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【结 构 式】 
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【分子编号】38750 【品名】4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(trifluoromethyl)sulfonyl]oxy]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate 【CA登记号】 |
【 分 子 式 】C18H17F3N2O9S 【 分 子 量 】494.4022696 【元素组成】C 43.73% H 3.47% F 11.53% N 5.67% O 29.12% S 6.49% |
合成路线1
该中间体在本合成路线中的序号：(III)The cyclization of the diazo azetidinone (I) by means of a Rhodium catalyst in dichloromethane gives the -methyl-2-oxocarbapenam derivative (II), which is treated with methanesulfonic anhydride and TEA in dichloromethane yielding the enol triflate (II). The silylation of the OH group of (III) with triethylsilyl triflate and TEA affords the silyl ether (IV), which is condensed with the fluorenone boronic acid (V) by means of KOH and a Pd catalyst giving the adduct (VI) (1). The mesylation of (VI) with MsCl and TEA in dichloromethane, followed by reaction with NaI in acetone yields the iodomethyl compound (VII), which is condensed with 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide triflate (VIII) by means of silver triflate in THF/acetonitrile to afford the protected intermediate (IX). 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 (VIII) has been obtained as follows: The condensation of 1,4-diazabicyclo[2.2.2]octane (X) with 2-bromoacetamide (XI) in acetonitrile gives 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide bromide (XII), which is then treated with silver triflate in acetonitrile/methanol to yield (VIII).
| 【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) | 38749 | 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate | C17H18N4O7 | 详情 | 详情 | |
| (II) | 37720 | 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C17H18N2O7 | 详情 | 详情 | |
| (III) | 38750 | 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(trifluoromethyl)sulfonyl]oxy]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C18H17F3N2O9S | 详情 | 详情 | |
| (IV) | 38751 | 4-nitrobenzyl (4R,5R,6S)-4-methyl-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-3-[[(trifluoromethyl)sulfonyl]oxy]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C24H31F3N2O9SSi | 详情 | 详情 | |
| (V) | 38752 | 7-(hydroxymethyl)-9-oxo-9H-fluoren-3-ylboronic acid | C14H11BO4 | 详情 | 详情 | |
| (VI) | 38753 | 4-nitrobenzyl (4S,5R,6S)-3-[7-(hydroxymethyl)-9-oxo-9H-fluoren-3-yl]-4-methyl-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C37H40N2O8Si | 详情 | 详情 | |
| (VII) | 38754 | 4-nitrobenzyl (4S,5R,6S)-3-[7-(iodomethyl)-9-oxo-9H-fluoren-3-yl]-4-methyl-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C37H39IN2O7Si | 详情 | 详情 | |
| (VIII) | 30156 | 1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate | C9H16F3N3O4S | 详情 | 详情 | |
| (IX) | 38755 | 1-(2-amino-2-oxoethyl)-4-[[6-((4S,5R,6S)-4-methyl-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 | C47H55F6N5O14S2Si | 详情 | 详情 | |
| (X) | 28358 | 1,4-diazabicyclo[2.2.2]octane | 280-57-9 | C6H12N2 | 详情 | 详情 |
| (XI) | 38747 | 2-bromoacetamide | 683-57-8 | C2H4BrNO | 详情 | 详情 |
| (XII) | 38748 | 1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane bromide | C8H16BrN3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Imidazothiazole (I) is converted into methylsulfanyl derivative (II) by first reaction with EtMgBr in THF followed by treatment with MeSSO2Me. Lithiation of derivative (II) by means of BuLi in THF/hexane, followed by reaction with tributyltin chloride and LiHMDS, provides tributyltin derivative (III), which is then condensed with carbapenem derivative (VI) by means of Pd(dba)3, P(2-furyl)3 and ZnCl2 in NMP to afford (VII). (Derivative (VI) in turn can be obtained by first cyclization of the diazo compound (IV) by means of ZnBr2 and Rh2Oct4 in MeOAc/THF to provide bicyclic ketoester (V), which is finally treated with triflic anhydride (Tf2O) and DIEA in acetonitrile. The target product is finally obtained by first N-alkylation of the imidazothiazole ring of (VII) with iodoacetamide (VIII) in acetonitrile followed by deprotection of the carboxylic acid by hydrogenation over Pd/C inTHF/H2O.
