A preparation method of a key intermediate bis-imidazole of telmisartan

Abstract

The application belongs to the field of pharmaceutical chemical industry, and particularly relates to a preparation method of a key intermediate bis-imidazole of telmisartan, which comprises the following steps: adding 2,3-diaminotoluene and n-butyl aldehyde into phosphorous acid to generate S-2 compound; reacting S-2 compound with hydrobromic acid and polyformaldehyde to generate S-3 compound; adding S-3 compound into urotropine to generate S-4 compound; and reacting S-4 compound with N-methyl-ortho-phenylenediamine to generate the key intermediate bis-imidazole. The method has the advantages of easy availability of raw materials, greatly reduced cost, short synthesis route, simple operation, high total yield, avoidance of dangerous reactions such as nitration, oxidation and reduction which are explosive and have high heat release, high controllability of production, avoidance of use of polyphosphoric acid or phosphorus pentoxide, mild reaction conditions, simple post-treatment operation and greatly reduced environmental pressure.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical industry, specifically relating to the preparation method of 2-n-propyl-4-methyl-6-(1'-methylbenzimidazole-2-yl)benzimidazole (abbreviated as bisimidazole), a key intermediate of telmisartan, a drug for treating hypertension. Background Technology

[0002] 2-n-propyl-4-methyl-6-(1'-methylbenzimidazole-2-yl)benzimidazole (hereinafter referred to as bisimidazole) is a key intermediate in the synthesis of the antihypertensive drug telmisartan. It is currently the only intermediate in the market for producing telmisartan, and its production capacity directly affects the stable market supply of telmisartan. Telmisartan is an antihypertensive drug of the sartan class developed by Boehringer Ingelheim Pharmaceuticals in Germany. It is mainly used for the treatment of essential hypertension in adults and to reduce the risk of cardiovascular disease. It has good overall drug performance and is a relatively mature angiotensin II receptor antagonist in the market. It is also one of the fastest-growing ARB drugs in recent years, with broad market prospects. The global telmisartan market size exceeded 20 billion yuan in 2022 and is expected to reach 30 billion yuan in 2026. To meet the market demand for telmisartan raw materials, research on the preparation process of the key intermediate telmisartan, bisimidazole, has significant socio-economic value and great market potential. The structural formula of diimidazole is as follows:

[0003] The literature reports two main synthetic processes for diimidazole: Patent EP502314 reports a method for synthesizing diimidazole, which uses methyl 3-methyl-4-aminobenzoate as the starting material, and proceeds through n-butyryl chloride acylation, benzene ring nitration, and then reduction of the nitro group with iron powder to obtain methyl 3-methyl-4-butamido-5-aminobenzoate. Under the action of acetic acid, the cyclization and saponification yield the compound 2-n-propyl-4-methyl-6-carboxybenzimidazole. Then, under the action of polyphosphoric acid (PPA), it reacts with N-methyl-o-phenylenediamine to generate a diimidazole structure, forming the core part of telmisartan, the diimidazole compound diimidazole.

[0004] .

[0005] Patent CN109320461B reports another method for synthesizing diimidazole, using butadiene nitrile as a starting material, reacting it with 3-methyl-4-aminobenzoic acid, the reduction product of 3-methyl-4-nitrobenzoic acid, to generate 3-methyl-4-butyrylimide benzoic acid, which is then oxidized by sodium hypochlorite to obtain the compound 2-n-propyl-4-methyl-6-carboxybenzimidazole, and then reacting it with N-methyl-o-phenylenediamine in the presence of phosphorus pentoxide (P2O5) to obtain diimidazole.

[0006] .

[0007] In summary, the above synthesis processes all involve dangerous reactions such as nitration (nitro group on benzene ring), oxidation (oxidation of sodium hypochlorite), and reduction (nitro group reduction). The production process is highly exothermic and explosive, and the production controllability is low. The materials used have strong oxidizing and corrosive properties, and the iron sludge, waste acid, and wastewater produced are also difficult to treat. All of these factors are not conducive to its industrial mass production. Summary of the Invention

