2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → N-(5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-amine

HRID 1431554노트

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HRID 1431554 반응식
[O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1.Cl[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]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=2)[C:16]=1[CH3:34].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.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>[O:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:8]=[C:9]([NH:13][C:15]3[C:24]4[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=4[F:25])[N:18]=[C:17]([C:27]4[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=4)[C:16]=3[CH3:34])[CH:10]=[N:11][CH:12]=2)[CH2:5][CH2:6]1

참가 물질

9

반응물 5

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 596311504-Chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinolineHCID 596311705-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-amineHCID 672859322-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

생성물 1

HCID 50907824N-(5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(4-methylpyridin-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-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-amine (38.8 mg, 0.22 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (52.8 mg, 0.17 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (14.4 mg, 0.03 mmol), tris(dibenzylideneacetone)dipalladium (0) (7.2 mg, 7.9 μmol), and sodium tert-butoxide (45.1 mg, 0.47 mmol) in dry toluene (1.5 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 basic alumina (0-30% EtOAc in hexanes) to afford an orange film as N-(5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.63 (1H, m), 8.28 (1H, d, J=2.0 Hz), 8.17 (1H, d, J=2.5 Hz), 7.66 (2H, m), 7.20 (1H, ddd, J=5.0, 1.7, 0.8 Hz), 7.14 (1H, d, J=11.9 Hz), 7.10 (2H, m), 6.20 (1H, tt, J=3.0, 1.5 Hz), 4.32 (2H, q, J=2.7 Hz), 3.93 (2H, t, J=5.4 Hz), 2.55 (5H, m), 2.14 (3H, s). Mass Spectrum (pos.) m/e: 445.1 (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 basic alumina (0-30% EtOAc in hexanes)

출처 및 근거

ORD 기록
ord-0d4f884bedea43d1a9d27dace1475cd1
출처 데이터셋
uspto-grants-2015_01
특허 번호
US08940724B2

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