Preparation method of benzimidazole derivative intermediate of a CRF1 receptor antagonist

Abstract

The invention discloses a preparation method of a benzimidazole derivative intermediate of a CRF1 receptor antagonist. The method comprises the following steps: 1) reacting a compound of formula I with methylamine to obtain 2-bromo-N-methyl-6-nitroaniline, wherein in formula I, group A is selected from mesyl, p-toluenesulfonyl or trifluoromethanesulfonyl; 2) carrying out a reduction reaction on 2-bromo-N-methyl-6-nitroaniline in the presence of a reducing agent to obtain 6-bromo-N1-methylbenzene-1,2-diamine, and the reducing agent is selected from sodium dithionite and / or stannous chloride; 3) reacting 6-bromo-N1-methylbenzene-1,2-diamine with N,N'-dicarbonylimidazole in an organic solvent to obtain the target product. The preparation method significantly reduces the cost on the premise of ensuring a high yield of the target product, and the reaction conditions and the reaction process are mild and easy to industrialize.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a benzimidazole derivative intermediate of a CRF1 receptor antagonist. Background Art

[0002] Corticotropin-releasing factor (CRF) is a polypeptide composed of 41 amino acids, which is mainly secreted by the paraventricular nucleus of the hypothalamus in the central nervous system. CRF is also distributed in peripheral tissues such as the testis, pancreas, stomach, and small intestine. Under basal and stress conditions, CRF is the main physiological regulator that induces the release of adrenocorticotropic hormone (ACTH), β-endorphin, and proopiomelanocortin from the anterior pituitary gland, and plays a key role in the neuroendocrine regulation of the hypothalamic-pituitary-adrenal (HPA) axis. In recent years, through the research on CRF and its receptors, it has been found that CRF plays an important role in mental and neurodegenerative diseases.

[0003] At present, people pay more and more attention to the research on the therapeutic effects of CRF receptor antagonists, which has important application value for the development of new drugs for treating stress-related diseases such as depression, anxiety, drug withdrawal or detoxification syndrome. A promising lead compound 1 in the benzimidazole series has been identified as a corticotropin-releasing factor 1 (CRF1) receptor antagonist, and 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one is an important intermediate of the CRF1 receptor antagonist.

[0004] The prior art such as PCT patent WO2022 / 147465Al discloses the following synthetic route of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one:

[0005]

[0006] This synthetic route uses 1-bromo-2-fluoro-3-nitro-benzene as the starting material, but this raw material is expensive, resulting in a high cost for the entire synthetic route. Moreover, the second-step reaction process is relatively violent, and there is a risk of material overflow during the scale-up test, making industrial production basically impossible. Although the yield of this synthetic route is relatively high, there is still room for further improvement. Summary of the Invention

[0007] The object of the present invention is to provide a preparation method of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, an intermediate of a benzimidazole derivative of a CRF1 receptor antagonist, aiming at the disadvantages and deficiencies of the prior art. This preparation method can significantly reduce the cost of the preparation method while ensuring a high yield of the target product, and even further improving the yield of the target product. Moreover, the reaction conditions and the reaction process are mild and easy to industrialize.

[0008] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0009] A preparation method of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, the preparation method comprising the following steps: 1) reacting a compound of formula I with methylamine to obtain 2-bromo-N-methyl-6-nitroaniline wherein, in formula I, the group A is selected from methanesulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl; 2) subjecting the 2-bromo-N-methyl-6-nitroaniline to a reduction reaction in the presence of a reducing agent to obtain 6-bromo-N1-methylbenzene-1,2-diamine The reducing agent is selected from sodium dithionite and / or stannous chloride; 3) reacting the 6-bromo-N1-methylbenzene-1,2-diamine with N,N'-dicarbonylimidazole in an organic solvent to obtain the 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one.

[0010] In some embodiments, in step 1), the molar ratio of the compound of formula I to methylamine is 1:1-2.

[0011] In some embodiments, in step 1), the methylamine directly exists in the form of liquid methylamine.

[0012] In some embodiments, in step 1), the methylamine exists in the form of an aqueous solution or an alcohol solution.

[0013] In some embodiments, in step 1), the temperature of the reaction is 50-100 °C.

[0014] In some embodiments, in step 1), the reaction time is 15-20 h.

[0015] In some embodiments, in step 1), after the reaction, the reaction system is extracted, the pH is adjusted by adding a base, and concentrated to obtain the 2-bromo-N-methyl-6-nitroaniline.

[0016] Further, the extractant used for the extraction is selected from one or a combination of more of butanol, dichloromethane, ethyl acetate, butyl acetate and amyl acetate.

