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【结 构 式】 
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【分子编号】38629 【品名】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 【CA登记号】 |
【 分 子 式 】C36H38N2O8Si 【 分 子 量 】654.7919 【元素组成】C 66.04% H 5.85% N 4.28% O 19.55% Si 4.29% |
合成路线1
该中间体在本合成路线中的序号：(VII)The bromination of 6-bromo-2-methylfluoren-9-one (I) with NBS and AIBN in refluxing CCl4 gives the 2-bromomethyl compound (II), which is treated with potassium acetate in DMF to afford the acetoxymethyl derivative (III). The hydrolysis of (III) with NaOMe in methanol provides the hydroxymethyl compound (IV), which is treated with hexamethyldistannane and Pd(PPh3)4 in refluxing toluene to give the trimethylstannyl derivative (V). The condensation of (V) with the carbapenem triflate (VI) by means of a Pd catalyst in THF yields the adduct (VII), which is condensed with 1-methylimidazole by means of Tf2O in dichloromethane affording the imidazolium derivative (IX). The desilylation of (IX) with TBAF in THF gives the 1-hydroxyethyl derivative (X), which is finally treated with H2 over Pd/C in THF/ethanol/water to obtain the target compound as an inner salt. The intermediate carbapenem triflate (VI) has been obtained by reaction of 2-oxocarbapenam (XI) with Tf2O, followed by silylation with Tes-OTf.
| 【1】 Greenlee, M.L.; Dininno, F.P.; Cama, L.D.; Heck, J.V. (Merck & Co., Inc.); 2-(9-Fluorenonyl)-carbapenem antibacterial agents. EP 0472306; JP 1993105679; US 5034384 . |
| 【2】 Greenlee, M.L.; Dininno, F.P.; Cama, L.D.; Heck, J.V. (Merck & Co., Inc.); 2-(9-Fluorenonyl)-carbapenem intermediates. US 5356889 . |
| 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) | 38623 | 6-bromo-2-methyl-9H-fluoren-9-one | C14H9BrO | 详情 | 详情 | |
| (II) | 38624 | 6-bromo-2-(bromomethyl)-9H-fluoren-9-one | C14H8Br2O | 详情 | 详情 | |
| (III) | 38625 | (6-bromo-9-oxo-9H-fluoren-2-yl)methyl acetate | C16H11BrO3 | 详情 | 详情 | |
| (IV) | 38626 | 6-bromo-2-(hydroxymethyl)-9H-fluoren-9-one | C14H9BrO2 | 详情 | 详情 | |
| (V) | 38627 | 2-(hydroxymethyl)-6-(trimethylstannyl)-9H-fluoren-9-one | C17H18O2Sn | 详情 | 详情 | |
| (VI) | 38628 | 4-nitrobenzyl (5R,6S)-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-3-[[(trifluoromethyl)sulfonyl]oxy]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C23H29F3N2O9SSi | 详情 | 详情 | |
| (VII) | 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 | |
| (VIII) | 38630 | 1-methyl-1H-imidazole | 616-47-7 | C4H6N2 | 详情 | 详情 |
| (IX) | 38631 | 1-methyl-3-[[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]-1H-imidazol-3-ium chloride | C40H43ClN4O7Si | 详情 | 详情 | |
| (X) | 38632 | 3-[[6-((5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[[(4-nitrobenzyl)oxy]carbonyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl)-9-oxo-9H-fluoren-2-yl]methyl]-1-methyl-1H-imidazol-3-ium chloride | C34H29ClN4O7 | 详情 | 详情 | |
| (XI) | 22686 | 4-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C16H16N2O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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 |