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With hydrogenchloride; In methanol; at 20℃;pH 2; |
Step 5 4-(Diethylamino)but-2-ynyl 2-cyclohexyl-2-hydroxy-2-phenylacetate hydrochloride: 1-Hydroxybenzotriazole hydrate (HOBT) (0.130 g, 0.85 mmol) and N-methylmorpholine (0.259 g, 2.56 mmol) were added sequentially to a mixture of 2-cyclohexyl-2-hydroxy-2-phenylacetic acid (0.20 g, 0.85 mmol), 4-(diethylamino)but-2-yn-1-ol (0.120 g, 0.85 mmol) and dichloromethane (5 mL) at 0 C. After 1 h, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl) (0.294 g, 1.53 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. Standard extractive work up provided a crude residue which was purified by silica gel column chromatography (30% ethyl acetate in petroleum ether) to give 4-(diethylamino)but-2-ynyl 2-cyclohexyl-2-hydroxy-2-phenylacetate as a pale yellow oil which was immediately converted to its hydrochloride salt. 4-(Diethylamino)but-2-ynyl 2-cyclohexyl-2-hydroxy-2-phenylacetate obtained above was dissolved in methanol (10 mL), and methanol saturated with HCl gas was added until pH 2. The mixture was stirred at room temperature for 0.5 h and concentrated under reduced pressure. The obtained residue was sequentially triturated with hexane, diethyl ether and ethyl acetate and the obtained solid was filtered and dried to give the title compound as a white solid (0.090 g, 27%). m.p. 122-126 C. 1H NMR (400 MHz, DMSO-d6) delta 1.02-1.78 (m, 16H), 2.16-2.22 (m, 1H), 2.96-3.07 (m, 4H), 4.11 (br s, 2H), 4.87 (br s, 2H), 5.73 (s, exchangeable with D20, 1H), 7.26-7.36 (m, 3H), 7.54-7.56 (m, 2H), 10.70 (br, exchangeable with D20, 1H); IR (KBr) upsilon 3511, 3444, 3323, 3098, 3040, 2930, 2857, 2774, 2617, 2564, 2476, 1742, 1624, 1534, 1457, 1393, 1347, 1249, 1209 cm-1; MS 358 (M+1). |