A process for the preparation of bumetanide

Abstract

The present application relates to a preparation method of bumetanide, and belongs to the technical field of pharmaceutical chemistry. The present application takes 4-chlorobromobenzene as a starting material, and is subjected to sulfonylation, nitration, ammonolysis, substitution, cyanation, nitro reduction, alkylation, and finally acidification to obtain bumetanide. In the synthetic route of the present application, the carboxyl group does not need to be protected, but a cyano group which does not need functional group protection is introduced, and finally the cyano group is directly hydrolyzed into a carboxyl group to obtain bumetanide. The present application has few side reactions, the intermediates can be precipitated in water, greatly reducing the solvent cost, being easier to purify, the quality of the intermediates and bumetanide being easy to control, reducing the production risk, and being more beneficial to industrial mass production.

Description

Technical Field

[0001] This invention relates to the technical field of medicinal chemistry, specifically to a method for preparing bumetanide. Background Technology

[0002] Bumetanide, chemically known as 5-n-butylamino-4-phenoxy-3-aminosulfonylbenzoic acid, is an organic compound with the chemical formula C. 17 H 20 N2O5S is a white crystalline powder, soluble in water, alcohol, and alkaline solutions, but sparingly soluble in acidic solutions. It is primarily used as a diuretic. Bumetanide can be used for various edematous diseases, hypertension, prevention of acute renal failure, hypercalcemia and hyperkalemia, dilutional hyponatremia, excessive secretion of antidiuretic hormone, acute drug poisoning, and cases unresponsive to furosemide. Therefore, it can be used in multiple departments, including cardiology, nephrology, hepatology / infectious disease, gastroenterology, respiratory medicine, neurology / surgery, oncology, endocrinology, emergency medicine / ICU, etc.

[0003] Bumetanib effectively reduces cardiopulmonary load and is a commonly used drug for treating various refractory edema and acute pulmonary edema, especially for heart failure. Loop diuretics can reduce effective circulating blood volume, lower capillary wedge pressure, reduce cardiac preload, and improve patients' clinical symptoms in a short time. Bumetanib has the characteristic of rapid onset of action. Furosemide takes 30-45 minutes to reach peak concentration, torasemide takes 1-2 hours, while bumetanib only takes 15-30 minutes. Its rapid onset of action buys valuable time for the rescue of patients with acute heart failure, acute renal failure, and acute cerebral edema.

[0004] Bumetanib injection has a wider range of applications and fewer side effects than torasemide, and its efficacy is also superior. Therefore, bumetanib injection is more potent and safer. Its significant pharmacodynamic characteristics of "rapid diuresis and immediate effect" have led to its clinical use in various refractory edema and heart failure patients, especially suitable for patients with acute heart failure and acute and chronic renal failure. Bumetanib has a unique nephroprotective effect. In addition to increasing renal perfusion and protecting renal function in the treatment of heart failure, indirectly and effectively reducing cardiopulmonary load, it has also been widely used in the treatment of renal edema, such as edema in acute and chronic glomerulonephritis, and acute and chronic renal failure. Clinical studies have shown that it can inhibit the activity of prostaglandin-degrading enzymes, increasing prostaglandin E2 levels, thereby having a vasodilatory effect. This dilation of renal vessels, reduction of renal vascular resistance, and increase in renal blood flow, especially deep renal cortical blood flow, are important factors in the diuretic effect of bumetanib and form the theoretical basis for its use in the prevention of acute renal failure.

[0005] Bumetanib has proven clinical efficacy and high safety, and is included in the national medical insurance catalog, indicating a promising market prospect. However, relying solely on API manufacturers for formulation development presents significant limitations, necessitating the development of in-house synthesis processes to address API supply issues.

