Preparation method of furosemide

Abstract

The invention provides a preparation method of furosemide, which comprises the following specific steps: (1) adding 2-amino-4-chlorobenzoic acid and 2-chloromethyl furan into a deep eutectic solvent, and carrying out microwave heating reaction to obtain a reaction solution; and (2) sequentially adding chlorosulfonic acid and thionyl chloride into the reaction liquid to react, adding ammonia water, and then performing supercritical CO2 fluid extraction to obtain furosemide. The synthetic method of the furosemide is simple, efficient and low in energy consumption, unnecessary side reactions can be avoided, extra impurities are not generated, post-treatment mother liquor does not exist, the synthesized furosemide is high in yield and purity, and the synthetic method is suitable for large-scale actual production. According to the method, the deep eutectic solvent is selected as a novel solvent, and compared with a single solvent, the deep eutectic solvent can improve the reaction rate and the product yield and can reduce environmental pollution.

Description

Technical Field

[0001] The present invention relates to the technical field of drug preparation, and in particular to a method for preparing furosemide. Background Art

[0002] Furosemide is a loop diuretic widely used in the treatment of congestive heart failure and edema. It can be used clinically to treat cardiac edema, renal edema, ascites due to cirrhosis, pulmonary edema, cerebral edema, acute renal failure or peripheral edema caused by vascular wall disorders. It has important application value, especially for cases where other diuretics are ineffective.

[0003] According to the 1980 edition of the National Compendium of Process Technology for Pharmaceutical Ingredients, 2,4-diaminotoluene is used as the starting material, and the target product furosemide is obtained through seven steps of diazotization, displacement, oxidation, chlorosulfonation, amination, acidification and condensation. At present, most domestic manufacturers use this route to produce furosemide. However, the yield of the last step of this process, the condensation reaction of 2,4-dichloro-5-sulfonamidobenzoic acid and furfurylamine, is only 40%.

[0004] Other common furosemide preparation methods are as follows:

[0005] Patent CN106117168A discloses a method for preparing furosemide, and the preparation steps are as follows: in the presence of an organic solvent, 2,4-dichloro-5-sulfonamidobenzoic acid and alkali react to obtain a reaction solution, and 2,4-dichloro-5-sulfonamidobenzoic acid sodium salt is obtained by post-treatment, in the presence of an organic solvent, 2,4-dichloro-5-sulfonamidobenzoic acid sodium salt reacts with furfurylamine, after the reaction is completed, furfurylamine and solvent are recovered by vacuum distillation to obtain a reaction solution, the reaction solution is mixed with isopropanol, stirred, crystallized, and filtered to obtain furosemide sodium salt; furosemide sodium salt is dissolved in water, decolorized with activated carbon, and acidified with glacial acetic acid to obtain a furosemide finished product. The method is low in cost, time-consuming, good in product quality, and high in yield, but the method uses an organic solvent, which not only increases costs, but also may bring environmental pollution problems, and the recovery and treatment of the solvent are more complicated, requiring additional equipment and steps, and the energy consumption required for vacuum distillation is large, which is not suitable for actual large-scale production.

[0006] Patent CN105566260A discloses a method for preparing furosemide, and the preparation steps are as follows: heating tetrahydrofuran compounds such as 2-chloromethylfuran and 2-aminobenzoic acid compounds such as 2-amino-4-chloro-5-sulfamoylbenzoic acid in a reaction solvent, the temperature is controlled to 80-150°C, a nucleophilic reaction is carried out under the action of an acid binding agent and / or a catalyst, and the reaction solution is separated and purified to obtain furosemide. This method can prepare furosemide with high purity and high yield through simple steps, with a yield of up to 97.0% and a purity of up to 99.8%. However, the reaction time of this method is too long, the temperature is high, and a reasonable catalyst and acid binding agent are required. The reaction conditions are harsh, which may lead to the instability of the reaction. The catalyst needs to be recovered, and the amount of waste liquid generated by post-treatment is also large. Excessive materials enter the mother liquor and cannot be recovered, and a large cost is required for treatment.

[0007] Patent CN105906589A discloses a method for preparing furosemide, and the preparation steps are as follows: 2,4-dichloro-5-sulfonylaminobenzoic acid and an acid binding agent are put into a suitable solvent, and under the protection of an inert gas, the temperature is raised to a certain temperature, and furfurylamine is added dropwise. After the reaction is completed, the pH value is adjusted with an acid, and crystals are precipitated. The crude furosemide is filtered out, and the crude product is refined using an organic solvent and water as a mixed solvent. The pH value is first adjusted to alkaline, and the crude product is dissolved by heating. Activated carbon is added for decolorization, and hot filtration is performed. After the filtrate is adjusted to pH with an acid, solids are precipitated, and furosemide is obtained by filtration and drying. The method has a high conversion rate, few by-products, high product purity, and a simple process flow. According to HPLC analysis, the purity is greater than 99.0%, and the total yield can reach 71.2%. However, the method requires the introduction of an inert gas for a long time during the production process, which increases the complexity and cost of the equipment. The solvents and acid-base treatments used in the crude product refining process are relatively large, which may result in the generation of a large amount of waste liquid, increase environmental pollution and operational complexity. In addition, the large-scale use of organic solvents not only increases costs, but also brings the burden of solvent recovery.

[0008] Patent CN117447427A discloses a method for preparing furosemide, which comprises the following steps: (1) chlorosulfonation: reacting chlorosulfonic acid and 2,4-dichlorobenzoic acid at 100-155°C for 2-6h, then adding the reactant into water for hydrolysis, filtering the hydrolyzate, and washing the filter cake with water until it is neutral, thereby obtaining 2,4-dichloro-5-sulfonyl chloride benzoic acid; (2) amination: adding 2,4-dichloro-5-sulfonyl chloride benzoic acid into ammonia water, reacting at 0-50°C for 2-4h, neutralizing, and filtering to obtain 2,4-dichloro-5-sulfonyl chloride benzoic acid. The crude product of sulfonylaminobenzoic acid is purified to obtain 2,4-dichloro-5-sulfonylaminobenzoic acid; (3) condensation: 2-furan methylamine and 2,4-dichloro-5-sulfonylaminobenzoic acid are reacted at 80-150°C for 5-12h, the reactant is added to an aqueous sodium hydroxide solution, washed with an organic solvent, neutralized, and crystallized to obtain a crude furosemide product; (4) decolorization: the crude furosemide product is added to a saturated sodium bicarbonate solution, heated to 70-100°C, and then activated carbon is added for decolorization, then neutralized, crystallized, and centrifuged to obtain a furosemide product. The overall production cycle of the method is short, the production method is simple, the production process is easy to control, the product obtained in each step will be tested, the product quality is stable and controllable, the purity of the prepared furosemide is above 99.95%, the content of a single impurity does not exceed 0.01%, the total impurity content is controlled below 0.05%, and the yield of each reaction stage is high, and the total yield reaches more than 55%. However, this method has a long synthesis route, cumbersome steps, and is prone to introducing impurities, requiring strict control of reaction conditions.

[0009] The above-mentioned preparation methods of furosemide have problems of high cost and high energy consumption, long reaction route, long reaction time, large temperature fluctuation, difficulty in treating mother liquor and waste liquid generated during the reaction, or the need to recover solvents, and are not suitable for large-scale industrial production.

[0010] Therefore, it is necessary to develop a method for preparing furosemide to solve the above problems. Summary of the invention

[0011] In view of this, the present invention provides a method for preparing furosemide.

[0012] The technical solution of the present invention is achieved in this way:

[0013] A method for preparing furosemide, the specific preparation steps comprising:

[0014] (1) adding 2-amino-4-chlorobenzoic acid and 2-chloromethylfuran to a deep eutectic solvent and performing microwave heating to react to obtain a reaction solution;

[0015] (2) Chlorosulfonic acid and thionyl chloride are sequentially added to the reaction solution for reaction, and aqueous ammonia is added for neutralization. After the reaction is completed, supercritical CO2 fluid extraction is performed to obtain furosemide.

[0016] Furthermore, in step (1), the deep eutectic solvent is composed of a hydrogen bond acceptor and a hydrogen bond donor in a molar ratio of 1:4-6, the hydrogen bond acceptor is choline chloride, and the hydrogen bond donor is any one of 1,3-propylene glycol, glycolic acid or polyethylene glycol.

