鸟苷
化学
非对映体
膦酸盐
产量(工程)
组合化学
高效液相色谱法
选择性
药品
核苷
立体化学
色谱法
作者
Oswaldo Pérez,Nicolaas Schipper,Martin Bollmark
标识
DOI:10.1021/acs.oprd.1c00230
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI