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【结 构 式】 
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【分子编号】40547 【品名】(3R,4S,5R)-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2,3,4-triol 【CA登记号】 |
【 分 子 式 】C8H16O5 【 分 子 量 】192.21204 【元素组成】C 49.99% H 8.39% O 41.62% |
合成路线1
该中间体在本合成路线中的序号：(V)4,7-Dihydroxy-8-methylcoumarin (I) was selectively protected as the monosilylated derivative (II) using tert-butyldiphenylsilyl chloride and Et3N. Subsequent Mitsunobu coupling of (II) with 2-bromoethanol (A) produced the bromoethoxy coumarin (III). After desilylation of (III) with a mixture of HF and KF, the resulting phenol (IV) was coupled with noviose triol (V) under Mitsunobu conditions to afford the alpha-glycoside (VI) as the major isomer. Esterification of (VI) with 5-methylpyrrole-2-carboxylic anhydride (VII) in the presence of CoCl2 yielded the desired 3'-ester (VIII) along with minor amounts of 2'-ester, which was separated by column chromatography. Finally, displacement of the bromide of (VIII) by 2-mercaptoimidazole (IX) furnished the corresponding thioether.
| 【1】 Ferroud, D.; Laurin, P.; Schio, L.; et al.; Structure-activity relationship in two series of aminoalkyl substituted coumarin inhibitors of gyrase B. Bioorg Med Chem Lett 1999, 9, 19, 2875. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (I) | 40543 | 4,7-dihydroxy-8-methyl-2H-chromen-2-one | C10H8O4 | 详情 | 详情 | |
| (II) | 40544 | 7-[[tert-butyl(diphenyl)silyl]oxy]-4-hydroxy-8-methyl-2H-chromen-2-one | C26H26O4Si | 详情 | 详情 | |
| (III) | 40545 | 4-(2-bromoethoxy)-7-[[tert-butyl(diphenyl)silyl]oxy]-8-methyl-2H-chromen-2-one | C28H29BrO4Si | 详情 | 详情 | |
| (IV) | 40546 | 4-(2-bromoethoxy)-7-hydroxy-8-methyl-2H-chromen-2-one | C12H11BrO4 | 详情 | 详情 | |
| (V) | 40547 | (3R,4S,5R)-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2,3,4-triol | C8H16O5 | 详情 | 详情 | |
| (VI) | 40548 | 4-(2-bromoethoxy)-7-[[(2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-8-methyl-2H-chromen-2-one | C20H25BrO8 | 详情 | 详情 | |
| (VII) | 40549 | 5-methyl-1H-pyrrole-2-carboxylic anhydride | C12H12N2O3 | 详情 | 详情 | |
| (VIII) | 40550 | (3R,4S,5R,6R)-6-[[4-(2-bromoethoxy)-8-methyl-2-oxo-2H-chromen-7-yl]oxy]-5-hydroxy-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl 5-methyl-1H-pyrrole-2-carboxylate | C26H30BrNO9 | 详情 | 详情 | |
| (IX) | 34456 | 1H-imidazole-2-thiol; 1H-imidazol-2-ylhydrosulfide | 872-35-5 | C3H4N2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Treatment of protected derivative (I) with ethyl chloroformate (II) and DMAP in dichloromethane yields (III), which is then protected by Mitsunobu reaction with benzyl alcohol (IV) in the presence of PPh3 and DEAD to provide (V). Coumarin (V) undergoes Mitsunobu reaction with noviose (VI) to afford alpha-glycoside (VII), which is converted into (VIII) by protection in 3'-OH by means of TESCl, imidazole and DIEA in dichloromethane (chromatographic separation of 3'- and 2'-TES-protected regioisomers is needed), followed by protection of the 2'-OH by treatment with DHP and catalytic TsOH in dichloromethane. Hydrogenolysis of (VIII) over Pd/C followed by desilylation with TBAF in THF affords intermediate (IX), which is then converted into N'-alkoxycarbamate (XII) by reaction with (X) and DMAP in dichloromethane to yield the corresponding p-nitrophenylcarbonate activated form, followed by reaction with hydroxylamine (XI) in DMF and catalysis of DMAP. Exchange of the 3-ester group in (XII) by hydroxylamine (XIII) in pyridine gives coumarin-3-hydroxamate derivative (XIV), which is finally deprotected of its THP form in MeOH and catalysis of TsOH.
| 【1】 Haesslein, J.-L.; Dupuis-Hamelin, C.; Periers, A.-M.; Ferroud, D.; Laurin, P.; Bonnefoy, A.; Lassaigne, P.; Misicki, B.; Klich, M.; Mauvais, P.; Coumarin inhibitors of gyrase B with N-propargyloxy-carbamate as an effective pyrrole bioisostere. Bioorg Med Chem Lett 2000, 10, 2, 161. |
| 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) | 42325 | 4-hydroxy-8-methyl-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2-one | C15H16O5 | 详情 | 详情 | |
| (II) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (III) | 42326 | ethyl 4-hydroxy-8-methyl-2-oxo-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromene-3-carboxylate | C18H20O7 | 详情 | 详情 | |
| (IV) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
| (V) | 42327 | ethyl 4-(benzyloxy)-7-hydroxy-8-methyl-2-oxo-2H-chromene-3-carboxylate | C20H18O6 | 详情 | 详情 | |
| (VI) | 40547 | (3R,4S,5R)-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2,3,4-triol | C8H16O5 | 详情 | 详情 | |
| (VII) | 42328 | ethyl 4-(benzyloxy)-7-[[(2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-2-oxo-2H-chromene-3-carboxylate | C27H30O10 | 详情 | 详情 | |
| (VIII) | 42329 | ethyl 4-(benzyloxy)-7-([(2R,3R,4R,5R)-5-methoxy-6,6-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-4-[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-2-oxo-2H-chromene-3-carboxylate | C38H52O11Si | 详情 | 详情 | |
| (IX) | 42330 | ethyl 4-hydroxy-7-[[(2R,3R,4R,5R)-4-hydroxy-5-methoxy-6,6-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-2-yl]oxy]-2-oxo-2H-chromene-3-carboxylate | C25H32O11 | 详情 | 详情 | |
| (X) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (XI) | 38197 | O-(2-propynyl)hydroxylamine; 3-(aminooxy)-1-propyne | C3H5NO | 详情 | 详情 | |
| (XII) | 42331 | ethyl 4-hydroxy-7-[[(2R,3R,4R,5R)-5-methoxy-6,6-dimethyl-4-([[(2-propynyloxy)amino]carbonyl]oxy)-3-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-2-yl]oxy]-2-oxo-2H-chromene-3-carboxylate | C29H35NO13 | 详情 | 详情 | |
| (XIII) | 42332 | 1-(aminooxy)-3-methyl-2-butene; O-(3-methyl-2-butenyl)hydroxylamine | C5H11NO | 详情 | 详情 | |
| (XIV) | 42333 | (3R,4R,5R,6R)-6-[[4-hydroxy-3-([[(3-methyl-2-butenyl)oxy]amino]carbonyl)-2-oxo-2H-chromen-7-yl]oxy]-3-methoxy-2,2-dimethyl-5-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-4-yl 2-propynyloxycarbamate | C32H40N2O13 | 详情 | 详情 |