THE SYNTHESIS OF LACTAM ANALOGS OF FENTANYL

Fentanyl, sufentanil and alfentanil are clinically widely used anaesth etics and are structurally related to drugs with entirely different ph armacological activity such as droperidol, loperamide and lorcainide, etc. Therefore, in order to test their pharmacological activity, lacta m analogues of fentanyl, a novel class of compounds, have been synthes ized. 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 malona te yields the amido esters, which have been further subjected to Dieck mann-type cyclization, to produce the corresponding 3-methoxycarbonylp iperidine-2,4-diones. The cyclization has been effected under phase-tr ansfer 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 d ecarboxylation furnish the substituted piperidine-2,4-diones in good y ields, as pure products. Alkylation of the N-phenethylpiperidine-2,4-d ione with methyl iodide and potassium carbonate in DMSO gives the 3,3- dimethyl derivative, The alkylation procedure is also applicable to ot her alkylating agents. Reductive amination of the prepared piperidine- 2,4-diones with aniline and NaBH3CN in buffered methanol gives the cor responding pure 4-anilino-2-piperidones. The lactam function can be re adily reduced (NaBH4-BF3 . Et(2)O), as exemplified with the 3,3-dimeth yl 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 triethylami ne as base. The prepared 4-propionanilido-2-piperidones and 4-propiona nilidopiperidines are expected to provide useful structure-activity re lationship data in the pharmacological studies.