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【结 构 式】 
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【分子编号】15072 【品名】(6R,7R)-7-amino-3-[[5-amino-2-chloro-1-(2-hydroxyethyl)-1H-2lambda(5)-pyrazol-2-yl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 【CA登记号】 |
【 分 子 式 】C33H36IN5O8S 【 分 子 量 】789.64821 【元素组成】C 50.19% H 4.6% I 16.07% N 8.87% O 16.21% S 4.06% |
合成路线1
该中间体在本合成路线中的序号：(V)FK-037 can be obtained by related ways: 1) The formylation of 5-amino-1-(2-hydroxyethyl)pyrazole (I) with formic acid - acetic anhydride gives 5-formamido-1-(2-hydroxyethyl)pyrazole (II), which is condensed with 7beta-(tert-butoxycarbonylamino)-3-(chloromethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester (III) by means of NaI in DMF, yielding 7beta-(tert-butoxycarbonylamino)-3-[3-formamido-2-(2-formyloxyethyl)-1-pyrazoliomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester iodide (IV). The treatment of (IV), first with trifluoroacetic acid and anisole and then with HCl, affords 7beta-amino-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazoliomethyl]-3-cephem-4-carboxylic acid chloride (V). The condensation of (V) with 2-(2-formamidothiazol-4-yl)-2(Z)-(methoxyimino)acetic acid (VI) by means of POCl3 in ethyl acetate gives 3-[3-amino-2-(2-hydroxyethyl)-1-pyrazoliomethyl]-7beta-[2-(2-formamido-thiazol-4-yl)-2(Z)-(methoxyimino)acetamido]-3-cephem-4-carboxylate (VII), which is deformylated with HCl affording 3-[3-amino-2-(2-hydroxyethyl)-1-pyrazoliomethyl]-7beta-[2-(2-aminothiazol-4-yl)-2(Z)-(methoxyimino)acetamido]-3-cephem-4-carboxylate (VIII). Finally, this compound is treated with H2SO4 to give FK-037. 2) Compound (VIII) can also be obtained by condensation of (V) with 1-[2-(2-aminothiazol-4-yl)-2(Z)-(methoxyimino)acetyl]benzo- triazole-3-oxide (IX) in THF.
| 【1】 Sakane, K.; Kawabata, K.; Miyai, K.; Inamoto, Y. (Fujisawa Pharmaceutical Co., Ltd.); New cephem cpd. and process for preparation thereof. AU 8822271; EP 0307804; JP 1989151589; US 4952578 . |
| 【2】 Sakane, K.; Kawabata, K.; Ohki, H. (Fujisawa Pharmaceutical Co., Ltd.); Process for the preparation of cephalosporin cpd. JP 1992173792 . |
| 【3】 Ohki, H.; Kawabata, K.; Okuda, S.; Kamimura, T.; Sakane, K.; FK037, a new parenteral cephalosporin with a broad antibacterial spectrum: Synthesis and antibacterial activity. J Antibiot 1993, 46, 2, 359. |
| 【4】 Prous, J.; Graul, A.; Castaner, J.; FK-037. Drugs Fut 1994, 19, 4, 325. |
| 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) | 15068 | 2-(5-amino-1H-pyrazol-1-yl)-1-ethanol | C5H9N3O | 详情 | 详情 | |
| (II) | 15069 | 2-[5-(formylamino)-1H-pyrazol-1-yl]ethyl formate | C7H9N3O3 | 详情 | 详情 | |
| (III) | 15070 | benzhydryl (6R,7R)-7-[(tert-butoxycarbonyl)amino]-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C26H27ClN2O5S | 详情 | 详情 | |
| (IV) | 15071 | benzhydryl (6R,7R)-7-[(tert-butoxycarbonyl)amino]-3-([5-(formylamino)-1-[2-(formyloxy)ethyl]-2-iodo-1H-2lambda(5)-pyrazol-2-yl]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C33H36IN5O8S | 详情 | 详情 | |
| (V) | 15072 | (6R,7R)-7-amino-3-[[5-amino-2-chloro-1-(2-hydroxyethyl)-1H-2lambda(5)-pyrazol-2-yl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C33H36IN5O8S | 详情 | 详情 | |
| (VI) | 15073 | 2-(2-Formamidothiazole-4-yl)-2-methoxyimino acetic acid; 2-[2-(formylamino)-1,3-thiazol-4-yl]-2-(methoxyimino)acetic acid | 83594-38-1 | C7H7N3O4S | 详情 | 详情 |
| (VII) | 15074 | (6R,7R)-3-[[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-2-ium-2-yl]methyl]-7-[[2-[2-(formylamino)-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C20H22N8O7S2 | 详情 | 详情 | |
| (VIII) | 15075 | (6R,7R)-3-[[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-2-ium-2-yl]methyl]-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C19H22N8O6S2 | 详情 | 详情 | |
| (IX) | 15076 | 3-[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]-3H-1,2,3-benzotriazol-1-ium-1-olate | C12H10N6O3S | 详情 | 详情 |