Purification method of empagliflozin

Abstract

The invention provides a purification method of empagliflozin. The method comprises the following steps: (1) extracting raw material liquid containing empagliflozin and impurities by using an extracting agent to obtain extract liquid containing empagliflozin; the impurities comprise one or more of an isomer, an ester and a hydrolysate of empagliflozin, the solvent in the raw material liquid is selected from a non-polar solvent and / or a weakly polar solvent, and the extraction agent comprises an ionic liquid or a mixture of the ionic liquid and a polar solvent; and (2) carrying out back extraction and concentration on the extract liquor containing empagliflozin to obtain empagliflozin. The method has the advantages of high separation efficiency, low solvent consumption, low production cost, safety, environment friendliness, easiness in industrial production and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical separation, and in particular to a method for purifying empagliflozin. Background Art

[0002] As a new oral hypoglycemic drug, empagliflozin has a unique glucose-lowering pathway that does not rely on insulin. It mainly blocks the reabsorption of glucose in the kidney by inhibiting SGLT-2 expressed in the kidney, and directly excretes sugar from the urine to achieve the purpose of lowering blood sugar. Moreover, it still has a glucose-lowering effect when the pancreatic β-cell function is damaged. In particular, in 2015, empagliflozin was confirmed by a large cardiovascular research center (CVOT) to be the world's first type 2 diabetes drug that can reduce the risk of cardiovascular death. This marks a major milestone in the clinical treatment of type 2 diabetes and is of epoch-making significance.

[0003] Empagliflozin (CAS registration number: 864070-44-0), the full chemical name is (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol. The structure of empagliflozin contains 6 chiral centers. There are many operation steps in the total synthesis route. During the reaction, a variety of impurities with structures similar to the raw materials or the target product of empagliflozin will be produced, which seriously affect its purity and quality. Therefore, it is urgent to develop a simple, efficient and highly selective purification method to separate empagliflozin from impurities with similar structures.

[0004] The existing separation and purification process mainly obtains the refined product of empagliflozin through crystallization and recrystallization. This method has low purification efficiency, consumes a large amount of organic solvents, and increases solvent recovery costs. At the same time, organic solvents are volatile, flammable, and toxic, which poses a threat to the environment and safety during use. It is also difficult to effectively remove impurities with similar structures.

[0005] At present, the separation of empagliflozin and its optical isomers with similar structures mainly involves chromatography. For example, CN106706769A discloses a high-performance liquid chromatography method, which uses a chiral column of amylose or cellulose derivatives as a chromatographic column to separate and determine empagliflozin and its optical isomers. However, such methods are difficult to achieve industrial application due to the limitations of cost and processing volume. Therefore, in order to ensure the controllable quality of empagliflozin and to ensure its effectiveness and safety, it is urgent to develop a purification method for empagliflozin to prepare a high-purity empagliflozin product. Summary of the invention

[0006] In order to solve one of the above technical problems existing in the prior art, the present invention provides a method for purifying empagliflozin. The present invention finds that empagliflozin can be effectively separated from empagliflozin impurities by using an extraction method with an extractant containing an ionic liquid.

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

[0008] The present invention provides a method for purifying empagliflozin, which comprises the following steps:

[0009] (1) extracting a raw material liquid containing empagliflozin and impurities with an extractant to obtain an extract containing empagliflozin; the impurities include one or more of isomers, esters, and hydrolysis products of empagliflozin, the solvent in the raw material liquid is selected from a non-polar solvent and / or a weakly polar solvent, and the extractant includes an ionic liquid or a mixture of an ionic liquid and a polar solvent;

[0010] (2) The extract containing empagliflozin is subjected to back extraction and concentration 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 therebetween. 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 ionic liquids to polar solvents can give Empagliflozin an appropriate distribution 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 the production cost.

[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 ethylene dichloride, n-octanol, n-decanol, ethyl acetate, butyl acetate, and isobutyl acetate.