[0017] Furthermore, the preparation method of the deep eutectic solvent includes: mixing a hydrogen bond donor and a hydrogen bond acceptor, heating and stirring at 40-60° C., adding water and stirring evenly, and cooling to room temperature to obtain a colorless transparent liquid, namely, a deep eutectic solvent.

[0018] Furthermore, in step (1), the molar ratio of 2-amino-4-chlorobenzoic acid to 2-chloromethylfuran is 1:1.2-1.5.

[0019] Furthermore, in step (1), the solid-liquid ratio of the 2-amino-4-chlorobenzoic acid to the deep eutectic solvent is 1:6-8 mg / mL.

[0020] Furthermore, in step (1), the microwave heating reaction has a power of 200-300 W, a temperature of 80-100° C., and a time of 30-60 min.

[0021] Furthermore, in step (2), the molar ratio of chlorosulfonic acid to thionyl chloride and 2-amino-4-chlorobenzoic acid is 1.5-1.8:0.6-0.8:1.

[0022] Furthermore, in step (2), the reaction temperature is 80-100° C., and the reaction time is 40-80 min.

[0023] Furthermore, in step (2), the concentration of the ammonia water is 8-10 v / v%; and the volume ratio of the ammonia water to the reaction solution is 0.1-0.2:1.

[0024] Furthermore, in step (2), the supercritical CO2 fluid extraction is performed at 20-30 MPa for 20-40 min.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] 1. The synthesis method of furosemide of the present invention is simple and efficient, has low energy consumption, can avoid unnecessary side reactions, does not produce additional impurities, does not have post-treatment mother liquor, and the synthesized furosemide has a high yield and high purity, and is suitable for large-scale practical production.

[0027] 2. The present invention uses a deep eutectic solvent. As a new type of solvent, the deep eutectic solvent can improve the reaction rate and product yield compared with a single solvent, and can also reduce environmental pollution. The starting materials of the present invention react in a deep eutectic solvent, which reduces the amount of solvent used, can lower the reaction temperature, improve the reaction efficiency, shorten the reaction time, improve the reaction selectivity, and reduce unnecessary side reactions. After the reaction is completed, the deep eutectic solvent can be stripped and recycled without generating three wastes.

[0028] 3. The present invention adopts microwave heating to more accurately control the reaction process, reduce unnecessary side reactions, and improve the yield; supercritical CO2 has high diffusivity, which can improve selectivity and product purity, and the purification step is simpler and more efficient, will not pollute the environment, and can be easily recovered after the reaction. DETAILED DESCRIPTION

[0029] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0030] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0031] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0032] Example 1

[0033] A method for preparing furosemide, the specific preparation steps comprising:

[0034] (1) adding 2-amino-4-chlorobenzoic acid and 2-chloromethylfuran in a molar ratio of 1:1.3 to a deep eutectic solvent, wherein the material-liquid ratio of 2-amino-4-chlorobenzoic acid to the deep eutectic solvent is 1:7 mg / mL, and performing a microwave heating reaction, specifically heating at 250 W and 90° C. for 45 min to obtain a reaction solution;

[0035] The deep eutectic solvent is composed of choline chloride and 1,3-propylene glycol in a molar ratio of 1:5;

[0036] The preparation method of the deep eutectic solvent comprises: mixing choline chloride and 1,3-propylene glycol, heating and stirring at 50° C., adding water and stirring evenly, cooling to room temperature, and obtaining a colorless transparent liquid, namely the deep eutectic solvent;

[0037] (2) Chlorosulfonic acid and thionyl chloride in a molar ratio of 1.7:0.7 are added to the reaction solution in sequence, and the molar ratio of chlorosulfonic acid to 2-amino-4-chlorobenzoic acid is 1.7:1. The mixture is reacted at 90° C. for 60 min, and then 9 v / v% ammonia water is added, and the volume ratio of ammonia water to the reaction solution is 0.15:1. The mixture is mixed and stirred evenly, and neutralized. After completion, supercritical CO2 fluid extraction is performed, specifically, extraction is performed at 25 MPa for 30 min to obtain furosemide.

