2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 5,7-difluoro-N-(5'-methoxy-5-morpholino-2,3'-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine

HRID 1431584노트

반응식

HRID 1431584 반응식
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([NH2:15])=[CH:13][C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:11][N:10]=2)[CH:6]=[N:7][CH:8]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([F:34])=[CH:30][C:31]=2[F:33])[N:26]=[C:25]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:24]=1[CH3:41].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:33][C:31]1[CH:30]=[C:29]([F:34])[CH:28]=[C:27]2[C:32]=1[C:23]([NH:15][C:14]1[C:9]([C:5]3[CH:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:10][CH:11]=[C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:13]=1)=[C:24]([CH3:41])[C:25]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)=[N:26]2

참가 물질

8

반응물 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl2회HCID 23676156Sodium t-butoxideHCID 596310254-Chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolineHCID 596313095'-Methoxy-5-morpholino-2,3'-bipyridin-3-amine

생성물 1

HCID 509076035,7-difluoro-N-(5'-methoxy-5-morpholino-2,3'-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine

시약·촉매·용매 3

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 962Water용매HCID 1140Toluene용매

반응 조건

온도
100 °C

실험 절차

A mixture of 5′-methoxy-5-morpholino-2,3′-bipyridin-3-amine (75.1 mg, 0.26 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.11 g, 0.4 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl, (X-Phos) (20.7 mg, 0.043 mmol), tris(dibenzylideneacetone)dipalladium (0) (11 mg, 0.012 mmol), and sodium tert-butoxide (76.4 mg, 0.8 mmol) in dry toluene (3.0 mL) was degassed by nitrogen. The resulting reaction was heated to 100° C. and monitored with TLC and LC-MS. After 18 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 (30-50% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM) to afford an impure yellow solid. The light yellow solid 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 light yellow solid as 5,7-difluoro-N-(5′-methoxy-5-morpholino-2,3′-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.76 (1H, d, J=1.5 Hz), 8.69 (1H, dt, J=4.6, 1.3 Hz), 8.39 (1H, d, J=2.9 Hz), 8.11 (1H, d, J=2.4 Hz), 7.96 (2H, m), 7.82 (1H, br. s.), 7.64 (1H, dt, J=9.4, 1.2 Hz), 7.44 (1H, m), 7.06 (2H, m), 6.57 (1H, d, J=2.4 Hz), 3.97 (3H, s), 3.89 (4H, m), 3.29 (4H, m), 2.24 (3H, s). Mass Spectrum (pos.) m/e: 541.2 (M+1).

후처리

  1. customwas degassed by nitrogen
  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 (30-50% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM)
  9. customto afford an impure yellow solid
  10. customThe light yellow solid 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

출처 및 근거

ORD 기록
ord-331c3d3c96ed498a81bd51005e02e91c
출처 데이터셋
uspto-grants-2015_01
특허 번호
US08940724B2

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