Hydrochloric Acid → HCID 18516448, compound

Temperature

-78 °C

2-Mercapto-1-methylimidazole (400 mg, 3.50 mmol) was dissolved in anhydrous THF (7.0 mL) under a stream of dry N2. The solution was then cooled to -78° C. and a solution of 2.8 mL of a 2.5M solution of n-butyllithium in hexanes was then added. After the addition was complete, the reaction mixture was warmed to ambient temperature and stirred at this temperature for 1 hour. The reaction mixture was then cooled to -78° C. and a solution of (4-chloro-benzoyl)-1-methyl-4-[3-(4-trityloxy-but-1-ynyl)-phenyl]-1H-quinolin-2-one in THF (7.0 mL) was added to the mixture. The reaction was warmed to ambient temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous NH4Cl (25 mL) and partitioned between DCM and water. The DCM layer was dried over Na2SO4, filtered and concentrated under vacuum to give a green solid. The green solid was dissolved in 30 mL of acetic acid (ACOH) and the solution was cooled to about 5° C. To this solution was added 2.0 mL of 30% aqueous hydrogen peroxide (H2O2) dropwise. After the addition was complete, the reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was then cooled to 0° C., 200 mL of water was added and the reaction was basified to pH32 10 with the slow addition of NaOH. Sodium sulfite was added portionwise until testing with starch-iodine paper showed no H2O2 left. The reaction mixture was partitioned between 0CM and water. The DCM layer was dried over Na2SO4, filtered and concentrated under vacuum to give a green solid. The green solid was dissolved in a solution of MeOH/DCM (25;3) to which was added 3N aqueous HCl (3.0 mL). The solution was then heated to 68° C. and reacted at this temperature for 2 hours. The solution was concentrated under vacuum to a thick sludge and then was partitioned between DCM and 0.01N aqueous NaOH. The DCM layer was concentrated under vacuum and chromatographed on flash silica gel eluting with a gradient of MeOH/EtOAc/NH4OH (5:95:.01) to MeOH/EtOAc/NH4OH (10:90:.01) to give the titled compound.

1. additionAfter the addition
2. temperaturethe reaction mixture was warmed to ambient temperature
3. temperatureThe reaction mixture was then cooled to -78° C.
4. temperatureThe reaction was warmed to ambient temperature
5. stirringstirred overnight
6. customThe reaction mixture was quenched with saturated aqueous NH4Cl (25 mL)
7. custompartitioned between DCM and water
8. dry with materialThe DCM layer was dried over Na2SO4
9. filtrationfiltered
10. concentrationconcentrated under vacuum
11. customto give a green solid
12. temperaturethe solution was cooled to about 5° C
13. additionAfter the addition
14. stirringthe reaction mixture was stirred at ambient temperature for 30 minutes
15. temperatureThe reaction mixture was then cooled to 0° C.
16. waitleft
17. customThe reaction mixture was partitioned between 0CM and water
18. dry with materialThe DCM layer was dried over Na2SO4
19. filtrationfiltered
20. concentrationconcentrated under vacuum
21. customto give a green solid
22. temperatureThe solution was then heated to 68° C.
23. customreacted at this temperature for 2 hours
24. concentrationThe solution was concentrated under vacuum to a thick sludge
25. customwas partitioned between DCM and 0.01N aqueous NaOH
26. concentrationThe DCM layer was concentrated under vacuum
27. customchromatographed on flash silica gel eluting with a gradient of MeOH/EtOAc/NH4OH (5:95:.01) to MeOH/EtOAc/NH4OH (10:90:.01)

ORD record

ord-4c74e6dae1cf49bb9fc414c7c449c779

Source dataset

uspto-grants-2000_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06150377