[0017] In some embodiments, in step 1), the compound of formula I is mixed with methylamine, heated to carry out the reaction, after the reaction, water and an organic extractant are added for extraction, the pH is adjusted to 9-10 by adding a base, and then water is added for extraction, and concentrated to obtain 2-bromo-N-methyl-6-nitroaniline.

[0018] In some embodiments, in step 2), the molar ratio of the 2-bromo-N-methyl-6-nitroaniline to the reducing agent is 1:1 - 4.

[0019] In some embodiments, in step 2), the temperature of the reduction reaction is 20 - 30 °C.

[0020] In some embodiments, in step 2), the time of the reduction reaction is 2 - 4 h.

[0021] In some embodiments, in step 2), the reduction reaction is carried out under alkaline conditions and in an organic solvent.

[0022] In some embodiments, in step 2), the reducing agent, the base, and the alcohol solvent are mixed in water to obtain a mixed solution, and an organic solution of 2-bromo-N-methyl-6-nitroaniline is added dropwise to the mixed solution to carry out the reduction reaction.

[0023] Further, the base is sodium carbonate.

[0024] In some embodiments, in step 2), after the reduction reaction is completed, an organic solvent is added to the reaction system for extraction, a base is added to adjust the pH, and concentration is carried out to obtain the 6-bromo-N1-methylbenzene-1,2-diamine.

[0025] Further, the base is selected from one or a combination of more of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, and sodium carbonate.

[0026] In some embodiments, in step 2), the reducing agent, the base, and the alcohol solvent are mixed in water to obtain a mixed solution, the temperature of the mixed solution is lowered to 10 - 30 °C, 2-bromo-N-methyl-6-nitroaniline is dissolved in an organic solvent to obtain an organic solution, the organic solution is added dropwise to the mixed solution, and the reduction reaction is carried out at 20 - 30 °C. After the reduction reaction is completed, water and an extraction solvent are added to the reaction system for extraction, a base is added to adjust the pH, and concentration is carried out to obtain the 6-bromo-N1-methylbenzene-1,2-diamine.

[0027] Further, the alcohol solvent is methanol.

[0028] Further, the organic solvent is selected from one or a combination of more of methanol, ethanol, isopropanol, n-butanol, tert-butanol, acetonitrile, and acetone.

[0029] Further, the extraction solvent is selected from one or a combination of more of butanol, dichloromethane, ethyl acetate, butyl acetate, and amyl acetate.

[0030] In some embodiments, in step 3), the molar ratio of 6-bromo-N1-methylbenzene-1,2-diamine to N,N'-dicarbonylimidazole is 1:1 - 3.

[0031] In some embodiments, in step 3), the reaction is carried out at the reflux temperature.

[0032] In some embodiments, in step 3), the organic solvent is selected from one or more combinations of methanol, ethanol, isopropanol, n-butanol, tert-butanol, acetonitrile, and acetone.

[0033] In some embodiments, in step 3), at 0 - 10°C, N,N'-dicarbonylimidazole is added in batches to the organic solution of 6-bromo-N1-methylbenzene-1,2-diamine, and then heated to the reflux temperature for reaction.

[0034] In some embodiments, the preparation method further includes: reacting 2-bromo-6-nitrophenol with methanesulfonyl chloride, p-toluenesulfonic anhydride, or trifluoromethanesulfonic anhydride in an organic solvent under basic conditions to form the compound of formula I.

[0035] In some embodiments, in the step of forming the compound of formula I, the basic conditions are formed by adding one or more bases selected from sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, and sodium carbonate.

[0036] In some embodiments, in the step of forming the compound of formula I, the organic solvent is selected from one or more combinations of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, pyridine, and dichloromethane.

[0037] In some embodiments, in the step of forming the compound of formula I, the reaction temperature is 20 - 80°C.

[0038] In some embodiments, in the step of forming the compound of formula I, the reaction time is 14 - 16 h.

[0039] In some embodiments, in the step of forming the compound of formula I, 2-bromo-6-nitrophenol is dissolved in the organic solvent to obtain an organic solution, the temperature of the organic solution is lowered to 0 - 15°C, an alkali solution is added dropwise to the organic solution, and then methanesulfonyl chloride, p-toluenesulfonic anhydride, or trifluoromethanesulfonic anhydride is added to the organic solution, and the temperature is raised for reaction.

[0040] In some embodiments, in the step of forming the compound of formula I, after the reaction, the reaction system is extracted, dried, filtered, and concentrated to obtain the compound of formula I.

