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在非β-内酰胺类抗菌药合成中,所需大量的6-氟萘啶酸(4),前系由6-硝基萘啶酸制得,但收率低且不稳定。现将收率易波动的Balz-Schiemann反应改在合成程序的早期而引入6-位氟,以下各步进行顺利且适于扩大制备。化合物1用48%氟硼酸和亚硝酸钠水溶液进行重氮化反应,所得无色晶状盐在甲苯中重排为氟化物2。水解脱去2的乙酰基后与乙氧基亚甲基丙二酸二乙酯(EMME)缩后得3。3不需纯化,在Dowtherm-A中回流闭环,然后用碘乙烷和碳酸钾在DMF中
In the synthesis of non-β-lactam antibiotics, a large amount of 6-fluoronitridic acid (4) was required, starting from 6-nitronixiridic acid, but the yield was low and unstable. The yield-sensitive Balz-Schiemann reaction is now introduced at the early stage of the synthesis procedure to introduce the 6-position fluorine. The following steps proceed smoothly and are suitable for extended preparation. Compound 1 was diazotized with 48% fluoroboric acid and aqueous sodium nitrite and the resulting colorless crystalline salt was rearranged to fluoride 2 in toluene. Hydrolysis to remove the acetyl group of 2 followed by reduction with diethyl ethoxymethylenemalonate (EMME) gave 3.3 without purification, refluxing in Dowtherm-A followed by cyclization with ethyl iodide and potassium carbonate In DMF