Preparation method and application of 5-(1H-pyrrole-1-yl)-2-mercaptobenzimidazole

Abstract

The invention relates to a preparation method and application of 5-(1H-pyrrole-1-yl)-2-mercaptobenzimidazole, according to the preparation method, key parameters such as an ester extraction solvent, a pH adjusting range, a pulping solvent, a ratio of a concentrated solution to the pulping solvent and the like are determined to cooperate with each other, and efficient separation and purification of a product are realized. And the synergistic improvement of economy, environmental protection, high yield and high content is realized. The solvents and reagents selected in the whole process are conventional chemical raw materials, are low in price and easy to obtain, and the solvents and mother liquor can be recycled and reused, so that the production cost is further reduced; the operation process is simplified, the production cost and the environmental protection pressure are reduced, and the environmental protection requirement of industrial production is met; the yield of the target product can be stably kept at 74% or above, the purity can reach 99% or above, and the content is higher than 97%. The prepared product can be applied to preparation of ilaprazole, meets the quality requirement for preparation of qualified ilaprazole bulk drugs, and has important industrial application value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and in particular to a method for preparing 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole and its application. Background Technology

[0002] Ilaprazole is an important oral anti-peptic ulcer drug, belonging to the benzimidazole class of irreversible proton pump inhibitors (PPIs). It was first developed by Ilyang Pharmaceuticals Co., Ltd. of South Korea, and later introduced and industrialized in China by Livzon Pharmaceutical Group. It was approved for marketing in China in 2007, filling the market gap for domestically produced original PPIs. Ilaprazole is mainly used to improve the treatment effect of acid-related diseases such as duodenal ulcers and reflux esophagitis. 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole is a key intermediate in the synthesis of iprarazole. The existing reported preparation methods and their drawbacks are as follows:

[0003] The method reported in CN101602758A, using acetic acid / water as the reaction medium and anhydrous sodium acetate as the buffer, suffers from uncontrollable byproduct formation and large purity fluctuations. Under the acetic acid catalytic system, 1,4-butanedialdehyde, generated from the ring-opening of 2,5-dimethoxytetrahydrofuran, readily undergoes nucleophilic addition with thiol groups, while amino groups readily polymerize to form dimer / trimer impurities (the lowest yield in the patent examples is only 35%). Although anhydrous sodium acetate is introduced as a buffer, it does not inhibit thiol oxidation, resulting in a darker product color, requiring multiple crystallization purifications. The yield stability is poor, and the process parameters are sensitive, with the reaction temperature significantly affecting the yield: the yield is only 53% after 10 hours of reaction at 10℃, and drops to 35% after reflux at 150℃ for 2 hours. The optimal temperature window (50-60℃) is narrow, and with a fixed raw material ratio, different solvent combinations (water / tetrahydrofuran, water / 1,2-dichloroethane) cause yield fluctuations of over 20%, making large-scale stable production difficult.

[0004] The optimized post-processing procedure reported in CN119504712A (water washing + high pH extraction) introduces new risks related to solvent dependence and pH control. Tar-like byproducts remain difficult to eliminate; dark tar impurities are still generated during the reaction at 50-60℃ in acetic acid medium. Although some are removed by strong alkaline conditions (pH 10.5-12.5), the target product is prone to hydrolysis at high pH, ​​resulting in a yield of only 30.1% for Comparative Example 5 (pH=13), and almost no product at pH=14. The solvent system is costly and difficult to recover, relying on tetrahydrofuran (solvent 2). The combined extraction with tetrahydrofuran (THF) and dichloromethane (solvent 3) requires strict control of the amounts of both at 4-6 times and 3-5 times the mass of the raw materials, respectively. Severe emulsification and even solid precipitation occur during the layering process. Insufficient amounts result in incomplete product dissolution (comparative example 7 yield 40.2%), while excessive amounts increase distillation energy consumption and residue risks (tetrahydrofuran has a boiling point of 66℃ and readily azeotropically reacts with water). The process is redundant, with a low yield ceiling. Post-reaction processing requires four steps: water washing and centrifugation, alkalization and dissolution, secondary extraction, concentration, and drying, resulting in significant material transfer losses between steps. Even after optimization, the highest yield in the examples is only 70%, far lower than similar processes, and the product content depends on high-performance liquid chromatography purification, increasing industrialization costs.

