A method of preparing esliconazole sulfate

Abstract

The application relates to a preparation method of esconazole sulfate. The method comprises realizing esconazole salt type conversion through nanofiltration in the presence of sulfate and / or hydrogen sulfate ions, and obtaining esconazole sulfate of formula I. The esconazole salt type conversion method is short in steps, simple in operation, low in cost, high in purity and yield, and easy to realize industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry, in particular to a preparation method of isavuconazonium sulfate. BACKGROUND

[0002] Isavuconazonium sulfate is a new triazole antifungal drug developed by Swiss Basel and Japanese Anselai Company, which was listed in the United States in March 2015 and used for treating severe infections caused by invasive aspergillosis and hair fungus in adults. Its chemical structure is shown in formula I. Isavuconazonium sulfate is a prodrug of isavuconazole shown in formula II. The design of the prodrug not only solves the problem of water solubility, but also reduces the toxic side effects, providing a new choice for clinical treatment of aspergillus, cryptococcus and other rare fungal infections.

[0003]

[0004] The compound 2 in the following formula is an essential intermediate for synthesizing isavuconazonium sulfate. Compound 2 is obtained by dissolving compound II in an organic solvent, adding sodium iodide, molecular sieve and compound 1, and reacting for a period of time. Compound 6 is obtained by deprotecting the group of compound 2, and isavuconazonium sulfate is further obtained by salt conversion. Compound 2 often contains excessive iodine ion impurities, which further leads to excessive iodine ion in compound 6 and isavuconazonium sulfate. In the prior art, compound 2 is directly deprotected with sulfuric acid or sulfate salt and salt conversion is simultaneously performed, but the isavuconazonium sulfate obtained still contains a relatively high content of iodine ion.

[0005]

[0006] In the preparation process of isavuconazonium sulfate, the salt conversion of isavuconazonium and the control of the content of impurity ions such as iodine ion are technical difficulties of the synthesis process and are also recognized as technical problems.

[0007] Jiangsu Osecon Pharmaceutical Patent (Patent Publication No. CN106467534B) adopts the original research method to synthesize isavuconazole chloride hydrochloride (4), which is washed by preparative liquid phase elution, freeze-dried, slurried with organic solvent, and water-soluble freeze-dried to synthesize the following route:

[0008]

[0009] The intermediates 2 and 3 in the process route need to be purified by column chromatography. The intermediate 4 is easily water-absorbing, and the moisture in the experimental process and the experimental environment needs to be strictly controlled. The salt type conversion is realized by preparative liquid phase elution, and isavuconazonium sulfate is obtained by twice freeze-drying. The process in the patent is not strong in operability, and it is difficult to realize industrial production.

[0010] Yangtze River Pharmaceutical patent (CN106916152B) uses oxidation-reduction method to prepare esconazole sulfate, and the intermediate 5 needs column chromatography purification in the method, and the synthetic route is shown as follows,

[0011]

[0012] It is found through experiments that copper sulfate is difficult to completely oxidize iodine ions into iodine element, and there are still a large amount of iodine ions in the intermediate 5 (the content of iodine ions is 15.32%, and the content of sulfate is 0.03%) detected by ion chromatography. The salt type conversion is difficult to completely realize through multiple copper sulfate oxidations, and thus a large amount of iodine ions are contained in the final product esconazole sulfate.

[0013] The patent (WO2016016766A2) of WOCKHARDT company in India reports that after the intermediate 2 is purified through column chromatography, the intermediate 2 is reacted with hydrogen chloride ethyl acetate solution to obtain the intermediate 6, and the intermediate 6 is replaced with ion exchange resin (sulfate form) in methanol to obtain esconazole sulfate. The experimental route is shown as follows. The purification of the intermediate 2 through column chromatography is not suitable for industrial production, and the intermediate 6 also has the phenomenon of easy moisture absorption, which needs to control the moisture content in the operation environment, and is not conducive to industrial mass production.

