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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。
Objective To synthesize R (+) and S (-) benproperine phosphate and study its antitussive activity. Methods The important intermediate S (-) 1 (2 - benzylphenoxy) 2 propanol was prepared from ethyl S (-) lactate. This intermediate was p-toluenesulfonated with piperidine once SN2 reaction to produce R benproperine; and LiBr and piperidine occurred two SN2 reaction S benproperine. R and S Benproperine salified with phosphoric acid and recrystallized from ethanol to give R (+) and S (-) benproperine phosphate. The optical purity of the product was determined by chiral HPLC. Antitussive Activity of Two Enantiomers in Guinea Pig Citric Acid-Coughing Model. Results The ee values of R (+) and S (-) benproperine phosphate were 96% and 95% respectively. Taking the number of coughs within 3 min as index, the ED50 values of (±) benproperine phosphate, R (+) and S (-) benproperine phosphate were 1 6 1, 23 3 and 25 4 mg / kg, respectively. The number of cough in the following 5min as the index, their ED50 values were 1 1 9,1 3 5,1 9 2mg / kg. Conclusions R (+) and S (-) benproperine phosphate all have antitussive activity, but slightly weaker than (±) benproperine phosphate.