Cesium carbonate → Ammonia methanol

HRID 1028804Notes

Reaction equation

HRID 1028804 reaction equation
I[C:2]1[N:3]=[C:4]([CH:12]2[CH2:15][CH:14]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=12.[CH3:23][C:24]1[C:33]2[C:28](=[CH:29][C:30](B3OC(C)(C)[C:36](C)(C)[O:35]3)=[CH:31][CH:32]=2)[N:27]=[C:26]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.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>[NH3:3].[CH3:36][OH:35].[CH3:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([C:2]3[N:3]=[C:4]([CH:12]4[CH2:15][CH:14]([N:16]5[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]5)[CH2:13]4)[N:5]4[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=34)=[CH:31][CH:32]=2)[N:27]=[C:26]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:25]=1

Participants

8

Reactant 3

HCID 10796Cesium carbonateHCID 536290544-Methyl-2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolineHCID 576810251-Iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine

Product 2

HCID 21705897Ammonia methanolHCID 576809301-(4-Methyl-2-phenyl-quinolin-7-yl)-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
75 °C

Procedure

A mixture of 1-iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine (206 mg, 0.500 mmol) and 4-methyl-2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (190 mg, 0.550 mmol) and cesium carbonate (326 mg, 1.00 mmol) in 1,2-dimethoxyethane (10.0 mL) and water (2.0 mL) was evacuated and refilled with nitrogen (3×), then charged with tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), and the flask was again evacuated and refilled with nitrogen (3×). The mixture was heated at 75° C. overnight. The mixture was cooled to rt and diluted with ethyl acetate (30 mL), then washed with brine (15 mL); the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afforded a yellow solid, which was purified by silica gel chromatography [CH2Cl2→5% MeOH/CH2Cl2→5% (2N NH3-MeOH)/CH2Cl2, then 10% (2N NH3-MeOH)/CH2Cl2 to give the title compound as a yellow solid; LC-MS (ES, Pos.): 504 [MH+]; 1H NMR (CDCl3, 400 MHz) δ 2.30 (s, 3H), 2.32-2.71 (m, 12H), 2.81 (d, J=0.9 Hz, 3H), 2.95 (m, 1H), 3.49 (m, 1H), 5.19 (brs, 2H), 7.11 (d, J=5.0 Hz, 1H), 7.19 (d, J=5.0 Hz, 1H), 7.45-7.55 (m, 3H), 7.75 (d, J=0.8 Hz, 1H), 7.94 (dd, J=8.6 Hz, 1.8 Hz, 1H), 8.12 (d, J=8.6 Hz, 1H), 8.16-8.19 (m, 2H), 8.39 (d, J=1.4 Hz, 1H).

Workup

  1. customwas evacuated
  2. additionrefilled with nitrogen (3×)
  3. customthe flask was again evacuated
  4. additionrefilled with nitrogen (3×)
  5. temperatureThe mixture was cooled to rt
  6. additiondiluted with ethyl acetate (30 mL)
  7. washwashed with brine (15 mL)
  8. dry with materialthe organic phase was dried over anhydrous sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto afforded a yellow solid, which
  12. customwas purified by silica gel chromatography [CH2Cl2→5% MeOH/CH2Cl2→5% (2N NH3-MeOH)/CH2Cl2

Sources & evidence

ORD record
ord-396e6e385a8a42a6a9aaa8f2ff9e57e9
Source dataset
uspto-grants-2014_05
Patent number
US08735405B2

Reaction notes

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