Synthesis Of (S)-Carteolol And (S)-Metoprolol

Carteolol and Metoprolol are the importantβ-adrenergic receptor blocking agents, and they possess striking drug action of depressing blood pressure and slowering heart rate clinically.Carteolol is the first choice for treatment of primary open-angle glaucoma and ocular hypertension,and in recent years Metoprolol is the first choice for treatment of depressing blood pressure in the whole world.Carteolol and Metoprolol are optical activity compounds,and have pairs of enantiomers.Literatures show that,(S)-Carteolol and(S)-Metoprolol have a higher activity,better results and less side effects.They have a great value for development.Starting from 1,3-cyclohexanedione,5-hydroxy-3,4-dihydrocarbostyril was prepared in three steps with the total yield of 71%.In the process the novel agent of ammonolysis reaction was evaluated and the solvent of dehydrogenation reaction was replaced by the new one.The yield of the dehydrogenation reaction was rised from 68%to 83%.And Carteolol was synthesized via 5-hydroxy-3,4-dihydrocarbostyril by epichlorothydrin.The reaction conditions were optimized by experimentals.Based on that,(S)-Carteolol was synthesized that startes from 5-hydroxy-3,4-dihydrocarbostyril by(R)-epichlorohydrin and tert-butylamine treatment. The synthetic route maintains a very good three-dimensional structure of compounds, e.e.98.5%.(S)-Metoprolol was synthesized in two different methods.A method, (S)-1-[4-(2-hydroxyethyl)phenoxy]-2,3-epoxypropane was synthesized that startes from p-hydroxyphenylethanol by(R)-epichlorohydrin treatment.(S)-Metoprolol was synthesized that startes from the chiral intermediate by methyl iodide and isopropylamine treatment.Another method,it was synthesized that startes from p-(2-methoxyetyl)phenol by(R)-epichlorohydrin and isopropylamine treatment.The both synthetic routes maintain a very good three-dimensional structure of compounds,e.e.92.4%.The results showed that the facile svnthetic schemes had the characteristic of mild reaction conditions,high yields and were simple to operate.Therefore,they had significant developing value and feasibility of industrial production.