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【结 构 式】 
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【分子编号】59863 【品名】(3aR,4R,8bR)-2,2-dimethyl-3a,4,5,8,8a,8b-hexahydro[1,3]dioxolo[4,5-e][2,1]benzisoxazol-4-yl 1-ethoxyethyl ether; (3aR,4R,8bR)-4-(1-ethoxyethoxy)-2,2-dimethyl-3a,4,5,8,8a,8b-hexahydro[1,3]dioxolo[4,5-e][2,1]benzisoxazole 【CA登记号】 |
【 分 子 式 】C14H23NO5 【 分 子 量 】285.34036 【元素组成】C 58.93% H 8.12% N 4.91% O 28.04% |
合成路线1
该中间体在本合成路线中的序号：(XV)A different synthetic strategy used 3,4:5,6-O-diisopropylidene-D-mannitol (VI) as the starting material. Dehydration of (VI) by means of dimethylformamide dimethylacetal and Ac2O provided olefin (VII). Selective hydrolysis of the terminal acetonide of (VII) was achieved by means of 80% AcOH to afford diol (VIII). Conversion of (VIII) to the primary tosylate (IX), followed by treatment with Na2CO3 gave epoxide (X). Oxirane ring opening in (X) with NaCN furnished the beta-hydroxy nitrile (XI). This was then protected as the unsymmetric acetal (XII) by acid-catalyzed addition of ethyl vinyl ether. Partial reduction of the nitrile function of (XII) with DIBAL in toluene at -78 C gave rise to aldehyde (XIII), which was further derivatized as the corresponding oxime (XIV). The nitrile oxide generated by treatment of oxime (XIV) with NaOCl and Et3N underwent a dipolar cycloaddition to the olefin, leading to isoxazoline (XV)
| 【1】 Takahashi, T.; Shiono, M. (Kuraray Co., Ltd.); Cyclohexanetriol derivs.. EP 0503630 . |
| 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) | 18762 | 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 |
| (VI) | 59854 | C12H22O6 | 详情 | 详情 | ||
| (VII) | 59855 | C12H20O4 | 详情 | 详情 | ||
| (VIII) | 59856 | (1R)-1-[(4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]-1,2-ethanediol | C9H16O4 | 详情 | 详情 | |
| (IX) | 59857 | (2R)-2-[(4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]-2-hydroxyethyl 4-methylbenzenesulfonate | C16H22O6S | 详情 | 详情 | |
| (X) | 59858 | (4R,5R)-2,2-dimethyl-4-[(2R)oxiranyl]-5-vinyl-1,3-dioxolane | C9H14O3 | 详情 | 详情 | |
| (XI) | 59859 | (3R)-3-[(4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]-3-hydroxypropanenitrile | C10H15NO3 | 详情 | 详情 | |
| (XII) | 59860 | (3R)-3-[(4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]-3-(1-ethoxyethoxy)propanenitrile | C14H23NO4 | 详情 | 详情 | |
| (XIII) | 59861 | (3R)-3-[(4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]-3-(1-ethoxyethoxy)propanal | C14H24O5 | 详情 | 详情 | |
| (XIV) | 59862 | (3R)-3-[(4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]-3-(1-ethoxyethoxy)propanal oxime | C14H25NO5 | 详情 | 详情 | |
| (XV) | 59863 | (3aR,4R,8bR)-2,2-dimethyl-3a,4,5,8,8a,8b-hexahydro[1,3]dioxolo[4,5-e][2,1]benzisoxazol-4-yl 1-ethoxyethyl ether; (3aR,4R,8bR)-4-(1-ethoxyethoxy)-2,2-dimethyl-3a,4,5,8,8a,8b-hexahydro[1,3]dioxolo[4,5-e][2,1]benzisoxazole | C14H23NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)Hydrogenolysis of the isoxazoline ring of (XV) in the presence of Raney-nickel and boric acid generated the (hydroxymethyl)cyclohexanone (XVI). After hydroxyl group protection of (XVI) as the silyl ether (XVII), Peterson olefination of the ketone function of (XVII) with the lithium derivative of ethyl trimethylsilylacetate (XVIII) furnished the unsaturated ester (XIX). Desilylation of (XIX) gave the primary alcohol (XX), which was dehydrated to (XXI) by treatment with methanesulfonyl chloride and pyridine. The 1-(ethoxy)ethoxy protecting group of (XXI) was then replaced by a silyl ether (XXII) by acidic ketal hydrolysis, followed by treatment with tert-butyldiphenylsilyl chloride and imidazole. Subsequent acetonide (XXII) hydrolysis gave diol (XXIII), which was regioselectively mono-silylated providing intermediate (XXIV)
| 【1】 Takahashi, T.; Shiono, M. (Kuraray Co., Ltd.); Cyclohexanetriol derivs.. EP 0503630 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 59863 | (3aR,4R,8bR)-2,2-dimethyl-3a,4,5,8,8a,8b-hexahydro[1,3]dioxolo[4,5-e][2,1]benzisoxazol-4-yl 1-ethoxyethyl ether; (3aR,4R,8bR)-4-(1-ethoxyethoxy)-2,2-dimethyl-3a,4,5,8,8a,8b-hexahydro[1,3]dioxolo[4,5-e][2,1]benzisoxazole | C14H23NO5 | 详情 | 详情 | |
| (XVI) | 59864 | (3aR,7R,7aR)-7-(1-ethoxyethoxy)-4-(hydroxymethyl)-2,2-dimethyltetrahydro-1,3-benzodioxol-5(4H)-one | C14H24O6 | 详情 | 详情 | |
| (XVII) | 59865 | (3aR,7R,7aR)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-(1-ethoxyethoxy)-2,2-dimethyltetrahydro-1,3-benzodioxol-5(4H)-one | C20H38O6Si | 详情 | 详情 | |
| (XVIII) | 49044 | ethyl 2-(trimethylsilyl)acetate | C7H16O2Si | 详情 | 详情 | |
| (XIX) | 59867 | ethyl 2-[(3aR,7R,7aR)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-(1-ethoxyethoxy)-2,2-dimethyltetrahydro-1,3-benzodioxol-5(4H)-ylidene]acetate | C24H44O7Si | 详情 | 详情 | |
| (XX) | 59866 | ethyl 2-[(3aR,7R,7aR)-7-(1-ethoxyethoxy)-4-(hydroxymethyl)-2,2-dimethyltetrahydro-1,3-benzodioxol-5(4H)-ylidene]acetate | C18H30O7 | 详情 | 详情 | |
| (XXI) | 59868 | ethyl 2-[(3aR,7R,7aR)-7-(1-ethoxyethoxy)-2,2-dimethyl-4-methylenetetrahydro-1,3-benzodioxol-5(4H)-ylidene]acetate | C18H28O6 | 详情 | 详情 | |
| (XXII) | 59869 | ethyl 2-[(3aR,7R,7aS)-7-{[tert-butyl(diphenyl)silyl]oxy}-2,2-dimethyl-4-methylenetetrahydro-1,3-benzodioxol-5(4H)-ylidene]acetate | C30H38O5Si | 详情 | 详情 | |
| (XXIII) | 59870 | ethyl 2-((3R,4S,5R)-5-{[tert-butyl(diphenyl)silyl]oxy}-3,4-dihydroxy-2-methylenecyclohexylidene)acetate | C27H34O5Si | 详情 | 详情 | |
| (XXIV) | 59871 | ethyl 2-((3R,4R,5R)-3,5-bis{[tert-butyl(diphenyl)silyl]oxy}-4-hydroxy-2-methylenecyclohexylidene)acetate | C43H52O5Si2 | 详情 | 详情 |