Tetrahydrofuran → 2-((3R)-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid

Participants

Reaction Steps

To a mixture of ethyl 2-((R)-1-((S)-2-hydroxy-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidin-3-yl)acetate (198 mg, 0.567 mmol) and DIEA (0.198 mL, 1.133 mmol) in acetonitrile (10 mL) was added 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride, Int-I-G (147 mg, 0.567 mmol). The reaction mixture was stirred at room temperature. After 1 hr, TBAF in THF (0.567 mL, 0.567 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated. The resulting solids were purified on a silica gel cartridge using an EtOAc/hexanes gradient. Isolated fractions with correct mass by LCMS were concentrated in vacuo. The product was then treated with 6N HCl/MeCN at 50° C. overnight. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 107 mg of 2-((3R)-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.13 (2H, d, J=8.35 Hz), 7.57-7.64 (4H, m), 7.44-7.55 (3H, m), 5.17 (1H, dd, J=9.23, 4.39 Hz), 3.81 (1H, d, J=11.86 Hz), 3.56 (1H, d, J=11.42 Hz), 3.24-3.31 (2H, m), 2.82-2.95(1H, m), 2.72 (1H, t, J=11.86 Hz), 2.16-2.40 (3H, m), 1.79-1.95 (3H, m), 1.10-1.34 (1H, m). MS (m+1)=543. HPLC Peak RT=3.26 minutes. Purity=98%.

Provenance & Evidence