Preparation method for pyridazinone compound of thyroid hormone analog and intermediate thereof

Abstract

The present invention provides a preparation method for Resmetirom and an intermediate I thereof. In the method, by means of a continuous process, there is no need to separate the intermediate and perform post-reaction work-up, thereby saving a plurality of procedures and operation time; and the work-up is simple and efficient, and the use of a highly polluting reagent pyridine is avoided. Moreover, by adjusting a material feeding order, the reaction can be promoted and the color of a product can be effectively improved. The entire process is simple to operate and cost-effective, uses a green and environmentally friendly reagent, and is suitable for large-scale industrial production.

Description

Process for the preparation of pyridazinone compounds of thyroid hormone analogs and intermediates thereof TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and relates to a preparation method of a pyridazinone compound of thyroid hormone analogs, resmetirom, and intermediates thereof. BACKGROUND

[0002] Non-alcoholic steatohepatitis (NASH) is a link in the development process of non-alcoholic fatty liver disease (NAFLD), and has pathological characteristics such as liver steatosis, hepatocyte ballooning and lobular inflammatory infiltration. At present, the global prevalence rate of NASH is 1.5% to 6.4%, and if no drug intervention is made, NASH will further develop into liver fibrosis or cirrhosis (which may need liver transplantation), portal hypertension, liver cancer or death in some patients. Its pathogenesis is extremely complex, and in recent years, researchers tend to believe that its pathogenesis belongs to “multiple parallel attacks”, that is, under the combined action of multiple pathogenic factors such as insulin resistance, lipid accumulation, adipose tissue dysfunction, mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, immune response, bile acid, intestinal flora, dietary factors and genetic and epigenetic factors, NAFLD is caused, and thyroid hormone receptor-β (THR-β) is responsible for regulating the metabolic pathway of the liver, and the liver thyroid hormone activity of patients with NASH is reduced, thereby causing impaired liver function.

[0003] Resmetirom is an oral small molecule liver-targeted thyroid hormone receptor-β (THR-β) selective agonist developed by Madrigal Pharmaceuticals Company in the United States, and is used for treating adult patients with non-alcoholic steatohepatitis (NASH). On April 13, 2024, the drug was approved for marketing by the FDA, and its structural formula is shown in the following formula:

[0004] Patents CN101228135B and CN112707892 report a preparation method of resmetirom: the method includes generating 3,6-dichloro-4-isopropylpyridazine from 3,6-dichloropyridazine and isobutyric acid in water under the action of silver nitrate and ammonium persulfate; 3,6-dichloro-4-isopropylpyridazine reacts with 4-amino-2,6-dichlorophenol under the action of cuprous iodide and potassium carbonate for 24 hours, the obtained mixture is adjusted to pH 8 with dilute hydrochloric acid, and after treatment, 3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)aniline is obtained with a yield of 53%; the obtained mixture of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)aniline, glacial acetic acid and sodium acetate is reacted at 100°C for 24 hours, cooled to room temperature and stirred for 2 days, the obtained mixture is diluted with water, and then adjusted to pH 9 with sodium hydroxide aqueous solution (1N), the obtained suspension is extracted with ethyl acetate, the aqueous phase is separated, then adjusted to pH 5 with concentrated hydrochloric acid, and then extracted with ethyl acetate, the organic phase is combined, dried, filtered, and the filtrate is concentrated under vacuum and dried, the obtained residue is diluted with methanol, and then an aqueous sodium hydroxide solution is added to obtain a reaction mixture, which is reacted at 120°C for 24 hours, then cooled to room temperature and the solvent is removed under reduced pressure, the residue is diluted with water, and then extracted with ethyl acetate, the organic phase is combined, and then washed with dilute hydrochloric acid aqueous solution and saturated brine, dried and filtered, the filtrate is concentrated under vacuum and reduced pressure, and the obtained residue is subjected to preparative chromatography to obtain pure 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one; an aqueous suspension of the obtained product is added with concentrated hydrochloric acid, stirred for 30 minutes after adding an aqueous sodium nitrite solution, quickly filtered and added into a mixed solution of N-cyanoacetylurea, water and pyridine pre-cooled to 0°C, stirred for 30 minutes, and then washed with water and petroleum ether in sequence to obtain (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)hydrazono)acetyl)carbamic acid ethyl ester; finally, resmetirom is obtained through a cyclization reaction, and the specific synthesis route is as follows:

