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

HRID 857951Notes

Reaction equation

HRID 857951 reaction equation
[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[Cl:6][C:7]1[C:8]([F:37])=[C:9]([CH:34]=[CH:35][CH:36]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:32][CH3:33])=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29][OH:30])[CH2:24][CH2:23]3)[CH:19]=2)[N:14]=[CH:13][N:12]=1>O.CC(O)C>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[Cl:6][C:7]1[C:8]([F:37])=[C:9]([CH:34]=[CH:35][CH:36]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:32][CH3:33])=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29][OH:30])[CH2:24][CH2:23]3)[CH:19]=2)[N:14]=[CH:13][N:12]=1

Participants

5

Reactant 2

HCID 6395Methanesulfonic AcidHCID 11213353HCID 11213353, compound

Product 1

HCID 866122834-(3-Chloro-2-fluoroanilino)-6-[1-(hydroxyacetyl)piperidin-4-yloxy]-7-methoxyquinazoline methanesulfonate saltYield 83.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 3776IsopropanolSolvent

Conditions

Temperature
80 °C

Procedure

A solution of methanesulfonic acid (1.02 g) in water (7 ml) was added to 4-(3-chloro-2-fluoroanilino)-6-[1-(hydroxyacetyl)piperidin-4-yloxy]-7-methoxyquinazoline (4.6 g) in IPA (25 ml) at 40° C. The mixture was heated to 80° C. during which all solids dissolved. The solution was filtered into a clean vessel maintaining the solution above 50° C. After a line wash of 15% aqueous IPA (18 ml), the combined filtrates and wash were heated at 40° C. On stirring, a solid crystallised. The mixture was cooled to ambient temperature over 30 minutes, stirred at this temperature for 1 hour. The solid was filtered, washed with IPA (2×7 ml) and dried at 50° C. under vacuum to constant weight to give 4-(3-Chloro-2-fluoroanilino)-6-[1-(hydroxyacetyl)piperidin-4-yloxy]-7-methoxyquinazoline methanesulfonate salt (4.66 g; 83% yield); NMR Spectrum: (DMSO d6) 1.63–1.81 (m, 2H); 2.00–2.14 (m, 2H); 2.34 (s, 3H); 3.30–3.48 (m, 2H); 3.57–3.69 (m, 1H); 3.80–3.90 (m, 1H); 4.03 (s, 3H); 4.14 (s, 2H); 4.47 (m, 1H); 7.36 (s, 1H); 7.40 (t, 1H); 7.59 (t, 1H); 7.68 (t, 1H); 8.11 (s, 1H); 8.85 (s, 1H) 11.24 (bs, 1H); Melting Point: Onset 228.9° C., peak 232° C.

Workup

  1. dissolutiondissolved
  2. filtrationThe solution was filtered into a clean vessel
  3. temperaturemaintaining the solution above 50° C
  4. washAfter a line wash of 15% aqueous IPA (18 ml)
  5. washthe combined filtrates and wash
  6. temperaturewere heated at 40° C
  7. customa solid crystallised
  8. temperatureThe mixture was cooled to ambient temperature over 30 minutes
  9. stirringstirred at this temperature for 1 hour
  10. filtrationThe solid was filtered
  11. washwashed with IPA (2×7 ml)
  12. customdried at 50° C. under vacuum to constant weight

Sources & evidence

ORD record
ord-97b4d3bccddb411b901429607b3e78fa
Source dataset
uspto-grants-2006_12
Patent number
US07148230B2

Reaction notes

Loading…