Preparative Synthesis of an R P-Guanosine-3',5'-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations.
Org Process Res Dev
; 25(11): 2453-2460, 2021 Nov 19.
Article
em En
| MEDLINE
| ID: mdl-34840493
ABSTRACT
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 R P-3',5'-cyclic phosphorothioate in 91 ratio to the undesired S P-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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Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article