1-Bromo-2-(trifluoromethoxy)benzene → (2-Amino-5-bromo-pyridin-3-yl)-(2-trifluoromethoxy-phenyl)-methanone

Temperature

-78 °C

To a flame-dried 100 ml round bottomed flask was added 1-bromo-2-(trifluoromethoxy)benzene (2.39 g, 9.9 mmol). The flask was fitted with a rubber septum, purged with nitrogen then charged with anhydrous THF (20 ml). The solution was cooled to −78° C. for 10 min, then a 2.5 M solution of n-butyl lithium in hexanes (3.9 ml, 9.8 mmol) was added dropwise over 3 minutes. The resulting solution was stirred at −78° C. for 40 minutes under nitrogen, then a solution of 739 mg (2.84 mmol) of 2-amino-5-bromo-N-methoxy-N-methyl-nicotinamide in 5 ml of THF was added dropwise over 3 minutes. The resulting red solution was allowed to warm to room temperature over 5 hours, then the reaction was quenched by addition of 10 ml of a saturated aqueous solution of ammonium chloride. Ethyl acetate (50 ml) was added, and the layers were separated. The aqueous fraction was extracted three times with ethyl acetate, and the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes gave 530 mg (52%) of (2-amino-5-bromo-pyridin-3-yl)-(2-trifluoromethoxy-phenyl)-methanone as a yellow-orange solid. 1H-NMR (CDCl3) δ=8.29 (d, 1H), 7.60 (m, 2H,), 7.45 (t, 1H), 7.42 (m, 3H), 1.79 (br. s, 2H); MS m/z: 361 [MH]+.

1. customThe flask was fitted with a rubber septum
2. custompurged with nitrogen
3. additionthen charged with anhydrous THF (20 ml)
4. temperatureto warm to room temperature over 5 hours
5. customthe reaction was quenched by addition of 10 ml of a saturated aqueous solution of ammonium chloride
6. additionEthyl acetate (50 ml) was added
7. customthe layers were separated
8. extractionThe aqueous fraction was extracted three times with ethyl acetate
9. washthe combined organic fractions were washed with brine
10. dry with materialdried (Na2SO4)
11. filtrationfiltered
12. concentrationconcentrated
13. customPurification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes

ORD record

ord-06f61814d1684adfb8e6ed4407193e62

Source dataset

uspto-grants-2010_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07709645B2