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【结 构 式】 
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【分子编号】16336 【品名】[2-ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]sodium 【CA登记号】 |
【 分 子 式 】C7H11NaO4 【 分 子 量 】182.151708 【元素组成】C 46.16% H 6.09% Na 12.62% O 35.13% |
合成路线1
该中间体在本合成路线中的序号：(III)An alternative synthesis of the key intermediate (II) in the synthesis of Sch-51048 published in the original monograph has been reported:The reaction of 2-(2,4-difluorophenyl)allyl alcohol (I) with PBr3 in dichloromethane gives the corresponding allyl bromide (II), which is condensed with sodium diethyl malonate (III), yielding the diester (IV). The reduction of (VI) with NaBH4 in ethanol affords the diol (V), which is submitted to an asymmetric acetylation with vinyl acetate catalyzed by the enzyme Novo SP435, giving the chiral monoester (VI). The cyclization of (VI) with I2 and NaHCO3 in acetonitrile affords the tetrahydrofuran derivative (VII), which is allowed to react with the sodium salt of 1,2,4-triazole (VIII) in DMF, yielding the corresponding condensation product (IX). Hydrolysis of (IX) with NaOH in methanol gives the alcohol (X), which is tosylated with tosyl chloride in pyridine.
| 【1】 Puar, M.S.; Girijavallabhan, V.M.; Saksena, A.K.; Lovey, R.G.; Ganguly, A.K.; Pike, R.E.; Wang, H.Y.; Zaks, A.; Morgan, B.; Highly stereoselective access to novel 2,2,4-trisubstituted tetrahydrofurans by halocyclization: Practical chemoenzymatic synthesis of SCH 51048, a broad-spectrum orally active antifungal agent. Tetrahedron Lett 1995, 36, 11, 1787. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 | |
| (I) | 15491 | 2-(2,4-difluorophenyl)-2-propen-1-ol | C9H8F2O | 详情 | 详情 | |
| (II) | 16335 | 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene | C9H7BrF2 | 详情 | 详情 | |
| (III) | 16336 | [2-ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]sodium | C7H11NaO4 | 详情 | 详情 | |
| (IV) | 16337 | diethyl 2-[2-(2,4-difluorophenyl)-2-propenyl]malonate | C16H18F2O4 | 详情 | 详情 | |
| (V) | 16338 | 2-[2-(2,4-difluorophenyl)-2-propenyl]-1,3-propanediol | C12H14F2O2 | 详情 | 详情 | |
| (VI) | 16339 | (2S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-4-pentenyl acetate | C14H16F2O3 | 详情 | 详情 | |
| (VII) | 16340 | [(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanyl]methyl acetate | C14H15F2IO3 | 详情 | 详情 | |
| (VIII) | 16341 | 1H-1,2,4-triazol-1-ylsodium | C2H2N3Na | 详情 | 详情 | |
| (IX) | 16342 | [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl acetate | C16H17F2N3O3 | 详情 | 详情 | |
| (X) | 16343 | [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methanol | C14H15F2N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The reaction of benzyl-alpha-D-mannoside (I) with Ts-Cl in pyridine gives the 6-O-tosylate (II), which is treated with 2,2-dimethoxypropane (III), trimethyl orthoacetate and naphthalenesulfonic acid to yield the acetonide (IV). The silylation of the remaining OH group of (IV) with Tms-Cl and TEA in THF affords the silyl ether (V), which is condensed with allylmagnesium bromide (VI) in ethyl ether to provide the olefinic compound (VII). The desilylation of (VII) by means of TBAF in THF gives the secondary alcohol (VIII); which is oxidized by means of (COCl)2, DMSO and TEA in dichloromethane to yield the ketone derivative (IX). The oxidation of the terminal double bond of (IX) by means of RuO2 and NaIO4 in CCl4/acetonitrile affords the carboxylic acid (X), which is methylated with diazomethane to provide the corresponding methyl ester (XI). Alternatively the propionic ester (XI) can also be obtained by the following sequence: The condensation of the silyl ether (V) with the sodium salt of diethyl malonate (XII) in refluxing toluene gives the malonyl derivative (XIII), which is treated with NaCl at 145 C, yielding the lactone (XIV). The methanolysis of (XIV) with KOH in methanol affords the hydroxyester (XV), which is finally oxidized with PCC in dichloromethane to provide the target ketoester (XI), already reported. The reduction of the carbonyl group of (XI) by means of NaBH4 in ethanol gives the hydroxyester (XVI), which is treated with triflic anhydride and pyridine to yield the corresponding triflate (XVII). The reaction of (XVII) with sodium azide in DMF affords the azido derivative (XVIII), which is reduced with H2 over Pd/C to provide the expected amino derivative (XIX). The cyclization of (XIX) in refluxing toluene gives the lactam (XX), which is finally reduced to the target perhydro-pyrano[3,2-b]pyridine (XXI) intermediate.
