Synthesis Of 1,3-disubstituted-2-propanols And Chiral Resolution Of Racemic Sibutramine

With the improvement of science and technology, new diseases continue to be discovered, requiring the continuous upgrading of treatments. Therefore, the synthesis of pharmaceutical intermediates and resolution of racemic compounds in drug synthesis plays an important role.The first part of this thesis focus on the synthesis of 1,3-disubstituted-2-propanols and their derivatives. They are important synthetic intermediates and their derivatives played an important role in organic chemistry due to their extensive applications. For example, some nucleoside analogues synthesized from them as the starting materials show certain antiviral activities, such as anti-HIV, anti-herpes virus and anti-human cytomegalovirus and so on. In this part, an efficient and practical route was used for the preparation of 1,3-disubstituted-2-propanols by bimolecular nucleophilic substitution and ring-opening reaction between epichlorohydrin and benzyl alcohol in the presence of KOH under solvent-free conditions at room temperature.The effects of alkaline catalyst, the amount of water, mole ratio of material and other related factors on the final yield of the product were investigated in order to find the optimal reaction conditions. In addition, by extending various substituted alcohols a series of 1,3-disubstituted-2-propanols were synthesized. Their structures are confirmed by IR,1H NMR and 13C NMR. Furthermore, we also studied the oxidation of 1,3-benzyloxy-2-propanol, which provided valuable basic data for its industrial-ization.The second section of this thesis maily researched the racemic resolution of sibutramine, which is a drug for obesity functioning through central nerve system and is used in the racemic form in the clinical. Many studies have shown that the racemic form of drug delivery may lead to serious adverse reactions. Moreover, the enantiomers of sibutramine showed different effects in pharmacodynamic and pharmacokinetic. Therefore, obtained optically pure sibutramine can highly devoted to the in-depth research of pharmacology, pharmacodynamics metabolism and the correct medication.In this section, tartaric acid and its derivatives (TA, DMTA, DTTA, DBTA) were used as the resolving agents to resolve sibutramine. Among them, when using DMTA as resolving agent, the salt of non-enantiomer can be facilely precipitated in ethyl acetate. Followed by recrystallization and dissociation, optically pure sibutramine was obtained. The difference between the two diastereoisomers were confirmed by IR, NMR, DSC-TGA and X-ray diffraction, and the optical purity of the two isomers were determined by high performance liquid chromatography (HPLC) analysis using Chiral pak OD-H at room temperature.