A purification method for empagliflozin

Abstract

This invention provides a method for purifying empagliflozin. The method comprises (1) extracting a feed solution containing empagliflozin and impurities with an extractant to obtain an extract containing empagliflozin; the impurities include one or more isomers of empagliflozin, esters, and hydrolysis products; the solvent in the feed solution is selected from nonpolar solvents and / or weakly polar solvents; and the extractant includes an ionic liquid or a mixture of an ionic liquid and a polar solvent; (2) the extract containing empagliflozin is back-extracted and concentrated to obtain empagliflozin. This method has advantages such as high separation efficiency, low solvent consumption, low production cost, safety and environmental friendliness, and ease of industrial production.

Description

Technical Field

[0001] This invention relates to the field of chemical separation technology, specifically to a method for purifying empagliflozin. Background Technology

[0002] Empagliflozin, a novel oral hypoglycemic agent, possesses a unique insulin-independent hypoglycemic pathway. It primarily lowers blood glucose by inhibiting SGLT-2 expression in the kidneys, blocking glucose reabsorption and directly excreting glucose in the urine. Furthermore, it retains its hypoglycemic effect even when pancreatic β-cell function is impaired. Notably, in 2015, empagliflozin was confirmed by a major cardiovascular research center (CVOT) as the world's first drug for type 2 diabetes to reduce the risk of cardiovascular death, marking a significant milestone in the clinical treatment of type 2 diabetes and holding epoch-making significance.

[0003] Empagliflozin (CAS Registry No.: 864070-44-0), chemically named (1S)-1,5-dehydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucanol, contains six chiral centers in its structure. The total synthetic route involves numerous steps, and various impurities with structures similar to the starting material or the target product are generated during the reaction, severely affecting its purity and quality. Therefore, there is an urgent need to develop simple, efficient, and highly selective purification methods to separate empagliflozin from structurally similar impurities.

[0004] Existing separation and purification processes mainly obtain empagliflozin purified products through crystallization and recrystallization. This method has low purification efficiency, consumes a large amount of organic solvent, increases solvent recovery costs, and organic solvents are volatile, flammable, and toxic, posing hazards to the environment and safety during use. Moreover, it is difficult to effectively remove impurities with similar structures.

[0005] Currently, the separation of empagliflozin from its structurally similar optical isomers mainly involves chromatography. For example, CN106706769A discloses a high-performance liquid chromatography (HPLC) method using a chiral column derived from amylose or cellulose derivatives to separate and determine empagliflozin and its optical isomers. However, such methods are difficult to implement industrially due to limitations in cost and throughput. Therefore, to ensure the quality control of empagliflozin and guarantee its efficacy and safety, it is urgent to develop purification methods for empagliflozin to prepare high-purity empagliflozin products. Summary of the Invention

[0006] To address one of the aforementioned technical problems in the prior art, this invention provides a method for purifying empagliflozin. This invention discovers that empagliflozin can be effectively separated from empagliflozin impurities using an extraction method with an extractant containing ionic liquids.

[0007] The technical solution of the present invention is as follows:

[0008] This invention provides a method for purifying empagliflozin, the purification method comprising the following steps:

[0009] (1) Extracting the feed liquid containing empagliflozin and impurities with an extractant to obtain an extract containing empagliflozin; the impurities include one or more of the isomers of empagliflozin, esters, and hydrolysis products; the solvent in the feed liquid is selected from non-polar solvents and / or weakly polar solvents; and the extractant includes ionic liquids or mixtures of ionic liquids and polar solvents.

[0010] (2) The extract containing empagliflozin is back-extracted and concentrated to obtain empagliflozin.

[0011] According to some embodiments of the present invention, the mass fraction of the ionic liquid in the extractant is 0-100%, for example, 0, 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 5%, 10%, 20%, 25%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 100%, or any value between them. In some embodiments, the mass fraction of the ionic liquid in the extractant is 0.01-90%. In some embodiments, the mass fraction of the ionic liquid in the extractant is 0.5-60%. In some embodiments, the mass fraction of the ionic liquid in the extractant is 1-60%. In some embodiments, the mass fraction of the ionic liquid in the extractant is 10-50%. Adding an ionic liquid to a polar solvent can give empagliflozin an appropriate partition coefficient and higher separation selectivity. If the mass fraction of the ionic liquid is too low, the separation efficiency will not be significantly improved; if the mass fraction of the ionic liquid is too high, the viscosity of the solution will increase, affecting the mass transfer rate and increasing production costs.

[0012] According to some embodiments of the present invention, the solvent in the raw material solution is selected from at least one of halogenated hydrocarbon solvents, C6-C10 alcohol solvents, and C2-C10 ester solvents. In some embodiments, the solvent in the raw material solution is at least one of dichloroethane, n-octanol, n-decanol, ethyl acetate, butyl acetate, and isobutyl acetate.

