A process for the preparation of bumetanide

Abstract

The application discloses a preparation process of bumetanide. 4-chloro-3-nitro-5-sulfamoylbenzoic acid is used as a starting material, and nucleophilic substitution is carried out with phenol in potassium hydroxide aqueous solution to obtain a compound with a structural formula Int01; in a methanol-water mixed solvent, palladium-carbon is used as a catalyst, and ammonium formate is used as a hydrogen source for transfer hydrogenation, so that the nitro group on the compound with the structural formula Int01 is reduced to an amino group, and a compound with a structural formula Int02 is obtained; the compound with the structural formula Int02 is subjected to reductive amination with n-butyl aldehyde and sodium triacetoxyborohydride to obtain a crude bumetanide product; after the crude bumetanide product is refined in an acetic acid and cyclohexane system, decolorization is carried out in methanol-water by using activated carbon, and crystallization is carried out to obtain a pure bumetanide product; and the pure bumetanide product is mixed with mannitol, an alkaline adjusting agent and taurine to obtain a finished product.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to a preparation process of bumetanide. BACKGROUND

[0002] Bumetanide is a strong diuretic, mainly used for the treatment of heart failure, liver disease, kidney disease edema, including various intractable edema and acute pulmonary edema, especially suitable for patients with acute and chronic renal failure. Its mechanism of action is to inhibit the active reabsorption of NaCl in the thick ascending limb of the loop of Henle, reduce the osmotic pressure, and reduce the concentrating function of the renal tubule, increase the excretion of water and electrolytes, thereby achieving diuretic effect. The chemical name of bumetanide is 5-n-butylamino-4-phenoxy-3-aminosulfonylbenzoic acid. The indications of bumetanide include edematous diseases (such as congestive heart failure, cirrhosis, kidney disease, etc.), hypertension, prevention of acute renal failure, hyperkalemia and hypercalcemia, dilution hyponatremia, syndrome of inappropriate antidiuretic hormone secretion (SIADH), acute drug poisoning, etc. It has the characteristics of high efficiency, rapid effect, short effect and low toxicity, and its maximum diuretic effect is the same as that of furosemide, but the required dose is only 1 / 50 of that of ethacrynic acid.

[0003] CN118986872A relates to the technical field of pharmaceutical preparations, in particular to a preparation method of bumetanide injection, comprising the following steps: adding polyethylene glycol, osmotic pressure additive, bumetanide and sodium hydroxide into water for injection, stirring until the drug solution is uniformly mixed, then filtering, finally performing filling and sealing and sterilization to obtain the bumetanide injection. The osmotic pressure additive is mannitol. The invention adds polyethylene glycol to the injection, which is a high molecular polymer that can control the release rate of the drug, avoid potential toxicity and side effects, and achieve a more stable therapeutic effect; at the same time, the water for injection used is 0.9% sodium chloride solution, which helps to improve the bioavailability of the drug in the body, and can also supplement the sodium content in the human body, avoiding sodium deficiency in the human body, so it has a wide application prospect.

[0004] CN118267349A relates to the technical field of medical technology, and in particular to a bumetanide injection, which is composed of the following components: bumetanide, xylitol, sodium dihydrogen phosphate and disodium hydrogen phosphate. The bumetanide injection of the invention ensures that the pH value of the drug solution is within the range of 7.3-7.7 while ensuring that bumetanide is completely dissolved. The invention also relates to a preparation method of bumetanide injection, which specifically comprises the following steps: (1) weighing 80% of the prescribed amount of water for injection; (2) weighing the prescribed amount of disodium hydrogen phosphate dodecahydrate, adding it to the water for injection and stirring to dissolve it; weighing the prescribed amount of bumetanide, adding it to the solution, stirring to dissolve it after ultrasonication; weighing the prescribed amount of xylitol, adding it to the solution and stirring to dissolve it; and adjusting the pH value of the drug solution to 7.3-7.7 with sodium dihydrogen phosphate; (3) fixing the volume; (4) filtering through a 0.22μm filter membrane; (5) filling and sealing; and (6) sterilizing by wet heat at 121℃ for 15 minutes. The preparation method of the invention is simple to operate and does not require operations such as activated carbon decolorization, thereby ensuring the content of the main drug. In addition, bumetanide is highly stable during the process, and the prepared bumetanide injection has better comprehensive performance.

[0005] Bumetanide is clinically available in tablet, lyophilized powder injection, and injection forms. The injection, due to its rapid action and high efficacy, is widely used in the treatment of edema, hypertension, and other conditions. However, bumetanide's poor solubility in water poses a challenge to its preparation and application.

