反应详情

5-Amino-3-methyl-isoxazole (100 mg, 1.02 mmol, 1.0 equiv.) was added to a vial and dissolved in anhydrous THF (EMD, 5 mL) and redistilled DIPEA (196 ul, 1.12 mmol, 1.1 equiv.) under atmosphere of N2. To this solution 4-nitrophenyl chloroformate (205 mg, 1.02 mmol, 1.0 equiv.) was added directly and the vial was purged again with nitrogen. After 10 minutes, the reaction turned off-white and opaque; after 12 hours of stirring at room temperature the mixture became yellow in color. The presence of the intermediate carbamate was confirmed by TLC (10% MeOH/DCM) and reverse phase LC/MS: a strong UV peak was observed but the mass was not observed in positive ionization mode. Ethyl 4-(3-(aminomethyl)-4-fluorobenzyl)piperazine-1-carboxylate (139 mg, 1.02 mmol, 1.0 equiv.) in a minimal amount of THF/DCM and added drop-wise to the reaction vessel under atmosphere of N2. The mixture was stirred for 1 hour then heated to 65° C. for 2 hours. The reaction was allowed to cool to room temperature and then diluted with ethyl acetate (30 mL), washed with 1N NaOH (2×10 mL) and brine (1×10 mL), and dried over Na2SO4. The organic layer was then concentrated under reduced pressure to yield a yellow oil. The yellow oil was loaded onto a Biotage samplet and purified via automated silica gel chromatography in MeCN/DCM (Linear gradient from 15% to 74% [300 mL], held at 74%[140 mL], linear gradient from 74% to 100% [300 mL], and held at 100% [400 mL]) to provide 24 mg of ethyl 4-(4-fluoro-3-((3-(3-methylisoxazol-5-yl)ureido)methyl)benzyl)piperazine-1-carboxylate.

1. customthe vial was purged again with nitrogen
2. stirringThe mixture was stirred for 1 hour
3. temperaturethen heated to 65° C. for 2 hours
4. temperatureto cool to room temperature
5. washwashed with 1N NaOH (2×10 mL) and brine (1×10 mL)
6. dry with materialdried over Na2SO4
7. concentrationThe organic layer was then concentrated under reduced pressure
8. customto yield a yellow oil
9. custompurified