[0008] To overcome the shortcomings of the prior art, this invention provides a method for preparing the key intermediate telmisartan, diimidazole, the technical solution of which is as follows: A method for preparing telmisartan key intermediate diimidazole, comprising the following steps: (1) Preparation of S-2 compound: 2,3-diaminotoluene and n-butyraldehyde were dissolved in ethanol, phosphorous acid was added, and the mixture was stirred and heated to keep warm. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The solvent was concentrated and then recrystallized with acetonitrile to obtain S-2 compound. (2) Preparation of compound S-3: Add hydrobromic acid and paraformaldehyde to compound S-2, stir evenly, add concentrated sulfuric acid dropwise, and after the addition is complete, heat the reaction; after the reaction is complete, cool to room temperature, add drinking water and dichloromethane for extraction, concentrate the solvent, add acetonitrile for recrystallization to obtain compound S-3; (3) Preparation of S-4 compound: Add acetic acid to S-3 compound, then add hexamethylenetetramine, heat to reflux, and keep the reaction at the temperature; after the reaction is completed, cool to room temperature, add water to quench the reaction, extract with ethyl acetate, wash with water, concentrate the solvent, and recrystallize with methanol to obtain S-4 compound; (4) Preparation of the key intermediate 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2-yl)benzimidazole: N-methyl-o-phenylenediamine and isopropanol were added to compound S-4, followed by phosphorous acid. The mixture was heated and stirred. After the reaction was completed, the temperature was lowered, the pH was adjusted with saturated sodium bicarbonate solution, and the mixture was separated. Water was added to the organic phase, and the mixture was cooled to crystallize. The crystals were obtained by filtration and the key intermediate 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2-yl)benzimidazole was obtained. Its synthetic route is as follows: .

[0009] Furthermore, in step (1), the molar ratio of 2,3-diaminotoluene to n-butyraldehyde is 1:0.9 to 1.5.

[0010] Furthermore, in step (1), the reaction temperature is from 50°C to reflux temperature, and the reaction time is 10-15 h; the pH is adjusted to 7-8 using saturated sodium bicarbonate solution.

[0011] Furthermore, in step (2), the molar ratio of compound S-2 to hydrobromic acid is 1:0.9 to 1.5.

[0012] Furthermore, in step (2), the temperature is controlled below 70°C when adding concentrated sulfuric acid; the temperature is then raised to 55-75°C and the reaction is carried out for 8-12 hours.

[0013] Furthermore, in step (3), the molar ratio of compound S-3 to hexamethylenetetramine is 1:0.9 to 2.

[0014] Furthermore, the reaction temperature in step (3) is from 70°C to reflux temperature.

[0015] Furthermore, in step (4), the molar ratio of compound S-4 to N-methyl-o-phenylenediamine is 1:0.9 to 1.5.

[0016] Furthermore, the reaction temperature in step (4) is 65°C to reflux temperature; the temperature is controlled at 70-80°C during separation.

[0017] Furthermore, in step (4), the pH is adjusted to 6.5 using a saturated sodium bicarbonate solution, and the temperature is controlled at 70-80°C.

[0018] Compared with the prior art, the present invention has the following main advantages: 1. This invention uses relatively inexpensive 2,3-diaminotoluene as a starting material, which is readily available and greatly reduces costs.

[0019] 2. The present invention has a short synthetic route, simple operation, and high overall yield.

[0020] 3. This invention avoids dangerous reactions such as nitration, oxidation, and reduction, which are highly exothermic and explosive, and the production process is highly controllable.

[0021] 4. The preparation of S-2 and the preparation of diimidazole by S-4 in this invention adopt phosphorous acid catalytic condensation, which avoids the use of polyphosphoric acid or phosphorus pentoxide, the reaction conditions are mild, the post-processing operation is simple, and the environmental pressure is greatly reduced. Detailed Implementation

[0022] The technical solution of the present invention is illustrated below with specific embodiments, but the scope of protection of the present invention is not limited thereto. The following embodiments are all methods for preparing the key intermediate of telmisartan, memidazole, and are all divided into four steps, each step being listed as a paragraph. In the first step, the solvent is ethanol, and the boiling point of ethanol is 78°C; in the third step, the solvent is acetic acid, and the boiling point is 118°C; in the fourth step, the solvent is isopropanol, and the boiling point is 83°C.

[0023] Example 1 2,3-Diaminotoluene (24.43 g, 0.20 mol) and 18.75 g n-butyraldehyde (18.75 g, 0.26 mol) were dissolved in 500 mL of ethanol, and 1.64 g of phosphorous acid was added. The mixture was stirred and heated to 50 °C and kept at that temperature for 15 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was then extracted twice with 100.00 g x 2 ethyl acetate. The organic phases were combined, washed once with 100.00 g of water, and the ethyl acetate was distilled under reduced pressure. The mixture was then recrystallized from acetonitrile to give 32.58 g of compound S-2, with a yield of 93.5%.

