Reaction Steps
To a mixture of rel-(4R,5R)-4-(4-chlorophenyl)-2-(2-methylpyridin-4-yl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-carboxylic acid (326.0 mg, 0.817 mmol) and HATU (435.1 mg, 1.144 mmol) in N,N-dimethylformamide (4.28 mL, 55.3 mmol) were added methylamine as a 2M solution in tetrahydrofuran (1.64 mL, 3.27 mmol) followed by N,N-diisopropylethylamine (0.427 mL, 2.45 mmol). The mixture was stirred at rt for 16 hr. The mixture was diluted with water (4 mL) and the precipitate was filtered. The aqueous solution was extracted with DCM (3×6 mL). The solid cake and DCM layers were combined and washed with water (3 mL) and brine (3 mL), dried over sodium sulfate, and evaporated. The obtained residue purified by preparative HPLC to give the title compound as a white solid (140 mg) then the racemic mixture was separated by chiral preparative HPLC to give 30.6 mg (9.0% yield) as a white solid for peak 1. LCMS: (FA) ES+ , 412/414. 1H NMR (400 MHz, DMSO) δ 8.46 (d, J=5.3 Hz, 1H), 8.16 (d, J=4.4 Hz, 1H), 7.94 (d, J=4.2 Hz, 1H), 7.62 (s, 1H), 7.55 (s, 1H), 7.49-7.37 (m, 3H), 7.25 (d, J=8.5 Hz, 2H), 4.66 (d, J=1.6 Hz, 1H), 4.14 (dd, J=4.2, 2.3 Hz, 1H), 2.59 (d, J=4.5 Hz, 3H). 37.0 mg (11% yield) as a white solid for peak 2. LCMS: (FA) ES+ , 412. 1H NMR (400 MHz, DMSO) δ 8.46 (d, J=5.2 Hz, 1H), 8.16 (d, J=4.4 Hz, 1H), 7.95 (d, J=4.3 Hz, 1H), 7.62 (s, 1H), 7.55 (s, 1H), 7.50-7.35 (m, 3H), 7.25 (d, J=8.5 Hz, 2H), 4.66 (d, J=1.8 Hz, 1H), 4.14 (dd, J=4.3, 2.3 Hz, 1H), 2.59 (d, J=4.5 Hz, 3H).
