CN113214169B - A kind of synthetic method of Selexipa intermediate - Google Patents

Abstract

The invention relates to the technical field of drug synthesis, in particular to a synthesis method of a celecoxib intermediate. The compound shown in the formula III and 2-aminoacetamidine hydrobromide react under the action of a catalyst to obtain a compound shown in a formula IV; reacting the compound shown in the formula IV with 4-bromo-1-butanol under the action of alkali to obtain a compound shown in a formula V; the compound shown in the formula V is subjected to N-alkylation reaction under the action of alkali to obtain a celecoxib intermediate shown in the formula I: 4- [ (5, 6-Diphenylpyrazin-2-yl) (isopropanoxy) amino ] -1-butanol. The invention creates a new synthesis method of the celecoxib intermediate, and the method has the advantages of cheap and easily obtained raw materials, simple operation, mild conditions and high yield.

Description

A kind of synthetic method of Selexipa intermediate

technical field

The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing a Celecipa intermediate.

Background technique

Celecipa (Formula A), chemical name is 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butyl}-N-(methylsulfonyl) Acyl) acetamide, the English name is Selexipag, the trade name is Uptravi, it is an oral Ip prostacyclin receptor agonist developed by the Swiss Aiketai Biopharmaceutical Company, the drug was once identified as an orphan drug by the FDA, in 2015 It was approved by the FDA in December and was approved by the EMA in May 2016 for the treatment of pulmonary arterial hypertension. Xelexipa has high selectivity for PGI2 receptors, and is not affected by the replacement and regeneration of vascular endothelial cells. It can relax the smooth muscle of the vascular wall, dilate the blood vessels, and reduce the pulmonary artery pressure.

The synthesis of celecipaz has been reported in the literature, and there are mainly two synthesis methods: one is to react the compound of formula I with tert-butyl bromoacetate to make the compound of formula II, and then the compound of formula II and methanesulfonamide generate amine solution to obtain the target product. The synthetic route is:

Another synthetic method is to directly react the compound of formula I with N-(2-chloroacetyl)methanesulfonamide to prepare celecipa. The synthetic route is:

Therefore, the compound of formula I, 4-[(5,6-diphenylpyrazin-2-yl)(isopropanolyl)amino]-1-butanol, is a key intermediate in the synthesis of Xeloxipa, and for Xelox The synthesis of SIPA is of great significance.

For the synthesis of formula I compound 4-[(5,6-diphenylpyrazin-2-yl)(isopropanol)amino]-1-butanol, there have been many literature reports, mainly the following methods:

Documents Bioorg Med Chem, 2007, 15(21): 6692-6704 etc. have reported the method of taking 2,3-diphenylpyrazine as raw material, and the synthetic route is:

In the method, 2,3-diphenylpyrazine is used as a raw material, and the compound of formula I is prepared through chlorination and substitution and other reactions. In this method, the raw materials 2,3-diphenylpyrazine and 4-(isopropylamino)-1-butanol are not easy to obtain, are expensive, and have high cost; phosphorus oxychloride is used as solvent in the chlorination reaction and chlorinating reagents, phosphorus oxychloride is used in a large amount, which is more corrosive to equipment; in the substitution reaction, 5-chloro-2,3-diphenylpyrazine and 4-(isopropylamino)-1-butanol The reactivity is low, resulting in a low yield in this step. These are not conducive to industrial production.

In order to improve the activity of 5-chloro-2,3-diphenylpyrazine, patents WO2011024874 and WO2010150865 also use 5-chloro-2,3-diphenylpyrazine as a raw material to obtain 5-iodo-2 through iodination, 3-diphenylpyrazine is then subjected to substitution reaction with 4-(isopropylamino)-1-butanol to obtain the compound of formula I. The synthetic route is:

The reaction raw materials 5-chloro-2,3-diphenylpyrazine and 4-(isopropylamino)-1-butanol used in this process are not easily available and expensive. In addition, although 5-iodo-2,3- The reactivity of diphenylpyrazine is relatively high, but its substitution reaction with 4-(isopropylamino)-1-butanol still requires high temperature reaction at 170-200° C. Therefore, the process is expensive, inconvenient to operate, and the process Poor safety, not conducive to industrial production.

