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【结 构 式】 
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【药物名称】FR-182024 【化学名称】(6R,7R)-3-(5-Methyl-1,3,4-thiadiazol-2-ylsulfanyl)-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid 【CA登记号】179034-83-4, 179035-89-3 (sodium salt) 【 分 子 式 】C18H16N4O4S3 【 分 子 量 】448.54462 |
【开发单位】Fujisawa (Originator) 【药理作用】Anti-Helicobacter Pylori Agents, Antiulcer Drugs, GASTROINTESTINAL DRUGS, Carbacephems |
合成路线1
The title compound has been prepared by two related procedures: Treatment of 3-hydroxy cephem derivative (I) with methanesulfonyl chloride and K2CO3 afforded mesylate (II), which was condensed with 2-mercapto-5-methyl-1,3,4-thiadiazole (III) in the presence of potassium tert-butoxide to give thioether (IV). The benzhydryl ester of (IV) was then deprotected by treatment with trifluoroacetic acid.
| 【1】 Tawara, S.; Sasaki, H.; Matsumoto, S.; Takasugi, H.; Yoshida, Y.; Matsumoto, Y.; Matsuda, K.; Studies of anti-Helicobacter pylori agents. Part 2: New cephem derivatives. Bioorg Med Chem 2000, 8, 9, 2317. |
| 【2】 Sasaki, H.; Takasugi, H.; Matsumoto, Y.; Yoshida, Y.; Matsuda, K.; Matsumoto, s.; Synthesis and anti-Helicobacter pylori activity of FR182024, a new cephem derivative. Bioorg Med Chem Lett 1999, 9, 21, 3123. |
| 【3】 Yoshida, Y.; Sasaki, H.; Matsuda, K.; Takasugi, H. (Fujisawa Pharmaceutical Co., Ltd.); Cephem cpds. and pharmaceutical use thereof. EP 0796263; JP 1998510258; WO 9617850 . |
| 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) | 37977 | benzhydryl (6R,7R)-3-hydroxy-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C28H24N2O5S | 详情 | 详情 | |
| (II) | 25091 | benzhydryl (6R,7R)-3-[(methylsulfonyl)oxy]-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C29H26N2O7S2 | 详情 | 详情 | |
| (III) | 37978 | 5-methyl-1,3,4-thiadiazole-2-thiol; 5-methyl-1,3,4-thiadiazol-2-ylhydrosulfide | 29490-19-5 | C3H4N2S2 | 详情 | 详情 |
| (IV) | 37979 | benzhydryl (6R,7R)-3-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C31H26N4O4S3 | 详情 | 详情 |
合成路线2
In an alternative method, benzhydryl ester (V) was cleaved with trifluoroacetic acid to give carboxylic acid (VI). After protection of (VI) by means of trimethylsilyl acetamide, the triflate group was displaced by the potassium salt of mercapto thiadiazole (III) to furnish the title compound.
| 【1】 Tawara, S.; Sasaki, H.; Matsumoto, S.; Takasugi, H.; Yoshida, Y.; Matsumoto, Y.; Matsuda, K.; Studies of anti-Helicobacter pylori agents. Part 2: New cephem derivatives. Bioorg Med Chem 2000, 8, 9, 2317. |
| 【2】 Yoshida, Y.; Okuda, S.; Sasaki, H.; Matsuda, K.; Takasugi, H. (Fujisawa Pharmaceutical Co., Ltd.); New cephem cpds. and pharmaceutical use thereof. EP 0882052; JP 2000505432; WO 9729111 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 37978 | 5-methyl-1,3,4-thiadiazole-2-thiol; 5-methyl-1,3,4-thiadiazol-2-ylhydrosulfide | 29490-19-5 | C3H4N2S2 | 详情 | 详情 |
| (V) | 37980 | benzhydryl (6R,7R)-8-oxo-7-[(2-phenylacetyl)amino]-3-[[(trifluoromethyl)sulfonyl]oxy]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C29H23F3N2O7S2 | 详情 | 详情 | |
| (VI) | 37981 | (6R,7R)-8-oxo-7-[(2-phenylacetyl)amino]-3-[[(trifluoromethyl)sulfonyl]oxy]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C16H13F3N2O7S2 | 详情 | 详情 | |
| (VII) | 37982 | trimethylsilyl (6R,7R)-8-oxo-7-[(2-phenylacetyl)amino]-3-[[(trifluoromethyl)sulfonyl]oxy]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C19H21F3N2O7S2Si | 详情 | 详情 |