3-Chloro-1H-pyrazol-4-ylaMine hydrochloride

2075-46-9

63680-90-0

Step 1: Preparation of 3-chloro-1H-pyrazol-4-amine hydrochloride Ethanol (600 mL) and 4-nitro-1H-pyrazole (50.6 g, 447 mmol) were added to a 2L three-necked round-bottomed flask fitted with an overhead stirrer, temperature probe, dosing funnel, and nitrogen inlet. Concentrated hydrochloric acid (368 mL) was added to this solution in a single addition (note: the reaction was exothermic and the temperature rapidly increased from 15°C to 39°C). The resulting mixture was purged with nitrogen for 5 minutes. Alumina-loaded palladium catalyst (5% w/w, 2.6 g, Alfa, black solid) was added to the mixture and stirred at room temperature while triethylsilane (208 g, 1789 mmol) was added drop-wise over 4 hours. The reaction was slowly warmed from 35 °C to 55 °C over 2.0 h and stirring was continued for a total of 16 h. The reaction was then purged with a diatomaceous earth plug. The reaction mixture was vacuum filtered through a diatomaceous earth plug to give a two-phase mixture. The mixture was transferred to a partition funnel, separated and the bottom aqueous layer was collected. The aqueous layer was extracted with acetonitrile (3 x 350 mL), the organic phases were combined and evaporated to dryness by rotary evaporation at 60 °C, 50 mmHg. The resulting yellow solid was suspended in acetonitrile (150 mL) and allowed to stand at room temperature for 2 hours, followed by 1 hour in a 0°C refrigerator. The solid was collected by filtration and washed with acetonitrile (100 mL) to afford 3-chloro-1H-pyrazol-4-amine hydrochloride (84 g, 97% yield, 80% purity) as a white solid with a melting point of 190-193 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.46-10.24 (broad peak, 2H), 8.03 (s, 0.54H), 7.75 (s, 0.46H), 5.95 (broad peak, 1H); 13C NMR (101 MHz, DMSO) δ 128.24, 125.97, 116.71.