[0006] The existing routes for synthesizing bumetanide are mainly as follows:

[0007]

[0008] All of the above routes use the key intermediate 4-chloro-3-chlorosulfonyl-5-nitrobenzoic acid. Routes one and three involve initial protection of the carboxyl group on the benzene ring, requiring subsequent protection and deprotection of the carboxyl group. This results in longer routes, lower atom utilization, poor reaction specificity, and numerous side reactions, increasing the difficulty of purifying intermediates and finished products, as well as impurity research. While route two does not protect the carboxyl group, shortening the reaction route, the coexistence of the carboxylic acid and amino group in the molecular structure leads to poor intermediate solubility, increasing the solvent volume required for subsequent reactions and causing more side reactions. Furthermore, the use of n-butanol / Lewis acid in the reaction results in a reaction time exceeding 60 hours, significantly increasing production time and costs.

[0009] Therefore, it is necessary to find a suitable route for bumetanide to solve the above problems. Summary of the Invention

[0010] In view of the above-mentioned shortcomings of the prior art, the present invention provides a method for preparing bumetanide.

[0011] The technical solution of the present invention is as follows:

[0012] A method for preparing bumetanide, the preparation route is as follows:

[0013] ;

[0014] The synthesis steps are as follows:

[0015] (1) 4-Chlorobromobenzene was used as a solvent to prepare intermediate 1 by targeted substitution;

[0016] (2) Intermediate 1 is prepared by nitration of intermediate 2 by adding nitric acid or fuming nitric acid dropwise with an appropriate amount of sulfuric acid as solvent;

[0017] (3) Intermediate 2 reacts in ammonia water to form intermediate 3;

[0018] (4) Intermediate 3 is added to a system of phenol, base and solvent to generate intermediate 4;

[0019] (5) Intermediate 4 reacts with cuprous cyanide in a solvent to generate intermediate 5;

[0020] (6) Intermediate 5 is selectively reduced by hydrogenation in a solvent under normal or high pressure to generate intermediate 6;

[0021] (7) Intermediate 6 and n-butyraldehyde first form a Schiff base in a solvent, and then are selectively reduced with sodium borohydride to generate intermediate 7;

[0022] (8) Intermediate 7 is hydrolyzed in an alkaline aqueous solution to generate bumetanide carboxylate, which is then acidified to generate bumetanide.

[0023] Preferably, the preparation method of step (1) is as follows: add chlorosulfonic acid to the reactor, then add 4-chlorobromobenzene, and control the temperature of the reaction solution to <60℃; after the addition is completed, raise the temperature to a certain level for reaction; after the raw materials have reacted, cool down to 20~30℃; add the reaction solution to ice water in batches, control the temperature of the reaction solution to <10℃, stir after the addition is completed, and filter; dissolve the filter cake in ethyl acetate, wash the organic phase with water, concentrate until solid precipitates, cool down to 0~5℃ to crystallize, and dry to obtain intermediate 1.

[0024] Preferably, the mass ratio of 4-chlorobromobenzene to chlorosulfonic acid is 1:2 to 10, more preferably 1:3.

[0025] Preferably, the temperature in step (1) is 60~130℃, more preferably 100~110℃.

[0026] Preferably, the preparation method of step (2) is as follows: sulfuric acid is added to the reactor, then intermediate 1 is added, the reaction temperature is controlled at <40°C, after the addition is completed, the temperature is raised to a certain level, fuming nitric acid is added dropwise, the reaction temperature is controlled at <60°C, after the addition is completed, the temperature is kept warm and the reaction continues until intermediate 1 is completely reacted, the temperature is lowered to 20~30°C, the reaction solution is added to ice water, the reaction temperature is controlled at <10°C, after the addition is completed, the mixture is stirred to precipitate crystals, filtered, and washed with water to obtain intermediate 2 wet product.

[0027] Preferably, the mass ratio of intermediate 1 to sulfuric acid is 1:2 to 10, more preferably 1:4; the molar ratio of intermediate 1 to nitric acid is 1:1 to 1.5, more preferably 1:1.2.

[0028] Preferably, the temperature in step (2) is 30~100℃, more preferably 40~60℃.

