2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl → HCID 67458930, compound

HRID 1853009Notes

Reaction equation

HRID 1853009 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:18]=3)[N:11]3[CH:27]=[CH:28][N:29]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.[CH:30]12[O:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][NH:32][CH2:31]2.CC([O-])(C)C.[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>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].C1COCC1>[CH3:24][Si:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][O:20][CH2:19][N:17]1[CH:18]=[C:14]([C:12]2[N:11]3[CH:27]=[CH:28][N:29]=[C:10]3[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:32]4[CH2:31][CH:30]5[O:37][CH:34]([CH2:35][CH2:36]5)[CH2:33]4)=[CH:3][CH:4]=3)[N:13]=2)[CH:15]=[N:16]1

Participants

7

Reactant 4

HCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 120692318-Oxa-3-azabicyclo[3.2.1]octaneHCID 23665647Potassium tert-butoxideHCID 67457604HCID 67457604, compound

Product 1

HCID 67458930HCID 67458930, compoundYield 49.9%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 8028TetrahydrofuranSolvent

Procedure

To a flask charged with 7-(4-bromophenyl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation L; 0.250 g, 0.531 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (0.430 g, 3.80 mmol), and potassium 2-methylpropan-2-olate (0.119 g, 1.06 mmol) was added 6 mL of THF at ambient temperature with stirring. Argon was bubbled through the reaction for 10 minutes before dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.0436 g, 0.106 mmol) and tris(dibenzylideneacetone)dipalladium (0.0487 g, 0.0531 mmol) were added. Argon was bubbled through the reaction for 15 minutes before the reaction was sealed and allowed to proceed at 40° C. for 4 hours. The reaction was charged with more tris(dibenzylideneacetone)dipalladium (0.0487 g, 0.0531 mmol) and purged with argon for 5 minutes before it was sealed and allowed to proceed at 40° C. for 7 hours. The reaction mixture was diluted with DCM and aqueous saturated sodium bicarbonate (2 mL) and stirred for 30 minutes. The layers were separated and the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 1% methanol in DCM to afford 3-(4-(5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)phenyl)-8-oxa-3-azabicyclo[3.2.1]octane (0.133 g, 0.265 mmol, 49.0% yield). MS (apci) m/z=503.2 (M+H).

Workup

  1. additionwere added
  2. customArgon was bubbled through the reaction for 15 minutes before the reaction
  3. customwas sealed
  4. custompurged with argon for 5 minutes before it
  5. customwas sealed
  6. waitto proceed at 40° C. for 7 hours
  7. additionThe reaction mixture was diluted with DCM and aqueous saturated sodium bicarbonate (2 mL)
  8. stirringstirred for 30 minutes
  9. customThe layers were separated
  10. dry with materialthe organic layer was dried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customThe crude residue was purified by silica gel chromatography
  14. washeluting with 1% methanol in DCM

Sources & evidence

ORD record
ord-4b99af690a214b7ba9b87e8a92d3a05c
Source dataset
uspto-grants-2015_02
Patent number
US08962596B2

Reaction notes

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