A process for the preparation of bumetanide

Abstract

The application provides a preparation method of bumetanide, and relates to the technical field of biological medicine synthesis. 4-chloro-3-nitro-5-sulfonamidobenzoic acid, an alkaline reagent, phenol and water are mixed to perform a phenoxylation reaction, the obtained 3-nitro-4-phenoxy-5-sulfonamidobenzoic acid is mixed with a reducing agent and palladium carbon to perform a reduction reaction, the obtained 3-amino-4-phenoxy-5-sulfonamidobenzoic acid is mixed with n-butyl aldehyde, sodium triacetoxyborohydride and an organic solvent to perform a reductive amination reaction, and then bumetanide is obtained. The preparation method provided by the application has a high total yield of products. Moreover, the preparation method provided by the application has the advantages of wide raw material sources, simple synthesis process route, mild reaction conditions, few by-products, high product quality, low cost and suitability for industrial production. As shown in the test results of examples, the total yield of bumetanide prepared by the preparation method provided by the application is more than 37.5%.

Description

Technical Field

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

[0002] Bumetanide is a loop diuretic, primarily used to inhibit the active reabsorption of sodium chloride in the thick-walled ascending limb of the loop of Henle, thereby inhibiting sodium reabsorption. Simultaneously, it dilates systemic arterioles, reduces peripheral vascular resistance, and increases renal blood flow without decreasing glomerular filtration rate, making it the most potent diuretic currently available. Bumetanide is a derivative of furosemide (Lasix). As a novel loop diuretic, it has a rapid onset of action and excellent diuretic effect. Compared to furosemide, it is characterized by high efficacy, rapid action, short duration of action, and low toxicity. Its structure is shown in Formula I below:

[0003]

[0004] The existing technology "Tang Weigao, Peng Chongying. Synthesis of bumetanide. Journal of Western Medicine, 1994, 9, 7-9" discloses a method for synthesizing bumetanide, using p-chlorobenzoic acid as the starting material, which is chlorosulfonated to produce 3-chlorosulfonyl-4-chlorobenzoic acid, nitrated to produce 3-chlorosulfonyl-4-chloro-5-nitrobenzoic acid, ammonolyzed to produce 3-aminosulfonyl-4-chloro-5-nitrobenzoic acid, phenoxylated to produce 3-aminosulfonyl-4-phenoxy-5-nitrobenzoic acid, reduced to produce 3-aminosulfonyl-4-phenoxy-5-aminobenzoic acid, and finally butylated to synthesize bumetanide. However, the overall yield of the three-step reaction of phenoxylation, reduction and butylation is only 20.67%, which is low. Summary of the Invention

[0005] In view of this, the purpose of the present invention is to provide a method for preparing bumetanide, wherein the preparation method provided by the present invention has a high total yield of bumetanide.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] This invention provides a method for preparing bumetanide, comprising the following steps:

[0008] 4-Chloro-3-nitro-5-sulfonamidobenzoic acid, a basic reagent, phenol, and water were mixed and subjected to a phenoxylation reaction to obtain 3-nitro-4-phenoxy-5-sulfonamidobenzoic acid;

[0009] The 3-nitro-4-phenoxy-5-sulfonamidobenzoic acid, a reducing agent, and palladium on carbon were mixed and a reduction reaction was carried out to obtain 3-amino-4-phenoxy-5-sulfonamidobenzoic acid.

[0010] The 3-amino-4-phenoxy-5-sulfonamide benzoic acid, n-butyraldehyde, sodium triacetoxyborohydride, and an organic solvent were mixed and subjected to a reductive amination reaction to obtain bumetanide.

[0011] Preferably, the molar ratio of 4-chloro-3-nitro-5-sulfonamide benzoic acid to phenol is 1:2 to 2.5.

[0012] Preferably, the alkaline reagent includes bicarbonate and / or carbonate;

[0013] The molar ratio of the 4-chloro-3-nitro-5-sulfonamide benzoic acid to the alkaline reagent is 1:2.5-3.

[0014] Preferably, the phenoxylation reaction is carried out at a temperature of 80–90°C for 16–17 hours.

[0015] Preferably, the reducing agent includes one or more of ammonium formate, potassium formate, and formic acid;

[0016] The molar ratio of 3-nitro-4-phenoxy-5-sulfonamide benzoic acid to the reducing agent is 1:3 to 4.

[0017] Preferably, the mass ratio of 3-nitro-4-phenoxy-5-sulfonamide benzoic acid to palladium on carbon is 1:0.01 to 0.02.

[0018] Preferably, the reduction reaction is carried out at a temperature of 50–55°C for 1–2 hours.

[0019] Preferably, the molar ratio of 3-amino-4-phenoxy-5-sulfonamide benzoic acid to n-butyraldehyde is 1:1.5 to 2;

[0020] The molar ratio of 3-amino-4-phenoxy-5-sulfonamide benzoic acid to sodium triacetoxyborohydride is 1:1 to 1.5.

[0021] Preferably, the organic solvent includes one or more of tetrahydrofuran, N,N-dimethylformamide, and acetonitrile.

[0022] Preferably, the reductive amination reaction is carried out at a temperature of 20–25°C for 1–2 hours.

[0023] This invention provides a method for preparing bumetanide, comprising the following steps: mixing 4-chloro-3-nitro-5-sulfonamidobenzoic acid, an alkaline reagent, phenol, and water, and performing a phenoxylation reaction to obtain 3-nitro-4-phenoxy-5-sulfonamidobenzoic acid; mixing the 3-nitro-4-phenoxy-5-sulfonamidobenzoic acid, a reducing agent, and palladium on carbon, and performing a reduction reaction to obtain 3-amino-4-phenoxy-5-sulfonamidobenzoic acid; and mixing the 3-amino-4-phenoxy-5-sulfonamidobenzoic acid, n-butyraldehyde, sodium triacetoxyborohydride, and an organic solvent, and performing a reductive amination reaction to obtain bumetanide. This invention uses 4-chloro-3-nitro-5-sulfonamidobenzoic acid as a starting material, performs a phenoxylation reaction with phenol under alkaline conditions, then performs reduction, and finally performs a reductive amination reaction with n-butyraldehyde in the presence of sodium triacetoxyborohydride to obtain bumetanide, with a high overall product yield. Moreover, the preparation method provided by this invention uses widely available raw materials, has a simple synthetic route, mild reaction conditions, few byproducts, high product quality, and low cost, making it suitable for industrial production. As shown in the test results of the examples, the total yield of bumetanide obtained by the preparation method provided by this invention is above 37.5%.

[0024] Furthermore, the bumetanide prepared by this invention has high purity, which meets the quality requirements of the European Pharmacopoeia, and is conducive to improving the quality of domestically produced drugs and the competitiveness of domestic enterprises. Detailed Implementation

[0025] This invention provides a method for preparing bumetanide, comprising the following steps:

[0026] 4-Chloro-3-nitro-5-sulfonamidobenzoic acid, a basic reagent, phenol, and water were mixed and subjected to a phenoxylation reaction to obtain 3-nitro-4-phenoxy-5-sulfonamidobenzoic acid;

[0027] The 3-nitro-4-phenoxy-5-sulfonamidobenzoic acid, a reducing agent, and palladium on carbon were mixed and a reduction reaction was carried out to obtain 3-amino-4-phenoxy-5-sulfonamidobenzoic acid.

[0028] The 3-amino-4-phenoxy-5-sulfonamide benzoic acid, n-butyraldehyde, sodium triacetoxyborohydride, and an organic solvent were mixed and subjected to a reductive amination reaction to obtain bumetanide.

[0029] Unless otherwise specified, all raw materials used in this invention are commercially available products.

