Cyanamide → 5-(6,7-dimethoxyquinazolin-4-yl)-N2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine

Participants

Reaction Steps

4-(Bromomethyl)-6,7-dimethoxyquinazoline (E-1) (291 mg), 1-(2-(4-isothiocyanatophenoxy)ethyl)pyrrolidine (C-1) (330 mg, 1 eq) and cyanamide (100 mg, 2 eq) were dissolved in 1/1 anhydrous t-butanol/acetonitrile (8 mL). The reaction was stirred for 3 h at room temperature, then quenched with brine. The reaction was extracted with a mixture of ethyl acetate and methanol. The organic layer was dried over anhydrous sodium sulfate, concentrated under vacuum and dried overnight under vacuum. The residue was taken up in anhydrous tetrahydrofuran (10 mL) and cooled to −70° C. under nitrogen. Then 2.5 mL of a 1.6 M solution of n-butyllithium in hexanes was added. After 0.5 h at −70° C. the cooling bath was removed. After a total of 4 h the reaction was quenched with water, extracted with a mixture of ethyl acetate and methanol, dried over anhydrous sodium sulfate and concentrated under vacuum. The highly polar product was purified by radial chromatography (chromatotron) eluting with 95% dichloromethane and 5% 2M ammonia in methanol to yield 5-(6,7-dimethoxyquinazolin-4-yl)-N2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine, compound #1, as a bright orange solid (39 mg); 1H NMR (DMSO-d6, 300 MHz) 8.60 (s, 1H), 8.46 (brs, 2H), 7.58 (m, 3H), 7.15 (s, 1H), 6.93 (d, 2H), 4.05 (t, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 2.83 (t, 2H), 2.50 (m, 4H), 1.70 (m, 4H) ppm; MS (ES) 493.17 (M+H).

Provenance & Evidence