反应详情

(+)-3-((αR*)-α-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide, the racemate of Example 1, was prepared according to the procedure of Example 1 using racemic trans-N-allyl-2,5-dimethylpiperazine. The material was de-allylated by the procedure of Example 2 to give (+)-3-((αR*)-α-((2S*,5R*)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (1.8 g, 4.6 mmol), which was treated with tert-butylchlorodimethylsilane (1.38 g, 9.2 mmol) and imidazole (0.78 g, 11.4 mmol) in dimethylformamide at room temperature under nitrogen overnight. The reaction mixture was poured into ice-water and extracted with diethyl ether. The ethereal layers were washed with water and brine, dried over sodium sulfate and the solvent was evaporated to give 1.61 g (69%) of the tert-butyldimethylsilyl ether as a beige solid. The product (0.30 g, 0.59 mmol) was alkylated with 1-iodopropane (63 mL, 0.65 mmol) and anhydrous sodium carbonate (0.31 g, 2.95 mmol) in tetrahydrofuran at reflux for 3 days. The solvent was evaporated and the residue was taken up in dichloromethane and filtered to remove the insoluble salts. The filtrate was evaporated to give 0.30 g of a dark yellow oil. The crude product was deprotected with tetraethylammonium fluoride dihydrate (0.15 g, 0.81 mmol) in acetonitrile at room temperature. The solvent was evaporated and the residue was taken up in aqueous 1M hydrochloric acid and extracted with diethyl ether. The aqueous layer was adjusted to pH 8 with aqueous sodium hydroxide and extracted with ethyl acetate. The ethyl acetate extracts were dried over sodium sulfate and evaporated to give 0.15 g (63%) of (±)-((αR*)-α-((2S*,5R*)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide as a beige solid. NMR (DMSO-d6, 200 MHz): δ 0.8 (t, J=8 Hz, 3H); 0.9 (d, J=6 Hz, 3H); 1.05 (d, J=6 Hz, 3H); 1.0 (br m, 6H); 1.3 (m, 2H); 1.9 (m, 1H); 2.1 (m, 2H); 2.4-2.7 (m, 4H); 2.8 (d, J=10 Hz, 1H); 3.1 (br m, 2H); 3.4 (m, 2H); 5.0 (s, 1H); 6.7 (m, 3H); 7.1 (m, 2H); 7.4 (m, 3H); 9.35(s, 1H). The product was dissolved in ethanol and titrated to pH 3 with ethanolic hydrogen chloride to give 0.073 g (45%) of the monohydrochloride as a white powder. Calc. for C27H39N3O2HCl 0.75 H2O: C, 66.51; H, 8.58; N, 8.62; Cl, 7.27. Found: C, 66.32; H, 8.49; N, 8.58; Cl, 7.32. Mass spectrum (CI--CH4) m/e: 438 (M+1, 76%).