CN118290370A

CN118290370A - Production process and purification method of furosemide

Info

Publication number: CN118290370A
Application number: CN202410260435.3A
Authority: CN
Inventors: 叶宏裕; 杨庆辉; 麦佛洪
Original assignee: Taishan Xinning Pharmaceutical Co ltd
Current assignee: Taishan Xinning Pharmaceutical Co ltd
Filing date: 2024-03-07
Publication date: 2024-07-05

Abstract

The invention discloses a production process and a purification method of furosemide, comprising the following steps: s1, adding the furosemide crude product into an inorganic alkali solution, fully reacting, decoloring, filtering, adjusting the pH value of the filtrate to an acidic condition by using acid liquor for crystallization, filtering and washing to obtain a solid substance; s2, adding the solid substances into a recrystallization solvent, heating the solution, refluxing the solution in a boiling state until the temperature of the solution is kept constant, filtering the solution while the solution is hot, transferring the filtrate into a crystallization kettle, heating the solution to the boiling temperature of the solution, stopping heating, setting the pressure of the crystallization kettle to 3-60 kPa for crystallization, extracting the evaporated solvent, cooling the solution to 10-15 ℃ by using circulating cooling water after the solution in the crystallization kettle stops boiling, continuing crystallization, filtering, washing and drying to obtain the furosemide finished product. The purification method can avoid cold wall precipitation of crystals, reduce the generation of waste liquid and obviously improve the purity and yield of the furosemide.

Description

Production process and purification method of furosemide

Technical Field

The invention relates to the technical field of medicine synthesis, in particular to a production process and a purification method of furosemide.

Background

Furosemide (Furosemide), chemical name 2- (2-furanmethyl) amino-5- (sulfonylamino) -4-chlorobenzoic acid, its structural formula is as follows:

furosemide is a loop diuretic widely applied to the treatment of congestive heart failure and edema, can be clinically used for treating cardiac edema, renal edema, cirrhosis ascites, pulmonary edema, cerebral edema, peripheral edema caused by acute renal failure or vascular wall disorder and the like, and has important application value especially for other cases where diuretics are ineffective.

At present, the synthesis of furosemide generally takes 2, 4-dichloro-5-sulfonamide benzoic acid and furfuryl amine as main raw materials, and the furosemide is prepared through condensation reaction. However, the furosemide prepared by the existing method often contains more impurities and has lower purity, so that the quality and the use effect of the obtained furosemide product are affected, and the application of the furosemide is limited to a certain extent. Therefore, how to effectively purify the prior furosemide crude product is the focus of the current research on furosemide.

Currently, purification of crude furosemide is mainly achieved by column chromatography, salifying hydrolysis, recrystallization by using an organic solvent and the like. The purification of the furosemide crude product by column chromatography has high cost, is limited in industrial production, and is difficult to apply on a large scale.

The purification method of the salified and hydrolyzed furosemide in the prior art comprises the following steps: and (3) adding the furosemide crude product into a sodium bicarbonate saturated solution, heating to 70-100 ℃, adding activated carbon for decolorization, filtering, neutralizing with glacial acetic acid, crystallizing and centrifuging to obtain a furosemide product, wherein the purity of the furosemide product prepared by the purification method for only once salifying and hydrolyzing can not meet the requirement in industrial production through verification. The prior art also discloses another refining method of furosemide by salifying and hydrolyzing for multiple times: (1) Mixing the furosemide crude product with saturated sodium bicarbonate, heating to dissolve, decolorizing with active carbon, filtering while the active carbon is hot, stirring and crystallizing the filtrate at room temperature for 3 hours, stirring and crystallizing the filtrate in an ice water bath for 1 hour, filtering, and washing a filter cake; (2) Adding the filter cake into saturated sodium bicarbonate, heating for dissolving, decoloring with active carbon, filtering while the filter cake is hot, stirring and crystallizing the filtrate at room temperature for 3 hours, stirring and crystallizing the filtrate in an ice water bath for 1 hour, filtering, and washing the filter cake; (3) Adding the filter cake into saturated sodium bicarbonate, heating for dissolving, decolorizing with active carbon, filtering while the filter cake is hot, stirring and crystallizing the filtrate at room temperature for 3 hours, stirring and crystallizing the filtrate with ice water bath for 1 hour, filtering and washing the filter cake, adding the filter cake into purified water, heating for dissolving, adjusting the pH to 3-4 with acetic acid, cooling to 10-20 ℃ in cold water bath for crystallizing for 0.5 hour, filtering and washing the filter cake, and drying to obtain the furosemide finished product, wherein the purity of the furosemide finished product prepared by the method is up to 99.965%. The furosemide prepared by the purification method has higher purity, but three purifications lead to lower purification efficiency and lower yield, and a large amount of saturated sodium bicarbonate is consumed in the purification process, so that a large amount of waste liquid is generated, and the purification cost and the waste liquid treatment cost are increased.

