4-Fluoromandelic acid → (2R)-2-(4-fluorophenyl)-2-hydroxyacetic acid

온도

60 °C

The reaction was performed in a 1 L reactor under an atmosphere of nitrogen with 200 rpm stirring. 2-(4-Fluorophenyl)-2-hydroxyacetic acid (139 g, 816.98 mmol) was charged into the reactor. Ethanol (800 mL) was added which resulted in a turbid mixture. The mixture was heated to reflux with a ramp of 1° C./min. (R)-(+)-1-phenylethylamine (68.5 mL, 531.04 mmol) was then added within 5 minutes. The clear homogenous solution was then allowed to slowly cool to 60° C. with a ramp of 1° C./min. When that temperature was reached, seeds of 95:5 diastereomeric purity was added (˜100 mg). Crystallisation now slowly initiated. The temperature was ramped down to 20° C. with 0.5° C./min. When that temperature was reached the mixture was allowed to stir for another 2 hours. The mixture was then filtrated. This furnished crystals of the ammonium salt (95 g). This salt was then re-crystallised from ETOH (99.5%, 800 mL) using the following procedure: In a 1 L reactor and under an atmosphere of nitrogen, the salt obtained above was charged into the reactor. EtOH (800 mL) was added (a suspension was obtained) and the temperature was then increased to reflux with a ramp of 1° C./min. When all salt was dissolved, the temperature was ramped down with 1° C./min-->65° C. When that temperature was reached (clear homogenous solution), seeding crystals were added (approximately 0.5 g was added). Crystallization initiated immediately but very slowly. The temperature was then ramped down to 20° C. with 0.5° C./min. The mixture was then stirred (200 rpm) over night. After filtration and drying in vacuo, 67.9 g of the salt was obtained. Chiral HPLC analysis of the free acid of the salt showed an enantiomeric excess of 95.2% (97.6:2.4 er). The salt was recrystallized one more time from ETOH (99.5%, 500 mL) using the same procedure as described above but the mixture was only allowed to stir for 2 hours at room temperature instead of stirring over night. After filtration and drying, 56.3 g of crystals of the ammonium salt were obtained. Chiral HPLC analysis of the free acid showed an enantiomeric excess of 99.1%.