Preparative Synthesis of an RP-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations
Post-print Cyclic guanosine monophosphorothioate analogue 1a is currently showing potential as a drug for the treatment of inherited retinal neurodegenerations. To support ongoing preclinical and clinical work, we have developed a diastereoselective synthesis via cyclization and sulfurization of the...
Published in: | Organic Process Research & Development |
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Main Authors: | , , |
Other Authors: | , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
American Chemical Society
2021
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Subjects: | |
Online Access: | https://hdl.handle.net/20.500.11815/2725 https://doi.org/10.1021/acs.oprd.1c00230 |
Summary: | Post-print Cyclic guanosine monophosphorothioate analogue 1a is currently showing potential as a drug for the treatment of inherited retinal neurodegenerations. To support ongoing preclinical and clinical work, we have developed a diastereoselective synthesis via cyclization and sulfurization of the nucleoside 5′-H-phosphonate monoester, which affords the desired RP-3′,5′-cyclic phosphorothioate in 9:1 ratio to the undesired SP-diastereomer. This route was made viable as a result of the silyl protection sequence used, which achieved >80% selectivity for 2′,5′-hydroxyls over 3′,5′-hydroxyls. Finally, the chromatography-free process allowed for a scale-up, as intermediates and the final product were isolated by crystallization to give 125 g of 1a (13.8% total yield) with over 99.9% HPLC purity. The authors would like to thank Professor Thorsteinn Loftsson at the University of Iceland for his continued support and guidance, particularly to O.P. as academic supervisor, and Professor Jacek Stawiński at Stockholm University for fruitful discussions. We also thank Dr. Frank Schwede at BIOLOG Life Science Institute (Bremen, Germany) for discussions about synthetic strategy as well as providing material for structural comparisons to our product. This work was supported by the European Commission (H2020-MSCA-765441; HEALTH-F2-2012-304963) Peer Reviewed |
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