Preparation process of bumetanib

Abstract

The invention discloses a preparation process of bumetanib. The preparation method comprises the following steps: carrying out nucleophilic substitution on 4-chloro-3-nitro-5-sulfamoyl benzoic acid serving as a starting material and phenol in a potassium hydroxide aqueous solution to obtain a compound with a structural formula Int01, carrying out transfer hydrogenation in a methanol-water mixed solvent by using palladium on carbon as a catalyst and ammonium formate as a hydrogen source, reducing nitro on the compound with the structural formula Int01 into amino, and carrying out recrystallization to obtain the compound with the structural formula Int01. The compound with the structural formula Int02 is obtained; the preparation method comprises the following steps: carrying out reductive amination on the compound with the structural formula Int02, n-butyraldehyde and sodium triacetoxyborohydride to obtain a bumetanib crude product, refining the bumetanib crude product in a glacial acetic acid and cyclohexane system, decolorizing the refined bumetanib crude product in methanol-water by using activated carbon, and crystallizing to obtain a pure bumetanib product. And mixing the pure bumetanib with mannitol, an alkaline regulator and taurine to prepare a finished product.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a preparation process of bumetanide. Background Art

[0002] Bumetanide is a potent diuretic, mainly used to treat edema caused by heart failure, liver disease, and kidney disease, including various refractory edema and acute pulmonary edema, and is especially suitable for patients with acute and chronic renal failure. Its mechanism of action is to inhibit the active reabsorption of NaCl by the thick ascending limb of the renal tubular loop, reduce osmotic pressure, reduce the concentrating function of the renal tubules, and increase the excretion of water and electrolytes, thereby achieving a 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, dilutional hyponatremia, antidiuretic hormone hypersecretion (SIADH), acute drug poisoning, etc. It has the characteristics of high efficiency, rapid effect, short effect and low toxicity. Its maximum diuretic effect is the same as furosemide, but the required dose is only 1 / 50 of ethacrynic acid.

[0003] CN118986872A relates to the technical field of pharmaceutical preparations, and specifically to a method for preparing bumetanide injection, comprising the following steps: adding polyethylene glycol, an osmotic pressure additive, bumetanide, and sodium hydroxide to water for injection, stirring until the liquid medicine is evenly mixed and then filtering, and finally filling and sterilizing to obtain bumetanide injection. The osmotic pressure additive is mannitol. The invention adds polyethylene glycol to the injection, and the high molecular polymer 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 a 0.9% sodium chloride solution, which, as a drug solvent, helps to improve the bioavailability of the drug in the body, and can also supplement the sodium content of the human body to avoid sodium deficiency in the human body, so it has a wide range of application prospects.

[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 bumetanide is completely dissolved while ensuring that the pH value of the drug solution is within the range of 7.3-7.7. The invention also relates to a preparation method for bumetanide injection, which specifically comprises the following steps: (1) weighing a prescription amount of 80% water for injection; (2) weighing a prescription amount of disodium hydrogen phosphate dodecahydrate, adding it to the water for injection and stirring to dissolve; weighing a prescription amount of bumetanide, adding it to the solution, stirring to dissolve it after ultrasonication; weighing a prescription 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; (6) sterilizing by wet heat at 121℃ for 15min. 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 mainly available in the form of tablets, lyophilized powder injections and injections in clinical applications. The injection is widely used in the treatment of edema diseases, hypertension and other diseases due to its rapid action and high efficiency. However, bumetanide has poor solubility in water, which poses a challenge to the preparation and application of its injection.