| 【1】 Bermejo Gonzalez, F.; et al.; Efficient preparation of a valuable intermediate in the synthesis of (-)-swainsonine. Bull Chem Soc Jpn 1992, 65, 2, 567. |
| 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) | 62617 | (2S,3S,4S,5S,6R)-2-(benzyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol | C13H18O6 | 详情 | 详情 | |
| (II) | 62659 | [(2R,3S,4S,5S,6S)-6-(benzyloxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl]methyl 4-methylbenzenesulfonate | C20H24O8S | 详情 | 详情 | |
| (III) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (IV) | 62660 | [(3aS,4S,6R,7R,7aS)-4-(benzyloxy)-7-hydroxy-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]methyl 4-methylbenzenesulfonate | C23H28O8S | 详情 | 详情 | |
| (V) | 62661 | {(3aS,4S,6R,7R,7aR)-4-(benzyloxy)-2,2-dimethyl-7-[(trimethylsilyl)oxy]tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl}methyl 4-methylbenzenesulfonate | C26H36O8SSi | 详情 | 详情 | |
| (VI) | 61128 | C4H8 | 详情 | 详情 | ||
| (VII) | 62662 | (3aS,4S,6R,7R,7aR)-4-(benzyloxy)-6-(3-butenyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl trimethylsilyl ether; {[(3aS,4S,6R,7R,7aR)-4-(benzyloxy)-6-(3-butenyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl]oxy}(trimethyl)silane | C22H34O5Si | 详情 | 详情 | |
| (VIII) | 62663 | (3aS,4S,6R,7R,7aS)-4-(benzyloxy)-6-(3-butenyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol | C19H26O5 | 详情 | 详情 | |
| (IX) | 62664 | (3aS,4S,6R,7aR)-4-(benzyloxy)-6-(3-butenyl)-2,2-dimethyldihydro-4H-[1,3]dioxolo[4,5-c]pyran-7(6H)-one | C19H24O5 | 详情 | 详情 | |
| (X) | 62665 | 3-[(3aS,4S,6R,7aR)-4-(benzyloxy)-2,2-dimethyl-7-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoic acid | C18H22O7 | 详情 | 详情 | |
| (XI) | 62667 | methyl 3-[(3aS,4S,6R,7aR)-4-(benzyloxy)-2,2-dimethyl-7-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate | C19H24O7 | 详情 | 详情 | |
| (XII) | 16336 | [2-ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]sodium | C7H11NaO4 | 详情 | 详情 | |
| (XIII) | 62666 | diethyl 2-({(3aS,4S,6R,7R,7aR)-4-(benzyloxy)-2,2-dimethyl-7-[(trimethylsilyl)oxy]tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl}methyl)malonate | C26H40O9Si | 详情 | 详情 | |
| (XIV) | 62669 | (3aS,4S,5aR,9aR,9bR)-4-(benzyloxy)-2,2-dimethylhexahydro[1,3]dioxolo[4,5-d]pyrano[3,2-b]pyran-8(4H)-one | C18H22O6 | 详情 | 详情 | |
| (XV) | 62668 | methyl 3-[(3aS,4S,6R,7R,7aS)-4-(benzyloxy)-7-hydroxy-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate | C19H26O7 | 详情 | 详情 | |
| (XVI) | 62670 | methyl 3-[(3aS,4S,6R,7S,7aS)-4-(benzyloxy)-7-hydroxy-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate | C19H26O7 | 详情 | 详情 | |
| (XVII) | 62671 | methyl 3-((3aS,4S,6R,7S,7aR)-4-(benzyloxy)-2,2-dimethyl-7-{[(trifluoromethyl)sulfonyl]oxy}tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl)propanoate | C20H25F3O9S | 详情 | 详情 | |
| (XVIII) | 62672 | methyl 3-[(3aS,4S,6R,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate | C19H25N3O6 | 详情 | 详情 | |
| (XIX) | 62673 | methyl 3-[(3aS,4S,6R,7R,7aS)-7-amino-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate | C19H27NO6 | 详情 | 详情 | |
| (XX) | 62674 | (3aS,4S,5aR,9aR,9bS)-4-(benzyloxy)-2,2-dimethylhexahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridin-8(5aH)-one | C18H23NO5 | 详情 | 详情 | |
| (XXI) | 62626 | (3aS,4S,5aR,9aR,9bS)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridin-4-yl benzyl ether; (3aS,4S,5aR,9aR,9bS)-4-(benzyloxy)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridine | C18H25NO4 | 详情 | 详情 |