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 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.
Triphenylphosphine selenide and its polymer-supported counterpart are found to be efficient selenium-transferring reagents for the conversion of H-phosphonate diesters and phosphite triesters into the corresponding phosphoroselenoate derivatives.
Ethyl 6-chloro-5-cyano-2-methylnicotinate (4) was coupled with 4-piperidinecarboxylic acid (isonipecotic acid) in 81% yield to pyridine acid 10. An amide coupling between 10 and benzylsulfonamide (6) afforded AZD1283 (1) in 79% yield using CDI as coupling reagent. The synthesis has been developed and scaled up to 20 kg batches of 1, supporting preclinical and clinical studies. Development work towards 2-chloropyridine 4 and benzylsulfonamide ( 6) is included.
The ability of Zn2+ dimethyl-dppz PNAzymes to cleave RNA target sequences with under 20 minute half-lives is critically dependent on the bulge-closing base pairs as well as their stacking interactions with the neighbouring nucleobases.
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