[0005] The method reported in CN117820299A, which uses Lewis acid catalysis and pure water solvent system, simplifies post-processing. However, it suffers from insufficient selectivity of Lewis acid catalyst. When using catalysts such as cuprous chloride and nickel chloride, it is easy to cause incomplete cleavage of the CO bond in 2,5-dimethoxytetrahydrofuran, resulting in residual raw materials (the yield in Example 3 was 93.8%, lower than the 99.8% in Example 2). The amount of some catalysts (such as zirconium oxychloride) used is only 0.002 eq. It is extremely sensitive to the water content and purity of the raw materials in the reaction system, resulting in poor batch stability. The purity of the product does not meet the high standards for pharmaceutical use. The product is a light gray solid, and the control data for the content of single impurities is not clearly defined. In a pure water system, the trace amounts of methanol generated during the reaction are difficult to remove, and the Lewis acid catalyst is easily hydrolyzed to form metal hydroxide precipitates that adsorb onto the product surface, increasing the risk of heavy metal residues and failing to meet the purity requirements for pharmaceutical intermediates. High-temperature reactions pose safety hazards, and the reaction temperature needs to be controlled between 60-100℃ (optimal 80℃). Reflux in a pure water system can easily lead to bumping, and 2,5-dimethoxytetrahydrofuran has a decomposition rate of about 5% at 80℃. The methanol and tetrahydrofuran vapors generated can easily form an explosive mixture, posing significant safety risks during industrial scale-up.

[0006] The method reported in CN113354623B involves reacting 2-nitro-1,4-phenylenediamine with 2,5-dimethoxytetrahydrofuran to generate an intermediate, followed by reduction and cyclization to obtain the target product. This reaction has low raw material utilization and high cost; the amount of 2,5-dimethoxytetrahydrofuran used is 1.5-2.0 times that of intermediate VII, and excess raw materials and decomposition products are lost with the ethyl acetate extract and cannot be recovered. Furthermore, the third-step cyclization reaction requires the addition of excess CS2 (up to 5.0 eq), increasing raw material consumption and the burden of waste treatment. Multiple reaction steps lead to impurity accumulation, making post-processing difficult. All three steps involve organic solvents (tetrahydrofuran, ethyl acetate, and dichloromethane), resulting in cumulative solvent residue risks. The brown solid intermediate V generated in the reduction step requires multiple steps of dichloromethane extraction, water washing, and drying, which is cumbersome and prone to product adsorption loss, resulting in an overall yield of only 67%, lower than the direct cyclization process.

[0007] In summary, the preparation of 5-(1H-pyrroli-1-yl)-2-mercaptobenzimidazole in existing technologies mostly involves the condensation reaction of aminobenzimidazole compounds with pyrrole cyclizing reagents. However, this method has several drawbacks: First, the reaction system often uses organic solvents as the reaction medium, which presents problems such as high solvent toxicity, volatility, and significant environmental impact. Second, the post-processing is complex, often involving multiple column chromatography or recrystallization operations, which is not only time-consuming and labor-intensive but also results in low product yields. Third, controlling the reaction conditions is difficult, easily generating byproducts that affect product purity and consequently the quality of subsequent elastosazole synthesis. Fourth, existing processes lack reasonable optimization of key parameters such as the selection of extraction solvents and pH adjustment range, leading to low product separation efficiency and high levels of residual impurities.

