II) with hydrobromic acid to obtain a reaction mixture; (iii) maintaining the reaction mixture to obtain a precipitate; and
(iv) recovering the hydrobromide salt of compound of formula (II).
Yet another embodiment of the present invention is to provide the hydrobromide salt of compound of formula (II) in an isolated form.
Yet another embodiment of the present invention is to provide the use of hydrobromide salt of compound of formula (II) for the preparation of prasugrel and its pharmaceutically acceptable salts.
Yet another embodiment of the present invention is to provide a process for the preparation of compound of formula (III),
Figure imgf000013_0001
(III) comprising the bromination of the compound of formula (IV)
Figure imgf000013_0002
(IV)
with l,3-Dibromo-5,5-dimethylhydantoin (DBDMH) optionally in presence of radical initiator in cyclic hydrocarbon.
Yet another embodiment of the present invention is to provide a process for the preparation of compound of formula (III) _
Figure imgf000013_0003
(»') comprising the bromination of the compound of formula (IV)
Figure imgf000014_0001
(IV) with NBS optionally in the presence of radical initiator in cyclohexane.
Yet another embodiment of the present invention is to provide a process for the preparation of compound of formula (III),
Figure imgf000014_0002
(III) comprising the bromination of the compound of formula (IV)
Figure imgf000014_0003
(IV)
with N-bromosuccinimide in presence of p-toluenesulfonic acid in suitable solvent. Yet another embodiment of the present invention is to provide the pharmaceutical composition of Prasugrel (I) and its pharmaceutically acceptable salts obtained according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein t can be used in the practice or testing of the present invention, the preferred methods and ' materials are described.
The term "Prasugrel" refers to 2-Acetoxy-5-(α-cycloprpylcarbonyl-2-fluorobenzyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine.
The term "DBDMH" refers to l,3-Dibromo-5,5-dimethylhydantoin.
The term "NBS" refers to N-bromo succinimide.
The term "acid addition salt of compound of formula (II)" refers to a halogen acid, sulfuric acid, phosphoric acid, carboxylic acid, phosphonic acid, sulfonic acid, or sulfamic acid such as perchlorate, hydrochloride, hydrobromide, sulphate, phosphate, oxalate, maleate, citrate, trifiuoroacetate, mesylate, besylate, p-toluenesulphonate, or 10-camphorsulphonate, etc. The term "Hydrobromide salt of compound of formula (II)" refers to Hydrobromide salt of 5- (α-cycloprpylcarbonyl-2-fluorobenzyl)-2-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of formula (II).
The first embodiment of the present invention is to provide a novel process for the preparation of prasugrel (I) or pharmaceutically acceptable salt thereof
Figure imgf000016_0001
(I) comprising the following steps:
a) acetylating the compound of formula (VII) in presence of base and suitable solvent
Figure imgf000016_0002
(VII) to obtain the compound of formula (VIII);
Figure imgf000016_0003
(VIII)
b) hydrolyzing the compound of formula (VIII) in presence of acid in suitable solvent to obtain the compound of formula (VI) or salt thereof;
Figure imgf000017_0001
(Vl) c) condensing the compound of formula (VI) or a salt thereof with the compound of formula (III) in presence of base and suitable solvent; and
Figure imgf000017_0002
(III)
d) isolating the compound of formula (I).
In Step a) of the above reaction the acetylation of the compound of formula (VII) can be done by using acetylating agent such as acetyl halide (like as acetyl chloride) or acetic anhydride. The amount of acetylating agent is not critical, but generally it can be from 3 to 5 times the equimolar amount with respect to the starting material of formula (VII). This reaction can be carried out in presence of suitable solvent and base.
The compound of formula (VII) i.e. 5-trityl-5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2- one can be prepared according the process described in US 4740150.
There is no limitation on the nature of the base employed in step a), and any base known for use in reactions of this type may equally be used here. Examples of suitable bases include: organic amines, such as triethylamine or tributylamine; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; alkali bicarbonate such as sodium bicarbonate or potassium bicarbonate. Among them, the alkali bicarbonates are preferred.
The above reaction is normally carried out in presence of a suitable solvent. Examples of suitable solvents include: ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate; alcohols, such as methanol, ethanol, propanol, isopropanol or butanol; nitriles, such as acetonitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide; and sulphoxides, such as dimethyl sulphoxide. Among the given suitable solvents, the amides are preferred, preferably N,N-dimethylformamide.
The acetylation can take place at temperature from O0C to 50°C. In general, it is convenient to carry out the reaction at a room temperature. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, the preferred period for acetylation is from 1 to 5 hours.
After completion of the acetylation, the compound of formula (VIII) can be obtained from the reaction mixture by conventional means. For example, a suitable recovery procedure comprises: adding water with any water-immiscible organic solvent such as ether like tert- butyl methyl ether; separating the layers and drying the organic layer; and distilling the solvent off. Optionally, the product thus obtained can be further purified by conventional means, such as recrystallization from the organic solvent or it can be taken as it is for hydrolysis.
