Production process and purification method for furosemide

Abstract

A production process and purification method for furosemide. The process comprises the following steps: S1, adding a crude furosemide product to an inorganic alkali solution, sufficiently reacting same, decolorizing and filtering same, adjusting the pH value of a filtrate with an acid solution to create acidic conditions, subjecting same to crystallization, and then filtering and washing same to obtain a solid substance; and S2, adding the solid substance to a recrystallization solvent, heating same to reflux same in a boiling state until the temperature of the solution is constant, then filtering same while the solution is still hot, transferring the resulting filtrate into a crystallization kettle, heating the solution to the boiling point temperature thereof, stopping heating, setting the pressure of the crystallization kettle to be 3-60 kPa, conducting crystallization, extracting the evaporated solvent, and after the solution in the crystallization kettle stops boiling, cooling the solution to 10-15ºC by using circulating cooling water, continuing crystallization, and then conducting filtering, washing and drying to obtain a finished furosemide product. The purification method provided can avoid the cold wall precipitation of crystals, reduce the generation of waste liquid, and significantly improve the purity and yield of furosemide.

Description

A production process and purification method of furosemide Technical Field

[0001] The present application relates to the technical field of drug synthesis, and in particular to a production process of furosemide and a purification method thereof. Background Art

[0002] Furosemide, whose chemical name is 2-(2-furylmethyl)amino-5-(sulfonylamino)-4-chlorobenzoic acid, has the following structural formula:

[0003] Furosemide is a loop diuretic widely used in the treatment of congestive heart failure and edema. It can be used clinically to treat cardiac edema, renal edema, ascites caused by cirrhosis, pulmonary edema, cerebral edema, acute renal failure or peripheral edema caused by vascular wall disorders. It has important application value, especially for cases where other diuretics are ineffective.

[0004] Currently, furosemide is typically synthesized using 2,4-dichloro-5-sulfonamidobenzoic acid and furfurylamine as the main raw materials, via a condensation reaction. However, furosemide prepared by existing methods often contains a high level of impurities and exhibits low purity, which impacts the quality and efficacy of the resulting furosemide product and, to a certain extent, limits its application. Therefore, effective purification of existing crude furosemide remains a key research priority.

[0005] Currently, crude furosemide is purified primarily through column chromatography, saline hydrolysis, and recrystallization using organic solvents. However, purification of crude furosemide via column chromatography is expensive and limited in industrial production, making it difficult to apply on a large scale.

[0006] The prior art method for purifying furosemide by salting and hydrolysis includes the following steps: adding crude furosemide to a saturated sodium bicarbonate solution, heating to 70-100°C, adding activated carbon for decolorization, filtering, neutralizing with glacial acetic acid, crystallizing, and centrifuging to obtain a furosemide product. It has been verified that in industrial production, the purity of the furosemide product obtained by the purification method of salting and hydrolysis performed only once cannot meet the requirements. The prior art also discloses another method for refining furosemide by multiple salting and hydrolysis: (1) mixing crude furosemide with saturated sodium bicarbonate, heating to dissolve, decolorizing with activated carbon, filtering while hot, stirring the filtrate at room temperature for crystallization for 3 hours, then stirring and crystallizing in an ice-water bath for 1 hour, filtering and washing the filter cake; (2) adding the filter cake to saturated sodium bicarbonate, heating to dissolve, decolorizing with activated carbon, filtering while hot, stirring the filtrate at room temperature for crystallization for 3 hours, then stirring and crystallizing in an ice-water bath for 1 hour, filtering and washing the filter cake. (3) adding the filter cake to saturated sodium bicarbonate and heating to dissolve it, decolorizing it with activated carbon, filtering it while it is hot, stirring the filtrate at room temperature for crystallization for 3 hours, then stirring it in an ice water bath for crystallization for 1 hour, filtering it with suction, washing the filter cake, then adding the filter cake to purified water and heating to dissolve it, adjusting the pH to 3-4 with acetic acid, cooling it to 10-20°C in a cold water bath for crystallization for 0.5 hours, filtering it with suction, washing the filter cake, and drying it to obtain the furosemide finished product. The furosemide finished product prepared by this method has a purity of up to 99.965%. The furosemide prepared by this purification method has a high purity, but the three purifications result in low purification efficiency and low yield, and a large amount of saturated sodium bicarbonate is consumed in the purification process, generating a large amount of waste liquid, resulting in increased purification costs and waste liquid treatment costs.

