A process for the preparation of bumetanide

Abstract

The application provides a preparation method of bumetanide, taking p-chlorobenzoic acid as a starting material, performing chlorosulfonation, nitration, and ammonolysis to obtain a key intermediate of 3-(N-(tert-butyl) sulfamoyl)-4-chloro-5-nitrobenzoic acid, then performing phenoxylation, nitro reduction, n-butylation, and tert-butyl removal, and finally obtaining the bumetanide. Compared with the synthesis process of the prior art, the method has less side reactions, low cost, high yield, high safety, and is beneficial to industrial production.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for preparing bumetanide. Background Technology

[0002] Bumetanide is a potent myelodiuretic, with a diuretic effect 40 to 60 times that of furosemide (Lasix). Clinically, it is mainly used for various types of cardiac, hepatic, renal, and nutritional edema. It is also used for patients with drug poisoning requiring forced diuresis and for patients with edema (including venous obstructive edema) and effusions in body cavities such as the pleural, abdominal, and pericardial cavities. It is particularly suitable for patients with acute and chronic renal failure who require diuresis and antihypertensive treatment. The chemical name of bumetanide is 5-n-butylamino-4-phenoxy-3-aminosulfonylbenzoic acid, and its English name is 3-(aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid.

[0003] All reported synthetic routes for bumetanide use the key intermediate 4-chloro-5-chlorosulfonyl-3-nitrobenzoic acid (synthesized from p-chlorobenzoic acid via chlorosulfonation and nitration) as the starting material. The differences lie in ① whether carboxyl protection and deprotection processes are used; ② different carboxyl protecting groups; and ③ butylation is achieved by reducing amination with n-butyraldehyde, condensing with n-butanol, or reducing with butyryl chloride and amino groups.

[0004] The route reported in US Patent 3991097A employs a carboxyl protection and deprotection process. In the fourth step, butyryl chloride is substituted with an amino group, followed by reduction of the carbonyl group with boron trifluoride or sodium borohydride to obtain a n-butyl group. The first step uses acid catalysis, which easily generates toxic sulfonate esters; the fourth step uses toxic acyl chlorides; and the fifth step uses boron trifluoride, posing safety risks in production. The reaction process is complex, cumbersome, and lacks controllability, making it unsuitable for industrial production. The reaction route is as follows:

[0005]

[0006] The route reported in US patent application US2008262086A1 still employs a carboxyl protection and deprotection process, replacing the methyl group with n-butyl to protect the carboxyl group. The fourth step, butyryl chloride substitution, is also changed to n-butyraldehyde reductive amination. The second step uses a hydrogenation process to reduce the nitro group; this reaction is hazardous, and the catalyst palladium on carbon is relatively expensive, requiring sophisticated reaction conditions and equipment. The third step uses acid catalysis, which easily generates sulfonate esters, a toxic impurity. The reaction route is as follows:

[0007]

[0008] Chinese invention patent CN106748906B reports a route that does not employ carboxyl protection and deprotection processes. The fourth step uses Lewis acid catalysis, where n-butanol directly substitutes for the amino group at the 3-position, esterifying the carboxyl group to n-butyl ester, followed by hydrolysis to yield bumetanide. This route, using acid catalysis, readily produces sulfonates, which are genotoxic. The reaction route is as follows:

[0009] Summary of the Invention

[0010] To address the aforementioned problems in the prior art, the present invention aims to provide a method for preparing bumetanide. This method does not employ carboxyl protection and deprotection processes; instead, it uses a sulfonamide-tert-butyl protection and deprotection process. Furthermore, the butylation process in this invention uses boron trifluoride diethyl ether as a catalyst and triethylsilane as a reducing agent. The reaction conditions are mild, the operation is simple, and it successfully avoids the dangerous reductive amination reactions traditionally performed with sodium borohydride and triacetylborohydride. Compared with existing synthetic processes, this method has fewer side reactions, lower cost, higher yield, and higher safety, making it suitable for industrial production.

