反应详情

A solution of 4-chloro-5-ethynyl-3′-fluoro-N-methoxy-N-methyl-6-[(E)-pyrrolidin-1-yldiazenyl]biphenyl-2-carboxamide (930 g, 2.2 mol) in tetrahydrofuran (4.3 L) at 0° C. under nitrogen was treated with 3.0 M methylmagnesium chloride in tetrahydrofuran (2.2 L, 6.7 mol) dropwise over 45 minutes. Gas formation was observed and the internal temperature ranged from 1-8° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 70 minutes. The reaction mixture was cooled to 0-5° C. and treated with 2.0 M hydrogen chloride in water (4.1 L, 8.3 mol) dropwise with gas formation observed. The solution was diluted with ethyl acetate (2 L) and stirred for 10 min. The aqueous layer was separated and extracted with ethyl acetate (1 L). The combined organic layers were washed with brine (0.7 L, 4 mol), dried over sodium sulfate, filtered, and concentrated to an oil. This material was azeotroped with toluene (1 L) to give the desired product. A small sample was purified by silica gel column for spectroscopic analysis. LCMS for C20H18ClFN3O (M+H)+: m/z=370.1; Found: 370.0; 1H NMR (400 MHz, DMSO-d6): δ 7.54 (s, 1H), 7.37-7.31 (m, 1H),7.14-7.09 (m, 1H), 6.94-6.86 (m, 2H), 4.54 (s, 1H), 3.68-3.59 (m, 2H), 3.22-3.13 (m, 2H), 2.11 (s, 3H), 1.89-1.78 (m, 4H).

1. customranged from 1-8° C
2. customThe ice bath was removed
3. temperatureThe reaction mixture was cooled to 0-5° C.
4. stirringstirred for 10 min
5. customThe aqueous layer was separated
6. extractionextracted with ethyl acetate (1 L)
7. dry with materialdried over sodium sulfate
8. filtrationfiltered
9. concentrationconcentrated to an oil
10. customThis material was azeotroped with toluene (1 L)