Synthetic process of ensefen

Abstract

The invention discloses a synthesis process of dual PDE3 / 4 inhibitor Encephaline. The synthesis process comprises the following steps: carrying out substitution reaction on initial raw materials of a compound shown in a formula 1 and a compound shown in a formula 2 to obtain a compound shown in a formula 3, carrying out intramolecular cyclization in an acidic environment to obtain a compound shown in a formula 4, and carrying out amination reaction on carbonyl in the compound shown in the formula 4 and amino in a compound shown in a formula 5 to obtain a compound shown in a formula 6, and carrying out substitution reaction on the acyl imine of the compound as shown in the formula 6 and a compound as shown in a formula 7 to obtain the product Encephaline. The method has the advantages of short reaction steps, easily available raw materials, simple operation method and high product yield, and is suitable for batch production.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a synthesis process of 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 synthesis process 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 synthesis process of the compound Ensefentin shown in Formula I. Compared with the prior art, the synthesis process described in the present invention is to subject the initial raw materials, the compound shown in Formula 1 and the compound shown in Formula 2, to a substitution reaction to obtain the compound shown in Formula 3, and to obtain the compound shown in Formula 4 through intramolecular cyclization under an acidic environment, and the carbonyl group in the compound shown in Formula 4 undergoes an amination reaction with the amine group in the compound shown in Formula 5 to obtain the compound shown in Formula 6, and the acyl imide of the compound shown in Formula 6 undergoes a substitution reaction with the compound shown in Formula 7 to obtain the product Ensefentin.

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

[0008] (1) contacting the compound represented by Formula 1 with the compound represented by Formula 2 and an inorganic base A to obtain the compound represented by Formula 3;

[0009] (2) contacting the compound represented by Formula 3 with trifluoromethanesulfonic acid (TfOH) to obtain the compound represented by Formula 4;

[0010] (3) contacting the compound represented by Formula 4 with the compound represented by Formula 5 and acetic acid to obtain the compound represented by Formula 6;

[0011] (4) contacting the compound represented by Formula 6 with the compound represented by Formula 7, potassium phosphate, and iodide to obtain the compound represented by Formula I, Ensefentin,

[0012]

[0013] Wherein, the inorganic base A is at least one selected from potassium carbonate, sodium carbonate, or cesium carbonate; the iodide is at least one selected from sodium iodide or potassium iodide.

[0014] The inventors have found that, by using the synthesis process of the present invention, using the compound represented by Formula 1 and the compound represented by Formula 2 as starting materials, a total of 4 steps of reaction can be performed to successfully synthesize and prepare the target product, Ensefentin.

[0015] 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.

[0016] 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.

[0017] According to an embodiment of the present invention, the method for preparing the compound represented by Formula 3, the compound represented by Formula 4, the compound represented by Formula 6, and the compound represented by Formula I may also have at least one of the following additional technical features:

[0018] 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 6, and the compound shown in Formula 1 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: 40173-90-8.

[0019] According to an embodiment of the present invention, in step (1), the contacting method of the compound represented by Formula 1, the compound represented by Formula 2, and the inorganic base A is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 1, the compound represented by Formula 2, and the inorganic base A can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula 3 by using this method can be further improved.

[0020] 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, and the inorganic base A are added to anhydrous DMF, heated to 90°C to 110°C, stirred and reacted for 7 hours to 10 hours, the reaction solution is cooled to room temperature, and then post-processed, concentrated under reduced pressure until an appropriate amount of solvent remains, chloroform is added to dilute the concentrated solution, the organic phase is washed with water three times, the remaining organic phase is washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and methanol is added, stirred at room temperature, a white solid appears, filtered, and the solid is vacuum dried 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 and the inorganic base A 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.

[0021] 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 and the inorganic base A is 1:(1.0-1.1):(1.3-1.8), and preferably the molar ratio of the compound represented by Formula 1 to the compound represented by Formula 2 and the inorganic base A is 1:1.02:1.5. Thus, the efficiency of preparing the compound represented by Formula 3 by this method can be further improved.

[0022] According to an embodiment of the present invention, in step (1), the inorganic base A is at least one selected from potassium carbonate, sodium carbonate, or cesium carbonate.

