反应详情

温度

0 °C

To a suspension of 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (Reference Example 2, 639 mg, 2.0 mmol) in DCM (30 ml) was added 1-methyl-3-pyrrolidinol (658 μl, 6.0 mmol) and triphenyl phosphine (1572 mg, 6.0 mmol). The suspension was cooled to 0° C. under a nitrogen atmosphere. Di-tent-butyl azodicarboxylate (1380 mg, 6 mmol) was added as a solution in DCM (20 ml), dropwise over the course of 15 minutes. The resulting light brown solution was allowed to warm to room temperature and was stirred overnight. The solution was evaporated, and the residue purified by chromatography, eluting with 0 to 5% methanol in DCM. The appropriate fractions were combined and evaporated, and the crude product (230 mg) re-dissolved in 1:1 methanol/DCM (5 ml). Ethereal HO (1M, 1.14 ml) was added, and the mixture evaporated. Crystallisation from ethanol diethyl ether gave the title product as a hydrochloride salt in the form of a white crystalline solid (154 mg, 16%); 1H NMR (hydrochloride salt): 2.30 (m, 1H), 2.65-2.75 (m, 1H), 2.88 (s, 3H), 3.30-3.80 (m, 3H), 3.85-4.05 (m, 1H), 4.00 (s, 3H), 5.46 (m, 1H), 7.35 (dd, 1H), 7.45 (s, 1H), 7.51 (dd, 1H), 7.62 (dd, 1H), 8.53 (s, 1H), 8.72 (s, 1H), 8.81 (s, 1H); Mass Spectrum: 403.3, 405.3.

1. temperatureto warm to room temperature
2. customThe solution was evaporated
3. customthe residue purified by chromatography
4. washeluting with 0 to 5% methanol in DCM
5. customevaporated
6. dissolutionthe crude product (230 mg) re-dissolved in 1:1 methanol/DCM (5 ml)
7. additionEthereal HO (1M, 1.14 ml) was added
8. customthe mixture evaporated
9. customCrystallisation from ethanol diethyl ether