[0014]

[0015] The patent (CN113024539A) of Shanghai Diseno Biological Medicine reports that the intermediate 2 is exchanged with sodium trifluoroacetate aqueous solution to obtain the intermediate 7, the intermediate 7 is deprotected by trifluoroacetic acid to obtain the intermediate 8, and the intermediate 8 is exchanged with sodium bisulfate solution to obtain esconazole sulfate. It is found through experiments that the ion exchange is difficult to completely exchange the iodine ions in the intermediate 2, and the complete exchange cannot be realized even through three times of repetition (the iodine ions are 2.00%, the chloride ions are 0.24%, and the trifluoroacetate ions are 11.68% measured through three times of repetition); and the intermediate 8 has a large solubility in water, and it is difficult to completely extract the intermediate 8 with an organic phase, the yield of the reaction is low, the production cost is high, and the process is not suitable for industrial production.

[0016] SUMMARY

[0017] In view of this, the problem to be solved by the present application is to provide a method for realizing salt type conversion of esconazole, which is completely ion exchanged, has strong operability, is simple and convenient to operate, has high yield and is suitable for large-scale industrial production.

[0018] SOLUTION TO THE PROBLEM

[0019] In one aspect, the present application provides a preparation method of esconazole sulfate, comprising the following steps:

[0020] The compound 6 is subjected to nanofiltration in the presence of hydrogen sulfate and / or bisulfate ions to obtain the esliconazole sulfate of formula I, and the specific reaction equation is as follows:

[0021]

[0022] HX in the compound 6 is any one of HCl, H2SO4, HBr, HI, CH3COOH and CF3COOH. When HX in the compound 6 is H2SO4, the esliconazole sulfate of formula I can be obtained directly by nanofiltration without adding sulfuric acid or sulfate again.

[0023] In some embodiments, the nanofiltration membrane has a molecular weight cut-off of 100-500 daltons; preferably, the nanofiltration membrane has a molecular weight cut-off of 100-400 daltons; further preferably, the nanofiltration membrane has a molecular weight cut-off of 100-300 daltons.

[0024] In some embodiments, the molar amount of the bisulfate ion and / or the sulfate ion is more than 1 times the molar amount of the compound 6.

[0025] In some embodiments, the bisulfate ion and / or the sulfate ion is derived from any one or more of sulfuric acid, bisulfate, and sulfate, such as dilute sulfuric acid, sodium sulfate or sodium bisulfate.

[0026] In some embodiments, the nanofiltration membrane is a polyamide nanofiltration membrane.

[0027] In some embodiments, the polyamide nanofiltration membrane is a SUEZ industrial separation nanofiltration membrane; preferably, the SUEZ industrial separation nanofiltration membrane is any one of DK membrane, DL membrane, HP membrane and HL membrane.

[0028] In some embodiments, the method for preparing the esliconazole sulfate described above further comprises one or more of the following features:

[0029] (1) In the nanofiltration to obtain the esliconazole sulfate of formula I, the content of iodine ions is not more than 0.5%; and / or

[0030] (2) In the nanofiltration to obtain the esliconazole sulfate of formula I, the content of chloride ions is not more than 0.5%.

[0031] In some embodiments, the method for preparing the esliconazole sulfate described above further comprises the following steps:

[0032] The esliconazole sulfate of formula I obtained by nanofiltration is subjected to preparative liquid chromatography purification, and the eluent is collected to obtain the pure esliconazole sulfate of formula I; optionally, after the eluent is collected, the nanofiltration step is repeated to obtain the pure esliconazole sulfate of formula I.

[0033] The preparation liquid chromatography filler is a polymer filler; preferably, the polymer filler is polymethacrylate, polystyrene / polymethacrylate or polystyrene divinylbenzene.

[0034] The polymer filler is a Uni reverse phase polymer chromatography filler; preferably, the Uni reverse phase polymer chromatography filler is any one of UniPS series, UniPMM series, UniPSN series, NM series.

