methyl 5-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]pentanoate -Drug Synthesis Database

【结构式】

【分子编号】58037

【品名】methyl 5-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]pentanoate

【CA登记号】

【分子式】C₁₂H₂₂O₄

【分子量】230.30428

【元素组成】C 62.58% H 9.63% O 27.79%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XII)

Racemic tetrahydro-2-furylmethanol (I) was converted to tosylate (II), which was further displaced by KCN to yield nitrile (III). Basic hydrolysis of nitrile (III), followed by Fischer esterification of the resultant carboxylic acid (IV) provided ethyl ester (V). Enzymatic resolution of racemic ester (V) by means of the lipase from Candida cylindracea generated a mixture of the (R)-acid (VI) and the unreacted (S)-ester (VII), which were separated by column chromatography. The desired (S) ester (VII) was then reduced to alcohol (VIII) with LiAlH4 in cold Et2O. Regioselective opening of the cyclic ether (VIII) with iodotrimethylsilane in acetone furnished the acetonide of 6-iodo-1,3-hexanediol (IX). Alkylation of benzyl methyl malonate (X) with iodide (IX) provided malonate (XI). Hydrogenolysis of the benzyl ester group of (XI), followed by thermal decarboxylation led to ester (XII). The target dihydroxy ester precursor (XIII) was then obtained by acid-catalyzed hydrolysis of the acetonide function.

参考文献中间体

合成目标

【1】 Laxmi, Y.R.S.; Iyengar, D.S.; Chemoenzymatic synthesis of methyl (6S)-(-)-6,8-dihydroxyoctanoate: A precursor to (R)-(+)-alpha-lipoic acid. Synthesis (Stuttgart) 1996, 5, 594.

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)	58026	2-(Hydroxymethyl)tetrahydrofuran; Tetrahydro-2-furancarbinol; Tetrahydro-2-furanmethanol; Tetrahydrofurfural alcohol; Tetrahydrofurfuryl alcohol	97-99-4	C₅H₁₀O₂	详情	详情
(II)	58027	Toluene-4-sulfonic acid tetrahydrofuran-2-ylmethyl ester		C₁₂H₁₆O₄S	详情	详情
(III)	58028	2-tetrahydro-2-furanylacetonitrile		C₆H₉NO	详情	详情
(IV)	58029	2-tetrahydro-2-furanylacetic acid		C₆H₁₀O₃	详情	详情
(V)	58030	methyl 2-tetrahydro-2-furanylacetate		C₇H₁₂O₃	详情	详情
(VI)	58031	2-[(2R)tetrahydro-2-furanyl]acetic acid		C₆H₁₀O₃	详情	详情
(VII)	58032	methyl 2-[(2S)tetrahydro-2-furanyl]acetate		C₇H₁₂O₃	详情	详情
(VIII)	58033	2-[(2S)tetrahydro-2-furanyl]-1-ethanol		C₆H₁₂O₂	详情	详情
(IX)	58034	(4S)-4-(3-iodopropyl)-2,2-dimethyl-1,3-dioxane		C₉H₁₇IO₂	详情	详情
(X)	58035	1-benzyl 3-methyl malonate		C₁₁H₁₂O₄	详情	详情
(XI)	58036	1-benzyl 3-methyl 2-{3-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]propyl}malonate		C₂₀H₂₈O₆	详情	详情
(XII)	58037	methyl 5-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]pentanoate		C₁₂H₂₂O₄	详情	详情
(XIII)	57977	methyl (6S)-6,8-dihydroxyoctanoate		C₉H₁₈O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXXVII)

A further procedure utilized the (S)-keto ester (XXXI) as the chiral starting material. Baeyer-Villiger oxidation of cyclohexanone (XXXI) with m-CPBA in the presence of a phosphate buffer at pH 8 provided two regioisomeric chiral lactones (XXXII) and (XXXIII), which were separated by column chromatography. The major isomer (XXXII) was subsequently reduced with LiAlH4 to furnish triol (XXXIV). The 1,3-dihydroxy moiety of (XXXIV) was then protected as the acetonide derivative (XXXV) employing 2,2-dimethoxypropane. The requisite ester (XXXVII) was prepared by stepwise oxidation of the primary alcohol (XXXV) to the aldehyde (XXXVI) using pyridinium dichromate, and then to the corresponding carboxylic acid with m-CPBA, followed by esterification with ethereal diazomethane to (XXXVII). Hydrolysis of the acetonide (XXXVII) by means of p-toluenesulfonic acid in methanol led to the target intermediate, the dihydroxy ester (XIII).

参考文献中间体

合成目标

【1】 Ganaha, M.; et al.; Synthesis of methyl (S)-(-)-6,8-dihydroxyoctanoate as a precursor of (R)-(+)-alpha-lipoic acid. Biosci Biotechnol Biochem 1999, 63, 11, 2025.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIII)	57977	methyl (6S)-6,8-dihydroxyoctanoate	C₉H₁₈O₄	详情	详情
(XXXI)	58053	methyl 2-[(1S)-2-oxocyclohexyl]acetate	C₉H₁₄O₃	详情	详情
(XXXII)	58054	methyl 2-[(2S)-7-oxooxepanyl]acetate	C₉H₁₄O₄	详情	详情
(XXXIII)	58055	methyl 2-[(3S)-2-oxooxepanyl]acetate	C₉H₁₄O₄	详情	详情
(XXXIV)	58056	(3S)-1,3,8-octanetriol	C₈H₁₈O₃	详情	详情
(XXXV)	58057	5-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-1-pentanol	C₁₁H₂₂O₃	详情	详情
(XXXVI)	58058	5-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]pentanal	C₁₁H₂₀O₃	详情	详情
(XXXVII)	58037	methyl 5-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]pentanoate	C₁₂H₂₂O₄	详情	详情

Extended Information