Copyright (c) 2026 Nandyala Malyadri Reddy, K.R.S. Prasad, N. Ravi Shekar Reddy, Katam Reddy Vinod Kumar Reddy, G. Pavana Kumari, Naveen Mulakayala
This work is licensed under a Creative Commons Attribution 4.0 International License.
Simple and Selective Synthesis of Critical α-Anomer Impurity of SGLT2 Inhibitors: Empagliflozin, Dapagliflozin and Canagliflozin
Corresponding Author(s) : K.R.S. Prasad
Asian Journal of Chemistry,
Vol. 38 No. 7 (2026): Vol. 38, No 7 (2026)
Abstract
The present study focuses on the selective synthesis of α-anomer impurities in SGLT2 inhibitors, namely empagliflozin, dapagliflozin and canagliflozin. Sodium‑glucose cotransporter‑2 (SGLT2) inhibitors are very important medication used for the treatment of type 2 diabetes. However, their safety profiles and therapeutic efficacy may be impacted by the existence of isomeric impurities. Herein, a simple and effective synthetic method is given to obtain these crucial α-anomers using aryl halides with C1-glycosyl halides using zinc powder, nickel(II) chloride hexahydrate and 4,4'-dimethoxy-2,2'-bipyridine in good yields. The obtained results serve as a foundation for standardizing quality control procedures and highlight the significance of thorough impurity profiling in pharmaceutical development. In addition to improving knowledge of SGLT2 inhibitors, this work advances the larger endeavor of guaranteeing patient safety through strict pharmaceutical procedures.
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- K. Haider, A. Pathak, A. Rohilla, M.R. Haider, K. Ahmad and M.S. Yar, Eur. J. Med. Chem., 184, 111773 (2019); https://doi.org/10.1016/j.ejmech.2019.111773
- É. Bokor, S. Kun, D. Goyard, M. Tóth, J.-P. Praly, S. Vidal and L. Somsák, Chem. Rev., 117, 1687 (2017); https://doi.org/10.1021/acs.chemrev.6b00475
- D.P. Rotella, J. Med. Chem., 47, 4111 (2004); https://doi.org/10.1021/jm030626a
- W. Animaw and Y. Seyoum, PLoS One, 12, e0187670 (2017); https://doi.org/10.1371/journal.pone.0187670
- R.A. Defronzo, E. Ferrannini, L. Groop, R.R. Henry, W.H. Herman, J.J. Holst, F.B. Hu, C.R. Kahn, I. Raz, G.I. Shulman, D.C. Simonson, M.A. Testa and R. Weiss, Nat. Rev. Dis. Primers, 1, 15019 (2015); https://doi.org/10.1038/nrdp.2015.19
- Y. Ohtake, T. Sato, T. Kobayashi, M. Nishimoto, N. Taka, K. Takano, K. Yamamoto, M. Ohmori, M. Yamaguchi, K. Takami, S.-Y. Yeu, K.-H. Ahn, H. Matsuoka, K. Morikawa, M. Suzuki, H. Hagita, K. Ozawa, K. Yamaguchi, M. Kato and S. Ikeda, J. Med. Chem., 55, 7828 (2012); https://doi.org/10.1021/jm300884k
- G. Abbas, A. Al Harrasi, H. Hussain, A. Hamaed and C.T. Supuran, Bioorg. Chem., 86, 305 (2019); https://doi.org/10.1016/j.bioorg.2019.02.009
- Y. Li, Z. Shi, L. Chen, S. Zheng, S. Li, B. Xu, Z. Liu, J. Liu, C. Deng and F. Ye, J. Med. Chem., 60, 4173 (2017); https://doi.org/10.1021/acs.jmedchem.6b01818
- E.C. Chao and R.R. Henry, Nat. Rev. Drug Discov., 9, 551 (2010); https://doi.org/10.1038/nrd3180
- A. Mather and C. Pollock, Kidney Int., 79, S1 (2011); https://doi.org/10.1038/ki.2010.509
- J.J. Neumiller, J.R. White Jr. and R.K. Campbell, Drugs, 70, 377 (2010); https://doi.org/10.2165/11318680-000000000-00000
- S. Nomura, S. Sakamaki, M. Hongu, E. Kawanishi, Y. Koga, T. Sakamoto, Y. Yamamoto, K. Ueta, H. Kimata, K. Nakayama and M. Tsuda-Tsukimoto, J. Med. Chem., 53, 6355 (2010); https://doi.org/10.1021/jm100332n
- T. Rieg and V. Vallon, Diabetologia, 61, 2079 (2018); https://doi.org/10.1007/s00125-018-4654-7
- ICH Harmonised Tripartite Guideline. Impurities in New Drug Substances Q3A(R2) (2006).