[0006] During the preparation of bumetanide finished products, an alkaline solution (such as sodium hydroxide or potassium hydroxide) is typically used to dissolve bumetanide powder to improve its solubility. Subsequently, the pH of the solution is adjusted to 6.5 to 8.5 by adding buffer salts to ensure drug stability and efficacy. Furthermore, the preparation process includes steps such as activated carbon decolorization and fine filtration sterilization to further improve the purity and quality of the injection. While these methods can improve bumetanide solubility, they also pose several potential problems. First, the stability of bumetanide in alkaline solutions may be reduced, and more impurities may be generated during the dissolution process. Second, the addition of buffer salt solutions or acidic solutions to adjust the pH during the preparation process increases process complexity and may lead to uncontrollable factors in quality control. Therefore, finding more efficient and stable preparation methods to improve the quality of bumetanide injection and the safety of clinical applications is an important research direction. Summary of the Invention

[0007] In view of the above-mentioned defects in the prior art, the technical problem to be solved by the present invention is to provide a preparation process of bumetanide.

[0008] Bumetanide is a white crystalline powder, its chemical properties determine that it is poorly soluble in water, almost insoluble in water, but soluble in acetone and alcohol, slightly soluble in dichloromethane. However, bumetanide can be dissolved in dilute solutions of alkali hydroxides, such as sodium hydroxide or potassium hydroxide solution. This is because the molecule of bumetanide contains sulfonyl and amino groups, under alkaline conditions, these groups can form ionic bonds with hydroxyl ions, thereby increasing the solubility of bumetanide in solution. The pH value of the finished product of bumetanide needs to be maintained between 6.5-8.5, mainly to ensure the stability and effectiveness of the drug. Within this pH range, the chemical structure of bumetanide can remain stable and is not prone to decomposition or deterioration, thereby ensuring the efficacy and safety of the drug. In addition, the appropriate pH range also helps to reduce the irritation of the drug to the blood vessels, reduce the discomfort during injection, and reduce the risk of adverse reactions between the drug and blood components.

[0009] The present application takes 4-chloro-3-nitro-5-sulfamoylbenzoic acid as the starting material, and performs nucleophilic substitution with phenol in potassium hydroxide aqueous solution to obtain a compound of structural formula Int01. In a methanol-water mixed solvent, using palladium-carbon as a catalyst and ammonium formate as a hydrogen source, the nitro group on the compound of structural formula Int01 is reduced to an amino group to obtain a compound of structural formula Int02. The compound of structural formula Int02 is subjected to reductive amination with n-butyl aldehyde and sodium triacetoxyborohydride to obtain a crude product of bumetanide. After refining in an acetic acid-cyclohexane system, the crude product of bumetanide is decolorized with activated carbon in methanol-water, and crystallized to obtain a pure product of bumetanide. The pure product of bumetanide is mixed with mannitol, an alkaline adjusting agent, and taurine to prepare a finished product. Taurine, as a sulfur-containing amino acid, can improve stability, and the alkaline adjusting agent is prepared from a carrier and an alkaline substance. The buffering effect after loading can avoid direct exposure of bumetanide to an alkaline environment, thereby affecting stability. The addition of the alkaline adjusting agent and taurine also avoids the need to add a buffer salt solution or an acidic solution to adjust the pH value later, which may result in uncontrollable quality problems.

[0010] Bumetanide can be dissolved in a dilute solution of alkali hydroxide, such as sodium hydroxide or potassium hydroxide solution. This is because the molecule of bumetanide contains sulfonyl and amino groups, which can form ionic bonds with hydroxyl ions under alkaline conditions, thereby increasing the solubility of bumetanide in solution. However, the safety of sodium hydroxide and potassium hydroxide is lower than that of magnesium hydroxide, aluminum hydroxide and calcium hydroxide, and magnesium hydroxide not only has good biocompatibility and low toxicity, but also is a stabilizer itself, so it can improve the physical properties and stability of the drug, while aluminum hydroxide and calcium hydroxide do not have the effect of stabilizer, so the effect may be poor in maintaining the stability of bumetanide. The solubility of magnesium hydroxide, aluminum hydroxide and calcium hydroxide in water is not high, so the application uses N,O-carboxymethyl chitosan with good water solubility as a carrier to load alkaline substances, thereby obtaining an alkaline regulator. In the preparation process of N,O-carboxymethyl chitosan, carboxymethyl will be substituted on the hydroxyl group and the amino group to generate O-carboxymethyl and N-carboxymethyl chitosan, so the water solubility is very good. The alkaline regulator not only provides an alkaline environment, but also is safer and milder, thereby greatly improving the stability of the effective ingredient of bumetanide.