[0029] Preferably, the preparation method of step (3) is as follows: add ammonia water to the reactor, cool down to a certain temperature, add wet intermediate 2, control the temperature of the reaction solution <10℃, filter after the reaction is completed, wash the filter cake with water until neutral, and dry to obtain intermediate 3.

[0030] Preferably, the mass ratio of the wet intermediate 2 to ammonia is 1:2 to 10, more preferably 1:4.

[0031] Preferably, the temperature in step (3) is 30~100℃, more preferably 40~60℃.

[0032] Preferably, the preparation method of step (4) is as follows: add solvent to the reactor, mix the original and sodium hydroxide in the solvent under nitrogen protection; then add intermediate 3, raise the temperature to a certain temperature for reaction; after the reaction is completed, lower the temperature to 40°C, filter, wash the filter cake with water, filter, dry the filter cake and recrystallize it with ethyl acetate to obtain intermediate 4.

[0033] Preferably, the molar ratio of intermediate 3 to phenol is 1:1 to 1.5, more preferably 1:1.1; the molar ratio of intermediate 3 to base is 1:1 to 1:1.5, more preferably 1:1.2; the base is selected from sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide or cesium carbonate, preferably sodium hydroxide; the solvent is selected from methanol, ethanol, isopropanol, N,N-dimethylformamide or N-methylpyrrolidone, preferably ethanol.

[0034] Preferably, the temperature in step (4) is 20~100℃, more preferably 75~85℃.

[0035] Preferably, the preparation method of step (5) is as follows: solvent and intermediate 4 are added sequentially to the reaction vessel, and then cuprous hydride is added in batches; after the addition is completed, the temperature is raised to a certain temperature for reaction; after the reaction is completed, the temperature is lowered to 20~30°C, filtered, the filtrate is added to water and stirred to precipitate crystals, and filtered; then the filter cake is added to water, ammonia is added, and the mixture is washed at 20~30°C and filtered; the filter cake is recrystallized with ethyl acetate to obtain intermediate 5.

[0036] Preferably, the molar ratio of intermediate 4 to cuprous cyanide is 1:1.0~2.0, more preferably 1:1.5; the reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone, more preferably N,N-dimethylformamide.

[0037] Preferably, the temperature in step (5) is 100~160℃, more preferably 125~135℃.

[0038] Preferably, the preparation method of step (6) is as follows: solvent, intermediate 5 and 5% Pd / C are added to the reactor in sequence, hydrogen is replaced and the reaction pressure and reaction temperature are controlled. After the reaction is completed, the reaction liquid containing intermediate 6 is filtered and the next step is carried out directly without further treatment.

[0039] Preferably, in step (6), the reaction solvent is selected from methanol or ethanol, preferably methanol; the reaction pressure is 0.1~4.0MPa, preferably 1.0MPa; the reaction temperature is 20~60℃, preferably 35~45℃; and the mass ratio of intermediate 5 to reaction solvent is 1:2~10, preferably 1:4.

[0040] Preferably, the preparation method of step (7) is as follows: n-Butyraldehyde is added dropwise to the reaction solution containing intermediate 6, and the temperature is controlled at 20~30℃ for reaction; after the reaction is completed, the temperature is lowered to 0~10℃, sodium borohydride is slowly added, and the temperature is controlled at 0~10℃. After the addition is completed, the reaction continues until the raw materials are completely reacted. Then, the pH of the reaction solution is adjusted to 1~2 with 10% hydrochloric acid, and then the pH is adjusted to 7~8 with saturated sodium bicarbonate aqueous solution. The solution is concentrated, the concentrate is washed with water, filtered, and intermediate 7 wet product is obtained.

[0041] Preferably, in step (7), the molar ratio of n-butyraldehyde to intermediate 6 is 1~1.5:1, preferably 1.2:1; the molar ratio of sodium borohydride to intermediate 6 is 0.25~1:1, preferably 0.4:1.