[0011] To achieve this objective, the present invention adopts the following technical solution:

[0012] A method for preparing bumetanide, characterized by using p-chlorobenzoic acid as a raw material and 3-(N-(tert-butyl)aminosulfonyl)-4-chloro-5-nitrobenzoic acid as a key intermediate, comprising the following steps:

[0013] Step 1: React p-chlorobenzoic acid and chlorosulfonic acid to prepare intermediate 4-chloro-3-(chlorosulfonyl)benzoic acid;

[0014] Step 2: 4-Chloro-3-(chlorosulfonyl)benzoic acid is nitrated in the presence of a nitrating agent to obtain the intermediate 4-chloro-3-(chlorosulfonyl)-5-nitrobenzoic acid;

[0015] Step 3: 4-Chloro-3-(chlorosulfonyl)-5-nitrobenzoic acid reacts with tert-butylamine to prepare the intermediate N-(tert-butyl)aminosulfonyl)-4-chloro-5-nitrobenzoic acid;

[0016] Step 4: N-(tert-butyl)aminosulfonyl)-4-chloro-5-nitrobenzoic acid undergoes a substitution reaction with phenol to obtain the intermediate 3-(N-(tert-butyl)aminosulfonyl)-5-nitro-4-phenoxybenzoic acid;

[0017] Step 5: 3-(N-(tert-butyl)aminosulfonyl)-5-nitro-4-phenoxybenzoic acid is reduced to obtain the intermediate 3-amino-5-(N-(tert-butyl)aminosulfonyl)-4-phenoxybenzoic acid;

[0018] Step 6: 3-amino-5-(N-(tert-butyl)aminosulfonyl)-4-phenoxybenzoic acid undergoes a reducing amination reaction with n-butyraldehyde to obtain the intermediate 3-(N-(tert-butyl)aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid;

[0019] Step 7: 3-(N-(tert-butyl)aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid is detert-butylated to obtain bumetanide.

[0020] The reaction equation is as follows:

[0021]

[0022] Further, step 1 includes the following steps:

[0023] Step 11: Using p-chlorobenzoic acid as a raw material, add it to chlorosulfonic acid in batches, heat to 120-140°C, and react for 2-5 hours, preferably 4 hours.

[0024] Step 12: After the reaction is complete, cool to room temperature, add dropwise to ice water, filter, wash and dry the filter cake to obtain 4-chloro-3-(chlorosulfonyl)benzoic acid.

[0025] Further, step 2 includes the following steps:

[0026] Step 21: Dissolve 4-chloro-3-(chlorosulfonyl)benzoic acid in concentrated sulfuric acid, heat to 60-90°C, preferably to 80°C, add nitrifying agent, heat to 80-100°C, preferably 90°C, and react for 4-6 hours;

[0027] Step 22: After the reaction is complete, cool to room temperature, pour into ice water, precipitate solid, filter, wash and dry the filter cake to obtain 4-chloro-3-(chlorosulfonyl)-5-nitrobenzoic acid.

[0028] Furthermore, step 3 includes the following steps:

[0029] Step 31: 4-Chloro-3-(chlorosulfonyl)-5-nitrobenzoic acid is dissolved in an organic solvent and slowly added dropwise to the organic solvent of tert-butylamine at low temperature (below 0°C). After the addition is complete, the reaction is carried out at low temperature (below 0°C) for 0.5-5 hours, preferably 1 hour; more preferably, the organic solvent is selected from one or more combinations of tetrahydrofuran, ethyl acetate, dichloromethane, isopropyl acetate, dioxane, dimethyl sulfoxide, N,N'-dimethylformamide, N,N'-dimethylacetamide, and N-methylpyrrolidone.

[0030] Step 32: After the reaction is complete, concentrate the mixture and then slurry it with a mixed organic solvent to obtain N-(tert-butyl)aminosulfonyl)-4-chloro-5-nitrobenzoic acid; preferably, the mixed organic solvent is ethyl acetate and petroleum ether.

[0031] Furthermore, step 4 includes the following steps:

[0032] Step 41: N-(tert-butyl)aminosulfonyl)-4-chloro-5-nitrobenzoic acid is dissolved in an organic solvent, phenol and a base are added, and the temperature is raised to 60-90°C, and the reaction is carried out for 10-40 hours; preferably, the temperature is raised to 80°C, and the reaction is carried out for 24 hours; more preferably, the organic solvent is one or more of N,N'-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, and acetonitrile, and the base is one or more of sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and lithium hydroxide.

[0033] Step 42: After the reaction is complete, cool to room temperature, adjust the acidity with dilute hydrochloric acid, add water, the solid precipitates, add water and stir, filter, wash the filter cake with water and dry to obtain 3-(N-(tert-butyl)aminosulfonyl)-5-nitro-4-phenoxybenzoic acid.

