反应详情

A mixture of 4,5-diphenylisoxazole-3-carboxylic acid (26.5 mg, 0.1 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int.1, (30.5 mg, 0.100 mmol), HOBT (16.85 mg, 0.110 mmol) and EDC (21.09 mg, 0.110 mmol) in DMF (1 mL) was stirred at rt for 18 hr. The reaction mixture was warmed to 60° C. for 2 hr and 70° C. for 2 hr. After cooling to rt overnight, the reaction mixture was partitioned between EtOAc (30 ml) and saturated sodium bicarbonate solution (30 ml). The organic layer was washed with water (2×30 ml) and brine (20 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to a yellow solid that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-60% EtOAc/Hex gradient. The pure fractions were concentrated to afford tert-butyl 1-(4-(5-(4,5-diphenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (37 mg, 0.069 mmol, 69.2% yield) as a white solid. HPLC retention time=1.90 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient.

1. temperatureThe reaction mixture was warmed to 60° C. for 2 hr and 70° C. for 2 hr
2. temperatureAfter cooling to rt overnight
3. customthe reaction mixture was partitioned between EtOAc (30 ml) and saturated sodium bicarbonate solution (30 ml)
4. washThe organic layer was washed with water (2×30 ml) and brine (20 ml)
5. customAfter drying
6. filtration(MgSO4) and filtration
7. concentrationthe organic layer was concentrated to a yellow solid
8. customthat was chromatographed on a 4 gm Isco silica gel cartridge
9. washeluting with a 0-60% EtOAc/Hex gradient
10. concentrationThe pure fractions were concentrated