[0013] In this invention, the ionic liquid is composed of cations and anions. According to some embodiments of the invention, the cation is selected from at least one of imidazole cations, pyridine cations, quinoline cations, isoquinoline cations, benzimidazole cations, piperidine cations, pyrrolidine cations, amino acid cations, quaternary ammonium cations, quaternary phosphorus cations, and choline cations. In some embodiments, to further improve the selective extraction and separation effect of empagliflozin, the cation is substituted with one or more substituents, wherein the substituents are selected from C1-C4 alkyl groups and / or C2-C4 hydrocarbon groups containing one or more functional groups selected from carbon-carbon double bonds, carbon-carbon triple bonds, hydroxyl groups, cyano groups, ether groups, ester groups, nitrile groups, sulfone groups, amino groups, carboxyl groups, and carbonyl groups. In some embodiments, the cation is selected from at least one of imidazole cations, piperidine cations, and choline cations. In some embodiments, the cation is substituted with one or more substituents selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, or ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, which contain one or more functional groups selected from carbon-carbon double bonds, carbon-carbon triple bonds, hydroxyl, cyano, ether, ester, nitrile, sulfone, amino, carboxyl, and carbonyl.

[0014] According to some embodiments of the present invention, the anion is selected from at least one of fluoride ions, chloride ions, bromide ions, iodide ions, nitrate ions, amino acid anions, trifluoroacetate ions, tetrafluoroborate ions, perchlorate ions, hydrogen sulfate ions, dicyandiamide ions, thiocyanate ions, saturated alkyl chain carboxylate ions with C2 to C24 carbon atoms, unsaturated alkyl chain carboxylate ions with C3 to C24 carbon atoms and containing 1 to 6 carbon-carbon double bonds, phosphate ions, hydrogen phosphate ions, or dihydrogen phosphate ions. In some embodiments, the anion is selected from at least one of fluoride ions, chloride ions, bromide ions, iodide ions, amino acid anions, and saturated alkyl chain carboxylate ions with C2 to C10 carbon atoms. In some embodiments, the anion is selected from at least one of fluoride ions, chloride ions, bromide ions, iodide ions, proline anions, tryptophan anions, alanine anions, proline anions, glycine anions, L-glutamate anions, and acetate ions.

[0015] According to some embodiments of the present invention, the ionic liquid is selected from at least one of 1-butyl-3-methylimidazolium proline, 1-ethyl-3-methylimidazolium chloride, 1-butyl-3-methylimidazolium chloride, 1-butyl-3-methylimidazolium acetate, 1-butyl-3-methylimidazolium tryptophan, 1-butyl-3-methylimidazolium trifluoroacetate, N-propyl-N-methylpiperidine bromide, choline alanine, choline proline, 1-hydroxyethyl-3-methylimidazolium bromide, 1-hydroxyethyl-3-methylimidazolium glycine, and 1-butyl-3-methylimidazolium L-glutamate.

[0016] The ionic liquid used in this invention has hydrogen-bonded basicity, which can identify minute differences between empagliflozin and structurally similar impurities, thereby achieving selective extraction and separation of empagliflozin.

[0017] According to some embodiments of the present invention, the polar solvent is selected from at least one of water, phosphate buffer solution, alcohol, nitrile, sulfone, sulfoxide, amide, and ketone. Examples of the polar solvent of the present invention include, but are not limited to, at least one of water, phosphate buffer solution, methanol, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone. In some embodiments, the polar solvent is selected from at least one of phosphate buffer solution, methanol, and acetonitrile. The phosphate buffer solution of the present invention includes, but is not limited to, disodium hydrogen phosphate-sodium dihydrogen phosphate buffer, potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer, etc. In some embodiments, the pH of the phosphate buffer solution is 2.0-6.0, for example, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, or any value between them. In the present invention, adding a polar solvent as an extractant to the ionic liquid not only reduces the viscosity of the extractant and promotes the two-phase transfer process, but also reduces the amount of ionic liquid used, thereby reducing production costs.

[0018] According to some embodiments of the present invention, the extractant is selected from a mixture of 1-butyl-3-methylimidazolium proline salt and phosphate buffer solution, 1-butyl-3-methylimidazolium chloride, choline proline salt, a mixture of choline proline salt and phosphate buffer solution, a mixture of 1-butyl-3-methylimidazolium tryptophan salt and phosphate buffer solution, a mixture of 1-hydroxyethyl-3-methylimidazolium glycine salt and methanol, a mixture of 1-butyl-3-methylimidazolium L-glutamate salt and acetonitrile, N-propyl-N-methylpiperidine bromide, and 1-ethyl-3-methylimidazolium chloride. The mixture of at least one of the following: a mixture of 1-butyl-3-methylimidazolium chloride and phosphate buffer; a mixture of 1-butyl-3-methylimidazolium acetate and phosphate buffer; a mixture of 1-butyl-3-methylimidazolium trifluoroacetate and phosphate buffer; a mixture of 1-butyl-3-methylimidazolium chloride and acetonitrile; a mixture of N-propyl-N-methylpiperidine bromide and N-methylpyrrolidone; a mixture of choline alanine salt and N,N-dimethylformamide; and a mixture of 1-hydroxyethyl-3-methylimidazolium bromide and methanol.

