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METHOD OF OBTAINING FLORPHENICOL, THIAMPHENICOL AND CHLORAMPHENICOL AS WELL AS INTERMEDIATE COMPOUNDS OF OXAZOLINE TYPE BY DISSYMMETRICAL SYNTHESIS
METHOD OF OBTAINING FLORPHENICOL, THIAMPHENICOL AND CHLORAMPHENICOL AS WELL AS INTERMEDIATE COMPOUNDS OF OXAZOLINE TYPE BY DISSYMMETRICAL SYNTHESIS
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机译:不对称合成获得氟苯,噻吩和氯酚以及草唑啉型中间体的方法
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摘要
The present invention comprises a process for the asymmetric synthesis of florfenicol, thiamphenicol or chloramphenicol, from a derivative of trans-cinnamic acid, comprising the steps: (a) converting the acid to an acid chloride using a chlorinating agent, and reducing the acid chloride to a trans allylic alcohol with a reducing agent; (b) asymmetrically epoxidizing the allylic alcohol of step (a), by reacting with t-butylhydroperoxide in the presence of a chiral epoxidation catalyst prepared from titanium (IV) isopropoxide and L-diisopropyltartaric acid, to form a chiral epoxide; (c) regioselectively opening the epoxide of step (b) by sequentially treating with sodium hydride, zinc chloride and dichloroacetonitrile to form an oxazoline; (d) stereoselective inversion/isomerization of the oxazoline of step (c) by sequentially treating with: (i) a lower alkylsulfonyl chloride and a tertiary amine base; (ii) sulfuric acid and water; (iii) an alkali metal hydroxide; to form an oxazoline; (e) optionally treating the oxazoline of step (d) with a fluorinating agent, for preparing florfenicol, then hydrolyzing with acid. In an alternative embodiment, the present invention comprises a process for isomerizing of the S,S-isomer of florfenicol to the R,S-isomer (I) by sequentially treating with: (i) a lower alkylsulfonyl chloride and a tertiary amine base; (ii) sulfuric acid and water; (iii) an alkali metal hydroxide. The present invention further comprises a process for regioselectively opening an epoxide to form a threo-oxazoline.
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