Benzimidazole compounds and methods for their preparation

Abstract

The application discloses a benzimidazole compound and a preparation method thereof, and also discloses application of the benzimidazole compound in preparation of telmisartan. The benzimidazole compound can be used for preparing telmisartan, the preparation method has low raw material cost, simple operation, safety and controllability, high product purity, high total yield, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and more specifically, to benzimidazole compounds and their preparation methods. Background Technology

[0002] Telmisartan is a novel antihypertensive drug, a specific angiotensin II receptor (AT1 type) antagonist. Telmisartan substitutes the angiotensin II receptor for the AT1 receptor subtype (the known site of action of angiotensin II). Telmisartan selectively binds to the AT1 receptor, and this binding effect is long-lasting. It has the characteristics of stable blood pressure reduction and does not cause cough.

[0003] Ries UJ et al. used chlorobenzene as a reaction solvent to react methyl 4-amino-3-methylbenzoate (compound 2) with n-butyryl chloride at 100℃ to synthesize methyl 4-butamido-3-methylbenzoate (compound 4); methyl 4-butamido-3-methylbenzoate (compound 4) was nitrated with fuming nitric acid in H2SO4 (60%) at 0℃ to synthesize methyl 4-butamido-3-methyl-5-nitrobenzoate (compound 5); methyl 4-butamido-3-methyl-5-nitrobenzoate (compound 5) was then hydrogenated and reduced in methanol with Pd / C catalytic hydrogen (5 bar) to synthesize methyl 3-amino-4-butamido-5-methylbenzoate (compound 6); methyl 3-amino-4-butamido-5-methylbenzoate (… Compound 6) was dehydrated and cyclized in glacial acetic acid under reflux to synthesize methyl 4-methyl-2-propyl-1H-benzo[d]imidazolium-6-carboxylate (Compound 7); methyl 4-methyl-2-propyl-1H-benzo[d]imidazolium-6-carboxylate (Compound 7) was hydrolyzed in methanol under reflux and then in NaOH aqueous solution to synthesize 4-methyl-2-propyl-1H-benzo[d]imidazolium-6-carboxylate (Compound 8); 4-methyl-2-propyl-1H-benzo[d]imidazolium-6-carboxylate (Compound 8) was dehydrated and cyclized with N-methyl-o-phenylenediamine in polyphosphoric acid at 150–155 °C to synthesize 1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-dibenzo[d]imidazolium (Compound 10) (Ries UJ, Mihm G., Narr B.. 6-Substituted Benzimidazoles as NewNonpeptide Angiotensin II Receptor Antagonists: Synthesis, Biological Activity, and Structure-Activity Relationships. J. Med. Chem. 1993, 36, 4040-4051).

[0004] The method involves fuming nitric acid and sulfuric acid nitration, which are troublesome to process and cause significant environmental pollution. Nitro reduction uses expensive Pd / C, resulting in high overall costs. Furthermore, it uses very viscous polyphosphoric acid as a dehydration and cyclization reagent, requiring the treatment of excess polyphosphoric acid after the reaction. This makes the operation cumbersome, and the entire process is complex and the synthetic route is too long.

[0005]

[0006] Reddy KS et al. synthesized methyl 3-amino-4-butamido-5-methylbenzoate (compound 6) by hydrogenation reduction of methyl 4-butamido-3-methyl-5-nitrobenzene (compound 5) in methanol via Pd / C catalysis and hydrogen (3.4 kg / cm2); methyl 3-amino-4-butamido-5-methylbenzoate (compound 6) was then subjected to reflux cyclization and hydrolysis in NaOH aqueous solution to synthesize 4-methyl-2-propyl-1H-benzo[d]imidazol-6-carboxylic acid (compound 8); 4-methyl-2-propyl-1H-benzo[d]imidazol-6-carboxylic acid (compound 8) was then subjected to dehydration and cyclization with N-methyl-o-phenylenediamine in polyphosphoric acid at 150–155 °C to synthesize 1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-dibenzo[d]imidazolium (compound 10). (Reddy KS, Srinivasan) N.,ReddyC.R.,et.al.An Efficient and Impurity-Free Process for Telmisartan:AnAntihypertensive.Drug,Org.Process Res.Dev.,2007,11,81-8).

