Preparation of (R)- and (S)-6-hydroxybuspirone by enzymatic resolution or hydroxylation

6-Hydroxybuspirone is an active metabolite of the antianxiety drug buspirone. The (R)- and (S)-enantiomers of 6-hydroxybuspirone were prepared using an enzymatic resolution process. l-Amino acid acylase from Aspergillus melleus (Amano Acylase 30000) was used to hydrolyze racemic 6-acetoxybuspirone to (S)-6-hydroxybuspirone in 95% ee after 45% conversion. The remaining (R)-6-acetoxybuspirone with 88% ee was converted to (R)-6-hydroxybuspirone by acid hydrolysis. The ee of both enantiomers could be improved to 99% by crystallization as a metastable polymorph. (S)-6-Hydroxybuspirone was also obtained in 88% ee and 14.5% yield by hydroxylation of buspirone using Streptomyces antibioticus ATCC 14890.

Figure optionsDownload as PowerPoint slide

(S)-6-HydroxybuspironeC21H31N5O3Ee = 99.6%[α]D32=-37.5 (c 1, 1 M HCl)Source of chirality: enzymatic resolutionAbsolute configuration: 6S