Formaldehyde → (R)-4-{[1-(1-Benzyl-pyrrolidin-3-yl)-cyclopropyl]-methyl-amino}-piperidine-1-carboxylic acid tert-butyl ester

Participants

Reaction Steps

To a solution of (R)-1-(1-benzyl-pyrrolidin-3-yl)-cyclopropylamine (18.6 g, 87 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (22.7 g, 113 mmol) in THF (500 mL) was added glacial HOAc (31 mL). The solution was stirred at room temperature for one hour and then NaBH(OAc)3 (65 g, 306 mmol) was added. The resulted suspension was stirred at room temperature overnight before 37% aqueous solution of formaldehyde (30 mL, 262 mmol) was added. The reaction mixture was allowed to stir for 3 hrs and completed, then added aqueous 20% NaOH (300 mL) at 0° C. The mixture was allowed to stir for 2 h, and layers were separated. The aqueous layer was extracted with EtOAc (3×300 mL). The combined organic phase was dried over sodium sulfate, concentrated in vacuo. The residue was purified by flash chromatography (gradient eluation, 1% to 10% methanol in dichloromethane) to give the title compound as a pale yellow oil (27 g): ESI MS m/z 414.3 (M+H+). 1H NMR (400 MHz, CDCl3) δ 7.33-7.23 (m, 5H), 4.24-4.02 (m, 2H), 3.88-3.80 (m, 1H), 3.60 (d, JAB=12.8 Hz, 1H), 3.53 (d, JAB=12.8 Hz, 1H), 2.82-2.57 (m, 5H), 2.31 (s, 3H), 2.28-2.22 (m, 1H), 1.94-1.80 (m, 4H), 1.44 (s, 9H), 1.42-1.28 (m, 3H), 0.55-0.53 (m, 4H). The chiral purity of the product was analyzed by Chiral-Cel OD column (0.46 cm×25 cm, Daicel Chemical industries, Ltd, column catalog no. OD00CE-E1031) with acetonitrile in the presence of 0.1% diethylamine as mobile phase (flow rate 1 mL/min; retention time 5.23 min desired, 5.93 isomer) to be 95% ee.

Provenance & Evidence