Process for preparing carboxylic acid derivative

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

1996-08-22

1998-05-26

Lambkin, Deborah

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549 62, 549 28, C07D33332, C07D33334

Patent

active

057567689

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP95/02674 Dec. 29, 1995.


TECHNICAL FIELD

The present invention relates to a process for preparing 3-(2-thienylthio)butyric acid having the formula (I): ##STR2##
The present compound is a compound as an important key intermediate in the preparation of a medicament having the 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 6 mol/l aqueous solution of hydrochloric acid of which hydrogen ion concentration is about 6 mol/l under refluxing conditions 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 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 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 a process for preparing 3-(2-thienylthio)butyric acid whereby the production of 3-(3-thienylthio)butyric acid as a by-product can be dramatically controlled to at most 0.1 mole % by controlling the concentration of an aqueous solution of acid to be used and, preferably, the kind of the acid. Consequently, the present invention has been accomplished.
Namely, the present invention relates to a process for preparing a compound having the formula (I): ##STR5## characterized by reacting a compound having the formula (III). ##STR6## wherein R is a straight chain or branched C.sub.1 to C.sub.4 alkyl group, with an aqueous solution of acid having a hydrogen ion concentration of at most 3.9 mol/l at a temperature of not more than reflux temperature of reaction mixture whereby the production of a by-product compound having the formula (II): ##STR7## is controlled to at most 0.1 mol %.


BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the relationship between an amount of 3-(3-thienylthio)butyric acid produced after 24 hours of reaction and a hydrogen ion concentration (mol/l) of an aqueous solution of acid in Examples 1 to 7 and Reference Examples 1 to 5.


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 component 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, phosphoric acid, hydrobromic acid, hydroiodic acid or hydrofluoric acid, and an organic acid such as trifluoroacetic acid, toluenesulfonic acid or methanesulfonic acid. 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 o

REFERENCES:
patent: 4021450 (1977-05-01), Ahrens et al.
patent: 4797143 (1989-01-01), Baldwin et al.
patent: 4968814 (1990-11-01), Blacklock et al.
patent: 4968815 (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, "An Enantioselective Synthesis of Topically-Active Carbonic Anhydrase Inhibitor MK--0507," J. Org. Chem. 58, 1672-79, 1993.

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