Reaktion #59700

Reaktionsgleichung

3-Fluoro-4-methylbenzoic acid

bromine

Cyclopropylamine

HOBT

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

DIPEA

→

3-bromo-N-cyclopropyl-5-fluoro4methylbenzamide

Ausbeute 44.0%

Lösungsmittel

Sodium thiosulphate

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.WAITleft
2. 2
   workup.WAITto stand for 16 hours
3. 3
   Extraktionthe product was extracted into ethyl acetate (3×150 ml)
4. 4
   Sonstigeevaporated in vacuo
5. 5
   workup.DISSOLUTIONThe crude product (mixture of isomers) was dissolved in dimethylformamide (7 ml)
6. 6
   workup.STIRRINGThe reaction was stirred for 5 hours at 20° C
7. 7
   SonstigeSolvent was removed in vacuo
8. 8
   Sonstigethe residue was partitioned between ethyl acetate and water
9. 9
   WaschenCombined ethyl acetate extracts were washed sequentially with aqueous sodium hydrogen carbonate and hydrochloric acid (0.5M)
10. 10
    Trocknendried (magnesium sulphate)
11. 11
    SonstigeThe ethyl acetate was evaporated in vacuo
12. 12
    Sonstigethe residue was purified by silica biotage chromatography
13. 13
    Wascheneluting with cyclohexane:ethyl acetate (6: 1)

Vorschrift

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%).

Quelle