Preparation method of ensafetine

Abstract

The invention discloses a preparation method of a dual PDE3 / 4 inhibitor Encephaline. The preparation method comprises the following steps: carrying out a sizuki coupling reaction on initial raw materials of a compound shown as a formula 1 and a compound shown as a formula 2 to obtain a compound shown as a formula 3, carrying out intramolecular cyclization to obtain a compound shown as a formula 4, converting carbonyl into a compound shown as a formula 5 by using POCl3, and carrying out an alkylation reaction on the compound shown as a formula 5 and a compound shown as a formula 6 to obtain a compound shown as a formula 7. Wherein the acyl imine of the compound as shown in the formula 7 and a compound as shown in a formula 8 are subjected to substitution reaction to obtain the product Encephaline. The selected raw materials are easy to obtain, the operation method is simple and convenient, the product yield is high, and the method is suitable for batch production.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a method for preparing ensefentin. Background Art

[0002] On June 26, 2024, the U.S. FDA approved Verona Pharma's Ohtuvayre (ensifentrine, Chinese name: Ensefentin) for the maintenance treatment of chronic obstructive pulmonary disease (COPD) in adults. Ensefentin is the first inhaled product with a novel mechanism of action in more than 20 years, providing a new treatment option for COPD patients. Ensefentin is a dual-target inhibitor developed by Verona that targets phosphodiesterase-3 (PDE3) and phosphodiesterase-4 (PDE4), with an affinity for PDE3 that is 3440 times that of PDE4. As a dual PDE3 / 4 inhibitor, Ensefentin can provide both bronchodilator and anti-inflammatory effects, significantly improving patients' respiratory function and quality of life; in addition, Ensefentin, as a nebulized inhalation preparation, helps avoid gastrointestinal-related side effects. As a drug with a new mechanism in the field of COPD, Ensefentin has good overall safety. More patients in the placebo group discontinued the drug due to side effects. Ensefentin has more side effects than the placebo group, including hypertension, back pain, nasopharyngitis, etc.

[0003] The chemical structure of Ensefentin is shown in Formula I:

[0004]

[0005] However, the current preparation method for ensefentin still needs to be improved. Summary of the invention

[0006] The present invention aims to solve one of the technical problems in the related art at least to a certain extent. To this end, one object of the present invention is to propose a method for preparing the compound of formula I, Ensefentin. Compared with the prior art, the preparation method of the present invention is to subject the initial raw materials, the compound of formula 1 and the compound of formula 2 to a sizuki coupling reaction to obtain a compound of formula 3, to obtain a compound of formula 4 through intramolecular cyclization, to convert the carbonyl group into a halide (compound of formula 5) by POCl3, and to obtain a compound of formula 7 through an alkylation reaction with a compound of formula 6, wherein the acyl imide of the compound of formula 7 is then subjected to a substitution reaction with a compound of formula 8 to obtain the product Ensefentin.

[0007] In one aspect of the present invention, the present invention provides a method for preparing Ensefentin, a compound represented by Formula I. According to an embodiment of the present invention, the preparation method comprises:

[0008] (1) contacting the compound represented by Formula 1 with the compound represented by Formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium to obtain the compound represented by Formula 3;

[0009] (2) contacting the compound represented by Formula 3 with trifluoroacetic anhydride (TFAA) to obtain the compound represented by Formula 4;

[0010] (3) contacting the compound represented by Formula 4 with phosphorus oxychloride to obtain the compound represented by Formula 5;

[0011] (4) contacting the compound represented by Formula 5 with the compound represented by Formula 6 to obtain the compound represented by Formula 7;

[0012] (5) contacting the compound represented by Formula 7 with the compound represented by Formula 8, potassium phosphate, and iodide to obtain the compound represented by Formula I, Ensefentin,

[0013]

[0014] Wherein, the iodide is at least one selected from sodium iodide or potassium iodide.

[0015] The inventors have found that, using the preparation method of the present invention, the compound represented by Formula 1 and the compound represented by Formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium are used as starting materials, and a total of 5 steps of reaction are performed to successfully synthesize and prepare the target product, Ensefentin.

[0016] The term "contact" as used herein should be understood in a broad sense, and can be any manner that allows at least two reactants to undergo a chemical reaction, such as mixing the two reactants under appropriate conditions. If necessary, the reactants to be contacted can be mixed under stirring, and thus, the type of stirring is not particularly limited, and can be mechanical stirring, i.e. stirring under the action of mechanical force.

[0017] In this document, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of the features. In the description of the present invention, the meaning of "plurality" is two or more, unless otherwise clearly and specifically defined.

[0018] According to an embodiment of the present invention, the method for preparing the compound shown in Formula 3, the compound shown in Formula 4, the compound shown in Formula 5, the compound shown in Formula 7, and the compound shown in Formula I may also have at least one of the following additional technical features:

[0019] According to an embodiment of the present invention, the chemical reaction described in the present invention can be carried out according to any method known in the art. The source of the raw materials of the compound shown in Formula 3, the compound shown in Formula 4, the compound shown in Formula 5, the compound shown in Formula 7, and the compound shown in Formula I is not particularly limited, and it can be prepared by any known method or commercially available. For example, the cas of the compound shown in Formula 1 is: 681431-18-5.

[0020] According to an embodiment of the present invention, in step (1), the contacting method of the compound represented by Formula 1 with the compound represented by Formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 1 and the compound represented by Formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula 3 using this method can be further improved.

