Formaldehyde → 4-[4-(4-Ethyl-5-fluoro-2-hydroxyphenoxy)-3-fluorobenzoyl]-1-(morpholinomethyl)piperazin-2-one

HRID 389996Notes

Reaction equation

HRID 389996 reaction equation
C=O.[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH2:9]([C:11]1[C:33]([F:34])=[CH:32][C:14]([O:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=[O:21])=[CH:18][C:17]=2[F:31])=[C:13]([OH:35])[CH:12]=1)[CH3:10].[C:36](OCC)(=O)C>CO.O.O>[CH2:9]([C:11]1[C:33]([F:34])=[CH:32][C:14]([O:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH2:36][N:3]4[CH2:8][CH2:7][O:6][CH2:5][CH2:4]4)[C:24](=[O:28])[CH2:23]3)=[O:21])=[CH:18][C:17]=2[F:31])=[C:13]([OH:35])[CH:12]=1)[CH3:10]

Participants

7

Reactant 4

HCID 712Formaldehyde2×HCID 8083Morpholine2×HCID 8857Ethyl AcetateHCID 513473574-[4-(4-Ethyl-5-fluoro-2-hydroxyphenoxy)-3-fluorobenzoyl]piperazin-2-one

Product 1

HCID 513567684-[4-(4-Ethyl-5-fluoro-2-hydroxyphenoxy)-3-fluorobenzoyl]-1-(morpholinomethyl)piperazin-2-one

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 22242641Methanol--water (1/1)Solvent

Conditions

Temperature
40 °C

Procedure

Formaldehyde (37% in water, 30 μL, 0.32 mmol) and morpholine (28 μL, 0.32 mmol) were successively added to a solution of 4-[4-(4-ethyl-5-fluoro-2-hydroxyphenoxy)-3-fluorobenzoyl]-piperazin-2-one (which may be prepared in accordance with the experimental described in Example 7, step 1; 100 mg, 0.26 mmol) in a mixture of methanol/H2O (0.8 mL/0.8 mL). The mixture was stirred at 40° C. for 2 hours prior to the addition of more formaldehyde (37% in water, 30 μL, 0.4 mmol) and more morpholine (32 μL, 0.4 mmol). The reaction mixture was then stirred at 40° C. for two days. The reaction mixture was diluted by addition of ethyl acetate (20 mL) and water (20 mL). After separation, the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (98:2 to 96:4) as eluent. The title product was obtained as a white solid (55 mg, 44%).

Workup

  1. custommay be prepared in accordance with the
  2. stirringThe reaction mixture was then stirred at 40° C. for two days
  3. customAfter separation
  4. extractionthe aqueous layer was extracted with ethyl acetate (2×20 mL)
  5. dry with materialThe combined organic phases were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under vacuum
  8. customThe residue was purified by chromatography on silica gel

Sources & evidence

ORD record
ord-1536929bd6424f3dbd3d5f13a6c3d66e
Source dataset
uspto-grants-2013_02
Patent number
US08383621B2

Reaction notes

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