[0041] In some embodiments, in the step of preparing the generative I compound, 2-bromo-6-nitrophenol reacts with methanesulfonyl chloride, and the organic solvent is selected from one or a combination of more than one of N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0042] In some embodiments, in the step of preparing the generative I compound, 2-bromo-6-nitrophenol reacts with p-toluenesulfonic anhydride, and the organic solvent is selected from pyridine and / or dichloromethane.

[0043] Preferably, the organic solvent is a mixture of pyridine and dichloromethane. More preferably, the volume ratio of pyridine to dichloromethane is 1:1 - 5.

[0044] In some embodiments, in the step of preparing the generative I compound, 2-bromo-6-nitrophenol reacts with trifluoromethanesulfonic anhydride, and the organic solvent is selected from pyridine and / or dichloromethane.

[0045] Preferably, the organic solvent is a mixture of pyridine and dichloromethane. More preferably, the volume ratio of pyridine to dichloromethane is 1:1 - 5.

[0046] The present invention further protects an intermediate for preparing 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, and the intermediate has the structure shown in Formula I:

[0047] Wherein, in Formula I, the group A is selected from a mesyl group, a p-toluenesulfonyl group, or a trifluoromethanesulfonyl group.

[0048] Compared with the prior art, the present invention has the following technical advantages:

[0049] (1) The prior art uses 1-bromo-2-fluoro-3-nitro-benzene as the starting material to synthesize the target product. However, the cost of this starting material is expensive. Although the starting material 2-bromo-6-nitrophenol used in the present invention is structurally similar to 1-bromo-2-fluoro-3-nitro-benzene in the prior art, due to the completely different electrical properties of the fluorine substituent and the hydroxyl substituent, the fluorine substituent is electron-withdrawing, while the hydroxyl group is electron-donating. As a result, if a similar scheme in the prior art is adopted and 2-bromo-6-nitrophenol is directly reacted with methylamine, the yield of the 2-bromo-N-methyl-6-nitroaniline intermediate is extremely low, and it is completely impossible to industrialize, and the problem of high cost of synthesizing the target product in the prior art cannot be solved. Through a large number of studies, the inventor of the present invention found that by first reacting 2-bromo-6-nitrophenol with a specific reagent such as methanesulfonyl chloride, p-toluenesulfonic anhydride or trifluoromethanesulfonic anhydride, the hydroxyl group in 2-bromo-6-nitrophenol is converted into an easily leaving group such as methanesulfonyloxy (-OMs), p-toluenesulfonyloxy (-OTs) or trifluoromethanesulfonyloxy (-OTf) to obtain an intermediate of formula I compound, and then reacting this intermediate with methylamine can significantly improve the yield of 2-bromo-6-nitrophenol to produce 2-bromo-N-methyl-6-nitroaniline. Furthermore, on the premise of ensuring the yield of the final target product, a starting material with low cost can be used, and the production cost of the entire synthesis route can be significantly reduced.

[0050] (2) The present invention uses sodium dithionite and / or stannous chloride as the reducing agent for 2-bromo-N-methyl-6-nitroaniline, avoiding the violent reaction process when Fe is used as the reducing agent in the prior art. The reaction conditions of the entire reaction route are mild and easy to industrialize.

[0051] (3) The yield of each step of the preparation method of the present invention is above 92%, and the yield of some steps can reach 99.5%, and the yield of the target product is high. Description of the Drawings

[0052] Figure 1 High performance liquid chromatography of 2-bromo-6-nitro-1-methylsulfonyl phenol in Example 1;

[0053] Figure 2 High performance liquid chromatography of 6-bromo-N1-methylbenzene-1,2-diamine in Example 1;

[0054] Figure 3 1H NMR spectrum of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one in Example 1. Detailed Description of the Invention

[0055] The present invention will be further described below in conjunction with embodiments. However, the present invention is not limited to the following embodiments. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use, and the implementation conditions not specified are conventional conditions in the industry. The technical features involved in each implementation manner of the present invention can be combined with each other as long as they do not conflict with each other.

[0056] The present invention will be further described in detail below in conjunction with specific embodiments.

