Preparation method of bumetanib

Abstract

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of bumetanib, which specifically comprises the following steps: S1) performing etherification reaction on starting materials 4-hydroxy-3-nitro-5-sulfonamido benzoic acid and bromobenzene to obtain an intermediate 1; s2) reducing the intermediate 1 by ferrous sulfate to obtain an intermediate 2; s3) carrying out amination reaction on the intermediate 2 through chloro-n-butane to obtain an intermediate 3; and S4) carrying out hydrolysis reaction through sodium hydroxide to obtain bumetanib. The invention provides a preparation method of bumetanib, 4-hydroxy-3-nitro-5-sulfonamido benzoic acid is used as a raw material, etherification, reduction, amination and hydrolysis reactions are adopted, the etherification yield of the process is high, expensive palladium-carbon catalysts do not need to be used in the steps of reduction and amination, special equipment is avoided, the operation of amination and hydrolysis is simple, the reaction is simple, and the yield is high.

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and particularly relates to a preparation method of bumetanide. Background Art

[0002] Bumetanide is a white crystalline powder with a melting point of 230 - 231 °C. It is soluble in methanol, acetone, ethanol, and dilute solutions of alkali metal hydroxides, and is almost insoluble in water. Bumetanide is a diuretic drug with rapid oral absorption, fast onset (15 - 30 min), and good diuretic effect. This drug is used to treat edematous diseases such as cardiogenic, hepatic, and renal edema, and is a commonly used drug for treating refractory edema and acute pulmonary edema.

[0003] There are mainly the following two routes for the synthesis of bumetanide:

[0004] Route 1: Patent document CN116283673A discloses a synthesis method of bumetanide, and its synthesis route is as follows:

[0005]

[0006] This method uses 4-chloro-3-nitro-5-sulfamoylbenzoic acid as the starting material, and obtains bumetanide through etherification, reduction, amination, and purification. This route requires the use of relatively expensive palladium-carbon catalyst, and also has high requirements for equipment. In the etherification reaction, the molar feeding ratio of 4-chloro-3-nitro-5-sulfamoylbenzoic acid:phenol;sodium bicarbonate (eq) = 1:5:8, reacts for 20 h. The reaction solution is extracted and cooled to crystallize to obtain intermediate 1, with a yield of 62.3%. This process route has a long reaction time, the phenol ratio reaches 5 equivalents, and the excessive phenol is not easy to recover, resulting in waste and environmental pollution, and the yield of 60% is also relatively low.

[0007] Patent document US20080262086A1 also uses 4-chloro-3-nitro-5-sulfamoylbenzoic acid as the starting material, and the yield of the etherification reaction is only 34%.

[0008] Route 2: Patent document CN106748906B discloses a synthesis method of bumetanide, and its synthesis route is as follows:

[0009]

[0010] This method uses 3-amino-4-phenoxy-5-sulfamoylbenzoic acid as the starting material, reacts in n-butanol under the condition of ferric chloride catalyst, and after the reaction, obtains bumetanide through concentration, hydrolysis, and acid adjustment for crystallization, with a yield of 64.5%. This process requires more energy consumption to concentrate n-butanol after the reaction, and the yield is also relatively low. Summary of the Invention

[0011] The object of the present invention is to overcome the drawbacks in the prior art and provide a method for preparing bumetanide.

[0012] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0013] A method for preparing bumetanide, characterized in that it is prepared by the following formula (I):

[0014]

[0015] Specifically, it includes the following steps: S1) Etherification reaction of the starting material 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid with bromobenzene to obtain intermediate 1; S2) Reduction of intermediate 1 with ferrous sulfate to obtain intermediate 2; S3) Alkylation reaction of intermediate 2 with n-butyl chloride to obtain intermediate 3; S4) Hydrolysis reaction with sodium hydroxide to obtain bumetanide.

[0016] The specific steps of step S1) are as follows: 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid, a base and bromobenzene are added to a solvent, and the temperature is raised to 90-95 °C for reaction to prepare;

[0017] Preferably, the molar ratio of 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid to bromobenzene is 1:

[0018] (1-10), more preferably 1:(2.5-5); more preferably 1:2.5;

[0019] Preferably, the molar ratio of 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid to the base is 1:(0.5-2); more preferably 1:1;

[0020] Preferably, the base is potassium carbonate or sodium carbonate; the solvent is DMF;

[0021] Preferably, after the reaction is completed, water is added, bromobenzene is recovered by stratification, and the aqueous phase is adjusted to pH = 1-2 to precipitate a solid to obtain intermediate 1.

