Production of optically active benzothiepin salts

Details Production of optically active benzothiepin salts Production of optically active benzothiepin salts

1996-09-11

1999-09-14

Lambkin, Deborah C.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D33712

Patent

active

059525126

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to an amine salt of an optically active benzothiepin derivative useful as a raw material of a pharmaceutical agent having an activity of accelerating bone formation and an activity of suppressing bone resorption, and to a method of producing it.


BACKGROUND ART

The present applicants found an optically active compound useful as a pharmaceutical agent having an activity of bone formation and a bone resorption activity, i.e. a prophylactic and therapeutic agent of bone diseases, and have filed a patent application on this compound
As methods of optically resolving a racemic modification, a mixture of optically active compounds, there have been generally employed, on a laboratory scale, and, in very limited cases, on an industrial scale, (1) preferential crystallization from a racemic modification, (2) a diastereomer method using an agent of optical resolution, (3) a fractionating method using a column chromatography packed with an optically active substance, (4) a fractionating method utilizing the stereospecificity of enzymic reaction and (5) a fractionating method using an optically active film.
As examples of norephedrine subjected to optical resolution of optical isomers, descriptions are found in, for example, JPA S60(1985)-224672, JPA S48(1973)-23724 (U.S. Pat. No. 3,966,752), Liebigs Ann. Chem. p.1995 (1982) and EP-A-128684. However, these are nothing more than examples attempted for a certain specific compound. In other words, since no general regularity has been established on the optical resolution of optical isomers, when conducting optical resolution of optical isomers, various methods have to be investigated on respective compounds at the present technical level in the relevant field.
So far, production of an optically active benzothiepin derivative which is a raw material of the above-mentioned optically active compound useful as a prophylactic and therapeutic agent of bone diseases, especially an optically active 3-benzothiepin-2-carboxylic acid derivative, has been conducted by, for example, allowing a racemic isomer of 1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carb oxylic acid to react with methyl mandelate, followed by recrystallization utilizing the difference in solubilities of diastereomers of the resulting ester derivative. This method, however, requires the formation of ester linkage and re-cleavage, and produces a relatively large amount of undesirable by-products, which requires complicated refining steps resulting in a low yield, thus a number of problems have been left to be solved for realizing the production on an industrial scale.
Circumstances being such as above, development of a method of producing efficiently an optically active benzothiepin derivative, especially (2R,4S)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepi n-2-carboxylic acid, as an optically active form in a substantially pure state, has been desired.
And, since the above-mentioned optically active compound useful as a prophylactic and therapeutic agent of bone diseases varies in its pharmaceutical activity and absorbability (especially oral absorbability), depending on the kind of an optically active form, production of a specific optically active compound which is excellent in a pharmaceutical activity and absorbability is desired. Accordingly, development of a method of producing an optically active benzothiepin derivative which is a raw material for production of the specific optically active compound is desired.


DISCLOSURE OF INVENTION

Taking the above circumstances into consideration, the present inventors have diligently conducted research work to find out an industrially advantageous method of producing an optically active benzothiepin derivative in a high purity and with a high yield by a simple procedure. As a result, they found out, unexpectedly, that a highly pure optically active benzothiepin derivative can be readily produced in a high yield by allowing a racemic mixture, trans-1,2,4,5-tetrahydro-4-methyl-7

REFERENCES:
patent: 3966752 (1976-06-01), Asinger et al.
patent: 5158943 (1992-10-01), Sohda et al.
patent: 5726325 (1998-03-01), Yoshida et al.
The Merck Index (1996), pp. 817 and 5667.
Liebigs Ann. Chem. (1982) 1995-1998.
Soda et al, "Preparation of Sulfur-containing heterocyclic compounds for the treatment of osteoporosis", Chem.Abs. 121:83085, 1993.
Sohda et al, "Preparation of 1,2,4,5-tetrahydro-5-oxobenzothiepines for prevention of treatment of osteoporosis", Chem. Abs. 116:151599, 1991.

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