[0021] According to an embodiment of the present invention, in step (1), the following steps are included: at room temperature, the compound of formula 1, the compound of formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium are added to anhydrous dioxane, nitrogen is replaced, and the reaction is heated at 95°C to 101°C for 3 hours and 45 minutes to 4 hours and 15 minutes. After the reaction solution is cooled to room temperature, it is filtered with diatomaceous earth, washed with water, and then extracted with ethyl acetate. The organic phase is washed with saturated brine, dried with anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure to evaporate the solvent. The concentrate is purified by silica gel column chromatography with a dichloromethane / methanol mixed solvent to obtain the compound of formula 3. Thus, the efficiency of the contact reaction between the compound of formula 1 and the compound of formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 3 by using this method can be further improved.

[0022] According to an embodiment of the present invention, in step (1), the molar ratio of the compound represented by Formula 1 to the compound represented by Formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium is 1:(1.0-1.1):(2.5-4.5):(0.05-0.15), and preferably the molar ratio of the compound represented by Formula 1 to the compound represented by Formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium is 1:1.02:3.0:0.1. Thus, the efficiency of preparing the compound represented by Formula 3 using this method can be further improved.

[0023] According to an embodiment of the present invention, in step (1), the volume ratio of dichloromethane / methanol in the dichloromethane / methanol mixed solvent is (8-12):1, and preferably the volume ratio of dichloromethane / methanol mixed solvent is 10:1.

[0024] According to an embodiment of the present invention, in step (1), heating is preferably performed at 98° C. to 101° C. for 4 hours.

[0025] According to a specific embodiment of the present invention, in step (1), the following steps are included: at room temperature, the compound represented by formula 1 (22.60g, 0.1mol), the compound represented by formula 2 (19.48g, 0.102mol), potassium carbonate (41.46g, 0.3mol) and tetrakis(triphenylphosphine)palladium (11.56g, 0.01mol) are added to anhydrous dioxane (260mL), nitrogen is replaced and heated at 98°C to 102°C for 4 hours. After the reaction solution is cooled to room temperature, it is filtered with diatomaceous earth, washed with 200mL of water, and then extracted with 200mL of ethyl acetate. The organic phase is washed with 200mL of saturated brine, dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure to evaporate the solvent. The concentrate is purified by silica gel column chromatography using a dichloromethane / methanol mixed solvent with a volume ratio of 10:1 to obtain a compound represented by formula 3, with an amount of 25.08g and a yield of 85.8%.

[0026] According to an embodiment of the present invention, in step (2), the contacting method of the compound represented by Formula 3 and trifluoroacetic anhydride is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 3 and trifluoroacetic anhydride can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula 4 by using this method can be further improved.

[0027] According to an embodiment of the present invention, in step (2), the following steps are included: adding trifluoroacetic anhydride (TFAA) to a dichloromethane solution containing the compound of formula 3 at 0°C, stirring the reaction at room temperature for 0.5 hours, and performing post-treatment after the reaction is completed. The reaction solution is quenched by adding ice water at 0°C, and a saturated sodium bicarbonate solution is added for washing after separation of the organic layer. After the organic phase is separated, saturated brine is added for washing, and the filtrate is dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure to evaporate the solvent. The concentrate is purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 3:1 to obtain a compound of formula 4. Thus, the efficiency of the contact reaction between the compound of formula 3 and trifluoroacetic anhydride can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 4 by using this method can be further improved.

[0028] According to an embodiment of the present invention, in step (2), the molar ratio of the compound represented by Formula 3 to trifluoroacetic anhydride is 1:(1.3-2.0), preferably the molar ratio of the compound represented by Formula 3 to trifluoroacetic anhydride is 1:1.5. Thus, the efficiency of preparing the compound represented by Formula 4 by this method can be further improved.

[0029] According to a specific embodiment of the present invention, in step (2), the following steps are included: at 0°C, trifluoroacetic anhydride (25.87 g, 123.17 mmol) is added to a dichloromethane solution (240 mL) containing the compound of formula 3 (24.0 g, 82.11 mmol), and the reaction is stirred at room temperature for 0.5 hours. After the reaction is completed, post-treatment is performed, the reaction solution is quenched by adding ice water (50 mL) at 0°C, and the organic layer is separated and then washed with 200 mL of saturated sodium bicarbonate solution. After the organic phase is separated, 100 mL of saturated brine is added for washing, and the filtrate is dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure to evaporate the solvent. The concentrate is purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 3:1 to obtain the compound of formula 4, with an amount of 20.29 g and a yield of 90.1%.

[0030] According to an embodiment of the present invention, in step (3), the contacting method of the compound represented by Formula 4 and phosphorus oxychloride is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 4 and phosphorus oxychloride can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula 5 by using this method can be further improved.

[0031] According to an embodiment of the present invention, in step (3), the following steps are included: adding the compound shown in Formula 4 to phosphorus oxychloride at room temperature, stirring and heating to reflux state to react for 3 hours, after the reaction solution is cooled to room temperature, reducing pressure and concentrating, adding an appropriate amount of ice water when a small amount of mixture remains, stirring rapidly, adding a saturated NaOH solution dropwise to pH = 10, filtering the solid, washing the filter cake with ice water, and drying to obtain the compound shown in Formula 5. Thus, the efficiency of the contact reaction between the compound shown in Formula 4 and phosphorus oxychloride can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound shown in Formula 5 by using this method can be further improved.

[0032] According to an embodiment of the present invention, in step (3), the weight ratio of the compound represented by formula 4 to phosphorus oxychloride is 1:(5-10), preferably the weight ratio of the compound represented by formula 4 to phosphorus oxychloride is 1:6.3. Thus, the efficiency of preparing the compound represented by formula 5 by this method can be further improved.

[0033] According to a specific embodiment of the present invention, in step (3), the following steps are included: adding the compound shown in formula 4 (19.0 g, 69.27 mmol) to phosphorus oxychloride (120 mL) at room temperature, stirring and heating to reflux state to react for 3 hours, after the reaction solution is cooled to room temperature, it is concentrated under reduced pressure, and when a small amount of mixture (about 30 mL) remains, an appropriate amount of ice water is added, stirred rapidly, and a saturated NaOH solution is added dropwise until the pH is 10, the solid is filtered, the filter cake is washed with ice water (50 mL), and dried to obtain the compound shown in formula 5, with an amount of 13.40 g and a yield of 66.1%.

[0034] According to an embodiment of the present invention, in step (4), the contacting method of the compound represented by Formula 5 and the compound represented by Formula 6 is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 5 and the compound represented by Formula 6 can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula 7 by using this method can be further improved.

[0035] According to an embodiment of the present invention, in step (4), the following steps are included: at room temperature, the compound of formula 5 is added to the short-chain alcohol A, the compound of formula 6 is added, and then the temperature is raised to reflux state, and the reaction is stirred for 3 hours to 3 hours and 30 minutes. The reaction is completed by monitoring by TLC, and the reaction liquid is cooled to room temperature, filtered, and the filter cake is washed with ice water and dried to obtain the compound of formula 7. In this way, the efficiency of the contact reaction between the compound of formula 5 and the compound of formula 6 can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 7 by using this method can be further improved.

[0036] According to an embodiment of the present invention, in step (4), the molar ratio of the compound represented by Formula 5 to the compound represented by Formula 6 is 1:(2.5-4.0), and preferably the molar ratio of the compound represented by Formula 5 to the compound represented by Formula 6 is 1:3.0. Thus, the efficiency of preparing the compound represented by Formula 7 by this method can be further improved.

[0037] According to an embodiment of the present invention, in step (4), the short-chain alcohol A is at least one selected from isopropanol or ethanol.

[0038] According to an embodiment of the present invention, in step (4), the reaction is preferably stirred for 3 hours and 15 minutes.

[0039] According to a specific embodiment of the present invention, in step (4), the following steps are included: at room temperature, the compound represented by formula 5 (10.0 g, 34.16 mmol) is added to isopropanol (100 mL), and the compound represented by formula 6 (13.86 g, 102.48 mmol) is added, and then the temperature is raised to reflux state, and the reaction is stirred for 3 hours and 15 minutes. The reaction is completed by TLC monitoring, and the reaction solution is cooled to room temperature, filtered, and the filter cake is washed with ice water (50 mL) and dried to obtain the compound represented by formula 7, with an amount of 12.40 g and a yield of 92.7%.

[0040] According to an embodiment of the present invention, in step (5), the contacting method of the compound represented by Formula 7 with the compound represented by Formula 8, potassium phosphate, and iodide is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 7 and the compound represented by Formula 8, potassium phosphate, and iodide can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula I by using this method can be further improved.

[0041] According to an embodiment of the present invention, in step (5), the following steps are included: at room temperature, the compound shown in formula 7, the compound shown in formula 8, potassium phosphate and iodide are mixed and dissolved in dry 2-butanone, the reaction solution is heated in a nitrogen atmosphere to maintain reflux state, and stirred for reaction for 17 to 20 hours. After the reaction is completed, it is cooled to room temperature and filtered with diatomaceous earth, the filter cake is washed with dichloromethane, dried over anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to evaporate the solvent, and the concentrate is purified by silica gel column chromatography with a dichloromethane / methanol mixed solvent to obtain the compound shown in formula I, Ensefentin. In this way, the efficiency of the contact reaction between the compound shown in formula 7 and the compound shown in formula 8, potassium phosphate and iodide can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound shown in formula I, Ensefentin, by using this method can be further improved.

[0042] According to an embodiment of the present invention, in step (5), the molar ratio of the compound represented by Formula 7 to the compound represented by Formula 8, potassium phosphate, and iodide is 1:(2.0-4.0):(4.0-6.0):(2.0-4.0), and preferably the molar ratio of the compound represented by Formula 7 to the compound represented by Formula 8, potassium phosphate, and iodide is 1:3.0:5.0:3.0. Thus, the efficiency of preparing the compound represented by Formula I by this method can be further improved.

[0043] According to an embodiment of the present invention, in step (5), the iodide is at least one selected from sodium iodide or potassium iodide, and preferably the iodide is selected from sodium iodide.

[0044] According to an embodiment of the present invention, in step (5), the volume ratio of dichloromethane to methanol in the dichloromethane / methanol mixed solvent is (15-25):1, preferably the volume ratio of dichloromethane to methanol is 20:1.

[0045] According to an embodiment of the present invention, in step (5), the reaction is preferably stirred for 18 hours.

[0046] According to a specific embodiment of the present invention, in step (5), the following steps are included: at room temperature, the compound represented by formula 7 (10.0 g, 25.55 mmol), the compound represented by formula 8 (12.80 g, 76.64 mmol), potassium phosphate (27.11 g, 127.73 mmol) and sodium iodide (11.49 g, 76.64 mmol) are mixed and dissolved in dry 2-butanone (300 mL), the reaction solution is heated in a nitrogen atmosphere and kept in a reflux state, and stirred for reaction for 18 hours. After the reaction is completed, it is cooled to room temperature and filtered with diatomaceous earth, the filter cake is washed with dichloromethane (100 mL), and dried over anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to evaporate the solvent, and the concentrate is purified by silica gel column chromatography using a dichloromethane / methanol mixed solvent with a volume ratio of 20:1 to obtain the compound represented by formula I, Ensefentin, with an amount of 9.44 g, a yield of 77.4%, and an HPLC purity of 99.6%.

[0047] According to a specific embodiment of the present invention, the synthesis route of the compound Ensefentin represented by Formula I can be as follows:

[0048]

[0049] Compared with the prior art, the preparation method of Ensefentin of the present invention has at least the following beneficial effects:

[0050] 1. Compared with the prior art, the beneficial effect of the preparation method of the present invention is that: in this method, the initial raw materials, the compound represented by formula 1 and the compound represented by formula 2, are subjected to sizuki coupling reaction to obtain the compound represented by formula 3, and the compound represented by formula 4 is obtained through intramolecular cyclization, and the carbonyl group is converted into a halide (compound represented by formula 5) by POCl3, and then the compound represented by formula 6 is subjected to alkylation reaction to obtain the compound represented by formula 7, wherein the acyl imide of the compound represented by formula 7 is then subjected to substitution reaction with urea bromide to obtain the product ensefentin.

[0051] 2. Compared with the prior art methods, the present invention has the following significant advantages: (1) When facing a compound with a hydroxyl group, WO2012037782 first protects the hydroxyl group and then undergoes a substitution reaction. The present invention selects a boric acid compound as a starting material and undergoes a Sizuki reaction with the compound. A higher reaction yield can be obtained without protecting the hydroxyl group, thereby reducing the two-step reaction of hydroxyl protection and deprotection. (2) In the document WO2023109802, the compound shown in formula 7 is reacted with 2-(2-bromoethyl)iso-doline-1,3-dione to obtain an easily removed compound, and then hydrazine hydrate is added to obtain an amino group, and potassium chlorate is added to obtain the final product (urea). The present invention directly reacts the compound shown in formula 7 with a halogenated urea to obtain the final product, shortening the two-step reaction and simplifying the reaction operation. (3) The raw materials selected in the present invention are easily available, the operation method is simple, the product yield is high, and it is suitable for mass production. DETAILED DESCRIPTION

[0052] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. If no specific techniques or conditions are specified in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used that do not specify the manufacturer are all conventional products that can be obtained commercially.

[0053] Example 1 Synthesis of the compound represented by formula 3

[0054] At room temperature, the compound represented by formula 1 (22.60 g, 0.1 mol), the compound represented by formula 2 (19.48 g, 0.102 mol), potassium carbonate (41.46 g, 0.3 mol) and tetrakis(triphenylphosphine)palladium (11.56 g, 0.01 mol) were added to anhydrous dioxane (260 mL), the nitrogen was replaced and the reaction was heated at 98°C to 101°C for 4 hours. After the reaction solution was cooled to room temperature, it was filtered with diatomaceous earth, washed with 200 mL of water, and then extracted with 200 mL of ethyl acetate. The organic phase was washed with 200 mL of saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to evaporate the solvent. The concentrate was purified by silica gel column chromatography using a dichloromethane / methanol mixed solvent with a volume ratio of 10:1 to obtain the compound represented by formula 3, with an amount of 25.08 g and a yield of 85.8%.

[0055] LC-MS (APCI): m / z = 293.1 (M+1) + .

[0056] Example 2 Synthesis of the compound represented by formula 3

[0057] At room temperature, the compound represented by formula 1 (22.60 g, 0.1 mol), the compound represented by formula 2 (19.10 g, 0.1 mol), potassium carbonate (34.55 g, 0.25 mol) and tetrakis(triphenylphosphine)palladium (5.78 g, 0.005 mol) were added to anhydrous dioxane (260 mL), the nitrogen was replaced and the mixture was heated at 95°C to 98°C for 3 hours and 45 minutes. After the reaction solution was cooled to room temperature, it was filtered with diatomaceous earth, washed with 200 mL of water, and then extracted with 200 mL of ethyl acetate. The organic phase was washed with 200 mL of saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to evaporate the solvent. The concentrate was purified by silica gel column chromatography using a dichloromethane / methanol mixed solvent with a volume ratio of 8:1 to obtain the compound represented by formula 3, with an amount of 23.88 g and a yield of 81.7%.

[0058] Example 3 Synthesis of the compound represented by formula 3

[0059] At room temperature, the compound represented by formula 1 (22.60 g, 0.1 mol), the compound represented by formula 2 (20.01 g, 0.11 mol), potassium carbonate (62.19 g, 0.45 mol) and tetrakis(triphenylphosphine)palladium (17.34 g, 0.015 mol) were added to anhydrous dioxane (260 mL), the nitrogen was replaced and the reaction was heated at 98°C to 101°C for 4 hours and 15 minutes. After the reaction solution was cooled to room temperature, it was filtered with diatomaceous earth, washed with 200 mL of water, and then extracted with 200 mL of ethyl acetate. The organic phase was washed with 200 mL of saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to evaporate the solvent. The concentrate was purified by silica gel column chromatography using a dichloromethane / methanol mixed solvent with a volume ratio of 12:1 to obtain the compound represented by formula 3, with an amount of 24.84 g and a yield of 85.0%.

[0060] Comparative Example 1 Synthesis of the Compound Represented by Formula 3

[0061] At room temperature, the compound represented by formula 1 (22.60 g, 0.1 mol), the compound represented by formula 2 (24.83 g, 0.13 mol), potassium carbonate (27.64 g, 0.2 mol) and tetrakis(triphenylphosphine)palladium (2.89 g, 0.0025 mol) were added to anhydrous dioxane (260 mL), the nitrogen was replaced and the reaction was heated at 90°C for 5 hours. After the reaction solution was cooled to room temperature, it was filtered with diatomaceous earth, washed with 200 mL of water, and then extracted with 200 mL of ethyl acetate. The organic phase was washed with 200 mL of saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to evaporate the solvent. The concentrate was purified by silica gel column chromatography using a dichloromethane / methanol mixed solvent with a volume ratio of 5:1 to obtain the compound represented by formula 3, with an amount of 23.18 g and a yield of 79.3%.

