Synthesis process of bumetanib

Abstract

The invention relates to a preparation method of bumetanib. Specifically, the invention discloses a method for preparing bumetanib by taking a compound with a higher atom utilization rate as a raw material in an inert solvent, introducing a sulfonyl chloride group into the compound and then carrying out a three-step substitution reaction. The method disclosed by the invention is simple to operate, the number of steps is obviously reduced, a noble metal catalyst is not needed, the cost is low, the method is environment-friendly, and industrial production is easy.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis, and more particularly to a synthetic process for bumetanide. Background Technology

[0002] Bumetanide is a derivative of m-aminobenzenesulfonamide and is a potent diuretic. Its diuretic mechanism involves inhibition of sodium... + -K + -It is related to the activity of ATPase. It mainly works by inhibiting the activity of Cl- in the thick ascending limb of the loop of Henle. - The active reabsorption of Cl- and the passive reabsorption of Na+ affect the urine concentration and dilution process, thus exerting a diuretic effect. Cl- also acts on the proximal convoluted tubule and has a certain renal vasodilatory effect. Cl- in the initial stage of diuresis... - Excretion increased 20-fold, Na + Excretion increased 13-fold; when medication continued, urinary Cl... - It will no longer be more than Na + Bumetanide has a weaker inhibitory effect on carbonic anhydrase than furosemide, therefore its potassium loss is also less. 1 mg of bumetanide is approximately equivalent to 40 mg of furosemide.

[0003] The existing synthetic routes are mainly as follows: However, this route requires nitration and catalytic hydrogenation, which places high demands on equipment and is environmentally unfriendly.

[0004] Therefore, there is a need in the art for a simple and mild synthetic process for bumetanide. Summary of the Invention

[0005] The purpose of this invention is to provide a simple, mild, low-cost, and easily industrialized synthetic process for bumetanide, in order to solve the problems of cumbersome steps and harsh reaction conditions in existing synthetic processes.

[0006] This invention provides a method for preparing bumetanide, the method comprising the following steps: (a) Compound BM1 is reacted with chlorosulfonic acid to produce compound BM2; (b) The chlorine atom of compound BM2 undergoes a substitution reaction to prepare compound BM3; (c) The fluorine atom of compound BM3 undergoes a substitution reaction to prepare compound BM4; (d) Compound of formula BM4 undergoes a coupling reaction with a coupling agent to prepare compound of formula BM.

[0007] In another preferred embodiment, the molar ratio of the BM1 compound to chlorosulfonic acid in step (a) is 1:(0.5-6).

[0008] In another preferred embodiment, the molar ratio of the BM1 compound to chlorosulfonic acid in step (a) is 1:(1-3).

[0009] In another preferred embodiment, step (a) is performed at a temperature of 60°C-120°C, preferably 70°C-110°C.

[0010] In another preferred embodiment, the reaction time in step (a) is 0.5h-4h.

[0011] In another preferred embodiment, the reaction time in step (a) is 1-3 hours.

[0012] In another preferred embodiment, step (a) further includes a post-processing step: the reaction solution after the reaction is completed is directly fed into the next reaction step after post-processing.

[0013] In another preferred embodiment, the post-processing includes the following steps: (s1) Provides the reaction solution and water after the reaction of compound BM1 with chlorosulfonic acid; (s2) The reaction solution is mixed with water to obtain a solid; (s3) The solid is washed and dried to obtain compound of formula BM2.

[0014] In another preferred embodiment, the water in step (s1) is water with a temperature of 0°C-10°C.

[0015] In another preferred embodiment, step (s2) involves pouring the reaction solution into water for mixing.

[0016] In another preferred embodiment, the drying temperature in step (s3) is 60°C-70°C.

[0017] In another preferred embodiment, the drying time in step (s3) is 10h-20h.

[0018] In another preferred embodiment, step (a) includes the following steps: mixing compound of formula BM1 with chlorosulfonic acid, heating to T1 and reacting to prepare compound of formula BM2.

[0019] In another preferred embodiment, the mixing is performed by adding the BM1 compound to chlorosulfonic acid and mixing.