At normal temperature, especially at low temperature of 10-15 ℃, the solubility of furosemide in ethanol is low, and at high temperature, the solubility of furosemide in ethanol is high, so in the prior art, ethanol is usually selected as a recrystallization solvent, and the furosemide crude product is recrystallized to obtain a furosemide finished product. However, in the ethanol recrystallization process, the use amount of the ethanol solution is large, the amount of the generated waste liquid is large, if the waste liquid is directly discarded, the purification cost and the waste liquid treatment cost are obviously increased, and the waste of the furosemide in the waste liquid is caused, and if the recrystallization filtrate is directly used as the mother liquor, although the yield of the furosemide can be improved, the use amount of the ethanol solution is reduced, impurities accumulated in the mother liquor can influence the formation of crystal nucleus, and the crystallization condition is changed, so that the yield and the purity of the furosemide finished product are influenced. If the amount of the recrystallization solution is reduced and the yield of furosemide is increased, additional post-treatment such as distillation and column chromatography is required for the mother solution, the process is complicated, and additional post-treatment cost is brought.

The prior art also discloses a purification method of furosemide by combining salification hydrolysis and organic solvent recrystallization, referring to fig. 1, the purification method comprises the following steps: dissolving the furosemide crude product in sodium hydroxide solution, heating to 70-80 ℃, adding active carbon for decoloring, filtering, neutralizing with glacial acetic acid, crystallizing, centrifuging to obtain a solid substance, refluxing the solid substance at 80 ℃ by using 95% ethanol, filtering while the solid substance is hot, cooling the filtrate to 10-15 ℃ by using circulating cooling water, crystallizing, filtering, washing and drying to obtain the furosemide finished product. The purification method generates a large amount of waste liquid, and the waste liquid is treated and discharged after reaching standards, so that the purification cost is increased. And part of organic impurities in the furosemide crude product are similar to the furosemide in dissolution property, so that when purified water or other solvents are adopted to wash filter cakes, the loss of the furosemide is caused while the organic impurities are removed, and the yield of the furosemide is reduced. In addition, the recrystallization is carried out by adopting a cooling crystallization method, so that the problems of reduced cooling rate, reduced product yield, nonuniform crystals and the like caused by precipitation of crystals on a cold wall affect the production efficiency and economic benefit of enterprises.

Therefore, there is still a need to provide a simple and efficient purification method of furosemide to increase the yield and purity of furosemide, reduce the cost of purification process and the volume of waste liquid generated.

Disclosure of Invention

Based on this, the present invention aims to provide a purification method of furosemide suitable for industrial production, so as to improve the yield and purity of furosemide, improve the effective utilization rate of recrystallization solution, reduce the cost and energy consumption of purification process, and solve the defects in the prior art.

In order to achieve the above purpose, the invention adopts the following technical scheme:

A method for purifying furosemide, comprising the following steps:

S1, adding the furosemide crude product into an inorganic alkali solution, fully reacting, decoloring, filtering, adjusting the pH value of the filtrate to an acidic condition by using acid liquor for crystallization, filtering and washing to obtain a solid substance;

s2, adding the solid substances into a recrystallization solvent, heating the solution, refluxing the solution in a boiling state until the temperature of the solution is kept constant, filtering the solution while the solution is hot, transferring the filtrate into a crystallization kettle, heating the solution to the boiling temperature of the solution, stopping heating, setting the pressure of the crystallization kettle to 3-60 kPa for crystallization, extracting the evaporated solvent, cooling the solution to 10-15 ℃ by using circulating cooling water after the solution in the crystallization kettle stops boiling, continuing crystallization, filtering, washing and drying to obtain the furosemide finished product.

Compared with the existing cooling crystallization method, the recrystallization method can avoid precipitation of cold walls of crystals, reduce the generation of waste liquid, obviously improve the purity and yield of the furosemide, and increase the concentration of the furosemide solute in the dissolution process, so that the furosemide crystallization system reaching the boiling point continuously and slowly increases the temperature to reach the new boiling point, the temperature of the crystallization system can be kept at the boiling state all the time, the solubility of the furosemide in the crystallization system can be improved, the temperature difference between the temperature of the crystallization system and the new boiling point of the crystallization system in the vacuum state can be increased, the rapid boiling of the crystallization system in the vacuum state can be further promoted, the temperature and the total volume of the crystallization system can be reduced, and the yield of the furosemide can be improved.

