反应详情

温度

80 °C

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.

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