Cesium carbonate → methyl 4-(1-(4-(3-methyl-5-(pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)ethyl)benzoate

HRID 595317Notes

Reaction equation

HRID 595317 reaction equation
[CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:25]1[CH:26]=[N:27][N:28]([CH:30]([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH3:31])[CH:29]=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-].[Cs+].[Cs+]>O1CCOCC1.O.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]>[CH3:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:26]=[N:27][N:28]([CH:30]([C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)[CH3:31])[CH:29]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:19]=[CH:20][CH:21]=[CH:22][N:23]=2)[CH:3]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 118208983methyl 4-(1-(4-bromo-1H-pyrazol-1-yl)ethyl)benzoateHCID 123317676N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine

Product 1

HCID 118208988methyl 4-(1-(4-(3-methyl-5-(pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)ethyl)benzoate

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine (100 mg, 0.321 mmol), methyl 4-(1-(4-bromo-1H-pyrazol-1-yl)ethyl)benzoate (139 mg, 0.450 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), X-phos (15 mg, 0.032 mmol), and cesium carbonate (314 mg, 0.964 mmol) was diluted with 1,4-dioxane (3 mL) and water (0.3 mL) at ambient temperature. The mixture was stirred for 5 minutes under a subsurface argon sparge, after which time the mixture was heated to 90° C. and stirred under an argon atmosphere for 2 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (100 mL) and water (25 mL). The organic layer was separated and washed with water (25 mL) and then brine (25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by column chromatography on silica (0-100% [5% methanol in ethyl acetate]/hexanes) to afford methyl 4-(1-(4-(3-methyl-5-(pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)ethyl)benzoate. MS ESI calcd. for C24H24N5O2 [M+H]+ 414. found 414. 1H NMR (500 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.46 (d, J=4.5 Hz, 2H), 8.24 (s, 1H), 7.91 (d, J=8.0 Hz, 2H), 7.80 (s, 1H), 7.72 (s, 1H), 7.41 (s, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.01 (s, 1H), 6.80 (t, J=5.0 Hz, 1H), 5.76-5.70 (m, 1H), 3.82 (s, 3H), 3.27 (s, 3H), 1.83 (d, J=7.0 Hz, 3H).

Workup

  1. customsparge
  2. stirringstirred under an argon atmosphere for 2 hours
  3. temperatureThe reaction mixture was cooled to ambient temperature
  4. additiondiluted with ethyl acetate (100 mL) and water (25 mL)
  5. customThe organic layer was separated
  6. washwashed with water (25 mL)
  7. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customto afford the crude product residue
  11. customThe crude product residue was purified by column chromatography on silica (0-100% [5% methanol in ethyl acetate]/hexanes)

Sources & evidence

ORD record
ord-a8be59f7b24f4477a160c73ee0ef61a8
Source dataset
uspto-grants-2016_01
Patent number
US09242984B2

Reaction notes

Loading…