A process for the preparation of telmisartan

Abstract

The application relates to a preparation method of telmisartan, and belongs to the field of medicine and chemical industry. The scheme comprises the following steps: reacting starting materials 1 and 2-cyano-4'-bromomethyl biphenyl to obtain compound 2, constructing an imidazole ring, reducing, hydrolyzing and finally obtaining telmisartan. The content of impurity B can be effectively reduced through the method, the content of impurity B can be effectively reduced through the preparation method, the purity of telmisartan is improved, the refining frequency is reduced, the reaction condition is mild, the post-treatment operation is simple, the total yield can reach more than 85%, and the method is more suitable for large-scale industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemical industry, and relates to a preparation method of a hypertension treatment drug, telmisartan, and an intermediate thereof. BACKGROUND

[0002] Telmisartan is a sartan antihypertensive drug developed by Boehringer in Germany. It has a long half-life and belongs to a long-acting antihypertensive drug. It is mainly used for the treatment of mild to moderate hypertension patients. Telmisartan has high lipophilicity, high membrane permeability, and high plasma protein binding rate. It has good comprehensive performance of the drug. It is a class of angiotensin II receptor antagonists that are more mature in market use. It is also the ARB drug with the fastest growth rate in market sales in recent years. Therefore, telmisartan has a broad market prospect. In 2022, the global telmisartan market size exceeded 20 billion yuan, and it is expected to reach 30 billion yuan in 2026. In order to meet the demand for telmisartan raw materials and ensure the supply, the process research on the key intermediate of telmisartan has important social and economic value and great market prospect.

[0003] Telmisartan is chemically 4-{[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1-yl]methyl}diphenyl-2-carboxylic acid. Its structural formula is

[0004]

[0005] Patents EP0502314 and WO2004087676 first reported a synthesis method of telmisartan. In this route, 4-amino-3-methyl-benzoic acid methyl ester is used as a raw material to undergo nucleophilic reaction with n-butyryl chloride. The generated reactant undergoes nitration reaction in the presence of sulfuric acid and nitric acid. Then, the nitro group is reduced to an amino group by Pt / C catalytic hydrogenation. Then, the reaction is refluxed in the presence of ice acetic acid as a solvent to form a benzimidazole ring. Then, hydrolysis reaction occurs in a methanol and sodium hydroxide system. The hydrolysis product undergoes nucleophilic reaction with methyl o-phenylenediamine to generate a key intermediate of telmisartan. Tert-butyl alcohol potassium is used as a catalyst to react with 4-bromomethylbiphenyl-2-carboxylic acid tert-butyl ester. The generated compound undergoes hydrolysis reaction to obtain telmisartan. The specific synthesis route is shown below.

[0006]

[0007] This route has a long synthesis step and low total yield. The yield of the synthesis of the bis-imidazole ring is less than 60%. The reaction temperature is high. Trifluoroacetic acid is used as a catalyst and participates in the hydrolysis. The reaction is slow. In addition, 4-bromomethylbiphenyl-2-carboxylic acid tert-butyl ester is very easy to hydrolyze under acidic conditions. The operation difficulty coefficient is high, which limits the industrial application of this process.

[0008] Patent CN1412183 reports a synthesis method of telmisartan, which is improved on the basis of route one, by converting the nitrile group into carboxyl group, using bis-imidazole intermediate and 4-bromomethyl biphenyl-2-carbonitrile to react, the generated compound is hydrolyzed to obtain telmisartan, the route is shown below.

[0009]

[0010] This synthesis route only improves the hydrolysis of tert-butyl ester to carboxylic acid to nitrile group, which is not much improved, in addition, impurity A is easily produced during the condensation of bis-imidazole intermediate and bromomethyl biphenyl, impurity A and telmisartan have similar structure and polarity, which is not easy to remove, affecting the quality of the drug substance.

