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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。在-5℃,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(2R,3R)-2,3-环氧丁酸(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5～6 h制得(2R,3R)-N-乙氧羰甲基-N-(4-甲氧基苯基)-2,3-环氧丁酰胺(中间体C),收率94.3%。中间体C在六甲基二硅氮烷、氨基锂作用下环合成(3S,4S)-3-[(1R)-1-羟乙基]-4-乙氧羰基-1-对甲氧苯基-2-氮杂环丁酮(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{(3R,4R)-3-[(1R)-叔丁基二甲基硅氧乙基]-4-乙酰氧基-2-氮杂环丁酮}。总收率达到34.5%,4-AA液相色谱纯度达到99.34%。
This article studies the production process of 4-AA, a key intermediate of penem and carbapenem. At -5 ° C, L-threonine diazotises with sodium nitrite, hydrochloric acid, and sodium hydroxide and undergoes an intramolecular nucleophilic substitution reaction to produce (2R, 3R) -2,3-epoxybutyric acid ), Yield 74.5%. A (2R, 3R) -N-ethoxycarbonylmethyl-N- (4-methoxyphenyl) -2 , 3-epoxybutanamide (Intermediate C) in a yield of 94.3%. The intermediate C is cyclized to form (3S, 4S) -3 - [(1R) -1-hydroxyethyl] -4-ethoxycarbonyl-1-p-methoxybenzene under the action of lithium hexamethyldisilazane and lithium amide 2-azetidinone (Intermediate D) in 72.1% yield. Finally, the intermediate D was protected by hydroxyl, hydrolysis, oxidative decarboxylation and ozonation to obtain 4-AA {(3R, 4R) -3 - [(1R) -tert- butyldimethylsilyloxyethyl] -4 -acetoxy-2-azetidinone}. The total yield reached 34.5%, 4-AA liquid chromatography purity of 99.34%.