R(+)-和S(-)-磷酸苯丙哌林的合成及镇咳活性  

Synthesis of R(+)- and S(-)-benproperine phosphate and their antitussive activity

作　　者：李岩[1] 陈思维[2] 钟大放[1] 甘春丽[1] 闵莉[2] 孙玉明[1] 谢智勇[1] 

机构地区：[1]沈阳药科大学药物代谢与药物动力学实验室 [2]沈阳药科大学药理教研室,辽宁沈阳110016

出　　处：《中国药物化学杂志》2004年第1期19-22,共4页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金资助项目 (3 993 0 1 80 )

摘　　要：目的合成R(+) 和S(-) 磷酸苯丙哌林并考察其镇咳活性。方法以S(-) 乳酸乙酯为原料制得重要中间体S(-) 1 (2 苄基苯氧基 ) 2 丙醇。该中间体经对甲苯磺酰化后 ,与哌啶发生一次SN2反应制得R 苯丙哌林 ;与LiBr和哌啶发生两次SN2反应制得S 苯丙哌林。R 和S 苯丙哌林与磷酸成盐 ,经乙醇重结晶得R(+) 和S(-) 磷酸苯丙哌林。采用手性HPLC法测定产物的光学纯度。采用豚鼠柠檬酸致咳模型考察两对映体的镇咳活性。结果R(+) 和S(-) 磷酸苯丙哌林ee值分别为 96%和 95 %。以 3min内咳嗽次数为考察指标 ,(± ) 磷酸苯丙哌林 ,R(+) 和S(-) 磷酸苯丙哌林ED50 值分别为 1 6 1、2 3 3、2 5 4mg/kg。以随后 5min内咳嗽次数为考察指标 ,它们的ED50 值分别为 1 1 9、1 3 5、1 9 2mg/kg。结论R(+) 和S(-) 磷酸苯丙哌林均具有镇咳活性 ,但稍弱于 (± ) 磷酸苯丙哌林。Aim To study the synthesis of R (+)- and S(-) -benproperine phosphate and their antitussive activity. Methods R (+)- and S(-) -enantiomers of benproperine phosphate were synthesized by using S(-) -ethyl lactate as chiral synthon.The key intermediate,S(-) -1-[2-(phenylmethyl)phenoxy]-2-propanol,was acetylated with TsCl,followed by the S_N2-type reaction with piperidine,furnishing R -benproperine. S -benproperine was obtained by submitting the same tosylate to two consecutive S_N2-type reactions with LiBr and piperidine. R (+)- and S(-) -benproperine phosphate were recrystallized by EtOH.The optical purity was determined by chiral HPLC.The antitussive effect of the R (+)- and S(-) -enantiomers of benproperine phosphate was evaluated in comparison with that of the racemate on cough induced by 0.35 mol/L citric acid in conscious Guinea pigs .Results The ee values were 96% and 95% for R (+)- and S(-) -benproperine phosphate respectively.The ED_ 50 values(with 95% confidence intervals)were 16.1,23.3,25.4 mg/kg for the times of cough in the 3 min of challenge,and 11.9,13.5,19.2 mg/kg for the times of cough in the 5 min immediately after the challenge,for(±)-benproperine phosphate,R (+)- and S(-) -enantiomers respectively. Conclusion Benproperine phosphate racemate and R (+)- and S(-) -enantiomers,given intraperitoneally,all had marked antitussive efficacy.Among them,benproperine phosphate racemate leads to greater activity than each of the two enantiomers alone.

关 键 词：药物化学 制备 化学合成 手性药物 苯丙哌林 镇咳活性 

分 类 号：R914[医药卫生—药物化学] R96[医药卫生—药学]