[0034] Furthermore, step 5 includes the following steps:

[0035] Step 51: 3-(N-(tert-butyl)aminosulfonyl)-5-nitro-4-phenoxybenzoic acid is dissolved in 20-28% ammonia water and water, preferably in 25% ammonia water and water, stirred until dissolved, and then added dropwise to an aqueous solution of ferrous sulfate heated to 60-90°C, preferably to an aqueous solution of ferrous sulfate heated to 80°C. After the addition is complete, the reaction is maintained at this temperature for 0.2-2 hours, preferably for 0.5 hours.

[0036] Step 52: After the reaction is complete, filter while hot, wash the filter cake with water, combine the filtrates, adjust the acidity with dilute hydrochloric acid, the solid precipitates, cool, filter, wash the filter cake with water and dry to obtain 3-amino-5-(N-(tert-butyl)aminosulfonyl)-4-phenoxybenzoic acid.

[0037] Furthermore, step 6 includes the following steps:

[0038] Step 61: 3-(N-(tert-butyl)aminosulfonyl)-5-amino-4-phenoxybenzoic acid, boron trifluoride ether, and triethylsilane are dissolved in an organic solvent, cooled, and an organic solvent solution of n-butyraldehyde is added dropwise. The reaction is carried out at a low temperature (below 0°C) for 0.5-2 hours, preferably for 1 hour. More preferably, the organic solvent is one or more of acetonitrile, tetrahydrofuran, ethyl acetate, dioxane, and dimethyl sulfoxide.

[0039] Step 62: After the reaction is complete, add water and stir, filter, wash the filter cake with water, and recrystallize with ethanol to obtain 3-(N-(tert-butyl)aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid.

[0040] Furthermore, step 7 includes the following steps:

[0041] Step 71: 3-(N-(tert-butyl)aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid is dissolved in acid and heated and stirred for 0.2-2 hours, preferably for 0.5 hours;

[0042] Step 72: After the reaction is complete, concentrate the solution to remove acid, and recrystallize with ethyl acetate to obtain pure bumetanide.

[0043] Preferably, the nitrating agent is one or more selected from sodium nitrate, nitric acid, fuming nitric acid, etc.

[0044] Preferably, the acid is selected from hydrochloric acid, trifluoroacetic acid, or a combination thereof.

[0045] Compared with the prior art, the present invention has the following advantages:

[0046] This route involves 4-chloro-coupling of a phenoxy group, nitro reduction, reductive amination with a reducing agent, and removal of the tert-butyl group in four steps to obtain bumetanide, with a total molar yield of approximately 50%. This route is short, has mild reaction conditions, avoids dangerous reactions such as hydrogenation, uses readily available and commonly available reagents, is low in cost, has no special toxicity, requires minimal equipment, and does not generate toxic sulfonates, making it suitable for industrial production. Detailed Implementation

[0047] The method of the present invention will be described below through specific embodiments. It should be understood that these embodiments are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments.

[0048] The following examples 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0049] The mass spectrometry results were obtained using an LC / MS instrument, with ESI as the ionization method.

[0050] High-performance liquid chromatograph (HPLC) models: Agilent 1260, Thermo Fisher U3000; Column model: Waters xbrige C18 (4.6*150 mm, 3.5 μm); Mobile phase: A: ACN, B: Water (0.1% H3PO4); Flow rate: 1.0 mL / min; Gradient: 5% A for 1 min, increase to 20% A within 4 min, increase to 80% A within 8 min, 80% A for 2 min, back to 5% A within 0.1 min; Wavelength: 220 nm; Column oven: 35℃.

[0051] TLC: Thin-layer chromatography. Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for TLC. The silica gel plates used in TLC have a diameter of 0.2mm-0.3mm, while those used for separating and purifying products are 0.4mm-0.5mm.

[0052] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0053] In the following examples, unless otherwise specified, all temperatures are in Celsius; unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods; commercially available materials and reagents are used directly without further purification; unless otherwise specified, commercially available manufacturers include, but are not limited to, Sinopharm Group, Bailingwei Technology Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd., and Shanghai Mairui Chemical Technology Co., Ltd.

[0054] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0055] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃-30℃.

[0056] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, or the developing solvent system for TLC included: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate. The volume ratio of the solvent varied depending on the polarity of the compound and could also be adjusted by adding a small amount of acidic or basic reagents, such as acetic acid or triethylamine.

