A method for preparing a benzimidazole pharmaceutical intermediate

Abstract

The present invention relates to the field of pharmaceutical technology, and in particular to a preparation method of a benzimidazole pharmaceutical intermediate. The preparation method comprises the following steps: in a solvent system, 3-amino-2-chlorobenzoic acid methyl ester and ethyl formate are heated and reacted under the action of a catalyst to obtain a 2-chloro-3-((ethoxymethylene)amino)benzoic acid methyl ester solution, wherein the catalyst is p-toluenesulfonic acid or glacial acetic acid; 4'-(aminomethyl)-[1,1'-biphenyl]-2-nitrile and a nitrogen oxide catalyst are added to the 2-chloro-3-((ethoxymethylene)amino)benzoic acid methyl ester solution, and then the reaction is carried out under oxygen conditions. After the reaction is completed, the benzimidazole pharmaceutical intermediate is obtained by post-processing. The preparation method has mild reaction conditions, simple operation, short route, is environmentally friendly, has high product quality yield, and is suitable for commercial production.

Description

Technical Field

[0001] The invention relates to a method for preparing a benzimidazole pharmaceutical intermediate, belonging to the technical field of medicines. Background Art

[0002] A benzimidazole pharmaceutical intermediate, chemical name: 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethoxy-benzimidazole-7-carboxylic acid methyl ester, the specific structure is as follows:

[0003] .

[0004] Sartan antihypertensive drugs are a type of antihypertensive drugs that are currently widely used, such as Olmesartan, valsartan, candesartan, azilsartan, and acesartan. Among them, azilsartan or its ester acesartan is known as the most effective antihypertensive drug in history and has been used in more than 35 countries and regions including the United States, Canada, France, the United Kingdom, and Japan.

[0005] At present, the mainstream preparation methods of azilsartan include the original Chinese patent application CN1067890A, patent application W02013186792A3, etc. However, these publicly reported preparation methods all require the preparation of a key intermediate, namely 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethoxy-benzimidazole-7-carboxylic acid methyl ester. In the process of preparing this intermediate, it is necessary to obtain a diamine structure of o-phenylenediamine or its derivatives. Such structures will produce a large number of isomers during cyclization or alkylation, resulting in reduced purity and yield, and the preparation route is long, which greatly increases the production cost. Summary of the invention

[0006] The present invention aims at the deficiencies in the prior art and provides a method for preparing a benzimidazole pharmaceutical intermediate. The preparation method has mild reaction conditions, simple operation, a short route, is environmentally friendly, has a high product quality yield, and is suitable for commercial production.

[0007] The technical solution of the present invention to solve the above technical problems is as follows: a preparation method of a benzimidazole pharmaceutical intermediate, the preparation method is:

[0008] S1. In a solvent system, methyl 3-amino-2-chlorobenzoate and ethyl formate are heated to react under the action of a catalyst to obtain a methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution, wherein the catalyst is p-toluenesulfonic acid or glacial acetic acid;

[0009] S2. Add 4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonitrile and a nitrogen oxide catalyst to a solution of methyl 2-chloro-3((ethoxymethylene)amino)benzoate, and then react under oxygen conditions. After the reaction is completed, post-treatment is performed to obtain a benzimidazole pharmaceutical intermediate, and the structural formula of the benzimidazole pharmaceutical intermediate is:

[0010] .

[0011] Furthermore, in step S1, the molar ratio of methyl 3-amino-2-chlorobenzoate to ethyl formate is 1:(1.0-1.1).

[0012] Furthermore, in step S1, the heating reaction temperature is 75-85°C and the reaction time is 2-3h.

[0013] Furthermore, in step S1, the solvent is toluene or xylene.

[0014] Furthermore, after the reaction in step S1 is completed, water is added to the system for washing, the organic phase is separated, and the methyl 2-chloro-3-((ethoxymethylene)amino)benzoate solution is obtained after drying, and then the operation of step S2 is performed.

[0015] Furthermore, in step S2, the nitrogen oxide catalyst is 2,2,6,6-tetramethylpiperidine.

