克拉维酸钾有关物质F的合成

Synthesis of the Related Substance F of Potassium Clavulanate

为了保证克拉维酸钾(1)的质量,本研究合成了欧洲药典收载的有关物质F,即4-[[[4-(2-羟乙基)-1H-吡咯-3-羰基]-氧]甲基]-1H-吡咯-3-羧酸。4-氯乙酰乙酸甲酯(2)与原甲酸三乙酯反应得4-氯-2-(二乙氧基甲基)-3-氧代丁酸甲酯(3),3与甘氨酸反应得烯胺。烯胺在乙酸酐中回流,经环合、脱羧得4-(氯甲基)-1H-吡咯-3-羧酸甲酯(5)。5和1的降解产物4-(2-羟乙基)-1H-吡咯-3-羧酸(8)反应得[4-(甲氧基羰基)-1H-吡咯-3-基]甲基4-(2-羟乙基)-1H-吡咯-3-羧酸甲酯(6),6经水解得有关物质F。产物结构经MS、1H NMR和13C NMR确证。

In order to guarantee the quality of potassium clavulanate(1), the related substance F reported in European pharmacopoeia, named 4-[[[[4-(2-hydroxyethyl)-1 H-pyrrole-3-yl]carbonyl]oxy]methyl]-1 H-pyrrole-3-carboxylic acid, was synthesized in this study. Methyl 4-chloroacetoacetate(2) reacted with triethyl orthoformate to give methyl 4-chloro-2-(diethoxymethyl)-3-oxobutanoate(3), and 3 reacted with glycine followed by the cyclization and decarboxylation in boiling acetic anhydride to give methyl 4-chloromethyl-1 H-pyrrole-3-carboxylate(5). Compound 5 reacted with 4-(2-hydroxyethyl)-1 H-pyrrole-3-carboxylic acid(8), a degradation product of 1, to give [4-(methoxycarbonyl)-1 H-pyrrole-3-yl]methyl 4-(2-hydroxyethyl)-1 H-pyrrole-3-carboxylate(6), then 6 was hydrolyzed to give the related substance F. The structure of target product was confirmed by MS, 1 H NMR and 13 C NMR.