A method for preparing furosemide

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of furosemide. The preparation method of furosemide comprises the following steps: chlorosulfonation: reacting chlorosulfonic acid and 2,4-dichlorobenzoic acid, hydrolyzing, filtering, and obtaining 2,4-dichloro-5-sulfonyl chlorobenzoic acid; amination: adding 2,4-dichloro-5-sulfonyl chlorobenzoic acid into ammonia water, reacting, neutralizing, filtering, purifying, and obtaining 2,4-dichloro-5-sulfonamidobenzoic acid; condensation: reacting 2-furfurylamine and 2,4-dichloro-5-sulfonamidobenzoic acid, and obtaining furosemide crude product; decolorization: adding the furosemide crude product into a saturated sodium bicarbonate solution, adding activated carbon for decolorization, neutralizing, and crystallizing, and thus furosemide product is obtained. The raw material used in the application is easy to obtain and low in price, the comprehensive reaction period is short, the amount of hazardous waste generated is small, the prepared furosemide is high in purity and high in total yield, the comprehensive cost of the whole preparation process is low, and the application is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and particularly relates to a preparation method of furosemide. BACKGROUND

[0002] Furosemide is a strong diuretic, which can inhibit the Cl - and Na + reabsorption in the ascending limb of the loop of Henle and the cortical part of the medulla to produce diuretic effect. It is mainly used in the treatment of cardiac edema, renal edema, ascites due to cirrhosis, peripheral edema caused by dysfunction or vascular dysfunction, and can promote the discharge of upper urethral calculi. Its chemical formula is C 12 H 11 ClN2O5S, and the structural formula is as follows:

[0003]

[0004] At present, common furosemide preparation methods mainly include the following methods:

[0005] The method disclosed in patent CN106117168A is that 2,4-dichloro-5-sulfonamido benzoic acid and a base are reacted in the presence of an organic solvent to obtain a reaction solution, and 2,4-dichloro-5-sulfonamido benzoic acid sodium salt is obtained by post-treatment; the 2,4-dichloro-5-sulfonamido benzoic acid sodium salt and furfurylamine are reacted in the presence of an organic solvent; after the reaction is completed, furfurylamine and the solvent are recovered by reduced pressure distillation to obtain a reaction solution; the reaction solution and isopropyl alcohol are mixed, stirred, crystallized, and filtered to obtain furosemide sodium salt; the furosemide sodium salt is dissolved in water, decolorized by activated carbon, acidified by glacial acetic acid, and furosemide product is obtained. The method has low cost, short time consumption, good product quality, and high yield. After the reaction is completed, the method needs to recover furfurylamine and the solvent by reduced pressure distillation, which not only increases the recovery energy consumption, but also produces mother liquor containing a large amount of organic impurities at the same time as the furosemide sodium salt is obtained, and the treatment amount of the mother liquor is large and the treatment difficulty is high.

[0006] The method disclosed in patent CN105566260A is that 2-chloromethyl furan and other tetrahydrofuran compounds and 2-amino-4-chloro-5-sulfamoyl benzoic acid and other 2-aminobenzoic acid compounds are heated and warmed in a reaction solvent, the temperature is controlled to be 80-150℃, and nucleophilic reaction is carried out under the action of an acid-binding agent and / or a catalyst; furosemide is obtained by separating and purifying the reaction solution. The method can prepare furosemide with high purity and high yield through simple steps, the yield is as high as 97.0%, and the purity is as high as 99.8%. The starting material of the method is not a common market material, and its price is expensive, resulting in high production cost. Moreover, the reaction time of the method is too long, the amount of waste liquid generated by post-treatment is also large, excessive materials enter the mother liquor, cannot be recovered, and a large cost needs to be invested for treatment.

[0007] The method disclosed in the patent CN105906589A, 2,4-dichloro-5-sulfonamido benzoic acid and acid binding agent are put into a suitable solvent, under the protection of inert gas, to a certain temperature, drop furoyl amine, after the reaction, adjust the pH value with acid, the crystal is precipitated, the crude furosemide is filtered out, the crude product is refined by using organic solvent and water as mixed solvent, first adjust the pH value to alkaline, heat to dissolve the crude product, add activated carbon to decolorize, hot filtration, the filtrate is adjusted to pH with acid, the solid is precipitated, after filtration and drying, furosemide is obtained. The method has high conversion rate, less by-product, high product purity, simple process flow, through HPLC analysis, the purity is greater than or equal to 99.0%, and the total yield can reach 71.2%. In the production process, inert gas needs to be introduced for a long time, the raw material 2,4-dichloro-5-sulfonamido benzoic acid has high market price, and the production cost is high.

