Preparation method of L-pyroglutamic acid etogliflozin

Abstract

The invention relates to the field of medicinal chemistry, in particular to a preparation method of L-pyroglutamic acid etogliflozin. An ethyl acetate / water system is adopted to dissolve an L-pyroglutamic acid etogliflozin crude product, after filtration, n-heptane is added, cooling and crystallization are performed to obtain the L-pyroglutamic acid etogliflozin, in the prepared product, the ratio of the etogliflozin to the L-pyroglutamic acid eutectic crystal is stable, the residual amount of a solvent is low, the content of an impurity Y can be controlled to be 0.05% or below, the minimum content can be controlled to be 0.02%, the product purity is high, and the yield is high. The yield is high. The method is low in production cost, simple to operate, high in yield, high in product purity, stable in quality and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a method for preparing L-pyroglutamic acid eletogliflozin, and particularly to a method for preparing high-quality L-pyroglutamic acid eletogliflozin. Background Technology

[0002] L-pyroglutamic acid eletogliflozin, chemically named (1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol and (2S)-5-pyrrolidone-2-carboxylic acid, is a novel SGLT-2 hypoglycemic drug jointly developed by Merck and Pfizer. It was approved by the FDA in the United States in December 2017 under the brand name STEGLATRO, and is available in 5mg (6.48mg L-pyroglutamic acid eletogliflozin) and 10mg (19.43mg L-pyroglutamic acid eletogliflozin). In July 2020, the 5mg formulation was approved for the Chinese market.

[0003] The chemical formula of L-pyroglutamic acid eletoggliflozin is: ; During the preparation of L-pyroglutamic acid eletogliflozin, degradation easily occurs, generating impurity Y, the structure of which is: .

[0004] The main preparation methods for L-pyroglutamic acid eletoggliflozin that have been publicly disclosed include: Patent WO2014159151 discloses a method for preparing L-pyroglutamic acid eletogliflozin. This patent employs a three-step purification process involving acetic anhydride protection and deprotection of crude eletogliflozin before forming a co-crystal compound with L-pyroglutamic acid. The yield of the co-crystal step is only 85%. The specific preparation process is as follows: Purified eletogliflozin is dissolved in methanol, concentrated, and then isopropanol is added. The mixture is heated to 60°C, water is added, and then 2.7 equivalents of an aqueous solution of L-pyroglutamic acid is added dropwise. The mixture is heated to 80°C. Seed crystals are added after cooling to 40°C, and the temperature is gradually lowered to 20°C. The mixture is then filtered and dried to obtain L-pyroglutamic acid eletogliflozin.

[0005] This patent uses an isopropanol / water system to prepare eutectic compounds, but the resulting product has a high content of isopropanol and a high content of impurity Y, resulting in low product purity.

[0006] The preparation method of L-pyroglutamic acid eletogliflozin disclosed in this patent is complicated. First, eletogliflozin is removed by a three-step reaction of acetic anhydride protection and deprotection. L-pyroglutamic acid is added to the reaction system at 60°C and then the temperature is raised to 80°C. The high temperature results in a high content of degradation impurity Y (produced by the reaction of L-pyroglutamic acid and eletogliflozin) in the product. The isopropanol / water system is used for co-crystallization, resulting in a high content of isopropanol in the product.

[0007] Patent CN107382952A discloses a method for preparing L-pyroglutamic acid eletogliflozin. This patent first purifies crude eletogliflozin through a two-step reaction involving protection and deprotection with pentovalinyl chloride. Then, the purified eletogliflozin is reacted with L-pyroglutamic acid in an ethanol / water solvent system to form a co-crystal compound, thus preparing L-pyroglutamic acid eletogliflozin. The detailed preparation process is as follows: anhydrous ethanol and water are added to the purified eletogliflozin after protection and deprotection with pentovalinyl chloride. After stirring to dissolve, an aqueous solution of L-pyroglutamic acid is added, and the mixture is heated to 75℃~80℃ and stirred for 1~2 hours. The mixture is then slowly cooled and stirred to crystallize. After cooling to 15℃~20℃, the mixture is slurried for 2~3 hours, filtered, and dried to obtain the co-crystal compound L-pyroglutamic acid eletogliflozin.

[0008] This patent uses an ethanol / water system to prepare eutectic compounds. The resulting product has high levels of residual ethanol and impurity Y, and the purity of the product is still not ideal.