[0007] At room temperature, especially at low temperatures of 10 to 15°C, the solubility of furosemide in ethanol is low, while at high temperatures, its solubility in ethanol is high. Therefore, in the prior art, ethanol is usually selected as a recrystallization solvent to recrystallize the crude furosemide to obtain a finished furosemide product. However, the ethanol recrystallization process requires a large amount of ethanol solution and a large amount of waste liquid. If the waste liquid is directly discarded, the purification cost and waste liquid treatment cost will increase significantly, and the furosemide in the waste liquid will be wasted. If the recrystallization filtrate is directly used as the mother liquor, although the yield of furosemide can be increased and the amount of ethanol solution can be reduced, the impurities accumulated in the mother liquor may affect the formation of crystal nuclei, resulting in changes in crystallization conditions, thereby affecting the yield and purity of the finished furosemide product. If you want to reduce the amount of recrystallization solution used and increase the yield of furosemide, you need to perform additional post-processing on the mother liquor, such as distillation and column chromatography. The process is cumbersome and brings additional post-processing costs.

[0008] The prior art also discloses a furosemide purification method that combines salt hydrolysis with organic solvent recrystallization. Referring to Figure 1, the purification method comprises the following steps: first, dissolving the crude furosemide in sodium hydroxide solution, heating to 70-80°C, then adding activated carbon for decolorization, filtering, neutralizing with glacial acetic acid, crystallizing, and centrifuging to obtain a solid substance. The solid substance is refluxed with 95% ethanol at 80°C, then filtered while hot, and the filtrate is cooled to 10-15°C with circulating cooling water, crystallized, filtered, washed, and dried to obtain the finished furosemide product. This purification method produces a large amount of waste liquid, which needs to be treated and discharged after meeting the standards, resulting in increased purification costs. However, some organic impurities in the crude furosemide product have similar solubility properties to furosemide. As a result, when the filter cake is washed with purified water or other solvents, furosemide is lost while removing the organic impurities, thereby reducing the yield of furosemide. In addition, when the cooling crystallization method is used for recrystallization, the crystals precipitate on the cold wall, resulting in a decrease in the cooling rate, a decrease in product yield, and uneven crystals, which affects the company's production efficiency and economic benefits.

[0009] Therefore, there is still a need to provide a simple and efficient method for purifying furosemide to improve the yield and purity of furosemide, reduce the cost of the purification process and the volume of waste liquid generated.

[0010] Summary of the Invention

[0011] Based on this, the purpose of this application is to provide a method for purifying furosemide suitable for industrial production, so as to improve the yield and purity of furosemide, improve the effective utilization rate of the recrystallization solution, reduce the cost and energy consumption of the purification process, and address the shortcomings of the existing technology.

[0012] To achieve the above objectives, this application adopts the following technical solutions:

[0013] A method for purifying furosemide comprises the following steps:

[0014] S1. Adding crude furosemide to an inorganic base solution, allowing the mixture to react fully, decolorizing and filtering, adjusting the pH of the filtrate to an acidic condition with an acid solution for crystallization, filtering, and washing to obtain a solid substance;

[0015] S2. Add the solid substance to the recrystallization solvent, heat it, and reflux it under boiling conditions until the solution temperature remains constant, filter it while hot, transfer the filtrate to a crystallization kettle, heat the solution to its boiling point and then stop heating, set the pressure of the crystallization kettle to 3-60 kPa for crystallization and extract the evaporated solvent, after the solution in the crystallization kettle stops boiling, use circulating cooling water to cool the solution to 10-15° C. and continue crystallization, filter, wash, and dry to obtain a furosemide product.

[0016] Compared with the prior art, the present application first salts and hydrolyzes the crude furosemide product, and then uses an organic solvent to recrystallize the solid material under vacuum conditions to obtain a furosemide product. Compared with the existing cooling crystallization method, the recrystallization method of the present application can avoid cold wall precipitation of crystals, reduce the generation of waste liquid, and significantly improve the purity and yield of furosemide. Moreover, during the dissolution process, the increase in the solute concentration of furosemide will lead to an increase in the boiling point of the solution and the cessation of boiling of the solution. Therefore, by continuing to slowly heat the crystallization system that has reached the boiling point so that it continuously reaches the new boiling point and maintains a boiling state, the temperature of the crystallization system can be increased, the solubility of furosemide in the crystallization system can be increased, and the temperature difference between the temperature of the crystallization system and the new boiling point of the crystallization system under the vacuum state can be increased, thereby promoting rapid boiling of the crystallization system under the vacuum state, thereby reducing the temperature and total volume of the crystallization system and improving the yield of furosemide.

[0017] Furthermore, in step S2, the pressure of the crystallization kettle is set to 3-30 kPa.

[0018] Furthermore, in step S2, the filtrate after crystallization is collected as a mother liquor, and the mother liquor is used as a washing solution in step S1.

[0019] Furthermore, the solvent evaporated during the crystallization process is condensed and recovered to obtain a recovered solvent.

[0020] Furthermore, the recrystallization solvent includes 95% ethanol, a recovery solvent, and a mixed solution of the recovery solvent and 95% ethanol.

[0021] Furthermore, in step S2, the heating and dissolving is carried out under the condition of 120-180 kPa.

