【结 构 式】 ![]() |
【分子编号】26062 【品名】(4S)-4-isobutyldihydro-2(3H)-furanone 【CA登记号】 |
【 分 子 式 】C8H14O2 【 分 子 量 】142.19796 【元素组成】C 67.57% H 9.92% O 22.5% |
合成路线1
该中间体在本合成路线中的序号:(XXIX)4) The deamination of L-leucine (XXIV) with NaNO2, NaBr and H2SO4 gives 2(S)-bromo-4-methylpentanoic acid (XXV), which is esterified with tert-butyl acetate and BF3.AcOH to yield the tert-butyl ester (XXVI). The condensation of (XXVI) with the sodium salt of diethyl malonate affords the substituted malonic ester (XXVII), which is selectively hydrolyzed at the tert-butyl ester group with formic acid, giving the monoacid (XXVIII). The decarboxylative reduction of (XXVIII) with BH3 and SMe2 provides 3(S)-isobutylbutano-4-lactone (XXIX). Lactone (XXIX) is submitted to ring opening by treatment with trimethylsilyl iodide in ethanol, yielding 3(S)-(iodomethyl)-5-methylhexanoic acid ethyl ester (XXX). The reaction of (XXX) with sodium azide yields azide (XXXI), which is hydrolyzed with KOH in ethanol/water to afford the free acid (XVII). Finally, this compound is reduced to pregabalin by treatment with H2 over Pd/C.
【1】 Newhouse, B.J.; Ibrahim, P.; Burgess, L.E.; et al.; Potent selective nonpeptidic inhibitors of human lung tryptase. Proc Natl Acad Sci USA 1999, 96, 15, 8348. |
【2】 Sobieray, D.M.; Hoekstra, M.S.; Schwindt, M.A.; et al.; Chemical development of CI-1008, an enantiomerically pure anticonvulsant. Org Process Res Dev 1997, 1, 1, 26. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XVII) | 26051 | (3S)-3-(azidomethyl)-5-methylhexanoic acid | C8H15N3O2 | 详情 | 详情 | |
(XXIV) | 26057 | L-Leucine | 61-90-5 | C6H13NO2 | 详情 | 详情 |
(XXV) | 26058 | (2S)-2-bromo-4-methylpentanoic acid | C6H11BrO2 | 详情 | 详情 | |
(XXVI) | 26059 | tert-butyl (2S)-2-bromo-4-methylpentanoate | C10H19BrO2 | 详情 | 详情 | |
(XXVII) | 26060 | 2-(tert-butyl) 1,1-diethyl (2S)-4-methyl-1,1,2-pentanetricarboxylate | C17H30O6 | 详情 | 详情 | |
(XXVIII) | 26061 | (2S)-2-[2-ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]-4-methylpentanoic acid | C13H22O6 | 详情 | 详情 | |
(XXIX) | 26062 | (4S)-4-isobutyldihydro-2(3H)-furanone | C8H14O2 | 详情 | 详情 | |
(XXX) | 26063 | ethyl (3S)-3-(iodomethyl)-5-methylhexanoate | C10H19IO2 | 详情 | 详情 | |
(XXXI) | 26064 | ethyl (3S)-3-(azidomethyl)-5-methylhexanoate | C10H19N3O2 | 详情 | 详情 |