[0009] The preparation method of L-pyroglutamic acid eletogliflozin disclosed in this patent is complicated. First, eletogliflozin needs to be purified through a two-step reaction, and then it needs to be co-crystallized with L-pyroglutamic acid. The addition of L-pyroglutamic acid to the reaction system requires heating to 75℃~80℃. If the temperature is too high, the content of degradation impurity Y (generated by the reaction of L-pyroglutamic acid and eletogliflozin) in the product may be too high. The co-crystallization preparation using an ethanol / water system may result in a higher ethanol content in the product.

[0010] Patent WO2021260498 discloses a method for preparing L-pyroglutamic acid eletogliflozin. This patent employs a three-step purification process: propionyl chloride protection, recrystallization, and deprotection, followed by the formation of a co-crystal compound with L-pyroglutamic acid. The preparation process is as follows: the purified eletogliflozin reaction solution (after propionyl chloride protection, recrystallization, and deprotection) is concentrated and then dissolved in isopropanol and heated to 60℃~65℃. An aqueous solution of L-pyroglutamic acid and activated carbon are added, and the mixture is heated to 70℃~80℃ for 30 minutes. The mixture is filtered, and the filtrate is concentrated at 40℃~50℃ to obtain a viscous residue. Methyl tert-butyl ether and n-heptane are then added for solidification. The mixture is filtered and dried to obtain L-pyroglutamic acid eletogliflozin.

[0011] The patent requires a three-step purification process for eletogliflozin before co-crystallization: propionyl chloride protection, recrystallization, and deprotection. This process is cumbersome. First, the co-crystallized compound is prepared using an isopropanol / water system. Then, methyl tert-butyl ether / n-heptane is added for solidification. L-pyroglutamic acid is added to the reaction system at approximately 60°C, and then the temperature is raised to 70°C–80°C. Higher temperatures result in a higher content of degradation impurity Y (a byproduct of the reaction between L-pyroglutamic acid and eletogliflozin) in the product. Furthermore, the use of an isopropanol / water system leads to a higher isopropanol content in the resulting product, resulting in a lower yield and purity after purification.

[0012] Similar methods for preparing L-pyroglutamic acid eletogliflozin are disclosed in patent CN102149717B, literature (Development of an Early-Phase Bulk Enabling Route to Sodium-Dependent Glucose Cotransporter 2 Inhibitor Ertugliflozin. Org. Process Res.Dev., 2014, 18, 57-65), and patent CN117551150A: An eletogliflozin dichloromethane solution is concentrated, then isopropanol is added for further concentration, followed by the addition of isopropanol and water, and the temperature is raised to 55°C. An aqueous solution of L-pyroglutamic acid is added dropwise, and the mixture is cooled to room temperature after 2 hours. A small amount of L-pyroglutamic acid eletogliflozin seed crystals are added, and the mixture is stirred at room temperature for 18 hours, then cooled to 3°C and stirred for 2 hours. The mixture is filtered, and the filter cake is dried at 45°C to constant weight to obtain L-pyroglutamic acid eletogliflozin.

[0013] The literature (Development of an Early-Phase Bulk Enabling Route to Sodium-Dependent Glucose Cotransporter 2 Inhibitor Ertugliflozin. Org. ProcessRes.Dev.,2014, 18, 57-65) clearly states that the ratio of eltogliflozin to L-pyroglutamic acid in the prepared L-pyroglutamic acid eltogliflozin cocrystal is 1:1.1. The theoretical ratio of eltogliflozin to L-pyroglutamic acid in L-pyroglutamic acid eltogliflozin should be 1:1.0. Due to the high content of L-pyroglutamic acid, the product obtained by this method has a lower content. When the method described in the literature was repeated to prepare eletogliflozin for L-pyroglutamic acid, the isopropanol residue was high, approximately 0.60%, which is higher than the limit of 0.5% for Class 3 solvents specified in ICH Q3. Increasing the drying temperature and extending the drying time did not reduce the isopropanol residue, indicating a quality risk of low co-crystallization ratio of eletogliflozin and L-pyroglutamic acid and high residual solvent content.

