Potassium Carbonate → 3-chloro-2'-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-4-((4-methoxybenzyl)oxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one

HRID 2199521Notes

Reaction equation

HRID 2199521 reaction equation
[C:1]([C:4]1[CH:9]=[C:8]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:12]([Cl:27])[C:11]2=[O:28])[C:7]([CH3:29])=[CH:6][N:5]=1)(=O)[CH3:2].[CH3:30]OC(OC)N(C)C.Cl.[OH:39][C:40]([CH3:45])([CH3:44])[C:41]([NH2:43])=[NH:42].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:27][C:12]1[C:11](=[O:28])[N:10]([C:8]2[C:7]([CH3:29])=[CH:6][N:5]=[C:4]([C:1]3[CH:2]=[CH:30][N:43]=[C:41]([C:40]([OH:39])([CH3:45])[CH3:44])[N:42]=3)[CH:9]=2)[C:15]([CH3:16])=[CH:14][C:13]=1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 78373Dimethylformamide dimethyl acetalHCID 426142842-Hydroxy-2-methylpropanimidamide hydrochlorideHCID 866993042'-acetyl-3-chloro-4-((4-methoxybenzyl)oxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one

Product 1

HCID 866993073-chloro-2'-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-4-((4-methoxybenzyl)oxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-oneYield 46.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
55 °C

Procedure

To a solution of 2′-acetyl-3-chloro-4-((4-methoxybenzyl)oxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one of step D (562 mg, 1.36 mmol) in N,N-dimethylformamide (5 mL) was added N,N-dimethylformamide dimethyl acetal (0.27 mL, 2.04 mmol) and the solution was heated to 55° C. for 18 hours. The solution was concentrated to half volume and partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate and concentrated to provide the crude enamine intermediate as an orange oil. The enamine was dissolved into N,N-dimethylformamide (7 mL) and 2-hydroxy-2-methylpropionamidine HCl (280 mg, 2.04 mmol) and potassium carbonate (563 mg, 4.08 mmol) were added. The slurry was heated at 75° C. for eighteen hours. The slurry was returned to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over magnesium sulfate. The solution was concentrated and purified using normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a light yellow solid (320 mg, 46%): MS (M+H) 508.

Workup

  1. concentrationThe solution was concentrated to half volume
  2. custompartitioned between ethyl acetate and brine
  3. dry with materialThe organic layer was dried over magnesium sulfate
  4. concentrationconcentrated
  5. customto provide the crude enamine intermediate as an orange oil
  6. additionwere added
  7. temperatureThe slurry was heated at 75° C. for eighteen hours
  8. customwas returned to ambient temperature
  9. custompartitioned between ethyl acetate and water
  10. washThe organic layer was washed with brine
  11. dry with materialdried over magnesium sulfate
  12. concentrationThe solution was concentrated
  13. custompurified

Sources & evidence

ORD record
ord-fa1c51db7dc245f48253b6849498e306
Source dataset
uspto-grants-2016_06
Patent number
US09359300B2

Reaction notes

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