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【结 构 式】 
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【分子编号】15443 【品名】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 【CA登记号】125971-94-0 |
【 分 子 式 】C14H23NO4 【 分 子 量 】269.34096 【元素组成】C 62.43% H 8.61% N 5.2% O 23.76% |
合成路线1
该中间体在本合成路线中的序号：(XLI)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 |
合成路线2
该中间体在本合成路线中的序号：(VII)The 6-cyanohexanoic ester (VII), intermediate in the synthesis of 180072 (see intermediate (XLI) in scheme no. 18007204a) has been obtained as follows: the reaction of 1,6-heptadien-4-ol (I) with BuLi, CO2, and I2 in THF gives the cyclic carbonate (II), which is treated with Ts-OH in acetone to yield the acetonide (III). The reaction of the iodine atom of (III) with KCN in hot DMSO affords the nitrile (IV), which is oxidized at the terminal double bond with OsO4 and NaIO4, or O3 and Me2S, to provide the carbaldehyde (V). The oxidation of (V) with CrO3/H2SO4 in acetone gives the carboxylic acid (VI), which is finally esterified with tert-butanol by means of DCC and DMAP in dichloromethane, yielding the target ester intermediate (VII).
| 【1】 Radl, S.; et al.; An improved synthesis of 1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for atorvastatin synthesis. Tetrahedron Lett 2002, 43, 11, 2087. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 56656 | 1,6-Heptadien-4-ol | 2883-45-6 | C7H12O | 详情 | 详情 |
| (II) | 56657 | (4S,6S)-4-allyl-6-(iodomethyl)-1,3-dioxan-2-one | C8H11IO3 | 详情 | 详情 | |
| (III) | 56658 | (4S,6S)-4-allyl-6-(iodomethyl)-2,2-dimethyl-1,3-dioxane | C10H17IO2 | 详情 | 详情 | |
| (IV) | 56659 | 2-[(4R,6S)-6-allyl-2,2-dimethyl-1,3-dioxan-4-yl]acetonitrile | C11H17NO2 | 详情 | 详情 | |
| (V) | 56660 | 2-[(4R,6R)-2,2-dimethyl-6-(2-oxoethyl)-1,3-dioxan-4-yl]acetonitrile | C10H15NO3 | 详情 | 详情 | |
| (VI) | 56661 | 2-[(4R,6R)-2,2-dimethyl-6-(2-nitriloethyl)-1,3-dioxan-4-yl]acetic acid | C10H15NO4 | 详情 | 详情 | |
| (VII) | 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 |