Thionyl Chloride → N-(3-chloro-4-(pyridin-2-ylmethoxy)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) (1.65 g, 10.0 mmol), thionyl chloride (30 ml) and a catalytic amount of DMF (3 drops) was stirred under reflux for 2 h 30 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 solution of 3-chloro-4-(pyridin-2-ylmethoxy)aniline (2.58 g, 11.0 mmol) in dry DMA (15 ml). The residue of 3-chloro-4-(pyridin-2-ylmethoxy)aniline was washed down with more DMA (2×5 ml). The reaction mixture was stirred at room temperature for 18 h. It was poured into water (300 ml). The pH was adjusted to ca. 9 using an aqueous solution of Na2CO3 at room temperature. Petroleum ether (300 mL) was added and stirred at room temperature for 30 min. The petroleum ether layer was decanted. It was repeated once more with petroleum ether (300 mL). The solid was collected by filtration and washed with water (4×50 mL). It was stirred with hot (ca. 50° C.) acetone (300 mL) for 15 min. The insoluble materials was filtered off and the filtrate was evaporated under reduced pressure to give N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (203) (3.18 g, 83%) as a yellow/orange solid, mp 216-219° C.; 1H NMR δ [(CD3)2SO] 10.04 (s, 1H), 8.94 (s, 1H), 8.69 (s, 1H), 8.63-8.57 (m, 1H), 8.22 (br s, 1H), 8.08 (d, J=2.6 Hz, 1H), 7.85 (td, J=7.7, 1.8 Hz, 1H), 7.75 (dd, J=9.0, 2.6 Hz, 1H), 7.59 (br d, J=7.8 Hz, 1H), 7.40-7.35 (m, 1H), 7.32 (d, J=9.0 Hz, 1H), 5.31 (s, 2H). Anal. Calcd for C19H13ClFN5O.0.9H2O: C, 57.34; H, 3.75; N, 17.60. Found C, 57.46; H, 3.82; N, 17.63.

Provenance & Evidence