Preparation Of Optical Pure Propranolol

Propranolol[1-iso-propylamino-3-(1-naphthoxy)-2-propranol],an importantβ-adrenergic blocking agent,is usually used in the treatment of hypertension and cardiovascular disorders.Currently,the commercially available propranolol is a racemic mixture,in which both S- and R-enantiomer coexist.Recently,it is found that theβ-adrenergic blocking activity of S-enantiomer is about one hudred times larger than that of R-enantiomer and S-enantiomer has a longer half life in blood,while the R-enantiomer merely have membrane stabilizing and contracepting effects.Based on their different pharmacological performances and metabolizing mechanisms,the preparation of optically pure S-propranolol and R-propranolol has been a hot topic.In this paper,two methods have been proposed for obtaining a single enantiomer of propranolol.One hand,the DL-propranolol is synthesized and then the enantiomers of propranolol separated by extraction with the l-octyl tartrate;other hand,the optically pure S-and R-propranolols are obtained by asymmetric synthesis.For the DL-propranolol synthesis,we mainly studied the synthesis of 3-(a-naphthoxy1)-1,2-epoxypropane,the important intermediate.By careful studies of factors effecting the product yield,the reaction conditions were optimized:using polyethylene glycol 400 as the phase transfer catalyst,a-naphthol reacts with epichlorohydrin under the alkaline condition(15%NaOH aq.) at 95℃for 10 h.The resulting product was characterized by IR and chemical analysis.The yield of product is 83%and the purity is 98%.Then,this product—3-(a-naphthoxy1)-1,2-epoxypropane was used as material for the preparation of the DL-propranolol.On the separation of propranolol enantiomers by extraction with l-octyl tartrate,distribution behavior of propranolol enantiomers was examined and the influences of pH value,concentrations of L-n-octyl tartrate and phosphate salt on partition coefficients(K) and separation factors(a) were investigated.The experimental results show that L-n-octyl tartrate can form more stable diasteromeric complexes with propranololⅠ(+)-enantiomer than withⅡ(-)-enantiomer.With the increase of pH value, K increases,but a decreases.With the increase of concentration of chiral selector,K increases;a increases in lower concentrations but decreases in higher concentrations. Concentration of phosphate salt also have large influence on K and a.The asymmetric synthesis of propranolol was as follow:Optically pure (S)-epichlorohydrin and(R)-3-chloro-1,2-propanediol were obtained from the kinetic hydrolysis of racemic epichlorohydrin under the catalysis of chiral salen-Co~Ⅲcomplex. Then,as a chiral reagent,through a series of reactions,(S)-epichlorohydrin was used to synthesize(S)-propranolol with yield of 80.9%and optical purity of higher than 99%. (R)-propranolol was also synthesized with yield of 74.5%and optical purity of higher than 99%by using(S)-epichlorohydrin as starting material through another route.