Sulfuric Acid → 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide

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2-chloro-7,7-difluoro-9-isopropyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (100 mg, 0.344 mmol) and 4-amino-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide (100 mg, 0.355 mmol) were suspended in water (2 mL) and sulfuric acid (118 mg, 1.20 mmol) was added. The reaction mixture was stirred in a closed vial at 100° C. for 18 h, cooled, diluted with water (5 mL) and brought to pH=7 using solid sodium carbonate. The resulting mixture was diluted with ethanol (0.5 mL) and stirred for 5 min. The precipitate was filtered, washed with water (5 mL) and dried in air for 20-30 min. It was then suspended in ethanol (˜10 mL), treated with solid sodium bicarbonate (130 mg) and stirred vigorously for 45 min. The insoluble salts were filtered off and filtrate was concentrated in vacuo. The residue was crystallized from ethanol-water (1:7; 8 mL) and dried in vacuum to afford the title compound as a white solid (65 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (d, J=6.82 Hz, 6 H) 1.49-1.62 (m, 2 H) 1.77 (br. d., 2 H) 1.95 (app. t, J=11.2 Hz, 2 H) 2.15 (s, 3 H) 2.73 (br. d., J=11.12 Hz, 2 H) 3.33 (s, 3 H) 3.71 (m, J=7.83 Hz, 1 H) 3.91 (s, 3 H) 4.07 (t, J=13.52 Hz, 2 H) 4.90 (m, 1 H) 7.19 (d, J=6.57 Hz, 1 H) 7.88 (dd, J=7.33, 3.03 Hz, 1 H) 7.97 (s, 1 H) 8.20-8.32 (m, 2 H); [M+H] calc'd for C25H32F3N7O3, 536; found 536.

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