Preparation method of proton pump inhibitor intermediate

Abstract

The invention discloses a preparation method of a proton pump inhibitor intermediate, which comprises the following steps: (1) carrying out condensation reaction on 2-mercapto-5-aminobenzimidazole and 2, 5-dimethoxytetrahydrofuran in an acetic acid medium; (2) after the reaction is finished, adding a solvent 1 into the obtained reaction liquid, and separating out a wet product solid; (3) dissolving the wet product solid obtained in the step (2) in a solvent 2, and then adjusting the pH value of the reaction solution to 10.5-12.5 by using an alkaline solution; then adding a solvent 3 to perform extraction operation on the reaction liquid, and collecting an organic phase; and (4) concentrating and drying: concentrating and drying the organic phase obtained in the step (3) to obtain the proton pump inhibitor intermediate 5-(1H-pyrrole-1-yl)-2-mercaptobenzimidazole, and the proton pump inhibitor intermediate obtained by the invention has high yield, high content and good appearance.

Description

Technical Field

[0001] The present application belongs to the field of pharmaceutical preparations, and in particular relates to a method for preparing a proton pump inhibitor intermediate. Background Art

[0002] Ilaprazole is a new type of proton pump inhibitor (PPI) that has shown significant efficacy in the treatment of indigestion, peptic ulcer disease, gastroesophageal reflux disease and duodenal ulcer. Since 2001, Livzon Pharmaceutical Group has obtained the patent right to use Ilaprazole through cooperation with Ilyang Pharmaceutical Co., Ltd. of South Korea, and successfully launched it on the market in 2008. The chemical structure is as follows:

[0003]

[0004] In the synthesis process of ilaprazole, 5-(1H-pyrrol-1-yl)-2-mercaptobenzimidazole (hereinafter referred to as "ilaprazole intermediate") is a key intermediate, and its synthesis efficiency and quality have a decisive influence on the performance of the final product. The chemical structure is as follows:

[0005]

[0006] Ilaprazole intermediates can be obtained by substitution reaction and oxidation reaction to obtain ilaprazole. The synthetic route is as follows:

[0007]

[0008] However, the existing synthetic route of prazole intermediates has many shortcomings, such as low yield, environmental unfriendliness, etc. Patent CN101602758A discloses a method for preparing 5-(1H-pyrrol-1-yl)-2-mercaptobenzimidazole, and the route is shown in the figure below:

[0009]

[0010] However, according to the literature (CN104650039A, CN113354623B, etc.), this method will produce pigments during the synthesis process, which not only affects the yield and purity of the intermediate, but may also have a negative impact on the properties, appearance and overall quality of ilaprazole. Summary of the invention

[0011] In view of the problems existing in the prior art, the present application provides a method for preparing a proton pump inhibitor intermediate, comprising the following steps:

[0012] (1) 2-mercapto-5-aminobenzimidazole and 2,5-dimethoxytetrahydrofuran are subjected to condensation reaction in an acetic acid medium;

[0013] (2) After the reaction is completed, solvent 1 is added to the obtained reaction solution to separate the wet solid;

[0014] (3) dissolving the wet solid obtained in step (2) in solvent 2, and then adjusting the pH value to 10.5-12.5; then, adding solvent 3 to extract the reaction solution, and collecting the organic phase;

[0015] (4) Concentration and drying: The organic phase obtained in step (3) is concentrated and dried to obtain the proton pump inhibitor intermediate 5-(1H-pyrrol-1-yl)-2-mercaptobenzimidazole.

[0016] Furthermore, the mass ratio of the solvent 2 to the 2-mercapto-5-aminobenzimidazole is (4-6):1.

[0017] Furthermore, the mass ratio of the solvent 3 to the 2-mercapto-5-aminobenzimidazole is (3-5):1.

[0018] Furthermore, the mass ratio of the solvent 3 to the 2-mercapto-5-aminobenzimidazole is 4:1.