[0019] According to some embodiments of the present invention, the extractant is selected from at least one of the following: a mixture of 1-butyl-3-methylimidazolium proline salt and phosphate buffer solution; a mixture of choline proline salt and phosphate buffer solution; a mixture of 1-butyl-3-methylimidazolium tryptophan salt and phosphate buffer solution; a mixture of 1-butyl-3-methylimidazolium L-glutamate salt and acetonitrile; and a mixture of 1-hydroxyethyl-3-methylimidazolium glycine salt and methanol.

[0020] According to some embodiments of the present invention, the mass percentage of empagliflozin in the raw material solution is not less than 60%, for example, 60%-99%, and in some embodiments, the mass percentage of empagliflozin in the raw material solution is 80%-90%.

[0021] The impurities described in this invention include, but are not limited to, isomers of empagliflozin, acetates, hydrolysis products, etc. In some embodiments, the impurities include one or more of the following compounds:

[0022]

[0023] According to some embodiments of the present invention, the total concentration of empagliflozin and impurities in the feed solution is 0.1 g / L to 6000 g / L, for example, 0.1 g / L, 1 g / L, 5 g / L, 10 g / L, 20 g / L, 50 g / L, 100 g / L, 150 g / L, 200 g / L, 250 g / L, 300 g / L, 350 g / L, 400 g / L, 500 g / L, 600 g / L, 800 g / L, 1000 g / L, 2000 g / L, 3000 g / L, 4000 g / L, 5000 g / L, 6000 g / L, or any value between them. In some specific embodiments, the total concentration of empagliflozin and impurities in the feed solution is 1 g / L to 400 g / L. In some specific embodiments, the total concentration of empagliflozin and impurities in the feed solution is 10 g / L-400 g / L. If the total concentration of empagliflozin and impurities in the feed solution is too high, it is not conducive to the effective separation of empagliflozin; if the total concentration of empagliflozin and impurities in the feed solution is too low, the processing capacity is small, which is not conducive to the economic efficiency of the process.

[0024] According to some embodiments of the present invention, the extraction temperature is 20°C-60°C, for example, 20°C, 30°C, 40°C, 50°C, 60°C, or any value between them. If the extraction temperature is too low, the viscosity of the feed liquid, extractant, and detergent will be high, the mass transfer rate will be reduced, the throughput will be small, and it will be detrimental to production operations; if the extraction temperature is too high, the solvent will evaporate severely, which will reduce the distribution ratio and selectivity of the fractionation extraction.

[0025] In this invention, the extraction includes multi-stage extraction, such as cross-flow extraction, countercurrent extraction, or fractional extraction. In some embodiments, the extraction is fractional extraction.

[0026] The fractional extraction described in this invention can be performed using existing fractional extraction equipment. The fractional extraction includes an extraction section and a washing section. The extractant enters the fractional extraction system from the first stage of the extraction section, the feed liquid enters from the last stage of the extraction section, and the detergent enters from the first stage of the washing section. The feed and wash liquids are combined and enter the extraction section together at the last stage. The extract and wash phases undergo multi-stage countercurrent contact. A raffinate enriched with impurities flows out from the first stage of the extraction section, and an extract enriched with empagliflozin flows out from the first stage of the washing section. The extract is collected and then subjected to back-extraction and vacuum concentration to obtain the empagliflozin product.

[0027] In some implementations, the extraction stage can be 2-30 stages, such as stages 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 25, 28, 30, etc.; the washing stage can be 2-20 stages, such as stages 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, etc.

[0028] According to some embodiments of the present invention, in step (1), the flow ratio of the extractant to the feed liquid is (0.05-20):1, for example, 0.05:1, 0.08:1, 0.1:1, 0.5:1, 1:1, 2:1, 5:1, 8:1, 10:1, 12:1, 15:1, 18:1, 20:1, or any value between them. In some embodiments, in step (1), the flow ratio of the extractant to the feed liquid is (0.1-10):1. In some embodiments, in step (1), the flow ratio of the extractant to the feed liquid is (0.5-5):1.

[0029] In some embodiments, in step (1), the flow ratio of the detergent used during extraction to the feed liquid is (0.02-10):1, for example, 0.02:1, 0.05:1, 0.08:1, 0.1:1, 0.5:1, 1:1, 2:1, 5:1, 8:1, 10:1, or any value between them. In some embodiments, in step (1), the flow ratio of the detergent used during extraction to the feed liquid is (0.05-5):1; in some embodiments, in step (1), the flow ratio of the detergent used during extraction to the feed liquid is (0.5-4):1.

[0030] In some embodiments, the detergent used during extraction is selected from nonpolar solvents and / or weakly polar solvents, such as at least one of halogenated hydrocarbon solvents, alcohol solvents (preferably C6-C10 alcohol solvents), and ester solvents (preferably C2-C10 ester solvents). In some embodiments, the detergent used during extraction is at least one of dichloroethane, n-octanol, n-decanol, ethyl acetate, butyl acetate, and isobutyl acetate. In some embodiments, the detergent used during extraction is of the same type as the solvent in the feed solution. In this invention, using the same solvent for both the detergent and the solvent in the feed solution not only provides good solubility for the feed but also allows for the formation of a liquid-liquid two-phase system with low miscibility with the extractant, thus achieving better separation results.

