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CN-118108635-B - Preparation method of high-purity edoxaban intermediate

CN118108635BCN 118108635 BCN118108635 BCN 118108635BCN-118108635-B

Abstract

The invention belongs to the technical field of medicine purification, and particularly discloses a preparation method of a high-purity edoxaban intermediate. The preparation method comprises the following steps of mixing raw materials of EDB070, triethylamine and a solvent, heating for the first time to dissolve, heating for the second time to react, obtaining a product of EDB080, adding pyridine and water, heating for the third time to react, obtaining a product of EDB090, purifying by adding NaCl solution into EDB090 to demulsify, adding NaOH solution, extracting, concentrating, evaporating to dryness, adding toluene, dissolving, dripping n-heptane to crystallize, and filtering to obtain the purified EDB090. In the post-treatment purification process, the invention adopts a toluene/n-heptane system for crystallization, has good impurity removal effect, and obtains the edoxaban intermediate EDB090 with the purity of 92.21-93.69% and the yield of 70-78%.

Inventors

  • BI BENWEI
  • CHEN QINGHUA
  • XU LIANG
  • LIANG DIHAO
  • MENG FAMING

Assignees

  • 中山奕安泰医药科技有限公司

Dates

Publication Date
20260512
Application Date
20221130

Claims (7)

  1. 1. The preparation method of the edoxaban intermediate is characterized by comprising the following steps of: (1) The synthesis process comprises the steps of mixing raw materials of EDB070, triethylamine and a solvent, heating for the first time to dissolve, heating for the second time to react to obtain a product of EDB080, adding pyridine and water, heating for the third time to react to obtain a product of EDB090, wherein the chemical structural formulas of the EDB070, the EDB080 and the EDB090 are as follows: ; (2) Adding NaCl solution into the EDB090 prepared in the step (1) to demulsify, then adding NaOH solution, extracting, concentrating, evaporating to dryness, adding toluene, dissolving clear, finally dripping n-heptane to crystallize, and filtering to obtain purified EDB090; The mass ratio of EDB070 to toluene to n-heptane is 1 (0.9-1.2): 1.9-2.2; the concentration of the NaOH solution is 40-50wt%, and the mass ratio of the NaOH solution to the EDB070 is (1.0-1.4): 1; At 25 The NaCl solution was added at 35℃to break the emulsion.
  2. 2. The method for preparing an intermediate of edoxaban according to claim 1, wherein in the step (1), the solvent is acetonitrile or a mixed solution of acetonitrile and water.
  3. 3. The method for preparing an edoxaban intermediate according to claim 1, wherein in the step (1), the molar ratio of EDB070, triethylamine and pyridine is 1 (1.0-1.2): 5.0-5.5.
  4. 4. The method for preparing the edoxaban intermediate according to claim 1 or 3, wherein in the step (1), the mass ratio of EDB070 to solvent to water is 1 (1.8-2.2): 0.3-0.6.
  5. 5. The method for preparing an intermediate according to claim 1, wherein in the step (1), the first temperature is raised to 40-60 ℃, the second temperature is raised to 65-70 ℃, and the third temperature is raised to 75-85 ℃.
  6. 6. The method for preparing the edoxaban intermediate according to claim 1, wherein the concentration of the NaCl solution is 20-25wt%, and the mass ratio of the NaCl solution to EDB070 is (2.0-3.0): 1.
  7. 7. The method for preparing an intermediate according to claim 1, wherein in the step (2), the crystallization temperature is-5~0 ℃.

