Novel synthesis method of Abemaciclib mesylate
A synthesis method and toluene technology, applied in the field of medicine and chemical industry, can solve the problems of multiple reaction yields, high environmental protection pressure, low yields, etc., and achieve the effects of avoiding precious metal catalysts, reducing route costs, and high product purity.
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Embodiment 1
[0046]
[0047] Add N-(4-bromo-2,6-difluorophenyl)acetamide compound 1 (25.00g, 100mmol), isopropylamine (6.50g, 110mmol), and acetonitrile (125mL) into the sealed reactor, stir well Add triethylamine (20.24g, 200mmol), raise the temperature to an internal temperature of 90-95°C and react for 8-10 hours, cool to room temperature after the reaction, add water, spin off acetonitrile and extract twice with dichloromethane (125mL). The combined organic phases were washed twice with saturated brine (125 mL), dried over sodium sulfate, filtered, and concentrated to obtain oil compound 2, which was directly used in the next reaction.
[0048] In Example 1, triethylamine can be used potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium bicarbonate, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undecane -7-ene (DBU) or triethylenediamine instead, the solvent acetonitrile can be replaced by dimethylformamide, dimethylacetamide, NMP or 1,4-dioxane.
Embodiment 2
[0050]
[0051] Compound 2 (100mmol, obtained from Example 1) and toluene (125mL) were added to the three-necked flask, p-toluenesulfonic acid (38.04g, 200mmol) was added, the temperature was raised to reflux and the water was separated for 16-24 hours, and after the reaction was completed, it was cooled to room temperature, and added Adjust the pH to 11-12 with 5% sodium hydroxide solution, separate the liquids, extract the aqueous phase once with ethyl acetate (125 mL), wash the combined organic phase with saturated brine twice (125 mL), dry over sodium sulfate, filter, and concentrate to remove Petroleum ether (125 mL) was added after part of the solvent, and the precipitated solid was slurried, filtered and dried to obtain compound 3 (21.42 g, two-step yield 79%).
[0052] In Example 2, p-toluenesulfonic acid can be replaced by hydrochloric acid, acetic acid, trifluoroacetic acid or fluoromethanesulfonic acid; the solvent toluene can be replaced by dichloromethane, 1,2-d...
Embodiment 3
[0054]
[0055] Add compound 3 (27.11g, 100mmol) and tetrahydrofuran (136mL) into the three-necked flask, stir and dissolve, cool to 0-5°C in an ice-salt bath, switch nitrogen in vacuum for 3 times, add dropwise 2.0M isopropylmagnesium chloride tetrahydrofuran solution (110mmol, 55.0 mL), keep the internal temperature at 0-5°C for 0.5-1 hour. 2,4-dichloro-5-fluoropyrimidine (18.37g, 110mmol) was dissolved in tetrahydrofuran (136mL) under nitrogen protection, and the catalyst iron triacetylacetonate (1.78g, 5mmol) was added, and the prepared Grignard The reagent solution is added dropwise into the reaction flask containing pyrimidine, and after the drop is completed, the temperature is raised to 55-60°C for 4-6 hours of reaction. Add saturated aqueous ammonium chloride solution to quench the reaction after the reaction is complete, the mixed solution is extracted 3 times with ethyl acetate (216mL), the combined organic phases are washed 2 times with water (216mL), dried over...
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