Document US10544107 has reported the method with 5-chloro-2,3-diphenylpyrazine as raw material, and the synthetic route is:

In this method, the compound of formula I is prepared by the substitution reaction of 5-chloro-2,3-diphenylpyrazine and 4-(isopropylamino)-1-butanol. Although there is only one step in the synthetic route, there is still the defect that 5-chloro-2,3-diphenylpyrazine and 4-(isopropylamino)-1-butanol are not easily obtained. In addition, when preparing the compound of formula I, The relatively expensive 4-(isopropylamino)-1-butanol of nearly 9 equivalents was used as the reactant and solvent, and the reaction was carried out at a high temperature of 190-195° C. for 10-12 h. Therefore, the process has high cost, high energy consumption, inconvenient operation, and poor process safety, which is not conducive to industrial production.

Document CN1516690A provides a method for synthesizing 5-chloro-2,3-diphenylpyrazine. Using bibenzoyl and glycinamide hydrochloride as starting materials, 5-chloro-5-chloro is prepared by cyclization and phenolic hydroxyl halide replacement. -2,3-diphenylpyrazine, then 5-chloro-2,3-diphenylpyrazine and 4-(isopropylamino)-1-butanol are subjected to substitution reaction to obtain the compound of formula I. The synthetic route is as follows:

In addition to providing a method for synthesizing 5-chloro-2,3-diphenylpyrazine, the method still has other defects of the first synthesis method except that the raw materials are not readily available.

Literature China Journal of New Drugs, 2018, 27(7), 822-826 Using the method of literature CN1516690A to improve the preparation of 5-chloro-2,3-diphenylpyrazine and 4-(isopropylamino)-1-butanol method. Although this process solves the problem that 5-chloro-2,3-diphenylpyrazine and 4-(isopropylamino)-1-butanol are not easily available, but due to 5-chloro-2,3-diphenylpyrazine The low activity of the oxazine resulted in a low total reaction yield of only 17.4%; in addition, expensive platinum oxide was used as a catalyst in the preparation of 4-(isopropylamino)-1-butanol, and the reaction required 5 to 9 The hydrogenation reaction was carried out under standard atmospheric pressure for 48h. Therefore, the reaction process has low yield, poor process safety, expensive reagents, high energy consumption and high cost, and is not suitable for industrial production.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to overcome the technology reported in the existing preparation formula I compound 4-[(5,6-diphenylpyrazin-2-yl)(isopropanol)amino]-1-butanol The raw materials are not easy to obtain, expensive, high production cost, low yield, complicated operation, poor process safety and other defects that are not conducive to industrialized production, provide a kind of effective preparation formula I compound 4-[(5,6-diphenylpyrazine -2-yl) (isopropanol group) amino]-1-butanol method, the method raw material is cheap, easy to obtain, few steps, mild reaction conditions, low production cost, suitable for industrial production.

In order to achieve the above object, the present invention specifically adopts the following technical solutions:

A kind of synthetic method of Selexipa intermediate, comprises the steps:

(1) Compound 1,2-diphenyloxirane shown in formula III and 2-aminoacetamidine hydrobromide react under the action of a catalyst to obtain compound 5,6-diphenylpyrazine shown in formula IV -2-amine;

(2) The compound 5,6-diphenylpyrazin-2-amine shown in formula IV reacts with 4-bromo-1-butanol under the action of a base to obtain the compound 4-[(5, 6-diphenylpyrazin-2-yl)amino]-1-butanol;

(3) The compound 4-[(5,6-diphenylpyrazin-2-yl)amino]-1-butanol shown in formula V reacts with bromoisopropane under the action of a base to obtain the compound shown in formula I The intermediate of Celecipa: 4-[(5,6-diphenylpyrazin-2-yl)(isopropanol)amino]-1-butanol.

Preferably, the catalyst in the step (1) includes lithium bromide.

Further preferably, in the step (1), the ratio of the amount of the catalyst to the compound represented by the formula III is 3-8:100.

More preferably, the reaction in step (1) is protected by inert gas or nitrogen gas. Inert gases refer to noble gases.

分子筛。A further preferred solution is to add molecular sieves in the reaction of the step (1). Of course the best is to use

Molecular Sieve.