[0013] The ionic liquid in the present invention is composed of cations and anions. According to some embodiments of the present invention, the cation is selected from at least one of imidazolium cation, pyridinium cation, quinolinium cation, isoquinolinium cation, benzimidazolium cation, piperidinium cation, pyrrolidinium cation, amino acid cation, quaternary ammonium cation, quaternary phosphonium cation, and choline cation. In some embodiments, in order to further improve the selective extraction and separation effect of empagliflozin, the cation is substituted by one or more substituents, and the substituents are selected from C1-C4 alkyl and / or C2-C4 hydrocarbon groups containing one or more functional groups in carbon-carbon double bonds, carbon-carbon triple bonds, hydroxyl, cyano, ether, ester, nitrile, sulfone, amino, carboxyl, and carbonyl. In some embodiments, the cation is selected from at least one of imidazolium cation, piperidinium cation, and choline cation. 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 containing one or more functional groups selected from carbon-carbon double bond, carbon-carbon triple bond, hydroxyl, cyano, ether, ester, nitrile, sulfone, amino, carboxyl, carbonyl.

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

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

[0016] The ionic liquid selected in the present invention has hydrogen bond alkalinity, which can identify the slight difference between empagliflozin and impurities with similar structures, 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 polar solvents 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, and the like. 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 therebetween. In the present invention, adding a polar solvent as an extractant to an ionic liquid can not only reduce the viscosity of the extractant and promote the two-phase transfer process, but also reduce the amount of ionic liquid used and reduce 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 and acetonitrile, N-propyl-N-methylpiperidinium bromide, 1-ethyl-3-methylimidazolium chloride At least one of 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-methylpiperidinium 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 a mixture of 1-butyl-3-methylimidazole proline salt and phosphate buffer solution, a mixture of choline proline salt and phosphate buffer solution, a mixture of 1-butyl-3-methylimidazole tryptophan salt and phosphate buffer solution, a mixture of 1-butyl-3-methylimidazole L-glutamate and acetonitrile, and a mixture of 1-hydroxyethyl-3-methylimidazole glycine salt-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%. In some embodiments, the mass percentage of empagliflozin in the raw material solution is 80%-90%.

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

[0022]

[0023] According to some embodiments of the present invention, in the raw material solution, the total concentration of empagliflozin and impurities is 0.1 g / L-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 therebetween. In some specific embodiments, the total concentration of empagliflozin and impurities in the raw material solution is 1 g / L-400 g / L. In some specific embodiments, the total concentration of empagliflozin and impurities in the raw material solution is 10 g / L-400 g / L. If the total concentration of empagliflozin and impurities in the raw material solution is too high, it is not conducive to the effective separation of empagliflozin; if the total concentration of empagliflozin and impurities in the raw material solution is too low, the processing volume 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 therebetween. If the extraction temperature is too low, the viscosity of the raw material liquid, the extractant, and the detergent is large, the mass transfer rate is reduced, the processing volume is small, and it is not conducive to production operation; if the extraction temperature is too high, the solvent evaporates seriously, which will reduce the distribution ratio and selectivity of the fractional extraction.

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

[0026] The fractionation extraction described in the present invention can be carried out using existing fractionation extraction equipment. The fractionation extraction includes an extraction section and a washing section. The extractant enters the fractionation extraction system from the first stage of the extraction section, the raw material liquid enters the fractionation extraction system from the last stage of the extraction section, the detergent enters the fractionation extraction system from the first stage of the washing section, and the feed liquid is combined at the last stage of the extraction section to enter the extraction section together. The extraction phase and the washing phase are in multi-stage countercurrent contact, and the raffinate enriched in impurities flows out from the first stage of the extraction section, and the extract enriched in empagliflozin flows out from the first stage of the washing section. The extract is collected, and the empagliflozin product is obtained by back extraction and vacuum concentration.

[0027] In some embodiments, the extraction section can be 2-30 stages, for example 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 25, 28, 30 stages, etc.; the washing section can be 2-20 stages, for example 2, 4, 6, 8, 10, 12, 14, 16, 18, 20 stages, etc.

[0028] According to some embodiments of the present invention, in step (1), the flow ratio of the extractant to the raw material solution 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 therebetween. In some embodiments, in step (1), the flow ratio of the extractant to the raw material solution is (0.1-10):1. In some embodiments, in step (1), the flow ratio of the extractant to the raw material solution is (0.5-5):1.

[0029] In some embodiments, in step (1), the flow ratio of the detergent used in the extraction to the raw material 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 therebetween. In some embodiments, in step (1), the flow ratio of the detergent used in the extraction to the raw material liquid is (0.05-5):1. In some embodiments, in step (1), the flow ratio of the detergent used in the extraction to the raw material liquid is (0.5-4):1.

