Tetrahydrofuran → HCID 66732474, compound

HRID 1963253Notes

Reaction equation

HRID 1963253 reaction equation
[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6](Cl)[CH:5]=1.O1CCCC1.[Br-].[F:18][C:19]1([F:27])[CH2:24][CH2:23][CH:22]([CH2:25][Zn+])[CH2:21][CH2:20]1>C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:18][C:19]1([F:27])[CH2:24][CH2:23][CH:22]([CH2:25][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][N:7]=2)[C:3]([O:2][CH3:1])=[O:11])[CH2:21][CH2:20]1

Participants

6

Reactant 3

HCID 8028TetrahydrofuranHCID 2736842Methyl 2-chloropyridine-4-carboxylateHCID 178506003HCID 178506003, compound

Product 1

HCID 66732474HCID 66732474, compoundYield 76.6%

Reagents, catalysts & solvents 2

HCID 178418851HCID 178418851, compoundCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

To methyl-2-chloroisonicotinate (1.664 g, 9.7 mmol) and bis(tri-tert-butylphosphine)palladium(0) (198 mg, 0.38 mmol) under nitrogen was added tetrahydrofuran (10 mL). To the resulting solution was added freshly prepared ((4,4-difluorocyclohexyl)methyl)zinc(II) bromide (14.55 mmol, 0.5 M in 29 mL DMA) and the resulting brown mixture heated to 60° C. for 4 h. The reaction mixture was diluted with ethyl acetate and washed with satd NaHCO3 (2 times), satd NH4Cl and brine. The organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM and added onto an SCX-2 cation exchange column. The column was washed with DCM, MeOH and then eluted with NH3/MeOH. The NH3/MeOH layer was evaporated leaving methyl 2-((4,4-difluorocyclohexyl)methyl)isonicotinate (2 g, 67%) as a yellow oil. 1H NMR (400 MHz, cdcl3) δ 1.30-1.46 (m, 2H), 1.58-1.79 (m, 4H), 1.87-2.14 (m, 3H), 2.82 (d, 2H), 3.96 (s, 3H), 7.65-7.73 (m, 2H), 8.70 (d, 1H). MS m/z 270 (M+H)+

Workup

  1. washwashed with satd NaHCO3 (2 times), satd NH4Cl and brine
  2. dry with materialThe organic layer was dried over MgSO4
  3. filtrationfiltered
  4. customevaporated
  5. dissolutionThe residue was dissolved in DCM
  6. additionadded onto an SCX-2 cation exchange column
  7. washThe column was washed with DCM, MeOH
  8. washeluted with NH3/MeOH
  9. customThe NH3/MeOH layer was evaporated

Sources & evidence

ORD record
ord-d328e236f09c446eb39621ace0e90099
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

Loading…