Efficient Novel Synthesis of Bexaglifazolin and Its Glycol Salt With Minimal Impurities

Abstract

An efficient and novel process for the synthesis of the antidiabetic drug bexagliflozin using 5-iodo-2-chlorobenzoic acid as the starting material was described in detail to identify and eliminate the critical impurities that may form during the various steps of the synthetic process. The best reaction parameters, including temperature, stoichiometry, and reaction time, were systematically evaluated by analyzing the impurity profile at each stage of the synthesis. The process was carefully optimized to effectively control the formation of these critical impurities, which was a key factor in ensuring the successful synthesis of pure bexagliflozin.

Keywords

Diabetes mellitus - Sodium-glucose - Bexagliflozin - Glycol - impurities

Publication History

Received: 02 April 2025

Accepted after revision: 19 May 2025

Accepted Manuscript online:
20 May 2025

Article published online:
30 July 2025

• References

• 1 Allegretti AS, Zhang W, Zhou W. et al. Am J Kidney Dis 2019; 74 (03) 328-337
• 2 Ghezzi C, Loo DDF, Wright EM. Diabetologia 2018; 61 (10) 2087-2097
• 3a Arakawa K. et al. Br J pharmacol 2001; 132: 578-586
• 3b Oku A. et al. Diabetes 1999; 48: 1794-1800
• 4 FDA. BRENZAVVY (bexagliflozin) tablets, for oral use Initial U.S. Approval. 2023
• 5 Tucker ME. FDA Approves New Type 2 Diabetes Drug Bexagliflozin. Medscape January 23 2023
• 6 Brian Park, PharmD, Brenzavvy Approved for Adults With Type 2 Diabetes, January 23, 2023, TheracosBio announces FDA approval of Brenzavvy™ (Bexagliflozin) for the treatment of adults with type 2 diabetes
• 7 News release. TheracosBio. Accessed January 23, 2023. https://www.businesswire.com/news/home/20230123005126/en/TheracosBio-Announces-FDA-Approval-of-Brenzavvy%E2%84%A2-bexagliflozin-for-the-Treatment-of-Adults-with-Type-2-Diabetes
• 8 Español FDA Approves First Oral Treatment for Cats with Diabetes Mellitus, December 8, 2022.
• 9 Zhang W, Welihinda A, Mechanic J. et al. Pharmacol Res 2011; 63 (04) 284-93
• 10 https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/214373s000lbl.pdf
• 11 Theracosbio LLC. Benzylbenzene derivatives and methods of use, Patent no US7838499
• 12 Theracos, Inc. Benzylbenzene derivatives and methods of use, WO2009026537A1
• 13 Theracos, Inc., Process for the preparation of benzyl benzene sodium-dependent glucose cotransporter 2 (sglt2) inhibitors, Patent no: WO2013152654A1
• 14 Standard Operating Procedure for the use of Diethyl Zinc, http://www.ansellpro.com/download/Ansell_8thEditionChemicalResistanceGuide.pdf
• 15 Authored By: Kevin McGhee, EH&S Professor Jack Norton, The Safe Use of Pyrophoric Reagents Dept. of Chemistry Revised November 2009, March 2010 and May 2010 Written April 2009
• 16 Krishna GG, Kilaru RP, Gutta M. et al. J Indian Chem Soc 2025; 102 (02) 101557
• 17 Peng P, Zhao C, Yang J, Liu X, Yu J, Zhang F. Org Prep Proc Int 2022; 54 (03) 203-219
• 18 Mirza-Aghayan M, Boukherroub R, Rahimifard M. J Organometall Chem 2008; 693 (24) 3567-3570
• 19 Pesti J, Gerald L. Larson Tetramethyldisiloxane: a practical Organosilane reducing agent. Organic Process Research and Development 2016; 20 (07) 1164-1181
• 20 Wang I, Zhang L, Byrne D. et al. Org Lett 2014; 16 (16) 4090-4093
• 21 Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein, US20060258749A1 2000
• 22 Barr D, Doyle MJ, Drake SR, Raithby PR, Snaith R, Wright DS. J Chem Soc, Chem Commun Issue 1988 21
• 23 Xu G, Xu B, Song Y, Sun X. Tetrahedron Lett 2016; 57 (42) 4684-4687
• 24 Govinda G KK, Pagadala R, Gutta M, Kondabattula CS, Rajkumar ST, Gundekari S, Varkolu M. Efficient and Facile Synthesis of Bexagliflozin: An SGLT-2 Inhibitor, Chemistryselect, 21 November 2024 https://doi.org/10.1002/slct.202404188