[0035] In some embodiments, the elution condition of the preparation liquid chromatography is gradient elution, mobile phase A is 0.004% sulfuric acid solution, and mobile phase B is acetonitrile.

[0036] The above elution condition is an elution condition:

[0037] Time (min) Phase A (5 L purified water + 200 μL concentrated sulphuric acid) Phase B (acetonitrile) 0 95 5 5 95 5 10 82 18 150 75 25

[0038] Effects of the present application

[0039] In the conversion of isavuconazole salt, the present application can be converted into sulfate by one-step nanofiltration, and most of the impurity ions such as iodine ions and chlorine ions are removed, and the content of iodine ions and chlorine ions in the isavuconazole sulfate obtained by one-step nanofiltration is less than 0.5%, and the removal effect is obviously better than that of the prior art (such as ion exchange resin method).

[0040] Specifically, the industrial separation nanofiltration membrane used in the present application has a molecular weight cut-off of 100-500 Dalton, preferably 100-400 Dalton, further preferably 100-300 Dalton, and more preferably 150-300 Dalton. The nanofiltration membrane used in the present application can allow monovalent salts to pass through while retaining divalent salts. The molecular weight of isavuconazole sulfate is 814 Dalton, and the molecular weight of the free base of hydrogen sulfate is 717 Dalton. At the same time, the impurities with a molecular weight of less than 150 produced in the process can also be removed by nanofiltration, reducing the subsequent purification pressure. During nanofiltration, chloride, iodide and hydrobromide pass through, and sulfate is retained. The salt type conversion can be efficiently realized by the nanofiltration membrane, which is very suitable for industrial production.

[0041] After nanofiltration, the preparation liquid phase is purified to realize complete conversion of the salt type of isavuconazole, and further remove impurity ions such as iodine ions and chlorine ions. The preparation liquid phase uses a polymer filler, which is cheap and suitable for industrial production.

[0042] Overall, the isavuconazole salt conversion method of the present application has short steps, simple operation, low cost, high purity and yield, and is easy to realize industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0043] Figure 1 : Ion chromatogram after nanofiltration;

[0044] Figure 2 : Liquid phase diagram of finished esokonazole sulfate;

[0045] Figure 3 : Ion chromatography detection diagram of finished esokonazole sulfate;

[0046] Figure 4 : Ion chromatography detection diagram of CN106916152B method;

[0047] Figure 5 : Ion chromatography detection diagram of CN113024539A method. DETAILED DESCRIPTION

[0048] In order to make the technical solutions and beneficial effects of the present application more obvious and easy to understand, the following will be described in detail by listing specific embodiments.

[0049] In one aspect, the present application provides a preparation method of esokonazole sulfate, comprising the following steps:

[0050] Nanofiltration: compound 6 is subjected to nanofiltration in the presence of bisulfate ions and / or sulfate ions to obtain esokonazole sulfate of formula I;

[0051]

[0052] HX in compound 6 is any one of HCl, H2SO4, HBr, HI, CH3COOH and CF3COOH. When HX in compound 6 is H2SO4, esokonazole sulfate of formula I can be directly obtained by nanofiltration without the need to add sulfuric acid or sulfate again.

[0053] The nanofiltration membrane has a molecular weight cut-off of 100-500 daltons.

[0054] In some embodiments, the molar amount of bisulfate ions and / or sulfate ions is more than 1 times the molar amount of compound 6. It can be understood that the molar amount of bisulfate ions and / or sulfate ions is 1 times, 2 times, 3 times, 4 times, 5 times or 6 times, etc. the molar amount of compound 6.

[0055] In some embodiments, the bisulfate ions and / or sulfate ions are derived from any one or more of sulfuric acid, bisulfate, sulfate, such as dilute sulfuric acid, sodium sulfate or sodium bisulfate.

[0056] In some embodiments, the nanofiltration membrane has a molecular weight cut-off of 100-500 daltons, preferably 100-400, further preferably 100-300 daltons, further preferably 150-300 daltons.

