CN101472929A - Process for producing high-purity prasugrel and acid addition salt thereof - Google Patents

Abstract

The present invention relates to the provision of prasugrel hydrochloride and the like having a reduced OXTP content. Also provided is a method for preparing prasugrel hydrochloride with reduced OXTP content, which comprises dissolving OXTP-containing free prasugrel in an inert solvent and optionally adding hydrochloric acid dropwise to the solution for reaction.

Description

Method for preparing high-purity prasugrel or its acid addition salt

technical field

The present invention relates to a process for the preparation of high-purity prasugrel or its acid addition salts.

Background technique

Compounds with the formula:

Known as prasugrel. Prasugrel and its pharmaceutically acceptable salts are known to have platelet aggregation-inhibiting action and are useful as pharmaceutical active ingredients (particularly, antithrombotic or antithrombotic agents) (JP06-41139 or JP2002-145883). However, the use of prasugrel or a pharmaceutically acceptable salt thereof as a medicine requires a technique for preparing high-purity prasugrel or a pharmaceutically acceptable salt thereof.

WO96/11203 describes a process for the preparation of prasugrel or a pharmaceutically acceptable salt thereof. Additionally, JP2002-145883 describes a process for the preparation of prasugrel hydrochloride or maleate which comprises reacting an acid with free prasugrel. However, these patent documents do not describe a method of reducing the by-product OXTP.

Patent Document 1: JP06-41139

Patent Document 2: JP2002-145883

Patent Document 3: WO96/11203

Contents of the invention

Technical problem to be solved by the present invention

The object of the present invention is to provide a method for preparing high-purity prasugrel or its acid addition salt by reducing the content of by-products such as OXTP.

The solution to this problem

As a result of extensive research into methods for the preparation of highly pure prasugrel or its hydrochloride in which impurities such as by-product OXTP are reduced, the present inventors have found that acids can react with free prasugrel containing OXTP to prepare acid addition salts To reduce the content of the by-product OXTP in the obtained prasugrel hydrochloride to prepare high-purity prasugrel hydrochloride. The present inventors have also found that recrystallization of OXTP-containing free prasugrel can reduce the content of by-product OXTP in the obtained free prasugrel to prepare high-purity free prasugrel. Thus, the present invention has been accomplished.

According to the present invention, the respective analogous substances in prasugrel and its acid addition salts in the chromatogram (for example, analogous substances with retention times of 26.81, 36.79, 38.84 or 52.49 minutes in Fig. 5 or retained in Fig. 6 time is 26.13, 35.52, 37.45 or 50.37 minutes) compared to the peak of OXTP in liquid chromatography (in Fig. 5, the retention time is 13.02 or 13.76 minutes or in Fig. 13.41 minute substance) was greatly reduced.

The present invention provides a process for the preparation of high-purity prasugrel or its acid addition salts (in particular, free prasugrel or its hydrochloride), each of which has a reduced OXTP content; obtained by the production process High-purity prasugrel or its acid addition salt (especially free prasugrel or its hydrochloride); containing high-purity prasugrel or its acid addition salt (especially free prasugrel or its salt salt) as the active ingredient in a pharmaceutical composition (especially for the prophylaxis or treatment of diseases caused by thrombus or embolism); high-purity prasugrel or its acid addition salt (especially free prasugrel or its hydrochloride) for the preparation of pharmaceutical compositions; and for the prevention or treatment of diseases (especially thrombosis or embolism), which includes administration of high Pharmaceutical compositions of pure prasugrel or its acid addition salts (in particular free prasugrel or its hydrochloride).

The present invention is as follows:

(1) A method for preparing prasugrel hydrochloride represented by the following formula with reduced OXTP content:

The method comprises dissolving free prasugrel containing OXTP in an inert solvent and optionally adding hydrochloric acid dropwise to the solution to react;

(2) A method for preparing prasugrel hydrochloride as described in item (1), wherein the inert solvent is acetone;

(3) Prasugrel hydrochloride containing 0.7% or less of OXTP produced by the production method as described in the item (1) or (2);

(4) Prasugrel hydrochloride containing 0.2% or less of OXTP produced by the production method as described in item (1) or (2);

(5) Prasugrel hydrochloride containing 0.09% or less of OXTP produced by the production method as described in item (1) or (2);

(6) Prasugrel hydrochloride containing 0.07% or less of OXTP produced by the production method as described in item (1) or (2);

(7) Prasugrel hydrochloride containing 0.05% or less of OXTP produced by the production method as described in item (1) or (2);

(8) Prasugrel hydrochloride characterized by comprising 0.7% or less OXTP;

(9) Prasugrel hydrochloride characterized by comprising 0.2% or less of OXTP;

(10) Prasugrel hydrochloride characterized by comprising 0.09% or less of OXTP;

(11) Prasugrel hydrochloride characterized by comprising 0.07% or less of OXTP;

(12) Prasugrel hydrochloride characterized by comprising 0.05% or less of OXTP;

(13) Prasugrel hydrochloride as described in any one of items (3)-(12), wherein prasugrel hydrochloride is crystal, which is obtained by irradiation with copper Kα rays in powder X In ray diffraction, the main peaks are shown at the interplanar distances (d) of 5.7, 4.4, 3.8, 3.5 and 3.3 angstroms;

