反应详情

Methylmagnesium iodide (3 mL, 9 mmol, 3 M in diethyl ether) was added to a suspension of 4-[4-(6-fluoro-5-methyl-2-oxo-1,3-benzoxazol-3(2H)-yl)-1-piperidinyl]tetrahydro-2H-pyran-4-carbonitrile (D4, 681 mg, 0.852 mmol) in tetrahydrofuran (10 mL) at 0° C. under argon. The reaction was stirred for 1 h at rt before being cooled to 0° C. and quenched with saturated aqueous NH4Cl (5 mL). The mixture was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a brown oil, which was purified via chromatography (silica, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) to give a brown oil. This was further purified by high pH MDAP to give 5-fluoro-4-methyl-2-{[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]-amino}phenol (D5, 47 mg 17% yield) as a brown solid.

1. temperaturebefore being cooled to 0° C.
2. customquenched with saturated aqueous NH4Cl (5 mL)
3. customThe mixture was partitioned between ethyl acetate and water
4. extractionthe aqueous layer was extracted with ethyl acetate
5. dry with materialThe combined organics were dried (Na2SO4)
6. concentrationconcentrated by rotary evaporation
7. customto give a brown oil, which
8. customwas purified via chromatography (silica, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane)
9. customto give a brown oil
10. customThis was further purified by high pH