[0022] The specific steps of step S2) are as follows: The etherification product intermediate 1 is added to concentrated ammonia water for dissolution to obtain an etherification product ammonium salt solution. The etherification product ammonium salt solution is added dropwise to a ferrous sulfate solution, and at the same time, concentrated ammonia water is added dropwise. After the addition is completed, the temperature is controlled at 90-95 °C for reaction to prepare;

[0023] Preferably, the molar ratio of the etherification product intermediate 1 to ferrous sulfate is 1:(5-10); preferably 1:7;

[0024] Preferably, the mass-volume ratio of the etherification product intermediate 1 to concentrated ammonia water is 1:(3-8); preferably 1:5; preferably, the ratio of the first addition of concentrated ammonia water to the second addition of concentrated ammonia water is 1:(10-30); preferably 1:20;

[0025] Preferably, after the reaction is completed, acetic acid is added dropwise to the filtrate after filtration until the pH = 4 - 5 to precipitate a solid to obtain Intermediate 2.

[0026] The specific steps of step S3) are as follows: The reduced product Intermediate 2, sodium hydroxide, and n-butyl chloride are added to acetonitrile, stirred and heated to reflux for 10 - 15 h until the reaction is complete;

[0027] Preferably, the molar ratio of the reduced product Intermediate 2 to n-butyl chloride is 1:(2 - 10); preferably 1:(4 - 6), more preferably 1:5;

[0028] Preferably, the molar ratio of the reduced product Intermediate 2 to sodium hydroxide is 1:(1 - 10); preferably 1:(1.5 - 2), more preferably 1:2;

[0029] Preferably, after the reaction is completed, the temperature is lowered to 0 - 5 °C, and ice water is quickly added and filtered to obtain the solid aminated product Intermediate 3.

[0030] The specific steps of step S4) are as follows: The aminated product Intermediate 3 is added with methanol, heated to 55 - 60 °C, and an aqueous sodium hydroxide solution is added dropwise; the temperature is controlled for the reaction to obtain the product;

[0031] Preferably, the molar ratio of the aminated product Intermediate 3 to sodium hydroxide is 1:(1 - 1.5); preferably 1:1.2;

[0032] Preferably, the molar concentration of the aqueous sodium hydroxide solution is (20 - 50) mol / L; preferably 30 mol / L;

[0033] Preferably, after the reaction is completed, hydrochloric acid is added to adjust the pH = 2 - 3; the temperature is lowered to 20 - 30 °C for crystallization to obtain bumetanide.

[0034] The starting material 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid is prepared by the following formula (II):

[0035]

[0036] Specifically, it includes the following steps: S01) The mixture of p-hydroxybenzoic acid and chlorosulfonic acid is heated to 100 - 150 °C for reaction, then cooled to room temperature, sulfuric acid is added dropwise, after addition, the temperature is raised to 40 - 70 °C for heat preservation, nitrate is added, and the temperature is continued to be raised to 80 - 90 °C for reaction to obtain 4-hydroxy-3-nitro-5-sulfonyl chloride benzoic acid;

[0037] S02) Purified 4-hydroxy-3-nitro-5-sulfonyl chloride benzoic acid is added to concentrated ammonia water, and the reaction is continued to stir at 5 - 10 °C. After completion, the excess ammonia is removed by reduced pressure concentration, and the acid is added to adjust the pH to 1 - 2 to precipitate a solid to obtain 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid.

[0038] In step S01), the molar ratio of p-hydroxybenzoic acid to chlorosulfonic acid is 1:(1 - 10); preferably 1:5;

[0039] Preferably, the molar ratio of p-hydroxybenzoic acid to nitrate is 1:(2 - 10); preferably 1:5; preferably, the nitrate is sodium nitrate;

[0040] Preferably, the steps for purifying 4-hydroxy-3-nitro-5-sulfonyl chloride benzoic acid are as follows: slowly pour the reaction solution cooled to room temperature into a container filled with crushed ice while continuously stirring, and at the same time cool the solvent in an ice-salt bath to keep the ice dissociation process at 0 °C, then perform suction filtration, wash the filter cake with ice water, suck dry the filter cake, and dry it under vacuum.

[0041] In step S02), the mass-to-volume ratio of 4-hydroxy-3-nitro-5-sulfonyl chloride benzoic acid to concentrated ammonia water is 1:(0.5 - 2) g / ml; preferably 1:1.5 g / ml; hydrochloric acid is used for pH adjustment.