(14) Prasugrel hydrochloride as described in any one of items (3)-(12), wherein prasugrel hydrochloride is a crystal in a powder obtained by irradiation with copper Kα rays Main peaks are shown in X-ray diffraction at interplanar distances (d) of 6.6, 6.1, 4.0, 3.5 and 3.4 angstroms;

(15) A pharmaceutical composition comprising prasugrel hydrochloride as described in any one of items (3)-(14) as an active ingredient;

(16) A prophylactic or therapeutic agent for diseases caused by thrombus or embolism in homeothermic animals, comprising prasugrel hydrochloride as described in any one of items (3) to (14) as an active ingredient ;

(17) A prophylactic or therapeutic agent for thrombosis or embolism in humans, comprising prasugrel hydrochloride as described in any one of items (3) to (14) as an active ingredient;

(18) A method for preparing free prasugrel with reduced OXTP content comprising recrystallizing free prasugrel containing OXTP;

(19) The production method as described in the item (18), wherein the recrystallization uses ether or nitrile as a solvent;

(20) The production method as described in item (18), wherein recrystallization uses acetonitrile as a solvent;

(21) Free prasugrel comprising 0.7% or less of OXTP, produced by the production method as described in any one of items (18)-(20);

(22) Free prasugrel comprising 0.2% or less of OXTP, which is produced by the production method as described in any one of items (18)-(20);

(23) Free prasugrel comprising 0.09% or less of OXTP, which is produced by the production method as described in any one of items (18)-(20);

(24) Free prasugrel comprising 0.05% or less of OXTP, which is produced by the production method as described in any one of items (18)-(20);

(25) Free prasugrel comprising 0.03% or less of OXTP, produced by the production method as described in any one of items (18)-(20);

(26) Free prasugrel hydrochloride characterized by comprising 0.7% or less OXTP;

(27) Free prasugrel hydrochloride characterized by comprising 0.2% or less OXTP;

(28) Free prasugrel hydrochloride characterized by comprising 0.09% or less of OXTP;

(29) Free prasugrel hydrochloride characterized by comprising 0.05% or less of OXTP;

(30) Free prasugrel hydrochloride characterized by comprising 0.03% or less of OXTP;

(31) Free prasugrel as described in any one of items (21)-(30), wherein free prasugrel is a crystal, which is obtained at 6.7 in powder X-ray diffraction obtained by irradiation with copper Kα rays. , 4.7, 4.6, 4.2 and 3.8 angstrom interplanar distances (d) show main peaks;

(32) A pharmaceutical composition comprising free prasugrel as described in any one of items (21)-(31) as an active ingredient;

(33) A prophylactic or therapeutic agent for a disease caused by thrombus or embolism in a homeothermic animal, comprising free prasugrel as described in any one of items (21)-(31) as an active ingredient;

(34) A prophylactic or therapeutic agent for thrombosis or embolism in humans, comprising free prasugrel as described in any one of items (21)-(31) as an active ingredient;

(35) A process for the preparation of an acid addition salt of prasugrel, characterized in that free prasugrel as described in any one of items (21)-(31) is mixed with an acid in an inert solvent or in the absence of Under the situation of solvent, carry out reaction;

(36) The production method as described in item (35), wherein the acid addition salt is hydrochloride, maleate or benzenesulfonate;

(37) The acid addition salt of prasugrel produced by the production method as described in item (35) or (36);

(38) A pharmaceutical composition comprising an acid addition salt as described in item (37) as an active ingredient;

(39) A prophylactic or therapeutic agent for a disease caused by thrombus or embolism in a homeothermic animal, comprising an acid addition salt as described in item (37) as an active ingredient; and

(40) A prophylactic or therapeutic agent for thrombosis or embolism in humans, comprising the acid addition salt as described in the item (37) as an active ingredient.

According to the invention, "acid addition salts" may be, for example, salts of inorganic acids, such as sulfates, hydrochlorides, nitrates or phosphates; or salts of organic acids, such as trifluoroacetate, maleate, methanesulfonate salt, benzenesulfonate or p-toluenesulfonate. Preferably, it is the hydrochloride, maleate or besylate, more preferably the hydrochloride.

Prasugrel or its acid addition salts according to the invention have asymmetric carbon atoms in the molecule; stereoisomers with R and S configurations exist. Stereoisomers and compounds containing them in any ratio are included in the present invention. For example, stereoisomers can be synthesized by using optically resolved starting compounds, or can be obtained by subjecting synthesized prasugrel or an acid addition salt thereof to optical resolution, if necessary, using conventional optical resolution or Separation method.

Prasugrel or an acid addition salt thereof according to the present invention may be allowed to stand in air or recrystallized to absorb water, thereby containing adsorbed water or becoming a hydrate. Such hydrous compounds are included in the present invention. In addition, solvates thereof each containing any amount of solvent are also included in the present invention.

