普拉佐米星的合成工艺优化  

Improved Synthetic Process of Plazomicin

作　　者：吕裕斌 郑直 郑鹛 胡志[2] 王国平[2] LÜ Yubin;ZHENG Zhi;ZHENG Mei;HU Zhi;WANG Guoping(Hangzhou East China Pharmaceutical Group New Drug Research Institute Co.,Ltd.,Hangzhou 310011;Shanghai Institute of Pharmaceutical Industry,China State Institute of Pharmaceutical Industry,Shanghai 201203)

机构地区：[1]杭州华东医药集团新药研究院有限公司,浙江杭州310011 [2]中国医药工业研究总院上海医药工业研究院,上海201203

出　　处：《中国医药工业杂志》2020年第7期823-827,共5页Chinese Journal of Pharmaceuticals

摘　　要：本研究改进了普拉佐米星(1)的合成工艺。以西索米星(2)为起始物料,用5-甲基苯并三唑-对硝基苄氧羰基羧酸酯(3)对7′-NH2进行选择性保护,再用Boc酸酐对3′,4-NH2进行保护,直接与N-叔丁氧羰基-4-氨基-2-(S)-羟基丁酸缩合,然后对4″-NH2进行Boc保护,硫代硫酸钠脱除7′-NH2的对硝基苄氧羰基(PNZ)后与2-碘乙醇缩合、磷酸脱除所有Boc保护,得到1的磷酸盐,最后阴离子树脂脱除磷酸得到1。该工艺以3代替对硝基苄氧羰基苯并三唑羧酸酯,选择性保护7′-NH2,减少了缩合杂质的生成;用磷酸脱除Boc后加入到乙醇中直接析出1的磷酸盐固体,简化了操作,总收率26%(以2计)。The synthetic process of plazomicin(1)was improved.Sisomicin(2)as starting material reacted with 5-methylbenzotriazole-4-nitrobenzyloxycarbonyl carboxylate(3)to selectively protect on C-7’-amino,and(Boc)2O was applied for C-3’and C-4 amino protection group,then directly condensed with N-tert-butoxycarbonyl-4-amino-2-(S)-hydroxybutyric acid,followed by Boc-protecting on C-4’’amino group.The C-7’-amino was deprotected by sodium thiosulfate and condensed with 2-iodoethanol.The removal of all Boc groups was achieved using phosphoric acid to give 1 in phosphate salt.With the help of negative ion exchange resin,the final purification was accomplished to produce 1.In this study,compound 3 instead of p-nitrobenzyloxycarbonyl benzotriazole carboxylate was used for selective protecting on C-7’-amino to decrease the formation of condensation impurities.The phosphoric acid has been proved efficient for global deprotection,and ethanol was added to precipitate 1 in phosphate salt,which could simplify the operation.The total yield was 26%(based on 2).

关 键 词：普拉佐米星 西索米星 氨基糖苷 合成 工艺优化 

分 类 号：R978.1[医药卫生—药品]