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Synthesis of metabolites of dapagliflozin: an SGLT2 inhibitor

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Abstract

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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Abbreviations

NBS:

N-Bromosuccinimide

AIBN:

Azobisisobutyronitrile

LiOH.H2O:

Lithium hydroxide momohydrate

PTSA:

p-Toluene sulphonic acid

MeOH:

Methanol

BF3.OEt2 :

Boron trifluoride diethyl etherate

Et3SiH:

Triethylsilane

MnO2 :

Manganese dioxide

NaBH4 :

Sodium borohydride

BBr3 :

Boron tribromide

DCM:

Dichloromethane

HBr:

Hydrobromic acid

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Acknowledgements

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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Authors and Affiliations

  1. Chemical Research and Development, APL Research Centre-II, Aurobindo Pharma Ltd., Survey No. 71 & 72, Indrakaran Village, Kandi Mandal, Sangareddy District, Telangana State, 502329, India

    KISHORE KARUMANCHI, SENTHIL KUMAR NATARAJAN & RAMADAS CHAVAKULA

  2. Department of Engineering Chemistry, A. U. College of Engineering (A), Andhra University, Visakhapatnam, Andhra Pradesh, 530003, India

    KISHORE KARUMANCHI, RAGHU BABU KORUPOLU & KISHORE BABU BONIGE

  3. Analytical Research and Development, APL Research Centre-II, Aurobindo Pharma Ltd, Survey No. 71 & 72, Indrakaran Village, Kandi Mandal, Sangareddy District, Telangana State, 502329, India

    BADARINADH GUPTA PERURI

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  1. KISHORE KARUMANCHI
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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). https://doi.org/10.1007/s12039-020-1747-x

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  • DOI: https://doi.org/10.1007/s12039-020-1747-x

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