盐酸氟桂利嗪的合成工艺改进

以氟苯和肉桂醇为起始原料,氟苯经傅克烷基化、水解、羰基还原和溴代得到双(4-氟苯基)溴甲烷,肉桂醇经氯代,再和哌嗪反应制得肉桂基哌嗪,然后与双(4-氟苯基)溴甲烷反应,最终制得产品.并做了重复性实验验证了稳定性.通过工艺条件的优化,确定合成盐酸氟桂利嗪的最佳工艺条件为:n(氟苯):n(AlCl₃):n(PEG-400)=1:1.1:0.04,45℃反应2h,n(4,4'-二氟二苯甲酮):n(硼氢化钠)=1:0.6,乙醇作溶剂,50℃保温2h,选择NBS作为4,4'-二氟二苯甲醇的溴代试剂,AIBN做引发剂,物料比为n(4,4'-二氟二苯甲醇):n(NBS):n(AIBN)=1:1:0.03,80℃反应3h,n(肉桂基氯):n(哌嗪)=1:3.5,50℃保温1.5h,粗品肉桂基哌嗪通过水洗、萃取和成盐等步骤提纯,收率达56.2%.盐酸氟桂利嗪的总收率由18.5%提高到30.0%,产物纯度在99%以上.产物结构经红外和质谱进行了表征确定.

Improved synthesis of flunarizine dihydrochloride

Flunarizine dihydrochloride was synthesized with fluorobenzene and cinnamyl alcohol as starting material; bis(4-fluorophenyl)methane bromide was formed through Friedel-Craft reaction,hydrolysis,reduction and bromination of fluorobenzene; trans-1-cinnamylpiperazine was prepared from cinnamyl alcohol and thionyl chloride,then reacted further with bis(4-fluorophenyl) methane bromide to form flunarizine dihydrochloride through chlorination and substitution reaction. Repetitive experiments were conducted to verify experiment stability. The optimal technological condition for the synthesis of flunarizine hydrochloride was found as n(fluorobenzene):n(AlCl₃):n(PEG-400)=1:1.1:0.04,stirred at 45℃ for 2h,n(bis(4-fluorophenyl)-methanone):n(sodium borohydride)=1:0.6 with ethyl alcohol as solvent,stirred at 50℃ for 2h,NBS and AIBN as the reactants,n(4,4'-difluorobenzhydrol):n(NBS):n(AIBN)=1:1:0.03,stirred at 80℃ for 3h,n(cinnamyl chloride):n(1,4-diazacyclohexane)=1:3.5,stirred at 50℃ for 1.5h,under which rough cinnamyl piperazine was purified by washing,extraction and saltification,and this single step yield was up to 56.2%,the total yield of flunarizine dihydrochloride was up to 30.0% with the purity over 99%,higher than 18.5% of original. The structure of product was characterized by IR and MS.