According to the present invention, depending on the reaction and crystallization conditions, prasugrel or its acid addition salts or their hydrates or solvates can form crystals with various internal structures and physicochemical properties (polymorphism of crystals). Crystals and mixtures thereof in any proportion are included in the present invention. Its crystalline solid and amorphous solid may exist as a mixture. Mixtures thereof in any proportion are included in the present invention. In particular, the content of the specific crystal form according to the present invention is preferably 50% or higher, more preferably 80% or higher, still more preferably 90% or higher, particularly preferably 95% or higher, most preferably 97% or higher higher.

According to the present invention, a crystal means a solid whose internal structure is composed of regularly repeating three-dimensionally of constituent atoms (or groups thereof), as opposed to amorphous solids which do not have such a regular internal structure. Whether a solid is crystalline can be checked by methods known in crystallography, such as powder X-ray crystallography or differential scanning calorimetry. For example, a solid is subjected to powder X-ray crystal diffraction using X-rays obtained by irradiation with copper Kα rays. When a distinct peak was observed in the X-ray diffraction pattern, the solid was determined to be crystalline, and when no distinct peak was observed, the solid was determined to be amorphous. When a peak was visible but not distinct (eg broad peak), the solid was determined to be a low crystallinity crystal. Crystals whose crystallinity is low are included in the crystals of the present invention.

In powder X-ray crystallography using copper Kα rays, the sample is generally irradiated with copper Kα rays (wherein the Kα1 and Kα2 rays are not separated). The X-ray diffraction pattern can be obtained by analyzing the diffraction derived from Kα rays, and only by analyzing the diffraction derived from Kα1 rays (taken from the diffraction derived from Kα rays). According to the present invention, the powder X-ray diffraction pattern obtained by irradiation with Kα rays includes an X-ray diffraction pattern obtained by analyzing diffraction derived from Kα rays and an X-ray diffraction pattern obtained by analyzing diffraction derived from Kα1 rays, and preferably The ground is an X-ray diffraction pattern obtained by analyzing diffraction derived from Kα1 rays.

Crystal A of prasugrel hydrochloride of the present invention can be, for example, as shown in FIG. A crystal showing a main peak at the interplanar distance (d).

Crystal B1 of prasugrel hydrochloride of the present invention can be, for example, as shown in FIG. The crystals showing the main peak at the interplanar distance (d) of .

Crystal B2 of prasugrel hydrochloride of the present invention can be, for example, as shown in FIG. Crystals with a main peak at the interplanar distance (d) of Angstroms.

The crystals of free prasugrel of the present invention can be, for example, as shown in FIG. d) Crystals showing the main peak.

In the powder X-ray diffraction diagrams of FIGS. 1-4 described below, the axis of ordinates represents diffraction intensity (counts/second (cps)) and the axis of abscissas represents diffraction angle 2θ (degrees). The interplanar distance d (angstroms) can be calculated by making n=1 in the equation: 2d sin θ=nλ. In this equation, the wavelength λ of the Kα ray is 1.54 Å, and the wavelength λ of the Kα1 ray is 1.541 Å. Even when the interplanar distance (d) is slightly different, the identity of the crystal form should be confirmed by referring to the graph of the entire map as required, because its position and relative intensity may vary slightly depending on the measurement conditions.

According to the present invention, "OXTP" is 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3, 2-c] pyridine, which is represented by the following formula:

或

or

For the OXTPs of the present invention, keto-enol tautomers exist. In addition, an asymmetric carbon and an optical isomer based on the asymmetric carbon exist in OXTP. These isomers and their mixtures also belong to the OXTP according to the invention.

Invention effect

According to the present invention, high-purity prasugrel and its acid addition salts (especially free prasugrel and its hydrochloride) can be provided, in each of which the content of impurities such as by-product OXTP is reduced.

Best Mode for Carrying Out the Invention

Free prasugrel can be prepared as a starting material for the present invention by the preparation method described in WO96/11203.

The method for carrying out the present invention to prepare high-purity prasugrel hydrochloride, free prasugrel and its acid addition salts is as follows.

Method for preparing high-purity prasugrel hydrochloride with free prasugrel

This method is a method comprising dissolving free prasugrel in an inert solvent, optionally adding hydrochloric acid dropwise thereto, and adding seed crystals as necessary to conduct a reaction to produce highly pure prasugrel hydrochloride.

In this method, the optional dropwise addition of hydrochloric acid may be performed by adding the acid dropwise or adding the acid all at once or in two or more divided portions.

The solvent used in this method is not particularly limited as long as it dissolves the starting materials to some extent and does not hinder the reaction. Solvents can be, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, light petroleum or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride , 1,2-dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diglyme ; ketones, such as acetone, methyl ethyl ketone, or diethyl ketone; esters, such as ethyl acetate, propyl acetate, or butyl acetate; carboxylic acids, such as acetic acid or propionic acid; or nitriles, such as acetonitrile or propionitrile. Preferably, it is an ether, ketone, ester, carboxylic acid or nitrile, more preferably tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate, acetic acid or acetonitrile, particularly preferably tetrahydrofuran , dioxane, acetic acid or acetone, most preferably acetone.

The reaction temperature in this method varies depending on reagents, solvents and the like. However, it is generally -20°C to 100°C, preferably 0°C to 70°C, more preferably 30°C to 60°C, most preferably 40°C to 55°C.

