L-Tartaric acid → 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester-L-(+)-tartrate salt

Participants

Reaction Steps

To a solution of L-(+)-tartaric acid in refluxing 2.5% water/2-butanone (105 mL) was added 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester (Preparation 2, Method C; 9.11 g, 25.8 mmol) in 2.5% water/2-butanone (20 mL). The resulting solution was allowed to cool to ambient temperature with stirring. As the mixture cooled, a white solid precipitated out. The suspension was allowed to stir at ambient temperature for 64 h. The precipitate was collected on a Buchner funnel and rinsed with 2-butanone and dried under vacuum to yield 5.66 g (44%) of 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester-L-(+)-tartrate salt (87.5% ee). The white solid was slurried in 2.5% water/2-butanone (59.5 mL) and heated to reflux. Water was added slowly until the milky suspension became clear. The resulting solution was allowed to cool to ambient temperature with stirring. As the mixture cooled, a white solid precipitated out. The suspension was allowed to stir at ambient temperature for 64 h. The precipitate was collected on a Buchner funnel and rinsed with 2-butanone and dried under vacuum to yield 4.86 g (37% overall) of (S)-2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester-L-(+)-tartrate salt (98% ee; [α]D25=11.2° (c 0.86, CH3OH); HPLC analysis: chiralpak AD 1.5 mL/min, 5% isopropanol/hexanes w/0.5% diethylamine, retention time=6.65 min (R) and 8.08 min (S)).

Provenance & Evidence