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【结 构 式】 
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【分子编号】35089 【品名】(2R,3S)-6-[([[(5S)-5-amino-6-methoxy-6-oxohexyl]amino]carbonyl)oxy]-3-(tert-butoxycarbonyl)-2-isobutylhexanoic acid 【CA登记号】 |
【 分 子 式 】C23H42N2O8 【 分 子 量 】474.59516 【元素组成】C 58.21% H 8.92% N 5.9% O 26.97% |
合成路线1
该中间体在本合成路线中的序号：(XIV)Simultaneous deprotection of the benzyl ester and the N-carbobenzoxy group of (XIII) by hydrogenolysis over Pd/C gave amino acid (XIV), which was cyclized by means of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and diisopropyl ethylamine (DIEA), yielding macrocycle (XV). Cleavage of the tert-butyl ester of (XV) with trifluoroacetic acid produced carboxylic acid (XVI), and this was converted to the O-benzyl hydroxamate (XVII) by coupling with O-benzyl hydroxylamine. Further hydrolysis of the methyl ester group of (XVII) to acid (XVIII) was followed by coupling with glycine morpholide (XIX) affording diamide (XX). The O-benzyl group of (XX) was finally removed by hydrogenation in the presence of Pd/C.
| 【1】 Xue, C.-B.; Cherney, R.J.; DeCicco, C.P.; Degrado, W.F.; He, X.; Hodge, C.N.; Jacobson, I.C.; Magolda, R.L.; Arner, E.C.; Duan, J.; Nelson, D.J. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0863885; JP 2000502050; WO 9718207 . |
| 【2】 Nelson, D.; Magolda, R.L.; Jacobson, I.C.; He, X.; Arner, E.; Cherney, R.J.; Duan, J.; Xue, C.-B.; Decicco, C.P.; Degrado, W.F. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0981521; WO 9851665 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 | |
| (XIII) | 35088 | 17-benzyl 16-(tert-butyl) 5-methyl (5S,16S,17R)-19-methyl-3,11-dioxo-1-phenyl-2,12-dioxa-4,10-diazaicosane-5,16,17-tricarboxylate | C38H54N2O10 | 详情 | 详情 | |
| (XIV) | 35089 | (2R,3S)-6-[([[(5S)-5-amino-6-methoxy-6-oxohexyl]amino]carbonyl)oxy]-3-(tert-butoxycarbonyl)-2-isobutylhexanoic acid | C23H42N2O8 | 详情 | 详情 | |
| (XV) | 35090 | 12-(tert-butyl) 8-methyl (8S,11R,12S)-11-isobutyl-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-8,12-dicarboxylate | C23H40N2O7 | 详情 | 详情 | |
| (XVI) | 35091 | (8S,11R,12S)-11-isobutyl-8-(methoxycarbonyl)-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-12-carboxylic acid | C19H32N2O7 | 详情 | 详情 | |
| (XVII) | 35092 | methyl (8S,11R,12S)-12-[[(benzyloxy)amino]carbonyl]-11-isobutyl-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-8-carboxylate | C26H39N3O7 | 详情 | 详情 | |
| (XVIII) | 35093 | (8S,11R,12S)-12-[[(benzyloxy)amino]carbonyl]-11-isobutyl-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-8-carboxylic acid | C25H37N3O7 | 详情 | 详情 | |
| (XIX) | 35094 | 2-amino-1-(4-morpholinyl)-1-ethanone | C6H12N2O2 | 详情 | 详情 | |
| (XX) | 35095 | (8S,11R,12S)-N(12)-(benzyloxy)-11-isobutyl-N(8)-[2-(4-morpholinyl)-2-oxoethyl]-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-8,12-dicarboxamide | C31H47N5O8 | 详情 | 详情 |