[0016] Furthermore, in step S2, the reaction temperature is 50-60° C., the reaction pressure is 0.1-0.2 MPa, and the reaction time is 1-5 hours.

[0017] Further, the molar ratio of methyl 3-amino-2-chlorobenzoate to 4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonitrile is 1:(1-1.05).

[0018] Furthermore, in step S2, the post-treatment operation is: after the reaction is completed, the system is cooled and crystallized, and then the benzimidazole pharmaceutical intermediate is obtained by solid-liquid separation.

[0019] Furthermore, the final crystallization temperature of the cooling crystallization is 0-10°C, and the crystallization time is 2-3h.

[0020] The beneficial effects of the present invention are:

[0021] 1) The preparation method of the benzimidazole pharmaceutical intermediate of the present invention uses 3-amino-2-chlorobenzoic acid methyl ester as a raw material, thereby avoiding the generation of multi-substituted impurities due to the similar activity of the two amino groups and poor selectivity caused by the cyclization of the o-phenylenediamine structure.

[0022] 2) In the preparation method of the benzimidazole pharmaceutical intermediate of the present invention, the substituted benzimidazole ring structure is directly prepared by one-step cyclization through an oxidation system in the presence of a free radical catalyst, thereby avoiding the problem of generating a large amount of tautomeric impurities when the benzimidazole structure reacts with an alkylating agent.

[0023] 3) The preparation method of the benzimidazole pharmaceutical intermediate of the present invention improves the reaction efficiency, simplifies the operation steps, shortens the working hours, and thus reduces the production cost through a one-pot process.

[0024] In summary, the present invention provides a method for efficiently preparing high-purity benzimidazole pharmaceutical intermediates. The method has mild reaction conditions and is environmentally friendly, simple operation, short steps, and high yield (yield ≥ 93%), and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is the H-NMR spectrum of the benzimidazole pharmaceutical intermediate prepared in Example 1. DETAILED DESCRIPTION

[0026] The specific implementation of the present invention is described in detail below. The present invention can be implemented in many other ways than those described herein, and those skilled in the art can make similar improvements without violating the connotation of the present invention, so the present invention is not limited by the specific embodiments disclosed.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. The terms used are only for describing specific embodiments and are not intended to limit the present invention.

[0028] A method for preparing a benzimidazole pharmaceutical intermediate, the preparation method comprising:

[0029] ;

[0030] S1. In a solvent system, methyl 3-amino-2-chlorobenzoate and ethyl formate are heated to react under the action of a catalyst to obtain a methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution, wherein the catalyst is p-toluenesulfonic acid or glacial acetic acid;

[0031] S2. Add 4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonitrile and a nitrogen oxide catalyst to a solution of methyl 2-chloro-3((ethoxymethylene)amino)benzoate, and then react under oxygen conditions. After the reaction is completed, post-treatment is performed to obtain a benzimidazole pharmaceutical intermediate.

[0032] Specifically, in step S1, the molar ratio of methyl 3-amino-2-chlorobenzoate to ethyl formate is 1:(1.0-1.1).

[0033] Specifically, in step S1, the heating reaction temperature is 75-85° C., and the reaction time is 2-3 h.

[0034] Specifically, in step S1, the solvent is toluene or xylene.

[0035] More specifically, the xylene is m-xylene, o-xylene or p-xylene. Industrial xylene can also be used. Industrial xylene is a mixture of m-xylene, o-xylene or p-xylene.

[0036] Specifically, after the reaction in step S1 is completed, water is added to the system for washing, the organic phase is separated, and the organic phase is dried to obtain a methyl 2-chloro-3-((ethoxymethylene)amino)benzoate solution, and then the operation of step S2 is performed.

[0037] Specifically, in step S2, the nitrogen oxide catalyst is 2,2,6,6-tetramethylpiperidine.

[0038] Specifically, in step S2, the reaction temperature is 50-60° C., the reaction pressure is 0.1-0.2 MPa, and the reaction time is 1-5 hours.