[0019] Furthermore, the reaction temperature of step (1) is 50°C to 60°C.

[0020] Furthermore, the temperature of step (2) is 20°C to 30°C.

[0021] Furthermore, the solvent 1 may be one or more of purified water, ethanol, acetone and / or acetonitrile.

[0022] Furthermore, the solvent 2 may be one or more of tetrahydrofuran, N,N-dimethylformamide, acetonitrile and / or acetone.

[0023] Furthermore, the solvent 3 may be one or more of dichloromethane, chloroform, n-butanol and / or toluene.

[0024] On the other hand, the present invention provides a proton pump inhibitor intermediate obtained by any of the above methods, wherein the proton pump inhibitor is preferably ilaprazole, and the ilaprazole is an off-white product with a content of greater than or equal to 96%.

[0025] Compared with the prior art, the preparation method of the proton pump inhibitor intermediate (hereinafter referred to as "ilaprazole intermediate") provided by the present invention has the following beneficial effects:

[0026] (1) High content: The ilaprazole intermediate obtained by the preparation method of the present invention has a higher content and can fully meet the requirements for pharmaceutical use.

[0027] (2) High yield: By optimizing the reaction conditions and extraction process, the method of the present invention can achieve a higher yield, which not only effectively reduces the production cost but also improves the economic benefits.

[0028] (3) Excellent appearance: The ilaprazole intermediate prepared by the present invention has an off-white appearance, which fully meets the appearance quality standards for drug production. In addition, this excellent appearance further ensures the properties, appearance and overall quality of the final product ilaprazole. DETAILED DESCRIPTION

[0029] The technical solutions in the embodiments of the present application are described clearly below. Obviously, the described embodiments are part of the embodiments of the present application, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments in the present application belong to the scope of protection of the present application.

[0030] The terms "first", "second", etc. in the specification and claims of this application are used to distinguish similar objects, and are not used to describe a specific order or sequence. It should be understood that the data used in this way can be interchangeable under appropriate circumstances, so that the embodiments of the present application can be implemented in an order other than those described here, and the objects distinguished by "first", "second", etc. are generally of one type, and the number of objects is not limited. For example, the first object can be one or more. In addition, "and / or" in the specification and claims represents at least one of the connected objects, and the character " / " generally indicates that the objects associated before and after are in an "or" relationship.

[0031] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples, unless otherwise specified, can be obtained from commercial channels.

[0032] The quality of ilaprazole intermediates is directly related to the quality of the final ilaprazole product. However, when the inventors studied the synthesis of ilaprazole intermediates, they found that the intermediates obtained had an abnormally obvious color. After in-depth research, it is speculated that this phenomenon may be due to the generation of darker tar impurities during the preparation process due to the influence of raw materials or reaction conditions. This tar is not only difficult to remove by conventional means, but also, if it is not removed, it will have an adverse effect on the purity and appearance of subsequent intermediates.

[0033] Through further exploration, the inventors have discovered a reasonable post-treatment method that can significantly improve the quality of the ilaprazole intermediate, thereby ensuring the excellent quality of the final product. The specific method for preparing the ilaprazole intermediate comprises the following steps:

[0034] (1) 2-mercapto-5-aminobenzimidazole as shown in compound I and 2,5-dimethoxytetrahydrofuran as shown in compound II are subjected to condensation reaction in an acetic acid medium, and the reaction liquid temperature is 50° C. to 60° C. The reaction process is as follows:

[0035]

[0036] (2) After the reaction is completed, the reaction solution is cooled to 20°C to 30°C, solvent 1 is added to the obtained reaction solution, and the wet solid is separated;

[0037] In one embodiment of the present invention, solvent 1 may be used to perform wet-solid extraction operations twice or more.

[0038] In a specific embodiment of the present invention, the specific operation is: after the reaction is completed, the reaction liquid is cooled to 20°C to 30°C, solvent 1 is added to the obtained reaction liquid, stirred, and the wet solid is collected; then solvent 1 is added to the wet solid, stirred and slurried, and the wet solid is collected.

