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【结 构 式】 
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【分子编号】14421 【品名】(2R,3S)-2,3-bis([[tert-butyl(dimethyl)silyl]oxy]methyl)cyclobutanone O-methyloxime 【CA登记号】 |
【 分 子 式 】C19H41NO3Si2 【 分 子 量 】387.71048 【元素组成】C 58.86% H 10.66% N 3.61% O 12.38% Si 14.49% |
合成路线1
该中间体在本合成路线中的序号：(LI)6) The stereoselective cyclization of bis[(-)-menthyl] fumarate (XLVII) with 1,1-bis(methylsulfanyl)ethylene (XX) by means of diisobutylaluminum chloride in hexane gives (1S-trans)-3,3-bis(methylsulfanyl)cyclobutane-1,2-dicarboxylic acid di-(-)-menthyl ester (XLVIII), which is reduced with LiAlH4 in THF yielding (1S-trans)-3,3-bis(methylsulfanyl)cyclobutane-1,2-dimethanol (XXIV). The silylation of (XXIV) with tert-butyldimethylsilyl chloride (TBMS-Cl) and imidazole in DMF affords the bis-silylated diol (II), which is treated with AgNO3 and N-chlorosuccinimide (NCS) in acetonitrile/water to give the cyclobutanone (L). The reaction of (L) with O-methylhydroxylamine in pyridine yields the corresponding O-methyloxime (LI), which is selectively reduced with NaBH4 in THF to the cyclobutylamine (LII). The condensation of (LII) with 4-chloro-6-hydroxy-5-nitropyrimidine-2-amine (LIII) by means of triethylamine in DMF affords the substituted 5-nitro-2,4-diaminopyrimidine (LIV), which is reduced with H2 over Pd/C in formic acid yielding the corresponding triaminopyrimidine (LV). Finally, this compound, without isolation, is cyclized with formic acid at 130 C.
| 【1】 Ireland, C.; Leeson, P.A.; Castaner, J.; Lobucavir. Drugs Fut 1997, 22, 4, 359. |
| 【2】 Pariza, R.J.; Hannick, S.M.; Sowin, T.J.; Doherty, E.M. (Bristol-Myers Squibb Co.); Process for preparing substd. Cyclobutanes. US 5399775 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IL) | 14419 | tert-butyl(dimethyl)silyl [(1S,2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3,3-bis(methylsulfanyl)cyclobutyl]methyl ether; tert-butyl[[(1S,4S)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2,2-bis(methylsulfanyl)cyclobutyl]methoxy]dimethylsilane | C20H44O2S2Si2 | 详情 | 详情 | |
| (XLVII) | 14417 | bis[(1R,2S,4S)-2-isopropyl-4-methylcyclohexyl] (E)-2-butenedioate | C24H40O4 | 详情 | 详情 | |
| (XLVIII) | 14418 | bis[(1R,2S,4S)-2-isopropyl-4-methylcyclohexyl] (1S,2S)-3,3-bis(methylsulfanyl)-1,2-cyclobutanedicarboxylate | C28H48O4S2 | 详情 | 详情 | |
| (L) | 14420 | (2S,3S)-2,3-bis([[tert-butyl(dimethyl)silyl]oxy]methyl)cyclobutanone | C18H38O3Si2 | 详情 | 详情 | |
| (LI) | 14421 | (2R,3S)-2,3-bis([[tert-butyl(dimethyl)silyl]oxy]methyl)cyclobutanone O-methyloxime | C19H41NO3Si2 | 详情 | 详情 | |
| (LII) | 14422 | (1R,2R,3S)-2,3-bis([[tert-butyl(dimethyl)silyl]oxy]methyl)cyclobutanamine; (1R,2R,3S)-2,3-bis([[tert-butyl(dimethyl)silyl]oxy]methyl)cyclobutylamine | C18H41NO2Si2 | 详情 | 详情 | |
| (LIII) | 14423 | 2-amino-6-chloro-5-nitro-4-pyrimidinol | C4H3ClN4O3 | 详情 | 详情 | |
| (LIV) | 14424 | 2-amino-6-[[(1R,2R,3S)-2,3-bis([[tert-butyl(dimethyl)silyl]oxy]methyl)cyclobutyl]amino]-5-nitro-4-pyrimidinol | C22H43N5O5Si2 | 详情 | 详情 | |
| (LV) | 14425 | 2,5-diamino-6-[[(1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl]amino]-4-pyrimidinol | C10H17N5O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)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 |