[0062] Example 4 Synthesis of the compound represented by formula 4

[0063] At 0°C, trifluoroacetic anhydride (25.87 g, 123.17 mmol) was added to a dichloromethane solution (240 mL) containing the compound of formula 3 (24.0 g, 82.11 mmol), and the reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, post-treatment was performed, and the reaction solution was quenched by adding ice water (50 mL) at 0°C. After the organic layer was separated, 200 mL of saturated sodium bicarbonate solution was added for washing. After the organic phase was separated, 100 mL of saturated brine was added for washing, and the filtrate was dried over anhydrous sodium sulfate. The solvent was evaporated, and the concentrate was purified by silica gel column chromatography using a mixed solvent of petroleum ether / ethyl acetate with a volume ratio of 3:1 to obtain the compound of formula 4, with an amount of 20.29 g and a yield of 90.1%.

[0064] LC-MS (APCI): m / z = 275.1 (M+1) + .

[0065] Example 5 Synthesis of the compound represented by formula 4

[0066] At 0°C, trifluoroacetic anhydride (22.42 g, 106.74 mmol) was added to a dichloromethane solution (240 mL) containing the compound of formula 3 (24.0 g, 82.11 mmol), and the reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, post-treatment was performed, and the reaction solution was quenched by adding ice water (50 mL) at 0°C. After the organic layer was separated, 200 mL of saturated sodium bicarbonate solution was added for washing. After the organic phase was separated, 100 mL of saturated brine was added for washing, and the filtrate was dried over anhydrous sodium sulfate. The solvent was evaporated, and the concentrate was purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 3:1 to obtain the compound of formula 4, with an amount of 19.89 g and a yield of 88.3%.

[0067] Example 6 Synthesis of the compound represented by formula 4

[0068] At 0°C, trifluoroacetic anhydride (34.49 g, 123.17 mmol) was added to a dichloromethane solution (240 mL) containing the compound of formula 3 (24.0 g, 82.11 mmol), and the reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, post-treatment was performed, and the reaction solution was quenched by adding ice water (50 mL) at 0°C. After the organic layer was separated, 200 mL of saturated sodium bicarbonate solution was added for washing. After the organic phase was separated, 100 mL of saturated brine was added for washing, and the filtrate was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to evaporate the solvent, and the concentrate was purified by silica gel column chromatography using a mixed solvent of petroleum ether / ethyl acetate with a volume ratio of 3:1 to obtain the compound of formula 4, with an amount of 20.16 g and a yield of 89.5%.

[0069] Example 7 Synthesis of the compound represented by formula 5

[0070] At room temperature, the compound shown in formula 4 (19.0 g, 69.27 mmol) was added to phosphorus oxychloride (120 mL), and the mixture was stirred and heated to reflux for 3 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. When a small amount of mixture (about 30 mL) remained, an appropriate amount of ice water was added, and the mixture was stirred rapidly. A saturated NaOH solution was added dropwise until the pH value was 10. The solid was filtered, and the filter cake was washed with ice water (50 mL). The compound shown in formula 5 was obtained by drying, with an amount of 13.40 g and a yield of 66.1%.

[0071] LC-MS (APCI): m / z = 293.1 (M+1) + .

[0072] Example 8 Synthesis of the compound represented by formula 5

[0073] At room temperature, the compound shown in formula 4 (24.0 g, 87.50 mmol) was added to phosphorus oxychloride (240 mL), and the mixture was stirred and heated to reflux for 3 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. When a small amount of mixture (about 60 mL) remained, an appropriate amount of ice water was added, and the mixture was stirred rapidly. A saturated NaOH solution was added dropwise until the pH value was 10. The solid was filtered, and the filter cake was washed with ice water (60 mL). The compound shown in formula 5 was obtained by drying, with an amount of 16.77 g and a yield of 65.6%.

[0074] Example 9 Synthesis of the compound represented by formula 5

[0075] At room temperature, the compound shown in formula 4 (24.0 g, 87.50 mmol) was added to phosphorus oxychloride (120 mL), and the mixture was stirred and heated to reflux for 3 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. When a small amount of mixture (about 30 mL) remained, an appropriate amount of ice water was added, and the mixture was stirred rapidly. A saturated NaOH solution was added dropwise until the pH value was 10. The solid was filtered, and the filter cake was washed with ice water (60 mL). The compound shown in formula 5 was obtained by drying, with an amount of 16.52 g and a yield of 64.5%.

[0076] Comparative Example 2 Synthesis of the Compound Represented by Formula 5

[0077] At room temperature, the compound of formula 4 (19.0 g, 69.27 mmol) was added to phosphorus oxychloride (38 mL), and the mixture was stirred and heated to reflux for 2.5 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. When a small amount of mixture (about 30 mL) remained, an appropriate amount of ice water was added, and the mixture was stirred rapidly. A saturated NaOH solution was added dropwise until the pH value was 10. The solid was filtered, and the filter cake was washed with ice water (50 mL). The compound of formula 5 was obtained by drying, with an amount of 12.65 g and a yield of 62.4%.

[0078] Example 10 Synthesis of the compound represented by formula 7

[0079] At room temperature, the compound represented by Formula 5 (10.0 g, 34.16 mmol) was added to isopropanol (100 mL), and the compound represented by Formula 6 (13.86 g, 102.48 mmol) was added, and then the temperature was raised to reflux state, and the reaction was stirred for 3 hours and 15 minutes. The reaction was completed by TLC monitoring. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with ice water (50 mL) and dried to obtain the compound represented by Formula 7, with an amount of 12.40 g and a yield of 92.7%.