Description

Preparation method of high-purity edoxaban intermediate Technical Field The invention belongs to the technical field of medicine purification, and particularly relates to a preparation method of a high-purity edoxaban intermediate. Background Edxaban, english name N-(5-chloropyridin-2-yl)-N'-[(1S,2R,4S)-4-(N,N-dimethylcarbamoyl)-2-(5-methyl -4,5,6, 7-Tetrahydroo [1,3] thiazolo [5,4-c ] pyridine-2-carboxamido) cyclohexyl ] oxamide, and its structural formula is shown in formula (1). The composition is mainly used for treating apoplexy, pulmonary vessel occlusion, deep vein thrombosis, apoplexy and systemic embolism, venous thromboembolism, and ischemic cerebral apoplexy. Currently, edoxaban intermediate EDB090 is mainly prepared by the following synthetic route: In the synthetic route, EDOX is taken as a raw material, ethanol (EtOH) is taken as a solvent, ethyl acetate (EtOAC) and a catalyst (Pd/C) are added, hydrogen is introduced, and EDB090 is synthesized by a catalytic hydrogenation mode. Therefore, there is a need to develop a green, efficient and safe synthesis method of the edoxaban intermediate, and further improve the purity and yield of the product. Disclosure of Invention The present invention aims to solve at least one of the technical problems in the prior art described above. Therefore, the invention provides a preparation method of a high-purity edoxaban intermediate. According to the invention, EDB070 is used as a raw material, EDB080 is synthesized by the EDB070 through the reaction of the EDB070 and triethylamine, and then EDB090 is prepared through the reaction of the EDB090 and pyridine. In order to overcome the technical problems, the first aspect of the invention provides a preparation method of an edoxaban intermediate. Specifically, the preparation method of the edoxaban intermediate comprises the following steps: (1) The synthesis process comprises the steps of mixing raw materials of EDB070, triethylamine and a solvent, heating for the first time to dissolve, heating for the second time to react to obtain a product of EDB080, adding pyridine and water, heating for the third time to react to obtain a product of EDB090, wherein the chemical structural formulas of the EDB070, the EDB080 and the EDB090 are as follows: (2) The purification process comprises the steps of adding NaCl solution into the EDB090 prepared in the step (1) to demulsify, then adding NaOH solution, extracting, concentrating, evaporating to dryness, adding toluene, dissolving clear, finally dripping n-heptane to crystallize, and filtering to obtain the purified EDB090. The edoxaban intermediate mainly comprises a synthesis process and a purification process, wherein EDB070 is used as a raw material in the synthesis process, EDB07 is reacted with Triethylamine (TEA) at a certain temperature to prepare a product EDB080, and EDB080 is reacted with pyridine (Py) at a certain temperature to prepare the product EDB090. The synthetic process comprises the following steps: In order to obtain EDB090 with higher purity and yield, the invention also carries out post-treatment purification process on the EDB090. In the purification process, the EDB090 is extracted, concentrated and dried, the precipitation of EDB090 crystals is promoted by controlling the water content, and then the crystallization is carried out in a toluene/n-heptane system, which has good impurity removing effect, thus obtaining the EDB090 which is an intermediate of the edexaban with high purity and high yield and stable quality. The purification process comprises the following steps: As a further improvement of the above-mentioned scheme, in steps (1) and (2), the solvent includes acetonitrile or a mixed solution of acetonitrile and water. Acetonitrile has good solvent performance, and can fully dissolve raw materials EDB070 and triethylamine. Preferably, the solvent is acetonitrile. As a further improvement of the scheme, in the step (1), the molar ratio of the EDB070 to the triethylamine to the pyridine is 1 (1.0-1.2) to 5.0-5.5. Preferably, in the step (1), the molar ratio of the EDB070 to the triethylamine to the pyridine is 1 (1.05-1.15) to 5.3-5.5. As a further improvement of the above scheme, in the step (1), the mass ratio of the EDB070, the solvent and the water is 1 (1.8-2.2): 0.3-0.6 Preferably, in the step (1), the mass ratio of the EDB070, the solvent and the water is 1 (1.9-2.0): 0.4-0.5. As a further improvement of the scheme, in the step (1), the temperature is raised to 40-60 ℃ for the first time, 65-70 ℃ for the second time and 75-85 ℃ for the third time. Preferably, in the step (1), the temperature is raised to 40-45 ℃ for the first time, 65-68 ℃ for the second time and 75-80 ℃ for the third time. Preferably, the reaction time for the second temperature increase is 2.5 to 3.5 hours. Preferably, the reaction time for the third temperature increase is 2.5 to 3.5 hours. As a further improvement of the above scheme, the mass ratio of EDB070,