Brifentanil Hydrochloride, ANQ-3331, A-3331, -Drug Synthesis Database

【结构式】

【药物名称】Brifentanil Hydrochloride, ANQ-3331, A-3331

【化学名称】(3R*,4S*)-(±)-N-[1-[2-(4-Ethyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)ethyl]-3-methyl-4-piperidinyl]-N-(2-fluorophenyl)-2-methoxyacetamide monohydrochloride

【CA登记号】117268-95-8, 101345-71-5 (free base)

【分子式】C₂₀H₃₀ClFN₆O₃

【分子量】456.9519

【开发单位】Baxter (Originator), BOC (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Opioid Analgesics, Opioid Agonists

合成路线1 合成路线2

合成路线1

Condensation of the piperidone (I) with 2-fluoroaniline (II), followed by reduction of the Schiff base with sodium borohydride afforded 1-benzyl-3-methyl-4-phenylaminopiperidine (III). Intermediate (III) was produced in an approximate 7:3 (cis/trans) isomeric ratio. Acylation of (III) with methoxyacetyl chloride gave compound (IV) and subsequent catalytic debenzylation gave the compound (V), which was N-alkylated in acetonitrile with 1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one (VI). Brifentanil is the cis-isomer obtained by the chromatographic separation of the isomeric mixture.

参考文献中间体

【1】 Huang, B.-S.; Deutsche, K.H.; Lalinde, N.L.; Terrell, R.C.; Kudzma, L.V. (BOC Health Care, Inc.); (BOC, Inc.). N-Aryl-N-(4-piperidinyl)amides and pharmaceutical compsns. and method employing such cpds. EP 0160422; ES 8609251; ES 8705387; JP 1985248670; US 4584303 .
【2】 Ossipov, M.H.; Wright, D.; Spencer, K.H.; Spaulding, T.C.; Lalinde, N.; Moliterni, J.; Rufo, F.G.; Synthesis and pharmacological evaluation of a series of new 3-methyl-1,4-disubstituted-piperidine analgesics. J Med Chem 1989, 33, 10, 2876-82.
【3】 Moliterni, J.; Spencer H.K.; Rudo, F.G.; Ossipov, M.H.; Spaulding, T.C.; Lalinde, N.; Wright, D.; Waters, S.J.; Brifentanil Hydrochloride. Drugs Fut 1991, 16, 8, 706.

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)	14714	1-Benzyl-3-methyl-4-piperidone; 1-benzyl-3-methyltetrahydro-4(1H)-pyridinone	34737-89-8	C₁₃H₁₇NO	详情	详情
(II)	22296	2-fluorophenylamine; 2-fluoroaniline	348-54-9	C₆H₆FN	详情	详情
(III)	14715	N-(1-benzyl-3-methyl-4-piperidinyl)-N-(2-fluorophenyl)amine; 1-benzyl-N-(2-fluorophenyl)-3-methyl-4-piperidinamine		C₁₉H₂₃FN₂	详情	详情
(IV)	14716	N-(1-benzyl-3-methyl-4-piperidinyl)-N-(2-fluorophenyl)-2-methoxyacetamide		C₂₂H₂₇FN₂O₂	详情	详情
(V)	14717	N-(2-fluorophenyl)-2-methoxy-N-(3-methyl-4-piperidinyl)acetamide		C₁₅H₂₁FN₂O₂	详情	详情
(VI)	14421	(2R,3S)-2,3-bis([[tert-butyl(dimethyl)silyl]oxy]methyl)cyclobutanone O-methyloxime		C₁₉H₄₁NO₃Si₂	详情	详情
(VII)	14718	N-[1-[2-(4-ethyl-5-oxo-4,5-dihydro-1H-1,2,3,4-tetraazol-1-yl)ethyl]-3-methyl-4-piperidinyl]-N-(2-fluorophenyl)-2-methoxyacetamide		C₂₀H₂₉FN₆O₃	详情	详情

合成路线2

The synthesis of tritium-labeled brifentanil has been described: The hydrogenolysis of 1-benzyl-3-methylpiperidin-4-one (I) with H2 over Pd/C in ethanol gives the free piperidone (II), which is condensed with 1-(2-bromoethyl)-4-ethyl-4,5-dihydro-1H-tetrazol-5-one (III) by means of NaI and Na2CO3 in acetonitrile, yielding the condensation product (IV). The reductocondensation of (IV) with 4-bromo-2-fluoroaniline by means of NaBH3CN and HCl in methanol affords the substituted aniline (VI), which is acylated with 2-methoxyacetyl chloride (VII) and submitted to chromatographic (HPLC) separation to obtain the cis-isomer of bromobrifentanil (VIII). Finally, this compound is submitted to debromination with tritium gas and Pd/C in ethanol to afford [3H]-brifentanil.

参考文献中间体

【1】 Nugent, R.P.; Huang, B.S.; Filer, C.N.; The synthesis of [fluorophenyl-H-3(N)]ocfentanil and [fluorophenyl-H-3(N)]brifentanil. J Label Compd Radiopharm 1995, 36, 11, 1019.

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)	14714	1-Benzyl-3-methyl-4-piperidone; 1-benzyl-3-methyltetrahydro-4(1H)-pyridinone	34737-89-8	C₁₃H₁₇NO	详情	详情
(II)	14720	3-methyltetrahydro-4(1H)-pyridinone		C₆H₁₁NO	详情	详情
(III)	14721	1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one		C₅H₉BrN₄O	详情	详情
(IV)	14722	1-[2-(4-ethyl-5-oxo-4,5-dihydro-1H-1,2,3,4-tetraazol-1-yl)ethyl]-3-methyltetrahydro-4(1H)-pyridinone		C₁₁H₁₉N₅O₂	详情	详情
(V)	14723	4-Bromo-2-fluorophenylamine; 4-Bromo-2-fluoroaniline	367-24-8	C₆H₅BrFN	详情	详情
(VI)	14724	1-[2-[4-(4-bromo-2-fluoroanilino)-3-methylpiperidino]ethyl]-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one		C₁₇H₂₄BrFN₆O	详情	详情
(VII)	13429	2-Methoxyacetyl chloride; Methoxyacetyl chloride	38870-89-2	C₃H₅ClO₂	详情	详情
(VIII)	14726	N-(4-bromo-2-fluorophenyl)-N-[(3R,4S)-1-[2-(4-ethyl-5-oxo-4,5-dihydro-1H-1,2,3,4-tetraazol-1-yl)ethyl]-3-methylhexahydro-4-pyridinyl]-2-methoxyacetamide		C₂₀H₂₈BrFN₆O₃	详情	详情

Extended Information