[0014] Given the unique physicochemical properties of eltoggliflozin L-pyroglutamic acid, most of the preparation methods in currently published literature and patents involve purifying eltoggliflozin before co-crystallization, without a method for refining eltoggliflozin L-pyroglutamic acid by recrystallization after co-crystallization. The preparation of the compound by directly co-crystallizing purified eltoggliflozin with L-pyroglutamic acid suffers from problems such as a low co-crystallization ratio of eltoggliflozin to L-pyroglutamic acid, high solvent residue, high content of degradation impurities (γ), and low content of γ, affecting product quality stability. Furthermore, the purification of eltoggliflozin before co-crystallization requires protection and deprotection steps, which are cumbersome. Therefore, it is necessary to develop a preparation method that simultaneously addresses the problems of low co-crystallization ratio of eltoggliflozin to L-pyroglutamic acid, high solvent residue, high content of degradation impurities, and low content of γ. Summary of the Invention

[0015] To address the problems of high impurity content, high solvent residue, low co-crystal ratio of eletogliflozin and L-pyroglutamic acid, and poor product quality stability caused by low content in existing technologies, this invention provides a method for preparing L-pyroglutamic acid eletogliflozin. The method involves dissolving crude L-pyroglutamic acid eletogliflozin in an ethyl acetate / water system, filtering, adding n-heptane, and then cooling to crystallize to obtain L-pyroglutamic acid eletogliflozin. The resulting product exhibits a stable co-crystal ratio of eletogliflozin and L-pyroglutamic acid, low solvent residue, and the impurity Y content can be controlled below 0.05%, with a minimum controllable level of 0.02%. The product boasts high purity and high yield. This method offers low production cost, simple operation, high yield, high product purity, and stable quality, making it suitable for industrial production.

[0016] The preparation method of L-pyroglutamic acid eletogliflozin provided by this invention is specifically as follows: S1. The crude L-pyroglutamic acid eletoggliflozin was dissolved in an ethyl acetate / water mixture and then filtered to remove insoluble impurities; The preparation method of crude L-pyroglutamic acid eletogliflozin is widely described and applied in the art. In the embodiments of the present invention, the method described in paragraph

[0076] of document CN102149717B is adopted. The method is roughly as follows: the dichloromethane solution of eletogliflozin is concentrated, then the solvent is exchanged for 2-propanol, water is added, then the mixture is heated to 55°C, an aqueous solution of L-pyroglutamic acid is added, and then the resulting solution is cooled to room temperature. Then, seed crystals are added to the solution and granulated for 18 hours. After cooling, the solid is collected, washed with heptane, and then dried. The product L-pyroglutamic acid eletogliflozin is separated as a solid.

[0017] The purity of the crude L-pyroglutamic acid eletogliflozin obtained was 95-99%, the content of impurity Y was 0.2-0.8%, and the content of other single impurities was 0.1-0.5%. The chemical structural formula of impurity Y is shown below: .

[0018] S2. Add n-heptane to the filtrate in S1, cool to allow crystallization, filter, and dry to obtain L-pyroglutamic acid etagliflozin.

[0019] This invention employs a purification process on the co-crystallized product of eletogliflozin and L-pyroglutamic acid, replacing the prior art method of purifying eletogliflozin before co-crystallization. Results show that the purification method following co-crystallization of this invention has advantages such as higher yield and higher product purity compared to the prior art method of purifying eletogliflozin before co-crystallization. Furthermore, it solves problems such as high solvent residue and high content of degradation impurities in the co-crystallized product, and also brings the molar ratio of L-pyroglutamic acid to eletogliflozin in the co-crystallized product closer to 1:1.

[0020] Preferably, the temperature at which the crude product in S1 dissolves is 20–70°C, the volume / mass ratio of n-heptane in S2 to crude L-pyroglutamic acid etanercept in S1 is 5–30 mL:1 g, and the crystallization temperature is -10–30°C.

[0021] More preferably, the temperature at which the crude product in S1 is dissolved is 20–30°C, the volume / mass ratio of n-heptane in S2 to crude L-pyroglutamic acid etanercept in S1 is 10 mL:1 g, and the crystallization temperature is 0–10°C.

[0022] When the dissolution temperature exceeds the aforementioned range, the impurity Y content in the product will increase, leading to a decrease in product yield and purity, and a decline in quality.

[0023] When the crystallization temperature is too high, the product yield decreases; when the crystallization temperature is too low, the product purity decreases. When the crystallization temperature is kept within the range of -10 to 30°C, both high yield and high purity can be achieved.

[0024] Preferably, in the ethyl acetate / water mixture in S1, the volume ratio of ethyl acetate to water is 5-20:1, and the volume-to-mass ratio of the ethyl acetate / water mixture to crude L-pyroglutamic acid etanercept is 4-8 mL:1 g.

