A method for preparing albendazole

Abstract

This invention discloses a method for preparing albendazole, belonging to the field of pharmaceutical preparation technology. The method includes: (1) cyclization reaction: using methyl cyanocarbamate and 4-(propylthio)phenyl-1,2-diamine or their hydrochloride as raw materials, reacting in water, methanol, ethanol or a mixed solvent in the presence of an acidic catalyst or an alkaline buffer; (2) crystallization and separation of crude product: adjusting the pH of the reaction solution to 3-5, and separating the solid and liquid to obtain the crude product; (3) washing and purification: the crude product is washed successively with toluene, methanol and water, and dried to obtain the purified product; (4) refining and post-treatment: dissolving, decolorizing and recrystallizing with a formic acid-water mixed solvent, drying, pulverizing and sieving, and packaging to obtain the finished product. This invention uses a green and environmentally friendly solvent system, suppresses side reactions through precise pH control, optimizes the three-stage washing and recrystallization process, achieves a molar yield of over 88%, a purity of 99.85%, meets pharmaceutical standards, and is suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to the field of drug preparation technology, specifically to a method for preparing albendazole. Background Technology

[0002] Albendazole is a highly effective, broad-spectrum benzimidazole anthelmintic that has a significant killing effect on a variety of parasites, including nematodes, tapeworms, and trematodes. It is widely used in clinical practice for the treatment of parasites in humans and animals.

[0003] Currently, the mainstream industrial synthesis of albendazole mainly involves a cyclization condensation reaction of methyl cyanocarbamate with 4-(propylthio)phenyl-1,2-diamine or its hydrochloride in an organic solvent. However, existing preparation methods still have many technical shortcomings that need to be addressed: First, traditional cyclization reactions often use a single high-boiling-point organic solvent system, resulting in large solvent consumption, high energy consumption for recovery, and environmental pollution risks, making it difficult to meet the requirements of green chemical production; Second, imprecise pH control during the reaction process can easily lead to an increase in side reactions, generating pigment impurities and isomers that are difficult to remove, resulting in low purity of the crude product and complex subsequent purification steps; Third, the post-processing of existing processes usually involves multiple extractions or column chromatography purification, which is cumbersome, consumes a lot of solvent, has a long production cycle, and generally has a low yield (usually only 70%~80%), significantly increasing production costs; Fourth, existing purification processes have limited effectiveness in removing residual solvents, inorganic salts, and specific impurities from the product, making it difficult to consistently meet pharmaceutical-grade quality standards.

[0004] Therefore, developing a method for preparing albendazole with mild reaction conditions, a green and environmentally friendly solvent system, simple operation, high product yield, and controllable purity is of great practical significance for reducing production costs, improving product quality, and realizing industrialized green manufacturing. Summary of the Invention

[0005] The purpose of this invention is to address the problems existing in the prior art by providing a method for preparing albendazole. This method uses a green and environmentally friendly mixed solvent system, suppresses side reactions through precise pH control, optimizes washing and recrystallization processes, significantly improves product yield and purity, and achieves efficient and low-cost industrial production.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is: a method for preparing albendazole, comprising the following steps: (1) Cyclic reaction: Using methyl cyanocarbamate and 4-(propylthio)phenyl-1,2-diamine or its hydrochloride as raw materials, a cyclization reaction is carried out; (2) Crystallization and separation of crude product: Adjust the pH value of the reaction solution in step (1) and obtain crude albendazole by solid-liquid separation; (3) Washing and purification: The crude albendazole was washed with toluene, methanol and water in sequence, and dried to obtain purified albendazole. (4) Refining and post-processing: The albendazole purified product is solvent refined, dried, pulverized and sieved to obtain the finished albendazole product.

[0007] Furthermore, the synthetic route for preparing albendazole is as follows: .

[0008] Further, in step (1), the molar equivalent ratio of 4-(propylthio)phenyl-1,2-diamine or its hydrochloride to methyl cyanocarbamate is 1:1.0~1.5; the cyclization reaction is carried out in a solvent, which is selected from water, methanol, ethanol or a mixture thereof.

[0009] Furthermore, pH adjustment is added to the cyclization reaction system described in step (1); The pH adjuster is selected from acidic catalysts or alkaline buffers, wherein the acidic catalyst is selected from at least one of hydrochloric acid, sulfuric acid, and p-toluenesulfonic acid, and the alkaline buffer is selected from sodium acetate. The cyclization reaction is limited to a temperature of 70℃ to 105℃ and a reaction time of 2 to 8 hours.

[0010] Furthermore, in step (2), the pH of the reaction solution is adjusted to 3-5 using hydrochloric acid, and then the crude albendazole is separated by sieving.

