Dexfenfluramine Synthesis Process Research

Dexfenfluramine is an important antiobesity drug, which suppresses the appetite through serotoninergic system. The levo-isomer of Fenfluramine has no effect of appetite, but relates to many adverse effects. In this thesis, a practical, effective, and diastereo-controlled synthetic approach to dexfenfluramine was established and had scaled up in industry in overall yeild 54% and more than 98% optical purity. The main points of the approach are as following: 1. The equilibrium of imine (7) formation was studied through GC and NMR. The equilibrium constant was calculated and the ratio of Z-7 and E-7 was also determined via 7NMR. 2. The factor that might influence the reductive amination of 4 was studied through GC. We found the pre-mixture of 4 and 6 for a certain time was one of the most simple and effective methods to improve the chemoselectivity. 8 was purified to improve it's optical purity through convenient work-up. The diastereoselectivity of hydrogenation of 7 was discussed by conformation analysis. 3. The debenzylation of 8.HC1 was preferred to its free base. 4. The main di-ethylated by-product of last step was isolated. The ratio of substrate that might affect the yield was studied through GC. The advance about the research of anti-obesity drugs was also reviewed in this thesis.