反应详情

温度

160 °C

A mixture of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxylphenyl)ethyl]3-bromo-5-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate formate salt (98 mg, 0.20 mmol), methylboroxine (0.03 mL, 0.20 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) in 10% dioxane in water (2.5 mL) was heated to 160° C. under microwave irradiation for 5 minutes. After cooling to room temperature, the reaction mixture was neutralized with 0.30 mL of 2 N HCl and filtered through celite, washed with EtOAc (50 mL) The solvent was removed in vacuo and the residue was azeotroped with toluene to yield a white foam that was redissolved in DMF (2 mL). (S)-3,5-dichloro-4-(2-(3,4-dimethoxylphenyl)-2-hydroxyethyl)pyridine 1-oxide (76 mg, 0.22 mmol) followed by 4-(dimethylamino)-pyridine (12 mg, 0.10 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (77 mg, 0.40 mmol) were then added, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was purified by preparative HPLC to provide [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxylphenyl)ethyl]3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-5-methyl-benzoate (19 mg) as white solid.

1. temperatureAfter cooling to room temperature
2. filtrationfiltered through celite
3. washwashed with EtOAc (50 mL) The solvent
4. customwas removed in vacuo
5. customthe residue was azeotroped with toluene
6. customto yield a white foam that
7. additionwere then added
8. customThe reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution
9. washThe organic layer was washed with brine
10. dry with materialdried over Na2SO4
11. filtrationfiltered
12. customthe solvent was removed in vacuo
13. customThe residue was purified by preparative HPLC