[0007]

[0008] The method uses expensive Pd / C for nitro reduction, resulting in high overall cost. In addition, it uses very viscous polyphosphoric acid as a dehydration and cyclization reagent, requiring the treatment of excess polyphosphoric acid after the reaction, making the operation cumbersome.

[0009] Wang Ping et al. synthesized 4-hydroxy-3-methylbenzaldehyde (compound 3) from 2-methylphenol (compound 2) via the Reimer-Tiemann reaction; 4-hydroxy-3-methylbenzaldehyde (compound 3) was nitrated with fuming nitric acid at -15℃ to synthesize 4-hydroxy-3-methyl-5-nitrobenzaldehyde (compound 4); 4-hydroxy-3-methyl-5-nitrobenzaldehyde (compound 4) was methylated with dimethyl sulfate in NaOH solution to synthesize 4-methoxy-3-methyl-5-nitrobenzaldehyde (compound 5); 4-methoxy-3-methyl-5-nitrobenzaldehyde (compound 5) was added to a methanol solution of N-methyl-o-phenylenediamine (compound 6), and the mixture was reacted with H2O2 at 5-10℃ to synthesize 2-(4-methoxy-3-methyl-5-nitrobenzaldehyde)-1H-benzo[d]imidazolium intermediate, 2-(4-methoxy-3-methyl-5-nitrobenzaldehyde)-1H-benzo[d]imidazolium. The intermediate benzo[d]imidazole was reacted with dimethyl sulfate in DMF using K2CO3 as a base to synthesize 2-(4-methoxy-3-methyl-5-nitrophenyl)-1-methyl-1H-benzo[d]imidazole (compound 7); 2-(4-methoxy-3-methyl-5-nitrophenyl)-1-methyl-1H-benzo[d]imidazole (compound 7) was reacted in a mixture of ethanol and concentrated ammonia in a high-pressure reactor at 90°C to synthesize 2-methyl- 4-(1-methyl-1H-benzo[d]imidazol-2-yl)-6-nitroaniline (compound 8); 2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)-6-nitroaniline (compound 8) was synthesized by reacting n-butyraldehyde and sodium dithionite under reflux in a mixed solvent of methanol and water to synthesize 1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-dibenzo[d]imidazolium (compound 9) (Wang Ping, Zheng Guo-jun, Wang Ya-ping. Highly practical and cost-efficient synthesis of telmisartan: an antihypertensive drug. Tetrahedron. 2012, 68, 2509-2512.).

[0010]

[0011] The nitration step in this method causes significant environmental pollution, and dimethyl sulfate, a highly toxic methylating agent, is used twice.

[0012] Tao Feng et al., in a fluorine two-phase system composed of toluene and perfluoronaphthalene, used 4-methyl-2-propyl-1H-benzo[d]imidazolium-6-carboxylic acid and N-methyl-o-phenylenediamine as raw materials, and 0.4 mol% ytterbium perfluorooctyl sulfonate [Yb(OSO2C8F] 17)3, abbreviated as Yb(OPf)3] as catalyst, synthesize 2-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole (Tao Feng, Yi Wenbin. Synthesis of 2-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole. China Pharmaceutical Industry Journal, 2007, 38(6):407-408.).

[0013]

[0014] The solvent perfluoronaphthene and the rare earth metal catalyst perfluorooctane ytterbium sulfonate are expensive in this method, resulting in a high cost for the entire route.

[0015] The current methods for preparing telmisartan still need improvement. Summary of the Invention

[0016] This invention aims to at least partially address one of the technical problems existing in the prior art. To this end, the present invention proposes a method for preparing 1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-dibenzo[d]imidazole. Specifically, the present invention proposes a 1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-dibenzo[d]imidazole intermediate, a method for preparing the intermediate, the use of the intermediate in the preparation of 1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-dibenzo[d]imidazole, and a method for preparing 1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-dibenzo[d]imidazole.