Further, in step S2, the pressure of the crystallization kettle is set to 3 to 30kPa.

Further, in step S2, the filtrate after crystallization is collected as a mother liquor, which is used as the washing solution of step S1.

And further, condensing and recycling the solvent evaporated in the crystallization process to obtain a recycled solvent.

Further, the recrystallization solvent includes 95% ethanol, a recovery solvent, and a mixed solution of the recovery solvent and 95% ethanol.

Further, in step S2, the heating and dissolution are performed under the condition of 120 to 180 kPa.

In step S2, the cooling rate is 15-25 ℃/h.

Further, in step S1, the inorganic alkaline solution includes a sodium hydroxide solution, a saturated sodium carbonate solution; the decolorization comprises activated carbon decolorization; the acid solution comprises glacial acetic acid solution.

The invention also provides a preparation method of the furosemide, which comprises the following steps:

(1) Adding 2, 4-dichlorobenzoic acid into chlorosulfonic acid to react, and performing post-treatment to obtain 2, 4-dichloro-5-sulfonyl chlorobenzoic acid;

(2) Adding 2, 4-dichloro-5-sulfonyl chlorobenzoic acid into ammonia water for reaction, and then performing post-treatment to prepare 2, 4-dichloro-5-sulfonyl aminobenzoic acid;

(3) Adding 2, 4-dichloro-5-sulfonylaminobenzoic acid into an organic solvent, adding alkali to react to obtain a reaction solution, preheating and mixing the reaction solution and furfuryl amine in a reaction kettle, carrying out substitution reaction, and carrying out aftertreatment to obtain a furosemide crude product;

(4) And the furosemide crude product is treated by the purification method to obtain a furosemide finished product.

Further, the reaction temperature in the step (1) is 125-130 ℃, and the reaction time is 2h.

Further, the reaction temperature in the step (2) is 10-20 ℃ and the reaction time is 2h.

Further, the reaction temperature of the 2, 4-dichloro-5-sulfonylaminobenzoic acid and the base in the step (3) is 65 ℃ and the reaction time is 0.5h.

Further, in the step (3), the molar ratio of the 2, 4-dichloro-5-sulfonylbenzoic acid to the furfuryl amine is 1:1.5-2; the preheating temperature is 130-140 ℃, and the mixing feeding time is 20-60min; the reaction time of the reaction solution and the furfuryl amine is 2-5h, and the reaction temperature is 120-140 ℃.

Further, in the 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-dimethylacetamide and dimethyl sulfoxide.

Drawings

Fig. 1 is a flow chart of a purification process of a crude furosemide product in the prior art.

Fig. 2 is a flow chart of a purification process of a furosemide crude product.

Fig. 3 is a reaction formula of a production process of a furosemide crude product.

Detailed Description

When the furosemide crude product is purified by adopting a purification method combining salifying hydrolysis and organic solvent recrystallization, the boiling point of the solution starts to rise along with the dissolution of the furosemide crude product and the increase of solutes in the solution in the recrystallization process, so that the solution is not boiled at the original heating temperature. In addition, in industrial production, the energy consumption of adopting circulating cooling water to cool and crystallize is large, and the system temperature is uneven, so that crystals are separated out from a cold wall, and the problems of reduced cooling rate, reduced product yield and the like are caused. Accordingly, referring to fig. 2, the present invention provides a purification process of furosemide, comprising the steps of:

s1, adding the furosemide crude product into an inorganic alkali solution, fully reacting, decoloring, filtering, adjusting the pH value of the filtrate to an acidic condition by using acid liquor for crystallization, filtering, washing and collecting solid matters;

S2, adding the solid substance into a recrystallization solvent, heating to dissolve the solution in a boiling state until the temperature of the solution is kept constant, filtering while the solution is hot, transferring the filtrate into a crystallization kettle, and heating to the boiling temperature of the filtrate; stopping heating, setting the pressure of the crystallization kettle to 3-60 kPa for crystallization, cooling the solution to 10-15 ℃ by using circulating cooling water after the solution in the crystallization kettle stops boiling, continuing crystallization, filtering, washing and drying to obtain the furosemide finished product.

Wherein, step S2 includes: collecting filtrate after crystallization as mother liquor, extracting solvent evaporated in crystallization process from crystallization kettle, condensing and recovering as recovered solvent. In the subsequent purification of the crude furosemide product, the mother liquor can be used as a washing solvent, the precipitate obtained by filtering in the step S1 is washed, and the recovered solvent can be used as a recrystallization solvent in the step S2 to dissolve the solid substance. Preferably, the recrystallization solvent is 95% ethanol, or a mixed solution of recovered ethanol and 95% ethanol.