[0031] According to some embodiments of the present invention, in step (2), the back-extraction agent used for back-extraction is selected from non-polar solvents and / or weakly polar solvents, such as halogenated hydrocarbon solvents, alcohol solvents (preferably C6-C10 alcohol solvents), ester solvents (preferably C2-C10 ester solvents), etc. In some embodiments, the back-extraction agent used for back-extraction is selected from at least one of dichloroethane, n-octanol, n-decanol, ethyl acetate, butyl acetate, and isobutyl acetate.

[0032] In some embodiments, the back-extraction agent is the same type of solvent as the feed liquid. In some embodiments, the back-extraction agent and the detergent are the same solvent.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] 1. This invention uses an extractant containing ionic liquids to extract (preferably multi-stage extraction) to achieve high selective separation of empagliflozin and impurities, removing structurally similar impurities. At the same time, the extractant used can be recycled and reused, reducing production costs and showing broad application prospects in industry.

[0035] 2. This invention uses fractional extraction technology, which can be operated continuously, has a large processing capacity, and is low in cost.

[0036] 3. The method of the present invention optimizes multi-stage extraction conditions and selects appropriate extraction process parameters (such as the flow ratio of multi-stage extraction, the mass fraction of ionic liquid in the extractant, temperature, number of plates, and other operating conditions). The purity of empagliflozin obtained after separation can reach more than 99%, and the yield can reach more than 98%. Attached Figure Description

[0037] Figure 1 A flow chart of the purification process of empagliflozin according to a specific embodiment of the present invention is shown. Detailed Implementation

[0038] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments and accompanying drawings. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of the invention in any way.

[0039] Unless otherwise specified, all reagents used in the following experiments of this invention are commercially available products or reagents prepared according to conventional methods. Unless otherwise specified, all methods used in the experiments are conventional experimental methods. Unless otherwise specified, all instruments used in the experiments are commercially available.

[0040] Ionic liquids are room-temperature molten salts composed entirely of ions. They possess excellent chemical and thermal stability, are non-toxic and harmless, non-flammable, have extremely low vapor pressure, and exhibit good solubility for most organic and inorganic substances, earning them the title of "green solvents." By designing the types of anions and cations and functional substituents in ionic liquids, their physicochemical properties, such as basicity, polarity, and viscosity, can be precisely controlled. This allows for the endowment of specific π-π, hydrogen bond, and dipole interactions, giving them a high affinity for the extracted components and achieving efficient separation of the corresponding solutes.

[0041] The purpose of this invention is to provide a method for separating empagliflozin from impurities that has a large processing capacity, simple process, and high efficiency. This method uses an ionic liquid or a mixture of an ionic liquid and a polar solvent as an extractant, which has a good separation effect on empagliflozin and impurities.

[0042] The polar solvents used in this invention can be, for example, phosphate buffer solutions, water, acetonitrile, methanol, dimethyl sulfoxide, etc., which have a certain separation effect on empagliflozin and impurities. If pure ionic liquids are used as extractants, there are drawbacks such as high viscosity leading to slow mass transfer rates, large dosage leading to high costs, and some ionic liquids being solids at room temperature requiring heating. Therefore, a third solvent is needed. This third solvent must have good miscibility with the ionic liquid, form a two-phase system with the raw material solvent, and allow for precise adjustment of the extractant's properties to improve the mass transfer rate and separation effect.

[0043] In one specific embodiment, the method includes: dissolving the crude product containing empagliflozin and impurities in a non-polar and / or weakly polar organic solvent to prepare a raw material solution; using an ionic liquid or a binary mixed solvent composed of an ionic liquid and a polar solvent as the extractant; using the same organic solvent as the raw material solution as the washing agent; performing fractional distillation extraction to obtain an extract; and obtaining high-purity empagliflozin through back-extraction and vacuum concentration.

[0044] like Figure 1As shown in the figure, as a specific embodiment, the purification method of empagliflozin includes: preparing a raw material solution by mixing a crude product containing empagliflozin and structurally similar impurities with a non-polar and / or weakly polar organic solvent; using an ionic liquid or a mixture of an ionic liquid and a polar solvent as the extractant and the raw material solvent as the washing agent for fractional extraction; the fractional extraction is divided into an extraction section and a washing section; the extractant enters the extraction system from the first stage of the extraction section, the raw material solution enters the extraction system from the last stage of the extraction section, and the washing agent enters the extraction system from the first stage of the washing section; the feed and wash phases are combined and enter the extraction section together at the last stage of the extraction section; the extraction phase and the washing phase undergo multi-stage countercurrent contact; the extract enriched with empagliflozin flows out from the first stage of the washing section, and the raffinate enriched with impurities flows out from the first stage of the extraction section; the extract is collected, and the empagliflozin product is obtained by back-extraction and vacuum concentration.

[0045] In some preferred embodiments, the nonpolar and / or weakly polar organic solvent is a hydrophobic organic solvent, the ionic liquid is a hydrophilic ionic liquid, and the polar solvent is water or a hydrophilic solvent.