[0011] To achieve the above-mentioned purpose, the application provides a preparation process of bumetanide, comprising the following steps:

[0012] S1, adding 4-chloro-3-nitro-5-sulfamoylbenzoic acid structural formula SM01, sodium iso-octoate to a solvent, heating to 55-60℃ and stirring for 20-40min, then cooling to 35-45℃, adding phenol structural formula SM02, and then adding potassium hydroxide in batches and heating to 85-90℃, and then reacting for 22-26h, until the peak area of 4-chloro-3-nitro-5-sulfamoylbenzoic acid structural formula SM01 is ≤5.0%, which is considered as the completion of the reaction, cooling to 50-60℃, adding solvent and acid respectively, and then cooling to 15-25℃ for crystallization for 1-3h, filtering, washing and drying the filter cake, and then adding to an alkali solution and an acid solution, stirring respectively, cooling to 5-15℃ for crystallization, filtering, washing and drying, and collecting the material with water content ≤3.0%, to obtain a compound of structural formula Int01;

[0013]

[0014] S2. Add a compound of the structural formula Int01 and 10 wt% palladium carbon to a solvent, continue to add solvent, raise the temperature to 45-55 ° C under a nitrogen atmosphere, add ammonium formate solution dropwise, react until the peak area ratio of the compound of the structural formula Int01 is ≤0.5%, and consider the reaction to be complete, filter, and distill the filtrate under reduced pressure until a large amount of solid is precipitated, add water thereto, and continue to distill under reduced pressure until no liquid flows out, add water to the residue, add acid at 40-50 ° C, crystallize, filter, and wash, mix the filter cake with the solvent, add acid, beat at 50-60 ° C for 1-2 h, cool to 20-30 ° C for crystallization for 0.5-1 h, filter, wash, and dry the filter cake to a moisture content of ≤1.0% before collecting the material to obtain a compound of the structural formula Int02;

[0015]

[0016] S3. Add sodium triacetoxyborohydride and a compound of the structural formula Int02 to a solvent and glacial acetic acid at 10-15°C, and mix n-butyraldehyde structural formula SM03 with a solvent to obtain an n-butyraldehyde solution. Add 55 wt% n-butyraldehyde solution dropwise to the reaction system, react at 10-15°C for 0.5-1.5 h after the addition is complete, continue to add 22.5 wt% n-butyraldehyde solution dropwise, react at 10-15°C for 0.5-1.5 h after the addition is complete, and continue to add the remaining n-butyraldehyde solution dropwise. After the addition is complete, react at 10-15°C until the peak area ratio of the compound of the structural formula Int02 is ≤9.0%, which is considered complete. Add a solvent to the system for quenching, let it stand, separate the layers, retain the organic phase, extract the aqueous phase, let it stand, separate the layers to obtain the organic phase; combine the two obtained The organic phase is washed with brine and water, and then allowed to stand for separation. The organic phase is mixed with an alkaline solution, stirred for 5 to 15 minutes, and then allowed to stand. The aqueous layer is separated for use. The alkaline solution is continued to be added to the organic layer, stirred for 5 to 15 minutes, and then allowed to stand. The aqueous layer is separated for use. The two aqueous layers are combined, acid is added at 20 to 30° C. to adjust the pH to 5 to 6, and a solid is precipitated. After filtering and washing, a filter cake is obtained. The filter cake is mixed with the solvent and heated to 75 to 80° C., acid is added, and the temperature is lowered to 15 to 20° C., stirred for 20 to 40 minutes, filtered, washed, and the filter cake is dried to a moisture content of ≤0.5% to obtain a crude bumetanide product. The crude bumetanide product is purified by glacial acetic acid and cyclohexane to obtain a refined bumetanide product. The refined bumetanide product is decolorized in methanol-water using activated carbon, and crystallized for 0.5 to 1.5 hours to obtain a pure bumetanide product.

[0017] S4. Add pure bumetanide, taurine, and mannitol to water, stir evenly, then add alkaline regulator, add enough water, filter, fill, and sterilize.

[0018] Further, the mass ratio of the 4-chloro-3-nitro-5-sulfamoylbenzoic acid with structural formula SM01, sodium iso-octanoate, phenol with structural formula SM02, potassium hydroxide is 1:0.6-0.64:1.05-1.09:0.78-0.82.

[0019] Further, the mass ratio of the compound with structural formula Int01, 10wt% palladium-carbon and ammonium formate is 1:0.09-0.11:1.38-1.42.

