Synthesis
GENERAL STEPS: 3-Amino-5-methyl-1H-pyrazole (2.0 g, 20.6 mmol) was dissolved in THF (40 ml) and cooled to 0 °C. NaH (95%, 0.57 g, 22.7 mmol) was added slowly with stirring. after 30 min, di-tert-butyl dicarbonate (Boc2O, 4.94 g, 22.7 mmol) was added and then the mixture was gradually warmed up to room temperature. The reaction mixture continued to be stirred at room temperature for 2 hours. After completion of the reaction, the mixture was poured into saturated aqueous NaHCO3 solution. The aqueous phase was extracted with CHCl3, the organic phases were combined and dried over Na2SO4. The solvent was removed by concentration under reduced pressure to give a crude mixture of 1-Boc-3-amino-5-methylpyrazole and its tert-butyl 2-carboxylate isomer. The separation and purification was carried out by silica gel column chromatography using ethyl acetate/heptane (2:1) as eluent. The target products 5-amino-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester and 1-Boc-3-amino-5-methylpyrazole were obtained in a yield of 2.4 g and 59%.1H-NMR (400 MHz, D6-DMSO): δ 5.60 (1H, s), 5.27 (2H, s), 2.34 (3H, s), 1.51 (9H, s); MS (ESI+): m/z = 198.26 ([M-H]+).
References
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 9, p. 2114 - 2124
[2] Patent: WO2006/32518, 2006, A1. Location in patent: Page/Page column 200
[3] Patent: WO2012/30944, 2012, A2. Location in patent: Page/Page column 81-82
[4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 9, p. 2114 - 2124
[5] Nucleosides, Nucleotides and Nucleic Acids, 2014, vol. 33, # 8, p. 552 - 582