- ICH Harmonised Tripartite Guideline. Impurities in New Drug Products Q3B(R2) (2006).
- T. Bililign, B.R. Griffith and J.S. Thorson, Nat. Prod. Rep., 22, 742 (2005); https://doi.org/10.1039/b407364a
- Y. Yang and B. Yu, Chem. Rev., 117, 12281 (2017); https://doi.org/10.1021/acs.chemrev.7b00234
- N.M. Reddy, K. Prasad, R.S.R. Nandipati, K.R.V.K. Reddy, K.R. Vineela, G.P. Kumari and N. Mulakayala, Asian J. Chem., 37, 698 (2025); https://doi.org/10.14233/ajchem.2025.33265
- R.K. Sadineni, R.K. Rapolu, V.V.N.K.V.P. Raju, N. Srinivasu, S. Malladi and N. Mulakayala, Chem. Pap., 75, 1475 (2021); https://doi.org/10.1007/s11696-020-01402-z
- R.K. Rapolu, S. Areveli, V.V.N.K.V.P. Raju, S. Navuluri, M. Chavali and N. Mulakayala, ChemistrySelect, 4, 4422 (2019); https://doi.org/10.1002/slct.201803825
- M.R. Gudisela, P. Bommu, S. Navuluri and N. Mulakayala, ChemistrySelect, 3, 7152 (2018); https://doi.org/10.1002/slct.201800948
- G. Vaddamanu, A. Goswami, N.R.S. Reddy, K.R.V. Kumar Reddy and N. Mulakayala, ACS Omega, 8, 9583 (2023); https://doi.org/10.1021/acsomega.3c00100
- G. Vaddamanu, A. Goswami, R.S.R. Nandipati, Y.T. Malireddy, V.K.R. Katam Reddy and N. Mulakayala, ACS Omega, 8, 38494 (2023); https://doi.org/10.1021/acsomega.3c05325
- R.U. Lemieux and R.M. Ratcliffe, Can. J. Chem., 57, 1244 (1979); https://doi.org/10.1139/v79-203
- C.S. Bennett and M.C. Galan, Chem. Rev., 118, 7931 (2018); https://doi.org/10.1021/acs.chemrev.7b00731
References
K. Haider, A. Pathak, A. Rohilla, M.R. Haider, K. Ahmad and M.S. Yar, Eur. J. Med. Chem., 184, 111773 (2019); https://doi.org/10.1016/j.ejmech.2019.111773
É. Bokor, S. Kun, D. Goyard, M. Tóth, J.-P. Praly, S. Vidal and L. Somsák, Chem. Rev., 117, 1687 (2017); https://doi.org/10.1021/acs.chemrev.6b00475
D.P. Rotella, J. Med. Chem., 47, 4111 (2004); https://doi.org/10.1021/jm030626a
W. Animaw and Y. Seyoum, PLoS One, 12, e0187670 (2017); https://doi.org/10.1371/journal.pone.0187670
R.A. Defronzo, E. Ferrannini, L. Groop, R.R. Henry, W.H. Herman, J.J. Holst, F.B. Hu, C.R. Kahn, I. Raz, G.I. Shulman, D.C. Simonson, M.A. Testa and R. Weiss, Nat. Rev. Dis. Primers, 1, 15019 (2015); https://doi.org/10.1038/nrdp.2015.19
Y. Ohtake, T. Sato, T. Kobayashi, M. Nishimoto, N. Taka, K. Takano, K. Yamamoto, M. Ohmori, M. Yamaguchi, K. Takami, S.-Y. Yeu, K.-H. Ahn, H. Matsuoka, K. Morikawa, M. Suzuki, H. Hagita, K. Ozawa, K. Yamaguchi, M. Kato and S. Ikeda, J. Med. Chem., 55, 7828 (2012); https://doi.org/10.1021/jm300884k