Preferably, the bases in the steps (2) and (3) are selected from carbonates or acetates. The carbonate can be carbonate such as sodium carbonate and potassium carbonate; the acetate can be sodium acetate, potassium acetate and the like.

Further preferably, the base in the step (2) is selected from carbonate, and the ratio of the amount of the carbonate to the compound represented by the formula IV is 1-1.4:1; the step (3) ) in the base is selected from acetate, and the ratio of the amount of acetate to the substance of the compound represented by formula V is 1-1.3:1.

Preferably, the reaction temperature of the step (1) is 5°C to 30°C; the reaction temperature of the step (2) is 50°C to 80°C; the reaction temperature of the step (3) is 30°C to 60°C. The reaction of step (1) can be carried out at room temperature, and the range of room temperature is approximately 5°C to 30°C.

Preferably, the reactions of the step (1), step (2) and step (3) are all carried out in a polar organic solvent. The polar organic solvent refers to a solvent containing polar groups.

Further preferably, the polar organic solvent is selected from 1,4-dioxane, acetone, ethanol, acetonitrile, tetrahydrofuran, methanol or DMF.

Further preferably, the polar organic solvent in the step (1) is selected from 1,4-dioxane; the polar organic solvent in the step (2) is selected from acetonitrile; the polar organic solvent in the step (3) is selected from acetonitrile; The organic solvent is selected from DMF.

Preferably, the specific steps of the synthetic method include the following:

step 1):

A. Mix the compounds required for the step (1) reaction except the compound shown in formula III, and the temperature is lowered to 5°C-10°C to obtain a low-temperature mixed solution;

B, the compound shown in formula III is dissolved in the polar organic solvent to form a mixed solution containing the compound of formula III; the polar solvent in this step is the same meaning as the polar solvent described above, and when step A also has polar When the solvent is used, the polar solvent of step B should be consistent with the polar solvent of step A;

C, drop the mixed solution containing the compound of formula III obtained in step B into the low-temperature mixed solution obtained in step A, stir at 5°C to 30°C, reflux, cool, filter, and dry under reduced pressure to obtain the compound shown in formula IV; The product is purer and can continue to be washed and recrystallized. In this step, after the reaction is stirred at 5° C. to 30° C. for a period of time, the reflux reaction is continued to ensure a more sufficient reaction.

Step (2):

The compound required for the reaction in the step (2) is mixed, reacted, cooled, added with water, stirred and filtered, and dried to obtain the compound shown in formula V;

Step (3):

The compound required for the reaction in step (3) is mixed, reacted, cooled, added with water, and extracted to obtain the compound represented by formula I.

The "compound required for the reaction" mentioned in the above description refers to all the raw materials required for the reaction in the current step, such as reaction substrates, catalysts, etc., if there is a reaction solvent, of course, also includes the reaction solvent and the like.

beneficial effect

(1) the present invention has created a kind of new synthetic route of preparing celecipaz intermediate;

(2) The method of the invention is simple to operate, cheap and easy to obtain raw materials, few steps, mild reaction conditions, low production cost, and is suitable for industrial production.

Detailed ways

The following will clearly and completely describe the technical solutions in the specific embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

The present invention will be described in detail below with reference to the embodiments, so as to facilitate the understanding of the present invention by those skilled in the art.

Example 1 Preparation of compound 5,6-diphenylpyrazin-2-amine of formula IV

分子筛和100mL1,4-二氧六环加入反应瓶中，室温搅拌，充氮气，将反应体系温度降5-10℃，再将50mmol式III化合物溶在50mL 1,4-二氧六环中，并滴入上述反应瓶中，滴完后于室温下搅拌反应3h，再升温至回流并保温反应3h，停止加热，冷却至室温，过滤，滤液进行减压蒸馏至干，加入150mL水，搅拌0.5h，过滤析出的固体，将粗固体用乙醇重结晶，减压干燥得式IV化合物，收率87％。ESI-LRMS m/z:248.1[M+H]⁺。65mmol 2-aminoacetamidine hydrobromide, 2.5mmol lithium bromide, 7.5g

Molecular sieves and 100 mL of 1,4-dioxane were added to the reaction flask, stirred at room temperature, filled with nitrogen, the temperature of the reaction system was lowered by 5-10 °C, and 50 mmol of the compound of formula III was dissolved in 50 mL of 1,4-dioxane, And dropwise into the above reaction flask, after the dropping is completed, the reaction is stirred at room temperature for 3 hours, then heated to reflux and incubated for 3 hours, the heating is stopped, cooled to room temperature, filtered, the filtrate is distilled under reduced pressure to dryness, 150 mL of water is added, and stirred for 0.5 h, filter the precipitated solid, recrystallize the crude solid from ethanol, and dry under reduced pressure to obtain the compound of formula IV with a yield of 87%. ESI-LRMS m/z: 248.1 [M+H] ⁺ .

