Production of epothilone compounds with taxol-like activity

摘要

Production of epothilone A and B of formula (I) comprises esterification of a thiazolyl-hydroxyalkyldiene (II) with a protected 3,7-dihydroxy-5-oxo-tridecenoic acid (III) and conversion of the resulting ester into (I) by the following sequence of reactions: (a) ring closure involving olefin metathesis in the presence of a noble metal catalyst; (b) optional deprotection of protected hydroxy groups, (c) epoxidation and (d) deprotection of protected hydroxy groups as required. R = H (epothilone A) or Me (epothilone B); B = benzyl; tetrahydropyranyl; or silyl protecting group. Also claimed are starting materials (II) and (III) and desoxy-epothilone intermediates (IV) (obtained from step (a) and optionally (b)): B1 = H; benzyl; p-methoxybenzyl; tetrahydropyranyl; or silyl protecting group. Further claimed are 2-(2,2-dimethyl-1,3dioxan-4-yl)-2-methyl-pentan-3-one (V); 2-methyl-6-heptenal (VI), 2,6-dimethyl-6-heptenal (VII) and (4S,6S)-2-(2,2-dimethyl-1,3-dioxan-4-yl)-5-hydroxy-2,4,6-trimethyl-und ecan-3-one (sic) (DDHTU); used for the preparation of (III); as well as protected thiazolyl-hydroxyalkyldienes (VIII) used for the preparation of (II): B2 = benzyl; p-methoxybenzyl; tetrahydropyranyl; or silyl protecting group. Note - The final claim appears to cover stereoisomers of all the above compounds except (DDHTU) and (VIII) sic; the phrasing of the claims is ambiguous. (I) are known from DE 4138042.