Since an increase in the concentration of the furosemide solute during the dissolution process will cause the boiling point of the solution to rise and the boiling of the solution to stop, the heating in step S2 to keep the boiling state for dissolution includes: heating the solution to boiling, then continuously heating slowly, and when the boiling point of the solution is increased to stop boiling, continuously heating to boiling until the temperature of the solution is kept constant and can not be continuously heated. The continuous temperature rise can raise the temperature of the solution, and the rise of the temperature of the solution causes the solubility of the furosemide in the solution to rise, so that when the furosemide is excessive, the furosemide concentration in the solution can be increased by continuous boiling dissolution, and when the furosemide is subsequently low Wen Xijing, the solubility of the furosemide is unchanged, thereby increasing the amount of the furosemide precipitated in the solution. In addition, the temperature difference between the temperature of the solution and the new boiling point of the solution under the vacuum condition can be increased by increasing the temperature of the solution, so that the solution is quickly boiled under the vacuum condition, the crystallization of furosemide is promoted, and the energy consumption is reduced. In addition, in the dissolving process, the evaporated recrystallization solvent can be condensed and recovered or reflowed into the solution, so that the problem of insufficient dissolution or solvent waste of the furosemide is avoided.

The furosemide purification method is suitable for the furosemide crude product prepared by the production process shown in figure 3, and the furosemide crude product preparation method comprises the following steps:

(1) Adding 2, 4-dichlorobenzoic acid and chlorosulfonic acid into a reaction kettle according to a molar ratio of 1:3, and stirring for 2 hours under the heating condition of 125-130 ℃; then stirring and cooling to 50 ℃ to obtain a reaction liquid A. Quenching the reaction solution A at a low temperature of 1-10 ℃, carrying out heat preservation and stirring for 1h, then carrying out multiple filtration and washing, and finally filtering to obtain the 2, 4-dichloro-5-sulfonyl chlorobenzoic acid.

(2) Slowly adding the 2, 4-dichloro-5-sulfonyl chlorobenzoic acid into 25% ammonia water with the molar ratio of 3 times at the temperature of 10-20 ℃ for reaction for 2 hours, and then adding concentrated hydrochloric acid to adjust the pH value to 1.5-2.0, thus obtaining a reaction liquid B. Filtering the reaction solution B, adding the reaction solution B into a 20% ethanol water solution, heating to reflux, performing hot suction filtration, cooling the filtrate to 10 ℃ for crystallization, and then filtering to obtain the 2, 4-dichloro-5-sulfonylaminobenzoic acid.

(3) Mixing 2, 4-dichloro-5-sulfonylaminobenzoic acid and dimethyl sulfoxide according to a mass ratio of 1:2, and stirring at 30-40 ℃ until the mixture is dissolved to obtain a mixed solution. According to 2, 4-dichloro-5-sulfonylaminobenzoic acid: the alkali mole ratio is 1:1.2, adding the alkali into the mixed solution at a constant speed within 10min, and stirring for 1h at 65-75 ℃ to obtain a reaction solution C. According to 2, 4-dichloro-5-sulfonylaminobenzoic acid: the molar ratio of furfuryl amine is 1:1.5-2, respectively preheating furfuryl amine and reaction liquid C to 130-140 ℃, adding the furfuryl amine and the reaction liquid C into a reaction kettle at 120-140 ℃ in a cross jet mode, sealing a charging port after the charging is finished, and introducing nitrogen to continuously stir for 2-5h until the reaction is complete, thus obtaining reaction liquid D. And pouring the reaction solution D into water at room temperature, adding sodium hydroxide to adjust the pH value to 12-13, adding dichloromethane for extraction, adding hydrochloric acid to adjust the pH value to 1.5-2 into the extracted water layer, stirring for crystallization, and then filtering, washing with water for multiple times, and filtering to obtain a furosemide crude product.

In order that the invention may be more readily understood, the invention will be further described with reference to the following examples. It is to be understood that these examples are for illustration of the invention only and are not intended to limit the scope of the invention; the drawings described are also only schematic and are non-limiting.

Example 1

S1, mixing 1g of furosemide crude product: 8-10 mL of 40% sodium hydroxide solution, adding the furosemide crude product into the sodium hydroxide solution, stirring at 70-80 ℃ until the furosemide crude product is dissolved, and mixing according to the furosemide crude product: adding active carbon in the mass ratio of 20:1, continuously heating and stirring for 30min, filtering while the active carbon is hot, regulating the pH value of the filtrate to 4-5 by using glacial acetic acid, and stirring at room temperature for 3h to ensure that the hydrolysis reaction is complete, and separating out the generated furosemide; and cooling the solution to 10-20 ℃ and stirring for 1h, so that the furosemide generated by hydrolysis is completely separated out from the acid liquor, carrying out suction filtration, washing a filter cake with purified water, and drying to obtain a solid substance.