[0042] Preferably, the preparation method of step (8) is as follows: In a reactor, water and alkali are added, the temperature is lowered to 20~30℃, intermediate 7 wet product is added, and the temperature is raised to a certain temperature for reaction. After the reaction is completed, the temperature is lowered to 10~20℃ to crystallize, filtered, and the filter cake is washed with water to pH=7~8. Then the filter cake is added to water, and the pH is adjusted to 5~6 with 10% hydrochloric acid or acetic acid. After stirring, filtering, washing with water, and drying, bumetanide crude product is obtained.

[0043] Preferably, step (8) further includes a purification step of bumetanide: mixing crude bumetanide with anhydrous ethanol, heating to 60~70℃ to dissolve, decolorizing with activated carbon, cooling the decolorized solution to 0~5℃ to crystallize, filtering, and drying to obtain bumetanide.

[0044] Preferably, in step (8), the alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, preferably sodium hydroxide; the mass ratio of wet intermediate 7 to alkali is 1:0.3~1, preferably 1:0.5.

[0045] Preferably, in step (8), the reaction temperature is 60~120℃, more preferably 95~100℃.

[0046] The beneficial effects of this invention are as follows:

[0047] Based on the original research route, this invention uses 4-bromochlorobenzene as the starting material, and performs chlorosulfonation and nitration reactions at the beginning of the route, converting bromine to cyano, and finally hydrolyzing the cyano to obtain bumetanide. In this synthetic route, there is no need to protect the carboxyl group; instead, a cyano group without functional group protection is introduced, and the cyano is directly hydrolyzed to the carboxyl group to obtain bumetanide. This invention has fewer side reactions, the intermediates can precipitate in water, greatly reducing solvent costs and making purification easier. The quality of the intermediates and bumetanide is easier to control, reducing production risks. This route is an eight-step synthesis. After process optimization, fewer types of solvents (ethyl acetate, methanol, DMF, and ethanol) are used, and they are inexpensive and readily available. The reaction conversion rate of each step is high, the reaction time is short, the post-processing of the production process is simple, solvent recovery and wastewater treatment are easy, solvent consumption and energy costs are reduced, and it is more conducive to large-scale industrial production. Attached Figure Description

[0048] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0049] Figure 1 This is the HNMR spectrum of bumetanide intermediate 1 prepared in Example 1 of the present invention.

[0050] Figure 2 This is the MS spectrum of bumetanide intermediate 1 prepared in Example 1 of the present invention.

[0051] Figure 3 This is the HPLC chromatogram of bumetanide prepared in Example 9 of this invention.

[0052] Figure 4 This is the HNMR spectrum of bumetanide prepared in Example 9 of this invention.

[0053] Figure 5 This is the MS (+) spectrum of bumetanide prepared in Example 9 of the present invention.

[0054] Figure 6 This is the MS (-) spectrum of bumetanide prepared in Example 9 of this invention. Detailed Implementation

[0055] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions of the embodiments of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this invention.

[0056] Example 1

[0057] Preparation of 5-bromo-2-chlorobenzenesulfonyl chloride (intermediate 1)

[0058] In a dry 100L reactor, 57.3 kg of chlorosulfonic acid was added, followed by 19.1 kg (1000 mol) of 4-chlorobromobenzene in portions. The temperature was controlled below 60℃. After stabilizing for 1 hour, the temperature was raised to 100-110℃ and reacted for 3 hours. TLC analysis (petroleum ether:ethyl acetate / 5:1) confirmed the reaction was complete. The temperature was then lowered to 20-30℃, and the reaction solution was added in portions to a 2000L reactor containing 600 kg of pre-cooled ice water. The temperature was controlled below 10℃, and the mixture was stirred for 2 hours after addition. The mixture was filtered, and the filter cake was dissolved in 80 kg of ethyl acetate, washed twice with 100 kg of water, dried with 5 kg of anhydrous sodium sulfate, filtered, and concentrated in a 200L reactor until a solid precipitated. The mixture was then cooled to 0-5℃ for 2 hours to crystallize, and dried under vacuum at 40-50℃ to obtain a yellow solid intermediate 1. 22.76 kg, yield 78.5%, HPLC purity 99.78%, melting point 66.5–67.3 °C. See detailed HNMR spectrum. Figure 1 For MS spectra, please see Figure 2 .