[0057] In some embodiments, the nanofiltration membrane is a polyamide membrane.

[0058] In some embodiments, the polyamide-based membrane is selected from SUEZ Industrial Separation nanofiltration membranes; the SUEZ Industrial Separation nanofiltration membranes can be any one of DK membrane, DL membrane, HP membrane, HL membrane.

[0059] It should be understood that other brands of nanofiltration membranes that meet the molecular weight cut-off of 100-500 Dalton are also within the scope of the present disclosure and protection.

[0060] In some embodiments, the nanofiltration results in a esoxiconazole sulfate of Formula I having an iodide ion content of no more than 0.5%, for example, no more than 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%.

[0061] In some embodiments, the nanofiltration results in a esoxiconazole sulfate of Formula I having a chloride ion content of no more than 0.5%, for example, no more than 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%.

[0062] In some embodiments, the nanofiltration results in a esoxiconazole sulfate of Formula I having a bromide ion content of no more than 0.5%, for example, no more than 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%.

[0063] In some embodiments, the nanofiltration results in a esoxiconazole sulfate of Formula I having an acetate ion content of no more than 0.5%, for example, no more than 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%.

[0064] In some embodiments, the nanofiltration results in a esoxiconazole sulfate of Formula I having a trifluoroacetate ion content of no more than 0.5%, for example, no more than 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%.

[0065] In some embodiments, the method of preparing esoxiconazole sulfate further comprises the following step:

[0066] Preparative liquid chromatography purification: purifying the nanofiltration- obtained esoxiconazole sulfate of Formula I by preparative liquid chromatography, collecting the eluent to obtain the pure esoxiconazole sulfate of Formula I.

[0067] Optionally, after collecting the eluent, repeating the nanofiltration step (re-nanofiltration) to obtain the pure esoxiconazole sulfate of Formula I.

[0068] In some embodiments, the preparative liquid chromatography packing is a polymeric packing, for example, polymethacrylate, polystyrene / poly-methacrylate, or polystyrene divinylbenzene.

[0069] In some embodiments, the polymeric packing is Uni reversed-phase polymeric chromatographic packing; preferably, the Uni reversed-phase polymeric chromatographic packing is any one of UniPS series, UniPMM series, UniPSN series, NM series.

[0070] In some embodiments, the nanofiltration step and the preparative liquid chromatography purification step can be repeated multiple times, respectively, or cross-repeated multiple times. For example, the nanofiltration step is repeated 1-3 times, or the preparative liquid chromatography purification is repeated 1-3 times, or cross-repeated steps of nanofiltration, preparative liquid chromatography purification, nanofiltration again are experienced.

[0071] In some embodiments, after the nanofiltration, respectively, or after the nanofiltration, preparative liquid chromatography purification, nanofiltration again, respectively, the content of iodide ion in the pure isavuconazole sulfate of formula I is not more than 0.5%, for example, not more than 0.5%, 0.4%, 0.3%, 0.2% or 0.1%. Preferably, in some embodiments, no iodide ion is detected in the pure isavuconazole sulfate of formula I.

[0072] In some embodiments, after the nanofiltration, respectively, or after the nanofiltration, preparative liquid chromatography purification, nanofiltration again, respectively, the content of chloride ion in the pure isavuconazole sulfate of formula I is not more than 0.5%, for example, not more than 0.5%, 0.4%, 0.3%, 0.2% or 0.1%. Preferably, in some embodiments, no chloride ion is detected in the pure isavuconazole sulfate of formula I.

[0073] In some embodiments, the compound 6 is prepared by the following method:

[0074] (1) reacting isavuconazole of formula II with compound 1 to obtain compound 2;

[0075] (2) removing the Boc (tert-butyloxy carbonyl) protecting group of compound 2 to obtain compound 6.

[0076]

[0077] In some embodiments, the isavuconazole of formula II can be synthesized by the method disclosed in US6300353B1, or purchased from Nantong Nuote Biological Medicine Technology Co., Ltd., etc.

