Recovery method and application of saxagliptin crude product and finished product

Abstract

The invention discloses a saxagliptin crude product and finished product recovery method, which comprises the following steps: (1) concentration process: merging the crude product and the finished product mother liquor, carrying out vacuum concentration at 30-50 DEG C under the vacuum condition of less than or equal to-0.085 MPa to a certain volume, cooling, crystallizing, carrying out suction filtration and drying to obtain a saxagliptin crude product solid with lower purity; and (2) a purification process: carrying out (1) salifying back extraction and impurity removal on the obtained saxagliptin crude product solid, (2) controlling the solution moisture, (3) dripping water for three times to hydrate and precipitate the crude product for impurity removal, and (4) carrying out evaporation solvent impurity removal on a first desolventizing solvent and a second desolventizing solvent, so that the purity of the obtained saxagliptin crude product is greater than or equal to 99.95%. The solid quality of the obtained crude product is better than that of a directly prepared crude product, the cost is saved, and the utilization efficiency of raw materials is improved.

Description

Technical Field

[0001] This invention relates to the field of compound crystallization and purification technology, specifically to a method and application for the recovery of crude and finished saxagliptin. Background Technology

[0002] Saxagliptin was jointly developed by Bristol-Myers Squibb and AstraZeneca. This drug regulates blood glucose by selectively inhibiting DPP-4, thereby increasing the levels of endogenous glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Saxagliptin has high raw material costs. Currently, approximately 15% of saxagliptin is lost in the mother liquor during the synthesis process, resulting in low yield and poor material utilization. This invention aims to develop a saxagliptin mother liquor concentration and purification process that can improve the yield, increase material utilization, and reduce raw material costs. Summary of the Invention

[0003] To address the aforementioned problems, this invention provides a method for recovering crude and finished saxagliptin. The crude solid obtained using this method has a higher quality than that obtained directly, saving costs and improving raw material utilization efficiency.

[0004] To achieve the above objectives, the present invention adopts the following technical solution:

[0005] A method for recovering crude and finished saxagliptin includes the following steps: (1) Combine crude saxagliptin and the finished mother liquor, concentrate under reduced pressure to a certain volume, cool down to crystallize, filter and dry to obtain crude saxagliptin solid with low purity.

[0006] The crude saxagliptin obtained in this step has a maximum single impurity of ≥0.2% and a total impurity of ≥5.0%, which is far greater than the quality standard requirements for crude products (maximum single impurity ≤0.10%, total impurity ≤0.7%).

[0007] (2) Add the crude saxagliptin solid obtained in step (1), the reaction solvent, and concentrated hydrochloric acid to the reaction vessel, raise the temperature until the solution is clear, and react for a certain time.

[0008] (3) Add purified water to the reaction vessel, cool down, add extraction solvent, stir and let stand, remove the organic phase after separation; add extraction solvent to the aqueous phase, stir and let stand, remove the organic phase after separation.

[0009] Adding hydrochloric acid in the above two steps causes the crude product to form salt, and a small amount of impurities to form salt. The impurities are then removed by extracting them with an organic phase, which can improve the purity of the crude product.

[0010] (4) Add isopropanol and dichloromethane to the water layer, add sodium hydroxide solution and stir slowly, then add 25% potassium carbonate aqueous solution, adjust the pH to 9.0-9.5, stir and let stand, separate into layers, collect the organic phase to the desolventing vessel, concentrate it to a certain volume, add dichloromethane to desolvent and remove water until the water content is less than 0.10%.

[0011] In this step, water is evaporated using dichloromethane solvent, and the moisture content of the organic phase is strictly controlled to be ≤0.10%, which is much lower than the free water content in the organic phase, thus reducing the impact of free water on the hydration and impurity removal process.

[0012] (5) Add purified water dropwise in three parts. After the addition is complete, add the first desolvation solution for the first desolvation treatment. After the desolvation is complete, add the second desolvation solution for the second desolvation treatment. After the desolvation is complete, add water dropwise again to cool down and stir to precipitate crystals. Filter and dry to obtain the product.

[0013] In this step, by limiting the amount and time of adding purified water in three separate drops, saxagliptin is combined with water to form saxagliptin hydrate. Saxagliptin hydrate has low solubility in the organic phase system and is easy to precipitate. Since impurities cannot be hydrated, the impurities are dissolved in the organic phase as much as possible, thus achieving purification. This can reduce the total impurities from about 5.0% to about 0.10%.

[0014] In this step, the solvents of the first and second desolvation solutions are also used for evaporation. The desolvation solution with slightly higher solubility for impurities and lower solubility for materials is selected for solvent replacement, thereby further improving the purity of the recovered materials and reducing the total impurity content to below 0.05%.

[0015] As a preferred embodiment, in step (1), the volume of saxagliptin is concentrated to 1% to 5% of the original volume under reduced pressure at 30 to 50°C and vacuum degree ≤ -0.085MPa, then cooled to -10 to 0°C for crystallization, filtered and dried to obtain crude solid saxagliptin with low purity.

[0016] In a preferred embodiment, in step (2), the reaction solvent is one or more of methanol, ethanol, isopropanol or purified water.

[0017] In a preferred embodiment, in step (2), the temperature is raised to 30-70°C and the reaction is carried out for 0.5-1 h.

[0018] In a preferred embodiment, in steps (3) and (4), the extraction solvent is dichloromethane and / or ethyl acetate.

[0019] In a preferred embodiment, the concentration of the sodium hydroxide solution in step (4) is 40 wt%.

[0020] As a preferred embodiment, in step (4), 25wt% potassium carbonate aqueous solution is then added dropwise to adjust the pH value to 9.0-9.5, stirred and allowed to stand, and the layers are separated. The aqueous layer is extracted twice with dichloromethane, and the organic phase is collected and sent to the desolvation vessel.

[0021] In a preferred embodiment, purified water is added dropwise in step (5) three times, with the amount of purified water added each time being [amount missing]. Purified water volume: crude product volume = 4%~40% : 1 The time for dripping water in the purification process is 10min~60min.

[0022] As a preferred embodiment, the first desolvation solution in step (5) is prepared according to the following mass ratio: dichloromethane: ethyl acetate: purified water = 21:8:1 to 18:6:1.

[0023] In a preferred embodiment, the second desolvation solution in step (5) is ethyl acetate or methanol, preferably ethyl acetate.

[0024] In a preferred embodiment, the temperature of the second solvent removal process in step (5) is less than 25°C, the temperature for cooling and crystallization is 10-20°C, the stirring time is 2-4 hours, the drying temperature is 35-45°C, and the drying time is 3-5 hours.

[0025] This invention utilizes a purification process to transform crude saxagliptin mother liquor into a valuable resource, significantly increasing the yield of crude saxagliptin and thus reducing production costs. The crude saxagliptin prepared by this method has a purity ≥99.95%, unaffected by recycled materials, and is of superior quality compared to crude saxagliptin prepared directly. Furthermore, the preparation method of this invention is simple, practical, and easy to promote. Attached Figure Description

[0026] Figure 1 HPLC quality data of crude saxagliptin obtained from the concentration process; Figure 2 HPLC quality data of crude saxagliptin recovered in Example 1; Figure 3 HPLC quality data of crude saxagliptin recovered in Example 3; Figure 4 The HPLC quality of crude saxagliptin recovered in Comparative Example 2 was analyzed. Detailed Implementation

[0027] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the embodiments of this invention pertain. If any definition stated in this section is contrary to or otherwise inconsistent with a definition stated in a patent, patent application, published patent application, or other publication incorporated herein by reference, the definitions listed here shall prevail over those incorporated herein by reference.

[0029] Unless otherwise specified, the methods used in the following embodiments are conventional methods. Unless otherwise specified, the materials, reagents, and instruments used are conventional materials, reagents, and instruments in the art, and can be obtained commercially by those skilled in the art.

[0030] The following methods were used to detect the impurity content in the examples below: Reagents: Methanol, ultrapure water (Milli-Q), trifluoroacetic acid, hydrochloric acid, 65-11 reference standard, 65-13 reference standard, saxagliptin reference standard; Instrument: High-performance liquid chromatograph; Chromatographic conditions: Mobile phase A: Methanol: Water: Trifluoroacetic acid = 10:90:0.08; Mobile phase B: Methanol: Water: Trifluoroacetic acid = 90:10:0.08; Column: Zorbax Eclipse AAA column, 150mm 3.0mm, 3.5µm; Detection wavelength: 215nm, flow rate: 0.6ml / min, injection volume: 20μl, column temperature: 40℃.

[0031] Example 1 This embodiment provides a method for recovering crude and finished saxagliptin, including the following steps: (1) Add crude saxagliptin and purified mother liquor to the reactor. Concentrate to 3% of the original volume under reduced pressure at 40℃ and vacuum ≤ -0.085MPa. Then cool to -5℃ and stir for 2 hours. Filter and dry to obtain solid saxagliptin mother liquor, which is used for subsequent purification processes. The maximum single impurity content in this step was 0.212%, and the total impurity content was 5.278%.

[0032] (2) Add 5.5 kg of ethanol, 7.0 kg of purified water, 5.0 kg of crude product of the sago mother liquor obtained in step (1), and 2.0 kg of concentrated hydrochloric acid to the main reactor in sequence, heat to 30°C, and stir for 1 h.

[0033] (3) Add 13.0 kg of purified water to the main reactor, cool down and add 25.0 kg of ethyl acetate, stir and let stand. Separate the upper organic phase.

[0034] (4) Add 5.5 kg of ethanol and 58.0 kg of dichloromethane to the reactor. Slowly add the prepared sodium hydroxide solution (0.6 kg of sodium hydroxide and 1.5 kg of purified water) dropwise into the main reactor, stir for 30 min, and add 25% potassium carbonate aqueous solution dropwise to the reactor to adjust the pH to 9.0-9.5. Stir and let stand, separate the layers, and collect the organic phase into the desolvation vessel. The aqueous layer is then treated with 40 kg of dichloromethane. Extract twice. The organic phase is distilled under reduced pressure in a solvent separator to 15.0-25.0 L. 58.3 kg of dichloromethane is added and concentrated to a water content of 0.08%. 6.0 kg of ethyl acetate is then added to the solvent separator.

[0035] (5) Add 230g of purified water to the crystallization vessel with stirring, the addition time is about 0.5 hours, and continue to keep warm and stir for 30 minutes. Add 270g of purified water to the crystallization vessel with stirring, the addition time is about 0.5 hours, and continue to keep warm and stir for 30 minutes. Add 1800g of purified water to the crystallization vessel with stirring, the addition time is about 0.5 hours. Mix 29.0kg of dichloromethane, 12.0kg of ethyl acetate and 1.0kg of purified water to prepare the first desolvation solution. Use 45.0kg of ethyl acetate as the second desolvation solution. Add the first desolvation solution while desolvating. After desolvation is completed, add the second desolvation solution while desolvating. At this time, the desolvation temperature is less than 25℃. After desolvation is completed, cool down to 20℃ and stir at this temperature for 3 hours. After filtration, the material is vacuum dried at 35℃ for 4 hours to obtain 4.6kg of crude saxagliptin. Testing revealed that the crude product contained 0.04% (65-11+65-13) of impurities, with a maximum single impurity content of 0.01% and a total impurity content of 0.05%. The HPLC quality data for the recovered crude saxagliptin is as follows: Figure 2 As shown.

[0036] Example 2 This embodiment provides a method for recovering crude and finished saxagliptin, including the following steps: (1) Add crude saxagliptin and purified mother liquor to the reaction vessel. Concentrate to 3% of the original volume under reduced pressure at 40℃ and vacuum ≤ -0.085MPa. Then cool to -5℃ and stir for 2 hours. Filter and dry to obtain solid saxagliptin mother liquor, which is used for subsequent purification processes. The results showed that in this step: 65-11+65-13=4.878%, the maximum single impurity content was 0.212%, and the total impurity content was 5.278%. The HPLC quality of crude saxagliptin obtained from the concentration process is as follows: Figure 1 As shown.

[0037] (2) Add 5.5 kg isopropanol, 7.0 kg purified water, 5.0 kg crude product of the sago mother liquor obtained in step (1), and 2.0 kg concentrated hydrochloric acid to the main reactor in sequence, heat to 50°C, and stir for 0.5 h.

[0038] (3) Add 13.0 kg of purified water to the main reactor, cool down and add 29.0 kg of dichloromethane, stir and let stand. Separate the lower organic phase. Add 25.0 kg of ethyl acetate, stir and let stand. Separate the upper organic phase.

[0039] (4) Add 5.5 kg isopropanol and 58.0 kg dichloromethane to the reactor. Slowly add the prepared sodium hydroxide solution (0.6 kg sodium hydroxide and 1.5 kg purified water) dropwise into the main reactor, stir for 30 min, and add 25% potassium carbonate aqueous solution dropwise to the reactor to adjust the pH to 9.0-9.5. Stir and let stand, separate the layers, and collect the organic phase to the desolvation vessel. The aqueous layer is then treated with 40 kg dichloromethane. Extract twice. The organic phase is distilled under reduced pressure in a desolventizing vessel to 15.0-25.0 L. 58.3 kg of dichloromethane is added and concentrated to a water content of 0.04%. 6.0 kg of ethyl acetate is then added to the desolventizing vessel.

[0040] (5) Add 230g of purified water to the crystallization vessel with stirring, the addition time is about 10 minutes, and continue to keep warm and stir for 30 minutes. Add 270g of purified water to the crystallization vessel with stirring, the addition time is about 10 minutes, and continue to keep warm and stir for 30 minutes. Add 1800g of purified water to the crystallization vessel with stirring, the addition time is about 10 minutes. Mix 31.0kg of dichloromethane, 10.0kg of ethyl acetate and 1.0kg of purified water to prepare the first desolvation solution. Use 45.0kg of ethyl acetate as the second desolvation solution. Add the first desolvation solution while desolvating. After desolvation is completed, add the second desolvation solution while desolvating. At this time, the desolvation temperature is less than 25℃. After desolvation is completed, cool down to 10℃ and stir at this temperature for 2 hours. After filtration, the material is vacuum dried at 40℃ for 3-5 hours to obtain 4.3kg of crude saxagliptin. Upon testing, the crude product contained 0.03% impurities (65-11+65-13), the largest single impurity was not detected, and the total impurity content was 0.03%.

[0041] Example 3 This embodiment provides a method for recovering crude and finished saxagliptin, including the following steps: (1) Add crude saxagliptin and purified mother liquor to the reactor. Concentrate to 3% of the original volume under reduced pressure at 40℃ and vacuum ≤ -0.085MPa. Then cool to -5℃ and stir for 2 hours. Filter and dry to obtain solid saxagliptin mother liquor, which is used for subsequent purification processes. The maximum single impurity content in this step was 0.212%, and the total impurity content was 5.278%.

[0042] (2) Add 5.5 kg of methanol, 7.0 kg of purified water, 5.0 kg of crude product of the sago mother liquor obtained in step (1), and 2.0 kg of concentrated hydrochloric acid to the main reactor in sequence, heat to reflux, and stir for 0.5 h.

[0043] (3) Add 13.0 kg of purified water to the main reactor, cool down and add 29.0 kg of dichloromethane, stir and let stand. Separate the lower organic phase. Add 29.0 kg of dichloromethane, stir and let stand. Separate the lower organic phase.

[0044] (4) Add 5.5 kg methanol and 58.0 kg dichloromethane to the reactor. Slowly add the prepared sodium hydroxide solution (0.6 kg sodium hydroxide and 1.5 kg purified water) dropwise into the main reactor, stir for 30 min, and add 25% potassium carbonate aqueous solution dropwise to the reactor to adjust the pH to 9.0-9.5. Stir and let stand, separate the layers, and collect the organic phase to the desolvation vessel. The aqueous layer is then treated with 40 kg dichloromethane. 2. Extract twice. The organic phase is distilled under reduced pressure in a desolventizing vessel to 15.0L-25.0L. 58.3kg of dichloromethane is added and concentrated to a water content of 0.06%. 6.0kg of ethyl acetate is added to the desolventizing vessel.

[0045] (5) Add 230g of purified water to the crystallization vessel with stirring, and add it dropwise over about 1 hour, while continuing to keep it warm and stirring for 30 minutes. Add 270g of purified water to the crystallization vessel with stirring, and add it dropwise over about 1 hour, while continuing to keep it warm and stirring for 30 minutes. Add 1800g of purified water to the crystallization vessel with stirring, and add it dropwise over about 1 hour. Mix 30.0kg of dichloromethane, 11.0kg of ethyl acetate and 1.0kg of purified water to prepare the first desolvation solution. Use 45.0kg of ethyl acetate as the second desolvation solution. Add the first desolvation solution while desolvating. After desolvation is completed, add the second desolvation solution while desolvating. At this time, the desolvation temperature is less than 25℃. After desolvation is completed, cool down to 15℃ and stir at this temperature for 4 hours. After filtration, vacuum dry the material at 45℃ for 3-5 hours to obtain 3.9kg of crude saxagliptin. Testing revealed the following in this step: the crude product contained 0.03% (65-11+65-13), the maximum single impurity content was 0.01%, and the total impurity content was 0.04%. The HPLC quality of the recovered crude saxagliptin is as follows: Figure 3 As shown.

[0046] Comparative Example 1 This comparative example provides a method for recovering crude and finished saxagliptin, comprising the following steps: (1) Add crude saxagliptin and purified mother liquor to the reactor. Concentrate to 3% of the original volume under reduced pressure at 40℃ and vacuum ≤ -0.085MPa. Then cool to -5℃ and stir for 2 hours. Filter and dry to obtain solid saxagliptin mother liquor, which is used for subsequent purification processes. The maximum single impurity content in this step was 0.212%, and the total impurity content was 5.278%.

[0047] (2) Add 5.5 kg isopropanol, 7.0 kg purified water, 5.0 kg crude product of the sago mother liquor obtained in step (1), and 2.0 kg concentrated hydrochloric acid to the main reactor in sequence, heat to 50°C, and stir for 0.5 h.

[0048] (3) Add 13.0 kg of purified water to the main reactor, cool down and add 29.0 kg of dichloromethane, stir and let stand. Separate the lower organic phase. Add 25.0 kg of ethyl acetate, stir and let stand. Separate the upper organic phase.

[0049] (4) Add 5.5 kg isopropanol and 58.0 kg dichloromethane to the reactor. Slowly add the prepared sodium hydroxide solution (0.6 kg sodium hydroxide and 1.5 kg purified water) dropwise into the main reactor, stir for 30 min, and add 25% potassium carbonate aqueous solution dropwise to the reactor to adjust the pH to 9.0-9.5. Stir and let stand, separate the layers, and collect the organic phase to the desolvation vessel. The aqueous layer is then treated with 40 kg dichloromethane. Extraction was performed twice. The organic phase was distilled under reduced pressure in a solvent separator to dryness. 30 kg of ethyl acetate was added to the material, and the temperature was lowered to 10 °C and stirred at this temperature for 2 hours. After filtration, the material was dried under vacuum at 40 °C for 3-5 hours to obtain 3.5 kg of crude saxagliptin.

[0050] The difference between this comparative example and Example 1 is that step (5) is not included; only hydrochloric acid is added to remove impurities. The crude product obtained was tested, and in this step: 65-11+65-13=4.16% of the crude product was impurity, the maximum single impurity content was 0.18%, and the total impurity content was 4.51%.

[0051] Comparative Example 2 This comparative example provides a method for recovering crude and finished saxagliptin, comprising the following steps: (1) Add crude saxagliptin and purified mother liquor to the reactor. Concentrate to 3% of the original volume under reduced pressure at 40℃ and vacuum ≤ -0.085MPa. Then cool to -5℃ and stir for 2 hours. Filter and dry to obtain solid saxagliptin mother liquor, which is used for subsequent purification processes. The maximum single impurity content in this step was 0.212%, and the total impurity content was 5.278%.

[0052] (2) Add 5.5 kg isopropanol, 7.0 kg purified water, 5.0 kg crude product of the sago mother liquor obtained in step (1), and 2.0 kg concentrated hydrochloric acid to the main reactor in sequence, heat to 50°C, and stir for 0.5 h.

[0053] (3) Add 13.0 kg of purified water to the main reactor, cool down and add 29.0 kg of dichloromethane, stir and let stand. Separate the lower organic phase. Add 25.0 kg of ethyl acetate, stir and let stand. Separate the upper organic phase.

[0054] (4) Add 5.5 kg isopropanol and 58.0 kg dichloromethane to the reactor. Slowly add the prepared sodium hydroxide solution (0.6 kg sodium hydroxide and 1.5 kg purified water) dropwise into the main reactor, stir for 30 min, and add 25% potassium carbonate aqueous solution dropwise to the reactor to adjust the pH to 9.0-9.5. Stir and let stand, separate the layers, and collect the organic phase to the desolvation vessel. The aqueous layer is then treated with 40 kg dichloromethane. Extract twice. The organic phase is distilled under reduced pressure in a desolventizing vessel to 15.0-25.0 L. 58.3 kg of dichloromethane is added and concentrated to a water content of 0.04%. 6.0 kg of ethyl acetate is then added to the desolventizing vessel.

[0055] (5) Add 230g of purified water to the crystallization vessel with stirring, the addition time is about 10 minutes, and continue to keep warm and stir for 30 minutes. Add 270g of purified water to the crystallization vessel with stirring, the addition time is about 10 minutes, and continue to keep warm and stir for 30 minutes. Add 1800g of purified water to the crystallization vessel with stirring, the addition time is about 10 minutes. After the addition is complete, cool down to 10℃ and stir at this temperature for 2 hours. After the material is filtered, vacuum dry at 40℃ for 3-5 hours to obtain 2.3kg of crude saxagliptin.

[0056] The difference between this comparative example and Example 1 is that the two solvent removal processes are not performed in step (5). The crude product obtained was tested, and in this step: the maximum single impurity content (65-11+65-13=0.12%) was 0.01%, and the total impurity content was 0.14%. The HPLC quality of the recovered crude saxagliptin is as follows: Figure 4 As shown.

[0057] Comparative Example 3 This comparative example provides a method for recovering crude and finished saxagliptin, comprising the following steps: (1) Add crude saxagliptin and purified mother liquor to the reactor. Concentrate to 3% of the original volume under reduced pressure at 40℃ and vacuum ≤ -0.085MPa. Then cool to -5℃ and stir for 2 hours. Filter and dry to obtain solid saxagliptin mother liquor, which is used for subsequent purification processes. The maximum single impurity content in this step was 0.212%, and the total impurity content was 5.278%.

[0058] (2) Add 5.5 kg isopropanol, 7.0 kg purified water, 5.0 kg crude product of the sago mother liquor obtained in step (1), and 2.0 kg concentrated hydrochloric acid to the main reactor in sequence, heat to 50°C, and stir for 0.5 h.

[0059] (3) Add 13.0 kg of purified water to the main reactor, cool down and add 29.0 kg of dichloromethane, stir and let stand. Separate the lower organic phase. Add 25.0 kg of ethyl acetate, stir and let stand. Separate the upper organic phase.

[0060] (4) Add 5.5 kg isopropanol and 58.0 kg dichloromethane to the reactor. Slowly add the prepared sodium hydroxide solution (0.6 kg sodium hydroxide and 1.5 kg purified water) dropwise into the main reactor, stir for 30 min, and add 25% potassium carbonate aqueous solution dropwise to the reactor to adjust the pH to 9.0-9.5. Stir and let stand, separate the layers, and collect the organic phase to the desolvation vessel. The aqueous layer is then treated with 40 kg dichloromethane. Extract twice. The organic phase is distilled under reduced pressure in a desolventizing vessel to 15.0-25.0 L. 58.3 kg of dichloromethane is added and concentrated to a water content of 0.04%. 6.0 kg of ethyl acetate is then added to the desolventizing vessel.

[0061] (5) Mix 31.0 kg of dichloromethane, 10.0 kg of ethyl acetate, and 1.0 kg of purified water to prepare the first desolvation solution. Use 45.0 kg of ethyl acetate as the second desolvation solution. While adding the first desolvation solution, desolvation is carried out. After desolvation is completed, the second desolvation solution is added while desolvation is carried out. At this time, the desolvation temperature is less than 25℃. After desolvation is completed, the temperature is lowered to 10℃ and stirred at this temperature for 2 hours. After filtration, the material is vacuum dried at 40℃ for 3-5 hours to obtain 2.6 kg of crude saxagliptin.

[0062] The difference between this comparative example and Example 1 is that the three-step addition of purified water step (5) is not performed. The crude product obtained was tested and found that in this step: 65-11+65-13=2.67% of the crude product, the maximum single impurity content was 0.20%, and the total impurity content was 2.98%.

[0063] Comparative Example 4 This comparative example provides a method for recovering crude and finished saxagliptin, comprising the following steps: (1) Add crude saxagliptin and purified mother liquor to the reactor. Concentrate to 3% of the original volume under reduced pressure at 40℃ and vacuum ≤ -0.085MPa. Then cool to -5℃ and stir for 2 hours. Filter and dry to obtain solid saxagliptin mother liquor, which is used for subsequent purification processes. The maximum single impurity content in this step was 0.212%, and the total impurity content was 5.278%.

[0064] (2) Add 5.5 kg isopropanol, 7.0 kg purified water, 5.0 kg crude product of the sago mother liquor obtained in step (1), and 2.0 kg concentrated hydrochloric acid to the main reactor in sequence, heat to 50°C, and stir for 0.5 h.

[0065] (3) Add 13.0 kg of purified water to the main reactor, cool down and add 29.0 kg of dichloromethane, stir and let stand. Separate the lower organic phase. Add 25.0 kg of ethyl acetate, stir and let stand. Separate the upper organic phase.

[0066] (4) Add 5.5 kg isopropanol and 58.0 kg dichloromethane to the reactor. Slowly add the prepared sodium hydroxide solution (0.6 kg sodium hydroxide and 1.5 kg purified water) dropwise into the main reactor, stir for 30 min, and add 25% potassium carbonate aqueous solution dropwise to the reactor to adjust the pH to 9.0-9.5. Stir and let stand, separate the layers, and collect the organic phase to the desolvation vessel. The aqueous layer is then treated with 40 kg dichloromethane. Extract twice. The organic phase is then distilled under reduced pressure in a desolvation vessel to a final volume of 15.0 L-25.0 L. The water content is determined to be 0.45%, and 6.0 kg of ethyl acetate is added to the desolvation vessel.

[0067] (5) Add 230g of purified water to the crystallization vessel with stirring, the addition time is about 10 minutes, and continue to keep warm and stir for 30 minutes. Add 270g of purified water to the crystallization vessel with stirring, the addition time is about 10 minutes, and continue to keep warm and stir for 30 minutes. Add 1800g of purified water to the crystallization vessel with stirring, the addition time is about 10 minutes. Mix 31.0kg of dichloromethane, 10.0kg of ethyl acetate and 1.0kg of purified water to prepare the first desolvation solution. Use 45.0kg of ethyl acetate as the second desolvation solution. Add the first desolvation solution while desolvating. After desolvation is completed, add the second desolvation solution while desolvating. At this time, the desolvation temperature is less than 25℃. After desolvation is completed, cool down to 10℃ and stir at this temperature for 2 hours. After filtration, the material is vacuum dried at 40℃ for 3-5 hours to obtain 3.1kg of crude saxagliptin.

[0068] The difference between this comparative example and Example 1 is that in step (4), the organic phase is distilled under reduced pressure in the solvent extraction vessel to 15.0L-25.0L, and then concentrated with dichloromethane until the water content is 0.45%. The crude product obtained was tested, and in this step, the crude product contained 65-11+65-13=0.78% impurities, the maximum single impurity content was 0.1%, and the total impurity content was 0.95%.

[0069] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for recovering crude and finished saxagliptin, characterized in that, Includes the following steps: (1) Combine crude saxagliptin and finished mother liquor, concentrate under reduced pressure to a certain volume, cool down to crystallize, filter and dry to obtain crude saxagliptin solid with low purity; (2) Add the crude saxagliptin solid obtained in step (1), the reaction solvent, and concentrated hydrochloric acid to the reaction vessel, raise the temperature until the solution is clear, and react for a certain time; (3) Add purified water to the reaction vessel, cool down, add extraction solvent, stir and let stand, remove the organic phase after separation; continue to add extraction solvent to the aqueous phase, stir and let stand, remove the organic phase after separation; (4) Add isopropanol and dichloromethane to the aqueous layer, add sodium hydroxide solution and stir slowly, then add 25% potassium carbonate aqueous solution to adjust the pH to 9.0-9.5, stir and let stand, separate into layers, collect the organic phase to the desolventizing vessel, concentrate it to a certain volume, add dichloromethane to desolvent and remove water until the water content is less than 0.10%; (5) Add purified water dropwise in three parts. After the addition is complete, add the first desolvation solution for the first desolvation treatment. After the desolvation is complete, add the second desolvation solution for the second desolvation treatment. After the desolvation is complete, add water dropwise again to cool down and stir to precipitate crystals. Filter and dry to obtain the product.

2. The method for recovering crude and finished saxagliptin according to claim 1, characterized in that, In step (1), the volume of saxagliptin is concentrated to 1% to 5% of the original volume under reduced pressure at 30 to 50°C and vacuum degree ≤ -0.085MPa. Then, it is cooled to -10 to 0°C for crystallization, filtered and dried to obtain crude solid saxagliptin with low purity.

3. The method for recovering crude and finished saxagliptin according to claim 1, characterized in that, In step (2), the reaction solvent is one or more of methanol, ethanol, isopropanol or purified water.

4. The method for recovering crude and finished saxagliptin according to claim 1, characterized in that, In step (2), the temperature is raised to 30-70℃ and the reaction is carried out for 0.5-1h.

5. The method for recovering crude and finished saxagliptin according to claim 1, characterized in that, In steps (3) and (4), the extraction solvent is dichloromethane and / or ethyl acetate.

6. The method for recovering crude and finished saxagliptin according to claim 1, characterized in that, In step (4), the concentration of the sodium hydroxide solution is 40 wt%.

7. The method for recovering crude and finished saxagliptin according to claim 1, characterized in that, In step (4), 25wt% potassium carbonate aqueous solution is added dropwise to adjust the pH value to 9.0-9.5, stirred and allowed to stand, and the layers are separated. The aqueous layer is extracted twice with dichloromethane, and the organic phase is collected and sent to the desolvation vessel.

8. The method for recovering crude and finished saxagliptin according to claim 1, characterized in that, In step (5), purified water is added dropwise three times. The amount of purified water added each time is 4% to 40% of the amount of purified water:

1. The time for adding water in the purification process is 10 min to 60 min.

9. A method for recovering crude and finished saxagliptin according to claim 1, characterized in that, In step (5), the first desolvation solution is prepared according to the following mass ratio: dichloromethane: ethyl acetate: purified water = 21:8:1 to 18:6:1; the second desolvation solution is ethyl acetate or methanol, preferably ethyl acetate.

10. A method for recovering crude and finished saxagliptin according to claim 1, characterized in that, In step (5), the temperature of the second desolvation treatment is less than 25°C, the temperature of cooling and crystallization is 10-20°C, the stirring time is 2-4 hours, the drying temperature is 35-45°C, and the drying time is 3-5 hours.

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