[0020] In another preferred embodiment, the mixing is performed by adding the BM1 compound to chlorosulfonic acid at a temperature of 20°C-40°C.

[0021] In another preferred embodiment, T1 is 80℃-90℃.

[0022] In another preferred embodiment, step (a) includes the following steps: (a-1) At 25℃-35℃, the compound of formula BM1 was added to chlorosulfonic acid, and then the temperature was raised to 75℃-90℃ to carry out the reaction, so as to obtain the reaction solution in which the compound of formula BM1 and chlorosulfonic acid had reacted completely. (a-2) The reaction solution was mixed with water at a temperature of 0℃-5℃ to obtain a solid, which was then washed and dried at 60℃-65℃ for 10h-15h to prepare the compound of formula BM2.

[0023] In another preferred embodiment, step (b) includes the following steps: reacting the compound of formula BM2 with an organic solution of ammonia to prepare the compound of formula BM3.

[0024] In another preferred embodiment, the organic solution of ammonia is selected from the group consisting of: a methanol solution of ammonia, an ethanol solution of ammonia, a 1,4-dioxane solution of ammonia, a tetrahydrofuran solution of ammonia, and an acetone solution of ammonia.

[0025] In another preferred embodiment, the molar ratio of the BM2 compound to the organic solution of ammonia is 1:(1-20), more preferably 1:(5-15).

[0026] In another preferred embodiment, step (b) is performed at a temperature of 0°C-40°C, preferably 0°C-20°C.

[0027] In another preferred embodiment, the reaction time in step (b) is 2h-8h.

[0028] In another preferred embodiment, step (b) further includes a post-processing step: the reaction solution after the reaction is completed is directly fed into the next reaction step after post-processing.

[0029] In another preferred embodiment, the post-processing step includes: (1) Provide the reaction solution and water after the organic solution of compound BM2 and ammonia have reacted; (2) Mix the reaction solution with water, and adjust the pH to acidic using a pH adjuster to obtain a solid; (3) After filtering, washing and drying the solid, the compound of formula BM3 is prepared.

[0030] In another preferred embodiment, the water is water with a temperature of 0°C to 10°C.

[0031] In another preferred embodiment, the reaction solution is mixed with water by adding the reaction solution to water and mixing.

[0032] In another preferred embodiment, the mixing is performed by adding the reaction solution to water at a temperature of 20°C-40°C.

[0033] In another preferred embodiment, the pH adjuster is selected from the group consisting of hydrochloric acid, phosphoric acid, citric acid, acetic acid, and formic acid, preferably hydrochloric acid.

[0034] In another preferred embodiment, the pH is adjusted to 1-5, more preferably to 2-3.

[0035] In another preferred embodiment, the drying temperature is 50°C-70°C, more preferably 60°C-65°C.

[0036] In another preferred embodiment, the drying time is 10-15 hours.

[0037] In another preferred embodiment, step (b) includes the following steps: (x1) Provide an organic solution of a compound of formula BM2 and ammonia; (x2) The compound of formula BM2 was mixed with an organic solution of ammonia and reacted to prepare the compound of formula BM3.

[0038] In another preferred embodiment, step (b) involves adding the BM2 compound to an organic solution of ammonia and mixing.

[0039] In another preferred embodiment, the BM2 compound is added in batches.

[0040] In another preferred embodiment, the BM2 compound is added in batches to an organic solution of ammonia at -5°C to -5°C.

[0041] In another preferred embodiment, step (b) includes the following steps: (i) At 0℃-5℃, BM2 is added in batches to an organic solution of ammonia to carry out the reaction, and the reaction solution of BM2 and the organic solution of ammonia is obtained. (ii) At 25℃-35℃, the reaction solution is poured into water at 0℃-10℃, and the pH value is adjusted to 2-3 with a pH adjuster to obtain a solid; (iii) The solid is washed with water at a temperature of 0℃-10℃ and dried at 60℃-65℃ for 10h-15h to prepare compound of formula BM3.