[0042] Compared with the prior art, the beneficial effects of the present invention are:

[0043] The present invention provides a preparation method of bumetanide, which uses 4-hydroxy-3-nitro-5-sulfamoyl benzoic acid as a raw material and adopts etherification, reduction, alkylation, and hydrolysis reactions. This process has a high etherification yield, and expensive palladium-carbon catalysts are not required in the reduction and alkylation steps, avoiding the use of special equipment. The operations of alkylation and hydrolysis are simple reactions with high yields.

[0044] Specifically, the yield of the etherification step is significantly improved. The etherification yield of Route 1 mentioned in the background technology is 62.3%, while the etherification yield of this process route can reach 85%, and the excess materials can be recycled through simple treatment. The reduction step uses ferrous sulfate reduction, avoiding the use of expensive catalysts and special equipment, which is convenient for industrial production. The alkylation process uses n-butyl chloride, and the product yield is also significantly improved. The yield of Route 2 in the background technology is 64.5%, and the yield of this route is 81%. Description of the Drawings

[0045] Figure 1 It is the mass spectrum of the starting material in the embodiment of the present invention;

[0046] Figure 2 It is the NMR spectrum of the starting material in the embodiment of the present invention;

[0047] Figure 3 It is the mass spectrum of Intermediate 1 in the embodiment of the present invention;

[0048] Figure 4 It is the NMR spectrum of Intermediate 1 in the embodiment of the present invention;

[0049] Figure 5Mass spectrum of Intermediate 2 in the embodiments of the present invention;

[0050] Figure 6 Nuclear magnetic spectrum of Intermediate 2 in the embodiments of the present invention;

[0051] Figure 7 Mass spectrum of Intermediate 3 in the embodiments of the present invention;

[0052] Figure 8 Nuclear magnetic spectrum of Intermediate 3 in the embodiments of the present invention;

[0053] Figure 9 Mass spectrum of bumetanide in the embodiments of the present invention;

[0054] Figure 10 Nuclear magnetic spectrum of bumetanide in the embodiments of the present invention. Detailed implementation manners

[0055] In order to enable those skilled in the art of the present technology to better understand the technical solutions of the present invention, the present invention will be further described in detail below with reference to the accompanying drawings and the best embodiments.

[0056] A preparation method of bumetanide, characterized in that it is prepared by the following formula (I):

[0057]

[0058] Specifically, it includes the following steps:

[0059] S1) Etherify the starting material 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid with bromobenzene to obtain Intermediate 1; add 50 ml of DMF to a 500 ml three-necked flask, add 25 g (89.1 mmol) of 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid, add 12.3 g (89.1 mmol) of potassium carbonate, add 70 g (445 mmol) of bromobenzene, stir and heat to 90 - 95 °C, and react for 10 - 12 h. After the reaction is completed, cool to 10 - 20 °C, and dropwise add 150 ml of purified water. Separate the layers (the lower layer of bromobenzene is added with a small amount of water for washing and recycled). Adjust the pH of the aqueous phase to 1 - 2 with hydrochloric acid, precipitate the solid, and stir for 2 h. Dry and discharge 25.6 g, with a molar yield of 79% and a purity of 99.5%.

[0060] S2) Intermediate 1 is reduced with ferrous sulfate to obtain Intermediate 2; in a 500 ml three-necked flask, 25 g (73.96 mmol) of Intermediate 1 is added, 300 ml of purified water is added, the temperature is raised to 40 - 50 °C, 6 ml of concentrated ammonia water is added dropwise, and stirred until dissolved. In a 1 L three-necked flask, 78.65 g (0.518 mol) of ferrous sulfate is added, 300 ml of purified water is added, the temperature is raised to 90 - 95 °C, and heated with stirring until dissolved. The temperature is controlled at 90 - 95 °C, the ammonium salt solution of the intermediate is added dropwise, and at the same time 120 ml of concentrated ammonia water is added dropwise over 3 h. After the addition is completed, continue to react at 90 - 95 °C for 0.5 h. Filter while it is hot, add 15 ml of glacial acetic acid dropwise to the filtrate until pH = 4 - 5, and cool to 10 - 20 °C after the addition is completed. Filter by suction, wash with 50 ml of purified water, and dry to obtain 20.53 g, with a molar yield of 90% and a purity of 99.0%.

