Preparation of estradienyl-benzaldoxime derivative preparation in high yield, for use e.g. in treating endometriosis, from epoxy-estrenone by multi-stage process including selective Grignard reaction

摘要

Preparation of estradienyl-benzaldoxime derivatives (I) involves: (i) reacting estr-9(11)-en-17-one (II) with active methylene compound; (ii) ring-opening 17(S)-spiro-epoxide (IX); (iii) reacting 17 alpha -substituted compound (X) with 4-bromobenzaldehyde ketal, magnesium and cuprous chloride; (iv) deprotecting ketal (XI); and (v) selectively oximating benzaldehyde compound (XII) using hydroxylammonium salt. Preparation of 4-(17 alpha -substituted-3-oxo-estra-4,9-dien-11 beta -yl)-benzaldehyde-(1E or 1Z)-oximes of formula (I) involves: (i) reacting an epoxy-estrenone of formula (II) with an active methylene compound in a solvent; (ii) ring-opening the obtained 17-spiro-epoxide of formula (IX) by regio- and stereo-selective cleavage of the spiro-epoxy group with alkali(ne earth) metal alcoholate, alkyl mercaptan in presence of alkali metal hydroxide or potassium tert. butanolate, alkali metal mercaptide or perfluoroalkanol in a solvent; (iii) reacting the obtained 17 alpha -substituted compound of formula (X) (optionally after etherification of the 17 beta -hydroxy group with an alkyl halide or haloalkyl fluoride in presence of strong base and a solvent) with 4-bromobenzaldehyde ketal, magnesium and cuprous chloride at -35 deg C to room temperature; (iv) cleaving the protective group of the obtained benzaldehyde ketal derivative of formula (XI) by acid hydrolysis; and (v) selectively converting the obtained benzaldehyde derivative of formula (XII) into the oxime (I) (as E/Z mixture) using a hydroxylammonium salt. R1 = H, 1-6C alkyl or Q; R2 = 1-4C alkyl; Y = 1-6C alkoxy, 1-6C alkylthio or OCH2Q; Q = 1-3C perfluoroalkyl; R3 = Me; or the two R3 groups together form ethylidene; and the oxime group has E- or Z- configuration.