合成路线1

Casopitant can be prepared by two related methods starting from either racemic 2-(4-fluoro-2-methylphenyl)-4-piperidinone (I) or from the corresponding (R)-enantiomer (II). Optically pure piperidinone (II), obtained either by asymmetric synthesis or by resolution of (I) with L-mandelic acid, is treated with triphosgene and NaHCO3 to give the carbamoyl chloride (III), which is then coupled with N-methyl-1(R)-[3,5-(bis-trifluoromethyl)phenyl]ethylamine (IV) to afford the urea adduct (V). Alternatively, reaction of racemic piperidinone (I) with triphosgene and DIEA followed by coupling of the resulting carbamoyl chloride (VI) with the 1-aryl-ethylamine (IV) leads to a diastereomeric mixture of urea adducts, from which the target (R,R)-diastereoisomer (V) can be isolated using flash column chromatography. The N-carbamoyl piperidone (V) is then subjected to reductive amination with N-acetylpiperazine (VII) in the presence of NaBH(OAc)3 to generate a mixture of epimeric 4-piperazinylpiperidines, from which the 4(S)-isomer casopitant is finally obtained through recrystallization as the corresponding methanesulfonate salt (1, 2). Scheme 1.