Method for the production of 4-(17$g(a)-methyl substituted 3-oxoestra-4 9-dien-11$g(b)-yl)benzaldehyd-(1e or 1z)-oximes

Process for the production of 4-(17α-methyl-substituted 3-oxoestra-4,9-dien-11-yl)benzaldehyde-(1E or 1Z)-oximes of general formula (I)

• 16
• in which R1 is a hydrogen atom, a C1-6-alkyl radical or a CnF2n+1 radical, whereby n is 1, 2 or 3, R2 is a C1-4-alkyl radical, X means an OH group in E- or Z-position, and Y is an OC1-6-alkyl group, an SC1-6-alkyl group or an OCH2CnF2n+1 group, whereby n is 1, 2 or 3, characterized in that the 3,3-dimethoxy-estra-5(10),9(11)-en-17-one of formula (IX)
• 17
• in which R2 has the above-indicated meaning, is converted with an active methylene reagent in an inert solvent into the spiroepoxide of formula (X)
• 18
• in which R2 has the above-indicated meaning, and which, after cleavage of the 17-spiroepoxy group by alkali or alkaline-earth alcoholate, alkali or alkaline-earth thiol alcoholate or by trifluoroalkyl alcohols and potassium-tert-butanolate in an inert solvent, is opened to the 17α-CH2Y compound of formula (XI)
• 19
• in which R1 represents a hydrogen atom and R2 and Y have the above-indicated meanings, and this compound optionally is reacted by reaction of the 17β-hydroxyl group with alkyl halides or fluoroalkyl iodide in the presence of strong bases in an inert solvent to form the 17β-ethers of formula (XI), in which R1 represents a C1-6-alkyl radical or a CnF2n+1 radical, and R2 and Y have the above-indicated meanings, the compound of formula (XI) is epoxidized on the 5(10)-double bond, whereby a mixture is produced from 5α,10α]-epoxy- and 5β,10β-epoxy-17α-methyl-substituted estr-9(11)-ene-3,3-dimethyl ketal of formula (XII)
• 20
• in which R1, R2 and Y have the above-indicated meanings, which is opened with a 4-bromobenzaldehyde ketal, magnesium and Cu(I)CI at temperatures of between −35° C. and room temperature to the corresponding 3,3-dimethoxy-5α-hydroxy-17α-methyl-substituted 11α,β-benzaldehydedimethyl ketal of formula (XIII)
• 21
• in which R1, R2 and Y have the above-indicated meanings, and which is subjected to acid hydrolysis to cleave the protective groups, whereby a mixture of the 11α,β-benzaldehyde derivatives of formula (XIV).
• 22
• is produced, in which R1, R2 and Y have the above-indicated meanings, from which the pure 11β-benzaldehydes of formula (VII) are isolated by crystallization, in which R1, R2 and Y have the above-indicated meanings, and the aldehyde function is converted by hydroxylammonium salts in the presence of bases, preferably pyridine, at room temperature into a mixture of the E/Z-benzaldoximes of general formula (I).