[0023] According to an embodiment of the present invention, in step (1), the reaction is preferably heated at 98° C. to 102° C. for 8 hours.

[0024] 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 (20.0 g, 81.6 mmol), the compound represented by formula 2 (10.66 g, 83.2 mmol), and potassium carbonate (16.91 g, 122.39 mmol) are added to anhydrous DMF (200 mL), heated to 98°C to 102°C, stirred and reacted for 8 hours, after the reaction solution is cooled to room temperature, it is concentrated under reduced pressure until the solvent remains about 50 mL, 150 mL of chloroform is added to dilute the concentrated solution, the organic phase is washed with water three times (200 mL of water is added each time), the remaining organic phase is washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and methanol (30 mL) is added, stirred at room temperature, a white solid appears, filtered, and the solid is dried in vacuo to obtain the compound represented by formula 3, with an amount of 17.12 g and a yield of 71.8%.

[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 (20.0 g, 81.6 mmol), the compound represented by formula 2 (10.66 g, 83.2 mmol), and sodium carbonate (12.97 g, 122.39 mmol) are added to anhydrous DMF (200 mL), heated to 98°C to 102°C, stirred and reacted for 8 hours, after the reaction solution is cooled to room temperature, it is concentrated under reduced pressure until the solvent remains about 50 mL, 150 mL of chloroform is added to dilute the concentrated solution, the organic phase is washed with water three times (200 mL of water is added each time), the remaining organic phase is washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and methanol (30 mL) is added, stirred at room temperature, a white solid appears, filtered, and the solid is dried in vacuo to obtain the compound represented by formula 3, with an amount of 17.08 g and a yield of 71.6%.

[0026] According to an embodiment of the present invention, in step (2), the contacting method of the compound represented by Formula 3 and trifluoromethanesulfonic acid is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 3 and trifluoromethanesulfonic acid 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 the compound shown in formula 3 to anhydrous dichloromethane at room temperature, stirring, cooling the mixed solution to 0°C, slowly dropping trifluoromethanesulfonic acid (TfOH), and continuing to stir and react at 0°C for 2 hours and 45 minutes to 3 hours and 30 minutes. After the reaction, pouring the reaction solution into ice water and rapidly stirring for 10 minutes, adding NaOH solution to adjust the pH to about 10, separating the liquids, adding dichloromethane to the aqueous phase for extraction, combining the organic phases, adding saturated brine for washing, and 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 with a volume ratio of 4:1 to obtain the compound shown in formula 4. Thus, the efficiency of the contact reaction between the compound shown in formula 3 and trifluoromethanesulfonic acid can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound shown in 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 trifluoromethanesulfonic acid is 1:(3-6), preferably the molar ratio of the compound represented by formula 3 to trifluoromethanesulfonic acid is 1:4. Thus, the efficiency of preparing the compound represented by formula 4 by this method can be further improved.

[0029] According to an embodiment of the present invention, in step (2), the reaction is preferably stirred for 3 hours.

[0030] According to a specific embodiment of the present invention, in step (2), the following steps are included: adding the compound represented by formula 3 (15.0 g, 51.32 mmol) to anhydrous dichloromethane (200 mL) at room temperature, stirring, cooling the mixed solution to 0°C, slowly adding trifluoromethanesulfonic acid (30.81 g, 205.28 mmol) dropwise, and continuing to stir the reaction at 0°C for 3 hours. After the reaction, pouring the reaction solution into ice water (100 mL) and rapidly stirring for 10 minutes, adding 10M NaOH solution to adjust the pH to about 10, separating the liquids, adding dichloromethane (3x100 ml) to the aqueous phase for extraction, combining the organic phases, adding saturated brine (200 mL) for washing, and 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 with a volume ratio of 4:1 to obtain the compound represented by formula 4, with an amount of 12.54 g and a yield of 89.1%.

[0031] According to an embodiment of the present invention, in step (3), the contacting method of the compound represented by Formula 4 with the compound represented by Formula 5 and acetic acid is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 4 and the compound represented by Formula 5 and acetic acid can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula 6 by using this method can be further improved.

