Study On The Synthesis Of SGLT2 Inhibitor Canagliflozin And Vitamin E Nicotinate

This paper describes the synthesis of SGLT2 inhibitor Canagliflozin（domestic unlisted hypoglycemic agents）and Vitamin E Nicotinate in two parts.Part one:studied on the synthesis of CanagliflozinFirst,a suitable synthetic route based on the existing synthetic process was selected.In this investigation,borohydride and aluminium trichloride were selected as the reducing agent for carbonyl reduction.The reaction time was shortened from 23h to 14h and the yield was increased from 70%to 87%.The post-treatment of this coupling reaction was optimized and the reaction time of methylation and deprotection of silicon ether from the original process was shortened from 6h to 4h.Then the dosage of methanesulfonic acid was reduced from 1.2eq to 0.4eq and the impurity content of side reaction was significantly reduced from 10.65%to 1.23%.Finally,ethyl acetate-heptane-water was selected as the best solvent for further recrystallization.Compared with the original patent,the whole process was more convenient,efficient and easier to handle after optimization.The whole process gave the product in 24.8%yield,and the purity of the product was 99.82%（impurities were no more than 0.1%）.Part two:studied on the synthesis of Vitamin E NicotinateIn this investigation,N,N-carbonyldiimidazole was selected as activator reagent,niacin and vitamin E as starting materials,CH₂Cl₂ as reaction solvent and vitamin E Nicotinate was synthesized via one-pot reaction at 30℃.Finally ethanol was chosed as a crystallization solvent,then remained at low temperature for 24h to get the crystal,the purity of product was more than 99.7%.By pilot-plant experiments,we confirmed the process has the advantages of absolute less pollution,safety,simple operations,environmentally-friendly and suitable for industrial production.