PROCESS FOR PRODUCING CARBOSTYRIL DERIVATIVE

Abstract: The present invention provides a process for producing carbostyril derivatives (I) which are known to be useful as medical drug such as antithrombotic agent, cerebral circulation improver, anti-inflammatory agent, antiulcer agent, etc. in a high yield and a high purity. The carbostyril derivatives (I) can be produced by reacting a carbostyril derivative (II) with a tetrazole derivative (III) in the presence of a phase transfer catalyst.

Description: TECHNICAL FIELD The present invention relates to a novel process for producing carbostyril derivatives, and more particularly to a novel process for producing carbostyril derivatives represented by the following general formula (I): wherein A represents a group of the formula -(CH 2 ) 4 -; R represents a cycloalkyl group; and the bond between the 3- and 4-positions of the carbostyril skeleton represents a single bond. BACKGROUND ART The compound represented by the above-mentioned general formula (I), namely the objective compound of the present invention, is known to be useful as an antithrombotic agent, a cerebral circulation improver, an anti-inflammatory agent, an antiulcer agent, a hypotensive agent, an antiasthmatic agent, and a phosphodiesterase inhibitor, etc. (see: JP-A-56-49378 and USP No. 4,277,479). Carbostyril derivatives represented by the general formula (I) have so far been produced by reacting a carbostyril derivative represented by the following general formula (II): wherein the bond between the 3- and 4-positions of the carbostyril skeleton is a single or double bond, with a tetrazole derivative represented by the following general formula (III'): wherein X' represents a halogen atom, A represents a lower alkylene group and R represents a cycloalkyl group, in the presence of an inorganic base or an organic base (see: JP-A-56-49378; USP No. 4,277,479; and Chem. Pharm. Bull., 31(4), 1151-1157 (1983)). DISCLOSURE OF THE INVENTION According to the above-mentioned known process, the yield of the compound of general formula (I) is as low as about 50 to 74%, because there is also formed a compound in which the tetrazole derivative of general formula (III') has reacted not only with the hydroxyl group of the carbostyril derivative of general formula (II) but also with the 1-position of the carbostyril derivative of general formula (II) simultaneously. Since the thus formed contaminative impurity is difficult to remove, production of a compound of general formula (I) having a high purity has required a complicated process of purification. It is an object of the present invention to provide a process for producing a carbostyril derivative represented by the general formula (I) at a low cost and by a simple procedure. It is another object of the present invention to provide a process for producing a carbostyril derivative represented by the general formula (I) without any complicated process of purification, in a high yield, and in a high purity. It is yet another object of the present invention to provide an industrially advantageous process for producing the carbostyril derivatives represented by the general formula (I). In view of the above-mentioned present situation, the present inventors have conducted various studies with the aim of achieving the above-mentioned objects. As a result, it has been found in the process of the studies surprisingly that, when a phase-transfer catalyst is used as a catalyst, a compound of general formula (I) given by a reaction between the hydroxyl group of the carbostyril derivative of general formula (II) and the tetrazole derivative of general formula (III') is formed, and a compound given by the reaction between the 1-position of the carbostyril derivative of general formula (I) and the tetrazole derivative of general formula (III') is scarcely formed, and the reaction progresses position-specifically, and thereby the objects of the present invention can be achieved. Based on this finding, the present invention has been accomplished. According to the present invention, the objective carbostyril derivative represented by the general formula (I) can be obtained in a high yield and a high purity by reacting a carbostyril derivative represented by the following general formula (II): with a tetrazole derivative represented by the following general formula (III): wherein X represents a halogen atom, A represents a tetramethylene group, and R represents a cyclohexyl group, in the presence of a phase-transfer catalyst in a solvent, which is water alone. According to the process of the present invention, the hydroxyl group of the carbostyril derivative of general formula (II) and the tetrazole derivative of the general formula (III) can be made to react selectively and thereby the objective carbostyril derivative of general formula (I) can be produced on an industrial scale, at a low cost, by a simple procedure, in a high yield and in a high purity. BEST MODE FOR CARRYING OUT THE INVENTION As the halogen atom represented by X in the general formula (III), mention can be made of fluorine atom, chlorine atom, bromine atom and iodine atom, among which particularly preferred is chlorine atom. Next, the process of the present invention will be explained in more detail with reference to reaction schemes. wherein X, A and R are as defined above. In the reaction Scheme-1, the reaction between a compound of general formula (II) and a compound of general formula (III) is carried out in water alone as a solvent in the presence of a phase-transfer catalyst and further a basic compound. As the basic compound, known ones can be used extensively. Examples thereof include inorganic bases such as sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, silver carbonate and the