[0032] According to an embodiment of the present invention, in step (3), the following steps are included: at room temperature, the compound of formula 4 and the compound of formula 5 are added to acetic acid, the reaction solution is heated to 70°C to 100°C under nitrogen protection and reacted for 2.5 hours to 4 hours, TLC shows that the compound of formula 4 is completely reacted, the reaction solution is cooled to room temperature, dichloromethane is added to dissolve, poured into ice water and stirred rapidly for 10 minutes, NaOH solution is added until the pH is about 10, after separation, dichloromethane is added to the aqueous phase for extraction, the organic phases are combined, washed with saturated brine, 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 petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain the compound of formula 6. Thus, the efficiency of the contact reaction between the compound of formula 4 and the compound of formula 5 and acetic acid can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 6 by using this method can be further improved.

[0033] According to an embodiment of the present invention, in step (3), the molar ratio of the compound represented by Formula 4 to the compound represented by Formula 5 is 1:(1-3), and preferably the molar ratio of the compound represented by Formula 4 to the compound represented by Formula 5 is 1:2. Thus, the efficiency of preparing the compound represented by Formula 6 by this method can be further improved.

[0034] According to an embodiment of the present invention, in step (3), the weight volume ratio (g / v) of the compound represented by formula 4 to acetic acid is 1:(0.5-1.0), preferably the weight volume ratio (g / v) of the compound represented by formula 4 to acetic acid is 1:0.8. Thus, the efficiency of preparing the compound represented by formula 6 by this method can be further improved.

[0035] According to an embodiment of the present invention, in step (3), the temperature is preferably raised to 80° C. to 85° C. and reacted for 3 hours.

[0036] According to a specific embodiment of the present invention, in step (3), the following steps are included: at room temperature, the compound represented by formula 4 (10.0 g, 36.46 mmol) and the compound represented by formula 5 (9.86 g, 72.92 mmol) are added to acetic acid (8 mL), the reaction solution is heated to 80°C to 85°C under nitrogen protection for 3 hours, TLC shows that the compound represented by formula 4 is completely reacted, the reaction solution is cooled to room temperature, dichloromethane (100 ml) is added to dissolve, poured into ice water (100 mL) and stirred rapidly for 10 minutes, 10M NaOH solution is added to pH about 10, after separation, dichloromethane (100 ml) is added to the aqueous phase for extraction, the organic phases are combined, saturated brine (100 mL) is added for washing, 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 petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain a compound represented by formula 6, with an amount of 8.95 g and a yield of 62.7%.

[0037] According to an embodiment of the present invention, in step (4), the contacting method of the compound represented by Formula 6 with the compound represented by Formula 7, potassium phosphate, and iodide is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 6 and the compound represented by Formula 7, 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.

[0038] According to an embodiment of the present invention, in step (4), the following steps are included: at room temperature, the compound shown in formula 6, the compound shown in formula 7, 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, 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 6 and the compound shown in formula 7, 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.

[0039] According to an embodiment of the present invention, in step (4), the molar ratio of the compound represented by Formula 6 to the compound represented by Formula 7, 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 6 to the compound represented by Formula 7, 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.

[0040] According to an embodiment of the present invention, in step (4), the iodide is at least one selected from sodium iodide or potassium iodide, and preferably the iodide is selected from sodium iodide.

[0041] According to an embodiment of the present invention, in step (4), 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.

[0042] According to an embodiment of the present invention, in step (4), the reaction is preferably stirred for 18 hours.

[0043] 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 6 (10.0 g, 25.55 mmol), the compound represented by formula 7 (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 with 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%.

[0044] According to a specific embodiment of the present invention, the synthesis route of the compound Ensefentin represented by Formula I can be as follows:

[0045]

[0046] Compared with the prior art, the synthesis process of Ensefentin described in the present invention has at least the following beneficial effects:

[0047] 1. Compared with the prior art, the beneficial effect of the synthesis process 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 substitution reaction to obtain the compound represented by formula 3, and the compound represented by formula 4 is obtained by intramolecular cyclization under an acidic environment. The carbonyl group in the compound represented by formula 4 undergoes an amination reaction with the amine group in the compound represented by formula 5 to obtain the compound represented by formula 6, and the acyl imide of the compound represented by formula 6 undergoes a substitution reaction with the compound represented by formula 7 to obtain the product ensefentin.

