Bexagliflozin

Bexagliflozin (EGT1442), sold under the brand name Brenzavvy by TheracosBio, is an antidiabetic medication used to improve glycemic control in adults with type 2 diabetes as an adjunct to diet and exercise. It is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that is taken by mouth and approved by the FDA on 20.01.2023. Similar to other SGLT2 inhibitors, bexagliflozin contains three basic moieties: glucose, two benzene rings and a methylene bridge. SGLT2 is responsible for 60% to 90% of renal glucose re-uptake, and unlike other isoforms such as SGLT1, SGLT2 is mainly expressed in the kidney. By inhibiting SGLT2, bexagliflozin reduces renal reabsorption of filtered glucose and increases urinary glucose excretion, which reduces blood glucose levels independently of insulin sensitivity. Its use is not recommended in patients with type 1 diabetes since it may increase their risk of diabetic ketoacidosis (1, 2).

The synthesis starts from the reduction of 2-chloro-5-iodobenzoic acid (1) by means of NaBH4 and I2 in THF for 19h to generate (2-chloro-5-iodophenyl)methanol (2, 70%), followed by condensation with phenol using ZnCl2 and HBr in CH2Cl2/hexane for 3 days leads to the formation of 3 in 65% yield. O-alkylation of phenol derivative (3) with 2-(cyclopropyloxy)ethanol tosylate using K2CO3 and Bu4NI in acetone yields ether (4) in 75%. Treatment of halide (4) with i-PrMgCl·LiCl in THF at -68 °C and subsequent condensation with penta-O-silylated gluconolactone gives the corresponding 1-aryl-D-glucopyranoside derivative (5, 94%), whose methyl ether moiety is cleaved by means of Et3SiH and BF3·Et2O to produce bexagliflozin (6, 99%). Finally, treatment of free base with L-Pro-OH in EtOH/H2O at 80 °C furnishes the target bexaglifozin (7, 60%) (3).