[0025] More preferably, in the ethyl acetate / water mixture in S1, the volume ratio of ethyl acetate to water is 12.5:1, and the volume-to-mass ratio of the ethyl acetate / water mixture to the crude L-pyroglutamic acid etanerceptin is 5.4 mL:1 g.

[0026] When the volume ratio of ethyl acetate to water exceeds the aforementioned range, the solubility of crude L-pyroglutamic acid eletoggliflozin in the ethyl acetate / water mixture decreases, thereby affecting the product yield, purity, and impurity Y content. Using the above method, the molar ratio of L-pyroglutamic acid to etogliflozin in the L-pyroglutamic acid etogliflozin prepared by S2 can be made close to 1:1.

[0027] The filtration described in S1 and S2 can be performed using filter paper or filter membrane, with no special requirements on the filter diameter. In the embodiments of the present invention, filter paper is used for filtration.

[0028] Compared with the prior art, the present invention has the following beneficial effects: 1) The present invention uses an ethyl acetate / water / n-heptane system for recrystallization, all of which are Class 3 solvents specified in ICH Q3C, and the residual solvents (ethyl acetate and n-heptane) can be well controlled without additional special processing.

[0029] 2) Low dissolution temperature and low energy consumption, resulting in lower production costs.

[0030] 3) In this invention, an ethyl acetate / water mixture is used as the recrystallization solvent, and n-heptane is used for recrystallization. The resulting product has a stable co-crystallization ratio of eletogliflozin and L-pyroglutamic acid, a stable L-pyroglutamic acid content, low solvent residue, high yield, and high purity. In particular, by controlling the dissolution temperature and the ratio of ethyl acetate to water, and by using n-heptane for crystallization, the content of impurity Y in the product is significantly reduced. The content of degradation impurity Y can be controlled to a minimum of 0.02%, which is far below the 0.5% limit in the import registration standard for pharmaceutical preparations.

[0031] In the prior art, in the co-crystallization of L-pyroglutamic acid and eletogliflozin, an excess of L-pyroglutamic acid is added to ensure complete co-crystallization of eletogliflozin. As a result, the co-crystallized product contains more L-pyroglutamic acid, causing the molar ratio of eletogliflozin to L-pyroglutamic acid in the co-crystallized product to deviate from 1:1. Purification can bring the molar ratio of eletogliflozin to L-pyroglutamic acid closer to 1:1, but at the same time, it produces other problems such as high solvent residue, high impurity Y content, low product purity, and low yield.

[0032] This method employs a specific ratio of ethyl acetate / water dissolution system and n-heptane crystallization system, and controls the dissolution and crystallization temperatures. This not only brings the co-crystallization molar ratio of eletogliflozin to L-pyroglutamic acid close to 1:1, but also reduces solvent residue and impurity Y content, thereby improving product purity and yield.

[0033] 4) By controlling the ratio of ethyl acetate to water in the ethyl acetate / water mixture, this scheme ensures the good solubility of L-pyroglutamic acid eletogliflozin in the system, providing a good foundation for subsequent crystallization operations and significantly improving the product yield, purity and impurity Y content.

[0034] 5) The entire process has mild reaction conditions, is easy to operate, reduces production costs, and is suitable for industrial production. Attached Figure Description

[0035] Figure 1 The hydrogen nuclear magnetic resonance (H-NMR) spectrum of L-pyroglutamic acid etoragliflozin prepared in this invention; Figure 2 The mass spectrum (MS) of L-pyroglutamic acid etorafenib obtained in this invention is shown. Figure 3 The high-performance liquid chromatography (HPLC) chromatogram of L-pyroglutamic acid eletogliflozin prepared in this invention is shown below. Figure 4 The image shows the gas chromatogram (GC) of L-pyroglutamic acid etoragliflozin prepared in this invention. Detailed Implementation

[0036] The technical solution of the present invention will be further described below with reference to specific embodiments. These embodiments are only used to illustrate the technical solution of the present invention in more detail and should not be construed as limiting the scope of protection of the present invention.