[0011] Patent CN101024631 reports a synthesis route, 3-methyl-4-amino-benzoic acid methyl ester is subjected to N-acylation, the reactants are subjected to nitration under the action of mixed acid, then subjected to Pt / C catalytic hydrogenation to reduce the nitro group to amino group, then subjected to reflux in glacial acetic acid as solvent to form a benzimidazole ring, then subjected to hydrolysis reaction in a methanol-sodium hydroxide system, the hydrolysis product is subjected to reaction under the action of thionyl chloride to generate 2-n-propyl-4-methyl-6-methyl chloroformate benzimidazole, 2-n-propyl-4-methyl-6-methyl chloroformate benzimidazole is reacted with N-methyl o-phenylenediamine hydrochloride, and an organic base is used as a catalyst to generate an unclosed telmisartan intermediate, then reacted with 4-bromomethyl biphenyl-2-carboxylic acid tert-butyl ester, and finally ring-closed to obtain telmisartan, the specific synthesis route is shown below.

[0012]

[0013] This process avoids high temperature reaction conditions by synthesizing acyl chloride and then ring-closing, reduces energy consumption, and makes the reaction conditions moderate, but the process impurities are not easy to control, the process steps are longer, the yield is lower, and the production cost is increased, which is not conducive to industrialization.

[0014] Overall, the existing process uses the condensation method of imidazole ring and bromomethyl biphenyl, which easily produces isomer impurity B, and the amplification effect is obvious, with the amplification of industrialization batch, the content is higher and higher, laboratory hundred gram scale can reach about 3%, pilot tens of kilograms scale can reach about 5%, industrialization hundred kilograms scale can reach more than 10%, and the limit of Japanese Pharmacopoeia is not higher than 0.10%. The impurity has similar structure to telmisartan, and is produced in the later step of drug substance production, which is very difficult to remove, so the product needs to be refined multiple times to meet the requirements of the Pharmacopoeia, resulting in low product yield and low production rate.

[0015]

[0016] In addition, the existing process steps are long, the industrial production operation is difficult, the treatment of three wastes is difficult, the yield of the key reaction is low, and the cost of the route is still high, so it is still necessary to find a method for synthesizing telmisartan with a simple process route, low cost and suitable for industrial production. SUMMARY

[0017] The present application provides a preparation method of telmisartan with controllable impurity B, short steps and high yield.

[0018] The technical concept of the present application: The preparation of telmisartan in the present application is by directly condensing 3-methyl-4-nitro-5-acetylamino benzoic acid methyl ester and 2-cyano-4'-bromomethyl biphenyl, then constructing an imidazole ring, greatly controlling the generation of isomer impurity B, reducing the number of product refining times, and improving the reaction yield. And by constructing new intermediate compounds 2 and 4, the experimental conditions are optimized, the yield of each reaction and the separation purity of the intermediate are improved. These improvements greatly improve the efficiency of the route, further reduce the process cost, reduce the generation of by-products and benefit the improvement of the purity of the final product. The process route has reduced steps and simple operation, not only has high yield, but also high purity of the obtained product, and is more suitable for industrial production. The reaction route is as follows:

[0019]

[0020] The specific scheme of the present application includes the following steps:

[0021] Step 1: The starting material 1 is reacted with 2-cyano-4'-bromomethyl biphenyl to obtain compound 2;

[0022] Step 2: Compound 2 is reacted with N-methyl o-phenylenediamine under the condition of polyphosphoric acid to obtain compound 3;

[0023] Step 3: Compound 3 is subjected to a reduction reaction to obtain compound 4;

[0024] Step 4: Compound 4 is reacted with triethyl orthobutyrate to obtain compound 5;

[0025] Step 5: Compound 5 is hydrolyzed under alkaline conditions to obtain telmisartan.

[0026] To achieve the purpose of the application, one of the purposes of the present application provides an intermediate compound 2 for preparing telmisartan and a synthesis method thereof, and the structural formula of the compound 2 is as follows:

[0027]

[0028] The synthesis method of the intermediate compound 2 of telmisartan is that the starting material 1 and 2-cyano-4'-bromomethyl biphenyl are added into a reaction bottle, an organic solvent and a basic reagent are added, the reaction temperature is controlled to be not more than 30 DEG C, after the reaction is completed, the temperature is lowered to precipitate crystals, and the compound 2 is obtained;

[0029]

[0030] The reaction temperature of the first step is controlled to be 20-30 DEG C, and after the reaction is completed, the temperature is lowered to 0-5 DEG C to precipitate crystals;

[0031] The organic solvent is acetone, acetonitrile or DMF;

[0032] The basic reagent is potassium hydroxide or potassium carbonate.

