| 82.3% |
With potassium carbonate; tricyclohexylphosphine;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; In water; toluene; for 24h;Inert atmosphere of nitrogen; Reflux; |
A mixture of 4-bromo-2-fluoro-6-methylbenzamide (10 g), cyclopropylboronic acid (4.87 g, 1.25 eq), tricyclohexylphosphine (725 mg, 0.06 eq), tris (dibenzyllideneacetone)dipalladium(0) chloroform adduct (446 mg, 0.01 eq) and potassium carbonate (17.9 g, 3 eq) in toluene (100 ml) and water (10 ml) was stirred under reflux in an inert (nitrogen) environment for about 24 h. The reaction mixture was then cooled to about 60 C. and treated with 10% aqueous ammonium hydroxide (60 ml) and then with ethyl acetate (60 ml). Layers were separated, the organic phase was washed with brine and filtered to remove particulate material. The extract was concentrated under reduced pressure to about 30 ml to obtain a slurry. This was diluted with heptane (80 ml) and ethyl acetate (20 ml) and then heated to reflux to dissolve all solids. The resulting solution cooled slowly to room temperature to allow the product to crystallize out. The precipitated product was isolated by filtration, washed with ethyl acetate-heptane (1:1) mixture (60 ml), dried under vacuum at about 60 C. to obtain 6.85 g (82.3% isolated yield) of product. |
| 5.3 g |
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; tricyclohexylphosphine; In water; toluene; at 115℃; for 14h;Inert atmosphere; |
Under nitrogen atmosphere, cyclopropylboronic acid (6.11 g, 71.1 mmol), tricyclohexylphosphine (0.80 g, 2.84 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.43 g, 0.47 mmol) and potassium carbonate (19.65 g, 142.0 mmol) were added to a mixed solution of 4-bromo-2-fluoro-6-methylbenzamide (11.0 g) in toluene (110 mL) and water (11 mL), and stirred at 115 C. for 14 h. After being cooled to ambient temperature, the precipitate was collected by filtration, washed with ether and water, then dried to afford 4-cyclopropyl-2-fluoro-6-methylbenzamide (3.3 g). The filtrate was extracted with ethyl acetate (2*200 mL), and the combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by chromatography on silica gel, eluted with hexane/ethyl acetate to afford 4-cyclopropyl-2-fluoro-6-methylbenzamide (5.3 g). 1H NMR (400 MHz, CDCl3) 6.80-6.70 (m, 1H), 6.60 (dd, J=11.3, 1.6 Hz, 1H), 5.99-5.59 (m, 2H), 2.43 (s, 3H), 1.89-1.80 (m, 1H), 1.03-0.98 (m, 2H), 0.73-0.65 (m, 2H); LCMS (m/z): 194.0 [M+H]+. |
| 5.3 g |
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; tricyclohexylphosphine; In water; toluene; at 115℃; for 14h;Inert atmosphere; |
Under nitrogen atmosphere, cyclopropylboronic acid (6.11 g, 71.1 mmol), tricyclohexylphosphine (0.80 g, 2.84 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.43 g, 0.47 mmol) and potassium carbonate (19.65 g, 142.0 mmol) were added to a mixed solution of 4-bromo-2-fluoro-6-methylbenzamide (11.0 g) in toluene (110 mL) and water (11 mL), and stirred at 115 C. for 14 h. After being cooled to ambient temperature, the precipitate was collected by filtration, washed with ether and water, then dried to afford 4-cy-clopropyl-2-fluoro-6-methylbenzamide (3.3 g). The filtrate was extracted with ethyl acetate (2x200 mL), and the combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by chromatography on silica gel, eluted with hexane/ ethyl acetate to afford 4-cyclopropyl-2-fluoro-6-methylbenzamide (5.3 g). |
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