[0042] In another preferred embodiment, step (c) includes the following steps: reacting compound of formula BM3 with n-butylamine in a first solvent to prepare compound of formula BM4.

[0043] In another preferred embodiment, the first solvent in step (c) is selected from the group consisting of alcoholic organic solvents, ketone organic solvents, ether organic solvents, toluene, acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or combinations thereof.

[0044] In another preferred embodiment, the first solvent in step (c) is selected from the group consisting of methanol, ethanol, isopropanol, acetone, methyl tert-butyl ether, toluene, acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or combinations thereof.

[0045] In another preferred embodiment, the first solvent in step (c) is selected from the group consisting of acetonitrile, dichloromethane, or combinations thereof.

[0046] In another preferred embodiment, the molar ratio of the BM3 compound to n-butylamine is 1:(0.5-6), more preferably 1:(1-3).

[0047] In another preferred embodiment, step (c) is performed at a temperature of 80°C-110°C, preferably 85°C-100°C.

[0048] In another preferred embodiment, the reaction time in step (c) is 2h-8h.

[0049] In another preferred embodiment, step (c) includes a post-processing step. Preferably, the post-processing step includes: mixing the reaction solution after the reaction of the BM3 compound with n-butylamine, adjusting the pH to acidic using a pH adjuster, and then filtering, washing, drying, and directly adding it to the next reaction step.

[0050] In another preferred embodiment, the water is water with a temperature of 0°C to 10°C.

[0051] In another preferred embodiment, the reaction solution is mixed with water by adding the reaction solution to water and mixing.

[0052] In another preferred embodiment, the pH adjuster is selected from the group consisting of hydrochloric acid, phosphoric acid, citric acid, acetic acid, and formic acid, preferably hydrochloric acid.

[0053] In another preferred embodiment, the pH is adjusted to 1-5, more preferably to 2-3.

[0054] In another preferred embodiment, the drying temperature is 60°C-70°C.

[0055] In another preferred embodiment, the drying time is 10-15 hours.

[0056] In another preferred embodiment, step (c) includes the following steps: (1) In the first solvent, BM3 is mixed with n-butylamine, and then the temperature is raised to 75℃-95℃ to carry out the reaction, and the reaction solution of BM3 and n-butylamine is obtained. (2) Pour the reaction solution into water and adjust the pH value to 2-3 with a pH adjuster to obtain a solid; (3) The solid was washed with water at a temperature of 0℃-10℃ and dried at 60℃-65℃ for 10h-15h to prepare the compound of formula BM3.

[0057] In another preferred embodiment, step (d) includes the following steps: under an inert gas atmosphere, in a second solvent, and in the presence of a catalyst, a base and a ligand, a coupling reaction is carried out between the BM4 compound and a coupling agent to prepare the BM5 compound.

[0058] In another preferred embodiment, the coupling agent is selected from the group consisting of iodobenzene, bromobenzene, chlorobenzene, and phenyl trifluoromethanesulfonate.

[0059] In another preferred embodiment, the catalyst is selected from the group consisting of: CuI (cuprous iodide), CuBr (cuprous bromide), CuCl (cuprous chloride), Cu(OAc)2 (copper acetate), Cu2O (cuprous oxide), or combinations thereof.

[0060] In another preferred embodiment, the base is selected from the group consisting of cesium carbonate, sodium carbonate, potassium carbonate, potassium phosphate, sodium phosphate, sodium hydride, sodium amino, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, triethylamine, diisopropylethylamine, tripropylamine, tributylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 2,6-dimethyl-4-tert-butylpyridine, DBU, DABCO, MTBD, or a combination thereof, preferably selected from cesium carbonate, potassium carbonate, and potassium tert-butoxide.

[0061] In another preferred embodiment, the ligand is selected from the group consisting of N,N-dimethylglycine, L-proline, N-methylglycine, and N,N-diethylglycine.

[0062] In another preferred embodiment, the molar ratio of the BM4 compound to the coupling agent is 1:(0.1-4), more preferably 1:(0.5-2).

[0063] In another preferred embodiment, the molar ratio of the BM4 compound to the catalyst is 1:(0.1-4), more preferably 1:(0.5-2).

