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【结 构 式】 
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【分子编号】69333 【品名】(1R,2S,5S)-N-(4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3-(2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide 【CA登记号】 |
【 分 子 式 】C27H47N5O5 【 分 子 量 】521.701 【元素组成】C 62.16% H 9.08% N 13.42% O 15.33% |
合成路线1
该中间体在本合成路线中的序号：(III)Coupling of dipeptide derivative (I) with 3-amino-4-cyclobutyl-2-hydroxybutyramide hydrochloride (II) using EDC by means of NMM in DMF/CH2Cl2 gives the α-hydroxy amide (III) , which is finally oxidized under modified Swern conditions (DMSO, EDC and dichloroacetic acid in toluene) or by means of NaOCl and catalytic TEMPO in the presence of KBr and NaOAc/AcOH in MTBE/H2O .
In a modified procedure, treatment of acid (I) with N,N-dicyclohexylamine (IV) gives the corresponding salt (V), which is then coupled with compound (II) using EDC by means of either HOBt and NMM or DIEA in EtOAc, 2-hydroxypyridine in DMF/MTBE, DMAP in EtOAc/DMF, or 1,3,5-trimethoxy-2,4,6-triazine (TMT) and NMM in EtOAc/DMF to afford compound (III). Similarly, treatment of dimethylcyclohexylamine salt (V) with carbonyldiimidazole (CDI) in the presence of DIEA in DMF produces the corresponding acyl imidazolide, which, without isolation, is then coupled with compound (II) to furnish adduct (III) .
In a related strategy, boceprevir is obtained by coupling of dipeptide derivative (I) with 3-amino-4-cyclobutyl-2-oxobutyramide (VI) using EDC, HOBt and NMM in acetonitrile or via activation of (I) as the mixed anhydride with isobutyl chloroformate and NMM in EtOAc .
| 【1】 Njoroge, F.G., Venkatraman, S. (Schering Corp.). An inhibitor of heptatitis C. US 2005249702, WO 2005107745. |
| 【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. |
| 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) | 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 | |
| (II) | 69332 | 3-amino-4-cyclobutyl-2-hydroxybutanamide hydrochloride | C8H16N2O2.HCl | 详情 | 详情 | |
| (III) | 69333 | (1R,2S,5S)-N-(4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3-(2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide | C27H47N5O5 | 详情 | 详情 | |
| (IV) | 69334 | N,N-Dimethylcyclohexylamine;Dimethylaminocyclohexane;Cyclohexyldimethylamine | 98-94-2 | C8H17N | 详情 | 详情 |
| (V) | 69335 | N,N-dimethylcyclohexanamine (1R,2S,5S)-3-(2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate | C19H33N3O4.C8H17N | 详情 | 详情 | |
| (VI) | 69336 | 3-amino-4-cyclobutyl-2-oxobutyramide | C8H14N2O2 | 详情 | 详情 |