2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 4-(3-(5,7-Difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinopyridin-2-yl)benzonitrile

HRID 1431586Notes

Reaction equation

HRID 1431586 reaction equation
[NH2:1][C:2]1[C:3]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[N:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([F:34])=[CH:30][C:31]=2[F:33])[N:26]=[C:25]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:24]=1[CH3:41].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:33][C:31]1[CH:30]=[C:29]([F:34])[CH:28]=[C:27]2[C:32]=1[C:23]([NH:1][C:2]1[C:3]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[N:4][CH:5]=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[CH:7]=1)=[C:24]([CH3:41])[C:25]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)=[N:26]2

Participants

8

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl2×HCID 23676156Sodium t-butoxideHCID 596310254-Chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolineHCID 596314364-(3-Amino-5-morpholinopyridin-2-yl)benzonitrile

Product 1

HCID 509073894-(3-(5,7-Difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinopyridin-2-yl)benzonitrile

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 4-(3-amino-5-morpholinopyridin-2-yl)benzonitrile (54.9 mg, 0.2 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (85.7 mg, 0.3 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl, (X-Phos) (15.2 mg, 0.03 mmol), tris(dibenzylideneacetone)dipalladium (0) (8.2 mg, 9 μmol), and sodium tert-butoxide (58.8 mg, 0.6 mmol) in dry toluene (2.0 mL) was degassed by nitrogen. The resulting reaction was heated to 100° C. and monitored with TLC and LC-MS. After 18 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-45% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM) to afford a film that was triturated with MeOH to afford a white solid as 4-(3-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinopyridin-2-yl)benzonitrile. 1H NMR (500 MHz, CDCl3) δ ppm 8.74 (1H, m), 8.06 (1H, d, J=2.4 Hz), 7.98 (2H, m), 7.95 (2H, m), 7.78 (2H, m), 7.65 (1H, d, J=7.8 Hz), 7.40 (1H, td, J=5.3, 2.8 Hz), 6.98 (1H, dd, J=13.6, 8.4 Hz), 6.98 (1H, dd, J=13.6, 8.4 Hz), 6.55 (1H, d, J=2.0 Hz), 3.90 (4H, m), 3.30 (4H, m), 2.25 (3H, s). Mass Spectrum (pos.) m/e: 535.2 (M+1).

Workup

  1. customwas degassed by nitrogen
  2. customThe resulting reaction
  3. temperaturethe reaction was cooled to rt
  4. extractionAfter extracting twice with EtOAc and twice with DCM
  5. extractionthe combined organic extractions
  6. dry with materialwere dried over anhydrous magnesium sulfate
  7. filtrationAfter filtration and concentration
  8. customthe residue was purified on silica gel (0-45% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM)
  9. customto afford a film that
  10. customwas triturated with MeOH

Sources & evidence

ORD record
ord-c37c96f8252140aca5b0faa66c5f6038
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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