Scalable Synthesis of a Nonracemic α-Arylpropionic Acid via Ketene Desymmetrization for a Glucokinase Activator

Process research and development for a synthesis of the chiral carboxylic acid ( R )-2 as a key intermediate of the glucokinase activator ( R )-1 is described. The construction of the stereocenter at the α-carbon is a key point for the synthesis of ( R )-2 . The proposed process utilizes desymmetrization of a ketene in situ generated from the corresponding racemic carboxylic acid Rac -2 with ( R )-pantolactone as a chiral auxiliary followed by hydrolysis of the resulting ester. This key step has been successfully scaled up to 20 kg, which demonstrates that this synthetic approach is comparable with a previously reported approach via enantioselective hydrogenation.