2-chloro-1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]ethanone

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexan-1-ol (40 mg, 0.13 mmol) in tetrahydrofuran (1 ml) and N,N-dimethylformamide (0.3 ml) was added sodium hydride (26 mg, 1.08 mmol, 8 eq) with stirring for 30 minutes at 0° C. Then 2-chloro-1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]ethan-1-one (90 mg, 0.27 mmol, 2 eq) in tetrahydrofuran (0.5 ml) was added with stirring for 5 hours at room temperature. The reaction mixture was quenched by water (20 ml) and extracted with ethyl acetate (3×30 ml). The organic layers were combined and dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified by Pre-TLC using 50% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (29.8 mg, 38%); (ES, m/z): [M+H]+ 597.35; 1H NMR (300 MHz, CDCl3): δ 8.02 (d, J=7.2 Hz, 1H), 7.04-7.12 (m, 2H), 6.84 (d, J=2.4 Hz, 1H), 6.61-6.71 (m, 2H), 5.01 (broad s, 1H), 4.46 (d, J=7.8 Hz, 1H), 4.19 (s, 2H), 3.60-3.73 (m, 3H), 3.40-3.47 (m, 2H), 3.23-3.32 (dd, J=9.3 Hz, 15.9 Hz, 1H), 2.92-2.99 (dd, J=7.8 Hz, 15.9 Hz, 1H), 2.77-2.84 (m, 1H), 2.62-2.77 (m, 4H), 2.12-2.16 (m, 4H), 1.41-1.52 (m, 3H), 1.22-1.30 (m, 3H). with stirring for 5 hours at room temperature The reaction mixture was quenched by water (20 ml) extracted with ethyl acetate (3×30 ml) dried over anhydrous magnesium sulfate filtered concentrated under vacuum The crude material was purified by Pre-TLC to elute concentrated under vacuum

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (1.3 g, 5.1 mmol) in dichloromethane (50 ml) was added triethylamine (782 mg, 7.73 mmol, 1.5 eq) and 2-chloroacetyl chloride (758 mg, 6.71 mmol, 1.3 eq) dropwise with stirring at 0° C. for 1 hour at room temperature. The reaction mixture was quenched by the addition of water (80 ml) and extracted with dichloromethane (3×50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 3% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 2-chloro-1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]ethan-1-one as yellow oil (1.0 g, 59%); (ES, m/z): [M+H]+ 329; 1H NMR (300 MHz, CDCl3): δ 7.04-7.12 (m, 2H), 6.69 (d, J=8.4 Hz, 1H), 4.95-5.08 (m, 1H), 4.11 (s, 2H), 3.56-3.73 (m, 5H), 3.23-3.32 (dd, J=9.3 Hz, 15.9 Hz, 1H), 2.91-2.99 (dd, J=7.8 Hz, 15.9 Hz, 1H), 2.77-2.84 (dd, J=7.8 Hz, 13.5 Hz, 1H), 2.48-2.75 (m, 4H). The reaction mixture was quenched by the addition of water (80 ml) extracted with dichloromethane (3×50 ml) dried over anhydrous magnesium sulfate filtered concentrated under vacuum The crude material was purified by silica gel chromatography to elute concentrated under vacuum