[0005] The synthesis route has 5 steps, and 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one is a key intermediate for synthesizing resmetirom, which has the defects of complex post-treatment process, great difficulty in purification, low yield and the like. Therefore, it is necessary to develop a preparation method of resmetirom which is simple in process operation, low in cost and suitable for industrial production. SUMMARY

[0006] The method for preparing resmetirom intermediate I provided in the present application comprises the following steps:

[0007] C) reacting intermediate II in a basic reagent and an organic solvent, followed by acid treatment to obtain a reaction system containing intermediate III;

[0008] D) adding a nitrosating reagent to the above reaction system, stirring for a period of time, then sequentially adding intermediate IV and sodium acetate, and stirring to obtain intermediate I;

[0009] In some embodiments, the basic reagent in step C) is selected from one or more combinations of sodium acetate, potassium acetate, potassium bicarbonate, sodium bicarbonate, potassium hydrogen phosphate, and sodium hydrogen phosphate, preferably sodium acetate.

[0010] In some embodiments, the organic solvent in step C) is selected from one or more combinations of acetic acid, butyric acid, formic acid, and dimethyl sulfoxide, preferably acetic acid.

[0011] In some embodiments, the acid in step C) is selected from hydrochloric acid, hydrobromic acid, and 40% sulfuric acid, preferably 36% hydrochloric acid.

[0012] In some embodiments, the molar volume ratio of intermediate II, basic reagent, and organic solvent in step C) is 1:0.9-3:2-20 mol / mol / L, preferably 1:1.2-2:1.5-5 mol / mol / L.

[0013] In some embodiments, the reaction temperature of intermediate II in the basic reagent in step C) is 50-150°C, and the reaction time is 5-20 hours; preferably, the reaction temperature is 100-120°C, and the reaction time is 10-16 hours.

[0014] In some embodiments, after the reaction of intermediate II in the basic reagent in step C) is completed, the temperature is lowered to 10-30°C, and the filtrate is obtained by filtration. Acid is added to the filtrate, and the temperature is raised to 50-100°C for stirring, with a stirring time of 5-10 hours.

[0015] In some embodiments, the molar ratio of intermediate II to acid in step C) is 1:8-12.

[0016] In some embodiments, the nitrosating reagent in step D) is selected from one or more of sodium nitrite, isoamyl nitrite, or tert-butyl nitrite, preferably sodium nitrite.

[0017] In some embodiments, the stirring temperature after adding the nitrosating reagent in step D) is 0-15°C, and the reaction time is 1-5 hours.

[0018] In some embodiments, the molar ratio of intermediate II, intermediate IV, and sodium acetate is 1:1-1.5:8-10.

[0019] In some embodiments, the sodium acetate in step D is prepared into an aqueous solution, which is then added dropwise into the reaction system at a temperature of 0-10°C; after the dropwise addition is completed, the temperature is controlled to 10-30°C for 10-20 hours of incubation.

[0020] In some embodiments, the crude product of intermediate I obtained in step D is further purified into a pure product by stirring in an organic solvent selected from one or more of acetic acid and alcohol; preferably acetic acid or ethanol.

[0021] In some embodiments, the molar volume ratio of the crude product of intermediate I to the organic solvent is 1:3-5 mol / L.

[0022] Another aspect of the present application provides a preparation method of intermediate II, characterized in that the method comprises the following steps:

[0023] A) dissolving 3,6-dichloropyridazine, isobutyric acid, silver nitrate and trifluoroacetic acid in a mixed solution of acetonitrile and water, slowly adding an aqueous solution of ammonium persulfate, after the dropwise addition is completed, the reaction is completed, and then the product is extracted with an organic solvent a to obtain intermediate V;

[0024] B) reacting intermediate V with intermediate VI in an organic solvent b in the presence of potassium carbonate and a catalyst cuprous iodide to obtain intermediate II;

[0025] In some embodiments, the organic solvent a is acetonitrile; the organic solvent b is one or more of dimethyl sulfoxide, N,N-dimethylacetamide, N-methyl pyrrolidone, and dimethylformamide, preferably dimethyl sulfoxide.