[0006] In the preparation process of bumetanide finished product, in order to improve its solubility, an alkaline solution (such as sodium hydroxide or potassium hydroxide) is usually used to dissolve bumetanide powder. Subsequently, the pH value of the solution is adjusted to 6.5 to 8.5 by adding buffer salts to ensure the stability and effectiveness of the drug. In addition, the preparation process also includes steps such as activated carbon decolorization and fine filtration sterilization to further improve the purity and quality of the injection. Although these methods can improve the solubility of bumetanide, they also bring some potential problems. First, the stability of bumetanide in alkaline solution may be reduced, and more impurities may be generated during the dissolution process. Secondly, the addition of buffered salt solution or acidic solution to adjust the pH value during the preparation process increases the complexity of the process and may lead to uncontrollable factors in quality control. Therefore, finding a more effective and stable preparation method to improve the quality of bumetanide injection and the safety of clinical application is an important research direction. Summary of the invention

[0007] In view of the above-mentioned defects of 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 has poor solubility in water and is almost insoluble in water, but it is soluble in acetone and alcohol and slightly soluble in dichloromethane. However, bumetanide can be dissolved in dilute solutions of alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide solutions. This is because the bumetanide molecule contains sulfonyl and amino groups. Under alkaline conditions, these groups can form ionic bonds with hydroxide ions, thereby increasing the solubility of bumetanide in solution. The pH value of the finished bumetanide product 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 stimulation 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 invention uses 4-chloro-3-nitro-5-sulfamoylbenzoic acid as a starting material, and performs nucleophilic substitution with phenol in a potassium hydroxide aqueous solution to obtain a compound of structural formula Int01; palladium carbon is used as a catalyst and ammonium formate is used as a hydrogen source to perform transfer hydrogenation in a methanol-water mixed solvent 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; the crude bumetanide product is refined in a glacial acetic acid and cyclohexane system, and then decolorized in methanol-water using activated carbon, and crystallized to obtain a pure bumetanide product. The finished product is prepared by mixing pure bumetanide with mannitol, an alkaline regulator and taurine. Taurine, as a sulfur-containing amino acid, can improve stability, and the alkaline regulator is prepared from a carrier and an alkaline substance. The buffering effect after loading can prevent bumetanide from being directly exposed to an alkaline environment, thereby affecting the stability. The addition of the alkaline regulator and taurine also avoids the need to add a buffered salt solution or an acidic solution to adjust the pH value at a later stage, which may lead to uncontrollable quality problems.

[0010] Bumetanide can be dissolved in a dilute solution of an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide solution. This is because the bumetanide molecule contains sulfonyl and amino groups, and under alkaline conditions, these groups can form ionic bonds with hydroxide ions, thereby increasing the solubility of bumetanide in the 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 is also a stabilizer, so it can improve the physical properties and stability of the drug, while aluminum hydroxide and calcium hydroxide do not have the effect of stabilizers, so they may be less effective in maintaining the stability of bumetanide. However, magnesium hydroxide, aluminum hydroxide and calcium hydroxide are not highly soluble in water. Therefore, in the present invention, N, O-carboxymethyl chitosan with good water solubility is used as a carrier to load an alkaline substance, thereby obtaining an alkaline regulator. During the preparation process of N, O-carboxymethyl chitosan, the carboxymethyl group is substituted on both 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 is also safer and milder, thereby greatly improving the stability of the bumetanide effective ingredient.

[0011] To achieve the above object, the present invention provides a preparation process of bumetanide, comprising the following steps:

[0012] 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 20-40min, then cool to 35-45°C, add phenol structural formula SM02, add potassium hydroxide in batches and heat to 85-90°C, react for 22-26h, and consider the reaction to be 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 for crystallization for 1-3h, filter, wash and dry the filter cake, add it to alkaline solution and acid solution, stir respectively, cool to 5-15°C for crystallization, filter, wash and dry, and collect the material with moisture ≤3.0% to obtain the compound of structural formula Int01;

[0013]

