Telmisartan intermediate and preparation method thereof
By using specific condensing agents and alkaline reagents in the preparation process of telmisartan intermediates, combined with the treatment of acidic reagents, the problems of high pollution and high cost in the prior art are solved, and an efficient, environmentally friendly and safe preparation method is achieved.
Patent Information
- Application Number
- CN202311521485.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-11-15
- Publication Date
- 2025-05-27
AI Technical Summary
The existing preparation method of the telmisartan intermediate 2-n-propyl-4-methyl-6-(1'-methylbenzimidazole-2-yl)benzimidazole has problems such as high pollution, serious environmental pollution, high production costs, and high equipment corrosion.
The reaction is carried out in the presence of a condensation agent and an alkaline reagent, and then in the presence of an acidic reagent, triazine-based condensation agent and suitable reaction conditions to avoid the use of highly contaminating reagents.
It achieves mild reaction conditions, high yield and high purity products, reduces environmental pollution and production costs, reduces equipment corrosion risks, and is suitable for mass production.
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Abstract
Description
Technical Field
[0001] The present invention relates to the field of chemical pharmaceuticals, and relates to a preparation method of 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2-yl)benzimidazole, an intermediate of telmisartan. Background Art
[0002] Telmisartan is a specific angiotensin II receptor antagonist, mainly used for reducing blood pressure, and can also be used for patients (aged 55 and above) who are at high risk of serious cardiovascular events and cannot receive angiotensin-converting enzyme (ACE) inhibitor treatment, to reduce the risk of myocardial infarction, stroke, or death due to cardiovascular disease. It is a commonly used drug for reducing blood pressure.
[0003] Molecular formula of telmisartan: C 33 H 30 N 4 O 2 ; CAS No.: 144701-48-4; Chemical name: 4'-[[4-methyl-6-(l-methyl-2-benzimidazolyl)-2-propyl-1-benzimidazolyl]methyl]-2-biphenylcarboxylic acid; The molecular structural formula is as follows:
[0004]
[0005] 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2-yl)benzimidazole is an important intermediate for preparing telmisartan, and its structural formula is as follows: Using 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2-yl)benzimidazole as the starting material to prepare telmisartan, the impurity research is sufficient, the synthesis process is simple, and the cost is low.
[0006] The most widely used preparation method of 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2-yl)benzimidazole is cyclization from 2-n-propyl-4-methyl-6-carboxybenzimidazole and N-methyl-o-phenylenediamine or its salt under the condition of polyphosphoric acid (PPA), as follows:
[0007]
[0008] The advantage of this method is that the cost of reaction reagents is low, and the defect is that the generated polyphosphoric acid system seriously pollutes the environment, the environmental protection treatment cost is high, resulting in a high potential production cost.
[0009] In addition, the widely used condition is to use acylating reagents such as thionyl chloride and phosphorus oxychloride, and the disadvantage is that a large amount of waste gas and waste water are generated, which is corrosive to production equipment.
[0010] There are many other synthesis conditions, but the cost advantage of the reagents used is not significant, the treatment cost of the waste liquid and wastewater generated is high, the reaction conditions are mostly high-temperature conditions, the reaction time is long, the energy consumption is high; the reaction conditions are harsh, and the requirements for equipment are high, etc.
[0011] Therefore, there is an urgent need for a preparation method of 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2-yl)benzimidazole with mild reaction conditions, high yield, and less environmental pollution. Summary of the Invention
[0012] In view of the above deficiencies of the prior art, the present invention provides a synthesis method of the telmisartan intermediate 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2-yl)benzimidazole. The technical solution of the present invention is as follows:
[0013] A preparation method of 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2-yl)benzimidazole, the preparation method comprising the following steps:
[0014] (1) Using 2-n-propyl-4-methyl-6-carboxybenzimidazole and N-methyl-o-phenylenediamine or its salt as raw materials, reacting in a reaction solvent in the presence of a condensing agent and a basic reagent;
[0015] (2) Then reacting in the presence of an acidic reagent to obtain 2-n-propyl-4-methyl-6-(1'-methyl-benzimidazol-2-yl)benzimidazole.
[0016] Further, the condensing agent described in step (1) is selected from triazine-based condensing agents.
[0017] Further, the triazine-based condensing agent described in step (1) is selected from one or more of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT),
[0018] 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (DMTMM), 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride), 2-chloro-4,6-diphenyl-1,3,5-triazine, 2-chloro-4,6-di-p-tolyl-1,3,5-triazine, 2-chloro-4,6-bis(ethylamino)-1,3,5-triazine, 2-chloro-4,6-bis(isopropylamino)-1,3,5-triazine;
[0019] Preferably, the triazine-based condensing agent is selected from one or more of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) or 4-(4,6-dimethoxy-1,3,5,-triazin-2-yl)-4-methylmorpholine hydrochloride (DMTMM).