[0008] The above-mentioned preparation methods of furosemide have problems of difficult to obtain starting materials, high price, difficult to treat mother liquor and waste liquid generated in the reaction process, high comprehensive production cost, and are not suitable for large-scale industrial production. Therefore, a new preparation method of furosemide needs to be researched to reduce the comprehensive production cost. SUMMARY

[0009] The purpose of the present application is to provide a preparation method of furosemide, the raw material used is easy to obtain and has low price, the comprehensive reaction period is short, the amount of hazardous waste generated is small, the prepared furosemide has high purity and high total yield, the comprehensive cost of the whole preparation process is low, and the method is suitable for industrial production.

[0010] The preparation method of furosemide provided by the present application comprises the following steps:

[0011] (1) chlorosulfonation: chlorosulfonic acid and 2,4-dichlorobenzoic acid are reacted at a temperature of 100-155 DEG C for 2-6 h, then the reaction product is added to water for hydrolysis, the hydrolysis liquid is filtered, and the filter cake is washed with water until neutral, to obtain 2,4-dichloro-5-sulfonamido benzoic acid;

[0012] (2) amination: 2,4-dichloro-5-sulfonamido benzoic acid is added to ammonia water, and reacted at 0-50 DEG C for 2-4 h, then neutralized, filtered, to obtain 2,4-dichloro-5-sulfonamido benzoic acid crude product, and purified to obtain 2,4-dichloro-5-sulfonamido benzoic acid;

[0013] (3) condensation: 2-furoylmethylamine and 2,4-dichloro-5-sulfonamido benzoic acid are reacted at 80-150 DEG C for 5-12 h, then the reaction product is added to sodium hydroxide aqueous solution, washed with organic solvent, neutralized, and the crystal is precipitated, to obtain furosemide crude product;

[0014] (4) decolorization: the crude furosemide is added into saturated sodium bicarbonate solution, heated to 70-100°C, then activated carbon is added for decolorization, followed by neutralization, crystallization, centrifugation, to obtain furosemide product.

[0015] In step (1), the molar ratio of chlorosulfonic acid to 2,4-dichlorobenzoic acid is (1-3):1.

[0016] In step (1), the amount of water used for hydrolysis is 2-10 times the mass of chlorosulfonic acid; the hydrolysis temperature is not higher than 0°C, and the hydrolysis time is 1-3 h.

[0017] In step (2), the concentration of ammonia water is 15-25 wt.%, preferably 20 wt.%; the molar ratio of 2,4-dichloro-5-sulfonic acid chloride benzene to NH3 is 1:(1-3) in terms of NH3 contained in ammonia water.

[0018] In step (2), hydrochloric acid is added for neutralization to adjust the pH value of the system to neutral.

[0019] In step (2), the purification process of 2,4-dichloro-5-sulfonamidobenzoic acid crude product is as follows: the 2,4-dichloro-5-sulfonamidobenzoic acid crude product is added into aqueous ethanol solution, and kept at 40-80°C for 0.5-2 h, then cooled and recrystallized, and dried, to obtain 2,4-dichloro-5-sulfonamidobenzoic acid.

[0020] In step (3), the molar ratio of 2-furfurylamine to 2,4-dichloro-5-sulfonamidobenzoic acid is 1:(1-3).

[0021] In step (3), the concentration of sodium hydroxide aqueous solution is 20-35 wt.%; the amount of sodium hydroxide aqueous solution is 1-3 times that of 2,4-dichloro-5-sulfonamidobenzoic acid.

[0022] In step (3), the organic solvent is dichloromethane; the amount of organic solvent is 10-15 times the mass of 2,4-dichloro-5-sulfonamidobenzoic acid.

[0023] In step (3), hydrochloric acid is added for neutralization to adjust the pH value of the system to neutral.

[0024] In step (4), the amount of saturated sodium bicarbonate solution (20-35°C) is 4-5 times the mass of furosemide crude product.

[0025] In step (4), the amount of activated carbon added is 0.1-0.3 times the mass of furosemide crude product; after adding activated carbon, decolorization is carried out at 40-80°C for 0.5-2 h.

[0026] In step (4), glacial acetic acid is added for neutralization to adjust the pH value of the system to neutral.