[0030] In some embodiments, the detergent used in the extraction is selected from non-polar solvents and / or weak polar solvents, for example: 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 in the extraction is at least one of dichloroethane, n-octanol, n-decanol, ethyl acetate, butyl acetate, and isobutyl acetate. In some embodiments, the detergent used in the extraction is of the same type as the solvent in the raw material solution. In the present invention, the detergent and the solvent in the raw material solution are selected from the same solvent, which not only has a good solubility for the raw material, but also can form a liquid-liquid two-phase system with a small mutual solubility with the extractant, and can achieve a better separation effect.

[0031] According to some embodiments of the present invention, in step (2), the stripping agent used in the stripping is selected from non-polar solvents and / or weak 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 stripping agent used in the stripping is selected from at least one of dichloroethane, n-octanol, n-decanol, ethyl acetate, butyl acetate, and isobutyl acetate.

[0032] In some embodiments, the stripping agent is of the same type as the solvent in the feed solution. In some embodiments, the stripping agent and the washing agent are of the same type.

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

[0034] 1. The present invention uses an ionic liquid-containing extractant through an extraction method (preferably multi-stage extraction) to achieve a higher selective separation ability between empagliflozin and impurities, thereby removing impurities with similar structures. At the same time, the extractant used can be recycled and reused, thereby reducing production costs and having broad application prospects in industry.

[0035] 2. The present invention adopts fractionation extraction technology, which can be operated continuously, has a large processing capacity and low cost.

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

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

[0038] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments and drawings. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation to the present invention.

[0039] The reagents used in the following experiments of the present invention, unless otherwise specified, are all conventional commercial products or reagents prepared by conventional methods, and the methods used in the experiments, unless otherwise specified, are all conventional experimental methods. The instruments used in the experiments, unless otherwise specified, can all be obtained through commercial channels.

[0040] Ionic liquids refer to room temperature molten salts composed entirely of ions. They have good chemical and thermal stability, are non-toxic, non-flammable, have extremely low vapor pressure, and have good solubility in most organic or inorganic substances. They are called green solvents. By designing the types of anions and cations and functional substitution groups of ionic liquids, the physicochemical properties of ionic liquids such as alkalinity, polarity, and viscosity can be finely controlled, thereby giving them specific π-π, hydrogen bonding, dipole and other interaction capabilities, making them have a high affinity for the extracted components and achieving efficient separation of the corresponding solutes.

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

[0042] The polar solvent in the present invention can be, for example, a phosphate buffer solution, water, acetonitrile, methanol, dimethyl sulfoxide and other solvents, which have a certain separation effect on empagliflozin and impurities. If a pure ionic liquid is used as an extractant, there are disadvantages such as the high viscosity of the ionic liquid resulting in a slow mass transfer rate, the large amount used resulting in high cost, and even some ionic liquids are solid at room temperature, resulting in the need for temperature increase operation, so a third solvent needs to be added. The added third solvent must have good mutual solubility with the ionic liquid, can form a two-phase system with the raw material solvent, and can also accurately adjust the properties of the extractant to achieve the purpose of increasing the mass transfer rate and improving the separation effect.

[0043] As a specific embodiment, the method comprises: dissolving a 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 consisting of an ionic liquid and a polar solvent as an extractant, and using the same organic solvent as that in the raw material solution as a detergent, performing fractional extraction to obtain an extract, and obtaining high-purity empagliflozin through back extraction and vacuum concentration.

[0044] like Figure 1As shown, as a specific embodiment, the method for purifying empagliflozin includes: preparing a crude product containing empagliflozin and structurally similar impurities with a non-polar and / or weakly polar organic solvent to form a raw material solution, using an ionic liquid or a mixture of an ionic liquid and a polar solvent as an extractant, and using the raw material solvent as a detergent, and performing 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, the detergent enters the extraction system from the first stage of the washing section, the feed liquid is combined at the last stage of the extraction section and enters the extraction section together, the extraction phase and the washing phase are in multi-stage countercurrent contact, an extract enriched in empagliflozin flows out from the first stage of the washing section, and a raffinate enriched in 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 non-polar 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 examples 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 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 calculation method of yield and HPLC purity among the present invention is as follows:

[0048] Empagliflozin yield = weight of empagliflozin in the product / weight of empagliflozin in the raw material × 100%;

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

[0050] In the following examples and comparative examples, the structures of the substances in the crude raw material of empagliflozin are as follows:

[0051]

[0052] Embodiment 1:

