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【结 构 式】

【分子编号】24386

【品名】benzyl (4S)-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate

【CA登记号】

【 分 子 式 】C22H25NO4

【 分 子 量 】367.44484

【元素组成】C 71.91% H 6.86% N 3.81% O 17.42%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(IV)

The sodium salt of L-phenylalanine (I) was condensed with pivalaldehyde (II) in boiling pentane to afford imine (III). Subsequent reaction of (III) with benzyl chloroformate generated oxazolidinone (IV) as a 9:1 mixture of diastereoisomers, which were separated chromatographically. The required cis compound was treated with allyl bromide (V) in the presence of potassium hexamethyldisilazide in THF at -78 C to provide (VI) as the major isomer. Aldehyde (VII) was then obtained by ozonolysis of (VI) at -78 C. Reductive amination of (VII) with L-homophenylalanine methyl ester (VIII) using NaBH3CN yielded the corresponding amine (IX) which, upon heating in toluene in the presence of 1-hydroxybenzotriazole, afforded pyrrolidinone (X). Reduction of the ester function of (X) with Ca(BH4)2 gave alcohol (XI), which was finally oxidized under Swern conditions to the target aldehyde.

1 Scheidt, K.A.; Roush, W.R.; McKerrow, J.H.; Selzer, P.M.; Hansell, E.; Rosenthal, P.J.; Structure-based design, synthesis and evaluation of conformationally constrained cysteine protease inhibitors. Bioorg Med Chem 1998, 6, 12, 2477.
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) 13952 (S)-(-)-Phenylalanine; L-Phenylalanine 63-91-2 C9H11NO2 详情 详情
(II) 19797 Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal 630-19-3 C5H10O 详情 详情
(III) 24385 sodium (2S)-2-[[(E)-2,2-dimethylpropylidene]amino]-3-phenylpropanoate C14H18NNaO2 详情 详情
(IV) 24386 benzyl (4S)-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate C22H25NO4 详情 详情
(V) 11463 3-Bromo-1-propene; 3-Bromopropene;allyl bromide 106-95-6 C3H5Br 详情 详情
(VI) 24388 benzyl (2S,4S)-4-allyl-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate C25H29NO4 详情 详情
(VII) 24389 benzyl (2S,4R)-4-benzyl-2-(tert-butyl)-5-oxo-4-(2-oxoethyl)-1,3-oxazolidine-3-carboxylate C24H27NO5 详情 详情
(VIII) 24390 methyl (2S)-2-amino-4-phenylbutanoate C11H15NO2 详情 详情
(IX) 24391 benzyl (2S,4R)-4-benzyl-2-(tert-butyl)-4-(2-[[(1S)-1-(methoxycarbonyl)-3-phenylpropyl]amino]ethyl)-5-oxo-1,3-oxazolidine-3-carboxylate C35H42N2O6 详情 详情
(X) 24392 methyl (2S)-2-((3R)-3-benzyl-3-[[(benzyloxy)carbonyl]amino]-2-oxopyrrolidinyl)-4-phenylbutanoate C30H32N2O5 详情 详情
(XI) 24393 benzyl (3R)-3-benzyl-1-[(1S)-1-(hydroxymethyl)-3-phenylpropyl]-2-oxopyrrolidinylcarbamate C29H32N2O4 详情 详情

合成路线2

该中间体在本合成路线中的序号:(IV)

The sodium salt of L-phenylalanine (I) was condensed with pivalaldehyde (II) in boiling pentane to afford imine (III). Subsequent reaction of (III) with benzyl chloroformate generated oxazolidinone (IV) as a 9:1 mixture of diastereoisomers, which were separated chromatographically. The required cis compound was treated with allyl bromide (V) in the presence of potassium hexamethyldisilazide in THF at -78 C to provide (VI) as the major isomer. Aldehyde (VII) was then obtained by ozonolysis of (VI) at -78 C. Reductive amination of (VII) with L-homophenylalanine methyl ester (VIII) using NaBH3CN yielded the corresponding amine (IX) which, upon heating in toluene in the presence of 1-hydroxybenzotriazole, afforded pyrrolidinone (X). The carbobenzoxy group of (X) was then removed by hydrogenolysis over Pd/C, and the resulting amine was acylated with benzenesulfonyl chloride to produce sulfonamide (XI). Finally, the target aldehyde was obtained by the sequence of ester reduction of (XI) with Ca(BH4)2, followed by Swern oxidation of the resulting alcohol.

1 Scheidt, K.A.; Roush, W.R.; McKerrow, J.H.; Selzer, P.M.; Hansell, E.; Rosenthal, P.J.; Structure-based design, synthesis and evaluation of conformationally constrained cysteine protease inhibitors. Bioorg Med Chem 1998, 6, 12, 2477.
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) 13952 (S)-(-)-Phenylalanine; L-Phenylalanine 63-91-2 C9H11NO2 详情 详情
(II) 19797 Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal 630-19-3 C5H10O 详情 详情
(III) 24385 sodium (2S)-2-[[(E)-2,2-dimethylpropylidene]amino]-3-phenylpropanoate C14H18NNaO2 详情 详情
(IV) 24386 benzyl (4S)-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate C22H25NO4 详情 详情
(V) 11463 3-Bromo-1-propene; 3-Bromopropene;allyl bromide 106-95-6 C3H5Br 详情 详情
(VI) 24388 benzyl (2S,4S)-4-allyl-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate C25H29NO4 详情 详情
(VII) 24389 benzyl (2S,4R)-4-benzyl-2-(tert-butyl)-5-oxo-4-(2-oxoethyl)-1,3-oxazolidine-3-carboxylate C24H27NO5 详情 详情
(VIII) 24390 methyl (2S)-2-amino-4-phenylbutanoate C11H15NO2 详情 详情
(IX) 24391 benzyl (2S,4R)-4-benzyl-2-(tert-butyl)-4-(2-[[(1S)-1-(methoxycarbonyl)-3-phenylpropyl]amino]ethyl)-5-oxo-1,3-oxazolidine-3-carboxylate C35H42N2O6 详情 详情
(X) 24392 methyl (2S)-2-((3R)-3-benzyl-3-[[(benzyloxy)carbonyl]amino]-2-oxopyrrolidinyl)-4-phenylbutanoate C30H32N2O5 详情 详情
(XI) 24394 methyl (2S)-2-[(3R)-3-benzyl-2-oxo-3-[(phenylsulfonyl)amino]pyrrolidinyl]-4-phenylbutanoate C28H30N2O5S 详情 详情
Extended Information