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【结 构 式】 
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【药物名称】Cefoselis sulfate, FK-037, Wincef 【化学名称】5-Amino-2-[(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2(Z)-(methoxyimino)acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-ylmethyl]-1-(2-hydroxyethyl)-1H-pyrazolium sulfate (1:1) 【CA登记号】122841-12-7, 122841-10-5 (free base) 【 分 子 式 】C19H24N8O10S3 【 分 子 量 】620.64273 |
【开发单位】Fujisawa (Originator), Johnson & Johnson (Licensee) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins |
合成路线1
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 |
合成路线2
3) The condensation of 4-chloro-2(Z)-(methoxyimino)-3-oxobutyric acid (IX) with 7beta-amino-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazoliomethyl]-3-cephem-4-carboxylate (X) by means of POCl3 in DMF gives the corresponding acetamide (XI), which is then cyclized with thiourea by means of sodium acetate in water to obtain compound (VII). Finally, this compound is treated with H2SO4 to give FK-037.
| 【1】 Sakane, K.; Kawabata, K.; Ohki, H. (Fujisawa Pharmaceutical Co., Ltd.); Process for the preparation of cephalosporin cpd. JP 1992173792 . |
| 【2】 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 |
|---|---|---|---|---|---|---|
| (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) | 15077 | 4-chloro-2-(methoxyimino)-3-oxobutyric acid | C5H6ClNO4 | 详情 | 详情 | |
| (X) | 15078 | (6R,7R)-7-amino-3-[[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-2-ium-2-yl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C13H17N5O4S | 详情 | 详情 | |
| (XI) | 15079 | (6R,7R)-3-[[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-2-ium-2-yl]methyl]-7-[[4-chloro-2-(methoxyimino)-3-oxobutanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C18H21ClN6O7S | 详情 | 详情 | |
| (XII) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |