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【结 构 式】 
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【分子编号】32662 【品名】tert-butyl (6R,7R)-3-[(acetoxy)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 】C20H25N5O7S2 【 分 子 量 】511.58 【元素组成】C 46.96% H 4.93% N 13.69% O 21.89% S 12.54% |
合成路线1
该中间体在本合成路线中的序号：(X)The methylation of ethyl 3-oxo-2-hydroxyiminobutyrate (I) with dimethyl sulfate and Na2CO3 in methanol gives ethyl 3-oxo-2-methoxyiminobutyrate (II), which is brominated with Br2 in CHCl3 to afford ethyl 4-bromo-3-oxo-2-methoxyiminobutyrate (III). The cyclization of (III) with thiourea (A) in refluxing ethanol affords ethyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (IV), which is acylated with chloroacetyl chloride in dimethylacetamide to yield ethyl 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetate (V). The hydrolysis of (V) with KOH in ethanol-water gives the corresponding free acid (VI), which is treated with PCl5 in methylene chloride to obtain the acyl chloride (VII). The condensation of tert-butyl 7-aminocephalosporanate (VIII) with (VII) by means of pyridine in methylene chloride gives tert-butyl 7-[alpha-methoxyimino-(2-chloroacetamidothiazol-4-yl)acetamido]cephalosporanate (IX), which is desacylated with thiourea and triethylbenzylammonium bromide in THF-ethanol yielding tert-butyl 7-[alpha-methoxyimino-alpha-(2-aminothiazol-4-yl)acetamido]cephalosporanate (X), which is hydrolyzed with trifluoroacetic acid to afford the free cephalosporanic acid (Xl). Finally, this compound is condensed with 1-methyl-5-mercaptotetrazol (XII) by means of NaHCO3 and triethylbenzylammoniurn bromide in water.
| 【1】 Ochiai, M.; et al.; New cephalosporin derivatives with high antibacterial activities. Chem Pharm Bull 1977, 25, 11, 3115-17. |
| 【2】 Ochiai, M.; et al.; Cephalosporin derivatives and their preparation. BE 0853545; JP 52125188; ZA 7702030 . |
| 【3】 Ochiai, M.; et al. (Takeda Chemical Industries, Ltd.); Thiazolylacetamido cephasloporin type compounds. DE 2556736; ES 464772; FR 2294690; GB 1536283; NL 7514811; US 4098888 . |
| 【4】 Serradell, M.N.; Castaner, J.; Blancafort, P.; SCE-1365. Drugs Fut 1980, 5, 3, 146. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (I) | 20853 | ethyl 2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate | C6H9NO4 | 详情 | 详情 | |
| (II) | 20854 | ethyl 2-(methoxyimino)-3-oxobutanoate | C7H11NO4 | 详情 | 详情 | |
| (III) | 10181 | ethyl 4-bromo-2-(methoxyimino)-3-oxobutanoate | 60845-87-6 | C7H10BrNO4 | 详情 | 详情 |
| (IV) | 10182 | Ethyl 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetate; 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic acid ethyl ester | 64485-88-7 | C8H11N3O3S | 详情 | 详情 |
| (V) | 20859 | ethyl 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetate | C10H12ClN3O4S | 详情 | 详情 | |
| (VI) | 20860 | 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetic acid | 64486-18-6 | C8H8ClN3O4S | 详情 | 详情 |
| (VII) | 32659 | 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl chloride | 75532-64-8 | C8H7Cl2N3O3S | 详情 | 详情 |
| (VIII) | 32660 | tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C14H20N2O5S | 详情 | 详情 | |
| (IX) | 32661 | tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-[[2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C22H26ClN5O8S2 | 详情 | 详情 | |
| (X) | 32662 | tert-butyl (6R,7R)-3-[(acetoxy)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 | C20H25N5O7S2 | 详情 | 详情 | |
| (XI) | 29686 | (6R,7R)-3-[(acetoxy)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-carboxylic acid | C16H17N5O7S2 | 详情 | 详情 | |
| (XII) | 28420 | 5-Mercapto-1-methyl-1H-tetrazole; 1-Methyl-1H-1,2,3,4-tetraazol-5-ylhydrosulfide | 13183-79-4 | C2H4N4S | 详情 | 详情 |