[0038] Example 2

[0039] A method for preparing furosemide, the specific preparation steps comprising:

[0040] (1) adding 2-amino-4-chlorobenzoic acid and 2-chloromethylfuran in a molar ratio of 1:1.2 to a deep eutectic solvent, wherein the material-liquid ratio of 2-amino-4-chlorobenzoic acid to the deep eutectic solvent is 1:6 mg / mL, and performing a microwave heating reaction, specifically heating at 200 W and 80° C. for 30 min to obtain a reaction solution;

[0041] The deep eutectic solvent consists of choline chloride and glycolic acid in a molar ratio of 1:4;

[0042] The preparation method of the deep eutectic solvent comprises: mixing choline chloride and glycolic acid, heating and stirring at 40° C., adding water and stirring evenly, cooling to room temperature to obtain a colorless transparent liquid, namely the deep eutectic solvent;

[0043] (2) Chlorosulfonic acid and thionyl chloride in a molar ratio of 1.5:0.6 are added to the reaction solution in sequence, and the molar ratio of chlorosulfonic acid to 2-amino-4-chlorobenzoic acid is 1.5:1. The mixture is reacted at 80° C. for 40 min, and then 8 v / v% ammonia water is added, and the volume ratio of ammonia water to the reaction solution is 0.1:1. The mixture is mixed and stirred evenly, and neutralized. After completion, supercritical CO2 fluid extraction is performed, specifically, extraction is performed at 20 MPa for 20 min to obtain furosemide.

[0044] Example 3

[0045] A method for preparing furosemide, the specific preparation steps comprising:

[0046] (1) adding 2-amino-4-chlorobenzoic acid and 2-chloromethylfuran in a molar ratio of 1:1.5 to a deep eutectic solvent, wherein the material-liquid ratio of 2-amino-4-chlorobenzoic acid to the deep eutectic solvent is 1:8 mg / mL, and performing a microwave heating reaction, specifically heating at 300 W and 100° C. for 60 min to obtain a reaction solution;

[0047] The deep eutectic solvent consists of choline chloride and polyethylene glycol in a molar ratio of 1:6;

[0048] The preparation method of the deep eutectic solvent comprises: mixing choline chloride and polyethylene glycol, heating and stirring at 60° C., adding water and stirring evenly, cooling to room temperature to obtain a colorless transparent liquid, namely the deep eutectic solvent;

[0049] (2) Chlorosulfonic acid and thionyl chloride in a molar ratio of 1.8:0.8 are added to the reaction solution in sequence, and the molar ratio of chlorosulfonic acid to 2-amino-4-chlorobenzoic acid is 1.8:1. The reaction is carried out at 100° C. for 80 minutes, and then 10 v / v% ammonia water is added, and the volume ratio of ammonia water to the reaction solution is 0.2:1. The mixture is mixed and stirred evenly, and neutralized. After completion, supercritical CO2 fluid extraction is performed, specifically, extraction is carried out at 30 MPa for 40 minutes to obtain furosemide.

[0050] Comparative Example 1

[0051] The difference from Example 1 is that the deep eutectic solvent is replaced with tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide organic solvent, and the rest is the same as Example 1.

[0052] The preparation method of furosemide in this comparative example comprises the following specific preparation steps:

[0053] (1) adding 2-amino-4-chlorobenzoic acid and 2-chloromethylfuran in a molar ratio of 1:1.3 to an organic solvent, wherein the material-liquid ratio of 2-amino-4-chlorobenzoic acid to the organic solvent is 1:7 mg / mL, and performing a microwave heating reaction, specifically heating at 250 W and 90° C. for 45 min to obtain a reaction solution;

[0054] The organic solvent may be tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide;

[0055] (2) Chlorosulfonic acid and thionyl chloride in a molar ratio of 1.7:0.7 are sequentially added to the reaction solution, the molar ratio of chlorosulfonic acid to 2-amino-4-chlorobenzoic acid is 1.7:1, the reaction is carried out at 90° C. for 60 min, and then 9 v / v% ammonia water is added, the volume ratio of ammonia water to the reaction solution is 0.15:1, the mixture is mixed and stirred evenly, and neutralized. After completion, supercritical CO2 fluid extraction is performed, specifically, extraction is carried out at 25 MPa for 30 min to obtain furosemide.