[0030] In this invention, 4-chloro-3-nitro-5-sulfonamidobenzoic acid, an alkaline reagent, phenol, and water are mixed and subjected to a phenoxylation reaction to obtain 3-nitro-4-phenoxy-5-sulfonamidobenzoic acid.

[0031] In this invention, the molar ratio of 4-chloro-3-nitro-5-sulfonamide benzoic acid to phenol is preferably 1:2 to 2.5, more preferably 1:2.2 to 2.5, and even more preferably 1:2.4 to 2.5.

[0032] In this invention, the alkaline reagent preferably includes bicarbonate and / or carbonate, and more preferably includes one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.

[0033] In this invention, the molar ratio of 4-chloro-3-nitro-5-sulfonamide benzoic acid to the alkaline reagent is preferably 1:2.5 to 3, more preferably 1:2.8 to 3.

[0034] In this invention, the molar ratio of 4-chloro-3-nitro-5-sulfonamide benzoic acid to the volume of water is preferably 1 g: 6-7 mL, more preferably 1 g: 6.5-7 mL.

[0035] In this invention, the mixing temperature is preferably 80-90°C, more preferably 85-90°C; the mixing is preferably stirring, and this invention does not have any special limitation on the stirring speed and time, stirring until the raw materials are dissolved is sufficient.

[0036] In this invention, the temperature of the phenoxylation reaction is preferably 80-90°C, more preferably 85-90°C, and the time of the phenoxylation reaction is preferably 16-17 h, more preferably 16-16.5 h.

[0037] Following the phenoxylation reaction, the present invention preferably includes a post-treatment process, which preferably includes: cooling the obtained phenoxylation reaction solution to 0-5°C (more preferably 5°C), adjusting the pH value to 1-2 (more preferably 1.5-2), stirring to induce crystallization, precipitating a large amount of yellow solid, continuing stirring for 20-30 min (more preferably 25-30 min), separating the solid and liquid, washing the obtained solid product with water, and drying to obtain 3-nitro-4-phenoxy-5-sulfonamidobenzoic acid. In this invention, the acid used to adjust the pH value is preferably concentrated hydrochloric acid, and the concentrated hydrochloric acid is preferably added dropwise. The present invention does not have a specific limitation on the rate of dropwise addition; it can be added dropwise at a uniform rate. The present invention does not have a specific limitation on the solid-liquid separation; any solid-liquid separation method well known to those skilled in the art can be used, such as filtration, vacuum filtration, or centrifugation. In this invention, the drying temperature is preferably 50-55°C, more preferably 52-55°C, and the present invention does not have a specific limitation on the drying time; drying to constant weight is sufficient. The drying method preferably includes forced-air drying.

[0038] After obtaining 3-nitro-4-phenoxy-5-sulfonamidobenzoic acid, the present invention mixes the 3-nitro-4-phenoxy-5-sulfonamidobenzoic acid, a reducing agent and palladium on carbon, and carries out a reduction reaction to obtain 3-amino-4-phenoxy-5-sulfonamidobenzoic acid.

[0039] In this invention, the reducing agent preferably includes one or more of ammonium formate, potassium formate, and formic acid. In this invention, the molar ratio of 3-nitro-4-phenoxy-5-sulfonamidobenzoic acid to the reducing agent is 1:3 to 4, more preferably 1:3.2 to 3.8, and even more preferably 1:3.4 to 3.7.

[0040] In this invention, the mass ratio of 3-nitro-4-phenoxy-5-sulfonamide benzoic acid to palladium on carbon is 1:0.01 to 0.02, more preferably 1:0.015 to 0.02. In this invention, the mass fraction of palladium on carbon is preferably 5 to 10%, more preferably 8 to 10%.

[0041] In this invention, the temperature of the reduction reaction is preferably 50-55°C, more preferably 50-52°C; the time of the reduction reaction is preferably 1-2 hours, more preferably 1-1.5 hours.

