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【结 构 式】 
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【分子编号】65709 【品名】(1S,3S,5S)-3-(Aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester 【CA登记号】361440-67-7 |
【 分 子 式 】C11H18N2O3 【 分 子 量 】226.2756 【元素组成】C 58.39% H 8.02% N 12.38% O 21.21% |
合成路线1
该中间体在本合成路线中的序号：(XXXVI)The bicyclic carboxamide (V) can be obtained as follows. Esterification of L-pyroglutamic acid (XXIX) with ethanolic H2SO4 followed by protection with Boc2O gives 1-Boc-5-oxoproline ethyl ester (XXXI). After reduction of (XXXI) with LiBHEt3, the obtained hemiaminal (XXXII) is dehydrated to the dehydroproline derivative (XXXIII) employing trifluoroacetic anhydride, DMAP and DIEA. Subsequent hydrolysis of ethyl ester (XXXIII) by means of LiOH leads to the carboxylic acid (XXXIV), which is converted to the corresponding carboxamide (XXXV) via activation with methanesulfonyl chloride, followed by reaction with ammonia. Simmons-Smith cyclopropanation of (XXXV) using diiodomethane and diethylzinc gives the bicyclic derivative (XXXVI), which is then deprotected under acidic conditions to furnish (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide (V) (2, 3). Scheme 4.
| 【2】 Vu, T.C., Hamann, L.G., Fox, R. et al. (Bristol-Myers Squibb Co.). Methods and compounds producing dipeptidyl peptidase IV inhibitors and intermediates thereof. JP 200651621, US 2005090539, WO 2004052850. |
| 【3】 Politino, M., Cadin, M.M., Skonezny, P.M., Chen, J.G. (Bristol-Myers Squibb Co.). EP 1737970, JP 2007532137, WO 2005106011. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 65682 | (1S,3S,5S)-2-Azabicyclo[3.1.0]hexane-3-carboxamide | 361440-68-8 | C6H10N2O | 详情 | 详情 |
| (XXIX) | 32406 | (2S)-5-oxo-2-pyrrolidinecarboxylic acid | 98-79-3 | C5H7NO3 | 详情 | 详情 |
| (XXX) | 65704 | Ethyl L-pyroglutamate; Ethyl 5-oxo-L-prolinate; Ethyl (S)-(+)-2-pyrrolidone-5-carboxylate; 5-Oxo-proline ethyl ester; L(+)-Pyroglutamic acid ethyl ester | 7149-65-7 | C7H11NO3 | 详情 | 详情 |
| (XXXI) | 43914 | 1-(tert-butyl) 2-ethyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate | 144978-35-8 | C12H19NO5 | 详情 | 详情 |
| (XXXII) | 65705 | C12H21NO5 | 详情 | 详情 | ||
| (XXXIII) | 65706 | (S)-1-Boc-2,3-dihydro-2-pyrrolecarboxylic acid ethyl ester; (S)-1-tert-Butyl 2-ethyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate; Ethyl N-Boc-L-proline-4-ene | 178172-26-4 | C12H19NO4 | 详情 | 详情 |
| (XXXIV) | 65707 | (S)-1-(tert-Butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid; Boc-3,4-Dehydro-Pro-OH | 51154-06-4 | C10H15NO4 | 详情 | 详情 |
| (XXXV) | 65708 | (2S)-2-(Aminocarbonyl)-2,3-dihydro-1H-pyrrole-1-carboxylic acid 1,1-dimethylethyl ester | 709031-38-9 | C10H16N2O3 | 详情 | 详情 |
| (XXXVI) | 65709 | (1S,3S,5S)-3-(Aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester | 361440-67-7 | C11H18N2O3 | 详情 | 详情 |