Реакция #2161262

Уравнение реакции

methyl isonicotinate

Sodium methoxide

sodium methoxide

hydrazine

methyl isonicotinate

4-fluorophenylacetone

→

title compound

Выход 40.0%

4-[5-(4-fluorobenzyl)-1H-pyrazol-3-yl]pyridine

Выход 40.0%

Растворители

THF

acetic acid

ethanol

Условия реакции

Обработка

1. 1
   ДругоеA 22 liter, three-neck, round bottom flask equipped with a mechanical stirrer
2. 2
   Температураthermocouple, and reflux condenser with N2 inlet adapter
3. 3
   Температураwas heated
4. 4
   Температураto reflux for 2 hours
5. 5
   Другоеdecreased to 45° C
6. 6
   ДругоеThe reflux condenser was then replaced with an addition funnel
7. 7
   workup.ADDITIONDuring the addition the temperature of the reaction
8. 8
   Другоеrose to 60° C
9. 9
   ДругоеThe majority of the solvents were removed by rotary evaporation
10. 10
    ДругоеThe reaction mixture was partitioned between water (4.5 L) and ethyl acetate (4.5 L)
11. 11
    ДругоеThe layers were separated
12. 12
    Экстракцияthe aqueous layer extracted with ethyl acetate (4.5 L)
13. 13
    ПромывкаThe combined organic layers were then washed with dilute NaHCO3, brine
14. 14
    Сушкаdried (Na2SO4)
15. 15
    Фильтрацияfiltered
16. 16
    Концентрированиеconcentrated
17. 17
    ДругоеThe resulting solid was triturated with ether (2 L)
18. 18
    Другоеthe solid isolated by filtration
19. 19
    ПромывкаThe solid was washed with ether (1.5 L) until the filtrate

Методика

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)+.

Источник