[0056] Comparative Example 2

[0057] The difference from Example 1 is that microwave heating is replaced by ordinary heating, and the rest is the same as Example 1.

[0058] The preparation method of furosemide in this comparative example comprises the following specific preparation steps:

[0059] (1) adding 2-amino-4-chlorobenzoic acid and 2-chloromethylfuran in a molar ratio of 1:1.3 to a deep eutectic solvent, wherein the material-liquid ratio of 2-amino-4-chlorobenzoic acid to the deep eutectic solvent is 1:7 mg / mL, and heating at 90° C. for 45 minutes to obtain a reaction solution;

[0060] The deep eutectic solvent is composed of choline chloride and 1,3-propylene glycol in a molar ratio of 1:5;

[0061] The preparation method of the deep eutectic solvent comprises: mixing choline chloride and 1,3-propylene glycol, heating and stirring at 50° C., adding water and stirring evenly, cooling to room temperature, and obtaining a colorless transparent liquid, namely the deep eutectic solvent;

[0062] (2) Chlorosulfonic acid and thionyl chloride in a molar ratio of 1.7:0.7 are sequentially added to the reaction solution, the molar ratio of chlorosulfonic acid to 2-amino-4-chlorobenzoic acid is 1.7:1, the reaction is carried out at 90° C. for 60 min, and then 9 v / v% ammonia water is added, the volume ratio of ammonia water to the reaction solution is 0.15:1, the mixture is mixed and stirred evenly, and neutralized. After completion, supercritical CO2 fluid extraction is performed, specifically, extraction is carried out at 25 MPa for 30 min to obtain furosemide.

[0063] Comparative Example 3

[0064] The difference from Example 1 is that thionyl chloride is not added, and the other steps are consistent with Example 1.

[0065] The preparation method of furosemide in this comparative example comprises the following specific preparation steps:

[0066] (1) adding 2-amino-4-chlorobenzoic acid and 2-chloromethylfuran in a molar ratio of 1:1.3 to a deep eutectic solvent, wherein the material-liquid ratio of 2-amino-4-chlorobenzoic acid to the deep eutectic solvent is 1:7 mg / mL, and performing a microwave heating reaction, specifically heating at 250 W and 90° C. for 45 min to obtain a reaction solution;

[0067] The deep eutectic solvent is composed of choline chloride and 1,3-propylene glycol in a molar ratio of 1:5;

[0068] The preparation method of the deep eutectic solvent comprises: mixing choline chloride and 1,3-propylene glycol, heating and stirring at 50° C., adding water and stirring evenly, cooling to room temperature, and obtaining a colorless transparent liquid, namely the deep eutectic solvent;

[0069] (2) Chlorosulfonic acid was added to the reaction solution, the molar ratio of chlorosulfonic acid to 2-amino-4-chlorobenzoic acid was 1.7:1, and the reaction was carried out at 90° C. for 60 min. Then, 9 v / v% ammonia water was added, and the volume ratio of ammonia water to the reaction solution was 0.15:1. The mixture was mixed and stirred evenly, and neutralized. After completion, supercritical CO2 fluid extraction was performed, specifically, extraction was carried out at 25 MPa for 30 min to obtain furosemide.

[0070] Comparative Example 4

[0071] The difference from Example 1 is that supercritical CO2 fluid extraction is replaced by conventional crystallization purification, and the rest is consistent with Example 1.

[0072] The preparation method of furosemide in this comparative example comprises the following specific preparation steps:

[0073] (1) adding 2-amino-4-chlorobenzoic acid and 2-chloromethylfuran in a molar ratio of 1:1.3 to a deep eutectic solvent, wherein the material-liquid ratio of 2-amino-4-chlorobenzoic acid to the deep eutectic solvent is 1:7 mg / mL, and performing a microwave heating reaction, specifically heating at 250 W and 90° C. for 45 min to obtain a reaction solution;

[0074] The deep eutectic solvent is composed of choline chloride and 1,3-propylene glycol in a molar ratio of 1:5;

[0075] The preparation method of the deep eutectic solvent comprises: mixing choline chloride and 1,3-propylene glycol, heating and stirring at 50° C., adding water and stirring evenly, cooling to room temperature, and obtaining a colorless transparent liquid, namely the deep eutectic solvent;