[0033] The second object of the present application provides an intermediate compound 4 for preparing telmisartan and a synthesis method thereof, and the structural formula of the compound 4 is as follows:

[0034]

[0035] The synthesis method of the intermediate compound 4 of telmisartan is that polyphosphoric acid is added into a reaction bottle, the compound 2 is added in batches, N-methyl o-phenylenediamine is finally added, the temperature is raised to not more than 150 DEG C to react, the compound 3 is obtained, the compound 3 is then put into a high-pressure reaction kettle, water-containing organic solvent or water, potassium hydroxide and platinum carbon are added, the reaction kettle is closed, the temperature is controlled to react for a period of time, then the temperature is lowered, hydrogen is introduced to reduce, and the compound 4 is obtained;

[0036]

[0037] The third object of the present application also provides a synthesis method of a key precursor compound 5 of telmisartan: the compound 4, N,N-dimethylformamide, triethyl orthobutyrate, methanesulfonic acid or glacial acetic acid are put into a reaction bottle, stirring and temperature rising are carried out to react, after the reaction is completed, the temperature is lowered to precipitate crystals, vacuum filtration is carried out, drying is carried out, and the white solid compound 5 is obtained.

[0038]

[0039] The fourth object of the present application is the preparation of telmisartan: the compound 5, industrial ethanol and potassium hydroxide are put into a reaction kettle, 155±5 DEG C is reacted for 25 h, then the temperature is lowered, the reaction liquid is acidified with glacial acetic acid, the temperature is lowered to 20-30 DEG C, crystals are precipitated for 3 h, vacuum filtration is carried out, and drying is carried out.

[0040]

[0041] Beneficial effects: the present application provides a preparation method of telmisartan, which has the following advantages compared with the prior art: firstly, the change of cyclization mode fundamentally avoids the generation of regioisomer impurities and reduces the generation of impurity B; secondly, the intermediates in the preparation method are easy to purify, the reaction conditions are mild, the post-treatment operation is simple, and the total yield can reach more than 85%, which is more suitable for large-scale industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0042] Figure 1 Telmisartan high performance liquid chromatogram DETAILED DESCRIPTION

[0043] The principles and characteristics of the present application are described below, and the embodiments are used to further explain the present application, but do not limit the scope of the present application.

[0044] 1. Put 3-methyl-4-nitro-5-acetylamino benzoic acid methyl ester (100 g, 396.5 mmol), 90% acetone (600.0 g), 2-cyano-4'-bromomethyl biphenyl (107.9 g, 396.5 mmol), potassium hydroxide (34.9 g, 872.3 mmol) into a 2L reaction bottle, open the stirring, and control the temperature not to exceed 30°C during the process. Stir for 2h under temperature control of 20~30°C. After the reaction is completed, cool to 0~5°C, and keep the temperature for 2h for crystallization. Filter, and place the filter cake at 80°C for air drying to obtain white or white-like powder, with a yield of 95.7% and a purity (HPLC) ≥98.0%.

[0045] 2. Put 3-methyl-4-nitro-5-acetylamino benzoic acid methyl ester (100 g, 396.5 mmol), DMF (300.0 g), 2-cyano-4'-bromomethyl biphenyl (105.7 g, 388.6 mmol), potassium hydroxide (34.9 g, 872.3 mmol) into a 2L reaction bottle, open the stirring, and control the temperature not to exceed 30°C during the process. Stir for 3h under temperature control of 20~30°C. After the reaction is completed, add drinking water (600.0 g), cool to 0~5°C, and keep the temperature for 2h for crystallization. Filter, and place the filter cake at 80°C for air drying to obtain white or white-like powder, with a yield of 92.2% and a purity (HPLC) ≥98.5%.

