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【结 构 式】 
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【分子编号】38197 【品名】O-(2-propynyl)hydroxylamine; 3-(aminooxy)-1-propyne 【CA登记号】 |
【 分 子 式 】C3H5NO 【 分 子 量 】71.07884 【元素组成】C 50.69% H 7.09% N 19.71% O 22.51% |
合成路线1
该中间体在本合成路线中的序号：(XVII)Acylation of (XII) with acetic anhydride and DMAP yielded the 3-acetyl coumarin (XIII). Following desilylation of (XIII) with tetrabutylammonium fluoride to give (XIV), condensation with O-methyl hydroxylamine gave oxime (XV). Treatment of (XV) with p-nitrophenyl chloroformate and DMAP generated carbonate (XVI), which was further coupled with O-propargyl hydroxylamine (XVII) to yield carbamate (XVIII). The tetrahydropyranyl group of (XVIII) was finally deprotected by methanolysis in the presence of p-toluenesulfonic acid.
| 【1】 Periers, A.-M.; Laurin, P.; Klich, M.; Musicki, B.; Haesslein, J.-L. (Aventis Pharma SA); Novel aromatic amides, preparation method and application as medicines. FR 2773369; WO 9935155 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 | |
| (XII) | 38192 | 4-hydroxy-7-([(7R,8R,9R,10R)-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-9-[(triethylsilyl)oxy]-6-oxaspiro[4.5]dec-7-yl]oxy)-8-methyl-2H-chromen-2-one | C31H46O9Si | 详情 | 详情 | |
| (XIII) | 38193 | 3-acetyl-4-hydroxy-7-([(7R,8R,9R,10R)-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-9-[(triethylsilyl)oxy]-6-oxaspiro[4.5]dec-7-yl]oxy)-8-methyl-2H-chromen-2-one | C33H48O10Si | 详情 | 详情 | |
| (XIV) | 38194 | 3-acetyl-4-hydroxy-7-[[(7R,8R,9R,10R)-9-hydroxy-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-6-oxaspiro[4.5]dec-7-yl]oxy]-8-methyl-2H-chromen-2-one | C27H34O10 | 详情 | 详情 | |
| (XV) | 38195 | 3-ethanimidoyl-4-hydroxy-7-[[(7R,8R,9R,10R)-9-hydroxy-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-6-oxaspiro[4.5]dec-7-yl]oxy]-8-methyl-2H-chromen-2-one | C28H37NO10 | 详情 | 详情 | |
| (XVI) | 38196 | (7R,8R,9R,10R)-7-[(3-ethanimidoyl-4-hydroxy-8-methyl-2-oxo-2H-chromen-7-yl)oxy]-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-6-oxaspiro[4.5]dec-9-yl 4-nitrophenyl carbonate | C35H40N2O14 | 详情 | 详情 | |
| (XVII) | 38197 | O-(2-propynyl)hydroxylamine; 3-(aminooxy)-1-propyne | C3H5NO | 详情 | 详情 | |
| (XVIII) | 38198 | (7R,8R,9R,10R)-7-[(3-ethanimidoyl-4-hydroxy-8-methyl-2-oxo-2H-chromen-7-yl)oxy]-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-6-oxaspiro[4.5]dec-9-yl 2-propynyloxycarbamate | C32H40N2O12 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The reaction of the spiro compound (I) with CDI in refluxing dichloroethane gives the cyclic carbonate (II), which is condensed with the benzopyranone (III) by means of DEAD and PPH3 in DMF, yielding the adduct (IV). Elimination of the diphenylmethyl protecting group by hydrogenation with H2 over Pd/C in THF affords compound (V), which is acylated with acetic anhydride to provide the acetyl derivative (VI). The reaction of (VI) with O-(2-propynyl)hydroxylamine (VII) by means of LiClO4 gives the propargyloxycarbamate (VIII) as a mixture of regioisomers that are separated by chromatography. The opening of the carbonate ring of (VII) is accompanied by the formation of the corresponding oxime at the acetyl group of the benzopyran. This oxime is easily exchanged for methoxy by reaction with an excess of O-methoxyhydroxylamine and K-OAc in ethanol to give rise to the target compound.
| 【1】 Laurin, P.; Periers, A.-M.; Musicki, B.; et al.; Improved antibacterial activities of coumarin antibiotics bearing 5',5'-dialkylnoviose: Biological activity of RU79115. Bioorg Med Chem Lett 2000, 10, 15, 1695. |
| 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) | 38187 | (8R,9S,10R)-10-methoxy-6-oxaspiro[4.5]decane-7,8,9-triol | C10H18O5 | 详情 | 详情 | |
| (II) | 47153 | C11H16O6 | 详情 | 详情 | ||
| (III) | 38188 | 4-(benzhydryloxy)-7-hydroxy-8-methyl-2H-chromen-2-one | C23H18O4 | 详情 | 详情 | |
| (IV) | 47154 | C34H32O9 | 详情 | 详情 | ||
| (V) | 47155 | C21H22O9 | 详情 | 详情 | ||
| (VI) | 47156 | C23H24O10 | 详情 | 详情 | ||
| (VII) | 38197 | O-(2-propynyl)hydroxylamine; 3-(aminooxy)-1-propyne | C3H5NO | 详情 | 详情 | |
| (VIII) | 47157 | C29H32N2O11 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)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 |