4-Chloro-6-methoxy-2-methylquinazoline synthesis

Yield:60395-90-6 56%

Reaction Conditions:

with trichlorophosphate for 60 h;Reflux;

Steps:

17 4.1.2.17
4-Chloro-6-methoxy-2-methylquinazoline (22)

6-methoxy-2-methylquinazolin-4-ol (233 mg, 1.23 mmol) was suspended in phosphorus oxychloride (POCl₃) (10 mL, 108 mmol) and the reaction mixture was stirred under reflux for 2.5 days during which the suspension turned into a reddish brown solution.
The mixture was allowed to cool down to room temperature and phosphorus oxychloride was evaporated under reduced pressure.
Then, the residue was partitioned between aqueous solution of sodium bicarbonate (NaHCO₃, 5%, 100 mL) and ethyl acetate (100 mL). The organic layers was washed with aqueous solution of sodium bicarbonate (NaHCO_3, 5%, 100 mL) and water (100 mL). Then, the organic layer was dried over sodium sulfate (Na₂SO₄) and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate as eluent. Yield 56% (white solid, 142 mg, 0681 mmol); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.92 (d, J = 9.1 Hz, 1H), 7.70 (dd, J = 9.1, 2.8 Hz, 1H), 7.42 (d, J = 2.8 Hz, 1H), 3.96 (s, 3H), 2.71 (s, 3H); UPLC-MS (ESI) (B); RT 3.88 min, m/z 209 [M+H]⁺ (>95%).

References:

Pitta, Eleni;Balabon, Olga;Rogacki, Maciej K.;Gómez, Jesús;Cunningham, Fraser;Joosens, Jurgen;Augustyns, Koen;van der Veken, Pieter;Bates, Robert [European Journal of Medicinal Chemistry,2017,vol. 125,p. 890 - 901]