A production process of furosemide and a purification method thereof

Abstract

This invention discloses a production process and purification method for furosemide, comprising the following steps: S1, adding crude furosemide to an inorganic alkaline solution, allowing it to react fully, decolorizing and filtering, adjusting the pH of the filtrate to acidic conditions with acid to induce crystallization, filtering and washing to obtain a solid substance; S2, adding the solid substance to a recrystallization solvent, heating and refluxing it at boiling point until the solution temperature remains constant, filtering while hot, transferring the filtrate to a crystallization vessel, heating the solution to its boiling point and then stopping heating, setting the pressure of the crystallization vessel to 3-60 kPa to induce crystallization, and extracting the evaporated solvent. After the solution in the crystallization vessel stops boiling, cooling the solution to 10-15°C using circulating cooling water to continue crystallization, filtering, washing, and drying to obtain the finished furosemide product. The purification method of this invention can avoid cold wall precipitation of crystals, reduce waste liquid generation, and significantly improve the purity and yield of furosemide.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and in particular to a production process and purification method for furosemide. Background Technology

[0002] Furosemide, chemically known as 2-(2-furanmethyl)amino-5-(sulfonamide)-4-chlorobenzoic acid, has the following structural formula:

[0003]

[0004] Furosemide is a loop diuretic widely used to treat congestive heart failure and edema. Clinically, it can be used to treat cardiac edema, renal edema, ascites due to cirrhosis, as well as pulmonary edema, cerebral edema, peripheral edema caused by acute renal failure or vascular wall disorders. It is particularly valuable for cases where other diuretics are ineffective.

[0005] Currently, furosemide is typically synthesized from 2,4-dichloro-5-sulfonamide benzoic acid and furfurylamine via a condensation reaction. However, furosemide prepared using existing methods often contains numerous impurities and has low purity, thus affecting the quality and efficacy of the resulting furosemide product and limiting its application to some extent. Therefore, effectively purifying existing crude furosemide products is a key focus of current furosemide research.

[0006] Currently, the purification of crude furosemide is mainly achieved through methods such as column chromatography, salt hydrolysis, and recrystallization using organic solvents. Among these methods, column chromatography for purifying crude furosemide is costly and limited for industrial production, making large-scale application difficult.

[0007] The existing method for purifying furosemide by salt formation and hydrolysis includes the following steps: adding crude furosemide to a saturated sodium bicarbonate solution, heating to 70-100℃, adding activated carbon for decolorization, filtering, neutralizing with glacial acetic acid, crystallizing, and centrifuging to obtain furosemide product. Verification has shown that in industrial production, the purity of furosemide obtained by the above-mentioned method of salt formation and hydrolysis alone cannot meet the requirements. Another method for refining furosemide by multiple salt formation and hydrolysis is also disclosed in the existing technology: (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 3 hours to crystallize, then stirring in an ice-water bath for 1 hour to crystallize, filtering, and washing the filter cake; (2) adding the filter cake to saturated sodium bicarbonate and heating to dissolve, decolorizing with activated carbon, filtering while hot, stirring the filtrate at room temperature for 3 hours to crystallize, then stirring in an ice-water bath for 1 hour to crystallize, filtering, and washing the filter cake. (3) The filter cake is added to saturated sodium bicarbonate and heated to dissolve. Activated carbon is used for decolorization. The filter cake is filtered while hot. The filtrate is stirred at room temperature for 3 hours to crystallize. Then, it is stirred in an ice-water bath for 1 hour to crystallize. The filter cake is filtered and washed. The filter cake is then added to purified water and heated to dissolve. The pH is adjusted to 3-4 with acetic acid. The filter cake is cooled to 10-20℃ in a cold water bath for 0.5 hours to crystallize. The filter cake is filtered, washed, and dried to obtain furosemide product. The purity of furosemide product prepared by this method is as high as 99.965%. The purity of furosemide prepared by this purification method is high, but the three purifications result in low purification efficiency and low yield. A large amount of saturated sodium bicarbonate is consumed during the purification process, generating a large amount of waste liquid, which increases the purification cost and waste liquid treatment cost.

