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【结 构 式】 
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【分子编号】69338 【品名】(S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid 【CA登记号】 |
【 分 子 式 】C11H22N2O3 【 分 子 量 】230.30736 【元素组成】C 57.37% H 9.63% N 12.16% O 20.84% |
合成路线1
该中间体在本合成路线中的序号：(X)After protection of L-tert-leucine (VIIa) as the corresponding silyl ester (VIII) with TMSCl by means of HMDS or Et3N in refluxing CH2Cl2, condensation with tert-butyl isocyanate (IX), followed by acidic work up leads to urea derivative (X) . Subsequent coupling of carboxylic acid (X) with methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate HCl salt (XI) in the presence of EDC, HOBt and 2,6-lutidine in acetonitrile yields the dipeptide ester (XII) , which is finally hydrolyzed with LiOH in THF/H2O and optionally purified via its α-methylbenzylamine salt .
Alternatively, coupling of N-Boc-L-tert-leucine (VIIb) with the bicyclic amino ester (XI) in the presence of BOP reagent and NMM in CH2Cl2/DMF affords the N-Boc dipeptide (XIII), which is then deprotected by means of HCl in dioxane to give compound (XIV) . Finally, intermediate (XIV) is condensed with tert-butyl isocyanate (IX) in CH2Cl2 to give the urea compound (XII).
| 【2】 Saksena, A., Nair, L.G., Lovey, R.G. et al. (Schering Corp.; Dendreon Corp.). Novel peptides as NS3-serine protease inhibitors of hepatitis C virus. CA 2473032, EP 1481000, JP 2005524628, US 2007032433, US 7244721, WO 2003062265. |
| 【3】 Lovey, R.G., Tamura, S.Y., Bennett, F. (Dendreon Corp.; Schering Corp.).Novel peptides as NS3-serine protease inhibitors of hepatitis C virus. CA 2410662, EP 1385870, JP 2004504404, JP 2009051860, US 2003216325, US 2004254117, US 7012066, WO 2002008244. |
| 【4】 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. |
| 【5】 Wu, G.G., Xie, J., Rashatasakhon, P. (Schering Corp.). An oxidation process for the preparation of N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[N-[(tert-butylamino)carbonyl]-3-methyl-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide and related compounds. CA 2628738, EP 1966233, JP 2009515894, US 2007149459, US 7528263, WO 2008010831. |
| 【6】 Wong, G.S.K., Lee, H.-C., Vance, J.A., Tong, W., Iwama, T. (Schering Corp.). Process for preparing (1R,2S,5S)-N-[(1S)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[(1,1-dimethylethyl)amino]-carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide. CA 2672620, WO 2008079216. |
| 【7】 Sudhakar, A., Dahanukar, V., Zavialov, I.A. et al. (Schering Corp.). Process and intermediates for the preparation of (1R,2S,5S)-3-azabicyclo-[3,1,0]hexane-2-carboxamide, N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[1,1-dimethylethyl]amino]carbonylamino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl. CA 2526629, EP 1641754, JP 2006528133, US 2005059800, US 7326795, WO 2004113294. |
| 【8】 Dener, J.M. (Virobay, Inc.). Process for the preparation of (S)-2-(3-tertbutylureido)-3,3-dimethylbutanoic acid. WO 2009039361. |
| 【1】 Njoroge, F.G., Venkatraman, S. (Schering Corp.). An inhibitor of heptatitis C. US 2005249702, WO 2005107745. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIa) | 69075 | (S)-2-amino-3,3-dimethylbutanoic acid;L-tert-leucine;L-2-Amino-3,3-dimethylbutanoic acid | 20859-02-3 | C6H13NO2 | 详情 | 详情 |
| (VIIb) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (I) | 69331 | (1R,2S,5S)-3-(2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid | C19H33N3O4 | 详情 | 详情 | |
| (VIII) | 69337 | (S)-trimethylsilyl 2-amino-3,3-dimethylbutanoate | C9H21NO2Si | 详情 | 详情 | |
| (IX) | 16976 | tert-butylisocyanate; tert-butyl isocyanate; 2-isocyanato-2-methylpropane | 1609-86-5 | C5H9NO | 详情 | 详情 |
| (X) | 69338 | (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid | C11H22N2O3 | 详情 | 详情 | |
| (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 |
| (XII) | 69340 | methyl (1R,2S,5S)-3-(2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate | C20H35N3O4 | 详情 | 详情 | |
| (XIII) | 69341 | methyl (1R,2S,5S)-3-(2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate | C20H34N2O5 | 详情 | 详情 | |
| (XIV) | 69342 | methyl (1R,2S,5S)-3-(2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride | C15H26N2O3.HCl | 详情 | 详情 |