P-toluenesulfonate for mek kinase inhibitor, method of preparation thereof, and method of use thereof
a technology of mek kinase inhibitor and ptoluenesulfonate, which is applied in the field of ptoluenesulfonate of a mek kinase inhibitor and crystal form i, can solve the problems of affecting the chemical stability of the drug, affecting the health of chinese people, and a free base compound is usually pharmaceutically unacceptabl
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example 1
Preparation of 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide
[0038]
[0039]Step 1
[0040]1-(2-fluoro-4-iodophenyl)urea
[0041]2-fluoro-4-iodoaniline 1a (50.80 g, 214 mmol) was dissolved in 254 mL of trichloromethane, followed by addition of triethylamine (60 mL, 429 mmol). The reaction solution was cooled down to 0° C., and added with N,N-carbonyldiimidazole (69.50 g, 429 mmol). After stirring for 15 minutes, the reaction solution was warmed up to room temperature and stirred for 4 hours. The reaction solution was cooled down to 0° C., then added with 254 mL of ammonia water and filtered. The filter cake was washed with water (50 mL×2), trichloromethane (20 mL×2) and ethyl acetate (50 mL×2) successively, and dried to obtain the crude title compound 1-(2-fluoro-4-iodophenyl)urea 1b (53 g, white solid), which was used directly in the next step without further purification.
[0042]MS m / z (ESI): 281.0 [M+1]
[0043]Step 2
[0044]2-cyan...
example 2
[0083]2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (1 g, 2.02 mmol), p-toluenesulfonic acid (0.39 g, 2.27 mmol) and isopropanol (20.41 g) were added to a flask, and refluxed for 2-2.5 h. The heating was stopped, and the reaction mixture was stirred continuously for 12-14 h. The reaction was terminated and filtered, and the filter cake was washed with isopropanol (100 g), and dried at 40-45° C. under reduced pressure for 6-7 hours to obtain a solid (1.10 g) in a yield of 81.6%. The X-ray powder diffraction spectrum of the crystal sample is shown in FIG. 1, in which there are characteristic peaks at about 10.18 (8.68), 11.51 (7.68), 12.34 (7.17), 12.97 (6.82), 13.72 (6.45), 14.83 (5.97), 15.76 (5.62), 17.13 (5.17), 17.59 (5.04), 17.92 (4.95), 18.50 (4.79), 19.72 (4.50), 20.03 (4.43), 20.42 (4.35), 21.04 (4.22), 21.51 (4.13), 21.88 (4.06), 23.15 (3.84), 24.14 (3.68), 24.53 (3.63), 24.77 (3.59), 25.88 (3.44) and 26.37 (3...
example 3
[0084]The compound of formula (I) (1.0 g, 1.50 mmol) (prepared according to Example 2) was added to a 50 mL one-necked flask, and dissolved in 28 mL of methanol under heating. The mixture was cooled to room temperature to precipitate a crystal under stirring. The mixture was filtered and dried in a vacuum to obtain a solid (0.30 g, yield: 30.0%). The product was identified as crystal form I after studying and comparing the X-ray diffraction and DSC spectra.
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