Methyl iodide → 7-[methyl(pyridin-3-ylsulfonyl)amino]-1H-indole-2-carboxylic acid

Temperature

50 °C

A mixture of pyridine-3-sulfonyl chloride (10.0 g), ethyl 7-amino-1-(methoxymethyl)-1H-indole-2-carboxylate (10.0 g) and pyridine (30 mL) was stirred at 50° C. for 2 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (500 mL) and 1N hydrochloric acid (500 mL). The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over sodium sulfate, and filtrated, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-hexane=3:7, volume ratio) to give a pale-yellow solid. The obtained solid was dissolved in N,N-dimethylformamide (100 mL), and potassium carbonate (11.6 g) and methyl iodide (8.0 g) were added. The reaction mixture was stirred at room temperature for 1 hr, and diluted with ethyl acetate (500 mL) and saturated brine (500 mL). The organic layer was washed with saturated brine, dried over sodium sulfate, and filtrated, and the filtrate was concentrated. The obtained residue was dissolved in a mixture of 6N hydrochloric acid (80 mL), tetrahydrofuran (100 mL) and ethanol (100 mL), and the mixture was stirred at 100° C. for 3 hr, and diluted with ethyl acetate (500 mL) and saturated brine (500 mL). The organic layer was dried over sodium sulfate, and filtrated, and the filtrate was concentrated. The residue was dissolved in a mixture of 2N aqueous sodium hydroxide solution (100 mL), tetrahydrofuran (100 mL) and ethanol (100 mL), and the mixture was stirred at 80° C. for 1 hr, and diluted with ethyl acetate (500 mL) and 1N hydrochloric acid (500 mL). The organic layer was washed with saturated brine, dried over sodium sulfate, and filtrated, and the filtrate was concentrated. The obtained crude solid was washed with ethyl acetate and hexane to give the title compound (4.92 g, yield 37%) as a pale-yellow solid. LC-MS: 332 (MH+).

1. concentrationThe reaction mixture was concentrated
2. additionthe residue was diluted with ethyl acetate (500 mL) and 1N hydrochloric acid (500 mL)
3. washThe organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine
4. dry with materialdried over sodium sulfate
5. filtrationfiltrated
6. concentrationthe filtrate was concentrated
7. customThe residue was purified by silica gel column chromatography (ethyl acetate-hexane=3:7, volume ratio)
8. customto give a pale-yellow solid
9. stirringThe reaction mixture was stirred at room temperature for 1 hr
10. washThe organic layer was washed with saturated brine
11. dry with materialdried over sodium sulfate
12. filtrationfiltrated
13. concentrationthe filtrate was concentrated
14. dissolutionThe obtained residue was dissolved in a mixture of 6N hydrochloric acid (80 mL), tetrahydrofuran (100 mL) and ethanol (100 mL)
15. stirringthe mixture was stirred at 100° C. for 3 hr
16. additiondiluted with ethyl acetate (500 mL) and saturated brine (500 mL)
17. dry with materialThe organic layer was dried over sodium sulfate
18. filtrationfiltrated
19. concentrationthe filtrate was concentrated
20. dissolutionThe residue was dissolved in a mixture of 2N aqueous sodium hydroxide solution (100 mL), tetrahydrofuran (100 mL) and ethanol (100 mL)
21. stirringthe mixture was stirred at 80° C. for 1 hr
22. additiondiluted with ethyl acetate (500 mL) and 1N hydrochloric acid (500 mL)
23. washThe organic layer was washed with saturated brine
24. dry with materialdried over sodium sulfate
25. filtrationfiltrated
26. concentrationthe filtrate was concentrated
27. customThe obtained crude solid
28. washwas washed with ethyl acetate and hexane

ORD record

ord-b39502d2a8424adcb992bd68f78c4804

Source dataset

uspto-grants-2010_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07777047B2