Hydrochloric Acid → Methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)isonicotinate

HRID 1963331Notes

Reaction equation

HRID 1963331 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:15]=[C:16]([CH:19]=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])[CH2:17][Zn+].Cl>O1CCCC1.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:15]=[C:16]([CH:19]=[CH:20][C:21]=1[C:22]([F:23])([F:24])[F:25])[CH2:17][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 178505820HCID 178505820, compound

Product 1

HCID 66731596Methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)isonicotinateYield 88%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
60 °C

Procedure

To a solution of methyl 2-chloroisonicotinate (5.15 g, 30 mmol) and Pd(PPh3)4 (0.693 g, 0.60 mmol) in tetrahydrofuran (40 mL) under nitrogen in a dried flask was added freshly prepared (3-fluoro-4-(trifluoromethyl)benzyl)zinc(II) bromide (12.55 g, 38.91 mmol) in tetrahydrofuran (50 mL). The resulting bright yellow mixture was heated to 60° C. for 2 h 20 min, then cooled to room temperature. The reaction was quenched by the addition of 10% NH4Cl. It was diluted with ethyl acetate. After phase separation, the organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was suspended in 150 mL MTBE and sonicated, then the yellow insolubles were filtered off and washed with MTBE. The volume of the filtrate was increased to ca. 200 mL, then hydrogen chloride (7.50 mL, 30.00 mmol) (4M in dioxane) was added dropwise. A colorless precipitate formed. The resulting suspension was stirred for ca. 1 h, then sonicated for 2 min. The formed solid was collected and washed with MTBE and dried. The solid was dissolved in DCM and washed with 10% K2CO3. After phase separation, the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated. Methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)isonicotinate (8.26 g, 88%) was isolated as a pale orange oil. 1H NMR (400 MHz, cdcl3) δ 3.94 (s, 3H), 4.24 (s, 2H), 7.06-7.18 (m, 2H), 7.52 (t, 1H), 7.69-7.75 (m, 2H), 8.68-8.75 (m, 1H). MS m/z 314 (M+H)+

Workup

  1. temperaturecooled to room temperature
  2. customThe reaction was quenched by the addition of 10% NH4Cl
  3. additionIt was diluted with ethyl acetate
  4. customAfter phase separation
  5. washthe organic layer was washed with brine
  6. dry with materialdried over MgSO4
  7. customevaporated
  8. customsonicated
  9. filtrationthe yellow insolubles were filtered off
  10. washwashed with MTBE
  11. temperatureThe volume of the filtrate was increased to ca. 200 mL
  12. customA colorless precipitate formed
  13. customsonicated for 2 min
  14. customThe formed solid was collected
  15. washwashed with MTBE
  16. customdried
  17. dissolutionThe solid was dissolved in DCM
  18. washwashed with 10% K2CO3
  19. customAfter phase separation
  20. extractionthe aqueous layer was extracted with DCM
  21. dry with materialThe combined organic layers were dried over MgSO4
  22. customevaporated

Sources & evidence

ORD record
ord-2568d6f7c708402d996ab1ec63cfb1bc
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

Loading…