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Potassium Phosphate, Tribasic → 4-(3-(5,7-Difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinopyridin-2-yl)phenol

HRID 1431591
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HRID 1431591 반응식
Cl[C:2]1[C:7]([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:6][C:5]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:4][N:3]=1.[OH:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[F:19][C:17]1[CH:16]=[C:15]([F:20])[CH:14]=[C:13]2[C:18]=1[C:9]([NH:8][C:7]1[C:2]([C:38]3[CH:39]=[CH:40][C:35]([OH:34])=[CH:36][CH:37]=3)=[N:3][CH:4]=[C:5]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:6]=1)=[C:10]([CH3:27])[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[N:12]2
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참가 물질

8

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HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 27343604-Hydroxyphenylboronic acidHCID 59631201N-(2-Chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine

생성물 1

HCID 1360270974-(3-(5,7-Difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinopyridin-2-yl)phenol

시약·촉매·용매

3
HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 962Water용매HCID 312751,4-Dioxane용매

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온도
90 °C

실험 절차

N-(2-chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine (60.6 mg, 0.13 mmol), 4-hydroxyphenylboronic acid (36.7 mg, 0.27 mmol), tricyclohexylphosphine (7.7 mg, 0.027 mmol), and tris(dibenzylideneacetone)dipalladium (0) (12.1 mg, 0.013 mmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (2.0 mL) and aq. 1.3M potassium phosphate tribasic (0.3 mL, 0.39 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 19 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 (0-55% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM) to afford a film that 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 yellow solid as 4-(3-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinopyridin-2-yl)phenol. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.49 (1H, s), 8.70 (1H, dq, J=4.8, 0.9 Hz), 8.01 (1H, td, J=7.7, 1.7 Hz), 7.94 (1H, d, J=2.4 Hz), 7.83 (1H, d, J=7.6 Hz), 7.65 (2H, m), 7.54 (4H, m), 6.79 (2H, m), 6.45 (1H, d, J=2.4 Hz), 3.76 (4H, m), 3.14 (4H, m), 2.13 (3H, s). Mass Spectrum (pos.) m/e: 526.2 (M+1).

후처리

  1. customthen degassed
  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 (0-55% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM)
  9. customto afford a film that
  10. customwas 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-8c3de7068fa24b7b91f9013b753f6141
출처 데이터셋
uspto-grants-2015_01
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08940724B2

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