反应详情

1,1′-Carbonyldiimidazole (2.8 kg) was added to a stirred solution of 2-(1,3-benzodioxol-5-yl)-2-(6-methoxycarbonyl-1-methyl-1H-indol-3-yl)acetic acid (from step (a), 5.0 kg) in dry tetrahydrofuran (50 liters) at room temperature under a nitrogen atmosphere. The suspension was heated to reflux for 1.5 h, allowed to cool to room temperature, and treated sequentially with 2-methoxy-4-methylbenzenesulfonamide (see Preparation 11, International Patent Application WO 97/43260; 3.0 kg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.3 kg). The mixture was heated to reflux for 3.5 h, allowed to cool to room temperature and quenched by the addition of 2M hydrochloric acid (40 liters). The product was extracted from the acidic aqueous solution with dichloromethane (40 liters) and the organic phase was washed with 2M hydrochloric acid (40 liters) and water (40 liters). The organic phase was concentrated to low volume, diluted with acetonitrile (93 liters) and the resulting suspension heated to reflux. The mixture was allowed to cool and the precipitated product collected by filtration to give the subtitle compound as a white crystalline solid (5.34 kg, 71.3%).

1. temperatureThe suspension was heated
2. temperatureto reflux for 1.5 h
3. temperatureThe mixture was heated
4. temperatureto reflux for 3.5 h
5. temperatureto cool to room temperature
6. customquenched by the addition of 2M hydrochloric acid (40 liters)
7. extractionThe product was extracted from the acidic aqueous solution with dichloromethane (40 liters)
8. washthe organic phase was washed with 2M hydrochloric acid (40 liters) and water (40 liters)
9. concentrationThe organic phase was concentrated to low volume
10. additiondiluted with acetonitrile (93 liters)
11. temperaturethe resulting suspension heated to reflux
12. temperatureto cool
13. filtrationthe precipitated product collected by filtration