[0020] Further, the mass ratio of the compound with structural formula Int02, glacial acetic acid, sodium triacetoxyborohydride and n-butyl aldehyde with structural formula SM03 is 1:0.6-0.62:3.9-3.94:0.5-0.54.

[0021] Further, the added amount of the pure bumetanide is 0.1-0.5mg / mL, based on water.

[0022] Further, the molar ratio of the bumetanide to taurine is 1:0.2-0.3.

[0023] Further, the added amount of the mannitol is 5-15g / L, based on water.

[0024] Further, the mass ratio of the bumetanide to the alkaline adjusting agent is 1:0.5-1, based on water.

[0025] The preparation method of the alkaline adjusting agent comprises the following steps:

[0026] After mixing the alkaline solution of N,O-carboxymethyl chitosan with the alkaline substance, the mixture is ultrasonically dispersed for 1-2h, then a crosslinking agent is added, and after stirring, the solvent is removed by drying to obtain the product.

[0027] Further, the mass ratio of the N,O-carboxymethyl chitosan to the alkaline substance is 1:2-5.

[0028] Further, the preparation method of the alkaline adjusting agent comprises the following steps:

[0029] After mixing the 1wt% sodium hydroxide aqueous solution of N,O-carboxymethyl chitosan with the alkaline substance, the mixture is ultrasonically dispersed for 1-2h, then 0.5wt% sodium tripolyphosphate is added, and after stirring for 1-2h, the solvent is removed by drying to obtain the product, and the mass ratio of the N,O-carboxymethyl chitosan to the alkaline substance is 1:2-5.

[0030] Preferably, the alkaline substance is one of magnesium hydroxide, aluminum hydroxide and calcium hydroxide.

[0031] The beneficial effects of the present application are:

[0032] 1. The application takes 4-chloro-3-nitro-5-sulfamoylbenzoic acid as a starting material, and performs nucleophilic substitution with phenol in potassium hydroxide aqueous solution to obtain a compound of structural formula Int01, and performs transfer hydrogenation in a methanol-water mixed solvent using palladium-carbon as a catalyst and ammonium formate as a hydrogen source to reduce the nitro group on the compound of structural formula Int01 to an amino group to obtain a compound of structural formula Int02; the compound of structural formula Int02 is subjected to reductive amination with n-butyraldehyde and sodium triacetoxyborohydride to obtain a crude bumetanide product, which is refined in an acetic acid-cyclohexane system, decolorized with activated carbon in methanol-water, and crystallized to obtain pure bumetanide.

[0033] 2. The pure bumetanide is mixed with mannitol, an alkaline adjusting agent, and taurine to obtain a finished product. Taurine, as a sulfur-containing amino acid, can improve stability. The alkaline adjusting agent is prepared from a carrier and an alkaline substance. The buffering effect of the carrier after loading can avoid direct exposure of bumetanide to an alkaline environment, thereby affecting the stability. The addition of the alkaline adjusting agent and taurine also avoids the need to add a buffer salt solution or an acidic solution to adjust the pH value later, which may result in uncontrollable quality problems. DETAILED DESCRIPTION

[0034] Example 1

[0035] A preparation process of bumetanide, comprising the following steps:

[0036] S1, 4-chloro-3-nitro-5-sulfamoylbenzoic acid of structural formula SM01 2.3 kg, sodium iso-octanoate 1.43 kg, and water 46 kg are added, and stirred at 58°C for 30 min, then cooled to 40°C, phenol of structural formula SM02 2.47 kg is added, and potassium hydroxide 1.84 kg is added in batches, then heated to 88°C, and reacted for 24 h, until the peak area of 4-chloro-3-nitro-5-sulfamoylbenzoic acid of structural formula SM01 is ≤5.0%, which is considered as the completion of the reaction, then cooled to 55°C, added with toluene and 36 wt% concentrated hydrochloric acid, then cooled to 20°C, and crystallized for 2 h, filtered, and the filter cake is washed, dried, and then added to 2 wt% sodium hydroxide aqueous solution and glacial acetic acid, respectively, stirred, cooled to 10°C, crystallized for 2 h, filtered, washed, and dried, and the moisture content is ≤3.0%, to obtain a compound of structural formula Int01;