[0027] The preparation method of the furosemide has the following synthetic route:

[0028]

[0029] Compared with the prior art, the present application has the following advantages:

[0030] (1) The present application uses chlorosulfonic acid, 2,4-dichlorobenzoic acid, ammonia, and 2-furfurylamine as main raw materials, which are easy to obtain and low in cost;

[0031] (2) The preparation method of the present application has a relatively short overall production cycle, a simple production mode, and an easy-to-control production process. The obtained products at each step are detected, and the product quality is stable and controllable;

[0032] (3) The reaction process of the present application produces a small amount of hazardous waste, and most of the waste liquid is an aqueous solution. The inorganic salt contained in the waste liquid has a low treatment difficulty;

[0033] (4) The furosemide prepared by the present application has a purity of more than 99.95%, a single impurity content of not more than 0.01%, a total impurity content of not more than 0.05%, and a high yield at each reaction stage, with a total yield of more than 55%. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 The infrared spectrum of the furosemide product prepared in Example 1 of the present application;

[0035] Figure 2 The HPLC spectrum of the furosemide product prepared in Example 1 of the present application. DETAILED DESCRIPTION

[0036] The present application will be further described below in conjunction with examples. In the examples, the raw materials used, unless otherwise specified, are all commercially available conventional raw materials; and the process methods used, unless otherwise specified, are all conventional methods in the art.

[0037] Example 1

[0038] The furosemide is synthesized by the preparation method of the present application, and the steps are as follows:

[0039] (1) Chlorosulfonation: 60 kg (515 mol) of chlorosulfonic acid and 30 kg (157 mol) of 2,4-dichlorobenzoic acid are added to a reaction kettle, and reacted at 100℃ for 6 h. Then, the reaction product is added to 500 kg of water with a temperature of not higher than 0℃ while stirring, and hydrolyzed for 2 h. The hydrolysis liquid is filtered, and the filter cake is washed with water until neutral, to obtain 2,4-dichloro-5-sulfonochlorobenzoic acid, weighing 35.6 kg, with a yield of 78.74% and a purity of 88.3%;

[0040] (2) amination: 20 kg (70 mol) of 2,4-dichloro 5-sulfonic acid chloride benzoic acid is added into 25 kg of ammonia water with a concentration of 20 wt.% (294 mol of ammonia), and reacted at 30°C for 2 h, then neutralized by adding hydrochloric acid, and the temperature and pH of the reaction system are adjusted to between 7 and 8, and then filtered, to obtain 2,4-dichloro-5-sulfonamidobenzoic acid crude product, which is added into 30 kg of an ethanol aqueous solution with a concentration of 70 wt.% and kept at 60°C for 1 h, and then recrystallized after cooling, and dried, to obtain 2,4-dichloro-5-sulfonamidobenzoic acid, with a weight of 16.8 kg, a yield of 89.92%, and a purity of 99.97%;

[0041] (3) condensation: 45 kg (463 nol) of 2-furfurylamine and 15 kg (56 mol) of 2,4-dichloro-5-sulfonamidobenzoic acid are reacted at 150°C for 5 h, dried under reduced pressure, and then added into 40 kg of a sodium hydroxide aqueous solution with a concentration of 30 wt.%, and then washed with an organic solvent for multiple times, neutralized by hydrochloric acid, and then the temperature and pH of the reaction system are adjusted to between 7 and 8, and then filtered, to obtain furosemide crude product, with a weight of 16.8 kg, a yield of 91.06%, and a yield of 90.18%;

[0042] (4) decolorization: 10 kg (30 mol) of furosemide crude product is added into 50 kg of a saturated sodium bicarbonate aqueous solution, heated to 100°C, and then added into 0.1 kg of activated carbon for decolorization for 0.5 h, filtered, neutralized by glacial acetic acid, and then crystallized, and then filtered, to obtain furosemide product, with a weight of 9.2 kg, a yield of 92%, and a purity of 99.97%.

[0043] The infrared spectrum of the furosemide product is shown in Figure 1 , the HPLC spectrum is shown in Figure 2 , and it can be seen from Figure 1 that the strongest absorption peak in the 400-1000 cm -1 region appears at 546 cm -1 ; the strongest absorption peak in the 1000-1850 cm -1 region appears at 1647 cm -1 ; and there are few absorption peaks in the 3000-3800 cm -1 region, and there is no strong absorption peak, which is consistent with the standard infrared spectrum characteristics of furosemide; it can be seen from Figure 2 that the purity of the furosemide product is 99.97%, the content of a single impurity is not more than 0.01%, and the total impurity content is controlled to be less than 0.05%.

