Synthesis of metabolites of dapagliflozin: an SGLT2 inhibitor


Dapagliflozin is one of the gliflozin class drugs, useful for the treatment of type-2 diabetes. Dapagliflozin undergoes extensive metabolism and transforms to metabolites in humans. The contribution of pharmacologically active metabolites in drug discovery and development is significant. A streamlined synthetic approach is devised to access three metabolites of dapagliflozin namely, benzylic hydroxy dapagliflozin, oxo dapagliflozin and desethyl dapagliflozin. Two synthetic protocols have been proposed for the synthesis of benzylic hydroxy dapagliflozin and oxo dapagliflozin. An enantioselective deethylation of dapagliflozin is also reported.

Graphic abstract

Synthesis of three metabolites of Dapagliflozin namely benzylic hydroxy dapagliflozin, oxo dapagliflozin and desethyl dapagliflozin is reported from commercially accessible raw materials.

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Figure 1
Figure 2
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5







Lithium hydroxide momohydrate


p-Toluene sulphonic acid



BF3.OEt2 :

Boron trifluoride diethyl etherate



MnO2 :

Manganese dioxide

NaBH4 :

Sodium borohydride

BBr3 :

Boron tribromide




Hydrobromic acid


  1. 1.

    Meng W, Bruce A E, Alexandra A N, Peggy J M, Manorama P, Ravindar N G, Gang W, Philip M S, Eamonn P M, Scott A B, Robert Z, Prashant P D, Annie P, Deborah L H, Nathan M, Joseph R T, Mary T O, William G H, Ashish K, Lorell D, James G R, Aiying W, Songping H, John R W, Evan B J, Oliver P F, Jean M W and William N W 2008 Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type-2 diabetes J. Med. Chem. 51 1145

    CAS  Article  Google Scholar 

  2. 2.

    Fura A 2006 Role of pharmacologically active metabolites in drug discovery and development Drug Discov. Today 11 133

    CAS  Article  Google Scholar 

  3. 3.

    Obermeier M, Yao M, Khanna A, Koplowitz B, Zhu M, Li W, Komoroski B, Kasichayanula S, Discenza L, Washburn W, Meng W, Ellsworth B A, Whaley J M and Humphreys W G 2010 In vitro characterization and pharmacokinetics of dapagliflozin (BMS-512148), a potent sodium-glucose co transporter type II inhibitor, in animals and humans Drug Metab. Dispos. 38 405

    CAS  Article  Google Scholar 

  4. 4.

    Timothy P R, Michael J G, Evan B J, Thomas E D, Craig F, Francis L, Jian C, Tai W, Jean M W and Mark T 2014 Carcinogenicity risk assessment supports the chronic safety of dapagliflozin, an inhibitor of sodium-glucose co-transporter 2, in the treatment of type 2 diabetes mellitus Diabetes Ther. 5 73

    Article  Google Scholar 

  5. 5.

    Japan Pharmaceutical interview form, 2015, 5th edition.

  6. 6.

    Seed B, Lv B, Roberge J Y, Chen Y, Peng K, Dong J, Xu B, Du J, Zhang L, Tang X, Xu G, Feng Y and Xu M 2015 Preparation of deuterated benzyl-benzene glycosides having an inhibitory effect on sodium-dependent glucose co-transporter U.S. Patent 9061060B2

  7. 7.

    TLC Pharmaceutical Standards Ltd. accessed on: 12th July, 2019

  8. 8.

    Bruce E, William N W, Philip M S, Gang W and Wei M 2003 C-aryl glucoside SGLT2 inhibitors and method U.S. Patent 6,515,117 B2

  9. 9.

    Djerassi C 1948 Brominations with N-bromosuccinimide and related compounds. The Wohl–Ziegler reaction Chem. Rev. 43 271

    CAS  Article  Google Scholar 

  10. 10.

    Ghosh S and Ghatak U R 1988 Carbon–carbon bond formation and annulation reactions using trimethyl and triethylorthoformates Proc. India Acad. Sci. (Chem. Sci) 100 235

    CAS  Google Scholar 

  11. 11.

    Ernest F P and Stuart P S 1963 Oxidation by solids II. The preparation of either tetraarylethanes or diaryl ketones by the oxidation of diarylmethanes with manganese dioxide J. Org. Chem. 28 638

    Article  Google Scholar 

  12. 12.

    Xu B, Feng Y, Cheng H, Song Y, Lv B, Wu Y, Wang C, Li S, Xu M, Du J, Peng K, Dong J, Zhang W, Zhang T, Zhu L, Ding H, Sheng Z, Welihinda A, Roberge J Y, Seed B and Chen Y 2011 C-Aryl glucosides substituted at the 4′-position as potent and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes Bioorg. Med. Chem. Lett. 21 4465

    CAS  Article  Google Scholar 

  13. 13.

    Chen Y, Cheng H, Li S, Wu Y, Feng Y, Lv B, Xu B, Seed B, Hadd M J, Du J, Wang C and Roberge J Y 2009 Benzylbenzene derivatives and methods of use PCT Int. Appl. 2009026537A1

  14. 14.

    Ranu B C and Bhar S 1996 Dealkylation of ethers. A review Org. Prep. Proced. Int. 28 371

    CAS  Article  Google Scholar 

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We are grateful to the management of Aurobindo Pharma Limited., for the generous support and constant encouragement. We are also thankful to the chemical and analytical research departments for their co-operation.

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Correspondence to KISHORE KARUMANCHI.

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KARUMANCHI, K., NATARAJAN, S.K., CHAVAKULA, R. et al. Synthesis of metabolites of dapagliflozin: an SGLT2 inhibitor. J Chem Sci 132, 42 (2020).

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  • Dapagliflozin
  • SGLT2 inhibitor
  • Anti diabetic drug
  • Metabolites
  • Synthesis