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【结 构 式】 
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【药物名称】GM-160575 【化学名称】(1R,3aR,4S,4aR,7R,7aR,8aS)-8a-(6-Deoxy-4-O-methyl-3-O-octanoyl-beta-D-altropyranosyloxymethyl)-4-formyl-3-isopropyl-7-methyl-1,3a,4,4a,5,6,7,7a,8,8a-decahydro-1,4-methano-s-indacene-3a-carboxylic acid 【CA登记号】179052-04-1 【 分 子 式 】C35H54O9 【 分 子 量 】618.81523 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY, Elongation Factor 2 (EF-2) Inhibitors |
合成路线1
Sordarin (I) was isolated from culture broths of Sordaria araneosa. Protection of the carboxyl group of (I) as the benzhydryl ester (II) was effected by treatment with diphenyl diazomethane. The 2'-hydroxyl group of (II) was subsequently blocked as the carbonate ester (III) by selective acylation with benzyl chloroformate in the presence of DMAP. Subsequent esterification of the 3'-hydroxyl of (III) with octanoyl chloride (IV) furnished the octanoate ester (V). The benzhydryl ester and benzyl carbonate protecting groups of (V) were finally removed by catalytic hydrogenation over Pd/C.
| 【1】 Fraile, M.T.; Ruiz, J.R.; Gómez de las Heras, F.; García-Ochoa, S.; Arribas, E.M.; Castro, J.; Clemens, I.R.; Cuevas, J.C.; Chicharro, J.; Antifungal sordarins. Synthesis and structure-activity relationships of 3'-O-substituted derivatives. Bioorg Med Chem Lett 2002, 12, 2, 117. |
| 【2】 Hayes, M.; Wildman, H.; Dawson, M.; Chalk, P.; Hall, R.; Ruiz Gomez, J.R. (GlaxoSmithKline plc); Antifungal sordarin derivs.. EP 0711783; EP 0791007; JP 1999502188; US 6054478; WO 9614327 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 59613 | (1R,2S,4R,5R,8R,9S,11R)-2-({[(2R,3S,4S,5S,6R)-3,4-dihydroxy-5-methoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}methyl)-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylic acid | C27H40O8 | 详情 | 详情 | |
| (II) | 59614 | benzhydryl (1R,2S,4R,5R,8R,9S,11R)-2-({[(2R,3S,4S,5S,6R)-3,4-dihydroxy-5-methoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}methyl)-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylate | C40H50O8 | 详情 | 详情 | |
| (III) | 59615 | benzhydryl (1R,2S,4R,5R,8R,9S,11R)-2-{[((2R,3S,4R,5S,6R)-3-{[(benzyloxy)carbonyl]oxy}-4-hydroxy-5-methoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy]methyl}-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylate | C48H56O10 | 详情 | 详情 | |
| (IV) | 11123 | Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride | 111-64-8 | C8H15ClO | 详情 | 详情 |
| (V) | 59616 | benzhydryl (1R,2S,4R,5R,8R,9S,11R)-2-({[(2R,3S,4R,5R,6R)-3-{[(benzyloxy)carbonyl]oxy}-5-methoxy-6-methyl-4-(octanoyloxy)tetrahydro-2H-pyran-2-yl]oxy}methyl)-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylate | C56H70O11 | 详情 | 详情 |