合成路线1

The intermediate 2-aryl-4-piperidinones (I) and (II) can be obtained by the following methods. Condensation of 2-methyl-4-fluorobenzaldehyde (VIII) with 4-amino-2-butanone ethylene ketal (IX) gives the imine ketal (X), which undergoes Mannich-type cyclization to the 4,4-ethylenedioxy piperidine (XI) upon refluxing in benzene in the presence of anhydrous p-TsOH. Subsequent acidic hydrolysis of the ethylene ketal (XI) yields the racemic piperidone (I). In a different strategy, condensation of 4-fluoro-2-methylphenylmagnesium bromide (XII) with 4-methoxypyridine (XIII) in the presence of benzyl chloroformate followed by acidic hydrolysis of the intermediate enol ether provides 1-(benzyloxycarbonyl)-2-(4-fluoro-2-methylphenyl)-2,3-dihydro-4-pyridone (XIV). After reduction of (XIV) to the corresponding piperidinone (XV) by means of L-selectride in cold THF, the protecting group is removed by hydrogenolysis over Pd/C to provide the deprotected amine (I) (1, 2). Similarly, condensation of the Grignard reagent (XII) with 4-methoxypyridine (XIII) in the presence of (–)-menthyl chloroformate followed by acidic enol ether hydrolysis gives the dihydropyridone menthyl carbamate (XVIa-b) as a mixture of diastereoisomers, which can be separated by flash column chromatography. The minor 2(R)-isomer is then hydrolyzed employing methanolic NaOMe to provide 2(R)-(4-fluoro-2-methylphenyl)-2,3-dihydro-4-pyridone (XVII), which is reduced to the chiral piperidinone (II) by catalytic hydrogenation over Pd/C (1). Scheme 2.