[0059] Example 2

[0060] Preparation of 5-bromo-2-chloro-3-nitrobenzenesulfonyl chloride (intermediate 2)

[0061] In a dry 200L reactor, 88kg of sulfuric acid was added, followed by 122.00kg (75.86mol) of intermediate in batches, with the temperature controlled below 40℃. After stabilizing for 1 hour, the temperature was raised to 40℃, and 6.37kg (91.03mol) of fuming nitric acid was added dropwise, with the temperature controlled below 60℃. After the addition was complete, the reaction was carried out for 2 hours. TLC analysis (petroleum ether:ethyl acetate / 5:1) confirmed that the reactants had reacted completely. The temperature was then lowered to 20-30℃, and the reaction solution was added in batches to a 2000L reactor containing 600kg of pre-cooled ice water, with the temperature controlled below 10℃. After the addition was complete, the mixture was stirred for 1 hour, filtered, and washed with water to obtain a pale yellow solid. The filter cake weighed 43.20kg and proceeded directly to the next step of the reaction.

[0062] Example 3

[0063] Preparation of 5-bromo-2-chloro-3-nitrobenzenesulfonamide (intermediate 3)

[0064] 172 kg of industrial ammonia was added to a 500 L reactor and cooled to 0-5 °C. 43.00 kg of wet intermediate 2 was added in batches, with the temperature controlled below 10 °C. After the addition was complete, the reaction was carried out for 1 hour. TLC analysis (petroleum ether:ethyl acetate / 3:1) showed that intermediate 2 was completely consumed. The mixture was filtered, washed with water until neutral, and dried in a forced-air oven at 50-60 °C for 6 hours to obtain 20.51 kg of pale yellow solid intermediate 3, with a yield of 85.56% and an HPLC purity of 99.92%.

[0065] Example 4

[0066] Preparation of 5-bromo-2-phenoxy-3-nitrobenzenesulfonamide (intermediate 4)

[0067] In a 200L reactor, 80kg of anhydrous ethanol was added. Under nitrogen protection, 6.55kg (69.62mol) of phenol and 3.04kg (75.95mol) of sodium hydroxide were mixed in a solvent for 1 hour. Then, 20.00kg (63.29mol) of intermediate 3 was added. The mixture was heated to 75-85℃ and reacted for 3 hours. TLC analysis (petroleum ether:ethyl acetate / 3:1) showed that intermediate 3 was completely consumed. The mixture was then cooled to 40℃, filtered, and the filtrate was concentrated into a paste in a 200L reactor. 100kg of water was added and the mixture was washed for 2 hours. The paste was then filtered, washed with water, and dried by forced air for 6 hours. The paste was then dissolved in 60kg of ethyl acetate at 60-70℃, decolorized with activated carbon, filtered, and cooled to 0-10℃ to crystallize for 1-2 hours. After filtration, the paste was dried under vacuum at 50-60℃ for 6 hours to obtain 20.68kg of pale yellow solid intermediate 4, with a yield of 87.62% and an HPLC purity of 99.89%.

