Sglt - 2 Inhibitor Ertugliflozin Synthesis

Sodium-glucose co-transporters are a family of glucose transporter found in the intestinal mucosa of the small intestine (SGLT-2) and the proximal tubule of the nephron (SGLT-1and SGLT-2). They contribute to renal glucose reabsorption and most of renal glucose (about90%) is reabsorbed by SGLT-2located in the proximal renal tubule. Selectively inhibiting activity of SGLT-2is an innovative therapeutic strategy for treatment of type2diabetes by enhancing urinary glucose excretion from the body. Therefore SGLT-2inhibitors are considered to be potential antidiabetic drugs with an unique mechanism.Several SGLT-2inhibitors have been on the market or in clinical recently, such as Dapagliflozin, Tofogliflonzin, Ertugliflozin and so on. Ertugliflozin developed by Pfizer is in phase III trials for the treatment of diabetes mellitus. Its hypoglycemic and metabolic activity are comprehensivly superior to dapagliflozin listed in the market. The synthetic rout of Ertugliflozin reported in the references has been in patent protection and many shortcomings such as the raw materials being more expensive and low yield and difficulties of separation and purification of the key intermediate6(YF-3)especially. The industrial production will not be realized domesticlly. A new synthetic route of Ertugliflozin has been designed in this paper. The key intermediate YF-3has been synthesized with the cheaply starting material of2-chloro-5-bromo-benzoic acid followed by nucleophilic substitution, Friedel-Crafts acylation, reduction and formylation with the yield of45%comparing to the yield of7.8%reported in the references and more simple purification relatively. Ertugliflozin(YF-13) has been synthesized by the key intermediate YF-3whose aldehyde was protected by mercaptan followed by five steps with the intermediate YF-8such as nucleophilic addition and hydroxy deprotection and so on. A new synthetic route of Ertugliflozin has been provided for the domestic industrialized production with simplified steps and the more high yield comparing to the synthetic rout reported in the references without the patent restrictions.