|
【结 构 式】 
|
【分子编号】69332 【品名】3-amino-4-cyclobutyl-2-hydroxybutanamide hydrochloride 【CA登记号】 |
【 分 子 式 】C8H16N2O2.HCl 【 分 子 量 】208.688 【元素组成】C 46.04% H 8.21% Cl 16.99% 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：(II)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 |
合成路线2
该中间体在本合成路线中的序号：(II)Alkylation of the benzophenone imine of ethyl glycinate (XV) with bromomethylcyclobutane (XVI) by means of t-BuOK in THF at –78 °C, followed by acidic hydrolysis of the imine intermediate (XVII) gives 3-cyclobutyl-DL-alanine ethyl ester (XVIII). Subsequent protection of the amino ester (XVIII) with Boc2O in CH2Cl2 yields the N-Boc derivative (XIX), which upon alkaline hydrolysis of its ethyl ester group with LiOH in THF/H2O gives the N-Boc-protected amino acid (XX). After coupling amino acid (XX) with N,O-dimethylhydroxylamine in the presence of BOP and NMM in CH2Cl2, the resulting Weinreb amide (XXI) is reduced to aldehyde (XXII) using LiAlH4 in cold THF. Aldehyde (XXII) is then reacted with 2-hydroxyisobutyronitrile and Et3N to give cyanohydrin (XXIII), which by treatment with methanolic hydrochloric acid yields amino ester (XXIV), and subsequently reprotection with Boc2O leads to the N-Boc-protected amino ester (XXV). Hydrolysis of methyl ester (XXV) using LiOH followed by coupling of the resulting carboxylic acid (XXVI) with NH4Cl in the presence of EDC, HOBt and NMM in DMF affords carboxamide (XXVII) . Alternatively, carboxamide (XXVII) also results from direct hydrolysis of nitrile (XXIII) using LiOH and H2O2 in MeOH . Finally, acidic N-Boc group cleavage in compound (XXVII) provides the key amino hydroxyamide intermediate (II) . The analogous amino ketoamide (VI) is obtained by Swern oxidation of alcohol (XXVII) with DMSO and EDC in the presence of dichloroacetic acid in i-PrOH/EtOAc followed by acidic Boc group cleavage with HCl/i-PrOH at 40-50 °C .
| 【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】 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. |
| 【6】 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 |
|---|---|---|---|---|---|---|
| (II) | 69332 | 3-amino-4-cyclobutyl-2-hydroxybutanamide hydrochloride | C8H16N2O2.HCl | 详情 | 详情 | |
| (VI) | 69336 | 3-amino-4-cyclobutyl-2-oxobutyramide | C8H14N2O2 | 详情 | 详情 | |
| (XV) | 26772 | ethyl 2-((diphenylmethylene)amino)acetate;N-(Diphenylmethylene)glycine ethyl ester;Ethyl N-(diphenylmethylene)glycinate;ethyl 2-[(dibenzylene)amino]acetate | 69555-14-2 | C17H17NO2 | 详情 | 详情 |
| (XVI) | 33931 | 1-(bromomethyl)cyclobutane;bromomethylcyclobutane;(Bromomethyl)cyclobutane;Cyclobutylmethyl bromide | 17247-58-4 | C5H9Br | 详情 | 详情 |
| (XVII) | 69343 | ethyl 3-cyclobutyl-2-((diphenylmethylene)amino)propanoate | C22H25NO2 | 详情 | 详情 | |
| (XVIII) | 69344 | ethyl 2-amino-3-cyclobutylpropanoate;3-cyclobutyl-DL-alanine ethyl ester;, a-amino-Cyclobutanepropanoicacid ethyl ester | 394735-17-2 | C9H17NO2 | 详情 | 详情 |
| (XIX) | 69345 | ethyl 2-((tert-butoxycarbonyl)amino)-3-cyclobutylpropanoate | C14H25NO4 | 详情 | 详情 | |
| (XX) | 69346 | 2-((tert-butoxycarbonyl)amino)-3-cyclobutylpropanoic acid | C12H21NO4 | 详情 | 详情 | |
| (XXI) | 69347 | tert-butyl (3-cyclobutyl-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate | C14H26N2O4 | 详情 | 详情 | |
| (XXII) | 69348 | tert-butyl (1-cyclobutyl-3-oxopropan-2-yl)carbamate | C12H21NO3 | 详情 | 详情 | |
| (XXIII) | 69349 | tert-butyl (1-cyano-3-cyclobutyl-1-hydroxypropan-2-yl)carbamate | C13H22N2O3 | 详情 | 详情 | |
| (XXIV) | 69350 | methyl 3-amino-4-cyclobutyl-2-hydroxybutanoate hydrochloride | C9H17NO3.HCl | 详情 | 详情 | |
| (XXV) | 69351 | methyl 3-((tert-butoxycarbonyl)amino)-4-cyclobutyl-2-hydroxybutanoate | C14H25NO5 | 详情 | 详情 | |
| (XXVI) | 69352 | 3-((tert-butoxycarbonyl)amino)-4-cyclobutyl-2-hydroxybutanoic acid | C13H23NO5 | 详情 | 详情 | |
| (XXVII) | 69353 | tert-butyl (4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)carbamate | C13H24N2O4 | 详情 | 详情 |