Nitrilase mediated mild hydrolysis of a carbon‐14 nitrile for the radiosynthesis of 4‐(7‐hydroxycarbamoyl‐[1‐14C‐heptanoyl]‐oxy)‐benzoic acid methyl ester, [14C]‐SHP‐141: A novel class I/II histone deacetylase (HDAC) inhibitor

Abstract

A strategy has been developed for the carbon‐14 radiosynthesis of [14C]‐SHP‐141, a 4‐(7‐hydroxycarbamoyl‐heptanoyloxy)‐benzoic acid methyl ester derivative containing a terminal hydroxamic acid. The synthesis involved four radiochemical transformations. The key step in the radiosynthesis was the conversion of the 7‐[14C]‐cyano‐heptanoic acid benzyloxyamide [14C]‐4 directly into the carboxylic acid derivative, 7‐benzyloxycarbamoyl‐[14C]‐heptanoic acid [14C]‐8 using nitrilase‐113 biocatalyst. The final step involved deprotection of the benzyloxy group using catalytic hydrogenation to facilitate the release of the hydroxamic acid without cleaving the phenoxy ester. [14C]‐SHP‐141 was isolated with a radiochemical purity of 90% and a specific activity of 190 μCi/mg from four radiochemical steps starting from potassium [14C]‐cyanide in a radiochemical yield of 45%.