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

• Published in: Journal of labelled compounds & radiopharmaceuticals 2014-10, Vol.57 (12), p.687-694
• Main Authors: Hrapchak, Matt, Latli, Bachir, Wang, Xiao-Jun, Lee, Heewon, Campbell, Scot, Song, Jinhua J., Senanayake, Chris H.
• Format: Article
• Language: English
• Subjects: Benzhydryl Compounds - chemical synthesis; Benzhydryl Compounds - pharmacology; Carbon; Carbon Radioisotopes - chemistry; carbon-13; carbon-14; diabetes mellitus; empagliflozin; Glucose; Glucosides - chemical synthesis; Glucosides - pharmacology; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - pharmacology; radiosynthesis; SGLT-2; Sodium-Glucose Transporter 2 - antagonists & inhibitors
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.3240

Empagliflozin, (2S,3R,4R,5S,6R)‐2‐[4‐chloro‐3‐[[4‐[(3S)‐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‐[13C6]. 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 [14C]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%. Carbon‐13‐labeled empagliflozin with more than 99% isotopic enrichment was prepared using the commercially available α‐d‐glucose‐[13C6]. The carbon‐14 was introduced in the drug in three different positions via three different syntheses using carbon‐14 d‐(+)‐gluconic acid δ‐lactone, carbon‐14 potassium cyanide, and carbon‐14 uniformly labeled phenol. In all these three radiosyntheses, the specific activities of the final compounds were higher than 53 mCi/mmol, and the radiochemical purities were above 98.5%.