TY  - JOUR
AU  - Kiricojević, Vesna D.
AU  - Ivanović, Milovan D.
AU  - Mićović, I.V.
AU  - Popović-Djordjević, Jelena
AU  - Roglić, Goran M.
AU  - Došen-Mićović, Ljiljana I.
PY  - 2002
UR  - http://aspace.agrif.bg.ac.rs/handle/123456789/493
AB  - 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.
AB  - U ovom radu razvijena je efikasna sinteza metil 4-[(1-oksopropil)fenilamino]piperidin-4-karboksilata (7), prolazeći od 1-benzil piperidin-4-on-1 (1). Jedinjenje 7 je ključni intermedijer u sintezi nove generacije visoko aktivnih narkotičkih analgetika, kao što je remifentanil a takođe i novih klasa analoga fentanyla. U optimizovanoj Strecker-ovoj kondenzaciji priperidona 1 sa anilinom i HCN, dobijen je anilino-nitril 2 (≈90%) prinos čijom je selektivnom hidrolizom pomoću konc. H2SO4 postao anilino-amid 3. Intenzivnom baznom hidrolizom ovog intermedijera, zakišeljavanjem a zatim sukcesivno reakcijom sa SOCl2 i MeOH sintetisan je anilino-estar 5 (≈40–45% prinos u 3 faze). N-acelovanjem anilino-estra 5 sa propionil hloridom postao je anilido-estar 6 (≈70–80% prinos). U poslednjom fazi sinteze izvršena je optimizacija katalitičkog N-debenzilovanja anilido-estra 6 do finalnog proizvoda 7, u približno kvantitativnom prinosu.
PB  - Srpsko hemijsko društvo, Beograd
T2  - JOURNAL OF THE SERBIAN CHEMICAL SOCIETY
T1  - An optimized synthesis of a key pharmaceutical intermediate methyl 4-[(1-oxopropyl)phenylamino]piperidine-4-carboxylate
T1  - Optimizovana sinteza značajnog farmaceutskog intermedijera metil 4-[(1-oksopropil)fenilamino]piperidin-4-karboksilata
EP  - 802
IS  - 12
SP  - 793
VL  - 67
DO  - 10.2298/JSC0212793K
ER  - 

@article{
author = "Kiricojević, Vesna D. and Ivanović, Milovan D. and Mićović, I.V. and Popović-Djordjević, Jelena and Roglić, Goran M. and Došen-Mićović, Ljiljana I.",
year = "2002",
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 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., U ovom radu razvijena je efikasna sinteza metil 4-[(1-oksopropil)fenilamino]piperidin-4-karboksilata (7), prolazeći od 1-benzil piperidin-4-on-1 (1). Jedinjenje 7 je ključni intermedijer u sintezi nove generacije visoko aktivnih narkotičkih analgetika, kao što je remifentanil a takođe i novih klasa analoga fentanyla. U optimizovanoj Strecker-ovoj kondenzaciji priperidona 1 sa anilinom i HCN, dobijen je anilino-nitril 2 (≈90%) prinos čijom je selektivnom hidrolizom pomoću konc. H2SO4 postao anilino-amid 3. Intenzivnom baznom hidrolizom ovog intermedijera, zakišeljavanjem a zatim sukcesivno reakcijom sa SOCl2 i MeOH sintetisan je anilino-estar 5 (≈40–45% prinos u 3 faze). N-acelovanjem anilino-estra 5 sa propionil hloridom postao je anilido-estar 6 (≈70–80% prinos). U poslednjom fazi sinteze izvršena je optimizacija katalitičkog N-debenzilovanja anilido-estra 6 do finalnog proizvoda 7, u približno kvantitativnom prinosu.",
publisher = "Srpsko hemijsko društvo, Beograd",
journal = "JOURNAL OF THE SERBIAN CHEMICAL SOCIETY",
title = "An optimized synthesis of a key pharmaceutical intermediate methyl 4-[(1-oxopropyl)phenylamino]piperidine-4-carboxylate, Optimizovana sinteza značajnog farmaceutskog intermedijera metil 4-[(1-oksopropil)fenilamino]piperidin-4-karboksilata",
pages = "802-793",
number = "12",
volume = "67",
doi = "10.2298/JSC0212793K"
}

Kiricojević, V. D., Ivanović, M. D., Mićović, I.V., Popović-Djordjević, J., Roglić, G. M.,& Došen-Mićović, L. I.. (2002). An optimized synthesis of a key pharmaceutical intermediate methyl 4-[(1-oxopropyl)phenylamino]piperidine-4-carboxylate. in JOURNAL OF THE SERBIAN CHEMICAL SOCIETY
Srpsko hemijsko društvo, Beograd., 67(12), 793-802.
https://doi.org/10.2298/JSC0212793K

Kiricojević VD, Ivanović MD, Mićović I, Popović-Djordjević J, Roglić GM, Došen-Mićović LI. An optimized synthesis of a key pharmaceutical intermediate methyl 4-[(1-oxopropyl)phenylamino]piperidine-4-carboxylate. in JOURNAL OF THE SERBIAN CHEMICAL SOCIETY. 2002;67(12):793-802.
doi:10.2298/JSC0212793K .

Kiricojević, Vesna D., Ivanović, Milovan D., Mićović, I.V., Popović-Djordjević, Jelena, Roglić, Goran M., Došen-Mićović, Ljiljana I., "An optimized synthesis of a key pharmaceutical intermediate methyl 4-[(1-oxopropyl)phenylamino]piperidine-4-carboxylate" in JOURNAL OF THE SERBIAN CHEMICAL SOCIETY, 67, no. 12 (2002):793-802,
https://doi.org/10.2298/JSC0212793K . .