G. Abbas, A. Al Harrasi, H. Hussain, A. Hamaed and C.T. Supuran, Bioorg. Chem., 86, 305 (2019); https://doi.org/10.1016/j.bioorg.2019.02.009
Y. Li, Z. Shi, L. Chen, S. Zheng, S. Li, B. Xu, Z. Liu, J. Liu, C. Deng and F. Ye, J. Med. Chem., 60, 4173 (2017); https://doi.org/10.1021/acs.jmedchem.6b01818
E.C. Chao and R.R. Henry, Nat. Rev. Drug Discov., 9, 551 (2010); https://doi.org/10.1038/nrd3180
A. Mather and C. Pollock, Kidney Int., 79, S1 (2011); https://doi.org/10.1038/ki.2010.509
J.J. Neumiller, J.R. White Jr. and R.K. Campbell, Drugs, 70, 377 (2010); https://doi.org/10.2165/11318680-000000000-00000
S. Nomura, S. Sakamaki, M. Hongu, E. Kawanishi, Y. Koga, T. Sakamoto, Y. Yamamoto, K. Ueta, H. Kimata, K. Nakayama and M. Tsuda-Tsukimoto, J. Med. Chem., 53, 6355 (2010); https://doi.org/10.1021/jm100332n
T. Rieg and V. Vallon, Diabetologia, 61, 2079 (2018); https://doi.org/10.1007/s00125-018-4654-7
ICH Harmonised Tripartite Guideline. Impurities in New Drug Substances Q3A(R2) (2006).
ICH Harmonised Tripartite Guideline. Impurities in New Drug Products Q3B(R2) (2006).
T. Bililign, B.R. Griffith and J.S. Thorson, Nat. Prod. Rep., 22, 742 (2005); https://doi.org/10.1039/b407364a
Y. Yang and B. Yu, Chem. Rev., 117, 12281 (2017); https://doi.org/10.1021/acs.chemrev.7b00234
N.M. Reddy, K. Prasad, R.S.R. Nandipati, K.R.V.K. Reddy, K.R. Vineela, G.P. Kumari and N. Mulakayala, Asian J. Chem., 37, 698 (2025); https://doi.org/10.14233/ajchem.2025.33265
R.K. Sadineni, R.K. Rapolu, V.V.N.K.V.P. Raju, N. Srinivasu, S. Malladi and N. Mulakayala, Chem. Pap., 75, 1475 (2021); https://doi.org/10.1007/s11696-020-01402-z
R.K. Rapolu, S. Areveli, V.V.N.K.V.P. Raju, S. Navuluri, M. Chavali and N. Mulakayala, ChemistrySelect, 4, 4422 (2019); https://doi.org/10.1002/slct.201803825
M.R. Gudisela, P. Bommu, S. Navuluri and N. Mulakayala, ChemistrySelect, 3, 7152 (2018); https://doi.org/10.1002/slct.201800948
G. Vaddamanu, A. Goswami, N.R.S. Reddy, K.R.V. Kumar Reddy and N. Mulakayala, ACS Omega, 8, 9583 (2023); https://doi.org/10.1021/acsomega.3c00100
G. Vaddamanu, A. Goswami, R.S.R. Nandipati, Y.T. Malireddy, V.K.R. Katam Reddy and N. Mulakayala, ACS Omega, 8, 38494 (2023); https://doi.org/10.1021/acsomega.3c05325
R.U. Lemieux and R.M. Ratcliffe, Can. J. Chem., 57, 1244 (1979); https://doi.org/10.1139/v79-203
C.S. Bennett and M.C. Galan, Chem. Rev., 118, 7931 (2018); https://doi.org/10.1021/acs.chemrev.7b00731
