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【结 构 式】 
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【分子编号】14714 【品名】1-Benzyl-3-methyl-4-piperidone; 1-benzyl-3-methyltetrahydro-4(1H)-pyridinone 【CA登记号】34737-89-8 |
【 分 子 式 】C13H17NO 【 分 子 量 】203.28412 【元素组成】C 76.81% H 8.43% N 6.89% O 7.87% |
合成路线1
该中间体在本合成路线中的序号：(I)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.
| 【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
该中间体在本合成路线中的序号：(I)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.
| 【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 |