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【结 构 式】 
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【药物名称】Cefprozil, BMY-28100-03-800(monohydrate), BMY-28100, Cefzil, Procef 【化学名称】(6R,7R)-7-[(R)-2-Amino-2-(p-hydroxyphenyl)acetamido]-8-oxo-3-[(Z)-propenyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 【CA登记号】92665-29-7, 121123-17-9 (monohydrate) 【 分 子 式 】C18H19N3O5S 【 分 子 量 】389.43323 |
【开发单位】Bristol-Myers Squibb (Originator), Dompè(Marketer) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins |
合成路线1
The partial hydrolysis of 7-(phenylacetamido) cephalosporanic acid (I) followed by esterification with diphenyldyazomethane (II) gives benzhydryl 3-(hydroxymethyl)-7-(phenylacetamido)-3-cephem-4-carboxylate (III), which by reaction with PCl5 affords benzhydryl 7-amino-3-(chloromethyl)-3- cephem-4-carboxylate (IV). The condensation of (IV) with N-(tert-butoxycarbonyl)-2(R)-(4-hydroxyphenyl) glycine (V) by means of dicyclohexylcarbodiimide (DCC) yields benzhydryl 7-[(R)-2-(tert-butoxycarbonylamino)-2-(4-hydroxypheny) acetamido]-3-(chloro-methyl)-3-cephem-4-carboxylate (VI), which by reaction with NaI in acetone is converted to the corresponding iodomethyl derivative (VII).The reaction of (VII) with triphenylphosphine in ethyl acetate affords the phosphonium salt (VIII), which is submitted to a Wittig condensation with acetaldehyde to yield benzhydryl 7-[(R)-2-(tert-butoxycarbonylamino)-2-(4-hydroxyphenyl)acetamido]-3-(propenyl)-3-cephem-4-carboxylate (IX). Finally this compound is deprotected by a treatment with trifluoroacetic acid.
| 【1】 Winocour, P.; Vezina, M.; Kornbrust, D.; Sullivan, T.; Durkin, J.; Synthesis and structure-activity relationsships of a new oral cephalosporin, BMY-28100 and related compounds. J Antibiot 1987, 40, 7, 991. |
| 【2】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; CEFPROZIL. Drugs Fut 1989, 14, 6, 507. |
| 【3】 Hoshi, H.; Okumura, J.; Naito, T.; Abe, Y.; Abukari, S. (Bristol-Myers Squibb Co.); Substituted vinyl cephalosporins. DE 3402642; US 4520022 . |
| 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) | 59721 | (6R,7R)-3-[(acetyloxy)methyl]-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C18H17N2O6S | 详情 | 详情 | |
| (II) | 40585 | 1-[diazo(phenyl)methyl]benzene | C13H10N2 | 详情 | 详情 | |
| (III) | 59722 | benzhydryl (6R,7R)-3-(hydroxymethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C29H26N2O5S | 详情 | 详情 | |
| (IV) | 31135 | benzhydryl (6R,7R)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C21H19ClN2O3S | 详情 | 详情 | |
| (V) | 59723 | (2R)-2-{[(2,2-dimethylpropanoyl)oxy]amino}-2-(4-hydroxyphenyl)ethanoic acid | C13H17NO5 | 详情 | 详情 | |
| (VI) | 59724 | diphenylmethyl 3-(chloromethyl)-7-{[2-{[(2,2-dimethylpropanoyl)oxy]amino}-2-(4-hydroxyphenyl)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C34H34ClN3O7S | 详情 | 详情 | |
| (VII) | 59725 | diphenylmethyl 7-{[2-{[(2,2-dimethylpropanoyl)oxy]amino}-2-(4-hydroxyphenyl)acetyl]amino}-3-(iodomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C34H34IN3O7S | 详情 | 详情 | |
| (VIII) | 59726 | [(7-{[2-{[(2,2-dimethylpropanoyl)oxy]amino}-2-(4-hydroxyphenyl)acetyl]amino}-2-{[(diphenylmethyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl](triphenyl)phosphonium | C52H49N3O7PS | 详情 | 详情 | |
| (IX) | 59727 | diphenylmethyl 7-{[2-{[(2,2-dimethylpropanoyl)oxy]amino}-2-(4-hydroxyphenyl)acetyl]amino}-8-oxo-3-(1-propenyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C36H37N3O7S | 详情 | 详情 |