Potassium Phosphate, Tribasic → 5,7-difluoro-3-methyl-N-(2-(4-(methylsulfonyl)phenyl)-5-morpholinopyridin-3-yl)-2-(pyridin-2-yl)quinolin-4-amine

HRID 1431589Notes

Reaction equation

HRID 1431589 reaction equation
Cl[C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=3[F:19])[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:10]=2[CH3:27])=[CH:6][C:5]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:4][N:3]=1.[CH3:34][S:35]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)(=[O:37])=[O:36].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[F:19][C:17]1[CH:16]=[C:15]([F:20])[CH:14]=[C:13]2[C:18]=1[C:9]([NH:8][C:7]1[C:2]([C:41]3[CH:42]=[CH:43][C:38]([S:35]([CH3:34])(=[O:37])=[O:36])=[CH:39][CH:40]=3)=[N:3][CH:4]=[C:5]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:6]=1)=[C:10]([CH3:27])[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[N:12]2

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 27343644-(Methanesulfonyl)phenylboronic acidHCID 59631201N-(2-Chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine

Product 1

HCID 509073875,7-difluoro-3-methyl-N-(2-(4-(methylsulfonyl)phenyl)-5-morpholinopyridin-3-yl)-2-(pyridin-2-yl)quinolin-4-amine

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

N-(2-chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine (60.7 mg, 0.13 mmol), 4-(methylsulfonyl)phenylboronic acid (40.1 mg, 0.2 mmol), tricyclohexylphosphine (6.2 mg, 0.022 mmol), and tris(dibenzylideneacetone)dipalladium (0) (10.4 mg, 0.011 mmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (2.0 mL) and aq. 1.3M potassium phosphate tribasic (0.3 mL, 0.39 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 19 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 film that was triturated with MeOH to afford a light yellow solid as 5,7-difluoro-3-methyl-N-(2-(4-(methylsulfonyl)phenyl)-5-morpholinopyridin-3-yl)-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.69 (1H, dt, J=4.8, 1.2 Hz), 8.12 (5H, m), 7.96 (2H, m), 7.62 (1H, d, J=8.8 Hz), 7.39 (1H, ddd, J=6.8, 4.8, 2.1 Hz), 7.02 (2H, m), 6.55 (1H, d, J=2.4 Hz), 3.91 (4H, m), 3.28 (4H, m), 3.09 (3H, s), 2.25 (3H, s). Mass Spectrum (pos.) m/e: 602.0 (M+1).

Workup

  1. customthen degassed
  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 film that
  10. customwas triturated with MeOH

Sources & evidence

ORD record
ord-00da4bef6bec48b5a426be45e48a487b
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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