[0078] In some embodiments, the present application provides a preparation method of isavuconazole sulfate, comprising the following steps:

[0079] Nanofiltration: the aqueous solution of compound 6-1 is adjusted to pH about 5.0, filtered, the filtrate is poured into a membrane separation device, the temperature of the filtrate is controlled below 10℃, dilute sulfuric acid or sodium sulfate solution (sulfate and / or bisulfate molar mass is twice the theoretical molar mass of compound 6-1) is added, nanofiltration is performed using a nanofiltration membrane with a molecular weight cut-off of 150-300 daltons to a solution concentration of about 100 mg / ml;

[0080] Preparative liquid chromatography purification: the nanofiltration solution is purified by preparative liquid chromatography, the filler is a polymer filler, and the eluate is collected;

[0081] Alternatively, the step comprises re-nanofiltration: the eluate is collected, concentrated by nanofiltration again, and freeze-dried to obtain pure eslicarbazepine acetate;

[0082]

[0083] The optional preparative chromatography conditions of the present application are as follows:

[0084] Preparation filler: NM100, flow rate: 200 ml / min, wavelength: 250 nm

[0085] Preparation sample size: 100 DAC, 80 g;

[0086] Elution conditions:

[0087] Time (min) Phase A (5 L purified water + 200 μL concentrated sulphuric acid) Phase B (acetonitrile) 0 95 5 5 95 5 10 82 18 150 75 25

[0088] The eluate refers to the component with a retention time of 70-150 min under the chromatography conditions.

[0089] In some embodiments, the compound 6-1 is prepared by the following method:

[0090] (1) The compound of formula II is dissolved in an organic solvent, sodium iodide, molecular sieves, and compound 1 are added, the mixture is stirred and heated to 50℃, the reaction is carried out for 16 hours, filtered, separated, washed, dried, and concentrated to obtain compound 2;

[0091] (2) Compound 2 is dissolved in an organic solvent, hydrogen chloride ethyl acetate solution is added, after the reaction is completed, water and organic solvent are added, separated to obtain an aqueous solution of compound 6-1;

[0092]

[0093] The optional ion chromatography detection conditions of the present application are as follows:

[0094] Chromatography conditions Anion exchange chromatography column (Dionex IonPac AS19 column or a chromatography column of equivalent performance) Guard column: Dionex IonPac AG19 Detector Conductivity detector Detection mode Suppressed conductivity detection Column temperature 30℃ Eluent 25 mmol / L potassium hydroxide solution Flow rate 1.0 ml per minute Mobile phase Water

[0095] For better understanding of the purpose of the present application, some terms of the present application are explained as follows:

[0096] The term "nanofiltration" means a membrane process that allows the passage of solvents or certain inorganic salts while hindering the passage of larger solute molecules when a pressure gradient is applied across the membrane.

[0097] The term "molecular weight cut-off" refers to the molecular mass that is 90% retained by the membrane, in units of Daltons (Da).

[0098] The term "polymer packing" refers to a chromatographic packing based on cross-linked organic macromolecular polymers, such as polymethacrylate, polystyrene / polymethacrylate or polystyrene divinylbenzene packing, which is different from C18, C8 and other functional group bonded silica gel reverse phase chromatographic packing, can tolerate the mobile phase and regeneration conditions in the full pH range, and under the same conditions, exhibits a longer service life than other materials. The polymer packing used in the present application can be Uni reverse phase polymer chromatographic packing of Suzhou Nanomicro Technology Co., Ltd., such as UniPS series, UniPMM series, UniPSN series, NM series.

[0099] It should be understood that there is an ionization equilibrium between sulfate and bisulfate in the nanofiltration step of the present application, for example, when dilute sulfuric acid, sodium sulfate and / or sodium bisulfate is added, according to the different pH conditions in the solution, it can only contain sulfate ions, or only contain bisulfate ions, or both sulfate ions and bisulfate ions exist, the content of sulfate ions and bisulfate ions changes according to the ionization equilibrium of the solution.

