TY  - JOUR
AU  - Mićović, Ivan V.
AU  - Roglić, Goran
AU  - Ivanović, Milovan
AU  - DosenMicovic, L
AU  - Kiricojevic, VD
AU  - Popovic, JB
PY  - 1996
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/2248
AB  - Fentanyl, sufentanil and alfentanil are clinically widely used anaesthetics and are structurally related to drugs with entirely different pharmacological activity such as droperidol, loperamide and lorcainide, etc. Therefore, in order to test their pharmacological activity, lactam analogues of fentanyl, a novel class of compounds, have been synthesized. In the first step, various primary amines have been selectively added to 1 equiv, of alpha,beta-unsaturated esters, to afford the beta-amino esters. N-Acylation of these intermediates with dimethyl malonate yields the amido esters, which have been further subjected to Dieckmann-type cyclization, to produce the corresponding 3-methoxycarbonylpiperidine-2,4-diones. The cyclization has been effected under phase-transfer conditions, utilizing potassium carbonate as base and 18-crown-6 as catalyst, This eliminates the need for strong and hazardous bases such as molten sodium or NaH, In the next step, acid hydrolysis and decarboxylation furnish the substituted piperidine-2,4-diones in good yields, as pure products. Alkylation of the N-phenethylpiperidine-2,4-dione with methyl iodide and potassium carbonate in DMSO gives the 3,3-dimethyl derivative, The alkylation procedure is also applicable to other alkylating agents. Reductive amination of the prepared piperidine-2,4-diones with aniline and NaBH3CN in buffered methanol gives the corresponding pure 4-anilino-2-piperidones. The lactam function can be readily reduced (NaBH4-BF3 . Et(2)O), as exemplified with the 3,3-dimethyl derivative, thus providing access to additional fentanyl analogues, not readily accessible by other routes. The synthesis is completed by N-acylation of the anilines with propionyl chloride using triethylamine as base. The prepared 4-propionanilido-2-piperidones and 4-propionanilidopiperidines are expected to provide useful structure-activity relationship data in the pharmacological studies.
PB  - Royal Soc Chemistry, Cambridge
T2  - Journal of the Chemical Society. Perkin Transactions 1
T1  - The synthesis of lactam analogues of fentanyl
IS  - 16
SP  - 2041
EP  - 2050
DO  - 10.1039/p19960002041
ER  - 

@article{
author = "Mićović, Ivan V. and Roglić, Goran and Ivanović, Milovan and DosenMicovic, L and Kiricojevic, VD and Popovic, JB",
year = "1996",
abstract = "Fentanyl, sufentanil and alfentanil are clinically widely used anaesthetics and are structurally related to drugs with entirely different pharmacological activity such as droperidol, loperamide and lorcainide, etc. Therefore, in order to test their pharmacological activity, lactam analogues of fentanyl, a novel class of compounds, have been synthesized. In the first step, various primary amines have been selectively added to 1 equiv, of alpha,beta-unsaturated esters, to afford the beta-amino esters. N-Acylation of these intermediates with dimethyl malonate yields the amido esters, which have been further subjected to Dieckmann-type cyclization, to produce the corresponding 3-methoxycarbonylpiperidine-2,4-diones. The cyclization has been effected under phase-transfer conditions, utilizing potassium carbonate as base and 18-crown-6 as catalyst, This eliminates the need for strong and hazardous bases such as molten sodium or NaH, In the next step, acid hydrolysis and decarboxylation furnish the substituted piperidine-2,4-diones in good yields, as pure products. Alkylation of the N-phenethylpiperidine-2,4-dione with methyl iodide and potassium carbonate in DMSO gives the 3,3-dimethyl derivative, The alkylation procedure is also applicable to other alkylating agents. Reductive amination of the prepared piperidine-2,4-diones with aniline and NaBH3CN in buffered methanol gives the corresponding pure 4-anilino-2-piperidones. The lactam function can be readily reduced (NaBH4-BF3 . Et(2)O), as exemplified with the 3,3-dimethyl derivative, thus providing access to additional fentanyl analogues, not readily accessible by other routes. The synthesis is completed by N-acylation of the anilines with propionyl chloride using triethylamine as base. The prepared 4-propionanilido-2-piperidones and 4-propionanilidopiperidines are expected to provide useful structure-activity relationship data in the pharmacological studies.",
publisher = "Royal Soc Chemistry, Cambridge",
journal = "Journal of the Chemical Society. Perkin Transactions 1",
title = "The synthesis of lactam analogues of fentanyl",
number = "16",
pages = "2041-2050",
doi = "10.1039/p19960002041"
}

Mićović, I. V., Roglić, G., Ivanović, M., DosenMicovic, L., Kiricojevic, V.,& Popovic, J.. (1996). The synthesis of lactam analogues of fentanyl. in Journal of the Chemical Society. Perkin Transactions 1
Royal Soc Chemistry, Cambridge.(16), 2041-2050.
https://doi.org/10.1039/p19960002041

Mićović IV, Roglić G, Ivanović M, DosenMicovic L, Kiricojevic V, Popovic J. The synthesis of lactam analogues of fentanyl. in Journal of the Chemical Society. Perkin Transactions 1. 1996;(16):2041-2050.
doi:10.1039/p19960002041 .

Mićović, Ivan V., Roglić, Goran, Ivanović, Milovan, DosenMicovic, L, Kiricojevic, VD, Popovic, JB, "The synthesis of lactam analogues of fentanyl" in Journal of the Chemical Society. Perkin Transactions 1, no. 16 (1996):2041-2050,
https://doi.org/10.1039/p19960002041 . .