Ethyl Acetate → 6-(1-Methyl-1H-pyrazol-4-yl)-3-[3-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-6-ylmethyl]-imidazo[1,2-b]pyridazine

HRID 69304Notes

Reaction equation

HRID 69304 reaction equation
Br[C:2]1[N:6]2[CH:7]=[C:8]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][N:24]1[CH:25]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([C:12]([CH2:11][C:8]4[CH:9]=[CH:10][C:5]5[N:6]([C:2]([C:31]6[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=6)=[CH:3][N:4]=5)[CH:7]=4)=[CH:13][N:14]=3)[N:17]=2)[CH:22]=[N:23]1

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 10340Sodium CarbonateHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 57917273HCID 57917273, compound

Product 1

HCID 579172646-(1-Methyl-1H-pyrazol-4-yl)-3-[3-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-6-ylmethyl]-imidazo[1,2-b]pyridazine

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
150 °C

Procedure

3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 296, 77 mg, 0.189 mmol) was dissolved in DME (0.629 mL) with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (39.2 mg, 0.189 mmol), 2 M Na2CO3 solution (0.339 mL, 0.679 mmol) and tetrakis(triphenylphosphine)palladium (10.9 mg, 0.009 mmol). The RM was heated at 150° C. 5 min under microwave irradiations. It was taken up with EtOAc and washed with 10% Na2CO3 solution and brine. Then it was dried over Na2SO4, filtered and concentrated. The residue was dissolved in MeOH and passed through an SPE cartridge of PL-Thiol MP to remove the palladium. Then the filtrate was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and acetonitrile was removed. The aqueous solution was basified with 5% NaHCO3 solution and was extracted with EtOAc twice. Combined organic layers was washed with brine and dried over Na2SO4. It was filtered to afford after evaporation of the solvent the title compound as a white solid (tR 0.7 min (conditions 2), MH+=410).

Workup

  1. custom5 min
  2. washwashed with 10% Na2CO3 solution and brine
  3. dry with materialThen it was dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. dissolutionThe residue was dissolved in MeOH
  7. customto remove the palladium
  8. customThen the filtrate was purified by preparative HPLC with acetonitrile and water (+0.1% TFA)
  9. customacetonitrile was removed
  10. extractionwas extracted with EtOAc twice
  11. washCombined organic layers was washed with brine
  12. dry with materialdried over Na2SO4
  13. filtrationIt was filtered
  14. customto afford
  15. customafter evaporation of the solvent the title compound as a white solid (tR 0.7 min (conditions 2), MH+=410)

Sources & evidence

ORD record
ord-99d3a263c1e1439b9b068c0bf836e704
Source dataset
uspto-grants-2014_09
Patent number
US08822468B2

Reaction notes

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