Potassium Carbonate → 5-chloro-6-((2,4-difluoro-5-methylbenzyl)oxy)-3-(5-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-2-methylphenyl)-2-methylpyrimidin-4(3H)-one

HRID 2172642Notes

Reaction equation

HRID 2172642 reaction equation
[Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])([CH3:24])[CH3:23])[N:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])[C:5]([CH3:9])=[N:6][C:7]=1[OH:8].Cl[CH2:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])([CH3:23])[CH3:24])[N:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])[C:5]([CH3:9])=[N:6][C:7]=1[O:8][CH2:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38]

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 2855718-Crown-6HCID 790018062,4-Difluoro-5-methylbenzyl chlorideHCID 1363878065-Chloro-6-hydroxy-3-{5-[2-(1-hydroxy-1-methyl-ethyl)-pyrimidin-4-yl]-2-methyl-phenyl}-2-methyl-3H-pyrimidin-4-one

Product 1

HCID 715825015-chloro-6-((2,4-difluoro-5-methylbenzyl)oxy)-3-(5-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-2-methylphenyl)-2-methylpyrimidin-4(3H)-oneYield 39%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of Intermediate 1 (50 mg, 0.13 mmol) in N,N-dimethylformamide (1.5 mL) was added 1-chloromethyl-2,4-difluoro-5-methyl-benzene from Step C (23 mg, 0.13 mmol), potassium carbonate (36 mg, 0.26 mmol) and 18-crown-6 (3 mg). The slurry was heated at 60° C. for five hours. After cooling to room temperature the reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a colorless oil. (27 mg, 39% yield). MS (M+H): 527; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.65 (s, 6H), 2.17 (s, 3H), 2.21 (s, 3H), 2.28 (s, 3H), 5.47-5.56 (m, 2H), 6.80-6.84 (m, 1H) 7.34-7.38 (m, 1H), 7.55-7.59 (m, 2H), 7.93 (s, 1H), 8.14 (d, J=7.05 Hz, 1H), 8.78 (d, J=5.09, 1H).

Workup

  1. temperatureAfter cooling to room temperature the reaction
  2. customwas partitioned between ethyl acetate and water
  3. washThe organic layer was washed with water and brine
  4. dry with materialdried over magnesium sulfate
  5. filtrationThe slurry was filtered
  6. concentrationconcentrated in vacuo
  7. customThe crude material was purified

Sources & evidence

ORD record
ord-ad5de70cf3a94957881c448061b6f190
Source dataset
uspto-grants-2015_06
Patent number
US09056110B2

Reaction notes

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