[0039] In one embodiment of the present invention, the solvent 1 can be one or more of purified water, ethanol, acetone and / or acetonitrile. The present invention does not limit the solvent 1, as long as it is miscible with acetic acid and immiscible with the material. The solvent 1 is used as an acid removal solvent, mainly to reduce the subsequent residual acetic acid, and the solvent 1 is preferably a solvent that does not introduce new impurities.

[0040] (3) dissolving the wet solid obtained in step (2) in solvent 2, and then adjusting the pH value of the reaction solution to 10.5 to 12.5, preferably 11 to 12. Then, adding solvent 3 to perform extraction operation on the reaction solution, and collecting the organic phase;

[0041] In one embodiment of the present invention, the solvent 2 is a benign solvent for the ilaprazole intermediate, which refers to a solvent with a high solubility for the ilaprazole intermediate. At the same time, the solvent 2 must also ensure that impurities are dissolved, thereby facilitating subsequent extraction. The solvent 2 can be one or more of tetrahydrofuran, N,N-dimethylformamide, acetonitrile and / or acetone.

[0042] In one embodiment of the present invention, the solvent for adjusting the pH value may be an alkaline solution and / or an acidic solution, and the alkali in the alkaline solution may be one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate or other alkalis that can adjust the pH value of the reaction solution, preferably sodium hydroxide. The acid in the acidic solution may be one or more of hydrochloric acid, citric acid, acetic acid, lactic acid or other acids that can adjust the pH value of the reaction solution.

[0043] In one embodiment of the present invention, the mass ratio of the solvent 2 to the 2-mercapto-5-aminobenzimidazole is (4-6):1, for example 4:1, 5:1 or 6:1, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0044] In one embodiment of the present invention, the aqueous phase may be treated with solvent 2 and solvent 3 twice or more.

[0045] In one embodiment of the present invention, the specific operation is as follows: dissolving the wet solid obtained in step (2) in solvent 2, and then adjusting the pH value of the reaction solution to 10.5-12.5 using an alkaline solution. Then, adding solvent 3 to the reaction solution for extraction, collecting the organic phase; adding solvent 2 to the aqueous phase and stirring, then adding solvent 3, stirring, separating, and collecting the organic phase; combining the organic phases obtained from the two extractions.

[0046] In one embodiment of the present invention, the solvent 3 is a poor solvent for the ilaprazole intermediate, and the poor solvent refers to a solvent with low solubility for the ilaprazole intermediate. The main purpose of the solvent 3 is to extract the target product from the organic solution. The solvent 3 can be one or more of dichloromethane, chloroform, n-butanol and / or toluene.

[0047] In one embodiment of the present invention, the mass ratio of the solvent 3 to the 2-mercapto-5-aminobenzimidazole is (3-5):1, for example 3:1, 4:1 or 5:1, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0048] (4) The organic phase obtained in step (3) is concentrated and dried to obtain an ilaprazole intermediate.

[0049] Patent CN101602758A provides a method for preparing an ilaprazole intermediate, which comprises: cyclizing compound I and compound II in an acid and a reaction solvent, then adding an extraction solvent to the cyclization reactant, neutralizing with an alkaline solution to remove excess acid, and performing layer separation, and then crystallizing with a crystallization solvent to obtain an ilaprazole intermediate.

[0050] The present invention has conducted in-depth research on the basis of the prior art and found that when only an alkaline solution is used to neutralize the excess acid in the reaction system to make the system neutral (such as pH 6-7), the resulting ilaprazole intermediate has poor performance in terms of content, appearance and yield. Further research found that the solubility of the ilaprazole intermediate is relatively special, so the acid removal method is to select water washing (remove most of the acid), adjust the pH value to remove tar and remove acid at the same time, which can significantly improve the quality of the ilaprazole intermediate. On this basis, the inventor further post-processed the reaction system after adjusting the pH value, and found that after treatment with a specific solvent, the content, appearance and yield of the ilaprazole intermediate can be effectively improved.