like; alkali metals such as sodium, potassium and the like; alcoholates such as sodium methylate, sodium ethylate and the like; metallic salts of organic acids such as sodium acetate and the like; and organic bases such as triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) and the like. Among these bases, inorganic bases such as potassium carbonate, cesium carbonate, lithium carbonate and the like are particularly preferred. As the phase transfer catalyst, mentioned can be made of, for example, quaternary ammonium salts substituted with a residue selected from the group consisting of straight or branched chain alkyl group having 1-18 carbon atoms, phenyl lower alkyl group and phenyl group, such as tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, tributylmethylammonium chloride, tributylbenzylammonium chloride, tetrapentylammonium chloride, tetrapentylammonium bromide, tetrahexylammonium chloride, benzyldimethyloctylammonium chloride, methyltrihexylammonium chloride, benzylmethyloctadecanylammonium chloride, methyltridecanylammonium chloride, benzyltripropylammonium chloride, benzyltriethylammonium chloride, phenyltriethylammonium chloride, tetraethylammonium chloride, tetramethylammonium chloride and the like; phosphonium salts substituted with a residue selected from the group consisting of straight or branched chain alkyl groups having 1-18 carbon atoms such as tetrabutylphosphonium chloride and the like; and pyridinium salts substituted with a straight or branched chain alkyl group having 1-18 carbon atoms such as 1-dodecanylpyridinium chloride and the like. Among these phase transfer catalysts, quaternary ammonium salts substituted with a straight or branched chain alkyl group having 1-18 carbon atoms such as tetrabutylammonium chloride and the like are particularly preferred. As the salt-forming ions in these salts, hydroxyl ion, hydrogen sulfate ion and halogen ions are preferred, among which chlorine ion is particularly preferred. If desired, sodium sulfite or the like may be added to the reaction system of the above-mentioned reaction for the purpose of preventing the coloration caused by oxidation. The reaction is carried out usually at a temperature not lower than ambient temperature and not higher than 200°C, and preferably at a temperature of 50-150°C. The reaction time is usually from about one hour to about 10 hours. It is recommended to use the compound (III) usually in an amount of at least 0.5 mol and preferably 0.5-1.5 mol per mol of the compound (II), to use the basic compound usually in an amount of 1-5 mol per mol of the compound (II), and to use the phase transfer catalyst usually in an amount of 0.1-1 mol and preferably 0.1-0.5 mol per mol of the compound (II). The compound of general formula (I) obtained by the above-mentioned reaction can easily be isolated by the conventional separating means. As said separating means, mention can be made of, for example, extraction method using a solvent, dilution method, recrystallization method, column chromatography, preparative thin layer chromatography, etc. Examples Next, the process of the present invention is more concretely explained below with reference to examples. The invention is by no means limited thereby. Reference Example 1 Into a three-necked flask having a capacity of 300 ml were introduced 10.00 g of 6-hydroxy-3,4-dihydrocarbostyril, 16.36 g of 1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole, 10.16 g of potassium carbonate, 3.00 g of tetrabutylammonium chloride, 0.05 g of sodium sulfite, 30 ml of toluene and 50 ml of water. The content of the flask was heated under reflux for 8 hours. After cooling the reaction mixture to ambient temperature, the deposited crystalline product was collected by filtration and washed with 50 ml of water. Then, the crude crystal thus obtained was introduced into 70 ml of 90% methanol cooled to 5°C, and stirred at 5°C for 10 minutes for the sake of washing. The crystal was collected by filtration and further washed on the suction filter with 20 ml of 90% methanol cooled to 5°C. The crystal was dried to obtain 21.46 g (yield 95%) of 6-[4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril as a colorless needle-like crystalline product. Purity: 99.80%; m.p.: 158-159°C The purity was measured by high performance liquid chromatography under the following conditions: Column YMC Pack SIL A-002 (manufactured by YMC Co.) Moving phase dichloromethane/n-hexane/methanol = 20/10/1 Detector UV, 254 nm Flow rate 0.90 ml/min. Retention time 4.7 min. Example 2 Into a flask having a capacity of 200 ml were introduced 12.00 g of 6-hydroxy-3,4-dihydrocarbostyril, 19.60 g of 1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole, 8.20 g of 50% aqueous solution of tetrabutylammonium chloride, 12.20 g of potassium carbonate, 0.60 g of sodium sulfite and 60 ml of water. The content of the flask was heated under reflux for 8 hours with stirring. After the reaction, the reaction mixture was cooled to ambient temperature, and the deposited crude crystal was once collected by filtration. After washing the crystal firstly with 36 ml of methanol and then with 60 ml of water, the crystal was again introduced into a flask having a capacity of 200 ml and heated under reflux together with 84 ml of methanol for 2 hours. The solution thus obtained was cooled to 10°C. The crystal was collected by filtration, washed firstly with 24 ml of methanol and then with 24 ml of water, and dried at 80°C. Thus, 23.84 g (yield 87.7%) of 6-[4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril was obtained as a colorless needle-like crystalline product. Purity: 99.89%; m.p.: 158-159°C The purity was measured by high performance liquid chromatography (HPLC) under the same conditions as in Reference Example 1.