Example 2 Preparation of compound 5,6-diphenylpyrazin-2-amine of formula IV

分子筛和100mL1,4-二氧六环加入反应瓶中，室温搅拌，充氮气，将反应体系温度降5-10℃，再将50mmol式III化合物溶在50mL 1,4-二氧六环中，并滴入上述反应瓶中，滴完后于室温下搅拌反应3h，再升温至回流并保温反应3h，停止加热，冷却至室温，过滤，滤液进行减压蒸馏至干，加入150mL水，搅拌0.5h，过滤析出的固体，将粗固体用乙醇重结晶，减压干燥得式IV化合物，收率74％。70mmol 2-aminoacetamidine hydrobromide, 1.5mmol lithium bromide, 7.5g

Molecular sieves and 100 mL of 1,4-dioxane were added to the reaction flask, stirred at room temperature, filled with nitrogen, the temperature of the reaction system was lowered by 5-10 °C, and 50 mmol of the compound of formula III was dissolved in 50 mL of 1,4-dioxane, And dropwise into the above reaction flask, after the dropping is completed, the reaction is stirred at room temperature for 3 hours, then heated to reflux and incubated for 3 hours, the heating is stopped, cooled to room temperature, filtered, the filtrate is distilled under reduced pressure to dryness, 150 mL of water is added, and stirred for 0.5 h, filter the precipitated solid, recrystallize the crude solid from ethanol, and dry under reduced pressure to obtain the compound of formula IV with a yield of 74%.

Example 3 Preparation of compound 5,6-diphenylpyrazin-2-amine of formula IV

分子筛和100mL1,4-二氧六环加入反应瓶中，室温搅拌，充氮气，将反应体系温度降5-10℃，再将50mmol式III化合物溶在50mL 1,4-二氧六环中，并滴入上述反应瓶中，滴完后于室温下搅拌反应3h，再升温至回流并保温反应3h，停止加热，冷却至室温，过滤，滤液进行减压蒸馏至干，加入150mL水，搅拌0.5h，过滤析出的固体，将粗固体用乙醇重结晶，减压干燥得式IV化合物，收率67％。60mmol 2-aminoacetamidine hydrobromide, 4mmol lithium chloride, 7.5g

Molecular sieves and 100 mL of 1,4-dioxane were added to the reaction flask, stirred at room temperature, filled with nitrogen, the temperature of the reaction system was lowered by 5-10 °C, and 50 mmol of the compound of formula III was dissolved in 50 mL of 1,4-dioxane, And dropwise into the above reaction flask, after the dropping is completed, the reaction is stirred at room temperature for 3 hours, then heated to reflux and incubated for 3 hours, the heating is stopped, cooled to room temperature, filtered, the filtrate is distilled under reduced pressure to dryness, 150 mL of water is added, and stirred for 0.5 h, filter the precipitated solid, recrystallize the crude solid from ethanol, and dry under reduced pressure to obtain the compound of formula IV with a yield of 67%.

Example 4 Preparation of compound 5,6-diphenylpyrazin-2-amine of formula IV

分子筛和100mL1,4-二氧六环加入反应瓶中，室温搅拌，充氮气，将反应体系温度降5-10℃，再将50mmol式III化合物溶在50mL 1,4-二氧六环中，并滴入上述反应瓶中，滴完后于室温下搅拌反应3h，再升温至回流并保温反应3h，停止加热，冷却至室温，过滤，滤液进行减压蒸馏至干，加入150mL水，搅拌0.5h，过滤析出的固体，将粗固体用乙醇重结晶，减压干燥得式IV化合物，收率76％。65mmol 2-aminoacetamidine hydrobromide, 4mmol lithium iodide, 7.5g