[0046] In the following embodiments of the present invention, high-performance liquid chromatography (HPLC) was used to analyze the sample composition. Isopropanol / n-hexane (25 / 75, v / v) was used as the mobile phase, the chromatographic column was a CHIRALPAK IK (150 mm × 4.6 mm, 5 μm), the injection volume was 10 μL, the flow rate was 1 mL / min, the column temperature was 35 °C, and the detection wavelength was 224 nm.

[0047] The methods for calculating yield and HPLC purity in this invention are as follows:

[0048] Empagliflozin yield = (weight of empagliflozin in product / weight of empagliflozin in feed) × 100%;

[0049] Empagliflozin HPLC purity = peak area of ​​empagliflozin in the product / sum of peak areas of all components in the product × 100%.

[0050] The structures of the various substances in the crude empagliflozin raw material in the following examples and comparative examples are shown below:

[0051]

[0052] Example 1:

[0053] Empagliflozin crude feedstock (containing 87 wt% empagliflozin, 4.0 wt% impurity A, 3.5 wt% impurity B, 1.9 wt% impurity C, 1.7 wt% impurity D, 1.5 wt% impurity E, and 0.4 wt% other impurities) was dissolved in ethyl acetate to prepare a feedstock solution with a total concentration of 100 g / L. A mixed solvent of 1-butyl-3-methylimidazolium proline salt and phosphate buffer solution was used as the extractant (the phosphate buffer solution was disodium hydrogen phosphate-sodium dihydrogen phosphate buffer, pH=5.0; the mass fraction of 1-butyl-3-methylimidazolium proline salt in the extractant was 20%), and ethyl acetate was used as the washing agent. The flow ratio of extractant, washing agent, and feed solution was 2:4:2. Fractional extraction was carried out at 30℃, consisting of an extraction section and a washing section (8 stages in the extraction section and 5 stages in the washing section). The extractant entered the fractional extraction system from the first stage of the extraction section, the feed solution entered from the last stage of the extraction section, and the washing agent entered from the first stage of the washing section. An extract rich in empagliflozin flowed out from the first stage of the washing section, and a raffinate rich in impurities flowed out from the first stage of the extraction section. The extract was collected, back-extracted with ethyl acetate, and concentrated under vacuum to obtain empagliflozin. HPLC analysis showed that the purity of empagliflozin was 99.5%, and the yield was 98%.

[0054] Example 2:

[0055] Empagliflozin crude feedstock (containing 87 wt% empagliflozin, 4.0 wt% impurity A, 3.5 wt% impurity B, 1.9 wt% impurity C, 1.7 wt% impurity D, 1.5 wt% impurity E, and 0.4 wt% other impurities) was dissolved in ethyl acetate to prepare a feedstock solution with a total concentration of 50 g / L. Using 1-butyl-3-methylimidazolium chloride as the extractant and ethyl acetate as the washing agent, with a flow ratio of extractant, washing agent, and feedstock solution of 4:3:2, fractional extraction was performed at 20 °C. The extract was collected, back-extracted with ethyl acetate, and concentrated under vacuum to obtain empagliflozin. HPLC analysis showed that the purity of empagliflozin was 92%, and the yield was 94%.

[0056] Example 3:

[0057] Empagliflozin crude feedstock (containing 87 wt% empagliflozin, 4.0 wt% impurity A, 3.5 wt% impurity B, 1.9 wt% impurity C, 1.7 wt% impurity D, 1.5 wt% impurity E, and 0.4 wt% other impurities) was dissolved in n-octanol to prepare a feedstock solution with a total concentration of 10 g / L. Choline-proline salt was used as the extractant, and n-octanol as the washing agent. The flow ratio of extractant, washing agent, and feedstock solution was 3:2:1.5. Fractional extraction was performed at 50 °C. The extract was collected, and after back-extraction with n-octanol and vacuum concentration, empagliflozin was obtained. HPLC analysis showed that the purity of empagliflozin was 97%, and the yield was 92%.

[0058] Example 4:

[0059] Empagliflozin crude feedstock (containing 87 wt% empagliflozin, 4.0 wt% impurity A, 3.5 wt% impurity B, 1.9 wt% impurity C, 1.7 wt% impurity D, 1.5 wt% impurity E, and 0.4 wt% other impurities) was dissolved in isobutyl acetate to prepare a feedstock solution with a total concentration of 1 g / L. A choline-proline salt-phosphate buffer solution was used as the extractant (the phosphate buffer solution was disodium hydrogen phosphate-sodium dihydrogen phosphate buffer, pH = 4.0; the choline-proline salt mass fraction in the extractant was 40%), and isobutyl acetate was used as the washing agent. The flow ratio of extractant, washing agent, and feedstock solution was 6:3:2. Fractional extraction was performed at 30°C. The extract was collected, and after back-extraction with isobutyl acetate and vacuum concentration, empagliflozin was obtained. HPLC analysis showed that the purity of empagliflozin was 99.8%, and the yield was 98%.

