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【结 构 式】 
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【分子编号】69363 【品名】(1R,2S,5S,6bS)-6,6-dimethyl-3-phenyltetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one 【CA登记号】 |
【 分 子 式 】C15H17NO2 【 分 子 量 】243.30552 【元素组成】C 74.05% H 7.04% N 5.76% O 13.15% |
合成路线1
该中间体在本合成路线中的序号：(XXXIX)Dehydrogenation of 2(R)-phenylperhydropyrrolo[1,2-c]oxazol-4-one (XXXVII) by α-selenylation with PhSeCl in the presence of KHMDS and TMSCl in THF, followed by oxidation with H2O2 in pyridine or EtOAc and elimination of the selenoxide intermediate produces the unsaturated analogue (XXXVIII) , which by cyclopropanation by means of isopropyl trimethylphosphonium bromide and BuLi in THF affords the tricyclic compound (XXXIX). Reductive ring opening of intermediate (XXXIX) by means of LiAlH4 in refluxing THF produces the N-benzylprolinol (XL), which is debenzylated to the prolinol (XLI) by catalytic hydrogenation over Pd/C in AcOH/EtOAc. After protection of amine (XLI) with Boc2O in CH2Cl2, the resulting N-Boccyclopropaprolinol (XLII) is subjected to Jones oxidation to furnish carboxylic acid (XLIII). Subsequent esterification of acid (XLIII) with (trimethylsilyl)diazomethane in toluene/MeOH affords the N-Boccyclopropaproline methyl ester (XLIV), which is finally deprotected with HCl in dioxane .
| 【1】 Venkatraman, S., Bogen, S.L., Arasappan, A. et al. Discovery of (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl] amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S) carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: A potential therapeutic agent for the treatment of hepatitis C infection. J Med Chem 2006, 49(20): 6074-86. |
| 【2】 Zhang, R., Mamai, A., Madalengoitia, J.S. Cyclopropanation reactions of pyroglutamic acid-derived synthons with alkylidene transfer reagents. J Org Chem 1999, 64(2): 547-55. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 69339 | methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate HCl salt | 565456-77-1 | C9H15NO2.HCl | 详情 | 详情 |
| (XXXVII) | 38561 | (3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | 103201-79-2 | C12H13NO2 | 详情 | 详情 |
| (XXXVIII) | 69362 | (3R,7aS)-3-phenyl-1,7a-dihydropyrrolo[1,2-c]oxazol-5(3H)-one | C12H11NO2 | 详情 | 详情 | |
| (XXXIX) | 69363 | (1R,2S,5S,6bS)-6,6-dimethyl-3-phenyltetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one | C15H17NO2 | 详情 | 详情 | |
| (XL) | 69364 | (1R,2S,5S)-(3-benzyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl)methanol | C15H21NO | 详情 | 详情 | |
| (XLI) | 69365 | ((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl)methanol | C8H15NO | 详情 | 详情 | |
| (XLII) | 69366 | (1R,2S,5S)-tert-butyl 2-(hydroxymethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate | C13H23NO3 | 详情 | 详情 | |
| (XLIII) | 69367 | (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid | C13H21NO4 | 详情 | 详情 | |
| (XLIV) | 69368 | (1R,2S,5S)-3-tert-butyl 2-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate | C14H23NO4 | 详情 | 详情 |