反应详情

温度

20 °C

3-Fluoro-4-methylbenzoic acid (462 mg, 3.0 mmol) was added to a stirred mixture of bromine (2.31 ml, 45 mmol) and iron powder (252 mg, 4.5 mmol) under nitrogen. The reaction was stirred at 20° C. for 4 hours and then left to stand for 16 hours. Sodium thiosulphate solution (200 ml) was added and the product was extracted into ethyl acetate (3×150 ml). Ethyl acetate extracts were combined and evaporated in vacuo. The crude product (mixture of isomers) was dissolved in dimethylformamide (7 ml). Cyclopropylamine (208 μl, 3.0 mmol), HOBT (405 mg, 3.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (575 mg, 3.0 mmol) and DIPEA (525 μl, 3.0 mmol) were added to the stirred solution. The reaction was stirred for 5 hours at 20° C. Solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. Combined ethyl acetate extracts were washed sequentially with aqueous sodium hydrogen carbonate and hydrochloric acid (0.5M), then dried (magnesium sulphate). The ethyl acetate was evaporated in vacuo and the residue was purified by silica biotage chromatography eluting with cyclohexane:ethyl acetate (6: 1) to give 3-bromo-N-cyclopropyl-5-fluoro4methylbenzamide (359 mg, 44%).

1. waitleft
2. waitto stand for 16 hours
3. extractionthe product was extracted into ethyl acetate (3×150 ml)
4. customevaporated in vacuo
5. dissolutionThe crude product (mixture of isomers) was dissolved in dimethylformamide (7 ml)
6. stirringThe reaction was stirred for 5 hours at 20° C
7. customSolvent was removed in vacuo
8. customthe residue was partitioned between ethyl acetate and water
9. washCombined ethyl acetate extracts were washed sequentially with aqueous sodium hydrogen carbonate and hydrochloric acid (0.5M)
10. dry with materialdried (magnesium sulphate)
11. customThe ethyl acetate was evaporated in vacuo
12. customthe residue was purified by silica biotage chromatography
13. washeluting with cyclohexane:ethyl acetate (6: 1)