A kind of preparation composition of fgfr4 inhibitor, preparation method and use thereof
A technology of FGFR4 and composition, which can be used in drug combinations, pharmaceutical formulations, and medical preparations containing active ingredients, etc., can solve problems such as side effects, reduce adverse reaction rates, and cannot distinguish tumor cells, and reduce the targeting effect of drugs. , reduce the adverse reaction rate and improve the effect of treatment
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[0051] Further, the preparation method of the active ingredient comprises the following steps:
[0052]
[0053] (1) Synthesis of Intermediate IV:
[0054] At a first preset temperature, compound II having a structure of formula II, compound III having a structure of formula III and a first base are dissolved in a first reaction solvent for reaction to obtain an intermediate IV having a structure of formula IV;
[0055] (2) Synthesis of compound I:
[0056] At a second preset temperature, the intermediate IV, the compound V having the structure of formula V, the catalyst, the ligand and the second base are dissolved in a second reaction solvent for reaction to obtain the compound I having the structure of formula I.
[0057] Further, in step (1), the first base is selected from triethylamine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium hydroxide, lithium hydroxide, sodium hydride, tertiary At least one of sodium butoxide, potassium tert-butoxide...
Embodiment 1
[0077] The preparation composition of the FGFR4 inhibitor includes the following ingredients in mass percentage:
[0078] name Weight ratio (%) effect FGFR4 inhibitors 2.5％ active ingredient microcrystalline cellulose 83％ filler Crospovidone 12％ disintegrant Hydroxypropyl Cellulose 1.5％ Adhesive Magnesium stearate 1％ lubricant
[0079] The active ingredient is 1-(4-(3-(2,6-dichlorophenyl)-1-methylureido)pyridin-2-yl)indoline-6-carboxamide, which is compound 4 .
[0080] Described preparation process comprises the steps:
[0081] Step S1, synthesis of compound 1c:
[0082]
[0083] Compound 1a (37.4g, 200.0mmol), 1b (37.2g, 200.0mmol), and potassium carbonate (41.4g, 300.0mmol) were dissolved in acetonitrile (500mL), reacted at room temperature for 10 hours, TLC monitored the reaction, and filtered after the reaction was completed , the filtrate was concentrated and separated by column chromatography to obtain 58.3 ...
Embodiment 2
[0094] The preparation composition of the FGFR4 inhibitor includes the following ingredients in mass percentage:
[0095] name Weight ratio (%) effect FGFR4 inhibitors 11％ active ingredient starch 78％ filler Croscarmellose Sodium 8％ disintegrant Povidone 2％ Adhesive Magnesium stearate 1％ lubricant
[0096] The active ingredient is 1-(2-(6-cyanoindoline-1-yl)pyridin-4-yl)-3-(2,6-dichlorophenyl)-1-methylurea, namely is compound 5.
[0097] Described preparation process comprises the steps:
[0098] Step S1, synthesis of compound 1c:
[0099]
[0100]Compound 1a (37.4g, 200.0mmol), 1b (37.2g, 200.0mmol), and potassium carbonate (41.4g, 300.0mmol) were dissolved in acetonitrile (500mL), reacted at room temperature for 10 hours, TLC monitored the reaction, and filtered after the reaction was completed , the filtrate was concentrated and separated by column chromatography to obtain 58.3 g of off-white (compound 1c), with...
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