[0014] S2, add the compound of structural formula Int01 and 10wt% 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 the reaction is considered complete, filter, and distill the filtrate under reduced pressure until a large amount of solid is precipitated, then 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 1-2h, cool to 20-30°C, crystallize for 0.5-1h, filter, wash, dry the filter cake until the moisture content is ≤1.0%, and then collect the material to obtain the compound of 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, mix n-butyraldehyde structural formula SM03 with a solvent to obtain a n-butyraldehyde solution, drip 55wt% of the n-butyraldehyde solution into the reaction system, react at 10-15°C for 0.5-1.5h after the addition is complete, continue to drip 22.5wt% of the n-butyraldehyde solution, react at 10-15°C for 0.5-1.5h after the addition is complete, and then continue to drip the remaining n-butyraldehyde solution, react at 10-15°C until the peak area ratio of the compound of the structural formula Int02 is ≤9.0%, and the reaction is considered complete, add a solvent to the system for quenching, let it stand, separate layers, retain the organic phase, extract the aqueous phase, let it stand, separate 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 stratification. The organic phase is mixed with an alkaline solution, stirred for 5 to 15 minutes and then allowed to stand, and 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, and the aqueous layer is separated for use. The two aqueous layers are combined, and the pH is adjusted to 5 to 6 by adding acid at 20 to 30° C., and a solid is precipitated. The filter cake is obtained after filtering and washing. 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., and the filter cake is stirred for 20 to 40 minutes. The process is filtered and washed, and the filter cake is dried to a moisture content of ≤0.5% and then the material is collected to obtain a crude bumetanide product. The crude bumetanide product is refined by glacial acetic acid and cyclohexane to obtain a fine bumetanide product. The fine 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 into water, stir evenly, then add alkaline regulator, add enough water, filter, fill and sterilize.

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

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

[0020] Furthermore, the mass ratio of the compound of structural formula Int02 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.

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

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

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

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

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

[0026] The alkaline solution of N,O-carboxymethyl chitosan is mixed with an alkaline substance, and then ultrasonically dispersed for 1 to 2 hours, and then a cross-linking agent is added, and the mixture is stirred and dried to remove the solvent.

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

[0028] Furthermore, the preparation method of the alkaline regulator comprises the following steps:

[0029] After mixing 1wt% sodium hydroxide aqueous solution of N,O-carboxymethyl chitosan with alkaline substances, 0.5wt% sodium tripolyphosphate is added after ultrasonic dispersion for 1-2h, and the mixture is stirred for 1-2h and dried to remove the solvent, wherein the mass ratio of N,O-carboxymethyl chitosan to alkaline substances is 1:2-5.

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

[0031] Beneficial effects of the present invention:

[0032] 1. The present invention uses 4-chloro-3-nitro-5-sulfamoylbenzoic acid as a starting material, and performs nucleophilic substitution with phenol in a potassium hydroxide aqueous solution to obtain a compound of 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 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. The crude bumetanide product is refined in a glacial acetic acid and cyclohexane system, and then decolorized with activated carbon in methanol-water, and crystallized to obtain a pure bumetanide product.

[0033] 2. The pure bumetanide is mixed with mannitol, an alkaline regulator and taurine to prepare a finished product. Taurine, as a sulfur-containing amino acid, can improve stability, and the alkaline regulator is prepared from a carrier and an alkaline substance. The buffering effect after loading can prevent bumetanide from being directly exposed to an alkaline environment, thereby affecting stability. The addition of the alkaline regulator and taurine also avoids the need to add a buffered salt solution or an acidic solution to adjust the pH value at a later stage, which may lead to uncontrollable quality problems. DETAILED DESCRIPTION

[0034] Example 1

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

[0036] S1. Add 2.3 kg of 4-chloro-3-nitro-5-sulfamoylbenzoic acid structural formula SM01 and 1.43 kg of sodium isooctanoate to 46 kg of water, heat to 58 ° C and stir for 30 min, then cool to 40 ° C, add 2.47 kg of phenol structural formula SM02, add 1.84 kg of potassium hydroxide in batches and heat to 88 ° C, react for 24 hours, and consider the reaction to be complete when the peak area of ​​4-chloro-3-nitro-5-sulfamoylbenzoic acid structural formula SM01 is ≤5.0%, cool to 55 ° C, add toluene and 36 wt% concentrated hydrochloric acid respectively, cool to 20 ° C and crystallize for 2 hours, filter, wash and dry the filter cake, add it to 2 wt% sodium hydroxide aqueous solution and glacial acetic acid, stir respectively, cool to 10 ° C and crystallize for 2 hours, filter, wash, dry, and collect the material with a moisture content of ≤3.0%, to obtain a compound of structural formula Int01;

