Nitric Acid → 5-Methyl-3-nitro-1H-pyrazole

Temperature

0 °C

Acetic anhydride (96.2 mL, 104.58 g, 1.02 mol) was cooled to −15° C. with an ice/NaCl bath and to this was dropwise, very slowly, added red fuming HNO3 (40.7 mL, 61.8 g, 0.98 mmol). The reaction is strongly exothermic and care must be taken to keep the temperature below 0° C. (inside temperature). This solution was then rapidly transferred with a teflon tube of sufficient diameter (to prevent warming on transfer) to an addition funnel with a cooling mantle. This solution was kept <0° C. at all times and the addition funnel mounted on a flask containing methylpyrazole (35 g, 0.427 mol) in glacial acetic acid (40 mL) at −5° C. The chilled (−15° C.) acetyl nitrate solution was then dropwise added to the methylpyrazole 8 solution at 0° C. The reaction was highly exothermic until ca. 1 eq. acetyl nitrate had been added and it must not be allowed to warm above 5° C. After 3 hours stirring at 0° C. the mixture was poured into ice/water (500 mL) and neutralized to ca. pH 7 with sodium carbonate. Extraction with DCM (3×200 mL), drying (sodium sulfate) and evaporation in vacuo afforded a 90:10 mixture of N-nitro intermediates (42.8 g, 0.337 mol, 79%), which was dissolved in perchloroethylene (4 L), heated at 140° C. ext. temperature for 18 hours and for 5 hours at 165° C. Evaporation of the solvent and drying in vacuo gave pure 9 (39.0 g, 0.307 mol, 72% both steps).

1. customthe temperature below 0° C. (inside temperature)
2. temperatureThis solution was then rapidly transferred with a teflon tube of sufficient diameter (to prevent warming on transfer) to an addition funnel with a cooling mantle
3. customwas kept <0° C. at all times
4. customthe addition funnel mounted on a flask
5. additionhad been added
6. temperatureto warm above 5° C
7. extractionExtraction with DCM (3×200 mL)
8. customdrying
9. custom(sodium sulfate) and evaporation in vacuo
10. customafforded
11. additiona 90:10 mixture of N-nitro intermediates (42.8 g, 0.337 mol, 79%), which
12. temperatureheated at 140° C. ext
13. waittemperature for 18 hours
14. waitfor 5 hours at 165° C
15. customEvaporation of the solvent
16. customdrying in vacuo
17. customgave pure 9 (39.0 g, 0.307 mol, 72% both steps)

ORD record

ord-d043e098d5f748bd8604a31cc87ca1ee

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08809344B2