Methyl iodide → 2-(2-Chloro-4-methoxy-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one

HRID 1095923Notes

Reaction equation

HRID 1095923 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=1)=[O:12].[H-].[Na+].[CH3:22]I>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:22])[C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=1)=[O:12]

Participants

5

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 666990882-(2-Chloro-4-methoxy-phenyl)-1-(2-methyl-pyridin-4-yl)-ethanone

Product 1

HCID 666991512-(2-Chloro-4-methoxy-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

A solution of 2-(2-chloro-4-methoxy-phenyl)-1-(2-methyl-pyridin-4-yl)-ethanone (7.56 g) in DMF (140 mL) was added slowly over 30 minutes to a suspension of NaH (50% in mineral oil, 2.24 g) in DMF (100 mL). Stirring was continued for 30 minutes at r.t. Then, methyl iodide (2.57 mL) was added dropwise over a period of 15 minutes. Stirring was continued for 2.5 hours at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residual DMF was removed by co-evaporation with toluene. 2-(2-chloro-4-methoxy-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one was obtained as an inseparable mixture with the dimethylated compound 4-[(E or Z)-2-(2-chloro-4-methoxy-phenyl)-1-methoxy-propenyl]-2-methyl-pyridine (10.22 g). This mixture was treated as follows: A mixture of 2-(2-chloro-4-methoxy-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one and 4-[(E or Z)-2-(2-chloro-4-methoxy-phenyl)-1-methoxy-propenyl]-2-methyl-pyridine (10.22 g) was treated with 50% aqueous H2SO4 (90 mL) at 100° C. for 30 minutes. The reaction mixture was cooled, poured into ice and basified with sat. Na2CO3 to pH 10. The aqueous phase was then extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a yellow oil (5.99 g, 56%). MS (m/e)=290.1 [MH+].

Workup

  1. stirringStirring
  2. waitwas continued for 2.5 hours at r.t
  3. extractionextracted two times with ethyl acetate
  4. washThe organic layers were washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. customthe solvent was evaporated
  8. customThe residual DMF was removed by co-evaporation with toluene

Sources & evidence

ORD record
ord-904c84c57fa745a1ae9429ee36e874eb
Source dataset
uspto-grants-2012_03
Patent number
US08138189B2

Reaction notes

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