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

HRID 644770Notes

Reaction equation

HRID 644770 reaction equation
[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[N:22]=[CH:21][C:20]([C:23]([N:25]([CH3:40])[C:26]3[CH:31]=[CH:30][C:29]([CH2:32][N:33]4[CH2:38][CH2:37][NH:36][C@@H:35]([CH3:39])[CH2:34]4)=[CH:28][CH:27]=3)=[O:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1>CCOC(C)=O>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[N:22]=[CH:21][C:20]([C:23]([N:25]([CH3:40])[C:26]3[CH:31]=[CH:30][C:29]([CH2:32][N:33]4[CH2:38][CH2:37][NH:36][C@@H:35]([CH3:39])[CH2:34]4)=[CH:28][CH:27]=3)=[O:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1

Participants

4

Reactant 2

HCID 444972Fumaric Acid5×HCID 237290236-[(4-Fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide

Product 1

HCID 675263896-[(4-Fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide fumarate

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent3×

Conditions

Temperature
70 °C

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-5d9cf03209b744a9a7df382b6e8d3de0
Source dataset
uspto-grants-2010_04
Patent number
US07700599B2

Reaction notes

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