[0008] Furosemide has low solubility in ethanol at room temperature, especially at low temperatures of 10–15°C, while its solubility is high at high temperatures. Therefore, in existing technologies, ethanol is usually chosen as the recrystallization solvent to recrystallize crude furosemide to obtain the finished product. However, the ethanol recrystallization process involves a large amount of ethanol solution and generates a large amount of waste liquid. Directly discarding the waste liquid would significantly increase purification and waste liquid treatment costs and waste furosemide in the waste liquid. While using the recrystallization filtrate as a mother liquor can improve the yield of furosemide and reduce the amount of ethanol solution used, impurities accumulated in the mother liquor may affect crystal nucleus formation, leading to changes in crystallization conditions and thus affecting the yield and purity of the finished furosemide product. To reduce the amount of recrystallization solution used and improve the yield of furosemide, additional post-treatments such as distillation and column chromatography are required for the mother liquor, which is cumbersome and incurs additional post-treatment costs.

[0009] The prior art also discloses a method for purifying furosemide by combining salt hydrolysis with recrystallization in an organic solvent, see reference. Figure 1The purification method includes the following steps: First, crude furosemide is dissolved in sodium hydroxide solution, heated to 70-80℃, then activated carbon is added for decolorization, followed by filtration, neutralization with glacial acetic acid, crystallization, centrifugation, and the preparation of a solid. The solid is then refluxed with 95% ethanol at 80℃, filtered while hot, and the filtrate is cooled to 10-15℃ using circulating cooling water to induce crystallization. The crystals are then filtered, washed, and dried to obtain the final furosemide product. This purification method generates a large amount of waste liquid, which requires treatment to meet standards before discharge, increasing purification costs. Furthermore, some organic impurities in the crude furosemide have similar solubility properties to furosemide, leading to furosemide loss during filter cake washing with purified water or other solvents, thus reducing the furosemide yield. Additionally, recrystallization using a cooling crystallization method results in crystal precipitation on the cold wall, causing a decrease in cooling rate, reduced product yield, and uneven crystal formation, impacting the company's production efficiency and economic benefits.

[0010] Therefore, it remains necessary to provide a simple and efficient method for purifying furosemide in order to improve the yield and purity of furosemide, reduce the cost of the purification process, and reduce the volume of waste liquid generated. Summary of the Invention

[0011] Therefore, the purpose of this invention is to provide a purification method for furosemide suitable for industrial production, so as to improve the yield and purity of furosemide, improve the effective utilization rate of recrystallization solution, and reduce the cost and energy consumption of the purification process, thereby overcoming the shortcomings of the prior art.

[0012] To achieve the above objectives, the present invention adopts the following technical solution:

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

[0014] S1. Add crude furosemide to an inorganic alkaline solution and allow it to react fully. After decolorization and filtration, adjust the pH of the filtrate to acidic conditions with acid to induce crystallization. After filtration and washing, obtain a solid substance.

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

[0016] Compared with existing technologies, this invention first performs salt formation and hydrolysis crystallization on crude furosemide, and then recrystallizes the solid substance under vacuum conditions using an organic solvent to obtain the finished furosemide product. Compared with existing cooling crystallization methods, the recrystallization method of this invention can avoid the precipitation of crystals on cold walls, reduce the generation of waste liquid, and significantly improve the purity and yield of furosemide. Furthermore, during the dissolution process, the increase in the concentration of furosemide solute will lead to an increase in the boiling point of the solution and the cessation of boiling. Therefore, by continuing to slowly heat the crystallization system that has reached its boiling point, allowing it to continuously reach new boiling points and maintain 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 crystallization system temperature and the new boiling point of the crystallization system under vacuum conditions can be increased. This, in turn, promotes rapid boiling of the crystallization system under vacuum conditions, thereby reducing the temperature and total volume of the crystallization system and increasing the yield of furosemide.

