【结 构 式】 |
【分子编号】17442 【品名】2-(6-ethynyl-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid 【CA登记号】 |
【 分 子 式 】C10H14O4 【 分 子 量 】198.21876 【元素组成】C 60.59% H 7.12% O 32.29% |
合成路线1
该中间体在本合成路线中的序号:(XXVIII)3) The condensation of 3-(trimethylsilyl)propynal (XXIII) with the dialkaline salt of ethylacetoacetate (XXIV) in THF gives 5-hydroxy-3-oxo-7-(trimethylsilyl)-6-heptynoic acid ethyl ester (XXV), which is reduced with NaBH4/diethylmethoxyborane to the racemic 3,5-dihydroxy-7-(trimethylsilyl)-6-heptynoic acid ethyl ester (XXVI). The protection and desilylation of (XXVI) with 2,2-dimethoxypropane and p-toluenesulfonic acid yields the protected heptynoic ester (XXVII), which is saponified to the corresponding acid (XXVIII) with NaOH. The optical resolution of the racemic acid (XXVIII) by treatment with 1(R)-(1-naphthyl)ethylamine (XXIX) and crystallization of the diastereomeric salts affords the protected (3R,5S)-isomer (XXX), which is esterified with ethyl iodide and DBU to the corresponding ester (XXXI). The condensation of (XXXI) with 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI, see Scheme 5) by means of disiamylborane, NaOEt and PdCl2 in acetonitrile gives the protected (3R,5S)-NK-104 ethyl ester (XXXII).
【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
【2】 Iwasaki, H.; Miyachi, N.; Yanagawa, Y.; Ohara, Y.; Hiyama, T.; A novel synthetic method of HMG-CoA reductase inhibitor NK-104 via a hydroboration-cross-coupling sequence. Tetrahedron Lett 1993, 34, 51, 8267-70. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XXI) | 17435 | 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline | C18H13FIN | 详情 | 详情 | |
(XXIII) | 17437 | 2-butynal | C4H4O | 详情 | 详情 | |
(XXIV) | 17438 | lithium sodium (1E)-1-ethoxy-1,3-butadiene-1,3-diolate | C6H8LiNaO3 | 详情 | 详情 | |
(XXV) | 17439 | ethyl 5-hydroxy-3-oxo-7-(trimethylsilyl)-6-heptynoate | C12H20O4Si | 详情 | 详情 | |
(XXVI) | 17440 | ethyl 3,5-dihydroxy-7-(trimethylsilyl)-6-heptynoate | C12H22O4Si | 详情 | 详情 | |
(XXVII) | 17441 | ethyl 2-(6-ethynyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate | C12H18O4 | 详情 | 详情 | |
(XXVIII) | 17442 | 2-(6-ethynyl-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid | C10H14O4 | 详情 | 详情 | |
(XXIX) | 17443 | (1R)-1-(1-naphthyl)ethylamine; (1R)-1-(1-naphthyl)-1-ethanamine | 3886-70-2 | C12H13N | 详情 | 详情 |
(XXX) | 17444 | 2-[(4R,6S)-6-ethynyl-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid | C10H14O4 | 详情 | 详情 | |
(XXXI) | 17445 | ethyl 2-[(4R,6S)-6-ethynyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate | C12H18O4 | 详情 | 详情 | |
(XXXII) | 17446 | ethyl 2-((4R,6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate | C30H32FNO4 | 详情 | 详情 |