TERT-BUTYL 2-(3-OXOCYCLOHEXYL)-4-PHENYLPIPERIDINE-1-CARBOXYLATE synthesis

Yield:1241505-11-2 46%

Reaction Conditions:

Stage #1: tert-butyl 4-phenylpiperidine-1-carboxylatewith N,N,N,N,-tetramethylethylenediamine;sec.-butyllithium in diethyl ether at -78; for 2 h;
Stage #2: with copper(I) cyanide di(lithium chloride) in tetrahydrofuran at -50; for 1 h;
Stage #3: cyclohexenonewith chloro-trimethyl-silane;water in diethyl ether at -50 - 20;

Steps:

II.1

To a solution of compound 1 (10.8g, 41.2 mmol) in Et₂O (150 mL) at -78 ⁰C was added TMEDA (6.2mL, 41.2 mmol), followed by sec-BuLi (41.4mL, 1.3eq, 53.8 mmol). The mixture was stirred at -78 ⁰C for 2 h before a solution of CuCN-2LiCl (3.6 g, 20.6 mmol) in THF (41.2 mL) was added. The reaction mixture was allowed to stir at -50⁰C for 1 h before a solution of compound 2 (4g, 41.2 mmol) in TMSCl (26mL, 206 mmol) was added. The reaction mixture was stirred at - 50⁰C for 30 min and then was allowed to stir at room temperature overnight. The reaction mixture was quenched with H₂O, stirred at room temperature briefly, diluted with EA, and filtered through Celite. The organic phase was separated, and the aqueous phase was extracted with EA (40 mL^χ4). The combined organic phases were washed with saturated NH4C1 (aq.), 5% NaHCO₃ (aq.), brine, and dried over a mixture of anhydrous Na₂SO₄ and K₂CO₃. Evaporation of the solvent in vacuo afforded the crude product which was purified by column chromatography to give 6.8 g of compound 3 in 46 % yields.

References:

WO2010/94242,2010,A1 Location in patent:Preparation II.1