Study On Some Key Synthetic Steps In Multikilogram Production Procedure Of SGLT2 Inhibitor Tianagliflozin

Type 2 diabetes is now the increasing concern throughout the world.Sodium-glucose co-transporters(SGLTs)is a novel target for type 2 diabetes with completely different mechanism of action from the current targets.In the earlier studies,based on the novel SGLT2 inhibitor dapagliflozin,which has been successfully marketed in Europe and the United States,as the lead compound,we have designed and synthesized a series of novel SGLT2 inhibitors.Finally we successfully discovered the most potent SGLT2 inhibitor,tianagliflozin.We found that the tianagliflozin is a more potent SGLT2 inhibitor than dapagliflozin,whose IC50 against SGLT2 is 0.67 nM as compared with dapagliflozin itself(1.1 nM).Currently,tianagliflozin has been successfully in the stage of IND.Therefore we need a large amount of tianagliflozin for the clinical trials.Unfortunately we encountered some problems during the process of synthesis tianagliflozin on multikilogram scales.For example,we used DMSO/Ac2O as the oxidant combination to make the lactol intermediate.But further examination and experimentations revealed that DMSO/Ac2O is associated with a long reaction time(usually overnight),unpleasant odor(arising from the byproduct dimethyl sulfide)and the difficulty to remove the residual DMSO.In addition,we found that the sample tianagliflozin was always accompanied with two byproducts.And one of the byproducts(about 1.5%to 3.0%in the crude product)was difficult to completely remove during the subsequent crystallization process.This paper is mainly devoted to solve the two problems aforementioned,which were encountered during the synthesis process of tianagliflozin on multikilogram scales.We decided to find a better oxidant to solve the first problem.Finally we have discovered a highly efficient green oxidant,iodine monochloride(ICl),and optimized the reaction condition,including the equivalent of ICl,the base and its equivalent,reaction temperature and solvent.The substrate scope of the oxidant has been intensively studied,and it is applicable to a variety of alcohol substrates with short reaction time and high yields,such as aldose hemica-cetals,diarylmethanols,arylalkylmethanols and dialkylmethanols.However,it is not applicable to olefin-bearing and primary alcohols.To solve the second problem we analyzed the structure of the byproducts a-nd found the step where the byproducts came from.We screened the debenzylat-ing reagent,Lewis acid,the solvent and the temperature.After considerable exp-erimentations,we finally obtained the preliminarily satisfactory results,based onwhich the optimized conditions are expected to be obtained by further studies.