[0048] 2. Compared with the prior art methods, the present invention has the following significant advantages: (1) In constructing the intramolecular ring, WO 2023138676 selects an amino compound to undergo dehydration condensation with urea, then reacts with diethyl malonate to form a cyclic compound (forming a ring with the urea molecule), and finally reacts with POCl 3The reaction forms an intramolecular cyclic compound (i.e., the compound shown in Formula 4 of the present invention). The present invention selects a halide to react with an imine to obtain the compound shown in Formula 4 of the present invention under TfOH conditions. Compared with the original literature route, one step of reaction is reduced. (2) In the document WO2023109802, the compound shown in Formula 6 of the present invention is reacted with 2-(2-bromoethyl)iso-doline-1,3-dione to obtain an easily removable compound, and then hydrazine hydrate is added to obtain an amine group, and potassium chlorate is added to obtain the final product (urea). The present invention directly reacts the compound shown in Formula 6 with a halourea to obtain the final product, shortening the reaction by 2 steps and simplifying the reaction operation. (3) The compound shown in Formula 4 directly undergoes an amination reaction with an aniline compound, avoiding the use of POCl in the original literature. 3 The carbonyl group is halogenated and then the substitution reaction occurs. This reduces the number of reactions and avoids the use of large amounts of POCl. 3 (4) The reaction steps of the present invention are short, the raw materials are easily available, the operation method is simple, the product yield is high, and it is suitable for mass production. DETAILED DESCRIPTION

[0049] 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.

[0050] Example 1 Synthesis of the compound represented by formula 3

[0051] At room temperature, the compound represented by formula 1 (20.0 g, 81.6 mmol), the compound represented by formula 2 (10.66 g, 83.2 mmol), and potassium carbonate (16.91 g, 122.39 mmol) were added to anhydrous DMF (200 mL), heated to 98°C to 102°C, stirred and reacted for 8 hours, and the reaction solution was cooled to room temperature and concentrated under reduced pressure until about 50 mL of solvent remained. 150 mL of chloroform was added to dilute the concentrated solution, and the organic phase was washed with water three times (200 mL of water was added each time), and the remaining organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and methanol (30 mL) was added. The mixture was stirred at room temperature until a white solid appeared. After filtering, the solid was dried in vacuo to obtain the compound represented by formula 3, with an amount of 17.15 g and a yield of 71.9%.

[0052] LC-MS (APCI): m / z = 293.1 (M+1) + .

[0053] Example 2 Synthesis of the compound represented by formula 3

[0054] At room temperature, the compound represented by formula 1 (20.0 g, 81.6 mmol), the compound represented by formula 2 (10.45 g, 81.6 mmol), and potassium carbonate (14.66 g, 106.08 mmol) were added to anhydrous DMF (200 mL), heated to 90°C to 94°C and stirred for 10 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure until about 50 mL of solvent remained. 150 mL of chloroform was added to dilute the concentrated solution, and the organic phase was washed with water three times (200 mL of water was added each time). The remaining organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and methanol (30 mL) was added. The mixture was stirred at room temperature until a white solid appeared. After filtering, the solid was dried in vacuo to obtain the compound represented by formula 3, with an amount of 16.80 g and a yield of 70.4%.

[0055] Example 3 Synthesis of the compound represented by formula 3

[0056] At room temperature, the compound represented by formula 1 (20.0 g, 81.6 mmol), the compound represented by formula 2 (10.45 g, 89.8 mmol), and potassium carbonate (20.30 g, 146.9 mmol) were added to anhydrous DMF (200 mL), heated to 105°C to 110°C, stirred and reacted for 7 hours, and the reaction solution was cooled to room temperature and concentrated under reduced pressure until the solvent remained about 50 mL, 150 mL of chloroform was added to dilute the concentrated solution, and the organic phase was washed with water three times (200 mL of water was added each time), and the remaining organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and methanol (30 mL) was added. Stirring at room temperature, a white solid appeared, and after filtering, the solid was dried in vacuo to obtain the compound represented by formula 3, with an amount of 16.98 g and a yield of 71.2%.

