Potassium Phosphate, Tribasic → HCID 57420249, compound

HRID 1431714Notes

Reaction equation

HRID 1431714 reaction equation
[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[C:28](I)=[CH:27][C:24]([C:25]#[N:26])=[C:23]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:22]=1)=[C:5]([CH3:19])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[N:7]2.[CH3:36][O:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[N:42][CH:43]=1.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:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[C:28]([C:40]3[CH:41]=[N:42][CH:43]=[C:38]([O:37][CH3:36])[CH:39]=3)=[CH:27][C:24]([C:25]#[N:26])=[C:23]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:22]=1)=[C:5]([CH3:19])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[N:7]2

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 27630875-Methoxypyridine-3-boronic AcidHCID 67507790HCID 67507790, compound

Product 1

HCID 57420249HCID 57420249, compound

Reagents, catalysts & solvents 3

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

Conditions

Temperature
90 °C

Procedure

4-(5,7-Difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-iodo-2-morpholinobenzonitrile (65.2 mg, 0.11 mmol), 5-methoxypyridin-3-ylboronic acid (26.6 mg, 0.17 mmol), tricyclohexylphosphine (5.9 mg, 0.021 mmol), and tris(dibenzylideneacetone)dipalladium (0) (9.7 mg, 10.6 μmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (2.0 mL) and aqueous 1.3M potassium phosphate tribasic (0.26 mL, 0.34 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 (0-50% of a premixed solution of 89:9:1 DCM:methanol: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 concd 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 yellow solid as 4-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-ylamino)-5-(5-methoxypyridin-3-yl)-2-morpholinobenzonitrile. 1H NMR (400 MHz, CDCl3) δ ppm 8.73 (1H, m), 8.41 (2H, d, J=2.0 Hz), 7.94 (2H, m), 7.64 (1H, m), 7.47 (3H, m), 7.25 (1H, m), 6.99 (1H, m), 6.87 (1H, m), 6.18 (1H, s), 3.96 (3H, s), 3.85 (4H, m), 3.16 (4H, m), 2.27 (3H, s). Mass Spectrum (pos.) m/e: 565.2 (M+H)+.

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 (0-50% of a premixed solution of 89:9:1 DCM:methanol: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.) The desired fractions
  11. additionwere concd 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-8e024d8e066244a1a5be82f4b2ddde63
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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