[0053] The crude empagliflozin raw material (containing 87wt% empagliflozin, 4.0wt% impurity A, 3.5wt% impurity B, 1.9wt% impurity C, 1.7wt% impurity D, 1.5wt% impurity E, and 0.4wt% other impurities) was dissolved in ethyl acetate to prepare a raw material solution with a total concentration of 100 g / L. A mixed solvent of 1-butyl-3-methylimidazole proline salt-phosphate buffer solution is used as an extractant (the phosphate buffer solution is a sodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution, pH=5.0; the mass fraction of 1-butyl-3-methylimidazole proline salt in the extractant is 20%), ethyl acetate is used as a detergent, and the flow ratio of the extractant, the detergent, and the raw material liquid is 2:4:2. Fractional extraction is performed at 30°C. The fractional extraction is divided into an extraction section and a washing section (the extraction section has 8 stages and the washing section has 5 stages). The extractant enters the fractional extraction system from the first stage of the extraction section, the raw material liquid enters the fractional extraction system from the last stage of the extraction section, the detergent enters the fractional extraction system from the first stage of the washing section, an extract rich in empagliflozin flows out from the first stage of the washing section, and a raffinate rich in impurities flows out from the first stage of the extraction section. The extract is collected, and empagliflozin is obtained after ethyl acetate back extraction and vacuum concentration. HPLC analysis shows that the purity of empagliflozin is 99.5% and the yield is 98%.

[0054] Embodiment 2:

[0055] The crude raw material of empagliflozin (containing 87wt% empagliflozin, 4.0wt% impurity A, 3.5wt% impurity B, 1.9wt% impurity C, 1.7wt% impurity D, 1.5wt% impurity E, and 0.4wt% other impurities) was dissolved in ethyl acetate to prepare a raw material solution with a total concentration of 50g / L. 1-Butyl-3-methylimidazolium chloride was used as an extractant, ethyl acetate was used as a detergent, and the flow ratio of the extractant, detergent, and raw material solution was 4:3:2. Fractional extraction was performed at 20°C, and the extract was collected. After ethyl acetate back extraction and vacuum concentration, empagliflozin was obtained. HPLC analysis showed that the purity of empagliflozin was 92% and the yield was 94%.

[0056] Embodiment 3:

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

[0058] Embodiment 4:

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

[0060] Embodiment 5:

[0061] The crude raw material of empagliflozin (containing 87wt% empagliflozin, 4.0wt% impurity A, 3.5wt% impurity B, 1.9wt% impurity C, 1.7wt% impurity D, 1.5wt% impurity E, and 0.4wt% other impurities) is dissolved in n-decanol to prepare a raw material solution with a total concentration of 400g / L. A mixed solvent of 1-butyl-3-methylimidazole tryptophanate-phosphate buffer solution is used as an extractant (the phosphate buffer solution is a potassium dihydrogen phosphate-potassium dihydrogen phosphate buffer, pH=3.0; the mass fraction of 1-butyl-3-methylimidazole tryptophanate in the extractant is 60%), n-decanol is used as a detergent, and the flow ratio of the extractant, detergent, and raw material solution is 6:2:2. Fractional extraction is performed at 40°C, and the extract is collected. After n-decanol back extraction and vacuum concentration, empagliflozin is obtained. HPLC analysis shows that the purity of empagliflozin is 98% and the yield is 95%.

[0062] Embodiment 6:

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

[0064] Embodiment 7:

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

[0066] Embodiment 8:

[0067] The crude raw material of empagliflozin (containing 87wt% empagliflozin, 4.0wt% impurity A, 3.5wt% impurity B, 1.9wt% impurity C, 1.7wt% impurity D, 1.5wt% impurity E, and 0.4wt% other impurities) was dissolved in ethyl acetate to prepare a raw material solution with a total concentration of 5000g / L. N-propyl-N-methylpiperidinium bromide solvent was used as an extractant, ethyl acetate was used as a detergent, and the flow ratio of the extractant, detergent, and raw material solution was 1:4:2. Fractional extraction was performed at 60°C, and the extract was collected. After ethyl acetate back extraction and vacuum concentration, empagliflozin was obtained. HPLC analysis showed that the purity of empagliflozin was 94% and the yield was 90%.