In step b), the hydrolysis of compound of formula (VIII) can be carried out in presence of acid, for example, an organic carboxylic acid such as acetic acid, etc., an organic sulfonic acid such as p-toluenesulfonic acid, etc., an inorganic acid such as hydrochloric acid. The preferred acid is p-toluenesulfonic acid. The hydrolysis is easily finished within 2 hour to 5 hour. The hydrolysis proceeds at a reaction temperature of about room temperature (25°C), and heating is not particularly required. The suitable organic solvent to be used for the hydrolysis is not particularly limited, examples of suitable solvents include: ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate; alcohols, such as methanol, ethanol, propanol, isopropanol or butanol; nitriles, such as acetonitrile; amides, such as N,N-dimethylformamide, N5N- dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide; and sulphoxides, such as dimethyl sulphoxide, an ether type solvent such as tetrahydrofuran is preferred.
Furthermore, the compound of formula (VI), obtainable after hydrolysis is obtained generally'' as a salt of the acid used in hydrolysis. After the hydrolysis, the compound of formula (VI) can be obtained from the reaction mixture by conventional means; generally it is obtained as solid, which can be separated simply by filtration. The obtained compound of formula (VI) can be further dried at 40°C-60°C for sufficient time.
In Step c) of the above reaction the compound of formula (VI) or a salt thereof is condensed with the compound (III) to give the compound of formula (I). This reaction is carried out in presence of suitable solvent and base.
There is no limitation on the nature of the base employed, and any base known for use in reactions of this type may equally be used here. Examples of suitable bases include: organic amines, such as triethylamine or tributylamine; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; alkali bicarbonate such as sodium bicarbonate or potassium bicarbonate. Among them, the alkali bicarbonates are preferred. The amount of base employed is not critical, but generally it can be from an equimolar amount to 4 times the equimolar amount with respect to the starting material of formula (VI).
The above reaction is normally carried out in presence of a suitable solvent. There is no particular restriction on the nature of the suitable solvent to be employed, provided that it has no adverse effect on the reaction, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate; alcohols, such as methanol, ethanol, propanol, isopropanol or butanol; nitriles, such as acetonitrile; amides, such as N5N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide; and sulphoxides, such as dimethyl sulphoxide. Among the given suitable solvents, the amides are preferred, preferably N,N-dimethylformamide.
The condensation reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it is convenient to carry out the reaction at a temperature from 0°C to 45°C/The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed, however the preferred time required for condensation can be of a period from 1 to 5 hours, which will usually suffice. Optionally, the reaction mixture can be added with some little amount of acetic anhydride after some time, which will convert the deacetylated intermediate (if formed) to prasugrel (I) as precautionary measure.
In step (d), after completion of the condensation reaction, the desired compound of formula (I) can be isolated from the reaction mixture by conventional means. For example, if the compound is produced immediately in the form of crystals, these can be separated simply by filtration and washed with suitable solvent such as mentioned in step (c). Alternatively, a suitable recovery procedure comprises: adding water with any water-immiscible organic solvent such as ether like tert-butyl methyl ether; separating the layers and drying the organic layer; and distilling the solvent off. Optionally, the product thus obtained can be further purified by conventional means, such as recrystallization from the organic solvent such as alcohol, preferably ethanol. The obtained compound of formula (I) can be further dried at 40°C-60°C for sufficient time.
Another embodiment of the present invention is to provide an improved process for the preparation of prasugrel (I) or pharmaceutically acceptable salt thereof
Figure imgf000021_0001
(I) comprising the following steps:
(a) acetylating the acid addition salt of compound of formula (II) using an acetylating agent in presence of base and in a suitable solvent;
Figure imgf000021_0002
(II)
(b) adding the reaction mixture obtained in step (a) into the water after completion of the acetylation; and
(c) isolating the compound of formula (I) In preferred embodiment, the present invention provides an improved process for the preparation of prasugrel (I) or pharmaceutically acceptable salt thereof comprising the following steps:
(a) acetylating the hydrobromide salt of compound of formula (II) using an acetylating agent in the presence of base and in a suitable solvent;
(b) adding the reaction mixture obtained in step (a) into the water after completion of the acetylation; and
(c) isolating the compound of formula (I).
In Step a), the acetylation of acid addition salt of compound of formula (II) can be carried out by using acetylating agent such as acetyl halide (like as acetyl chloride) or acetic anhydride. The amount of acetylating agent is not critical, but generally it can be from 1 to 5 times the equimolar amount with respect to the acid addition salt of compound of formula (II). This reaction is carried out in presence of suitable solvent and base. The acetylating agent can be also added in step wise manner.
The "acid addition salt of compound of formula (II)" is selected from the group comprising of halogen acid, sulfuric acid, phosphoric acid, carboxylic acid, phosphonic acid, sulfonic acid, or sulfamic acid such as perchlorate, hydrochloride, hydrobromide, sulphate, phosphate, oxalate, maleate, citrate, trifluoroacetate, mesylate, besylate, p-toluenesulphonate, or 10- camphorsulphonate, etc. More preferred acid addition salt is halogen acid.