[0037] In the following examples, the determination of the relevant substance and impurity Y, as well as its purity, was performed using high-performance liquid chromatography (HPLC), with the following chromatographic conditions: The chromatographic column was Waters Acquity BEH Phenyl, 2.1 × 100 mm, 1.7 μm; Mobile phase A: 0.1% phosphoric acid solution; Mobile phase B: Acetonitrile; Perform linear gradient elution according to Table 1; The flow rate was 0.4 ml per minute, and the detection wavelength was 225 nm. The column temperature was 30℃; the injection volume was 2μl.

[0038] Table 1 Gradient elution settings for related substance detection

[0039] In the following examples, the residual solvent was detected using gas chromatography under the following chromatographic conditions: The chromatographic column was a 6% cyanopropyl / phenyl and 94% polydimethylsiloxane capillary column (VF-624ms, 30m × 0.53 mm, 3μm). Temperature rise program: Initial temperature 40℃, maintain for 5 minutes; increase temperature to 220℃ at a rate of 10℃ per minute, maintain for 2 minutes; Carrier gas: Nitrogen; Pressure: 2.1226 psi, constant pressure mode; Inlet temperature: 250℃; Detector: Flame ionization detector (FID), 280℃; Injection method: direct injection; Injection volume: 1 μl; Split ratio: 10:1.

[0040] In the following examples, the molar ratio of eletogliflozin to L-pyroglutamic acid in the final cocrystal product obtained from L-pyroglutamic acid eletogliflozin is calculated using the following formulas:

[0041] Note: M 艾托格列净 M is the molar molecular weight of eletogliflozin. L-焦谷氨酸 is the molar molecular weight of L-pyroglutamic acid.

[0042] The L-pyroglutamic acid content in the cocrystallized product was detected by high performance liquid chromatography (HPLC), under the following chromatographic conditions: Chromatographic column: Kromasil 100-5-C18(W), 4.6 mm × 250 mm, 5 µm; Mobile phase A: 25 mmol / L potassium hexafluorophosphate solution (pH 2.5, pH adjusted with phosphoric acid); Mobile phase B: Acetonitrile; A standard solution of impurity Y was used as a control for liquid chromatography detection. Impurity Y was purchased from CATO (Guangzhou Jiatu Technology Co., Ltd.), product number C4X-30111.

[0043] Perform linear gradient elution according to Table 2; The flow rate was 1.0 ml per minute, and the detection wavelength was 205 nm. The column temperature was 35℃; the injection volume was 20μl.

[0044] Table 2 Gradient elution settings for high-performance liquid chromatography (HPLC) detection of L-pyroglutamic acid content in eletogliflozin. In the following embodiments, the purity was detected and calculated using the aforementioned methods for detecting related substances, the yield was calculated based on the amount of reactants produced, and the molar ratio of L-pyroglutamic acid to etogliflozin in L-pyroglutamic acid etogliflozin was obtained by detecting the L-pyroglutamic acid content, as shown above.

[0045] The crude L-pyroglutamic acid etogliflozin used in the following examples was prepared according to the method described in paragraph

[0076] of document CN102149717B. The crude L-pyroglutamic acid etogliflozin prepared in the following examples and comparative examples all used the same batch of crude L-pyroglutamic acid etogliflozin. The content of crude L-pyroglutamic acid etogliflozin, the content of impurity Y, and the content of single impurities were detected (the detection method is the same as described above). The results showed that the purity of L-pyroglutamic acid etogliflozin in the crude product was 95.05%, the content of impurity Y was 0.75%, and the maximum single impurity was 0.49%.

[0046] Example 1: Preparation of L-pyroglutamic acid eletogliflozin S1. Add ethyl acetate / water (50 mL / 4 mL) to a 500 mL three-necked flask, start stirring, add 10.00 g of crude L-pyroglutamic acid eletoggliflozin, heat to the dissolution temperature of 20-30℃ to dissolve the crude solid, and filter to remove insoluble impurities; S2. Control the temperature at 20-30℃ and add 100 mL of n-heptane dropwise. Cool down to the crystallization temperature of 0-10℃, stir to crystallize for 4 hours, filter, and vacuum dry at 50℃ to constant weight to obtain L-pyroglutamic acid etagliflozin.

[0047] The 1H NMR, MS, HPLC, and GC spectra of L-pyroglutamic acid eletogliflozin prepared in Example 1 are shown below. Figure 1 , Figure 2 , Figure 3 and Figure 4 As shown.

