反应详情

温度

130 °C

Compound 18 was prepared as outlined in Scheme 4. Accordingly, potassium t-butoxide (6.1 g) was added slowly to a stirred solution of tert-butylnitrite (5.5 mL) and 2-fluoro-4-methylpyridine (compound 1001, 4.0 g) in 75 mL of THF at 0° C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the crude product extracted with ethyl acetate (4×50 mL). The resulting solid was washed with hexanes to yield (2-fluoropyridin-4-yl)methan-N-hydroxyimine (compound 1002; 4.0 g; ESMS: M+H+=141). Thionyl chloride (2.6 mL) was added slowly to a stirred solution of compound 1002 (4.0 g in 40 mL of THF) at 0° C. After stirring for 1 hour at room temperature, the volatiles were removed in vacuo. The residue was taken up in ethyl acetate (50 mL) and the organics were washed with water and brine. The organics were concentrated in vacuo to give 2-fluoropyridine-4-carbonitrile (compound 1003) as a white solid (3.0 g; ESMS: M+H+=123). Compound 1003 (1.0 g) and 4-methoxybenzylamine were combined and heated at 130° C. for 1 hour. The crude product was partitioned between water and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate and the combined organics dried over Na2SO4, concentrated, and recrystallized from ethyl acetate/hexanes to provide 2-(4-methoxybenzylamino)pyridine-4-carbonitrile (compound 1004; 1.7 g; ESMS: M+H+=238) as pale yellow solid. Compound 1004 (1.6 g) was dissolved in 50 mL of anhydrous ether and 9 mL of 3M methyl magnesium bromide in ether was added. The reaction mixture was stirred at room temperature for 16 hours and poured over ice (c. 50 g), which was subsequently acidified with 6M HCl, followed by basicification with 1M ammonium hydroxide. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organics were concentrated in vacuo and purified by silica gel chromatography to provide 1-(2-(4-methoxybenzylamino)pyridin-4-yl)ethanone (Compound 1005; 1.2 g; ESMS: M+H+=257) as a yellow solid.

1. customThe crude product was partitioned between water and ethyl acetate (50 mL)
2. extractionThe aqueous layer was extracted with ethyl acetate
3. dry with materialthe combined organics dried over Na2SO4
4. concentrationconcentrated
5. customrecrystallized from ethyl acetate/hexanes