Reaction Steps
Hydroxylamine hydrochloride (139 mg) was added to 1-(4-chlorobenzyl)-4-(3-hydroxy-1-oxo-3-(4-chlorophenyl)prop-2-en-1-yl)piperidine obtained from Example 1 (399 mg) and ethyldiisopropylamine (0.35 ml) in methanol (5 ml) and DMF (2 ml). After stirring for 16 h hydroxylamine hydrochloride (139 mg) and ethyldiisopropylamine (0.35 ml) were added and the mixture stirred at 50° C. for 4 h. Water (50 ml) was added, the mixture extracted with ethyl acetate (3×25 ml) and the combined organic layers washed with water and brine, dried (MgSO4), evaporated in vacuo, and purified by flash chromatography, eluting with dichloromethane:methanol:triethylamine (96:4:1 v/v) to give a mixture of 5-(1-(4-chlorobenzyl)-4-piperidinyl)-3-(4-chlorophenyl)-3-hydroxy-3,4-dihydroisoxazole and 3-(1-(4-chlorobenzyl)-4-piperidinyl)-5-(4-chlorophenyl)-3-hydroxy-3,4-dihydroisoxazole (287 mg). 209 mg of this oil was dissolved in dichloromethane (5 ml), cooled to 0° C., and triethylamine (161 mg) and methanesulphonyl chloride (81 mg) added. After 1 h ethyl acetate (25mg) was added, and the mixture washed with water and brine, dried (MgSO4), and evaporated in vacuo, and purified by preparative thin layer chromatography, eluting with dichloromethane:methanol:triethylamine (97:3:1 v/v) to give 5-(1-(4-chlorobenzyl)-4-piperidinyl)-3-(4-chlorophenyl)isoxazole (107 mg); oxalate salt: amorphous white solid, m.p.227°-230° C. (from ethanol) (Found: C, 58.91; H, 4.95; N, 6.15%. C21H20N2OCl2. (0.8C2H2O4) requires C, 59.09; H, 4.74; N, 6.10%); δH (360 MHz, d6 -DMSO) 1.7-1.8 (2H, m, CHCHAHB), 2.08 (2H, d, J=11, CHCHAHB), 2.3-2.4 (2H, m, NCHAHB), 3.0-3.1 (3H, m, NCHAHB and CH2CH), 3.82 (2H, s, ArCH2), 6.92 (1H, s, CHCO), 7.4-7.5 (4H, m, ArHCH2), 7.59 (2H, d, J=8, ArH), 7.88 (2H, d, J=8, ArH); m/z (CI+, NH3) 387 (M+ +H); and 3-(1-(4-chlorobenzyl)-4-piperidinyl)-5-(4-chlorophenyl)isoxazole (51 mg); oxalate salt: white plates, m.p. 240°-242° C. (from ethanol) (Found: C, 57.85; N, 4.74; H, 5.92. C21H20N2OCl2.C2H2O4 requires C, 57.87; H, 4.64; N 5.87%); δH (d6 -DMSO) 1.8-1.9 (2H, m, CHAHBCH), 2.05 (2H, d, J=11, CHAHBCH), 2.6-2.7 (2H, m, NCHAHB), 2.9-3.0 (1H, m, CH2CH), 3.1-3.2 (2H, m, NCHAHB), 3.97 (2H, s, ArCH2), 7.07 (1H, s, CHCO), 7.4-7.5 (4H, m ArHCH2), 7.61 (2H, d, J=8, ArH), 7.85 (2H, d, J=8, ArH); m/z (CI+, NH3) 387 (M+ +H). The isoxazole regiochemistry was proved by X-ray.
