Syntheses of isotope-labeled SGLT2 inhibitor canagliflozin (JNJ-28431754)

Canagliflozin (Invokana, JNJ-28431754) is an orally bioavailable and selective SGLT2 (subtype 2 sodium-glucose transport protein) inhibitor approved for the treatment of type 2 diabetes. Herein, we report the synthesis of C-13 and C-14-labeled canagliflozin. Stable isotope-labeled [C-13(6)]canagliflozin was synthesized in 4 steps starting from [C-13(6)]-labeled glucose. The [C-14]-Labeled canagliflozin was synthesized by incorporation of [C-14] into the benzylic position between the thiophene and benzene rings of the compound. Detailed synthesis of the isotope-labeled compounds is reported.