2-chloro-1-(4,4-difluorocyclohexyl)ethanone synthesis

Yield:1037834-16-4 85%

Reaction Conditions:

Stage #1: 4,4-difluorocyclohexane-1-carbonyl chloride;diazomethyl-trimethyl-silanewith triethylamine in diethyl ether at -25 - 20; for 5 h;
Stage #2: with hydrogenchloride in diethyl ether at -20 - 20; for 5 h;

Steps:

Preparation of 2-chloro-1-(4,4-difluorocyclohexyl)ethanone; To a solution containing trimethylsilyldiazomethane in ether (1.70 g, 15.0 mmol 7.50 mL) and triethylamine (15.0 mmol) at -25 °C, was dropwise added a solution of commercially available cyclohexanecarboxylic acid chloride (1.00 g, 6.80 mmol) in anhydrous ether (25 mL). While agitated the reaction mixture was allowed to warm to room temperature for 5 h. The reaction mixture was concentrated to obtain the desired trimethylsilyl intermediate. The intermediate was directly added to 1N HCI in ether at 0 ⁰C and warmed to room temperature for 5 h. The reaction mixture was then evaporated under reduced pressure. The residue was diluted with EtOAc (50.0 mL) and washed with 1M NaHCO₃ (10 mL), water (15 ml_x2) and brine. The organic layer was dried over MgSO₄ and filtered. The filtrate was then concentrated under reduced pressure to give a pale- yellow liquid. The crude material was used to the next reaction without further purification (0.928 g, yield, 85%). ¹H NMR (DMSO-d_β) δ 4.11 (s, 2 H), 1.78 (m, 4 H), 1.25 (m, 6 H).

References:

WO2008/84300,2008,A1 Location in patent:Page/Page column 39-40