Potassium Carbonate → HCID 86682697, compound

HRID 1755295Notes

Reaction equation

HRID 1755295 reaction equation
[C:1]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([NH:16][C:17]3[C:18]4[N:19]([CH:24]=[CH:25][N:26]=4)[N:20]=[C:21]([Cl:23])[CH:22]=3)[CH:13]=[CH:12][CH:11]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CO.Cl.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]>[ClH:23].[C:1]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([NH:16][C:17]3[C:18]4[N:19]([CH:24]=[CH:25][N:26]=4)[N:20]=[C:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:22]=3)[CH:13]=[CH:12][CH:11]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]

Participants

10

Reactant 4

HCID 11430Potassium CarbonateHCID 66827Phenylboronic AcidHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 86682699HCID 86682699, compound

Product 1

HCID 86682697HCID 86682697, compoundYield 39%

Reagents, catalysts & solvents 5

HCID 313Hydrochloric AcidCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of N-(6-(1-tert-butyl-1H-pyrazol-3-yl)pyridin-2-yl)-6-chloroimidazo[1,2-b]pyridazin-8-amine (168 mg, 0.58 mmol), phenylboronic acid (105 mg, 0.86 mmol), Pd2(dba)3 (34 mg, 0.06 mmol), X-phos (114 mg, 0.24 mmol) and K2CO3 (240 mg, 1.74 mmol) in dioxane (10 mL) and water (1 mL) was heated to 100° C. with stirring for 4 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=180:1) to give crude product. This solid was further purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give a white solid. This was dissolved in methanol and three drops of concentrated HCl added. The mixture was stirred for 5 minutes, then concentrated in vacuo to give the final product N-(6-(1-tert-butyl-1H-pyrazol-3-yl)pyridin-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine hydrochloride (72 mg, 39%) as an HCl salt. 1H NMR (300 MHz, DMSO): δ 10.26 (s, 1H), 8.58 (d, 1H, J=1.8 Hz), 8.32 (s, 1H), 7.83-7.79 (m, 2H), 7.56-7.51 (m, 4 h), 6.62 (s, 1H), 6.39 (d, 1H, J=1.5 Hz), 1.61 (s, 9H). LC-MS: [M+H]+, 333, tR=1.648 min, HPLC: 98.3% at 214 nm, 99.29% at 254 nm, tR=6.1 min.

Workup

  1. customThe solvent was removed in vacuo
  2. customthe resulting mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=180:1)
  3. customto give crude product
  4. customThis solid was further purified by prep-HPLC (Gemini 5u C18 150×21.2 mm
  5. waitgradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min
  6. custom) to give a white solid
  7. stirringThe mixture was stirred for 5 minutes
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-0737357b61e04c0c85801feb249f6565
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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