4-Nitro-1H-pyrazole-3-carboxylic acid (1.117 kg, 7.11 mol, 1.0 equiv.) and methanol (8.950 L, 8.0 v/v) were added to a 20 L reactor equipped with a digital thermometer and a mechanical stirrer. The reaction mixture was cooled to 0-5 °C under nitrogen protection and thionyl chloride (0.581 L, 7.96 mol, 0.52 v/v) was slowly added dropwise over 180 min. After the dropwise addition, the reaction mixture was gradually warmed to 18-25 °C and stirred overnight. After confirming the completion of the reaction by 1H NMR (d6-DMSO), the reaction mixture was concentrated at 40-45 °C under reduced pressure. The residue was treated with toluene (3 x 2.250 L, 3 x 2 v/v) and concentrated under reduced pressure at the same temperature to afford methyl 4-nitro-1H-pyrazole-3-carboxylate as an off-white solid (1.210 kg, 99.5% yield).
In another experiment, 4-nitro-1H-pyrazole-3-carboxylic acid (1.00 kg, 6.37 mol, 1.0 eq.) and methanol (8.00 L, 8.0 v/v) were added to a flanged flask fitted with a mechanical stirrer, condenser and thermometer. The suspension was cooled to 0-5 °C under nitrogen protection and thionyl chloride (0.52 L, 7.12 mol, 0.52 v/v) was slowly added at this temperature. The mixture was gradually warmed to 15-25 °C over 16-24 h and the completion of the reaction was confirmed by 1H NMR (d6-DMSO). The reaction mixture was concentrated under reduced pressure at 35-45 °C and the residue was treated with toluene (2.00 L, 2.0 v/v) and the solvent was removed under reduced pressure at the same temperature. This process was repeated twice to give the final methyl 4-nitro-1H-pyrazole-3-carboxylate as an off-white solid (1.071 kg, 98.3% yield).
In a small-scale experiment, thionyl chloride (2.90 mL, 39.8 mmol) was slowly added to a methanol (100 mL) solution of 4-nitro-1H-pyrazole-3-carboxylic acid (5.68 g, 36.2 mmol) at room temperature and the mixture was stirred for 48 hours. Upon completion of the reaction, the mixture was concentrated under reduced pressure and residual water was removed by azeotropy with toluene to afford methyl 4-nitro-1H-pyrazole-3-carboxylate as a white solid.1H NMR (400 MHz, DMSO-d6) δ 14.4 (s, 1H), 8.9 (s, 1H), 3.9 (s, 3H).
Finally, 4-nitro-1H-pyrazole-3-carboxylic acid (1.350 kg, 8.59 mol, 1.0 eq.) and methanol (10.80 L, 8.0 v/v) were added to a flanged flask fitted with a mechanical stirrer, condenser and thermometer. The suspension was cooled to 0-5 °C under nitrogen protection and thionyl chloride (0.702 L, 9.62 mol, 0.52 v/v) was slowly added at this temperature. The mixture was gradually warmed to 15-25 °C over 16-24 h and the completion of the reaction was confirmed by 1H NMR (d6-DMSO). The reaction mixture was concentrated under reduced pressure at 35-45 °C and the residue was treated with toluene (2.70 L, 2.0 v/v) and the solvent was removed under reduced pressure at the same temperature. This procedure was repeated twice to give methyl 4-nitro-1H-pyrazole-3-carboxylate as an off-white solid (1.467 kg, 99.8% yield).1H NMR (d6-DMSO) was consistent with the structure and no entrapped solvent was detected.