[0064] In another preferred embodiment, the molar ratio of the BM4 compound to the base is 1:(0.5-10), more preferably 1:(1-5).

[0065] In another preferred embodiment, the molar ratio of the BM4 compound to the ligand is 1:(0.01-0.5), more preferably 1:(0.05-0.3).

[0066] In another preferred embodiment, the inert gas is selected from the group consisting of nitrogen, argon, and helium.

[0067] In another preferred embodiment, the second solvent is selected from the group consisting of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane, dichloromethane, dichloroethane, toluene, acetonitrile, alcohol solvents, ether solvents, or combinations thereof.

[0068] In another preferred embodiment, the second solvent is selected from the group consisting of N,N-dimethylformamide (DMF), dichloromethane, dichloroethane, toluene, acetonitrile, methanol, ethanol, isopropanol, acetone, methyl tert-butyl ether, or combinations thereof.

[0069] In another preferred embodiment, the second solvent is selected from the group consisting of N,N-dimethylformamide (DMF), dichloromethane, toluene, acetonitrile, or combinations thereof.

[0070] In another preferred embodiment, step (d) is performed at a temperature of 90°C-120°C, preferably 100°C-110°C.

[0071] In another preferred embodiment, the reaction time for step (d) is 6h-20h.

[0072] In another preferred embodiment, step (d) includes a post-processing step. Preferably, the post-processing step includes: mixing the reaction solution after the reaction of the BM4 compound with the coupling agent, adjusting the pH to acidity using a pH adjuster, and then filtering, washing, drying, and directly adding it to the next reaction step.

[0073] In another preferred embodiment, the water is water at 0°C-10°C.

[0074] In another preferred embodiment, the reaction solution is mixed with water by adding the reaction solution to water and mixing.

[0075] In another preferred embodiment, the pH adjuster is selected from the group consisting of hydrochloric acid, phosphoric acid, citric acid, acetic acid, and formic acid.

[0076] In another preferred embodiment, the pH value is adjusted to 2-3.

[0077] In another preferred embodiment, the drying temperature is 60°C-70°C.

[0078] In another preferred embodiment, the drying time is 10-15 hours.

[0079] In another preferred embodiment, step (d) includes the following steps: (n1) Under an inert gas atmosphere, in a second solvent, the compound of formula BM4, coupling agent, catalyst, base and ligand are mixed and heated to T2 to carry out the reaction to prepare the compound of formula BM.

[0080] In another preferred embodiment, T2 is 95℃-100℃.

[0081] In another preferred embodiment, step (d) includes the following steps: (I) Under an inert gas atmosphere, in a second solvent, the BM4 compound, coupling agent, catalyst, base and ligand are mixed, heated to 100℃-110℃ and reacted for 10h-15h to obtain the reaction solution in which the reaction of the BM4 compound and the coupling agent is completed. (II) Pour the reaction solution into water and adjust the pH value to 2-3 with a pH adjuster to obtain a solid; (III) The solid is washed with water at a temperature of 0℃-10℃ and dried at 60℃-65℃ for 10h-15h to prepare compound BM5.

[0082] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0083] Figure 1 The proton NMR spectrum of the BM3 compound is shown.

[0084] Figure 2 The high-resolution mass spectrum of the BM3 compound is shown.

[0085] Figure 3 The high-performance liquid chromatogram of compound BM5 is shown. Detailed Implementation

[0086] Through extensive and in-depth research, the inventors have discovered for the first time a highly efficient method for the synthesis of bumetanide using readily available raw materials and involving a concise process. Compared to traditional processes that require nitration with concentrated nitric acid and concentrated sulfuric acid, as well as catalytic hydrogenation, this invention uses only common reagents and operates under mild conditions, making it highly suitable for industrial production. This invention was completed based on this discovery.

[0087] the term Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0088] As used herein, the terms “comprising,” “including,” and “containing” are used interchangeably and include not only closed definitions but also semi-closed and open definitions. In other words, the terms include “consisting of” and “substantially consisting of”.

