Research And Development Of Synthetic Process Of SGLT-2 Inhibitor

SGLT-2 inhibitors is a new kind of drugs for the treatment of Type 2 diabetes mellitus listed in recent years. The mechanism of action of the drug is to selectively inhibit SGLT-2 protein, which can reduce the glucose absorption of renal tubule in patients with diabetes and increase urine sugar, thus improving the blood glucose level. So far,6 SGLT-2 inhibitors have been granted. Due to good hypoglycemic effect and less side effects, the drug has a good market prospect.The key step in the synthesis process is the formation of carbon-glycosidic bond with organometallic reagents, and it needs harsh (-70 ?) and anhydrous anaerobic condition.So greening research of the technology, to reduce the SGLT-2 prices, improve the level of China's pharmaceutical technology is of great significance.A kind of composite organic metallic reagent was prepared by lithium chloride and butyl lithium in this researsh, which rise the temperature of key process coupling reaction of SGLT-2 inhibitor synthesis from-70 ? to-10 ? with greatly improve the reaction conditions and is of great significance to reduce production costs and promote industrial application.In the synthesis of Ipragliflozin, under -10 ?, in THF, 2-(5-bromo-2-fluorobenzyl)benzothiophene react with composite organic metallic reagent. The resulting intermediate coupled with 2,3,4,6-Tetrakis-O-trimethylsilyl-D-gluconolactone to get intermediate with 70% yield, followed by deprotection, reduction, acylation and hydrolyzation giving Ipragliflozin with an overall yield of 42%.Then to expand the technology application, successfully synthesized Dapagliflozin, Canagliflozin and Empagliflozin with yield of 23.1%,20.1%,11.4%.Finally, the switch from batch reaction to continuous reaction was researched. We set up a complete set of micro reaction system and succesfully processed Lithium halogen exchange reaction in 16s with 87% conversion and 77% selectivity and coupled reaction with 22.1% yield. The feasibility of synthesis SGLT-2 inhibitor in micro reactor was verified.