S2, adding excessive solid matters prepared in the step S1 into 95% ethanol, heating to enable the solution to flow back in a boiling state until the temperature of the solution is kept constant for a period of time, filtering the solution while the solution is hot to obtain reaction liquid and solid matters which are not completely dissolved, rapidly transferring the reaction liquid to a crystallization kettle, heating the reaction liquid to boiling or constant temperature thereof, stopping heating, setting the pressure in the crystallization kettle to 3-30 kPa for crystallization, extracting ethanol vapor evaporated in the crystallization kettle, cooling the reaction liquid to 10-15 ℃ by using circulating cooling water after stopping boiling or weakening boiling of the reaction liquid in the crystallization kettle, filtering the reaction liquid to obtain filtrate and a filter cake, washing the filter cake, and drying the filter cake at about 60 ℃ under negative pressure to obtain white solids, namely furosemide finished products, wherein the filtrate is recovered as mother liquor; wherein, the extracted ethanol vapor is condensed and recovered to obtain recovered ethanol.

Wherein, the proper usage amount of 95% ethanol (the usage ratio of the solid substance to 95% ethanol) in the subsequent production can be calculated according to the mass of the solid substance and the mass of the solid substance which is not completely dissolved, and the heating time in the subsequent production can be calculated according to the heating time in the step S2, thereby leading the reaction condition to be consistent and avoiding the trouble of measuring the temperature for a plurality of times.

In the embodiment, the recrystallization method under the vacuum condition can obviously reduce the consumption of circulating cooling water, improve the yield of the furosemide finished product, and can distill the reaction liquid in the crystallization process, so that the mass fraction of the ethanol in the mother liquor is reduced on the one hand, the furosemide solution degree is reduced, and on the other hand, the recovered ethanol and the mother liquor can be obtained and used in the next purification, so that the purification cost is reduced and the energy consumption in the purification process is reduced.

Under normal pressure, the boiling point of pure ethanol is about 78 ℃, so that the prior art generally selects excessive ethanol to reflux and dissolve the furosemide crude product at 80 ℃, but the influence of solute concentration on the boiling point of the solution is not considered. In this example, the excessive solid material is heated and refluxed with 95% ethanol, and the solution is kept boiling, so that the solution temperature is increased to increase the concentration of furosemide in the solution, thereby increasing the utilization rate of 95% ethanol, while furosemide which is not completely dissolved can be used in the next batch of recrystallization, thereby reducing the consumption of recrystallization reagent (95% ethanol) in industrial production.

In addition, the recrystallization is carried out under the vacuum condition, the solution with high temperature is kept boiling for a long time under the low pressure condition by utilizing the principle that the boiling point of the solution is reduced under the low pressure condition, and the vaporized ethanol vapor is pumped out of a crystallization kettle for condensation recovery, and the method has the following advantages: ① The volatilization of the ethanol reduces the total volume of the solution, so that the concentration of the solute such as furosemide in the solution is increased, and the precipitation of furosemide is promoted; ② The solubility of the solutes such as the furosemide in the ethanol is far greater than the solubility of the solutes in the water, so that the volatilization of the ethanol solvent in the ethanol aqueous solution reduces the mass fraction of the ethanol in the solution, so that the solubility of the furosemide in the solution is reduced, and the precipitation of the furosemide is promoted; ③ The solubility of the furosemide in the ethanol increases along with the rise of the temperature, and the heat of the solution is absorbed when the ethanol is vaporized, so that the temperature of the solution is reduced, the solubility of the furosemide is reduced, and the precipitation of the furosemide is promoted. In addition, the amount of the mother liquor is reduced, precipitation of furosemide in the mother liquor is promoted, the amount of furosemide which is not precipitated in the mother liquor can be reduced, and even if the mother liquor is directly discarded, the waste of furosemide can be reduced. The higher the vacuum degree, i.e., the lower the pressure, the lower the boiling point of the solution, so theoretically, when the vacuum degree is high enough, the boiling point of the solution can be reduced to 10-15 ℃ or even lower, but the higher vacuum degree is difficult to realize, and has higher requirements on materials of a crystallization kettle, a vacuum pump and the like, resulting in increased cost. In theory, at 3 to 3-kPa, the 95% ethanol boiling point range is about 5 to 55 ℃. Therefore, 3-30 kPa is selected in the embodiment, when the temperature of the solution is reduced to be lower than the boiling point and the boiling is stopped, the circulating cooling water is adopted to assist the solution to be reduced to 10-15 ℃ for crystallization, and at the moment, the crystallization kettle can keep 3-30 kPa continuously, and the normal pressure can be recovered. In addition, compared with cooling of the circulating cooling water while the solution is boiling, the embodiment uses the circulating cooling water to cool after the solution stops boiling, and has the following advantages: the solution is prevented from being rapidly cooled under the combined action of vacuum and circulating cooling water, so that the evaporated ethanol is less, the yield of furosemide is reduced, the grain size of crystals is reduced, and the purity of the crystals is reduced; and after the solution is cooled to the temperature below the boiling point temperature, the temperature difference between the solution temperature and the circulating cooling water is small, the consumption of the cooling water required by cooling is reduced, and the circulating cooling water is used for cooling at the moment, so that the advantages of energy conservation and emission reduction are achieved.

