Hydrochloric Acid → (1S)-2-Bromo-1-(4-fluorophenyl)ethanol

Temperature

40 °C

Under a nitrogen atmosphere, charge a 30 liter round bottom flask with a solution of (S)-1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborole (1 M in toluene; 44 mL; 44 mmol) at 22° C. Add a solution of borane-N,N-diethylaniline complex (1230 g; 7540 mmol) in methyl t-butyl ether (4.5 L). Heat and maintain the mixture at 40° C. for 30 min. Add a solution of bromo-4-fluoroacetophenone (1640 g; 7530 mmol) in methyl t-butyl ether (4.5 L) drop-wise over 30 min. Stir the mixture at 40° C. for 2 hours. Cool to 10° C. using an ice water bath; then slowly add MeOH (590 mL) to quench the reaction. Stir the mixture for 30 min while maintaining it at 10-20° C. Add hydrochloric acid (3.0 M, 7.5 L) to the mixture while it is at 10° C. Stir for one hour and filter. Collect the filtrate. Separate the layers in the filtrate; extract the aqueous phase with methyl tert-butyl ether (1×3 L); combine the organic phases and wash with brine; dry over Na2SO4; and filter; and remove the volatiles from the filtrate under reduced pressure to give the title compound as a pale yellow oil (1650 g, 99%). MS (m/z): 201 (M-OH); ee value: 97.5% (AD-H 250 mm×4.6 mm×5 μm column using 99:1 hexanes:EtOH at 25° C. with a flow rate of 1.0 mL/min).

1. temperatureHeat
2. temperatureCool to 10° C.
3. customthen slowly add MeOH (590 mL) to quench
4. customthe reaction
5. stirringStir the mixture for 30 min
6. temperaturewhile maintaining it at 10-20° C
7. customis at 10° C
8. stirringStir for one hour
9. filtrationfilter
10. customCollect the filtrate
11. customSeparate the layers in the filtrate
12. extractionextract the aqueous phase with methyl tert-butyl ether (1×3 L)
13. washwash with brine
14. dry with materialdry over Na2SO4
15. filtrationand filter
16. customand remove the volatiles from the filtrate under reduced pressure

ORD record

ord-5caadcc3ebfd448980c1c17361282e7c

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08993568B2