Maleic Acid → 4-(3-Chloro-2-fluoroanilino)-6-[1-(hydroxyacetyl)piperidin-4-yloxy]-7-methoxyquinazoline maleate salt

HRID 857950Notes

Reaction equation

HRID 857950 reaction equation
[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[Cl:9][C:10]1[C:11]([F:40])=[C:12]([CH:37]=[CH:38][CH:39]=1)[NH:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:35][CH3:36])=[C:21]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31](=[O:34])[CH2:32][OH:33])[CH2:27][CH2:26]3)[CH:22]=2)[N:17]=[CH:16][N:15]=1>O>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[Cl:9][C:10]1[C:11]([F:40])=[C:12]([CH:37]=[CH:38][CH:39]=1)[NH:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:35][CH3:36])=[C:21]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31](=[O:34])[CH2:32][OH:33])[CH2:27][CH2:26]3)[CH:22]=2)[N:17]=[CH:16][N:15]=1

Participants

4

Reactant 2

HCID 444266Maleic AcidHCID 11213353HCID 11213353, compound

Product 1

HCID 694379584-(3-Chloro-2-fluoroanilino)-6-[1-(hydroxyacetyl)piperidin-4-yloxy]-7-methoxyquinazoline maleate saltYield 52.3%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

A solution of maleic acid (0.66 g) in IMS (10 ml) was added to 4-(3-chloro-2-fluoroanilino)-6-[1-(hydroxyacetyl)piperidin-4-yloxy]-7-methoxyquinazoline (2.5 g) in IMS (25 ml) at 80° C. Water (3 ml) was added. After stirring at 80° C. for 5 minutes, the solution was cooled to ambient temperature over 1 hour. At approximately 50° C., a solid crystallised. The mixture was stirred at ambient temperature for 30 minutes before cooling to 0–5° C. The solid was filtered and washed with IMS (2×7.5 ml). The solid was dried at 50° C. under vacuum to constant weight. The solid was then heated in 10% aqueous IPA at 82–85° C. for 1 hour before cooling to ambient temperature over 1 hour. The solid was filtered and washed with IPA (2×5 ml). The solid was dried at 50° C. under vacuum to constant weight to give the title product (1.63 g; 52.3% yield); NMR Spectrum: (DMSO d6) 1.63–1.82 (m, 2H); 2.00–2.10 (m, 2H); 3.28–3.45 (m, 2H); 3.59–3.67 (m, 1H); 3.83–3.90 (m, 1H); 3.98 (s, 3H); 4.14 (s, 2H); 4.79 (m, 1H); 6.19 (s, 2H); 7.25 (s, 1H); 7.33 (t, 1H); 7.52–7.59 (m, 2H); 7.95 (s, 1H); 8.54 (s, 1H) 10.14 (bs, 1H); Melting Point: Onset 165.4° C., peak 169.7° C.

Workup

  1. temperaturethe solution was cooled to ambient temperature over 1 hour
  2. customAt approximately 50° C., a solid crystallised
  3. stirringThe mixture was stirred at ambient temperature for 30 minutes
  4. temperaturebefore cooling to 0–5° C
  5. filtrationThe solid was filtered
  6. washwashed with IMS (2×7.5 ml)
  7. customThe solid was dried at 50° C. under vacuum to constant weight
  8. temperatureThe solid was then heated in 10% aqueous IPA at 82–85° C. for 1 hour
  9. temperaturebefore cooling to ambient temperature over 1 hour
  10. filtrationThe solid was filtered
  11. washwashed with IPA (2×5 ml)
  12. customThe solid was dried at 50° C. under vacuum to constant weight

Sources & evidence

ORD record
ord-7c8d085891de4630b52a5e8c0b758137
Source dataset
uspto-grants-2006_12
Patent number
US07148230B2

Reaction notes

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