[0076] (2) adding chlorosulfonic acid and thionyl chloride in a molar ratio of 1.7:0.7 to the reaction solution in sequence, and the molar ratio of chlorosulfonic acid to 2-amino-4-chlorobenzoic acid is 1.7:1, reacting at 90° C. for 60 min, then adding 9 v / v% ammonia water, the volume ratio of ammonia water to the reaction solution is 0.15:1, mixing and stirring evenly, neutralizing, and precipitating crystals to obtain a crude furosemide product;

[0077] (3) The crude furosemide is added to a saturated sodium bicarbonate solution, the amount of which is 4 times the quality of the crude furosemide, and the temperature is raised to 80° C., and activated carbon is added for decolorization for 1 hour, the amount of which is 0.2 times the quality of the crude furosemide, and then the mixture is neutralized, crystallized, and centrifuged to obtain the furosemide product.

[0078] Test Case

[0079] The yield, purity and impurity A content of the furosemide products of Examples 1-3 and Comparative Examples 1-4 were calculated and counted;

[0080] The purity was determined by high performance liquid chromatography (HPLC): chromatographic column: MegresTM C18 (Hanbang Technology); eluent: water / tetrahydrofuran / glacial acetic acid = 70 / 30 / 1; flow rate: 1.0 mL / min; detection wavelength: 272 nm UV.

[0081] The structural formula of impurity A is:

[0082]

[0083] The results are shown in Table 1.

[0084] Table 1

[0085]

[0086]

[0087] As can be seen from Table 1, the furosemide obtained by the synthesis method of Examples 1-3 of the present invention has a high yield and a purity of up to 99.97%, and the content of impurity A is at most 0.02%.

[0088] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing furosemide, characterized in that: The specific preparation steps include: (1) adding 2-amino-4-chlorobenzoic acid and 2-chloromethylfuran to a deep eutectic solvent and performing microwave heating to react to obtain a reaction solution; (2) Chlorosulfonic acid and thionyl chloride are sequentially added to the reaction solution for reaction, and aqueous ammonia is added for neutralization. After the reaction is completed, supercritical CO2 fluid extraction is performed to obtain furosemide.

2. The method for preparing furosemide according to claim 1, characterized in that: In step (1), the deep eutectic solvent is composed of a hydrogen bond acceptor and a hydrogen bond donor in a molar ratio of 1:4-6, the hydrogen bond acceptor is choline chloride, and the hydrogen bond donor is any one of 1,3-propylene glycol, glycolic acid or polyethylene glycol.

3. The method for preparing furosemide according to claim 2, characterized in that: The preparation method of the deep eutectic solvent comprises: mixing a hydrogen bond donor and a hydrogen bond acceptor, heating and stirring at 40-60° C., adding water and stirring evenly, and cooling to room temperature to obtain a colorless transparent liquid, namely the deep eutectic solvent.

4. The method for preparing furosemide according to claim 1, characterized in that: In step (1), the molar ratio of 2-amino-4-chlorobenzoic acid to 2-chloromethylfuran is 1:1.2-1.

5.

5. The method for preparing furosemide according to claim 1, characterized in that: In step (1), the solid-liquid ratio of the 2-amino-4-chlorobenzoic acid to the deep eutectic solvent is 1:6-8 mg / mL.

6. The method for preparing furosemide according to claim 1, characterized in that: In step (1), the microwave heating reaction has a power of 200-300 W, a temperature of 80-100° C., and a time of 30-60 min.

7. The method for preparing furosemide according to claim 1, characterized in that: In step (2), the molar ratio of chlorosulfonic acid to thionyl chloride and 2-amino-4-chlorobenzoic acid is 1.5-1.8:0.6-0.8:

1.

8. The method for preparing furosemide according to claim 1, characterized in that: In step (2), the reaction temperature is 80-100° C. and the reaction time is 40-80 min.

9. The method for preparing furosemide according to claim 1, characterized in that: In step (2), the concentration of the ammonia water is 8-10 v / v%; the volume ratio of the ammonia water to the reaction solution is 0.1-0.2:

1.

10. The method for preparing furosemide according to claim 1, characterized in that: In step (2), the supercritical CO2 fluid extraction is performed at 20-30 MPa for 20-40 min.

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