[0020] Furthermore, the molar ratio of 2-n-propyl-4-methyl-6-carboxybenzimidazole to the triazine condensing agent in step (1) is 1:1.0 - 2.0, preferably 1:1.1 - 1.5, and more preferably 1:1.2 - 1.4.
[0021] Furthermore, the basic reagent in step (1) is selected from one or more of N-methylmorpholine, triethylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, DMAP, and DBU; preferably, the basic reagent is selected from one or more of N-methylmorpholine and triethylamine;
[0022] Furthermore, the molar ratio of the 2-n-propyl-4-methyl-6-carboxybenzimidazole to the basic reagent is 1:0.5 - 5, preferably 1:0.8 - 4 or 1:1 - 3.
[0023] Furthermore, the reaction temperature in step (1) is -20°C to 40°C, preferably 0°C to 30°C, and more preferably 10 - 30°C.
[0024] Furthermore, the reaction time in step (1) is 0.5 - 4 hours, preferably 1 - 3 hours.
[0025] Furthermore, the reaction solvent in step (1) is selected from C1-4 alkyl alcohols; preferably, the reaction solvent is one or more of methanol, ethanol, n-propanol, and 2-propanol.
[0026] Furthermore, step (1) also includes the steps of separating the product and / or purifying after the reaction ends;
[0027] Preferably, the separated product is to separate the solid product in the reaction system by centrifugation, filtration, or water precipitation crystallization;
[0028] More preferably, the separated product is by water precipitation crystallization;
[0029] Even more preferably, the weight ratio of 2-n-propyl-4-methyl-6-carboxybenzimidazole to water is 1:10 - 20;
[0030] Even more preferably, the weight ratio of 2-n-propyl-4-methyl-6-carboxybenzimidazole to water is 1:14 - 16.
[0031] Furthermore, the acidic reagent in step (2) is selected from C1-4 carboxylic acids and C1-4 halo-carboxylic acids; preferably formic acid, acetic acid, propionic acid, butyric acid, and trifluoroacetic acid.
[0032] Furthermore, the reaction temperature in step (2) is 50 - 100°C, preferably 60 - 90°C.
[0033] Further, the reaction time of step (2) is 1 to 4 hours, preferably 2 to 3 hours.
[0034] In a particular embodiment, step (2) is terminated by adding water and sodium hydroxide solution to the reaction system, followed by filtration and drying to obtain 2-n-propyl-4-methyl-6-(1'-methyl-benzimidazol-2-yl) benzimidazole product.
[0035] Advantages of the present invention:
[0036] (1) Avoid using highly polluting reagents such as thionyl chloride and phosphorus oxychloride. The waste water and waste liquid generated by the process are easy to treat, reducing potential environmental protection treatment costs and pollution.
[0037] (2) The reaction conditions are mild, with little corrosion to equipment, few restrictions, and easy to scale up for mass production; the reaction time is short, avoiding high temperature, high pressure and long-time reactions, and the operation is safe.
[0038] (3) The product has high purity, purity > 98.5%; high yield, molar yield 90 - 95%.
[0039] (4) The reagents used are simple and easily available, and the cost proportion is small. Detailed implementation mode
[0040] The following examples are used to further explain the present invention, but the examples do not limit the present invention in any form.
[0041] In the said embodiment, the reaction formula is:
[0042]
[0043] Example 1
[0044] 874 g of methanol was added to a reaction flask, followed by 2-n-propyl-4-methyl-6-carboxybenzimidazole (0.5 mol, 109 g), 196 g of DMTMM (about 0.6 mol, containing water), and N-methyl-o-phenylenediamine hydrochloride (0.55 mol, 107 g). Under the condition of 0 - 10 °C, triethylamine (1.25 mol, 127 g) was added, and the temperature was raised to 15 °C. After reacting for 2 hours, 1748 g of water was added for crystallization, and stirring was continued for 2 hours. Then, filtration was carried out to separate the solid and liquid, and the solid was dried;
[0045] 155 g of the dried product was added to the reaction flask, 310 g of acetic acid was added, and the temperature was raised to 70 °C. After holding the temperature for reaction for 2 hours, water and sodium hydroxide solution were added to terminate the reaction, followed by filtration and drying to obtain the product, with a molar yield of 94% and a purity > 98.5%.