[0008] To address the shortcomings of the existing technologies, developing a method for preparing 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole that features mild reaction conditions, environmental friendliness, safety, ease of operation, low cost, high yield, and high purity has become an urgent technical problem to be solved in this field. Summary of the Invention

[0009] The first technical problem solved by this invention is to provide a method for preparing 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole, which addresses the current state of the prior art. This method uses an acidic aqueous solution as the reaction medium and achieves efficient separation and purification of the product by precisely controlling the pH adjustment range after the reaction, optimizing the extraction solvent and process parameters. It is environmentally friendly and safe, easy to operate, and has a high yield and high purity.

[0010] The second technical problem solved by this invention is to provide an application of the above-mentioned 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole in the preparation of ipramazole, thereby providing a high-quality intermediate for the industrial production of ipramazole, in light of the current state of the prior art.

[0011] The technical solution adopted by the present invention to solve the above-mentioned technical problems is as follows:

[0012] This invention provides a method for preparing 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole, as shown in compound (III), by reacting 2-mercapto-5-aminobenzimidazole, as shown in compound (I), with 2,5-dimethoxytetrahydrofuran, as shown in compound (II). The preparation method comprises the following reaction steps:

[0013] S1: Compounds of formula (I) and (II) undergo a condensation reaction upon heating in acetic acid medium;

[0014] S2: After the reaction is complete, cool down, add an ester solvent to the resulting reaction solution, then add an alkaline solution to adjust the pH to greater than or equal to 9, use the above ester solvent to extract the reaction solution, and collect the organic phase;

[0015] S3: The organic phase of step S2 is concentrated, and then a pulping solvent is added to the concentrate for pulping. The filter cake is collected by filtration and dried to obtain compound (III). The pulping solvent is a mixture of water and alcohol.

[0016]

[0017] In some embodiments of the present invention, the pH range is greater than or equal to 13, preferably 14.

[0018] In some embodiments of the present invention, the ester solvent is at least one of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and isobutyl acetate, preferably ethyl acetate or isopropyl acetate.

[0019] In some embodiments of the present invention, the volume ratio of concentrate to pulping solvent is 1:1 to 1.5, preferably 1:1.3 to 1.5, and more preferably 1:1.3, 1:1.33, 1:1.34, 1:1.35, 1:1.4, 1:1.45 or 1:1.5.

[0020] In some embodiments of the present invention, the pulping solvent is a mixed solvent of water and alcohol solvent in a volume ratio of 3:0 to 1, preferably water or a mixed solvent of water and alcohol solvent in a volume ratio of 3:1.

[0021] In some embodiments of the present invention, the alcohol solvent is methanol or ethanol.

[0022] In some embodiments of the present invention, the alkaline solution is a lithium hydroxide solution, a sodium hydroxide solution, or a potassium hydroxide solution, preferably a 30% sodium hydroxide solution or a 30% potassium hydroxide solution. Using sodium hydroxide solution to adjust the pH is fast and does not introduce other impurities; the salt impurities generated in the reaction can then be removed by filtration.

[0023] In some embodiments of the present invention, the extraction temperature is 20–40°C. Within this temperature range, the extraction performance of organic solvents such as ethyl acetate is stable, and the product will not degrade due to excessively high temperatures, nor will the solvent viscosity increase or the separation rate slow down due to excessively low temperatures. Preferably, the extraction temperature is 20–30°C, at which point the extraction efficiency is highest, and no additional heating or cooling equipment is required, reducing production energy consumption.

[0024] In some embodiments of the present invention, the concentration of the acetic acid medium is 1–3 mol / L, preferably 1 mol / L. This concentration range provides a suitable acidic environment for the condensation reaction, promoting the reaction between the compounds of formula (I) and (II), and achieving a conversion rate of over 98%. If the acetic acid concentration is too low, the reaction rate is slow and the reaction is incomplete; if the acetic acid concentration is too high, the compound of formula (II) is prone to decomposition, reducing the utilization rate of raw materials.

