LpxC抑制剂ACHN-975的合成工艺优化  

Improved Synthesis of LpxC Inhibitor ACHN-975

作　　者：杜潇楠 张国宁[1] 朱梅[1] 王明华[1] 王玉成[1] 王菊仙[1] DU Xiaonan;ZHANG Guoning;ZHU Mei;WANG Minghua;WANG Yucheng;WANG Juxian(Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences,Beijing 100050)

机构地区：[1]中国医学科学院医药生物技术研究所

出　　处：《中国医药工业杂志》2019年第5期514-519,共6页Chinese Journal of Pharmaceuticals

基　　金：国家自然科学基金青年项目(81703366);中国医学科学院医学与健康科技创新工程——协同创新团队项目(2016-I2M-3-014)

摘　　要：本研究对LpxC 抑制剂ACHN-975(1)的合成工艺进行改进。(E)-丁基-2-烯-1,4-二醇(2)经乙酰化反应得(E)- 4-羟基丁基-2-烯基乙酸酯(3)。以1.05 倍摩尔量的戴斯-马丁试剂代替10 倍摩尔量的二氧化锰,氧化3 得(E)-4-氧代丁基-2-烯基乙酸酯(4),反应时间由48 h 缩短至3 h,收率由64%提高至84%。4 经醛基保护后,以甲苯代替毒性较大的苯作溶剂,与(2R,3R)-2,3-二羟基丁二酸二异丙酯反应得(4R,5R,E)-2-(3-乙酰氧基丙-1-烯基)-1,3-二氧戊环-4,5-二羧酸二异丙酯。而后经不对称Simmons-Smith 反应、水解反应、Corey-Fuchs 反应得[(1R,2R)-2-(2,2-二溴乙烯基)环丙基]甲基乙酸酯。然后以Pd2(dba)3 和(4-MeOPh)3P 代替Pd(dba)2 和(4-MePh)3P 作催化剂,与4-乙炔基苯甲酸甲酯经 Sonogashira 偶联反应成功制得4-[[(1R,2R)-2-(乙酰氧基甲基)环丙基]丁-1,3-二炔基]苯甲酸甲酯,收率44.2%。最后经水解、缩合、脱保护、羟胺化反应制得1。优化后的工艺氧化剂用量少,反应时间短,避免了一类溶剂苯的使用,操作安全,总收率也由文献的0.26%提高至0.66%(以2 计)。The synthetic route of LpxC inhibitor ACHN-975 (1) was improved.(E)-But-2-ene-1,4-diol (2) was acetylated to obtain (E)-4-hydroxybut-2-en-1-yl acetate (3). Then compound 3 was oxidized by Dess-Martin periodinane instead of manganese dioxide to obtain (E)-4-oxobut-2-en-1-yl acetate (4). The reaction time of this step was shortened from 48 h to 3 h and the yield was increased from 64% to 84%. After an aldehyde protection, the corresponding product reacted with diisopropyl (2R,3R)-2,3-dihydroxysuccinate in low-toxic solvent toluene rather than benzene to afford diisopropyl (4R,5R,E)-2-(3-acetoxyprop-1-enyl)-1,3-dioxolane-4,5-dicarboxylate. Then the latter was subjected to Simmons-Smith reaction, hydrolysis and Corey-Fuchs reaction to prepare [(1R,2R)-2-(2,2-dibromovinyl)cyclopropyl]- methyl acetate. Then the latter reacted with methyl 4-ethynylbenzoate via Sonogashira coupling under the catalysis of high efficiency Pd2(dba)3 and (4-MeOPh)3P to produce methyl 4-[[(1R,2R)-2-(acetoxymethyl)cyclopropyl]buta-1,3- diynyl]benzoate in 44.2% yield. Then after hydrolysis, condensation, deprotection and hydroxylamine reaction, the target compound was obtained in an overall yield of 0.66%(based on 2), which was 2.5 times higher than that reported in the literature(0.26%).

关 键 词：ACHN-975 LpxC 抑制剂 抗菌药 SONOGASHIRA 偶联 工艺优化 

分 类 号：R978[医药卫生—药品] R914.5[医药卫生—药学]