[0060] Example 5:

[0061] Empagliflozin crude feedstock (containing 87 wt% empagliflozin, 4.0 wt% impurity A, 3.5 wt% impurity B, 1.9 wt% impurity C, 1.7 wt% impurity D, 1.5 wt% impurity E, and 0.4 wt% other impurities) was dissolved in n-decyl alcohol to prepare a feedstock solution with a total concentration of 400 g / L. A mixed solvent of 1-butyl-3-methylimidazolium tryptophan salt and phosphate buffer was used as the extractant (the phosphate buffer was a dipotassium hydrogen phosphate-potassium dihydrogen phosphate buffer, pH = 3.0; the extractant contained 60% 1-butyl-3-methylimidazolium tryptophan salt by mass fraction), with n-decyl alcohol as the washing agent. The flow ratio of extractant, washing agent, and feedstock solution was 6:2:2. Fractional extraction was performed at 40 °C. The extract was collected, and after back-extraction with n-decyl alcohol and vacuum concentration, empagliflozin was obtained. HPLC analysis showed that the purity of empagliflozin was 98%, and the yield was 95%.

[0062] Example 6:

[0063] Empagliflozin crude feedstock (containing 87 wt% empagliflozin, 4.0 wt% impurity A, 3.5 wt% impurity B, 1.9 wt% impurity C, 1.7 wt% impurity D, 1.5 wt% impurity E, and 0.4 wt% other impurities) was dissolved in dichloroethane to prepare a feedstock solution with a total concentration of 1000 g / L. A mixed solvent of 1-hydroxyethyl-3-methylimidazolium glycinate and methanol was used as the extractant (1-hydroxyethyl-3-methylimidazolium glycinate mass fraction was 80%), and dichloroethane was used as the washing agent. The flow ratio of extractant, washing agent, and feedstock solution was 4:2:3. Fractional extraction was performed at 30°C. The extract was collected, and after back-extraction with dichloroethane and vacuum concentration, empagliflozin was obtained. HPLC analysis showed that the purity of empagliflozin was 95%, and the yield was 96%.

[0064] Example 7:

[0065] Empagliflozin crude feedstock (containing 87 wt% empagliflozin, 4.0 wt% impurity A, 3.5 wt% impurity B, 1.9 wt% impurity C, 1.7 wt% impurity D, 1.5 wt% impurity E, and 0.4 wt% other impurities) was dissolved in n-hexane to prepare a feedstock solution with a total concentration of 3000 g / L. A mixed solvent of 1-butyl-3-methylimidazolium L-glutamate and acetonitrile was used as the extractant (10% by mass of 1-butyl-3-methylimidazolium L-glutamate in the extractant), and n-hexane was used as the washing agent. The flow ratio of extractant, washing agent, and feedstock solution was 2:4:1. Fractional extraction was performed at 30°C. The extract was collected, and after back-extraction with n-hexane and vacuum concentration, empagliflozin was obtained. HPLC analysis showed that the purity of empagliflozin was 94%, and the yield was 95%.

[0066] Example 8:

[0067] Empagliflozin crude feedstock (containing 87 wt% empagliflozin, 4.0 wt% impurity A, 3.5 wt% impurity B, 1.9 wt% impurity C, 1.7 wt% impurity D, 1.5 wt% impurity E, and 0.4 wt% other impurities) was dissolved in ethyl acetate to prepare a feedstock solution with a total concentration of 5000 g / L. Using N-propyl-N-methylpiperidine bromide as the extractant and ethyl acetate as the washing agent, with a flow ratio of extractant, washing agent, and feedstock solution of 1:4:2, fractional extraction was performed at 60 °C. The extract was collected, back-extracted with ethyl acetate, and concentrated under vacuum to obtain empagliflozin. HPLC analysis showed that the purity of empagliflozin was 94%, and the yield was 90%.

[0068] Comparative Example 1:

[0069] Empagliflozin crude feedstock (containing 87 wt% empagliflozin, 4.0 wt% impurity A, 3.5 wt% impurity B, 1.9 wt% impurity C, 1.7 wt% impurity D, 1.5 wt% impurity E, and 0.4 wt% other impurities) was dissolved in ethyl acetate to prepare a feedstock solution with a total concentration of 100 g / L. A sodium dihydrogen phosphate-hydrogen phosphate buffer solution (pH 5.0) was used as the extractant, and ethyl acetate as the washing agent. The flow ratio of extractant, washing agent, and feed solution was 2:4:2. Fractional extraction was performed at 30°C, consisting of an extraction section and a washing section (8 stages in the extraction section and 5 stages in the washing section). The extractant entered the fractional extraction system from the first stage of the extraction section, the feed solution entered from the last stage of the extraction section, and the washing agent entered from the first stage of the washing section. An extract rich in empagliflozin flowed out from the first stage of the washing section, while a raffinate rich in impurities flowed out from the first stage of the extraction section. The extract was collected, back-extracted with ethyl acetate, and concentrated under vacuum to obtain empagliflozin. HPLC analysis showed that the purity of empagliflozin was 90%, and the yield was 10.2%.

