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【结 构 式】 
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【药物名称】AM-112 【化学名称】(5R,6R)-2-(4-Amino-1,1-dimethylbutyl)-6-[1(R)-hydroxyethyl]-1-oxa-2-penem-3-carboxylic acid 【CA登记号】 【 分 子 式 】C14H22N2O5 【 分 子 量 】298.34184 |
【开发单位】Amura (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, beta-Lactam Enhancers, beta-Lactamase Inhibitors, Penems |
合成路线1
The reaction of azetidinone (I) with sodium methyl mercaptan in acetonitrile gives the methylsulfanyl derivative (II), which is alkylated with para-methoxybenzyl 2-iodoacetate (III) by means of BuLi in THF to yield the azetidine-acetic acid derivative (IV). The acylation of (IV) with 5-azido-2,2-dimethylpentanoyl chloride (V) by means of LiHMDS affords the beta-oxopentanoate (VI), which is desilylated by means of TBAF and AcOH in THF to provide the 1-hydroxyethyl-azetidine (VII). The reaction of (VII) with chlorine or methyl sulphenyl chloride furnishes the chloroazetidine (VIII), which, without isolation, is cyclized by means of TEA in THF to give the precursor (IX). Finally, this compound is submitted to hydrogenation with H2 over Pd/C to provide the target aminoacid.
| 【1】 Simpson, I.N.; et al.; Broad-spectrum beta-lactamase inhibitor AM-112: Synthesis and enhancement of the in vitro activity of ceftazidime and piperacillin. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-345. |
| 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) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (II) | 61726 | (3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(methylsulfanyl)-2-azetidinone | C12H25NO2SSi | 详情 | 详情 | |
| (III) | 54841 | 4-nitrobenzyl 2-iodoacetate | C9H8INO4 | 详情 | 详情 | |
| (IV) | 54842 | 4-nitrobenzyl 2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]acetate | C21H32N2O6SSi | 详情 | 详情 | |
| (V) | 61727 | 5-azido-2,2-dimethylpentanoyl chloride | C7H12ClN3O | 详情 | 详情 | |
| (VI) | 61728 | 4-nitrobenzyl 7-azido-2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxoheptanoate | C28H43N5O7SSi | 详情 | 详情 | |
| (VII) | 61729 | 4-nitrobenzyl 7-azido-2-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxoheptanoate | C22H29N5O7S | 详情 | 详情 | |
| (VIII) | 61730 | 4-nitrobenzyl 7-azido-2-{(3S)-2-chloro-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl}-4,4-dimethyl-3-oxoheptanoate | C21H26ClN5O7 | 详情 | 详情 | |
| (IX) | 61731 | 4-nitrobenzyl (5R,6R)-3-(5-azido-1,1-dimethylpentyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C22H27N5O7 | 详情 | 详情 |