[0026] In some embodiments, after the reaction in step B) is completed, the reaction solution is quenched with water, the temperature is then controlled, concentrated hydrochloric acid is added dropwise to adjust the pH to 1-3, sodium thiosulfate is then added for neutralization, and the solid is obtained by filtration; the solid is then dissolved by heating in isopropyl alcohol, and the crystal is precipitated by cooling.

[0027] A third aspect of the present application provides a preparation method of resmetirom, characterized in that the preparation method comprises the following steps:

[0028] A) dissolving 3,6-dichloropyridazine, isobutyric acid, silver nitrate and trifluoroacetic acid in a mixed solution of acetonitrile and water, slowly adding an aqueous solution of ammonium persulfate, after the dropwise addition is completed, the reaction is completed, and then the product is extracted with an organic solvent a to obtain intermediate V;

[0029] B) reacting intermediate V with intermediate VI in dimethyl sulfoxide in the presence of potassium carbonate and a catalyst cuprous iodide to obtain intermediate II;

[0030] C) reacting intermediate II in sodium acetate and acetic acid, after the reaction, adding hydrochloric acid to obtain a reaction system containing intermediate III;

[0031] D) adding sodium nitrite to the above reaction system, stirring for a period of time, then adding intermediate IV and sodium acetate in sequence to obtain intermediate I;

[0032] E) cyclizing compound I in the presence of an organic solvent and a base to obtain resmetirom;

[0033] In some embodiments, the organic solvent in step E) is selected from aprotic polar solvents, and the base is selected from sodium acetate and potassium acetate; preferably, the aprotic polar solvent is selected from one or more of dimethyl sulfoxide, acetone, and acetonitrile; more preferably, the aprotic polar solvent is dimethyl sulfoxide, and the base is sodium acetate.

[0034] In some embodiments, the cyclization reaction temperature is 80-110°C, and the reaction time is 2-20 hours.

[0035] Compared with the prior art, the present application has the following positive technical effects:

[0036] 1. The method for preparing intermediate I of resmetirom provided by the present application adopts a continuous process, does not require separation of intermediates, and does not require post-reaction treatment, thereby saving multiple processes and time, and the post-treatment is simple and effective, which is suitable for industrial production.

[0037] 2. The method for preparing intermediate I of resmetirom provided by the present application has a small reagent dosage multiple, a more obvious cost advantage, and avoids the use of pyridine, a highly polluting reagent, which is green, low-toxic, and environmentally friendly.

[0038] 3. The method for preparing intermediate I of resmetirom provided by the present application can promote the reaction and effectively improve the color of the product by adding intermediate IV first and then adding sodium acetate.

[0039] 4. The method for preparing resmetirom provided by the present application is simple to operate, has a cost advantage, and uses green and environmentally friendly reagents, which is suitable for industrial mass production. Specific embodiments

[0040] The specific embodiments of the present application will be further described in detail below in combination with examples. The following examples are only used to illustrate the present application, but not to limit the scope of the present application.

[0041] All ranges recited in the specification are inclusive of the recited endpoints and are inclusive of the endpoints themselves, unless specifically indicated otherwise. All values recited in the specification are inclusive of the expected experimental error, technique error, and instrument error of the given technique used to measure the value, unless otherwise indicated. When no degree of error is recited, all values recited in the specification include a range of ±10% of the recited value.

[0042] In the present invention, % is weight / weight (w / w) percentage, unless otherwise specified.

[0043] Other reagents and materials used in the present invention are conventional reagents, all of which are commercially available.