[0057] Comparative Example 1 Synthesis of the Compound Represented by Formula 3

[0058] At room temperature, the compound represented by formula 1 (20.0 g, 81.6 mmol), the compound represented by formula 2 (9.93 g, 77.52 mmol), and potassium carbonate (12.41 g, 89.8 mmol) were added to anhydrous DMF (200 mL), heated to 85 ° C and stirred for 12 hours. After the reaction solution cooled to room temperature, it was concentrated under reduced pressure until the solvent remained about 50 mL, 150 mL of chloroform was added to dilute the concentrated solution, and the organic phase was washed with water three times (200 mL of water was added each time), and the remaining organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and methanol (30 mL) was added. Stir at room temperature to produce a white solid. After filtering, the solid was dried in vacuo to obtain the compound represented by formula 3, with an amount of 16.12 g and a yield of 67.6%.

[0059] Comparative Example 2 Synthesis of the Compound Represented by Formula 3

[0060] At room temperature, the compound represented by formula 1 (20.0 g, 81.6 mmol), the compound represented by formula 2 (13.59 g, 106.1 mmol), and potassium carbonate (22.55 g, 163.2 mmol) were added to anhydrous DMF (200 mL), heated to 100 ° C and stirred for 11 hours. After the reaction solution cooled to room temperature, it was concentrated under reduced pressure until the solvent remained about 50 mL, and 150 mL of chloroform was added to dilute the concentrated solution. The organic phase was washed with water three times (200 mL of water was added each time), and the remaining organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and methanol (30 mL) was added. Stir at room temperature to produce a white solid. After filtering, the solid was dried in vacuo to obtain the compound represented by formula 3, with an amount of 16.48 g and a yield of 69.1%.

[0061] Example 4 Synthesis of the compound represented by formula 3

[0062] At room temperature, the compound represented by formula 1 (20.0 g, 81.6 mmol), the compound represented by formula 2 (10.66 g, 83.2 mmol), and sodium carbonate (12.97 g, 122.39 mmol) were added to anhydrous DMF (200 mL), heated to 98°C to 102°C, stirred and reacted for 8 hours, and the reaction solution was cooled to room temperature and concentrated under reduced pressure until about 50 mL of solvent remained. 150 mL of chloroform was added to dilute the concentrated solution, and the organic phase was washed with water three times (200 mL of water was added each time), and the remaining organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and methanol (30 mL) was added. The mixture was stirred at room temperature until a white solid appeared. After filtering, the solid was dried in vacuo to obtain the compound represented by formula 3, with an amount of 17.08 g and a yield of 71.6%.

[0063] Example 5 Synthesis of the compound represented by formula 3

[0064] At room temperature, the compound represented by formula 1 (20.0 g, 81.6 mmol), the compound represented by formula 2 (10.66 g, 83.2 mmol), and cesium carbonate (39.88 g, 122.39 mmol) were added to anhydrous DMF (200 mL), heated to 98°C to 102°C, stirred and reacted for 8 hours, and the reaction solution was cooled to room temperature and concentrated under reduced pressure until about 50 mL of solvent remained. 150 mL of chloroform was added to dilute the concentrated solution, and the organic phase was washed with water three times (200 mL of water was added each time), and the remaining organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and methanol (30 mL) was added. The mixture was stirred at room temperature until a white solid appeared. After filtering, the solid was dried in vacuo to obtain the compound represented by formula 3, with an amount of 17.03 g and a yield of 71.4%.

[0065] Example 6 Synthesis of the compound represented by formula 4

[0066] At room temperature, the compound of formula 3 (15.0 g, 51.32 mmol) was added to anhydrous dichloromethane (200 mL) and stirred. The mixture was cooled to 0°C, trifluoromethanesulfonic acid (TfOH) (30.81 g, 205.28 mmol) was slowly added dropwise, and the mixture was kept stirring at 0°C for 3 hours. After the reaction, the reaction solution was poured into ice water (100 mL) and stirred rapidly for 10 minutes. A 10M NaOH solution was added to adjust the pH to about 10, and the liquids were separated. The aqueous phase was extracted with dichloromethane (3x100 ml). The organic phases were combined, washed with saturated brine (200 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 petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain the compound of formula 4, with an amount of 12.54 g and a yield of 89.1%.

[0067] LC-MS (APCI): m / z = 275.1 (M+1) + .

