Hydrochloric Acid → N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride

HRID 1046033노트

반응식

HRID 1046033 반응식
[NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:11]=2[O:12][C:13]2[C:18]([F:19])=[CH:17][C:16]([NH:20][C:21]([C:23]3[C:24](=[O:39])[N:25]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[CH:26]=[CH:27][C:28]=3[O:29][CH2:30][CH3:31])=[O:22])=[C:15]([F:40])[CH:14]=2)[CH:3]=[N:2]1.[ClH:41]>C(#N)C.O>[ClH:41].[NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:11]=2[O:12][C:13]2[C:18]([F:19])=[CH:17][C:16]([NH:20][C:21]([C:23]3[C:24](=[O:39])[N:25]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[CH:26]=[CH:27][C:28]=3[O:29][CH2:30][CH3:31])=[O:22])=[C:15]([F:40])[CH:14]=2)[CH:3]=[N:2]1

참가 물질

5

반응물 2

HCID 313Hydrochloric AcidHCID 54596553N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

생성물 1

HCID 68009253N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride수율 93.8%

시약·촉매·용매 2

HCID 962Water용매HCID 6342Acetonitrile용매

실험 절차

In a sealed tube, N-(4-(3-bromopyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.124 g, 0.221 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.064 g, 0.332 mmol), potassium carbonate (0.092 g, 0.664 mmol), and tetrakistriphenylphosphine palladium (0) (0.026 g, 0.022 mmol) were suspended in dioxane (6 mL) and water (1.5 mL). The mixture was degassed with Ar and heated at 85° C. overnight. Additional 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg) and tetrakistriphenylphosphine palladium (0) (0.026 g, 0.022 mmol) were added. The reaction mixture was degassed with Ar and heated at 85° C. for 2 days. The mixture was diluted with EtOAc and extracted with sat. NaHCO3 (aq). The organic extract was washed with brine, dried and evaporated. The crude product was purified by silica gel chromatography (25 g) eluting with CH2Cl2/MeOH to yield N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (69 mg, 56.9% yield). The hydrochloride salt was formed by suspending N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.069 g, 0.126 mmol) in acetonitrile (2 ml) and adding 0.1N HCl (1.51 mL, 0.151 mmol). The mixture was sonicated for 10 min. The solution was diluted with water (2 mL), frozen and lyophilized. The crude lyophilate was dried at 80° C. for 4 h under vacuum to yield N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride (0.069 g, 87% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.32 (s, 1H); 9.15 (s, 1H); 8.49 (d, J=6.5 Hz, 1H); 8.43 (dd, J=12.5, 7.0 Hz, 1H); 8.33 (s, 2H); 7.93 (d, J=7.8 Hz, 1H); 7.69 (dd, J=10.8, 7.3 Hz, 1H); 7.48 (dd, J=8.8, 4.9 Hz, 2H); 7.37 (t, J=8.8 Hz, 2H); 7.25 (d, J=6.5 Hz, 1H); 6.56 (d, J=7.9 Hz, 1H); 4.28 (q, J=7.0 Hz, 2H); 1.34 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 508.2 (M+H+).

후처리

  1. customThe mixture was sonicated for 10 min
  2. temperaturefrozen
  3. customThe crude lyophilate was dried at 80° C. for 4 h under vacuum

출처 및 근거

ORD 기록
ord-73a2a314765e430b98f7855d4b62bb87
출처 데이터셋
uspto-grants-2013_10
특허 번호
US08569319B2

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