Preparative Synthesis of an RP-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations

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 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.

Automated summary

The synthesis of the cyclic guanosine monophosphorothioate analogue 1a was achieved through a diastereoselective route, utilizing a silyl protection sequence to achieve high selectivity for the desired product. This chromatography-free process allowed for a successful scale-up production of the compound.