Process for preparing carboxylic acid derivative

Details Process for preparing carboxylic acid derivative Process for preparing carboxylic acid derivative

1996-08-22

1998-03-03

Dees, Jose G.

Harness for working animal

C07D33316

Patent

active

057236283

DESCRIPTION:

BRIEF SUMMARY
SPECIFICATION

This application is a 371 of PCT/JP/02673 filed Dec. 25, 1995.


TECHNICAL FIELD

The present invention relates to a process for preparing 3-(2-thienylthio)butyric acid having the structural formula (I): ##STR2##
The present compound is an important key intermediate in the preparation of a medicament having the structural formula (V): ##STR3## which is used in the treatment of glaucoma, MK-507 (see Fortschritte der Ophthalmologie, 88, 513 (1991)).


BACKGROUND ART

As a process for preparing 3-(2-thienylthio)butyric acid, there is known a process wherein 3-(2-thienylthio)butyric acid methyl ester is hydrolyzed with an about 6N aqueous solution of hydrochloric acid under refluxing Pat. No. 4,968,814 and Japanese Unexamined Patent Publication No. 224576/1992).
However, in the above-mentioned process, the production of 3-(3-thienylthio)butyric acid having the structural formula (II): ##STR4## as a by-product is unavoidable. Furthermore, the removal of this by-product is extremely difficult because in the subsequent process for the synthesis of the medicament used in the treatment of glaucoma having the structural formula (V), this by-product is subjected to the chemical conversion in the same way as in 3-(2-thienylthio)butyric acid.
Therefore, in order to use the obtained 3-(2-thienylthio)butyric acid as an intermediate for a medicament, it has been desired to develop a process for preparing 3-(2-thienylthio)butyric acid wherein the content of 3-(3-thienylthio)butyric acid is controlled to at most 0.1 mol %.


DISCLOSURE OF THE INVENTION

As the result of the detailed investigation of the present inventors to control the production of 3-(3-thienylthio)butyric acid as a by-product, they have found that in a contact reaction of a compound having the formula (III): ##STR5## wherein R is a straight chain or branched C.sub.1 to C.sub.4 alkyl group, with an aqueous solution of acid, the production of 3-(3-thienylthio)butyric acid as a by-product can be dramatically controlled to at most 0.1 mol % by adding an organic solvent or an organic acid. Consequently, the present invention has been accomplished.
Namely, the present invention relates to a process for preparing a compound having the structural formula (I): ##STR6## characterized by, in a reaction of a compound having the formula (III): ##STR7## wherein R is a straight chain or branched C.sub.1 to C.sub.4 alkyl group, with an aqueous solution of acid, adding an organic solvent or an organic acid whereby the production of a by-product compound having the structural formula (II): ##STR8## is controlled to at most 0.1 mol %.


BEST MODE FOR CARRYING OUT THE INVENTION

The compound having the formula (III) as a starting compound can be prepared according to the process described in U.S. Pat. No. 4,968,814.
To be concrete, the compound (III) can be prepared by reacting an alkaline metal salt of 2-thiophenethiol with a 3-tosyloxybutyric acid ester.
Examples of the group represented by R in the formula (III) are, for instance, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, tert-butyl group and the like. Among these, methyl group is preferable from the viewpoint that an alcohol or alcohol derivative produced during the reaction is easily removed by distillation.
Examples of the acid in the aqueous solution of acid to be used are, for instance, an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid; an organic acid such as trifluoroacetic acid, toluenesulfonic acid or methanesulfonic acid; and a Lewis acid such as boron trifluoride-diethyl ether complex or a boron fluoride. It is desirable to use hydrochloric acid or sulfuric acid because it is easy to industrially handle them in the waste disposal etc.
The concentration of the aqueous solution of acid to be used can be freely determined.
Examples of the organic solvent or the organic acid to be added are, for instance, an organic solvent such as dioxane, toluene, dichloromethane, chloroform, acetone or dimethoxyethane, and

REFERENCES:
patent: 4968814 (1990-11-01), Blacklock et al.
patent: 5474919 (1995-12-01), Chartrain et al.
patent: 5574176 (1996-11-01), Mathre et al.
Blacklock et al., Journal of Organic Chemistry, vol. 58 pp. 1672-1679, 1993.
Morrison et al., "Organic Chemistry" 5th ed., Allyn & Bacon, Inc., (1987), pp. 880-881.

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