[0024] Compound S-2 (23.18 g, 0.13 mol), 40% hydrobromic acid solution (32.37 g, 0.16 mol), and 4.82 g paraformaldehyde were added to a reaction flask and stirred until homogeneous. 34.5 g of concentrated sulfuric acid was added dropwise (temperature controlled below 70 °C). After the addition was complete, the temperature was raised to 75 °C and the reaction was carried out for 8 hours. The mixture was then cooled to room temperature, and 10.15 g of drinking water and 130.56 g of dichloromethane were added for extraction. The solvent was concentrated, and the mixture was recrystallized with acetonitrile to obtain 30.46 g of compound S-3, with a yield of 87.7%.

[0025] 75 mL of acetic acid and compound S-3 (30.00 g, 0.11 mol) were added to a reaction flask, followed by hexamethylenetetramine (31.48 g, 0.22 mol). The mixture was heated to 70 °C and stirred. After the reaction was complete, the mixture was cooled to room temperature, and 150.00 g of drinking water was added to quench the reaction. The mixture was then extracted twice with 150.00 g of ethyl acetate. The organic phases were combined, washed twice with 100.00 g of drinking water, and the solvent was concentrated under reduced pressure. The mixture was then recrystallized from methanol to obtain 18.98 g of compound S-4, with a yield of 85.30%.

[0026] N-methyl-o-phenylenediamine (11.18 g, 0.1 mol) and compound S-4 (18.50 g, 0.1 mol) were added to 100.00 g of isopropanol, followed by 0.75 g of phosphorous acid. The mixture was heated to reflux and stirred. After the reaction was completed, the temperature was controlled at 70-80 °C and the pH was adjusted to 6.5 with saturated sodium bicarbonate solution. The mixture was then separated at 70-80 °C. 100.00 g of drinking water was added dropwise to the organic phase, and the mixture was cooled to allow crystals to precipitate. The crystals were then filtered to obtain 27.85 g of diimidazole, with a yield of 91.5%.

[0027] Example 2 2,3-Diaminotoluene (24.43 g, 0.20 mol) and n-butyraldehyde (14.45 g, 0.20 mol) were dissolved in 500 mL of ethanol, and 1.64 g of phosphorous acid was added. The mixture was stirred and heated to 60 °C and kept at that temperature for 12 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was then extracted twice with 100.00 g of ethyl acetate. The organic phases were combined, washed once with 100.00 g of water, and the ethyl acetate was distilled under reduced pressure. The mixture was then recrystallized with acetonitrile to give 31.42 g of compound S-2, with a yield of 90.2%.

[0028] Compound S-2 (23.18 g, 0.13 mol), 32.37 g of 40% hydrobromic acid solution (26.30 g, 0.13 mol), and 4.82 g of paraformaldehyde were added to a reaction flask and stirred until homogeneous. 34.5 g of concentrated sulfuric acid was added dropwise (temperature controlled below 70 °C). After the addition was complete, the reaction was carried out at 65 °C for 10 h. The mixture was then cooled to room temperature, and 10.15 g of drinking water and 130.56 g of dichloromethane were added for extraction. The solvent was concentrated, and the mixture was recrystallized with acetonitrile to obtain 29.76 g of compound S-3, with a yield of 85.7%.

[0029] 75 mL of acetic acid and 30.00 g of compound S-3 (30.00 g, 0.11 mol) were added to a reaction flask, followed by hexamethylenetetramine (18.22 g, 0.13 mol). The mixture was heated to 80 °C and stirred. After the reaction was complete, the mixture was cooled to room temperature, and 150.00 g of drinking water was added to quench the reaction. The mixture was then extracted twice with 150.00 g of ethyl acetate. The organic phases were combined, washed twice with 100.00 g of drinking water, and the solvent was concentrated under reduced pressure. The mixture was then recrystallized from methanol to obtain 18.44 g of compound S-4, with a yield of 82.9%.

[0030] 18.32 g (0.15 mol) of N-methyl-o-phenylenediamine and 18.50 g (0.1 mol) of S-4 compound were added to 100.00 g of isopropanol, followed by the addition of 0.75 g of phosphorous acid. The mixture was heated to 70 °C and stirred. After the reaction was complete, the temperature was controlled at 70-80 °C and the pH was adjusted to 6.5 with saturated sodium bicarbonate solution. The mixture was then separated at 70-80 °C. 100.00 g of drinking water was added dropwise to the organic phase, and the mixture was cooled to allow crystals to precipitate. The crystals were then filtered to obtain 28.52 g of diimidazole, with a yield of 93.7%.

[0031] Example 3 2,3-Diaminotoluene (24.43 g, 0.20 mol) and 18.75 g n-butyraldehyde (21.63 g, 0.30 mol) were dissolved in 500 mL of ethanol, and 1.64 g of phosphorous acid was added. The mixture was stirred and refluxed at 75 °C for 10 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was then extracted twice with 100.00 g x 2 ethyl acetate. The organic phases were combined, washed once with 100.00 g of water, and the ethyl acetate was distilled under reduced pressure. The mixture was then recrystallized with acetonitrile to give 32.31 g of compound S-2, with a yield of 92.7%.

[0032] Compound S-2 (23.18 g, 0.13 mol), 40% hydrobromic acid solution (39.44 g, 0.20 mol), and 4.82 g paraformaldehyde were added to a reaction flask and stirred until homogeneous. 34.5 g of concentrated sulfuric acid was added dropwise (temperature controlled below 70 °C). After the addition was complete, the reaction was carried out at 55 °C for 12 h. The mixture was then cooled to room temperature, and 10.15 g of drinking water and 130.56 g of dichloromethane were added for extraction. The solvent was concentrated, and the mixture was recrystallized with acetonitrile to obtain 30.18 g of compound S-3, with a yield of 86.9%.

[0033] 75 mL of acetic acid and 30.00 g of compound S-3 (30.00 g, 0.11 mol) were added to a reaction flask, followed by hexamethylenetetramine (23.13 g, 0.17 mol). The mixture was heated to 100 °C and stirred. After the reaction was complete, the mixture was cooled to room temperature, and 150.00 g of drinking water was added to quench the reaction. The mixture was then extracted twice with 150.00 g of ethyl acetate. The organic phases were combined, washed twice with 100.00 g of drinking water, and the solvent was concentrated under reduced pressure. The mixture was then recrystallized from methanol to obtain 18.51 g of compound S-4, with a yield of 83.2%.

[0034] 10.99 g (0.09 mol) of N-methyl-o-phenylenediamine and 18.50 g (18.50 g, 0.1 mol) of S-4 compound were added to 100.00 g of isopropanol, followed by the addition of 0.75 g of phosphorous acid. The mixture was heated to 65 °C and stirred. After the reaction was completed, the temperature was controlled at 70-80 °C and the pH was adjusted to 6.5 with saturated sodium bicarbonate solution. The mixture was then separated at 70-80 °C. 100.00 g of drinking water was added dropwise to the organic phase, and the mixture was cooled to allow crystals to precipitate. The crystals were then filtered to obtain 27.06 g of diimidazole, with a yield of 88.9%.

[0035] Example 4 2,3-Diaminotoluene (24.43 g, 0.20 mol) and 18.75 g n-butyraldehyde (12.98 g, 0.18 mol) were dissolved in 500 mL of ethanol, and 1.64 g of phosphorous acid was added. The mixture was stirred and refluxed for 10 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was then extracted twice with 100.00 g x 2 ethyl acetate. The organic phases were combined, washed once with 100.00 g of water, and the ethyl acetate was distilled under reduced pressure. The mixture was then recrystallized with acetonitrile to give 30.89 g of compound S-2, with a yield of 88.6%.

[0036] Compound S-2 (23.18 g, 0.13 mol), 40% hydrobromic acid solution (24.28 g, 0.12 mol), and 3.62 g paraformaldehyde were added to a reaction flask and stirred until homogeneous. 34.5 g of concentrated sulfuric acid was added dropwise (temperature controlled below 70 °C). After the addition was complete, the reaction was carried out at 75 °C for 8 h. The mixture was then cooled to room temperature, and 10.15 g of drinking water and 130.56 g of dichloromethane were added for extraction. The solvent was concentrated, and the mixture was recrystallized with acetonitrile to obtain 28.75 g of compound S-3, with a yield of 82.8%.

[0037] 75 mL of acetic acid and 30.00 g of compound S-3 (30.00 g, 0.11 mol) were added to a reaction flask, followed by hexamethylenetetramine (14.02 g, 0.10 mol). The mixture was heated to reflux and stirred. After the reaction was complete, the mixture was cooled to room temperature, and 150.00 g of drinking water was added to quench the reaction. The mixture was then extracted twice with 150.00 g of ethyl acetate. The organic phases were combined, washed twice with 100.00 g of drinking water, and the solvent was concentrated under reduced pressure. The mixture was then recrystallized from methanol to obtain 18.12 g of compound S-4, with a yield of 81.4%.