[0046] 3. Into a 2L reaction flask, put 3-methyl-4-nitro-5-acetylamino benzoic acid methyl ester (100 g, 396.5 mmol), 90% acetonitrile (600.0 g), 2-cyano-4'-bromomethyl biphenyl (107.9 g, 396.5 mmol), potassium hydroxide (34.9 g, 872.3 mmol), open the stirring, control the temperature not more than 30°C during the process. Stirring reaction for 2h under temperature control of 20~30°C. After the reaction is completed, cool to 0~5°C, and keep for 4h. Filter, and filter cake is placed at 80°C for air drying to get white or white-like powder, with a yield of 95.1% and purity (HPLC) ≥98.0%.

[0047] 4. Into a 2L reaction flask, put 3-methyl-4-nitro-5-acetylamino benzoic acid methyl ester (100 g, 396.5 mmol), 90% acetonitrile (600.0 g), 2-cyano-4'-bromomethyl biphenyl (107.9 g, 396.5 mmol), potassium hydroxide (34.9 g, 872.3 mmol), open the stirring, control the temperature not more than 30°C during the process. Stirring reaction for 2h under temperature control of 20~30°C. After the reaction is completed, cool to 0~5°C, and keep for 4h. Filter, and filter cake is placed at 80°C for air drying to get white or white-like powder, with a yield of 95.1% and purity (HPLC) ≥98.0%.

[0048] 1. Into a 2L four-port reaction flask, add polyphosphoric acid (300.0 g), and heat to 70~90°C, and open the stirring; add compound 2 (100 g, 232.8 mmol) in batches, after adding, control the temperature to 90~100°C, and drop N-methyl-phenylenediamine (28.5 g, 232.8 mmol); after adding, control the temperature to 140~150°C, and react for 20h. After the reaction is completed, cool to 90~100°C, drop drinking water (144.0 g), cool to 70~80°C, add isopropyl alcohol (600.0 g), drop 42% liquid alkali (520.0 g), adjust the pH to 6.5~7.0, and adjust to return to flow after dissolving; separate the liquid, take the organic phase (upper layer), transfer into a 2L four-port reaction flask, control the temperature to 70~80°C, and slowly drop drinking water (720.0 g). After the drop is completed, cool to 10-20°C, stir for 1h, filter, and filter cake is reserved.

[0049] Put the above filter cake into a 2L high-pressure reaction kettle, put industrial ethanol (300.0 g), potassium hydroxide (9.3 g, 232.8 mmol), and 1% platinum carbon (1.0 g), close the reaction kettle, control the temperature to 80~90°C, and react for 2h; cool to 50~60°C, and reduce by hydrogen gas, until the hydrogen pressure no longer decreases. After the reaction is completed, the liquid is put into a 2L reaction flask, cool to 0~10°C, and stir for 2h. Filter, and filter cake is air-dried at 60°C to get yellow or white-like powder, with a yield of 94.6% and purity (HPLC) ≥99.0%.

[0050] 2. Into a 2L four-necked flask, add polyphosphoric acid (300.0g), heat to 70~90℃, and start stirring; add compound 2 (100g, 232.8mmol) in batches, and after addition, control the temperature at 90~100℃, and drop N-methyl-phenylenediamine (27.9g, 228.1mmol); after addition, control the temperature at 140~150℃, and react for 20h. After completion of the reaction, cool to 90~100℃, drop drinking water (144.0g), cool to 70~80℃, add isopropyl alcohol (600.0g), drop 42% liquid alkali (520.0g), adjust the pH to 6.5~7.0, and after adjustment, reflux to dissolve; separate, take the organic phase (upper layer), transfer into a 2L four-necked flask, control the temperature at 70~80℃, and slowly drop drinking water (720.0g). After completion of the dropping, cool to 10~20℃, stir for 1h, filter, and the filter cake is ready for use.

[0051] Put the filter cake into a 2L high-pressure reaction kettle, add 80% methanol (300.0g), potassium hydroxide (9.3g, 232.8mmol), and 1% platinum carbon (1.0g), close the reaction kettle, control the temperature at 70~80℃, and react for 3h; cool to 50~60℃, and reduce by hydrogen until the hydrogen pressure no longer decreases. After completion of the reaction, transfer the liquid into a 2L flask, cool to 0~10℃, and stir for 2h. Filter, and the filter cake is dried at 60℃ under air blast to obtain a yellow or white powder with a yield of 95.4% and a purity (HPLC) ≥99.0%.

