Maleic Acid → Afatinib Dimaleate
Reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:29][C@H:30]4[CH2:34][CH2:33][O:32][CH2:31]4)=[C:17]([NH:20][C:21](=[O:28])/[CH:22]=[CH:23]/[CH2:24][N:25]([CH3:27])[CH3:26])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39]>C(O)C>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39].[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:29][C@H:30]4[CH2:34][CH2:33][O:32][CH2:31]4)=[C:17]([NH:20][C:21](=[O:28])/[CH:22]=[CH:23]/[CH2:24][N:25]([CH3:26])[CH3:27])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]Participants
4
Reactant 2
Product 1
Reagents, catalysts & solvents 1
Conditions
- Temperature
- 70 °C
Procedure
6.0 kg (12.35 mol) of (E)-4-dimethylamino-but-2-enoic acid-(4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-yl)-amide are placed in 84 litres of ethanol and heated to 70° C. and combined with a solution of 2.94 kg (25.31 mol) of maleic acid in 36 liters of ethanol. After crystallisation has set in, first the mixture is cooled to 20° C. and stirred for 2 hours, then for 3 hours at 0° C. The precipitate is suction filtered, washed with 19 liters of ethanol and dried in vacuo at 40° C.