1,2-Dichloroethane → HCID 57884062, compound

Temperature

-78 °C

To cooled (−78° C.) solution of 6-trifluoromethyl indole (1.44 g, 7.77 mmol) in THF (10 mL) was added n-BuLi (5.1 mL, 1.6 M in hexanes, 8.2 mmol). After 30 min, a stream of dry CO2 (Aldrich lecture bottle) was bubbled through the mixture for 10 min. The resultant mixture was held at −78° C. for a further 10 min, then was concentrated in vacuo. The resultant solid was dissolved in THF (10 mL), cooled to −78° C., and t-BuLi (4.8 mL, 1.7 M in pentane, 8.2 mmol) was added. After 1 h, a stream of dry CO2 was bubbled through the reaction mixture for 10 min. After an additional 1 h at −78° C., the mixture was quenched with H2O and allowed to warm to room temperature. The mixture was diluted with EtOAc, then poured into a mixture of sat. aq. NH4Cl and 1 N HCl (1:1). The phases were separated, and aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. To a flask containing the crude product obtained above were added EDC (2.97 g, 15.5 mmol), HOBt (2.10 g, 15.5 mmol), N,O-dimethylhydroxylamine hydrochloride (1.52 g, 15.5 mmol). The resultant mixture was dissolved in DMF (20 mL), DIEA (6.9 mL, 39 mmol) was added, and the reaction mixture was stirred at 50° C. for 18 h. The mixture was quenched by addition of sat. aq. NaHCO3. The aqueous phase was extracted with EtOAc and the organic phase was concentrated in vacuo. Purification by flash chromatography on silica gel (10 to 60%, then 60 to 100% EtOAc in hexanes) provided the title compound: LCMS A, tr=3.23 min, m/z 273.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.67 (s, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.75 (s, 1H), 7.36 (d, J=9.0 Hz, 1H), 7.28 (s, 1H), 3.87 (s, 3H), 3.46 (s, 3H).

1. customa stream of dry CO2 (Aldrich lecture bottle) was bubbled through the mixture for 10 min
2. waitThe resultant mixture was held at −78° C. for a further 10 min
3. concentrationwas concentrated in vacuo
4. dissolutionThe resultant solid was dissolved in THF (10 mL)
5. waitAfter 1 h
6. customa stream of dry CO2 was bubbled through the reaction mixture for 10 min
7. waitAfter an additional 1 h at −78° C.
8. customthe mixture was quenched with H2O
9. temperatureto warm to room temperature
10. additionThe mixture was diluted with EtOAc
11. additionpoured into a mixture of sat. aq. NH4Cl and 1 N HCl (1:1)
12. customThe phases were separated
13. extractionaqueous phase was extracted with EtOAc
14. dry with materialThe combined organic phases were dried over Na2SO4
15. concentrationconcentrated in vacuo
16. additionTo a flask containing the crude product
17. customobtained above
18. customThe mixture was quenched by addition of sat. aq. NaHCO3
19. extractionThe aqueous phase was extracted with EtOAc
20. concentrationthe organic phase was concentrated in vacuo
21. customPurification by flash chromatography on silica gel (10 to 60%

ORD record

ord-c3435ce9e9b9478798d141edaa69fbcb

Source dataset

uspto-grants-2009_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07598398B2