Methyl 2-chloropyridine-4-carboxylate → HCID 66731569, compound

HRID 1963309Notes

Reaction equation

HRID 1963309 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].[Br-].[F:13][C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[CH2:16][Zn+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[CH2:16][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]

Participants

5

Reactant 2

HCID 2736842Methyl 2-chloropyridine-4-carboxylateHCID 178505810HCID 178505810, compound

Product 1

HCID 66731569HCID 66731569, compoundYield 79.1%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of methyl 2-chloroisonicotinate (5.6 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) in anhydrous THF (100 mL) was added (2,5-difluorobenzyl)zinc(II) bromide (0.5 M in THF) (100 mL, 50.00 mmol) dropwise under nitrogen. The reaction mixture was heated at 60° C. for 15 h. The reaction mixture was quenched by addition of methanol (50 mL) and then filtered. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with satd NH4Cl solution and brine, then dried. The solvent was evaporated under reduced pressure. The residue was suspended in ethanol, filtered and the solid washed with ethanol. The filtrate was concentrated. The residue was dissolved in MTBE (150 mL), then HCl (4 M in dioxane, (8.15 mL) and MeOH (7.5 mL) were added. The resulting suspension was stirred for 20 min, the solid collected, washed with MTBE (×2) and air dried. The solid was dissolved in DCM (200 mL) and washed with satd NaHCO3. The organic phase was dried using a phase separator and evaporated to yield methyl 2-(2,5-difluorobenzyl)isonicotinate (6.8 g, 79%). MS m/z 264 (M+H)+

Workup

  1. customThe reaction mixture was quenched by addition of methanol (50 mL)
  2. filtrationfiltered
  3. customThe solvent was evaporated under reduced pressure
  4. dissolutionThe residue was dissolved in ethyl acetate
  5. washwashed with satd NH4Cl solution and brine
  6. customdried
  7. customThe solvent was evaporated under reduced pressure
  8. filtrationfiltered
  9. washthe solid washed with ethanol
  10. concentrationThe filtrate was concentrated
  11. dissolutionThe residue was dissolved in MTBE (150 mL)
  12. additionHCl (4 M in dioxane, (8.15 mL) and MeOH (7.5 mL) were added
  13. customthe solid collected
  14. washwashed with MTBE (×2) and air
  15. customdried
  16. dissolutionThe solid was dissolved in DCM (200 mL)
  17. washwashed with satd NaHCO3
  18. customThe organic phase was dried
  19. customevaporated

Sources & evidence

ORD record
ord-a0d9d95bf2f74599b783e2df21a1afc5
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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