[0037] S2, add 1.31kg of the compound of structural formula Int01 and 0.131kg of 10wt% palladium carbon to 10.48kg of methanol, continue to add 0.131kg of water, heat to 50°C under nitrogen atmosphere, drop ammonium formate solution, 5.48kg of methanol, 1.83kg of ammonium formate and 1.834kg of water in the ammonium formate solution, react until the peak area ratio of the compound of structural formula Int01 is ≤0.5%, and consider the reaction to be complete, filter, distill the filtrate under reduced pressure until a large amount of solid precipitates, add water thereto, continue to distill under reduced pressure until no liquid flows out, add water to the residue, add glacial acetic acid at 45°C, crystallize for 1h, filter, wash, mix the filter cake with water and methanol, add 36wt% concentrated hydrochloric acid, beat at 55°C for 1.5h, cool to 25°C for crystallization for 45min, filter, wash, dry the filter cake until the moisture content is ≤1.0% and collect the material to obtain the compound of structural formula Int02;

[0038] S3, at 12 ℃, add 3.49 kg of sodium triacetoxyborohydride and 0.89 kg of the compound of the structural formula Int02 to 8.9 kg of 2-methyltetrahydrofuran and 0.543 kg of glacial acetic acid, separately mix 0.450 kg of n-butyraldehyde structural formula SM03 with 8.9 kg of 2-methyltetrahydrofuran to obtain n-butyraldehyde solution, drip 55 wt% n-butyraldehyde solution to the reaction system, react at 12 ℃ for 1 hour after the dripping is complete, continue to drip 22.5 wt% n-butyraldehyde solution, react at 12 ℃ for 1 hour after the dripping is complete, continue to drip the remaining n-butyraldehyde solution, after the dripping is complete, react at 12 ℃ until the structural formula Int02 The reaction is considered complete when the peak area ratio of the compound is ≤9.0%. Methanol and water are added to the system for quenching, and then the system is allowed to stand for separation. The organic phase is retained. The aqueous phase is extracted, allowed to stand for separation, and the organic phase is obtained after separation. The organic phases obtained twice are combined, washed with saturated brine and water, and then allowed to stand for separation. After the organic phase is obtained, it is mixed with a 13wt% aqueous sodium hydroxide solution, stirred for 10min, and then allowed to stand. The aqueous layer is separated for use. 13wt% aqueous sodium hydroxide solution is continued to be added to the organic layer, stirred for 10min, and then allowed to stand for separation. The aqueous layer is separated for use. The two aqueous layers are combined, 36wt% concentrated hydrochloric acid is added at 25°C to adjust the pH to 5.5, and a solid is precipitated. After filtering and washing, a filter cake is obtained. , the filter cake was mixed with ethylene glycol dimethyl ether and water and heated to 78°C, 36wt% concentrated hydrochloric acid was added, the temperature was lowered to 18°C, the mixture was stirred for 30min, filtered and washed, the filter cake was dried to a moisture content of ≤0.5%, and the crude bumetanide was obtained. 8.62kg of glacial acetic acid was raised to 92°C, 0.98kg of crude bumetanide was added, the temperature was lowered to 78°C, 12.15kg of cyclohexane was added dropwise, the temperature of the system was lowered to 18°C, the mixture was stirred for 30min, filtered and washed, 7.79kg of glacial acetic acid was added to the filter cake and stirred at 92°C to dissolve, the temperature was immediately lowered to 78°C, 10.93kg of cyclohexane was added dropwise, the temperature of the system was lowered to To 18°C, keep warm and stir for 30 minutes, filter, wash, dry and collect the bumetanide fine product, add 0.04kg of activated carbon and 0.81kg of bumetanide fine product to 9.72kg of methanol and 4.05kg of water, heat to 72°C, keep warm and stir for 30 minutes, control the pressure to <0.2MPa for pressure filtration, filter through 1μm titanium rod filter and 0.22μm microporous filter, reduce the feed liquid to 8°C, keep warm and stir for 60min for crystallization, discharge the material to a centrifuge and centrifuge to dryness, use pre-cooled 70wt% methanol aqueous solution at 8°C to rinse the filter cake, centrifuge to dryness, dry to moisture ≤0.5% and collect the material to obtain bumetanide pure product.

