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【结 构 式】 
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【分子编号】26051 【品名】(3S)-3-(azidomethyl)-5-methylhexanoic acid 【CA登记号】 |
【 分 子 式 】C8H15N3O2 【 分 子 量 】185.22612 【元素组成】C 51.88% H 8.16% N 22.69% O 17.28% |
合成路线1
该中间体在本合成路线中的序号：(XVII)2) The reaction of 4-methylpentanoic acid (I) with SOCl2 in refluxing chloroform gives the acyl chloride (II), which is condensed with the chiral oxazolidinone (III) by means of BuLi in THF, yielding the corresponding N-acyl derivative (IV). The regioselective alkylation of (IV) with tert-butyl bromoacetate (XI) by means of LDA in THF affords the (S)-adduct (XII). The elimination of the chiral auxiliary with LiOH and H2O2 gives the glutaric acid monoester (XIII), which is reduced with BH3/SMe2 in THF, yielding compound (XIV). The reaction of (XIV) with tosyl chloride in pyridine yields the tosylate (XV), which is treated with sodium azide in DMSO, affording the azide (XVI). The hydrolysis of the tert-butyl group of (XVI) affords the free acid (XVII), which is reduced 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 |
|---|---|---|---|---|---|---|
| (I) | 25389 | 4-methylpentanoic acid | 646-07-1 | C6H12O2 | 详情 | 详情 |
| (II) | 25390 | 4-methylpentanoyl chloride | 38136-29-7 | C6H11ClO | 详情 | 详情 |
| (III) | 26040 | (4R,5S)-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C10H11NO2 | 详情 | 详情 | |
| (IV) | 26041 | (4R,5S)-4-methyl-3-(4-methylpentanoyl)-5-phenyl-1,3-oxazolidin-2-one | C16H21NO3 | 详情 | 详情 | |
| (XI) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (XII) | 26047 | tert-butyl (3S)-5-methyl-3-[[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]carbonyl]hexanoate | C22H31NO5 | 详情 | 详情 | |
| (XIII) | 25393 | (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid | C12H22O4 | 详情 | 详情 | |
| (XIV) | 26048 | tert-butyl (3S)-3-(hydroxymethyl)-5-methylhexanoate | C12H24O3 | 详情 | 详情 | |
| (XV) | 26049 | tert-butyl (3S)-5-methyl-3-([[(4-methylphenyl)sulfonyl]oxy]methyl)hexanoate | C19H30O5S | 详情 | 详情 | |
| (XVI) | 26050 | tert-butyl (3S)-3-(azidomethyl)-5-methylhexanoate | C12H23N3O2 | 详情 | 详情 | |
| (XVII) | 26051 | (3S)-3-(azidomethyl)-5-methylhexanoic acid | C8H15N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)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 |