Oxalyl chloride → 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid

Participants

Reaction Conditions

Reaction Steps

To a solution of commercially available 4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylic acid (44.0 mg, 0.162 mmol) in DCM (4 mL) was added oxalyl chloride (45 μL, 0.514 mmol) followed by a drop of DMF. The solution bubbled. After 1 h, diisopropylethylamine (45 μL, 0.258 mmol) was added followed by ethyl 2-((R)-1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidin-3-yl)acetate (50.0 mg, 0.108 mmol) in THF (2 mL). The reaction mixture was stirred overnight and the next day LCMS showed the product had formed so the reaction was treated with TBAF (216 μL, 0.216 mmol) and then heated to 60° C. overnight. The next day, the reaction was extracted from 1 M HCl using EtOAc×3 and the organics layers were combined and concentrated in vacuo. This residue was taken up in a 1:1 mixture of THF and 6 M HCl and heated for 2 h. LCMS after this time showed the desired product so the reaction was concentrated and then purified by HPLC to give 2-((R)-1-((S)-2-hydroxy-2-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid (42 mg, 98% yield). MS (M+1)=558.3; HPLC RT=2.11 minutes. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.27 (1H, br. s.), 9.72 (1H, br. s.), 8.14-8.26 (1H, m), 8.05 (2H, m, J=8.36 Hz), 7.61 (2H, m, J=8.14 Hz), 7.41-7.53 (5H, m), 6.35 (1H, br. s.), 5.18 (1H, br. s.), 3.42-3.71 (2H, m), 3.10-3.21 (1H, m), 2.63-2.94 (2H, m), 2.08-2.31 (3H, m), 1.66-1.91 (3H, m), 0.99-1.24 (1H, m).

Provenance & Evidence