[0039] Example 2

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

[0041] S1. Add 2.3 kg of 4-chloro-3-nitro-5-sulfamoylbenzoic acid structural formula SM01 and 1.43 kg of sodium isooctanoate to 46 kg of water, heat to 58 ° C and stir for 30 min, then cool to 40 ° C, add 2.47 kg of phenol structural formula SM02, add 1.84 kg of potassium hydroxide in batches and heat to 88 ° C, react for 24 hours, and consider the reaction to be complete when the peak area of ​​4-chloro-3-nitro-5-sulfamoylbenzoic acid structural formula SM01 is ≤5.0%, cool to 55 ° C, add toluene and 36 wt% concentrated hydrochloric acid respectively, cool to 20 ° C and crystallize for 2 hours, filter, wash and dry the filter cake, add it to 2 wt% sodium hydroxide aqueous solution and glacial acetic acid, stir respectively, cool to 10 ° C and crystallize for 2 hours, filter, wash, dry, and collect the material with a moisture content of ≤3.0%, to obtain a compound of structural formula Int01;

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

[0043] S3. Add 3.49 kg of sodium triacetoxyborohydride and 0.89 kg of the compound of the structural formula Int02 to 8.9 kg of 2-methyltetrahydrofuran and 0.543 kg of glacial acetic acid at 12°C, mix 0.45 kg of n-butyraldehyde structural formula SM03 with 8.9 kg of 2-methyltetrahydrofuran to obtain n-butyraldehyde solution, drip 55 wt% n-butyraldehyde solution to the reaction system, react at 12°C for 1 hour after the dripping, continue to drip 22.5 wt% n-butyraldehyde solution, react at 12°C for 1 hour after the dripping, continue to drip the remaining n-butyraldehyde solution, and after the dripping, react at 12°C until the structural formula Int02 The peak area ratio of the compound is ≤9.0%, and the reaction is considered complete. Methanol and water are added to the system for quenching, and then the system is allowed to stand for separation. The organic phase is retained. The aqueous phase is extracted, allowed to stand for separation, and the organic phase is obtained after separation. The organic phases obtained twice are combined, washed with brine and water, and then allowed to stand for separation. After the organic phase is obtained, it is mixed with a 13wt% sodium hydroxide aqueous solution, stirred for 10min, and then allowed to stand, and the aqueous layer is separated for use. The organic layer continues to be added with a 13wt% sodium hydroxide aqueous solution, stirred for 10min, and then allowed to stand, and the aqueous layer is separated for use. The two aqueous layers are combined, and 36wt% concentrated hydrochloric acid is added at 25°C to adjust the pH to 5.5, and a solid is precipitated. After filtering and washing, a filter cake is obtained. The filter cake was mixed with ethylene glycol dimethyl ether and water and heated to 78°C. 36wt% concentrated hydrochloric acid was added and cooled to 18°C. The mixture was stirred for 30min and filtered and washed. The filter cake was dried until the moisture content was ≤0.5% and then the crude bumetanide was obtained. 8.62kg of glacial acetic acid was heated to 92°C, and 0.98kg of crude bumetanide was added. The mixture was cooled to 78°C and 12.15kg of cyclohexane was added dropwise. After the addition was completed, the system temperature was reduced to 18°C. The mixture was stirred for 30min and filtered and washed. 7.79kg of glacial vinegar was added to the filter cake and stirred at 92°C to dissolve. The mixture was then cooled to 78°C and 10.93kg of cyclohexane was added dropwise. After the addition was completed, the system temperature was reduced to 18°C. The mixture was stirred for 30min and filtered and washed. 7.79kg of glacial vinegar was added to the filter cake and stirred at 92°C to dissolve. The mixture was then cooled to 78°C and 10.93kg of cyclohexane was added dropwise. After the addition was completed, the system temperature was reduced to 18°C. 18°C, keep warm and stir for 30 minutes, filter, wash, dry and collect the material to obtain bumetanide fine product, add 0.04kg of activated carbon and 0.81kg of bumetanide fine product to 9.72kg of methanol and 4.05kg of water, heat to 72°C, keep warm and stir for 30 minutes, control the pressure <0.2MPa for pressure filtration, filter through 1μm titanium rod filter and 0.22μm microporous filter, cool the feed liquid to 8°C, keep warm and stir for 60 minutes for crystallization, discharge the material to a centrifuge and centrifuge to dryness, use a pre-cooled 70wt% methanol aqueous solution at 8°C to rinse the filter cake, centrifuge to dryness, dry to a moisture content of ≤0.5% and collect the material to obtain bumetanide pure product;

