不对称合成(S)-(-)-3-氯-1-苯基-1-丙醇和(S)-盐酸氟西汀的工艺研究

Study on asymmetric synthesis of (S)-(-)-3-chloro-1-phenyl-1-propanol and synthesis technology of (S)-fluoxetine hydrochloride

采用自制高活性面包酵母细胞不对称生物还原3-氯代苯丙酮合成高纯度(S)-(-)-3-氯-1-苯基-1-丙醇,考查了pH值、温度、反应时间、有氧无氧对反应产率和对映体过量值的影响。然后与甲胺和1-氯-4-三氟甲基苯反应制备(S)-盐酸氟西汀。结果表明,合成(S)-(-)-3-氯-1-苯基-1-丙醇的最佳工艺条件为:在无氧环境下,在pH值为7的500mL缓冲溶液中,加入3-氯代苯丙酮1.5g,D-葡萄糖30g,活化酵母30g和6mL乙醇,在23℃反应63h,最终产率为61.3%,对映体过量值大于99%。(S)-盐酸氟西汀的总收率约为61.7%(以(S)-(-)-3-氯-1-苯基-1-丙醇计)。

（S）-（-）-3-Chloro-1-phenyl-propanol was synthesized by asymmetric bioredution with highly active bread yeast cells for 3-chloropropiophenone. The method of extraction and purification and bioreduction condition were im-proved. The effects of pH value, temperature, reaction time and anaerobic or aerobic circumstance on the yield and the enantiometric excess of the product were evaluated. （S）-fluoxetine hydrochloride was synthesized with（S）-（-）-3-chlo- ro-l-phenyl-propanol, methylamine and 1-chloro-4-benzotrifluoride. Under the optimum biotransformation condition, the reaction field of （S）-（-）-3-chloro-1-phenyl-1-propanol was 61.3%, and the enantiomeric excess value was more than 99. 6%. The overall yield of （S）-fluoxetine hydrochloride was about 61.7% （based on （S）-（-）-3-chloro-l-phenyl-1-propanol ）.