[0042] Following the reduction reaction, the present invention preferably further includes post-treatment, which preferably includes: concentrating the obtained reduction reaction solution until no distillate is precipitated; adding water to the obtained concentrate; stirring at 20–25°C for 20–30 min (more preferably 25–30 min); then adding glacial acetic acid and stirring at 20–25°C for 20–30 min (more preferably 25–30 min); performing solid-liquid separation; washing the obtained solid product with water and drying it to obtain 3-amino-4-phenoxy-5-sulfonamide benzoic acid. In the present invention, the concentration is preferably vacuum concentration, and the concentration temperature is preferably 40–50°C, more preferably 45°C; in the present invention, the mass ratio of 3-nitro-4-phenoxy-5-sulfonamide benzoic acid to the volume ratio of glacial acetic acid is preferably 1 g: 0.4–0.6 mL, more preferably 1 g: 0.5–0.6 mL. The present invention does not have any particular limitation on the solid-liquid separation, and any solid-liquid separation method well known to those skilled in the art can be used, such as filtration, vacuum filtration, or centrifugation. In this invention, the drying temperature is preferably 50-55°C, more preferably 52-55°C. This invention does not have a special limitation on the drying time; drying to constant weight is sufficient. The drying method preferably includes forced air drying.

[0043] After obtaining 3-amino-4-phenoxy-5-sulfonamide benzoic acid, the present invention mixes the 3-amino-4-phenoxy-5-sulfonamide benzoic acid, n-butyraldehyde, sodium triacetoxyborohydride and an organic solvent to carry out a reducing amination reaction to obtain bumetanide.

[0044] In this invention, the molar ratio of 3-amino-4-phenoxy-5-sulfonamide benzoic acid to n-butyraldehyde is preferably 1:1.5 to 2, more preferably 1:1.6 to 2, and even more preferably 1:1.8 to 2.

[0045] In this invention, the molar ratio of 3-amino-4-phenoxy-5-sulfonamide benzoic acid to sodium triacetoxyborohydride is preferably 1:1 to 1.5, more preferably 1:1.2 to 1.5, and even more preferably 1:1.4 to 1.5.

[0046] In this invention, the organic solvent preferably includes one or more of tetrahydrofuran, N,N-dimethylformamide, and acetonitrile. In this invention, the molar ratio of 3-amino-4-phenoxy-5-sulfonamide benzoic acid to the volume of the organic solvent is preferably 1 g: 9-10 mL, more preferably 1 g: 9.5-10 mL.

[0047] In this invention, the mixing is preferably performed by stirring and mixing the 3-amino-4-phenoxy-5-sulfonamide benzoic acid, sodium triacetoxyborohydride, and an organic solvent, and then adding butyraldehyde dropwise to the resulting mixture at 20–25°C (more preferably 22–25°C). This invention does not have specific limitations on the stirring speed and time, as long as the raw materials are mixed evenly. Similarly, this invention does not have specific limitations on the dropping rate; it is sufficient to add the mixture dropwise at a uniform rate.

[0048] In this invention, the temperature of the reductive amination reaction is preferably 20-25°C, more preferably 22-25°C; the time of the reductive amination reaction is preferably 1-2 hours, more preferably 1-1.5 hours.

[0049] Following the reductive amination reaction, the present invention preferably includes a post-treatment process, which preferably includes: adding water to the obtained reductive amination reaction solution and stirring and mixing at 45-55°C (more preferably 50°C), cooling to 20-25°C (more preferably 20-22°C), and then separating the solid and liquid components. The obtained solid product is washed with water and dried to obtain bumetanide. In the present invention, the molar ratio of 3-amino-4-phenoxy-5-sulfonamide benzoic acid to the volume of water used for stirring and mixing is preferably 1 g: 2.5-3 mL, more preferably 1 g: 2.8-3 mL. The purpose of adding water and stirring is to quench unreacted sodium triacetoxyborohydride. The present invention does not have a special limitation on the solid-liquid separation process; any solid-liquid separation method known to those skilled in the art can be used, such as filtration, vacuum filtration, or centrifugation. In the present invention, the drying temperature is preferably 55-60°C, more preferably 58-60°C. The present invention does not have a special limitation on the drying time; drying to constant weight is sufficient. The drying method preferably includes forced-air drying.

