Diisopropylamine → [4,6-Bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl](2-thiazolyl)methanone

HRID 2082034Notes

Reaction equation

HRID 2082034 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[S:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[CH3:18][C:19]([C:22]1[C:27]([OH:28])=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:24]([C:33](N(OC)C)=[O:34])[N:23]=1)([CH3:21])[CH3:20]>O1CCCC1.C1CCCCC1>[CH3:21][C:19]([C:22]1[C:27]([OH:28])=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:24]([C:33]([C:14]2[S:13][CH:17]=[CH:16][N:15]=2)=[O:34])[N:23]=1)([CH3:18])[CH3:20]

Participants

7

Reactant 4

HCID 7912DiisopropylamineHCID 9256ThiazoleHCID 100401704,6-Bis(1,1-dimethylethyl)-5-hydroxy-N-methoxy-N-methyl-2-pyrimidinecarboxamideHCID 178418339Butyllithium

Product 1

HCID 19779332[4,6-Bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl](2-thiazolyl)methanoneYield 55.2%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8078CyclohexaneSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of diisopropylamine (0.39 mL, 4.2 mmol) in tetrahydrofuran (8 mL) at -78° C. under nitrogen atmosphere is added a 2.1M solution of n-butyllithium (2.0 mL, 4.2 mmol) in cyclohexane. This mixture is stirred at -78° C. for 1 hour and thiazole (0.3 mL, 4.2 mmol) added. After stirring 1 hour at -78° C., the reaction mixture is warmed to ~0° C. and stirred 0.5 hours. The mixture is cooled to -78° and 4,6-bis(1,1-dimethylethyl)-5-hydroxy-N-methoxy-N-methyl-2-pyrimidinecarboxamide (0.50 g, 1.7 mmol) in a mixture of tetrahydrofuran (5 mL) and N,N,N'N'-tetramethylethylenediamine (2 mL). After stirring 1 hour at 78° C., the resulting mixture is warmed to room temperature and stirred 16 hours. The mixture is then quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extracts are washed with water and brine. The organic phase is dried over magnesium sulfate and concentrated under vacuum. The organic residue is purified by flash chromatography (SiO2, 10% methanol/dichloromethane) followed by recrystallization from ethyl acetate and hexane to give 0.30 g (53%) of the title compound, mp 181°-184° C.

Workup

  1. stirringAfter stirring 1 hour at -78° C.
  2. temperaturethe reaction mixture is warmed to ~0° C.
  3. stirringstirred 0.5 hours
  4. temperatureThe mixture is cooled to -78°
  5. stirringAfter stirring 1 hour at 78° C.
  6. temperaturethe resulting mixture is warmed to room temperature
  7. stirringstirred 16 hours
  8. customThe mixture is then quenched with aqueous ammonium chloride solution
  9. extractionextracted with ethyl acetate
  10. washThe combined extracts are washed with water and brine
  11. dry with materialThe organic phase is dried over magnesium sulfate
  12. concentrationconcentrated under vacuum
  13. customThe organic residue is purified by flash chromatography (SiO2, 10% methanol/dichloromethane)
  14. customfollowed by recrystallization from ethyl acetate and hexane

Sources & evidence

ORD record
ord-2667fedeafc94ceda740393c916fd6b2
Source dataset
uspto-grants-1993_02
Patent number
US05187175

Reaction notes

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