[0080] LC-MS (APCI): m / z = 392.2 (M+1) + .

[0081] Example 11 Synthesis of the compound represented by formula 7

[0082] At room temperature, the compound represented by Formula 5 (10.0 g, 34.16 mmol) was added to isopropanol (100 mL), and the compound represented by Formula 6 (11.55 g, 85.4 mmol) was added, and then the temperature was raised to reflux state, and the reaction was stirred for 3 hours. The reaction was completed by TLC monitoring. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with ice water (50 mL) and dried to obtain the compound represented by Formula 7, with an amount of 11.94 g and a yield of 89.3%.

[0083] Example 12 Synthesis of the compound represented by formula 7

[0084] At room temperature, the compound represented by Formula 5 (10.0 g, 34.16 mmol) was added to isopropanol (100 mL), and the compound represented by Formula 6 (18.48 g, 136.68 mmol) was added, and then the temperature was raised to reflux state, and the reaction was stirred for 3 hours and 30 minutes. The reaction was completed by TLC monitoring. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with ice water (50 mL) and dried to obtain the compound represented by Formula 7, with an amount of 12.22 g and a yield of 91.4%.

[0085] Example 13 Synthesis of the compound represented by formula 7

[0086] At room temperature, the compound represented by Formula 5 (10.0 g, 34.16 mmol) was added to ethanol (100 mL), and the compound represented by Formula 6 (13.86 g, 102.48 mmol) was added, and then the temperature was raised to reflux and the reaction was stirred for 3 hours and 30 minutes. The reaction was completed by TLC monitoring. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with ice water (50 mL) and dried to obtain the compound represented by Formula 7, with an amount of 12.33 g and a yield of 92.2%.

[0087] Example 14 Preparation of Ensefentin, a compound represented by Formula I

[0088] At room temperature, the compound represented by formula 7 (10.0 g, 25.55 mmol), the compound represented by formula 8 (12.80 g, 76.64 mmol), potassium phosphate (27.11 g, 127.73 mmol) and sodium iodide (11.49 g, 76.64 mmol) were mixed and dissolved in dry 2-butanone (300 mL). The reaction solution was heated in a nitrogen atmosphere and kept in a reflux state, and stirred for 18 hours. After the reaction was completed, it was cooled to room temperature and filtered with diatomaceous earth. The filter cake was washed with dichloromethane (100 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to evaporate the solvent. The concentrate was purified by silica gel column chromatography using a dichloromethane / methanol mixed solvent with a volume ratio of 20:1 to obtain the compound represented by formula I, Ensefentin, with an amount of 9.44 g, a yield of 77.4%, and an HPLC purity of 99.6%.

[0089] LC-MS (APCI): m / z = 478.2 (M+1) + .

[0090] 1 H NMR(400MHz,DMSO-d6)δppm 1.97(s,6H)2.22(s,3H)2.90(t,J=5.93Hz,2H)3.07-3.50(m,1H)3.33(s,3H)3.62(s,3H)3.92(t,J=5.99Hz,2H )4.18(t,J=6.72Hz,2H)5.32(s,1H)5.45(br.s.,2H)6.11(t,J=5.75Hz,1H)6.66(s,1H)6.86(s,2H)6.96(s,1H)

[0091] Example 15 Preparation of Ensefentin, a compound represented by Formula I

[0092] At room temperature, the compound represented by formula 7 (10.0 g, 25.55 mmol), the compound represented by formula 8 (8.53 g, 51.1 mmol), potassium phosphate (21.69 g, 102.2 mmol) and sodium iodide (7.66 g, 51.1 mmol) were mixed and dissolved in dry 2-butanone (300 mL). The reaction solution was heated in a nitrogen atmosphere and kept under reflux, and stirred for 17 hours. After the reaction was completed, it was cooled to room temperature and filtered with diatomaceous earth. The filter cake was washed with dichloromethane (100 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to evaporate the solvent. The concentrate was purified by silica gel column chromatography using a dichloromethane / methanol mixed solvent with a volume ratio of 15:1 to obtain the compound represented by formula I, Ensefentin, with an amount of 9.18 g, a yield of 75.2%, and an HPLC purity of 99.5%.

[0093] Example 16 Preparation of the compound Ensefentin represented by formula I

[0094] At room temperature, the compound represented by formula 7 (10.0 g, 25.55 mmol), the compound represented by formula 8 (17.07 g, 102.2 mmol), potassium phosphate (32.54 g, 153.3 mmol) and sodium iodide (15.32 g, 102.2 mmol) were mixed and dissolved in dry 2-butanone (300 mL). The reaction solution was heated in a nitrogen atmosphere and kept under reflux, and stirred for 20 hours. After the reaction was completed, it was cooled to room temperature and filtered with diatomaceous earth. The filter cake was washed with dichloromethane (100 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to evaporate the solvent. The concentrate was purified by silica gel column chromatography using a dichloromethane / methanol mixed solvent with a volume ratio of 25:1 to obtain the compound represented by formula I, Ensefentin, with an amount of 9.39 g, a yield of 77.0%, and an HPLC purity of 99.3%.

[0095] Example 17 Preparation of Ensefentin, a compound represented by Formula I

[0096] At room temperature, the compound represented by formula 7 (10.0 g, 25.55 mmol), the compound represented by formula 8 (12.8 g, 76.64 mmol), potassium phosphate (27.11 g, 127.73 mmol) and potassium iodide (12.72 g, 76.64 mmol) were mixed and dissolved in dry 2-butanone (300 mL). The reaction solution was heated in a nitrogen atmosphere and kept under reflux, and stirred for 18 hours. After the reaction was completed, it was cooled to room temperature and filtered with diatomaceous earth. The filter cake was washed with dichloromethane (100 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to evaporate the solvent. The concentrate was purified by silica gel column chromatography using a dichloromethane / methanol mixed solvent with a volume ratio of 20:1 to obtain the compound represented by formula I, Ensefentin, with an amount of 9.42 g, a yield of 77.2%, and an HPLC purity of 99.7%.