[0025] In some embodiments of the present invention, the molar ratio of compound (I) to compound (II) is 1:1.0 to 1.5, preferably 1:1.2. This molar ratio ensures that compound (I) reacts fully while avoiding waste of raw materials and increased difficulty in subsequent impurity separation due to excessive amount of compound (II).

[0026] In some embodiments of the present invention, the condensation reaction temperature is 50–80°C, and the reaction time is 2–6 h; preferably, the condensation reaction temperature is 55–60°C, and the reaction time is 3 h. Under these reaction conditions, compounds of formula (I) and formula (II) can react fully, resulting in a high conversion rate and low byproduct formation. If the reaction temperature is too low, the reaction rate is slow, the reaction time is prolonged, and the production efficiency is low; if the reaction temperature is too high, side reactions are easily generated, reducing the purity of the product.

[0027] In some embodiments of the present invention, the pulping temperature is 20–50°C, and the pulping time is 1–3 hours. Through pulping, trace impurities in the product can be further removed, increasing the product purity to over 99%. After pulping, the filter cake obtained by filtration is vacuum dried at 50–80°C for 4–8 hours to obtain a high-purity off-white solid compound of formula (III).

[0028] This invention also provides an application of 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole with the structure shown in formula (III). The 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole obtained according to the above preparation method is used to prepare ilaprazole. Because the compound of formula (III) prepared by this invention has high purity (≥99%) and low impurity content, when used to prepare ilaprazole, it can improve the selectivity and conversion rate of subsequent reactions, reduce the formation of by-products, thereby improving the product quality of ilaprazole and reducing the purification difficulty.

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

[0030] (1) High product yield and high purity: By optimizing key parameters such as the extraction solvent (preferably ethyl acetate), precisely controlling the pH range after the reaction (greater than 9, preferably greater than 13), the pulping solvent (water or a mixture of water and alcohol), and the ratio of concentrate to pulping solvent (concentrate:pulping solvent volume ratio = 1:1~1.5, preferably concentrate:pulping solvent volume ratio = 1:1.3~1.5), the product compound (III) can be extracted only from the organic phase, while impurities and pigments remain in the aqueous layer, achieving efficient separation and purification of the product. The yield of the compound (III) prepared by this invention can be stably maintained above 74%, and the purity can reach above 99%.

[0031] (2) Simple operation process and environmentally friendly and safe production: The post-processing process of this invention only includes simple steps such as extraction, pH adjustment, distillation concentration, pulping, filtration and drying. It does not require complicated column chromatography operations, which simplifies the production process. It can effectively remove tar-like by-products, and retain impurities and pigments in the water layer. The product obtained is an off-white solid, which shortens the production cycle and improves production efficiency. The entire reaction process does not use highly toxic solvents and reagents, which reduces environmental pressure and production safety risks. It is in line with the development trend of green chemical industry and is suitable for large-scale industrial production.

[0032] (3) Low production cost: The raw materials, acid reagents, alkali reagents, extraction solvents and pulping solvents selected in this invention are all conventional chemical raw materials, which are inexpensive and easy to obtain; at the same time, the optimized process parameters reduce the amount of solvent used and energy consumption, and the solvent and mother liquor can be recycled and reused, further reducing the production cost.

[0033] (4) High application value: The high-purity (III) compound prepared by this invention is an off-white solid. The content detected by external standard method is higher than 97%, which can meet the quality requirements for preparing qualified esomeprazole raw materials. When used to prepare esomeprazole, it can effectively improve the synthesis quality and yield of esomeprazole and reduce the subsequent purification cost, which has important industrial application value. Attached Figure Description

[0034] Figure 1 From left to right, the images show the extraction processes of comparative examples A1 to A11 after adding extraction solvent and adjusting the pH to 7 with liquid alkali, as well as the extraction of the organic and aqueous phases.

[0035] Figure 2 From left to right, the images show the extraction processes of comparative examples B1 to B11 after adding extraction solvent and adjusting the pH to 10 with liquid alkali, as well as the extraction conditions of the organic and aqueous phases.