[0011] Furthermore, in the toluene washing step described in step (3), the crude albendazole is washed with toluene and then filtered, and the mother liquor generated from the filtration is collected for the recovery of toluene.

[0012] Furthermore, the methanol washing step in step (3) includes two consecutive washings: first washing with methanol and then sifting and filtering, and then washing with methanol (3) and sifting and filtering again; the sifting mother liquor generated in the step is combined and used to recover methanol.

[0013] Further, in step (3), the material after being washed with methanol is washed with purified water and then filtered. The resulting wet material is then dried to obtain the purified albendazole.

[0014] Furthermore, the purification step described in step (4) specifically involves using a mixed solvent of formic acid and water as the purification solvent to dissolve, decolorize, and recrystallize the purified albendazole.

[0015] Furthermore, after the purification step is completed, the material is sequentially filtered and dried to obtain purified albendazole dried material.

[0016] Furthermore, the post-processing steps described in step (4) specifically include: pulverizing, sieving, mixing, and packaging the refined and dried material sequentially in a Class D clean area, and finally removing it from the clean area for outer packaging.

[0017] Compared with the prior art, the beneficial effects of the present invention are: This preparation method uses water, methanol, ethanol, or a mixture thereof as the reaction medium, replacing traditional high-boiling-point organic solvents. This significantly reduces energy consumption and environmental pollution risks associated with solvent recovery, aligning with the concept of green chemical production. Precise pH control using acidic catalysts or alkaline buffers effectively suppresses side reactions in the cyclization reaction, reducing pigment impurities and isomer formation, and improving reaction selectivity. Post-treatment employs a hydrochloric acid crystallization combined with a toluene-methanol-water three-stage washing process, which is simple and efficient, avoiding complex extraction or column chromatography purification steps and significantly improving single-pass yield. The separate collection and reuse of toluene and methanol mother liquors greatly reduces solvent consumption and production costs. Recrystallization purification using a formic acid-water mixed solvent provides excellent decolorization and purification effects, resulting in a high-purity product with low residual solvent and stable quality meeting pharmaceutical-grade standards. The entire process is continuous and controllable, facilitating large-scale continuous production. Detailed Implementation

[0018] The following will provide a clear and complete description of the technical solutions of this invention. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention. Example 1

[0019] Preparation of albendazole: (1) Cyclic formation reaction: In a 500 mL reaction flask equipped with a stirrer and thermometer, 150 mL of purified water, 18.23 g (0.1 mol) of 4-(propylthio)phenyl-1,2-diamine, 1.0 g of p-toluenesulfonic acid (as an acidic catalyst to adjust the pH of the system), and 11.0 g (0.11 mol) of methyl cyanocarbamate (molar equivalent ratio 1:1.1) were added sequentially. The stirring was turned on, and the reaction system was slowly heated to 85 °C and kept at this temperature for 5 hours. (2) Separation of crystallization and crude product: The reaction solution in step (1) is cooled naturally to about 25°C. A 15% dilute hydrochloric acid solution is added dropwise while stirring to precisely adjust the pH of the reaction solution to 4.0. At this time, a large amount of solid precipitates out. Stirring and slurrying are continued for 30 minutes to promote crystal growth. Then, solid-liquid separation is carried out by centrifugation and filtration to obtain albendazole wet crude product. (3) Washing and purification: ① Toluene washing: Add 40 mL of toluene to the above albendazole wet crude material, stir and slurry and wash for 30 minutes, then filter and collect the toluene mother liquor produced by filtration, and place it in a recovery tank for subsequent toluene recovery. ② Methanol washing: Add 40 mL of methanol to the filter cake, slurry and wash for 30 minutes, then filter. Add another 40 mL of methanol to the filter cake, slurry and wash for a second time for 30 minutes, then filter. Combine the methanol mother liquor from the two filtrations and collect it in a recovery tank for subsequent methanol recovery. ③ Washing and drying: Add 60 mL of purified water to the filter cake, slurry and wash for 30 minutes, then filter to remove residual water-soluble salts and solvents. Place the final wet product in a vacuum drying oven and dry at 65℃ and -0.08 MPa for 6 hours to obtain purified albendazole, weighing 24.3 g. (4) Refining and post-processing: The purified albendazole obtained in step (3) was added to a reaction flask containing 45 mL of formic acid (concentration 98%), heated to 50 °C and stirred to dissolve. After the material was completely dissolved, 1.0 g of pharmaceutical grade activated carbon was added, and the mixture was kept at a constant temperature for decolorization and stirred for 30 minutes. The activated carbon was removed by vacuum filtration while hot. The filtrate was transferred to a crystallization vessel, and 120 mL of purified water was slowly added dropwise with stirring to recrystallize. After the addition was complete, the mixture was cooled to room temperature (approximately 20°C) and stirred for another hour to allow crystal growth. The mixture was then filtered, and the filter cake was washed with a small amount of purified water. The cake was then placed in a vacuum drying oven and dried at 70°C for 8 hours to obtain albendazole crystals.

