Phenyl isocyanate → HCID 44629309, compound

Participants

Reaction Steps

A solution of (S)-5-chloro-1-(cyclopropyl-2-hydroxyethyl)-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)pyrazin-2(1H)-one (20 mg, 0.055 mmol) from Part M in THF (1 mL) at 0° C. was treated with NaH (7 mg, 0.275 mmol, prewashed with hexanes). The cooling bath was removed and the mixture was allowed to warm to room temperature and was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. and a solution of phenyl isocyanate (9 μL, 0.083 mmol) in 0.5 mL THF was added via cannula. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 20 min. The reaction mixture was then cooled to 0° C. and was quenched by the addition of saturated aqueous NaHCO3. The mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 (5 mL) and the aqueous layer was extracted with EtOAc (3×10 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 (20% 30% ethyl acetate in hexanes) to furnish (S)-2-(5-chloro-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)-2-oxopyrazin-1(2H)-yl)-2-cyclopropylethyl phenylcarbamate (14 mg, 52% yield) as a colorless amorphous solid: 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.92 (s, 1H), 7.30-7.26 (m, 4H), 7.06 (t, J=8.3 Hz, 1H), 6.82 (s, 1H), 6.63 (s br, 1H), 4.58 (dd, JAB=11.9, JAX=4.1 Hz, 1H), 4.48 (dd, JBA=11.9, JBX=7.6 Hz, 1H), 4.26-4.21 (m, 1H), 4.05 (s, 3H), 2.51 (s, 3H), 2.19 (s, 3H), 1.26-1.21 (m, 1H), 0.88-0.80 (m, 1H), 0.67-0.57 (m, 2H), 0.40-0.36 (m, 1H); HRMS (ESI) m/e 484.1753 [(M+H)+, calcd for C24H27N5O4Cl 484.1752].

Provenance & Evidence