CBS Reduction Synthesis Of L-phenylephrine Research

L-phenylephrine is an α1 receptor agonist drug, with vasoconstriction, which is widely used in clinical practice, and shows a trend of steady growth. This article first synthesized by using CBS new route reducing L-phenylephrine. The reaction intermediates and products were analyzed and characterized by HPLC, 1H NMR, 13 C NMR, IR.First inter-hydroxyacetophenone as a starting material, esterification reaction with acetic anhydride to generate 3-acetoxy acetophenone, then use of bromine were brominated generation α- bromo-3-acetoxy acetophenone. The effects of reaction temperature, molar ratio, pH, dropping time and other factors were investigated. The optimal conditions were: The esterification reaction temperature was 0℃, inter-hydroxyacetophenone and acetic anhydride molar ratio was 1:2, maintaining the solution pH was 7.5, acetic anhydride dropping time was 1.5h, 3- acetoxy acetophenone yield was 94.93%; The bromo reaction temperature is-6℃, 3-acetoxy acetophenone and bromine molar ratio was 1:1.05, bromine dropping time was 4h, α-bromo-3-acetoxy-acetophenone(BAAP) yield was 85%. Then use diphenyl prolinol and borane tetrahydrofuran generate CBS-H catalyst. In its catalytic action α-bromo-3-acetoxy-acetophenone(BAAP) is reduced to R-3-(2- bromo-1-hydroxyethyl) phenyl acetate, and then methylamine amination, concentrated hydrochloric acid deesterification to give L-phenylephrine hydrochloride. The effects of the reduction factors of the reaction temperature, molar ratio, addition time, amine catalyst, reflux time were investigated. Optimal conditions were: reaction temperature of the reduction was-30℃, borane and α-bromo-3-acetoxy acetophenone molar ratio was 1:1.1, α-bromo-3-acetoxy acetophenone dropwise add time was 2h, R-3-(2-bromo-1-hydroxyethyl) phenyl acetate yield was 92%, ee value was 91.02%. Amination reaction temperature is room temperature, 0.5 equivalents of cesium hydroxide as a catalyst, methylamine and R-3-(2- bromo-1-hydroxyethyl) phenyl acetate molar ratio was 30:1, R-3-(2-bromo-1-hydroxyethyl) phenyl acetate addition time was 3h, concentrated hydrochloric acid reflux time was 4h, Lphenylephrine hydrochloride yield was 89%, ee value was 85.34%. Five-step overall yield was 66.07%, the final product was 85.34% ee.Diethyl ether to recover CBS-H catalyst, the recycling rate is 94%. Then reuse experiments were carried out. When it was reused 4 times, the R-3-(2-bromo-1-hydroxye- thyl) phenyl acetate ee value is still higher than 85%.