[0057] Example 1

[0058] The reaction formula of this example is as follows:

[0059]

[0060] (1) Preparation of 2-bromo-6-nitro-1-methylsulfonylphenol

[0061] Dissolve 2-bromo-6-nitrophenol (2.14 g, 9.8 mmol) in N,N-dimethylformamide (6.4 mL) at room temperature. When the temperature is lowered to 15 °C, potassium carbonate (total addition amount is 4.07 g) is added in batches, the temperature is controlled to be less than 20 °C, and the addition time is 30 minutes (the first 1 g added needs to be added slowly). Then methanesulfonyl chloride MsCl (2.78 g) is quickly added. After adding, the temperature is raised to 40 °C and the reaction is carried out for 16 h. Sampling is taken, water and ethyl acetate are used for extraction, and TLC plate spotting shows that there is basically no raw material, and HPLC is used to judge that the content of the raw material 2-bromo-6-nitrophenol is less than 1% at 214 nm, indicating the end of the reaction.

[0062] The reaction system is cooled to room temperature, water (10 mL) and methyl tert-butyl ether (15 mL) are added, stirred for 10 minutes, allowed to stand for layer separation, and extracted once; methyl tert-butyl ether (10 mL) is added again, stirred for 10 minutes, allowed to stand for layer separation, and extracted for the second time. The organic layers of the two times are combined, dried with anhydrous sodium sulfate (0.5 g) (stirred for 30 minutes), filtered, and rinsed with methyl tert-butyl ether (0.5 mL). The filtrate is concentrated under reduced pressure (45 °C, -0.1 MPa) to remove methyl tert-butyl ether. The pale yellow liquid 2-bromo-6-nitro-1-methylsulfonylphenol is obtained The yield is 99.5% and the purity is 93%. At room temperature, 2-bromo-6-nitro-1-methylsulfonylphenol turns into a pale yellow solid, and its high performance liquid chromatography diagram is as Figure 1 shown.

[0063] (2) Preparation of 2-bromo-N-methyl-6-nitroaniline

[0064] Add an aqueous solution of methylamine with a mass percentage of 40% (solution volume: 2.286 g) to a four-necked flask, start stirring, and then add 2-bromo-6-nitrophenol methylsulfonate (2.27 g). Raise the temperature to 80 °C, react for 18 h, take a sample and extract it with ethyl acetate. TLC plate spotting reveals that part of 2-bromo-6-nitrophenol is formed, and the reaction is terminated. Cool the reaction system to 30 °C, add 15 mL of ethyl acetate and 10 mL of water, stir for 10 minutes, let it stand for liquid separation, and extract once. Then add 5 mL of an aqueous solution of potassium carbonate with a mass percentage of 14% to the reaction solution to adjust its pH to 9. Add 5 mL of water to the reaction solution, stir for 10 minutes, let it stand for liquid separation, and extract once. Add another 5 mL of water, stir for 10 minutes, let it stand for liquid separation, and extract once again. Concentrate the extract under reduced pressure (45 °C, -0.1 MPa) to remove ethyl acetate, and obtain the red liquid 2-bromo-N-methyl-6-nitroaniline The yield is 97%. The red liquid gradually turns into red crystals at room temperature.

[0065] (3) Preparation of 6-bromo-N1-methylbenzene-1,2-diamine

[0066] Dissolve sodium carbonate (3.48 g) in water (20 mL), then add sodium dithionite (5.72 g) and methanol (5 mL) thereto to obtain a mixed solution, and cool the temperature of the mixed solution to 20 °C. Dissolve 2-bromo-N-methyl-6-nitroaniline in 5 mL of methanol, and then slowly drop this methanol solution into the mixed solution, controlling the temperature of the reaction system to remain at 25 °C, and reacting for 3 h with stirring. Take a sample, extract it with water and ethyl acetate, and stop the reaction when there is no raw material by TLC plate spotting. Add 15 mL of water and 10 mL of ethyl acetate to the reaction solution, and stir for 1 h. Filter the reaction solution, wash the filter cake with ethyl acetate, re-stir the filtrate for 10 minutes, let it stand for liquid separation, and extract once. Adjust the pH value of the aqueous phase to 9 with 1.3 g of sodium hydroxide. Add 18 mL of ethyl acetate, stir for 10 min, let it stand for liquid separation, and extract once. Then add 15 mL of ethyl acetate, stir for 10 minutes, let it stand for liquid separation, and extract once again. Combine the organic phases and concentrate under reduced pressure (45 °C, -0.1 MPa) to remove ethyl acetate. Obtain the black liquid 6-bromo-N1-methylbenzene-1,2-diamine The yield is 92%. Its high performance liquid chromatography diagram is as Figure 2 shown.

