Acetic Anhydride → tert-Butyl 5-iodo-1H-indazole-1-carboxylate

To an ice bath cooled solution of 4-iodo-2-methylaniline (20 g, 83.24 mmol) in chloroform (250 mL) was added dropwise a solution of acetic anhydride (21.2 g, 208.11 mmol) in chloroform (50 mL). Upon completion of the addition, the mixture was stirred at room temperature for 1 hour. Potassium acetate (2.5 g, 24.97 mmol) and isoamylnitrite (22.3 mL, 166.48 mmol) were added and the mixture was heated at 70° C. for 20 hours. The mixture was cooled and quenched with saturated aqueous NaHCO3 to pH 7. The mixture was extracted with dichloromethane, and the organics were dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The crude solid was washed with methanol, dissolved in tetrahydrofuran (200 mL) and treated with a warm solution of KOH (60 g) in water (200 mL). The mixture was stirred for 15 minutes and was treated with 6 N HCl to pH 1. The layers were separated, the organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The crude solid was dissolved in dichloromethane (500 mL) and triethylamine (23 mL, 166.48 mmol), and di-tert-butyldicarbonate (23.6 g, 108.2 mmol) and a catalytic amount of dimethylaminopyridine (˜5 mg) were added. The mixture was stirred at room temperature for 2 hours, diluted with water, extracted with dichloromethane, and dried with sodium sulfate and filtered. The solvent was evaporated under reduced pressure to afford the title compound. MS (ESI+) m/z 344.9 (M+H)+.

1. additionUpon completion of the addition
2. temperaturethe mixture was heated at 70° C. for 20 hours
3. temperatureThe mixture was cooled
4. customquenched with saturated aqueous NaHCO3 to pH 7
5. extractionThe mixture was extracted with dichloromethane
6. dry with materialthe organics were dried over sodium sulfate
7. filtrationfiltered
8. customThe solvent was evaporated under reduced pressure
9. washThe crude solid was washed with methanol
10. dissolutiondissolved in tetrahydrofuran (200 mL)
11. additiontreated with a warm solution of KOH (60 g) in water (200 mL)
12. stirringThe mixture was stirred for 15 minutes
13. additionwas treated with 6 N HCl to pH 1
14. customThe layers were separated
15. dry with materialthe organic layer was dried over sodium sulfate
16. filtrationfiltered
17. customthe solvent was evaporated under reduced pressure
18. dissolutionThe crude solid was dissolved in dichloromethane (500 mL)
19. stirringThe mixture was stirred at room temperature for 2 hours
20. extractionextracted with dichloromethane
21. dry with materialdried with sodium sulfate
22. filtrationfiltered
23. customThe solvent was evaporated under reduced pressure

ORD record

ord-4d394b9f90f74f848398e99318637eed

Source dataset

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08648069B2