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【结 构 式】 
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【药物名称】Cefozopran hydrochloride, SCE-2787.HCl, Firstcin 【化学名称】[6R-[6alpha,7beta(Z)]]-1-[[7-[[(5-Amino-1,2,4-thiadiazol-3-yl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1H-imidazo[1,2-b]pyridazinium chloride 【CA登记号】125905-00-2, 113981-44-5 (former CAS), 113359-04-9 (free base) 【 分 子 式 】C19H18ClN9O5S2 【 分 子 量 】551.99361 |
【开发单位】Takeda (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins |
合成路线1
This compound can be prepared by two related ways: 1) The condensation of (6R,7R)-7-amino-3-(3-oxobutyryloxy)-3-cephem-4-carboxylic acid (I) with 2-[5-(tert-butoxycarbonylamino)-1,2,4-thiadiazol-3-yl]-2(Z)-(methoxyimino)acetic acid (II), by means of PCl5 and bis(trimethylsilyl)acetamide (BSA) gives the corresponding amide (III), which is thencondensed with imidazo[1,2-b]pyridazine (IV) by means of KI in hot aqueous acetonitrile. 2) The condensation of 2-[2-(tert-butoxycarbonylamino)thiazol-4-yl]-2(Z)-(methoxyimino)acetic acid (V) with cephem compound (I) by means of PCl5 and triethylamine yields the corresponding amide (VI), which is deprotected with trifluoroacetic acid to afford free amide (III), already obtained.
| 【1】 Miyake, A.; Kondo, M.; Fujino, M. (Takeda Chemical Industries, Ltd.); Antibacterial cpds., their production and use. AU 8541700; AU 8654168; EP 0160252; EP 0203271; ES 8606363; ES 8705892; ES 8706692; ES 8707245; JP 1985231684; JP 1987149682; WO 8504879; WO 8505620; WO 8605183; WO 8605184 . |
| 【2】 Prous, J.; Castaner, J.; Cefozopran Hydrochloride. Drugs Fut 1992, 17, 9, 771. |
| 【3】 Yoshimura, Y.; Hashimoto, N.; Miyake,A.; Nishimura, T.; Yamaoka, M.; Imada, A.; Studies on condensed-heterocyclic azolium cephalosporins. IV. Synthesis and antibacterial activity of 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-alkoxyiminoacetamido]-3-(condensed-heterocyclic azolium)methyl cephalosporins including SCE-2787. J Antibiot 1992, 45, 5, 709-20. |
| 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) | 15748 | (6R,7R)-3-[(acetoacetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C12H14N2O6S | 详情 | 详情 | |
| (II) | 11757 | 2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid | C5H6N4O3S | 详情 | 详情 | |
| (III) | 15750 | (6R,7R)-3-[(acetoacetoxy)methyl]-7-[[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C17H18N6O8S2 | 详情 | 详情 | |
| (IV) | 15751 | imidazo[1,2-b]pyridazine | C6H5N3 | 详情 | 详情 | |
| (V) | 15752 | 2-[5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]-2-(methoxyimino)acetic acid | C10H14N4O5S | 详情 | 详情 | |
| (VI) | 15753 | (6R,7R)-3-[(acetoacetoxy)methyl]-7-[[2-[5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C22H26N6O10S2 | 详情 | 详情 |
合成路线2
Alternatively, the title compound can be prepared by acylation of the imidazopyridazinium cephem derivative (IX) with acid chloride (II) in the presence of NaOAc.
| 【1】 Hamamura, K.; Shinohara, H.; Kodama, M.; Kuroda, H. (Eisai Co., Ltd.); Process for the production of cephem cpds.. EP 0832893 . |