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

HRID 1431588Notes

Reaction equation

HRID 1431588 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[C:15]([NH2:16])=[CH:14][C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:12][N:11]=2)=[C:5]([CH3:23])[CH:4]=1.Cl[C:25]1[C:34]2[C:29](=[CH:30][C:31]([F:36])=[CH:32][C:33]=2[F:35])[N:28]=[C:27]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[C:26]=1[CH3:43].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:35][C:33]1[CH:32]=[C:31]([F:36])[CH:30]=[C:29]2[C:34]=1[C:25]([NH:16][C:15]1[C:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:23])=[N:11][CH:12]=[C:13]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[CH:14]=1)=[C:26]([CH3:43])[C:27]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)=[N:28]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 596311642-(4-Methoxy-2,6-dimethylphenyl)-5-morpholinopyridin-3-amine

Product 1

HCID 509073885,7-difluoro-N-(2-(4-methoxy-2,6-dimethylphenyl)-5-morpholinopyridin-3-yl)-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-(4-methoxy-2,6-dimethylphenyl)-5-morpholinopyridin-3-amine (41 mg, 0.13 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (57 mg, 0.2 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl, (X-Phos) (7.9 mg, 0.017 mmol), tris(dibenzylideneacetone)dipalladium (0) (7.8 mg, 8.5 μmol), and sodium tert-butoxide (36.9 mg, 0.38 mmol) in dry toluene (2 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 (0-60% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM) to afford a yellow film that was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as 5,7-difluoro-N-(2-(4-methoxy-2,6-dimethylphenyl)-5-morpholinopyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.69 (1H, dt, J=4.7, 1.3 Hz), 8.00 (1H, d, J=2.5 Hz), 7.93 (2H, m), 7.63 (1H, m), 7.38 (1H, ddd, J=6.1, 4.8, 2.7 Hz), 6.95 (1H, ddd, J=13.3, 8.6, 2.5 Hz), 6.75 (2H, s), 6.60 (2H, m), 3.95 (7H, m), 3.28 (4H, m), 2.21 (3H, s), 2.15 (6H, s). Mass Spectrum (pos.) m/e: 568.2 (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 (0-60% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM)
  9. customto afford a yellow film that
  10. customwas further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution)
  11. additionThe desired fractions were cond then diluted with EtOAc
  12. washAfter washing twice with satd aq. sodium bicarbonate solution and once with brine
  13. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-05e37a4ff8ab4fc39dcb7534e5e13050
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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