[0068] Example 5

[0069] Preparation of 5-cyano-2-phenoxy-3-nitrobenzenesulfonamide (intermediate 5)

[0070] In a 200L reactor, 80kg of N,N-dimethylformamide, 20.00kg (53.63mol) of intermediate 4 were added sequentially, followed by 7.20kg (80.43mol) of cuprous cyanide in portions. After the addition was complete, the temperature was raised to 125-135℃ and the reaction was carried out for 14 hours. TLC was used for detection (petroleum ether:ethyl acetate / 3:1). After the reaction of intermediate 4 was completed, the temperature was lowered to 20-30℃, and the mixture was filtered. The filtrate was then added dropwise to 600kg of water in the reaction solution, stirred for 2 hours, filtered again, and 43.22kg of wet filter cake was weighed. The wet filter cake was then added to 216kg of water, and 20kg of industrial ammonia was added. The mixture was washed at 20-30℃ for 1-2 hours, filtered, washed with water, and dried in a forced-air environment at 50-60℃ for 6 hours. The mixture was then dissolved in 40kg of ethyl acetate at 60-70℃, filtered, and the filtrate was cooled to -5-0℃ to crystallize for 2 hours. After filtration, the mixture was dried under vacuum at 50-60℃ for 6 hours to obtain a pale yellow solid intermediate 5. 14.24 kg, yield 83.21%, HPLC purity 99.80%.

[0071] Example 6

[0072] Preparation of 5-cyano-2-phenoxy-3-aminobenzenesulfonamide (intermediate 6)

[0073] In a 500L hydrogenation reactor, 56kg of methanol, 14.00kg (43.89mol) of intermediate 5 and 186g (0.088mol) of 5% Pd / C were added sequentially. After vacuuming and two hydrogen exchanges, the pressure was increased to 1.0MPa and the reaction was carried out at 35~45℃ for 7 hours. TLC analysis (petroleum ether: ethyl acetate / 3:1) showed that intermediate 5 had reacted completely. The pressure was released and the reaction solution was filtered through diatomaceous earth to obtain a brown methanol reaction solution of intermediate 6, which was then directly proceeded to the next step.

[0074] Example 7

[0075] Preparation of 5-cyano-2-phenoxy-3-n-butylaminobenzenesulfonamide (intermediate 7)

[0076] Transfer the methanol solution of intermediate 6 to a 200L reactor, add 3.79kg (52.67mol) of n-butyraldehyde dropwise, maintain the temperature at 20-30℃, and react for 2 hours after the addition is complete. TLC detection (petroleum ether:ethyl acetate / 1:1) indicates that intermediate 6 has reacted completely. Cool down to 0-10℃, slowly add 664g (17.56mol) of sodium borohydride, maintain the temperature at 0-10℃, and react for 2 hours after the addition is complete. TLC detection (petroleum ether:ethyl acetate / 1:1) indicates that the intermediate has been consumed completely. Adjust the pH of the reaction solution to 1-2 with 10% hydrochloric acid, stir for 2 hours, then add saturated sodium bicarbonate aqueous solution to adjust the pH to 7-8, concentrate to a paste, add 70kg of water and wash for 2 hours, filter, wash with water to obtain a brown solid, weigh 27.58kg wet, and proceed directly to the next step.

[0077] Example 8

[0078] Preparation of bumetanide

[0079] In a 200L reactor, 110kg of water and 13.50kg of sodium hydroxide were added, and the temperature was lowered to 20-30℃. 27.00kg of wet intermediate 7 was added in batches. After the addition was complete, the temperature was raised to 95-100℃ and the reaction was carried out for 16 hours. TLC analysis (petroleum ether:ethyl acetate / 1:1) indicated the intermediate 7 had reacted completely. The reaction solution was then cooled to 10-20℃ and kept at this temperature for 2 hours. After filtration, the solution was washed with water until the pH reached 7-8. 23.44kg of the filter cake was weighed and added back to 94kg of water. The pH was adjusted to 5-6 with 10% hydrochloric acid, and the mixture was stirred for 2 hours. After filtration, washing with water, and drying, 12.38kg of crude bumetanide (brown-yellow solid) was obtained. The HPLC purity was 99.35%, and the three-step yield was 77.49%.