There is no limitation on the nature of the base employed, and any base known for use in reactions of this type may equally be used here. Examples of suitable bases include: organic amines, such as triethylamine or tributylamine; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; alkali bicarbonate such as sodium bicarbonate or potassium bicarbonate. Among them, the alkali metal carbonates are preferred. The amount of base employed is not critical, but generally it can be from an equimolar amount to 3 times the equimolar amount with respect to the acid addition salt of compound of formula (II).
The above reaction is normally carried out in presence of a suitable solvent. Examples of suitable solvents include: ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate; alcohols, such as methanol, ethanol, propanol, isopropanol or butanol; nitriles, such as acetonitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide; and sulphoxides, such as dimethyl sulphoxide. Among the given suitable solvents, the amides are preferred, preferably N,N-dimethylformamide.
The acetylation can take place at temperature from -100C to 50°C. In general, it is convenient to carry out the reaction at -10°C to 100C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, the preferred period for acetylation is from 1 to 5 hours. The completeness of acetylation can be checked by using any known analytical method i.e. TLC or HPLC.
In step (b), after the completion of acetylation of compound of formula (II), the obtained reaction mixture is added into the water. Generally, the addition of the reaction mixture obtained in step (a) into the water is carried out at 00C to 100C over a period of 30 minutes to 1 hour.
In step (c), the isolation of compound of formula (I) is simply carried out by maintaining the reaction mixture obtained in step (b) at 00C to 100C with stirring till the precipitation is complete. Generally, the isolation of compound of formula (I) is completed in less than 1 hour. The obtained compound of formula (I) is then isolated by technique known in the art such as filtration followed by washing with suitable solvent or prasugrel base can be optionally re-crystallized by using one or more suitable solvent like water, alcohol, ester or etc. at ambient temperature. The obtained compound of formula (I) i.e. Prasugrel base is further dried under vacuum for 2-12 hrs to obtain dry product at 35-65°C.
The compound of formula (I) i.e. prasugrel base obtained according to the present invention can be optionally converted into its pharmaceutically acceptable salt such as hydrochloride and hydrobromide by method known in the art.
Another embodiment of the present invention provides a process for the preparation of acid addition salt particularly hydrobromide salt of compound of formula (II) comprising the following steps:
(i) providing the solution of compound of formula (II) in a suitable solvent;
(ii) acidifying the solution of compound of formula (II) with hydrobromic acid to obtain a reaction mixture;
(iii) maintaining the reaction mixture to obtain a precipitate; and
(iv) recovering the hydrobromide salt of compound of,formula (II).
Examples of suitable solvents in step (i) include, but are not limited to ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate; alcohols, such as methanol, ethanol, propanol, isopropanol or butanol; nitriles, such as acetonitrile; amides, such as N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide; and sulphoxides, such as dimethyl sulphoxide. More preferably the solvent is selected from the group consisting of water, ketones, ethers, ester and alcohol. Most preferably the solvent is acetone.
Acidifying the mixture can be either with aqueous Hydrobromic acid or solution of hydrobromic acid in glacial acetic acid, preferably 30-33% solution of hydrobromic acid in glacial acetic acid. Preferably, when the solution is acidified with hydrobromic acid in glacial acetic acid, the hydrobromic acid is in an amount sufficient to react with substantially entire amount of the compound of formula (II), more preferably an amount from about 1 to about 2 moles per mole of compound of formula (II). The solution of hydrobromic acid may be added drop wise at 0°C to 10°C over a period of 1 hour to 2 hour.
Preferably, the reaction mixture obtained after the addition of hydrobromic acid solution is stirred for about 30 minutes to about 20 hours at 0°C to 100C.
Hydrobromide salt of compound of formula (II) may be recovered by any method known in the art, such as by filtering, washing, preferably with the solvent used, and drying. Drying is preferably performed until a constant weight is obtained, preferably at a temperature of from about 350C to about 65°C under reduced pressure.
Other acid addition salts of compound of formula (II) as mentioned herein above can be prepared using the same method as above or any other method known in the art.
Another embodiment of the present invention is to provide a process for the preparation of compound of formula (III)
Figure imgf000025_0001
C") comprising the'bromination of the compound of formula (IV)
Figure imgf000026_0001
(IV) with l,3-Dibromo-5,5-dimethylhydantoin (DBDMH) optionally in presence of radical initiator in cyclic hydrocarbon.
In the above bromination reaction, a compound of formula (III) is prepared by reacting a compound of formula (IV) with a l,3-Dibromo-5,5-dimethylhydantoin (DBDMH) in presence of a radical initiator, such as benzoyl peroxide or azo-bis-isobutyronitrile (AIBN), in cyclic hydrocarbon such as benzene, cyclohexane, toluene, more preferred is cyclohexane. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it is convenient to carry out the reaction at a reflux temperature. The time required for the reaction may also vary widely, however it is generally completed within 2 to 3 hours.
