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【结 构 式】 
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【药物名称】MC-04124 【化学名称】4(R)-(Aminomethyl)-D-prolyl-3-benzyl-D-alanine 6-quinolinylamide 【CA登记号】 【 分 子 式 】C25H29N5O2 【 分 子 量 】431.54218 |
【开发单位】Essential Therapeutics (Originator) 【药理作用】Antibacterial Activity Enhancers, Antibacterial Drugs, ANTIINFECTIVE THERAPY, Bacterial Efflux Pump Inhibitors |
合成路线1
The protected amino acid precursor (VI) was synthesized as follows. cis-4-Hydroxy-D-proline (I) was esterified with EtOH/HCl and subsequently protected as the N-Boc derivative (II). Treatment of (II) with methanesulfonyl chloride and triethylamine afforded the corresponding mesylate (III), which was displaced with NaCN in DMSO to produce nitrile (IV). Reduction of nitrile (IV) to the primary amine (V) was effected by catalytic hydrogenation over PtO2. Acylation of the free amino group of (V) with Boc2O, followed by basic hydrolysis of the ethyl ester, furnished the di-Boc-protected (aminomethyl)proline (VI).
| 【1】 Renau, T.E.; et al.; Conformationally restricted analogs of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-341. |
| 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) | 27400 | (2R,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid | C5H9NO3 | 详情 | 详情 | |
| (II) | 52877 | 1-(tert-butyl) 2-ethyl (2R,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C12H21NO5 | 详情 | 详情 | |
| (III) | 52878 | 1-(tert-butyl) 2-ethyl (2R,4R)-4-[(methylsulfonyl)oxy]-1,2-pyrrolidinedicarboxylate | C13H23NO7S | 详情 | 详情 | |
| (IV) | 52879 | 1-(tert-butyl) 2-ethyl (2R,4S)-4-cyano-1,2-pyrrolidinedicarboxylate | C13H20N2O4 | 详情 | 详情 | |
| (V) | 52880 | 1-(tert-butyl) 2-ethyl (2R,4R)-4-(aminomethyl)-1,2-pyrrolidinedicarboxylate | C13H24N2O4 | 详情 | 详情 | |
| (VI) | 52881 | (2R,4R)-1-(tert-butoxycarbonyl)-4-{[(tert-butoxycarbonyl)amino]methyl}-2-pyrrolidinecarboxylic acid | C16H28N2O6 | 详情 | 详情 |
合成路线2
Coupling of N-Boc-D-benzylalanine (VII) and 6-aminoquinoline (VIII) by means of EDC provided amide (IX). After trifluoroacetic acid-promoted Boc group cleavage in (IX), the resultant amino amide (X) was coupled with the proline derivative (VI), yielding (XI). The Boc protecting groups of (XI) were finally removed by treatment with trifluoroacetic acid.
| 【1】 Renau, T.E.; et al.; Conformationally restricted analogs of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-341. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 52881 | (2R,4R)-1-(tert-butoxycarbonyl)-4-{[(tert-butoxycarbonyl)amino]methyl}-2-pyrrolidinecarboxylic acid | C16H28N2O6 | 详情 | 详情 | |
| (VII) | 52886 | Boc-(-)-alpha-amino-4-phenylbutyric acid; Boc-D-Homophenylalanine | 82732-07-8 | C15H21NO4 | 详情 | 详情 |
| (VIII) | 52882 | 6-Aminoquinoline; 6-Quinolinamine | 580-15-4 | C9H8N2 | 详情 | 详情 |
| (IX) | 52883 | tert-butyl (1R)-3-phenyl-1-[(6-quinolinylamino)carbonyl]propylcarbamate | C24H27N3O3 | 详情 | 详情 | |
| (X) | 52884 | (2R)-2-amino-4-phenyl-N-(6-quinolinyl)butanamide | C19H19N3O | 详情 | 详情 | |
| (XI) | 52885 | tert-butyl (2R,4R)-4-{[(tert-butoxycarbonyl)amino]methyl}-2-[({(1R)-3-phenyl-1-[(6-quinolinylamino)carbonyl]propyl}amino)carbonyl]-1-pyrrolidinecarboxylate | C35H45N5O6 | 详情 | 详情 |