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

HRID 595322Notes

Reaction equation

HRID 595322 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]2[CH2:33][CH:32]([C:34]([O:36][CH3:37])=[O:35])[CH2:31]2)[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]3[CH2:33][CH:32]([C:34]([O:36][CH3:37])=[O:35])[CH2:31]3)[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 118208770Methyl 3-(4-bromo-1H-pyrazol-1-YL)cyclobutane-1-carboxylateHCID 123317676N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine

Product 1

HCID 118208777methyl 3-(4-(3-methyl-5-(pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)cyclobutanecarboxylate

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 (220 mg, 0.707 mmol), methyl 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanecarboxylate (Isomer 1) (183 mg, 0.707 mmol), Pd2(dba)3 (32 mg, 0.035 mmol), X-phos (34 mg, 0.071 mmol), and cesium carbonate (691 mg, 2.12 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was degassed via a subsurface argon sparge for 5 minutes. The mixture was then heated to 90° C. 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% ethyl acetate/hexanes) to afford methyl 3-(4-(3-methyl-5-(pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)cyclobutanecarboxylate (Isomer 1) MS ESI calc'd. for C20H22N5O2 [M+H]+ 364. found 364. 1H NMR (500 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.46 (d, J=4.5 Hz, 2H), 8.16 (s, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.40 (s, 1H), 6.98 (s, 1H), 6.81 (t, J=5.0 Hz, 1H), 5.05-5.00 (m, 1H), 3.67 (s, 3H), 3.24-3.17 (m, 1H), 2.81-2.74 (m, 2H), 2.67-2.60 (m, 2H), 2.27 (s, 3H).

Workup

  1. customwas degassed via a subsurface argon
  2. customsparge for 5 minutes
  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% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-79465fc7d37c4854880ff849195e68b6
Source dataset
uspto-grants-2016_01
Patent number
US09242984B2

Reaction notes

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