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

Participants

Reaction Conditions

Reaction Steps

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%).

Provenance & Evidence