[0039] Specifically, the molar ratio of methyl 3-amino-2-chlorobenzoate to 4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonitrile is 1:(1-1.05).

[0040] Specifically, in step S2, the post-treatment operation is: after the reaction is completed, the system is cooled and crystallized, and then the benzimidazole pharmaceutical intermediate is obtained by solid-liquid separation.

[0041] Specifically, the final crystallization temperature of the cooling crystallization is 0-10°C, and the crystallization time is 2-3h.

[0042] Example 1

[0043] (1) In a 2L reaction bottle, add 1000g toluene, 185g (1mol) methyl 3-amino-2-chlorobenzoate, 74g (1mol) ethyl formate, and 1g p-toluenesulfonic acid, stir and heat to 80°C for reaction for 2.5 hours. After the reaction is completed, cool to room temperature, add 500g of water for washing, separate the toluene layer, add anhydrous sodium sulfate, dry for 1 hour, and filter to obtain a methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution.

[0044] (2) In a 2L autoclave, methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution, 208g (1mol) 4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonitrile, and 1g 2,2,6,6-tetramethylpiperidinoxide were added, and the atmosphere was replaced with nitrogen and oxygen. The reaction was continued at 60°C and 0.1MPa until there was no pressure drop. The reaction was continued for 1 hour, and the temperature was lowered to 5°C for crystallization for 2.5 hours. The benzimidazole pharmaceutical intermediate was filtered, rinsed, and dried to obtain 390g of white crystalline solid. The yield was 95%, the purity was 99.5%, and the H NMR spectrum was as follows: Figure 1 shown.

[0045] Example 2

[0046] (1) In a 2L reaction bottle, add 1000g of industrial xylene, 185g (1mol) of methyl 3-amino-2-chlorobenzoate, 74g (1mol) of ethyl formate, and 1g of glacial acetic acid, stir and heat to 75°C for 3 hours, check the completion of the reaction, cool to room temperature, add 500g of water for washing, separate the xylene layer, add anhydrous sodium sulfate to dry for 1 hour, and filter to obtain a solution of methyl 2-chloro-3((ethoxymethylene)amino)benzoate.

[0047] (2) In a 2L autoclave, methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution, 208 g (1 mol) of 4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonitrile, and 1 g of 2,2,6,6-tetramethylpiperidinoxide were added, and the atmosphere was replaced with nitrogen and oxygen. The reaction was continued at 55°C and 0.1 MPa until there was no pressure drop. The reaction was continued for 1 hour, and the temperature was lowered to 10°C for crystallization for 3 hours. The mixture was filtered, rinsed, and dried to obtain 382 g of a white crystalline solid of a benzimidazole pharmaceutical intermediate with a yield of 93% and a purity of 98.5%.

[0048] Example 3

[0049] (1) In a 2L reaction bottle, add 1000g toluene, 185g (1mol) methyl 3-amino-2-chlorobenzoate, 81.4g (1.1mol) ethyl formate, and 1g p-toluenesulfonic acid, stir and heat to 85°C for 2 hours. After the reaction is completed, cool to room temperature, add 500g of water for washing, separate the toluene layer, add anhydrous sodium sulfate, dry for 1 hour, and filter to obtain a methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution.

[0050] (2) In a 2L autoclave, methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution, 218.4 g (1.05 mol) of 4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonitrile, and 1 g of 2,2,6,6-tetramethylpiperidinoxide were added. The mixture was replaced with nitrogen and oxygen. The reaction was continued at 50°C and 0.2 MPa until there was no pressure drop. The reaction was continued for 5 hours, and the temperature was lowered to 0°C for crystallization for 2 hours. The mixture was filtered, rinsed, and dried to obtain 392 g of a white crystalline solid of a benzimidazole pharmaceutical intermediate with a yield of 95.5% and a purity of 99.4%.

[0051] Example 4

[0052] (1) In a 2L reaction bottle, add 1000g of m-xylene, 185g (1mol) of methyl 3-amino-2-chlorobenzoate, 77.7g (1.05mol) of ethyl formate, and 1g of glacial acetic acid. Stir and heat to 85°C for 2 hours. After the reaction is completed, cool to room temperature, add 500g of water for washing, separate the xylene layer, add anhydrous sodium sulfate, dry for 1 hour, and filter to obtain a solution of methyl 2-chloro-3((ethoxymethylene)amino)benzoate.

[0053] (2) In a 2L autoclave, methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution, 208 g (1 mol) of 4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonitrile, and 1 g of 2,2,6,6-tetramethylpiperidinoxide were added, and the atmosphere was replaced with nitrogen and oxygen. The reaction was continued at 50°C and 0.2 MPa until there was no pressure drop. The reaction was continued for 1.5 hours, and the temperature was lowered to 0°C for crystallization for 3 hours. The mixture was filtered, rinsed, and dried to obtain 390 g of a white crystalline solid of a benzimidazole pharmaceutical intermediate with a yield of 95% and a purity of 99.0%.

[0054] Comparative Example 1

[0055] The benzimidazole pharmaceutical intermediate was prepared by the same method as in Example 1, except that the reaction temperature was increased in step (1). The specific preparation process is as follows:

[0056] (1) In a 2L reaction bottle, add 1000g toluene, 185g (1mol) methyl 3-amino-2-chlorobenzoate, 74g (1mol) ethyl formate, and 1g p-toluenesulfonic acid, stir and heat to 110°C for reaction for 2.5 hours. After the reaction is completed, cool to room temperature, add 500g of water for washing, separate the toluene layer, add anhydrous sodium sulfate, dry for 1 hour, and filter to obtain a methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution.

[0057] (2) In a 2L autoclave, methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution, 208 g (1 mol) of 4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonitrile, and 1 g of 2,2,6,6-tetramethylpiperidinoxide were added, and the atmosphere was replaced with nitrogen and oxygen. The reaction was continued at 60°C and 0.1 MPa until there was no pressure drop. The reaction was continued for 1 hour, and the temperature was lowered to 5°C for crystallization for 2.5 hours. The white crystalline solid of the benzimidazole pharmaceutical intermediate was obtained by filtration, leaching, and drying. The yield was 83.6% and the purity was 93.2%.

[0058] From the comparison of the experimental results of Example 1 and Comparative Example 1, it can be seen that if the reaction temperature is increased in step (1), the yield and purity of the target product will decrease. This is because ethyl formate has both aldehyde and ester properties. Although under the set reaction conditions and catalyst, the activity of aromatic amine is low and no ester aminolysis reaction will occur, as the reaction temperature increases, a small part of the aminolysis reaction will occur, ultimately resulting in a decrease in product yield and purity.

[0059] Comparative Example 2

[0060] The benzimidazole pharmaceutical intermediate was prepared by the same method as in Example 1, except that the reaction temperature was lowered in step (1). The specific preparation process is as follows:

[0061] (1) In a 2L reaction bottle, add 1000g toluene, 185g (1mol) methyl 3-amino-2-chlorobenzoate, 74g (1mol) ethyl formate, and 1g p-toluenesulfonic acid, stir and heat to 50°C for reaction for 2.5 hours, cool to room temperature, add 500g water for washing, separate the toluene layer, add anhydrous sodium sulfate, dry for 1 hour, and filter to obtain a methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution.

[0062] (2) In a 2L autoclave, methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution, 208 g (1 mol) of 4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonitrile, and 1 g of 2,2,6,6-tetramethylpiperidinyl oxide were added, and the atmosphere was replaced with nitrogen and oxygen. The reaction was continued at 60°C and 0.1 MPa until there was no pressure drop. The reaction was continued for 1 hour, and the temperature was lowered to 5°C for crystallization for 2.5 hours. The white crystalline solid of the benzimidazole pharmaceutical intermediate was obtained by filtration, leaching, and drying. The yield was 87.0% and the purity was 95.0%.