[0022] Furthermore, in step S2, the cooling rate is 15-25°C / h.

[0023] Furthermore, in step S1, the inorganic alkaline solution includes sodium hydroxide solution and saturated sodium carbonate solution; the decolorization includes activated carbon decolorization; and the acid solution includes glacial acetic acid solution.

[0024] The present application also provides a method for preparing furosemide, comprising the following steps:

[0025] (1) adding 2,4-dichlorobenzoic acid to chlorosulfonic acid to react, and then post-treating to obtain 2,4-dichloro-5-sulfonylchlorobenzoic acid;

[0026] (2) adding 2,4-dichloro-5-sulfonylchlorobenzoic acid to ammonia water for reaction, and then post-treating to obtain 2,4-dichloro-5-sulfonylaminobenzoic acid;

[0027] (3) adding 2,4-dichloro-5-sulfonylaminobenzoic acid to an organic solvent, then adding a base to react to obtain a reaction solution, then preheating and mixing the reaction solution with furfurylamine in a reactor, and performing a substitution reaction, followed by post-processing to obtain a crude furosemide product;

[0028] (4) The crude furosemide product is treated by the purification method to obtain the finished furosemide product.

[0029] Furthermore, the reaction temperature of step (1) is 125-130° C., and the reaction time is 2 h.

[0030] Furthermore, the reaction temperature of step (2) is 10-20° C., and the reaction time is 2 h.

[0031] Furthermore, in step (3), the reaction temperature of 2,4-dichloro-5-sulfonylaminobenzoic acid and the base is 65° C., and the reaction time is 0.5 h.

[0032] Furthermore, in step (3), the molar ratio of 2,4-dichloro-5-sulfonamidobenzoic acid to furfural amine is 1:1.5-2; the preheating temperature is 130-140°C, and the mixing time is 20-60 minutes; the reaction time of the reaction solution and furfural amine is 2-5 hours, and the reaction temperature is 120-140°C.

[0033] Furthermore, in step (3), the base is selected from one or more of sodium ethoxide and sodium methoxide; and the organic solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] FIG1 is a flow chart of a purification process of crude furosemide in the prior art.

[0035] FIG2 is a flow chart of a purification process of crude furosemide provided in this application.

[0036] FIG3 is a reaction formula for a production process of crude furosemide provided in this application. DETAILED DESCRIPTION

[0037] When a purification method combining salt hydrolysis with organic solvent recrystallization was used to purify crude furosemide, it was found that during the recrystallization process, as the crude furosemide dissolved and the solute in the solution increased, the boiling point of the solution began to rise, causing the solution to no longer boil at the original heating temperature. In addition, in industrial production, the energy consumption of cooling crystallization using circulating cooling water is high, and the system temperature is uneven, resulting in crystals precipitating on the cold wall, causing problems such as a decrease in cooling rate and a decrease in product yield. Therefore, referring to Figure 2, the present application provides a purification process for furosemide, comprising the following steps:

[0038] S1. Adding crude furosemide to an inorganic base solution, allowing the mixture to react fully, decolorizing and filtering, adjusting the pH of the filtrate to an acidic condition with an acid solution for crystallization, filtering, washing, and collecting the solid matter;

[0039] S2. Add the solid substance to the recrystallization solvent and heat to dissolve the solution under boiling conditions until the solution temperature remains constant. Filter while hot, transfer the filtrate to a crystallization kettle and heat to its boiling point. Stop heating and set the pressure of the crystallization kettle to 3-60 kPa for crystallization. After the solution in the crystallization kettle stops boiling, cool the solution to 10-15° C. using circulating cooling water and continue crystallization. Filter, wash, and dry to obtain a furosemide product.

[0040] Step S2 includes collecting the filtrate after crystallization as a mother liquor, extracting the solvent evaporated during the crystallization process from the crystallization kettle, and condensing and recovering it as a recovery solvent. In the subsequent purification of crude furosemide, the mother liquor can be used as a washing solvent to wash the precipitate filtered from step S1. The recovery solvent can be used as the recrystallization solvent in step S2 to dissolve the solid material. Preferably, the recrystallization solvent is 95% ethanol, or a mixture of recovered ethanol and 95% ethanol.

