Hydroxyamine hydrochloride → 4,4,4-trifluoro-N'-hydroxy-3-methoxybut-2-enimidamide

Temperature

0 °C

Hydroxylamine hydrochloride (2.88 g, 41.5 mmol) was dissolved in methanol (20 mL) and cooled to 0° C. in an ice-bath. Sodium methoxide (2.24 g, 41.5 mmol) was added and the resulting suspension stirred at room temperature for 15 minutes. The suspension was cooled to 0° C., 4,4,4-trifluoro-3-methoxybut-2-enenitrile (26 mmol) was added dropwise and the mixture allowed to slowly warm to room temperature. The mixture was then heated to 60° C. overnight. The white solid was removed by filtration, washed with dichloromethane and the filtrate concentrated under reduced pressure to afford 4,4,4-trifluoro-N′-hydroxy-3-methoxybut-2-enimidamide as a solid, which was used directly in the next step without further purification. The solid was taken in ethanol (25 mL) and the solution acidified (pH=1) with 37% aqueous hydrochloric acid. The resulting mixture was heated to 60° C. for 2 h. Ethanol was removed under reduced pressure and the residue diluted with dichloromethane. A saturated solution of sodium bicarbonate was added (pH=14) and the organic phase separated. The aqueous phase was back extracted three times with dichloromethane, the organics combined, dried (MgSO4) and concentrated under reduced pressure. The resulting crude material was purified by silica gel chromatography (dichloromethane/ethyl acetate 95:5) to isolate 3-(trifluoromethyl)isoxazol-5-amine (446 mg, 11%) along with 5-(trifluoromethyl)isoxazol-3-amine as a minor product. 1H NMR (300 MHz, CDCl3) d 5.31 (s, 1H), 5.03 (bs, 2H).

1. temperatureThe suspension was cooled to 0° C.
2. temperatureto slowly warm to room temperature
3. temperatureThe mixture was then heated to 60° C. overnight
4. customThe white solid was removed by filtration
5. washwashed with dichloromethane
6. concentrationthe filtrate concentrated under reduced pressure

ORD record

ord-d16d68d21647476a99fb748168385fcd

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08969587B2