Intermediates for the preparation of ticagrelor and preparation methods thereof
A technology for controlling temperature and white solids, applied in the field of medicine, can solve the problems of high cost, difficult to control cost, risk of sodium hydride explosion, etc., and achieve the effects of mild reaction conditions, reduction of synthetic routes, and short and novel routes.
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[0034] The preparation method of some intermediates according to claim 1 of the present invention is characterized in that it comprises: subjecting 3,4-difluorostyrene to an addition and cyclization reaction to obtain compound (II); compound (II ) synthetic reaction scheme is as follows:
[0035]
[0036] Among them, compound (I) can be prepared from cheap and easy-to-obtain o-difluorobenzene through Friedel-Crafts, reduction, and dehydration at high yields, and can also be purchased directly.
[0037] According to some embodiments, the cycloaddition reaction of 3,4-difluorostyrene to obtain compound (II) specifically includes: after reacting dimethylacetamide (DMA) and trifluoromethanesulfonic anhydride in the first solvent , and then carry out cycloaddition reaction with 3,4-difluorostyrene and organic base. Dimethylacetamide is first sulfonated under the action of trifluoromethanesulfonic anhydride, and then undergoes cycloaddition with 3,4-difluorostyrene, that is, com...
Embodiment 1
[0073]Dissolve 1.05g of DMA in 14mL of chloroform, lower the temperature to 5°C, add dropwise 3.95g of trifluoromethanesulfonic anhydride, and control the temperature at 5°C, a large amount of white solids precipitate out. solution. 1.4 g of compound (I) and 1.69 g of 2,4,6-collidine were dissolved in 2 mL of chloroform. This solution was added dropwise to the first solution, refluxed for 18h, then 5mL of water was added, and refluxed for 18h. The solution after the reaction was lowered to room temperature, separated into layers, the aqueous layer was extracted with 5 mL of chloroform, the organic layers were combined, the combined organic layers were dried with anhydrous sodium sulfate, and column chromatography was carried out to obtain 1.45 g of a light yellow liquid that is the compound (II), yield 80%.
Embodiment 2
[0075] 2g of compound (II) was dissolved in 20mL of tetrahydrofuran, cooled to -78°C, 12mL of LiHMDS (1M inTHF) was added dropwise, and the temperature was controlled at -60°C. After dropping, keep warm at -60°C for 20 minutes. Then add NBS, raise the temperature to 0°C and keep it warm for 20min. Dissolve 1.1 g of sodium hydroxide in 10 mL of water, add it to the solution after adding NBS and stir overnight at room temperature. Then, the mixed product after stirring and reacting was separated into layers, and the pH of the aqueous layer was adjusted to 4 with 1M dilute hydrochloric acid. The aqueous layer was extracted with 10 mL*2 ethyl acetate, the organic layers were combined, and the organic layer was dried with anhydrous sodium sulfate. Finally, 1.65 g of off-white solid, namely compound (III), was obtained by column chromatography with a yield of 76%.
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