Claims: A process for producing a carbostyril derivative represented by the following general formula (I): wherein A represents a group of the formula: (CH 2 ) 4 -, and R represents a cyclohexyl group, which comprises reacting a carbostyril derivative represented by the following general formula (II): with a tetrazole derivative represented by the following general formula (III) : wherein X represents a halogen atom, and A and R are as defined above, in the presence of a phase transfer catalyst in a solvent which is water alone. A process for producing a carbostyril derivative according to Claim 1, wherein the reaction is carried out at a reaction temperature not lower than the ambient temperature and not higher than 200°C in the presence of a basic compound. A process for producing a carbostyril derivative according to Claim 2, wherein the reaction temperature is 50°C to 150°C. A process for producing a carbostyril derivative according to Claim 2, wherein said basic compound is an inorganic base. A process for producing a carbostyril derivative according to Claim 1, wherein X in the tetrazole derivative represented by general formula (III) is a chlorine atom. A process for producing a carbostyril derivative according to Claim 1, wherein said phase transfer catalyst is a quaternary ammonium salt substituted with a residue selected from the group consisting of straight or branched chain alkyl groups having 1-18 carbon atoms, phenyl lower alkyl groups and phenyl groups, a phosphonium salt substituted with a straight or branched chain alkyl group having 1-18 carbon atoms, or a pyridinium salt substituted with a straight or branched chain alkyl group having 1-18 carbon atoms, and the salt-forming ion in these salts is a hydroxyl ion, a hydrogen sulfate ion or a halogen ion. A process for producing a carbostyril derivative according to Claim 6, wherein said phase transfer catalyst is a quaternary ammonium salt substituted with a residue selected from the group consisting of straight or branched chain alkyl groups having 1-18 carbon atoms, phenyl lower alkyl groups and phenyl groups, and the salt forming ion in this said salt is a halogen ion. A process for producing a carbostyril derivative according to Claim 7, wherein said phase transfer catalyst is a quaternary ammonium salt substituted with a straight or branched chain alkyl group having 1-18 carbon atoms. A process for producing a carbostyril derivative according to Claim 7, wherein said salt-forming ion in the salt is a chlorine ion. A process for producing a carbostyril derivative according to Claim 7, wherein said phase transfer catalyst is tetrabutylammonium chloride. A process for producing a carbostyril derivative according to Claim 10, wherein said phase transfer catalyst is used in an amount of 0.1 to 1 mol per mol of the compound of general formula (II). A process for producing a carbostyril derivative according to Claim 11, wherein said phase transfer catalyst is used in an amount of 0.1 to 0.5 mol per mol of the compound of general formula (II). A process for producing a carbostyril derivative according to Claim 1, wherein the reaction is carried out in the presence of an agent for preventing the coloration caused by oxidation. A process for producing a carbostyril derivative according to Claim 13, wherein the agent for preventing the coloration caused by oxidation is sodium sulfite. A process for producing a carbosytril derivative according to Claim 4, wherein said inorganic base is chosen from potassium carbonate, cesium carbonate, cesium hydroxide, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and mixtures thereof.

Inventors: AKI SHINJI, FUKUYAMA NORIHIRO, KURIMURA MUNEAKI, MINAMIKAWA JUN-ICHI, NISHI TAKAO, TOMINAGA MICHIAKI, YAMAMOTO AKIHIRO, AKI, SHINJI, FUKUYAMA, NORIHIRO, KURIMURA, MUNEAKI, MINAMIKAWA, JUN-ICHI, NISHI, TAKAO, TOMINAGA, MICHIAKI, YAMAMOTO, AKIHIRO
Applicants: OTSUKA PHARMA CO LTD, OTSUKA PHARMACEUTICAL CO., LTD.
Application year: 2001
Main classification: C07D401
IPC codes: A61K31, C07D401