Study On The Synthesis Of Empagliflozin Drug Substance

1.Study on the synthesis of Empagliflozin drug substanceEmpagliflozin is a drug substance for the treatment of type 2 diabetes,and it is known as a kind of SGLT2 inhibitors by inhibiting the SGLT2 expressed in the kidneys to reduce glucose level in the plasma.On the basis of literatures,we selected two process routes simultaneously to develop and optimize the conditions,and the best process route was obtained by comparision of them.(1)Study on the synthesis of the first routeThe synthesis of Empagliflozin was designed by using 1-chloro-4-(1-methoxy-D-glucopyranosyl-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl)-benzene as the starting material.At first.N-methylmorpholine was used as an acid-binding agent,and the starting material was acetylated with acetic anhydride under the conditions of 4-dimethylaminopyridine as a catalyst,with toluene and ethyl acetate as the mixed solvent.Then with boron trifluoride etherate as a catalyst and triethylsilane as the hydrogen-donating reagent,the obtained crude product was subjected to reduction reaction.Futhermore,the reduced product reacted with sodium methoxide as the base to give a white powdery crude product.Finally,it was recrystallized by anhydrous ethanol and toluene to obtain a purified product.The conditions of each step have been carried out screening and optimizing to improve the yield,and the purity of the product reached the new drug registration standards.(2)Study on the synthesis of the second routeOn the basis of the first route,we selected the same starting material.Firstly,the starting material was reduced with the mixed system of acetonitrile and dichloromethane as a solvent,boron trifluoride etherate and triethylsilane were used as catalyst and hydrogen donor,respectively.Then the product was acetylated with acetic anhydride in the presence of triethylamine as an acid-binding agent and 4-dimethylaminopyridine as the catalyst.Subsequently,the intermediate product was subjected to the same alcoholysis and purification procedures as the first route to obtain the purified product.Owing to the conditions of each step were optimized,especially with the re-selection of solvents and acid-binding agent,the purity of the product was higher and the cost of raw materials was reduced.The target product was complied with pharmaceutical standards.Soon afterwards,the entire operation process and the quality of the target product of the two routes were compared,and we found that there is always an unknown impurity in the first route that was difficult to remove,while this unknown impurity was not detected in the second route or the content was very few.And the entire operation processes,such as crystallization,filtration and other operations are simpler than that of the first route,which used the extraction,separation,drying,vacuum distillation and other operations.Additionaly,the total molar yield was also slightly higher than that of the first route.In conclusion,the second route was choosed as the best route,and the pilot test was carried on,the post-processing operation is simple,and the starting materials as well as reagents of the route were obtained easily,the quality was stable and reliable,furthermore,the synthetic process is low toxicity and the safety performance is excellent.2.Study on the synthesis of the intermediate of metconazole Metconazole is a kind of triazole fungicides,its spectrum sterilization is broad,and it also has the inner absorption property,protection and bactericidal effect.On the basis of a large number of patents and literatures,we found that most of the synthetic methods of metconazole were synthesized from 2.2-dimethyl-5-(4-chlorobenzyl)cyclopentanone,which is an important intermediate.In this paper,we selected five steps synthesis of this important intermediate by choosing ethyl 2-oxocyclopentanecarboxylate as the starting material.The starting material was subjected to methylation under the alkaline condition of potassium carbonate,then the product was hydrolyzed to decarboxylate in the presence of acidic conditions of dilute sulfuric acid,and followed by reaction with p-chlorobenzaldehyde,then followed by re-methylation with sodium hydride as the base and finally palladium carbon was used as a catalysis,the product undergone a hydrogenation reduction reaction to give the intermediate product.The reaction conditions of each step were optimized,and this process has the characteristics of low cost,simple operation and high application value,so it is suitable for industrial production.