[0020] Subsequently, the dried material is transferred to a Class D clean area, where it is pulverized using a pulverizer, sieved through an 80-mesh vibrating screen, and then mixed evenly in a three-dimensional mixer before being packaged and inner-packaged. Finally, it is removed from the clean area to complete the outer packaging.

[0021] Result characterization: After weighing, 23.6 g of albendazole product was finally obtained in this example, with a molar yield of 88.9% based on 4-(propylthio)phenyl-1,2-diamine. The purity of the product was 99.85% and the single largest unknown impurity was 0.05% as detected by high performance liquid chromatography (HPLC). All indicators met the quality standards of the latest edition of the Pharmacopoeia of the People's Republic of China. Example 2

[0022] A method for preparing albendazole: Referring to the preparation method of Example 1, the "150 mL of purified water" and "1.0 g of p-toluenesulfonic acid" were replaced with "150 mL of methanol" and "1.5 g of sodium acetate (as an alkaline buffer)" respectively, and the remaining steps and operating conditions were kept the same as in Example 1.

[0023] Result characterization: After weighing, 23.2 g of albendazole product was finally obtained in this example, with a molar yield of 87.4% based on 4-(propylthio)phenyl-1,2-diamine. The purity of the product was 99.80% and the single largest unknown impurity was 0.08% as detected by high performance liquid chromatography (HPLC). All indicators met the quality standards of the latest edition of the Pharmacopoeia of the People's Republic of China. Example 3

[0024] A method for preparing albendazole: Referring to the preparation method of Example 1, the cyclization reaction temperature and time were changed from "reaction at 85°C for 5 hours" to "reaction at 70°C for 8 hours", while the remaining steps and operating conditions remained the same as in Example 1.

[0025] Result characterization: After weighing, 23.0 g of albendazole product was finally obtained in this embodiment, with a molar yield of 86.7% based on 4-(propylthio)phenyl-1,2-diamine. The purity of the product was 99.82% and the single largest unknown impurity was 0.07% as detected by high performance liquid chromatography (HPLC). All indicators met the quality standards of the latest edition of the Pharmacopoeia of the People's Republic of China. Example 4

[0026] A method for preparing albendazole: Referring to the preparation method of Example 1, the amount of raw material "11.0 g (0.11 mol) of methyl cyanocarbamate (molar equivalent ratio of 1:1.1)" was replaced with "15.0 g (0.15 mol) of methyl cyanocarbamate (molar equivalent ratio of 1:1.5)", and the remaining steps and operating conditions were the same as in Example 1.

[0027] Result characterization: After weighing, 23.7g of albendazole product was finally obtained in this example, with a molar yield of 89.3% based on 4-(propylthio)phenyl-1,2-diamine. The purity of the product was 99.88% and the single largest unknown impurity was 0.04% as determined by high performance liquid chromatography (HPLC). All indicators met the quality standards of the latest edition of the Pharmacopoeia of the People's Republic of China.

[0028] Comparative Example 1 A method for preparing albendazole: Referring to the preparation method of Example 1, the cyclization reaction step was modified to "not add any pH adjuster or catalyst such as p-toluenesulfonic acid", while the remaining steps and operating conditions remained the same as in Example 1.

[0029] Result characterization: After weighing, the comparative example yielded 19.9g of albendazole product, with a molar yield of only 75.0% based on 4-(propylthio)phenyl-1,2-diamine. High-performance liquid chromatography (HPLC) analysis showed a product purity of 98.50%, with a single largest unknown impurity of 0.85% (increased byproducts). All indicators failed to meet the quality standards of the latest edition of the Pharmacopoeia of the People's Republic of China.

[0030] Comparative Example 2 A method for preparing albendazole: Referring to the preparation method of Example 1, the washing and purification step (3) is modified to "omit the toluene washing and methanol washing steps, and directly add 140 mL of purified water to the crude filter cake for pulping and washing", and the remaining steps and operating conditions are the same as in Example 1.

[0031] Result characterization: After weighing, this comparative example yielded 21.5g of albendazole product, with a molar yield of 81.0% based on 4-(propylthio)phenyl-1,2-diamine. High-performance liquid chromatography (HPLC) analysis showed a product purity of 97.20%, with a single largest unknown impurity of 1.50% (lipid-soluble impurities were not completely removed). The product also exhibited significant pigment precipitation, and all indicators failed to meet the quality standards of the latest edition of the Pharmacopoeia of the People's Republic of China.