[0017] In one aspect of the invention, a compound of formula (I) is proposed:

[0018]

[0019] In another aspect of the invention, a method for preparing the compound of formula (I) is provided. The method comprises: reacting the compound of formula (II) with n-butyramide via a dehydration reaction to obtain the compound of formula (I), as shown in the following reaction formula:

[0020]

[0021] According to an embodiment of the present invention, 2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline (shown in formula (II)) is reacted with n-butyramide via a dehydration reaction to obtain N-(2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)butamidine (shown in formula (I)). The method of the present invention has a simple reaction process, is easy to operate, produces products with high purity and yield, and the raw materials are readily available and low in cost, making it suitable for industrial production.

[0022] This invention does not strictly limit the temperature of the dehydration reaction, as long as the dehydration reaction can occur and the compound shown in formula (I) is produced. In some embodiments, the dehydration reaction is carried out at 100°C to 160°C. In some embodiments, the dehydration reaction is carried out at 120°C to 160°C. In other embodiments, the dehydration reaction is carried out at 150°C to 160°C, under which the dehydration reaction is complete and the purity and yield of the compound shown in formula (I) are further improved.

[0023] This invention does not strictly limit the time of the dehydration reaction, as long as the dehydration reaction can be guaranteed to occur and the compound shown in formula (I) is produced. In some embodiments, the dehydration reaction time is 12 h to 24 h. Under these conditions, the dehydration reaction is complete, and the purity and yield of the compound shown in formula (I) are further improved. If the time is too short, the reaction will not be complete, and the yield of the product will be low. If the time is too long, by-products are likely to be generated, which will reduce the purity of the compound shown in formula (I).

[0024] In some embodiments, the dehydration reaction is carried out in a dehydrating agent, which includes a phosphorus pentoxide-methanesulfonic acid mixture, a polyphosphoric acid solution, or a POCl3 solution. The inventors unexpectedly discovered that using a phosphorus pentoxide-methanesulfonic acid mixture, a polyphosphoric acid solution, or a POCl3 solution as the dehydrating agent resulted in a more complete dehydration reaction and yielded compounds of formula (I) with higher purity and yield. In other embodiments, the dehydrating agent is a phosphorus pentoxide-methanesulfonic acid mixture. The inventors found that using a phosphorus pentoxide-methanesulfonic acid mixture as the dehydrating agent resulted in compounds of formula (I) with higher purity and yield.

[0025] In actual production, phosphorus pentoxide and methanesulfonic acid can be mixed in any proportion, as long as it can achieve a dehydration effect, allowing the dehydration reaction to occur and producing the compound shown in formula (I). In some embodiments, the inventors unexpectedly discovered that different mixing ratios of phosphorus pentoxide and methanesulfonic acid affect the ease of stirring during the reaction. When the mass ratio of phosphorus pentoxide to methanesulfonic acid in the phosphorus pentoxide-methanesulfonic acid mixture is 1:5 to 1:12, stirring is easy, which is beneficial for the reaction. In some embodiments, the mass ratio of phosphorus pentoxide to methanesulfonic acid in the phosphorus pentoxide-methanesulfonic acid mixture is 1:5, 1:7, 1:10, or 1:12, which makes stirring easy, ensures a complete reaction, and results in a high purity and yield of the compound shown in formula (I). In other embodiments, the mass ratio of phosphorus pentoxide to methanesulfonic acid in the phosphorus pentoxide-methanesulfonic acid mixture is 1:10, resulting in a high purity and yield of the compound shown in formula (I).

[0026] This invention does not strictly limit the ratio between the reaction substrates, as long as the dehydration reaction occurs and the compound shown in formula (I) is generated. The molar ratio of the compound shown in formula (II) to the n-butyramide can be 1:3 to 1:36. In some embodiments, the molar ratio of the compound shown in formula (II) to the n-butyramide is 1:5 to 1:25. The inventors have found that under these conditions, the dehydration reaction can occur sufficiently, and the purity and yield of the compound shown in formula (I) are further improved. In other embodiments, the molar ratio of the compound shown in formula (II) to the n-butyramide is 1:12, resulting in a higher purity and yield of the compound shown in formula (I).

