反应详情

温度

70 °C

A suspension of finely ground fumaric acid (13.84 g) in EtOAc (500 mL) was stirred and heated at 70° C. This was added portion-wise to a stirred solution of E2 free base (57.80 g) in EtOAc (1 L) heated at 70° C. When ˜80-100 mL of the fumaric acid suspension had been added, the solution was seeded with previously obtained fumarate salt (40 mg) (prepared using a method similar to that described in Example 2B, Method 4). To the resulting faintly turbid solution was added further fumaric acid suspension (˜50 mL) giving a cloudy solution. On addition of further seeds (40 mg), crystallization started. Addition of the remaining fumaric acid suspension in 8-10 mL portions continued over ˜4 h. Further EtOAc (˜30 mL) was used to aid transfer of the final solid residues of fumaric acid to the reaction vessel. The reaction mixture was stirred at 70° C. for a further 4 h then slowly allowed to cool to room temperature overnight with stirring. The crystalline solid was collected by filtration, washed with EtOAc and dried under argon; then further dried under vacuum at 60° C. overnight to give the title compound (60.8 g).

1. temperatureheated at 70° C
2. customprepared
3. customgiving a cloudy solution
4. additionOn addition of further seeds (40 mg), crystallization
5. stirringThe reaction mixture was stirred at 70° C. for a further 4 h
6. temperatureto cool to room temperature overnight
7. stirringwith stirring
8. filtrationThe crystalline solid was collected by filtration
9. washwashed with EtOAc
10. customdried under argon
11. customthen further dried under vacuum at 60° C. overnight