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CN-121990973-A - Recovery method and application of saxagliptin crude product and finished product

CN121990973ACN 121990973 ACN121990973 ACN 121990973ACN-121990973-A

Abstract

The invention discloses a recycling method of a saxagliptin crude product and a finished product, which comprises (1) a concentration process, namely, merging crude product mother liquor and finished product mother liquor, concentrating under reduced pressure at 30-50 ℃, concentrating under vacuum at less than or equal to-0.085 MPa to a certain volume, cooling, crystallizing, and performing suction filtration and drying to obtain a saxagliptin crude product solid with lower purity, (2) a purification process, namely, performing salt-forming back extraction and impurity removal on the obtained saxagliptin crude product solid, (2) controlling solution moisture, (3) performing water dripping for three times to enable the crude product to be hydrated and separated out for impurity removal, and (4) performing solvent evaporation and impurity removal on a first desolventizing solvent and a second desolventizing solvent, so that the purity of the obtained saxagliptin crude product is more than or equal to 99.95%. The crude solid obtained by the method has better quality than the crude solid obtained by directly preparing, saves the cost and improves the utilization efficiency of raw materials.

Inventors

  • WANG DONGJUN
  • ZHANG QUANSHENG
  • HE FENGXIA
  • Ren Huanhui
  • LI XIA
  • LIANG XINGWANG

Assignees

  • 江苏联环药业股份有限公司

Dates

Publication Date
20260508
Application Date
20260128

Claims (10)

  1. 1. The method for recovering the crude product and the finished product of the saxagliptin is characterized by comprising the following steps of: (1) Combining the saxagliptin crude product and the finished mother liquor, concentrating under reduced pressure to a certain volume, cooling, crystallizing, filtering and drying to obtain a saxagliptin crude product solid with lower purity; (2) Adding the saxagliptin crude product solid obtained in the step (1), a reaction solvent and concentrated hydrochloric acid into a reaction kettle, raising the temperature until the solution is clear, and reacting for a certain time; (3) Adding purified water into a reaction kettle, cooling, adding an extraction solvent, stirring and standing, and removing an organic phase after layering; (4) Adding isopropanol and dichloromethane into a water layer, adding a sodium hydroxide solution, slowly stirring, adding a 25% potassium carbonate aqueous solution, regulating the pH to 9.0-9.5, stirring, standing, layering, collecting an organic phase to a desolventizing kettle, concentrating to a certain volume, and adding dichloromethane to desolventize and carry out water removal until the water content is less than 0.10%; (5) Adding purified water dropwise for three times, adding a first desolventizing solution for first desolventizing treatment after the dropwise addition is finished, adding a second desolventizing solution for continuing second desolventizing treatment after the desolventizing is finished, dripping water again for cooling, stirring for crystallization, and carrying out suction filtration and drying to obtain the product.
  2. 2. The method for recycling the crude saxagliptin and the finished product according to claim 1, wherein in the step (1), the crude saxagliptin and the finished product are concentrated to 1% -5% of the original volume under the conditions of 30-50 ℃ and the vacuum degree of less than or equal to-0.085 MPa, cooled to-10-0 ℃ for crystallization, filtered and dried by suction, and the crude saxagliptin solid with lower purity is obtained.
  3. 3. The method for recovering a crude product and a finished product of saxagliptin according to claim 1, wherein in the step (2), the reaction solvent is one or more of methanol, ethanol, isopropanol and purified water.
  4. 4. The method for recovering a crude product and a finished product of saxagliptin according to claim 1, wherein in the step (2), the temperature is raised to 30-70 ℃ and the reaction is carried out for 0.5-1h.
  5. 5. The method for recovering a crude product and a finished product of saxagliptin according to claim 1, wherein in the steps (3) and (4), the extraction solvent is dichloromethane and/or ethyl acetate.
  6. 6. The method for recovering a crude product and a finished product of saxagliptin according to claim 1, wherein in the step (4), the concentration of the sodium hydroxide solution is 40wt%.
  7. 7. The method for recovering a crude product and a finished product of saxagliptin according to claim 1, wherein in the step (4), 25wt% of potassium carbonate aqueous solution is then dripped to adjust the pH value to 9.0-9.5, stirring and standing are carried out, layering is carried out, the aqueous layer is extracted twice by dichloromethane, and the organic phases are combined and collected to a desolventizing kettle.
  8. 8. The method for recycling the crude product and the finished product of saxagliptin according to claim 1, wherein in the step (5), purified water is added dropwise three times, the amount of purified water added dropwise each time is the amount of purified water, the crude product amount=4% -40%: 1, and the time for dripping water in the purification process is 10 min-60 min.
  9. 9. The method for recycling the crude saxagliptin and the finished product according to claim 1, wherein the first stripping solution in the step (5) is prepared from dichloromethane and ethyl acetate in a mass ratio of (purified water=21:8:1-18:6:1), and the second stripping solution is ethyl acetate or methanol, preferably ethyl acetate.
  10. 10. The method for recycling a crude product and a finished product of saxagliptin according to claim 1, wherein the temperature of the second desolventizing treatment in the step (5) is less than 25 ℃, the temperature of cooling crystallization is 10-20 ℃, the stirring time is 2-4 h, the drying temperature is 35-45 ℃, and the drying time is 3-5 h.

