methyl (5R)-6-cyano-5-hydroxy-3-oxohexanoate -Drug Synthesis Database

【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%

与该中间体有关的原料药合成路线共 1 条

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.

参考文献中间体

合成目标

【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

Extended Information