2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → N-(2-Chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine

HRID 1431570Notes

Reaction equation

HRID 1431570 reaction equation
[Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][N:3]=1.Br[C:16]1[C:25]2[C:20](=[CH:21][C:22]([F:27])=[CH:23][C:24]=2[F:26])[N:19]=[C:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:17]=1[CH3:34].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.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>[Cl:1][C:2]1[C:7]([NH:8][C:16]2[C:25]3[C:20](=[CH:21][C:22]([F:27])=[CH:23][C:24]=3[F:26])[N:19]=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:17]=2[CH3:34])=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][N:3]=1

Participants

9

Reactant 5

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 596310392-Chloro-5-morpholinopyridin-3-amineHCID 59631437HCID 59631437, compoundHCID 672859322-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

Product 1

HCID 59631201N-(2-Chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 2-chloro-5-morpholinopyridin-3-amine (183.1 mg, 0.86 mmol), 4-bromo-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (160.1 mg, 0.48 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (37.7 mg, 0.079 mmol), tris(dibenzylideneacetone)dipalladium (0) (17.5 mg, 0.019 mmol), and sodium tert-butoxide (120.7 mg, 1.26 mmol) in dry toluene (3.0 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 basic alumina (5-20% EtOAc in hexanes) to afford a light yellow solid as N-(2-chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.69 (1H, dt, J=4.8, 1.3 Hz), 7.98 (2H, m), 7.73 (2H, m), 7.41 (1H, q, J=4.8 Hz), 7.21 (1H, d, J=9.8 Hz), 7.07 (1H, ddd, J=13.2, 8.6, 2.4 Hz), 6.42 (1H, d, J=2.7 Hz), 3.86 (4H, m), 3.71 (1H, s), 3.17 (4H, m), 2.21 (3H, s). Mass Spectrum (pos.) m/e: 468.1 (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 basic alumina (5-20% EtOAc in hexanes)

Sources & evidence

ORD record
ord-932db466c00f47678a68b128e9b699c7
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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