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

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

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

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

[0021] Furthermore, in step S2, the heating and dissolving process is carried out under conditions 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] This invention also provides a method for preparing furosemide, comprising the following steps:

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

[0026] (2) 2,4-dichloro-5-sulfonylchlorobenzoic acid was added to ammonia water and reacted, and then post-treated to prepare 2,4-dichloro-5-sulfonylaminobenzoic acid;

[0027] (3) 2,4-dichloro-5-sulfonamide benzoic acid is first added to an organic solvent, and then an alkali is added to react and a reaction solution is obtained. The reaction solution is then preheated and mixed with furfurylamine in a reaction vessel and a substitution reaction is carried out. After post-treatment, crude furosemide is obtained.

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

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

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

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

[0032] Further, in step (3), the molar ratio of 2,4-dichloro-5-sulfonamide benzoic acid and furfurylamine is 1:1.5-2; the preheating temperature is 130-140℃; the mixing and feeding time is 20-60 min; the reaction time of the reaction solution and furfurylamine is 2-5 h; and the reaction temperature is 120-140℃.

[0033] Furthermore, in step (3), the alkali 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. Attached Figure Description

[0034] Figure 1 This is a flow chart of a purification process for crude furosemide in the prior art.

[0035] Figure 2 A purification process flow diagram of crude furosemide provided by the present invention.

[0036] Figure 3 The present invention provides a reaction formula for the production process of crude furosemide. Detailed Implementation

[0037] When purifying crude furosemide using a purification method combining salt hydrolysis and organic solvent recrystallization, it was found that during recrystallization, as the crude furosemide dissolved and the amount of solute in the solution increased, the boiling point of the solution began to rise, causing the solution to stop boiling at the original heating temperature. Furthermore, in industrial production, using circulating cooling water for cooling crystallization consumes a lot of energy, and the uneven temperature of the system leads to crystal precipitation on the cold walls, resulting in a decrease in cooling rate and product yield. Therefore, see [reference needed]. Figure 2This invention provides a purification process for furosemide, comprising the following steps:

[0038] S1. Add crude furosemide to an inorganic alkaline solution and allow it to react fully. After decolorization and filtration, adjust the pH of the filtrate to acidic conditions with acid to induce crystallization. Filter, wash, and collect the solid material.

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

[0040] Step S2 includes: collecting the filtrate after crystallization as the mother liquor, and extracting the solvent evaporated during crystallization from the crystallization vessel and condensing it for recovery as the recycled solvent. In the subsequent purification of crude furosemide, the mother liquor can be used as a washing solvent to wash the precipitate obtained from filtration in step S1, and the recycled solvent can be used as the recrystallization solvent in step S2 to dissolve the solid substance. Preferably, the recrystallization solvent is 95% ethanol, or a mixture of recycled ethanol and 95% ethanol.

[0041] Since the increase in furosemide solute concentration during dissolution will lead to an increase in the boiling point of the solution and cessation of boiling, step S2, which involves heating to maintain a boiling state for dissolution, includes: first heating the solution to boiling, then continuing to slowly increase the temperature so that when the boiling point stops, the temperature can be further increased to boiling point until it remains constant and cannot be further increased. Continuous heating raises the solution temperature, which in turn increases the solubility of furosemide in the solution. Therefore, when furosemide is in excess, continuous boiling dissolution can increase the concentration of furosemide in the solution. During subsequent low-temperature crystallization, the solubility of furosemide remains unchanged, thereby increasing the amount of furosemide precipitated in the solution. Furthermore, increasing the solution temperature increases the temperature difference between the solution temperature and the new boiling point under vacuum conditions, allowing the solution to boil rapidly under vacuum conditions, promoting furosemide crystallization and reducing energy consumption. Additionally, during the dissolution process, the evaporated recrystallization solvent can be condensed and recovered or refluxed back into the solution to avoid incomplete dissolution of furosemide or solvent waste.

[0042] The furosemide purification method of the present invention is applicable to Figure 3 The crude furosemide is prepared by the production process shown. The preparation method of the crude furosemide includes the following steps:

[0043] (1) 2,4-Dichlorobenzoic acid and chlorosulfonic acid were added to a reaction vessel at a molar ratio of 1:3 and stirred at 125-130℃ for 2 hours. Then, the mixture was stirred and cooled to 50℃ to obtain reaction solution A. Reaction solution A was quenched at 1-10℃, and after stirring at the same temperature for 1 hour, it was filtered and washed multiple times. Finally, it was filtered dry to obtain 2,4-dichloro-5-sulfonylchlorobenzoic acid.

