反应详情

4-Oxo-1,4-dihydroquinoline-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di-tert-butylphenyl methyl carbonate, 32, (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P®50% solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5+/−5.0° C. and held at this temperature for 8 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 25.0° C.+/−2.5° C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume of reaction to 40.0 vol (˜16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv) to perform the methanolysis. The reaction was stirred for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1N HCl (10.0 vol), and washed with 0.1N HCl (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 35° C. (jacket temperature) and no less than 8.0° C. (internal reaction temperature) under reduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at no more than 35° C. (jacket temperature) and no less than 8.0° C. (internal reaction temperature) to 20 vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH3CN was added followed by 4.0 vol of H2O to make a final concentration of 40 vol of 10% H2O/CH3CN relative to the starting acid. This slurry was heated to 78.0° C.+/−5.0° C. (reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.0° C.+/−5° C. over 5 hours, and filtered. The cake was washed with 0.0° C.+/−5.0° C. CH3CN (5 vol) 4 times. The resulting solid (compound 34) was dried in a vacuum oven at 50.0° C.+/−5.0° C. 1H NMR (400 MHz, DMSO-d6) δ 12.8 (s, 1H), 11.8 (s, 1H), 9.2 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.2 (s, 1H), 7.9 (t, 1H), 7.8 (d, 1H), 7.5 (t, 1H), 7.1 (s, 1H), 1.4 (s, 9H), 1.4 (s, 9H).

1. washThe T3P charged vessel was washed with 2-MeTHF (0.6 vol)
2. temperaturethe resulting suspension was heated to 47.5+/−5.0° C.
3. temperatureOnce complete, the resulting mixture was cooled to 25.0° C.+/−2.5° C
4. additionto dilute the mixture
5. washThe reaction mixture was washed with water (10.0 vol) 2 times
6. addition2-MeTHF was added
7. customthe total volume of reaction
8. additionto 40.0 vol (˜16.5 vol charged)
9. customOnce complete, the reaction was quenched with 1N HCl (10.0 vol)
10. washwashed with 0.1N HCl (10.0 vol)
11. filtrationfiltered
12. customto remove any particulates
13. customplaced in a second reactor
14. concentrationThe filtered solution was concentrated at no more than 35° C. (jacket temperature) and no less than 8.0° C. (internal reaction temperature) under reduced pressure to 20 vol. CH3CN
15. additionwas added to 40 vol
16. concentrationthe solution concentrated at no more than 35° C. (jacket temperature) and no less than 8.0° C. (internal reaction temperature) to 20
17. additionThe addition of CH3CN and concentration cycle
18. concentrationfor a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final
19. concentrationconcentration to 20 vol, 16.0 vol of CH3CN
20. additionwas added
21. temperatureThis slurry was heated to 78.0° C.+/−5.0° C.
22. temperature(reflux)
23. stirringThe slurry was then stirred for no less than 5 hours
24. temperatureThe slurry was cooled to 0.0° C.+/−5° C. over 5 hours
25. filtrationfiltered
26. washThe cake was washed with 0.0° C.+/−5.0° C
27. dry with materialThe resulting solid (compound 34) was dried in a vacuum oven at 50.0° C.+/−5.0° C