[0037] S2, to methanol 10.48 kg was added compound of structural formula Int01 1.31 kg and 10 wt% palladium on carbon 0.131 kg, water 0.131 kg was continuously added, heated to 50 °C under nitrogen atmosphere, dropwise added ammonium formate solution, ammonium formate solution was ammonium formate 1.83 kg, water 1.834 kg in methanol 5.48 kg, the reaction was considered complete when the peak area ratio of compound of structural formula Int01 was ≤0.5%, filtered, the filtrate was distilled under reduced pressure until a large amount of solid was precipitated, then water was added and distilled under reduced pressure until no liquid flowed out, ice acetic acid was added to the residue at 45 °C, crystallized for 1 h, filtered, washed, the filter cake was mixed with water and methanol, then 36 wt% concentrated hydrochloric acid was added and the mixture was paddled at 55 °C for 1.5 h, cooled to 25 °C and crystallized for 45 min, filtered, washed, the filter cake was dried to a moisture content of ≤1.0% and the compound of structural formula Int02 was obtained;

[0038] S3, to 2-methyltetrahydrofuran 8.9 kg and glacial acetic acid 0.543 kg at 12 °C, add sodium triacetoxyborohydride 3.49 kg and compound of structural formula Int02 0.89 kg, and further mix n-butyraldehyde of structural formula SM03 0.450 kg with 2-methyltetrahydrofuran 8.9 kg to obtain a n-butyraldehyde solution, dropwise add the n-butyraldehyde solution to the reaction system, after the dropwise addition is completed, react at 12 °C for 1 h, continue to dropwise add the n-butyraldehyde solution of 22.5 wt%, after the dropwise addition is completed, react at 12 °C for 1 h, and then continue to dropwise add the remaining n-butyraldehyde solution, after the dropwise addition is completed, react at 12 °C until the peak area ratio of the compound of structural formula Int02 is ≤9.0% to consider that the reaction is complete, add methanol and water to quench the system, and then stand still, separate the layers, reserve the organic phase, extract the aqueous phase, stand still, separate the layers to obtain the organic phase, combine the organic phases obtained twice, wash with saturated brine, stand still, separate the layers to obtain the organic phase, mix the organic phase with 13 wt% sodium hydroxide aqueous solution, stir for 10 min, stand still, separate the water layer for standby, continue to add 13 wt% sodium hydroxide aqueous solution to the organic layer, stir for 10 min, stand still, separate the water layer for standby, combine the two water layers, add 36 wt% concentrated hydrochloric acid at 25 °C to adjust the pH to 5.5, and precipitate the solid, filter and wash to obtain a filter cake, mix the filter cake with ethylene glycol dimethyl ether and water, heat to 78 °C, add 36 wt% concentrated hydrochloric acid, cool to 18 °C, stir for 30 min, filter and wash, dry the filter cake until the water content is ≤0.5%, and then collect the material to obtain a crude bumetanide, heat glacial acetic acid 8.62 kg to 92 °C, add the crude bumetanide 0.98 kg, cool to 78 °C, dropwise add cyclohexane 12.15 kg, after the addition is completed, cool the system to 18 °C, stir for 30 min, and then filter and wash, add glacial acetic acid 7.79 kg to the filter cake to stir and dissolve at 92 °C, immediately cool to 78 °C, dropwise add cyclohexane 10.93 kg, after the addition is completed, cool the system to 18 °C, stir for 30 min, filter and wash, dry and collect the material to obtain a fine bumetanide, add activated carbon 0.04 kg and the fine bumetanide 0.81 kg to methanol 9.72 kg and water 4.05 kg, heat to 72 °C, stir for 30 min, control the pressure to be <0.2 MPa, filter, filter through a 1 μm titanium rod filter and a 0.22 μm microporous filter, cool the material liquid to 8 °C, stir for 60 min, centrifuge until dry, use pre-cooled 8 °C 70 wt% methanol aqueous solution to elute the filter cake, centrifuge until dry, dry until the water content is ≤0.5%, and then collect the material to obtain a pure bumetanide.

[0039] Example 2

[0040] A preparation process of bumetanide, comprising the following steps:

[0041] S1, to 46 kg of water, add 4-chloro-3-nitro-5-sulfamoylbenzoic acid of structural formula SM012.3 kg, sodium iso-octoate 1.43 kg, heat to 58°C and stir for 30 min, then cool to 40°C, add phenol of structural formula SM022.47 kg, add potassium hydroxide 1.84 kg in batches, then heat to 88°C, react for 24 h, then 4-chloro-3-nitro-5-sulfamoylbenzoic acid of structural formula SM01 peak area ≤5.0% is considered to be completed, cool to 55°C, add toluene and 36 wt% concentrated hydrochloric acid, then cool to 20°C, crystallize for 2 h, filter, wash and dry the filter cake, then add to 2 wt% sodium hydroxide aqueous solution and glacial acetic acid, stir, cool to 10°C, crystallize for 2 h, filter, wash and dry, and collect the material with water content ≤3.0%, to obtain the compound of structural formula Int01;