[0061] S3) Intermediate 2 is subjected to a butyl chloride reaction to obtain Intermediate 3; in a 500 ml three-necked flask, 20 g (64.87 mmol) of Intermediate 2 is added, 120 ml of acetonitrile, 3.89 g (97.3 mmol) of sodium hydroxide and 30 g (324 mmol) of butyl chloride are added, and the temperature is raised to reflux for 10 - 15 h. After the reaction is completed, cool to 0 - 5 °C, and add 120 ml of ice water. Stir for 30 min, filter, wash with 40 ml of purified water, and dry to obtain 24.28 g, with a molar yield of 89.0% and a purity of 99.3%.

[0062] S4) It is hydrolyzed with sodium hydroxide to obtain bumetanide. In a 1 L three-necked flask, 24 g (57.0 mmol) of Intermediate 3 is added, 360 ml of methanol is added, the temperature is raised to 55 - 60 °C, 2.74 g (68.49 mmol) of sodium hydroxide and 180 ml of purified water solution are added. Stir with temperature control for 1 h. Add 7.0 g of concentrated hydrochloric acid and 180 ml of purified water solution dropwise until pH = 2 - 3. Slowly cool to 20 - 30 °C. Wash with 40 ml of purified water and dry to obtain 18.92 g, with a molar yield of 91% and a purity of 99.9%.

[0063] Among them, the starting material 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid is prepared by the following formula (II):

[0064]

[0065] Specifically, it includes the following steps: S01) In a 1000 mL three-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser (connected to an acidic gas absorption device), add 60 g (0.43 mol) of p-hydroxybenzoic acid and 160 mL (2.12 mol) of chlorosulfonic acid. Start stirring and heat to 115 - 120 °C in an oil bath. React for 2 h, then raise the temperature to 135 - 140 °C and react for another 2 h. Stop heating. After cooling to room temperature, slowly add 60 ml of sulfuric acid while stirring evenly. After adding, gradually raise the temperature to 60 °C and keep stirring for 50 h. Then, add 180 g (2.12 mol) of solid sodium nitrate in small portions over about 1 h. Continue to raise the temperature to 85 - 90 °C and react for 6 h. Stop heating. After cooling to room temperature, slowly pour the reaction solution into a large beaker containing 1800 g of crushed ice while constantly stirring (cool with an ice-salt bath outside to keep the ice melting process at about 0 °C). Filter by suction, wash the filter cake with ice water 3 times, drain the filter cake by suction, and dry it in vacuo (about 50 °C) to obtain 68.5 g of 4-hydroxy-3-nitro-5-sulfonylchlorobenzoic acid, with a molar yield of 56.4%.

[0066] S02) Place 100 ml of concentrated ammonia water in a three-necked flask equipped with a mechanical stirrer. Start stirring and cool to 5 - 10 °C in an ice-water bath. Add 65 g (0.23 mol) of 4-hydroxy-3-nitro-5-sulfonylchlorobenzoic acid within 0.5 h while stirring. After adding, the reaction solution changes from clear to turbid and immediately precipitates. Continue to stir at 5 - 10 °C for 4 h, and concentrate under reduced pressure to remove the excess ammonia. Add about 30 ml of concentrated hydrochloric acid to acidify to pH = 1 - 2. Filter by suction, wash with a small amount of water, and drain by suction. Dry in vacuo (about 50 °C) to obtain 42.8 g of 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid, with a molar yield of 70%.

[0067] Example 2

[0068] On the basis of Example 1, prepare Intermediate 1 with a reduced amount of bromobenzene. React the starting material 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid with bromobenzene to obtain Intermediate 1; add 50 ml of DMF to a 500 ml three-necked flask, add 25 g (89.1 mmol) of 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid, add 12.3 g (89.1 mmol) of potassium carbonate, add 35 g (223 mmol) of bromobenzene, stir and raise the temperature to 90 - 95 °C, and react for 10 - 12 h. After the reaction is completed, cool to 10 - 20 °C and add 150 ml of purified water dropwise. Separate the layers (wash the lower layer of bromobenzene with a small amount of water and recycle it). Adjust the pH of the aqueous phase to 1 - 2 by adding hydrochloric acid, precipitate the solid, and stir for 2 h. Dry and discharge 26.8 g, with a molar yield of 84% and a purity of 99.5%.