[0027] In some embodiments, the method for preparing the compound of formula (I) further includes post-treatment of the reaction system after dehydration reaction. The post-treatment includes: cooling the reaction system to 40°C–70°C, adding water, then cooling to room temperature, adding acetone; adjusting the pH of the system to 10–12 with sodium hydroxide; then stirring the resulting mixture at room temperature for 3–6 hours, separating, removing the solvent, and obtaining the compound of formula (I). The obtained compound of formula (I) can be further purified by washing, pulping, crystallization, recrystallization, etc. In some embodiments, the reaction system is mixed with acetone, stirred at room temperature for 2–16 hours, then the solid is separated, the solvent is removed, and the product of formula (I) is obtained.

[0028] In some embodiments, a method for preparing the compound of formula (I) includes: reacting the compound of formula (II) with n-butyramide in a phosphorus pentoxide-methanesulfonic acid mixture at 120°C to 160°C for 12 h to 24 h under dehydration conditions, followed by post-treatment to obtain the compound of formula (I). The molar ratio of the compound of formula (II) to n-butyramide is 1:5 to 1:20; the mass ratio of phosphorus pentoxide to methanesulfonic acid in the phosphorus pentoxide-methanesulfonic acid mixture is 1:5 to 1:12.

[0029] In another aspect of the invention, the invention provides for the use of the compound of formula (I) in the preparation of the compound of formula (III). The use includes subjecting the compound of formula (I) to a cyclization reaction to obtain the compound of formula (III):

[0030]

[0031] In another aspect of the invention, a method for preparing the compound of formula (III) is provided. The method comprises: subjecting the compound of formula (I) to a cyclization reaction to obtain the compound of formula (III):

[0032]

[0033] According to an embodiment of the present invention, N-(2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)butamidine (the compound shown in formula (I)) is used as the reaction substrate, and the compound shown in formula (III) is synthesized through a cyclization reaction. The method of the present invention has a simple reaction process, is easy to operate, produces products with high purity and yield, and the raw materials are readily available and low in cost, making it suitable for industrial production.

[0034] This invention does not strictly limit the temperature of the ring-closing reaction, as long as the ring-closing reaction can occur and the compound shown in formula (III) is generated. In some embodiments, the ring-closing reaction is carried out at 8°C to 50°C. Under these conditions, the ring-closing reaction is complete, and the purity and yield of the compound shown in formula (III) are further improved. In other embodiments, the ring-closing reaction is carried out at 15°C to 30°C, and the purity and yield of the compound shown in formula (III) are higher. If the temperature is too low, the reaction is incomplete, and the yield of the product is low. If the temperature is too high, by-products are easily generated, which reduces the purity of the compound shown in formula (III).

[0035] This invention does not strictly limit the time of the ring-closing reaction, as long as the ring-closing reaction can be guaranteed to occur and the compound shown in formula (III) is generated. In some embodiments, the ring-closing reaction time is 1 h to 4 h. Under these conditions, the ring-closing reaction proceeds fully, and the purity and yield of the compound shown in formula (III) are further improved. In other embodiments, the ring-closing reaction time is 1 h. As a result, the purity and yield of the compound shown in formula (III) are higher. If the time is too short, the reaction will not be complete, and the yield of the product will be low. If the time is too long, by-products are likely to be generated, which will reduce the purity of the compound shown in formula (III).

[0036] In some embodiments, the ring-closing reaction is carried out in a chlorinating reagent, which includes at least one of NaClO, Ca(ClO)₂, and N-bromosuccinimide. The inventors have found that the presence of the chlorinating reagent promotes the ring-closing reaction, primarily because the chlorinating reagent first replaces the hydrogen atom bonded to the nitrogen atom of the imine group in the compound of formula (I), forming an intermediate, which then undergoes further ring closure to obtain the compound of formula (III). In some embodiments, the chlorinating reagent is solid NaClO or a solution containing NaClO. In some embodiments, the chlorinating reagent is a NaClO solution. Therefore, the obtained compound of formula (III) has high purity and yield.

[0037] In some embodiments, the mass fraction of NaClO in the NaClO solution is not less than 1.0%. The inventors have found that if the mass fraction of NaClO is too low, the tendency for side reactions will be enhanced, and more impurities will be generated in the reaction, resulting in lower purity and yield of the compound shown in formula (Ⅲ).

