Dimethylformamide → HCID 178495259, 화합물

HRID 897597노트

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HRID 897597 반응식
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.F[C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH2:41][CH2:42]OC)[C:33]=1[C:34]#[N:35].[C:45](=[O:48])([O-])[O-].[K+].[K+].[OH-].[Na+].[CH3:53]N(C)C=O>C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:32]4[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH2:41][CH2:42][CH2:53][O:48][CH3:45])[C:33]=4[C:34]#[N:35])=[CH:13][CH:12]=3)[C:3]=12

참가 물질

7

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HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 223466972-Fluoro-6-[(2-methoxyethyl)amino]benzonitrileHCID 178481007HCID 178481007, 화합물

생성물 1

HCID 178495259HCID 178495259, 화합물수율 48%

시약·촉매·용매 1

HCID 8857Ethyl Acetate용매

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온도
120 °C

실험 절차

A solution of trans-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol (0.100 g, 0.245 mmol) in dimethylformamide (25 mL), was treated with 2-fluoro-6-[(2-methoxyethyl)amino]benzonitrile (0.128 g, 0.613 mmol) and potassium carbonate (0.068, 0.49 mmol). The reaction mixture was stirred at 120° C. over night under a nitrogen atmosphere. Ethyl acetate and 1 N sodium hydroxide solution were added to the reaction mixture. The organic layer was washed with 1 N sodium hydroxide solution (1 L). The layers were partitioned and the organic layer was washed with water and brine (500 mL each), dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel using 10% methanol in dichloromethane as eluent, to afford 71 mg (48%) of trans-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-[(3-methoxypropyl)amino]benzonitrile. A warm solution of trans-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-dupyrimidin-3-yl}phenoxy)-6-[(3-methoxypropyl)amino]benzonitrile (0.071 g, 0.119 mmol) in ethyl acetate was treated with a warm solution of maleic acid (0.042 g, 0.358 mmol) in ethyl acetate. The precipitate was filtered under nitrogen and dried under high vacuum to give trans-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-[(3-methoxypropyl)amino]benzonitrile tris-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 8.23 (s, 1H), 7.69-7.67 (d, 2H, J=8 Hz), 7.37-7.33 (m, 1H), 7.25-7.23 (d, 2H, J=8 Hz), 6.53-6.51 (d, 1H, J=8 Hz), 6.30-6.29 (m, 1H), 6.19-6.17 (d, 1H, J=8 Hz), 6.17 (s, 6H), 4.65-4.64 (m, 1H), 3.45-3.42 (m, 2H), 3.27 (s, 3H), 2.55-2.50 (m, 4H), 2.50-2.30 (m, 5H), 2.33 (br. s., 3H), 2.01-1.96 (m, 8 Hz), 1.84-1.80 (m, 2H), 1.49-1.46 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.181 min (95%).

후처리

  1. washThe organic layer was washed with 1 N sodium hydroxide solution (1 L)
  2. customThe layers were partitioned
  3. washthe organic layer was washed with water and brine (500 mL each)
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. customevaporated under reduced pressure
  7. customThe crude product was purified by flash chromatography on silica gel using 10% methanol in dichloromethane as eluent

출처 및 근거

ORD 기록
ord-836a1e990f4142f58b3b099a4c26198a
출처 데이터셋
uspto-grants-2005_07
특허 번호
US06921763B2

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