Synthesis Of β-blockers (S)-(-)-betaxolol Hydrochloride And (S)-(-)-metoprolol Hydrochloride

Betaxolol and metoprolol are important drugs inβ-adrenergic antagonists, the former is a stong antiglaucoma agent , and the latter one is widely used in the treatment of hypertension. The aim of this experimentation is to find a simple industrial method to preparedβ-blockers. Concerning their structure and the reported methods, we successfully synthesized the two drugs through experimental design. That offers a method for preparing compounds in the series.Herein we describe a procedure for the preparation of both enantiomers of (1). In this paper, hydrolytic kinetic resolution of epichlorohydrin catalyzed by chiral (salen) complex(1).OAc affords unreacted epoxide in highly enantioenriched form. Concerning the characteristic of hydrolytic kinetic resolution, we annihilated racemization of epichloro- hydrin by adding the strong reducing agent Vc at the end of the reaction.In this paper, we focused our efforts on improvement of aryloxypropanolamines Synthesis. After studied the reported methods, we developed a new shorter synthetic way, which contains four steps, to obtain (S)-(-)-betaxolol(32%) and (S)-(-)-metoprolol(35%) better global yield(32%). First, O-alkylation of 2-(4-hydroxy phenyl)-ethanol in the present of methyl cyanides and potassium carbonate affored (S)-(+)-1-[4-(2-hydroxyethyl) phenoxy] -2,3-epoxypropane(8) with excellent yield (94%). Compound 9 and 10,or 12 and 13 can be purified together. Concerning the similarity between betaxolol and metoprolol , we synthesized them from the same raw material and purified the intermediate with the same condition.The experimental results and data showed that the synthetic scheme had the characteristic of mild reaction condition, high yield and was simple to operate. Therefore, the synthetic technology of betaxolol and metoprolol had significant developing value and feasibility of industrial production.