title: Synthesis of empagliflozin, a novel and selective sodium-glucose co-transporter-2 inhibitor, labeled with carbon-14 and carbon-13.
abstract: 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-[(13)C6]. 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%.
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Hrapchak
authors.forename: Bachir
authors.initials: B
authors.lastname: Latli
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Wang
authors.forename: Heewon
authors.initials: H
authors.lastname: Lee
authors.forename: Scot
authors.initials: S
authors.lastname: Campbell
authors.forename: Jinhua J
authors.initials: JJ
authors.lastname: Song
authors.forename: Chris H
authors.initials: CH
authors.lastname: Senanayake
mesh_terms: D001559:Benzhydryl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D002250:Carbon Radioisotopes / Q000737:chemistry; D005960:Glucosides / Q000138:chemical synthesis* / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000494:pharmacology; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001559:Benzhydryl Compounds; D002250:Carbon Radioisotopes; D005960:Glucosides; D019275:Radiopharmaceuticals; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C570240:empagliflozin
keywords: SGLT-2; carbon-13; carbon-14; diabetes mellitus; empagliflozin; radiosynthesis