[0044] (2) The above-mentioned 2,4-dichloro-5-sulfonylchlorobenzoic acid was slowly added to 25% ammonia water at a molar ratio of 3 at 10-20℃ and reacted for 2 hours. Then, concentrated hydrochloric acid was added to adjust the pH value to 1.5-2.0 to obtain reaction solution B. Reaction solution B was filtered and then added to 20% ethanol aqueous solution. The mixture was heated to reflux, hot-filtered, and the filtrate was cooled to 10℃ to crystallize. The filtrate was then filtered dry to obtain 2,4-dichloro-5-sulfonylaminobenzoic acid.

[0045] (3) Mix 2,4-dichloro-5-sulfonamide benzoic acid and dimethyl sulfoxide at a mass ratio of 1:2 and stir at 30-40℃ until dissolved to obtain a mixed solution. Take alkali according to a molar ratio of 2,4-dichloro-5-sulfonamide benzoic acid to alkali of 1:1.2 and add the alkali to the above mixed solution at a uniform rate over 10 min. Stir at 65-75℃ for 1 h to obtain reaction solution C. Weigh furfurylamine according to a molar ratio of 2,4-dichloro-5-sulfonamide benzoic acid to furfurylamine of 1:1.5-2, and preheat furfurylamine and reaction solution C to 130-140℃ respectively. Add furfurylamine and reaction solution C to a reaction vessel at 120-140℃ using a cross-jet method. After the addition is completed, seal the feeding port, introduce nitrogen gas and continue stirring for 2-5 h until the reaction is complete to obtain reaction solution D. At room temperature, reaction solution D was poured into water, sodium hydroxide was added to adjust the pH to 12-13, then dichloromethane was added for extraction, hydrochloric acid was added to the aqueous layer after extraction to adjust the pH to 1.5-2, and the mixture was stirred to induce crystallization. The mixture was then filtered and washed with water multiple times, and the crude furosemide was obtained after filtration.

[0046] To make the present invention easier to understand, specific embodiments are described below to further illustrate the invention. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention; the described drawings are also illustrative only and are considered non-limiting.

[0047] Example 1

[0048] S1. Add crude furosemide to sodium hydroxide solution at a ratio of 1g crude furosemide to 8-10mL 40% sodium hydroxide solution. Stir at 70-80℃ until dissolved. Add activated carbon at a mass ratio of crude furosemide to activated carbon of 20:1. Continue heating and stirring for 30min. Filter while hot. Adjust the pH of the filtrate to 4-5 using glacial acetic acid. Stir at room temperature for 3h to ensure complete hydrolysis and precipitation of the generated furosemide. Then cool the solution to 10-20℃ and stir for 1h to ensure complete precipitation of the hydrolyzed furosemide from the acid solution. Filter by suction. Wash and dry the filter cake with purified water to obtain a solid substance.

[0049] S2. Add excess of the solid obtained in step S1 to 95% ethanol, heat to boiling and reflux until the solution maintains a constant temperature for a period of time, then filter the solution while hot to obtain the reaction solution and the undissolved solid. Quickly transfer the reaction solution to a crystallization vessel, heat the reaction solution to boiling or its constant temperature, stop heating, set the pressure in the crystallization vessel to 3-30 kPa to crystallize, and extract the evaporated ethanol vapor from the crystallization vessel. After the reaction solution in the crystallization vessel stops boiling or the boiling weakens, use circulating cooling water to cool the reaction solution to 10-15°C, and after crystallization, filter the reaction solution to obtain filtrate and filter cake. After washing and drying the filter cake under negative pressure at about 60°C, a white solid is obtained, which is the furosemide product. The filtrate is recovered as the mother liquor; the extracted ethanol vapor is condensed and recovered to obtain recovered ethanol.

