A kind of azaspirone pharmaceutical composition and preparation method thereof
A composition and compound technology, applied in the directions of drug combination, drug delivery, pharmaceutical formulation, etc., to achieve the effect of reducing adverse reactions, shortening production cycle, and low content of related substances
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Embodiment 1
[0046] 1. Preparation of cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboximide
[0047] The cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboximide was prepared according to the method reported in the literature (China New Technology and New Products. 2014, 8, 13), which was measured by HPLC. The content of related substances is 2.7%. Among them, HPLC (high performance liquid chromatography) test conditions are: use octadecylsilane bonded silica gel as filler, 0.01mol / L potassium dihydrogen phosphate solution (adjust pH to 7.5 with 10% sodium hydroxide solution)-acetonitrile (80:20) is the mobile phase, the detection wavelength is 243 nm, and the purity of the measured result is 97.3%.
[0048] 2. Purification of cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboximide
[0049] (i) Weigh 100.0 g of cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboximide prepared in the above step 1, add a mixed solvent of 400 mL of ethanol and 400 mL of water, and heat until the solvent is refluxed , after stirring for 1...
Embodiment 2
[0058] Using the cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboximide prepared under the conditions 1-5 in Table 1 as raw materials, tandospirone citrate was prepared according to the above method The composition was detected by HPLC, and the content of tandospirone citrate was all above 98.0%, and the content of related substances was shown in Table 2.
[0059] Table 2. Test results
[0060]
[0061]
[0062] Note: "--" means not detected.
[0063] From the above content, it can be seen that the purification process of the intermediate cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboximide in Examples 1 and 2 uses environmental protection, safety, low toxicity / non-toxicity and has the advantages of high yield and high purity; in addition, the preparation of the tandospirenone composition adopts a two-step one-pot process, which does not need to separate the intermediate products generated by the reaction, which greatly improves the industrial production efficiency and shortens the...
Embodiment 3
[0065] 1. The preparation of cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboximide is the same as in step 1 of Example 1.
[0066] 2. Purification of cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboximide
[0067] (i) Weigh 100.0 g of cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboximide prepared in the above step 1, add a mixed solvent of 400 mL of ethanol and 400 mL of water, and heat until the solvent is refluxed , stirred for 1 h, cooled to room temperature naturally, placed at -10 ± 5 °C for 2 to 3 h, suction filtered, added a mixed solvent of 200 mL of ethanol and 200 mL of water to the filter cake, heated to solvent reflux, stirred for 1 h, naturally cooled to room temperature, Place at 5±5°C for 2-3 hours, filter, and dry the filter cake to obtain 99.5 g of cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboximide with a yield of 99.5%. The purity measured by HPLC was greater than 99.5%, and the detection conditions were the same as in step 1 of Example 1, wherein the impurity 1 (cis-exo-bicyclo[...
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