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【结 构 式】 
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【分子编号】17434 【品名】tert-butyl 2-[(4R,6S)-6-ethynyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate 【CA登记号】 |
【 分 子 式 】C14H22O4 【 分 子 量 】254.32628 【元素组成】C 66.12% H 8.72% O 25.16% |
合成路线1
该中间体在本合成路线中的序号：(XX)2) Lactone form: The regioselective opening of (R)-2-(tert-butyldimethylsilylethynyl)oxirane (XIV) with KCN in ethanol gives 3(S)-hydroxy-5-(tert-butyldimethylsilyl)-4-pentynenitrile (XV), which is condensed with tert-butyl bromoacetate (XVI) by means of Zn in refluxing THF to afford the 5(S)-hydroxyketoester (XVII). The controlled reduction of (XVII) with NaBH4/diethylmethoxyborane yields the 3(R),5(S)-dihydroxy ester (XVIII), which is deprotected with 2,2-dimethoxypropane and p-toluenesulfonic acid in THF/methanol to the protected heptynoic ester (XIX). The desilylation of (XIX) with tetrabutylammonium fluoride (TBAF) in THF affords the protected heptynoic ester (XX), which is condensed with 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI, see Scheme 5) to give the protected NK-104 tert-butyl ester (XXII). Finally, this compound is treated with trifluoroacetic acid in dichloromethane.
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
| 【2】 Minami, T.; Hiyama, T.; Takahashi, K.; Ohara, Y.; Synthesis of an artificial HMG-CoA reductase inhibitor NK-104 via a hydrosilylation-cross-coupling reaction. Bull Chem Soc Jpn 1995, 68, 5, 2649-56. |
| 【3】 Takahashi, K.; Minami, T.; Ohara, Y.; Hiyama, T.; A new synthesis of HMG-CoA reductase inhibitor NK-104 through hydrosilylation-cross coupling reaction. Tetrahedron Lett 1993, 34, 51, 8263-6. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 17428 | tert-butyl(dimethyl)[2-[(2R)oxiranyl]ethynyl]silane | C10H18OSi | 详情 | 详情 | |
| (XV) | 17429 | (3S)-5-[tert-butyl(dimethyl)silyl]-3-hydroxy-4-pentynenitrile | C11H19NOSi | 详情 | 详情 | |
| (XVI) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (XVII) | 17431 | tert-butyl (5S)-7-[tert-butyl(dimethyl)silyl]-5-hydroxy-3-oxo-6-heptynoate | C17H30O4Si | 详情 | 详情 | |
| (XVIII) | 17432 | tert-butyl (3R,5S)-7-[tert-butyl(dimethyl)silyl]-3,5-dihydroxy-6-heptynoate | C17H32O4Si | 详情 | 详情 | |
| (XIX) | 17433 | tert-butyl 2-((4R,6S)-6-[2-[tert-butyl(dimethyl)silyl]ethynyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate | C20H36O4Si | 详情 | 详情 | |
| (XX) | 17434 | tert-butyl 2-[(4R,6S)-6-ethynyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate | C14H22O4 | 详情 | 详情 | |
| (XXI) | 17435 | 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline | C18H13FIN | 详情 | 详情 | |
| (XXII) | 17436 | tert-butyl 2-((4R,6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate | C32H36FNO4 | 详情 | 详情 | |
| (XLIV) | 64696 | (4R,6S)-6-{(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl}-4-hydroxytetrahydro-2H-pyran-2-one | C25H22FNO3 | 详情 | 详情 |