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【结 构 式】 
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【分子编号】49228 【品名】methyl 6-chloro-6-oxohexanoate 【CA登记号】 |
【 分 子 式 】C7H11ClO3 【 分 子 量 】178.61524 【元素组成】C 47.07% H 6.21% Cl 19.85% O 26.87% |
合成路线1
该中间体在本合成路线中的序号：(XIV)The reaction of adipic acid monomethyl ester (XIII) with SOCl2 gives the acyl chloride (XIV), which is brominated with NBS in carbon tetrachloride to yield 5-bromo-5-(chloroformyl)pentanoic acid methyl ester (XV). The reaction of (XV) with phenol (XVI) by means of DIEA in ethyl ether affords the mixed diester (XVII), which is reduced with tri-tert-butoxylithiumaluminum hydride in THF to provide 5-bromo-5-formylpentanoic acid methyl ester (XVIII). The cyclization of (XVIII) with chiral ethanone (XIX) by means of DIEA in hot dioxane gives the methyl ester (XX) of the target compound, which is finally hydrolyzed with NaOH in ethanol/water to obtain the target acid . The intermediate chiral ethanone (XIX) has been obtained as follows: The reaction of the chiral alcohol (VIII) with 4-hydroxybenzoic acid methyl ester (XXI) under Mitsunobu conditions (DEAD, PPh3) gives the chiral ether (XXII), which is then condensed with 2-methylpyridine (XXIII) by means of LiHMDS in THF to yield the target ethanone.
| 【1】 Sawada, K.; Tanaka, H.; Watanabe, S.; Kuroda, A.; Okada, S. (Fujisawa Pharmaceutical Co., Ltd.); Process for the preparation of indolizine derivs.. WO 9507279 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 49223 | (1R)-1-(4-isobutylphenyl)-1-butanol | C14H22O | 详情 | 详情 | |
| (XIII) | 49227 | 6-methoxy-6-oxohexanoic acid | C7H12O4 | 详情 | 详情 | |
| (XIV) | 49228 | methyl 6-chloro-6-oxohexanoate | C7H11ClO3 | 详情 | 详情 | |
| (XV) | 49229 | methyl 5-bromo-6-chloro-6-oxohexanoate | C7H10BrClO3 | 详情 | 详情 | |
| (XVI) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (XVII) | 49230 | 6-methyl 1-phenyl 2-bromohexanedioate | C13H15BrO4 | 详情 | 详情 | |
| (XVIII) | 49231 | methyl 5-bromo-6-oxohexanoate | C7H11BrO3 | 详情 | 详情 | |
| (XIX) | 49232 | 1-(4-[[(1S)-1-(4-isobutylphenyl)butyl]oxy]phenyl)-2-(2-pyridinyl)-1-ethanone | C27H31NO2 | 详情 | 详情 | |
| (XX) | 49233 | methyl 4-[1-(4-[[(1S)-1-(4-isobutylphenyl)butyl]oxy]benzoyl)-3-indolizinyl]butanoate | C34H39NO4 | 详情 | 详情 | |
| (XXI) | 10251 | methyl 4-hydroxybenzoate; Methyl p-hydroxybenzoate | 99-76-3 | C8H8O3 | 详情 | 详情 |
| (XXII) | 49234 | methyl 4-[[(1S)-1-(4-isobutylphenyl)butyl]oxy]benzoate | C22H28O3 | 详情 | 详情 | |
| (XXIII) | 17590 | 2-methylpyridine; 2-picoline | 109-06-8 | C6H7N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(LI)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 |