[0044] S4. Add 250 mg of pure bumetanide, 18 mg of taurine, and 10 g of mannitol to 500 mL of water, stir evenly, then add 150 mg of alkaline regulator, fill the volume to 1000 mL with water, filter, fill, and sterilize.

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

[0046] A 1 wt % sodium hydroxide aqueous solution of N,O-carboxymethyl chitosan is mixed with aluminum hydroxide, with a mass ratio of N,O-carboxymethyl chitosan to aluminum hydroxide being 1:2.5. After ultrasonic dispersion for 1 hour, 0.5 wt % sodium tripolyphosphate is added, and the mixture is stirred for 2 hours and then dried to remove the solvent.

[0047] Example 3

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

[0049] Example 4

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

[0051] Comparative Example 1

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

[0053] Test Example 1

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

[0055] Table 1 Bumetanide finished product stability test

[0056]

[0057]

[0058] It can be seen from Table 1 that compared with the control example, the bumetanide finished product in the example has better stability. This may be because the sodium hydroxide used in the control example 1 is not loaded, so the alkaline environment formed is not buffered to a certain extent, which may reduce the stability of bumetanide and affect the stability.

[0059] Compared with Examples 2 to 3, Example 4 has better stability performance, which may be due to the fact that magnesium hydroxide itself is a stabilizer, so it can improve the physical properties and stability of the drug, while aluminum hydroxide and calcium hydroxide do not have the effect of stabilizers, so they may 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 are not highly soluble in water, the present invention uses N, O-carboxymethyl chitosan with good water solubility as a carrier to load alkaline substances to obtain an alkaline regulator. During the preparation process of N, O-carboxymethyl chitosan, the carboxymethyl group will be substituted on the hydroxyl group and the amino group to generate O-carboxymethyl and N-carboxymethyl chitosan, so it has good water solubility. The alkaline 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 finished product is prepared by mixing pure bumetanide with mannitol, an alkaline regulator and taurine. Taurine, as a sulfur-containing amino acid, can improve stability, and the alkaline regulator is prepared from a carrier and an alkaline substance. The buffering effect after loading can prevent bumetanide from being directly exposed to an alkaline environment, thereby affecting the stability. The addition of the alkaline regulator and taurine also avoids the need to add a buffered salt solution or an acidic solution to adjust the pH value at a later stage, which may lead to uncontrollable quality problems.