| 【2】 Lynch, J.E.; Liu, T.M.-H.; Volante, R.P. (Merck & Co., Inc.); Process for synthesizing carbapenem intermediates using a rhodium catalyst and Lewis acid. US 5493018 . |
| 【1】 Sakakibara, S.; Takata, T.; Yamamoto, K.; Shitara, E.; Shibasaki, Y.; Shimizu, A.; Komiya, I.; CP5068, a new carbapenem: Synthesis and structure-activity relationships. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1236. |
| 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) | 47193 | 7-iodoimidazo[5,1-b][1,3]thiazole | C5H3IN2S | 详情 | 详情 | |
| (II) | 47194 | 7-(methylsulfanyl)imidazo[5,1-b][1,3]thiazole; imidazo[5,1-b][1,3]thiazol-7-yl methyl sulfide | C6H6N2S2 | 详情 | 详情 | |
| (III) | 47195 | 7-(methylsulfanyl)-2-(tributylstannyl)imidazo[5,1-b][1,3]thiazole; methyl 2-(tributylstannyl)imidazo[5,1-b][1,3]thiazol-7-yl sulfide | C18H32N2S2Sn | 详情 | 详情 | |
| (IV) | 38749 | 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate | C17H18N4O7 | 详情 | 详情 | |
| (V) | 22575 | 4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C17H18N2O7 | 详情 | 详情 | |
| (VI) | 38750 | 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(trifluoromethyl)sulfonyl]oxy]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C18H17F3N2O9S | 详情 | 详情 | |
| (VII) | 47196 | 4-nitrobenzyl (4S,5R)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[7-(methylsulfanyl)imidazo[5,1-b][1,3]thiazol-2-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C23H22N4O6S2 | 详情 | 详情 | |
| (VIII) | 47197 | 2-iodoacetamide | 144-48-9 | C2H4INO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Metalation of 7-iodoimidazo[5,1-b]thiazole (I) with ethylmagnesium bromide, followed by addition to 3-pyridinecarboxaldehyde (II) provides carbinol (III), which is further oxidized to ketone (IV) by means of MnO2. Lithiation of (IV) and further treatment with chlorotributyltin affords the stannyl derivative (V). The carbapenem ketone (VI) is converted into the vinyl triflate (VII) upon treatment with trifluoromethanesulfonic anhydride and diisopropyl ethylamine. Then, Stille coupling between vinyl triflate (VII) and the stannyl derivative (V) gives rise to the imidazothiazolyl carbapenem (VIII). Quaternization of the pyridine ring of (VIII) with iodoacetamide furnishes the pyridinium salt (IX). Finally the p-nitrobenzyl ester group of (IX) is removed by hydrogenolysis over Pd/C to provide the title compound
| 【1】 Shitara, E.; Yamamoto, Y.; Kano, Y.; Maruyama, T.; Takahashi, M.; Atsumi, K.; CP5609, a novel parenteral carbapenem: Synthesis and structure-activity relationships. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-319. |
| 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) | 47193 | 7-iodoimidazo[5,1-b][1,3]thiazole | C5H3IN2S | 详情 | 详情 | |
| (II) | 12849 | Nicotinaldehyde; 3-Pyridinecarboxaldehyde | 500-22-1 | C6H5NO | 详情 | 详情 |
| (III) | 62675 | imidazo[5,1-b][1,3]thiazol-7-yl(3-pyridinyl)methanol | C11H9N3OS | 详情 | 详情 | |
| (IV) | 62676 | imidazo[5,1-b][1,3]thiazol-7-yl(3-pyridinyl)methanone | C11H7N3OS | 详情 | 详情 | |
| (V) | 62677 | 3-pyridinyl[2-(tributylstannyl)imidazo[5,1-b][1,3]thiazol-7-yl]methanone | C23H33N3OSSn | 详情 | 详情 | |
| (VI) | 22575 | 4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C17H18N2O7 | 详情 | 详情 | |
| (VII) | 38750 | 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(trifluoromethyl)sulfonyl]oxy]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C18H17F3N2O9S | 详情 | 详情 | |
| (VIII) | 62678 | 4-nitrobenzyl (4S,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[7-(3-pyridinylcarbonyl)imidazo[5,1-b][1,3]thiazol-2-yl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C28H23N5O7S | 详情 | 详情 | |
| (IX) | 62679 | 1-(2-amino-2-oxoethyl)-3-{[2-((4S,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-{[(4-nitrobenzyl)oxy]carbonyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl)imidazo[5,1-b][1,3]thiazol-7-yl]carbonyl}pyridinium iodide | C30H27IN6O8S | 详情 | 详情 |