[0080] Example 9

[0081] Refined bumetanide

[0082] In a 100L reactor, 12.00 kg of crude product and 36 kg of anhydrous ethanol were mixed and dissolved at 60-70℃. 600 g of activated carbon was added and stirred for decolorization for 1 hour. After hot filtration, the product was stirred and decolorized again with 600 g of activated carbon for 1 hour. The mixture was then filtered into a 100L reactor and cooled to 0-5℃ for crystallization for 2 hours. After filtration, the product was washed with anhydrous ethanol and dried under vacuum at 50-60℃ to obtain 10.23 kg of white bumetanide powder, with a yield of 85.25% and a purity of 99.97%.

[0083] Examples 1-8 consist of eight steps of reaction followed by a single-step purification process, with an overall molar yield of 28.10%.

[0084] For detailed HPLC chromatogram of bumetanide, please refer to [link / reference]. Figure 3 The test results are as follows:

[0085] Table 1 - HPLC Detection Results of Bumetanide

[0086] Serial Number Retention time (minutes) area purity 1 2.909 3494 0.019 2 8.630 1251 0.007 3 14.304 18135185 99.974

[0087] For detailed bumetanide HNMR spectra, please refer to Figure 4 .

[0088] 1H NMR (400 MHz, DMSO) δ 13.18(br, 1H), 7.70 (d, 1H), 7.42 (d, 1H), 7.35(s, 2H), 7.27(t, 2H), 7.01(t, 1H), 6.84(d, 2H), 5.06(t, 1H), 3.06(m, 2H), 1.37(m, 2H), 1.11(m, 2H), 0.78(t, 3H).

[0089] bumetanide positive ion mass spectra are shown below Figure 5 LC-MS(M+1): 365.1.

[0090] Bumetanide negative ion mass spectrometry Figure 6 LC-MS(M-1): 363.1.

[0091] Although the present invention has been described in detail with reference to the accompanying drawings and preferred embodiments, the invention is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of the invention by those skilled in the art without departing from the spirit and essence of the invention, and such modifications or substitutions should all be within the scope of the invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the invention should also be covered within the protection scope of the invention. Therefore, the protection scope of the invention should be determined by the scope defined in the claims.

Claims

1. A method for preparing bumetanide, characterized in that, The preparation route is as follows: ； The synthesis steps are as follows: (1) 4-Chlorobromobenzene was used as a solvent to prepare intermediate 1 by targeted substitution; (2) Intermediate 1 is prepared by nitration of intermediate 2 by adding nitric acid or fuming nitric acid dropwise with an appropriate amount of sulfuric acid as solvent; (3) Intermediate 2 reacts in ammonia water to form intermediate 3; (4) Intermediate 3 is added to a system of phenol, base and solvent to generate intermediate 4; (5) Intermediate 4 reacts with cuprous cyanide in a solvent to generate intermediate 5; (6) Intermediate 5 is selectively reduced by hydrogenation in a solvent under normal or high pressure to generate intermediate 6; (7) Intermediate 6 and n-butyraldehyde first form a Schiff base in a solvent, and then are selectively reduced with sodium borohydride to generate intermediate 7; (8) Intermediate 7 is hydrolyzed in an alkaline aqueous solution to generate bumetanide carboxylate, which is then acidified to generate bumetanide; The preparation method of step (4) is as follows: add solvent to the reactor, mix phenol and sodium hydroxide in the solvent under nitrogen protection, then add intermediate 3, raise the temperature to a certain temperature for reaction, lower the temperature to 40°C after the reaction is completed, filter, wash the filter cake with water, filter, dry the filter cake and recrystallize it with ethyl acetate to obtain intermediate 4.

2. The method for preparing bumetanide as described in claim 1, characterized in that, The preparation method of step (1) is as follows: add chlorosulfonic acid to the reactor, then add 4-chlorobromobenzene, and control the temperature of the reaction solution to <60℃; after the addition is completed, raise the temperature to a certain level for reaction; after the raw materials have reacted, cool down to 20~30℃; add the reaction solution to ice water in batches, control the temperature of the reaction solution to <10℃, stir after the addition is completed, and filter; dissolve the filter cake in ethyl acetate, wash the organic phase with water, concentrate until solid precipitates, cool down to 0~5℃ to crystallize, and dry to obtain intermediate 1.