[0050] The appropriate amount of 95% ethanol to be used in subsequent production can be calculated based on the mass of the solid material and the mass of the undissolved solid material (the ratio of solid material to 95% ethanol). The heating time in subsequent production can also be calculated based on the heating time in step S2, thus ensuring consistent reaction conditions and avoiding the tedious process of measuring the temperature multiple times.

[0051] In this embodiment, the recrystallization method under vacuum conditions can significantly reduce the consumption of circulating cooling water and increase the yield of furosemide. Furthermore, during the crystallization process, the reaction solution can be distilled, which reduces the mass fraction of ethanol in the mother liquor, thereby reducing the solubility of furosemide. Additionally, it allows for the recovery of ethanol and mother liquor, which can then be used in the next purification process, thereby reducing purification costs and energy consumption during the purification process.

[0052] At normal pressure, the boiling point of pure ethanol is around 78°C. Therefore, existing technologies generally use excess ethanol to reflux and dissolve crude furosemide at 80°C. However, this does not consider the effect of solute concentration on the boiling point of the solution. In this embodiment, 95% ethanol is used to heat and reflux the excess solid material. By keeping the solution boiling, the solution temperature is increased, raising the concentration of furosemide in the solution and thus increasing the utilization rate of 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] Furthermore, this embodiment performs recrystallization under vacuum conditions, utilizing the principle that the boiling point of a solution decreases under low pressure. The high-temperature solution is kept boiling for an extended period under low pressure, and the evaporated ethanol vapor is extracted from the crystallization vessel and condensed for recovery. This method has the following advantages: ① The evaporation of ethanol reduces the total volume of the solution, increasing the concentration of solutes such as furosemide in the solution, thereby promoting furosemide precipitation; ② The solubility of solutes such as furosemide in ethanol is much greater than their solubility in water. Therefore, the evaporation of ethanol solvent in the ethanol-water solution reduces the mass fraction of ethanol in the solution, decreasing the solubility of furosemide in the solution, thus promoting furosemide precipitation; ③ The solubility of furosemide in ethanol increases with increasing temperature. Ethanol vaporization absorbs heat from the solution, lowering the solution temperature, thereby reducing the solubility of furosemide and promoting its precipitation. Moreover, reducing the amount of mother liquor and promoting the precipitation of furosemide in the mother liquor reduces the amount of unprecipitated furosemide in the mother liquor. Even if the mother liquor is directly discarded, the amount of wasted furosemide can be reduced. The higher the vacuum level, the lower the pressure, and the lower the boiling point of the solution. Therefore, theoretically, with a sufficiently high vacuum, the boiling point of the solution can be lowered to 10-15°C, or even lower. However, achieving higher vacuum levels is difficult and places higher demands on the materials of the crystallizer and vacuum pump, leading to increased costs. Theoretically, at 3-3 kPa, the boiling point of 95% ethanol ranges from approximately 5-55°C. Therefore, this embodiment uses 3-30 kPa. Once the solution temperature drops below the boiling point and boiling stops, circulating cooling water is used to assist in cooling the solution to 10-15°C for crystallization. At this point, the crystallizer can continue to maintain 3-30 kPa or return to atmospheric pressure. In addition, compared with cooling the solution with circulating cooling water while it is boiling, this embodiment uses circulating cooling water to cool the solution after it has stopped boiling, which has the following advantages: it avoids the solution from cooling down rapidly under the combined action of vacuum and circulating cooling water, which would result in less ethanol evaporation, a lower yield of furosemide, and smaller crystal size and lower purity; and when the solution is cooled below its boiling point, the temperature difference between the solution and the circulating cooling water is smaller, 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, in industrial production processes, recrystallization mother liquor and washing solutions are directly treated as waste liquids, undergoing neutralization and microbial treatment to meet emission standards before being discharged. This waste liquid is not recycled, increasing both solvent and waste liquid treatment costs. In this embodiment, however, the solution is kept boiling in the crystallization vessel under reduced pressure for an extended period. The evaporated ethanol vapor is extracted from the crystallization vessel, condensed, and recovered to obtain recycled ethanol. This recycled ethanol can be used in furosemide production and purification processes. For example, the recycled ethanol can be 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 recovering 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 1g crude furosemide to 8-10mL 40% sodium hydroxide solution. Stir at 70-80℃ until dissolved. Add activated carbon at a mass ratio of crude furosemide to activated carbon of 20:1. Continue heating and stirring for 30min. Filter while hot. Adjust the pH of the filtrate to 4-5 using glacial acetic acid. Stir at room temperature for 3h. Then cool the solution to 10-20℃ and stir for 1h to induce crystallization. Filter by suction. Wash and dry the filter cake with the mother liquor from Example 1 to obtain a solid substance.