After the halogenation, the compound of formula (III) can be obtained from the reaction mixture by any conventional means; alternatively, a suitable recovery procedure comprises: cooling the reaction mass, filtering the unwanted solid mass, washing the organic layer with sodium metabisulphite; and distilling the solvent off. Optionally, the product thus obtained can be further purified by any conventional means.
Another embodiment of the present invention provides a process for the preparation of compound of formula (III)
Figure imgf000027_0001
(III) comprising the bromination of the compound of formula (IV)
Figure imgf000027_0002
(IV) with NBS optionally in presence of radical initiator in cyclohexane.
In the above bromination reaction, a compound of formula (III) is prepared by reacting a compound of formula (IV) with NBS in presence of a radical initiator, such as benzoyl peroxide or azo-bis-isobutyronitrile (AIBN), in cyclohexane. The overall reaction parameters, reaction methodology and work-up process remain same as described for halogenation of compound of formula (IV) by using DBDMH.
In another embodiment, present invention provides a process for the preparation of compound of formula (III)
Figure imgf000028_0001
(III) comprising the bromination of the compound of formula (IV)
Figure imgf000028_0002
(IV) with N-bromosuccinimide in presence of p-toluenesulfonic acid in suitable solvent.
In the above bromination reaction, a compound of formula (III) is prepared by reacting a compound of formula (IV) with an NBS in presence of a radical initiator p-toluenesulfonic acid in a suitable solvent. Examples of suitable solvents include, but are not limited to ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate; alcohols, such as methanol, ethanol, propanol, isopropanol or butanol; nitriles, such as acetonitrile; amides, such as N5N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide; and sulphoxides, such as dimethyl sulphoxide; cyclic hydrocarbon such as benzene, cyclohexane , toluene and chlorinated solvents like methylene dichloride and mixture of methylene dichloride and N,N-dimethylformamide . More preferably the solvent is selected from the group comprising of methanol, cyclohexane, dimethyl sulphoxide, acetonitrile, dimethylformamide, methylene dichloride and mixture of methylene dichloride and N, N-dimethylformamide .
The amount of PTSA can be 0.1 - 1.5 mole equivalent to starting raw material i.e. compound of formula (IV). More preferably the amount of PTSA is 0.1-0.2 mole equivalent to compound of formula (IV).
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it is convenient to carry out the reaction at a reflux temperature. The time required for the reaction may also vary widely, however it is generally completed within 2 to 6 hours.
After the halogenation, the compound of formula (III) can be obtained from the reaction mixture by any conventional means; alternatively, a suitable recovery procedure comprises: cooling the reaction mass, quenching with organic solvent, washing the organic layer with sodium metabi sulphite; and distilling the solvent off. Optionally, the product thus obtained can be further purified by any conventional means.
Furthermore, inventors of present invention have also observed when bromination of compound of formula (IV) is carried out with NBS particularly in presence of P- toluenesulfonic acid in suitable solvent to prepare the compound of formula (III), doesn't the require column chromatography for the purification of compound of formula (III) and yield is also improved .
The prasugrel (I) and its pharmaceutically acceptable salts obtained according to the present invention can be administered alone or as a mixture with pharmaceutically acceptable excipients, diluents and the like, in suitable dosage forms such as tablets, capsules, granules, powders, syrups or the like for oral administration; and injections, suppositories or the like for parenteral administration.
The above described formulations can be prepared by well-known methods using additives for the formulation such as diluents, lubricants, binders, disintegrants, emulsifiers, stabilizers, organoleptic agent.
Examples of diluents include lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, cellulose derivatives such as crystalline cellulose; calcium hydrogenphosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, and the like.
Examples of lubricants include stearic acid; metal stearate derivatives such as calcium stearate or magnesium stearate; talc; DL-Leucine; lauryl sulfate derivatives such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acid derivatives such as silicic anhydride or silicic acid hydrate; and starch derivatives, sodium stearyl fumarate.
Examples of binders include cellulose derivative such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol and gums.
Examples of disintegrants include cellulose derivatives such as lower-substituted hydroxypropylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose or internally cross-linked sodium carboxymethylcellulose; chemically modified starch or cellulose derivatives such as carboxymethylstarch or sodium carboxymethylstarch; cross- linked polyvinylpyrrolidine; and starch derivatives.
Examples of emulsifiers include colloidal clay such as bentonite or veegum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as benzalkonium chloride; non-ionic surfactants such as polyoxyethylene alkyl ether, polyoxyethyene sorbitan esters of fatty acids or sucrose esters of fatty acids.
Examples of stabilizers include para-hydroxybenzoic acid ester derivatives such as methylparaben or propylparaben; alcohol derivatives such as chlorobutanol, benzyl alcohol or phenethyl alcohol; benzalkonium chloride; phenol derivatives such as phenol or cresol; thimerosal; dehydroacetic acid or sorbic acid.