[0036] Figure 3 From left to right, the images show the extraction processes of comparative examples C1 to C11 after adding extraction solvent and adjusting the pH to 13 with liquid alkali, as well as the extraction of the organic and aqueous phases.

[0037] Figure 4 This is the HPLC spectrum of compound (III) from Example 1 of the present invention. Detailed Implementation

[0038] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments.

[0039] To make the above-mentioned objects, features, and advantages of the present invention more apparent and understandable, specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings. Many specific details are set forth in the following description to provide a thorough understanding of the present invention. However, the present invention can be practiced in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0040] As used herein, the terms “comprising” or “including” mean to include the stated elements, integers, or steps, but do not exclude any other elements, integers, or steps. In this document, when the terms “comprising” or “including” are used, unless otherwise specified, they also cover combinations of the stated elements, integers, or steps.

[0041] The present invention will be further described in detail below with reference to the embodiments.

[0042] Example 1

[0043] In this embodiment, 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole (compound (I)) was synthesized from 2-mercapto-5-aminobenzimidazole (compound (I)) and 2,5-dimethoxytetrahydrofuran (compound (II)). The reaction steps are as follows:

[0044]

[0045] Compound (I) (10 g, 0.061 mol), compound (II) (8.8 g, 0.067 mol), and acetic acid (3.6 g, 0.060 mol) were added to 60 mL of water. The mixture was purged with nitrogen three times, and the temperature was raised to 55 °C for 3 hours. The reaction mixture was cooled to room temperature, and 80 mL of ethyl acetate was added. The pH was adjusted to 14 with 30% sodium hydroxide aqueous solution, and the organic layer was collected. The aqueous layer was repeatedly extracted three times with 50 mL of ethyl acetate, and the organic layers were combined. The organic layer was concentrated to approximately 30 mL, cooled to room temperature, and slurried with 40 mL of water. The mixture was filtered and dried to obtain a white solid of compound (III), with a molar yield of 79.7%. The HPLC purity was 99.42%. Figure 4 Content: 98.7%.

[0046] Example 2

[0047] Compound (I) (10 g, 0.061 mol), compound (II) (8.8 g, 0.067 mol), and acetic acid (3.6 g, 0.060 mol) were added to 60 mL of water. The mixture was purged with nitrogen three times, and the temperature was raised to 55–60 °C for 3 hours. The reaction solution was cooled to room temperature, and 80 mL of isopropyl acetate was added. The pH was adjusted to 14 with 30% sodium hydroxide aqueous solution, and the organic layer was collected. The aqueous layer was repeatedly extracted with isopropyl acetate three times, and the organic layers were combined. The organic layer was concentrated under reduced pressure to about 30 mL, cooled to room temperature, and 40 mL of water was added. The temperature was raised to 40–45 °C, and the mixture was stirred for 1 hour. The mixture was cooled to room temperature, filtered, and dried to obtain a white solid of compound (III), with a molar yield of 74%. The HPLC purity was 99.52%, and the content was 97.9%.

[0048] Example 3

[0049] Compound (I) (10 g, 0.061 mol), compound (II) (8.8 g, 0.067 mol), and acetic acid (3.6 g, 0.060 mol) were added to 60 mL of water. The mixture was purged with nitrogen three times, and the temperature was raised to 55–60 °C for 3 hours. The reaction solution was cooled to room temperature, and 80 mL of isopropyl acetate was added. The pH was adjusted to 14 with 30% potassium hydroxide aqueous solution, and the organic layer was collected. The aqueous layer was repeatedly extracted with isopropyl acetate three times, and the organic layers were combined. The organic layer was concentrated to approximately 30 mL, cooled to room temperature, and 45 mL of a water:ethanol mixture (3:1 v / v) was added. The temperature was raised to 40–45 °C, and the mixture was stirred for 1 hour. The mixture was cooled to room temperature, filtered, and dried to obtain a white solid of compound (III) with a molar yield of 75%. The HPLC purity was 99.23%, and the content was 97%.