The reaction time in this method varies depending on reagents, solvents, reaction temperature and the like. However, it is generally 5 minutes to 10 hours, preferably 10 minutes to 5 hours.

A preferred aspect of the method is a method comprising dissolving free prasugrel in acetone and adding half the required amount of Concentrated hydrochloric acid (generally, equimolar to the thienopyridine form), if necessary, add seed crystals to react at the same temperature for 30 minutes to 2 hours, and further dropwise add the remaining Concentrated hydrochloric acid in required amount to react at 0-70°C (preferably 25-55°C) for 1 hour to 3 hours.

After the reaction process is completed, the prasugrel hydrochloride of the present invention is collected from the reaction mixture according to conventional methods. For example, the desired compound can be obtained by collecting precipitated crystals by filtration after completion of the reaction or distilling off the solvent after completion of the reaction. The obtained desired compound can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography, if necessary.

The highly pure prasugrel hydrochloride obtained in this method can be measured for OXTP content using the following method.

The OXTP content in prasugrel hydrochloride was measured by liquid chromatography and expressed as area percent (%) with respect to the OXTP content in free prasugrel.

The OXTP content in the highly pure prasugrel hydrochloride according to the present invention is generally 0.7% or less, preferably 0.2% or less, more preferably 0.09% or less, still more preferably 0.07% or less, particularly preferably 0.05% or less.

The purity of prasugrel hydrochloride, ie the content of prasugrel, can be measured as described for the content of OXTP.

The high purity prasugrel hydrochloride according to the present invention generally has a purity of 95% or higher, preferably 97% or higher, more preferably 99% or higher. Method for preparing high-purity prasugrel hydrochloride from free prasugrel

This method is a method comprising dissolving free prasugrel in a solvent and then recrystallizing to prepare high-purity free prasugrel.

The solvent used in this method is not particularly limited as long as it dissolves the starting materials to some extent and does not hinder the reaction. Solvents can be, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, light petroleum or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride , 1,2-dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diglyme ; ketones, such as acetone, methyl ethyl ketone, or diethyl ketone; esters, such as ethyl acetate, propyl acetate, or butyl acetate; carboxylic acids, such as acetic acid or propionic acid; or nitriles, such as acetonitrile or propionitrile. Preferably, it is an ether, acetonitrile, ester, carboxylic acid or nitrile, more preferably tetrahydrofuran, dioxane, acetonitrile, methylethylacetonitrile, ethyl acetate, acetic acid or acetonitrile, particularly preferably tetrahydrofuran , acetic acid, acetone or acetonitrile, most preferably acetonitrile.

The temperature during recrystallization is generally 20-80°C, preferably 30-70°C, more preferably 30-50°C. After dissolution, the solution was cooled slowly. Preferably, a weak solvent (preferably water) is added to the solution at -20 to -10°C, followed by stirring for 10 minutes to 3 hours. Seed crystals can also be added as needed.

The highly pure free prasugrel obtained in this method can be used to measure the OXTP content using the following method.

The OXTP content in free prasugrel can be measured as described for the OXTP content measurement method in prasugrel hydrochloride.

The OXTP content in the high-purity free prasugrel according to the present invention is generally 0.7% or lower, preferably 0.2% or lower, more preferably 0.09% or lower, still more preferably 0.05% or lower, especially Preferably 0.03% or less.

The purity of free prasugrel, ie the content of prasugrel, can be measured as described for the content of OXTP.

The high-purity free prasugrel according to the invention generally has a purity of 95% or higher, preferably 97% or higher, more preferably 99% or higher.

Process for the preparation of acid addition salts of prasugrel from highly pure free prasugrel

This method is a method which comprises adding high purity free prasugrel to an acid in an inert solvent or without a solvent, preferably in an inert solvent, or in an inert solvent or without a solvent The acid addition salt of prasugrel is prepared by adding (optionally dropwise) acid to free prasugrel of high purity, preferably in an inert solvent.

The acid used in this method may be, for example, an inorganic acid such as sulfuric acid, hydrochloric acid, nitric acid or phosphoric acid; or an organic acid such as trifluoroacetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. It is preferably hydrochloric acid, maleic acid or benzenesulfonic acid, more preferably hydrochloric acid.

In this method, the addition (optionally dropwise) of the acid can be performed by adding the acid dropwise or adding the acid all at once or in two or more divided portions.

The inert solvent used in this method is not particularly limited as long as it dissolves the starting materials to some extent and does not hinder the reaction. Solvents can be, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, light petroleum or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride , 1,2-dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diglyme ; ketones, such as acetone, methyl ethyl ketone, or diethyl ketone; esters, such as ethyl acetate, propyl acetate, or butyl acetate; carboxylic acids, such as acetic acid or propionic acid; or nitriles, such as acetonitrile or propionitrile. For the hydrochloride, it is preferably an ether, ketone, ester, carboxylic acid or nitrile, more preferably tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate, acetic acid or acetonitrile, especially Preferably tetrahydrofuran, dioxane, acetic acid or acetone, most preferably acetone. On the other hand, for the maleate salt, it is preferably an ether, ketone, ester or nitrile, more preferably tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate or acetonitrile, especially Preferably tetrahydrofuran, dioxane or acetone, most preferably acetone.