[0044] HPLC analysis method used in the present invention to determine the purity of intermediate II:

[0045] Column: XSelect CSH Fluoro-Phenyl 150*4.6mm, 3.5μm

[0046] Mobile phase A: 1.0mL perfluorobutyric acid was dissolved in 1000mL purified water, shaken, ultrasonic, ready for use

[0047] Mobile phase B: 1.0mL perfluorobutyric acid was dissolved in 1000mL acetonitrile, shaken, ultrasonic, ready for use

[0048] Detection wavelength: 275nm

[0049] Flow rate: 1.0mL / min

[0050] Injection volume: 10μL

[0051] Column temperature: 45℃

[0052] Run time: 35min

[0053] HPLC analysis method used in the present invention to determine the purity of intermediate I:

[0054] Column: SHIMADZU AQ-C18 150*4.6mm 3μm

[0055] Mobile phase A: 25mM ammonium acetate was dissolved in 1000mL purified water, shaken, ultrasonic, ready for use

[0056] Mobile phase B: methanol

[0057] Detection wavelength: 275nm

[0058] Flow rate: 1.0mL / min

[0059] Injection volume: 10μL

[0060] Column temperature: 45℃

[0061] Runtime: 52 min

[0062] The HPLC analytical method used in this invention to determine the purity of resmetidine is as follows:

[0063] Column: ACE Excel 3Amide 150*4.6mm 3μm

[0064] Mobile phase A: 1.0 mL of perfluorobutyric acid dissolved in 1000 mL of purified water, shaken well, sonicated, and set aside.

[0065] Mobile phase B: 1.0 mL of perfluorobutyric acid dissolved in 1000 mL of methanol, shaken well, sonicated, and ready for use.

[0066] Detection wavelength: 265nm

[0067] Flow rate: 1.0 mL / min

[0068] Injection volume: 10 μL

[0069] Column temperature: 45℃

[0070] Runtime: 48min

[0071] Example 1:

[0072] Step 1: Preparation of 3,6-dichloro-4-isopropylpyridazine

[0073] Under nitrogen protection, 2 kg of water was added to a 50 L reactor, and stirring was started. 3,6-Dichloropyridazine (1 kg, 6.7 mol), acetonitrile (3.2 kg, 4 L), isobutyric acid (0.65 kg, 7.37 mol), trifluoroacetic acid (0.08 kg, 0.7 mol), and silver nitrate (0.11 kg, 0.65 mol) were added sequentially. The temperature was raised to 60–70 °C, and under controlled temperature, ammonium persulfate aqueous solution (8.2 kg, 10 mol; 28%) was added dropwise to the reactor. After the reaction was complete, the temperature was lowered to 15–25 °C, and the mixture was filtered. The filter cake was washed with acetonitrile, allowed to stand for 30 minutes, and then separated. The aqueous phase was extracted with acetonitrile (1.58 kg, 2 L) with stirring, allowed to stand, and then separated. The organic phase was then washed with saturated sodium bicarbonate aqueous solution, stirred for 15–30 minutes, allowed to stand, and then separated. Control the water bath temperature to 30–40℃ and the vacuum gauge pressure to ≤-0.08–-0.10 MPa. Concentrate the organic phase in the rotary evaporator under reduced pressure until no distillate flows out, yielding a pale yellow liquid with a purity of 94.4%.

[0074] Second step: preparation of 3, 5-dichloro-4-((6-chloro-5-isopropylpyridazin-3- yl)oxy)aniline, i.e. preparation of intermediate II

[0075] Third step: preparation of (2-cyano-2-(2-(3, 5-dichloro-4-((5-isopropyl-6-oxo-1, 6- dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl)glycine, i.e. preparation of intermediate I

[0076] Into a 50 L reactor, add 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (1 kg, 3 mol), acetic acid (5.25 kg, 5 L) and sodium acetate (0.37 kg, 4.5 mol) under nitrogen protection. Start stirring and heat the reactor to 105-115 °C. After 12 hours, start cooling to 15-25 °C. Filter to obtain the filtrate. Into the filtrate, add concentrated hydrochloric acid (3.04 kg, 30 mol; 36%) and heat to 80-90 °C. After 6 hours, cool to 0-10 °C. Add sodium nitrite aqueous solution (0.86 kg, 3.8 mol; 30%) dropwise at 0-10 °C. After 3 hours, add N-cyanoacetylurea (0.5 kg, 3.2 mol) quickly and then sodium acetate aqueous solution (10.22 kg, 27 mol; 22%) dropwise at 0-10 °C. After the addition, heat to 20-30 °C and stir for 14 hours. After the reaction is completed, filter and wash with drinking water. Into the filter cake, add drinking water (10 kg) and acetic acid (0.26 kg, 0.25 L) and stir for 2-3 hours. Filter and wash with drinking water. Into the filter cake, add ethanol (7.9 kg, 10 L) and stir for 2-3 hours. Filter and dry in a vacuum oven to obtain the intermediate I as a yellow solid in a yield of 85% and a purity of 95.9%.

