Potassium Carbonate → 2-Chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine

To a solution of 2-chloropyridin-4-ol (100 g, 772 mmol) in anhydrous DMF (2 L) was added K2CO3 (128 g, 926 mmol) in one portion at RT. The mixture was stirred for 10 min at RT, and was then treated with 1,2,4-trifluoro-5-nitrobenzene (88 mL, 772 mmol) slowly over 10 min. The internal temp of the reaction mixture was maintained below 24° C. during the addition. The reaction was stirred at RT for 1 h and then it was stopped by adding ice/water (10 L). The mixture was stirred for 2 h and then filtered to remove the solids. The solids were washed with water (5 L), hexanes (3 L) and then dried under vacuum at 50° C. to give 194.7 g of crude material. The solids were treated with MTBE (200 mL), stirred for 2 h, collected by filtration, washed with MTBE (50 mL) and dried under vacuum at 40° C. for 3 h to afford 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (164.6 g, 74.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.48 (dd, J=10.2, 7.0 Hz, 1H), 8.41 (d, J=5.6 Hz, 1H), 7.90 (dd, J=11.6, 6.7 Hz, 1H), 7.41 (d, J=2.1 Hz, 1H), 7.26 (dd, J=5.6, 2.4 Hz, 1H); MS (ESI): m/z 287.0 (M+H+).

1. temperatureThe internal temp of the reaction mixture was maintained below 24° C. during the addition
2. stirringThe reaction was stirred at RT for 1 h
3. stirringThe mixture was stirred for 2 h
4. filtrationfiltered
5. customto remove the solids
6. washThe solids were washed with water (5 L), hexanes (3 L)
7. customdried under vacuum at 50° C.
8. customto give 194.7 g of crude material
9. stirringstirred for 2 h
10. filtrationcollected by filtration
11. washwashed with MTBE (50 mL)
12. customdried under vacuum at 40° C. for 3 h

ORD record

ord-26f54593d1b44e798049482868b83776

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08921565B2