[0041] Since the increase in the concentration of furosemide solutes during the dissolution process will cause the boiling point of the solution to increase and the boiling of the solution to stop, the heating of step S2 keeps it in a boiling state for dissolution, and includes: first heating the solution to boiling, then continuing to slowly heat it up, so that the boiling point of the solution stops boiling, and then continuing to heat it up to boiling, until the solution temperature remains constant and cannot continue to heat up. Continuously heating can increase the solution temperature, and the increase in the solution temperature causes the solubility of furosemide in the solution to increase. Therefore, when furosemide is excessive, continuous boiling and dissolving can increase the concentration of furosemide in the solution, and during subsequent low-temperature crystallization, the solubility of furosemide remains unchanged, thereby increasing the amount of furosemide precipitated in the solution. In addition, the increase in the solution temperature can increase the temperature difference between the temperature of the solution and the new boiling point of the solution under vacuum conditions, thereby causing the solution to boil rapidly under vacuum conditions, promote the crystallization of furosemide, and reduce energy consumption. In addition, during the dissolution process, the evaporated recrystallization solvent can be condensed and recovered or refluxed into the solution to avoid insufficient dissolution of furosemide or solvent waste.

[0042] The furosemide purification method of the present application is applicable to the crude furosemide prepared by the production process shown in FIG3 . The preparation method of the crude furosemide comprises the following steps:

[0043] (1) 2,4-dichlorobenzoic acid and chlorosulfonic acid were added to a reaction kettle in a molar ratio of 1:3, and stirred at 125-130°C for 2 hours; then cooled to 50°C with stirring to obtain reaction solution A. The reaction solution A was quenched at 1-10°C, stirred at this temperature for 1 hour, filtered and washed several times, and finally filtered to obtain 2,4-dichloro-5-sulfonylchlorobenzoic acid.

[0044] (2) The 2,4-dichloro-5-sulfonylchlorobenzoic acid was slowly added to 25% ammonia water at a molar ratio of 3 times at 10-20° C., and the reaction was continued for 2 h. Then, concentrated hydrochloric acid was added to adjust the pH to 1.5-2.0 to obtain reaction solution B. The reaction solution B was filtered, and then added to 20% ethanol aqueous solution, heated to reflux, and hot filtered. The filtrate was cooled to 10° C. for crystallization, and then filtered to obtain 2,4-dichloro-5-sulfonylaminobenzoic acid.

[0045] (3) 2,4-dichloro-5-sulfonylaminobenzoic acid and dimethyl sulfoxide were mixed in a mass ratio of 1:2, and stirred at 30-40°C until dissolved to obtain a mixed solution. Alkali was prepared in a molar ratio of 2,4-dichloro-5-sulfonylaminobenzoic acid to alkali of 1:1.2, and the alkali was uniformly added to the mixed solution over 10 minutes, and stirred at 65-75°C for 1 hour to obtain a reaction solution C. Furfurylamine was weighed in a molar ratio of 2,4-dichloro-5-sulfonylaminobenzoic acid to furfurylamine of 1:1.5-2, and furfurylamine and reaction solution C were preheated to 130-140°C respectively, and the furfurylamine and reaction solution C were added to a reactor at 120-140°C in a cross-jet manner. After the addition was completed, the feed port was closed, nitrogen was introduced, and stirring was continued for 2-5 hours until the reaction was complete to obtain a reaction solution D. At room temperature, the reaction solution D was poured into water, and sodium hydroxide was added to adjust the pH value to 12-13. Then, dichloromethane was added for extraction. Hydrochloric acid was added to the extracted aqueous layer to adjust the pH value to 1.5-2. The mixture was stirred for crystallization, and then filtered and washed with water several times. After filtration, the crude furosemide was obtained.

[0046] To make this application easier to understand, the following further describes this application with reference to specific embodiments. It should be understood that these embodiments are only used to illustrate this application and are not intended to limit the scope of this application; the drawings described are also only schematic and are considered non-limiting.

[0047] Example 1

[0048] S1. Add crude furosemide to sodium hydroxide solution at a ratio of 1 g of crude furosemide to 8-10 mL of 40% sodium hydroxide solution, stir at 70-80° C. until dissolved, add activated carbon at a mass ratio of crude furosemide to activated carbon of 20:1, continue heating and stirring for 30 minutes, filter while hot, adjust the pH of the filtrate to 4-5 with glacial acetic acid, stir at room temperature for 3 hours to complete the hydrolysis reaction and allow the generated furosemide to begin to precipitate; then cool the solution to 10-20° C. and stir for 1 hour to allow the hydrolyzed furosemide to completely precipitate from the acid solution, filter with suction, wash the filter cake with purified water, and dry to obtain a solid material.

[0049] S2. Add an excess of the solid substance obtained in step S1 to 95% ethanol, heat the solution to reflux under boiling conditions, and keep the solution at a constant temperature for a period of time. Then, filter the solution while hot to obtain a reaction solution and an incompletely dissolved solid substance. Rapidly transfer the reaction solution to a crystallization kettle, heat the reaction solution to boiling or a constant temperature thereof, stop heating, set the pressure in the crystallization kettle to 3-30 kPa for crystallization, and extract the evaporated ethanol vapor in the crystallization kettle. After the reaction solution in the crystallization kettle stops boiling or the boiling is weakened, use circulating cooling water to cool the reaction solution to 10-15° C., fully crystallize, and filter the reaction solution to obtain a filtrate and a filter cake. Wash the filter cake and dry it under negative pressure at about 60° C. to obtain a white solid, i.e., the finished furosemide product. The filtrate is recovered as a mother liquor. The extracted ethanol vapor is condensed and recovered to obtain recovered ethanol.

