Process for producing optically active imidazole compounds, inte

Details Process for producing optically active imidazole compounds, inte Process for producing optically active imidazole compounds, inte

1999-07-23

2000-05-23

McKane, Joseph

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D23358

Patent

active

060667397

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a method for producing an optically active imidazole compound, namely, an optically active 4-[.alpha.-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid, which is useful as a thromboxane synthetase inhibitor and an agent for the prophylaxis and treatment of diabetic complications, a synthetic intermediate therefor and a production method thereof.


BACKGROUND ART

Japanese Patent Examined Publication No. 41143/1993 discloses that 4-[.alpha.-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid and pharmaceutically acceptable salts thereof have pharmacological actions such as potent TXA2 biosynthesis inhibitory action, platelet aggregation inhibitory action and vasodilating action, and that they are useful for the prophylaxis and treatment of thrombosis, cerebral apoplexy, myocardial infarction, acute heart death, angina pectoris, hypertension, asthma, nephritis and the like. In addition, 4-[.alpha.-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid, an optically active compound thereof and a pharmaceutically acceptable salt thereof have been found to be useful for the prophylaxis and treatment of diabetic complications, such as diabetic neuropathy, nephropathy, ophthalmopathy and arteriosclerosis (Japanese Patent Application No. 340161/1995).
This pharmaceutically useful 4-[.alpha.-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid has an asymmetric carbon in the molecular structure. When a compound having an asymmetric carbon is developed as a pharmaceutical agent, the corresponding optically active compound is used in view of provision of a chemically pure compound, reinforcement of pharmacological activity, removal of side effect, lowering of toxicity, simplification of absorption, metabolism, distribution and excretion, improvement in solubility and the like. This in turn renders resolution of the optical isomer an important matter for the development of a compound having an asymmetric carbon as a pharmaceutical agent.
As a method for resolving the optical isomer of 4[.alpha.-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid, Japanese Patent Unexamined Publication No. 215771/1990 discloses a method for resolving the optical isomer of 4-[.alpha.-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid, which comprises ester-bonding hydroxyl group bonded to the asymmetric carbon of 4-[.alpha.-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoate and an optically pure chiral carboxylic acid compound, to give two kinds of diastereomers, subjecting the diastereomers to column chromatography and then to hydrolysis reaction.
However, this optical resolution by column chromatography requires a large amount of a filer, a large amount of a solvent and a large separation device for the small amount of a substance to be resolved. This method is effective for the separation of a trace amount, but when operability and cost are taken into consideration, is unsuitable for industrial scale mass production.
Therefore, there has been a demand for a practical and useful method for the resolution of the optical isomer of 4-[.alpha.-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid.


DISCLOSURE OF THE INVENTION

To solve the above-mentioned problems, the present inventors have conducted various studies of a method for optical resolution by fractional crystallization utilizing the difference in physical properties between two kinds of diastereomers generated by ester-bonding a hydroxyl group bonded to an asymmetric carbon and an optically pure chiral carboxylic acid compound, in an attempt to provide a method for industrial production of an optically active 4-[.alpha.-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid in a large amount, and completed the present invention.
Accordingly, the present invention provides the following.
(1) A compound of the formula (I) ##STR2## wherein R.sup.1 is a lower alkyl, a phenylalkyl or a substituted phenylalkyl; thieny

REFERENCES:
CA 114: 101990 Preparation of optically . . . diastereoisomeric esters. Tsuruta et al., Aug. 28, 1990.

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