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 1 N HCl (10.0 vol), and washed with 0.1 N 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. 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 1 N HCl (10.0 vol)
10. washwashed with 0.1 N 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