Dichloromethane → HCID 72943527, compound

HRID 1505717Notes

Reaction equation

HRID 1505717 reaction equation
Br[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2([F:14])[F:13])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][N:22]1[CH:26]=[C:25]([C:27]2[CH:28]=[C:29]([C:33]3[N:38]=[CH:37][C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][N:34]=3)[CH:30]=[CH:31][CH:32]=2)[CH:24]=[N:23]1.ClCCl>C1OCCOC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[F:13][C:8]1([F:14])[CH:7]([N:5]2[CH:6]=[C:2]([C:36]3[CH:35]=[N:34][C:33]([C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([C:25]5[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=5)[CH:28]=4)=[N:38][CH:37]=3)[CH:3]=[N:4]2)[CH2:12][CH2:11][NH:10][CH2:9]1

Participants

9

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 89924330HCID 89924330, compound2×HCID 89924468HCID 89924468, compound2×

Product 1

HCID 72943527HCID 72943527, compoundYield 11.4%

Reagents, catalysts & solvents 4

HCID 24290Palladium ChlorideCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 4-(4-Bromo-pyrazol-1-yl)-3,3-difluoro-piperidine (intermediate 29; 150 mg; 0.50 mmol; 1.0 eq.) in Dioxane-1,4 (12 mL) and Water (3.0 mL) was added Potassium carbonate (141 mg; 0.99 mmol; 2.0 eq.) and 2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine (intermediate 30; 221 mg; 0.60 mmol; 1.2 eq.). The reaction mixture was degasified for 15 min and then 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (20.88 mg; 0.02 mmol; 0.05 eq.) was added. The reaction mixture was then heated at 100° C. for 90 min. It was concentrated under reduced pressure, diluted with Water (15 mL) and extracted with ethylacetate (2×25 mL). Combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM: MeOH, 9:1) afforded the title compound as a brown solid (24 mg; 11%). 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 2H), 8.53-8.52 (m, 2H), 8.26 (s, 1H), 8.23-8.20 (m, 2H), 7.91 (s, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 4.96-4.86 (m, 1H), 3.89 (s, 3H), 3.22-3.15 (m, 1H), 3.08-3.05 (m, 1H), 2.98-2.87 (m, 1H), 2.72-2.67 (m, 1H), 2.66-2.59 (m, 1H), 2.36-2.29 (m, 1H), 2.08-2.05 (m, 1H). HPLC (Condition A): Rt 3.00 min (purity 96.8%). MS (ESI+): 422.2.

Workup

  1. concentrationIt was concentrated under reduced pressure
  2. additiondiluted with Water (15 mL)
  3. extractionextracted with ethylacetate (2×25 mL)
  4. washCombined organic layers were washed with brine
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customPurification by flash chromatography on silica (DCM: MeOH, 9:1)

Sources & evidence

ORD record
ord-124d1938696746599f686ea6f13a1d4a
Source dataset
uspto-grants-2015_12
Patent number
US09216991B2

Reaction notes

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