Titill: | Preparative Synthesis of an RP-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations |
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Útgáfa: | 2021-10-19 |
Tungumál: | Enska |
Umfang: | 2453-2460 |
Háskóli/Stofnun: | Háskóli Íslands University of Iceland |
Svið: | Heilbrigðisvísindasvið (HÍ) School of Health Sciences (UI) |
Deild: | Lyfjafræðideild (HÍ) Faculty of Pharmaceutical Sciences (UI) |
Birtist í: | Organic Process Research and Development;25(11) |
ISSN: | 1083-6160 1520-586X (eISSN) |
DOI: | https://doi.org/10.1021/acs.oprd.1c00230 |
Efnisorð: | Organic Chemistry; Physical and Theoretical Chemistry; preclinical development; process development; retinal neurodegenerations; nucleotide H-phosphonate; cyclic guanosine monophosphorothioate; cyclic guanosine monophosphate; Lífræn efnafræði |
URI: | https://hdl.handle.net/20.500.11815/2725 |
Tilvitnun:Pérez, O., Schipper, N., & Bollmark, M. (2021). Preparative Synthesis of an RP-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations. Organic Process Research & Development, 25(11), 2453-2460. doi:10.1021/acs.oprd.1c00230
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Útdráttur: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.
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Athugasemdir:Post-print
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