The reaction temperature in this method varies depending on reagents, solvents and the like. However, it is generally -20°C to 100°C, preferably 0°C to 70°C, more preferably 30°C to 60°C, most preferably 40°C to 55°C.

The reaction time in this method varies depending on reagents, solvents, reaction temperature and the like. However, it is generally 5 minutes to 10 hours, preferably 10 minutes to 5 hours.

A preferred embodiment of the process for the preparation of prasugrel maleate from highly purified free prasugrel is a process comprising dissolving maleic acid in acetone and adding thereto a highly purified The free prasugrel was reacted at the same temperature for 1 hour to 3 hours.

A preferred embodiment of the method for preparing prasugrel hydrochloride from high-purity free prasugrel is a process comprising dissolving high-purity free prasugrel in acetone at 0-70°C (preferably at 35-60° C.), dropwise add half of the required amount of concentrated hydrochloric acid (generally, equimolar to the thienopyridine form) within 2-10 minutes, and if necessary, add seed crystals to react at the same temperature for 30 minutes to 2 hours, and further add the remaining required amount of concentrated hydrochloric acid dropwise within 30 minutes to 2 hours to react at 0-70°C (preferably 25-55°C) for 1 hour to 3 hours.

After the reaction process is complete, the acid addition salt of prasugrel according to the invention is collected from the reaction mixture according to conventional methods. For example, the desired compound is obtained by collecting precipitated crystals by filtration after completion of the reaction or by distilling off the solvent after completion of the reaction. The obtained desired compound can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography, if necessary.

The high-purity prasugrel or its acid addition salt obtained in the present invention is excellent in oral absorbability and activation of metabolism and inhibition of platelet aggregation activity, and its toxicity is weak, in addition, it has good storage and handling stability, And therefore can be used as medicine (preferably for the prevention or treatment agent (especially therapeutic agent) of the disease that is caused by thrombus or embolism, more preferably for the prevention or treatment agent (especially treatment agent) of thrombosis or embolism agent)). In addition, the medicament is preferably used in warm-blooded animals, more preferably in humans.

When used as a therapeutic or prophylactic agent for diseases, the highly pure prasugrel or its acid addition salt according to the present invention can be administered orally by itself or in the form of tablets, capsules, granules, powders, syrups or by injection , suppositories, etc., in which pharmaceutically acceptable excipients, diluents, etc. are mixed as necessary.

These formulations are prepared by well-known methods using additives comprising excipients (which may be, for example, organic excipients (for example sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives, such as corn starch, potato starch, pregelatinized starch, or dextrin; cellulose derivatives, such as crystalline cellulose; gum arabic; dextran; or pullulan); or inorganic excipients (such as bright white anhydrous silica Acid or silicate derivatives, such as synthetic aluminum, calcium or magnesium aluminosilicates; phosphates, such as calcium hydrogen phosphate; carbonates, such as calcium carbonate; or sulfates, such as calcium sulfate)), lubricating agents (which may be, for example, stearic acid or metallic stearates such as calcium or magnesium stearate; talc; waxes such as beeswax or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; Glycols; fumaric acid; sodium benzoate; D,L-leucine; lauryl sulfates, such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids, such as silicic anhydride or silicic acid hydrate; or as above defined starch derivatives), a binder (which may be, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol or a compound similar to an excipient as defined above ), a disintegrant (which can be, for example, a cellulose derivative such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium or internally crosslinked carboxymethyl cellulose sodium; chemical Modified starches/celluloses such as carboxymethyl starch, sodium carboxymethyl starch or cross-linked polyvinylpyrrolidone; or starch derivatives as defined above), emulsifiers (which may be e.g. colloidal clays such as bentonite Earth or propolis; 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; or nonionic surfactants agents such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters or fatty acid sugar esters), stabilizers (which may be, for example, p-hydroxybenzoates such as methyl p-hydroxybenzoate or p-hydroxybenzoate Propyl hydroxybenzoate; alcohols, such as chlorobutanol, benzyl alcohol, or phenylethyl alcohol; benzalkonium chloride; phenols, such as phenol or cresol; ethylmercuric thiosalicylate; dehydroacetic acid; or sorbic acid ), flavor enhancers (such as, for example, commonly used sweeteners, acidulants or spices), and diluents.

The dose of highly purified prasugrel or an acid addition salt thereof according to the present invention may vary depending on various conditions such as the activity of the agent and the symptoms, age and weight of the patient. For oral administration, the dose can be each generally 0.01 mg/day/adult (preferably 1 mg/day/adult) as the lower limit, and 200 mg/day/adult (preferably 100 mg/day/adult) adults) as the upper limit.

Example

The present invention is described in more detail below by way of Reference Examples, Comparative Examples and Test Examples. However, it is not intended that the present invention be limited to these Examples.

