Tetrabutylammonium Hydroxide → 2-((3R)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid

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Reaction Conditions

Reaction Steps

(R)-tert-Butyl 2-(piperidin-3-yl)acetate (66 mg, 0.331 mmol) was treated with 4N HCl/dioxane for 30 minutes. The reaction mixture was concentrated in vacuo and dried. The solid material was dissolved in DMSO (2 mL) and tetrabutylammonium hydroxide (0.352 mL, 0.352 mmol) was added. After stirring 15 minutes, 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (40 mg, 0.088 mmol) was added. The reaction mixture was heated at 80° C. for 2 hours, and then filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 20 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 9 mg of 2-((3R)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-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 8.11 (2H, m), 7.68-7.75 (2H, m), 7.59 (2H, m, J=8.35 Hz), 7.43-7.55 (3H, m), 5.16 (1H, dd, J=9.01, 4.61 Hz), 3.71-3.89 (1H, m), 3.50-3.67 (2H, m), 3.24 (1H, d, J=2.42 Hz), 2.96 (2H, dd, J=8.90, 6.92 Hz), 2.83-2.93 (1H, m), 2.72 (1H, td, J=11.86, 5.27 Hz), 2.16-2.39 (3H, m), 1.77-2.00 (3H, m), 1.59-1.75 (2H, m, J=7.61, 7.61, 7.61, 7.61, 7.36 Hz), 1.13-1.32 (1H, m), 0.95 (3H, t, J=7.25 Hz). MS (m+1)=517. HPLC Peak RT=3.32 minutes (Analytical Method A). Purity=95%.

Provenance & Evidence