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【结 构 式】 
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【分子编号】49511 【品名】[(2,2-dimethylpropanoyl)oxy]methyl (6R,7R)-7-[[2-[2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]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 】C27H36N6O10S2 【 分 子 量 】668.74928 【元素组成】C 48.49% H 5.43% N 12.57% O 23.92% S 9.59% |
合成路线1
该中间体在本合成路线中的序号：(VII)Coupling of ethyl glyoxylate derivative (I) with Boc-L-Alanine (II) by means of EDC and DMAP in DMF provides compound (III), whose ethyl ester is subjected to saponification by treatment with NaOH in EtOH to furnish carboxylic acid (IV). Condensation of (IV) with methoxyamine (NH2OMe) in THF/H2O yields methoxyimino acetic acid derivative (V), which is then coupled to pivaloyloxymethyl 7-amino-3-cephem-4-carboxylate (VI) in CH2Cl2 by means of phosphorus oxychloride (POCl3) in DMF/EtOAc and N-trimethylsilylacetamide to give compound (VII). Finally, the desired compound is obtained after treatment of (VII) with TFA and anisole in CH2Cl2 for Boc removal . Alternatively, methoxyimino acetic acid derivative (V) can be converted into intermediate (VII) by coupling with 7-amino-3-cephem-4-carboxylic acid (VIII) by means of POCl3 in DMF/EtOAc and N-trimethylsilylacetamide in CH2Cl2 to provide derivative (IX), followed by condensation with iodomethyl pivalate (X) by means of potassium acetate in DMF.
| 【1】 Muro, H.; Kasai, M.; Hatano, s.; Nishimura, K.-I.; Nishizawa, S.; Kakeya, N. (Kyoto Pharmaceutical Industries, Ltd.); Cephalosporin cpds. and production thereof. EP 0497978; JP 1991204883; US 5389625; WO 9106549 . |
| 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) | 49506 | Ethyl 2-amino-4-thiazoleglyoxylate | C7H8N2O3S | 详情 | 详情 | |
| (II) | 26450 | Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid | 15761-38-3 | C8H15NO4 | 详情 | 详情 |
| (III) | 49507 | ethyl 2-[2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-4-yl]-2-oxoacetate | C15H21N3O6S | 详情 | 详情 | |
| (IV) | 49508 | 2-[2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-4-yl]-2-oxoacetic acid | C13H17N3O6S | 详情 | 详情 | |
| (V) | 49509 | 2-[2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-4-yl]-2-(methoxyimino)acetic acid | C14H20N4O6S | 详情 | 详情 | |
| (VI) | 49510 | [(2,2-dimethylpropanoyl)oxy]methyl (6R,7R)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C13H18N2O5S | 详情 | 详情 | |
| (VII) | 49511 | [(2,2-dimethylpropanoyl)oxy]methyl (6R,7R)-7-[[2-[2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C27H36N6O10S2 | 详情 | 详情 | |
| (VIII) | 49512 | (6R,7R)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C7H8N2O3S | 详情 | 详情 | |
| (IX) | 49513 | (6R,7R)-7-[[2-[2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C21H26N6O8S2 | 详情 | 详情 | |
| (X) | 11159 | iodomethyl pivalate | C6H11IO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Coupling of pivaloyloxymethyl 7-amino-3-cephem-4-carboxylate (VI) and methoxyimino acetic acid derivative (XI) by means of POCl3 and pyridine in CH2Cl2 gives compound (XII) (alternatively (XII) can be obtained by condensation of ceftizoxime (CZX) (XIII) with iodomethyl pivalate (X) in N,N-dimethylacetamide (DMAc) in the presence of dicyclohexylamine). Coupling of (XII) with Boc-L-alanine (II) by means of EDC and DMAP in CH2Cl2 gives intermediate (VII), whose Boc protecting group is removed by treatment with either HCl/isopropanol in formic acid or TFA and anisole in CH2Cl2. Yet another strategy can be followed, involving the coupling of pivaloyloxymethyl 7-amino-3-cephem-4-carboxylate (VI) with derivative (XIV) by means of Et3N in N,N-dimethylacetamide.
| 【1】 Shirahase, H.; Hatano, S.; Yoshimi, A.; Kitagawa, M.; Kasai, M.; Nishimura, K.; Kakeya, N.; AS-924, a novel bifunctional prodrug of ceftizoxime. J Antibiot 1999, 52, 5, 491. |
| 【2】 Kasai, M.; et al.; AS-924, a novel orally active bifunctional prodrug of ceftizoxime. Synthesis and relationship between physicochemical properties and oral absorption. Chem Pharm Bull 1999, 47, 8, 1081. |
| 【3】 Muro, H.; Kasai, M.; Hatano, s.; Nishimura, K.-I.; Nishizawa, S.; Kakeya, N. (Kyoto Pharmaceutical Industries, Ltd.); Cephalosporin cpds. and production thereof. EP 0497978; JP 1991204883; US 5389625; WO 9106549 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 26450 | Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid | 15761-38-3 | C8H15NO4 | 详情 | 详情 |
| (VI) | 49510 | [(2,2-dimethylpropanoyl)oxy]methyl (6R,7R)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C13H18N2O5S | 详情 | 详情 | |
| (VII) | 49511 | [(2,2-dimethylpropanoyl)oxy]methyl (6R,7R)-7-[[2-[2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C27H36N6O10S2 | 详情 | 详情 | |
| (X) | 11159 | iodomethyl pivalate | C6H11IO2 | 详情 | 详情 | |
| (XI) | 24737 | 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid | 65872-41-5 | C6H7N3O3S | 详情 | 详情 |
| (XII) | 49514 | [(2,2-dimethylpropanoyl)oxy]methyl (6R,7R)-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 | C19H23N5O7S2 | 详情 | 详情 | |
| (XIII) | 49515 | (6R,7R)-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-carboxylic acid | C13H13N5O5S2 | 详情 | 详情 | |
| (XIV) | 49516 | 2-(2-[[(2S)-2-aminopropanoyl]amino]-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl chloride | C9H11ClN4O3S | 详情 | 详情 |