Synthesis
The general procedure for the synthesis of 1-BOC-piperidine-3-carboxylic acid from di-tert-butyl dicarbonate and 3-piperidinecarboxylic acid was as follows:
1. To a solution of piperidine-3-carboxylic acid (50.0 g, 387.5 mmol) in tert-butanol (464.0 mL) was slowly added 1N NaOH solution (464.0 mL) at 0 °C and stirred for 10 min.
2. Di-tert-butyl dicarbonate (Boc-anhydride, 143.6 g, 659.0 mmol) was then added.
3. The reaction mixture was stirred continuously at room temperature for 12 hours.
4. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure and then neutralized to neutrality with 1N HCl solution.
5. The precipitated solid product was collected by filtration and dried to give 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (1, 86.0 g, 97% yield) as a white solid.
Product characterization data: 1H NMR (400 MHz, DMSO-d6) δ 1.38 (s, 9H), 1.47 (m, 1H), 1.59 (dt, J = 3.8 Hz, 1H), 1.87 (m, 1H), 2.28 (m, 1H), 2.77-2.84 (dt, J = 2.5,3.0 Hz, 1H), 3.0 (brs. 1H), 3.67 (d, J = 11.0 Hz, 1H), 3.87 (brs, 1H), 12.2 (s, 1H).
References
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 8, p. 2118 - 2122
[2] Patent: WO2014/149164, 2014, A1. Location in patent: Paragraph 00604
[3] Journal of Medicinal Chemistry, 2004, vol. 47, # 7, p. 1719 - 1728
[4] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 966 - 973
[5] European Journal of Organic Chemistry, 2005, # 4, p. 673 - 682
