2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 5,7-difluoro-N-(2-(6-methoxypyridin-3-yl)-5-morpholinophenyl)-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-amine

HRID 1431561노트

반응식

HRID 1431561 반응식
[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][C:10]=2[NH2:11])=[CH:5][CH:4]=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]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=2)[C:24]=1[CH3:42].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>[F:33][C:31]1[CH:30]=[C:29]([F:34])[CH:28]=[C:27]2[C:32]=1[C:23]([NH:11][C:10]1[CH:12]=[C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:14]=[CH:15][C:9]=1[C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[C:24]([CH3:42])[C:25]([C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1)=[N:26]2

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 596313512-(6-Methoxypyridin-3-yl)-5-morpholinoanilineHCID 672859322-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

생성물 1

HCID 596313915,7-difluoro-N-(2-(6-methoxypyridin-3-yl)-5-morpholinophenyl)-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 2-(6-methoxypyridin-3-yl)-5-morpholinoaniline (61.1 mg, 0.21 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (53.9 mg, 0.18 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (17.2 mg, 0.036 mmol), tris(dibenzylideneacetone)dipalladium (0) (7.1 mg, 7.75 mmol), and sodium tert-butoxide (44.4 mg, 0.46 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 20 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 (10-30% 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 an orange solid as 5,7-difluoro-N-(2-(6-methoxypyridin-3-yl)-5-morpholinophenyl)-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (1H, d, J=5.1 Hz), 7.99 (1H, d, J=2.2 Hz), 7.65 (1H, m), 7.58 (4H, m), 7.14 (1H, d, J=8.4 Hz), 6.80 (1H, d, J=7.8 Hz), 6.62 (2H, d, J=8.6 Hz), 3.84 (7H, m), 3.18 (4H, m), 2.48 (3H, s), 2.06 (3H, s). Mass Spectrum (pos.) m/e: 554.2 (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 basic alumina (10-30% 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

출처 및 근거

ORD 기록
ord-ffce0324e1784572aad208e2f087e991
출처 데이터셋
uspto-grants-2015_01
특허 번호
US08940724B2

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