Synthesis
General procedure for the synthesis of 4-Boc-piperazine-2-carboxylic acid from di-tert-butyl dicarbonate and piperazine-2-carboxylic acid dihydrochloride: sodium bicarbonate (3.1 g, 36.9 mmol) was added to a stirred suspension of piperazine-2-carboxylic acid (5 g, 24.6 mmol) in 1,4-dioxane and water (1:1, 100 mL) under nitrogen protection. Subsequently, di-tert-butyl dicarbonate (5.6 mL, 24.6 mmol) was added slowly at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred continuously for 16 hours. The progress of the reaction was monitored by thin layer chromatography (TLC) and after confirming complete consumption of the raw materials, the reaction mixture was diluted with water (50 mL) and extracted with ether (2 x 100 mL). The aqueous phase was acidified with 2N hydrochloric acid solution and then extracted with n-butanol. The organic phases were combined, dried with anhydrous sodium sulfate and concentrated under reduced pressure to afford the target compound 4-Boc-piperazine-2-carboxylic acid (5 g, 88% yield) as a white solid.1H-NMR (500 MHz, DMSO-d6): δ 10.18 (broad peak, 1H), 4.08 (broad peak, 1H), 3.81-3.71 (multiple peaks, 2H), 3.63 (triple peak, J=6.5Hz, 1H), 3.17-3.15 (multiple peaks, 2H), 2.91-2.86 (multiple peaks, 1H), 1.36 (single peak, 9H), 1.31-1.26 (multiple peaks, 0.5H), 0.87-0.84 (multiple peaks, 0.5H). lcms (esi): m/z 229.0 [M+H]+.
References
[1] Patent: WO2018/26782, 2018, A1. Location in patent: Page/Page column 30-31
[2] Journal of Medicinal Chemistry, 2000, vol. 43, # 3, p. 369 - 380