[0050] Among them, the appropriate amount of 95% ethanol used in subsequent production (the ratio of solid matter to 95% ethanol used) can be calculated based on the mass of the solid matter and the mass of the incompletely dissolved solid matter, and the heating time in subsequent production can be calculated based on the heating time of step S2, so as to make the reaction conditions consistent and avoid the tediousness of multiple temperature measurements.

[0051] In this embodiment, the recrystallization method under vacuum conditions can significantly reduce the consumption of circulating cooling water and improve the yield of the furosemide product. In addition, during the crystallization process, the reaction liquid can be distilled, which, on the one hand, reduces the mass fraction of ethanol in the mother liquor, thereby reducing the solubility of furosemide, and on the other hand, recovers ethanol and mother liquor and uses them in the next purification, thereby reducing the purification cost and the energy consumption of the purification process.

[0052] At normal pressure, the boiling point of pure ethanol is around 78°C. Therefore, existing techniques generally use excess ethanol to reflux and dissolve crude furosemide at 80°C. However, this method does not consider the effect of solute concentration on the boiling point of the solution. In this example, 95% ethanol is used to heat and reflux the excess solid material. By keeping the solution boiling, the solution temperature is increased, and the furosemide concentration in the solution is increased, thereby increasing the utilization rate of the 95% ethanol. The incompletely dissolved furosemide can be used in the next batch of recrystallization, thereby reducing the amount of recrystallization reagent (95% ethanol) used in industrial production.

[0053] In addition, this embodiment performs recrystallization under vacuum conditions, utilizing the principle that the boiling point of a solution decreases under low pressure conditions, allowing the high-temperature solution to boil for a long time under low pressure conditions, and extracting the evaporated ethanol vapor from the crystallization kettle for condensation recovery. This method has the following advantages: ① The volatilization of ethanol reduces the total volume of the solution, increasing the concentration of solutes such as furosemide in the solution, thereby promoting the precipitation of furosemide; ② The solubility of solutes such as furosemide in ethanol is much greater than its solubility in water. Therefore, the volatilization of the ethanol solvent in the ethanol-water solution reduces the mass fraction of ethanol in the solution, reducing the solubility of furosemide in the solution, thereby promoting the precipitation of furosemide; ③ The solubility of furosemide in ethanol increases with increasing temperature. When ethanol vaporizes, it absorbs heat from the solution, lowering the temperature of the solution, thereby reducing the solubility of furosemide and promoting the precipitation of furosemide. In addition, reducing the amount of mother liquor and promoting the precipitation of furosemide in the mother liquor can reduce the amount of unprecipitated furosemide in the mother liquor. Even if the mother liquor is directly discarded, the waste of furosemide can be reduced. The higher vacuum degree is that pressure is lower, and the boiling point of solution is lower, so in theory, when vacuum degree is high enough, the boiling point of solution can be reduced to 10~15 ℃, even lower temperature, but, higher vacuum degree is more difficult to realize, and it has higher requirement to the material of crystallization kettle, vacuum pump etc., causes cost to increase.In theory when 3~3-kPa, the scope of 95% ethanol boiling point is approximately 5~55 ℃.Therefore, present embodiment is selected 3~30kPa for use, treats that solution temperature is reduced to when being lower than boiling point, stops boiling, adopts recirculating cooling water auxiliary solution to be cooled to 10~15 ℃ and carries out crystallization again, at this moment, crystallization kettle can continue to keep 3~30kPa, also can recover normal pressure. In addition, compared with cooling the solution with circulating cooling water while the solution is boiling, this embodiment uses circulating cooling water to cool the solution after the solution stops boiling, which has the following advantages: it avoids rapid cooling of the solution under the combined action of vacuum and circulating cooling water, resulting in less evaporation of ethanol, a lower yield of furosemide, and a smaller crystal size and lower purity; and, after the solution is cooled to below its boiling point, the temperature difference between the solution temperature and the circulating cooling water is small, and the amount of cooling water required for cooling is reduced. At this time, using circulating cooling water for cooling has the advantages of energy saving and emission reduction.

[0054] Furthermore, during industrial production, recrystallization mother liquor, washing solution, and the like are directly treated as waste liquids, which undergo neutralization, microbial treatment, and other waste liquid treatment processes to meet emission standards before being discharged. The waste liquids are not recycled, increasing both solvent costs and waste liquid treatment costs. In this embodiment, however, the solution is kept boiling for a long time within the crystallization kettle by reducing pressure, and the evaporated ethanol vapor is extracted from the crystallization kettle and condensed and recovered to obtain recycled ethanol. The recycled ethanol can be used in furosemide production and purification processes. For example, the recycled ethanol is mixed with 95% ethanol and used in step S2 to dissolve crude furosemide. The recycled ethanol can also be used in other industrial production processes. By recycling the ethanol vapor, solvent usage and waste liquid treatment volume are reduced, saving costs.

