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【结 构 式】 
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【药物名称】 【化学名称】N-(L-Leucyl)sulfamic acid 1-[4-(2-phenylethyl)thiazol-2-yl]-beta-D-ribofuranos-5-O-yl ester 【CA登记号】 【 分 子 式 】C22H31N3O7S2 【 分 子 量 】513.63627 |
【开发单位】Cubist (Originator) 【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Leucyl-tRNA Synthetase Inhibitors |
合成路线1
Reaction of 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose (I) with trimethylsilyl cyanide in the presence of boron trifluoride gave nitrile (II), which was treated with liquid hydrogen sulfide and DMAP to yield thioamide (III). Condensation of this thioamide with bromoketone (IV) in acetonitrile afforded the thiazole derivative (V). Hydrolysis of the benzoate esters of (V) using sodium methoxide in methanol, followed by protection of the resulting 2,3-diol with acetone and triethyl orthoformate produced the corresponding isopropylidene ketal (VI). Treatment of the primary alcohol group of (VI) with sulfamoyl chloride gave rise to the sulfamate ester (VII). Further condensation of (VII) with N-Boc-L-leucine furnished (IX). The Boc and isopropylidene groups of (IX) were finally eliminated with trifluoroacetic acid to provide the title compound.
| 【1】 Wang, W.; Gallant, P.; Hill, J.M.; Yu, G.; Wendler, P.; Kluge, A.F.; Yu, X.Y.; Synthesis and structure-activity relationships of a series of novel thiazoles as inhibitors of aminoacyl-tRNA synthetases. Bioorg Med Chem Lett 1999, 9, 3, 375. |
| 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) | 20984 | methyl (Z)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E)-3-oxo-3-(4-propylcyclohexyl)-1-propenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C33H52O7 | 详情 | 详情 | |
| (II) | 29143 | (2S,3S,4R,5R)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]-2-cyanotetrahydro-3-furanyl benzoate | C27H21NO7 | 详情 | 详情 | |
| (III) | 29144 | (2R,3S,4R,5R)-2-(aminocarbothioyl)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C27H23NO7S | 详情 | 详情 | |
| (IV) | 29211 | 1-bromo-4-phenyl-2-butanone | C10H11BrO | 详情 | 详情 | |
| (V) | 29212 | [(2R,3R,4S,5R)-3,4-bis(benzoyloxy)-5-(4-phenethyl-1,3-thiazol-2-yl)tetrahydro-2-furanyl]methyl benzoate | C37H31NO7S | 详情 | 详情 | |
| (VI) | 29213 | [(3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-phenethyl-1,3-thiazol-2-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol | C19H23NO4S | 详情 | 详情 | |
| (VII) | 29214 | [(3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-phenethyl-1,3-thiazol-2-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylsulfamate | C19H24N2O6S2 | 详情 | 详情 | |
| (VIII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (IX) | 29215 | tert-butyl (1S)-1-[[([[(3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-phenethyl-1,3-thiazol-2-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methoxy]sulfonyl)amino]carbonyl]-3-methylbutylcarbamate | C30H43N3O9S2 | 详情 | 详情 |