Examples of organoleptic agent include sweeteners, souring agents, flavorings or the like which are conventionally used.
Prasugrel or its pharmaceutically acceptable salt such as hydrochloride exhibits defined' micrometric properties such as particle size distribution. A particle size distribution where 90 volume percent of the particles have specified size is referred to as "dgo".
In one embodiment Prasugrel or it's pharmaceutically acceptable salt such as hydrochloride exhibits d9o less than about 50 μm or about 30 μm. Prasugrel and its salts such as hydrochloride with desired d90 can directly be obtained from a synthesis process, or alternatively, any known particle size reduction processes can be employed, such as but not limited to sifting, milling, micronization, fluid energy milling, ball milling, and the like to obtain the material with desired d90.
The processes described in the present invention were 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 l-cyclopropyl-2-(2-fluorophenyI) ethanone (IV)
To a suspension of magnesium powder (1.39 gm) in diethyl ether (50 ml) with catalytic amount of methyl iodide was added a solution of 2-fluorobenzylbromide (10 gm) in diethyl ether (30 ml) over period of 45 minutes, then the mixture was stirred at room temperature for 1 hour. The reaction mixture was added drop wise to a solution of cyclopropanecarbonitrile (3.2 gm) in diethyl ether (15 ml) over 15 minutes. After stirring for 90 minutes at room temperature the stirred mixture was cooled to 0°C and quenched with ammonium chloride solution. The reaction mixture was extracted with ethyl acetate: diethyl ether and washed successively with water, saturated aqueous sodium bicarbonate solution, and diluted hydrochloric acid, dried over anhydrous sodium sulfate, and then organic layer was evaporated under reduced pressure to afford the desired product 6.8 gm (Yield = 72.18%).
ExampIe-2: Preparation of 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone (III)
To a solution of l-cyclopropyl-2-(2-fluorophenyl) ethanone (3.0 gm) in cyclohexane (60 ml) was added DBDMH (7.2 gm) and AIBN (0.27 g) and then the mixture was heated under reflux for 3 hours. The reaction mass was cooled to 10°C and stirred for 2 hours and was filtered off to remove unwanted solid. The filtrate was washed with 5% sodium metabisulphite, water and sodium bicarbonate solution, and then concentrated under reduced pressure to afford 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone (4.03 g Yield = 93.28%) as a oil.
Example-3: Preparation of 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone (III)
To a solution of l-cyclopropyl-2-(2-fluorophenyl) ethanone (3.0 gm) in cyclohexane (60 ml) was added N-bromo succinimide (9.2 gm) and AIBN (0.27 g) and the mixture was heated under reflux for 3 hours. The reaction mass was then cooled to 10°C and stirred for 2 hours and was filtered off to remove unwanted solid. The filtrate was washed with 5% sodium metabisulphite, water and sodium bicarbonate solution, and then concentrated under reduced pressure to afford 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone (3.42 g, Yield = 79.16%) as a oil.
Example-4:
Preparation of 2-acetoxy-5-trityl-4,5,6,7-tetrahydrothieno[3,2-c] pyridine (VIII).
To a solution of 5-trityl-5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one (10 gm) in Dimethyl formamide (100 ml) was added with acetic anhydride (10 ml) at room temperature and then cooled to 0°C. The reaction mass was added with sodium bicarbonate (1.2 gm) and stirred for 3 hours at room temperature. The reaction mass was then cooled to 0°C and added with chilled water (100 ml) and tert-butyl methyl ether (100 ml). Obtained organic layer was washed with excess water (2 χ 200 ml) and dried over sodium sulphate. Distilled off the organic layer under vacuum to obtain 2-acetoxy-5-trityl-4,5,6,7-tetrahydrothieno[3,2- c]pyridine (12.0 gm) as a semi solid.
Example-5:
Preparation of 2-acetoxy-4,5,6,7-tetrahydrothieno [3,2-c] py ridine-p-toluenesulfonate
(VI).
To a solution of 2-acetoxy-5-trityl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (10 gm) in tetrahydrofuran (100 ml) was added with p-toluene sulfonic acid (5.18 gm) at room temperature and then stirred for 3 hrs. The obtained solid product was filtered and washed with little amount of tetrahydrofuran (20 ml). The obtained solid was dried under vacuum at 500C for 24 hrs to obtain 2-acetoxy- -4,5,6,7-tetrahydrothieno[3,2-c]pyridine-p- toluenesulfonate (6.8 gm) as a solid (Yield = 80.95%).
Example-6:
Preparation of 2-Acetoxy-5-(α-cycloprpylcarbonyl-2-fluorobenzyl)-4,5,6,7- tetrahydrothieno [3,2-c] pyridine (I).
