Acryloyl chloride → N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)-4-hydroxyphenyl)acrylamide

HRID 1482691Notes

Reaction equation

HRID 1482691 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([NH:9][C:10]2[C:15]([F:16])=[CH:14][N:13]=[C:12]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:20][CH:19]=3)[N:11]=2)[CH:3]=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31].CCCCCC.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O>[F:16][C:15]1[C:10]([NH:9][C:4]2[CH:3]=[C:2]([NH:1][C:29](=[O:32])[CH:30]=[CH2:31])[CH:7]=[CH:6][C:5]=2[OH:8])=[N:11][C:12]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:20][CH:19]=2)=[N:13][CH:14]=1

Participants

6

Reactant 4

HCID 13140Acryloyl chlorideHCID 516892Sodium BicarbonateHCID 21226206Ethyl acetate hexaneHCID 867243454-Amino-2-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenol

Product 1

HCID 86724346N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)-4-hydroxyphenyl)acrylamideYield 3.2%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

To a 25 mL 3-neck RBF previously equipped with a magnetic stirrer and CaCl2 guard tube was added 4-amino-2-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenol (0.075 g in 5 mL DCM) and it was cooled to −40° C. and acryloyl chloride (0.019 g in 3 mL DCM) was slowly added. The reaction was warmed to room temperature and stirred for 30 min. The reaction was monitored on TLC using hexane:ethyl acetate (7:3) as mobile phase. The reaction was complete after 30 min. The reaction mixture was poured in water (100 mL) and basified using sodium bicarbonate. The mixture was extracted with DCM (2×25 mL) and the combined organic layer was washed with brine solution, dried over sodium sulfate and concentrated completely under reduced pressure at 40° C. Crude material was purified by preparative-HPLC to give 2.7 mg of N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)-4-hydroxyphenyl)acrylamide. 1H NMR: DMSO-d6 (400 MHz) 3.25 (s, 3H), 3.58 (s, 2H), 3.91 (s, 2H), 5.70 (d, 1H, J=10), 6.20 (d, 1H, J=16.8), 6.39 (dd, 1H, J=10.4, 17.2), 6.65 (d, 2H, J=8.8), 6.87 (d, 1H, J=8.8), 7.45 (m, 3H), 7.78 (s, 1H), 8.01 (s, 1H), 8.21 (s, 1H), 8.48 (s, 1H), 8.92 (s, 1H), 9.98 (s, 1H).

Workup

  1. customTo a 25 mL 3-neck RBF previously equipped with a magnetic stirrer and CaCl2 guard tube
  2. temperatureThe reaction was warmed to room temperature
  3. waitThe reaction was complete after 30 min
  4. extractionThe mixture was extracted with DCM (2×25 mL)
  5. washthe combined organic layer was washed with brine solution
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated completely under reduced pressure at 40° C
  8. customCrude material was purified by preparative-HPLC

Sources & evidence

ORD record
ord-4aa5db17c6404cd9a759f1bf5ea1c461
Source dataset
uspto-grants-2016_08
Patent number
US09415049B2

Reaction notes

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