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【结 构 式】

【分子编号】15075

【品名】(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

【CA登记号】

【 分 子 式 】C19H22N8O6S2

【 分 子 量 】522.566

【元素组成】C 43.67% H 4.24% N 21.44% O 18.37% S 12.27%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(VIII)

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

该中间体在本合成路线中的序号:(VIII)

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
Extended Information