[0048] Comparative Examples 1-12 were prepared using essentially the same method as in Example 1, except that an equal volume (54 mL) of other recrystallization solvents were added instead of ethyl acetate / water in Example 1, and the dissolution temperatures of Comparative Examples 1-12 were changed to the optimal dissolution temperatures corresponding to each recrystallization solvent (determined through preliminary experiments). The recrystallization solvents used in Example 1 and Comparative Examples 1-12, as well as the yields, purity, and residual solvents of the products, are shown in Table 3. Table 3. Recrystallization solvents, yields, purity, and residual solvents for Examples 1 and Comparative Examples 1–12 Experimental results show that the product yield varies significantly when recrystallization is performed using different solvents, and the crude product is almost insoluble in n-heptane. Recrystallization with alcohols and ketones results in high solvent residue levels, approaching the upper limit specified in ICH Q3C (≤0.5% for Class 3 solvents), and impurity removal is poor. Using ethyl acetate / water as the solvent yields the highest yield, with ethyl acetate residue levels far below the specified limit, and good impurity removal. Under different recrystallization solvent systems, only when using ethyl acetate / water as the solvent in Example 1 does the molar ratio of eletogliflozin to L-pyroglutamic acid approach 1:1.00. Considering both yield and product quality, using ethyl acetate / water yields the best results.

[0049] Comparative Examples 13-15 were prepared using essentially the same method as in Example 1, except that an equal volume (100 mL) of other crystallization solvents were added to replace the n-heptane used in Example 1. The recrystallization solvents, crystallization solvents used in Examples 1 and Comparative Examples 13-15, as well as the yield, purity, and impurity Y content of the products, are shown in Table 4. Table 4. Crystallization solvents, yields, and purity of Examples 1 and Comparative Examples 13-15

[0050] Experimental results show that, considering both yield and product purity, using n-heptane as the reverse crystallization solvent yields the best results.

[0051] Examples 2-5 prepared L-pyroglutamic acid eletogliflozin using essentially the same method as Example 1, the only difference being the use of different dissolution temperatures. Table 5 shows the dissolution temperatures used in Examples 1-5, as well as the product yield, purity, impurity Y content, and the molar ratio of eletogliflozin to L-pyroglutamic acid in the cocrystallized product.

[0052] Table 5. Dissolution temperature, yield, purity, and impurity content of Examples 1-5 Experimental results show that when the dissolution temperature in Example 1 is 20-30℃, the product yield and purity are higher than those in Examples 2-5.

[0053] Examples 6-11 and Comparative Examples 16 and 17 were prepared using essentially the same method as in Example 1, with the only difference being the use of different ethyl acetate / water ratios (the total volume remained 54 mL), as shown in Table 6.

[0054] Table 6. Ethyl acetate / water ratio, yield, purity, and impurity content for Examples 1, 6-11, and Comparative Examples 16 and 17. Experimental results show that when the volume ratio of ethyl acetate to water is in the range of 5 to 20:1, the yield and purity of the product are relatively high. In Example 1, the ethyl acetate / water volume ratio of 12.5:1 resulted in the highest yield and purity, and the lowest impurity content compared to Examples 6 to 11. When the ratio of ethyl acetate to water exceeds the above range, the solubility of crude L-pyroglutamic acid eletogliflozin will decrease, which will lead to the inability to purify the product or a decrease in product purity and yield, and an increase in impurity content.

[0055] Examples 12-15 were prepared using essentially the same method as in Example 1, with the only difference being the addition of different volumes of n-heptane, as shown in Table 7.

[0056] Table 7. Heptane dosage, yield, purity, and impurity content in Examples 1 and 12-15 The results showed that when a 10 mL:1 g ratio of n-heptane to crude product was used in Example 1, the product yield and purity were the highest compared to Examples 12-15.

[0057] Examples 16-18 prepared L-pyroglutamic acid eletogliflozin using essentially the same method as in Example 1, with the only difference being the crystallization temperature. The crystallization temperatures, product yields, purity, and impurity contents of Examples 1 and 16-18 are shown in Table 8.

[0058] Table 8. Crystallization temperature, product yield, purity, and impurity content for Examples 1 and 16-18 Experimental results show that the crystallization temperature affects the yield and purity of the product. When the crystallization temperature is between -10 and 10℃, the yield and purity of the product are relatively high. When the crystallization temperature is between -10 and 0℃, the yield is relatively high and the impurity content is low, but the purity is relatively slightly low. When the crystallization temperature is between 0 and 10℃, the impurity content is low and the purity is high, but the yield is relatively slightly low.

