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.
Hauck
Willy
W
Novasep Inc., Boothwyn, Pennsylvania, USA.
Adam
Philippe
P
Bobier
Christelle
C
Landmesser
Nelson
N
D001559:Benzhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D002845:Chromatography / Q000379:methods*; D003460:Crystallization; D000077408:Modafinil; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013237:Stereoisomerism
D001559:Benzhydryl Compounds; D012997:Solvents; D000077408:Modafinil