[0070] Comparative Example 2:

[0071] Empagliflozin crude feedstock (containing 87 wt% empagliflozin, 4.0 wt% impurity A, 3.5 wt% impurity B, 1.9 wt% impurity C, 1.7 wt% impurity D, 1.5 wt% impurity E, and 0.4 wt% other impurities) was dissolved in dichloroethane to prepare a feedstock solution with a total concentration of 1000 g / L. Methanol was used as the extractant, and dichloroethane as the washing agent, with a flow ratio of extractant, washing agent, and feedstock solution of 4:2:3. Fractional extraction was performed at 30°C. The extract was collected, and after back-extraction with dichloroethane and vacuum concentration, empagliflozin was obtained. HPLC analysis showed that the purity of empagliflozin was 88%, and the yield was 8.9%.

[0072] Comparative Example 3:

[0073] Empagliflozin crude feedstock (containing 87 wt% empagliflozin, 4.0 wt% impurity A, 3.5 wt% impurity B, 1.9 wt% impurity C, 1.7 wt% impurity D, 1.5 wt% impurity E, and 0.4 wt% other impurities) was dissolved in n-hexane to prepare a feedstock solution with a total concentration of 3000 g / L. Acetonitrile was used as the extractant, and n-hexane as the washing agent, with a flow ratio of extractant, washing agent, and feedstock solution of 2:4:1. Fractional extraction was performed at 30°C. The extract was collected, and after back-extraction with n-hexane and vacuum concentration, empagliflozin was obtained. HPLC analysis showed that the purity of empagliflozin was 89%, and the yield was 5.8%.

[0074] The technical solutions of the present invention are not limited to the specific embodiments described above. Any technical modifications made in accordance with the technical solutions of the present invention fall within the protection scope of the present invention.

Claims

1. A method for purifying empagliflozin, comprising the following steps: (1) The feed solution containing empagliflozin and impurities is extracted with an extractant to obtain an extract containing empagliflozin; the impurities include one or more of empagliflozin isomers, esters, and hydrolysis products; the solvent in the feed solution is selected from at least one of haloalkanes, C6-C10 alcohols, and C2-C10 esters; and the extractant includes an ionic liquid or a mixture of an ionic liquid and a polar solvent. in, The ionic liquid is composed of cations and anions and has hydrogen-bonded basicity. The cations are selected from at least one of imidazole cations, pyridine cations, quinoline cations, isoquinoline cations, benzimidazole cations, piperidine cations, pyrrolidine cations, amino acid cations, quaternary ammonium cations, quaternary phosphorus cations, and choline cations. Optionally, the cations are substituted by one or more substituents, which are selected from C1-C4 alkyl groups and / or C2-C4 hydrocarbon groups containing one or more functional groups selected from carbon-carbon double bonds, carbon-carbon triple bonds, hydroxyl groups, cyano groups, ether groups, ester groups, nitrile groups, sulfone groups, amino groups, carboxyl groups, and carbonyl groups. The anion is selected from at least one of the following: fluoride ion, chloride ion, bromide ion, iodide ion, nitrate ion, amino acid anion, trifluoroacetate ion, tetrafluoroborate ion, perchlorate ion, hydrogen sulfate ion, dicyandiamide ion, thiocyanate ion, saturated alkyl chain carboxylate ion with C2 to C24 carbon atoms, unsaturated alkyl chain carboxylate ion with C3 to C24 carbon atoms and containing 1 to 6 carbon-carbon double bonds, phosphate ion, hydrogen phosphate ion, or dihydrogen phosphate ion. The polar solvent is selected from at least one of water, phosphate buffer solution, alcohol, nitrile, sulfone, sulfoxide, amide, and ketone; The extractant contains an ionic liquid with a mass fraction of 0.01-100%. (2) The extract containing empagliflozin is back-extracted and concentrated to obtain empagliflozin, wherein the back-extraction agent used in the back-extraction is selected from at least one of halogenated hydrocarbon solvents, C6-C10 alcohol solvents, and C2-C10 ester solvents.

2. The purification method according to claim 1, characterized in that, The extractant contains an ionic liquid with a mass fraction of 0.01-90%.

3. The purification method according to claim 1, characterized in that, The extractant contains an ionic liquid with a mass fraction of 0.5-60%.

4. The purification method according to claim 1, characterized in that, The extractant contains 1-60% ionic liquid by mass.

5. The purification method according to claim 1, characterized in that, The extractant contains 5-60% ionic liquid by mass.

6. The purification method according to claim 1, characterized in that, The extractant contains 10-50% ionic liquid by mass.

7. The purification method according to claim 1, characterized in that, The solvent in the raw material solution is selected from at least one of dichloroethane, n-octanol, n-decanol, ethyl acetate, butyl acetate, and isobutyl acetate.

