Hydrochloric Acid → 7-Bromo-5-fluoro-1H-indazole

Temperature

0 °C

To a suspension of 2-bromo-4-fluoro-6-methylaniline (5 g, 24.51 mmol) in hydrochloric acid (8 M, 22 mL, 176 mmol) at 0° C. was added a solution of sodium nitrite (1.78 g, 25.7 mmol) in water (ca. 5.5 mL) dropwise. After 10 min, the resulting solution was neutralized (pH 4-5) by addition of solid sodium acetate. The resulting solution was added to a solution of 2-methyl-2-propanethiol (2.76 mL, 24.5 mmol) in ethanol (57 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The resulting mixture was poured onto ice and the resulting mixture was extracted into diethyl ether (2×). The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. The resulting residue was dissolved in dimethylsulfoxide (14 mL) and transferred to a solution of potassium tert-butoxide (22 g, 196 mmol) in dimethylsulfoxide (140 mL) in a cool water bath (ca. 10° C.) via canula. The bath was removed and stirring continued for 30 min. The reaction mixture was poured onto ice/concentrated hydrochloric acid. The resulting mixture was extracted with dichloromethane (2×), washed with water (3×), then brine, dried over magnesium sulfate and concentrated. Prep HPLC gave 1.66 g (31.5%) as a pale solid. LC/MS (HPLC method 3): tR=2.337 min, 215.01(MH)+.

1. additionThe resulting mixture was poured onto ice
2. extractionthe resulting mixture was extracted into diethyl ether (2×)
3. washThe ethereal was washed with water
4. dry with materialbrine, dried over magnesium sulfate
5. concentrationconcentrated
6. dissolutionThe resulting residue was dissolved in dimethylsulfoxide (14 mL)
7. custom(ca. 10° C.)
8. customThe bath was removed
9. stirringstirring
10. waitcontinued for 30 min
11. additionThe reaction mixture was poured onto ice/concentrated hydrochloric acid
12. extractionThe resulting mixture was extracted with dichloromethane (2×)
13. washwashed with water (3×)
14. dry with materialbrine, dried over magnesium sulfate
15. concentrationconcentrated
16. customPrep HPLC gave 1.66 g (31.5%) as a pale solid

ORD record

ord-94a8784b80784450bcf6ff5150a43011

Source dataset

uspto-grants-2011_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08026257B2