Alfentanil hydrochloride, R-39209, Fentalim, Alfenta, Rapifen, -Drug Synthesis Database

【结构式】

【药物名称】Alfentanil hydrochloride, R-39209, Fentalim, Alfenta, Rapifen

【化学名称】N-[1-[2-(4-Ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide hydrochloride
　　　　　　N-[1-[2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-(methoxymethyl)-4-piperidyl]propionanilide hydrochloride

【CA登记号】69049-06-5, 71195-58-9 (free base), 70879-28-6 (monohydrate)

【分子式】C₂₁H₃₃ClN₆O₃

【分子量】452.98856

【开发单位】Janssen-Cilag (Originator)

【药理作用】Adjuncts to Anesthesia, Agents for Premedication, ANALGESIC AND ANESTHETIC DRUGS

合成路线1 合成路线2

合成路线1

The cyclization of ethyl isocyanate (I) with sodium azide (II) by means of AlCl3 in refluxing THF gives 1-ethyl-1,4-dihydro-5H-tetrazol-5-one (III), which is alkylated with 1-chloro-2-bromoethane (IV) by means of Na2CO3 and KI in refluxing 4-methyl-2-pentanone to afford 1-ethyl-4-(2-chloroethyl)-1,4-dihydro-5H-tetrazol-5-one (V). Finally, this compound is condensed with N-(4-methoxymethyl-4-piperidinyl)propionanilide (VI) by means of Na2CO4 - KI in refluxing 4-methyl-2-pentanone.

参考文献中间体

【1】 Janssen, F. (Janssen Pharmaceutica NV); N-Phenyl-N-(4-piperidinyl)amides. DE 2819873; ES 469473; FR 2389622; GB 1598872; JP 53149980 .
【2】 Castaner, J.; Leeson, P.A.; Blancafort, P.; Mealy, N.E.; Serradell, M.N.; Alfentanil hydrochloride. Drugs Fut 1981, 6, 6, 335.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	28738	ethyl isocyanate	109-90-0	C₃H₅NO	详情	详情
(III)	32218	1-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one	69048-98-2	C₃H₆N₄O	详情	详情
(IV)	24271	1-bromo-2-chloroethane	107-04-0	C₂H₄BrCl	详情	详情
(V)	32219	1-(2-chloroethyl)-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one		C₅H₉ClN₄O	详情	详情
(VI)	32220	N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide		C₁₆H₂₄N₂O₂	详情	详情

合成路线2

The reaction of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with CHCl3, benzyl triethylammonium chloride and NaOH in THF/water gives the spirooxirane (II), which is treated with aniline (III) and NaOH to yield the anilide (IV). The methylation of the amide nitrogen by means of NaH and CH3I in THF affords the methylated anilide (V). The reaction of (V) with KOH in refluxing isopropanol causes elimination of its ethoxycarbonyl group, providing compound (VI), which is reduced with lithium triethylborohydride in THF to give 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII). The condensation of (VII) with tetrazolone derivative (VIII) by means of KI in refluxing acetonitrile (or propionitrile) yields the adduct (XI), which is methylated with NaH and CH3I in THF to afford the methoxy derivative (XII). Finally, this compound is acylated with propionyl chloride (XIII) in chloroform to provide the target compound. The intermediate tetrazolone derivative (VIII) has been obtained by reaction of 1-ethyl-4,5-dihydro-1H-tetrazol-5-one (IX) with 1,2-dibromoethane (X) by means of TEA in acetonitrile.

参考文献中间体

【1】 Killgore, J.K.; Jacob, M. (Mallinckrodt Medical Inc.); New methods for the syntheses of alfentanil, sufentanil and remifentanil. WO 0140184 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	13486	Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone	29976-53-2	C₈H₁₃NO₃	详情	详情
(II)	49678	ethyl 2,2-dichloro-1-oxa-6-azaspiro[2.5]octane-6-carboxylate		C₉H₁₃Cl₂NO₃	详情	详情
(III)	12294	Aniline; Phenylamine	62-53-3	C₆H₇N	详情	详情
(IV)	49679	ethyl 4-anilino-4-(anilinocarbonyl)-1-piperidinecarboxylate		C₂₁H₂₅N₃O₃	详情	详情
(V)	49680	ethyl 4-anilino-4-[(methylanilino)carbonyl]-1-piperidinecarboxylate		C₂₂H₂₇N₃O₃	详情	详情
(VI)	49681	4-anilino-N-methyl-N-phenyl-4-piperidinecarboxamide		C₁₉H₂₃N₃O	详情	详情
(VII)	49682	(4-anilino-4-piperidinyl)methanol		C₁₂H₁₈N₂O	详情	详情
(VIII)	14721	1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one		C₅H₉BrN₄O	详情	详情
(IX)	32218	1-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one	69048-98-2	C₃H₆N₄O	详情	详情
(X)	10252	1,2-Dibromoethane; Ethylene dibromide	106-93-4	C₂H₄Br₂	详情	详情
(XI)	49683	1-[2-[4-anilino-4-(hydroxymethyl)-1-piperidinyl]ethyl]-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one		C₁₇H₂₆N₆O₂	详情	详情
(XII)	49684	1-[2-[4-anilino-4-(methoxymethyl)-1-piperidinyl]ethyl]-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one		C₁₈H₂₈N₆O₂	详情	详情
(XIII)	15967	propanoyl chloride; propionyl chloride	79-03-8	C₃H₅ClO	详情	详情

Extended Information