Dicyclohexylcarbodiimide → HCID 66823503, compound

A stirred solution of DCC (633 mg, 3.07 mmol) in THF (2 mL) under nitrogen was treated with a solution of acid 9 (506 mg, 3.07 mmol) in anhydrous THF (2 mL) at 0° C. The mixture was stirred for 2 h, then treated with compound 168 (200 mg, 0.62 mmol) in DMA (2 mL) followed by di-iso-propylethylamine (DIPEA) (535 μL, 3.07 mmol), before being stirred for a further 3 h at 0° C. The resulting crude (E)-4-bromo-N-(4-(4-fluoro-3-(trifluoromethyl)phenylamino)pyrido[3,4-d]pyrimidin-6-yl)but-2-enamide thus formed was treated in situ with 40% aqueous dimethylamine (942 μL, 18.60 mmol) at 0° C. with stirring for 1 h. The mixture was then diluted with ethyl acetate (300 mL), then poured into a beaker of ice-water (600 mL), stirred for 10 min and then extracted with EtOAc. The combined organic extracts were washed with 2% cold aqueous Na2CO3, water and brine before being dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc/MeOH (9:1). Recrystallization from CH2Cl2/diisopropyl ether then gave (2E)-4-(dimethylamino)-N-{4-[4-fluoro-3-(trifluoromethyl)anilino]pyrido[3,4-d]pyrimidin-6-yl}-2-butenamide (170) (175 mg, 65%) as a pale yellow solid, 170-172° C. 1H NMR [(CD)2SO] δ 10.93 (s, 1H), 10.42 (s, 1H), 9.04 (s, 1H), 9.01 (s, 1H), 8.64 (s, 1H), 8.24-8.28 (m, 2H), 7.56 (t, J=9.6 Hz, 1H), 6.88 (dt, J=15.4, 6.0 Hz, 1H), 6.53 (d, J=15.4 Hz, 1H), 3.10 (dd, J=6.0, 1.1 Hz, 2H), 2.19 (s, 6H). Anal. Calcd for C20H18F4N6O.0.4CH2Cl2: C, 52.32; H, 4.05; N, 17.94%. found: C, 51.99; H, 4.28; N, 18.07%.

1. stirringbefore being stirred for a further 3 h at 0° C

ORD record

ord-11d83dc7c33e4d758e6a2e9915e6b601

Source dataset

uspto-grants-2015_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09073916B2