[0051] The following are specific examples of the present invention and comparative examples, but the present invention is not limited to the following examples.

[0052] Example 1

[0053] The reaction process is as follows:

[0054]

[0055] The specific preparation method is as follows:

[0056] (1) Condensation reaction: Add purified water to a 500L glass-lined reactor and start stirring. Add 24kg of compound I (2-mercapto-5-aminobenzimidazole), 21kg of compound II (2,5-dimethoxytetrahydrofuran) and 78.24kg of glacial acetic acid to the reactor in sequence. Heat the reaction solution to 50°C to 60°C and react for 3h.

[0057] (2) Water washing: After the reaction is completed, the reaction liquid is cooled to 20℃~30℃, purified water is added to the reaction liquid, the temperature is controlled at 20℃~30℃, and stirring is carried out for 30min. The reaction liquid is centrifuged until no liquid flows out, and the wet solid is collected. The wet solid and purified water are added to the glass-lined reactor in sequence, stirring is started, the temperature is controlled at 20℃~30℃, stirring and beating for 1h, the reaction liquid is centrifuged until no droplets flow out, and the wet solid is collected for later use.

[0058] (3) Extraction: Add 96 kg of tetrahydrofuran to a glass-lined reactor. Control the temperature at 20°C to 30°C and add the wet solid to the reactor. After the addition, control the temperature at 20°C to 30°C and slowly add the 5% sodium hydroxide aqueous solution prepared above to adjust the pH value of the reaction solution to 11.0. After the adjustment, add 96 kg of dichloromethane and stir for 15 minutes. Let stand for 50 minutes, separate the liquids, and collect the organic phase. Add 96 kg of tetrahydrofuran and the aqueous phase to the reactor and start stirring. Add 96 kg of dichloromethane to the reactor and stir for 15 minutes. Stop stirring, let stand for 50 minutes, separate the liquids, and collect the organic phase. Add the organic phase to the reactor, add purified water, and stir for 15 minutes. Stop stirring, let stand for 50 minutes, separate the liquids, and collect the organic phase.

[0059] (4) Concentration and drying: Combine the organic phases and transfer them to a glass-lined reactor in batches, control the temperature at 40℃~50℃, and vacuum degree ≤-0.08MPa, and concentrate under reduced pressure until no liquid flows out of the condenser. Add purified water to the concentrated residue and stir and slurry for 1h. Centrifuge the reaction solution until no liquid flows out, collect the wet solids and transfer them to a double cone dryer, control the temperature at 60℃~70℃, and vacuum degree ≤-0.08MPa for drying.

[0060] Example 2

[0061] The pH value of the reaction solution in step (3) was adjusted to 12, and the other operations and conditions were the same as those in Example 1.

[0062] Example 3

[0063] The amount of tetrahydrofuran in step (3) was adjusted from 96 kg to 144 kg, and the specific operation was as follows. Other operations and conditions were the same as those in Example 1.

[0064] (3) Extraction: Add 144 kg of tetrahydrofuran to a glass-lined reactor. Control the temperature at 20°C to 30°C and add the wet solid to the reactor. After the addition, control the temperature at 20°C to 30°C and slowly add the 5% sodium hydroxide aqueous solution prepared above to adjust the pH value of the reaction solution to 11.0. After the adjustment, add 96 kg of dichloromethane and stir for 15 minutes. Let stand for 50 minutes, separate the liquids, and collect the organic phase. Add 144 kg of tetrahydrofuran and the aqueous phase to the reactor and start stirring. Add 96 kg of dichloromethane to the reactor and stir for 15 minutes. Stop stirring, let stand for 50 minutes, separate the liquids, and collect the organic phase. Add the organic phase to the reactor, add purified water, and stir for 15 minutes. Stop stirring, let stand for 50 minutes, separate the liquids, and collect the organic phase.

