反应详情

A 22 liter, three-neck, round bottom flask equipped with a mechanical stirrer, thermocouple, and reflux condenser with N2 inlet adapter was charged with THF (6.0 L), methyl isonicotinate (259.1 g, 1.89 mol), and 4-fluorophenylacetone (287.5 g, 1.89 mol). Sodium methoxide (204.3 g, 3.78 mol) was added in several portions. The addition of sodium methoxide is slightly exothermic. The reaction mixture turned orange and was heated to reflux for 2 hours. After 2 hours, the absence of methyl isonicotinate and the formation of the β-diketone were verified by LC-MS. After the addition of ethanol (6 L) and acetic acid (380 mL), the temperature of the reaction mixture decreased to 45° C. The reflux condenser was then replaced with an addition funnel and hydrazine (387 g, 6.0 mol) was added drop-wise. During the addition the temperature of the reaction rose to 60° C. The reaction mixture was then stirred overnight slowly cooling to room temperature. The majority of the solvents were removed by rotary evaporation. The reaction mixture was partitioned between water (4.5 L) and ethyl acetate (4.5 L). The layers were separated and the aqueous layer extracted with ethyl acetate (4.5 L). The combined organic layers were then washed with dilute NaHCO3, brine, dried (Na2SO4), filtered and concentrated. The resulting solid was triturated with ether (2 L) and the solid isolated by filtration. The solid was washed with ether (1.5 L) until the filtrate was colorless. This process gave 190 g (40%) of the title compound. Additional material (5 g) was then isolated by column chromatography using 5% methanol:95% methylene chloride. 1H NMR (400 MHz, DMSO-D6) δ ppm 13.10 (s, 1 H), 8.44-8.60 (m, 2 H), 7.68 (d, 2 H), 7.30 (t, 2 H), 7.13 (t, 2 H), 6.62 (s, 1 H), 4.00 (s, 2 H); m/z (APCI+) for C15H12N3F 254.2 (M+H)+.

1. customA 22 liter, three-neck, round bottom flask equipped with a mechanical stirrer
2. temperaturethermocouple, and reflux condenser with N2 inlet adapter
3. temperaturewas heated
4. temperatureto reflux for 2 hours
5. customdecreased to 45° C
6. customThe reflux condenser was then replaced with an addition funnel
7. additionDuring the addition the temperature of the reaction
8. customrose to 60° C
9. customThe majority of the solvents were removed by rotary evaporation
10. customThe reaction mixture was partitioned between water (4.5 L) and ethyl acetate (4.5 L)
11. customThe layers were separated
12. extractionthe aqueous layer extracted with ethyl acetate (4.5 L)
13. washThe combined organic layers were then washed with dilute NaHCO3, brine
14. dry with materialdried (Na2SO4)
15. filtrationfiltered
16. concentrationconcentrated
17. customThe resulting solid was triturated with ether (2 L)
18. customthe solid isolated by filtration
19. washThe solid was washed with ether (1.5 L) until the filtrate