[0068] Comparative Example 1:

[0069] The crude empagliflozin raw material (containing 87wt% empagliflozin, 4.0wt% impurity A, 3.5wt% impurity B, 1.9wt% impurity C, 1.7wt% impurity D, 1.5wt% impurity E, and 0.4wt% other impurities) was dissolved in ethyl acetate to prepare a raw material solution with a total concentration of 100 g / L. A disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution with a pH of 5.0 is used as an extractant, ethyl acetate is used as a detergent, and the flow ratio of the extractant, the detergent, and the raw material liquid is 2:4:2. Fractional extraction is performed at 30°C. The fractional extraction is divided into an extraction section and a washing section (8 stages in the extraction section and 5 stages in the washing section). The extractant enters the fractional extraction system from the first stage of the extraction section, the raw material liquid enters the fractional extraction system from the last stage of the extraction section, and the detergent enters the fractional extraction system from the first stage of the washing section. An extract rich in empagliflozin flows out from the first stage of the washing section, and a raffinate rich in impurities flows out from the first stage of the extraction section. The extract is collected, and empagliflozin is obtained after ethyl acetate back extraction and vacuum concentration. HPLC analysis shows that the purity of empagliflozin is 90% and the yield is 10.2%.

[0070] Comparative Example 2:

[0071] The crude raw material of empagliflozin (containing 87wt% empagliflozin, 4.0wt% impurity A, 3.5wt% impurity B, 1.9wt% impurity C, 1.7wt% impurity D, 1.5wt% impurity E, and 0.4wt% other impurities) was dissolved in dichloroethane to prepare a raw material solution with a total concentration of 1000g / L. Methanol was used as an extractant and dichloroethane was used as a detergent. The flow ratio of the extractant, the detergent, and the raw material solution was 4:2:3. Fractional extraction was performed at 30°C, and the extract was collected. After dichloroethane back extraction 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] The crude raw material of empagliflozin (containing 87wt% empagliflozin, 4.0wt% impurity A, 3.5wt% impurity B, 1.9wt% impurity C, 1.7wt% impurity D, 1.5wt% impurity E, and 0.4wt% other impurities) was dissolved in n-hexane to prepare a raw material solution with a total concentration of 3000g / L. Acetonitrile was used as an extractant and n-hexane was used as a detergent. The flow ratio of the extractant, detergent, and raw material solution was 2:4:1. Fractional extraction was performed at 30°C, and the extract was collected. After n-hexane back extraction 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 solution of the present invention is not limited to the above-mentioned specific embodiments. All technical variations made according to the technical solution 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) extracting a raw material liquid containing empagliflozin and impurities with an extractant to obtain an extract containing empagliflozin; the impurities include one or more of isomers, esters, and hydrolysis products of empagliflozin, the solvent in the raw material liquid is selected from a non-polar solvent and / or a weakly polar solvent, and the extractant includes an ionic liquid or a mixture of an ionic liquid and a polar solvent; (2) The extract containing empagliflozin is subjected to back extraction and concentration to obtain empagliflozin.

2. The purification method according to claim 1, characterized in that In the extractant, the mass fraction of the ionic liquid is 0-100%, preferably 0.01-90%, more preferably 0.5-60%, and further preferably 10-50%.

3. The purification method according to claim 1 or 2, characterized in that The solvent in the raw material liquid is selected from at least one of halogenated hydrocarbon solvents, C6-C10 alcohol solvents, and C2-C10 ester solvents; preferably at least one of dichloroethane, n-octanol, n-decanol, ethyl acetate, butyl acetate, and isobutyl acetate.

4. The purification method according to any one of claims 1 to 3, characterized in that The ionic liquid is composed of cations and anions, wherein the cation is selected from at least one of imidazolium cations, pyridinium cations, quinolinium cations, isoquinolinium cations, benzimidazolium cations, piperidinium cations, pyrrolidinium cations, amino acid cations, quaternary ammonium cations, quaternary phosphonium cations, and choline cations; optionally, the cation is substituted by one or more substituents, and the substituents are selected from C1-C4 alkyl groups and / or C2-C4 hydrocarbon groups containing one or more functional groups of 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 fluoride, chloride, bromide, iodide, nitrate, amino acid anion, trifluoroacetate, tetrafluoroborate, perchlorate, hydrogen sulfate, dicyanamide, thiocyanate, saturated alkyl chain carboxylates with carbon numbers of C2 to C24, unsaturated alkyl chain carboxylates with carbon numbers of C3 to C24 and containing 1 to 6 carbon-carbon double bonds, phosphate, hydrogen phosphate or dihydrogen phosphate ions; Preferably, the ionic liquid is selected from at least one of 1-butyl-3-methylimidazolium proline salt, 1-ethyl-3-methylimidazolium chloride salt, 1-butyl-3-methylimidazolium chloride salt, 1-butyl-3-methylimidazolium acetate salt, 1-butyl-3-methylimidazolium tryptophanate salt, 1-butyl-3-methylimidazolium trifluoroacetate salt, N-propyl-N-methylpiperidinium bromide salt, choline alanine salt, choline proline salt, 1-hydroxyethyl-3-methylimidazolium bromide salt, 1-hydroxyethyl-3-methylimidazolium glycinate salt, and 1-butyl-3-methylimidazolium L-glutamate salt.