In addition, in the industrial production process, the recrystallization mother liquor, the washing solution and the like are directly used as waste liquid, and the waste liquid is treated by neutralization, microorganism treatment and the like to reach the discharge standard and is discharged, so that the waste liquid is not recycled, the solvent cost is increased, and the waste liquid treatment cost is also increased. In this embodiment, the solution is kept boiling for a long time in the crystallization kettle by decompressing, and the ethanol vapor evaporated at this time is pumped out of the crystallization kettle to be condensed and recovered, so as to obtain recovered ethanol, and the recovered ethanol can be used in the furosemide production and purification process, for example, the recovered ethanol is mixed with 95% ethanol and used in step S2 to dissolve furosemide crude product, and the recovered ethanol can also be used in other industrial production processes.

Example 2

S1, mixing 1g of furosemide crude product: 8-10 mL of 40% sodium hydroxide solution, adding the furosemide crude product into the sodium hydroxide solution, stirring at 70-80 ℃ until the furosemide crude product is dissolved, and mixing according to the furosemide crude product: adding active carbon in the mass ratio of 20:1, continuously heating and stirring for 30min, filtering while the active carbon is hot, regulating the pH value of the filtrate to 4-5 by using glacial acetic acid, stirring for 3h at room temperature, cooling the solution to 10-20 ℃, stirring for 1h, crystallizing, filtering, washing the filter cake by the mother liquor of the embodiment 1, and drying to obtain a solid substance.

S2, adding excessive solid substances into 95% ethanol, heating to enable the solution to flow back in a boiling state until the temperature of the solution is kept constant for a period of time, filtering the solution while the solution is hot to obtain reaction liquid and solid substances which are not completely dissolved, rapidly transferring the reaction liquid to a crystallization kettle, heating the reaction liquid to boiling or constant temperature thereof, stopping heating, setting the pressure in the crystallization kettle to 3-30 kPa for crystallization, extracting ethanol vapor evaporated in the crystallization kettle, cooling the reaction liquid to 10-15 ℃ by using circulating cooling water after stopping boiling or weakening boiling of the reaction liquid in the crystallization kettle, filtering the reaction liquid after full crystallization to obtain filtrate and filter cake, washing the filter cake, and drying the filter cake at about 60 ℃ under negative pressure to obtain white solids, namely furosemide finished products, wherein the filtrate is recovered as mother liquor; wherein, the extracted ethanol vapor is condensed and recovered to obtain recovered ethanol.

Wherein the excessive solid matter includes the solid matter which is not completely dissolved in the embodiment 1, and the solid matter obtained in the step S1 in the present embodiment.

Part of impurities generated in the furosemide crude product synthesis process are similar to the solubility of the furosemide, namely, the solubility in ethanol and purified water is similar, so that when ethanol or purified water is used to wash a filter cake in the step S1, part of the furosemide and the impurities are dissolved in the ethanol or the purified water together, and the yield of the furosemide is reduced. In the mother liquor of example 1, however, the impurity concentration is low and the furosemide is saturated, so that the mother liquor of example 1 is used for washing the filter cake in step S1 of this example, and only the impurities are dissolved in the mother liquor, thereby improving the yield and purity of the furosemide product, reducing the consumption of purified water or other solvents, and reducing the purification cost. In addition, in example 1, crystallization and filtration are carried out at 10-15 ℃, so that the temperature of the mother liquor is 10-15 ℃, and in continuous industrial production, the low-temperature mother liquor is used for washing the filter cake of step S1, so that the energy consumption for cooling the washing solution to 10-15 ℃ is reduced.

