Studies On The Asymmetric Synthesis Of (S)-3-Chloro-1-Phenyl-1-Propanol Via An Efficient Chiral Reducing Agent

Chiral drugs have been studied more and more deeply. Drugs with different enantiomeric configurations may have quite distinct active functions. Most natural drugs exist in monoenantiomorph, while synthetical drugs always in receme. Studies on pharmacology of chiral drugs promote the research on preparation of monoenantiomorph drugs. Raceme resolution, chemical equivalent asymmetric synthesis, and catalytic asymmetric synthesis are main recent advance in preparation of optically active compounds.Tomoxetine, Fluoxetine and Nisoxetine are important anti-depressant drugs. We have studied the synthesis routes of these chiral drugs and concluded that alhough the synthesis routs are different in detail, the whole synthesis rout can be considered as three units, preparation of the chiral alcohol intermediate, methoxylation condensation reaction, and animation reaction. The preparation of the chiral alcohol intermediate is the key unit, and has been studied widely.The chrial alcohol can be prepared by raceme resolution and asymmetric reduction, however the application of preparative raceme resolution is limited due to rigorous resolving reagent and condition. It is very important and necessary to investigate a practical asymmetric synthesis method via an efficient chiral reducing agent.In this thesis, the asymmetric Synthesis of optical intermediate (S)-3-chloro-l -phenyl- 1-propanol was investigated by reducing prochiral 3-chloropropiophenone via an efficient chiral reducing agent Dissopinocampheylchloroborane, (-)-Ipc2BCl.In the research of asymmetric reduction, the analytical method by HPLC was investigated by adjusting chromatography condition. In this optimized chromatography condition we plotted standard curves of (S)-3-chloro-1-phenyl-1-propanol and 3-chloropropiophenone about the input quantity and the chromatography peak area. The process of the reduction was tracked and the influence effects of reduction reaction, such as temperature, solvent, and the reactant adding method, were investigated. The experiment results indicated that -20 ℃, THF as the solvent, 1.1-1.2: 1 as the ratio of (-)-Ipc2BCl and 3-chloropropiophenone, was the optimized reduction condition, and agitation or shake was needed to accelerate the reduction in the reaction process. The reduction process would be lasted about 7h in above condition.The product (S)-3-chloro-1-phenyl-1-propanol, by-product a...