[0059] Comparative Example 18: L-pyroglutamic acid eletogliflozin was prepared using the preparation method in Example 6 of patent WO2014159151. The test results of the obtained product are shown in Table 9. Table 9. Product yield, purity, residual solvent and impurity content of Comparative Example 18 The experimental results show that in this comparative example, after eletogliflozin forms a co-crystal compound with L-pyroglutamic acid, the resulting product has a high residual solvent content and an isopropanol content higher than the limit specified in ICH Q3C (Class 3 solvents should be ≤0.5%); the content of degradation impurity Y is 0.58%, and the product purity is low.

[0060] Comparative Example 19: L-pyroglutamic acid eletogliflozin was prepared using the preparation method in Example 4 of patent WO2021260498. The test results of the obtained product are shown in Table 10. Table 10. Product yield, purity, residual solvent and impurity content of Comparative Example 19 The experimental results showed that after eletogliflozin and L-pyroglutamic acid formed a co-crystal compound in Comparative Example 19, the residual isopropanol in the resulting product was still relatively high, close to the limit specified in ICH Q3C (Class 3 solvents should be ≤0.5%); the content of degradation impurity Y was 0.53%, and the product purity was low.

[0061] Comparative Example 20: Following the instructions on page 64, "Preparation of 1-L-PGA," of the literature (Development of an Early-Phase Bulk Enabling Route to Sodium-Dependent Glucose Cotransporter 2 Inhibitor Ertugliflozin. Org. Process Res.Dev., 2014, 18, 57-65), L-pyroglutamic acid eletogliflozin was prepared. The test results of the obtained product are shown in Table 11. Table 11 Product yield, purity, and residual solvent of Comparative Example 20 The experimental results showed that the product obtained after eletogliflozin and L-pyroglutamic acid formed a co-crystal compound in Comparative Example 20 had a high solvent residue and an isopropanol content higher than the limit specified in ICH Q3C (Class 3 solvents should be ≤0.5%). The co-crystal ratio was eletogliflozin:L-pyroglutamic acid = 1:1.10, the product content was low, and it deviated from the theoretical co-crystal ratio of 1:1.00.

[0062] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any equivalent substitutions or modifications made by those skilled in the art within the spirit and principle of the present invention without any creative effort should be included within the protection scope of the present invention.

Claims

1. A method for preparing L-pyroglutamic acid etogliptin, characterized by, The specific steps are as follows: S1. Dissolve the crude L-pyroglutamic acid etogliptin in an ethyl acetate / water mixed system, and then filter to remove insoluble impurities; S2. Add n-heptane to the filtrate in S1, and then filter after crystallization at a reduced temperature, and dry to obtain L-pyroglutamic acid etogliptin.

2. The method for preparing L-pyroglutamic acid eletogliflozin according to claim 1, characterized in that: The crude L-pyroglutamic acid etogliptin has a purity of 95-99%, an impurity Y content of 0.2-0.8%, and other single impurity contents of 0.1-0.5%, and the chemical structural formula of the impurity Y is as follows: 。 3. The method for preparing L-pyroglutamic acid eletogliflozin according to claim 1 or 2, characterized in that: The crude product dissolving temperature in S1 is 20-70°C; the volume / mass ratio of n-heptane to the crude L-pyroglutamic acid etogliptin in S1 is 5-30 mL:1 g, and the crystallization temperature is -10-30°C.

4. The method for preparing L-pyroglutamic acid eletogliflozin according to claim 3, characterized in that: The crude product dissolving temperature in S1 is 20-30°C; the volume / mass ratio of n-heptane to the crude L-pyroglutamic acid etogliptin in S1 is 10 mL:1 g, and the crystallization temperature is 0-10°C.

5. The method for preparing L-pyroglutamic acid eletogliflozin according to claim 1 or 2, characterized in that: In the ethyl acetate / water mixed system in S1, the volume ratio of ethyl acetate to water is 5-20:1, and the volume / mass ratio of the ethyl acetate / water mixed system to the crude L-pyroglutamic acid etogliptin is 4-8 mL:1 g.

6. The method for preparing L-pyroglutamic acid eletogliflozin according to claim 5, characterized in that: In the ethyl acetate / water mixed system in S1, the volume ratio of ethyl acetate to water is 12.5:1, and the volume / mass ratio of the ethyl acetate / water mixed system to the crude L-pyroglutamic acid etogliptin is 5.4 mL:1 g.

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