8. The purification method according to claim 1, characterized in that, The ionic liquid is selected from at least one of 1-butyl-3-methylimidazolium proline, 1-ethyl-3-methylimidazolium chloride, 1-butyl-3-methylimidazolium chloride, 1-butyl-3-methylimidazolium acetate, 1-butyl-3-methylimidazolium tryptophan, 1-butyl-3-methylimidazolium trifluoroacetate, N-propyl-N-methylpiperidine bromide, choline alanine, choline proline, 1-hydroxyethyl-3-methylimidazolium bromide, 1-hydroxyethyl-3-methylimidazolium glycine, and 1-butyl-3-methylimidazolium L-glutamate.

9. The purification method according to claim 1, characterized in that, The polar solvent is selected from at least one of water, phosphate buffer solution, methanol, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone.

10. The purification method according to claim 1, characterized in that, The polar solvent is selected from at least one of phosphate buffer solution, methanol, and acetonitrile.

11. The purification method according to claim 9, characterized in that, The pH of the phosphate buffer solution is 2.0-6.

0.

12. The purification method according to claim 9, characterized in that, The pH of the phosphate buffer solution is 3.0-5.

0.

13. The purification method according to claim 9, characterized in that, The phosphate buffer solution includes at least one of disodium hydrogen phosphate-sodium dihydrogen phosphate buffer and potassium dihydrogen phosphate-dipoxetine hydrogen phosphate buffer.

14. The purification method according to any one of claims 1-13, characterized in that, The extractant is selected from a mixture of 1-butyl-3-methylimidazolium proline salt and phosphate buffer solution, 1-butyl-3-methylimidazolium chloride, choline proline salt, a mixture of choline proline salt and phosphate buffer solution, a mixture of 1-butyl-3-methylimidazolium tryptophan salt and phosphate buffer solution, a mixture of 1-hydroxyethyl-3-methylimidazolium glycine salt and methanol, a mixture of 1-butyl-3-methylimidazolium L-glutamate and acetonitrile, N-propyl-N-methylpiperidine bromide, 1-ethyl-3-methylimidazolium chloride and phosphate buffer solution. The mixture of liquids, a mixture of 1-butyl-3-methylimidazolium chloride and phosphate buffer solution, a mixture of 1-butyl-3-methylimidazolium acetate and phosphate buffer solution, a mixture of 1-butyl-3-methylimidazolium trifluoroacetate and phosphate buffer solution, a mixture of 1-butyl-3-methylimidazolium chloride and acetonitrile, a mixture of N-propyl-N-methylpiperidine bromide and N-methylpyrrolidone, a mixture of choline alanine and N,N-dimethylformamide, and a mixture of 1-hydroxyethyl-3-methylimidazolium bromide and methanol.

15. The purification method according to any one of claims 1-13, characterized in that, The extractant is selected from at least one of the following: a mixture of 1-butyl-3-methylimidazolium proline salt and phosphate buffer solution; a mixture of choline proline salt and phosphate buffer solution; a mixture of 1-butyl-3-methylimidazolium tryptophan salt and phosphate buffer solution; a mixture of 1-butyl-3-methylimidazolium L-glutamate salt and acetonitrile; and a mixture of 1-hydroxyethyl-3-methylimidazolium glycine salt and methanol.

16. The purification method according to any one of claims 1-13, characterized in that, The mass percentage of empagliflozin in the feed solution is not less than 60%; and / or, The total concentration of empagliflozin and impurities in the feed solution is 0.1 g / L-6000 g / L; and / or, The impurities include one or more of the following compounds:

17. The purification method according to claim 16, characterized in that, The mass percentage of empagliflozin in the feed solution is 60%-99%; and / or the total concentration of empagliflozin and impurities in the feed solution is 1g / L-400g / L.

18. The purification method according to claim 16, characterized in that, The mass percentage of empagliflozin in the feed solution is 80%-90%.

19. The purification method according to any one of claims 1-13, characterized in that, The extraction temperature is 20℃-60℃; and / or the extraction includes multi-stage extraction.

20. The purification method according to claim 19, characterized in that, The extraction is cross-current extraction, countercurrent extraction, or fractional extraction.

21. The purification method according to any one of claims 1-13, characterized in that, In step (1), the flow ratio of the extractant to the feed liquid is (0.05-20):1; and / or, The flow ratio of the detergent used during extraction to the feed liquid is (0.02-10):1; and / or, The detergent used during extraction is selected from at least one of dichloroethane, n-octanol, n-decanol, ethyl acetate, butyl acetate, and isobutyl acetate.

22. The purification method according to claim 21, characterized in that, In step (1), the flow ratio of the extractant to the feed liquid is (0.1-10):1; and / or, The flow ratio of the detergent used during extraction to the feed liquid is (0.05-5):

1.

23. The purification method according to any one of claims 1-13, characterized in that, In step (1), the flow ratio of the extractant to the feed liquid is (0.5-5):1; and / or, the flow ratio of the detergent used during extraction to the feed liquid is (0.5-4):

1.

24. The purification method according to any one of claims 1-13, characterized in that, In step (2), the back-extraction agent used in the back-extraction is selected from at least one of dichloroethane, n-octanol, n-decanol, ethyl acetate, butyl acetate, and isobutyl acetate.

25. The purification method according to any one of claims 1-13, characterized in that, The back-extraction agent is the same type of solvent as the raw material solution.

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