Hydrochloric Acid → Methyl 2-(2,4-difluorobenzyl)isonicotinate

Temperature

60 °C

Methyl 2-chloroisonicotinate (5.2 g, 30.31 mmol) and Pd(PPh3)4 (0.700 g, 0.61 mmol) were dissolved in THF (100 mL) under nitrogen and (2,4-difluorobenzyl)zinc(II) chloride (0.5 M in THF, 90 mL, 45.00 mmol) was added and the brown solution was stirred at 60° C. overnight (18 h). The reaction was quenched by addition of methanol (50.0 mL). The solution was diluted with EtOAc and washed with NH4Cl (aq) and brine and dried over Na2SO4 to give a red oil. The crude was redissolved in MTBE (200 mL) and solids were filtered off. Hydrogen chloride (4 M in dioxane, 7.58 mL, 30.31 mmol) was added dropwise during stirring and a suspension was formed. The suspension was stirred at room temperature for 15 min. The solid was collected by filtration and washed with MTBE. The solid was dissolved in MTBE/satd NaHCO3. The phases were separated, the organic phase dried over Na2SO4, filtered and evaporated to yield methyl 2-(2,4-difluorobenzyl)isonicotinate (7.011 g, 88%) as a red oil. 1H NMR (400 MHz, cdcl3) δ 3.93 (s, 3H), 4.20 (s, 2H), 6.77-6.88 (m, 2H), 7.18-7.25 (m, 1H), 7.62-7.73 (m, 2H), 8.69 (dd, 1H). MS m/z 264 (M+H)+

1. customThe reaction was quenched by addition of methanol (50.0 mL)
2. additionThe solution was diluted with EtOAc
3. washwashed with NH4Cl (aq) and brine
4. dry with materialdried over Na2SO4
5. customto give a red oil
6. filtrationsolids were filtered off
7. stirringduring stirring
8. customa suspension was formed
9. stirringThe suspension was stirred at room temperature for 15 min
10. filtrationThe solid was collected by filtration
11. washwashed with MTBE
12. dissolutionThe solid was dissolved in MTBE/satd NaHCO3
13. customThe phases were separated
14. dry with materialthe organic phase dried over Na2SO4
15. filtrationfiltered
16. customevaporated

ORD record

ord-776a694fab324a369f648519381e7f51

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08415378B2