Synthesis
Example 1: 5.00 g (0.0499 mol) of racemic 2-methylpiperazine was added to a 100 mL four-necked flask and dissolved in 44 g of 1-butanol (0.05 wt% in water). The solution was cooled to 0°C and 8.47 g of benzyl chloroformate (0.0489 mol, 98.5% purity as determined by HPLC, equivalent to 0.98 equivalents) was added slowly dropwise over a temperature range of 0 to 8°C. After the dropwise addition, the reaction mixture was stirred at 0 to 5 °C for 2 hours. During this time, a sample was taken and analyzed by HPLC using the internal standard method (internal standard: anisole), and the yield of 1-Benzyloxycarbonyl-3-methylpiperazine was measured to be 83.9% (based on 2-methylpiperazine). Subsequently, the reaction mixture was continued to be stirred at room temperature for 12 hours and analyzed again and the yield was increased to 85.1%.
Example 3: The reaction conditions were the same as in Example 1 , with the difference that the amount of benzyl chloroformate was increased to 10.1 g (0.0597 mol, 1.17 eq.). After 2 hours of reaction at 0 to 5 °C, HPLC analysis showed 93.8% yield of 1 -benzyloxycarbonyl-3-methylpiperazine (based on 2-methylpiperazine). The yield was further increased to 95.1% after continued stirring at room temperature for 12 hours.
References
[1] Patent: EP1548010, 2005, A1. Location in patent: Page/Page column 16; 17
[2] Patent: EP1548010, 2005, A1. Location in patent: Page/Page column 18
[3] Patent: EP1548010, 2005, A1. Location in patent: Page/Page column 19
[4] Synthetic Communications, 2007, vol. 37, # 20, p. 3623 - 3634
[5] Patent: EP3124482, 2017, A1. Location in patent: Paragraph 0476; 0477