[0077] Fourth step: preparation of risarestat

[0078] Into a reactor, add dimethyl sulfoxide (4.02 kg, 3.65 L), intermediate I (1.22 kg, 2.53 mol) and sodium acetate (0.32 kg, 3.9 mol) under nitrogen protection. Heat the reaction mixture to 90-100 °C and react for 12 hours. After the conversion of the raw material is completed, cool the reaction mixture to 15-25 °C, add water (7.32 kg) and stir for 6 hours. Filter to obtain a solid. Add the solid into DMSO, heat to 65 °C, stir to dissolve, add ethanol (10 kg, 12.7 L) dropwise into the reaction system, control the temperature at 65 °C, stir for 1-2 hours, slowly cool to 10 °C, stir for 2-3 hours, filter and dry the solid in a vacuum oven at 50 °C for 16 hours to obtain risarestat in a yield of 70% and a purity of 99.35%.

[0079] Example 2: preparation of (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl)aminoformate, i.e. intermediate I

[0080] Into a 500ml three-necked flask, 3,5-dichloro-4-((6-chloro-5- isopropylpyridazin-3-yl)oxy)aniline (5g, 0.015mol), acetic acid (26.25g, 25ml) and sodium acetate (1.85g, 0.02mol) were added under nitrogen protection. The reaction flask was stirred and heated to 110°C. After 12 hours, the reaction flask was cooled to 25°C. The reaction mixture was filtered. Into the filtrate, concentrated hydrochloric acid (14.75g, 36%) was added. The reaction flask was heated to 85°C. After 6 hours, the reaction was cooled to 10°C. Sodium nitrite aqueous solution (51.1g, 30%) was added dropwise at 10°C. After 3 hours, N-cyanoacetylurea (2.35g, 0.015mol) was added. The reaction mixture was stirred and heated to 25°C. After 14 hours, the reaction was filtered. The filtrate was washed with drinking water. Into the filter cake, drinking water (10kg) and acetic acid (1.3g) were added. The mixture was stirred for 3 hours. The mixture was filtered. The filter cake was washed with drinking water. Into the filter cake, ethanol (39.5g) was added. The mixture was stirred for 2 hours. The mixture was filtered. The filter cake was dried in vacuum oven. The yellow solid was intermediate I. The yield was 86.7%. The purity was 96.3%.

[0081] The specific embodiments described herein are only examples of the present application. Various modifications or changes can be made to the described embodiments without departing from the spirit of the present application. The modifications or changes are intended to fall within the scope of the appended claims.

Claims

1. A process for the preparation of the intermediate I of resmetirom, characterized by, The method comprises the following steps: C) reacting intermediate II in a basic reagent and an organic solvent, and then adding an acid to obtain a reaction system containing intermediate III; D) To the above reaction system, a nitrosating agent is added and stirred for a period of time, then intermediate IV and sodium acetate are added successively and stirred to obtain intermediate I; 2. The method of claim 1, wherein, The basic reagent in step C) is selected from one or more combinations of sodium acetate, potassium acetate, potassium bicarbonate, sodium bicarbonate, potassium hydrogen phosphate, and sodium hydrogen phosphate, and is preferably sodium acetate; the organic solvent is selected from one or more combinations of acetic acid, butyric acid, formic acid, and dimethyl sulfoxide, and is preferably acetic acid; and the acid is selected from hydrochloric acid, hydrobromic acid, and 40% sulfuric acid, and is preferably 36% hydrochloric acid.

3. The preparation method according to claim 1, characterized in that, The molar volume ratio of intermediate II, the basic reagent, and the organic solvent in step C) is 1:0.9-3:1-20 mol / mol / L, and is preferably 1:1.2-2:1.5-5 mol / mol / L.

4. The production method according to claim 1, characterized by, The reaction temperature of intermediate II in the basic reagent in step C) is 50-150°C, and the reaction time is 5-20 hours; preferably, the reaction temperature is 100-120°C, and the reaction time is 10-16 hours.