Molecular sieves and 100 mL of 1,4-dioxane were added to the reaction flask, stirred at room temperature, filled with nitrogen, the temperature of the reaction system was lowered by 5-10 °C, and 50 mmol of the compound of formula III was dissolved in 50 mL of 1,4-dioxane, And dropwise into the above reaction flask, after the dropping is completed, the reaction is stirred at room temperature for 3 hours, then heated to reflux and incubated for 3 hours, the heating is stopped, cooled to room temperature, filtered, the filtrate is distilled under reduced pressure to dryness, 150 mL of water is added, and stirred for 0.5 h, filter the precipitated solid, recrystallize the crude solid from ethanol, and dry under reduced pressure to obtain the compound of formula IV with a yield of 76%.

Example 5 Preparation of compound 4-[(5,6-diphenylpyrazin-2-yl)amino]-1-butanol of formula V

50 mmol of the compound of formula IV, 60 mmol of anhydrous potassium carbonate and 50 mL of acetonitrile were added to the reaction flask, and the reaction was stirred at 70 °C for 4 h. TLC tracked the end of the reaction, cooled to room temperature, added 150 mL of water, stirred for 0.5 h, filtered the precipitated solid, reduced Press drying to obtain the compound of formula V in a yield of 87%. The crude solid was directly carried to the next step without purification.

Example 6 Preparation of compound 4-[(5,6-diphenylpyrazin-2-yl)amino]-1-butanol of formula V

50 mmol of the compound of formula IV, 70 mmol of anhydrous sodium carbonate and 50 mL of acetonitrile were added to the reaction flask, and the reaction was stirred and refluxed for 4 h. The reaction was followed by TLC, cooled to room temperature, 150 mL of water was added, and stirred for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain Compound of formula V, yield 88%. The crude solid was directly carried to the next step without purification.

Example 7 Preparation of compound 4-[(5,6-diphenylpyrazin-2-yl)amino]-1-butanol of formula V

50 mmol of the compound of formula IV, 50 mmol of anhydrous potassium carbonate and 50 mL of acetonitrile were added to the reaction flask, the reaction was stirred at 50°C, the reaction was followed by TLC, cooled to room temperature, 150 mL of water was added, stirred for 0.5 h, the precipitated solid was filtered, and the pressure was reduced. The compound of formula V was obtained by drying, and the yield was 75%. The crude solid was directly carried to the next step without purification.

Example 8 Preparation of compound 4-[(5,6-diphenylpyrazin-2-yl)(isopropanol)amino]-1-butanol of formula I

50 mmol of the compound of formula V, 60 mmol of anhydrous sodium acetate and 50 mL of DMF were added to the reaction flask, and the reaction was stirred at 50 °C for 5 h. TLC tracked the end of the reaction, cooled to room temperature, added 200 mL of water, stirred for 0.5 h, and separated with 90 mL of dichloromethane. Extracted three times, combined the organic phases, washed the organic phase with 90 mL of saturated brine, dried over anhydrous sodium sulfate, evaporated the solvent under reduced pressure to obtain a crude solid, which was recrystallized from isopropyl acetate and dried under reduced pressure to obtain formula I Compound, the yield is 86%, and the reaction product is the target product after characterization and verification.

Example 9 Preparation of compound 4-[(5,6-diphenylpyrazin-2-yl)(isopropanol)amino]-1-butanol of formula I

50 mmol of the compound of formula V, 50 mmol of anhydrous sodium acetate and 50 mL of DMF were added to the reaction flask, and the reaction was stirred at 60°C. The reaction was followed by TLC, cooled to room temperature, added with 200 mL of water, stirred for 0.5 h, and divided into three times with 90 mL of dichloromethane. Extract, combine the organic phases, wash the organic phase with 90 mL of saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a crude solid, recrystallize the crude solid from isopropyl acetate, and dry under reduced pressure to obtain the compound of formula I , the yield is 84%, and the reaction product is the target product after characterization and verification.

Example 10 Preparation of compound 4-[(5,6-diphenylpyrazin-2-yl)(isopropanol)amino]-1-butanol of formula I

50 mmol of the compound of formula V, 65 mmol of anhydrous sodium acetate and 50 mL of DMF were added to the reaction flask, and the reaction was stirred at 30°C. The reaction was followed by TLC, cooled to room temperature, 200 mL of water was added, stirred for 0.5 h, and divided into three times with 90 mL of dichloromethane. Extract, combine the organic phases, wash the organic phase with 90 mL of saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a crude solid, recrystallize the crude solid from isopropyl acetate, and dry under reduced pressure to obtain the compound of formula I , the yield is 74%, and the reaction product is the target product after characterization and verification.

