A versatile route to single enantiomer verapamil from readily available raw materials is described. The key intermediate, 4-cyano-4-(3,4-dimethoxyphenyl)-5-methyl hexanoic acid (verapamilic acid), was resolved efficiently with r-methyl benzylamine. Stereochemical integrity at the quarternary carbon centre was preserved through subsequent steps to give either (R)-or (S)-verapamil in good overall yield. This sequence incorporated a selective borane-mediated reduction of a tertiary amide. Process scale-up to the pilot plant has been demonstrated successfully for the resolution step.
The absolute configuration of natural ( +)-a-lipoic acid is confirmed to be R by the synthesis of its enantiomer from (S)-malic acid.cc-( +)-Lipoic acid, the coenzyme for a-ketoacid dehydrogenases,l was assigned the (R)-configuration (la) by Mislow and Meluch,2 by comparison of the melting point-composition diagrams for mixtures of (R)-( +)-3-methyloctanedioic acid with (+)-and with (-)-3-mercapto-octanedioic acid, respectively. By synthesis, these mercapto-diacids had been correl-
Malic acid has been converted into a-(R)-and a-(S)-lipoic acid [ ( l a ) and (1 b), respectively] via ( R ) -and (S)-(2-phenylmethoxyethyI)oxirane [(2a) and (2b), respectively]. The (R)-oxirane (2a) was cleaved w i t h but-3-enylmagnesium bromide (cuprate catalysis) t o give (S) -1 -(pheny1methoxy)oct-7en-3-01 (4a). This was converted into methyl (S)-6,8-dihydroxyoctanoate (5a), the d i -0methanesulphonate (6a) of which was treated with sodium sulphide and sulphur in dimethylformamide to yield methyl IX-( R ) -1ipoate (7a), that was saponified t o a-(R)-lipoic acid (1 a). The (S) -oxirane (2b) was similarly converted into CX-(S) -1ipoic acid ( I b).
1. Das aus dem Dimethyltartrat (Ia) erhältliche (Literaturangaben) Dioxolan (II) wird in das [vom Nebenprodukt (III) abtrennbare] Diol (IV) übergeführt, dessen Hydrierungsprodukt (V) nach bekanntem Verfahren in (R)‐Ethyloxiran (VI) übergeführt wird.
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