[0057] Step 1: Synthesis of 4-chloro-3-(chlorosulfonyl)benzoic acid

[0058] Example 1: Chlorosulfonic acid (1.49 kg, 12.77 mol) was added to a 2 L three-necked flask and stirred. p-Chlorobenzoic acid (400.00 g, 2.55 mol) was added in portions at room temperature. After the addition was complete, the temperature was raised to 120 °C and stirred for 2 hours, then raised to 140 °C and stirred for 4 hours. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature and slowly added dropwise to ice water, maintaining the temperature between 0 and 5 °C. After the addition was complete, the mixture was stirred for 10 minutes below 0-5 °C. The mixture was filtered, and the filter cake was washed with water and dried to obtain a white solid compound, 4-chloro-3-(chlorosulfonyl)benzoic acid (484.88 g, yield 74.4%).

[0059] Step 2: Synthesis of 4-chloro-3-(chlorosulfonyl)-5-nitrobenzoic acid

[0060] Example 2: 100.00 g (0.392 mol) of 4-chloro-3-(chlorosulfonyl)benzoic acid was dissolved in 500 mL of concentrated sulfuric acid and stirred. The mixture was heated to 80 °C, and sodium nitrate (83.31 g, 0.980 mmol) was added in batches, with slight increases in temperature during the process. The mixture was then heated to 90 °C and stirred for 4 hours. The reaction was monitored by TLC until complete. The reaction solution was slowly poured into ice water, and a solid precipitated. The solid was filtered, and the filter cake was washed with water to obtain a white solid compound, 4-chloro-3-(chlorosulfonyl)-5-nitrobenzoic acid (62.00 g, yield 52.7%).

[0061] Example 3: 140.00 g (0.548 mol) of 4-chloro-3-(chlorosulfonyl)benzoic acid was dissolved in 270 mL of concentrated sulfuric acid and stirred. The mixture was heated to 80 °C, and a mixture of fuming nitric acid (85 mL) and concentrated sulfuric acid (80 mL) was added dropwise. The temperature rose slightly during the addition, and then the temperature was raised to 90 °C and stirred for 6 hours. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature and slowly poured into ice water, precipitating a solid. The solid was filtered, the filter cake was dissolved in ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a white solid compound, 4-chloro-3-(chlorosulfonyl)-5-nitrobenzoic acid (120.0 g, yield 72.8%).

[0062] Step 3: Synthesis of N-(tert-butyl)aminosulfonyl)-4-chloro-5-nitrobenzoic acid

[0063] Example 4: 120.00 g (0.400 mol) of 4-chloro-3-(chlorosulfonyl)-5-nitrobenzoic acid was dissolved in 250 mL of tetrahydrofuran and slowly added dropwise to a 360 mL solution of tert-butylamine (117.00 g, 1.600 mol) in tetrahydrofuran. The temperature was kept below 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 1 hour, and the reaction was monitored by TLC to ensure completeness. The reaction solution was concentrated to obtain a yellow solid. After adding water, the pH was adjusted to 3 with dilute hydrochloric acid, and a yellow solid precipitated. The solid was filtered, the filter cake was washed with water, and dried to obtain a crude yellow solid. The crude solid was slurried with ethyl acetate / petroleum ether (3 / 1) to obtain a light yellow solid N-(tert-butyl)aminosulfonyl)-4-chloro-5-nitrobenzoic acid (98.8 g, yield 74.0%, purity 96.1%).

[0064] LC-MS: m / z = 335.0 [MH] -

[0065] 1 H NMR (400MHz, DMSO-d6) δ14.13 (s, 1H), 8.68 (dd, J = 4.0, 2.0Hz, 1H), 8.27 (s, 1H), 1.16 (s, 9H).

[0066] Example 5: 4-Chloro-3-(chlorosulfonyl)-5-nitrobenzoic acid (23.55 g, 0.078 mol) was dissolved in ethyl acetate (40 mL) and slowly added dropwise to an ethyl acetate solution of tert-butylamine (22.96 g, 0.314 mol) (85 mL). The temperature was kept below 0°C. After the addition was complete, the mixture was stirred at 0°C for 1 hour, and the reaction was monitored by TLC to ensure completeness. The reaction solution was concentrated to obtain a yellow solid. After adding water, the pH was adjusted to 3 with dilute hydrochloric acid, and a yellow solid precipitated. The solid was filtered, the filter cake was washed with water, and dried to obtain a crude yellow solid. The crude solid was slurried in ethyl acetate / petroleum ether (3 / 1) to obtain a light yellow solid N-(tert-butyl)aminosulfonyl)-4-chloro-5-nitrobenzoic acid (19.8 g, yield 75.0%, purity 96.0%).

