Potassium Phosphate, Tribasic → N-(6'-ethoxy-5-morpholino-2,3'-bipyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine

HRID 1431574Notes

Reaction equation

HRID 1431574 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.[CH2:34]([O:36][C:37]1[N:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)[CH3:35].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>[CH2:34]([O:36][C:37]1[N:42]=[CH:41][C:40]([C:2]2[C:7]([NH:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=4[F:19])[N:12]=[C:11]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:10]=3[CH3:27])=[CH:6][C:5]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:4][N:3]=2)=[CH:39][CH:38]=1)[CH3:35]

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 120122372-Ethoxypyridine-5-boronic AcidHCID 59631201N-(2-Chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine

Product 1

HCID 50907605N-(6'-ethoxy-5-morpholino-2,3'-bipyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

N-(2-Chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine (32.7 mg, 0.07 mmol), 6-ethoxypyridin-3-ylboronic acid (14.1 mg, 0.084 mmol), tris(dibenzylideneacetone)dipalladium (0) (3.3 mg, 3.6 μmol), and tricyclohexylphosphine (2.1 mg, 7.5 μmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (0.5 mL) and aq. 1. 3M potassium phosphate tribasic (0.1 mL, 0.13 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 basic alumina (0-45% EtOAc in hexanes) to afford a light yellow solid as N-(6′-ethoxy-5-morpholino-2,3′-bipyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.71 (1H, d, J=4.9 Hz), 8.66 (1H, d, J=2.4 Hz), 8.10 (2H, m), 7.94 (2H, d, J=3.9 Hz), 7.68 (1H, m), 7.46 (1H, m), 7.01 (2H, ddd, J=13.4, 8.6, 2.4 Hz), 6.93 (1H, d, J=8.8 Hz), 6.62 (1H, m), 4.45 (2H, q, J=7.1 Hz), 3.90 (4H, m), 3.28 (4H, m), 2.28 (3H, s), 1.45 (3H, t, J=7.1 Hz). Mass Spectrum (pos.) m/e: 555.2 (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 basic alumina (0-45% EtOAc in hexanes)

Sources & evidence

ORD record
ord-60d707e937734b3d84e0e3071044a566
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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