The Synthesis of the High-Potency Sweetener, NC-00637. Part 2: Preparation of the Pyridine Moiety

The pyridine moiety within the high-potency sweetener, NC-00637 ( 1 ), 5-amino-2-cyanopyridine ( 4 ), was prepared from 2-hydroxy-5-nitropyridine ( 10 ). The sequence involved the conversion of the hydroxy group to bromide followed by substitution with cyanide to give 2-cyano-5-nitropyridine ( 8 ). Reduction of the nitro group proved to be troublesome when catalytic hydrogenation was used. Iron with an acid gave a reproducible reaction that could be used at scale.