Ethyl 5-bromo-1-methyl-1H-pyrazole-4-carboxylate

Synthesis

General procedure for the synthesis of ethyl 5-bromo-1-methyl-1H-pyrazole-4-carboxylate from ethyl 5-amino-1-methylpyrazole-4-carboxylate: Intermediate 1: (5-bromo-1-methyl-1H-pyrazol-4-yl)-(octahydro-quinolin-1-yl)methanone; Step 1: To a mixed solution containing tert-butyl nitrite (29.5 mL, 221.5 mmol), copper bromide (39.7 g, 177.5 mmol), and acetonitrile, ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (25 g, 148 mmol) was slowly added over a 30-minute period. The reaction mixture was stirred at room temperature for 2 hours, followed by warming up to 65 °C and continued stirring for 1 hour. After completion of the reaction, the mixture was poured into 6N HCl (400 mL) and extracted with dichloromethane. The organic phase was concentrated in vacuum and the resulting crude product was purified by fast chromatography using a 0-20% ethyl acetate/hexane gradient elution to give ethyl 5-bromo-1-methyl-1H-pyrazole-4-carboxylate (28 g, 81% yield).

References

[1] Patent: US2006/223852, 2006, A1. Location in patent: Page/Page column 10
[2] Patent: WO2013/189904, 2013, A1. Location in patent: Page/Page column 49
[3] Patent: US2012/214791, 2012, A1. Location in patent: Page/Page column 23
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 1001 - 1018