1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 1-(2-Bromo-4-(5-(4-ethyl-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid

Participants

Reaction Conditions

Reaction Steps

A solution of 4-ethyl-5-phenylisoxazole-3-carboxylic acid, Int.5-D (7.83 mg, 0.036 mmol), EDCI (6.91 mg, 0.036 mmol), and HOBt (5.52 mg, 0.036 mmol) in DMF (2 mL) was stirred at RT for 5 minutes before being transferred to a flask containing (Z)-tert-butyl 1-(2-bromo-4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int.5-B (12.60 mg, 0.033 mmol). The reaction was placed in an oil bath and heated overnight at 55° C. then the temperature was raised to 90° C. for 3 hours. The solution was cooled and the volatiles were removed under vacuum. The resulting residue was treated with TFA (2 mL) at RT for 3 hours. The TFA was evaporated and the residue was treated with triethylamine (3-4 mL) before again being evaporated to dryness. The residue was loaded onto a 4 g silica gel Isco cartridge (which had been pre-equilibrated with DCM) and purified by flash chromatography. Eluent: 0-20% MeOH in DCM (plus 5% NH4OH). The product containing fractions were evaporated and placed under high vacuum to afford 1-(2-bromo-4-(5-(4-ethyl-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid as a pale yellow solid (13.1 mg, 0.024 mmol). The compound had an HPLC retention time=3.97 min.−Column: PHENOMENEX® Luna 3 u C18 4.6×30 mm (5 min. gradient; 4 mL/min); Solvent A=10% MeOH, 90% H2O, 0.05% TFA; Solvent B=90% MeOH, 10% H2O, 0.05% TFA. LC/MS M+1=509/511. 1H NMR (500 MHz, MeOD) δ ppm 1.39 (t, J=7.5 Hz, 3H), 3.11 (q, J=7.5 Hz, 2H), 3.36-3.44 (m, 1H), 3.92 (dd, J=8.5 Hz, 8.5 Hz 2H), 4.01 (dd, J=8.8 Hz, 9.0 Hz 2H), 4.26 (s, 2H), 7.56-7.72 (m, 4H), 7.81-7.83 (m, 2H), 8.22 (dd, J=6.3, 1.8 Hz, 1H), 8.42 (d, 1.8 Hz).

Provenance & Evidence