Use of large‐scale chromatography in the preparation of armodafinil

Armodafinil, the ( R )‐enantiomer of modafinil, is a medication used to treat the excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder. We report here the chemical development of armodafinil and the investigations that led to a commercial route to prepare this pure enantiomer. Three synthetic approaches were used to provide the chiral sulfoxide. Resolution via preferential crystallization was used for phase I clinical trials and was subsequently replaced by chiral chromatography, enabling us to pursue a rapid filing and registration of the API. Finally, the commercial route was developed and employed asymmetric oxidation catalyzed by a titanium(IV) isopropoxide and diethyl tartrate system. The advantages of choosing a chromatographic development pathway to expedite registration while concurrently developing an economical chiral synthesis route is discussed in the context of armodafinil development. Chirality, 2008. © 2008 Wiley‐Liss, Inc.