[0067] LC-MS: m / z = 335.0 [MH] -

[0068] 1 H NMR (400MHz, DMSO-d6) δ14.13 (s, 1H), 8.68 (dd, J = 4.0, 2.0Hz, 1H), 8.27 (s, 1H), 1.16 (s, 9H).

[0069] Step 4: Synthesis of 3-(N-(tert-butyl)aminosulfonyl)-5-nitro-4-phenoxybenzoic acid

[0070] Example 6: N-(tert-butyl)aminosulfonyl)-4-chloro-5-nitrobenzoic acid (30.52 g, 90.63 mmol), phenol (17.06 g, 180.27 mmol), and lithium hydroxide monohydrate (9.51 g, 226.58 mmol) were dispersed in N,N-dimethyl sulfoxide (150 mL). The mixture was heated to 60 °C and stirred for 6 hours. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and the pH was adjusted to 3 with dilute hydrochloric acid. Petroleum ether (150 mL) and ethyl acetate (30 mL) were added and stirred overnight. A large amount of solid precipitated. Water (300 mL) was added and stirring was continued for half an hour. The mixture was filtered, the filter cake was washed with water, and dried to obtain a pale yellow solid, 3-(N-(tert-butyl)aminosulfonyl)-5-nitro-4-phenoxybenzoic acid (33.8 g, yield 94.6%, purity 97.7%).

[0071] 1 H NMR (400MHz, DMSO-d6) δ14.02(s,1H),8.71(d,J=2.0Hz,1H),8.63(d,J=2.0Hz, 1H),7.86(s,1H),7.34-7.30(m,2H),7.10(t,J=7.6Hz,1H)

[0072] Example 7: N-(tert-butyl)aminosulfonyl)-4-chloro-5-nitrobenzoic acid (50.00 g, 148.5 mmol), phenol (20.96 g, 222.3 mmol), and sodium carbonate (31.48 g, 279.0 mmol) were dispersed in N,N-dimethyl sulfoxide (200 mL). The mixture was heated to 80 °C and stirred for 24 hours. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and the pH was adjusted to 3 with dilute hydrochloric acid. Petroleum ether (250 mL) and ethyl acetate (50 mL) were added and stirred overnight. A large amount of solid precipitated. Water (500 mL) was added and stirring was continued for half an hour. The mixture was filtered, the filter cake was washed with water, and dried to obtain a pale yellow solid, 3-(N-(tert-butyl)aminosulfonyl)-5-nitro-4-phenoxybenzoic acid (55.30 g, yield 94.4%, purity 97.5%).

[0073] LC-MS: m / z = 393.0 [MH] -

[0074] 1 H NMR (400MHz, DMSO-d6) δ14.02 (s, 1H), 8.71 (d, J = 2.0Hz, 1H), 8.63 (d, J = 2.0Hz, 1H),7.86(s,1H),7.34-7.30(m,2H),7.10(t,J=7.6Hz,1H),6.92(d,J=8.0Hz,2H),1.13(s,9H).

[0075] Example 8: N-(tert-butyl)aminosulfonyl)-4-chloro-5-nitrobenzoic acid (60.00 g, 178.2 mmol), phenol (25.17 g, 267.5 mmol), and potassium carbonate (61.61 g, 443.2 mmol) were dispersed in N,N-dimethyl sulfoxide (300 mL). The mixture was heated to 85 °C and stirred for 24 hours. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, the pH was adjusted to 1-2 with dilute hydrochloric acid, and water (800 mL) was added. The mixture was stirred at room temperature for 2 hours, and a large amount of solid precipitated. Water (300 mL) was added, and stirring was continued for another half hour. The mixture was filtered, the filter cake was washed with water, and dried to obtain a pale yellow solid compound 3-(N-(tert-butyl)aminosulfonyl)-5-nitro-4-phenoxybenzoic acid (64.30 g, yield 91.5%, purity 98.8%).

[0076] LC-MS: m / z = 393.0 [MH] -

[0077] 1 H NMR (400MHz, DMSO-d6) δ14.02 (s, 1H), 8.71 (d, J = 2.0Hz, 1H), 8.63 (d, J = 2.0Hz, 1H),7.86(s,1H),7.34-7.30(m,2H),7.10(t,J=7.6Hz,1H),6.92(d,J=8.0Hz,2H),1.13(s,9H).

