Trifluoroacetic acid → 3-Chloro-5-[(3-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine

A stirred solution of 3-chloro-6-methylphenanthridine (0.40 g, 1.76 mmol) in tetrahydrofuran (7 mL) was treated with freshly crushed sodium borohydride (0.33 g, 8.8 mmol). Trifluoroacetic acid (0.54 mL, 7.0 mmol) was added dropwise at a rate to keep the exothermic reaction and gas evolution under control. After the addition was complete the heterogeneous reaction mixture was stirred until the temperature returned to 23° C. The mixture was then heated at reflux for 14 hours. The reaction was cooled to room temperature and neutralized with a saturated, aqueous sodium bicarbonate solution (150 mL). The mixture was filtered through a plug of glass wool into a separatory funnel and extracted with diethyl ether (4×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a light brown paste. The crude 3-chloro-6-methyl-5,6-dihydrophenanthridine was dissolved in pyridine (12 mL), treated with 3-methoxybenzenesulfonyl chloride (0.55 g, 2.64 mmol) and 4-(dimethylamino)pyridine (0.01 g, 0.08 mmol), and stirred at 80° C. for 14 hours. The reaction mixture cooled to room temperature, treated with a 0.1 N aqueous sodium hydroxide solution (100 mL, 10 mmol), and extracted with dichloromethane (6×50 mL). The combined organic phase was washed with a 2 N hydrochloric acid solution (2×40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a brown solid. The brown solid was purified by flash column chromatography, eluting with a mixture of ethyl acetate:hexane (1:4), followed by crystallization from ethyl acetate-hexane, to afford the title compound as a homogeneous, white, crystalline solid (0.38 g, 54%), m.p. 117-118° C.;

1. customthe exothermic reaction and gas evolution under control
2. additionAfter the addition
3. customreturned to 23° C
4. temperatureThe mixture was then heated
5. temperatureat reflux for 14 hours
6. filtrationThe mixture was filtered through a plug of glass wool into a separatory funnel
7. extractionextracted with diethyl ether (4×50 mL)
8. dry with materialThe combined organic phase was dried over anhydrous sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated in vacuo to a light brown paste
11. dissolutionThe crude 3-chloro-6-methyl-5,6-dihydrophenanthridine was dissolved in pyridine (12 mL)
12. stirringstirred at 80° C. for 14 hours
13. temperatureThe reaction mixture cooled to room temperature
14. extractionextracted with dichloromethane (6×50 mL)
15. washThe combined organic phase was washed with a 2 N hydrochloric acid solution (2×40 mL)
16. dry with materialdried over anhydrous sodium sulfate
17. filtrationfiltered
18. concentrationconcentrated in vacuo to a brown solid
19. customThe brown solid was purified by flash column chromatography
20. washeluting with a mixture of ethyl acetate:hexane (1:4)
21. customfollowed by crystallization from ethyl acetate-hexane

ORD record

ord-0c842c38794843e4b36bf33d38a3bf60

Source dataset

uspto-grants-2005_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06894061B2