[0052] 3. Into a 2L four-necked flask, add polyphosphoric acid (300.0g), heat to 70~90℃, and start stirring; add compound 2 (100g, 232.8mmol) in batches, and after addition, control the temperature at 90~100℃, and drop N-methyl-phenylenediamine (27.9g, 228.1mmol); after addition, control the temperature at 140~150℃, and react for 20h. After completion of the reaction, cool to 90~100℃, drop drinking water (144.0g), cool to 70~80℃, add isopropyl alcohol (600.0g), drop 42% liquid alkali (520.0g), adjust the pH to 6.5~7.0, and after adjustment, reflux to dissolve; separate, take the organic phase (upper layer), transfer into a 2L four-necked flask, control the temperature at 70~80℃, and slowly drop drinking water (720.0g). After completion of the dropping, cool to 10~20℃, stir for 1h, filter, and the filter cake is ready for use.

[0053] Put the filter cake into a 2L autoclave, add drinking water (300.0 g), potassium hydroxide (9.3 g, 232.8 mmol), 1% platinum carbon (1.0 g), close the autoclave, control the temperature at 80-90°C and react for 4 h; reduce by hydrogen until the hydrogen pressure no longer decreases. After the reaction is completed, the liquid is poured into a 2L reaction bottle, cooled to 0-10°C, and stirred for 2 h. Filter, filter cake at 60°C, and dry by blowing, to obtain a white to yellow solid, with a yield of 93.6% and a purity (HPLC) ≥98.0%.

[0054] 4. Add polyphosphoric acid (300.0 g) to a 2L four-port reaction bottle, heat to 70-90°C, and start stirring; add compound 2 (100 g, 232.8 mmol) in batches, after adding, control the temperature at 90-100°C, and add N-methyl-phenylenediamine (27.9 g, 228.1 mmol) dropwise; after adding, control the temperature at 140-150°C and react for 20 h. After the reaction is completed, cool to 90-100°C, add drinking water (144.0 g) dropwise, cool to 70-80°C, add isopropyl alcohol (600.0 g), add 42% liquid alkali (520.0 g) dropwise, adjust the pH to 6.5-7.0, and dissolve completely under reflux; separate the liquid, take the organic phase (upper layer), transfer into a 2L four-port reaction bottle, control the temperature at 70-80°C, and slowly add drinking water (720.0 g) dropwise. After the addition is completed, cool to 10-20°C, stir for 1 h, filter, and reserve the filter cake.

[0055] Put the filter cake into a 2L autoclave, add 80% ethanol (300.0 g), potassium hydroxide (9.3 g, 232.8 mmol), 1% platinum carbon (1.0 g), close the autoclave, control the temperature at 80-90°C and react for 2 h; cool to 50-60°C, reduce by hydrogen until the hydrogen pressure no longer decreases. After the reaction is completed, the liquid is poured into a 2L reaction bottle, cooled to 0-10°C, and stirred for 2 h. Filter, filter cake at 60°C, and dry by blowing, to obtain a yellow powder, with a yield of 92.4% and a purity (HPLC) ≥99.0%.

[0056] 1. Add compound 4 (100.0 g, 225.5 mmol) to a 2L reaction bottle, N,N-dimethylformamide (300.0 g), triethyl orthobutyrate (43.7 g, 230.0 mmol), methyl sulfonic acid (100.0 g), stir, and heat to 70°C, and react for 8 h. After the reaction is completed, cool in an ice water bath for 2 h, and filter under reduced pressure. Dry the wet product at 80°C to obtain a white solid (compound 5), with a yield of 95.1% and a purity (HPLC) ≥99.5%.