[0042] S2, to 10.48 kg of methanol, add 1.31 kg of the compound of structural formula Int01 and 10 wt% palladium on carbon 0.131 kg, continue to add 0.131 kg of water, heat to 50°C under nitrogen atmosphere, and dropwise add ammonium formate solution, ammonium formate solution: methanol 5.48 kg, ammonium formate 1.83 kg, water 1.834 kg, react until the peak area ratio of the compound of structural formula Int01 ≤0.5% is considered to be completed, filter, distill the filtrate under reduced pressure until a large amount of solid is precipitated, then add water to continue distillation under reduced pressure until no liquid is discharged, add glacial acetic acid to the residue at 45°C, crystallize for 1 h, filter, wash, mix the filter cake with water and methanol, add 36 wt% concentrated hydrochloric acid at 55°C, and pulp for 1.5 h, cool to 25°C, crystallize for 45 min, filter, wash, dry the filter cake to a water content ≤1.0%, and collect the material, to obtain the compound of structural formula Int02;

[0043] S3, to 2-methyltetrahydrofuran 8.9 kg and glacial acetic acid 0.543 kg, add sodium triacetoxyborohydride 3.49 kg and the compound of structural formula Int02 0.89 kg, and further mix n-butyraldehyde of structural formula SM03 0.45 kg with 2-methyltetrahydrofuran 8.9 kg to obtain a n-butyraldehyde solution, dropwise add the n-butyraldehyde solution with a concentration of 55 wt% to the reaction system, after the dropwise addition is completed, react at 12℃ for 1 h, continue to dropwise add the n-butyraldehyde solution with a concentration of 22.5 wt%, after the dropwise addition is completed, react at 12℃ for 1 h, then continue to dropwise add the remaining n-butyraldehyde solution, after the dropwise addition is completed, react at 12℃ until the peak area ratio of the compound of structural formula Int02 is ≤9.0% to consider that the reaction is complete, add methanol and water to quench the system, then stand, separate the organic phase, extract the aqueous phase, then stand, separate the organic phase, combine the organic phases obtained twice, wash with brine and water, then stand to separate the organic phase, mix the organic phase with a 13 wt% sodium hydroxide aqueous solution, stir for 10 min, then stand, separate the water layer for standby, continue to add the 13 wt% sodium hydroxide aqueous solution to the organic layer, stir for 10 min, then stand, separate the water layer for standby, combine the two water layers, add 36 wt% concentrated hydrochloric acid at 25℃ to adjust the pH to 5.5, precipitate the solid, filter and wash to obtain a filter cake, mix the filter cake with ethylene glycol dimethyl ether and water, then heat to 78℃, add 36 wt% concentrated hydrochloric acid, cool to 18℃, stir for 30 min, filter and wash, dry the filter cake until the water content is ≤0.5%, then collect the material to obtain a crude bumetanide, heat glacial acetic acid 8.62 kg to 92℃, then add the crude bumetanide 0.98 kg, cool to 78℃, dropwise add cyclohexane 12.15 kg, after the addition is completed, cool the system to 18℃, stir for 30 min, then filter and wash, add glacial acetic acid 7.79 kg to the filter cake, stir to dissolve at 92℃, then immediately cool to 78℃, dropwise add cyclohexane 10.93 kg, after the addition is completed, cool the system to 18℃, stir for 30 min, then filter and wash, dry and collect the material to obtain a fine bumetanide, add activated carbon 0.04 kg and the fine bumetanide 0.81 kg to methanol 9.72 kg and water 4.05 kg, heat to 72℃, stir for 30 min, control the pressure to be <0.2 MPa, filter under pressure, filter the material through a titanium rod filter with a pore size of 1 μm and a micro porous filter with a pore size of 0.22 μm, then cool the material to 8℃, stir for 60 min to precipitate crystals, centrifuge the material until dry, use pre-cooled 70 wt% methanol aqueous solution to elute the filter cake, centrifuge the material until dry, dry until the water content is ≤0.5%, then collect the material to obtain a pure bumetanide;

[0044] S4, add 250 mg of the pure bumetanide, 18 mg of taurine and 10 g of mannitol to 500 mL of water, stir until uniform, then add 150 mg of an alkaline adjusting agent, make up the volume to 1000 mL, filter, fill, sterilize and obtain the product.

