合成路线1

This compound has been obtained by two related ways: 1. The reaction of 1-benzyl-3-bromopiperidin-4-one (I) with sodium methoxide in methanol gives the intermediate epoxide, which in the reaction medium yields 1-benzyl-3-hydroxypiperidin-4-one dimethylacetal (III). The hydrogenation of (III) with H2 over Pd/C in methanol affords 3-hydroxypiperidin-4-one dimethylacetal (IV), which is condensed with ethyl chloroformate (V) by means of NaOH in THF to provide 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylic acid ethyl ester (VI), which is methylated with methyl iodide and NaH in DMF to give the 3,4,4-trimethoxy compound (VII). The hydrolysis of the acetal group of (VII) by means of H2SO4 in refluxing water yields the piperidinone (VIII), which by reductocondensation with benzylamine and H2 over Pd/C in methanol affords the cis- 4-(benzylamino)-3-methoxypiperidine-1-carboxylic acid ethyl ester (IX). The decarboxylation of (IX) by means of KOH in refluxing isopropanol provides the cis-4-(benzyloxy)-3-methoxypiperidine (X), which is alkylated with 3-(4-fluorophenoxy)propyl chloride (XI) by means of TEA in DMF, giving the N-substituted piperidine (XII). The deprotection of the amino group of (XII) by hydrogenation with H2 over Pd/C in methanol yields the 4-aminopiperidine (XIII), which is finally condensed with 4-amino-5-chloro-2-methoxybenzoic acid (XIV) by means of ethyl chloroformate and TEA in chloroform to obtain the target carboxamide. 2. The debenzylation of the cis- 4-(benzylamino)-3-methoxypiperidine-1-carboxylic acid ethyl ester (IX) with H2 over Pd/C in methanol gives the cis-4-amino-3-methoxypiperidine-1-carboxylic acid ethyl ester (XV), which is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (XIV) by means of ethyl chloroformate and TEA in chloroform to yield the corresponding amide (XVI). The decarboxylation of (XVI) with KOH in refluxing isopropanol affords (XVII), with a free NH group that is alkylated with 3-(4-fluorophenoxy)propyl chloride (XI) by means of TEA in DMF to obtain the target carboxamide.