Tetrabutylammonium Hydroxide → ((3S)-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

To (S)-tert-butyl 2-(piperidin-3-yl)acetate, HCl (31.1 mg, 0.132 mmol) was added 4M HCl/dioxane (3 mL) and the reaction mixture was stirred for 30 minutes. Next, the reaction mixture was concentrated in vacuo and dried. This crude material was dissolved in DMSO (2 mL) and tetrabutylammonium hydroxide (0.198 mL, 0.198 mmol) was added. The reaction mixture was stirred for 30 minutes, followed by the addition of 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol). 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 5 mg of ((3S)-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 8.12 (2H, m, J=8.35 Hz), 7.69-7.75 (2H, m), 7.60 (2H, m, J=8.13 Hz), 7.43-7.55 (3H, m), 5.16 (1H, dd, J=9.34, 4.50 Hz), 3.71-3.89 (1H, m), 3.52-3.68 (3H, m), 3.23-3.28 (1H, m), 2.96 (2H, dd, J=8.90, 6.92 Hz), 2.84-2.92 (1H, m), 2.17-2.38 (3H, m), 1.76-1.93 (3H, m), 1.62-1.73 (2H, m), 1.21 (1H, dd, J=12.30, 4.17 Hz), 0.95 (3H, t, J=7.25 Hz). MS (m+1)=517. HPLC Peak RT=3.37 minutes. (Analytical Method A). Purity=94%.

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