中试规模合成青霉烯和碳青霉烯类抗生素关键中间体4-AA

Scale-up Synthesis of Key Intermediate 4-AA of Penem and Carbapenem Antibiotics

摘要:

摘要：该文研究了青霉烯和碳青霉烯关键中间体4-AA的生产工艺。首先L-苏氨酸与亚硝酸钠、盐酸、氢氧化钠发生重氮化、分子内亲核取代反应生成中间体（A），收率74.5%。（A）再与对甲氧苯氨基乙酸乙酯（中间体B）反应制得中间体（C），收率84.3%。（C）在六甲基二硅氮烷、氨基锂作用下，发生环合反应生成中间体（D），收率72.1%。最后中间体（D）经羟基保护、水解、氧化脱羧、臭氧化脱保护基制得4-AA。总收率达到34.5%，液相纯度达到 99.34%。

Abstract:

Abstract :The synthetic process of important penem and carbapenem antibiotics intermediate 4-AA was studied. Intermediate (A) in 74.5% yield was prepared by diazotization and nucleophilic substitution reaction of L-thronine with sodium nitrite, hydrochloride acid and sodium hydroxide at -5℃. Intermediate (A) reacted with Intermediate (B) (p-methoxylphenylaminoethyl acetate) for 5 h t o give intermediate(C) in 84.3% yield. Then intermediate (D) in 72.1% yield was synthesized by cyclization reaction of intermediate(C) in the presence of hexamethyldisilazane and lithium amide. Finally, 4-AA was prepared by Hydroxyl protection agent, Hydrolysis, decarboxylation oxidation reaction and deprotection agent with ozone. The tolal yield is 34.5％, HPLC purity is 99.34%.