Example 3

S2, adding excessive solid matters prepared in the step S1 into 95% ethanol, heating and pressurizing to enable the solution to flow back in a boiling state under 120-180 kPa until the temperature of the solution is kept constant for a period of time, filtering the solution while the solution is hot to obtain reaction liquid and solid matters which are not completely dissolved, rapidly transferring the reaction liquid to a crystallization kettle, heating the reaction liquid to boiling or constant temperature thereof, stopping heating, setting the pressure in the crystallization kettle to 3-30 kPa for crystallization, extracting ethanol vapor evaporated in the crystallization kettle, cooling the reaction liquid to 10-15 ℃ by using circulating cooling water after the reaction liquid stops boiling or weakening, filtering the reaction liquid to obtain filtrate and filter cakes, washing the filter cakes, and drying the filter cakes under negative pressure at about 60 ℃ to obtain white solids, namely furosemide finished products, wherein the filtrate is recovered as mother liquor; wherein, the extracted ethanol vapor is condensed and recovered to obtain recovered ethanol.

The boiling point of the reaction liquid can be improved by improving the pressure of the solution system during dissolution, so that the solubility of solutes such as furosemide in the reaction liquid is increased, in addition, the boiling reaction liquid reaches a crystallization kettle after being filtered while the reaction liquid is hot, recrystallization is carried out under a vacuum condition, the temperature difference between the temperature of the reaction liquid after being filtered while the reaction liquid is hot and the boiling point of the reaction liquid under the pressure of the crystallization kettle is further increased, the reaction liquid is rapidly boiled in the crystallization kettle, ethanol is evaporated and a large amount of heat is taken away, the solubility of the solutes such as furosemide in the reaction liquid is reduced, and the precipitation of furosemide is promoted. In addition, the pressurizing is carried out during the dissolution, so that the boiling point of the ethanol mixed solution is improved, the solubility of solutes such as furosemide and the like is increased, the use amount of the ethanol mixed solution during the furosemide ethanol dissolution is reduced, the volume of the generated waste liquid is further reduced, and the cost of waste liquid treatment is reduced, thereby being beneficial to the environment.

Example 4

S1, mixing 1g of furosemide crude product: 8-10 mL of 40% sodium hydroxide solution, adding 10g of furosemide crude product into the sodium hydroxide solution, stirring at 70-80 ℃ until the furosemide crude product is dissolved, and mixing according to the furosemide crude product: adding active carbon in the mass ratio of 20:1, continuously heating and stirring for 30min, filtering while the active carbon is hot, regulating the pH value of the filtrate to 4-5 by using glacial acetic acid, stirring for 3h at room temperature, cooling the solution to 10-20 ℃, stirring for 1h, crystallizing, filtering, washing the filter cake by mother liquor, and drying to obtain a solid substance.

S2, according to 1g of solid matter: 3-6 mL of 95% ethanol, adding solid substances into 95% ethanol, heating and pressurizing to enable the solution to reflux for 30-60 min under the boiling state of 120-180 kPa, filtering the solution while the solution is hot to obtain a reaction solution, rapidly transferring the reaction solution to a crystallization kettle, heating the reaction solution to boiling or constant temperature thereof, stopping heating, setting the pressure in the crystallization kettle to 3-30 kPa for crystallization, extracting ethanol vapor evaporated in the crystallization kettle, cooling the reaction solution to 10-15 ℃ by using circulating cooling water at the cooling rate of 15-25 ℃/h after stopping boiling or weakening boiling, filtering the reaction solution to obtain filtrate and a filter cake, washing the filter cake at about 60 ℃ and drying the filter cake under negative pressure to obtain white solid, namely obtaining a furosemide finished product, and recovering the filtrate as mother liquor; wherein, the extracted ethanol vapor is condensed and recovered to obtain recovered ethanol.

The particle size, purity and yield of the furosemide crystals are affected by the cooling rate, and the too fast cooling results in the lower particle size, lower purity and higher yield of the furosemide crystals, the larger the particle size, higher purity and lower yield of the furosemide crystals, and the energy consumption is increased. The furosemide finished product with moderate crystal grain diameter, high purity and high yield can be obtained by adopting the cooling rate of 15-25 ℃/h.

In summary, compared with the existing cooling crystallization method, the method provided by the invention has the advantages that recrystallization is carried out under vacuum conditions, the yield of furosemide is improved by reducing the total volume of the solution and the mass fraction of ethanol in the solution, the cooling rate of a crystallization system is controllable, the non-uniform system temperature is avoided, crystals tend to grow on crystal nuclei rather than to be separated out along walls, the quality of the crystals is uniform, and the problems of reduced cooling rate, reduced product yield and the like caused by separation of the crystals from cold walls are avoided. And furosemide spontaneously nucleates in the solvent without adding extra seed crystal and is not limited by the form of stirring paddles. In addition, the solution with the increased boiling point caused by the increased concentration of the solute is kept boiling by continuous heating, so that the concentration of the furosemide is increased to increase the utilization rate of the ethanol solvent, and the filtrate obtained after the solution is filtered while the solution is hot is heated to a new boiling point to increase the temperature difference between the temperature of the solution and the boiling point temperature of the solution under the vacuum condition, thereby enabling the solution to be rapidly boiled under the vacuum condition, reducing energy consumption and promoting the evaporation of the ethanol solvent. And the solution is placed under high pressure for reflux, so that the boiling point of the solution can be further improved, and the solubility of the furosemide and the temperature of the solution are further improved, thereby promoting the precipitation of the furosemide and reducing the use amount of the ethanol solvent and the amount of the generated waste liquid.