[0055] Example 2

[0056] S1. Add crude furosemide to sodium hydroxide solution at a ratio of 1 g of crude furosemide: 8-10 mL of 40% sodium hydroxide solution, stir at 70-80° C. until dissolved, add activated carbon at a mass ratio of crude furosemide: activated carbon of 20:1, continue heating and stirring for 30 minutes, filter while hot, adjust the pH of the filtrate to 4-5 with glacial acetic acid, stir at room temperature for 3 hours, then cool the solution to 10-20° C. and stir for 1 hour, crystallize, filter with suction, wash the filter cake with the mother liquor of Example 1, and dry to obtain a solid substance.

[0057] S2. Add excess solid matter to 95% ethanol, heat the solution to reflux under boiling conditions, and keep the solution at a constant temperature for a period of time. Filter the solution while hot to obtain a reaction solution and incompletely dissolved solid matter. Rapidly transfer the reaction solution to a crystallizer, heat the reaction solution to boiling or a constant temperature thereof, stop heating, set the pressure in the crystallizer to 3-30 kPa for crystallization, and extract the evaporated ethanol vapor in the crystallizer. After the reaction solution in the crystallizer stops boiling or the boiling weakens, use circulating cooling water to cool the reaction solution to 10-15° C., after sufficient crystallization, filter the reaction solution to obtain a filtrate and a filter cake. Wash the filter cake and dry it under negative pressure at about 60° C. to obtain a white solid, which is a finished furosemide product. The filtrate is recovered as a mother liquor. The extracted ethanol vapor is condensed and recovered to obtain recovered ethanol.

[0058] The excess solid matter includes the solid matter that is not completely dissolved in Example 1 and the solid matter obtained in step S1 of this embodiment.

[0059] Some impurities produced during the synthesis of crude furosemide have similar solubility properties to furosemide, that is, their solubility in ethanol and purified water is similar. As a result, when the filter cake in step S1 is washed with ethanol or purified water, part of the furosemide dissolves in ethanol or purified water together with the impurities, resulting in a decrease in the yield of furosemide. In the mother liquor of Example 1, the impurity concentration is low, and the furosemide is saturated. Therefore, the mother liquor of Example 1 is used to wash the filter cake in step S1 of this embodiment. The mother liquor only dissolves impurities, thereby improving the yield and purity of the finished furosemide product, and can reduce the amount of purified water or other solvents used, reducing the purification cost. In addition, Example 1 is crystallized and filtered at 10-15°C, so the mother liquor temperature is 10-15°C. In continuous industrial production, the low-temperature mother liquor is used to wash the filter cake in step S1, reducing the energy consumption of cooling the washing solution to 10-15°C.

[0060] Example 3

[0061] S1. Add crude furosemide to sodium hydroxide solution at a ratio of 1 g of crude furosemide: 8-10 mL of 40% sodium hydroxide solution, stir at 70-80° C. until dissolved, add activated carbon at a mass ratio of crude furosemide: activated carbon of 20:1, continue heating and stirring for 30 minutes, filter while hot, adjust the pH of the filtrate to 4-5 with glacial acetic acid, stir at room temperature for 3 hours, then cool the solution to 10-20° C. and stir for 1 hour, crystallize, filter with suction, wash the filter cake with the mother liquor of Example 1, and dry to obtain a solid material.

[0062] S2. Add an excess of the solid substance obtained in step S1 to 95% ethanol, heat and pressurize the solution to reflux at 120-180 kPa under boiling conditions, until the solution maintains a constant temperature for a period of time, filter the solution while hot to obtain a reaction solution and undissolved solid substance, quickly transfer the reaction solution to a crystallization kettle, heat the reaction solution to boiling or a constant temperature thereof, stop heating, set the pressure in the crystallization kettle to 3-30 kPa for crystallization and extract the evaporated ethanol vapor in the crystallization kettle, after the reaction solution in the crystallization kettle stops boiling or the boiling is weakened, use circulating cooling water to cool the reaction solution to 10-15° C., after sufficient crystallization, filter the reaction solution to obtain a filtrate and a filter cake, wash the filter cake, and dry it under negative pressure at about 60° C. to obtain a white solid, i.e., the finished furosemide product, and recover the filtrate as the mother liquor; wherein the extracted ethanol vapor is condensed and recovered to obtain recovered ethanol.

