Citric Acid → (S)-3-(Isoxazol-3-yl)-3-(4-((4-methyl-2-(4-chlorophenyl)thiazol-5-yl)methoxy)phenyl)propanoic acid

Beteiligte Stoffe

Reaktionsschritte

Cesium carbonate (170 mg, 0.52 mmol) was added to a mixture of 7.5 (140 mg, 0.36 mmol) and 5-(chloromethyl)-4-methyl-2-(4-chlorophenyl)thiazole (110 mg, 0.43 mmol, commercially available from Bionet Research Intermediates, UK) in DMSO (3 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was treated with EtOAc (25 mL) and water (15 mL). The organic layer was separated, washed twice with brine, dried, and concentrated. The crude product (210 mg, 0.32 mmol) was treated with THF (3 mL) and hydrogen peroxide (35 wt %, 1.0 mL) and cooled to 0° C. Aqueous LiOH (2.0 M, 1.0 mL, 2.0 mmol) was added. The resulting mixture was stirred at 0° C. for 10 minutes and then at room temperature for 2 Hours. The crude mixture LCMS analysis showed reaction to complete. The mixture was diluted with EtOAc (50 mL) and 5 mL of aqueous citric acid (0.5 M, 2.5 mmol) was added. The mixture was washed with water. The organic layer was separated, and concentrated under reduced pressure. The residue was purified by reverse phase prep HPLC (5-95% water-MeCN, gradient, with 0.1% TFA). The desired fraction was collected and treated by lyophilizing to give 57 (21 mg) as a white powder. MS API-ES m/e: 453 (M−H). 1H NMR (500 MHz) (CDCl3) δ 8.33 (1H, s); 7.93 (2H, d, J=10Hz); 7.49 (2H, d, J=5Hz); 7.25 (2H, d, J=5 Hz); 6.95 (2H, d, J=10Hz); 6.11 (1H, s); 5.19 (2H, s); 4.60 (1H, m); 3.38 (1H, m), 3.03 (1H, m), 2.57 (3H, s).

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