Ammonium Chloride → HCID 178419286, compound

Temperature

0 °C

To a suspension of 4-bromo-5-(cyclobutylmethoxy)-2-nitroaniline (0.4967 g, 1.649 mmol) in 1:1 ethyl acetate/methanol (17.2 mL) was added saturated NH4Cl solution (1.9 mL). The mixture was cooled to 0° C. in ice bath, and then zinc powder (0.9 g, 10 mmol) was added in two portions over 2 minutes. The reaction mixture was stirred for 5 min, the ice bath was removed, and the flask was allowed to warm to room temperature. The suspension was then stirred for 1 h at 55° C. The reaction mixture was diluted with CH2Cl2, filtered through a Celite plug, and the filter cake was washed with CH2Cl2. The resulting filtrate was washed with saturated solution of NaHCO3. The aqueous layer was then extracted with CH2Cl2 (50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford the crude intermediate as a dark purple oil. To a solution of the crude intermediate in THF (20 mL) was added ethyl orthoformate (0.88 mL, 5.3 mmol) and p-toluenesulfonic acid monohydrate (54.5 mg, 0.286 mmol). The mixture was heated for 1 h at 55° C. The reaction mixture was concentrated, and the resulting residue was diluted with EtOAc (25 ml). This solution was washed with saturated solution of NaHCO3 (25 mL), and the aqueous layer was subsequently extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. Recrystallization from 9:1 CH2Cl2/MeOH and hexanes afforded the title compound as a yellow solid (0.2280 g) after collection via filtration. The remaining filtrate was concentrated and suspended in MeOH and 1 M solution of HCl (aq) (60 mL). The aqueous solution was extracted with Et2O (3×30 mL). The aqueous layer was then adjusted to pH 9 using solid K2CO3. The aqueous layer was extracted with CH2Cl2 (3×40 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford a second portion of the title compound as a yellow-brown solid (0.1275 g, 77% overall). 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.78 (s, 1H), 7.19 (s, 1H), 4.01 (d, J=6.0 Hz, 2H), 2.91-2.76 (m, 1H), 2.23-2.11 (m, 2H), 2.10-1.93 (m, 4H). LCMS calculated for C12H14BrN2O (M+H)+: m/z=281.0, 283.0. found: 281.0, 283.0.

1. customthe ice bath was removed
2. temperatureto warm to room temperature
3. stirringThe suspension was then stirred for 1 h at 55° C
4. additionThe reaction mixture was diluted with CH2Cl2
5. filtrationfiltered through a Celite plug
6. washthe filter cake was washed with CH2Cl2
7. washThe resulting filtrate was washed with saturated solution of NaHCO3
8. extractionThe aqueous layer was then extracted with CH2Cl2 (50 mL)
9. dry with materialThe combined organic layers were dried over Na2SO4
10. filtrationfiltered
11. concentrationconcentrated
12. customto afford the crude intermediate as a dark purple oil
13. temperatureThe mixture was heated for 1 h at 55° C
14. concentrationThe reaction mixture was concentrated
15. additionthe resulting residue was diluted with EtOAc (25 ml)
16. washThis solution was washed with saturated solution of NaHCO3 (25 mL)
17. extractionthe aqueous layer was subsequently extracted with EtOAc (2×20 mL)
18. dry with materialThe combined organic layers were dried over MgSO4
19. filtrationfiltered
20. concentrationconcentrated
21. customRecrystallization from 9:1 CH2Cl2/MeOH and hexanes

ORD record

ord-4064ff21465f4dfdbe4e2cd52fe4e574

Source dataset

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09315501B2