[0038] This invention does not strictly limit the ratio between the reaction substrates, as long as the ring-closing reaction can be guaranteed to occur and the compound shown in formula (III) is produced. In some embodiments, the molar ratio of the compound shown in formula (I) to the chlorinating reagent is 1:1.1 to 1:1.4. In some embodiments, the molar ratio of the compound shown in formula (I) to the chlorinating reagent is 1:1.15 to 1:1.3. In other embodiments, the molar ratio of the compound shown in formula (I) to the chlorinating reagent is 1:1.2. The inventors have found that under these conditions, the ring-closing reaction can occur fully and the formation of impurities can be avoided, resulting in further improvements in the purity and yield of the compound shown in formula (III).

[0039] In some embodiments, the ring-closure reaction is carried out in the presence of a base, which includes at least one of NaOH, KOH, Ca(OH)₂, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, triethylamine, diisopropylethylamine, and 1,8-diazabicycloundec-7-ene. The inventors have found that a base can neutralize or act as an acid-binding agent to form a salt with the hydrogen halides generated in the ring-closure reaction, thereby promoting the ring-closure of the compound shown in formula (I) to the compound shown in formula (III). The presence of the aforementioned base ensures that the ring-closure reaction occurs sufficiently, and the purity and yield of the obtained compound shown in formula (III) are further improved. In other embodiments, the base is at least one of NaOH, KOH, Ca(OH)₂, sodium tert-butoxide, potassium tert-butoxide, and lithium tert-butoxide. In other embodiments, the base is at least one of NaOH, KOH, Ca(OH)₂, and sodium tert-butoxide. In other embodiments, the base is NaOH. Thus, the obtained compound shown in formula (III) has higher purity and yield.

[0040] The inventors unexpectedly discovered that the ratio of the compound shown in formula (I) to the base significantly affects the occurrence of the ring-closing reaction, thereby affecting the purity and yield of the compound shown in formula (III). In some embodiments, the molar ratio of the compound shown in formula (I) to the base is 1:1 to 1:6. The inventors found that under these conditions, the ring-closing reaction can occur fully, and the purity and yield of the obtained compound shown in formula (III) are further improved. If the amount of base is insufficient, the raw materials may not react completely or the intermediates formed during the reaction may not be completely converted into the compound shown in formula (III), thereby reducing the yield; if the amount of base is excessive, it will not only increase the production cost, but also cause the compound shown in formula (I) to hydrolyze into amide impurities during the reaction, resulting in lower purity and yield of the compound shown in formula (III). In other embodiments, the molar ratio of the compound shown in formula (I) to the base is 1:3 to 1:4. As a result, the purity and yield of the obtained compound shown in formula (III) are higher.

[0041] In some embodiments, the ring-closing reaction is carried out in a reaction solvent, which includes at least one of water, acetonitrile, ethanol, methanol, isopropanol, N,N-dimethylformamide, and N,N-dimethylacetamide. The inventors have found that the compound represented by formula (I) can be fully dissolved in the above-mentioned reaction solvent to form a homogeneous reaction system or a liquid-liquid two-phase reaction system. Compared to a solid-liquid two-phase reaction system, a homogeneous reaction system or a liquid-liquid two-phase reaction system is more conducive to collisions between reactant molecules, thereby more conducive to the occurrence of the chemical reaction. In other embodiments, the reaction solvent includes acetonitrile and water, ethanol and water, and methanol and water. Therefore, the compound represented by formula (III) obtained has higher purity and yield.

[0042] In some embodiments, based on 1g of the compound represented by formula (I), the amount of reaction solvent used is 10mL to 40mL. The inventors have found that under these conditions, the cyclization reaction can be fully carried out, and the purity and yield of the compound represented by formula (III) are further improved.

[0043] In some embodiments, the method for preparing the compound of formula (III) further comprises: cooling the reaction system obtained by the cyclization reaction to -5°C to 30°C, adding 0.5 to 4 times the volume of water (by volume) of the reaction solvent to the reaction system, and stirring at -5°C to 30°C for 1 to 4 hours to obtain a mixture; and separating the solid from the mixture, optionally washing the solid with water, acetonitrile, ethanol, methanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, or combinations thereof, and removing the solvent to obtain the compound of formula (III). Thus, the compound of formula (III) obtained has high purity and yield. In some embodiments, the reaction system obtained by the cyclization reaction is cooled to 0°C to 20°C, then 0.5 to 4 times the volume of water (by volume) of the reaction solvent is added, and stirring at 0°C to 30°C for 1 to 2 hours; then the solid is separated, washed with water, ethanol, or combinations thereof, and dried to remove the solvent to obtain the compound of formula (III). Therefore, the compound shown in formula (Ⅲ) has high purity and yield.