Description

Recovery method and application of saxagliptin crude product and finished product Technical Field The invention relates to the technical field of compound crystallization and purification, in particular to a method for recovering a crude product and a finished product of saxagliptin and application thereof. Background Saxagliptin was developed in combination with the company aslick. The composition can increase endogenous glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels by selectively inhibiting DPP-4, thereby regulating blood glucose. The invention aims to develop a saxagliptin mother liquor concentration and purification process, which can improve the yield of the saxagliptin, improve the material utilization rate of the saxagliptin and reduce the raw material cost of the saxagliptin. Disclosure of Invention In order to solve the problems, the invention provides a method for recycling the crude product and the finished product of saxagliptin, and the crude product solid quality obtained by the method is better than that obtained by directly preparing the crude product, so that the cost is saved, and the utilization efficiency of raw materials is improved. In order to achieve the above purpose, the present invention adopts the following technical scheme: a method for recovering a crude product and a finished product of saxagliptin comprises the following steps: (1) And combining the saxagliptin crude product and the finished mother liquor, concentrating under reduced pressure to a certain volume, cooling, crystallizing, filtering and drying to obtain the saxagliptin crude product solid with lower purity. The maximum single impurity in the solid of the crude saxagliptin obtained by the step is more than or equal to 0.2%, the total impurity is more than or equal to 5.0%, and the impurity condition is far greater than the quality standard requirement of the crude saxagliptin (the maximum single impurity is less than or equal to 0.10%, and the total impurity is less than or equal to 0.7%). (2) Adding the saxagliptin crude product solid obtained in the step (1), a reaction solvent and concentrated hydrochloric acid into a reaction kettle, and raising the temperature until the solution is clear, and reacting for a certain time. (3) Adding purified water into a reaction kettle, cooling, adding an extraction solvent, stirring and standing, removing an organic phase after layering, continuously adding the extraction solvent into an aqueous phase, stirring and standing, and removing the organic phase after layering. Hydrochloric acid is added in the two steps to form salt of the crude product, a small amount of impurities are formed into salt, and the impurities are extracted through an organic phase to remove impurities to a certain extent, so that the purity of the crude product can be improved. (4) Adding isopropanol and dichloromethane into a water layer, adding a sodium hydroxide solution, slowly stirring, adding a 25% potassium carbonate aqueous solution, regulating the pH to 9.0-9.5, stirring, standing, layering, collecting an organic phase to a desolventizing kettle, concentrating to a certain volume, and adding dichloromethane to desolventize and carry out water removal until the water content is less than 0.10%. In the step, the water is distilled through a dichloromethane solvent, the water content of an organic phase is strictly controlled to be less than or equal to 0.10 percent, so that the water content of the organic phase is extremely low, and the influence of the free water in the hydration impurity removal process is reduced. (5) Adding purified water dropwise for three times, adding a first desolventizing solution for first desolventizing treatment after the dropwise addition is finished, adding a second desolventizing solution for continuing second desolventizing treatment after the desolventizing is finished, dripping water again for cooling, stirring for crystallization, and carrying out suction filtration and drying to obtain the product. In the step, the saxagliptin is combined with water by limiting the amount and time of three times of dropwise adding of purified water, so that the saxagliptin hydrate is generated, the solubility in an organic phase system is small, the saxagliptin hydrate is easy to separate out, the impurities cannot be hydrated, the impurities are dissolved in the organic phase as much as possible, the purification characteristic is achieved, and the total impurities can be reduced to about 0.10% from about 5.0%. In the step, the solvent of the first stripping solution and the solvent of the second stripping solution are steamed, the solvent of the stripping solution with slightly higher impurity solubility and the solvent of the stripping solution with lower material solubility are selected for replacement, so that the purity of the recovered material is improved again, and the total impurity content can be reduced to below