[0061] The preferred specific embodiments of the present invention are described in detail above. It should be understood that a person skilled in the art can make many modifications and changes based on the concept of the present invention without creative work. Therefore, any technical solution that can be obtained by a person skilled in the art through logical analysis, reasoning or limited experiments based on the concept of the present invention on the basis of the prior art should be within the scope of protection determined by the claims.

Claims

1. A process for preparing 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 20-40min, then cool to 35-45°C, add phenol structural formula SM02, add potassium hydroxide in batches and heat to 85-90°C, react for 22-26h, and consider the reaction to be 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 for crystallization for 1-3h, filter, wash and dry the filter cake, add it to alkaline solution and acid solution, stir respectively, cool to 5-15°C for crystallization, filter, wash and dry, and collect the material with moisture ≤3.0% to obtain the compound of structural formula Int01; S2, add the compound of structural formula Int01 and 10wt% 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 the reaction is considered complete, filter, and distill the filtrate under reduced pressure until a large amount of solid is precipitated, then 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 1-2h, cool to 20-30°C, crystallize for 0.5-1h, filter, wash, dry the filter cake until the moisture content is ≤1.0%, and then collect the material to obtain the compound of structural formula Int02; S3. Add sodium triacetoxyborohydride and a compound of the structural formula Int02 to a solvent and glacial acetic acid at 10-15°C, mix n-butyraldehyde structural formula SM03 with a solvent to obtain a n-butyraldehyde solution, drip 55wt% of the n-butyraldehyde solution into the reaction system, react at 10-15°C for 0.5-1.5h after the addition is complete, continue to drip 22.5wt% of the n-butyraldehyde solution, react at 10-15°C for 0.5-1.5h after the addition is complete, and then continue to drip the remaining n-butyraldehyde solution, react at 10-15°C until the peak area ratio of the compound of the structural formula Int02 is ≤9.0%, and the reaction is considered complete, add a solvent to the system for quenching, let it stand, separate layers, retain the organic phase, extract the aqueous phase, let it stand, separate 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 stratification. The organic phase is mixed with an alkaline solution, stirred for 5 to 15 minutes and then allowed to stand, and 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, and the aqueous layer is separated for use. The two aqueous layers are combined, and the pH is adjusted to 5 to 6 by adding acid at 20 to 30° C., and a solid is precipitated. The filter cake is obtained after filtering and washing. 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., and the filter cake is stirred for 20 to 40 minutes. The process is filtered and washed, and the filter cake is dried to a moisture content of ≤0.5% and then the material is collected to obtain a crude bumetanide product. The crude bumetanide product is refined by glacial acetic acid and cyclohexane to obtain a fine bumetanide product. The fine 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; S4. Add pure bumetanide, taurine and mannitol into water, stir evenly, then add alkaline regulator, add enough water, filter, fill and sterilize.

2. The process for preparing bumetanide according to claim 1, characterized in that: 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 preparing bumetanide according to 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 preparing bumetanide according to 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 preparing bumetanide according to 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 preparing bumetanide according to claim 1, wherein: The molar ratio of bumetanide to taurine in step S4 is 1:0.2-0.

3.

7. The process for preparing bumetanide according to claim 1, wherein: The amount of mannitol added in step S4 is 5-15 g / L, based on water.

8. The process for preparing bumetanide according to claim 1, wherein: Based on water, the mass ratio of bumetanide to the alkaline regulator is 1:0.5-1.

9. The process for preparing bumetanide according to claim 1, wherein: The preparation method of the alkaline regulator comprises the following steps: The alkaline solution of N,O-carboxymethyl chitosan is mixed with an alkaline substance, and then ultrasonically dispersed for 1 to 2 hours, and then a cross-linking agent is added, and the mixture is stirred and dried to remove the solvent.

10. The process for preparing bumetanide according to claim 9, characterized in that: The mass ratio of the N,O-carboxymethyl chitosan to the alkaline substance is 1:2-5.

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