18α(18β)-甘草次酸30位酰胺衍生物的合成工艺研究

Synthesis of 30-amined 18α(18β)-glycyrrhetinic acid derivatives

目的制备甘草次酸30位酰胺类衍生物N-β-羟乙基-18β-甘草次酸-30-酰胺(Ⅲ)和N-β-羟乙基-18α-甘草次酸-30-酰胺(IV),并优化其制备工艺。方法 18β-甘草次酸(18β-GA,Ⅰ)经高温碱催化进行构型转化反应得到18α-甘草次酸(18α-GA,Ⅱ);化合物Ⅰ、Ⅱ分别与2-氨基乙醇缩合制得目标化合物Ⅲ、Ⅳ;用常规光谱方法鉴定结构;同时考察不同种类缩合剂、溶剂量、物料比、处理方法对目标化合物产率的影响,筛选最佳制备工艺。结果目标化合物Ⅲ、Ⅳ的产率分别为63%、48%。结论确定以EDCI、HOBt、DMAP为催化系统,配料比分别为18β-GA-EDCI-HOBt-DMAP(1∶1.5∶1∶0.5)及18α-GA-EDCI-HOBt-DMAP(1∶2∶1∶0.5),二氯甲烷为溶剂,化合物Ⅲ、Ⅳ的反应时间分别为18、28h,所用工艺是制备甘草次酸30位酰胺类衍生物的较好工艺。

OBJECTIVE To synthesize two glycyrrhetinic acid （GA） 30 -amined derivatives, 18 -glycyrrhetinic acid- 30 - hydroxyethyl - amide（ 18 - GA - HEA, I ） and 18c - glycyrrhetinic acid - 30 - hydroxyethyl amide（ 18a - GA - HEA, IV ） , and to optimize the synthesis process. METHODS 18 - Glycyrrhetinic （ 18 - GA, I ） acid was converted to its optical isomer 18c - glycyrrhetinic acid（ 18α - GA, II ） by base catalysis under high temperature condition. The target compounds III and IV were obtained by the reaction of base- catalyzed condensation between 18β -GA or 18α -GA with 2 -aminoethanol. Routine spectrometric method was used for chemical structure determination. In parallel, the different condensing agents, solvents, ratio of reactants and treatment methods aiming to increase the production yield were investigated. RESULTS The two target compounds were obtained with the yield of 63 % and 48% , respectively. CONCLUSION The optimal reaction conditions for target compounds were 18 - GA - EDCI - HOBt - DMAP（ 1 ： 1.5 ： 1 ： 0.5 ） and 18c - GA - EDCI - HOBt - DMAP （ 1 ： 2 ： 1 ： 0.5 ）, respectively, with dichloromethane as slovent. The reaction time was 24 h for III and 28 h for IV, respectively.