[0044] Example 2

[0045] The furosemide is synthesized by using the preparation method of the present application, and the steps are as follows:

[0046] (1) chlorosulfonation: 90 kg (772 mol) of chlorosulfonic acid and 30 kg (157 mol) of 2,4-dichlorobenzoic acid were added into a reaction kettle, reacted at 155°C for 2 h, then the reaction product was added into 400 kg of water with a temperature of not higher than 0°C while stirring, and hydrolyzed for 1 h while stirring. The hydrolyzate was filtered, and the filter cake was washed with water until neutral, to obtain 2,4-dichloro-5-sulfonyl chloride benzoic acid, with a weight of 36.5 kg, a yield of 80.73%, and a purity of 89.6%;

[0047] (2) amination: 22 kg (76 mol) of 2,4-dichloro-5-sulfonyl chloride benzoic acid was added into 26 kg of ammonia water with a concentration of 25 wt.% (382 mol of ammonia), and reacted at 0°C for 4 h, then neutralized by adding hydrochloric acid, and the temperature and pH value of the reaction system were adjusted to between 7 and 8. Filtration was performed, to obtain 2,4-dichloro-5-sulfonamidobenzoic acid crude product. The 2,4-dichloro-5-sulfonamidobenzoic acid crude product was added into 35 kg of an ethanol aqueous solution with a concentration of 70 wt.%, and was kept at 60°C for 1 h. Recrystallization was performed after cooling, and drying was performed, to obtain 2,4-dichloro-5-sulfonamidobenzoic acid, with a weight of 18.8 kg, a yield of 91.48%, and a purity of 99.98%;

[0048] (3) condensation: 30 kg (309 mol) of 2-furfurylamine and 15 kg (56 mol) of 2,4-dichloro-5-sulfonamidobenzoic acid were reacted at 80°C for 12 h, and dried under reduced pressure. Then, 30 kg of a sodium hydroxide aqueous solution with a concentration of 30 wt.% was added, and the reaction system was washed with an organic solvent for multiple times. Neutralization was performed by adding hydrochloric acid, and the temperature and pH value of the reaction system were adjusted to between 7 and 8. Filtration was performed, to obtain furosemide crude product, with a weight of 17.4 kg and a yield of 94.32%.

[0049] (4) decolorization: 10 kg (30 mol) of furosemide crude product was added into 45 kg of a saturated sodium bicarbonate aqueous solution, and heated to 70°C. 0.1 kg of activated carbon was added for decolorization for 1 h. Filtration was performed, and neutralization was performed by adding glacial acetic acid. Crystallization was performed, and filtration was performed, to obtain furosemide product, with a weight of 8.9 kg, a yield of 89%, and a purity of 99.98%.

[0050] Example 3

[0051] Furosemide was synthesized by using the preparation method of the present application, and the steps were as follows:

[0052] (1) chlorosulfonation: 60 kg (515 mol) of chlorosulfonic acid and 60 kg (314 mol) of 2,4-dichlorobenzoic acid were added into a reaction kettle, and reacted at 130 °C for 4 h. Then the reaction product was added into 600 kg of water with a temperature of not higher than 0 °C while stirring, and hydrolyzed for 2 h. The hydrolyzate was filtered under suction, and the filter cake was washed with water until neutral, to obtain 2,4-dichloro-5-sulfonyl chloride benzoic acid, with a weight of 73.6 kg, a yield of 81.39%, and a purity of 90.6%;

[0053] (2) amination: 35 kg (122 mol) of 2,4-dichloro-5-sulfonyl chloride benzoic acid was added into 60 kg of ammonia water with a concentration of 20 wt.% (706 mol of ammonia), and reacted at 20 °C for 3 h. Then hydrochloric acid was added for neutralization, and the temperature and pH value of the reaction system were adjusted to between 7 and 8. Filtration under suction was performed to obtain 2,4-dichloro-5-sulfonamidobenzoic acid crude product. The 2,4-dichloro-5-sulfonamidobenzoic acid crude product was added into 70 kg of an ethanol aqueous solution with a concentration of 70 wt.%, and was kept at 60 °C for 1 h. Crystallization was performed after cooling, and drying was performed, to obtain 2,4-dichloro-5-sulfonamidobenzoic acid, with a weight of 30 kg, a yield of 91.75%, and a purity of 99.96%;

