Potassium Phosphate, Tribasic → 2-(2-(4-(7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)spiro[3.3]heptan-2-yl)acetonitrile

HRID 1853090Notes

Reaction equation

HRID 1853090 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:20][C:21]#[N:22])[CH2:16][C:15]4([CH2:19][CH2:18][CH2:17]4)[CH2:14]3)[CH:12]=2)[N:5]2[CH:23]=[CH:24][N:25]=[C:4]2[CH:3]=1.[O:26]1[CH2:29][CH:28]([N:30]2[CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=[N:31]2)[CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:26]1[CH2:29][CH:28]([N:30]2[CH:34]=[C:33]([C:2]3[N:7]=[C:6]([C:8]4[CH:9]=[N:10][N:11]([C:13]5([CH2:20][C:21]#[N:22])[CH2:14][C:15]6([CH2:17][CH2:18][CH2:19]6)[CH2:16]5)[CH:12]=4)[N:5]4[CH:23]=[CH:24][N:25]=[C:4]4[CH:3]=3)[CH:32]=[N:31]2)[CH2:27]1

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 67455169HCID 67455169, compound2×HCID 866853442-(2-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)spiro[3.3]heptan-2-yl)acetonitrile

Product 1

HCID 674578972-(2-(4-(7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)spiro[3.3]heptan-2-yl)acetonitrileYield 74%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

2-(2-(4-(7-Chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)spiro[3.3]heptan-2-yl)acetonitrile (0.200 g, 0.567 mmol), 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Table 2, compound f; 0.213 g, 0.850 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.054 g, 0.113 mmol) and K3PO4 (0.85 mL, 1.7 mmol) were suspended in 1,4-dioxane (10 mL) and purged with Ar (g). Pd2dba3 (0.052 g, 0.057 mmol) was added, and the system sealed and heated at 80° C. overnight. The reaction mixture was cooled to ambient temperature and partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography, eluting with 2-3% (9:1 MeOH:NH4OH)/DCM to provide 2-(2-(4-(7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)spiro[3.3]heptan-2-yl)acetonitrile (0.184 g, 0.418 mmol, 74% yield). MS (apci) m/z=441.2 (M+H).

Workup

  1. custompurged with Ar (g)
  2. customthe system sealed
  3. temperatureThe reaction mixture was cooled to ambient temperature
  4. custompartitioned between saturated aqueous NaHCO3 and EtOAc
  5. washThe organic layer was washed with brine
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customto afford the crude material, which
  10. customwas purified by flash column chromatography
  11. washeluting with 2-3% (9:1 MeOH:NH4OH)/DCM

Sources & evidence

ORD record
ord-0001426a4d65497098c728ce4cb39ce1
Source dataset
uspto-grants-2015_02
Patent number
US08962596B2

Reaction notes

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