A kind of preparation method of ticagrelor intermediate oxide impurity
A technology of oxide impurity, ticagrelor, applied in directions such as organic chemistry, can solve problems such as difficulty in obtaining a large amount of high-purity compound VII, lack of reference substance, and difficulty in separation, achieving improved yield, simple steps, cost saving effect
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Embodiment 1
[0068] The preparation of embodiment 1 ticagrelor intermediate oxide impurity
[0069] The following method is used to prepare and separate the oxide impurities of the ticagrelor intermediate:
[0070] S1. Dissolve 10.00g of compound I, 10.13g of compound II, and 23.29g of triethylamine in 100mL of ethanol, stir for 10min, reflux at 60°C for 8h, add 500mL of ice-cold brine to cool, let stand to precipitate, filter, and vacuum the filtrate at 30°C Dry to obtain 10.84g of compound III, yield 74.20%, purity 97.46%, ESI (m / z) [M+H] + :318.27;
[0071] S2. Add 10.84g of compound III obtained in step S1 and 15.71g of phosphorus oxychloride to the reaction flask, and slowly add 8.83g of N,N-diisopropylethylamine dropwise at 0°C in an ice bath, and keep The temperature of the reaction system does not exceed 25°C. After the drop is completed, the temperature is raised to 110°C for 4.5 hours. After the reaction is completed, cool to room temperature, slowly add 150mL of water, extract...
experiment example 1
[0074] The influence of experimental example 1 different basic catalysts, solvent, temperature on compound III yield, purity
[0075] Reference Example 1 Preparation of ticagrelor intermediate oxide impurity, the difference is that in step S1., compound III is prepared by using different basic catalysts, solvents, and reaction temperatures, and the yield of compound III obtained is calculated and detected. rate and purity. See Table 1 for the specific basic catalyst, solution, reaction temperature and experimental results.
[0076] The influence of table 1 different basic catalysts, solvent, temperature on compound III yield, purity
[0077]
[0078]
[0079] It can be seen from Table 1:
[0080] (1) The yield of compound III prepared in step S1 of the present invention increases significantly with the increase of temperature, wherein the yield is higher at 60-70°C, and the purity is similar, considering the energy consumption problem in production , 60°C is the best ...
experiment example 2
[0082] Experimental example 2 High-performance liquid chromatography detection of ticagrelor intermediate oxide impurity VII
[0083] The ticagrelor intermediate oxide impurity VII prepared in Example 1 is detected by high performance liquid chromatography, and obtained figure 2 .
[0084] Wherein, the detection method of high performance liquid chromatography is:
[0085] Take an appropriate amount of the ticagrelor intermediate oxide impurity VII prepared in Example 1, accurately weigh it, and refer to the fourth general rule of "Chinese Pharmacopoeia" (2015 edition) 0512 high performance liquid chromatography, bonded with octadecylsilane Silica gel is used as filler, the detection wavelength is set to 242nm, the flow rate is 1.0mL / min, the injection volume is 10μl, 0.01mol / L sodium dihydrogen phosphate solution (pH=4.2) is used as mobile phase A, acetonitrile is used as mobile phase B, Perform gradient elution according to the conditions in Table 2, and record the chroma...
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