Lithium Hydroxide → 4-Chloro-1H-indazole

Temperature

0 °C

To a 250 ml flask with stir bar was added 3-chloro-2-methylaniline 11 (8.4 ml, 9.95 g, 70.6 mmol), potassium acetate (8.3 g, 84.7 mmol) and chloroform (120 ml). This mixture was cooled to 0° C. with stirring. To the cooled mixture was added acetic anhydride (20.0 ml, 212 mmol) drop wise over 2 minutes. The reaction mixture was warmed to 25° C. and stirred for 1 hour. At this point, the reaction was heated to 60° C. Isoamyl nitrite (18.9 ml, 141 mmol) was added and the reaction was stirred overnight at 60° C. Once complete, water (75 ml) and THF (150 ml) were added and the reaction was cooled to 0° C. Lithium hydroxide (LiOH, 20.7 g, 494 mmol) was added and the reaction was stirred at 0° C. for 3 hours. Water (200 ml) was added and the product was extracted with EtOAc (300 ml, 100 ml). The organic layers were combined, dried with MgSO4 and concentrated to yield 4-chloro-1H-indazole 12 as an orange solid (11.07 g (100%). 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=1 Hz, 1H), 7.33 (d, J=8 Hz 1H), 7.31 (t, J=7 Hz, 1H), 7.17 (dd, J=7 Hz, 1 Hz 1H). LCMS (ESI pos) m/e 153 (M+1).

1. stirringwith stirring
2. temperatureThe reaction mixture was warmed to 25° C.
3. stirringstirred for 1 hour
4. temperatureAt this point, the reaction was heated to 60° C
5. stirringthe reaction was stirred overnight at 60° C
6. temperaturethe reaction was cooled to 0° C
7. stirringthe reaction was stirred at 0° C. for 3 hours
8. extractionthe product was extracted with EtOAc (300 ml, 100 ml)
9. dry with materialdried with MgSO4
10. concentrationconcentrated

ORD record

ord-56d6f101e48a48b99af0d476faace98b

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08431694B1