反应详情

N-Methylmorpholine (6.7 mL, 60 6 mmol) and 4-[bromo-(4-carboxy-phenyl)-methylene]-piperidine-1-carboxylic acid tert-butyl ester (prepared as for compound 5 in WO2001074806) (20.0 g, 50.5 mmol) in DMF (240 mL) were treated with TBTU (17.8 g, 55.6 mmol) under nitrogen. After stirring for 10 min., 2-(methylamino)ethanol (5.3 mL, 65.7 mmol) was added and the solution stirred for 2 h. The reaction was diluted with EtOAc (350 mL), washed with 2% citric acid, 3% NaHCO3, and brine. The aq. washes were extracted with EtOAc (50 mL). The combined organic phases were dried over Na2SO4 then concentrated in vacuo to a solid. After stirring in hexanes for 5 h, the white solid was collected by filtration and dried under high vacuum to afford 21.0 g (92%) of 1A. 1H NMR (500.333 MHz, CDCl3) δ 7.44 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 3.91 (br s, 2H), 3.74 (br s, 2H), 3.54 (t, J=5.8 Hz, 3H), 3.34 (t, J=5.7 Hz, 2H), 3.09 (s, 3H), 3.01 (br s, 1H), 2.64 (t, J=5.9 Hz, 2H), 2.23 (t, J=5.8 Hz, 2H), 1.47 (s, 9H). MS ES+ 453.1.

1. stirringthe solution stirred for 2 h
2. washwashed with 2% citric acid, 3% NaHCO3, and brine
3. extractionThe aq. washes were extracted with EtOAc (50 mL)
4. dry with materialThe combined organic phases were dried over Na2SO4
5. concentrationthen concentrated in vacuo to a solid
6. stirringAfter stirring in hexanes for 5 h
7. filtrationthe white solid was collected by filtration
8. customdried under high vacuum