Hydrochloric Acid → Methyl 2-(2,4-difluorophenyl)isonicotinate hydrochloride

HRID 1963169Notes

Reaction equation

HRID 1963169 reaction equation
[Cl:1][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])[CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>CO.CC(OC)(C)C.Cl[Pd]Cl>[ClH:1].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[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

8

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 27343342,4-Difluorophenylboronic acidHCID 2736842Methyl 2-chloropyridine-4-carboxylate

Product 1

HCID 66731571Methyl 2-(2,4-difluorophenyl)isonicotinate hydrochlorideYield 80.1%

Reagents, catalysts & solvents 3

HCID 24290Palladium ChlorideCatalystHCID 887MethanolSolventHCID 15413tert-Butyl methyl etherSolvent2×

Conditions

Temperature
100 °C

Procedure

Methyl 2-chloroisonicotinate (3 g, 17.48 mmol), 2,4-difluorophenylboronic acid (4.14 g, 26.23 mmol), potassium carbonate (1.812 g, 13.11 mmol) and PdCl2 (dppf) (0.380 g, 0.52 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were 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 solid was dissolved in MTBE and stirred for 15 minutes, then filtered. The orange MTBE layer was treated with hydrogen chloride (4 M in dioxane, 4.37 mL, 17.48 mmol) and stirred for 1 h at room temperature. The formed solid was collected by filtration. Methyl 2-(2,4-difluorophenyl)isonicotinate hydrochloride (4.0 g, 80%) was isolated as a slightly orange solid. MS m/z 250 (M+H)+

Workup

  1. customseparate 20 mL microwave vials
  2. customThe vials were capped
  3. additionWater and DCM were added
  4. customthe phases were separated
  5. extractionThe water phase (pH 9) was extracted with DCM
  6. washthe combined organic phase washed with brine
  7. customevaporated
  8. customto yield a brown solid
  9. filtrationfiltered
  10. stirringstirred for 1 h at room temperature
  11. filtrationThe formed solid was collected by filtration

Sources & evidence

ORD record
ord-2b1a32d5167649dd8c7de89e2bc44b15
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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