反应详情

A mixture of 4-(methylcarbamoyl)-3-phenylisoxazole-5-carboxylic acid (32 mg, 0.130 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int.1, (39.7 mg, 0.130 mmol), HOBT (31.8 mg, 0.208 mmol), EDC (58.5 mg, 0.305 mmol) and diisopropylethylamine (0.091 mL, 0.520 mmol) in DMF (1 mL) was stirred at rt for 18 hr. After warming to 60° C. for 3 hr, 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 (30 mL). After drying (MgSO4) and filtration, the organic layer was concentrated to a yellow oil that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-90% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford tert-butyl 1-(4-(5-(4-(methylcarbamoyl)-3-phenylisoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (29 mg, 0.056 mmol, 43.3% yield) as a colorless glassy solid. HPLC retention time=1.50 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient. MS: (M+H)=516.27.

1. temperatureAfter warming to 60° C. for 3 hr
2. customthe reaction mixture was partitioned between EtOAc (30 mL) and saturated sodium bicarbonate solution (30 mL)
3. washThe organic layer was washed with water (2×30 mL) and brine (30 mL)
4. customAfter drying
5. filtration(MgSO4) and filtration
6. concentrationthe organic layer was concentrated to a yellow oil that
7. customwas chromatographed on a 4 gm Isco silica gel cartridge
8. washeluting with a 0-90% EtOAc/Hex gradient
9. additionThe essentially pure fractions containing product
10. concentrationwere concentrated