[0044] In some embodiments, the compound of formula (III) obtained may be further purified. The purification process includes: mixing the compound of formula (III) with water, acetonitrile, ethanol, methanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, or combinations thereof to obtain a mixture; then slurrying the mixture; separating the solid; optionally washing the obtained solid; and then drying the obtained solid. The temperature of the mixture is controlled at -5°C to 30°C.

[0045] Definitions and general terms

[0046] In the context of this invention, all figures disclosed herein are approximate values. The value of each figure may vary by 1%, 2%, 5%, 7%, 8%, or 10%, etc. Whenever a figure with a value of N is disclosed, any figure having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where "+ / -" refers to addition or subtraction. Whenever a lower limit, DL, and an upper limit, DU, of a numerical range are disclosed, any value within that disclosed range is explicitly disclosed.

[0047] All reaction steps described in this invention proceed to post-processing after reaching a certain stage, such as when the raw material consumption is approximately greater than 70%, 80%, 90%, or 95%, or after detection that the raw materials have been completely consumed. This post-processing includes cooling, collection, extraction, filtration, separation, purification, or combinations thereof. The degree of reaction can be detected using conventional methods such as thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), and gas chromatography (GC). Conventional methods can be used to post-process the reaction solution. For example, the crude product can be collected by vacuum evaporation or conventional distillation of the reaction solvent and directly added to the next reaction step; or the crude product can be obtained by direct filtration and directly added to the next reaction step; or the supernatant can be poured off after settling to obtain the crude product, which can then be directly added to the next reaction step; or appropriate organic solvents or combinations thereof can be selected for extraction, distillation, crystallization, column chromatography, rinsing, slurrying, and other purification steps.

[0048] In this invention, "room temperature" refers to a temperature of 10℃~25℃ or 15℃~25℃.

[0049] General synthesis methods

[0050] In this specification, if there are any differences between chemical names and chemical structures, the structure is preferred.

[0051] In the examples described below, all temperatures are specified in °C (degrees Celsius) unless otherwise stated. Unless otherwise stated, reagents were purchased from commercial suppliers such as Aladdin Reagents (Shanghai) Co., Ltd., Shanghai Lingkai Pharmaceutical Technology Co., Ltd., Shanghai Demo Pharmaceutical Technology Co., Ltd., and Beijing Coupling Technology Co., Ltd., and were used without further purification. Common reagents were purchased from Chengdu Kelong Chemical Reagent Factory, Taizhou Haichuan Chemical Co., Ltd., Sichuan Weibao Technology Development Co., Ltd., and Zhejiang Pukang Chemical Co., Ltd.

[0052] Nuclear magnetic resonance (NMR) spectral data were determined using a Bruker NMR spectrometer, with CDCl3 or d6-DMSO as solvents (reported in ppm), and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet). The coupling constant is expressed in Hertz (Hz).

[0053] Low-resolution mass spectrometry was performed using a liquid chromatography-mass spectrometry (LC-MS) system, instrument model: HPLC1260MSD6120, column: Agilent Zorbax SB-C18 (2.1×30mm, 3.5μm).

[0054] The purity / content of the compounds was evaluated by Agilent 1200 high performance liquid chromatography (HPLC) with a Zorbax Eclipse Plus C18 column (4.6 × 100 mm, 3.5 μm).

