Water → 6-chloro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine

HRID 1852950Notes

Reaction equation

HRID 1852950 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[N:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[Cl:9][C:4]1[N:3]=[C:2]([C:18]2[CH:19]=[N:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=2)[N:7]=[C:6]([NH2:8])[CH:5]=1

Participants

7

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 823874-Pyrimidinamine, 2,6-dichloro-HCID 574776664-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

Product 1

HCID 866852946-chloro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amineYield 25.2%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
50 °C

Procedure

A flask was charged with 2,6-dichloropyrimidin-4-amine (10.0 g, 61.0 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Preparation E; 29.7 g, 91.5 mmol), and K2CO3 (25.3 g, 183 mmol) in dioxane (40 mL) before 300 mL of dioxane and 11 mL of water were added to the reaction mixture. The reaction mixture was then purged with argon for 30 minutes before tetrakis(triphenylphosphine)palladium (0) (3.52 g, 3.05 mmol) was added in one portion to the reaction which was then purged with argon for another 30 minutes. The reaction mixture was then sealed and heated at 50° C. overnight. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate (300 mL) and aqueous saturated sodium bicarbonate (300 mL). The aqueous layer was then extracted with ethyl acetate twice more and separated. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexanes to afford 6-chloro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (5.00 g, 15.3 mmol, 25.2% yield). MS (apci) m/z=326.1 (M+H). Structure and regioisomer confirmed by observed nOe.

Workup

  1. additionwere added to the reaction mixture
  2. additionwas added in one portion to the reaction which
  3. customwas then purged with argon for another 30 minutes
  4. customThe reaction mixture was then sealed
  5. temperatureThe reaction mixture was cooled to ambient temperature
  6. custompartitioned between ethyl acetate (300 mL) and aqueous saturated sodium bicarbonate (300 mL)
  7. extractionThe aqueous layer was then extracted with ethyl acetate twice more
  8. customseparated
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe resulting residue was purified by silica gel column chromatography
  13. washeluting with 20-100% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-166deb068637452eb2615f695e8202fa
Source dataset
uspto-grants-2015_02
Patent number
US08962596B2

Reaction notes

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