Fumaric Acid → 6-[(4-Fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide fumarate

Participants

Reaction Conditions

Reaction Steps

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).

Provenance & Evidence