3. The method for preparing bumetanide as described in claim 1, characterized in that, The preparation method of step (2) is as follows: sulfuric acid is added to the reactor, then intermediate 1 is added, the reaction temperature is controlled at <40°C, after the addition is completed, the temperature is raised to a certain level, fuming nitric acid is added dropwise, the reaction temperature is controlled at <60°C, after the addition is completed, the temperature is kept warm and the reaction continues until intermediate 1 is completely reacted, the temperature is lowered to 20~30°C, the reaction solution is added to ice water, the reaction temperature is controlled at <10°C, after the addition is completed, the mixture is stirred to precipitate crystals, filtered, and washed with water to obtain intermediate 2 wet product.

4. The method for preparing bumetanide as described in claim 1, characterized in that, The preparation method of step (3) is as follows: add ammonia water to the reactor, cool down to a certain temperature, add wet intermediate 2, control the temperature of the reaction solution <10℃, filter after the reaction is completed, wash the filter cake with water until neutral, and dry to obtain intermediate 3.

5. The method for preparing bumetanide as described in claim 1, characterized in that, The preparation method of step (5) is as follows: add solvent and intermediate 4 to the reaction vessel in sequence, and then add cuprous hydride in batches; after the addition is completed, raise the temperature to a certain temperature for reaction; after the reaction is completed, cool down to 20~30℃, filter, add the filtrate to water and stir to precipitate crystals, filter; then add the filter cake to water, add ammonia water, wash at 20~30℃, filter; recrystallize the filter cake with ethyl acetate to obtain intermediate 5.

6. The method for preparing bumetanide as described in claim 1, characterized in that, The preparation method of step (6) is as follows: solvent, intermediate 5 and 5% Pd / C are added to the reactor in sequence, hydrogen is replaced and the reaction pressure and reaction temperature are controlled. After the reaction is completed, the reaction liquid containing intermediate 6 is obtained by filtration. No further treatment is required to proceed to the next step.

7. The method for preparing bumetanide as described in claim 1, characterized in that, The preparation method of step (7) is as follows: n-Butyraldehyde is added dropwise to the reaction solution containing intermediate 6, and the temperature is controlled at 20~30℃ for reaction; after the reaction is completed, the temperature is lowered to 0~10℃, sodium borohydride is slowly added, and the temperature is controlled at 0~10℃. After the addition is completed, the reaction continues until the raw materials are completely reacted. Then, the pH of the reaction solution is adjusted to 1~2 with 10% hydrochloric acid, and then the pH is adjusted to 7~8 with saturated sodium bicarbonate aqueous solution. The solution is concentrated, the concentrate is washed with water, filtered, and intermediate 7 wet product is obtained.

8. The method for preparing bumetanide as described in claim 1, characterized in that, The preparation method of step (8) is as follows: In a reactor, water and alkali are added, the temperature is lowered to 20~30℃, intermediate 7 wet product is added, and the temperature is raised to a certain temperature for reaction. After the reaction is completed, the temperature is lowered to 10~20℃ to crystallize, filtered, and the filter cake is washed with water to pH=7~8. Then the filter cake is added to water, and the pH is adjusted to 5~6 with 10% hydrochloric acid or acetic acid. After stirring, filtering, washing with water, and drying, bumetanide crude product is obtained.

9. The method for preparing bumetanide as described in claim 1, characterized in that, Step (8) also includes a purification step of bumetanide: the crude bumetanide is mixed with anhydrous ethanol, heated to 60-70°C to dissolve, decolorized with activated carbon, the decolorized solution is cooled to 0-5°C to crystallize, filtered, and dried to obtain bumetanide.

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