[0046] ESI-MS: 305.2 [M+H] +, 327.2 [M+Na] +
[0047] 1 HNMR(400 MHz, DMSO-d6): δ 12.472 (S, 1H), δ 7.680 - 7.840 (m, 2H), δ 7.595 (D, 1H), δ 7.465 (S, 1H), δ 7.248 - 7.287 (m, 2H), δ 3.912 (S, 3H), δ 2.832 (T, 2H), δ 2.605 (S, 3H), δ 1.857 (m, 2H), δ 0.922 (T, 3H)
[0048] Example 2
[0049] Add 4700 g of methanol, 2-n-propyl-4-methyl-6-carboxybenzimidazole (4.58 mol, 1000 g), and 510 g of N-methylmorpholine to the reaction kettle. Control the temperature to -10°C to 10°C, add 960 g of CDMT (about 5.47 mol), stir for 1 hour, then continue to add N-methyl-o-phenylenediamine hydrochloride (4.81 mol, 940 g) and triethylamine (11.36 mol, 1150 g). Control the temperature at 25°C and react for 2 hours. Add 15 kg of water for crystallization, stir for 1.5 hours, filter, separate the solid and liquid, and dry the solid;
[0050] Add the dried product to the reaction kettle, add 2800 g of acetic acid, heat up to 80°C, keep the temperature for reaction for 1.5 hours, add water and sodium hydroxide solution to terminate the reaction, filter, and dry to obtain the product with a molar yield of 95% and a purity > 98.5%.
[0051] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.
Claims
1. A preparation method of 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2-yl)benzimidazole, characterized in that, the preparation method comprises the following steps: (1) Using 2-n-propyl-4-methyl-6-carboxybenzimidazole and N-methyl-o-phenylenediamine or its salt as raw materials, reacting in a reaction solvent in the presence of a condensing agent and a basic reagent; (2) Then reacting in the presence of an acidic reagent to obtain 2-n-propyl-4-methyl-6-(1'-methyl-benzimidazol-2-yl)benzimidazole.
2. The preparation method according to claim 1, characterized in that, the condensing agent described in step (1) is selected from triazine-based condensing agents.
3. The preparation method according to claim 2, characterized in that, the triazine-based condensing agent described in step (1) is selected from 2- chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (DMTMM), 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride), 2-chloro-4,6-diphenyl-1,3,5-triazine, 2-chloro -4,6-di-p-tolyl-1,3,5-triazine, 2-chloro-4,6-bis(ethylamino)-1,3,5-triazine, 2-chloro-4,6-bis(isopropylamino yl)-1,3,5-triazine, one or more of them; Preferably, the triazine-based condensing agent is selected from one or more of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) or 4-(4,6-dimethoxy-1,3,5,-triazin-2-yl)-4-methylmorpholine hydrochloride (DMTMM).
4. The preparation method according to claim 1, characterized in that, the molar ratio of 2-n-propyl-4-methyl-6-carboxybenzimidazole to the triazine-based condensing agent in step (1) is 1:1.0 to 2.0, preferably 1:1.1 to 1.5, more preferably 1:1.2 to 1.
4.
5. The preparation method according to claim 1, characterized in that, the basic reagent described in step (1) is selected from one or more of N-methylmorpholine, triethylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, DMAP, DBU; Preferably, the basic reagent is selected from one or more of N-methylmorpholine and triethylamine.
6. The preparation method according to claim 1, characterized in that, the molar ratio of 2-n-propyl-4-methyl-6-carboxybenzimidazole to the basic reagent in step (1) is 1:0.5 to 5, preferably 1:0.8 to 4 or 1:1 to 3.
7. The preparation method according to claim 1, characterized in that, the reaction temperature in step (1) is -20°C to 40°C, preferably 0°C to 30°C, more preferably 10 - 30°C.
8. The preparation method according to claim 1, characterized in that, the reaction time in step (1) is 0.5 to 4 hours, preferably 1 to 3 hours.
9. The preparation method according to claim 1, characterized in that, The reaction solvent described in step (1) is selected from C1-4 alkyl alcohols; preferably, the reaction solvent is one or more of methanol, ethanol, n-propanol, and 2-propanol.
10. According to the preparation method described in claim 1, it is characterized in that step (1) further includes the steps of separating the product and / or purification after the reaction ends; preferably, the separation of the product is to separate the solid product in the reaction system by centrifugation, filtration, or crystallization by adding water; more preferably, the separation of the product is by crystallization by adding water; even more preferably, the weight ratio of 2-n-propyl-4-methyl-6-carboxybenzimidazole to water is 1:10 to 20; even more preferably, the weight ratio of 2-n-propyl-4-methyl-6-carboxybenzimidazole to water is 1:14 to 16.
11. According to the preparation method described in claim 1, it is characterized in that the acidic reagent in step (2) is selected from C1-4 carboxylic acids and C1-4 halo-carboxylic acids; preferably, the acidic reagent is formic acid, acetic acid, propionic acid, butyric acid, and trifluoroacetic acid.
12. According to the preparation method described in claim 1, it is characterized in that the reaction temperature in step (2) is 50 to 100 °C, preferably 60 to 90 °C.
13. According to the preparation method described in claim 1, it is characterized in that the reaction time in step (2) is 1 to 4 hours, preferably 2 to 3 hours.