[0063] From the comparison of the experimental results of Example 1 and Comparative Example 2, it can be seen that if the reaction temperature is lowered in step (1), within the same reaction time, the reaction of step (1) will be incomplete, and the yield of the target product benzimidazole pharmaceutical intermediate will be significantly reduced. Therefore, the reaction temperature defined in the present invention is more conducive to obtaining the target product with high yield and high purity.

[0064] Comparative Example 3

[0065] The benzimidazole pharmaceutical intermediate was prepared by the same method as in Example 1, except that no water washing operation was performed in step (1). The specific preparation process is as follows:

[0066] (1) In a 2 L reaction bottle, add 1000 g of toluene, 185 g (1 mol) of methyl 3-amino-2-chlorobenzoate, 74 g (1 mol) of ethyl formate, and 1 g of p-toluenesulfonic acid. Stir and heat to 80 °C for 2.5 hours. After the reaction is completed, cool to room temperature to obtain a methyl 2-chloro-3 ((ethoxymethylene)amino)benzoate solution.

[0067] (2) In a 2L autoclave, methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution, 208 g (1 mol) of 4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonitrile, and 1 g of 2,2,6,6-tetramethylpiperidinoxide were added, and the atmosphere was replaced with nitrogen and oxygen. The reaction was continued at 60°C and 0.1 MPa until there was no pressure drop. The reaction was continued for 1 hour, and the temperature was lowered to 5°C for crystallization for 2.5 hours. The white crystalline solid of the benzimidazole pharmaceutical intermediate was obtained by filtration, leaching, and drying. The yield was 89.0% and the purity was 94.5%.

[0068] From the comparison of the experimental results of Example 1 and Comparative Example 3, it can be seen that if the water washing operation is not performed in step (1), the yield of the target product benzimidazole pharmaceutical intermediate is significantly reduced, because the water washing process can wash away the p-toluenesulfonic acid in the system. If the water washing operation is not performed, the p-toluenesulfonic acid in the system will enter step (2) and undergo a condensation reaction with 4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonitrile to generate amide impurities, thereby resulting in a decrease in product yield and purity.

[0069] Comparative Example 4

[0070] The benzimidazole pharmaceutical intermediate was prepared by the same method as in Example 1, except that the reaction temperature and pressure were increased in step (2). The specific preparation process is as follows:

[0071] (1) In a 2L reaction bottle, add 1000g toluene, 185g (1mol) methyl 3-amino-2-chlorobenzoate, 74g (1mol) ethyl formate, and 1g p-toluenesulfonic acid, stir and heat to 80°C for reaction for 2.5 hours. After the reaction is completed, cool to room temperature, add 500g of water for washing, separate the toluene layer, add anhydrous sodium sulfate, dry for 1 hour, and filter to obtain a methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution.

[0072] (2) In a 2L autoclave, add methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution, 208g (1mol) 4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonitrile, and 1g 2,2,6,6-tetramethylpiperidinoxide. Replace the mixture with nitrogen and oxygen. React at 100°C and 0.3MPa until there is no pressure drop. Continue the reaction for 1 hour, then reduce the temperature to 5°C for crystallization for 2.5 hours. Filter, rinse, and dry to obtain a white crystalline solid of a benzimidazole pharmaceutical intermediate with a yield of 85% and a purity of 92%.

[0073] From the comparison of the experimental results of Example 1 and Comparative Example 4, it can be seen that if the reaction temperature and pressure are increased in step (2), the yield and purity of the target product, the benzimidazole pharmaceutical intermediate, will decrease. Because the methyleneethoxy group of methyl 2-chloro-3-((ethoxymethylene)amino)benzoate has a structure similar to that of an ester, although its activity is low, a small part of it will undergo aminolysis reaction with the amino group as the reaction temperature and pressure increase.

[0074] Comparative Example 5

[0075] The benzimidazole pharmaceutical intermediate was prepared by the same method as in Example 1, except that the reaction temperature and pressure were lowered in step (2). The specific preparation process is as follows:

[0076] (1) In a 2L reaction bottle, add 1000g toluene, 185g (1mol) methyl 3-amino-2-chlorobenzoate, 74g (1mol) ethyl formate, and 1g p-toluenesulfonic acid, stir and heat to 80°C for reaction for 2.5 hours. After the reaction is completed, cool to room temperature, add 500g of water for washing, separate the toluene layer, add anhydrous sodium sulfate, dry for 1 hour, and filter to obtain a methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution.

