p-Toluenesulfonic acid monohydrate → Benzimidazole

A suspension of 4-[5-amino-2-(2,4-difluorophenoxy)-4-(methylamino)phenyl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.045 g, 0.082 mmol) in tetrahydrofuran (0.80 mL) was treated with ethyl orthoformate (0.041 mL, 0.245 mmol) and p-toluenesulfonic acid monohydrate (1.6 mg, 8.2 μmol) and at 50° C. for 1 h. The reaction mixture was concentrated to give a residue. This residue was diluted with ethyl acetate (30 mL), washed with saturated sodium bicarbonate solution (20 mL), dried with sodium sulfate, filtered, and concentrated to give the intermediate benzimidazole which was used immediately without further purification. The intermediate benzimidazole was dissolved in ethanol (1.00 mL), treated with 1.0 M sodium hydroxide in water (0.327 mL, 0.327 mmol), and heated at 80° C. for 1 h. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (19.5 mg, 59%). 1H NMR (300 MHz, DMSO-d6) δ 11.97 (br s, 1H), 8.19 (s, 1H), 7.68 (s, 1H), 7.40-7.28 (m, 1H), 7.26-7.21 (m, 2H), 7.17 (s, 1H), 7.08-6.88 (m, 2H), 6.24-6.10 (m, 1H), 3.77 (s, 3H), 3.52 (s, 3H); LCMS calculated for C22H17F2N4O2 (M+H)+: m/z=407.1. found: 407.1.

1. concentrationThe reaction mixture was concentrated
2. customto give a residue
3. washwashed with saturated sodium bicarbonate solution (20 mL)
4. dry with materialdried with sodium sulfate
5. filtrationfiltered
6. concentrationconcentrated

ORD record

ord-d721c1910657496f8164a0d9a09bcca8

Source dataset

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09315501B2