WO2009122440A1 - Procédé de préparation de 2-acétoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tétrahydrothiéno[3,2-c]pyridine - Google Patents

Procédé de préparation de 2-acétoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tétrahydrothiéno[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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English (en)
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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/fr

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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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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur un procédé de préparation de la 2-acétoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tétrahydrothiéno[3,2-c]pyridine et d'un sel pharmaceutiquement acceptable de celle-ci à l'aide de dérivés de 2-acétoxy-tétrahydrothiénopyridine, à savoir le composé de formule (VI) et (VIII) ou un sel de ceux-ci ou un sel d'addition avec les acides de 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-4,5,6,7-tétrahydrothiéno[3,2-c]pyridine de formule (II). La présente invention porte également sur le procédé de préparation de dérivés de 2-acétoxy-tétrahydrothiénopyridine, à savoir d'un composé de formule (VI) et (VIII) ou d'un sel de celui-ci et d'un sel d'addition avec les acides du composé de formule (II).
PCT/IN2009/000209 2008-03-31 2009-03-30 Procédé de préparation de 2-acétoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tétrahydrothiéno[3,2-c]pyridine WO2009122440A1 (fr)

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IN694MU2008 2008-03-31
IN694/MUM/2008 2008-03-31
IN178MU2009 2009-01-30
IN178/MUM/2009 2009-01-30

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Cited By (14)

* Cited by examiner, † Cited by third party
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WO2011029456A1 (fr) * 2009-09-09 2011-03-17 Synthon Bv Procédé pour la fabrication de prasugrel et ses intermédiaires
WO2011077173A1 (fr) * 2009-12-21 2011-06-30 Egis Gyógyszergyár Nyilánosan Működő Részvénytársaság Procédé amélioré de fabrication de composé pharmaceutique
WO2011098536A1 (fr) * 2010-02-11 2011-08-18 Ratiopharm Gmbh Prasugrel sous forme cristalline, micronisée, et composition pharmaceutique de celui-ci
CN102219792A (zh) * 2011-04-27 2011-10-19 苏州立新制药有限公司 一种普拉格雷的新型制备方法
CN102268009A (zh) * 2011-06-13 2011-12-07 陕西瑞科新材料股份有限公司 氢化吡啶衍生物的制备方法
WO2012001486A1 (fr) * 2010-06-28 2012-01-05 Mayuka Labs Pvt. Ltd. Procédé perfectionné pour la préparation de chlorhydrate de prasugrel et de ses intermédiaires
WO2012052788A1 (fr) 2010-10-22 2012-04-26 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Procédé de préparation d'une substance pharmaceutiquement active et de ses intermédiaires
KR20120070353A (ko) * 2010-12-21 2012-06-29 대봉엘에스 주식회사 올메사탄 메독소밀의 유연물질의 제조방법
CN102675338A (zh) * 2011-03-11 2012-09-19 上海现代制药股份有限公司 微粉化普拉格雷及其药用组合物
EP2601200A2 (fr) * 2010-08-06 2013-06-12 Dr. Reddy's Laboratories Ltd. Préparation de chlorhydrate de prasugrel
CN103694251A (zh) * 2014-01-06 2014-04-02 南京简成医药科技有限公司 一种制备盐酸普拉格雷的新工艺
US20140142311A1 (en) * 2009-08-26 2014-05-22 Zhejiang Huahai Pharmaceutical Co., Ltd. Method for preparing prasugrel
WO2014114964A2 (fr) 2013-01-24 2014-07-31 Egis Pharmaceuticals Public Limited Company Procédé amélioré pour la préparation de prasugrel et son intermédiaire
WO2017221187A1 (fr) 2016-06-23 2017-12-28 Richter Gedeon Nyrt. Procédé de préparation de prasugrel de haute purete

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WO2009062044A2 (fr) * 2007-11-09 2009-05-14 Dr. Reddy's Laboratories Ltd. Procédés de préparation de prasugrel et ses sels et polymorphes

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WO2009062044A2 (fr) * 2007-11-09 2009-05-14 Dr. Reddy's Laboratories Ltd. Procédés de préparation de prasugrel et ses sels et polymorphes

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140142311A1 (en) * 2009-08-26 2014-05-22 Zhejiang Huahai Pharmaceutical Co., Ltd. Method for preparing prasugrel
WO2011029456A1 (fr) * 2009-09-09 2011-03-17 Synthon Bv Procédé pour la fabrication de prasugrel et ses intermédiaires
WO2011077173A1 (fr) * 2009-12-21 2011-06-30 Egis Gyógyszergyár Nyilánosan Működő Részvénytársaság Procédé amélioré de fabrication de composé pharmaceutique
EA021934B1 (ru) * 2009-12-21 2015-09-30 Эгиш Дьёдьсердьяр Ньильваношан Мюкеде Ресвеньтаршашаг Улучшенный способ получения фармацевтического соединения
US20130030183A1 (en) * 2009-12-21 2013-01-31 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Process for preparing a pharmaceutical compound
WO2011098536A1 (fr) * 2010-02-11 2011-08-18 Ratiopharm Gmbh Prasugrel sous forme cristalline, micronisée, et composition pharmaceutique de celui-ci
EP2360159A1 (fr) * 2010-02-11 2011-08-24 Ratiopharm GmbH Prasugrel de forme cristalline et micronisée et composition pharmaceutique le contenant
US8940757B2 (en) 2010-02-11 2015-01-27 Ratiopharm Gmbh Prasugrel in micronized, crystalline form and pharmaceutical composition thereof
WO2012001486A1 (fr) * 2010-06-28 2012-01-05 Mayuka Labs Pvt. Ltd. Procédé perfectionné pour la préparation de chlorhydrate de prasugrel et de ses intermédiaires
EP2601200A4 (fr) * 2010-08-06 2014-01-08 Reddys Lab Ltd Dr Préparation de chlorhydrate de prasugrel
EP2601200A2 (fr) * 2010-08-06 2013-06-12 Dr. Reddy's Laboratories Ltd. Préparation de chlorhydrate de prasugrel
WO2012052788A1 (fr) 2010-10-22 2012-04-26 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Procédé de préparation d'une substance pharmaceutiquement active et de ses intermédiaires
KR20120070353A (ko) * 2010-12-21 2012-06-29 대봉엘에스 주식회사 올메사탄 메독소밀의 유연물질의 제조방법
KR101696851B1 (ko) 2010-12-21 2017-01-17 대봉엘에스 주식회사 올메사탄 메독소밀의 유연물질의 제조방법
CN102675338A (zh) * 2011-03-11 2012-09-19 上海现代制药股份有限公司 微粉化普拉格雷及其药用组合物
CN102219792A (zh) * 2011-04-27 2011-10-19 苏州立新制药有限公司 一种普拉格雷的新型制备方法
CN102268009A (zh) * 2011-06-13 2011-12-07 陕西瑞科新材料股份有限公司 氢化吡啶衍生物的制备方法
WO2014114964A2 (fr) 2013-01-24 2014-07-31 Egis Pharmaceuticals Public Limited Company Procédé amélioré pour la préparation de prasugrel et son intermédiaire
CN103694251A (zh) * 2014-01-06 2014-04-02 南京简成医药科技有限公司 一种制备盐酸普拉格雷的新工艺
CN103694251B (zh) * 2014-01-06 2018-08-10 南京简成医药科技有限公司 一种制备盐酸普拉格雷的新工艺
WO2017221187A1 (fr) 2016-06-23 2017-12-28 Richter Gedeon Nyrt. Procédé de préparation de prasugrel de haute purete

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