Synthesis
For the preparation of 1-Cbz-4-piperidineacetic acid (compound 2), the method was modified as described in DE 4304650 A1. The procedure was as follows: 2-(piperidin-4-yl)acetic acid hydrochloride (3000 mg, 16.7 mmol; Iris Biotech, Marktredwitz, Germany) was dissolved in 46 mL of 1 M NaOH aqueous solution and cooled in an ice bath. Under stirring conditions, benzyloxycarbonyl chloride (Cbz-Cl, 3350 μL, 23.46 mmol, 4002 mg) was slowly added dropwise for a controlled time of 5 min. Subsequently, the reaction mixture was gradually warmed up to room temperature and stirred continuously for 16 hours. Upon completion of the reaction, the aqueous phase was washed twice with water (20 mL) and a solvent mixture of diethyl ether/petroleum ether (4:1, v/v), and then acidified to pH 1 with aqueous 4 M HCl. The reaction product was extracted with diisopropyl ether (3 × 50 mL). The organic phases were combined, dried with anhydrous MgSO4 and concentrated under reduced pressure to give compound 2 as a colorless solid (4383 mg, 15.8 mmol, 95% yield).1H NMR (400 MHz, CDCl3) δ 7.40-7.27 (m, 5H), 5.13 (s, 2H), 4.18 (d, J = 13.3 Hz, 2H), 2.81 ( t, J = 12.8 Hz, 2H), 2.29 (d, J = 7.0 Hz, 2H), 1.96 (tp, J = 11.2, 3.5 Hz, 1H), 1.75 (d, J = 12.1 Hz, 2H), 1.30-1.09 (m, 2H).
References
[1] Patent: WO2014/125084, 2014, A1. Location in patent: Page/Page column 33; 34
[2] Patent: WO2016/51193, 2016, A1. Location in patent: Paragraph 00344; 00345; 00346