To a solution of 2-acetoxy- -4,5,6,7-tetrahydrothieno[3,2-c]ρyridine-p-toluenesulfonate (7.0 gm) in dimethylformamide (35 ml) was cooled to 5 -100C and was added with sodium bicarbonate (2.38 gm). The reaction mass was stirred for 15 minutes and added with 2- bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone (5.1 gm) in dimethylformamide (15 ml) and stirred for 5 hours at room temperature and followed by addition of acetic anhydride (3.8 ml) and stirred for 3 hrs at RT. After then reaction mass was cooled to 5 -10°C and added with water (700 ml) and tert-butyl methyl ether (105 ml). Stirred the mixture at room temperature and filtered through celite bed. The celite bed was washed with TBME. The obtained TBME layer was washed with water and brine solution, dried the organic layer, and distilled solvent under reduced pressure to get the oily mass. The oily product was crystallized from ethanol to afford the good crystal of prasugrel free base, which was dried under vacuum at 50°C for 24 hours (2.3 g, yield = 32.85%).
Example-7:
Preparation of l-cyclopropyl-2-(2-fluorophenyl) ethanone (IV)
To a suspension of magnesium powder (13.9 gm) in diethyl ether (500 ml) with catalytic amount of iodide (0.1 gm) was added a solution of 2-fiuorobenzylbromide (100 gm) in diethyl ether (325 ml) over period of 45 minutes, then the mixture was stirred at 30°C-35°C for 1 hour. The reaction mixture was added drop wise to a solution of cyclopropanecarbonitrile (32.39 gm) in diethyl ether (325 ml) over a period of 45-60 minutes at room temperature. After stirring the reaction mixture for 2 hours at room temperature the stirred mixture was cooled to 0°C-5°C and slowly added with ammonium chloride solution (30%, 325 ml). The reaction mixture was extracted with ethyl acetate: water (450 ml: 350 ml) and obtained organic layer washed successively with aqueous sodium bicarbonate solution and aqueous sodium chloride solution (10%, 250 ml), then dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to afford the desired product 40- 43 gm.
ExampIe-8: Preparation of 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone (III)
To a solution of l-cyclopropyl-2-(2-fluorophenyl) ethanone (200 gm) in methanol (1000 ml) was added first lot of N-bromosuccinimide (99.9 gm) and PTSA (21.35 gm) at room temperature and temp was raised to 50°-55°C and stirred for 1 hour. Then charged second lot of N-bromosuccinimide (99.9 gm) at 50°C-55°C to the reaction mixture and stirred the reaction mixture at the same temperature for 3 hours. Charged third lot of N- bromosuccinimide (50.0 gm) at 50°C-55°C to the reaction mixture and stirred the reaction mixture at the same temperature for 1 hour. The reaction mass was then cooled to 25°C-30°C and was added with cyclohexane (1000 ml) and sodium metabisulphate (10% solution, 2000 ml.) and stirred the reaction mixture for 15-20 minutes. The separated organic layer was added with sodium bicarbonate solution (2000 ml) and stirred for 15-20 minutes and separated organic layer. The obtained organic layer was washed with 2x2000 ml of RO water and dried over 25 gm of sodium sulphate. Finally organic layer was distilled off under reduced pressure to afford 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone (287 g m) as an oil.
Example-9:
Preparation of 5-(α-cycloprpylcarbonyl-2-fluorobenzyl)-2-oxo-4,5,6,7- tetrahydrothieno[3,2-c] pyridine of formula (II).
To a solution of 2-bromo-l-cyclopropyl-2-(2 -fluorophenyl) ethanone (20 gm) in acetonitrile (90 ml) was cooled to 10°C-15°C and was added with potassium bicarbonate (19.3 gm). The reaction mass was added with 4,5,6,7-tetrahydrothieno[3,2-C] pyridine-2-one.PTSA (20.62 gm) in step wise manner over period of two hours and stirred for 2-3 hours at 10°C-15°C. The reaction mixture was added with 180 ml of pre-chilled water and 90 ml of ethyl acetate at the room temperature and stirred for 10-15 minutes and separated the layers. The organic layer was washed with 10% aqueous solution of sodium chloride solution (90 ml) and charged with activated charcoal and stirred for 15 minutes at room temperature. Filtered the through hyflow bed and washed with 2><18 ml. of ethyl acetate, then filtrate was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the titled compound as an oil (20 gm). Example-10:
Preparation of Hydrobromide salt of 5-(α-cycloprpylcarbonyl-2-fluorobenzyl)-2-oxo- 4,5,6,7-tetrahydrothieno [3 ,2-c] pyridine of formula (II). To a solution of 5-(a-cycloprpylcarbonyl-2-fluorobenzyl)-2-oxo-4,5,6,7- tetrahydrothieno[3,2-c]pyridine ( 50 mg) in a acetone (500 ml) was added with 29.0 ml of hydrobromic acid solution (~ 30-33% solution in glacial acetic acid) at 0°C-5°C. The reaction mixture was stirred for 1 hour at 0°C-5°C and obtained precipitate was filtered and washed with 2χ50 ml. pre-chilled acetone. The resulting solid was dried under vacuum at 35°C-40°C for 6-8 hrs to obtain the title compound (weight 24.10 gm). Example-11:
Preparation of 2-Acetoxy-5-(α-cycloprpylcarbonyl-2-fluorobenzy.)-4,5,6,7- tetrahydrothieno [3 ,2-c] pyridine (I)
To a cooled (0±3°C ) solution of Hydrobromide salt of 5-(α-cycloprpylcarbonyl-2- fluorobenzyl)-2-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of formula (II) (20 gm) in a dimethylformamide (140 ml) and acetic anhydride (9.9 gm) was added with potassium carbonate (15.05 in dimethylformamide (20 ml), then mixture was stirred at the same temperature for 45 minutes. The reaction mixture further added with 4.95 gm of acetic anhydride at the same temperature and was stirred at the same temperature for 30 minutes. After the acetylation, the mixture was added to the pre-cooled (5±3°C) water at 5±3°C over a period of 30-45 minutes and stirred for 1 hrs. at the same temperature, filtered the obtained solid and washed with 3x20 ml of pre-chilled water and suck dried well. The obtained wet mass was charged in methanol (100 ml) at 25°C-30°C and stirred for 1 hour, filtered and washed with 2x20 ml of methanol. Dried the obtained title compound under reduced pressure at 35°C-40°C for 12 hrs. (Weight = 14.5 gm, Purity = 99%).

