Potassium Phosphate, Tribasic → N-(5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-5'-fluoro-2'-methoxy-3,4'-bipyridin-5-amine

HRID 1431454

반응식

HRID 1431454 반응식
Br[C:2]1[CH:3]=[C:4]([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:5]=[N:6][CH:7]=1.[F:28][C:29]1[C:30](B(O)O)=[CH:31][C:32]([O:35][CH3:36])=[N:33][CH:34]=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:4]1[CH:3]=[C:2]([C:30]3[C:29]([F:28])=[CH:34][N:33]=[C:32]([O:35][CH3:36])[CH:31]=3)[CH:7]=[N:6][CH:5]=1)=[C:10]([CH3:27])[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[N:12]2

참가 물질

9

반응물 5

HCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 44754837(5-Fluoro-2-methoxypyridin-4-yl)boronic acidHCID 59631407N-(5-bromo-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamineHCID 665453372-Dicyclohexylphosphino-2,6-dimethoxybiphenyl

생성물 1

HCID 59631426N-(5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-5'-fluoro-2'-methoxy-3,4'-bipyridin-5-amine

시약·촉매·용매 3

HCID 167845palladium(II) acetate촉매HCID 962Water용매HCID 6228Dimethylformamide용매

반응 조건

온도
90 °C

실험 절차

A mixture of N-(5-bromo-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine (28.1 mg, 0.066 mmol), 5-fluoro-2-methoxypyridin-4-ylboronic acid (commercially available from Asymchem) (17.7 mg, 0.104 mmol), 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl, (S-Phos) (5.9 mg, 0.014 mmol), palladium(II) acetate (5.1 mg, 7.57 μmol), and potassium phosphate tribasic (45.1 mg, 0.21 mmol) in DMF (1.0 mL) and water (0.05 mL) was degassed by nitrogen. The mixture was heated to 90° C. After 21.5 h, the reaction was cooled to rt, then treated with water. After extracting twice with EtOAc, the organic layers were combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-35% EtOAc in hexanes) to afford an impure yellow residue. The light yellow film was further purified by HPLC (10-60% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions were concentrated 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 white solid as N-(5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-5′-fluoro-2′-methoxy-3,4′-bipyridin-5-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.77 (1H, ddd, J=4.8, 1.8, 0.9 Hz), 8.43 (1H, t, J=1.7 Hz), 8.36 (1H, d, J=2.7 Hz), 8.09 (1H, d, J=2.2 Hz), 7.94 (2H, m), 7.66 (1H, ddd, J=9.6, 2.5, 1.4 Hz), 7.40 (1H, ddd, J=7.4, 4.8, 1.5 Hz), 7.11 (2H, m), 6.86 (1H, d, J=5.3 Hz), 3.95 (3H, s), 2.24 (3H, s). Mass Spectrum (pos.) m/e: 474.1 (M+1).

후처리

  1. customwas degassed by nitrogen
  2. temperaturethe reaction was cooled to rt
  3. additiontreated with water
  4. extractionAfter extracting twice with EtOAc
  5. dry with materialdried over anhydrous magnesium sulfate
  6. filtrationAfter filtration and concentration
  7. customthe residue was purified on basic alumina (0-35% EtOAc in hexanes)
  8. customto afford an impure yellow residue
  9. customThe light yellow film was further purified by HPLC (10-60% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions
  10. concentrationwere concentrated
  11. additionthen 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

출처 및 근거

ORD 기록
ord-de3b253560e1477aa3ad780f204f5851
출처 데이터셋
uspto-grants-2015_01
특허 번호
US08940724B2

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