[0050] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0051] Example 1

[0052] (1) Preparation of 3-nitro-4-phenoxy-5-sulfonamide benzoic acid

[0053] 80g of 4-chloro-3-nitro-5-sulfonamidobenzoic acid, 72g of sodium bicarbonate, 67.2g of phenol, and 560mL of purified water were added to a 1L three-necked flask. The mixture was heated to 90℃ and stirred until dissolved. The reaction was continued for 16h. After cooling to 5℃, 16mL of concentrated hydrochloric acid was added dropwise to adjust the pH to 2. The mixture was stirred to induce crystallization. After a large amount of yellow solid precipitated, the mixture was stirred for another 30min. The mixture was then filtered, and the resulting filter cake was washed with 40mL of purified water and dried at 55℃ to constant weight to obtain 3-nitro-4-phenoxy-5-sulfonamidobenzoic acid (47.3g, yield 49%).

[0054] (2) Preparation of 3-amino-4-phenoxy-5-sulfonamide benzoic acid

[0055] Add 40g of 3-nitro-4-phenoxy-5-sulfonamidobenzoic acid, 30g of ammonium formate, 400mL of methanol, and 0.8g of palladium on carbon (palladium mass fraction 10%) to a 1L reaction flask. Heat to 50℃ and react for 1h. Filter and concentrate the filtrate under reduced pressure at 45℃ until no distillate is precipitated. Add 400mL of purified water to the concentrate and stir at 25℃ for 30min. Add 21mL of glacial acetic acid, and a large amount of solid precipitates. Stir at 20-25℃ for 30min, filter, wash the filter cake with 80mL of purified water, and dry the filter cake at 55℃ to constant weight to obtain 3-amino-4-phenoxy-5-sulfonamidobenzoic acid (32.8g, yield 90%).

[0056] (3) Preparation of bumetanide

[0057] 3-Amino-4-phenoxy-5-sulfonamidobenzoic acid (90.82 mmol), tetrahydrofuran (280 mL), and sodium triacetoxyborohydride (90.82 mmol) were added to a 1 L reaction flask. Butyraldehyde (136.23 mmol) was added dropwise under stirring at 25 °C. After reacting for 1 h, 840 mL of purified water was added, and the mixture was stirred at 50 °C for 1 h. The mixture was then cooled to 20 °C, filtered, and the filter cake was washed with 140 mL of purified water. The filter cake was dried at 60 °C to constant weight to obtain bumetanide product (28.1 g, yield 85%, HPLC purity 99.8%).

[0058] Bumetanide structural characterization data: 1 HNMR(600MHz,DMSO):13.10(s,1H),7.72(s,1H),7.39(s,1H,),7.33(s,2H),7.23(t,2H,),7.03(t ,1H),6.82(s,2H,),5.03(t,1H),3.08(q,2H),1.31-1.37(m,2H),1.06-1.10(m,2H),0.77(d,3H).

[0059] Example 2

[0060] 28 g (90.82 mmol) of 3-amino-4-phenoxy-5-sulfonamide benzoic acid, 280 mL of N,N-dimethylformamide, and 136.23 mmol of sodium triacetoxyborohydride were added to a 1 L reaction flask. Butyraldehyde (136.23 mmol) was added dropwise at 25 °C with stirring. After reacting for 1 h, 840 mL of purified water was added and stirred at 50 °C for 1 h. The mixture was then cooled to 20 °C, filtered, and the filter cake was washed with 140 mL of purified water. The filter cake was dried at 60 °C with forced air to constant weight to obtain bumetanide product (29.4 g, yield 89%, HPLC purity 99.9%).

