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%.

Synthesis of unlabelled and stable-isotope-labelled glucuronide metabolites of dapagliflozin and synthesis of stable-isotope-labelled dapagliflozin

“…The work was first presented at IIS NE US chapter meeting . Similar syntheses for other gliflozins, for example, empagliflozin and canagliflozin were also reported.…”

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

“…A similar synthetic strategy was used for preparation of the carbon-14-labeled compound and is shown in Scheme 2. Cyanation of 2-iodotoluene using cuprous [ 14 C]cyanide (8) provided [nitrile-14 C]2-tolunitrile (9). Hydrolysis of the resultant [nitrile-14 C]2-tolunitrile (9) provided [ 14 C]2-toluic acid (10), which was then converted to [ 14 C]5-iodo-2-methylbenzoic acid (11) through iodination and high-performance liquid chromatography (HPLC) purification to remove the unwanted 3-iodo-2-methylbenzoic acid by-product.…”

“…Various approaches for the synthesis of canagliflozin have been reported in literature. Syntheses of carbon‐14– and carbon‐13–labeled empagliflozin and stable‐isotope–labeled dapagliflozin have also been reported. Herein, we report the synthesis procedures and analysis of stable isotope‐labeled [ 13 C 6 ]JNJ‐28431754 ( 2 ) and radioactive 14 C‐labeled JNJ‐28431754 (ie, canagliflozin, 3 ).…”

Development and Recent Advancement of SGLT2 Inhibitors for the Treatment Regime of T2DM

“…Hydroxyl groups of 15 are then protected using trimethylsilyl chloride, in presence of NMM using THF to yield 16. Simultaneously, 17 is lithiated and treated with 16 to give 18, followed by treatment with methanesulfonic acid in methanol resulting the formation of 19 and further reduction of 19 using Et 3 SiH and BF 3 OEt 2 , afforded the desired product (46). SAR study of empagliflozin highlighted the significance of tetrahydrofuran moiety on the second aryl ring of the molecule, which improved its efficacy compare to other counterparts.…”