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【结 构 式】 
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【分子编号】69339 【品名】methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate HCl salt 【CA登记号】565456-77-1 |
【 分 子 式 】C9H15NO2.HCl 【 分 子 量 】205.684 【元素组成】C 52.56% H 7.84% Cl 17.24% N 6.81% O 15.56% |
合成路线1
该中间体在本合成路线中的序号：(XI)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 |
合成路线2
该中间体在本合成路线中的序号：(XI)Dehydrogenation of 2(R)-phenylperhydropyrrolo[1,2-c]oxazol-4-one (XXXVII) by α-selenylation with PhSeCl in the presence of KHMDS and TMSCl in THF, followed by oxidation with H2O2 in pyridine or EtOAc and elimination of the selenoxide intermediate produces the unsaturated analogue (XXXVIII) , which by cyclopropanation by means of isopropyl trimethylphosphonium bromide and BuLi in THF affords the tricyclic compound (XXXIX). Reductive ring opening of intermediate (XXXIX) by means of LiAlH4 in refluxing THF produces the N-benzylprolinol (XL), which is debenzylated to the prolinol (XLI) by catalytic hydrogenation over Pd/C in AcOH/EtOAc. After protection of amine (XLI) with Boc2O in CH2Cl2, the resulting N-Boccyclopropaprolinol (XLII) is subjected to Jones oxidation to furnish carboxylic acid (XLIII). Subsequent esterification of acid (XLIII) with (trimethylsilyl)diazomethane in toluene/MeOH affords the N-Boccyclopropaproline methyl ester (XLIV), which is finally deprotected with HCl in dioxane .
| 【1】 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. |
| 【2】 Zhang, R., Mamai, A., Madalengoitia, J.S. Cyclopropanation reactions of pyroglutamic acid-derived synthons with alkylidene transfer reagents. J Org Chem 1999, 64(2): 547-55. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (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 |
| (XXXVII) | 38561 | (3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | 103201-79-2 | C12H13NO2 | 详情 | 详情 |
| (XXXVIII) | 69362 | (3R,7aS)-3-phenyl-1,7a-dihydropyrrolo[1,2-c]oxazol-5(3H)-one | C12H11NO2 | 详情 | 详情 | |
| (XXXIX) | 69363 | (1R,2S,5S,6bS)-6,6-dimethyl-3-phenyltetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one | C15H17NO2 | 详情 | 详情 | |
| (XL) | 69364 | (1R,2S,5S)-(3-benzyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl)methanol | C15H21NO | 详情 | 详情 | |
| (XLI) | 69365 | ((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl)methanol | C8H15NO | 详情 | 详情 | |
| (XLII) | 69366 | (1R,2S,5S)-tert-butyl 2-(hydroxymethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate | C13H23NO3 | 详情 | 详情 | |
| (XLIII) | 69367 | (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid | C13H21NO4 | 详情 | 详情 | |
| (XLIV) | 69368 | (1R,2S,5S)-3-tert-butyl 2-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate | C14H23NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)In an alternative method to intermediate (XI), dehydration of caronic acid (XLV) by heating with Ac2O and H2SO4 in toluene at 190 °C produces caronic anhydride (XLVI) , which is then condensed with benzylamine in tert-butyl methyl ether at 170-180 °C to yield the bicyclic imide (XLVII). Subsequent reduction of imide (XLVII) with LiAlH4 in refluxing THF followed by debenzylation of the obtained pyrrolidine derivative (XLVIII) by catalytic hydrogenation over Pd/C in AcOH furnishes 6,6-dimethyl-3-azabicyclo[3.1.0]hexane (XLIX) .
Alternatively, caronic anhydride (XLVI) is reacted with NH4OH in H2O at 155 °C or THF at 180 °C to give 6,6-dimethyl-3-azabicyclo[3.1.0]-hexane-2,4-dione (L), which can also be prepared by debenzylation of intermediate (XLVII) with H2 in the presence of Pd/C or Pt/C. Reduction of imide (L) with LiAlH4 in refluxing THF then yields the bicyclic amine (XLIX). This secondary amine is converted to the corresponding imine (LII) by chlorination with NaClO in methyl tertbutyl ether, followed by treatment of the intermediate chloramine (LI) with NaOH in the presence of Bu4NOH or NBC in MeOH , or alternatively by direct oxidation of amine (XLIX) with K2S2O8 in the presence of AgNO3 and NaOH in acetonitrile. Addition of sodium bisulfite to the imine (LII) produces the racemic sulfonate (LIII), which upon cyanation with NaCN yields the α-amino nitrile (LIV). After methanolysis of nitrile (LIV) with HCl in MeOH/MTBE, resolution of the racemic amino ester employing di-p-toluoyl-D-tartaric acid in MeOH affords intermediate (XI) .
