合成路线1

Ethoxycarbonylpiperidone (I) was converted into enol triflate (II), and this was coupled with either phenylboronic acid or phenyl trimethylstannane using Pd catalysts to give 4-phenyltetrahydro-pyridine (III). Subsequent double bond hydrogenation produced a racemic mixture of cis piperidines (IV) and (V), from which several routes were used to synthesize the chiral title compounds. Removal of BOC protecting groups with HCl in EtOAc gave racemic (VI), which was alkylated with bromide (VII) in the presence of diisopropylethylamine to afford racemic (VIII). The enantiomers of (VIII) were separated utilizing chiral HPLC on a Chiralcel OD column, yielding the (-)(S,S) compound (XV, 247751) and the (+)(R,R) compound (XIV, 247752). Alternatively, racemic piperidine (VI) could be separated using a Chiralcel OD column into enantiomers (-)(S,S) (IX) and (+)(R,R) (X), which were separately alkylated with bromide (VII) to furnish (XV) and (XIV), respectively. Resolution of the racemic mixture (IV) and (V) was also achieved by hydrolysis to the racemic acids (XI) with LiOH under controlled conditions, followed by treatment with (S)-a-methylbenzylamine (XII) and crystallization of the resulting salt (XIII), whose absolute configuration was determined by X-ray diffraction. Liberation of the (S,S) acid, followed by BOC removal and esterification with an ethanolic solution of HCl then provided ester (IX), which could be alkylated with bromide (VII) to afford (XV).