反应详情

温度

75 °C

To a vial charged with Intermediate 1 (781 mg, 2.174 mmol) and Intermediate 7 (500 mg, 2.174 mmol) was added glyoxylic acid monohydrate (230 mg, 2.500 mmol) followed by acetonitrile (12 mL) and DMF (4 mL). The suspension was heated at 75° C. overnight. After it cooled to rt, 4-bromo-3-((methylamino)methyl)aniline HCl salt (751 mg, 2.61 mmol) was added, followed by additional DMF (8.000 mL) and DIEA (1.519 mL, 8.70 mmol). The reaction mixture was cooled to 0° C. HATU (909 mg, 2.391 mmol) was added. The reaction was stirred for 0.5 h then the cooling bath was removed and the reaction stirred for 2.5 h. The reaction was poured into 10% LiCl (100 mL) and extracted with EtOAc (3×100 mL). The combined organics were washed with 10% LiCl (100 mL), dried (Na2SO4), filtered and concentrated. The residue was chromatographed on Isco (120 g) eluting with 5 to 80% EtOAc/dichloromethane. Fractions containing desired material were rechromatographed using 0 to 10% MeOH/dichloromethane to give 4A (289 mg, 0.362 mmol, 16.64% yield) as a pale orange solid. MS and 1H NMR are consistent with the desired product.

1. temperatureAfter it cooled to rt
2. temperatureThe reaction mixture was cooled to 0° C
3. customthe cooling bath was removed
4. stirringthe reaction stirred for 2.5 h
5. additionThe reaction was poured into 10% LiCl (100 mL)
6. extractionextracted with EtOAc (3×100 mL)
7. washThe combined organics were washed with 10% LiCl (100 mL)
8. dry with materialdried (Na2SO4)
9. filtrationfiltered
10. concentrationconcentrated
11. customThe residue was chromatographed on Isco (120 g)
12. washeluting with 5 to 80% EtOAc/dichloromethane
13. additionFractions containing desired material
14. customwere rechromatographed