[0038] N-methyl-o-phenylenediamine (14.63 g, 0.12 mol) and S-4 compound (18.50 g, 0.1 mol) were added to 100.00 g of isopropanol, followed by 0.75 g of phosphorous acid. The mixture was heated to reflux and stirred. After the reaction was completed, the temperature was controlled at 70-80 °C and the pH was adjusted to 6.5 with saturated sodium bicarbonate solution. The mixture was then separated at 70-80 °C. 100.00 g of drinking water was added dropwise to the organic phase, and the mixture was cooled to allow crystals to precipitate. The crystals were then filtered to obtain 27.85 g of diimidazole, with a yield of 91.5%.

Claims

1. A method for preparing diimidazole, a key intermediate of telmisartan, characterized in that, Includes the following steps: (1) Preparation of S-2 compound: 2,3-diaminotoluene and n-butyraldehyde were dissolved in ethanol, phosphorous acid was added, and the mixture was stirred and heated to keep warm. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The solvent was concentrated and then recrystallized with acetonitrile to obtain S-2 compound, wherein the molar ratio of 2,3-diaminotoluene to n-butyraldehyde was 1:0.9 to 1.

5. (2) Preparation of compound S-3: Add hydrobromic acid and paraformaldehyde to compound S-2, stir evenly, add concentrated sulfuric acid dropwise, and after the addition is complete, heat the reaction; after the reaction is complete, cool to room temperature, add drinking water and dichloromethane for extraction, concentrate the solvent, add acetonitrile for recrystallization to obtain compound S-3; (3) Preparation of S-4 compound: Add acetic acid to S-3 compound, then add hexamethylenetetramine, heat to reflux, and keep the reaction at the temperature; after the reaction is completed, cool to room temperature, add water to quench the reaction, extract with ethyl acetate, wash with water, concentrate the solvent, and recrystallize with methanol to obtain S-4 compound; (4) Preparation of the key intermediate 2-n-propyl-4-methyl-6-(1'-methylbenzimidazole-2-yl)benzimidazole: N-methyl-o-phenylenediamine and isopropanol were added to the S-4 compound, followed by the addition of phosphorous acid. The mixture was heated and stirred. After the reaction was completed, the temperature was lowered, the pH was adjusted with saturated sodium bicarbonate solution, and the mixture was separated. Water was added to the organic phase, and the mixture was cooled to crystallize. The crystals were obtained by filtration and the key intermediate 2-n-propyl-4-methyl-6-(1'-methylbenzimidazole-2-yl)benzimidazole, abbreviated as bisimidazole, wherein the molar ratio of the S-4 compound to N-methyl-o-phenylenediamine was 1:0.9 to 1.

5. Its synthetic route is as follows: 。 2. The method for preparing the key intermediate telmisartan, memidazole, according to claim 1, is characterized in that, In step (1), the reaction temperature is from 50°C to reflux temperature, and the reaction time is 10-15 h; the pH is adjusted to 7-8 using saturated sodium bicarbonate solution.

3. The method for preparing the key intermediate telmisartan, memidazole, according to claim 1, is characterized in that, In step (2), the molar ratio of compound S-2 to hydrobromic acid is 1:0.9 to 1.

5.

4. The method for preparing the key intermediate telmisartan, memidazole, according to claim 1, is characterized in that, In step (2), the temperature is controlled below 70°C when adding concentrated sulfuric acid; the temperature is then raised to 55-75°C and the reaction is carried out for 8-12 hours.

5. The method for preparing the key intermediate telmisartan, memidazole, according to claim 1, characterized in that, In step (3), the molar ratio of compound S-3 to hexamethylenetetramine is 1:0.9 to 2.

6. The method for preparing the key intermediate telmisartan, memidazole, according to claim 1, is characterized in that, The reaction temperature in step (3) is from 70°C to reflux temperature.

7. The method for preparing the key intermediate telmisartan, memidazole, according to claim 1, is characterized in that, The reaction temperature in step (4) is 65°C to reflux temperature; the temperature is controlled at 70-80°C during separation.

8. The method for preparing the key intermediate telmisartan, memidazole, according to claim 1, is characterized in that, In step (4), the pH is adjusted to 6.5 using a saturated sodium bicarbonate solution, and the temperature is controlled at 70-80℃.

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