Compared with the existing purification method (figure 1), the method provided by the invention has the advantages that the extracted ethanol vapor is condensed and recovered while the recrystallization is carried out under the vacuum condition, the solution after crystallization and filtration is collected and used as the mother solution, and the mother solution is used for washing the filtration precipitate in the step S1 in the next purification, on one hand, the furosemide in the mother solution is saturated in concentration, the concentration of other solutes is lower, impurities, especially impurities similar to the furosemide in dissolution property, can be removed to the maximum extent by adopting the mother solution for washing the precipitate, and the furosemide is hardly lost, so that the yield and purity of the furosemide are improved, and on the other hand, the mother solution is used for washing instead of purified water or other solvents, so that the consumption of the purified water or other solvents can be reduced, and the cost is reduced. The recovered ethanol can be used in recrystallization or other production process flows, so that the ethanol utilization rate is increased, and the total consumption of ethanol solvents is reduced. In addition, the prior method generates waste liquid during each filtering and washing, and the invention reduces the volume of mother liquor after crystallization and filtration, uses the mother liquor for the first step of washing, and reduces the waste liquid generated during the first step of washing, thus reducing the total volume of the waste liquid and the waste liquid treatment cost.

The above-described embodiments are merely preferred embodiments for fully explaining the present invention, and the scope of the present invention is not limited thereto. Equivalent substitutions and modifications will occur to those skilled in the art based on the present invention, and are intended to be within the scope of the present invention. The protection scope of the invention is subject to the claims.

Claims

1. The purification method of furosemide is characterized by comprising the following steps:

S2, adding the solid substances into a recrystallization solvent, heating, refluxing the solution in a boiling state until the temperature of the solution is kept constant, filtering while the solution is hot, transferring the filtrate into a crystallization kettle, heating the solution to the boiling temperature of the solution, stopping heating, setting the pressure of the crystallization kettle to 3-60 kPa for crystallization, extracting the evaporated solvent, cooling the solution to 10-15 ℃ by using circulating cooling water after the solution in the crystallization kettle stops boiling, continuing crystallization, filtering, washing and drying to obtain the furosemide finished product.

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

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

4. The purification method of furosemide according to claim 2, wherein the solvent evaporated in 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 comprises 95% ethanol, a recovery solvent, and a mixed solution of the recovery solvent and 95% ethanol.

6. The process for purifying furosemide according to any one of claims 1 to 5, wherein in step S2, the heating and dissolution are performed under 120 to 180 kPa.

7. The method for purifying furosemide according to claim 6, wherein in the step S2, the cooling rate is 15-25 ℃/h.

8. The method for purifying furosemide according to claim 7, wherein in step S1, the inorganic alkali solution comprises sodium hydroxide solution, saturated sodium carbonate solution; the decolorization comprises activated carbon decolorization; the acid solution comprises glacial acetic acid solution.

9. The production process of the pure furosemide is characterized by comprising the following steps of:

(4) The furosemide crude product is treated by the purification method of any one of claims 1 to 8 to obtain a furosemide finished product.

10. The process for producing pure furosemide according to claim 9, wherein the reaction temperature in the step (1) is 125-130 ℃ and the reaction time is 2h.

11. The process for producing pure furosemide according to claim 9, wherein the reaction temperature in the step (2) is 10-20 ℃ and the reaction time is 2h.

12. The process for producing pure furosemide according to claim 9, wherein the reaction temperature of 2, 4-dichloro-5-sulfonylaminobenzoic acid and base in step (3) is 65 ℃ and the reaction time is 0.5h.

13. The process for the production of pure furosemide according to claim 12, characterized in that in step (3) the molar ratio of 2, 4-dichloro-5-sulfonylbenzoic acid to furfuryl amine is 1:1.5-2; the preheating temperature is 130-140 ℃, and the mixing feeding time is 20-60min; the reaction time of the reaction solution and the furfuryl amine is 2-5h, and the reaction temperature is 120-140 ℃.

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