【结 构 式】 |
【分子编号】15447 【品名】methyl (5R)-6-cyano-5-hydroxy-3-oxohexanoate 【CA登记号】 |
【 分 子 式 】C8H11NO4 【 分 子 量 】185.17968 【元素组成】C 51.89% H 5.99% N 7.56% O 34.56% |
合成路线1
该中间体在本合成路线中的序号:(L)5) The hydrolysis of methyl (Et or Bu) 3(R)-(tert-butyldimethylsilyloxy)-4-cyanobutyrate (XXV) with NaOH gives the corresponding free acid (XXXVI), which is condensed with malonic acid mono-tert-butyl ester magnesium salt (XXXVII) by means of carbonyldiimidazole (CDI) yielding tert-butyl 5(R)-(tert-butyldimethylsilyloxy)-6-cyano-3-oxohexanoate (XXXVIII). The desilylation of (XXXVIII) with tetrabutylammonium fluoride in acetic acid affords the expected hydroxylated ketoester (XXXIX), which is reduced with diethylmethoxyborane and NaBH4 in methanol giving tert-butyl 6-cyano-3(R),5(R)-dihydroxyhexanoate (XL). The protection of the two OH groups of (XL) with acetone dimethylketal (XXIX) and methanesulfonic acid affords the 1,3-dioxane (XLI) (6), which by reduction of its CN group by hydrogenation with H2 over Pd/C gives intermediate (4R,6R)-2-[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester (XLII). 6) The (4R,6R)-2-[6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester (XLI) can also be obtained by reaction of (4R,6R)-2-[6-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester (XLVIII) with tosyl chloride to give the corresponding tosylate (XVIX), which is then treated with NaCN. 7) The tert-butyl 6-cyano-5(R)-hydroxy-3-oxohexanoate (XXXIX) can also be obtained by condensation of methyl 4-cyano-3(R)-hydroxybutyrate (L) with tert-butyl acetate (XXIII) by means of LDA in THF.
【1】 Graul, A.; Castaner, J.; Atorvastatin Calcium. Drugs Fut 1997, 22, 9, 956. |
【2】 Roth, B.D.; Baumann, K.L.; Butler, D.E.; Deering, C.F.; Mennen, K.E.; Millar, A.; Nanninga, T.N.; Palmer, C.W.; The convergent synthesis of CI-981, an optically active, highly potent, tissue selective inhibitor of HMG-CoA reductase. Tetrahedron Lett 1992, 33, 17, 2283-4. |
【3】 Brower, P.L.; Butler, D.E.; Deering, C.F.; Le, T.V.; Millar, A.; Nanninga, T.N.; Roth, B.D.; The synthesis of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for the preparation of CI-981, a highly potent, tissue selective inhibitor of HMG-CoA reductase. Tetrahedron Lett 1992, 33, 17, 2279-82. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XXIII) | 15097 | 7-[(2-aminopropyl)amino]-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C17H20FN3O3 | 详情 | 详情 | |
(XXIX) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
(XXXV) | 15437 | methyl (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-cyanobutanoate | C12H23NO3Si | 详情 | 详情 | |
(XXXVI) | 15438 | (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-cyanobutyric acid | C11H21NO3Si | 详情 | 详情 | |
(XXXVII) | 15439 | Bis(malonic acid mono-tert-butyl ester)magnesium salt | C14H22MgO8 | 详情 | 详情 | |
(XXXVIII) | 15440 | tert-butyl (5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-cyano-3-oxohexanoate | C17H31NO4Si | 详情 | 详情 | |
(XXXIX) | 15441 | tert-butyl (5R)-6-cyano-5-hydroxy-3-oxohexanoate | C11H17NO4 | 详情 | 详情 | |
(XL) | 15442 | tert-butyl (3R,5R)-6-cyano-3,5-dihydroxyhexanoate | C11H19NO4 | 详情 | 详情 | |
(XLI) | 15443 | tert-Butyl (4R,3R)-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate;tert-butyl 2-[(4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate | 125971-94-0 | C14H23NO4 | 详情 | 详情 |
(XLII) | 15444 | (4R,6R)-tert-Butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate; (4R-Cis)-1,1-Dimethylethyl-6-aminoethyl-2,2-dimethyl-1,3-dioxoane-4-acetate | 125995-13-3 | C14H27NO4 | 详情 | 详情 |
(XLVIII) | 15445 | tert-butyl 2-[(4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate | 124655-09-0 | C13H24O5 | 详情 | 详情 |
(XLIX) | 15446 | tert-butyl 2-[(4R,6S)-2,2-dimethyl-6-([[(4-methylphenyl)sulfonyl]oxy]methyl)-1,3-dioxan-4-yl]acetate | C20H30O7S | 详情 | 详情 | |
(L) | 15447 | methyl (5R)-6-cyano-5-hydroxy-3-oxohexanoate | C8H11NO4 | 详情 | 详情 |