Hydrochloric Acid → Methyl 2-(2,4,5-trifluorophenyl)isonicotinate

HRID 1963200Notes

Reaction equation

HRID 1963200 reaction equation
Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>CO.CC(OC)(C)C.Cl[Pd]Cl.O.C(Cl)Cl>[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]

Participants

10

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 2736842Methyl 2-chloropyridine-4-carboxylateHCID 27831332,4,5-Trifluorophenylboronic acid

Product 1

HCID 66732429Methyl 2-(2,4,5-trifluorophenyl)isonicotinateYield 33.1%

Reagents, catalysts & solvents 5

HCID 24290Palladium ChlorideCatalystHCID 887MethanolSolvent2×HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
100 °C

Procedure

Methyl 2-chloroisonicotinate (3.25 g, 18.94 mmol), 2,4,5-trifluorophenylboronic acid (5.00 g, 28.41 mmol), potassium carbonate (3.93 g, 28.41 mmol) and PdCl2 (dppf) (0.411 g, 0.57 mmol) were mixed in methanol (20 mL) in two 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. The reaction mixture was suspended in methanol, filtered and the filtrate evaporated to yield a dark red slurry. DCM and water were added and the phases separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a brown solid. The crude brown solid was dissolved in MTBE (120 mL) and solids filtered off. Hydrogen chloride (4 M in dioxane, 4.74 mL, 18.94 mmol) was added dropwise and a suspension was formed. The suspension was stirred at room temperature for 45 min. The solid was collected by filtration and washed with MTBE. MTBE and satd NaHCO3 were added. The organic phase was dried over Na2SO4, filtered and evaporated to yield methyl 2-(2,4,5-trifluorophenyl)isonicotinate (1.676 g, 33%) as a beige solid. The MTBE-filtrate was washed with satd NaHCO3, dried over Na2SO4, filtered and evaporated to yield a brown solid. The residue was purified via Biotage (0=>20% EtOAc in heptane, 6 CV; Biotage® KP-SIL 100 g column) to yield methyl 2-(2,4,5-trifluorophenyl)-isonicotinate (0.86 g, 17%) as a white solid. 1H NMR (600 MHz, cdcl3) δ 3.97 (s, 3H), 7.00-7.07 (m, 1H), 7.81 (dd, 1H), 7.90-7.97 (m, 1H), 8.32-8.33 (m, 1H), 8.83 (dd, 1H). MS m/z 268 (M+H)+

Workup

  1. customThe vials were capped
  2. filtrationfiltered
  3. customthe filtrate evaporated
  4. customto yield a dark red slurry
  5. customthe phases separated
  6. extractionThe water phase (pH 9) was extracted with DCM
  7. washthe combined organic phase washed with brine
  8. customevaporated
  9. customto yield a brown solid
  10. filtrationsolids filtered off
  11. customa suspension was formed
  12. filtrationThe solid was collected by filtration
  13. washwashed with MTBE
  14. additionwere added
  15. dry with materialThe organic phase was dried over Na2SO4
  16. filtrationfiltered
  17. customevaporated

Sources & evidence

ORD record
ord-462f460fffba468cb1f356636c04d0a7
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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