[0089] As used herein, when referring to a specific enumerated value, the term “about” means that the value can vary by no more than 1% from the enumerated values. For example, as used herein, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0090] As used herein, the terms “comprising,” “including,” and “containing” are used interchangeably and include not only closed definitions but also semi-closed and open definitions. In other words, the terms include “consisting of” and “substantially consisting of”.

[0091] As used herein, the terms "method of the present invention" and "preparation method of the present invention" are used interchangeably and refer to the method described in the first aspect of the present invention.

[0092] The "inert solvent" mentioned in this invention refers to a solvent that does not react with the compounds in the reaction system.

[0093] Preparation method of bumetanide Typically, the preparation method of the BM compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased commercially unless otherwise specified.

[0094] This invention provides a method for preparing bumetanide, the method comprising the following steps: (a) Compound BM1 is reacted with chlorosulfonic acid to produce compound BM2; (b) The chlorine atom of compound BM2 undergoes a substitution reaction to prepare compound BM3; (c) The fluorine atom of compound BM3 undergoes a substitution reaction to prepare compound BM4; (d) Compound of formula BM4 undergoes a coupling reaction with a coupling agent to prepare compound of formula BM.

[0095] This invention innovatively modifies the molecular structure of a key precursor compound, replacing the chlorine atom on the original benzene ring with a hydroxyl group and simultaneously introducing a fluorine atom at its ortho position, thus designing the BM1 compound. This structural design produces multiple unexpected technical effects: First, the introduction of fluorine atoms effectively improves atom utilization and reduces material consumption at the source. Second, the hydroxyl, fluorine, and carboxylic acid groups in the BM1 compound together form a unique combination of substituents, and the resulting electronic and positioning effects ensure that the sulfonyl reference is located at the ortho position of the hydroxyl group in the next chlorosulfonic acid reaction step.

[0096] The improvements and optimizations of this invention fundamentally simplify the total synthesis route, successfully avoiding the harsh and dangerous reactions such as nitration and catalytic hydrogenation that must be used in the original route, significantly shortening the overall process route, making the reaction conditions milder and safer, and easier to industrialize.

[0097] The main advantages of this invention include: (1) The preparation method of the present invention is simple to operate, does not require harsh reaction conditions (such as strong acid), the reaction conditions are relatively mild, and it is also environmentally friendly.

[0098] (2) The preparation method of the present invention does not require the use of precious metal catalysts, and the cost is low.

[0099] (3) The preparation method of the present invention is novel and the number of steps is significantly reduced, making it easy to industrialize.

[0100] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0101] Example 1: Preparation of BM2 BM1 (90 g, 0.58 mol) was slowly added to chlorosulfonic acid (100.76 g, 0.86 mol) at room temperature, and the temperature was slowly raised to 80 °C. After 2 h, TLC showed that the reaction of the starting material was complete. After cooling to room temperature, the mixture was slowly poured into ice water, and a large amount of white solid precipitated. The solid was filtered and washed with ice water, and dried overnight in a vacuum drying oven at 60-65 °C to obtain 126 g of white solid, with a yield of 85.84%.

[0102] 1 H NMR (400Hz, DMSO-) d6 ): 7.90-7.91 (1H, m), 7.62 (1H, dd, J=4Hz, 12Hz), MS: 254.95[M+H]. Example 2: Preparation of BM3 Compound BM2 (10.3 g, 40 mmol) was added in portions to a methanol solution of ammonia (50 ml) under ice-water bath cooling. After the addition was complete, the solution turned yellow and clear. TLC after 4 hours showed that the starting material had reacted completely. The reaction solution was poured into ice water, and a solid precipitated. The pH was adjusted to 2-3 with hydrochloric acid, and the amount of precipitated solid increased. The mixture was filtered, the filter cake was washed with ice water, and dried overnight in a vacuum drying oven at 60-65 °C to obtain 8.2 g of white solid, yield: 86.19%. The 1H NMR spectrum of BM3 is shown below. Figure 1 As shown, the high-resolution mass spectrum is as follows: Figure 2 As shown.