[0100] It should be understood that directly nanofiltrating the mixture of compound 2 before Boc deprotection, organic solvent, sulfuric acid or sulfate salt through a nanofiltration membrane to obtain esacribsazole sulfate is also within the scope of the present application. At this time, only a nanofiltration membrane resistant to organic solvents is required.

[0101] Example 1: Preparation of compound 6-1

[0102]

[0103] Take 177.83g esacribsazole (Nantong Notai Biomedical Technology Co., Ltd.) into a 2L three-necked flask, add 444ml ethyl acetate to dissolve, 73.10g sodium iodide, 219.76g molecular sieve, stir for 10 minutes; another 219.76g compound 1 (synthesized according to patent document CN1185230C) is dissolved in 333ml ethyl acetate and added to the three-necked flask, heated to 50°C, and kept overnight. Add 1433ml ethyl acetate to the reaction solution, stir for 5 minutes, filter, wash with 2083ml 0.12mol / L dilute hydrochloric acid three times, then wash with 1433ml purified water. Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 400.00g of compound 2;

[0104] 3L three-necked flask was added 400 g of compound 2, 800 ml of methanol, and the temperature was lowered to 15-20°C. Dilute sulfuric acid aqueous solution (138 ml of concentrated sulfuric acid dissolved in 276 ml of purified water) was added dropwise, and the temperature was controlled to be no more than 20°C. After the dropwise addition was completed, the reaction was maintained at 15-20°C for 2 hours. Then 4 L of purified water was added to the reaction solution, and 2 L of ethyl acetate was used to extract the impurities twice, and 2.7 L of dichloromethane was used to extract the impurities twice. The pH of the aqueous phase was adjusted to about 5.0, and then filtered to obtain an aqueous solution containing compound 6-2.

[0105] Preparation of compound 6-2 in Example 2

[0106]

[0107] 3L three-necked flask was added 400 g of compound 2, 800 ml of methanol, and the temperature was lowered to 15-20°C. Dilute sulfuric acid aqueous solution (138 ml of concentrated sulfuric acid dissolved in 276 ml of purified water) was added dropwise, and the temperature was controlled to be no more than 20°C. After the dropwise addition was completed, the reaction was maintained at 15-20°C for 2 hours. Then 4 L of purified water was added to the reaction solution, and 2 L of ethyl acetate was used to extract the impurities twice, and 2.7 L of dichloromethane was used to extract the impurities twice. The pH of the aqueous phase was adjusted to about 5.0, and then filtered to obtain an aqueous solution containing compound 6-2.

[0108] The aqueous solutions of compounds 6-3, 6-4, and 6-5 were prepared by using a method similar to that of Example 2.

[0109]

[0110] Example 3: Preparation of eslicarbazepine acetate by nanofiltration of compound 6-1

[0111] The aqueous solution containing compound 6-1 prepared in Example 1 was poured into a membrane separation device (WTM-1769 from Hangzhou Woteng Membrane Engineering Co., Ltd.), and 90 L of 9.39 mmol / L dilute sulfuric acid solution was added. When the volume was about 3.5 L, the nanofiltration liquid was collected, and the ion chromatography method described in the present application was used for detection. The nanofiltration liquid contained 16.75% of sulfate, 0.13% of iodine ion, and 0.13% of chloride ion, as shown in Table 1. Figure 1 The nanofiltration membrane used in the membrane separation device in this example was DL membrane. The molar ratio of dilute sulfuric acid to compound 6-1 was 2:1. It should be noted that: Figure 1 only the peak area of each ion is shown in Table 1. The concentrations of the above-mentioned sulfate, iodine ion, and chloride ion can be calculated by using the external standard method of the control sample, and the content can be calculated by the formula. For example:

[0112]

[0113] In the formula, Cs is the concentration of the control sample, mg / ml.

