An optimized synthesis of a key pharmaceutical intermediate methyl 4-[(1-oxopropyl)phenylamino]piperidine-4-carboxylate

Abstract

An efficient synthesis of methyl 4-[(1-oxopropyl)phenylamino]piperidine-4-carboxylate (7) has been developed, starting from 1-benzylpiperidin-4-one (1). The compound is a key intermediate in the synthesis of new generation, highly active narcotic analgesics, such as remifintanil, as well as the novel classes of fentanyl analogues. An optimized Strecker-type condensation of piperidone 1 with aniline and HCN yielded the anilino-nitrile 2(»90 %) which, upon selective hydrolysis with conc.H2SO4, gave the anilino-amide 3.After vigorous basic hydrolysis of 3, followed by acidification and successive treatment with SOCl2and MeOH, the anilino-ester 5 was obtained (40–45 %, in 3 steps). N-Acylation of 5 with propionyl chloride yielded the anilido-ester6(70–80 %). In the final step, the catalytic N-debenzylation of6was examined under various conditions and optimized to yield 7 in near quantitative yields.

Keywords

• optimized Strecker reaction
• functionalized piperidines
• fentanyl-type central analgesics