4-Fluoromandelic acid → 4-Fluoro-D-mandelic acid

Temperature

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%.

1. customThe reaction was performed in a 1 L reactor under an atmosphere of nitrogen with 200 rpm
2. customresulted in a turbid mixture
3. temperatureThe mixture was heated
4. additionwas then added within 5 minutes
5. additionseeds of 95:5 diastereomeric purity was added (˜100 mg)
6. customCrystallisation
7. customwas ramped down to 20° C. with 0.5° C./min
8. stirringto stir for another 2 hours
9. filtrationThe mixture was then filtrated
10. customThis salt was then re-crystallised from ETOH (99.5%, 800 mL)
11. customIn a 1 L reactor and under an atmosphere of nitrogen, the salt obtained
12. additionabove was charged into the reactor
13. customwas obtained) and the temperature
14. temperaturewas then increased
15. temperatureto reflux with a ramp of 1° C./min
16. dissolutionWhen all salt was dissolved
17. additionwere added
18. addition(approximately 0.5 g was added)
19. customCrystallization
20. customwas then ramped down to 20° C. with 0.5° C./min
21. stirringThe mixture was then stirred (200 rpm) over night
22. filtrationAfter filtration
23. customdrying in vacuo

ORD record

ord-4c298b410ba2474f8258b7d222430b4c

Source dataset

uspto-grants-2012_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08119673B2