Chloroacetyl chloride → HCID 118276741, compound

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).

1. customto give a yellow solution
2. additionThe reaction mixture was poured onto water
3. extractionThe resultant aqueous phase was extracted 4 times with dichloromethane
4. washThe combined organic extracts were washed with brine
5. extractionfurther extracted with dichloromethane (2×)
6. dry with materialThe combined organic layers were dried over Na2SO4
7. concentrationconcentrated in vacuo
8. customto give a light yellow solution
9. customReaction
10. concentrationwas concentrated
11. customat 40° C
12. additionAnother 50 mL of isopropanol was added
13. concentrationthe mixture was concentrated under reduced pressure to 50 mL
14. additionAnother 50 mL of isopropanol was added
15. temperatureWarming at 50° C. for 1 h
16. customdid not lead to any more product formation, so reaction
17. concentrationThe reaction mixture was concentrated to reduced volume (5 mL)
18. additionThe resultant solution was diluted with ethyl acetate and water
19. customThe layers were separated
20. extractionthe aqueous phase was extracted with ethyl acetate (2×)
21. extractionextracted again with ethyl acetate (2×)
22. washThe combined ethyl acetate extracts were washed with brine
23. dry with materialdried over MgSO4
24. concentrationconcentrated in vacuo
25. customThe crude residue was purified by flash chromatography (silica gel, 40 g, 0% to 2% MeOH in dichloromethane)
26. customto afford a white solid, which
27. customwas triturated with ether

ORD record

ord-bfee1344b7c24c9a9ee6be812f63c6c2

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09353096B2