【结 构 式】 |
【分子编号】17484 【品名】3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline 【CA登记号】 |
【 分 子 式 】C19H15BrFN 【 分 子 量 】356.2372432 【元素组成】C 64.06% H 4.24% Br 22.43% F 5.33% N 3.93% |
合成路线1
该中间体在本合成路线中的序号:(LXXI)8) Open form: The silylation of (S,S)-tartaric acid diisopropyl ester (LXI) with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF gives the bissilylated compound (LXII), which is condensed with the disodium salt of tert-butyl acetoacetate (LXIII) in THF, yielding (S,S)-7-(tert-butoxycarbonyl)-2,3-bis (tert-butyldimethylsilyloxy)-4,6-dioxoheptanoic acid isopropyl ester (LXIV). The selective reduction of (LXIV) with DIBAL in THF affords the monohydroxylated compound (LXV), which is further reduced with diethylmethoxyborane in THF to the dihydroxylated compound (LXVI). The protection of the OH groups of (LXVI) with 2,2-dimethoxypropane and p-toluenesulfonic acid gives the 1,3-dioxane derivative (LXVII), which is desilylated with TBAF in THF to the gem-diol (LXVIII). Oxidation of the diol (LXVIII) with sodium metaperiodate in water/ethyl ether affords the aldehyde (LXIX), which is then condensed with 2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-ylmethyl(diphenyl)phosphine oxide (LXX) by means of lithium 2,2,6,6-tetramethylpiperidine (TMPip-Li) or butyllithium in THF, giving the protected tert-butyl ester (XXII). Finally, this compound is deprotected and hydrolyzed with trifluoroacetic acid in dichloromethane. 9) The phosphine oxide (LXX) has been obtained as follows: 2-Cyclopropyl-4-(4-fluorophenyl)-3-(hydroxy-methyl)quinoline (LIX, Scheme 5) was treated with PBr3, yielding the corresponding bromomethyl derivative (LXXI), which was then treated with diphenyl(ethoxy)phosphorane in refluxing toluene.
【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
【2】 Hiyama, T.; Takahashi, K.; Minami, T.; Synthesis of artificial HMG-CoA reductase inhibitors based on the olefination strategy. Bull Chem Soc Jpn 1995, 68, 1, 364-72. |
【3】 Yanagawa, E.; Minami, T.; Obara, Y.; Kaiyama, T. (Nissan Chemical Industry, Ltd.; Sagami Chemical Research Center); Condensed pyridines mevalonolactone intermediates and their preparation method. JP 1993310700 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(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 | |
(LIX) | 17472 | [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methanol | C19H16FNO | 详情 | 详情 | |
(LXI) | 17474 | diisopropyl (2S,3S)-2,3-dihydroxybutanedioate | C10H18O6 | 详情 | 详情 | |
(LXII) | 17475 | diisopropyl (2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxybutanedioate | C16H32O6Si | 详情 | 详情 | |
(LXIII) | 17476 | disodium (1E)-1-(tert-butoxy)-1,3-butadiene-1,3-diolate | C8H12Na2O3 | 详情 | 详情 | |
(LXIV) | 17477 | 8-(tert-butyl) 1-isopropyl (2S,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-hydroxy-4,6-dioxooctanedioate | C21H38O8Si | 详情 | 详情 | |
(LXV) | 17478 | 8-(tert-butyl) 1-isopropyl (2S,3S,6R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dihydroxy-4-oxooctanedioate | C21H40O8Si | 详情 | 详情 | |
(LXVI) | 17479 | 8-(tert-butyl) 1-isopropyl (2S,3R,4S,6R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4,6-trihydroxyoctanedioate | C21H42O8Si | 详情 | 详情 | |
(LXVII) | 17480 | isopropyl (2S,3S)-3-[(4S,6R)-6-[2-(tert-butoxy)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl]-3-[[tert-butyl(dimethyl)silyl]oxy]-2-hydroxypropanoate | C24H46O8Si | 详情 | 详情 | |
(LXVIII) | 17481 | isopropyl (2S,3S)-3-[(4S,6R)-6-[2-(tert-butoxy)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl]-2,3-dihydroxypropanoate | C18H32O8 | 详情 | 详情 | |
(LXIX) | 17482 | tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate | C13H22O5 | 详情 | 详情 | |
(LXX) | 17483 | [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methyl(diphenyl)phosphine oxide; 2-cyclopropyl-3-[(diphenylphosphoryl)methyl]-4-(4-fluorophenyl)quinoline | C31H25FNOP | 详情 | 详情 | |
(LXXI) | 17484 | 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline | C19H15BrFN | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(LXXI)10) Lactone form: The reduction of 7-phenyl-3,5-dioxo-6(E)-heptenoic acid methyl ester (LXXII) with diethylmethoxyborane and NaBH4 in THF/methanol gives the (3R*,5S*,6E)-dihydroxy ester (LXXIII), which by reaction with acetone dimethylacetal and p-toluenesulfonic acid yields the acetonide (LXXIV). The ozonolysis of (LXXIV) with O3 and dimethylsulfide in methanol affords the aldehyde (LXXV), which is condensed with 2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-ylmethylphosphonic acid diethyl ester (LXXVI) by means of butyllithium to give the acetonide of the methyl ester (LXXVII). Finally, this compound is treated with trifluoroacetic acid to yield the lactone (XLVI). The phosphonate (LXXVI) has been obtained by reaction of the bromomethyl derivative (LXXI) with triethylphosphite (8).
【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
【2】 Yanagawa, E.; Minami, T.; Obara, Y.; Kaiyama, T. (Nissan Chemical Industry, Ltd.; Sagami Chemical Research Center); Condensed pyridines mevalonolactone intermediates and their preparation method. JP 1993310700 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XLVI) | 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 | |
(LXXI) | 17484 | 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline | C19H15BrFN | 详情 | 详情 | |
(LXXII) | 17485 | methyl (E)-3,5-dioxo-7-phenyl-6-heptenoate | C14H14O4 | 详情 | 详情 | |
(LXXIII) | 17486 | methyl (3R,5S,6E)-3,5-dihydroxy-7-phenyl-6-heptenoate | C14H18O4 | 详情 | 详情 | |
(LXXIV) | 17487 | methyl 2-[(4R,6S)-2,2-dimethyl-6-[(E)-2-phenylethenyl]-1,3-dioxan-4-yl]acetate | C17H22O4 | 详情 | 详情 | |
(LXXV) | 17488 | methyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate | C10H16O5 | 详情 | 详情 | |
(LXXVI) | 17489 | diethyl [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methylphosphonate | C23H25FNO3P | 详情 | 详情 | |
(LXXVII) | 64695 | methyl 2-((4R,6S)-6-{(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl}-2,2-dimethyl-1,3-dioxan-4-yl)acetate | C29H30FNO4 | 详情 | 详情 |