[0063] Increasing the pressure of the solution system during dissolution can increase the boiling point of the reaction solution, thereby increasing the solubility of solutes such as furosemide in the reaction solution. In addition, the boiling reaction solution during dissolution is filtered while hot and then reaches the crystallization kettle, where it is recrystallized under vacuum conditions. The temperature difference between the temperature of the reaction solution after hot filtration and its boiling point under the pressure of the crystallization kettle is further increased, causing the reaction solution to boil rapidly in the crystallization kettle, evaporating ethanol and removing a large amount of heat, thereby reducing the solubility of solutes such as furosemide in the reaction solution and promoting the precipitation of furosemide. In addition, pressurizing during dissolution increases the boiling point of the ethanol mixed solution and increases the solubility of solutes such as furosemide, thereby reducing the amount of ethanol mixed solution used during the dissolution of furosemide in ethanol, further reducing the volume of waste liquid generated and reducing the cost of waste liquid treatment, which is beneficial to the environment.

[0064] Example 4

[0065] S1. Add 10 g of crude furosemide to 8-10 mL of 40% sodium hydroxide solution at a ratio of 1 g of crude furosemide to 8-10 mL of 40% sodium hydroxide solution, stir at 70-80° C. until dissolved, add activated carbon at a mass ratio of crude furosemide to activated carbon of 20:1, continue heating and stirring for 30 minutes, filter while hot, adjust the pH of the filtrate to 4-5 with glacial acetic acid, stir at room temperature for 3 hours, then cool the solution to 10-20° C. and stir for 1 hour, crystallize, filter, wash the filter cake with the mother liquor, and dry to obtain a solid material.

[0066] S2. Add the solid material to 95% ethanol at a ratio of 1 g of solid material: 3-6 mL of 95% ethanol, heat and pressurize, and reflux the solution at 120-180 kPa under boiling conditions for 30-60 minutes. Then, filter the solution while hot to obtain a reaction solution, quickly transfer the reaction solution to a crystallization kettle, heat the reaction solution to boiling or a constant temperature thereof, stop heating, set the pressure in the crystallization kettle to 3-30 kPa for crystallization, and extract the evaporated ethanol vapor in the crystallization kettle. After the reaction solution in the crystallization kettle stops boiling or the boiling subsides, cool the reaction solution to 10-15° C. using circulating cooling water at a cooling rate of 15-25° C. / h. After sufficient crystallization, filter the reaction solution to obtain a filtrate and a filter cake. Wash the filter cake and dry it under negative pressure at about 60° C. to obtain a white solid, which is the finished furosemide product. The filtrate is recovered as a mother liquor. The extracted ethanol vapor is condensed and recovered to obtain recovered ethanol.

[0067] The cooling rate affects the particle size, purity, and yield of furosemide crystals. Cooling too quickly results in smaller furosemide crystals and lower purity, but higher yield. A slower cooling rate results in larger crystals and higher purity, but lower yield and increased energy consumption. A cooling rate of 15-25°C / h can produce furosemide crystals with an appropriate particle size, high purity, and high yield.

[0068] In summary, compared with the existing cooling crystallization method, the present application is recrystallized under vacuum conditions, and the yield of furosemide is improved by reducing the total volume of the solution and reducing the mass fraction of ethanol in the solution. Moreover, this method makes the cooling rate of the crystallization system controllable, avoids the system temperature being uneven, and the crystals tend to grow on the nucleus rather than precipitate along the wall to make the crystal quality uniform, avoids the problems such as the cooling rate decreasing and the product yield decreasing caused by the precipitation of crystals on the cold wall. Moreover, furosemide spontaneously nucleates in the solvent, without the need to add additional crystal seeds, and is not limited by the form of stirring paddles. In addition, the present application keeps boiling the solution with the boiling point increased by continuously heating so that the solute concentration is increased, thereby increasing the concentration of furosemide to increase the utilization rate of the ethanol solvent, and heating the filtrate after the solution is filtered while hot to the new boiling point to increase the temperature difference between the solution temperature and the boiling point temperature of the solution under vacuum conditions, so that the solution can boil rapidly under vacuum conditions, reduce energy consumption and promote the evaporation of the ethanol solvent. Refluxing the solution under high pressure can further increase the boiling point of the solution, further increase the solubility of furosemide and the temperature of the solution, thereby promoting the precipitation of furosemide and reducing the amount of ethanol solvent used and the amount of waste liquid generated.