[0069] Example 3

[0070] On the basis of Example 1, Intermediate 1 was prepared with sodium carbonate used instead of the base. The starting material 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid and bromobenzene were subjected to an etherification reaction to obtain Intermediate 1; into a 500 ml three-necked flask, 50 ml of DMF was added, 25 g (89.1 mmol) of 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid was added, 9.4 g (89.1 mmol) of sodium carbonate was added, 70 g (445 mmol) of bromobenzene was added, and the mixture was stirred and heated to 90 - 95 °C for 10 - 12 h. After the reaction was completed, the temperature was lowered to 10 - 20 °C, and 150 ml of purified water was added dropwise. Layer separation was carried out (the lower layer of bromobenzene was washed with a small amount of water and recycled). The pH of the aqueous phase was adjusted to 1 - 2 by adding hydrochloric acid, a solid was precipitated, and stirring was carried out for 2 h. After drying, 26.0 g of the product was obtained, with a molar yield of 81% and a purity of 99.6%.

[0071] Example 4

[0072] On the basis of Example 1, Intermediate 3 was prepared with the amount of n-butyl chloride reduced. Into a 500 ml three-necked flask, 20 g (64.87 mmol) of Intermediate 2 was added, 120 ml of acetonitrile, 3.89 g (97.3 mmol) of sodium hydroxide and 15 g (162 mmol) of n-butyl chloride were added, and the mixture was heated to reflux for 10 - 15 h. After the reaction was completed, the temperature was lowered to 0 - 5 °C, and 120 ml of ice water was added. Stirring was carried out for 30 min, filtration was carried out, and the product was washed with 40 ml of purified water and dried to obtain 24.5 g, with a molar yield of 90.0% and a purity of 99.6%.

[0073] Example 5

[0074] On the basis of Example 1, Intermediate 3 was prepared with the amount of sodium hydroxide increased. Into a 500 ml three-necked flask, 20 g (64.87 mmol) of Intermediate 2 was added, 120 ml of acetonitrile, 5.19 g (129.74 mmol) of sodium hydroxide and 30 g (324 mmol) of n-butyl chloride were added, and the mixture was heated to reflux for 10 - 15 h. After the reaction was completed, the temperature was lowered to 0 - 5 °C, and 120 ml of ice water was added. Stirring was carried out for 30 min, filtration was carried out, and the product was washed with 40 ml of purified water and dried to obtain 25.2 g, with a molar yield of 92.4% and a purity of 99.5%.

[0075] In summary, the present invention provides a method for preparing bumetanide, which uses 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid as a raw material and adopts etherification, reduction, amination and hydrolysis reactions. This process has a high etherification yield, and the reduction and amination steps do not require the use of expensive palladium-carbon catalysts, avoiding the use of special equipment. The operations of amination and hydrolysis are simple reactions with high yields.

[0076] Specifically, the yield of the etherification step is significantly improved. The etherification yield of Route 1 mentioned in the background technology is 62.3%, while the etherification yield of this process route can reach 85%. Moreover, the excessive materials can be recycled through simple treatment. The reduction step uses ferrous sulfate for reduction, avoiding the use of expensive catalysts and special equipment, which is convenient for industrial production. The chlorination process uses n-butyl chloride, and the product yield is also significantly improved. The yield of Route 2 in the background technology is 64.5%, and the yield of this route is 81%.

[0077] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can still be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A preparation method of bumetanide, characterized in that, It is prepared by the following formula (I):

2. The preparation method of bumetanide according to claim 1, characterized in that, Specifically, it includes the following steps: S1) An etherification reaction is carried out between the starting material 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid and bromobenzene to obtain intermediate 1; S2) Intermediate 1 is reduced with ferrous sulfate to obtain intermediate 2; S3) Intermediate 2 undergoes an alkylation reaction with n-butyl chloride to obtain intermediate 3; S4) It is hydrolyzed with sodium hydroxide to obtain bumetanide.

3. The preparation method of bumetanide according to claim 2, wherein, The specific steps of step S1) are as follows: 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid, a base, and bromobenzene are added to a solvent, and the temperature is raised to 90 - 95 °C for reaction to prepare; Preferably, the molar ratio of 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid to bromobenzene is 1: (1 - 10), more preferably 1:(2.5 - 5); even more preferably 1:2.5; Preferably, the molar ratio of 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid to the base is 1:(0.5 - 2); more preferably 1:1; Preferably, the base is potassium carbonate or sodium carbonate; the solvent is DMF; Preferably, after the reaction is completed, water is added, bromobenzene is separated and recovered, and the aqueous phase is acidified to pH = 1 - 2 to precipitate a solid to obtain intermediate 1.