[0065] Comparative Example 1

[0066] Referring to the parameter conditions of Example 1 of patent CN101602758A, the specific preparation method is as follows:

[0067] (1) Condensation reaction: Take water (100 ml) and anhydrous sodium acetate (16.02 g, 0.20 mol), add 2-mercapto-5-aminobenzimidazole (32.27 g, 0.20 mol), 2,5-dimethoxytetrahydrofuran (28.4 g, 0.21 mol) and acetic acid (100 ml), and then stir at 50° C. for 4 hours.

[0068] (2) Acid removal

[0069] 1) Extraction: After cooling the reactant to 5°C, tetrahydrofuran (420 ml) was added.

[0070] 2) Neutralization: Neutralize with 5% sodium hydroxide aqueous solution and adjust the pH to 6-7.

[0071] 3) Layer separation: Water (130 ml) was added to separate the layers, and the organic layer was washed with a 5% aqueous sodium hydroxide solution.

[0072] (3) Drying: The organic layer was dried over anhydrous magnesium sulfate and concentrated, and crystallized with ethyl acetoacetate and n-hexane to obtain the target compound 5-(1H-pyrrol-1-yl)-2-mercaptobenzimidazole.

[0073] Comparative Example 2

[0074] The pH value of the reaction solution in step (3) was adjusted to 6-7, and the other operations and conditions were the same as those in Example 1.

[0075] Comparative Example 3

[0076] The pH value of the reaction solution in step (3) was adjusted to 9, and the other operations and conditions were the same as those in Example 1.

[0077] Comparative Example 4

[0078] The pH value of the reaction solution in step (3) was adjusted to 10, and the other operations and conditions were the same as those in Example 1.

[0079] Comparative Example 5

[0080] The pH value of the reaction solution in step (3) was adjusted to 13, and the other operations and conditions were the same as those in Example 1.

[0081] Comparative Example 6

[0082] The pH value of the reaction solution in step (3) was adjusted to 14, and the other operations and conditions were the same as those in Example 1.

[0083] Comparative Example 7

[0084] The amount of tetrahydrofuran and dichloromethane in step (3) was adjusted from 96 kg to 48 kg, and the specific operation was as follows. Other operations and conditions were the same as those in Example 1.

[0085] (3) Extraction: Add 48 kg of tetrahydrofuran to a glass-lined reactor. Control the temperature at 20°C to 30°C and add the wet solid to the reactor. After the addition, control the temperature at 20°C to 30°C and slowly add the 5% sodium hydroxide aqueous solution prepared above to adjust the pH value of the reaction solution to 11.0. After the adjustment, add 48 kg of dichloromethane and stir for 15 min. Let stand for 50 min, separate the liquids and collect the organic phase. Add 48 kg of tetrahydrofuran and the aqueous phase to the reactor and start stirring. Add 48 kg of dichloromethane to the reactor and stir for 15 min. Stop stirring, let stand for 50 min, separate the liquids and collect the organic phase. Add the organic phase to the reactor, add purified water and stir for 15 min. Stop stirring, let stand for 50 min, separate the liquids and collect the organic phase.

[0086] Comparative Example 8

[0087] The amount of dichloromethane in step (3) was adjusted from 96 kg to 144 kg. The specific operation was as follows. Other operations and conditions were the same as those in Example 1.

[0088] (4) Extraction: Add 96 kg of tetrahydrofuran to a glass-lined reactor. Control the temperature at 20°C to 30°C and add the wet solid to the reactor. After the addition, control the temperature at 20°C to 30°C and slowly add the 5% sodium hydroxide aqueous solution prepared above to adjust the pH value of the reaction solution to 11.0. After the adjustment, add 144 kg of dichloromethane and stir for 15 minutes. Let stand for 50 minutes, separate the liquids, and collect the organic phase. Add 96 kg of tetrahydrofuran and the aqueous phase to the reactor and start stirring. Add 144 kg of dichloromethane to the reactor and stir for 15 minutes. Stop stirring, let stand for 50 minutes, separate the liquids, and collect the organic phase. Add the organic phase to the reactor, add purified water, and stir for 15 minutes. Stop stirring, let stand for 50 minutes, separate the liquids, and collect the organic phase.