Example 1

The embodiment that uses free prasugrel to prepare high-purity prasugrel hydrochloride

To 8.00g of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 398 mg of activated clay was added to 43 g of acetone, and the resulting mixture was stirred at 32°C. The reaction solution was filtered, the residue was washed with 4.41 g of acetone, and then 1.12 g of 36% concentrated hydrochloric acid was added dropwise to the solution at 52°C over a period of 1 minute. Thereto was added 238 mg of Crystal B2 obtained by the method described in JP2002-145883 as a seed crystal, and then the obtained mixture was stirred at the same temperature for one hour. Further, 1.07 g of 36% concentrated hydrochloric acid was added dropwise thereto over a period of one hour, and then the obtained mixture was stirred at 40°C for 2 hours and further stirred at 30°C for 1 hour. Precipitated crystals were collected by filtration, washed with 15.8 g of acetone, and dried at 50° C. under reduced pressure for 5 hours to provide 8.01 g of the title compound.

The liquid chromatogram of the obtained high-purity prasugrel hydrochloride is shown in FIG. 5 .

The measurement conditions in Fig. 5 are as follows.

(Measurement Conditions) Detector: Ultraviolet Absorption Meter (Measurement Wavelength: 240nm)

Analytical column: Cadenza CD-C18, inner diameter: 4.6mm, length: 15cm, particle size: 3μm

Guard column: no

Column temperature: 40°C

Mobile phase: 0.01mol/L potassium dihydrogen phosphate aqueous solution: tetrahydrofuran: acetonitrile = 13:5:2 (V/V/V)

Flow rate: 1.0 mL/min.

Example 2

The embodiment that uses free prasugrel to prepare high-purity free prasugrel

To 7.00 g of Compound (I) was added 46.3 g of acetonitrile, and the resulting mixture was stirred at 40°C for 10 minutes, and then the reaction solution was cooled to -15°C. Thereto was added dropwise 29.4 g of water precooled to the same temperature over a period of 35 minutes, and then the resulting mixture was stirred at the same temperature for 30 minutes. Precipitated crystals were collected by filtration, washed with 10.5 g of a precooled acetonitrile-water mixed solvent, and dried at 45° C. under reduced pressure for 5 hours to provide 6.50 g of the title compound.

The liquid chromatogram of the obtained high-purity free prasugrel is shown in Figure 6.

The measurement conditions in Fig. 6 are as follows.

(Measurement Conditions) Detector: Ultraviolet Absorption Meter (Measurement Wavelength: 240nm)

Analytical column: Cadenza CD-C18, inner diameter: 4.6mm, length: 15cm, particle size: 3μm

Guard column: no

Column temperature: 40°C

Mobile phase: 0.01mol/L potassium dihydrogen phosphate aqueous solution: tetrahydrofuran: acetonitrile = 13:5:2 (V/V/V)

Flow rate: 1.0 mL/min.

Comparative Example 1

2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

(1) 2-fluoro-α-cyclopropylcarbonylbenzyl chloride

A mixture of 100 g of cyclopropyl 2-fluorobenzophenone and 886 g of methylene chloride was stirred while cooling with ice to provide a mixed solution. To the obtained mixed solution was blown 3.98 g (0.1 equivalent) of chlorine gas over 20 minutes while maintaining the solution temperature at 0°C, and then the obtained mixture was stirred for 0.5 hours while maintaining the solution temperature at 0°C. Further, 39.8 g (1 equivalent) of chlorine gas was blown thereinto for 220 minutes while maintaining the solution temperature at 0°C, and it was reacted by stirring for one hour while maintaining the solution temperature at 0°C.

After the reaction was completed, 236 g of a 3% sodium thiosulfate aqueous solution was added dropwise to the obtained reaction solution while stirring while maintaining the solution temperature at not more than 15°C. After the dropwise addition, the solution was stirred for 10 minutes, and then the solution was subjected to a liquid-separation operation. With 589g of pre-cooled 8% sodium bicarbonate aqueous solution, then with 168g of pre-cooled water washing the obtained organic layer, and concentrated under reduced pressure to provide 145g of the title compound in the form of oil (pure content: 95.4g, yield rate: 80%).

(2) 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[ 3,2-c]pyridine

To 115g of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one p-toluenesulfonate, 60.7g of tert-butyldimethylchlorosilane and 277g To the mixture of dichloromethane was added 40.7 g of triethylamine, and then the obtained mixture was stirred at 25° C. for one hour to provide a mixed solution. To this mixed solution were added 78.1 g of 2-fluoro-α-cyclopropylcarbonylbenzyl chloride obtained in (1), 70.8 g of triethylamine and 1.57 g of sodium iodide, which were then stirred to It was reacted at 45°C for one hour and further reacted at 52°C for 5 hours.

After the reaction was finished, the obtained reaction solution was added with a whole amount of phosphate buffer obtained by adding distilled water to 9.50 g of KH ₂ PO ₄ and 0.95 g of Na ₂ HPO ₄ 12H ₂ O to obtain 358 g of The total weight was then subjected to a liquid separation operation, and the aqueous layer was extracted with 116 g of dichloromethane. The obtained organic layers were combined and concentrated under reduced pressure until the residue reached a volume of 218 mL. Thereto was added 476 g of acetonitrile, and then the obtained mixture was concentrated under reduced pressure until the residue reached a volume of 517 mL. To the obtained residue was added 238 g of acetonitrile, and then the obtained mixture was stirred at 30° C. for 30 minutes. Subsequently, 122 g of water was added thereto, and the resulting mixture was stirred at 0° C. for 3 hours. Precipitated crystals were collected by filtration, washed with 69.0 g of pre-cooled acetonitrile and dried under reduced pressure to provide 131 g of a crude material of the title compound.