4. The preparation method of bumetanide according to claim 2, characterized in that, The specific steps of step S2) are as follows: The etherification product intermediate 1 is dissolved in concentrated ammonia water to obtain an ammonium salt solution of the etherification product. The ammonium salt solution of the etherification product is added dropwise to a ferrous sulfate solution, and at the same time, concentrated ammonia water is added dropwise. After the addition is completed, the temperature is controlled at 90 - 95 °C for reaction to prepare; Preferably, the molar ratio of the etherification product intermediate 1 to ferrous sulfate is 1:(5 - 10); preferably 1:7; Preferably, the mass - volume ratio of the etherification product intermediate 1 to concentrated ammonia water is 1:(3 - 8) g / ml; preferably 1:5 g / ml; preferably, the ratio of the first dropwise addition of concentrated ammonia water to the second dropwise addition of concentrated ammonia water is 1:(10 - 30); preferably 1:20; Preferably, after the reaction is completed, the filtrate is added dropwise with acetic acid to pH = 4 - 5 to precipitate a solid to obtain intermediate 2.

5. The preparation method of bumetanide according to claim 2, wherein, The specific steps of step S3) are as follows: The reduction product intermediate 2, sodium hydroxide, and n-butyl chloride are added to acetonitrile, stirred and heated to reflux for 10 - 15 h until the reaction is complete; Preferably, the molar ratio of the reduction product intermediate 2 to n-butyl chloride is 1:(2 - 10); preferably 1:(4 - 6), more preferably 1:5; Preferably, the molar ratio of the reduction product intermediate 2 to sodium hydroxide is 1:(1 - 10); preferably 1:(1.5 - 2), more preferably 1:2; Preferably, after the reaction is completed, the temperature is lowered to 0 - 5 °C, and ice water is quickly added and filtered to obtain the solid amination product intermediate 3.

6. The preparation method of bumetanide according to claim 2, wherein, The specific steps of step S4) are as follows: The amination product intermediate 3 is added with methanol, the temperature is raised to 55 - 60 °C, and an aqueous sodium hydroxide solution is added dropwise; the temperature is controlled for reaction to obtain the product; Preferably, the molar ratio of the amination product intermediate 3 to sodium hydroxide is 1:(1 - 1.5); preferably 1:1.2; Preferably, the molar concentration of the aqueous sodium hydroxide solution is (20 - 50) mol / L; preferably 30 mol / L; Preferably, after the reaction is completed, hydrochloric acid is added to adjust the pH to 2 - 3; the temperature is lowered to 20 - 30 °C for crystallization to obtain bumetanide.

7. The preparation method of bumetanide according to claim 1, characterized in that, The starting material 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid is prepared by the following formula (II):

8. The preparation method of bumetanide according to claim 7, characterized in that, Specifically, it includes the following steps: S01) Heat the mixture of p-hydroxybenzoic acid and chlorosulfonic acid to 100-150 °C for reaction, then cool it to room temperature and dropwise add sulfuric acid. After addition, heat it to 40-70 °C for heat preservation, add nitrate, and continue to heat it to 80-90 °C for reaction to obtain 4-hydroxy-3-nitro-5-sulfonyl chloride benzoic acid; S02) Add the purified 4-hydroxy-3-nitro-5-sulfonyl chloride benzoic acid to concentrated ammonia water, and continue to stir and react at 5-10 °C. After completion, concentrate under reduced pressure to remove excessive ammonia, adjust the pH to 1-2 with acid, and precipitate a solid to obtain 4-hydroxy-3-nitro-5-sulfamoylbenzoic acid.

9. The preparation method of bumetanide according to claim 8, characterized in that, In step S01), the molar ratio of p-hydroxybenzoic acid to chlorosulfonic acid is 1:(1-10); preferably 1:5; Preferably, the molar ratio of p-hydroxybenzoic acid to nitrate is 1:(2-10); preferably 1:5; preferably, the nitrate is sodium nitrate; Preferably, the step of purifying 4-hydroxy-3-nitro-5-sulfonyl chloride benzoic acid is: slowly pour the reaction solution cooled to room temperature into a container filled with crushed ice while constantly stirring, and at the same time cool the solvent in an ice-salt bath to keep the ice dissolution process at 0 °C, filter by suction, wash the filter cake with ice water, drain the filter cake by suction, and dry it under vacuum.

10. The preparation method of bumetanide according to claim 8, characterized in that, In step S02), the mass-volume ratio of 4-hydroxy-3-nitro-5-sulfonyl chloride benzoic acid to concentrated ammonia water is 1:(0.5-2) g / ml; preferably 1:1.5 g / ml; hydrochloric acid is used for pH adjustment.

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