[0054] (3) condensation: 60 kg (318 mol) of 2-furfurylamine and 30 kg (112 mol) of 2,4-dichloro-5-sulfonamidobenzoic acid were reacted at 120 °C for 9 h, and were dried under reduced pressure. Then 80 kg of a sodium hydroxide aqueous solution with a concentration of 30 wt.% was added, and the reaction system was washed with an organic solvent for multiple times. Hydrochloric acid was added for neutralization, and the temperature and pH value of the reaction system were adjusted to between 7 and 8. Filtration under suction was performed to obtain furosemide crude product, with a weight of 33.8 kg and a yield of 91.61%;

[0055] (4) decolorization: 20 kg (60 mol) of furosemide crude product was added into 40 kg of a saturated sodium bicarbonate aqueous solution, and was heated to 90 °C. Then 0.1 kg of activated carbon was added for decolorization for 2 h. Filtration was performed, and glacial acetic acid was added for neutralization. Crystallization was performed, and filtration under suction was performed, to obtain furosemide product, with a weight of 18.5 kg, a yield of 92.5%, and a purity of 99.97%.

Claims

1. A process for the preparation of furosemide, characterized by: The process comprises the following steps: (1) chlorosulfonation: reacting chlorosulfonic acid and 2,4-dichlorobenzoic acid at a temperature of 100-155℃ for 2-6h, then adding the reaction product into water for hydrolysis, filtering the hydrolysis solution, and washing the filter cake with water until neutral to obtain 2,4-dichloro-5-sulfuryl chloride benzoic acid; (2) amination: adding 2,4-dichloro-5-sulfuryl chloride benzoic acid into ammonia water, reacting at 0-50℃ for 2-4h, neutralizing, filtering to obtain 2,4-dichloro-5-sulfuryl amido benzoic acid crude product, and purifying to obtain 2,4-dichloro-5-sulfuryl amido benzoic acid; (3) condensation: reacting 2-furfurylamine and 2,4-dichloro-5-sulfuryl amido benzoic acid at 80-150℃ for 5-12h, drying under reduced pressure, adding sodium hydroxide aqueous solution, washing with an organic solvent, neutralizing, and crystallizing to obtain furosemide crude product; (4) decolorization: adding furosemide crude product into a saturated sodium bicarbonate solution, heating to 70-100℃, then adding activated carbon for decolorization, neutralizing, crystallizing, and centrifuging to obtain furosemide product. In step (3), the concentration of sodium hydroxide aqueous solution is 20-35wt.%; the amount of sodium hydroxide aqueous solution is 1-3 times of 2,4-dichloro-5-sulfuryl amido benzoic acid. In step (3), the organic solvent is dichloromethane. In step (4), the amount of saturated sodium bicarbonate solution is 4-5 times of the mass of furosemide crude product.

2. The process for the preparation of furosemide according to claim 1, characterized in that: In step (1), the molar ratio of chlorosulfonic acid to 2,4-dichlorobenzoic acid is (1-3):

1.

3. The process for the preparation of furosemide according to claim 1, characterized in that: In step (1), the amount of water used for hydrolysis is 2-10 times of the mass of chlorosulfonic acid; the hydrolysis temperature is not higher than 0℃, and the hydrolysis time is 1-3h.

4. The process for the preparation of furosemide according to claim 1, characterized in that: In step (2), the concentration of ammonia water is 15-25wt.%; the molar ratio of 2,4-dichloro-5-sulfuryl chloride benzoic acid to NH3 contained in ammonia water is 1:(1-3).

5. The process for the preparation of furosemide according to claim 1, characterized in that: In step (2), the purification process of 2,4-dichloro-5-sulfuryl amido benzoic acid crude product is as follows: adding 2,4-dichloro-5-sulfuryl amido benzoic acid crude product into an ethanol aqueous solution, keeping at 40-80℃ for 0.5-2h, cooling and recrystallizing, and drying to obtain 2,4-dichloro-5-sulfuryl amido benzoic acid.

6. The process for the preparation of furosemide according to claim 1, characterized in that: In step (3), the amount of organic solvent is 10-15 times of the mass of 2,4-dichloro-5-sulfuryl amido benzoic acid.

7. The process for the preparation of furosemide according to claim 1, characterized in that: In step (4), the amount of activated carbon added is 0.1-0.3 times of the mass of furosemide crude product; after adding activated carbon, decolorization is performed at 40-80℃ for 0.5-2h.

Images