[0077] (2) In a 2L autoclave, add methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution, 208g (1mol) 4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonitrile, and 1g 2,2,6,6-tetramethylpiperidinoxide. Replace the mixture with nitrogen and oxygen. React at 40°C and 0.1MPa until there is no pressure drop. Continue the reaction for 1 hour, then reduce the temperature to 5°C for crystallization for 2.5 hours. Filter, rinse, and dry to obtain a white crystalline solid of a benzimidazole pharmaceutical intermediate with a yield of 83% and a purity of 96%.

[0078] From the comparison of the experimental results of Example 1 and Comparative Example 5, it can be seen that if the reaction temperature is lowered in step (2), the reaction of step (2) will be incomplete within the same reaction time, and the yield of the target product, the benzimidazole pharmaceutical intermediate, will be significantly reduced. Therefore, the reaction temperature defined in the present invention is more conducive to obtaining the target product with high yield and high purity.

[0079] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are exhaustively listed. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0080] For those skilled in the art, several modifications and improvements may be made without departing from the concept of the present invention, all of which belong to the protection scope of the present invention. The protection scope of the present invention shall be based on the attached claims.

Claims

1. A method for preparing a benzimidazole pharmaceutical intermediate, characterized in that: The preparation method is: S1. In a solvent system, methyl 3-amino-2-chlorobenzoate and ethyl formate are heated to react under the action of a catalyst to obtain a methyl 2-chloro-3((ethoxymethylene)amino)benzoate solution, wherein the catalyst is p-toluenesulfonic acid or glacial acetic acid; S2. Add 4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonitrile and a nitrogen oxide catalyst to a solution of methyl 2-chloro-3((ethoxymethylene)amino)benzoate, and then react under oxygen conditions. After the reaction is completed, post-treatment is performed to obtain a benzimidazole pharmaceutical intermediate, and the structural formula of the benzimidazole pharmaceutical intermediate is: ； In step S1, the heating reaction temperature is 75-85°C; After the reaction in step S1 is completed, water is added to the system for washing, and the organic phase is separated and dried to obtain a methyl 2-chloro-3-((ethoxymethylene)amino)benzoate solution, and then the operation of step S2 is performed; In step S2, the nitrogen oxide catalyst is 2,2,6,6-tetramethylpiperidine; In step S2, the reaction temperature is 50-60°C and the reaction pressure is 0.1-0.2MPa.

2. A method for preparing a benzimidazole pharmaceutical intermediate according to claim 1, characterized in that: In step S1, the molar ratio of methyl 3-amino-2-chlorobenzoate to ethyl formate is 1:(1.0-1.1).

3. The method for preparing a benzimidazole pharmaceutical intermediate according to claim 1, characterized in that: In step S1, the reaction time is 2-3 hours.

4. The method for preparing a benzimidazole pharmaceutical intermediate according to claim 1, characterized in that: In step S1, the solvent is toluene or xylene.

5. The method for preparing a benzimidazole pharmaceutical intermediate according to claim 1, characterized in that: In step S2, the reaction time is 1-5 hours.

6. The method for preparing a benzimidazole pharmaceutical intermediate according to claim 1, characterized in that: The molar ratio of methyl 3-amino-2-chlorobenzoate to 4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonitrile is 1:(1-1.05).

7. The method for preparing a benzimidazole pharmaceutical intermediate according to claim 1, characterized in that: In step S2, the post-treatment operation is: after the reaction is completed, the system is cooled to crystallize, and then solid-liquid separation is performed to obtain the benzimidazole pharmaceutical intermediate.

8. The method for preparing a benzimidazole pharmaceutical intermediate according to claim 7, characterized in that: The final crystallization temperature of the cooling crystallization is 0-10°C, and the crystallization time is 2-3h.

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