Synthesis of empagliflozin, a novel and selective sodium‐glucose co‐transporter‐2 inhibitor, labeled with carbon‐14 and carbon‐13

Empagliflozin, (2 S ,3 R ,4 R ,5 S ,6 R )‐2‐[4‐chloro‐3‐[[4‐[(3 S )‐oxolan‐3‐yl]oxyphenyl]methyl]phenyl]‐6‐(hydroxymethyl)oxane‐3,4,5‐triol was recently approved by the FDA for the treatment of chronic type 2 diabetes mellitus. Herein, we report the synthesis of carbon‐13 and carbon‐14 labeled empagliflozin. Carbon‐13 labeled empagliflozin was prepared in five steps and in 34% overall chemical yield starting from the commercially available α‐D‐glucose‐[ 13 C 6 ]. For the radiosynthesis, the carbon‐14 atom was introduced in three different positions of the molecule. In the first synthesis, Carbon‐14 D‐(+)‐gluconic acid δ‐lactone was used to prepare specifically labeled empagliflozin in carbon‐1 of the sugar moiety in four steps and in 19% overall radiochemical yield. Carbon‐14 labeled empagliflozin with the radioactive atom in the benzylic position was obtained in eight steps and in 7% overall radiochemical yield. In the last synthesis carbon‐14 uniformly labeled phenol was used to give [ 14 C]empagliflozin in eight steps and in 18% overall radiochemical yield. In all these radiosyntheses, the specific activities of the final compounds were higher than 53 mCi/mmol, and the radiochemical purities were above 98.5%.