[0114] r i for the test solution The peak area of ​​sulfate in a chromatogram;

[0115] C i for the test sample Concentration, mg / ml;

[0116] r s This represents the average area of ​​the sulfate peak in the chromatogram of the reference solution.

[0117] Example 4: Preparation and purification of isaconazole sulfate by liquid phase

[0118] Using the preparative liquid chromatography conditions described above, the nanofiltration solution obtained in Example 3 was subjected to liquid chromatography preparation. The eluent fraction with a retention time of 70-150 min was collected, freeze-dried, and 250 g of pure isaconazole sulfate was obtained. The purity of isaconazole sulfate was determined to be 99.21%. Figure 2 As shown. According to the ion chromatography method described in this invention, sulfate ions were 15%, and iodide and chloride ions were not detected. Figure 3 As shown.

[0119] Example 5

[0120] The aqueous solution containing compound 6-1 prepared in Example 1 was poured into a membrane separation device (Hangzhou Woteng Membrane Engineering Co., Ltd. WTM-1769), and sodium sulfate solution was added. The molar ratio of sodium sulfate to compound 6-1 was 3:1. The nanofiltration solution was collected, and the nanofiltration solution was detected by the ion chromatography method described in this invention. The nanofiltration solution contained 18.5% sulfate, 0.08% iodide, and 0.1% chloride. The nanofiltration membrane used in the membrane separation device in this example was a DK membrane.

[0121] Example 6

[0122] The aqueous solution containing compound 6-1 prepared in Example 1 was poured into a membrane separation device (Hangzhou Woten Membrane Engineering Co., Ltd. WTM-1769), and sodium bisulfate solution was added. The molar ratio of sodium bisulfate to compound 6-1 was 4:1. The nanofiltration solution was collected, and the nanofiltration solution was detected by the ion chromatography method described in this invention. The nanofiltration solution contained 20.25% sulfate, 0.1% iodide, and 0.15% chloride. The nanofiltration membrane used in the membrane separation device in this example was an HP membrane.

[0123] Example 7

[0124] The aqueous solution containing compound 6-2 prepared in Example 2 was poured into a membrane separation device (WTM-1769 of Hangzhou Woten Membrane Engineering Co., Ltd.), and the nanofiltration solution was collected. According to the ion chromatography method described in this invention, the nanofiltration solution contained 19.55% sulfate, 0.09% iodide, and 0.08% chloride. The nanofiltration membrane used in the membrane separation device in this example is an HL membrane.

[0125] In other embodiments of the present application, the aqueous solution containing compound 6-3 or 6-4 or 6-5 is poured into a membrane separation device (Hangzhou Woteng Membrane Engineering Co., Ltd. WTM-1769), sodium sulfate or sulfuric acid solution is added, and the nanofiltrate is collected. The effect of removing iodide ions and bromide ions, acetate ions, and trifluoroacetate ions comparable to Example 3 can also be achieved.

[0126] Comparative Example 1: According to the method in the patent WO2016016766A2:

[0127] 10 g of intermediate 2 was purified by silica gel column chromatography (dichloromethane / methanol), and then reacted with hydrogen chloride ethyl acetate solution. After the reaction was completed, solid was precipitated, and the solid was filtered and became sticky when filtered.

[0128] Comparative Example 2: According to the method disclosed in the patent CN106916152B:

[0129] 1.0 g of intermediate 2 was dissolved in a mixture of 10 ml of ethyl acetate / 10 ml of purified water, 3.8 equivalents of copper sulfate were added, stirred, layered, and the organic phase was collected and concentrated to obtain intermediate 5. It was detected that there was almost no sulfate in the sample of intermediate 5, as shown in Figure 4 .