[0078] Step 5: Synthesis of 3-amino-5-(N-(tert-butyl)aminosulfonyl)-4-phenoxybenzoic acid

[0079] Example 9: 3-(N-(tert-butyl)aminosulfonyl)-5-nitro-4-phenoxybenzoic acid (40.00 g, 101.4 mmol) was dissolved in ammonia water (25%, 200 mL), and stirred until dissolved to obtain an ammonium salt solution. Ferrous sulfate heptahydrate (137.87 g, 495.9 mmol) was dissolved in water (500 mL), and heated to 80 °C to obtain a ferrous sulfate solution. The ammonium salt solution was added dropwise to the ferrous sulfate solution, and the reaction was maintained at this temperature for 30 minutes after the addition was complete. The reaction was monitored by TLC until complete. The reaction solution was filtered while hot, the filter cake was washed with water, the filtrates were combined, and the pH was adjusted to 4-5 with dilute hydrochloric acid. A large amount of solid precipitated out. The mixture was cooled to 0-10℃, stirred for 1 hour, filtered, and the filter cake was washed with water and dried to obtain a white solid 3-amino-5-(N-(tert-butyl)aminosulfonyl)-4-phenoxybenzoic acid (32.08 g, yield 86.7%, purity 98.3%).

[0080] LC-MS: m / z = 363.1 [MH] -

[0081] 1 H NMR (400MHz, DMSO-d6) δ13.04(s,1H),7.67(d,J=2.0Hz,1H),7.61(d,J=2.0Hz, 1H),7.28(t,J=8.0Hz,2H),7.02-6.98(m,2H),6.83(d,J=8.0Hz,2H),5.75(s,1H),5.29(s,2H), 1.06(s,9H).

[0082] Step 6: Synthesis of 3-(N-(tert-butyl)aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid

[0083] Example 10: 3-Amino-5-(N-(tert-butyl)aminosulfonyl)-4-phenoxybenzoic acid (27.08 g, 74.3 mmol), boron trifluoride diethyl ether (7.91 g, 55.7 mmol), and triethylsilane (17.27 g, 148.52 mmol) were dissolved in acetonitrile (100 mL). A solution of n-butyraldehyde (8.43 g, 116.9 mmol) in acetonitrile (40 mL) was added dropwise at 0 °C. After the addition was complete, the mixture was kept at 0 °C and stirred for 1 hour. The reaction was monitored by TLC until complete. Water was added to the reaction solution, and the mixture was stirred for 2 hours. The mixture was filtered, the filter cake was washed with water, and recrystallized from ethanol to give a white solid compound 3-(N-(tert-butyl)aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid (25.30 g, yield 80.9%, purity 98.9%).

[0084] LC-MS: m / z = 421.2 [M+H] +

[0085] 1 H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 7.70 (d, J = 2.0Hz, 1H), 7.42 (d, J = 2.0Hz, 1H),7.28(t,J=7.2Hz,2H),7.04-7.00(m,2H),6.83(d,J=8.0Hz,1H),5.06(t,J=5.6Hz,1H), 3.05(dd,J=12.8,6.8Hz,2H),1.40-1.33(m,2H),1.15-1.06(m,11H),0.77(t,J=7.6Hz,3H).

[0086] Example 11: 3-(N-(tert-butyl)aminosulfonyl)-5-amino-4-phenoxybenzoic acid (10.00 g, 27.4 mmol), boron trifluoride diethyl ether (2.92 g, 25.1 mmol), and triethylsilane (6.38 g, 54.9 mmol) were dissolved in tetrahydrofuran (100 mL). A tetrahydrofuran (10 mL) solution of n-butyraldehyde (3.00 g, 41.6 mmol) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 1 hour, and the reaction was monitored by TLC until completion. Water was added to the reaction solution, and the mixture was stirred for 2 hours. The mixture was filtered, the filter cake was washed with water, and recrystallized from ethanol to give a white solid compound 3-(N-(tert-butyl)aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid (9.30 g, yield 80.7%, purity 98.7%).

[0087] LC-MS: m / z = 421.2 [M+H] +

[0088] 1 H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 7.70 (d, J = 2.0Hz, 1H), 7.42 (d, J = 2.0Hz, 1H),7.28(t,J=7.2Hz,2H),7.04-7.00(m,2H),6.83(d,J=8.0Hz,1H),5.06(t,J=5.6Hz,1H), 3.05(dd,J=12.8,6.8Hz,2H),1.40-1.33(m,2H),1.15-1.06(m,11H),0.77(t,J=7.6Hz,3H).

[0089] Step 7: Synthesis of Bumetanide

[0090] Example 12: 3-(N-(tert-butyl)aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid (15.57 g, 37.0 mmol) was dissolved in trifluoroacetic acid (70 mL), heated to 70 °C and stirred for half an hour. The reaction was monitored by TLC until the reactants were completely reacted. The reaction solution was concentrated to remove trifluoroacetic acid, and recrystallized from ethyl acetate to give a white solid of pure bumetanide (10.20 g, yield 75.5%, purity 99.9%).

