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

2002; Serbian Chemical Society; Volume: 67; Issue: 12 Linguagem: Inglês

10.2298/jsc0212793k

1820-7421

Vesna D. Kiricojević, Milovan Ivanović, I. V. MICOVIC, Jelena Djordjevic, Goran Roglić, Ljiljana Došen‐Mićović,

Chemical Synthesis and Analysis

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.