Acetic Acid → tert-butyl (3R,4R)-4-(benzylamino)-3-hydroxypiperidine-1-carboxylate

Participants

Reaction Steps

Add benzaldehyde (0.24 mol, 26.3 g) to a solution of racemic trans-4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.24 mol, 53.7 g), and acetic acid (92 mL) in ethanol (400 mL) and stir the reaction mixture at room temperature for 30 min. Add sodium cyanoborohydride (0.49 mol, 31.2 g) and stir the reaction mixture for 3 h. Quench the reaction mixture with sodium bicarbonate solution and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Dissolve the residue in a minimum amount of dichloromethane and add 0.1 N aqueous hydrochloric acid to maintain the pH between 4-5. Discard the organic layer. Wash the acidic aqueous layer three times with dichloromethane and discard the organic layer. Adjust the pH of the aqueous layer between 10-12 and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (35.7 g, 46%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.35-1.40 (m, 2H), 1.45 (s, 9H), 2.05 (br s 1H), 2.43 (t, 1H), 2.57 (t, 1H), 2.69 (br s, 1H), 3.27 (br s, 1H), 3.70 (d, 1H), 3.94 (d, 1H), 4.15 (br s, 1H), 4.26 (d, 1H), 7.23-7.29 (m, 1H), 7.30-7.32 (m, 2H), 7.33-7.36 (m, 2H).

Provenance & Evidence