tert-Butyl cyanoacetate → 2-(6-Chloro-2-methoxypyridin-3-yl)propanenitrile

온도

75 °C

To a suspension of 3-bromo-6-chloro-2-methoxypyridine (99.9 g, 449 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (2.76 g, 3.38 mmol), and NaOtBu (105 g, 1090 mmol) in dioxane (805 mL) was added tert-butyl cyanoacetate (64.8 mL, 454 mmol) under nitrogen. The reaction mixture was heated for 235 min while maintaining the internal reaction temperature at 75° C. under nitrogen. After being cooled to 20° C., to the reaction mixture was added Mel (55.9 mL, 898 mmol) in one portion, and the resulting mixture was stirred overnight at r.t. Celite® (24 g) was added to the reaction mixture, and the resulting mixture was filtered through a 370 g silica plug. The plug was eluted with EtOAc/heptanes (1/3, 2.0 L), and the combined filtrate was concentrated. A solution of the crude residue (133.9 g) in DMSO (330 mL) and water (67 mL) was heated at 130° C. for 15.8 h. The reaction mixture was filtered through a plug of Celite®, and the filter cake was rinsed with MTBE and water. The filtrate was filtered again through a plug of Celite® and the filter cake was washed with MTBE and water. The filtrate was partitioned between MTBE (total volume=2.0 L), water (total volume=1.0 L) and brine (100 mL). The layers were separated and the organic layer was washed with water (1.0 L) and brine (750 mL), dried over Na2SO4, and concentrated to afford the crude 2-(6-Chloro-2-methoxypyridin-3-yl)propanenitrile (87.6 g, 99%) as a dark brown oil, which was used for the next step without any further purification. 1H NMR (600 MHz, CDCl3) δ 1.58 (d, 3H), 4.01 (s, 3H), 4.11 (q, 1H), 6.97 (d, 1H), 7.66 (d, 1H). MS (ES+)(M+H) 197.

1. temperatureThe reaction mixture was heated for 235 min
2. temperatureAfter being cooled to 20° C., to the reaction mixture
3. additionwas added Mel (55.9 mL, 898 mmol) in one portion
4. additionCelite® (24 g) was added to the reaction mixture
5. filtrationthe resulting mixture was filtered through a 370 g silica plug
6. washThe plug was eluted with EtOAc/heptanes (1/3, 2.0 L)
7. concentrationthe combined filtrate was concentrated
8. temperatureA solution of the crude residue (133.9 g) in DMSO (330 mL) and water (67 mL) was heated at 130° C. for 15.8 h
9. filtrationThe reaction mixture was filtered through a plug of Celite®
10. washthe filter cake was rinsed with MTBE and water
11. filtrationThe filtrate was filtered again through a plug of Celite®
12. washthe filter cake was washed with MTBE and water
13. customThe filtrate was partitioned between MTBE (total volume=2.0 L), water (total volume=1.0 L) and brine (100 mL)
14. customThe layers were separated
15. washthe organic layer was washed with water (1.0 L) and brine (750 mL)
16. dry with materialdried over Na2SO4
17. concentrationconcentrated

ORD 기록

ord-614e668d93ce4572a401f3b1b25e6aca

출처 데이터셋

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US09278953B2