5. The preparation method according to claim 1, characterized in that, After the reaction of intermediate II in the basic reagent in step C) is completed, the temperature is lowered to 10-30°C, and the filtrate is obtained by filtration; an acid is added to the filtrate, and the temperature is raised to 50-100°C for stirring, and the stirring time is 5-10 hours.

6. The method of claim 1, wherein, The molar ratio of intermediate II to the acid in step C) is 1:8-12.

7. The preparation method according to claim 1, characterized in that, The nitrosating reagent in step D) is selected from one or more of sodium nitrite, isoamyl nitrite, or tert-butyl nitrite, and is preferably sodium nitrite.

8. The method of claim 1, wherein, After the nitrosating reagent is added in step D), the stirring temperature is 0-15°C, and the stirring time is 1-5 hours.

9. The method of claim 1, wherein, The molar ratio of intermediate II, intermediate IV, and sodium acetate is 1:1-1.5:8-10.

10. The method of claim 1, wherein, After the sodium acetate in step D) is prepared into an aqueous solution and then added dropwise to the reaction system, the dropping temperature is 0-10°C; after the dropping is completed, the temperature is controlled to 10-30°C for incubation for 10-20 hours.

11. The method of claim 1, wherein, Further comprising the step of further purifying the crude intermediate I obtained in step D) into a pure product by stirring in an organic solvent; the organic solvent is selected from one or more combinations of acetic acid and alcohols; and is preferably acetic acid or ethanol.

12. The method of claim 11, wherein, The molar volume ratio of the crude intermediate I to the organic solvent is 1:3-5 mol / L.

13. The method of claim 1, wherein, The preparation of the intermediate II comprises the following steps: A) dissolving 3,6-dichloropyridazine, isobutyric acid, silver nitrate and trifluoroacetic acid in a mixed solution of acetonitrile and water, slowly adding an aqueous solution of ammonium persulfate, after the addition is completed, performing reaction, after the reaction is completed, extracting with an organic solvent a to obtain the intermediate V; B) reacting the intermediate V with the intermediate VI in an organic solvent b in the presence of potassium carbonate and a catalyst cuprous iodide to obtain the intermediate II; The organic solvent a is acetonitrile; the organic solvent b is one or more combinations of methyl sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethylformamide; and is preferably dimethyl sulfoxide.

14. The method of claim 13, wherein, After the reaction in step B) is completed, the reaction solution is quenched with water, and then concentrated hydrochloric acid is added dropwise to control the pH to 1-3; then sodium thiosulfate is added for neutralization, and a solid is obtained by filtration; then the solid is dissolved in isopropyl alcohol by heating, and is crystallized by cooling.

15. A process for the preparation of resmetiromide, characterized by, The preparation method comprises the following steps: A) dissolving 3,6-dichloropyridazine, isobutyric acid, silver nitrate, and trifluoroacetic acid in a mixed solution of acetonitrile and water, slowly adding an aqueous solution of ammonium persulfate dropwise, and then performing reaction; after the reaction is completed, acetonitrile is used for extraction to obtain intermediate V; B) reacting intermediate V with intermediate VI in dimethyl sulfoxide in the presence of potassium carbonate and a catalyst cuprous iodide to obtain intermediate II; C) reacting intermediate II in sodium acetate and acetic acid, and after the reaction is completed, treating with hydrochloric acid to obtain a reaction system containing intermediate III; D) adding sodium nitrite to the above reaction system, stirring for a period of time, and then adding intermediate IV and sodium acetate successively to obtain intermediate I; E) cyclization of compound I in the presence of an organic solvent and a base to give resmetiromel; 16. The method of claim 15, wherein, Step E) the organic solvent is selected from aprotic polar solvents, and the base is selected from sodium acetate and potassium acetate; preferably, the aprotic polar solvent is selected from one or more of dimethyl sulfoxide, acetone, and acetonitrile; preferably, the aprotic polar solvent is dimethyl sulfoxide; and the base is preferably sodium acetate.

17. The method of claim 16, wherein, The ring formation reaction temperature is 80-110°C, and the reaction time is 2-20 hours.

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