Trifluoroacetic acid → 6-fluoro-5-morpholin-4-yl-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one

To a flask charged with 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (from Example 4 above) (220 mg, 0.39 mmol) was added morpholine (Aldrich, 2 mL, 23 mmol) and the red solution was stirred under argon at room temperature for 10 minutes. The reaction was then quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were successively washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue obtained was re-dissolved in CH2Cl2 (2 mL) and treated with trifluoroacetic acid at 0° C. for 1 hour. The reaction was then quenched with a saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were successively washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The dark-brown material was then suspended in 0.5 N NaOH (8 mL) and heated to 90° C. for 6 hours. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC (silica gel, 50% ethyl acetate in hexanes) to afford 6-fluoro-5-morpholin-4-yl-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 15.1 mg, 11.6%).

1. customThe reaction was then quenched
2. additionby pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (50 mL)
3. extractionextracted with ethyl acetate (3×50 mL)
4. washThe combined organic extracts were successively washed with water (50 mL) and brine (50 mL)
5. dry with materialdried over anhydrous sodium sulfate
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customThe residue obtained
9. customThe reaction was then quenched with a saturated aqueous sodium bicarbonate solution (5 mL)
10. extractionextracted with ethyl acetate (3×10 mL)
11. washThe combined organic extracts were successively washed with water (5 mL) and brine (5 mL)
12. dry with materialdried over anhydrous sodium sulfate
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. temperatureheated to 90° C. for 6 hours
16. customThe reaction was quenched
17. additionby pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (10 mL)
18. extractionextracted with ethyl acetate (3×20 mL)
19. washThe combined organic extracts were successively washed with water (10 mL) and brine (10 mL)
20. dry with materialdried over anhydrous sodium sulfate
21. filtrationfiltered
22. concentrationconcentrated in vacuo
23. customThe crude product was purified by preparative TLC (silica gel, 50% ethyl acetate in hexanes)

ORD record

ord-1adf61f2ecc14d1f800c7f8c46030bf8

Source dataset

uspto-grants-2003_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06504034B2