To 40.0 g of crude material was added 252 g of acetonitrile, they were stirred at 50°C for 10 minutes, and then cooled to 30°C. Subsequently, 40 g of water was added dropwise thereto at the same temperature over a period of 30 minutes, and then the obtained mixture was cooled to 0° C. and stirred at the same temperature for 3 hours. Precipitated crystals were collected by filtration, washed with 30 g of pre-cooled acetonitrile, and dried under reduced pressure to provide 37.6 g of the title compound.

(3) 2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

A mixed solution of 6.20 g of acetic anhydride and 5.90 g of acetonitrile was added dropwise to 22.5 g of 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl) obtained in (2). -2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 7.65g of triethylamine, 62.0mg of 4-dimethylaminopyridine and 113g of In a mixture of acetonitrile, the reaction was carried out with stirring at -15°C for one hour.

After the reaction was completed, 75.9 g of cold water was added to the obtained reaction solution, and then the obtained mixture was stirred at -10°C for 30 minutes. Precipitated crystals were collected by filtration, washed with a mixture of 22.7 g of pre-cooled acetonitrile and 17.8 g of cold water, and dried under reduced pressure to provide 16.4 g of the title compound.

Test Example 1

Preparation of impurity OXTP standards

OXTP can be produced by, for example, the method described in Example 20 of Japanese Patent Laid-Open No. 06-41139.

Method for determining prasugrel content and OXTP content in prasugrel hydrochloride or free prasugrel

The content of prasugrel in free prasugrel or its hydrochloride was measured as follows.

Dissolve 150 mg of free prasugrel or its hydrochloride in an acetonitrile-water mixture (7:3) to 100 ml. Under the following conditions, 10 µL of this solution was injected into a liquid chromatograph for measurement.

Measurement Conditions (Liquid Chromatography)

(Measurement Conditions) Detector: Ultraviolet Absorption Meter (Measurement Wavelength: 240nm)

Analytical column: Cadenza CD-C18, inner diameter: 4.6mm, length: 15cm, particle size: 3μm

Guard column: no

Column temperature: 40°C

Mobile phase: 0.01mol/L potassium dihydrogen phosphate aqueous solution: tetrahydrofuran: acetonitrile = 13:5:2 (V/V/V)

Flow rate: 1.0 mL/min.

Table 1. Measurement of prasugrel and OXTP content in prasugrel hydrochloride or free prasugrel

The prasugrel hydrochloride of Example 1 prepared by reacting OXTP-containing free prasugrel with hydrochloric acid had a reduced OXTP content, indicating that high-purity prasugrel hydrochloride had been successfully prepared. The free prasugrel of Example 2 prepared by recrystallization of free prasugrel containing OXTP has a further reduced OXTP content, indicating that high-purity free prasugrel has been successfully prepared.

Industrial Applicability

According to the invention, prasugrel and its acid addition salts (in particular hydrochloride) are obtained in high purity with reduced content of impurities such as by-product OXTP.

Description of drawings

Fig. 1 is a powder X-ray diffraction pattern of crystal A of prasugrel hydrochloride obtained by irradiation with copper Kα rays (wavelength λ = 1.54 angstroms). In the powder X-ray diffraction pattern, the axis of ordinates represents the diffraction intensity in counts per second (cps) and the axis of abscissas represents the diffraction angle 2θ in degrees;

Fig. 2 is a powder X-ray diffraction pattern of crystal B1 of prasugrel hydrochloride obtained by irradiation with copper Kα rays (wavelength λ = 1.54 angstroms). In the powder X-ray diffraction pattern, the axis of ordinates represents the diffraction intensity in counts per second (cps) and the axis of abscissas represents the diffraction angle 2θ in degrees;

Fig. 3 is a powder X-ray diffraction pattern of crystal B2 of prasugrel hydrochloride obtained by irradiation with copper Kα rays (wavelength λ = 1.54 angstroms). In the powder X-ray diffraction pattern, the axis of ordinates represents the diffraction intensity in counts per second (cps) and the axis of abscissas represents the diffraction angle 2θ in degrees;

Fig. 4 is a powder X-ray diffraction pattern of crystals of free prasugrel obtained by irradiation with copper Kα rays (wavelength λ = 1.54 angstroms). In the powder X-ray diffraction pattern, the axis of ordinates represents the diffraction intensity in counts per second (cps) and the axis of abscissas represents the diffraction angle 2θ in degrees;

Fig. 5 is the result of the liquid chromatography of the prasugrel hydrochloride obtained in embodiment 1; With

FIG. 6 is the result of liquid chromatography of free prasugrel obtained in Example 2. FIG.