[0057] S2. Add excess solid material to 95% ethanol, heat to reflux the solution at boiling point until the solution maintains a constant temperature for a period of time, then filter the solution while hot to obtain the reaction solution and undissolved solid material. Quickly transfer the reaction solution to a crystallization vessel, heat the reaction solution to boiling point or its constant temperature, stop heating, set the pressure inside the crystallization vessel to 3-30 kPa for crystallization, and extract the evaporated ethanol vapor from the crystallization vessel. After the reaction solution in the crystallization vessel stops boiling or the boiling weakens, use circulating cooling water to cool the reaction solution to 10-15°C, and after crystallization, filter the reaction solution to obtain filtrate and filter cake. After washing and drying the filter cake under negative pressure at about 60°C, a white solid is obtained, which is the furosemide product. The filtrate is recovered as the mother liquor; the extracted ethanol vapor is condensed and recovered to obtain recovered ethanol.

[0058] The excess solid material includes the undissolved solid material in Example 1, as well as the solid material obtained in step S1 of this example.

[0059] Some impurities generated during the synthesis of crude furosemide have similar solubility properties to furosemide, meaning their solubility in ethanol and purified water is similar. This leads to some furosemide dissolving along with the impurities in ethanol or purified water when washing the filter cake in step S1 with ethanol or purified water, resulting in a lower furosemide yield. However, the mother liquor from Example 1 has a lower impurity concentration, while furosemide is already saturated. Therefore, using the mother liquor from Example 1 to wash the filter cake in step S1 of this example only dissolves the impurities, thereby improving the yield and purity of the furosemide product and reducing the amount of purified water or other solvents used, thus lowering purification costs. Furthermore, Example 1 involves crystallization and filtration at 10–15°C, resulting in a mother liquor temperature of 10–15°C. In continuous industrial production, using the low-temperature mother liquor to wash the filter cake in step S1 reduces 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 1g crude furosemide to 8-10mL 40% sodium hydroxide solution. Stir at 70-80℃ until dissolved. Add activated carbon at a mass ratio of crude furosemide to activated carbon of 20:1. Continue heating and stirring for 30min. Filter while hot. Adjust the pH of the filtrate to 4-5 using glacial acetic acid. Stir at room temperature for 3h. Then cool the solution to 10-20℃ and stir for 1h to induce crystallization. Filter by suction. Wash and dry the filter cake with the mother liquor from Example 1 to obtain a solid substance.

[0062] S2. Add excess of the solid obtained in step S1 to 95% ethanol, heat and pressurize, and reflux the solution 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 the reaction solution and incompletely dissolved solid. Quickly transfer the reaction solution to a crystallization vessel, heat the reaction solution to boiling or its constant temperature, stop heating, set the pressure inside the crystallization vessel to 3-30 kPa for crystallization, and extract the evaporated ethanol vapor from the crystallization vessel. After the reaction solution in the crystallization vessel stops boiling or the boiling weakens, use circulating cooling water to cool the reaction solution to 10-15°C. After crystallization, filter the reaction solution to obtain filtrate and filter cake. After washing and drying the filter cake under negative pressure at about 60°C, a white solid is obtained, which is the furosemide product. The filtrate is recovered as the mother liquor. The extracted ethanol vapor is condensed and recovered to obtain recovered ethanol.

