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

Kiricojević Vesna D. (IHTM - Center for Chemistry, Belgrade)
Ivanović Milovan D. (IHTM - Center for Chemistry, Belgrade)
Mićović I.V. (Faculty of Chemistry, Belgrade)
Đorđević J.B. (Faculty of Agriculture, Belgrade)
Roglić Goran M. (Faculty of Chemistry, Belgrade)
Došen-Mićović Ljiljana I. (Faculty of Chemistry, Belgrade)

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 SOCl2 and MeOH, the anilino-ester 5 was obtained (40–45%, in 3 steps). N-Acylation of 5 with propionyl chloride yielded the anilido-ester 6(70–80%) In the final step, the catalytic N-debenzylation of 6 was examined under various conditions and optimized to yield 7 in near quantitative yields.

Keywords: optimized Strecker reaction, functionalized piperidines, fentanyl-type central analgesics.