Nitric Acid → 4-Cyclopropyl-4H-1,2,4-triazole-3-methanol

Temperature

20 °C

To a methanol (50 ml) solution of glycolic acid hydrazide (5.0 g) was added cyclopropyl isothiocyanate (5.5 g) at 20° C. The mixture was stirred for one hour, to which was then added water (30 ml) at 0° C. To the resultant mixture was added dropwise a 5N aqueous solution of NaOH (11 ml), the temperature of which was raised to 20° C., followed by stirring for 3 hours. The reaction mixture was concentrated under reduced pressure to make its volume about 10 ml. The concentrate was diluted with ethanol (100 ml), to which was added dropwise a 5N aqueous solution of HCl (11 ml) under ice-cooling. Insoluble substances were filtered off, and the filtrate was concentrated to dryness under reduced pressure to give crude crystals (6.4 g) of 4-cyclopropyl-5-hydroxymethyl-3-mercapto-4H-1,2,4-triazole. This compound (3.0 g) was added to a mixture of concentrated nitric acid (d=1.38) (4.6 ml), water (12 ml) and sodium nitrite (10 mg) at 60° C. Then, concentrated nitric acid (1.0 ml) was added. When a portion of nitric acid was contacted with small amount of a triazole compound on the inside wall of the reaction vessel, the reaction started and the reaction temperature reached 90° C.~100° C., then the reaction was completed. The reaction mixture was cooled with ice, neutralized with an aqueous solution of NaOH, and concentrated under reduced pressure. The concentrate was subjected to a silica gel chromatography (3×10 cm), eluting with methanol-dichloromethane (1:4). The desired fraction was concentrated to give 4-cyclopropyl-3-hydroxymethyl-4H-1,2,4-triazole (2.0 g). This product (1.0 g) was added to thionyl chloride (10 ml) at 0° C., which was refluxed for 20 minutes. The mixture was cooled, then excess volume of thionyl chloride was distilled off under reduced pressure. To the residue was added diethyl ether, and the resulting powder was collected by filtration. This product was recrystallized from a mixture of ethanol and ethyl acetate to give 4-cyclopropyl-3-chloromethyl-1,2,4-triazole hydrochloride (1.34 g).

1. customat 0° C
2. stirringby stirring for 3 hours
3. concentrationThe reaction mixture was concentrated under reduced pressure
4. additionThe concentrate was diluted with ethanol (100 ml), to which
5. additionwas added dropwise a 5N aqueous solution of HCl (11 ml) under ice-
6. temperaturecooling
7. filtrationInsoluble substances were filtered off
8. concentrationthe filtrate was concentrated to dryness under reduced pressure
9. customto give crude crystals (6.4 g) of 4-cyclopropyl-5-hydroxymethyl-3-mercapto-4H-1,2,4-triazole
10. customreached 90° C.~100° C.
11. temperatureThe reaction mixture was cooled with ice
12. concentrationconcentrated under reduced pressure
13. washeluting with methanol-dichloromethane (1:4)
14. concentrationThe desired fraction was concentrated

ORD record

ord-784d889b2544491da8684b0541926627

Source dataset

uspto-grants-1995_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05405861