Claims

1. A process for the preparation of prasugrel (I) or pharmaceutically acceptable salt thereof
Figure imgf000037_0001
(I) comprising the following steps:
a) acetylating the compound of formula (VII) in presence of base and suitable solvent
Figure imgf000037_0002
(VII) to obtain the compound of formula (VIII);
Figure imgf000037_0003
(VIII)
b) hydrolyzing the compound of formula (VIII) in presence of acid in suitable solvent to obtain the compound of formula (VI) or salt thereof;
c) condensing the compound of formula (VI) or a salt thereof with the compound of formula (III) in presence of base and suitable solvent; and
Figure imgf000038_0001
(Vl) (III)
d) isolating the compound of formula (I).
process for the preparation of prasugrel (I) or a pharmaceutically acceptable salt thereof
Figure imgf000038_0002
(I) comprising the following steps:
(a) condensing the compound of formula (VI) or a salt thereof with the compound of formula (III) in presence of base and suitable solvent; and
Figure imgf000038_0003
(Vl) (III) (b) isolating the compound of formula (I).
3. A process for the preparation of compound of formula (VI) or salt thereof
Figure imgf000039_0001
(Vl) comprising the following steps:
a) acetylating the compound of formula (VII) in presence of base and suitable solvent
Figure imgf000039_0002
(VII) to obtain the compound of formula (VIII); and
Figure imgf000039_0003
(VIM)
b) hydrolyzing the compound of formula (VIII) in presence of acid in suitable solvent to obtain the compound of formula (VI) or salt thereof.
4. The process according to claim 1 or 2, wherein the compound of formula (VI) is used as an acid addition salt.
5. The process according to claim 1, 2 or 3, wherein the base is selected from the group comprising of organic amines, alkali metal alkoxide, alkali metal hydroxide, alkali metal carbonate and alkali bicarbonate.
6. The process according to claim 5, wherein the base is alkali bicarbonate.
7. The process according to claim 1, 2 or 3, wherein the solvent as used in step (a), (b) or (c) is selected from the group comprising of ethers, ketones, esters, alcohols, nitriles, amides and sulphoxides.
8. The process according to claim 7, wherein the solvent as used in step (a) is amides.
9. The process according to claim 7, wherein the solvent as used in step (b) is ethers.
10. The process according to claim 7, wherein the solvent as used in step (c) is amide.
11. The process according to claim 1 or 3, wherein the acid as used in step (b) is selected from the group comprising of an organic carboxylic acid, an organic sulfonic acid and an inorganic acid.
12. The process according to claim 11, wherein the acid is p-toluenesulfonic acid.
13. The compound of formula (VI) or salt thereof.
Figure imgf000040_0001
(Vl)
14. The compound of formula (VIII).
Figure imgf000041_0001
(VIII)
15. The use of a compound of formula (VI) or salt thereof for the preparation of prasugrel or a pharmaceutically acceptable salt thereof.
16. The use of a compound of formula (VIII) for the preparation of prasugrel or a. pharmaceutically acceptable salt thereof.
17. A process for the preparation of prasugrel (I) or pharmaceutically acceptable salt thereof
Figure imgf000041_0002
(I) comprising the following steps:
(a) acetylating the acid addition salt of compound of formula (II) using an acetylating agent in presence of base and in a suitable solvent;
Figure imgf000042_0001
(H)
(b) adding the reaction mixture obtained in step (a) into the water after completion of the acetylation; and
(c) isolating the compound of formula (I).
18. The process according to claim 17, wherein acetylating agent is acetic anhydride.
19. The process according to claim 17, wherein acid addition salt of compound of formula (II) is hydrobromide.
20. The process according to claim 17, wherein the base is selected from the group comprising of organic amines, alkali metal alkoxide, alkali metal hydroxide, alkali metal carbonate and alkali bicarbonate.
