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【结 构 式】

【分子编号】57981

【品名】dimethyl 3-oxooctanedioate

【CA登记号】

【 分 子 式 】C10H16O5

【 分 子 量 】216.23404

【元素组成】C 55.55% H 7.46% O 37%

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:(LVI)

A synthetic route based on the asymmetric reduction of oxo diesters has been reported. Meldrum's acid (LII) was acylated by methyl adipoyl chloride (LI) in the presence of pyridine to produce the intermediate (LIII) which, upon alcoholysis with isobutanol, led to oxo diester (LIV). Enantioselective reduction of (LIV) by means of baker's yeast furnished the (S)-hydroxy diester (LV). Alternatively, the analogous oxo diester (LVI) was prepared by acylation of methyl acetoacetate with methyl adipoyl chloride (LI), followed by deacetylation in the presence of ammonium hydroxide. Then, asymmetric chemical reduction of (LVI) by hydrogenation in the presence of the chiral catalyst Ru2Cl4[(S)-BINAP]2 provided the (S)-hydroxy diester (LVII). Regioselective reduction of either diester (LV) or (LVII) by means of NaBH4 in refluxing THF furnished dihydroxy ester (XLVIII). After conversion of (XLVIII) to the dimesylate (XLIX), displacement with potassium thioacetate afforded the bis(acetylthio) derivative (LVIII), which was further hydrolyzed with KOH to provide dihydrolipoic acid (LIX). In a related procedure, dihydrolipoic acid (LIX) was prepared by reaction of dimesylate (XLIX) with sodium disulfide, followed by reductive treatment with NaBH4 and NaOH. The title cyclic disulfide was then obtained by oxidation of the dithiol (LIX) using oxygen in the presence of FeCl3.

1 Bringmann, G.; et al.; A short and productive synthesis of (R)-alpha-lipoic acid. Z Naturforsch B - J Chem Sci 1999, 54, 5, 655.
2 Laban, G.; Gewald, R. (Asta Medica AG); Process for the preparation of enantiomerically pure diesters of 3-hydroxyoctandioic acid by asymmetric catalytic hydrogenation. DE 19709069; EP 0863125; US 6013833 .
3 Paust, J.; Klatt, M.J.; Niebel, M. (BASF AG); Method for producing lipoic acid and dihydrolipoic acid. WO 0210151 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XLVIII) 57977 methyl (6S)-6,8-dihydroxyoctanoate C9H18O4 详情 详情
(XLIX) 57975 methyl (6S)-6,8-bis[(methylsulfonyl)oxy]octanoate C11H22O8S2 详情 详情
(LI) 49228 methyl 6-chloro-6-oxohexanoate C7H11ClO3 详情 详情
(LII) 14738 Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione;Malonic acid cyclic isopropylidene ester 2033-24-1 C6H8O4 详情 详情
(LIII) 57978 methyl 6-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-6-hydroxyhexanoate C13H18O7 详情 详情
(LIV) 57979 1-isobutyl 8-methyl 3-oxooctanedioate C13H22O5 详情 详情
(LV) 57980 1-isobutyl 8-methyl (3S)-3-hydroxyoctanedioate C13H24O5 详情 详情
(LVI) 57981 dimethyl 3-oxooctanedioate C10H16O5 详情 详情
(LVII) 57982 dimethyl (3S)-3-hydroxyoctanedioate C10H18O5 详情 详情
(LVIII) 57983 methyl (6R)-6,8-bis(acetylsulfanyl)octanoate C13H22O4S2 详情 详情
(LIX) 57984 (6R)-6,8-disulfanyloctanoic acid C8H16O2S2 详情 详情
Extended Information