[0050] Example 4

[0051] Compound (II) (10 g, 0.061 mol), compound (II) (8.8 g, 0.067 mol), and acetic acid (3.6 g, 0.060 mol) were added to 60 mL of water. The mixture was purged with nitrogen three times, and the temperature was raised to 55–60 °C for 3 hours. The reaction solution was cooled to room temperature, 80 mL of ethyl acetate was added, and the pH was adjusted to 14 with 30% potassium hydroxide aqueous solution. The organic layer was collected. The aqueous layer was extracted three times with ethyl acetate, and the organic layers were combined. The organic layer was concentrated to approximately 30 mL, cooled to room temperature, 45 mL of water was added, the temperature was raised to 40–45 °C, and the mixture was stirred for 1 hour. The mixture was cooled to room temperature, filtered, and dried to obtain a white solid of compound (III), with a molar yield of 79%. The HPLC purity was 99.20%, and the content was 98%.

[0052] Comparative Examples A1-A11: The reaction steps were the same as in Example 1. The reaction solution was cooled to room temperature, and 80 mL of the following extraction solvent was added. The pH was adjusted to 7 with liquid alkali. The extraction of the organic and aqueous phases (layer separation, solution color change) was observed, as shown in Table 1 below. Figure 1 .

[0053] Comparative Examples B1-B11: The reaction steps were the same as in Example 1. The reaction solution was cooled to room temperature, and 80 mL of the following extraction solvent was added. The pH was adjusted to 10 with liquid alkali. The extraction of the organic and aqueous phases (layer separation, solution color change) was observed, as shown in Table 1 below. Figure 2 .

[0054] Comparative Examples C1-C11: The reaction steps were the same as in Example 1. The reaction solution was cooled to room temperature, and 80 mL of the following extraction solvent was added. The pH was adjusted to 13 with liquid alkali. The extraction of the organic and aqueous phases (layer separation, solution color change) was observed, as shown in Table 1 below. Figure 3 .

[0055] Table 1. pH and solution changes in the organic and aqueous phases of the extraction solvent, and extraction results.

[0056]

[0057]

[0058] It can be seen that when the reaction system is neutralized to pH=7 using an alkaline solution to remove acid, the emulsification phenomenon is severe and difficult to separate into layers when extracted with various types of solvents, with most of the organic layer appearing yellow. When the reaction system is neutralized to pH=10 using an alkaline solution to remove acid, the emulsification phenomenon and separation effect are improved when extracted with various types of solvents, with most of the organic layer appearing brownish-yellow. When the reaction system is neutralized to pH=13 using an alkaline solution to remove acid, the emulsification phenomenon is significantly improved when extracted with various types of solvents, the separation effect is obvious, and most of the organic layer appears colorless and transparent. The darkening of the organic layer is mainly due to the enrichment of impurities and pigments; at the same time, the organic solvents have insufficient extraction ability for compounds of formula (III), resulting in most of the compounds of formula (III) existing in the aqueous phase. After being oxidized and degraded under alkaline conditions, this also causes the organic layer to darken.