[0097] Comparative Example 3 Preparation of Ensefentin, a Compound Represented by Formula I

[0098] At room temperature, the compound represented by formula 7 (10.0 g, 25.55 mmol), the compound represented by formula 8 (4.27 g, 25.55 mmol), potassium phosphate (10.59 g, 76.65 mmol) and sodium iodide (4.98 g, 33.22 mmol) were mixed and dissolved in dry 2-butanone (300 mL). The reaction solution was heated in a nitrogen atmosphere and kept in a reflux state, and stirred for reaction for 15 hours. After the reaction was completed, it was cooled to room temperature and filtered with diatomaceous earth. The filter cake was washed with dichloromethane (100 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to evaporate the solvent. The concentrate was purified by silica gel column chromatography using a dichloromethane / methanol mixed solvent with a volume ratio of 10:1 to obtain the compound represented by formula I, Ensefentin, with an amount of 8.99 g, a yield of 73.7%, and an HPLC purity of 98.6%.

[0099] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0100] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A method for preparing Ensefentin, characterized in that: include: (1) contacting the compound represented by Formula 1 with the compound represented by Formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium to obtain the compound represented by Formula 3; (2) contacting the compound represented by Formula 3 with trifluoroacetic anhydride to obtain the compound represented by Formula 4; (3) contacting the compound represented by Formula 4 with phosphorus oxychloride to obtain the compound represented by Formula 5; (4) contacting the compound represented by Formula 5 with the compound represented by Formula 6 to obtain the compound represented by Formula 7; (5) contacting the compound represented by Formula 7 with the compound represented by Formula 8, potassium phosphate, and iodide to obtain the compound represented by Formula I, Ensefentin, Wherein, the iodide is at least one selected from sodium iodide or potassium iodide.

2. The method according to claim 1, characterized in that: In step (1), the following steps are included: at room temperature, adding the compound represented by formula 1, the compound represented by formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium to anhydrous dioxane, replacing nitrogen and heating the reaction at 95°C to 101°C for 3 hours and 45 minutes to 4 hours and 15 minutes. After the reaction solution is cooled to room temperature, it is filtered with diatomaceous earth, washed with water, and then extracted with ethyl acetate. The organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate is concentrated under reduced pressure to evaporate the solvent, and the concentrate is purified by silica gel column chromatography using a dichloromethane / methanol mixed solvent to obtain the compound represented by formula 3.

3. The method according to claim 2, characterized in that In step (1), the molar ratio of the compound represented by formula 1 to the compound represented by formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium is 1:(1.0-1.1):(2.5-4.5):(0.05-0.15), preferably the molar ratio of the compound represented by formula 1 to the compound represented by formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium is 1:1.02:3.0:0.1; Optionally, in step (1), the volume ratio of dichloromethane / methanol in the dichloromethane / methanol mixed solvent is (8-12):1, preferably the volume ratio of dichloromethane / methanol mixed solvent is 10:1; Optionally, in step (1), the reaction is preferably heated at 98° C. to 101° C. for 4 hours.

4. The method according to claim 1, characterized in that: In step (2), the following steps are included: adding trifluoroacetic anhydride (TFAA) to a dichloromethane solution containing the compound of formula 3 at 0°C, stirring the reaction at room temperature for 0.5 hours, and after the reaction is completed, performing post-treatment, quenching the reaction solution by adding ice water at 0°C, washing with a saturated sodium bicarbonate solution after separation of the organic layer, washing with saturated brine after separation of the organic phase, drying over anhydrous sodium sulfate, concentrating the filtrate under reduced pressure to evaporate the solvent, and purifying the concentrate by silica gel column chromatography with a petroleum ether / ethyl acetate mixed solvent in a volume ratio of 3:1 to obtain a compound of formula 4; Optionally, in step (2), the molar ratio of the compound represented by formula 3 to trifluoroacetic anhydride is 1:(1.3-2.0), preferably the molar ratio of the compound represented by formula 3 to trifluoroacetic anhydride is 1:1.

5.

5. The method according to claim 1, characterized in that In step (3), the following steps are included: adding the compound shown in formula 4 to phosphorus oxychloride at room temperature, stirring and heating to reflux state to react for 3 hours, after the reaction solution is cooled to room temperature, it is concentrated under reduced pressure, and when a small amount of mixture remains, an appropriate amount of ice water is added, rapidly stirred, and a saturated NaOH solution is added dropwise until the pH is 10, the solid is filtered, the filter cake is washed with ice water, and dried to obtain the compound shown in formula 5; Optionally, in step (3), the weight ratio of the compound represented by formula 4 to phosphorus oxychloride is 1:(5-10), preferably the weight ratio of the compound represented by formula 4 to phosphorus oxychloride is 1:6.

3.

6. The method according to claim 1, characterized in that In step (4), the following steps are included: at room temperature, adding the compound represented by formula 5 to short-chain alcohol A, adding the compound represented by formula 6, then heating to reflux, stirring and reacting for 3 hours to 3 hours and 30 minutes, monitoring the completion of the reaction by TLC, cooling the reaction solution to room temperature, filtering, washing the filter cake with ice water, and drying to obtain the compound represented by formula 7.

