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【结 构 式】 
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【分子编号】69353 【品名】tert-butyl (4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)carbamate 【CA登记号】 |
【 分 子 式 】C13H24N2O4 【 分 子 量 】272.34464 【元素组成】C 57.33% H 8.88% N 10.29% O 23.5% |
合成路线1
该中间体在本合成路线中的序号：(XXVII)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 |
合成路线2
该中间体在本合成路线中的序号：(XXVII)Oxidation of cyclobutanemethanol (XXVIII) with NaOCl and catalytic TEMPO by means of KBr and NaHCO3 in CH2Cl2/H2O gives cyclobutanecarboxaldehyde (XXIX), which is then condensed with nitromethane in the presence of Et3N in toluene to yield the nitro alcohol (XXX). Subsequent treatment of alcohol (XXX) with acetic anhydride in the presence of DMAP furnishes a mixture of the acetate ester (XXXI) and the dehydration compound (2-nitrovinyl)cyclobutane (XXXII), which can also be obtained as the only reaction product by dehydration of nitro alcohol (XXX) with MsCl in the presence of Et3N. Reduction of the mixture of compounds (XXXI) and (XXXII) or the nitro olefin (XXXII) by catalytic hydrogenation over Pd/C in MeOH optionally in the presence of Et3N, or with NaBH4 in PEG-400/H2O or t-BuOH, affords (2-nitroethyl)cyclobutane (XXXIII), which is condensed with glyoxylic acid (XXXIV) in the presence of Et3N to yield the nitro hydroxy acid (XXXV). Then, compound (XXXV) is reduced with H2 over Pd/C in MeOH and esterified with MeOH and p-TsOH·H2O to give amino ester (XXXVI). Finally, aminolysis of methyl ester (XXXVI) with NH3 and NH4OH in MeOH followed by N-protection by means of Boc2O and K2CO3 in MeOH/H2O yields intermediate (XXVII) .
| 【1】 Park, J., Vater, E.J., Dong, S., Iwama, T., Raghavan, R.R., Lee, H.-C.,Wong, G.S.K. (Schering Corp.). Preparation of 3-amino-3-(cyclobutylmethyl)-2-(hydroxy)-propionamide hydrochloride. CA 2672570, WO 2008082486. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXVII) | 69353 | tert-butyl (4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)carbamate | C13H24N2O4 | 详情 | 详情 | |
| (XXVIII) | 69354 | cyclobutanemethanol;Cyclobutylcarbinol;Hydroxymethylcyclobutane | 4415-82-1 | C5H10O | 详情 | 详情 |
| (XXIX) | 69355 | cyclobutanecarbaldehyde;Cyclobutanaldehyde;Cyclobutylcarboxaldehyde;Formylcyclobutane | 2987-17-9 | C5H8O | 详情 | 详情 |
| (XXX) | 69356 | 1-cyclobutyl-2-nitroethanol | C6H11NO3 | 详情 | 详情 | |
| (XXXI) | 69357 | 1-cyclobutyl-2-nitroethyl acetate | C8H13NO4 | 详情 | 详情 | |
| (XXXII) | 69358 | (E)-(2-nitrovinyl)cyclobutane | C6H9NO2 | 详情 | 详情 | |
| (XXXIII) | 69359 | (2-nitroethyl)cyclobutane | C6H11NO2 | 详情 | 详情 | |
| (XXXIV) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (XXXV) | 69360 | 4-cyclobutyl-2-hydroxy-3-nitrobutanoic acid | C8H13NO5 | 详情 | 详情 | |
| (XXXVI) | 69361 | methyl 3-amino-4-cyclobutyl-2-hydroxybutanoate 4-methylbenzenesulfonate | C9H17NO3.C7H8O3S | 详情 | 详情 |