Synthetic Process Research Of Chiral Bisoprolol Fumarate

Bisoprolol fumarate is a new generation of selectiveβ1-adrenergic receptor blocking agent, and it has a highly selectivity, has become one of the preferred drugs for treatment of primary hypertension and angina pectoris. Bisoprolol fumarate has one chiral center, and pairs of enantiomers, respectively for the R/S configuration. At present, the drug in research of clinical medicine, pharmacology and toxicology is supplyed by racemic mixture form. It is reported in the literatures, the (S)-enantiomer of bisoprolol fumarate exhibits the activity to blockβ-adrenergic receptors 80 times as large as that of the (R)-enantiomer, the bioavailability of (S)-enantiomer is 1.5 times higher than that of (R)-enantiomer.Based on they have different of pharmacologicals and toxicologicals. In this paper, we designed a new synthetic route, firstly (R)-epichlorohydrin was used as chiral reagent to directly react with 4-[(2-isoproxyethoxy)-methyl]-phenol, then further reacted with isopropylamine, finally reacted with fumarate, gived the target product (S)-bisoprolol fumarate, and used the same method to be (R)-bisoprolol fumarate. The enantiomeric excess value of intermediates and chiral bisoprolol fumarate were determined by HPLC with a chiral column, and discussed the effects of concentration of the alcoholic modifier and temperature on the separation capability.Through optimization of the experimental conditions obtained better proeesses conditions for each step of the synthesis.The optimum synthesis conditions of (R)-and (S)-2-[(4-((2-isopropoxyethoxy) -methyl)-phenoxy)-methyl]-oxirane was as follows: the molar ratio of 4-[(2-isoproxy ethoxy)-methyl]-phenol, optically pure epichlorohydrin and NaOH was 1:1.1:1.1, with water as solvent, reaction temperature was 65-70℃, and reaction time was 4 h. Under these conditions, the yield was up to 83.7 % and the optical purity was higher than 92 %.The optimum synthesis conditions of (R)-and (S)-bisoprolol was as follows: with methanol and isopropylamine as solvent, the reaction temperature was 40-45℃, and the reaction time was 3 h. Under these conditions, the yield was 86.2 % and the optical purity was higher than 92 %.The optimum synthesis conditions of (R)-and (S)-bisoprolol fumarate was as follows: the molar ratio of (R)-and (S)-bisoprolol and fumarate was 2:1, with acetone as solvent, reflux for 3 h, stir for 1 h at room temperature, and cooled to 0-5℃, the yield was up to 84.3 % and the optical purity was higher than 92 %.The synthetic route had the characteristic of mild reaction conditions, simple operation, high yield and good optical purity, was the most direct way to synthesize bisoprolol fumarate, and had significant developing value and feasibility for industrial application.