7. The method according to claim 6, characterized in that In step (4), the molar ratio of the compound represented by Formula 5 to the compound represented by Formula 6 is 1:(2.5-4.0), preferably the molar ratio of the compound represented by Formula 5 to the compound represented by Formula 6 is 1:3.0; Optionally, in step (4), the short-chain alcohol A is at least one selected from isopropanol or ethanol; Optionally, in step (4), the reaction is preferably stirred for 3 hours and 15 minutes.

8. The method according to claim 1, characterized in that In step (5), the following steps are included: at room temperature, the compound represented by formula 7, the compound represented by formula 8, potassium phosphate and iodide are mixed and dissolved in dry 2-butanone, the reaction solution is heated in a nitrogen atmosphere to maintain reflux state, and stirred for reaction for 17 hours to 20 hours. After the reaction is completed, it is cooled to room temperature and filtered with diatomaceous earth, the filter cake is washed with dichloromethane, and dried over anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to evaporate the solvent, and the concentrate is purified by silica gel column chromatography using a dichloromethane / methanol mixed solvent to obtain the compound ensefentin represented by formula I.

9. The method according to claim 8, characterized in that In step (5), the molar ratio of the compound represented by formula 7 to the compound represented by formula 8, potassium phosphate, and iodide is 1:(2.0-4.0):(4.0-6.0):(2.0-4.0), preferably the molar ratio of the compound represented by formula 7 to the compound represented by formula 8, potassium phosphate, and iodide is 1:3.0:5.0:3.0; Optionally, in step (5), the iodide is at least one selected from sodium iodide or potassium iodide, preferably the iodide is selected from sodium iodide; Optionally, in step (5), the volume ratio of dichloromethane to methanol in the dichloromethane / methanol mixed solvent is (15-25):1, preferably the volume ratio of dichloromethane to methanol is 20:1; Optionally, in step (5), the reaction is preferably stirred for 18 hours.

10. The method according to claim 1, characterized in that In step (1), the following steps are included: at room temperature, adding the compound represented by formula 1 (22.60 g, 0.1 mol), the compound represented by formula 2 (19.48 g, 0.102 mol), potassium carbonate (41.46 g, 0.3 mol) and tetrakis(triphenylphosphine)palladium (11.56 g, 0.01 mol) to anhydrous dioxane (260 mL), replacing nitrogen and heating the mixture at 98°C to 102°C for 4 hours, after the reaction solution is cooled to room temperature, filtering with diatomaceous earth, adding 200 mL of water for washing, then adding 200 mL of ethyl acetate for extraction, adding 200 mL of saturated brine for washing the organic phase, drying over anhydrous sodium sulfate, concentrating the filtrate under reduced pressure to evaporate the solvent, and purifying the concentrate by silica gel column chromatography with a dichloromethane / methanol mixed solvent having a volume ratio of 10:1 to obtain the compound represented by formula 3, with an amount of 25.08 g and a yield of 85.8%; In step (2), the following steps are included: adding trifluoroacetic anhydride (25.87 g, 123.17 mmol) to a dichloromethane solution (240 mL) containing the compound of formula 3 (24.0 g, 82.11 mmol) at 0°C, stirring the reaction at room temperature for 0.5 hours, and after the reaction is completed, post-treatment is performed, the reaction solution is quenched by adding ice water (50 mL) at 0°C, the organic layer is separated, and then 200 mL of saturated sodium bicarbonate solution is added for washing, the organic phase is separated, and then 100 mL of saturated brine is added for washing, and the filtrate is dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure to evaporate the solvent, and the concentrate is purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 3:1 to obtain a compound of formula 4, with an amount of 20.29 g and a yield of 90.1%; In step (3), the following steps are included: adding the compound shown in formula 4 (19.0 g, 69.27 mmol) to phosphorus oxychloride (120 mL) at room temperature, stirring and heating to reflux state to react for 3 hours, after the reaction solution is cooled to room temperature, it is concentrated under reduced pressure, and when a small amount of mixture (about 30 mL) remains, an appropriate amount of ice water is added, and it is rapidly stirred, and a saturated NaOH solution is added dropwise until the pH is 10, and the solid is filtered, and the filter cake is washed with ice water (50 mL), and dried to obtain the compound shown in formula 5, with an amount of 13.40 g and a yield of 66.1%; In step (4), the following steps are included: at room temperature, the compound represented by formula 5 (10.0 g, 34.16 mmol) is added to isopropanol (100 mL), the compound represented by formula 6 (13.86 g, 102.48 mmol) is added, and then the temperature is raised to reflux state, and the reaction is stirred for 3 hours and 15 minutes. The reaction is completed by TLC monitoring, and the reaction solution is cooled to room temperature, filtered, and the filter cake is washed with ice water (50 mL) and dried to obtain the compound represented by formula 7, with an amount of 12.40 g and a yield of 92.7%; In step (5), the following steps are included: at room temperature, the compound represented by formula 7 (10.0 g, 25.55 mmol), the compound represented by formula 8 (12.80 g, 76.64 mmol), potassium phosphate (27.11 g, 127.73 mmol) and sodium iodide (11.49 g, 76.64 mmol) are mixed and dissolved in dry 2-butanone (300 mL); the reaction solution is heated in a nitrogen atmosphere and kept in a reflux state, and stirred for reaction for 18 hours; after the reaction is completed, the mixture is cooled to room temperature and filtered through diatomaceous earth; the filter cake is washed with dichloromethane (100 mL), dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure to evaporate the solvent; the concentrate is purified by silica gel column chromatography using a dichloromethane / methanol mixed solvent with a volume ratio of 20:1 to obtain the compound represented by formula I, Ensefentin, with an amount of 9.44 g, a yield of 77.4%, and an HPLC purity of 99.6%.

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