[0130] Comparative Example 3: According to the method disclosed in the patent CN113024539A:

[0131] 11.40 g of intermediate 2 was dissolved in 30 ml of dichloromethane, 30 ml of 10% sodium trifluoroacetate aqueous solution was added, stirred for 2 hours, layered, and the organic phase was collected and concentrated to obtain intermediate 7. The iodide ion content in 7 was 5.87%, the chloride ion content was 0.28%, and the trifluoroacetic acid content was 6.59%, as shown in Figure 5 ; Note that: Figure 5 Only the peak area of each ion is shown, and the content of the above sulfate, chloride ion, and trifluoroacetic acid can be calculated by using the external standard method of the reference substance.

[0132] 5.57 g of intermediate 7 was dissolved in 16 ml of ethyl acetate, 6 ml of acetonitrile was added, and the temperature was lowered to 0-5°C. 24.6 g of 85% trifluoroacetic acid aqueous solution was added, and the temperature was controlled to be less than 10°C. After the drop was completed, the room temperature was recovered and stirred. After the reaction was completed, 16 ml of ethyl acetate was added for dilution, and repeated washing with purified water until the water phase pH was 4-6. The organic phase was collected, dried, and concentrated to obtain 2.5 g of intermediate 8. The yield was too low to be suitable for industrial production.

[0133] It should be understood that the above examples are exemplary and are not intended to limit the scope of the claims encompassing all possible embodiments. Various modifications and changes can also be made on the basis of the above examples without departing from the scope of the present disclosure. Similarly, various technical features of the above examples can be combined arbitrarily to form additional embodiments of the present application that can not be explicitly described. Therefore, the above examples merely express several embodiments of the present application and do not limit the scope of protection of the present patent.

Claims

1. A method for preparing esconazole sulfate, comprising the following steps: obtaining esconazole sulfate of formula I by nanofiltration in the presence of sulfate and / or bisulfate ions, and the specific reaction equation is as follows: ； purifying esconazole sulfate of formula I obtained by nanofiltration by preparative liquid chromatography, and collecting the eluent to obtain pure esconazole sulfate of formula I; HX in the compound 6 is any one of HCl, H 2 SO 4, HBr, HI, CH 3 COOH and CF 3 COOH; the nanofiltration uses a nanofiltration membrane, and the molecular weight cut-off of the nanofiltration membrane is 100-500 Daltons; the nanofiltration membrane is a polyamide nanofiltration membrane, and the polyamide nanofiltration membrane is a SUEZ industrial separation nanofiltration membrane; the preparative liquid chromatography filler is a polymer filler, and the polymer filler is polymethacrylate, polystyrene / polymethacrylate or polystyrene divinylbenzene.

2. The production method according to claim 1, characterized by, The molecular weight cut-off of the nanofiltration membrane is 100-400 Daltons.

3. The production method according to claim 2, characterized by, The molecular weight cut-off of the nanofiltration membrane is 100-300 Daltons.

4. The method of claim 1, wherein, The molar amount of the sulfate and / or bisulfate ions is more than 1 times the molar amount of the salt of the compound 6.

5. The preparation method according to claim 1, characterized in that, The SUEZ industrial separation nanofiltration membrane is any one of DK membrane, DL membrane, HP membrane and HL membrane. 6.The method according to any one of claims 1-5, further comprising one or more of the following features: (1) the content of iodine ions in esconazole sulfate of formula I obtained by nanofiltration is not more than 0.5%; and / or (2) the content of chloride ions in esconazole sulfate of formula I obtained by nanofiltration is not more than 0.5%. 7.The method according to any one of claims 1-5, further comprising the following step: after the eluent is collected, repeating the nanofiltration step to obtain pure esconazole sulfate of formula I.

8. The method of claim 1, wherein, The preparative liquid chromatography filler is a polymer filler, and the polymer filler is Uni reverse-phase polymer chromatography filler.

9. The production method according to claim 8, characterized by, The Uni reverse-phase polymer chromatography filler is any one of UniPS series, UniPMM series, UniPSN series and NM series.

10. The method of claim 1, wherein, The elution condition of the preparative liquid chromatography is gradient elution, the mobile phase A is 0.004% sulfuric acid solution, and the mobile phase B is acetonitrile.

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