Hydrochloric Acid → Methyl 2-(2,6-difluorobenzyl)isonicotinate

HRID 1963313Notes

Reaction equation

HRID 1963313 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][CH:19]=[C:18]([F:22])[C:15]=1[CH2:16][Zn+].Cl>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][CH:19]=[C:18]([F:22])[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

6

Reactant 3

HCID 313Hydrochloric AcidHCID 2736842Methyl 2-chloropyridine-4-carboxylateHCID 178505728HCID 178505728, compound

Product 1

HCID 66731334Methyl 2-(2,6-difluorobenzyl)isonicotinateYield 58.6%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

Methyl 2-chloroisonicotinate (5.600 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved in THF (100 mL) under nitrogen and (2,6-difluorobenzyl)zinc(II) bromide (0.5 M in THF, 100 mL, 50.00 mmol) was added and the resulting solution was stirred at 60° C. for 4 h before it was cooled to room temperature and quenched with methanol (50.0 mL). The mixture was diluted with EtOAc and washed with satd NH4Cl. The organic phase was dried with MgSO4, filtered and evaporated. The crude product was dissolved in MTBE (200 mL), solids were filtered off, and HCl (4 M in dioxane, 8.16 mL, 32.64 mmol) was added dropwise. The mixture was stirred for 10 minutes before the precipitate was filtered off, washed with MTBE and dissolved in MTBE/satd NaHCO3. The organic layer was dried with MgSO4, filtered and evaporated to give methyl 2-(2,6-difluorobenzyl)isonicotinate (5.03 g, 58.6%) as a white solid. 1H NMR (400 MHz, cdcl3) δ 3.92 (s, 3H), 4.29 (s, 2H), 6.87-6.97 (m, 2H), 7.18-7.29 (m, 1H), 7.61-7.73 (m, 2H), 8.63-8.70 (m, 1H). MS m/z 264 (M+H)+

Workup

  1. temperaturewas cooled to room temperature
  2. customquenched with methanol (50.0 mL)
  3. additionThe mixture was diluted with EtOAc
  4. washwashed with satd NH4Cl
  5. dry with materialThe organic phase was dried with MgSO4
  6. filtrationfiltered
  7. customevaporated
  8. dissolutionThe crude product was dissolved in MTBE (200 mL)
  9. filtrationsolids were filtered off
  10. stirringThe mixture was stirred for 10 minutes before the precipitate
  11. filtrationwas filtered off
  12. washwashed with MTBE
  13. dissolutiondissolved in MTBE/satd NaHCO3
  14. dry with materialThe organic layer was dried with MgSO4
  15. filtrationfiltered
  16. customevaporated

Sources & evidence

ORD record
ord-ea9e7a8d5549486f9713f3301b3e68e2
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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