Thionyl Chloride → N-(3-chloro-4-(3-chlorobenzyloxy)phenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine

Participants

Reaction Steps

A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.0 g, 6.06 mmol), thionyl chloride (20 mL) and a catalytic amount of DMF (2 drops) was stirred under reflux for 40 min to give a homogeneous mixture. It was evaporated under reduced pressure at 40° C. (bath temperature) to give a light brown solid. To this solid was added a mixture of 3-chloro-4-(3-chlorobenzyloxy)aniline (1.79 g, 6.67 mmol) and dry DMA (10 mL). The residue of 3-chloro-4-(3-chlorobenzyloxy)aniline was washed down with more DMA (2×2 mL). The reaction mixture was stirred at room temperature for 1 h 30 min. It was partitioned in between ethyl acetate (400 mL) and water (400 mL). The ethyl acetate layer was separated and washed further with water (2×200 mL), dried (MgSO4) and evaporated to give a crude product of N-(3-chloro-4-(3-chlorobenzyloxy)phenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (201). Chromatography on silica gel (dichloromethane/MeOH=25:1) gave pure 201 (2.52 g, 100%) as a yellow/orange solid, mp 196-198° C.; 1H NMR δ [(CD3)2SO] 10.03 (s, 1H), 8.94 (s, 1H), 8.69 (s, 1H), 8.21 (s, 1H), 8.07 (d, J=2.5 Hz, 1H), 7.75 (dd, J=9.0, 2.5 Hz, 1H), 7.57-7.54 (m, 1H), 7.49-7.39 (m, 3H), 7.31 (d, J=9.0 Hz, 1H). Anal. Calcd for C20H13Cl2FN4O: C, 57.85; H, 3.16; N, 13.49. Found C, 57.60; H, 3.45; N, 13.32.

Provenance & Evidence