Synthesis
General procedure for the synthesis of 4-tert-butoxycarbonyl-2-methylpiperazine from di-tert-butyl dicarbonate and 2-methylpiperazine: 1) Di-tert-butyl dicarbonate (21.7 g) was slowly added to a solution of 2-methylpiperazine (10.0 g) in methanol (200 mL) at room temperature, followed by continuous stirring of the reaction mixture for 24 hours. Upon completion of the reaction, the methanol solvent was removed by distillation under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: chloroform-methanol mixed solvent) to finally obtain tert-butyl 3-methylpiperazine-1-carboxylate as a colorless oily product (19.3 g, 96.5% yield). The product was characterized by 1H-NMR (300 MHz, CDCl3): δ1.04 (3H, d, J=6.24 Hz), 1.46 (9H, s), 2.39 (1H, br s), 2.70-2.77 (3H, m), 2.94 (1H, br s), 3.93 (2H, br s). Mass spectrometry analysis (FAB) showed the molecular ion peak M/Z: 201 (M+H)+.
References
[1] Patent: US2003/153556, 2003, A1
[2] Patent: EP1621537, 2006, A1. Location in patent: Page/Page column 33
[3] Patent: WO2016/168619, 2016, A1. Location in patent: Paragraph 00286
[4] Patent: EP1548010, 2005, A1. Location in patent: Page/Page column 19
[5] Journal of Medicinal Chemistry, 2016, vol. 59, # 11, p. 5432 - 5448
