加米霉素的合成及其晶体结构测定  

Synthesis and Crystal Structure Determination of Gamithromycin

作　　者：崔志刚 王建 甄盼盼 余贵菊 杨雪 王猛 姜淋洁 娄艳华 程雪娇 CUI Zhi-gang;WANG-Jian;ZHEN Pan-pan;YU Gui-ju;YANG-Xue;WANG Meng;JIANG Lin-jie;LOU Yan - hua;CHENG Xue-jiao(Tianjin Speerise Challenge Biotechnology Co., Ltd,Tianjin 300380,China)

机构地区：[1]天津市中升挑战生物科技有限公司,天津300380

出　　处：《中国兽药杂志》2020年第9期49-54,共6页Chinese Journal of Veterinary Drug

摘　　要：通过更换反应试剂和改变中间体的纯化方法,对加米霉素的合成进行了工艺优化,使整个反应过程更适合放大生产,且安全环保、成本更低廉。以9-脱氧-9-同型红霉素A(E)肟为原料,在碱性催化剂作用下生成9-脱氧-9-同型红霉素A(Z)肟,再经过贝克曼重排反应生成红霉素亚胺醚,然后硼氢化钠还原生成9-脱氧-8a-氮杂-8a-同型红霉素A,最后还原胺化反应得到加米霉素;并首次获得加米霉素单晶,X-射线衍射单晶结构测定表明,其结构为单斜晶系,C2空间群,具有手性,晶胞参数:a[A]=27.536(6),b[A]=9.6582(19),c[A]=18.529(4),α[°]=90,β[°]°=114.00(3),γ[°]=90,V[A3]=4501.6(15),Z=4,Dc[mg/m^3]=1.177,m[mm^–1]=0.086,F(000)=1750,GOF=1.043,Rint=0.0417,R1a,wR2b[I>2σ(I)]=0.0492,0.1291,Residuals[eA-3]=0.0564,0.1354。加米霉素晶型的确定为后续研究加米霉素制剂新剂型等方面提供了新选择。In this paper,the synthesis process of gamamycin was optimized by changing the reaction reagent and the purification method of the intermediate,so that the whole reaction process is more suitable for the scale-up production,and more safe for environmental protection and lower cost.9(Z)-9-deoxo-9-hydroxyiminoerythromycin A is generated from the starting material 9(E)-9-deoxo-9-hydroxyiminoerythromycin A in the presence of base catalyst,following by Beckmann rearrangement to give the erythromycin imines ether mixture.Then 9-deoxo-8a-aza-8a-homoerythromycin A is obtained via reduction by sodium borohydride reagent.Finally,gamithromycin is synthesized by the reductive amination.Notably,the single crystal of gamithromycin was firstly obtained and determined by X-ray single crystal diffraction study.The single crystal data demonstrates that it belongs to monoclinic crystal system and space group C2,and has chirality,with parameters:a[A]=27.536(6),b[A]=9.6582(19),c[A]=18.529(4),α[°]=90,β[°]=114.00(3),γ[°]=90,V[A3]=4501.6(15),Z=4,Dc[mg/m^3]=1.177,m[mm^-1]=0.086,F(000)=1750,GOF=1.043,Rint=0.0417,R1a,wR2b[I>2σ(I)]=0.0492,0.1291,Residuals[eA-3]=0.0564,0.1354.The determination of the crystalline structrue of gamithromycin provides new options for the subsequent study of new dosage forms of gamithromycin preparations.

关 键 词：加米霉素 合成 晶体结构 

分 类 号：S859.796[农业科学—临床兽医学]