[0061] 28 g (90.82 mmol) of 3-amino-4-phenoxy-5-sulfonamide benzoic acid, 280 mL of acetonitrile, and 28.88 g (136.23 mmol) of sodium triacetoxyborohydride were added to a 1 L reaction flask. Butyraldehyde (13.09 g, 181.64 mmol) was added dropwise at 25 °C with stirring. After reacting for 2 h, 840 mL of purified water was added, and the mixture was stirred at 50 °C for 1 h. The mixture was then cooled to 20 °C, filtered, and the filter cake was washed with 140 mL of purified water. The filter cake was dried at 60 °C with forced air to constant weight to obtain bumetanide product (30.1 g, yield 91%, HPLC purity 99.9%).

[0062] Bumetanide structural characterization data: 1 HNMR(600MHz,DMSO):13.10(s,1H),7.72(s,1H),7.39(s,1H,),7.33(s,2H),7.23(t,2H,),7.03(t ,1H),6.82(s,2H,),5.03(t,1H),3.08(q,2H),1.31-1.37(m,2H),1.06-1.10(m,2H),0.77(d,3H).

[0063] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing bumetanide, characterized in that, Includes the following steps: 4-Chloro-3-nitro-5-sulfonamidobenzoic acid, an alkaline reagent, phenol, and water were mixed and subjected to a phenoxylation reaction. The resulting phenoxylation reaction solution was cooled to 0–5°C, and the pH was adjusted to 1–2. The mixture was stirred to induce crystallization, and a large amount of yellow solid precipitated. Stirring was continued for 20–30 min, followed by solid-liquid separation. The obtained solid product was washed with water and dried to obtain 3-nitro-4-phenoxy-5-sulfonamidobenzoic acid. The alkaline reagent included bicarbonate and / or carbonate. The molar ratio of 4-chloro-3-nitro-5-sulfonamidobenzoic acid to the alkaline reagent was 1:2.5–3. The molar ratio of 4-chloro-3-nitro-5-sulfonamidobenzoic acid to phenol was 1:2.2–2.

5. The 3-nitro-4-phenoxy-5-sulfonamidobenzoic acid, a reducing agent, and palladium on carbon are mixed and subjected to a reduction reaction to obtain 3-amino-4-phenoxy-5-sulfonamidobenzoic acid; the reducing agent includes one or more of ammonium formate, potassium formate, and formic acid; the reduction reaction is carried out at a temperature of 50-55°C for 1-2 hours. The 3-amino-4-phenoxy-5-sulfonamide benzoic acid, n-butyraldehyde, sodium triacetoxyborohydride, and an organic solvent were mixed and subjected to a reductive amination reaction to obtain bumetanide.

2. The preparation method according to claim 1, characterized in that, The phenoxylation reaction is carried out at a temperature of 80–90 °C for 16–17 h.

3. The preparation method according to claim 1, characterized in that, The molar ratio of 3-nitro-4-phenoxy-5-sulfonamide benzoic acid to the reducing agent is 1:3 to 4.

4. The preparation method according to claim 1, characterized in that, The mass ratio of 3-nitro-4-phenoxy-5-sulfonamide benzoic acid to palladium on carbon is 1:0.01 to 0.

02.

5. The preparation method according to claim 1, characterized in that, The molar ratio of 3-amino-4-phenoxy-5-sulfonamide benzoic acid to n-butyraldehyde is 1:1.5-2; The molar ratio of 3-amino-4-phenoxy-5-sulfonamide benzoic acid to sodium triacetoxyborohydride is 1:1 to 1.

5.

6. The preparation method according to claim 1, characterized in that, The organic solvent includes one or more of tetrahydrofuran, N,N-dimethylformamide, and acetonitrile.

7. The preparation method according to claim 1, 5, or 6, characterized in that, The reductive amination reaction is carried out at a temperature of 20–25°C for 1–2 hours.

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