The above-mentioned embodiments only represent several embodiments of the present invention, and the descriptions thereof are specific and detailed, but should not be construed as a limitation on the scope of the patent of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can also be made, which all belong to the protection scope of the present invention.

Claims (10)

1. a synthetic method of Selexipa intermediate, is characterized in that, comprises the steps:

(1) Compound 1,2-diphenyloxirane shown in formula III and 2-aminoacetamidine hydrobromide react under the action of a catalyst to obtain compound 5,6-diphenylpyrazine shown in formula IV -2-amine; (2) The compound 5,6-diphenylpyrazin-2-amine shown in formula IV reacts with 4-bromo-1-butanol under the action of a base to obtain the compound 4-[(5, 6-diphenylpyrazin-2-yl)amino]-1-butanol; (3) The compound 4-[(5,6-diphenylpyrazin-2-yl)amino]-1-butanol shown in formula V reacts with bromoisopropane under the action of a base to obtain the compound shown in formula I The intermediate of Celoxipa: 4-[(5,6-diphenylpyrazin-2-yl)(isopropanol)amino]-1-butanol; The catalyst in the step (1) is lithium bromide, and molecular sieves are added in the step (1). 2. the synthetic method of Selexipa intermediate according to claim 1, is characterized in that, in described step (1), the ratio of the amount of material of catalyzer and compound shown in formula III is 3～8:100 . 3. the synthetic method of Selexipa intermediate according to claim 1, is characterized in that, described step (1) reaction is protected with inert gas or nitrogen. 4. the synthetic method of Selexipa intermediate according to claim 1, is characterized in that, the alkali in described step (2) and step (3) is selected from carbonate or acetate. 5. the synthetic method of Selexipa intermediate according to claim 4, is characterized in that, the alkali in described step (2) is selected from carbonate, and described carbonate and shown in formula IV The ratio of the substance of the compound is 1～1.4:1; the base in the step (3) is selected from acetate, and the ratio of the acetate to the substance of the compound represented by formula V is 1～1.3 :1. 6. the synthetic method of the Selexipa intermediate according to claim 1, is characterized in that, described step (1) reaction temperature is 5 ℃～30 ℃; Described step (2) reaction temperature is 50 ℃～ 80°C; the reaction temperature of the step (3) is 30°C to 60°C. 7. The synthetic method of Selexipa intermediate according to claim 1, is characterized in that, the reaction of described step (1), step (2), step (3) is all carried out in polar organic solvent. 8. the synthetic method of Selexipa intermediate according to claim 7, is characterized in that, described polar organic solvent is selected from 1,4-dioxane, acetone, ethanol, acetonitrile, tetrahydrofuran, methanol or DMF. 9. the synthetic method of Selexipa intermediate according to claim 8, is characterized in that, the polar organic solvent of described step (1) is selected from 1,4-dioxane; Described step (2) ) polar organic solvent is selected from acetonitrile; the polar organic solvent of described step (3) is selected from DMF. 10. according to the synthetic method of the described Selexipa intermediate of any one of claim 1～9, it is characterized in that, the concrete steps of described synthetic method comprise as follows: step 1): A. Mix the compounds required in step (1) except the compound represented by formula III, and the temperature is lowered to 5°C-10°C to obtain a low-temperature mixed solution; B, the compound shown in formula III is dissolved in polar organic solvent to form a mixed solution containing the compound of formula III; C, drop the mixed solution containing the compound of formula III obtained in step B into the low-temperature mixed solution obtained in step A, stir at 5°C to 30°C, reflux, cool, filter, and dry under reduced pressure to obtain the compound shown in formula IV; Step (2): The compound required for the reaction in the step (2) is mixed, reacted, cooled, added with water, stirred and filtered, and dried to obtain the compound shown in formula V; Step (3): The compound required for the reaction in step (3) is mixed, reacted, cooled, added with water, and extracted to obtain the compound represented by formula I.