Process for producing 1-oxacephalosporin-7alpha-methoxy-3-chloromethyl derivative

Abstract

To provide a novel production method of oxacephem compound. [Solution] A method of producing Compound (IV) shown by the formula: (wherein R represents an acyl residue; R 1 represents carboxy protecting group; Me represents methyl and X represents halogen), the method comprising the steps of: (First step) letting Compound (I) shown by Formula: (wherein, R represents an acyl residue; R 1 represents carboxy protecting group) react with a halogenating agent in the presence of a base; (Second step) adding MOMe (M represents alkaline metal; Me represents methyl) in the presence of a halogenating agent after completion of the first step; and (Third step) adding a reducing agent after completion of the second step.

Description

technical field [0001] The present invention relates to a production method of an intermediate for the synthesis of 1-oxacephalosporin which can be used as an antimicrobial agent. Background technique [0002] 1-Oxacephalosporin-7α-methoxy- 3-Chloromethyl derivatives (hereinafter also simply referred to as 7α-methoxy-3-chloromethyl compounds) are known. As a production method thereof, there is known a method in which a raw material 3-exomethylene compound is added with Cl 2 7α-Methoxylation then occurs by light irradiation. However, photoirradiation generally requires expensive optical reaction equipment and thus is not industrially advantageous. For example, Non-Patent Document 1 describes the following reaction. [chemical formula 1] Non-Patent Documents 2 and 3 describe the following methods. [chemical formula 2] On the other hand, Patent Document 1 describes a production method that avoids optical reactions. The outline of this reaction is as follo...

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Problems solved by technology

In Example 4, intermediate 6 was synthesized by reacting 3-exomethylene compound 1 with chlorine in the presence of quinoline as a base, however, the yield was as low as about 9.6%. In Example 5 , the chlorination was carried out using α-picoline as a base, however, optical reactions were also used, and the yields were still not satisfactory

In the step from intermediate 6 to compound 4, NaOMe / MeOH was used as methoxylating agent, however column chromatography was also used to remove by-products, therefore, this method also cannot be regarded as industrially favorable

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