Chloroacetyl chloride → HCID 118276741, compound

Participants

Reaction Steps

2-amino-1-(6-(trifluoromethyl)pyridin-3-yl)ethanol (1.05 g, 5.09 mmol) and triethylamine (567 mg, 781 μl, 5.6 mmol) were combined with dichloromethane (50 ml) to give a yellow solution. To this chloroacetyl chloride (633 mg, 449 μl, 5.6 mmol) in 20 mL dichloromethane was added by dropwise addition at 0° C. After 1 h at 0° C. the reaction mixture was complete by LCMS. The reaction mixture was poured onto water. The pH adjusted to 8 with saturated NaHCO3. The resultant aqueous phase was extracted 4 times with dichloromethane. The combined organic extracts were washed with brine. Brine and aqueous phase were combined and further extracted with dichloromethane (2×). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting residue, 2-chloro-N-(2-hydroxy-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)acetamide (1.5 g, 5.31 mmol) was combined with methanol (100 ml) to give a light yellow solution. KOH (357 mg, 6.37 mmol) was added. Reaction was checked by LCMS after and showed only starting material. A solvent exchange was done with isopropanol as follows: 50 mL of isopropanol was added to the reaction mixture and it was concentrated to ¼ volume under reduced pressure at 40° C. Another 50 mL of isopropanol was added and the mixture was concentrated under reduced pressure to 50 mL. Another 50 mL of isopropanol was added. LCMS showed a ratio of 81:19 starting material:product. The reaction mixture was stirred at room temperature overnight. LCMS showed a ratio of 15:52 starting material: product. Warming at 50° C. for 1 h did not lead to any more product formation, so reaction was stopped. The reaction mixture was concentrated to reduced volume (5 mL). The resultant solution was diluted with ethyl acetate and water and the aqueous phase adjusted to pH=6 (with 1N HCl). The layers were separated and the aqueous phase was extracted with ethyl acetate (2×). The aqueous phase was made basic with NaOH and extracted again with ethyl acetate (2×). The combined ethyl acetate extracts were washed with brine and dried over MgSO4, and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 40 g, 0% to 2% MeOH in dichloromethane) to afford a white solid, which was triturated with ether to afford 6-(6-(trifluoromethyl)pyridin-3-yl)morpholin-3-one as an off-white powder (659 mg). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.45-3.69 (m, 2H) 4.25-4.61 (m, 2H) 4.93 (dd, J=10.01, 3.59 Hz, 1H) 6.62 (br. s., 1H) 7.74 (d, J=8.31 Hz, 1H) 7.96 (dd, J=8.31, 1.89 Hz, 1H) 8.75 (d, J=1.89 Hz, 1H).

Provenance & Evidence