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

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.