[0069] Compared with the existing purification method (Figure 1), the present application performs recrystallization under vacuum conditions while condensing and recovering the extracted ethanol vapor, and collects the solution after crystallization filtration as a mother liquor, and uses the mother liquor for washing the filtered precipitate in step S1 during the next purification. On the one hand, the furosemide in the mother liquor is at a saturated concentration, while the concentration of other solutes is low. Using the mother liquor to wash the precipitate can remove impurities to the maximum extent, especially impurities with similar solubility properties to furosemide, and almost no loss of furosemide, thereby improving the yield and purity of furosemide. On the other hand, the mother liquor replaces purified water or other solvents for washing, which can reduce the amount of purified water or other solvents used, thereby reducing costs. The recovered ethanol can be used in recrystallization or other production process flows, increasing ethanol utilization and reducing the total amount of ethanol solvent used. In addition, the existing method generates waste liquid every time it is filtered and washed, while the present application reduces the volume of the mother liquor after crystallization filtration and uses the mother liquor for the first step of washing, reducing the waste liquid generated during the first step of washing. Therefore, the present application reduces the total volume of waste liquid, thereby reducing the waste liquid treatment cost.

[0070] The above-described embodiments are merely preferred embodiments for the purpose of fully illustrating the present application, and the scope of protection of the present application is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art based on the present application are within the scope of protection of the present application. The scope of protection of the present application shall be subject to the claims.

Claims

1. A method for purifying furosemide, characterized in that: The steps include: S1. Adding crude furosemide to an inorganic base solution, allowing the mixture to react fully, decolorizing and filtering, adjusting the pH of the filtrate to an acidic condition with an acid solution for crystallization, filtering, and washing to obtain a solid substance; S2. Add the solid substance to the recrystallization solvent, heat the solution, reflux it under boiling conditions until the temperature remains constant, filter it while hot, transfer the filtrate to a crystallization kettle, heat the solution to its boiling point and then stop heating, set the pressure of the crystallization kettle to 3-60 kPa for crystallization and extract the evaporated solvent, after the solution in the crystallization kettle stops boiling, cool the solution to 10-15° C. using circulating cooling water, continue crystallization, filter, wash, and dry to obtain a furosemide product.

2. The method for purifying furosemide according to claim 1, wherein In step S2, the pressure of the crystallization kettle is set to 3-30 kPa.

3. The method for purifying furosemide according to claim 2, wherein In step S2, the filtrate after crystallization is collected as a mother liquor, and the mother liquor is used as a washing solution in step S1.

4. The method for purifying furosemide according to claim 2, wherein The solvent evaporated during the crystallization process is condensed and recovered to obtain a recovered solvent.

5. The method for purifying furosemide according to claim 4, wherein: The recrystallization solvent includes 95% ethanol, a recovery solvent, and a mixed solution of the recovery solvent and 95% ethanol.

6. The method for purifying furosemide according to any one of claims 1 to 5, characterized in that: In step S2, the heating and dissolving is carried out under the condition of 120-180 kPa.

7. The method for purifying furosemide according to claim 6, characterized in that: In step S2, the cooling rate is 15-25°C / h.

8. The method for purifying furosemide according to claim 7, characterized in that: In step S1, the inorganic alkaline solution includes sodium hydroxide solution and saturated sodium carbonate solution; the decolorization includes activated carbon decolorization; and the acid solution includes glacial acetic acid solution.

9. A production process of pure furosemide, characterized in that: The steps include: (1) adding 2,4-dichlorobenzoic acid to chlorosulfonic acid to react, and then post-treating to obtain 2,4-dichloro-5-sulfonylchlorobenzoic acid; (2) adding 2,4-dichloro-5-sulfonylchlorobenzoic acid to ammonia water for reaction, and then post-treating to obtain 2,4-dichloro-5-sulfonylaminobenzoic acid; (3) adding 2,4-dichloro-5-sulfonylaminobenzoic acid to an organic solvent, then adding a base to react to obtain a reaction solution, then preheating and mixing the reaction solution with furfurylamine in a reactor, and performing a substitution reaction, followed by post-processing to obtain a crude furosemide product; (4) The crude furosemide is treated by the purification method according to any one of claims 1 to 8 to obtain the finished furosemide product.

10. The production process of pure furosemide according to claim 9, characterized in that: The reaction temperature of step (1) is 125-130° C., and the reaction time is 2 h.

11. The production process of pure furosemide according to claim 9, characterized in that: The reaction temperature of step (2) is 10-20° C., and the reaction time is 2 h.

12. The production process of pure furosemide according to claim 9, characterized in that: The reaction temperature of 2,4-dichloro-5-sulfonylaminobenzoic acid and the base in step (3) is 65° C., and the reaction time is 0.5 h.

13. The production process of pure furosemide according to claim 12, characterized in that: In step (3), the molar ratio of 2,4-dichloro-5-sulfonamidobenzoic acid to furfural amine is 1:1.5-2; the preheating temperature is 130-140°C, and the mixing time is 20-60 minutes; the reaction time of the reaction solution and furfural amine is 2-5 hours, and the reaction temperature is 120-140°C.

14. The production process of pure furosemide according to claim 14, characterized in that: In step (3), the base is selected from one or more of sodium ethoxide and sodium methoxide; the organic solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

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