1-(4-Bromophenyl)-2-chloroethan-1-one → HCID 25324183, compound

Temperature

45 °C

Borane dimethylsulfide (2.0 kg, 24.8 moles, 94% w/w) was mixed in toluene (8 L) at tjacket=20° C. (R)-(+)-Methyl-CBS-oxazaborolidine (2.6 kg, 2.74 moles, 1M) as a toluene solution was added. The charging vessel was rinsed with toluene (0.5 L) and tjacket was set to 45° C. 1-(4-Bromo-phenyl)-2-chloro-ethanone (7.84 kg, 33.6 moles), which is commercially available from Jiangyan Keyan Fine Chemical Co. Ltd, was dissolved in 2-MeTHF (75 L) in a separate vessel and when tinner was above 40° C. in the first vessel, the 2-MeTHF solution was added during 3 h. The latter vessel was rinsed with 2-MeTHF (2 L) and added to the reaction mixture, which was left stirring at tjacket=45° C. for 1 h. Analysis of a sample on HPLC indicated full conversion at this point using the following gradient method (mobile phase 20-95% B; A: 5% CH3CN in H2O with 0.1% TFA, B: 95% CH3CN in H2O with 0.085% TFA, 10 min run) on Chromolith Performance RP-18e, 4.6×100 mm. The reaction mixture was cooled to tjacket=10° C. before slow quench with MeOH (36 L). The first liter of MeOH was added during 30 min. and the rest during additional 30 min. MeOH was distilled off under vacuum at tjacket=50° C. The organic solution left was cooled to tjacket=20° C., washed with 1M HCl in H2O (7 L conc HCl+73 L H2O) and concentrated under vacuum at tjacket=50° C. to approximately 40 L. Example 1 obtained in a 2-MeTHF solution can be stored at 10° C. for 20 h or used directly in the next synthetic step.

1. additionwas added
2. washThe charging vessel was rinsed with toluene (0.5 L) and tjacket
3. customwas set to 45° C
4. customwas above 40° C. in the first vessel
5. washThe latter vessel was rinsed with 2-MeTHF (2 L)
6. additionadded to the reaction mixture, which
7. waitwas left
8. customwith 0.085% TFA, 10 min
9. temperatureThe reaction mixture was cooled
10. custom=10° C.
11. custombefore slow quench with MeOH (36 L)
12. additionThe first liter of MeOH was added during 30 min.
13. waitthe rest during additional 30 min
14. distillationMeOH was distilled off under vacuum at tjacket=50° C
15. waitThe organic solution left
16. temperaturewas cooled
17. custom=20° C.
18. washwashed with 1M HCl in H2O (7 L conc HCl+73 L H2O)
19. concentrationconcentrated under vacuum at tjacket=50° C. to approximately 40 L

ORD record

ord-1cf616d624644d87b5659a8816f43175

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09012452B2