Potassium Phosphate, Tribasic → 7-((2-Cyclopropylpyrimidin-5-yl)methyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbonitrile

HRID 922789Notes

Reaction equation

HRID 922789 reaction equation
Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](Cl)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1.[CH:16]1([C:19]2[N:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][N:20]=2)[CH2:18][CH2:17]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:42][N:43]1[CH:47]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:45]=[N:44]1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:16]1([C:19]2[N:20]=[CH:21][C:22]([CH2:2][C:3]3[CH:12]=[C:11]4[C:6]([C:7]([C:46]5[CH:45]=[N:44][N:43]([CH3:42])[CH:47]=5)=[CH:8][C:9]([C:13]#[N:14])=[N:10]4)=[CH:5][CH:4]=3)=[CH:23][N:24]=2)[CH2:17][CH2:18]1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 457872832-Cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidineHCID 667895247-(Bromomethyl)-4-chloroquinoline-2-carbonitrile

Product 1

HCID 715661297-((2-Cyclopropylpyrimidin-5-yl)methyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbonitrileYield 77%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

After degassing with N2, a mixture of 7-(bromomethyl)-4-chloroquinoline-2-carbonitrile (2-4, 650 mg, 2.31 mmol), 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (580 mg, 2.36 mmol), Pd(dppf)Cl2—CH2Cl2 adduct (94 mg, 0.11 mmol), and K3PO4 (1960 mg, 9.24 mmol) in 1,4-dioxane (13.7 mL) and H2O (1.7 mL) was heated at 100° C. for 30 min under microwave condition. The mixture was cooled to room temperature, and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (528 mg, 2.54 mmol) was added. After degassing with N2, the mixture was then heated at 115° C. for 30 min under microwave condition. The reaction mixture was cooled, diluted with H2O (10 mL) and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic fractions were washed with brine, dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with EtOAc/Hexane (0-100%) to afford 7-((2-cyclopropylpyrimidin-5-yl)methyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbonitrile (6-1, 649 mg, 77%). LRMS m/z (M+H)+ 367.3 found, 367.2 required.

Workup

  1. customAfter degassing with N2
  2. temperatureThe mixture was cooled to room temperature
  3. customAfter degassing with N2
  4. temperaturethe mixture was then heated at 115° C. for 30 min under microwave condition
  5. temperatureThe reaction mixture was cooled
  6. additiondiluted with H2O (10 mL)
  7. extractionthe mixture was extracted with ethyl acetate (2×50 mL)
  8. washThe combined organic fractions were washed with brine
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. customthe solvent was evaporated under reduced pressure
  12. customThe crude product was purified by column chromatography on silica gel
  13. washeluting with EtOAc/Hexane (0-100%)

Sources & evidence

ORD record
ord-f1d466450eee417b9b29893b1cf65528
Source dataset
uspto-grants-2016_03
Patent number
US09278960B2

Reaction notes

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