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

HRID 1431580
Notes
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Reaction equation

HRID 1431580 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][O:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][C:41]=1B(O)O.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:40]=[CH:39][N:38]=[CH:37][C:36]=3[O:35][CH3:34])=[N:3][CH:4]=[C:5]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]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
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 467390193-Methoxypyridine-4-boronic acidHCID 59631201N-(2-Chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine

Product 1

HCID 509076075,7-difluoro-N-(3'-methoxy-5-morpholino-2,4'-bipyridin-3-yl)-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-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine (60.5 mg, 0.13 mmol), 3-methoxypyridin-4-ylboronic acid (97.1 mg, 0.63 mmol), tris(dibenzylideneacetone)dipalladium (0) (7.5 mg, 8.2 μmol), and tricyclohexylphosphine (4.8 mg, 0.017 mmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (1.0 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 basic alumina (0-100% EtOAc in hexanes) to afford an impure orange residue. The light orange film 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 film as 5,7-difluoro-N-(3′-methoxy-5-morpholino-2,4′-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.73 (2H, m), 8.47 (1H, d, J=5.3 Hz), 8.22 (1H, d, J=2.5 Hz), 7.95 (3H, m), 7.76 (1H, d, J=5.1 Hz), 7.69 (1H, dt, J=9.2, 1.2 Hz), 7.41 (1H, ddd, J=7.4, 4.9, 1.4 Hz), 7.06 (1H, ddd, J=13.8, 8.4, 2.4 Hz), 6.69 (1H, d, J=2.5 Hz), 4.15 (3H, s), 3.90 (4H, m), 3.31 (4H, m), 1.94 (3H, s). Mass Spectrum (pos.) m/e: 541.2 (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 (0-100% EtOAc in hexanes)
  9. customto afford an impure orange residue
  10. customThe light orange film was 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-b34369e613494cc2936177a86cbed95b
Source dataset
uspto-grants-2015_01
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08940724B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes