A method for efficient recovery of vildagliptin from vildagliptin mother liquor

Abstract

This application provides a method for the efficient recovery of vildagliptin from vildagliptin mother liquor, belonging to the field of medicinal chemistry technology. Using vildagliptin mother liquor containing disubstituted impurities as the treatment target, an N-dealkylation reaction is used to selectively remove additional alkyl substituents from the disubstituted impurities, directionally converting the impurities into the target product vildagliptin, thus achieving waste resource utilization. This application requires no complex equipment, uses mild reaction conditions, achieves a disubstituted impurity conversion rate ≥90%, increases the total vildagliptin yield by 5-8%, and does not generate new process impurities. Hydrogen peroxide, as a commonly used industrial oxidant, is inexpensive, and the only byproduct is water, significantly reducing environmental pressure. It is fully compatible with existing industrial production processes and has outstanding economic value and environmental significance.

Description

Technical Field

[0001] This application relates to the field of medicinal chemistry technology, specifically to a method for efficiently recovering vildagliptin from vildagliptin mother liquor. Background Technology

[0002] Vildagliptin, a commonly used clinical dipeptidyl peptidase-IV (DPP-IV) inhibitor, presents a core environmental and resource waste issue in its synthesis process: when preparing vildagliptin using L-prolylamide, the crude vildagliptin contains approximately 1-3% disubstituted impurities (see...). Figure 1 To meet pharmaceutical quality standards (impurities in the finished product ≤ 0.1%), crude vildagliptin requires multiple recrystallization purification processes.

[0003] Multiple refining processes generate a large amount of refining mother liquor: approximately 8-12 ml is produced for every ton of vildagliptin finished product. 3 The refined mother liquor contains 3-40% disubstituted impurities and 15-65% vildagliptin product. Because the disubstituted impurities are structurally highly similar to vildagliptin, they cannot be effectively recovered using conventional separation methods. Therefore, the mother liquor must be treated as waste liquid and residue. Direct discharge of this waste liquid and residue would cause serious environmental pollution, while entrusting professional disposal would incur high treatment costs. Furthermore, discarding the residual vildagliptin product with the mother liquor would reduce raw material utilization and increase production costs.

[0004] Existing technologies for treating impurities in vildagliptin are limited to "optimizing reaction conditions to reduce impurity formation" or "removing impurities through multiple purification processes," without addressing the recovery and utilization of impurities and residual products in the purification mother liquor. For example, some processes reduce the content of disubstituted impurities in the reaction solution to 1.5-2.0% by optimizing the reaction solvent, the dropping method, or increasing the molar equivalent of 3-aminoadamantanol, but the resulting product still requires purification. Although this reduces the number of purification steps, it still cannot avoid the generation of purification mother liquor. Summary of the Invention

[0005] To address the issues of large amounts of mother liquor containing disubstituted impurities (3-20%) generated during the multiple refining processes of vildagliptin, and the resulting product waste and significant environmental pressure, this application provides a method for recovering vildagliptin from the mother liquor (especially the mother liquor generated during refining). In this method, the disubstituted impurities are directionally converted into vildagliptin through an N-dealkylation reaction, which not only improves the utilization rate of raw materials and the yield of finished products, but also reduces the discharge of waste liquid and waste residue.

[0006] A method for efficiently recovering vildagliptin from vildagliptin mother liquor involves using vildagliptin mother liquor containing disubstituted impurities as raw material. The method involves an N-dealkylation reaction at 5–25°C for 4–24 h to selectively remove the extra alkyl group from the disubstituted impurities in the mother liquor, converting the disubstituted impurities into vildagliptin for recovery. The recovery process is complete when the content of the disubstituted impurities drops below 0.1% as monitored by HPLC. The disubstituted impurities are derivatives of the vildagliptin molecule with an additional alkyl substitution on the tetrahydropyrrole ring or the 3-aminoadamantanool structural unit. The mass content of the disubstituted impurities in the purified mother liquor is 3–40%.

[0007] This application creatively employs peroxyacid compounds as oxidants, completely eliminating the use of highly toxic reagents—the byproducts of peroxyacid oxidants are clean and pollution-free, exhibiting significantly superior green and environmentally friendly properties compared to conventional methods. Addressing the challenges of separating disubstituted impurities (alkyl-linked electron-withdrawing structures) in the vildagliptin refining mother liquor from the target product due to their high structural similarity, and the potential presence of sensitive functional groups in the vildagliptin molecule, this application utilizes the unique technical characteristics of N-dealkylation reactions to design a customized reaction system. This system achieves the targeted and efficient conversion of disubstituted impurities in the mother liquor to vildagliptin, while simultaneously recovering residual products, fundamentally resolving the resource waste and environmental pressures caused by the refining mother liquor.

[0008] Furthermore, as a preferred option: The purified mother liquor contains 15-65% vildagliptin by mass.

[0009] The vildagliptin mother liquor contains 3-15% (excluding 15%) of disubstituted impurities, and an oxidizing agent is added to the vildagliptin mother liquor; the vildagliptin mother liquor contains 15-40% of disubstituted impurities, and an oxidizing agent and Fe are added to the vildagliptin mother liquor. 2+ Salt.

[0010] The oxidant is hydrogen peroxide or a peroxyacid compound. More preferably, the peroxyacid compound is at least one of m-chloroperoxybenzoic acid, peracetic acid, peroxybenzoic acid, and hydrogen peroxide. The molar ratio of the disubstituted impurity to the peroxyacid compound is 1:1.5~5.0.

[0011] The oxidant is added dropwise over a period of 1 to 3 hours, and the temperature of the mother liquor is controlled to be ≤15℃ during the addition process.

[0012] The Fe 2+ The salt is any one of ferrous sulfate (FeSO4・7H2O), ferrous chloride, or ferrous acetate.

[0013] The Fe 2+ The molar percentage of salt relative to disubstituted impurities is 8–20 mol.

[0014] When the content of disubstituted impurities in the vildagliptin mother liquor is 3-15% (excluding 15%), the temperature of the N-dealkylation reaction is 20-25℃ and the duration is 15-24h.

[0015] When the content of disubstituted impurities in the vildagliptin mother liquor is 15-40%, the temperature of the N-dealkylation reaction is 5-15℃ and the duration is 4-10h.

[0016] More preferably, When the content of disubstituted impurities in the vildagliptin mother liquor is 3-20%, the oxidant used is 10-30% industrial-grade hydrogen peroxide. The molar ratio of disubstituted impurities to oxidant can be increased to 1:5.0-8.0, which can shorten the reaction time to 4-6 hours.

[0017] The Fe 2+ The salt is ferrous sulfate, which is widely available and inexpensive in industry. At this time, the molar percentage of ferrous sulfate relative to the disubstituted impurities is 12-15 mol%, which can further shorten the reaction time to 6-8 hours.

[0018] The solvent added in the N-dealkylation reaction is at least one of ethyl acetate, dichloromethane, and acetonitrile, preferably ethyl acetate which is compatible with the vildagliptin mother liquor.

[0019] The amount of solvent used is 1 to 3 times the mass of the vildagliptin mother liquor.

[0020] The above-mentioned N-dealkylation reaction includes a pretreatment process: the purified vildagliptin mother liquor (containing approximately 3-40% disubstituted impurities and 15-65% vildagliptin) is concentrated under reduced pressure to 1 / 3 to 1 / 2 of its original volume to remove some of the recrystallization solvent (such as methyl ethyl ketone or ethanol), yielding the vildagliptin mother liquor. The mother liquor after this pretreatment does not require deep drying, and the small amount of residual recrystallization solvent (such as methyl ethyl ketone) will not affect the selectivity of the dealkylation reaction, thus reducing the energy consumption of the pretreatment.

[0021] The above N-dealkylation reaction also includes post-treatment: When only an oxidant is added to the vildagliptin mother liquor, the post-treatment process is as follows: saturated sodium sulfite aqueous solution is added to the N-dealkylation reaction solution to quench excess hydrogen peroxide, and the mixture is stirred until no bubbles are generated. The organic phase obtained by separation is then washed with water and saturated brine in sequence, and concentrated under reduced pressure to obtain the crude vildagliptin product.

[0022] When both an oxidant and a catalyst are added to the vildagliptin mother liquor, the post-treatment process is as follows: First, the organic phase obtained from the N-dealkylation reaction is mixed with an EDTA aqueous solution and washed to remove iron ions. The resulting organic phase is then separated and washed successively with water and saturated brine, followed by vacuum concentration to obtain crude vildagliptin recovery. More preferably, the crude vildagliptin recovery is purified by recrystallization. The recrystallization solvent is butanone, acetone, isopropanol, or ethanol, and the recrystallization temperature is 0-8°C.

[0023] The crude vildagliptin obtained from the post-processing is purified to obtain vildagliptin. The purification process is as follows: the crude vildagliptin is added to solvents such as butanone, acetone, isopropanol or ethanol (volume ratio of crude vildagliptin to solvent is 8~12:1), heated to reflux temperature to complete dissolution, and then slowly cooled to 0~8℃ to crystallize. The mixture is kept warm and stirred for 2~3 hours, filtered, and vacuum dried at 45~50℃ for 4~6 hours to obtain the finished vildagliptin product.

[0024] The innovativeness and technological advantages of this application are reflected in the following aspects: 1) Precise treatment target: For the first time, a recovery process was designed specifically for the mother liquor of vildagliptin refining (rather than the reaction liquid or crude product), solving the core pain points of waste liquid discharge and product waste caused by multiple refining processes and filling the gap in existing technology.

[0025] 2) Industrial-grade reagents: Peroxyacid compounds (including industrial-grade hydrogen peroxide, peracetic acid, etc.) are selected as oxidants, combining high reaction efficiency with industrial applicability. Hydrogen peroxide is the mainstream choice, with water as the only byproduct and no harmful waste generated. The treated aqueous phase is neutralized to pH 7-8 with a 10% sodium hydroxide solution, and after solvent recovery by distillation, the COD drops to below 5000 mg / L, a reduction of over 70%, allowing it to be directly introduced into conventional wastewater treatment systems. Environmental pressure is significantly reduced; the overall byproducts of peroxyacids are clean and controllable, avoiding the environmental and safety hazards associated with traditional highly toxic reagents. In terms of cost, industrial-grade hydrogen peroxide is only 1 / 5 the price of reagents such as mCPBA. Other peroxyacid reagents, such as peracetic acid, also have the advantages of wide availability and high cost-effectiveness in industrial applications. Compared with traditional oxidants and highly toxic reagents, the production cost of the recovery process is significantly reduced, fully adapting to the needs of large-scale industrial applications.

[0026] 3) High resource utilization rate: The conversion rate of double-substituted impurities is ≥92%, which not only recovers the residual vildagliptin in the mother liquor, but also converts the impurities into the target product in a targeted manner. 3~8kg of finished product can be recovered from every 100L of refined mother liquor, and the raw material utilization rate is increased by 8~12%.

[0027] 4) Strong process adaptability: The reaction conditions are mild (5~25℃), no high pressure or high temperature equipment is required, and it can be directly connected to the existing refining section of vildagliptin production without large-scale modification and low modification cost.

[0028] 5) Simple operation: The mother liquor only requires simple concentration pretreatment, and the post-treatment steps are conventional. No complex separation equipment is required, making it suitable for large-scale continuous industrial operation. Attached Figure Description

[0029] To more clearly illustrate the technical solutions in the embodiments of this application, the accompanying drawings used in the embodiments will be briefly introduced below.

[0030] Figure 1 This is the mainstream synthetic process route for vildagliptin.

[0031] Figure 2 The HPLC chromatogram of the purified mother liquor of vildagliptin.

[0032] Figure 3 This is the HPLC chromatogram of the product after the N-dealkylation reaction.

[0033] Figure 4 This is a schematic diagram of the dealkylation reaction mechanism for disubstituted impurities.

[0034] Figure 5 shows the HPLC chromatogram of the recovered vildagliptin product. Detailed Implementation

[0035] The technical solution of this application will be described in detail below with reference to specific embodiments. These embodiments are only used to explain this application and do not limit the scope of protection of this application.

[0036] Example 1

[0037] This embodiment involves the treatment of mother liquor with high impurity content. During the treatment process, oxidants and catalysts are added to the mother liquor.

[0038] The steps for efficient recovery of vildagliptin using vildagliptin refining mother liquor are as follows: S1, Mother liquor pretreatment: Take 100L of purified mother liquor of vildagliptin butyric acid, and the HPLC detection results are as follows: Figure 2 As shown: the retention time of the disubstituted impurity peak was 26.86 min, and the content was 18.06%; the retention time of the vildagliptin peak was 18.32 min, and the content was 60.05%; the mother liquor was concentrated under reduced pressure to 40 L to obtain concentrated mother liquor (density: 1.12 g / mL).

[0039] S2, N-Dealkylation reaction: Add 80 L of ethyl acetate to the concentrated mother liquor, stir until homogeneous, and then cool to 10 °C. Add 3.2 kg of FeSO4·7H2O (i.e., 15% of the molar amount of the disubstituted impurity); slowly add 12.5 kg of 30% industrial-grade hydrogen peroxide (the molar ratio of the disubstituted impurity to hydrogen peroxide is 1:5.0) dropwise over 2 h, maintaining the temperature at 12 °C, and stirring for 6 h. HPLC monitoring results are as follows: Figure 3 As shown, the peak area of ​​vildagliptin accounts for 99.49%, the peak of disubstituted impurities disappears, and the content of disubstituted impurities decreases to 0.09%.

[0040] The mechanism of N-dealkylation reaction is as follows: Figure 4 As shown, the additional alkyl break-off sites and the vildagliptin formation pathway are marked.

[0041] S3, Post-processing: Add 30L of saturated sodium sulfite aqueous solution to the reaction solution, stir for 15min until no bubbles are generated, and separate the liquids; add 40L of 0.1M EDTA aqueous solution to the organic phase and wash once, then wash with water (40L×2) and saturated brine (40L×1), and concentrate under reduced pressure to dryness to obtain 16.8kg of vildagliptin crude product.

[0042] S4, Purification: The crude vildagliptin was recovered and added to 60 L of a butanone-ethanol mixed solvent (volume ratio 4:1). The mixture was heated to reflux to dissolve, then slowly cooled to 5 °C and stirred for 2 h to induce crystallization. After filtration, the crystals were dried under vacuum at 48 °C for 5 h to obtain 15.2 kg of vildagliptin product with an HPLC purity of 99.89% (see chromatogram). Figure 5 The content of disubstituted impurities is 0.03%.

[0043] S5, Wastewater Treatment: The aqueous phase is neutralized to pH=7.5 with 10% sodium hydroxide aqueous solution, and 18L of butanone and 65L of ethyl acetate are recovered by distillation. The remaining wastewater has a COD of 4200mg / L and enters the conventional wastewater treatment system.

[0044] In this embodiment, the conversion rate of disubstituted impurities is 98.7%, 100L of refined mother liquor yields 15.2kg of finished product, the raw material utilization rate is increased by 10.3%, and the waste liquid discharge is reduced by 75%.

[0045] Example 2

[0046] This embodiment treats mother liquor with low impurity content. During the treatment process, only an oxidant needs to be added to the mother liquor, and no catalyst is required.

[0047] The steps for efficient recovery of vildagliptin using vildagliptin refining mother liquor are as follows: S1, Mother liquor pretreatment: Take 80L of vildagliptin ethanol purified mother liquor, HPLC detection: disubstituted impurity content 3.2%, vildagliptin content 19.5%; concentrate to 30L to obtain concentrated mother liquor.

[0048] S2,N-Dealkylation reaction: Add 50L of ethyl acetate to the concentrated mother liquor, heat to 23℃, and slowly add 6.8kg of 30% industrial-grade hydrogen peroxide (the molar ratio of disubstituted impurities to hydrogen peroxide is 1:8.0) dropwise over 1.5h. Stir the reaction for 18h, and monitor the HPLC to reduce the content of disubstituted impurities to 0.08%.

[0049] S3, Post-processing: Add 20L of saturated sodium sulfite aqueous solution for quenching, separate the liquid and liquid phases, wash the organic phase with water (30L×2) and saturated brine (30L×1), concentrate to dryness, and obtain 8.7kg of recovered crude product.

[0050] S4, Purification: The recovered crude product was added to 60L of a mixed solvent of butanone and ethanol (butanone to ethanol volume ratio 4:1), heated to reflux to dissolve, slowly cooled to 5℃, kept warm and stirred for 2h to crystallize, filtered, and dried under vacuum at 48℃ for 5h to obtain 7.9kg of vildagliptin product with HPLC purity of 99.89% and disubstituted impurity content of 0.06%.

[0051] S5, Wastewater Treatment: After neutralization in the aqueous phase, 12L of ethanol and 42L of ethyl acetate are recovered by distillation, and the COD of the remaining wastewater is 3800mg / L.

[0052] In this embodiment, the conversion rate of disubstituted impurities is 97.5%, 7.9 kg of finished product is recovered from 80 L of refined mother liquor, the raw material utilization rate is increased by 8.5%, and the waste liquid discharge is reduced by 70%.

[0053] Comparative Example 1

[0054] This comparative example represents the existing processing method: 100L of the same purified mother liquor as in Example 1 was taken and directly entrusted to an environmental protection company for disposal, with a disposal cost of RMB 12,000. All of the 28.3kg vildagliptin and 6.8kg disubstituted impurities (which can be converted into 4.7kg vildagliptin) contained therein were wasted, and no solvent was recovered. The wastewater was directly discharged, causing environmental pollution.

[0055] Comparing Example 1 and Comparative Example 1, it can be seen that this application utilizes an N-dealkylation reaction to specifically treat the vildagliptin refining mother liquor, achieving the directional conversion of disubstituted impurities into the target product, while simultaneously recovering residual vildagliptin and solvent from the mother liquor. This method boasts high impurity conversion rates and stable product yields, significantly reducing wastewater discharge and environmental treatment costs, improving raw material utilization, and fully meeting the needs of large-scale industrial production. It possesses significant economic value, environmental significance, and promising industrial application prospects.

[0056] The embodiments described above are merely preferred embodiments of this application, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of this application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the scope of protection of this application. The scope of protection of this application is determined by the appended claims.

Claims

1. A method for efficiently recovering vildagliptin from vildagliptin mother liquor, characterized in that: Using vildagliptin mother liquor containing disubstituted impurities as raw material, an N-dealkylation reaction is carried out at 5~25℃ for 4~24h to selectively remove the extra alkyl group of the disubstituted impurities in the mother liquor, so that the disubstituted impurities are converted into vildagliptin and recovered; the disubstituted impurities are derivatives of the tetrahydropyrrole ring or 3-aminoadamantaneol structural unit in the vildagliptin molecule with an additional alkyl substitution, and the mass content of the disubstituted impurities in the purified mother liquor is 3~40%.

2. The method for efficiently recovering vildagliptin from vildagliptin mother liquor according to claim 1, characterized in that: The vildagliptin mother liquor contains 3-15% (excluding 15%) of disubstituted impurities, and an oxidizing agent is added to the vildagliptin mother liquor; the vildagliptin mother liquor contains 15-40% of disubstituted impurities, and an oxidizing agent and Fe are added to the vildagliptin mother liquor. 2+ Salt.

3. The method for efficiently recovering vildagliptin from vildagliptin mother liquor according to claim 2, characterized in that: The oxidant is hydrogen peroxide or a peroxyacid compound.

4. The method for efficiently recovering vildagliptin from vildagliptin mother liquor according to claim 3, characterized in that: The peroxyacid compound is at least one of m-chloroperoxybenzoic acid, peracetic acid, peroxybenzoic acid, and hydrogen peroxide, and the molar ratio of the disubstituted impurity to the peroxyacid compound is 1:1.5~5.

0.

5. The method for efficiently recovering vildagliptin from vildagliptin mother liquor according to claim 2, characterized in that: The oxidant is added dropwise over a period of 1 to 3 hours, and the temperature of the mother liquor is controlled to be ≤15℃ during the addition process.

6. The method for efficiently recovering vildagliptin from vildagliptin mother liquor according to claim 2, characterized in that: The Fe 2+ The salt is any one of ferrous sulfate, ferrous chloride, or ferrous acetate, Fe 2+ The molar percentage of salt relative to disubstituted impurities is 8–20 mol.

7. The method for efficiently recovering vildagliptin from vildagliptin mother liquor according to claim 2, characterized in that: The vildagliptin mother liquor contains 3-15% (excluding 15%) of disubstituted impurities, and the N-dealkylation reaction is carried out at a temperature of 20-25°C for 15-24 hours; the vildagliptin mother liquor contains 15-40% of disubstituted impurities, and the N-dealkylation reaction is carried out at a temperature of 5-15°C for 4-10 hours.

8. The method for efficiently recovering vildagliptin from vildagliptin mother liquor according to claim 1, characterized in that: The solvent added in the N-dealkylation reaction is at least one of ethyl acetate, dichloromethane, and acetonitrile, and the amount of solvent used is 1 to 3 times the mass of the vildagliptin mother liquor.

9. A method for efficiently recovering vildagliptin from vildagliptin mother liquor according to any one of claims 1 to 8, characterized in that, The N-dealkylation reaction also includes post-processing: saturated sodium sulfite aqueous solution is added to the reaction solution of the N-dealkylation reaction to quench excess hydrogen peroxide, and the mixture is stirred until no bubbles are generated. The organic phase obtained by separation is then washed with water and saturated brine in sequence, and concentrated under reduced pressure to obtain crude vildagliptin recovery product; or, the organic phase obtained by N-dealkylation reaction is first mixed with EDTA aqueous solution to remove iron ions, and the organic phase obtained by separation is then washed with water and saturated brine in sequence, and concentrated under reduced pressure to obtain crude vildagliptin recovery product.

10. A method for efficiently recovering vildagliptin from vildagliptin mother liquor according to claim 9, characterized in that: The crude vildagliptin was purified by recrystallization. The solvent for recrystallization was butanone, acetone, isopropanol, or ethanol, and the recrystallization temperature was 0-8℃.

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