Claims (40)

1. A process for the preparation of prasugrel hydrochloride represented by the following formula with reduced OXTP content:

It comprises dissolving free prasugrel represented by the following formula containing OXTP in an inert solvent:

And optionally, hydrochloric acid is added dropwise to the solution for reaction. 2. The process for preparing prasugrel hydrochloride according to claim 1, wherein said inert solvent is acetone. 3. Prasugrel hydrochloride comprising 0.7% or less of OXTP, produced by the production process according to claim 1 or 2. 4. Prasugrel hydrochloride comprising 0.2% or less of OXTP, produced by the production method according to claim 1 or 2. 5. Prasugrel hydrochloride comprising 0.09% or less of OXTP, produced by the production method according to claim 1 or 2. 6. Prasugrel hydrochloride comprising 0.07% or less of OXTP, produced by the production method according to claim 1 or 2. 7. Prasugrel hydrochloride comprising 0.05% or less of OXTP, produced by the production method according to claim 1 or 2. 8. Prasugrel hydrochloride characterized by comprising 0.7% or less of OXTP. 9. Prasugrel hydrochloride characterized by comprising 0.2% or less of OXTP. 10. Prasugrel hydrochloride characterized by comprising 0.09% or less of OXTP. 11. Prasugrel hydrochloride characterized by comprising 0.07% or less of OXTP. 12. Prasugrel hydrochloride characterized by comprising 0.05% or less of OXTP. 13. Prasugrel hydrochloride according to any one of claims 3-12, wherein prasugrel hydrochloride is a crystal which is obtained at 5.7, 4.4 , 3.8, 3.5, and 3.3 Angstroms interplanar distances (d) show major peaks. 14. The prasugrel hydrochloride according to any one of claims 3-12, wherein prasugrel hydrochloride is a crystal which is obtained in powder X-ray diffraction at 6.6, 6.1 by irradiation with copper Kα rays , 4.0, 3.5 and 3.4 angstrom interplanar distances (d) show main peaks. 15. A pharmaceutical composition comprising prasugrel hydrochloride according to any one of claims 3-14 as active ingredient. 16. A preventive or therapeutic agent for a disease caused by thrombus or embolism in a homeothermic animal, comprising prasugrel hydrochloride according to any one of claims 3-14 as an active ingredient. 17. A prophylactic or therapeutic agent for thrombosis or embolism in humans, comprising prasugrel hydrochloride according to any one of claims 3 to 14 as an active ingredient. 18. A process for the preparation of free prasugrel having a reduced OXTP content comprising recrystallizing free prasugrel comprising OXTP. 19. The production method according to claim 18, wherein the recrystallization uses ether or nitrile as a solvent. 20. The production method according to claim 18, wherein the recrystallization uses acetonitrile as a solvent. 21. Free prasugrel comprising 0.7% or less of OXTP, produced by a production process according to any one of claims 18-20. 22. Free prasugrel comprising 0.2% or less of OXTP, produced by a production process according to any one of claims 18-20. 23. Free prasugrel comprising 0.09% or less of OXTP, produced by a production process according to any one of claims 18-20. 24. Free prasugrel comprising 0.05% or less of OXTP, produced by a production process according to any one of claims 18-20. 25. Free prasugrel comprising 0.03% or less of OXTP, produced by a production process according to any one of claims 18-20. 26. Free prasugrel characterized by comprising 0.7% or less of OXTP. 27. Free prasugrel characterized by comprising 0.2% or less of OXTP. 28. Free prasugrel characterized by comprising 0.09% or less of OXTP. 29. Free prasugrel characterized by comprising 0.05% or less of OXTP. 30. Free prasugrel characterized by comprising 0.03% or less of OXTP. 31. Free prasugrel according to any one of claims 21-30, wherein free prasugrel is crystalline at 6.7, 4.7, 4.6, 4.2 in powder X-ray diffraction obtained by irradiation with copper Kα rays and 3.8 angstroms interplanar distance (d) shows the main peak. 32. A pharmaceutical composition comprising free prasugrel according to any one of claims 21-31 as active ingredient. 33. A preventive or therapeutic agent for a disease caused by thrombus or embolism in a homeothermic animal, comprising free prasugrel according to any one of claims 21 to 31 as an active ingredient. 34. A prophylactic or therapeutic agent for thrombosis or embolism in humans, comprising free prasugrel according to any one of claims 21 to 31 as an active ingredient. 35. Process for the preparation of acid addition salts of prasugrel, characterized in that free prasugrel according to any one of claims 21-31 is reacted with an acid in an inert solvent or without a solvent. 36. The production method according to claim 35, wherein the acid addition salt is hydrochloride, maleate or benzenesulfonate. 37. An acid addition salt of prasugrel, prepared by a preparation process according to claim 35 or 36. 38. A pharmaceutical composition comprising an acid addition salt according to claim 37 as active ingredient. 39. A preventive or therapeutic agent for diseases caused by thrombus or embolism in homeothermic animals, comprising the acid addition salt according to claim 37 as an active ingredient. 40. A prophylactic or therapeutic agent for thrombosis or embolism in humans, comprising the acid addition salt according to claim 37 as an active ingredient.

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