| 【3】 Smith, J.P. Treatment options for patients with hepatitis C: Role of pharmacists in optimizing treatment response and managing adverse events. Pharmacotherapy 2008, 28(9): 1151-61. |
| 【1】 Kwok, D.-L., Lee, H.-C., Zavialov, I.A. (Schering Corp.). Dehydrohalogenation process for the preparation of intermediates useful in providing 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane compounds. WO 2009073380. |
| 【2】 Berranger, T., Demonchaux, P. (Schering Corp.). Process for the preparation of 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane compounds utilizing bisulfite intermediate. WO 2008082508. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (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 |
| (XLV) | 69369 | 3,3-dimethylcyclopropane-1,2-dicarboxylic acid | 497-42-7 | C7H10O4 | 详情 | 详情 |
| (XLVI) | 69370 | 6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione | C7H8O3 | 详情 | 详情 | |
| (XLVII) | 69371 | 3-benzyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione | C14H15NO2 | 详情 | 详情 | |
| (XLVIII) | 69372 | 3-benzyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane | C14H19N | 详情 | 详情 | |
| (XLIX) | 69373 | 6,6-dimethyl-3-azabicyclo[3.1.0]hexane | C7H13N | 详情 | 详情 | |
| (L) | 69374 | 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione | C7H9NO2 | 详情 | 详情 | |
| (LI) | 69375 | 3-chloro-6,6-dimethyl-3-azabicyclo[3.1.0]hexane | C7H12ClN | 详情 | 详情 | |
| (LII) | 69376 | 6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-ene | C7H11N | 详情 | 详情 | |
| (LIII) | 69377 | sodium 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-sulfonate | C7H12NNaO3S | 详情 | 详情 | |
| (LIV) | 69378 | 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile | C8H12N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)In a further process, the proline analogue (XI) is prepared starting from ethyl chrysanthemate (LV). Oxidative cleavage of the isobutenyl side-chain of compound (LV) with KMnO4 followed by alkaline hydrolysis of the ethyl ester group provides caronic acid (XLV) as a mixture of cis- and trans-isomers. Diacid (XLV) is then converted to the bicyclic anhydride (XLVI) using either trifluoroacetic anhydride or acetic anhydride as dehydrating reagents. Ring opening opening of anhydride (XLVI) with allyl alcohol and quinidine, followed by resolution with (R)-(+)-α-methylbenzylamine gives the chiral monoallyl ester (LVI), which is subsequently coupled with ammonium bicarbonate by means of di-tert-butyl dicarbonate and pyridine to afford the amide ester (LVII). After reduction of compound (LVII) with LiAlH4, the resulting amino alcohol (LVIII) is protected as the benzyl carbamate (LIX) by treatment with benzyl chloroformate and K2CO3. The primary alcohol (LIX) is then oxidized to aldehyde (LX) by means of sodium hypochlorite and a catalytic amount of TEMPO. Cyclization of aldehyde (LX) with AcOH in EtOH followed by replacement of the EtOH solvent with THF gives a mixture of the bicyclic hemiaminal (LXI) and its O-ethyl derivative (LXII), which, without separation, is treated with cyanotrimethylsilane and boron trifluoride etherate to afford nitrile (LXIII). Addition of NaOMe to the nitrile (LXIII) followed by aqueous hydrolysis of the obtained imidate (LXIV) provides ester (LXV), which can be alternatively obtained by treatment of nitrile (LXIII) with acetyl chloride in MeOH, followed by addition of water. Finally, the benzyl carbamate (LXV) is then deprotected by hydrogenation over Pd/C to yield the cyclopropanefused prolinate ester (XI) .
| 【1】 Park, J., Sudhakar, A., Wong, G.S. (Schering Corp.). Process and intermediates for the preparation of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo-[3,1,0]hexane-2-carboxylates or salts thereof. JP 2007520434, US 2005059648, WO 2004113295. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (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 |
| (XLV) | 69369 | 3,3-dimethylcyclopropane-1,2-dicarboxylic acid | 497-42-7 | C7H10O4 | 详情 | 详情 |
| (XLVI) | 69370 | 6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione | C7H8O3 | 详情 | 详情 | |
| (LV) | 69379 | Ethyl chrysanthemumate;ethyl 2,2-dimethyl-3-(2-methylprop-1-en-1-yl)cyclopropanecarboxylate | 97-41-6 | C12H20O2 | 详情 | 详情 |
| (LVI) | 69380 | 3-((allyloxy)carbonyl)-2,2-dimethylcyclopropanecarboxylic acid | C10H14O4 | 详情 | 详情 | |
| (LVII) | 69381 | allyl 3-carbamoyl-2,2-dimethylcyclopropanecarboxylate | C10H15NO3 | 详情 | 详情 | |
| (LVIII) | 69382 | (3-(aminomethyl)-2,2-dimethylcyclopropyl)methanol | C7H15NO | 详情 | 详情 | |
| (LIX) | 69383 | benzyl ((3-(hydroxymethyl)-2,2-dimethylcyclopropyl)methyl)carbamate | C15H21NO3 | 详情 | 详情 | |
| (LX) | 69384 | benzyl ((3-formyl-2,2-dimethylcyclopropyl)methyl)carbamate | C15H19NO3 | 详情 | 详情 | |
| (LXI) | 69385 | benzyl 2-hydroxy-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate | C15H19NO3 | 详情 | 详情 | |
| (LXII) | 69386 | benzyl 2-ethoxy-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate | C17H23NO3 | 详情 | 详情 | |
| (LXIII) | 69387 | benzyl 2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate | C16H18N2O2 | 详情 | 详情 | |
| (LXIV) | 69388 | benzyl 2-(imino(methoxy)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate | C17H22N2O3 | 详情 | 详情 | |
| (LXV) | 69389 | 3-benzyl 2-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate | C17H21NO4 | 详情 | 详情 |