Potassium Phosphate, Tribasic → 5,7-Difluoro-n-(2-(5-methoxypyridin-3-yl)-5-morpholinophenyl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine

HRID 1431590Notes

Reaction equation

HRID 1431590 reaction equation
Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=2[F:25])[N:18]=[C:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:16]=1[CH3:33].[CH3:34][O:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[N:40][CH:41]=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:25][C:23]1[CH:22]=[C:21]([F:26])[CH:20]=[C:19]2[C:24]=1[C:15]([NH:14][C:3]1[CH:4]=[C:5]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[CH:6]=[CH:7][C:2]=1[C:38]1[CH:39]=[N:40][CH:41]=[C:36]([O:35][CH3:34])[CH:37]=1)=[C:16]([CH3:33])[C:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[N:18]2

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 27630875-Methoxypyridine-3-boronic AcidHCID 59631089N-(2-chloro-5-morpholinophenyl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine

Product 1

HCID 596315415,7-Difluoro-n-(2-(5-methoxypyridin-3-yl)-5-morpholinophenyl)-3-methyl-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-morpholinophenyl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (62.7 mg, 0.13 mmol), 5-methoxypyridin-3-ylboronic acid (31.9 mg, 0.21 mmol), tricyclohexylphosphine (6.3 mg, 0.022 mmol), and tris(dibenzylideneacetone)dipalladium (0) (10.6 mg, 0.012 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 (0.31 mL, 0.4 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 22 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 (0-45% 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 yellow solid as 5,7-difluoro-N-(2-(5-methoxypyridin-3-yl)-5-morpholinophenyl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.69 (1H, d, J=4.4 Hz), 8.42 (1H, d, J=1.7 Hz), 8.28 (1H, d, J=2.7 Hz), 7.88 (1H, td, J=7.6, 1.7 Hz), 7.82 (1H, d, J=7.8 Hz), 7.71 (1H, m), 7.43 (2H, m), 7.22 (1H, d, J=8.6 Hz), 6.93 (1H, dd, J=8.4, 2.6 Hz), 6.95 (1H, dd, J=8.6, 2.4 Hz), 6.65 (1H, dd, J=8.4, 2.3 Hz), 6.36 (1H, d, J=2.2 Hz), 3.89 (3H, s), 3.86 (4H, m), 3.21 (4H, m), 2.18 (3H, s). Mass Spectrum (pos.) m/e: 540.1 (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 (0-45% 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-2d7ba7c3fb4b4b84a2da598cb421798e
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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