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

HRID 1431571
Notes
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Reaction equation

HRID 1431571 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[C:41](B(O)O)=[CH:40][CH:39]=[CH:38][N:37]=1.C1(P(C2CCCCC2)C2(OC)CC=CC(OC)=C2C2C=CC=CC=2)CCCCC1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[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[C:36]([O:35][CH3:34])=[N:37][CH:38]=[CH:39][CH:40]=3)=[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

9

Reactant 5

HCID 62657Potassium Phosphate, TribasicHCID 2762709(2-Methoxypyridin-3-yl)boronic acidHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 59631201N-(2-Chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amineHCID 665453372-Dicyclohexylphosphino-2,6-dimethoxybiphenyl

Product 1

HCID 509078205,7-difluoro-N-(2'-methoxy-5-morpholino-2,3'-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

A stirred mixture of N-(2-chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (50.1 mg, 0.11 mmol), 2-methoxypyridin-3-ylboronic acid (32.9 g, 0.22 mmol), ground 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl, (S-Phos) (9.1 mg, 0.022 mmol), palladium (II) acetate (2.7 mg, 0.012 mmol), and potassium phosphate tribasic (70.5 g, 0.33 mmol) in DMF (1.0 mL) and Water (0.04 mL) was purged 3 times with argon and placed under vacuum 3 times. The reaction mixture was carefully heated to 90° C. After 21 h, the reaction was cooled to rt, then diluted with water and extracted 3 times with EtOAc. The organic extractions were combined and washed twice with brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was purified over basic alumina (0-50% EtOAc in hexanes) to afford an impure yellow film. This 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 solid as 5,7-difluoro-N-(2′-methoxy-5-morpholino-2,3′-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. Mass Spectrum (pos.) m/e: 541.2 (M+1).

Workup

  1. customwas purged 3 times with argon
  2. temperaturethe reaction was cooled to rt
  3. additiondiluted with water
  4. extractionextracted 3 times with EtOAc
  5. extractionThe organic extractions
  6. washwashed twice with brine
  7. dry with materialAfter drying over anhydrous sodium sulfate and filtration
  8. customthe organic solvent was removed under reduced pressure
  9. customThe residue was purified over basic alumina (0-50% EtOAc in hexanes)
  10. customto afford an impure yellow film
  11. customThis film was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution)
  12. additionThe desired fractions were cond then diluted with EtOAc
  13. washAfter washing twice with satd aq. sodium bicarbonate solution and once with brine
  14. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-346e723473604bc8969e1ef84878c3e8
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