5. The purification method according to any one of claims 1 to 4, characterized in that The polar solvent is selected from at least one of water, phosphate buffer solution, alcohol, nitrile, sulfone, sulfoxide, amide, and ketone; Preferably, the polar solvent is selected from at least one of water, phosphate buffer solution, methanol, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone; Preferably, the polar solvent is selected from at least one of phosphate buffer solution, methanol and acetonitrile; Preferably, the pH of the phosphate buffer solution is 2.0-6.0, preferably 3.0-5.0; Preferably, the phosphate buffer solution includes at least one of disodium hydrogen phosphate-sodium dihydrogen phosphate buffer and potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer.

6. The purification method according to any one of claims 1 to 5, characterized in that The extractant is selected from a mixture of 1-butyl-3-methylimidazole proline salt and phosphate buffer solution, 1-butyl-3-methylimidazole chloride, choline proline salt, a mixture of choline proline salt and phosphate buffer solution, a mixture of 1-butyl-3-methylimidazole tryptophan salt and phosphate buffer solution, a mixture of 1-hydroxyethyl-3-methylimidazole glycine salt and methanol, a mixture of 1-butyl-3-methylimidazole L-glutamate and acetonitrile, N-propyl-N-methylpiperidinium bromide, 1-ethyl-3-methylimidazole chloride and phosphate buffer solution. at least one of 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-methylpiperidinium 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; Preferably, the extractant is selected from at least one of a mixture of 1-butyl-3-methylimidazole proline salt and phosphate buffer solution, a mixture of choline proline salt and phosphate buffer solution, a mixture of 1-butyl-3-methylimidazole tryptophan salt and phosphate buffer solution, a mixture of 1-butyl-3-methylimidazole L-glutamate and acetonitrile, and a mixture of 1-hydroxyethyl-3-methylimidazole glycine salt-methanol.

7. The purification method according to any one of claims 1 to 6, characterized in that In the raw material solution, the mass percentage of empagliflozin is not less than 60%, preferably 60%-99%, more preferably 80%-90%; and / or, In the raw material solution, the total concentration of empagliflozin and impurities is 0.1 g / L-6000 g / L, preferably 1 g / L-400 g / L; and / or, The impurities include one or more of the following compounds:

8. The purification method according to any one of claims 1 to 7, characterized in that The extraction temperature is 20° C.-60° C.; and / or, the extraction comprises multi-stage extraction, preferably cross-current extraction, countercurrent extraction or fractional extraction, more preferably fractional extraction.

9. The purification method according to any one of claims 1 to 8, characterized in that In step (1), the flow ratio of the extractant to the raw material solution is (0.05-20):1, preferably (0.1-10):1, more preferably (0.5-5):1; and / or, The flow ratio of the detergent used during extraction to the raw material liquid is (0.02-10):1, preferably (0.05-5):1, more preferably (0.5-4):1; and / or, The detergent used in the extraction is selected from non-polar solvents and / or weak polar solvents; preferably selected from at least one of halogenated hydrocarbon solvents, C6-C10 alcohol solvents, and C2-C10 ester solvents; more preferably selected from at least one of dichloroethane, n-octanol, n-decanol, ethyl acetate, butyl acetate, and isobutyl acetate; More preferably, the detergent used during extraction is of the same type as the solvent in the raw material solution.

10. The purification method according to any one of claims 1 to 9, characterized in that: In step (2), the stripping agent used in the stripping is selected from a non-polar solvent and / or a weakly polar solvent; preferably selected from at least one of a halogenated hydrocarbon solvent, a C6-C10 alcohol solvent, and a C2-C10 ester solvent; more preferably selected from at least one of ethylene dichloride, n-octanol, n-decanol, ethyl acetate, butyl acetate, and isobutyl acetate; Further preferably, the stripping agent is of the same type as the solvent in the raw material solution.

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