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【结 构 式】 
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【分子编号】69075 【品名】(S)-2-amino-3,3-dimethylbutanoic acid;L-tert-leucine;L-2-Amino-3,3-dimethylbutanoic acid 【CA登记号】20859-02-3 |
【 分 子 式 】C6H13NO2 【 分 子 量 】131.17476 【元素组成】C 54.94% H 9.99% N 10.68% O 24.39% |
合成路线1
该中间体在本合成路线中的序号：(XXV)Benzylic bromination of 3-bromo-o-xylene (IX) with NBS in the presence of benzoyl peroxide in refluxing CCl4 or chlorobenzene at 80 °C gives 1-bromo-2,3-bis(bromomethyl)benzene (X), which then cyclizes with benzylamine in the presence of KHCO3 in acetonitrile to yield 2-benzyl-4-bromoisoindoline (XI). Alkenylation of compound (XI) with tributyl(vinyl)tin (XII) by means of Pd(PPh3)4 in toluene provides the isoindoline (XIII), which is then deprotected by means of 1-chloroethyl chloroformate (ACE-Cl) in refluxing 1,2-dichloroethane to afford 4-vinylisoindoline (XIV). Finally, coupling of 4-vinylisoindoline (XIV) with N-Boc-trans-4-hydroxyproline methyl ester (XV), previously activated with CDI, in DMF at 60 °C results in carbamate (XVI) .
Alternatively, debenzylation of 2-benzyl-4-bromoisoindoline (XI) by means of ACE-Cl in chlorobenzene at 90 °C, followed by condensation of the deprotected isoindoline (XVII) with N-Boc-trans-4-hydroxyproline methyl ester (XV), previously treated with CDI, by means of DIEA in DMF at 50 °C furnishes carbamate (XVIII). Then, alkenylation of the aryl bromide (XVIII) with potassium vinyltrifluoroborate (XIX) and Et3N in refluxing EtOH affords the vinyl isoindoline derivative (XVI) .
Finally, Boc-deprotection of proline derivative (XVI) by means of HCl in dioxane gives the corresponding amine (XX), which is then coupled with the L-tert-leucine carbamate derivative (XXI) in the presence of EDC, DIEA and HOAt or HOBt in DMF to yield the building block diene (I) .
The L-tert-leucine carbamate (XXI) is prepared by alkylation of ethyl isobutyrate (XXII) with 4-bromo-1-butene (XXIII) and LDA in HMPA, followed by ester group reduction with LiAlH4 in Et2O, affording 2,2-dimethyl-5-hexen-1-ol (XXIV) . After treatment of hexenol (XXIV) with triphosgene by means of DIEA and NaOH in 1,4-dioxane, the resulting chloroformate is condensed with L-tert-leucine (XXV) to give carbamate (XXI) .
| 【1】 Holloway, M.K., Liverton, N.J., Ludmerer, S.W. et al. (Merck & Co., Inc.). HCV NS3 protease inhibitors. EP 1910404, EP 924593, JP 2009502793, US 2007027071, WO 2007015787, WO 2007015855. |
| 【2】 McCauley, J.A., McIntyre, C.J., Rudd, M.T. et al. Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor. J Med Chem 2010, 53(6): 2443-63. |
| 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) | 69055 | (3S,5R)-1-(2-((((2,2-dimethylhex-5-en-1-yl)oxy)carbonyl)amino)-3,3-dimethylbutanoyl)-5-(methoxycarbonyl)pyrrolidin-3-yl 4-vinylisoindoline-2-carboxylate | C32H45N3O7 | 详情 | 详情 | |
| (IX) | 69063 | 3-bromo-o-xylene;2,3-Dimethylbromobenzene;3-Bromo-1,2-dimethylbenzene | 576-23-8 | C8H9Br | 详情 | 详情 |
| (X) | 69064 | 1-bromo-2,3-bis(bromomethyl)benzene | C8H7Br3 | 详情 | 详情 | |
| (XI) | 69065 | 2-benzyl-4-bromoisoindoline | C15H14BrN | 详情 | 详情 | |
| (XII) | 24920 | tributyl(vinyl)stannane；Tributylvinylstannane;Vinyltributylstannane | 7486-35-3 | C14H30Sn | 详情 | 详情 |
| (XIII) | 69066 | 2-benzyl-4-vinylisoindoline | C17H17N | 详情 | 详情 | |
| (XIV) | 69067 | 4-vinylisoindoline | C10H11N | 详情 | 详情 | |
| (XV) | 15780 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate;(2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (XVI) | 69070 | (2S,4S)-1-tert-butyl 2-methyl 4-((4-vinylisoindoline-2-carbonyl)oxy)pyrrolidine-1,2-dicarboxylate | C22H28N2O6 | 详情 | 详情 | |
| (XVII) | 69068 | 4-bromoisoindoline hydrochloride;3-Bromo-1H-isoindoline Hydrochloride;4-Bromo-1H-isoindoline hydrochloride;4-Bromo-2,3-dihydro-1H-isoindole hydrochloride | 923590-95-8 | C8H8BrN.HCl | 详情 | 详情 |
| (XVIII) | 69071 | (2S,4S)-1-tert-butyl 2-methyl 4-((4-bromoisoindoline-2-carbonyl)oxy)pyrrolidine-1,2-dicarboxylate | C20H25BrN2O6 | 详情 | 详情 | |
| (XIX) | 69072 | potassium vinyltrifluoroborate;potassium trifluoro(vinyl)borate | C2H3BF3K | 详情 | 详情 | |
| (XX) | 69069 | (3S,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl 4-vinylisoindoline-2-carboxylate hydrochloride | C17H20N2O4.HCl | 详情 | 详情 | |
| (XXI) | 69073 | 2-((((2,2-dimethylhex-5-en-1-yl)oxy)carbonyl)amino)-3,3-dimethylbutanoic acid | C15H27NO4 | 详情 | 详情 | |
| (XXII) | 28650 | ethyl 2-methylpropanoate；ethyl isobutyrate | 97-62-1 | C6H12O2 | 详情 | 详情 |
| (XXIII) | 11720 | 4-Bromo-1-butene | 5162-44-7 | C4H7Br | 详情 | 详情 |
| (XXIV) | 69074 | 2,2-dimethyl-5-hexen-1-ol | C8H16O | 详情 | 详情 | |
| (XXV) | 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 |
合成路线2
该中间体在本合成路线中的序号：(VIIa)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 |