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【结 构 式】 
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【分子编号】33931 【品名】1-(bromomethyl)cyclobutane;bromomethylcyclobutane;(Bromomethyl)cyclobutane;Cyclobutylmethyl bromide 【CA登记号】17247-58-4 |
【 分 子 式 】C5H9Br 【 分 子 量 】149.03046 【元素组成】C 40.3% H 6.09% Br 53.62% |
合成路线1
该中间体在本合成路线中的序号：(B)Compound can be prepared in three different ways all starting from 14-hydroxydihydronormorphinone (I): 1) The condensation of (I) with cyclobutanecarboxyl chloride (A) by means of triethylamine in CH2Cl2 gives the bis(cyclobutylcarbonyl) derivative (II), which is then reduced and hydrolyzed with LiAlH4 in THF. 2) The condensation of (I) with cyclobutylmethyl bromide (B) in DMF gives the N-cyclobutylmethyl derivative (III), which is then reduced with NaBH4 in ethanol. 3) The reduction of (I) with NaBH4 as before gives 14-hydroxydihydronormophine (IV), which is then alkylated with cyclobutylmethyl bromide (B) in DMF.
| 【1】 Blumberg, H.; et al.; Verfahren zur Herstellung von N-substituierten 14-Hydroxydihydronormorphinen. CH 493522; DE 1670616; DE 1795707; ES 334942; FR 6112M; GB 1119270 . |
| 【2】 Blumberg, H.; et al.; 14-Hydroxydihydronormorphinone derivatives. US 3332950 . |
| 【3】 Castaner, J.; Roberts, P.J.; Nalbuphine. Drugs Fut 1977, 2, 9, 613. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 18589 | cyclobutanecarbonyl chloride | 5006-22-4 | C5H7ClO | 详情 | 详情 |
| (B) | 33931 | 1-(bromomethyl)cyclobutane;bromomethylcyclobutane;(Bromomethyl)cyclobutane;Cyclobutylmethyl bromide | 17247-58-4 | C5H9Br | 详情 | 详情 |
| (I) | 33927 | (1S,5R,13R,17S)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one | C16H17NO4 | 详情 | 详情 | |
| (II) | 33928 | (1S,5R,13R,17S)-4-(cyclobutylcarbonyl)-17-hydroxy-14-oxo-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-10-yl cyclobutanecarboxylate | C26H29NO6 | 详情 | 详情 | |
| (III) | 33929 | (1S,5R,13R,17S)-4-(cyclobutylmethyl)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one | C21H25NO4 | 详情 | 详情 | |
| (IV) | 33930 | (1S,5R,13R,14S,17S)-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-triene-10,14,17-triol | C16H19NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)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 |