[0091] LC-MS: m / z = 365.2 [M+H] +

[0092] 1H NMR (400MHz, DMSO-d6) δ13.17(s,1H),7.69(d,J=1.6Hz,1H),7.42(d,J=2.0Hz, 1H),7.34(s,2H),7.27(dd,J=8.4,7.6Hz,2H),7.01(t,J=7.2Hz,1H),6.84(d,J=12Hz,2H), 5.06(t,J=5.6Hz,1H),3.06(dd,J=8.8,6.4Hz,2H),1.40-1.33(m,2H),1.16-1.07(m,2H),0.77(t,J=7.2Hz,3H).

[0093] Example 13: 3-(N-(tert-butyl)aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid (3.00 g, 7.1 mmol) was dissolved in concentrated hydrochloric acid (15 mL), and the solution was heated to 45–50 °C. After dissolution, the solution was stirred for 0.5 hours, and the reaction was monitored by TLC until complete. The reaction solution was filtered, and the filter cake was washed with water to obtain a white solid crude product. Recrystallization from ethyl acetate gave a white solid pure bumetanide (1.95 g, yield 75.4%, purity 99.8%).

[0094] LC-MS: m / z = 365.2 [M+H] +

[0095] 1 H NMR (400MHz, DMSO-d6) δ13.17(s,1H),7.69(d,J=1.6Hz,1H),7.42(d,J=2.0Hz, 1H),7.34(s,2H),7.27(dd,J=8.4,7.6Hz,2H),7.01(t,J=7.2Hz,1H),6.84(d,J=12Hz,2H), 5.06(t,J=5.6Hz,1H),3.06(dd,J=8.8,6.4Hz,2H),1.40-1.33(m,2H),1.16-1.07(m,2H),0.77(t,J=7.2Hz,3H).

[0096] The above embodiments are only for illustrating the technical concept and features of the present invention. Their purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be used to limit the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A process for the preparation of bumetanide, characterized in that, The preparation method uses p-chlorobenzoic acid as a raw material and includes the following steps: Step 1: React p-chlorobenzoic acid and chlorosulfonic acid to prepare intermediate 4-chloro-3-(chlorosulfonyl)benzoic acid; Step 2: 4-Chloro-3-(chlorosulfonyl)benzoic acid is nitrated in the presence of a nitrating agent to obtain the intermediate 4-chloro-3-(chlorosulfonyl)-5-nitrobenzoic acid; Step 3: 4-Chloro-3-(chlorosulfonyl)-5-nitrobenzoic acid reacts with tert-butylamine to prepare the intermediate. N -(tert-butyl)aminosulfonyl)-4-chloro-5-nitrobenzoic acid; Step 4, N -(tert-butyl)aminosulfonyl)-4-chloro-5-nitrobenzoic acid undergoes a substitution reaction with phenol to yield the intermediate 3-( N -(tert-butyl)aminosulfonyl)-5-nitro-4-phenoxybenzoic acid; Step 5, 3-( N -(tert-butyl)aminosulfonyl)-5-nitro-4-phenoxybenzoic acid was reduced to give the intermediate 3-amino-5-( N -(tert-butyl)aminosulfonyl)-4-phenoxybenzoic acid; Step 6, 3-amino-5-( N -(tert-butyl)aminosulfonyl)-4-phenoxybenzoic acid undergoes a reductive amination reaction with n-butyraldehyde to yield the intermediate 3-( N -(tert-butyl)aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid; Step 7, 3-( N -(tert-butyl)aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid is detert-butylated to give bumetanide; Step 6 includes the following steps: Step 61, 3-( N (tert-butyl)aminosulfonyl)-5-amino-4-phenoxybenzoic acid, boron trifluoride ether and triethylsilane are dissolved in an organic solvent, cooled, and an organic solvent solution of n-butyraldehyde is added dropwise. The reaction is carried out at low temperature for 0.5-2 hours. Step 62: After the reaction is complete, add water and stir, filter, wash the filter cake with water, and recrystallize with ethanol to obtain 3-( N -(tert-butyl)aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid.

