Hydrochloric Acid → HCID 66732272, compound

HRID 1963293Notes

Reaction equation

HRID 1963293 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]([F:25])([F:24])[O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][Zn+])=[CH:18][CH:17]=1.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]([F:24])([F:25])[O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:18][CH:17]=1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 2736842Methyl 2-chloropyridine-4-carboxylateHCID 178506382HCID 178506382, compound

Product 1

HCID 66732272HCID 66732272, compoundYield 92.3%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
60 °C

Procedure

To a solution of methyl 2-chloroisonicotinate (4.80 g, 28 mmol) and Pd(PPh3)4 (0.647 g, 0.56 mmol) in tetrahydrofuran (50 mL) under nitrogen in a dried flask was added a freshly prepared solution of (4-(trifluoromethoxy)benzyl)zinc(II) bromide (12.56 g, 39.20 mmol) in tetrahydrofuran (90 mL). The resulting bright yellow mixture was heated to 60° C. for 2 h 30 min, then cooled to room temperature. The reaction was quenched by the addition of 10% aqueous 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 50 mL MTBE and sonicated, then the yellow insolubles were filtered off and washed with MTBE. The volume of the filtrate was increased to ca. 150 mL, then 5 mL MeOH was added, followed by hydrogen chloride (4 M in dioxane) (7.00 mL, 28.00 mmol). A colorless precipitate formed, which then dissolved again. The solvents were evaporated. The residue was dissolved in ca. 15 mL DCM and then MTBE and heptanes were added. An oil had formed that was triturated and after a few minutes a solid started to form. It was sonicated and then stirred at room temperature for 20 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-(4-(trifluoromethoxy)benzyl)isonicotinate (8.04 g, 92%) was isolated as a pale yellow oil. 1H NMR (400 MHz, cdcl3) δ 3.93 (s, 3H), 4.22 (s, 2H), 7.11-7.17 (m, 2H), 7.24-7.31 (m, 2H), 7.67-7.72 (m, 2H), 8.68-8.72 (m, 1H). MS m/z 312 (M+H)+

Workup

  1. temperaturecooled to room temperature
  2. customThe reaction was quenched by the addition of 10% aqueous 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. 150 mL
  12. addition5 mL MeOH was added
  13. customA colorless precipitate formed
  14. dissolutionwhich then dissolved again
  15. customThe solvents were evaporated
  16. dissolutionThe residue was dissolved in ca. 15 mL DCM
  17. additionMTBE and heptanes were added
  18. customAn oil had formed
  19. customthat was triturated and after a few minutes a solid
  20. customto form
  21. customIt was sonicated
  22. customThe formed solid was collected
  23. washwashed with MTBE
  24. customdried
  25. dissolutionThe solid was dissolved in DCM
  26. washwashed with 10% K2CO3
  27. customAfter phase separation
  28. extractionthe aqueous layer was extracted with DCM
  29. dry with materialThe combined organic layers were dried over MgSO4
  30. customevaporated

Sources & evidence

ORD record
ord-c85ce13be79b4bf3a6be0ae0bb3a12ee
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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