合成路线1

Taranabant can be prepared by two different synthetic strategies. 2-Methyl-2-[5-(trifluoromethyl)pyridin-2-yloxy]propionic acid (I) is chlorinated with oxalyl chloride and DMF in CH2Cl2, and the resulting acid chloride is then coupled with 3-(4-chlorophenyl)-2(R,S)-(3-cyanophenyl)-1(R,S)-methylpropylamine (IIa) by means of NMM in CH2Cl2 to produce racemic taranabant, which is finally resolved employing chiral HPLC (1-3). Similarly, the target enantiomer is obtained by condensation of acid (I) with the (S,S)-amine (IIb) using cyanuric chloride and NMM as the coupling reagents (4). In an alternative method, acid (I) is converted to the carboxamide (III) by chlorination with SOCl2 followed by treatment with ammonium hydroxide. Subsequent coupling of amide (III) with the enol tosylate (IV) in the presence of Pd2(dba)3 and 1,4-bis(diphenylphosphino)butane (dppb) gives the N-acyl enamine (V). After hydrolysis of the cyano group to the corresponding carboxamide with K2CO3 and H2O2, asymmetric hydrogenation of the enamine double bond over chiral rhodium catalysts (generated from a dienerhodium complex salt and chiral diphosphine ligands) provides the desired isomer (VI). Reconversion of carboxamide (VI) to the target nitrile is finally accomplished by treatment with cyanuric chloride in DMF/MTBE (5, 6). Scheme 1.