Hydrochloric Acid → HCID 86713379, compound

Temperature

75 °C

2-Isopropylaniline (3 mL, 21.19 mmol) was added dropwise to a solution of trichloroborane (1M in dichloromethane) (23.31 mL, 23.31 mmol) and dichloroethane (50 mL) at 0° C. and the mixture was stirred for 10 min. Next, 3-chlorobenzonitrile (5.83 g, 42.4 mmol), followed by aluminum trichloride (3.11 g, 23.31 mmol) were added and the mixture was stirred at 0° C. for 25 minutes. The ice bath was removed and the mixture was heated to 75° C. overnight. The mixture was then cooled to room temperature. Next, 6N HCl (60 mL, 10 eq) was added and the mixture was heated to 75° C. After 4 hrs, 12N HCl (10 mL) was added and heating was continued overnight at 75° C. The mixture was cooled to room temperature, transferred to an Erlenmeyer flask, diluted with ethyl acetate, cooled to 0° C., and cautiously raised to pH 10 with 50% aqueous NaOH. The resulting mixture was extracted with ethyl acetate (4×). The ethyl acetate extracts were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a clear amber oil. The oil was suspended in a minimum of heptane and purified on an ISCO companion chromatography system (220 g silica cartridge, eluting with 0-20% ethyl acetate/heptane, 150 mL/min) to provide Intermediate A-10 (2.85 g, 10.41 mmol, 49.1% yield). HPLC RT=3.876 min 10/90 to 90/10 (MeOH/H2O/0.1% TFA, Waters Sunfire C18 3.5 μm, 2.1×30 mm, 1 mL/min, 4 min gradient, wavelength=254 nm); MS(ES): m/z=274 [M+H+]; 1H NMR (400 MHz, chloroform-d) δ 7.63 (t, J=1.7 Hz, 1H), 7.55-7.48 (m, 2H), 7.44-7.29 (m, 3H), 6.65 (t, J=7.7 Hz, 1H), 6.43 (br. s., 2H), 3.11-2.87 (m, 1H), 1.34 (d, J=6.8 Hz, 6H).

1. additionwere added
2. stirringthe mixture was stirred at 0° C. for 25 minutes
3. customThe ice bath was removed
4. temperatureThe mixture was then cooled to room temperature
5. temperaturethe mixture was heated to 75° C
6. waitAfter 4 hrs
7. temperatureheating
8. waitwas continued overnight at 75° C
9. temperatureThe mixture was cooled to room temperature
10. temperaturecooled to 0° C.
11. extractionThe resulting mixture was extracted with ethyl acetate (4×)
12. washwashed with brine
13. dry with materialdried over anhydrous sodium sulfate
14. filtrationfiltered
15. concentrationconcentrated
16. customto give a clear amber oil
17. custompurified on an ISCO companion chromatography system (220 g silica cartridge, eluting with 0-20% ethyl acetate/heptane, 150 mL/min)
18. customto provide Intermediate A-10 (2.85 g, 10.41 mmol, 49.1% yield)

ORD record

ord-2e6f73913b6e48e4bb4ec803351d5a3f

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09273014B2