Studies Of 3 - (1 - Naphthyloxy) -1,2 - Epoxy Propane Hydrolytic Kinetic Resolution, And Its Application

Chiral terminal epoxides are important building blocks in organic synthesis, the status and needs of which is increasingly prominent in the preparation of bioactive compounds. Although the asymmetric synthesis method to obtain high optical purity of terminal epoxides has made tremendous progress, from the perspective of cost, efficiency and environment-friendly, the method of hydrolytic kinetic resolution created by Jacobson's group still has certain advantages.One of the product of the hydrolytic kinetic resolution for 3-(1-naphthyloxy)-1,2-epoxypropane is the key intermediate for (S)-naftopidil, which is the important drug for treatment of arterial hypertension and cardiovascular disease. We explored the various factors of hydrolytic kinetic resolution of terminal epoxides by chiral Salen(III) complex and applied the split product for the preparation of (S)-naftopidil. The major research and result was as followings:(1) 3-(1-naphthyloxy)-1,2-epoxypropane was treated by the standardized reaction of hydrolytic kinetic resolution. Based on the quantitative analysis method of the conversion rate and the optical purity, further detailed study of the type and amount of catalyst, reaction time, temperature, the amount of water, solvents how to affect these aforesaid factors, we obtained the optimized reaction condition:the solvent was tetrahydrofuran, the water was 0.55 euqivalent, the amount of catalyst was 0.75mol% that was prepared by the chiral ligand 1,2-diaminocyclohexane, the temperature was at room temperature, reaction time was 40 hours. Under the reaction condition, we acquired 49% yield and 100% ee for (S)-3-(1-naphthyloxy)-1,2-epoxypropane.(2) Based on some synthetic route reported, we applied the split product (S)-3-(1-naphthyloxy)-1,2-epoxypropane to synthesize the (S)-naftopidil analogues. We adopted ultrasound-promoted method to achieve the reaction between 3-(1-naphthyloxy)-1,2-epoxypropane and N-substituted piperazine derivatives. While the reaction under conventional condition required high-temperature refluxing for 30 hours, under ultrasound-assisted condition it finished at room temperature for 5 hours, significantly improving the efficiency. The method proved to contain aliphatic, aromatic, heteroaromatic and heterocyclic substituted piperazine derivatives were effective and could obtain good yield. The prepared (S)-naftopidil analogues were characterized by melting point, specific rotation, IR,1H NMR,13C NMR and MS in detail. It fast and efficiently provided a new way for acquiring (S)-naftopidil analogues.