[0089] Calculate the yield and content of the ilaprazole intermediate prepared in Examples 1 to 3 and Comparative Examples 1 to 8:

[0090] Yield calculation formula:

[0091]

[0092] Note: 165.21 is the molecular weight of compound I, and 215.27 is the molecular weight of ilaprazole intermediate.

[0093] Content determination method:

[0094] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512).

[0095] Solvent methanol-water (4:1)

[0096] Test solution Take an appropriate amount of the product, weigh it accurately, dissolve it in solvent and quantitatively dilute it to make a solution containing about 4μg per 1ml as the test solution.

[0097] Reference solution: Take an appropriate amount of ilaprazole intermediate reference substance, accurately weigh it, dissolve it in a solvent, and quantitatively dilute it to make a solution containing about 4 μg of ilaprazole intermediate reference substance per 1 ml, which is used as the reference solution.

[0098] Chromatographic conditions: octadecylsilane bonded silica gel as filler (ArtChrom WP C18 4.6 mm × 150 mm, 5 μm or chromatographic column of equivalent performance); acetonitrile-0.01 mol / L potassium dihydrogen phosphate buffer (pH adjusted to 7.5 with phosphoric acid) (35:65) as mobile phase; flow rate of 1.0 ml per minute; column temperature of 25°C; detection wavelength of 237 nm; injection volume of 10 μl.

[0099] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate the peak area according to the external standard method.

[0100] Table 1 Content, yield and appearance of ilaprazole intermediates obtained in Examples 1 to 3 and Comparative Examples 1 to 8

[0101] batch Receipt of material(kg) content(%) Yield (%) Appearance of intermediate finished product Example 1 22.0 99.5 70.0 Off-white Example 2 16.6 97.8 53.0 Off-white Example 3 18.9 96.4 60.1 Off-white Comparative Example 1 11.8 70.3 37.6 Light yellow Comparative Example 2 8.3 70.6 26.4 Brown Comparative Example 3 9.9 85.2 31.5 Light yellow Comparative Example 4 11.1 96.2 35.5 Light yellow Comparative Example 5 9.5 97.1 30.1 Off-white Comparative Example 6 2.5 / 8.0 Off-white Comparative Example 7 12.6 95.4 40.2 Light yellow Comparative Example 8 11.0 96.2 35.0 Light yellow

[0102] From the data in Table 1, it can be seen that after the reaction is completed, patent CN101602758A (Comparative Example 1) uses an alkaline solution to remove acid and neutralize the reaction system to neutrality, and simultaneously uses ethyl acetoacetate and n-hexane for crystallization. The resulting ilaprazole intermediate not only has a light yellow appearance, but also has a low yield and content.

[0103] It can be seen from Examples 1 to 2 and Comparative Examples 2 to 6 that controlling the pH value within a reasonable range (such as pH 11 to 12) can ensure that the target product is effectively extracted, thereby improving the yield. In this way, a high content of ilaprazole intermediates can be separated in the end, and the appearance of these intermediates is off-white. On the contrary, if the pH value is low (as shown in Comparative Examples 2 to 4), not only will the content and yield of the ilaprazole intermediates decrease, but its appearance will also turn yellow. In particular, when the pH value is between 6 and 7, that is, close to neutral (such as Comparative Example 2), the color of the ilaprazole intermediate will become darker and present a brownish yellow color. On the other hand, if the pH value is too high (as shown in Comparative Examples 5 and 6), although the appearance of the obtained ilaprazole intermediate is still off-white, the yield of the product will be greatly reduced. Especially when the pH value is 14 (such as Comparative Example 6), only a very small amount of product can be obtained. In summary, only by controlling the pH value within a specific range can we ensure the quality of the ilaprazole intermediate.

