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【结 构 式】 
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【药物名称】 【化学名称】(1R,5S,6S)-2-[2(S)-[4-(Carbamoylmethyl)-4-methylhexahydro-1,4-diazepinium-1-ylcarbonyl]pyrrolidin-4(S)-ylsulfanyl]-6-[1(R)-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate hydrochloride 【CA登记号】138604-02-1 (free base), 138603-96-0 (undefined isomer; free base) 【 分 子 式 】C23H36ClN5O6S 【 分 子 量 】546.09027 |
【开发单位】Sankyo (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Carbapenems |
合成路线1
Mercaptoproline derivative (I) was condensed with N-(carbamoylmethyl)homopiperazine (II) via activation with carbonyl diimidazole to afford amide (III). The 4-methoxybenzyl group of (III) was then removed with trifluoromethanesulfonic acid in the presence of anisole and trifluoroacetic acid, and the resulting mercaptan (IV) was condensed with carbapenem phosphate (VI), (prepared from ketone (V) and diphenylphosphorochloridate), to afford thioether (VII). N-Methylation of (VII) was carried out using methyl fluorosulfonate to yield quaternary ammonium salt (VIII). Finally, the 4-nitrobenzyl ester and carbamate groups of (VIII) were eliminated by hydrogenation in the presence of Pd/C, and the target product was isolated by ion-exchange chromatography.
| 【1】 Ishikawa, K.; Kojima, K.; Miyauchi, M.; Endo, R.; Yasuda H; Kawamoto I.; Synthesis and structure-activity relationships of 1beta-methylcarbapenems with quaternary ammonium side chains. J Antibiot 1998, 51, 8, 757. |
| 【2】 Kawamoto, I.; Miyauchi, M.; Nakayama, E.; Endo, R.; Ohya, S.; Utsui, Y. (Sankyo Co., Ltd.); Carbapenem derivs. having antibiotic activity, their preparation and their use. EP 0443883; JP 1992211083; US 5310735 . |
| 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) | 26814 | (2S,4S)-4-[(4-methoxybenzyl)sulfanyl]-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid | C21H22N2O7S | 详情 | 详情 | |
| (II) | 26815 | 2-(1,4-diazepan-1-yl)acetamide | C7H15N3O | 详情 | 详情 | |
| (III) | 26816 | 4-nitrobenzyl (2S,4S)-2-[[4-(2-amino-2-oxoethyl)-1,4-diazepan-1-yl]carbonyl]-4-[(4-methoxybenzyl)sulfanyl]-1-pyrrolidinecarboxylate | C28H35N5O7S | 详情 | 详情 | |
| (IV) | 26817 | 4-nitrobenzyl (2S,4S)-2-[[4-(2-amino-2-oxoethyl)-1,4-diazepan-1-yl]carbonyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C20H27N5O6S | 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) | 13224 | 4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | 90776-59-3 | C29H27N2O10P | 详情 | 详情 |
| (VII) | 26818 | 4-nitrobenzyl (4R,5S,6S)-3-[((3S,5S)-5-[[4-(2-amino-2-oxoethyl)-1,4-diazepan-1-yl]carbonyl]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C37H43N7O12S | 详情 | 详情 | |
| (VIII) | 26819 | (1R,5S,6S)-2-[5(S)-[4-(carbamoylmethyl)-4-methylperhydro-1,4-diazepinium-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-(S)-ylsulfanyl]-6-(1(R)-hydroxyethyl)-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester fluorosulfonate; (1R,5S,6S)-2-[5(S)-[4-(carbamoylmethyl)-4-methylperhydro-1,4-diazepinium-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-(S)-ylsulfanyl]-6-(1(R)-hydroxyethyl)-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester fluorosulfonate | C38H46FN7O15S2 | 详情 | 详情 |