反应详情

温度

37.5 °C

A reactor was charged with 2-(5-(2-(aminomethyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethanol (12.13 kg, 40.27 mol) and phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (14.00 kg, 40.07 mol). The solids were suspended in isopropanol (172.8 kg, 220 L). The suspension was heated from 20° C. to 35° C. and stirred at 35-40° C. for 5 hours to form 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea. The solution was cooled to 25° C. and subsequently polish filtered. To the filtered solution of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea in isopropanol was added HCl (4.80 kg of 32% aqueous HCl, 1.05 eq.) through a polish filter at 22-23° C., and the mixture was stirred at 18-23° C. overnight (14 hours). The bulk solution was seeded with 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea hydrochloride Form B by adding 20.0 g 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea hydrochloride Form B suspended in 300-400 mL of isopropanol to the bulk solution. The mixture was stirred for 3 days (convenience). Analysis showed complete crystallization, at which time 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea hydrochloride From B was isolated by filtration. The product was washed with isopropanol (64 kg, 81.4 L) added via polish filter in portions and dried under vacuum at 55° C. for about 28 hours to provide 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea hydrochloride Form B (92.3% yield). Methods used to characterize this material are described in Examples 2-F and 2-G. Form B prepared according to this method was anhydrous, as confirmed by single X-ray crystallography.

1. temperatureThe suspension was heated from 20° C. to 35° C.