[0068] Example 7 Synthesis of the compound represented by formula 4

[0069] At room temperature, the compound of formula 3 (15.0 g, 51.32 mmol) was added to anhydrous dichloromethane (200 mL) and stirred. The mixture was cooled to 0°C, trifluoromethanesulfonic acid (23.11 g, 153.96 mmol) was slowly added dropwise, and the mixture was kept stirring at 0°C for 2 hours and 45 minutes. After the reaction, the reaction solution was poured into ice water (100 mL) and stirred rapidly for 10 minutes. A 10M NaOH solution was added to adjust the pH to about 10, and the liquids were separated. The aqueous phase was extracted with dichloromethane (3x100 ml). The organic phases were combined, washed with saturated brine (200 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 petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain the compound of formula 4 with an amount of 12.33 g and a yield of 87.6%.

[0070] Example 8 Synthesis of the compound represented by formula 4

[0071] At room temperature, the compound of formula 3 (15.0 g, 51.32 mmol) was added to anhydrous dichloromethane (200 mL) and stirred. The mixture was cooled to 0°C, trifluoromethanesulfonic acid (46.22 g, 307.92 mmol) was slowly added dropwise, and the mixture was kept stirring at 0°C for 3 hours and 30 minutes. After the reaction, the reaction solution was poured into ice water (100 mL) and stirred rapidly for 10 minutes. A 10M NaOH solution was added to adjust the pH to about 10, and the liquids were separated. The aqueous phase was extracted with dichloromethane (3x100 ml). The organic phases were combined, washed with saturated brine (200 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 petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain the compound of formula 4 with an amount of 12.46 g and a yield of 88.5%.

[0072] Example 9 Synthesis of the compound represented by formula 6

[0073] At room temperature, the compound represented by formula 4 (10.0 g, 36.46 mmol) and the compound represented by formula 5 (9.86 g, 72.92 mmol) were added to acetic acid (8 mL). The reaction solution was heated to 80°C to 85°C under nitrogen protection for 3 hours. TLC showed that the reaction of the compound represented by formula 4 was complete. After the reaction solution was cooled to room temperature, dichloromethane (100 ml) was added to dissolve it, poured into ice water (100 mL) and stirred rapidly for 10 minutes, 10M NaOH solution was added to pH about 10, and after separation, dichloromethane (100 ml) was added to the aqueous phase for extraction, the organic phases were combined, saturated brine (100 mL) was added for washing, and 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 with a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 4:1 to obtain the compound represented by formula 6, with an amount of 8.95 g and a yield of 62.7%.

[0074] LC-MS (APCI): m / z = 392.2 (M+1) + .

[0075] Example 10 Synthesis of the compound represented by formula 6

[0076] At room temperature, the compound represented by formula 4 (10.0 g, 36.46 mmol) and the compound represented by formula 5 (4.93 g, 36.46 mmol) were added to acetic acid (5 mL). The reaction solution was heated to 70°C to 75°C under nitrogen protection for 4 hours. TLC showed that the reaction of the compound represented by formula 4 was complete. After the reaction solution was cooled to room temperature, dichloromethane (100 ml) was added to dissolve it, poured into ice water (100 mL) and stirred rapidly for 10 minutes, 10M NaOH solution was added to pH about 10, and after separation, dichloromethane (100 ml) was added to the aqueous phase for extraction, the organic phases were combined, saturated brine (100 mL) was added for washing, and 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 with a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 4:1 to obtain the compound represented by formula 6, with an amount of 8.61 g and a yield of 60.3%.

[0077] Example 11 Synthesis of the compound represented by formula 6

[0078] At room temperature, the compound represented by formula 4 (10.0 g, 36.46 mmol) and the compound represented by formula 5 (9.86 g, 145.84 mmol) were added to acetic acid (10 mL). The reaction solution was heated to 95°C to 100°C under nitrogen protection for 2.5 hours. TLC showed that the reaction of the compound represented by formula 4 was complete. After the reaction solution was cooled to room temperature, dichloromethane (100 ml) was added to dissolve it, poured into ice water (100 mL) and stirred rapidly for 10 minutes, 10M NaOH solution was added to pH about 10, and after separation, dichloromethane (100 ml) was added to the aqueous phase for extraction, the organic phases were combined, saturated brine (100 mL) was added for washing, and 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 petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain the compound represented by formula 6, with an amount of 8.85 g and a yield of 62.0%.