[0063] Increasing the pressure of the solution system during dissolution raises the boiling point of the reaction solution, thereby increasing the solubility of solutes such as furosemide in the reaction solution. Furthermore, after hot filtration, the boiling reaction solution reaches the crystallization vessel for recrystallization under vacuum conditions. The temperature difference between the hot filtration temperature of the reaction solution and its boiling point under the pressure of the crystallization vessel further increases, causing the reaction solution to boil rapidly in the crystallization vessel. Ethanol evaporates, carrying away a large amount of heat, which reduces the solubility of solutes such as furosemide in the reaction solution and promotes the precipitation of furosemide. Additionally, pressurizing during dissolution raises the boiling point of the ethanol mixture and increases the solubility of solutes such as furosemide, thus reducing the amount of ethanol mixture used in the furosemide ethanol dissolution process, further reducing the volume of waste liquid generated, lowering waste liquid treatment costs, and thus benefiting the environment.

[0064] Example 4

[0065] S1. Add 10g of crude furosemide to sodium hydroxide solution at a ratio of 1g crude furosemide to 8-10mL 40% sodium hydroxide solution. Stir at 70-80℃ until dissolved. Add activated carbon at a mass ratio of crude furosemide to activated carbon of 20:1. Continue heating and stirring for 30min. Filter while hot. Adjust the pH of the filtrate to 4-5 using glacial acetic acid. Stir at room temperature for 3h. Then cool the solution to 10-20℃ and stir for 1h to induce crystallization. Filter by suction. Wash and dry the filter cake with mother liquor to obtain a solid substance.

[0066] S2. Add the solid substance to 95% ethanol at a ratio of 1g solid substance to 3-6mL 95% ethanol. Heat and pressurize the solution, refluxing it at 120-180kPa and boiling for 30-60 minutes. Filter the solution while hot to obtain the reaction solution. Quickly transfer the reaction solution to a crystallization vessel, heat it to boiling or its constant temperature, stop heating, set the pressure inside the crystallization vessel to 3-30kPa for crystallization, and extract the evaporated ethanol vapor from the crystallization vessel. After the reaction solution in the crystallization vessel stops boiling or the boiling weakens, use circulating cooling water at a cooling rate of 15-25℃ / h to cool the reaction solution to 10-15℃. After crystallization, filter the reaction solution to obtain filtrate and filter cake. The filter cake is washed and dried under negative pressure at about 60℃ to obtain a white solid, which is the furosemide product. The filtrate is recovered as the 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. Too rapid a cooling rate results in smaller crystal size and lower purity, but a higher yield. Conversely, a slower cooling rate leads to larger crystal size and higher purity, but a lower yield and increased energy consumption. A cooling rate of 15–25 °C / h yields furosemide with a suitable crystal size, high purity, and high yield.

[0068] In summary, compared with existing cooling crystallization methods, this invention performs recrystallization under vacuum conditions. By reducing the total solution volume and the mass fraction of ethanol in the solution, the yield of furosemide is improved. Furthermore, this method allows for controllable cooling rates in the crystallization system, avoiding temperature inhomogeneity. Crystals tend to grow on nuclei rather than precipitate along the walls, resulting in more uniform crystal quality and avoiding problems such as decreased cooling rates and product yield caused by crystal precipitation on cold walls. Moreover, furosemide spontaneously nucleates in the solvent, eliminating the need for additional seed crystals and not being limited by the type of stirring paddle. In addition, this invention continuously heats the solution, keeping it at a constant boiling point due to increased solute concentration, thereby increasing the furosemide concentration and ethanol solvent utilization. The filtrate after hot filtration is then heated to a new boiling point, increasing the temperature difference between the solution and its boiling point under vacuum conditions. This allows the solution to boil rapidly under vacuum, reducing energy consumption and promoting ethanol solvent evaporation. By refluxing the solution under high pressure, the boiling point of the solution can be further increased, thereby increasing the solubility of furosemide and the temperature of the solution, which promotes the precipitation of furosemide and reduces the amount of ethanol solvent used and the amount of waste liquid generated.