21. The process according to claim 20, wherein the base is alkali carbonate.
22. The process according to claim 17, wherein the solvent is selected from the group comprising of ethers, ketones, esters, alcohols, nitriles, amides and sulphoxides.
23. The process according to claim 22, wherein the solvent is amide.
24. A process for the preparation of prasugrel or a pharmaceutically acceptable salt thereof substantially as herein described, particularly with reference to the foregoing examples.
PCT/IN2009/000209 2008-03-31 2009-03-30 PROCESS FOR THE PREPARATION OF 2-ACETOXY-5-(α -CYCLOPRPYLCARBONYL -2-FLUOROBENZYL)-4,5,6,7-TETRAHYDROTHIENO[3,2-C]PYRIDINE WO2009122440A1 (en)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011029456A1 (en) * 2009-09-09 2011-03-17 Synthon Bv A process for making prasugrel and its intermediates
WO2011077173A1 (en) * 2009-12-21 2011-06-30 Egis Gyógyszergyár Nyilánosan Működő Részvénytársaság Improved process for preparing a pharmaceutical compound
WO2011098536A1 (en) * 2010-02-11 2011-08-18 Ratiopharm Gmbh Prasugrel in micronized, crystalline form and pharmaceutical composition thereof
CN102219792A (en) * 2011-04-27 2011-10-19 苏州立新制药有限公司 Novel method for preparing prasugrel
CN102268009A (en) * 2011-06-13 2011-12-07 陕西瑞科新材料股份有限公司 Preparation method for hydrogenated pyridine derivative
WO2012001486A1 (en) * 2010-06-28 2012-01-05 Mayuka Labs Pvt. Ltd. An improved process for the preparation of prasugrel hydrochloride and its intermediates
WO2012052788A1 (en) 2010-10-22 2012-04-26 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Method for preparing pharmaceutically active ingredient and intermediates thereof
KR20120070353A (en) * 2010-12-21 2012-06-29 대봉엘에스 주식회사 Method of producing related substance of olmesartan medoxomil
CN102675338A (en) * 2011-03-11 2012-09-19 上海现代制药股份有限公司 Micronization prasugrel and medicinal composition of prasugrel
EP2601200A2 (en) * 2010-08-06 2013-06-12 Dr. Reddy's Laboratories Ltd. Preparation of prasugrel hydrochloride
CN103694251A (en) * 2014-01-06 2014-04-02 南京简成医药科技有限公司 Novel preparation process of prasugrel hydrochloride
US20140142311A1 (en) * 2009-08-26 2014-05-22 Zhejiang Huahai Pharmaceutical Co., Ltd. Method for preparing prasugrel
WO2014114964A2 (en) 2013-01-24 2014-07-31 Egis Pharmaceuticals Public Limited Company Improved process for the preparation of prasugrel and intermediate thereof
WO2017221187A1 (en) 2016-06-23 2017-12-28 Richter Gedeon Nyrt. Process for the preparation of high-purity prasugrel

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5288726A (en) * 1991-09-09 1994-02-22 Ube Industries Limited Tetrahydrothienopyridine derivatives, furo and pyrrolo analogs thereof and their preparation and uses for inhibiting blood platelet aggregation
US5874581A (en) * 1994-10-07 1999-02-23 Ube Industries, Ltd. 2-silyloxy-tetrahydrothienopyridine, salt thereof and process for preparing the same
WO2009062044A2 (en) * 2007-11-09 2009-05-14 Dr. Reddy's Laboratories Ltd. Processes for the preparation of prasugrel, and its salts and polymorphs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5288726A (en) * 1991-09-09 1994-02-22 Ube Industries Limited Tetrahydrothienopyridine derivatives, furo and pyrrolo analogs thereof and their preparation and uses for inhibiting blood platelet aggregation
US5874581A (en) * 1994-10-07 1999-02-23 Ube Industries, Ltd. 2-silyloxy-tetrahydrothienopyridine, salt thereof and process for preparing the same
WO2009062044A2 (en) * 2007-11-09 2009-05-14 Dr. Reddy's Laboratories Ltd. Processes for the preparation of prasugrel, and its salts and polymorphs

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* Cited by examiner, † Cited by third party
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EA021934B1 (en) * 2009-12-21 2015-09-30 Эгиш Дьёдьсердьяр Ньильваношан Мюкеде Ресвеньтаршашаг Improved process for preparing a pharmaceutical compound
US20130030183A1 (en) * 2009-12-21 2013-01-31 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Process for preparing a pharmaceutical compound
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CN103694251A (en) * 2014-01-06 2014-04-02 南京简成医药科技有限公司 Novel preparation process of prasugrel hydrochloride
CN103694251B (en) * 2014-01-06 2018-08-10 南京简成医药科技有限公司 A kind of new process preparing prasugrel hydrochloride
WO2017221187A1 (en) 2016-06-23 2017-12-28 Richter Gedeon Nyrt. Process for the preparation of high-purity prasugrel

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