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. 2014 Feb 24;5(5):572–575. doi: 10.1021/ml500019s

Scheme 1. Synthesis of the 2-Substituted Piperidine Core and Key Analogues.

Scheme 1

Reagents and conditions: (a) methyl chloroformate, Et3N, CHCl3 0 °C to r.t., 57%; (b) 1. pyrrolidine, benzene reflux; 2. allyl bromide, MeCN, 70 °C, 67%; (c) 4-trifluoromethylphenol, NaOH, CHCl3, 0–40 °C; (d) TMS-CHN2, MeCN, MeOH, 0 °C to r.t., ∼40% overall yield from 5; (e) chiral HPLC (see Supporting Information for the condition), 27%; (f) iodotrimethylsilane, CH2Cl2, r.t., >95%; (g) 4-trifluoronicotinic acid, HATU, Et2NiPr, CH2Cl2, rt to 45 °C, >85%; (h) KOH, EtOH, H2O, 65 °C, 88%; (i) HATU, 1-[2-(2-methoxy–ethoxy)-phenyl]-piperazine, Et2NiPr, CH2Cl2, r.t. to 40 °C, 53%.