Phenol → HCID 9849074, compound

Participants

Reaction Conditions

Reaction Steps

Treat a stirred solution of the example 1 phenol (2.17 g, 0.010 mol) and N-methyl pyrrolidinone (30 mL) at 10° C. with solid potassium t-butoxide (1.12 g, 0.010 mol). Cool the reaction after 30 min. to 0–5° C. and treat with (2R)-(−)-glycidyl 3-nitrobenzenesulfonate (2.59 g, 0.010 mol, 99% ee, Aldrich Chemical Company). Monitor reaction progress by HPLC (Waters μ-Bondapak C-18 column, 0.1 N ammonium formate/acetonitrile (40:60); flow rate 1 mL/min., UV detection at 240 nm). After 2 hours, add 0.1 equivalent of both potassium t-butoxide and the glycidyl nitrobenzenesulfonate and stir for one hour. HPLC indicated >98% conversion to the intermediate epoxide. Add 1-(4-chlorophenyl)-piperazine (5.93 g, 0.030 mol) and water (3 mL) and heat to 70° C. HPLC analysis indicates >98% conversion of the epoxide to product after 5 hours. Cool to 23° C., pour into water (250 mL) and extract with ethyl acetate (150 mL, then 2×100 mL). Wash the combined extracts with 5% NaCl solution, concentrate in vacuo and purify the crude material by chromatography (silica gel, elute with ethyl acetate). Recrystallize the purified material from ethyl acetate:heptane (50:50) to give the free base of the title compound. Treat a slurry of the free base in methanol (25 mL) at 23° C. with 37% HCl (0.67 mL, 1.05 equiv.) to give the title compound (3.62 g, 76% yield) after drying (90° C., 6 hours), m.p. 163–165° C., chiral HPLC purity >98% ee; MS (Cl, methane) m/e 470 (MH+)

Provenance & Evidence