[0103] 1 H NMR (400Hz, DMSO-) d6 ): 11.30 (s, br, 1H), 8.10-8.11 (m, 1H) 7.98-7.99 (1H, d, J=8Hz), 7.90-7.91 (m, 1H), 7.62 (1H, d, J=8Hz), MS: 249.10[M+CH4]. Example 3: Preparation of BM4 BM3 (30.0 g, 0.13 mol) and n-butylamine (18.66 g, 0.26 mol) were added to 150 mL of acetonitrile and heated to 90 °C under reflux. After 4 h, TLC showed that the starting materials had reacted completely. The reaction solution was poured into water, and a small amount of solid precipitated. The pH was adjusted to 2-3 with hydrochloric acid, and the amount of precipitated solid increased. The mixture was filtered, the filter cake was washed with ice water, and dried overnight in a vacuum drying oven at 60-65 °C to obtain 28.0 g of white solid, yield: 76.13%.

[0104] 1 H NMR (400Hz, DMSO-) d6 ): 11.50 (s, br, 1H), 8.12-8.15 (m, 1H) 7.96-7.99 (1H, d, J=8Hz), 7.90-7.91 (m, 1H), 7.62 (1H, d, J=8Hz), 6.79 (s, br, 1H), 3.23-3.30 (m, 2H), 1.43-1.48 (m, 1H), 1.30-1.35 (m, 1H), 0.850-0.88 (1H, t, J=7.4Hz), MS: 289.07[M+H]. Example 4: Preparation of BM5 BM4 (10.0 g, 34.68 mmol), iodobenzene (7.08 g, 34.68 mmol), CuI (7.27 g, 38.15 mmol), cesium carbonate (28.25 g, 86.71 mmol), and N,N-dimethylglycine (0.72 g, 6.49 mmol) were added to 100 mL of DMF. The mixture was heated to 100-110 °C under nitrogen protection and reacted for 12 h. TLC showed a small amount of reactant remaining. The reaction solution was cooled to room temperature and poured into water. The pH was then adjusted to 2-3 with hydrochloric acid, resulting in an increased amount of precipitated solid. The mixture was filtered, the filter cake was washed with ice water, and dried overnight in a vacuum oven at 60-65 °C to obtain 8.6 g of a white solid. Yield: 68%, Purity: 99%. The high-performance liquid chromatogram of BM5 is shown below. Figure 3 As shown.

[0105] 1 H NMR (400Hz, DMSO-) d6 ): δ13.18 (s, br, 1H), 7.71 (d, J = 1. 6Hz, 1H), 7.45 (d, J = 2.0Hz, 1H), 7.36 (s, 2H), 7.28 (dd, J = 8.4, 7.6Hz, 2H), 7.05 (t, J = 7.2Hz, 1H) ,6.86 (d, J = 12Hz, 2H), 5.08 (t, J = 5.6Hz, 1H), 3.06 (dd, J = 8.8, 6.4Hz, 2H), 1.35-1.42 (m, 2H) ,1.08- 1.17 (m, 2H), 0.77 (t, J = 7.2Hz, 3H). MS: 365.20[M+H]. All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing bumetanide, characterized in that, The method includes the following steps: (a) Compound BM1 undergoes a chlorosulfonation reaction to prepare compound BM2; (b) The chlorine atom of compound BM2 undergoes a substitution reaction to prepare compound BM3; (c) The fluorine atom of compound BM3 undergoes a substitution reaction to prepare compound BM4; (d) Compound BM4 undergoes a coupling reaction with a coupling agent to prepare compound BM5.

2. The method as described in claim 1, characterized in that, Step (a) includes one or more features selected from the group consisting of: A. The molar ratio of the BM1 compound to chlorosulfonic acid is 1:(0.5-6), preferably 1:(1-3). B. Step (a) is performed at a temperature of 60°C-120°C, preferably 70°C-110°C; C. The reaction time of step (a) is 0.5h-4h, preferably 1h-3h; D. Step (a) includes: after post-processing the reaction solution, directly input it into the next reaction step.