[0059] Comparative examples A1 to A11 show that when the pH is neutral, the separation effect between the organic phase and the aqueous phase is poor, and the organic phase extract has a darker color. The extraction of compound (III) is incomplete and the content of impurities in the extracted organic phase is high, resulting in a lower yield and content of compound (III). Comparative examples B1-B11 and C1-C11 show that using ester-based extraction solvents ensures that compound (III) is effectively extracted into the organic phase. Controlling the pH value within a reasonable range above 9 significantly improves the stratification effect and separation, while impurities and pigments remain in the aqueous phase, thus increasing the yield and content of compound (III). Furthermore, compound (III) appears as a white solid after pulping, filtration, and drying. When using non-ester-based extraction solvents (tetrahydrofuran, toluene, dichloromethane, ethanol, methanol) and readjusting the pH, the solution turns black. The oxidation degradation experiment below shows that compound (I) or compound (III) is easily oxidized, resulting in a darker solution color. Non-ester-based extraction solvents have poor extraction ability for compound (III) but good extraction ability for impurities and pigments, leading to the final separation of compound (III) (esomeprazole intermediate) with poor appearance, low yield, and low content. Based on the combined results of Examples 1-4 and Comparative Examples A1-A11, B1-B11, and C1-C11, it can be seen that adding an ester solvent as an extractant first and then adjusting the pH of the reaction system to be greater than 9 can extract the compound of formula (III) into the upper organic solvent, preventing the target compound from being oxidized under alkaline conditions in the subsequent process. Adding alkali then removes tar and acid, and ensures that impurities and pigments remain in the aqueous phase, significantly improving the quality of the compound of formula (III). The yield of the finished product of formula (III) can be stably maintained above 74%, the purity can reach above 99%, and the content of the finished product is higher than 97%, ensuring the quality of the esomeprazole intermediate and meeting the quality requirements for preparing qualified esomeprazole raw materials when used in the preparation of esomeprazole.

[0060] Oxidative degradation experiment

[0061] I. Experimental Objective

[0062] To investigate the degradation characteristics of compound (I) (2-mercapto-5-aminobenzimidazole) and compound (III) (5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole) under room temperature hydrogen peroxide oxidation conditions, to clarify the oxidative stability of the two types of compounds, and to provide data support for process development (such as separation and selection of reaction conditions).

[0063] II. Experimental Materials and Instruments

[0064] Experimental materials: 2-mercapto-5-aminobenzimidazole (compound of formula (I), purity ≥98%), 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole (compound of formula (III), purity ≥98%), 30% hydrogen peroxide solution (analytical grade), 30% sodium hydroxide solution

[0065] III. Experimental Methods

[0066] 1. Preparation of the test solution

[0067] Accurately weigh 0.01 g each of compound (I) (2-mercapto-5-aminobenzimidazole) and compound (III) (5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole), place them in a 50 mL stoppered conical flask, add 20 mL of water:ethanol at a volume ratio of 3:1, and sonicate to prepare a test solution with a concentration of approximately 0.5 mg / mL.

[0068] 2. Oxidative Degradation Experiment

[0069] Compound of Formula (I) in Experimental Group 1: Add 0.5 mL of 30% hydrogen peroxide solution to the test sample solution of Compound (I), stir magnetically until homogeneous, and leave open at room temperature (25±5℃) to observe the changes in the appearance of the solution; take samples at 0 h (before adding hydrogen peroxide) and after overnight (12 h) for HPLC detection.

[0070] Compound (III) of Formula 2 in Experimental Group 1: The procedure is the same as in Experimental Group 1, except that the test solution is replaced with compound (III). The sampling time points are 0h and overnight (12h). The appearance is observed and samples are taken for HPLC detection.

[0071] Compound (III) of Experimental Group 3: The procedure was the same as that of Experimental Group 2, except that 30% sodium hydroxide solution was added to adjust the pH to 13. The sampling time points were 0h and overnight (12h). The appearance was observed and samples were taken and sent for HPLC detection.

[0072] Table 2 Results of oxidative degradation

[0073]

[0074] Experimental Conclusions: As shown in Table 2, both the raw material compound (I) (2-mercapto-5-aminobenzimidazole) and the intermediate compound (III) (5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole) are easily oxidized and degraded. The solution immediately changes color upon the addition of hydrogen peroxide. HPLC analysis revealed a significant decrease in the content of both the target compounds (I and III), especially under alkaline conditions, where the oxidative degradation rate of compound (III) accelerated. Therefore, the oxidative degradation of compound (III) under alkaline conditions is a major reason for its low yield and content.

