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Morpholine → 5,7-Difluoro-N-(2-(4-methoxyphenyl)-5-(4-morpholinyl)-3-pyridinyl)-3-methyl-2-(2-pyridinyl)-4-quinolinamine

HRID 1431371
ノート
印刷プレビュー

反応式

HRID 1431371 の反応式
Br[C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[CH:24][C:25]=3[F:27])[N:20]=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:18]=2[CH3:35])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+].[NH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1.C([O-])([O-])=O.[Na+].[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]>[F:27][C:25]1[CH:24]=[C:23]([F:28])[CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:4]1[C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)=[N:6][CH:7]=[C:2]([N:76]3[CH2:81][CH2:80][O:79][CH2:78][CH2:77]3)[CH:3]=1)=[C:18]([CH3:35])[C:19]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[N:20]2
参加物反応条件実験手順後処理出典と根拠反応ノート

参加物

8

反応物 5

HCID 8083MorpholineHCID 10340Sodium CarbonateHCID 23676156Sodium t-butoxideHCID 59631355N-(5-bromo-2-(4-methoxyphenyl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amineHCID 672859322-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

生成物 1

HCID 50907823
5,7-Difluoro-N-(2-(4-methoxyphenyl)-5-(4-morpholinyl)-3-pyridinyl)-3-methyl-2-(2-pyridinyl)-4-quinolinamine

試薬・触媒・溶媒 2

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 1140Toluene溶媒

反応条件

温度
100 °C

実験手順

A stirred mixture of mostly N-(5-bromo-2-(4-methoxyphenyl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.093 g, 0.18 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl (0.017 g, 0.035 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.017 g, 0.018 mmol), and sodium tert-butoxide (0.058 g, 0.60 mmol) in dry toluene (3.0 mL) was purged three times with argon and placed under vacuum three times, then morpholine (0.2 mL, 2.30 mmol) was added to the mixture by syringe. Upon complete addition, the mixture was heated to 100° C. After 23.5 h, the reaction was cooled to rt, then treated with 1M Na2CO3 solution. After extracting twice with DCM:MeOH (95:5), the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentration the residue was purified on silica gel (0-40% of 89:9:1 DCM:MeOH:ammonium hydroxide solution in DCM) to afford an impure light yellow film. This film was submitted to analytical group for SFC purification. After concentration, the residue was identified as 5,7-difluoro-N-(2-(4-methoxyphenyl)-5-(4-morpholinyl)-3-pyridinyl)-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (1H, m), 8.05 (1H, m), 7.94 (2H, m), 7.76 (2H, m), 7.64 (1H, m), 7.42 (1H, m), 7.07 (3H, m), 6.99 (1H, m), 6.54 (1H, m), 3.92 (7H, m), 3.22 (4H, m), 2.22 (3H, s). Mass Spectrum ESI (pos.) m/e: 540.3 (M+H)+.

後処理

  1. customwas purged three times with argon
  2. additionUpon complete addition
  3. temperaturethe reaction was cooled to rt
  4. extractionAfter extracting twice with DCM:MeOH (95:5)
  5. dry with materialdried over anhydrous magnesium sulfate
  6. filtrationAfter filtration and concentration the residue
  7. customwas purified on silica gel (0-40% of 89:9:1 DCM:MeOH:ammonium hydroxide solution in DCM)
  8. customto afford an impure light yellow film
  9. customThis film was submitted to analytical group for SFC purification
  10. concentrationAfter concentration

出典と根拠

ORDレコード
ord-dc66dd188d7144be94d6c703b2271bc8
出典データセット
uspto-grants-2015_01
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US08940724B2

反応ノート

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