Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-01
2003-10-07
Seaman, D. Margaret (Department: 1645)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S157000
Reexamination Certificate
active
06630590
ABSTRACT:
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 lower alkylene group; R represents a cycloalkyl group; and the bond between the 3- and 4-positions of the carbostyril skeleton represents a single bond or a double 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 U.S. Pat. No.
4,277,479).
The 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 as defined above, 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 an inorganic base or an organic base (see: JP-A-56-49378; U.S. Pat. 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 (I) 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).
Further, on the basis of the growing conscious to international environmental conservation in recent years, great demands become arisen in a chemical industry to make every effort decreasing use of the solvents and reagents pointed out the harmfulness, and preventing those materials from discharging into the environment. In order to fulfil those demands, established processes have to be down for a consideration, alternative raw materials, reagents and solvents being less harmful have to be found out, and the processes having higher conversion rate, yield and selectivity have to be developed; so that the environmental load can be diminished. Under the circumstances with these social demands, it is further object of the present invention to provide a process being safe for the environment, for producing a carbostyril derivative represented by the general formula (I) with using phase transfer catalyst in water.
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):
wherein the bond between the 3- and 4-positions of the carbostyril skeleton represents a single bond or a double bond, with a tetrazole derivative represented by the following general formula (III):
wherein X represents a halogen atom or a group causing the same substitution reaction as that caused by halogen atom, A represents a lower alkylene group, and R represents a cycloalkyl group, in the presence of a phase-transfer catalyst.
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 examples of the lower alkylene group represented by A in the general formulas (I) and (III) of this specification, mention can be made of, straight chain or branched chain alkylene groups having 1-6 carbon atoms such as methylene, ethylene, propylene, tetramethylene, 2-ethylethylene, pentamethylene, hexamethylene, 2-methyltrimethylene, 2,2-dimethyl-trimethylene, 1-methyltrimethylene and the like. Among these lower alkylene groups, particularly preferred is tetramethylene group.
As the cycloalkyl group represented by R in the general formulas (I) and (III), mention can be made of, for example, cycloalkyl groups having 3-8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Among these cycloalkyl groups, particularly preferred is cyclohexyl group.
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.
As specific examples of the group causing the same substitution reaction as that caused by the halogen atom represented by X in the compound of general formula (III), mention can be made of lower alkanesulfonyloxy group, arylsulfonyloxy group, aralkylsulfonyloxy group and the like. As specific examples of the lower alkanesulfonyloxy group, mention can be made of methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy, pentanesulfonyloxy, hexanesulfonyloxy and the like. As specific examples of the arylsulfonyloxy group, mention can be made of substituted or unsubstituted arylsulfonyloxy groups such as phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, &agr;-naphthylsulfonyloxy and the like. As specific examples of the aralkylsulfonyloxy group, mention can be made of substituted or unsubstituted aralkylsulfonyloxy groups such as benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, &agr;-naphthylmethylsuflonyloxy and the like. Among the groups represented by X, particularly preferred are halogen atoms.
As the bond between the 3- and 4-positions of the carbostyril skeleton in the general formulas (I) and (II), a single bond is particularly preferred.
Next, the proces
Aki Shinji
Fukuyama Norihiro
Kurimura Muneaki
Minamikawa Jun-ichi
Nishi Takao
Finnegan Henderson Farabow Garrett and Dunner, LLP
Otsuka Pharmaceutical Co. Ltd.
Seaman D. Margaret
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