[0104] Through comparative analysis of Example 1, Example 3, Comparative Examples 7 and 8, it can be seen that the solvent used and its dosage have a significant effect in the process of extracting the ilaprazole intermediate from the reaction system. Specifically, tetrahydrofuran is a good solvent. Although the increase in its equivalent will cause a slight decrease in the reaction yield, the overall quality of the ilaprazole intermediate still meets the requirements, which is reflected in Example 3. On the contrary, dichloromethane is a poor solvent. The increase in its equivalent will make the solid unable to be completely dissolved, resulting in a loss of yield, which is shown in Comparative Example 8. At the same time, the ilaprazole intermediate obtained in Comparative Example 8 is also more obvious in appearance color. In addition, if the equivalents of tetrahydrofuran and dichloromethane are reduced at the same time, due to the poor dissolution effect, the solid cannot be completely dissolved, which leads to a decrease in yield, and the appearance of the ilaprazole intermediate will also be affected, which can be seen in Comparative Example 7. Therefore, only by properly adjusting the dosage of tetrahydrofuran and dichloromethane can the yield, content and appearance quality of the ilaprazole intermediate be effectively guaranteed.

[0105] The embodiments of the present application are described above, but the present application is not limited to the above-mentioned specific implementation modes. The above-mentioned specific implementation modes are merely illustrative and not restrictive. Under the guidance of the present application, ordinary technicians in this field can also make many forms without departing from the purpose of the present application and the scope of protection of the claims, all of which are within the protection of the present application.

Claims

1. A method for preparing a proton pump inhibitor intermediate, characterized in that: The steps include: (1) 2-mercapto-5-aminobenzimidazole and 2,5-dimethoxytetrahydrofuran are subjected to condensation reaction in an acetic acid medium; (2) After the reaction is completed, solvent 1 is added to the obtained reaction solution to separate the wet solid; (3) dissolving the wet solid obtained in step (2) in solvent 2, and then adjusting the pH value to 10.5-12.5; then, adding solvent 3 to extract the reaction solution, and collecting the organic phase; (4) Concentration and drying: The organic phase obtained in step (3) is concentrated and dried to obtain the proton pump inhibitor intermediate 5-(1H-pyrrol-1-yl)-2-mercaptobenzimidazole.

2. The method for preparing a proton pump inhibitor intermediate according to claim 1, characterized in that: The mass ratio of the solvent 2 to the 2-mercapto-5-aminobenzimidazole is (4-6):

1.

3. The method for preparing a proton pump inhibitor intermediate according to claim 1, characterized in that: The mass ratio of the solvent 3 to the 2-mercapto-5-aminobenzimidazole is (3-5):

1.

4. The method for preparing a proton pump inhibitor intermediate according to claim 3, characterized in that: The mass ratio of the solvent 3 to the 2-mercapto-5-aminobenzimidazole is 4:

1.

5. The method for preparing a proton pump inhibitor intermediate according to any one of claims 1 to 4, characterized in that: The reaction temperature of step (1) is 50°C to 60°C.

6. The method for preparing a proton pump inhibitor intermediate according to claim 5, characterized in that: The temperature of step (2) is 20°C to 30°C.

7. The method for preparing a proton pump inhibitor intermediate according to claim 6, characterized in that: The solvent 1 can be one or more of purified water, ethanol, acetone and / or acetonitrile.

8. The method for preparing a proton pump inhibitor intermediate according to claim 7, characterized in that: The solvent 2 may be one or more of tetrahydrofuran, N,N-dimethylformamide, acetonitrile and / or acetone.

9. The method for preparing a proton pump inhibitor intermediate according to claim 8, characterized in that: The solvent 3 may be one or more of dichloromethane, chloroform, n-butanol and / or toluene.

10. The proton pump inhibitor intermediate obtained by the method according to any one of claims 1 to 9, wherein the proton pump inhibitor is preferably ilaprazole, and the ilaprazole is an off-white product with a content of greater than or equal to 96%.

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