[0075] This invention provides a method for preparing 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole, as shown in compound (III). This method determines the synergistic interaction of key parameters such as ester extraction solvent (preferably ethyl acetate), pH adjustment range (greater than 9, preferably greater than 13), slurry solvent (water or a mixture of water and alcohol), and the solvent ratio of concentrate to slurry solvent (concentrate:slurry solvent volume ratio = 1:1 to 1.5, preferably concentrate:slurry solvent volume ratio = 1:1.3 to 1.5). This achieves efficient separation and purification of the product (compound (III)), resulting in a synergistic improvement in economy, environmental friendliness, high yield, and high content. First, an ester extraction solvent is added, causing the product, impurities, and pigments to remain in the organic layer. Then, the pH is adjusted to a range greater than 9, ensuring that after adding the ester extraction solvent, the product remains in the organic layer while the impurities and pigments remain in the aqueous layer. Finally, water or a mixture of water and alcohol is used to slurry the mixture. After drying, the resulting product is a white solid. All solvents and reagents used in the entire process are conventional chemical raw materials, inexpensive and readily available. Simultaneously, optimized process parameters reduce solvent consumption and energy consumption, and the solvent and mother liquor can be recycled, further reducing production costs. The simplified operation process reduces production costs and environmental pressure, avoiding complex operations such as column chromatography, thus reducing production difficulty and energy consumption. Low-toxicity and environmentally friendly solvents and reaction media are used, meeting the environmental requirements for industrial production. The yield of the target product is consistently maintained above 74%, with a purity exceeding 99% and a content higher than 97%. The prepared product can be used in the preparation of esomeprazole, meeting the quality requirements for preparing qualified esomeprazole raw materials, and has significant industrial application value.

[0076] The above description of the embodiments disclosed in this application enables those skilled in the art to make or use this application. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of this application. Therefore, this application is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A process for the preparation of 5-(1 H-pyrrol-1 -yl)-2-mercaptobenzimidazole, characterized in that, The compound was prepared by reacting 2-mercapto-5-aminobenzimidazole (structure shown in formula (I)) with 2,5-dimethoxytetrahydrofuran (structure shown in formula (II)). The preparation method comprises the following reaction steps: S1: Compounds of formula (I) and (II) undergo a condensation reaction upon heating in acetic acid medium; S2: After the reaction is complete, cool down, add an ester solvent to the resulting reaction solution, then add an alkaline solution to adjust the pH to greater than or equal to 9, use the above ester solvent to extract the reaction solution, and collect the organic phase; S3: The organic phase of step S2 is concentrated, and then a pulping solvent is added to the concentrate for pulping. The filter cake is collected by filtration and dried to obtain compound (III). The pulping solvent is a mixture of water and alcohol.

2. The process for the preparation of 5-(1 H-pyrrol-1 -yl)-2-mercaptobenzimidazole according to claim 1, characterized in that, The pH range is greater than or equal to 13.

3. The method for preparing 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole according to claim 1, characterized in that, The ester solvent is at least one of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and isobutyl acetate.

4. The method for preparing 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole according to claim 1, characterized in that, The organic solvent is ethyl acetate or isopropyl acetate.

5. The method for preparing 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole according to claim 1, characterized in that, The volume ratio of the concentrate to the pulping solvent is 1:1 to 1.

5.

6. The method for preparing 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole according to claim 5, characterized in that, The volume ratio of the concentrate to the pulping solvent is 1:1.3 to 1.

5.

7. The method for preparing 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole according to claim 1, characterized in that, The pulping solvent is a mixed solvent with a volume ratio of water to alcohol solvent of 3:0 to 1.

8. The preparation method according to claim 7, characterized in that, The alcohol solvent is methanol or ethanol, and the pulping solvent is water or a water:alcohol solvent volume ratio of 3:

1.

9. The preparation method according to claim 1, characterized in that, The alkaline solution is selected from lithium hydroxide solution, sodium hydroxide solution, and potassium hydroxide solution.

10. An application of 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole, characterized in that: The 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole obtained by the preparation method according to any one of claims 1 to 9 is used to prepare iprazolbazole.

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