2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → ethyl rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethenyl}-2-methylcyclohexanecarboxylate

HRID 1482898Notes

Reaction equation

HRID 1482898 reaction equation
Cl[C:2]1[CH:3]=[N:4][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][C@@H:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C@@H:12]([CH3:21])[CH2:11]2)=[CH2:9])=[N:6][CH:7]=1.[F:22][CH:23]([F:47])[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]2[CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:34]=[C:33]([CH3:46])[CH:32]=2)[N:25]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CN(C)C=O.[Cl-].[Na+].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]>[F:47][CH:23]([F:22])[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]2[CH:36]=[C:35]([C:2]3[CH:3]=[N:4][C:5]([C:8]([CH:10]4[CH2:15][CH2:14][C@@H:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C@@H:12]([CH3:21])[CH2:11]4)=[CH2:9])=[N:6][CH:7]=3)[CH:34]=[C:33]([CH3:46])[CH:32]=2)[N:25]=1

Participants

7

Reactant 3

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 584561714-(difluoromethyl)-N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineHCID 118126819ethyl rel-(1R,2S)-4-[1-(5-chloropyrimidin-2-yl)ethenyl]-2-methylcyclohexanecarboxylate

Product 1

HCID 118126870ethyl rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethenyl}-2-methylcyclohexanecarboxylate

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of ethyl rel-(1R,2S)-4-[1-(5-chloropyrimidin-2-yl)ethenyl]-2-methylcyclohexanecarboxylate (480 mg, 1.6 mmol), 4-(difluoromethyl)-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (570 mg, 1.6 mmol), tris(dibenzylideneacetone)-dipalladium(0) (140 mg, 0.16 mmol), XPhos (140 mg, 0.32 mmol) and potassium phosphate tribasic trihydrate (1.25 g, 4.8 mmol) in N,N-dimethylformamide (2 mL) was stirred at 90° C. under a nitrogen atmosphere for 12 hours. After cooling to 20° C., the mixture was diluted with brine and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to afford ethyl rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethenyl}-2-methylcyclohexanecarboxylate. MS ESI calc'd for C28H32F2N5O2[M+G]+ 508. found 508. 1H NMR: (400 MHz, CD3OD) δ 9.02 (s, 2H), 8.64 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.60 (s, 1H), 7.21 (s, 1H), 7.04 (d, J=5.0 Hz, 1H), 6.58 (t, J=54.4 Hz, 1H), 6.36 (s, 1H), 5.52-5.49 (m, 1H), 4.16-4.10 (m, 2H), 2.44 (s, 3H), 1.94-1.59 (m, 7H), 1.25-1.24 (m, 5H), 1.03 (d, J=7.0 Hz, 3H).

Workup

  1. temperatureAfter cooling to 20° C.
  2. extractionextracted with ethyl acetate
  3. dry with materialThe combined organic layers were dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether)

Sources & evidence

ORD record
ord-370f1794e16e49008ccc3e90a0ec6923
Source dataset
uspto-grants-2016_08
Patent number
US09416111B2

Reaction notes

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