反应详情

To a mixture of 4-(methoxycarbonyl)-3-(pyridin-2-yl)isoxazole-5-carboxylic acid (79 mg, 0.318 mmol), tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int. 1 (97 mg, 0.318 mmol), and BOP—Cl (97 mg, 0.382 mmol) in dimethylformamide (1.5 mL) at room temperature was added triethylamine (0.133 mL, 0.955 mmol). The reaction mixture was allowed to stir at room temperature overnight. Some uncyclized material remained, so stirring was continued for an additional 24 hrs. At this time, the reaction mixture was partitioned between ethyl acetate (30 mL) and a saturated aqueous solution of sodium bicarbonate (30 mL). The organic layer was washed with water (2×30 mL), washed with brine (30 mL), and dried over anhydrous magnesium sulfate. Concentration afforded a brown oil that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-70% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford methyl 5-(3-(4-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-(pyridin-2-yl)isoxazole-4-carboxylate (80 mg, 0.155 mmol, 48.6% yield) as a light purple solid. HPLC retention time=2.91 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=518.20.

1. stirringso stirring
2. waitwas continued for an additional 24 hrs
3. customAt this time, the reaction mixture was partitioned between ethyl acetate (30 mL)
4. washThe organic layer was washed with water (2×30 mL)
5. washwashed with brine (30 mL)
6. dry with materialdried over anhydrous magnesium sulfate
7. concentrationConcentration
8. customafforded a brown oil that
9. customwas chromatographed on a 4 gm Isco silica gel cartridge
10. washeluting with a 0-70% EtOAc/Hex gradient
11. additionThe essentially pure fractions containing product
12. concentrationwere concentrated