[0079] Example 12 Preparation of Ensefentin, a compound represented by Formula I

[0080] At room temperature, the compound represented by formula 6 (10.0 g, 25.55 mmol), the compound represented by formula 7 (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 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 9.44 g, a yield of 77.4%, and an HPLC purity of 99.6%.

[0081] LC-MS (APCI): m / z = 478.2 (M+1) + .

[0082] 1 H NMR (400 MHz, DMSO-d 6 )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)

[0083] Example 13 Preparation of Ensefentin, a compound represented by Formula I

[0084] At room temperature, the compound represented by formula 6 (10.0 g, 25.55 mmol), the compound represented by formula 7 (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%.

[0085] Example 14 Preparation of Ensefentin, a compound represented by Formula I

[0086] At room temperature, the compound represented by formula 6 (10.0 g, 25.55 mmol), the compound represented by formula 7 (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%.

[0087] Example 15 Preparation of Ensefentin, a compound represented by Formula I

[0088] At room temperature, the compound represented by formula 6 (10.0 g, 25.55 mmol), the compound represented by formula 7 (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 with 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%.

[0089] Comparative Example 3 Preparation of Ensefentin, a Compound Represented by Formula I

[0090] 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%.

[0091] 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.

[0092] 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 synthesis process of Ensefentin, characterized in that: include: (1) contacting the compound represented by Formula 1 with the compound represented by Formula 2 and an inorganic base A to obtain the compound represented by Formula 3; (2) contacting the compound represented by Formula 3 with trifluoromethanesulfonic acid to obtain the compound represented by Formula 4; (3) contacting the compound represented by Formula 4 with the compound represented by Formula 5 and acetic acid to obtain the compound represented by Formula 6; (4) contacting the compound represented by Formula 6 with the compound represented by Formula 7, potassium phosphate, and iodide to obtain the compound represented by Formula I, Ensefentin, Wherein, the inorganic base A is at least one selected from potassium carbonate, sodium carbonate, or cesium carbonate; 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, and the inorganic base A to anhydrous DMF, heating to 90°C to 110°C and stirring for reaction for 7 hours to 10 hours, after the reaction solution is cooled to room temperature, post-treatment is performed, and the solution is concentrated under reduced pressure until an appropriate amount of solvent remains, chloroform is added to dilute the concentrated solution, the organic phase is washed three times with water, the remaining organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and methanol is added. The mixture is stirred at room temperature until a white solid appears. After filtering, the solid is dried in vacuo 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 and the inorganic base A is 1:(1.0-1.1):(1.3-1.8), preferably the molar ratio of the compound represented by formula 1 to the compound represented by formula 2 and the inorganic base A is 1:1.02:1.5; Optionally, in step (1), the inorganic base A is at least one selected from potassium carbonate, sodium carbonate, or cesium carbonate; Optionally, in step (1), the reaction is preferably heated at 98° C. to 102° C. for 8 hours.

4. The method according to claim 1, characterized in that In step (2), the following steps are included: adding the compound shown in formula 3 to anhydrous dichloromethane at room temperature, stirring, cooling the mixed solution to 0°C, slowly adding trifluoromethanesulfonic acid, and continuing to stir the reaction at 0°C for 2 hours and 45 minutes to 3 hours and 30 minutes. After the reaction is completed, pouring the reaction solution into ice water and rapidly stirring for 10 minutes, adding NaOH solution to adjust the pH to about 10, separating the liquids, adding dichloromethane to the aqueous phase for extraction, combining the organic phases, adding saturated brine for washing, and drying 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 petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain the compound shown in formula 4.

5. The method according to claim 4, characterized in that In step (2), the molar ratio of the compound represented by formula 3 to trifluoromethanesulfonic acid is 1:(3-6), preferably the molar ratio of the compound represented by formula 3 to trifluoromethanesulfonic acid is 1:4; Optionally, in step (2), the reaction is preferably stirred for 3 hours.

