Asymmetric process for preparing florfenicol, thiamphenicol, chloramphenicol and oxazoline intermediates
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 a...
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Main Authors | , |
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Format | Patent |
Language | English |
Published |
19.07.1994
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Edition | 5 |
Subjects | |
Online Access | Get full text |
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Summary: | 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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Bibliography: | Application Number: AU5748494 |