Trifluoroacetic acid → [(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]sulfamoyl]benzoate

Temperatur

0 °C

Trifluoroacetic acid (5.0 mL) was added to a stirred solution of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2-tert-butoxy-2-oxo-1-phenyl-ethyl)sulfamoyl]benzoate (1.0 g, 1.39 mmol) in dichloromethane (5.0 mL) at 0° C., and stirring was maintained at 0° C. for 2.5 hours. The reaction mixture was then stirred at ambient temperature for 30 minutes, after which time toluene (50 mL) was added and the solvent removed under reduced pressure to yield a yellow solid, inferred as the intermediate 2-[[3-[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethoxy]carbonylphenyl]sulfonylamino]-2-phenyl-acetic acid. The crude was subsequently dissolved in THF (20 mL), and N,N′-dicyclohexylcarbodiimide (431 mg, 2.09 mmol), 1-hydroxybenzotriazole hydrate (282 mg, 2.09 mmol) and (R)-quinuclidin-3-ol (355 mg, 2.79 mmol) were sequentially added. The resulting reaction mixture was stirred at ambient temperature for 18 hours, after which time the reaction mixture was filtered through a pad of Celite®, washing with tetrahydrofuran (10 mL). The filtrate was concentrated under reduced pressure and the resulting crude was partitioned between ethyl acetate (20 mL) and water (10 mL), the organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The resulting crude was triturated in diethyl ether, and final purification was achieved by preparative HPLC and subsequent SFC to afford the title compound as a pale yellow solid (17.9 mg, de=100%).

1. stirringThe reaction mixture was then stirred at ambient temperature for 30 minutes
2. customthe solvent removed under reduced pressure
3. customto yield a yellow solid
4. customThe resulting reaction mixture
5. stirringwas stirred at ambient temperature for 18 hours
6. filtrationafter which time the reaction mixture was filtered through a pad of Celite®
7. washwashing with tetrahydrofuran (10 mL)
8. concentrationThe filtrate was concentrated under reduced pressure
9. customthe resulting crude was partitioned between ethyl acetate (20 mL) and water (10 mL)
10. dry with materialthe organic phases were dried over magnesium sulfate
11. concentrationconcentrated under reduced pressure
12. customThe resulting crude was triturated in diethyl ether
13. customfinal purification

ORD-Eintrag

ord-c0070199bb77434f97b632030e9f52cc

Quelldatensatz

uspto-grants-2015_07

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09090606B2