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【结 构 式】 
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【药物名称】L-741462 【化学名称】(5R,6S)-2-[7-[4-(Carbamoylmethyl)-1,4-diazabicyclo[2.2.2]octane-1,4-diylium-1-ylmethyl]-9-oxofluoren-3-yl]-6-[1(R)-hydroxyethyl]-1-carba-2-penem-3-carboxylate chloride 【CA登记号】 【 分 子 式 】C31H33ClN4O6 【 分 子 量 】593.08486 |
【开发单位】Merck & Co. (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Carbapenems |
合成路线1
The mesylation of carbapenem (I) with MsCl and TEA in dichloromethane, followed by reaction with NaI in acetone yields the iodomethyl compound (II), which is condensed with 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide triflate (III) by means of silver triflate in THF/acetonitrile to afford the protected intermediate (IV). Finally, this compound is deprotected first with HCl in THF/water and then by hydrogenation with H2 over Rh/C The intermediate 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide triflate (III) has been obtained as follows: The condensation of 1,4-diazabicyclo[2.2.2]octane (V) with 2-bromoacetamide (VI) in acetonitrile gives 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide bromide (VII), which is then treated with silver triflate in acetonitrile/methanol to yield (III).
| 【1】 DiNinno, F.; Laub, J.B.; Greenlee, M.L.; Rouen, G.P.; Hammond, G.G.; Sundelof, J.G.; Hammond, M.L.; Huber, J.L.; Dicationic 2-fluorenylcarbapenems: Potent anti-MRS agents with improved solubility and pharmacokinetic properties. Bioorg Med Chem Lett 1999, 9, 22, 3225. |
| 【2】 Greenlee, M.L.; Dininno, F.P.; Hammond, M.L. (Merck & Co., Inc.); 1-beta-Methyl-carbapenem, compsns. containing same and methods of use. US 5451579; WO 9521841 . |
| 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) | 38629 | 4-nitrobenzyl (5R,6S)-3-[7-(hydroxymethyl)-9-oxo-9H-fluoren-3-yl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C36H38N2O8Si | 详情 | 详情 | |
| (II) | 38745 | 4-nitrobenzyl (5R,6S)-3-[7-(iodomethyl)-9-oxo-9H-fluoren-3-yl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C36H37IN2O7Si | 详情 | 详情 | |
| (III) | 30156 | 1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate | C9H16F3N3O4S | 详情 | 详情 | |
| (IV) | 38746 | 1-(2-amino-2-oxoethyl)-4-[[6-((5R,6S)-2-[[(4-nitrobenzyl)oxy]carbonyl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-en-3-yl)-9-oxo-9H-fluoren-2-yl]methyl]-1,4-diazoniabicyclo[2.2.2]octane di(trifluoromethanesulfonate) | C46H53F6N5O14S2Si | 详情 | 详情 | |
| (V) | 28358 | 1,4-diazabicyclo[2.2.2]octane | 280-57-9 | C6H12N2 | 详情 | 详情 |
| (VI) | 38747 | 2-bromoacetamide | 683-57-8 | C2H4BrNO | 详情 | 详情 |
| (VII) | 38748 | 1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane bromide | C8H16BrN3O | 详情 | 详情 |