Water → (4-(1-(1-Ethoxyethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate

HRID 1959910Notes

Reaction equation

HRID 1959910 reaction equation
[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCOCC1.[CH2:25]([O:27][CH:28]([N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1)[CH3:29])[CH3:26].O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:33]3[CH:32]=[N:31][N:30]([CH:28]([O:27][CH2:25][CH3:26])[CH3:29])[CH:34]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]

Participants

7

Reactant 5

HCID 962WaterHCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 467367981-(1-Ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 57868847Propanoic acid, 2,2-dimethyl-, (4-chloro-7H-pyrrolo(2,3-d)pyrimidin-7-yl)methyl ester

Product 1

HCID 57868870(4-(1-(1-Ethoxyethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate

Reagents, catalysts & solvents 1

HCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
85 °C

Procedure

To a 250 mL round bottom flask equipped with a stir bar, condenser and 3-way valve was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (3f, 30 g, 0.112 mol), 1,4-dioxane (300 mL, 4.0 mol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14, 35.8 g, 0.134 mol, 1.2 equiv), water (150 mL, 8.3 mol) and potassium carbonate (K2CO3, 61.9 g, 0.448 mol, 4.0 equiv) at room temperature. The resulting mixture was degassed four times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (5.0 g, 0.00433 mol, 0.039 equiv). The reaction mixture was then degassed four times back filling with nitrogen each time before being warmed to 85° C. The reaction mixture was stirred at 85° C. for 2-5 h. When the reaction was deemed complete, the reaction mixture was allowed to cool to room temperature before being diluted with 20% aqueous brine (250 mL) and ethyl acetate (250 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (250 mL). The combined organic fractions was washed with water and brine, dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 25% to 40% ethyl acetate/hexane gradient elution) to afford {4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (18) as a orange oil, which was directly used in the subsequent reaction assuming the theoretical yield. For 18: C19H25N5O3 (MW, 371.43), LCMS (EI) m/e 372 (M++H).

Workup

  1. customTo a 250 mL round bottom flask equipped with a stir bar, condenser and 3-way valve
  2. customThe resulting mixture was degassed four times
  3. customThe reaction mixture was then degassed four times
  4. temperatureto cool to room temperature
  5. additionbefore being diluted with 20% aqueous brine (250 mL) and ethyl acetate (250 mL)
  6. customThe two layers were separated
  7. extractionthe aqueous layer was extracted with ethyl acetate (250 mL)
  8. washThe combined organic fractions was washed with water and brine
  9. dry with materialdried over magnesium sulfate (MgSO4)
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was purified by flash column chromatography (SiO2, 25% to 40% ethyl acetate/hexane gradient elution)

Sources & evidence

ORD record
ord-98e2b1326eda4862a8d75e7a715a7d04
Source dataset
uspto-grants-2013_04
Patent number
US08410265B2

Reaction notes

Loading…