Scalable Synthesis of High-Purity (R, R)-Dexmethylphenidate Free Base

A practical method for the preparation of high-purity (R, R)-dexmethylphenidate free base was developed. The method involves a substitution reaction of 2-chloropyridine and phenylacetonitrile via hydrolysis followed by hydrogenation, configuration inversion, chiral resolution, methyl esterification, and salification to give high-purity dexmethylphenidate hydrochloride. The hydrochloride salt was then neutralized by powder sodium hydroxide overnight to give dexmethylphenidate free base with over 99% purity. This method can be used for the industrial production of the dexmethylphenidate patch API, which could also be further applied for the preparation of other types of amino acid ester free bases.