Hydrochloric Acid → ethyl [5-(5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetate

Participants

Reaction Conditions

Reaction Steps

A solution of 1-[5-(2H-tetrazol-5-yl)-1,3,4-thiadiazol-2-yl]-4-[2-(trifluoromethyl)phenoxy]piperidine (262 mg, 0.66 mmol) in DMF (5 mL) was treated with NaH (60% in oil) (42 mg, 1.05 mmol) at −78° C. The mixture was warmed to 0° C. and, after 10 min, ethyl bromoacetate (150 μL, 1.35 mmol) was added dropwise. The final reaction mixture was warmed and stirred at room temperature until TLC indicated disappearance of the starting material. The reaction mixture was poured into aqueous 1 N HCl, extracted with EtOAc and washed with brine. The organic layer was dried (Na2SO4) and filtered. Solvents were removed in vacuo to afford the crude product, which was purified by column chromatography on silica gel (eluting with 10-50% EtOAc/hexanes) to afford ethyl [5-(5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetate as the more polar regioisomer, Rf=0.2 (50% EtOAc/hexanes). 1H NMR (400 MHz, acetone-d6): δ7.70-7.61 (m, 2H), 7.40 (d, 1H), 7.14 (t, 1H), 5.81 (s, 2H), 5.10-5.04 (m, 1H), 4.31 (q, 2H), 3.94-3.85 (m, 2H), 3.86-3.77 (m, 2H), 2.29-2.20 (m, 2H), 2.11-2.03 (dd, 2H), 1.31 (t, 3H).

Provenance & Evidence