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【结 构 式】 
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【分子编号】26041 【品名】(4R,5S)-4-methyl-3-(4-methylpentanoyl)-5-phenyl-1,3-oxazolidin-2-one 【CA登记号】 |
【 分 子 式 】C16H21NO3 【 分 子 量 】275.34768 【元素组成】C 69.79% H 7.69% N 5.09% O 17.43% |
合成路线1
该中间体在本合成路线中的序号：(IV)1) 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 benzyl bromoacetate (V) by means of LDA in THF affords the (S)-adduct (VI) with >95% e.e. purity. The elimination of the chiral auxiliary with LiOH and H2O2 gives the glutaric acid monoester (VII), which is reduced with BH3/SMe2 in THF, yielding compound (VIII). The reaction of (VIII) with tosyl chloride in pyridine yields the tosylate (IX), which is treated with sodium azide in DMSO, affording the azide (X). Finally, this compound is reduced and debenzylated with H2 over Pd/C in THF.
| 【1】 Bryans, J.S.; Wustrow, D.J.; 3-Substituted GABA analogs with central nervous system activity: A review. Med Res Rev 1999, 19, 2, 149. |
| 【2】 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. |
| 【3】 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. |
| 【4】 Taylor, C.P.; Kanter, G.D.; Vartanian, M.G.; Yuen, P.; Enantioselective synthesis of PD144723: A potent stereospecific anticonvulsant. Bioorg Med Chem Lett 1994, 4, 6, 823. |
| 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 | |
| (V) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (VI) | 26042 | benzyl (3S)-5-methyl-3-[[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]carbonyl]hexanoate | C25H29NO5 | 详情 | 详情 | |
| (VII) | 26043 | (2S)-2-[2-(benzyloxy)-2-oxoethyl]-4-methylpentanoic acid | C15H20O4 | 详情 | 详情 | |
| (VIII) | 26044 | benzyl (3S)-3-(hydroxymethyl)-5-methylhexanoate | C15H22O3 | 详情 | 详情 | |
| (IX) | 26045 | benzyl (3S)-5-methyl-3-([[(4-methylphenyl)sulfonyl]oxy]methyl)hexanoate | C22H28O5S | 详情 | 详情 | |
| (X) | 26046 | benzyl (3S)-3-(azidomethyl)-5-methylhexanoate | C15H21N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)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 |