2. The method for preparing bumetanide as described in claim 1, characterized in that, Step 1 includes the following steps: Step 11: Using p-chlorobenzoic acid as a raw material, add it to chlorosulfonic acid in batches, heat to 120~140℃, and react for 2-5 hours; Step 12: After the reaction is complete, cool to room temperature, add dropwise to ice water, filter, wash and dry the filter cake to obtain 4-chloro-3-(chlorosulfonyl)benzoic acid.

3. The method for preparing bumetanide as described in claim 1, characterized in that, Step 2 includes the following steps: Step 21: Dissolve 4-chloro-3-(chlorosulfonyl)benzoic acid in concentrated sulfuric acid, heat to 60-90℃, add nitrifying reagent, heat to 80-100℃, and react for 4-6 hours; Step 22: After the reaction is complete, cool to room temperature, pour into ice water, precipitate solid, filter, wash and dry the filter cake to obtain 4-chloro-3-(chlorosulfonyl)-5-nitrobenzoic acid.

4. The method for preparing bumetanide as described in claim 1, characterized in that, Step 3 includes the following steps: Step 31: 4-Chloro-3-(chlorosulfonyl)-5-nitrobenzoic acid is dissolved in an organic solvent and slowly added dropwise to the organic solvent solution of tert-butylamine at low temperature. After the addition is complete, the reaction is carried out at low temperature for 0.5-5 hours. Step 32: After the reaction is complete, concentrate the mixture and then slurry it with the mixed organic solvent to obtain... N -(tert-butyl)aminosulfonyl)-4-chloro-5-nitrobenzoic acid.

5. The method for preparing bumetanide as described in claim 4, characterized in that, In step 31, the organic solvent is selected from tetrahydrofuran, ethyl acetate, dichloromethane, isopropyl acetate, dioxane, dimethyl sulfoxide, etc. N , N' -Dimethylformamide, N , N' -dimethylacetamide and N A combination of one or more methylpyrrolidones.

6. The method for preparing bumetanide as described in claim 4, characterized in that, In step 32, the mixed organic solvent is ethyl acetate and petroleum ether.

7. The method for preparing bumetanide as described in claim 1, characterized in that, Step 4 includes the following steps: Step 41, N -(tert-butyl)aminosulfonyl)-4-chloro-5-nitrobenzoic acid is dissolved in an organic solvent, phenol and base are added, the temperature is raised to 60-90℃, and the reaction is carried out for 10-40 hours; Step 42: After the reaction is complete, cool to room temperature, adjust the acidity with dilute hydrochloric acid, add water, the solid precipitates, add water and stir, filter, wash the filter cake with water and dry to obtain 3-( N -(tert-butyl)aminosulfonyl)-5-nitro-4-phenoxybenzoic acid.

8. The method for preparing bumetanide as described in claim 7, characterized in that, The organic solvent is N , N' -Dimethylformamide, N 1-Methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran and acetonitrile, wherein the base is selected from one or more of sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and lithium hydroxide.

9. The method for preparing bumetanide as described in claim 1, characterized in that, Step 5 includes the following steps: Steps 51, 3-( N -(tert-butyl)aminosulfonyl)-5-nitro-4-phenoxybenzoic acid is dissolved in 20-28% ammonia water and water, stirred until dissolved, and then added dropwise to an aqueous solution of ferrous sulfate heated to 60-90℃. After the addition is complete, the reaction is maintained at the temperature for 0.2-2 hours. Step 52: After the reaction is complete, filter while hot, wash the filter cake with water, combine the filtrates, adjust the acidity with dilute hydrochloric acid, the solid precipitates, cool, filter, wash the filter cake with water and dry to obtain 3-amino-5-( N -(tert-butyl)aminosulfonyl)-4-phenoxybenzoic acid.

10. The method for preparing bumetanide as described in claim 1, characterized in that, In step 61, the organic solvent is one or more of acetonitrile, tetrahydrofuran, ethyl acetate, dioxane, and dimethyl sulfoxide.

11. The method for preparing bumetanide as described in claim 1, characterized in that, Step 7 includes the following steps: Step 71, 3-( N -(tert-butyl)aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid is dissolved in acid and heated and stirred for 0.2-2 hours; Step 72: After the reaction is complete, concentrate the solution to remove acid, and recrystallize with ethyl acetate to obtain pure bumetanide.

12. The method for preparing bumetanide as described in claim 1 or 3, characterized in that, The nitrifying agent is one or more selected from sodium nitrate, nitric acid, and fuming nitric acid.

13. The method for preparing bumetanide as described in claim 11, characterized in that, The acid is selected from hydrochloric acid, trifluoroacetic acid, or a combination thereof.

Images