[0045] The preparation method of the alkaline adjusting agent comprises the following steps:

[0046] The 1wt% sodium hydroxide aqueous solution of N,O-carboxymethyl chitosan was mixed with aluminum hydroxide, the mass ratio of N,O-carboxymethyl chitosan to aluminum hydroxide was 1:2.5, 0.5wt% sodium tripolyphosphate was added after ultrasonic dispersion for 1h, and the solvent was removed after stirring for 2h and drying to obtain.

[0047] Example 3

[0048] The same as Example 2, the only difference is that the aluminum hydroxide is replaced by calcium hydroxide.

[0049] Example 4

[0050] The same as Example 2, the only difference is that the aluminum hydroxide is replaced by magnesium hydroxide.

[0051] Comparative Example 1

[0052] The same as Example 2, the only difference is that the basic regulator is replaced by sodium hydroxide.

[0053] Test Example 1

[0054] The bumetanide products obtained in the examples and comparative examples were placed at 60℃, relative humidity 80% for 6 months, and samples were taken at 0th month, 1st month, 2nd month, 3rd month and 6th month respectively for pH, content, clarity detection, the specific data are shown in Table 1.

[0055] Table 1 Stability test of bumetanide product

[0056]

[0057]

[0058] From Table 1, it can be seen that the stability of the bumetanide product in the examples is better than that in the comparative examples, which may be due to the fact that the sodium hydroxide used in Comparative Example 1 is not loaded, so the alkaline environment formed is not buffered, which may reduce the stability of bumetanide, resulting in the stability being affected.

[0059] The stability of Example 4 is better than that of Examples 2-3, which can be due to the fact that magnesium hydroxide itself is a stabilizer, and thus can improve the physical properties and stability of the drug, while aluminum hydroxide and calcium hydroxide do not have the effect of a stabilizer, and thus can be less effective in maintaining the stability of bumetanide. In addition, magnesium hydroxide also has good biocompatibility and low toxicity. Since magnesium hydroxide, aluminum hydroxide and calcium hydroxide have low solubility in water, the present application uses N,O-carboxymethyl chitosan with good water solubility as a carrier to load the basic substance, thereby obtaining the basic regulator. During the preparation of N,O-carboxymethyl chitosan, the carboxymethyl group can be substituted on the hydroxyl group and the amino group to form O-carboxymethyl and N-carboxymethyl chitosan, thus having good water solubility. The basic regulator not only provides an alkaline environment, but is also safer and milder, thereby greatly improving the stability of the bumetanide active ingredient.

[0060] The pure bumetanide is mixed with mannitol, a basic regulator, and taurine to prepare the finished product. Taurine, as a sulfur-containing amino acid, can improve stability, while the basic regulator is prepared from a carrier and a basic substance. The buffering effect after loading can avoid direct exposure of bumetanide to an alkaline environment, thereby affecting stability. The addition of the basic regulator and taurine also avoids the need to add a buffer salt solution or an acidic solution to adjust the pH value later, which can lead to quality control problems.

[0061] The above describes the preferred embodiments of the present application in detail. It should be understood that those skilled in the art can make many modifications and changes to the present application without creative labor, based on the concept of the present application. Therefore, any technical solution that can be obtained by logical analysis, reasoning or limited experiments by those skilled in the art based on the prior art and the concept of the present application shall be within the scope of protection determined by the claims.

