The Racemization Of 1-substituted Indan And 3-substituted Quinuclidine

1-substituted indans and 3-substituted quinuclidines are important pharmaceutical intermediates.These motifs are incorporated into many drugs.For example,both melatonin receptor agonist Ramelton and the monoamine oxidase inhibitor Rasagiline bear 1-substituted indan,while M3 receptor antagonist Solifenacin and AZD9164 include 3-substituted quinuclidinol.1-substituted indans and 3-substituted quinuclidines with chiral center play an important role in pharmaceutical research.Preparation methods for these chiral compounds include extraction from natural products,biological method,asymmetric synthesis and resolution of theracemate.Resolution,characterized with simple operatation and low cost,is frequently employed,but often result in low yield.The main reason is that only half of the racemate can be utilized through resolution in theory,whereas another half is generally wasted.So the yield can be increased if racemization of the waste and recycling resolution are achieved.A variety of methods for racemization have been reported,such as acid,base or enzyme catalyzed racemizations.Racemization methods can be selected for chiral compounds of different kind,and degree of difficulty of racemization differs greatly.In this article,1-substituted indan(compound 7?)was racemized through free radical oxidation and hydrogenation.Racemization of 3-substituted quinuclidine(compound 15?)was achieved through redox reaction catalyzed by Raney-Ni.The method for the racemization of 15? was applied to the optimized process for the synthesis of(R)-3-quinuclidinol.The optimized process was proved consecutively by three batches,and the data showed that the yield was as twice as the literature,besides,labor and discharge of wastewater were greatly reduced.It poses a positive meaning for the environment protection and meets the requirement of the green chemistry.