[0057] 2. Into a 2L reaction flask, compound 4 (100.0 g, 225.5 mmol), N,N-dimethylformamide (300.0 g, ), triethyl orthobutyrate (43.1 g, 225.5 mmol), methyl sulfonic acid (100.0 g) were charged. The mixture was stirred and warmed to 90°C. The reaction was allowed to proceed for 6h. The reaction was completed. The mixture was cooled in an ice water bath for 2h. The mixture was filtered under reduced pressure. The wet product was dried at 80°C to give a white solid (compound 5) in a yield of 95.1% and a purity (HPLC) ≥ 99.5%.

[0058] Into a 2L autoclave, industrial ethanol (600 g), telmisartan nitrile (100 g, 201.7 mmol), potassium hydroxide (56.5 g, 1005 mmol) were charged in sequence. The autoclave was closed, the stirring was started, and the nitrogen was introduced to check the airtightness. The nitrogen was used to replace the air in the autoclave for 3 times. The autoclave was evacuated and the valves were closed. The heating was started and the temperature was raised to 150°C. The temperature was maintained at 155±5°C for 25h. The reaction was completed. The temperature was lowered to 50-60°C. The mixture was transferred to a 2L reaction flask. The temperature was controlled at 60-70°C. Glacial acetic acid (100.1 g, 1674 mmol) was added dropwise. The mixture was stirred for 0.5h after the addition was completed. The temperature was lowered to 20-30°C. The mixture was crystallized for 3h. The mixture was filtered. The filter cake was slurried with purified water (1000 g) at 20-30°C for 1h. The mixture was filtered. The wet product was dried at 80-100°C for 8h to give a white or off-white powder in a yield of 96.7% and a purity (HPLC) ≥ 99.8%. The high performance liquid chromatogram is shown in Figure 1 .

Claims

1. A process for the preparation of telmisartan, characterized in that The method comprises the following steps: The first step: the starting material 1 and 2-cyano-4'-bromomethyl biphenyl are added to a reaction bottle, and an organic solvent and a basic reagent are added, and the reaction temperature is controlled to be not more than 30 DEG C, and after the reaction is completed, the temperature is lowered to obtain compound 2; The second step: the reaction bottle is added with polyphosphoric acid, and then compound 2 is added in batches, and finally N-methyl phenylenediamine is added, and the temperature is raised to not more than 150 DEG C for reaction; The third step: compound 3 is put into a high-pressure reaction kettle, and water-containing organic solvent or water, potassium hydroxide and platinum carbon are added, the reaction kettle is closed, the temperature is controlled for a period of time, then the temperature is lowered, hydrogen is introduced for reduction, and compound 4 is obtained; The fourth step: compound 4, N,N-dimethylformamide, triethyl orthobutyrate, methanesulfonic acid or glacial acetic acid are put into a reaction bottle, stirring and temperature rising are carried out, after the reaction is completed, the temperature is lowered to obtain compound 5, which is white solid, and then vacuum filtration and drying are carried out; The fifth step: compound 5, industrial ethanol and potassium hydroxide are put into a reaction kettle, and reaction is carried out at 155 DEG C for 25h, then the temperature is lowered, the reaction liquid is acidified with glacial acetic acid, the temperature is lowered to 20-30 DEG C, crystallization is carried out for 3h, and then filtration and drying are carried out. 。 2. The method of claim 1, wherein: The reaction temperature of the first step is 20-30 DEG C, and the temperature is lowered to 0-5 DEG C for crystallization; the organic solvent is acetone, acetonitrile or DMF; and the basic reagent is potassium hydroxide or potassium carbonate.

3. The method of claim 1, wherein The reaction temperature of the second step is 140-150 DEG C, and after the reaction is completed, isopropyl alcohol and water are added to the reaction liquid, the pH is adjusted to 6.5-7.0 by using liquid alkali, organic phase is extracted, water is added dropwise, the temperature is lowered to 10-20 DEG C, and then solid compound 3 is obtained by filtration.

4. The method of claim 1, wherein The water-containing organic solvent of the third step is water-containing methanol or water-containing ethanol, the temperature is controlled to 70-90 DEG C for 1-4h, and then the temperature is lowered to 50-60 DEG C for hydrogen introduction.

5. The method of claim 1, wherein The reaction temperature of the fourth step is 70 DEG C-90 DEG C, and the reaction is carried out for 8-12h.

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