6. The method according to claim 1, characterized in that In step (3), the following steps are included: at room temperature, adding the compound represented by formula 4 and the compound represented by formula 5 to acetic acid, heating the reaction solution to 70°C to 100°C under nitrogen protection for reaction for 2.5 hours to 4 hours, TLC showing that the compound represented by formula 4 is completely reacted, adding dichloromethane to dissolve the reaction solution after cooling to room temperature, pouring it into ice water and rapidly stirring for 10 minutes, adding NaOH solution until the pH value is about 10, after separation, adding dichloromethane to the aqueous phase for extraction, combining the organic phases, adding saturated brine for washing, and 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 4:1 to obtain the compound represented by formula 6.

7. The method according to claim 6, characterized in that In step (3), the molar ratio of the compound represented by formula 4 to the compound represented by formula 5 is 1:(1-3), preferably the molar ratio of the compound represented by formula 4 to the compound represented by formula 5 is 1:2; Optionally, in step (3), the weight volume ratio (g / v) of the compound represented by formula 4 to acetic acid is 1:(0.5-1.0), preferably the weight volume ratio (g / v) of the compound represented by formula 4 to acetic acid is 1:0.8; Optionally, in step (3), the temperature is preferably raised to 80°C to 85°C for reaction for 3 hours.

8. The method according to claim 1, characterized in that In step (4), the following steps are included: at room temperature, the compound represented by formula 6, the compound represented by formula 7, 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 (4), the molar ratio of the compound represented by Formula 6 to the compound represented by Formula 7, 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 6 to the compound represented by Formula 7, potassium phosphate, and iodide is 1:3.0:5.0:3.0; Optionally, in step (4), the iodide is at least one selected from sodium iodide or potassium iodide, preferably the iodide is selected from sodium iodide; Optionally, in step (4), 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 (4), 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, the compound represented by formula 1 (20.0 g, 81.6 mmol), the compound represented by formula 2 (10.66 g, 83.2 mmol), and potassium carbonate (16.91 g, 122.39 mmol) are added to anhydrous DMF (200 mL), heated to 98°C to 102°C, stirred and reacted for 8 hours, after the reaction solution is cooled to room temperature, it is concentrated under reduced pressure until the solvent remains about 50 mL, 150 mL of chloroform is added to dilute the concentrated solution, the organic phase is washed with water three times (200 mL of water is added each time), the remaining organic phase is washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and methanol (30 mL) is added, stirred at room temperature, a white solid appears, filtered, and the solid is dried in vacuo to obtain the compound represented by formula 3, with an amount of 17.12 g and a yield of 71.8%; In step (2), the following steps are included: adding the compound represented by formula 3 (15.0 g, 51.32 mmol) to anhydrous dichloromethane (200 mL) at room temperature, stirring, cooling the mixed solution to 0°C, slowly adding trifluoromethanesulfonic acid (TfOH) (30.81 g, 205.28 mmol) dropwise, and continuing to stir and react at 0°C for 3 hours. After the reaction is completed, pouring the reaction solution into ice water (100 mL) and rapidly stirring for 10 minutes, adding 10M NaOH solution to adjust the pH to about 10, separating the liquids, adding dichloromethane (3x100 ml) to extract the aqueous phase, combining the organic phases, adding saturated brine (200 mL) for washing, and drying 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 petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain the compound represented by formula 4, with an amount of 12.54 g and a yield of 89.1%; In step (3), the following steps are included: at room temperature, the compound represented by formula 4 (10.0 g, 36.46 mmol) and the compound represented by formula 5 (9.86 g, 72.92 mmol) are added to acetic acid (8 mL), the reaction solution is heated to 80°C to 85°C under nitrogen protection for 3 hours, TLC shows that the compound represented by formula 4 is completely reacted, the reaction solution is cooled to room temperature, dichloromethane (100 ml) is added to dissolve, poured into ice water (100 mL) and stirred rapidly for 10 minutes, 10M NaOH solution is added to pH about 10, after separation, dichloromethane (100 ml) is added to the aqueous phase for extraction, the organic phases are combined, saturated brine (100 mL) is added for washing, 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 petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain a compound represented by formula 6, with an amount of 8.95 g and a yield of 62.7%; In step (4), the following steps are included: at room temperature, the compound represented by formula 6 (10.0 g, 25.55 mmol), the compound represented by formula 7 (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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