Method for the production of diarylcycloalkyl derivatives

A process for preparing a compound of the formula (I), comprising the steps according to the following scheme:

• in which, in the individual steps,
• a1) a compound of the formula (IX) is reacted with water to give a compound of the formula (V) in the presence of lipase enzyme which affords a suitable enantiomeric excess of the compound (V), or
• a2) a compound of the formula (X) is reacted with at least one acyl donor to give the compound (V) in the presence of lipase enzyme which affords a suitable enantiomeric excess of the compound (V),
• b) the compound (V) is reacted in the presence of an acidic catalyst with a compound which can form the base-stable and acid-labile protecting group Z3 to give the compound of the formula (VIII) and
• c) the compound (VIII) is converted in the presence of a nucleophile to a compound of the formula (II),
• d) the compound (II) is reacted in the presence of a base B1 with a compound of the formula (VI) to give a compound of the formula (Ma) or with a compound of the formula (VII) to give a compound of the formula (IIIb),
• e) the compound (IIIa) is converted to a compound of the formula (IVa) or the compound (IIIb) to a compound of the formula (IVb), the particular reaction being effected with an alcohol in the presence of an acidic catalyst,
• f) the compound (IVa) is reacted with the compound (VII) or the compound (IVb) with the compound (VI) to give a compound of the formula (Ia) in the presence of the base B1 and
• g) if appropriate, the compound (Ia) is hydrolyzed or hydrogenolyzed to give the compound (I) when R3 is H,
• the compounds (IX) and (X) each being present as the pure cis isomer or as cis/trans mixtures,
• and in which the variables and substituents are each defined as follows:
• Ring A is C3-C8-cycloalkyl or C3-C8-cycloalkenyl, in which one or more carbon atoms in the cycloalkyl or cycloalkenyl rings may be replaced by oxygen atoms,
• R1, R2, R4 and R5 are each independently H, F, Cl, Br, OH, NO2, CF3, OCF3, C1-C6-alkyl or —O—(C1-C6-alkyl),
• R3 is H, C1-C6-alkyl or benzyl, which may optionally be substituted by F, Cl, Br, OH, NO2, CF3, OCF3, C1-C6-alkyl or —O—(C1-C6-alkyl),
• R6 is C1-C6-alkyl or benzyl, which may optionally be substituted by F, Cl, Br, OH, NO2, CF3, OCF3, C1-C6-alkyl or —O—(C1-C6-alkyl),
• X is C1-C6-alkyl, in which one or more carbon atoms in the alkyl group may be replaced by oxygen atoms,
• Y is C1-C6-alkyl, in which one or more carbon atoms in the alkyl group may be replaced by oxygen atoms,
• Z1 and Z2 are each independently an acid-stable protecting group,
• Z3 is a base-stable and acid-labile protecting group,
• Z4 and Z5 are each independently a leaving group, and
• B1 is a tertiary alkaline earth metal alkoxide, tertiary alkali metal alkoxide, alkaline earth metal amide, alkali metal amide, alkaline earth metal silazide, alkali metal silazide or alkali metal hydride.