[0055] The following abbreviations are used throughout this invention:

[0056] MsOH Methanesulfonic Acid

[0057] D2O heavy water

[0058] DMSO-d6 Deuterated dimethyl sulfoxide

[0059] P2O5 (phosphorus pentoxide)

[0060] CH3CN Acetonitrile

[0061] NaClO sodium hypochlorite

[0062] NaOH (sodium hydroxide)

[0063] kg

[0064] g gram

[0065] mg

[0066] mol

[0067] mmol or mM millimole

[0068] L rise

[0069] mL

[0070] μL

[0071] equivalent

[0072] HPLC (High Performance Liquid Chromatography)

[0073] mm

[0074] μm micrometer

[0075] nm nanometer

[0076] h hours

[0077] min minutes Specific implementation methods

[0078] This invention discloses telmisartan intermediates, their preparation methods, and methods for preparing telmisartan. Those skilled in the art can refer to this invention and appropriately modify the process parameters to achieve the desired results. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The methods of this invention have been described through preferred embodiments, and those skilled in the art can clearly modify or appropriately change and combine the methods described herein without departing from the content, spirit, and scope of this invention to implement and apply the technology of this invention.

[0079] To further understand the present invention, the present invention will be described in detail below with reference to embodiments. Example

[0080] Example 1 Synthesis of N-(2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)butamidine (compound shown in formula (I))

[0081]

[0082] P₂O₅ (4.5 g, 31.5 mmol) and MsOH (45.0 g, 468 mmol) were added to a 500 mL reaction flask equipped with a magnetic stir bar and a thermometer. The reaction mixture was heated to 150 °C. After the reaction solution became clear, n-butyramide (22 g, 252 mmol) and 2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline (the compound shown in formula (II)) (5 ​​g, 21 mmol) were added sequentially. The reaction solution was stirred at 150 °C for 21 h. The reaction mixture was then cooled to 60 °C and 100 mL of water was added. After the reaction solution cooled to room temperature, 25 mL of acetone was added to the reaction solution. Then, the pH of the reaction solution was adjusted to 11–12 with a 20 wt% sodium hydroxide aqueous solution. A large amount of solid precipitated in the reaction solution. The reaction solution was stirred at room temperature for 5 h and then filtered. The filter cake was dried under vacuum at 70 °C for 24 h to obtain 11.28 g of crude product. The crude product (11.28 g) was added to acetone (44 mL), and the mixture was stirred at room temperature for 12 hours. After filtration, the filter cake was dried under vacuum at 50 °C for 24 h to obtain N-(2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)butamidine (5.63 g, yield: 87.2%, purity: 97.63%) (the compound shown in formula (I)).

[0083] Structural characterization data: 1 H NMR (CDCl3, 600MHz) δ7.78 (d, J = 6.0 Hz, 1H), 7.62 (s, 1H), 7.48 (d, J = 12.0 Hz, 1H), 7.36 (d, J = 6.0 Hz, 1H), 7.28-7.30 (m, 2H), 6.91 (d, J = 12. 0Hz,1H),4.42(s,2H),3.86(s,3H),2.34(t,J=6.0Hz,2H),2.21(s,3H),1.77-1.81(m,2H),1.07(t,J=6.0Hz,3H).LC-MS: (ESI)m / z=[M+H] + =307.10.

[0084] Example 2 Synthesis of 1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-benzo[d]imidazole (compound shown in formula (III))

[0085]

[0086] At room temperature (17°C), N-(2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)butamidine (5.33 g, 17.40 mmol, compound of formula (I)) and NaOH (2.78 g, 69.58 mmol) were suspended in acetonitrile (200 mL), and an aqueous solution of NaClO (65.83 g, 2.42 wt%, 21.40 mmol) was added to the reaction mixture. The reaction mixture was heated to 30°C and stirred at this temperature for 2.5 h. The reaction mixture was cooled to room temperature, and water (154 mL) was added dropwise to the reaction mixture. After the water addition was completed, the reaction mixture was stirred at room temperature for 2 h. After filtration, the filter cake was washed with water (3 × 20 mL) and placed in a vacuum drying oven. It was then dried under vacuum at 60 °C for 24 h to obtain 1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-benzo[d]imidazolium white solid (4.94 g, yield: 93.30%, purity: 99.84%) (the compound shown in formula (III)).

[0087] Structural characterization data: 1 H NMR(DMSO-d6,400MHz)δ12.39(s,1H),7.73(s,1H),7.65(d,J=4.0Hz,1H),7.58(d,J=8.0Hz,1H),7.42(s,1H),7.21-7.29 (m,2H),3.89(s,3H),2.84(t,J=8.0Hz,2H),2.58(s,3H),1.79-1.88(m,2H),0.98(t,J=8.0Hz,3H).LCMS:(ESI)m / z=[M+H] + =305.20.