[0069] Compared with existing purification methods ( Figure 1 In contrast, this invention, while recrystallizing under vacuum conditions, simultaneously condenses and recovers the extracted ethanol vapor and collects the solution after crystallization filtration as a mother liquor. This mother liquor is used for washing the precipitate in step S1 of the next purification process. Firstly, the mother liquor contains a saturated concentration of furosemide, while other solute concentrations are low. Washing the precipitate with the mother liquor can remove impurities to the maximum extent, especially those with similar solubility properties to furosemide, with almost no loss of furosemide, thereby improving the yield and purity of furosemide. Secondly, using the mother liquor instead of purified water or other solvents for washing reduces the amount of purified water or other solvents used, thus lowering costs. The recovered ethanol can be used in recrystallization or other production processes, increasing ethanol utilization and reducing the total amount of ethanol solvent used. Furthermore, existing methods generate waste liquid during each filtration and washing step, while this invention reduces the volume of the mother liquor after crystallization filtration and uses it for the first washing step, reducing the waste liquid generated in the first washing step. Therefore, this invention reduces the total volume of waste liquid, thereby reducing waste liquid treatment costs.

[0070] The embodiments described above are merely preferred embodiments for fully illustrating the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are all within the scope of protection of the present invention. The scope of protection of the present invention is defined by the claims.

Claims

1. A method for purifying furosemide, characterized in that, Includes the following steps: S1. Add crude furosemide to sodium hydroxide solution at a ratio of 1g crude furosemide to 8-10mL 40% sodium hydroxide solution. Stir at 70-80℃ until dissolved. Add activated carbon at a mass ratio of crude furosemide to activated carbon of 20:

1. Continue heating and stirring for 30min. Filter while hot. Adjust the pH of the filtrate to 4-5 using glacial acetic acid. Stir at room temperature for 3h to ensure complete hydrolysis and precipitation of the generated furosemide. Cool the solution to 10-20℃ and stir for 1h. Filter and wash to obtain the solid substance. S2. Add excess of the solid substance to the recrystallization solvent, heat, and reflux the solution while it is boiling until the temperature remains constant. Filter while hot, transfer the filtrate to a crystallization vessel, heat the solution to its boiling point, and then stop heating. Set the pressure in the crystallization vessel to 3-30 kPa to crystallize and remove the evaporated solvent. After the solution in the crystallization vessel stops boiling, use circulating cooling water to cool the solution to 10-15°C to continue crystallization. Filter, wash, and dry to obtain furosemide product; wherein, the recrystallization solvent is 95% ethanol. In step S2, the filter residue from hot filtration is collected, and the filter residue is recycled back to step S2, mixed with the solid material, and added to the recrystallization solvent. In step S2, the solvent evaporated during the crystallization process is condensed and recovered to obtain a recovered solvent, which is recycled back to step S2 as a recrystallization solvent; and the filtrate after crystallization is collected as a mother liquor, which is used as a washing solution in step S1. In step S2, the heating to keep the solution in a boiling state and the reflux is carried out under conditions of 120~180 kPa; In step S2, the cooling rate is 15~25℃ / h.

2. A production process for pure furosemide, characterized in that, Includes the following steps: (1) 2,4-Dichlorobenzoic acid is added to chlorosulfonic acid to react, and then post-processed to obtain 2,4-dichloro-5-sulfonylchlorobenzoic acid; (2) 2,4-dichloro-5-sulfonylchlorobenzoic acid was reacted with ammonia water and then post-treated to prepare 2,4-dichloro-5-sulfonylaminobenzoic acid; (3) 2,4-dichloro-5-sulfonamide benzoic acid is first added to an organic solvent, and then an alkali is added to react and a reaction solution is obtained. The reaction solution is then preheated and mixed with furfurylamine in a reaction vessel and a substitution reaction is carried out. After post-treatment, crude furosemide is obtained. (4) The crude furosemide described above is purified by the purification method described in claim 1 to obtain the finished furosemide product.

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

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

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

6. The production process of pure furosemide according to claim 5, characterized in that, In step (3), the molar ratio of 2,4-dichloro-5-sulfonamide benzoic acid and furfurylamine is 1:1.5-2; the preheating temperature is 130-140℃; the mixing and feeding time is 20-60 min; the reaction time of the reaction solution and furfurylamine is 2-5 h; and the reaction temperature is 120-140℃.

7. The production process of pure furosemide according to claim 6, characterized in that, In step (3), the alkali 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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