3. The method as described in claim 2, characterized in that, The post-processing includes the following steps: (s1) Provides the reaction solution and water after the reaction of compound BM1 with chlorosulfonic acid; (s2) The reaction solution is mixed with water to obtain a solid; (s3) The solid is washed and dried to prepare compound BM2.

4. The method as described in claim 1, characterized in that, Step (b) includes the following steps: Compound BM2 undergoes a chlorine atom substitution reaction with an organic solution of ammonia to prepare compound BM3.

5. The method as described in claim 4, characterized in that, Step (b) includes one or more features selected from the group consisting of: A. The organic solution of ammonia is selected from the following group: methanol solution of ammonia, ethanol solution of ammonia, 1,4-dioxane solution of ammonia, tetrahydrofuran solution of ammonia, and acetone solution of ammonia. B. The molar ratio of the BM2 compound to the organic solution of ammonia is 1:(1-20), preferably (5-15). C. Step (b) is performed at a temperature of 0°C-40°C, preferably 0°C-20°C; D. Step (b) further includes a post-processing step: the reaction solution after the reaction is completed is directly fed into the next reaction step after post-processing.

6. The method as described in claim 5, characterized in that, The post-processing steps include: (1) Provide the reaction solution and water after the organic solution of compound BM2 and ammonia have reacted; (2) Mix the reaction solution with water, and adjust the pH to acidic using a pH adjuster to obtain a solid; (3) After filtering, washing and drying the solid, the compound of formula BM3 is prepared.

7. The method as described in claim 1, characterized in that, Step (c) includes the following steps: in a first solvent, compound BM3 undergoes a fluorine atom substitution reaction with n-butylamine to prepare compound BM4.

8. The method as described in claim 7, characterized in that, Step (c) includes one or more features selected from the group consisting of: A. The molar ratio of the BM3 compound to n-butylamine is 1:(0.5-6), preferably 1:(1-3). B. Step c is performed at a temperature of 80℃-110℃, preferably 85℃-100℃; C. The post-processing step in step (c), preferably, includes: mixing the reaction solution after the reaction of the BM3 compound with n-butylamine is completed with water, adjusting the pH to acidic using a pH adjuster, and then filtering, washing, drying, and directly adding it to the next reaction step.

9. The method as described in claim 1, characterized in that, Step (d) includes the following steps: under an inert gas atmosphere, in a second solvent, and in the presence of a catalyst, a base, and a ligand, the BM4 compound undergoes a coupling reaction with a coupling agent to prepare the BM5 compound.

10. The method as described in claim 9, characterized in that, Step (d) includes one or more features selected from the group consisting of: A. The coupling agent is selected from the group consisting of: iodobenzene, bromobenzene, chlorobenzene, and phenyl trifluoromethanesulfonate; B. The catalyst is selected from the following group: CuI (cuprous iodide), CuBr (cuprous bromide), CuCl (cuprous chloride), Cu(OAc)2 (copper acetate), Cu2O (cuprous oxide); C. The base is selected from the group consisting of cesium carbonate, sodium carbonate, potassium carbonate, potassium phosphate, sodium phosphate, sodium hydride, sodium amino, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyloxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, triethylamine, diisopropylethylamine, tripropylamine, tributylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 2,6-dimethyl-4-tert-butylpyridine, DBU, DABCO, MTBD, or a combination thereof, preferably selected from cesium carbonate, potassium carbonate, and potassium tert-butoxide; D. The ligand is selected from the group consisting of: N,N-dimethylglycine, L-proline, N-methylglycine, and N,N-diethylglycine; E. The molar ratio of the BM4 compound to the coupling agent is 1:(0.1-4), preferably 1:(0.5-2). F. The molar ratio of the BM4 compound to the catalyst is 1:(0.1-4), preferably 1:(0.5-2). G. The molar ratio of the BM4 compound to the base is 1:(0.5-10), preferably 1:(1-5). H. The molar ratio of the BM4 compound to the ligand is 1:(0.01-0.5), preferably 1:(0.05-0.3). I. Step (d) is performed at a temperature of 90℃-120℃, preferably 100℃-110℃.

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