[0088] Example 3 Synthesis of N-(2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)butamidine (compound shown in formula (I))

[0089] P2O5 (0.9 g, 6.3 mmol) and MsOH (9.0 g, 93.6 mmol) were added to a 50 mL reaction flask equipped with a magnetic stir bar and a thermometer. The reaction mixture was heated to 150 °C. After the reaction solution became clear, n-butyramide (according to the ratio in Table 1 below) and 2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline (the compound shown in formula (II)) (1.0 g, 4.2 mmol) were added sequentially. The reaction solution was stirred at 150 °C for 21 h, and then a sample of the reaction solution was sent for analysis. The HPLC results are shown in Table 1.

[0090] It can be seen that when the molar ratio of the compound shown in formula (II) to n-butyramide is 1:12, the content of the compound shown in formula (I) in the reaction solution is the highest, which indicates that the yield of the compound shown in formula (I) is high. If the amount of n-butyramide is too small, the reaction will be incomplete; if the amount of n-butyramide is too large, the impurities will increase.

[0091] Table 1: Effect of n-Butyramide dosage

[0092]

[0093]

[0094] Example 4 Synthesis of 1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-benzo[d]imidazole (compound shown in formula (III))

[0095] At room temperature (19°C), N-(2-methyl-4-(1-methyl-1H-benzo[D]imidazol-2-yl)phenyl)butamidine (the compound shown in formula (I)) (1.5334 g, 5.00 mmol) and NaOH (400.6 mg, 10.02 mmol) were suspended in ethanol (30.6 mL). The reaction mixture was heated to 30°C and stirred. NaClO solution (18.98 g, 2.42 wt%, 6.17 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 30°C for 1.0 h. The reaction mixture was cooled to room temperature, and water (30.6 mL) was added dropwise to the reaction mixture. The addition was completed after 5 min. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered, and the filter cake was washed with water (3 × 15 mL) and then dried under vacuum at 60 °C for 24 h to obtain 1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-benzo[D]imidazole (the compound shown in formula (III)) white solid or off-white solid (1.1379 g, yield: 74.35%, purity: 99.44%).

Claims

1. A method for preparing the compound of formula (III), comprising: The compound shown in formula (II) was reacted with n-butyramide through a dehydration reaction to obtain the compound shown in formula (I), as shown in the following reaction formula: The compound shown in formula (I) is subjected to a ring-closure reaction. The reaction system obtained after the ring-closure reaction is cooled to -5°C to 30°C. Water, with a volume of 0.5 to 4 times the volume of the reaction solvent, is added to the reaction system, and the mixture is stirred at -5°C to 30°C for 1 to 4 hours to obtain a mixture. The solid is then separated from the mixture, and the solid is washed with water, acetonitrile, ethanol, methanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, or a combination thereof to remove the solvent, thereby obtaining the compound shown in formula (III). The dehydration reaction is carried out in a dehydration reagent, which is a mixture of phosphorus pentoxide and methanesulfonic acid, wherein the mass ratio of phosphorus pentoxide to methanesulfonic acid in the mixture is 1:5 to 1:

12. The molar ratio of the compound shown in formula (II) to the n-butyramide is 1:12; The dehydration reaction is carried out at 100℃ to 160℃; the dehydration reaction time is 12h to 24h. The ring-closing reaction is carried out in the presence of a chlorinating reagent, which is solid NaClO or a NaClO solution with a mass fraction of not less than 1.0%; the molar ratio of the compound shown in formula (I) to the chlorinating reagent is 1:1.1 to 1:1.

4. The ring-closing reaction is carried out in the presence of a base, which is at least one of NaOH, KOH and Ca(OH)2; the molar ratio of the compound shown in formula (I) to the base is 1:1 to 1:

6. The cyclization reaction is carried out in a reaction solvent, which is at least one of acetonitrile, ethanol, methanol and isopropanol; the amount of the reaction solvent used is 10 mL to 40 mL based on 1 g of the compound shown in formula (I); The ring-closing reaction is carried out at 15℃ to 30℃; the ring-closing reaction time is 1h to 4h.

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