Claims

1. A process for the preparation of bumetanide, characterized in that, The steps include: S1. Add 4-chloro-3-nitro-5-sulfamoylbenzoic acid structural formula SM01 and sodium isooctanoate to the solvent, heat to 55-60°C and stir for 20-40 minutes, then cool to 35-45°C, add phenol structural formula SM02, add potassium hydroxide in batches, heat to 85-90°C, react for 22-26 hours, and consider the reaction complete when the peak area of ​​4-chloro-3-nitro-5-sulfamoylbenzoic acid structural formula SM01 is ≤5.0%. Cool to 50-60°C, add solvent and acid respectively, cool to 15-25°C, crystallize for 1-3 hours, filter, wash and dry the filter cake, add alkaline solution and acid solution after washing and drying, stir respectively, cool to 5-15°C, crystallize, filter, wash and dry, and the moisture content is ≤3.0%. The material is collected to obtain a compound of structural formula Int01; S2. Add the compound of structural formula Int01 and 10 wt% palladium carbon to the solvent, continue to add solvent, heat to 45-55 ° C under nitrogen atmosphere, add ammonium formate solution dropwise, react until the peak area ratio of the compound of structural formula Int01 is ≤0.5%, and consider the reaction to be complete, filter, and distill the filtrate under reduced pressure until a large amount of solid precipitates, add water thereto, and continue to distill under reduced pressure until no liquid flows out, add water to the residue, add acid at 40-50 ° C, crystallize, filter, wash, mix the filter cake with the solvent, add acid, beat at 50-60 ° C for 1-2 hours, cool to 20-30 ° C, crystallize for 0.5-1 hour, filter, Washing, drying the filter cake until the moisture content is ≤1.0%, and then collecting the material to obtain a compound of structural formula Int02; S3, at 10-15℃, to the solvent and glacial acetic acid, add sodium triacetoxyborohydride and the compound of structural formula Int02, also mix the n-butyraldehyde of structural formula SM03 with solvent to obtain n-butyraldehyde solution, drop 55wt% n-butyraldehyde solution into the reaction system, after dropwise addition is completed, react at 10-15℃ for 0.5-1.5h, continue to dropwise add 22.5wt% n-butyraldehyde solution, after dropwise addition is completed, react at 10-15℃ for 0.5-1.5h, then continue to dropwise add the remaining n-butyraldehyde solution, after dropwise addition is completed, react at 10-15℃ until the peak area ratio of the compound of structural formula Int02 is ≤9.0% to consider that the reaction is complete, add solvent to the system for quenching, then stand, separate the layers, reserve the organic phase, extract the aqueous phase, stand, separate the layers to obtain the organic phase; combine the organic phases obtained twice, wash with brine and water, then stand and separate the layers to obtain the organic phase, mix the organic phase with base solution, stir for 5-15min, then stand, separate the water layer for standby, continue to add base solution to the organic layer, stir for 5-15min, then stand, separate the water layer for standby, combine the two water layers, add acid to adjust the pH to 5-6 at 20-30℃, precipitate solid, filter and wash to obtain filter cake, mix the filter cake with solvent, then warm to 75-80℃, add acid, cool to 15-20℃, stir for 20-40min, then filter and wash, dry the filter cake until the moisture content is ≤0.5% to obtain crude bumetanide, refine the crude bumetanide with glacial acetic acid and cyclohexane to obtain fine bumetanide, use activated carbon in methanol-water to decolorize and crystallize for 0.5-1.5h to obtain pure bumetanide; S4. Add pure bumetanide, taurine, and mannitol to water, stir evenly, then add an alkaline regulator, make up with enough water, filter, fill, and sterilize. The preparation method of the alkaline regulator comprises the following steps: After mixing 1 wt% sodium hydroxide aqueous solution of N,O-carboxymethyl chitosan with an alkaline substance, ultrasonically disperse the mixture for 1 to 2 hours, add 0.5 wt% sodium tripolyphosphate, stir the mixture for 1 to 2 hours, and then dry and remove the solvent to obtain the product. The mass ratio of N,O-carboxymethyl chitosan to the alkaline substance is 1:2 to 5. The alkaline substance is one of magnesium hydroxide, aluminum hydroxide and calcium hydroxide.

2. The process for the preparation of bumetanide as claimed in claim 1, wherein, The mass ratio of 4-chloro-3-nitro-5-sulfamoylbenzoic acid structural formula SM01, sodium isooctanoate, phenol structural formula SM02, and potassium hydroxide in step S1 is 1:0.6-0.64:1.05-1.09:0.78-0.

82.

3. The process for the preparation of bumetanide as claimed in claim 1, wherein, In step S2, the mass ratio of the compound of structural formula Int01, 10 wt % palladium carbon, and ammonium formate is 1:0.09-0.11:1.38-1.

42.

4. The process for the preparation of bumetanide as claimed in claim 1, wherein, The mass ratio of the compound of structural formula Int02 in step S3 to glacial acetic acid, sodium triacetoxyborohydride, and n-butyraldehyde structural formula SM03 is 1:0.6-0.62:3.9-3.94:0.5-0.

54.

5. The process for the preparation of bumetanide as claimed in claim 1, wherein, The amount of pure bumetanide added in step S4 is 0.1-0.5 mg / mL, based on water.

6. The process for the preparation of bumetanide as claimed in claim 1, wherein, The molar ratio of bumetanide to taurine in step S4 is 1:0.2-0.

3.

7. The process for the preparation of bumetanide as claimed in claim 1, wherein, The amount of mannitol added in step S4 is 5 to 15 g / L, based on water.

8. The process for the preparation of bumetanide as claimed in claim 1, wherein, The mass ratio of bumetanide to the basicity adjusting agent is 1:0.5 to 1, based on water.

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