[0032] Comparative Example 3 A method for preparing albendazole: Referring to the preparation method of Example 1, the purification step (4) is modified to "use anhydrous ethanol as a single purification solvent to replace the mixed solvent composed of formic acid and water, and perform heating dissolution and recrystallization", while the remaining steps and operating conditions are the same as in Example 1.

[0033] Result characterization: After weighing, the comparative example yielded 17.2g of albendazole product. The molar yield, calculated as 4-(propylthio)phenyl-1,2-diamine, dropped sharply to 64.8% (due to poor solubility and crystallization properties). High-performance liquid chromatography (HPLC) analysis showed that the product purity was 98.80%, and the single largest unknown impurity was 0.60%. All indicators did not meet the quality standards of the latest edition of the Pharmacopoeia of the People's Republic of China.

[0034] In the refining process, replacing the mixed solvent system of this invention with a single conventional solvent (such as anhydrous ethanol) leads to a significant deterioration in the solubility and crystallization properties of the material. The results show that this change in solvent system not only causes a sharp drop in the yield but also results in incomplete impurity removal, significantly higher levels of single unknown impurities, and a marked deterioration in overall purity, ultimately causing the product to fail to meet the quality standards of the current pharmacopoeia. This comparative analysis powerfully demonstrates that the specific mixed solvent refining process used in this patent plays an irreplaceable and crucial role in ensuring a high yield and pharmaceutical-grade purity of the final product.

[0035] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing albendazole, characterized in that, Includes the following steps: (1) Cyclic reaction: Using methyl cyanocarbamate and 4-(propylthio)phenyl-1,2-diamine or its hydrochloride as raw materials, a cyclization reaction is carried out; (2) Crystallization and separation of crude product: Adjust the pH value of the reaction solution in step (1) and obtain crude albendazole by solid-liquid separation; (3) Washing and purification: The crude albendazole was washed with toluene, methanol and water in sequence, and dried to obtain purified albendazole. (4) Refining and post-processing: The albendazole purified product is solvent refined, dried, pulverized and sieved to obtain the finished albendazole product.

2. The method for preparing albendazole according to claim 1, characterized in that, In step (1), the molar equivalent ratio of 4-(propylthio)phenyl-1,2-diamine or its hydrochloride to methyl cyanocarbamate is 1:1.0~1.5; the cyclization reaction is carried out in a solvent, which is selected from water, methanol, ethanol or a mixture thereof.

3. The method for preparing albendazole according to claim 1, characterized in that, pH adjustment is added to the cyclization reaction system described in step (1); The pH adjuster is selected from acidic catalysts or alkaline buffers, wherein the acidic catalyst is selected from at least one of hydrochloric acid, sulfuric acid, and p-toluenesulfonic acid, and the alkaline buffer is selected from sodium acetate. The cyclization reaction is limited to a temperature of 70℃ to 105℃ and a reaction time of 2 to 8 hours.

4. The method for preparing albendazole according to claim 1, characterized in that, In step (2), the pH of the reaction solution is adjusted to 3-5 using hydrochloric acid, and then the crude albendazole is separated by sieving.

5. The method for preparing albendazole according to claim 1, characterized in that, In the toluene washing step described in step (3), the crude albendazole is washed with toluene and then filtered. The mother liquor generated from the filtration is collected for the recovery of toluene.

6. The method for preparing albendazole according to claim 1, characterized in that, The methanol washing step in step (3) includes two consecutive washings: first washing with methanol and then sifting and filtering, and then washing with methanol (3) and sifting and filtering again; the sifting mother liquor generated in the step is combined and used to recover methanol.

7. The method for preparing albendazole according to claim 1, characterized in that, In step (3), the material washed with methanol is washed with purified water and then filtered. The resulting wet material is then dried to obtain the purified albendazole.

8. The method for preparing albendazole according to claim 1, characterized in that, The purification step described in step (4) specifically involves using a mixed solvent of formic acid and water as the purification solvent to dissolve, decolorize, and recrystallize the purified albendazole.

9. The method for preparing albendazole according to claim 1, characterized in that, After the refining step is completed, the albendazole is filtered and dried in sequence to obtain the refined albendazole dried material.

10. A method for preparing albendazole according to claim 1, characterized in that, The post-processing steps described in step (4) specifically include: pulverizing, sieving, mixing, and packaging the refined and dried material in a Class D clean area, and finally removing it from the clean area for outer packaging.