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A facile and economic method for the synthesis of (S)-N-Boc-3′-hydroxyadamantylglycine

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Abstract

(S)-N-Boc-3′-hydroxyadamantylglycine (I) is an important intermediate of saxagliptin for type 2 diabetes mellitus (T2DM). It was prepared from 1-adamantanecarboxylic acid(1) via mild reaction with sulfuric acid/nitric acid, VHA reagent (SOCl2/DMF) and sodium diethyl malonate, then was treated with hydrolysis, decarboxylation, alkalization and oxidation to give 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid (4), then through oximation, reduction and (Boc)2O protection to give the N-Boc-3′-hydroxyadamantylglycine(6), then was treated with quinidine to get (S)- N-Boc-3′-hydroxyadamantylglycine(I) and quinine to get (R)–N-Boc-3′-hydroxyadamantylglycine(II). Finally, Compound II was racemized by dicyclohexylcarbodiimide (DCC) and sodium hydride (NaH) to afford compound 6. In this route, the overall yield of preparing compound I was about 35 % and the enantiomeric excess (ee) reach to 99 %. This route provided a novel idea for the preparation of (S)-N-Boc-3′-hydroxyadamantylglycine.

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Acknowledgments

We deeply appreciate the financial support of this research by a grant from the graduate scientific research and innovation projects of Chongqing Education Committee (No. CYS15142). We are also grateful for all that Chongqing Medical University and Chongqing Research Center for Pharmaceutical Engineering have done for accomplishing this study.

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Authors and Affiliations

  1. Pharmacy College, Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Jie Li, Xue Jiang, Run Gan, Ming Zhang, Xinmei Pan & Xiangnan Hu

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  1. Jie Li
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  2. Xue Jiang
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  3. Run Gan
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  4. Ming Zhang
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Correspondence to Xiangnan Hu.

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Li, J., Jiang, X., Gan, R. et al. A facile and economic method for the synthesis of (S)-N-Boc-3′-hydroxyadamantylglycine. Res Chem Intermed 42, 5709–5721 (2016). https://doi.org/10.1007/s11164-015-2398-2

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  • DOI: https://doi.org/10.1007/s11164-015-2398-2

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