tert-Butyl isocyanate → 2-bromo-N-tert-butyl-4-(2-cyanopropan-2-yl)-6-fluorobenzamide

温度

-76 °C

To a solution of 2-(3-bromo-5-fluorophenyl)-2-methylpropanenitrile (30 g, 124 mmol, 1.0 equiv.) in 180 mL THF was added lithium diisopropylamide (82.6 ml of 1.8 M, 149 mmol, 1.2 equiv.) dropwise at −75° C. The reaction mixture was stirred at −76° C. for 2 hr. The tert-butylisocyanate (18.4 g, 21.8 ml, 186 mmol, 1.5 equiv.) was added dropwise at −75° C. and stirring was continued for 2 hr. An additional 0.5 equiv. of tert-butylisocyanate was added and the reaction mixture was allowed to warm gradually to room temperature and stirred overnight. The reaction mixture was quenched with 180 mL water and the THF was then removed under reduced pressure at 60° C. IPA was added at 60° C. and the product was crystallized out from 180 mL H2O and 120 mL IPA at 60° C. The mixture was cooled to room temperature slowly overnight. The crystals were collected by filtration, washed with H2O, H2O/IPA (1/1), and heptane, and dried overnight to afford 2-bromo-N-tert-butyl-4-(2-cyanopropan-2-yl)-6-fluorobenzamide (34.7 g, 102 mmol, 82.1% yield) as white crystalline solid with >99% HPLC purity. 1H NMR (300 MHz, DMSO-d6) 8 ppm 1.34 (s, 9 H) 1.70 (s, 6 H) 7.47 (dd, J=10.01, 1.70 Hz, 1 H) 7.60 (s, 1 H) 8.34 (s, 1 H).

1. stirringstirring
2. waitwas continued for 2 hr
3. temperatureto warm gradually to room temperature
4. stirringstirred overnight
5. customThe reaction mixture was quenched with 180 mL water
6. customthe THF was then removed under reduced pressure at 60° C
7. additionIPA was added at 60° C.
8. customthe product was crystallized out from 180 mL H2O and 120 mL IPA at 60° C
9. temperatureThe mixture was cooled to room temperature slowly overnight
10. filtrationThe crystals were collected by filtration
11. washwashed with H2O, H2O/IPA (1/1), and heptane
12. customdried overnight

ORDレコード

ord-de6a8837ef204b708215a65fbb12f73a

出典データセット

uspto-grants-2014_11

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08889682B2