N-Nitrosodimethylamine → 4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazole

To a pre cooled (−78° C., internal temp. −70° C.) solution of diisopropyl amine (193.13 g, 1899.04 mmol) in THF (1500 ml) under nitrogen atmosphere was added n-Butyllithium (759.617 ml, 1899.04 mmol, 2.5 M solution in hexane) and stirred for 90 min. Then N,N-dimethyl nitrous amide 2 (134.57 g, 1816.48 mmol) in THF (500 ml) was cannulated portion wise during a period of 30 min. and stirred for 1 h. Then a solution of 2-Fluorobenzonitrile 1 (100.0 g, 825.671 mmol) in THF (500 ml) was cannulated portion wise during a period of 30 min and stirred at −78° C. (internal temp. −70° C.) for 1 h. Then cooling bath was removed and stirred at room temperature for 2 h. The reaction was monitored by TLC and UPLC. The above reaction mass was slowly quenched with saturated solution of ammonium chloride (2000 ml) at room temperature and the aqueous layer was extracted with dichloromethane (5×2000 ml). The combined organic layer was dried over sodium sulphate, filtered and concentrated to afford crude mass (170.0 g, 116.21% mass balance). It was purified by gravity column using 30% ethyl acetate in pet ether as an eluent to furnish desired product 4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazole (64.52 g, 44.10% mass balance) as reddish gum. Then it was triturated with methyl tert-butyl ether (1000 ml) and hexane (500 ml), the supernant layer was decanted and the solid was dried to furnish desired product 4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazole (32.9 g, 22.49%) as yellowish solid.

1. customof 30 min.
2. stirringstirred for 1 h
3. customof 30 min
4. stirringstirred at −78° C. (internal temp. −70° C.) for 1 h
5. temperatureThen cooling bath
6. customwas removed
7. stirringstirred at room temperature for 2 h
8. customThe above reaction mass
9. customwas slowly quenched with saturated solution of ammonium chloride (2000 ml) at room temperature
10. extractionthe aqueous layer was extracted with dichloromethane (5×2000 ml)
11. dry with materialThe combined organic layer was dried over sodium sulphate
12. filtrationfiltered
13. concentrationconcentrated
14. customto afford crude mass (170.0 g, 116.21% mass balance)
15. customIt was purified by gravity column

ORD record

ord-5b81ce3623b843bbabb2e709c9c4cdfa

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09206160B2