Studies On The Synthesis Of Ipragliflozin And ITS L-Proline Cocrystal

Sodium-glucose cotransporter 2 (SGLT2) is almost exclusively expressed in the proximal renal tubules. It is responsible for about 90％of the glucose reabsorption from tubular fluid. Selective inhibition of SGLT2 is expected to favor in the normalization of plasma glucose levels in T2DM patients through the prevention of renal glucose reabsorption and the promotion of glucose excretion from urine. Selective SGLT2 inhibitors have the merits to minimize the gastrointestinal side effects associated with SGLT1 inhibition, and selective SGLT2 inhibition may have a low risk of hypoglycemia. Since the C-aryl glucosides are metabolically more stable than the O-glucosides, numerous efforts have been made in the development of potent and selective C-aryl glucoside SGLT2 inhibitors, and a number of them are now used as anti-diabetes drugs in clinic or at various stages of clinical developments. Ipragliflozin is a new SGLT2 inhibitor, approved by the Japanese PMDA as a drug for type 2 diabetes. This drug is co-developed by Astellas Pharma and Japan Kotobuki corporation, manufactured by Astellas and saled by a combination of Astellas, Kotobuki Pharmaceutical and Merck. As a selective SGLT2 inhibitor, it can inhibit the glucose reabsorption and boost the glycemia excretion in urine. The inhibition of SGLT2 is 254-fold more potent than SGLT1.Several synthetic methods for ipragliflozin are reported in the literatures, but there are shortcomings related to high cost, strict reaction conditions, environmental pollution, complex operations and low yield. Therefore, it is of necessary to develop novel method for the preparation of ipragliflozin and L-proline ipragliflozin cocrystal.Treatment benzothiophene with n-butyllithium in THF followed by the reaction with 5-bromo-2-fluorobenzaldehyde gave secondary alcohol 1 through the nucleophilic addition. In the presence of Et3SiH and BF3·OEt2, the benzylic hydroxyl in 1 was removed to give the methylene intermediate 2. After the bromo-lithium exchange by the treatment of 2 with n-butyllithium, the resulting anion was reacted with 2,3,4,6-tetrakis-O-trimethylsilyl-D-gluconolactone to generate trimethylsilyl C-aryl glucoside with a tertiary anomeric alcohol, which was reacted with sulfuric acid and methanol to remove the TMS protactive group and to form the anomeric methyl ether 3. After the acetylation of the glucose hydroxyl groups by acetic anhydride, the anomeric methyl ether was removed by the reaction with Et3SiH in the presence of BF3·OEt2. Hydrolyzation of ethyl ester in intermediate 5 provided ipragliflozin. Finally, the cocrystallization of ipragliflozin with L-proline led to the cocrystallization product.In the process of preparing intermediates 1 and 3, the synthetic route avoided the ultralow temperature conditions (-78℃). In the synthesis of intermediate 2, the temperature was adjusted from -20℃ to 0℃ that was more suitable for industrial production. Recycle toluene was used as a major solvent in the synthesis of intermediate 3, so the cost may be reduced in this process. Through these studies, the synthetic process for ipragliflozin was established. Furthermore, the main related impurities in the synthesis of ipragliflozin were also prepared.