Synthesis
General Steps:
Step 1: Synthesis of (R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate. A solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (1.0 g, 5.3 mmol) and triethylamine (2.77 mL, 20 mmol) was cooled in an ice water bath in dichloromethane (20 mL). To this solution was added methosulfonyl chloride (1.15 mL, 15 mmol) diluted in dichloromethane (10 mL) dropwise. The reaction mixture was stirred at room temperature for 12 hours. Upon completion of the reaction, water was added and the organic phase was extracted with dichloromethane (3 x 50 mL). The combined organic phases were dried and purified by silica gel chromatography (50% ethyl acetate:hexane to 100% ethyl acetate gradient) to afford (R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate (1.53 g, brown oil, 100% yield).
References
[1] Patent: WO2010/45542, 2010, A2. Location in patent: Page/Page column 73
[2] Patent: WO2012/62783, 2012, A1. Location in patent: Page/Page column 75
[3] Patent: WO2017/12576, 2017, A1. Location in patent: Page/Page column 187
[4] Patent: WO2018/71454, 2018, A1. Location in patent: Paragraph 001372; 001373; 001374
[5] Journal of Enzyme Inhibition and Medicinal Chemistry, 2018, vol. 33, # 1, p. 1460 - 1471
