Maleic Acid → Afatinib dimaleate

HRID 1969316Notes

Reaction equation

HRID 1969316 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

HCID 444266Maleic AcidHCID 10184653Afatinib

Product 1

HCID 15606394Afatinib dimaleate

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

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.

Workup

  1. customAfter crystallisation
  2. temperatureis cooled to 20° C.
  3. waitfor 3 hours at 0° C
  4. filtrationfiltered
  5. washwashed with 19 liters of ethanol
  6. customdried in vacuo at 40° C.

Sources & evidence

ORD record
ord-a8983b73521b421f95d61c8121e4a5fd
Source dataset
uspto-grants-2013_04
Patent number
US08426586B2

Reaction notes

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