Tetrahydrofuran → 5-chloro-1-[(2S)-2-cyclopropyl-2-methoxyethyl]-3-[[6-(difluoromethoxy)-2,5-dimethylpyridin-3-yl]amino]pyrazin-2-one

Participants

Reaction Conditions

Reaction Steps

(S)-3,5-Dichloro-1-(1-cyclopropyl-2-methoxyethyl)pyrazin-2(1H)-one (15.0 g, 57.01 mmol) from Example 1 Part G and 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine (10.73 g, 57.01 mmol) from Part G were combined in a 2 L, 3-neck round bottom flask equipped with a thermometer and an addition funnel and placed under N2. THF (570 mL) was added and the mixture was cooled to 0° C. NaHMDS (119.7 mL, 119.7 mmol, 1 M in THF) was added dropwise via the addition funnel over 20 min (the internal temperature was maintained below 5° C.). After the addition was complete, the reaction mixture was stirred at 0° C. for an additional 15 min. The reaction was quenched by the addition of saturated aqueous NH4Cl (60 mL). The mixture was transferred to a separatory funnel containing water (400 mL) and the aqueous layer was extracted with ether (3×300 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel (30% ethyl acetate in hexanes) to afford (S)-5-chloro-1-(cyclopropyl-2-methoxyethyl)-3-[6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino]pyrazin-2(1H)-one (22.14 g, 94% yield) as a pale yellow solid which was subsequently recrystallized from heptane to furnish colorless needles: mp 103.4-104.4° C.; [α]25D −41.9 (c 0.807, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 8.02 (s, 1H), 7.46 (t, J=74.0 Hz, 1H), 6.96 (s, 1H), 4.19-4.14 (m, 1H), 3.75 (dd, JAB10.3, JAX=6.3 Hz, 1H), 3.67 (dd, JBA=10.3, JBX=3.5 Hz, 1H), 3.34 (s, 3H), 2.44 (s, 3H), 2.26 (s, 3H), 1.32-1.26 (m, 1H), 0.81-0.74 (m, 1H), 0.63-0.54 (m, 1H), 0.52-0.47 (m, 1H), 0.36-0.29 (m, 1H); HRMS (ESI) m/e 415.1360 [(M+H)+, calcd for C18H22N4O3ClF2 415.1349].

Provenance & Evidence