tert-butyl 4-(2-Methoxyethyl)piperidine-1-carboxylate synthesis

Yield:509147-79-9 94%

Reaction Conditions:

Stage #1: 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl esterwith sodium hydride in N,N-dimethyl-formamide at 20; for 0.5 h;
Stage #2: methyl iodide in N,N-dimethyl-formamide; for 18 h;

Steps:

Sodium hydride (202 mg, 8.0 mmol, 95%) was added in portions to a solution of tert-butyl-4- (2-hydroxyethyl) piperidine-1-carboxylate (917 mg, 4.0 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 0.5 h and methyl iodide (1.14 g, 8.0 mmol) in DMF (3 mL) was added slowly. The reaction was quenched after 18 h by addition of water (10 mL), and the resulting aqueous phase was extracted with EtOAc (3x20 mL). The combined organic phases were washed with brine (2x5 mL), dried over MgSO₄, and concentrated in vacuo to yield 1.177 g of crude material as a light yellow oil. Purification by flash chromatography (silica, 10-20% EtOAc in n-hexane) yielded 912 mg (94%) of pure tert-butyl 4-(2- methoxyethyl)piperidine-1-carboxylate as a colorless oil.1H NMR (600 MHz, CD3OD) δ ppm 4.04 (d, J=13.4 Hz, 2 H) 3.45 (t, J=6.4 Hz, 2 H) 3.31 (s, 3 H) 2.73 (br. s., 2 H) 1.69 (d, J=12.5 Hz, 2 H) 1.54 - 1.64 (m, 1 H) 1.51 (q, J=6.6 Hz, 2 H) 1.45 (s, 9 H) 1.07 (qd, J=12.2, 4.4 Hz, 2 H). MS (ESI+) m/z 188 [M+H-t-Bu] + .

References:

WO2018/11138,2018,A1 Location in patent:Page/Page column 115-116