[0067] (4) Preparation of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

[0068] Dissolve 6-bromo-N1-methylbenzene-1,2-diamine (1.8 g) in acetonitrile (30 g), lower the temperature to below 10 °C, and add N,N'-dicarbonylimidazole CDI (2.91 g) in batches. After the addition, stir at 10 °C for 1 h. Heat the reaction system to 85 °C and reflux overnight. Take a sample, extract with ethyl acetate and water, and terminate the reaction when there is no raw material on the TLC plate. Lower the temperature of the reaction system to room temperature, then filter the reaction solution, collect the filtrate, and concentrate it under reduced pressure (45 °C, -0.1 MPa) to remove acetonitrile. Wash the filter cake and the concentrated filtrate with 5 mL of acetonitrile and 20 mL of water, filter, wash with 2 mL of water, wash and filter with 3 mL of petroleum ether and 1 mL of ethyl acetate, wash with 0.5 mL of petroleum ether, and dry to obtain a pink solid, 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, with a yield of 92% and a purity of 97%. Its 1H NMR spectrum is as shown in Figure 3 shown.

[0069] Comparative Example 1

[0070] Add an aqueous solution of methylamine with a mass percentage of 40% (solution volume is 2.286 g) to a four-necked flask, start stirring, and then add 2-bromo-6-nitrophenol (2.14 g, 9.8 mmol). Raise the temperature to 80 °C and react for 18 h. Take a sample and extract with ethyl acetate. When it is found by TLC plate that part of 2-bromo-6-nitrophenol is generated, terminate the reaction. Cool the reaction system to 30 °C, add 15 mL of ethyl acetate and 10 mL of water, stir for 10 minutes, let it stand for layer separation, and extract once. Then add 5 mL of an aqueous solution of potassium carbonate with a mass percentage of 14% to the reaction solution to adjust its pH to 9. Add 5 mL of water to the reaction solution, stir for 10 minutes, let it stand for layer separation, and extract once. Add another 5 mL of water, stir for 10 minutes, let it stand for layer separation, and extract once again. Concentrate the extract under reduced pressure (45 °C, -0.1 MPa) to remove ethyl acetate to obtain a red liquid, 2-bromo-N-methyl-6-nitroaniline with a yield of 20%. The red liquid gradually turns into red crystals at room temperature.

[0071] It can be seen that when 2-bromo-6-nitrophenol reacts directly with methylamine, the yield is very low.

[0072] Example 2

[0073] This example is basically the same as Example 1, with the only difference being that steps (1) and (2) are different. Steps (1) and (2) are as follows:

[0074] (1) Preparation of 2-bromo-6-nitrophenyl-4-methylbenzenesulfonate

[0075] Dissolve 2-bromo-6-nitrophenol The product (2.14 g, 9.8 mmol) was dissolved in a mixture of pyridine and dichloromethane (1:5 volume ratio, total volume 6.4 mL) at room temperature. When the temperature dropped to 15°C, potassium carbonate (4.07 g total) was added portionwise. The temperature was then lowered to 0°C, and p-toluenesulfonic anhydride (2.78 g) was added. The reaction was then stirred at -10°C for 16 hours. A sample was taken, extracted with water and ethyl acetate, and a TLC plate was spotted, revealing the absence of the starting material. HPLC analysis at 214 nm indicated that the content of the starting material, 2-bromo-6-nitrophenol, was less than 1%, indicating the completion of the reaction.

[0076] The reaction system was warmed to room temperature, water (10 mL) and methyl tert-butyl ether (15 mL) were added, stirred for 10 minutes, allowed to stand for stratification, and extracted once; methyl tert-butyl ether (10 mL) was added again, stirred for 10 minutes, allowed to stand for stratification, and extracted a second time. The two organic layers were combined, dried over anhydrous sodium sulfate (0.5 g) (stirred for 30 minutes), filtered, and rinsed with methyl tert-butyl ether (0.5 mL). The filtrate was concentrated under reduced pressure (45 ° C, -0.1 MPa) to remove methyl tert-butyl ether. A light yellow liquid 2-bromo-6-nitrophenyl-4-methylbenzenesulfonate was obtained. The yield was 92% and the purity was 93%. It turned into a light yellow solid at room temperature.

[0077] (2) Preparation of 2-bromo-N-methyl-6-nitroaniline

[0078] Add 40% methylamine aqueous solution (2.286 g) into a four-necked flask and stir, then add 2-bromo-6-nitrophenyl-4-methylbenzenesulfonate. (2.10g). The temperature was raised to 80°C, the reaction was allowed to proceed for 18 hours, a sample was taken and extracted with ethyl acetate, and TLC was performed to detect the formation of some 2-bromo-6-nitrophenol, and the reaction was terminated. The reaction system was cooled to 30°C, 15mL of ethyl acetate and 10mL of water were added, the mixture was stirred for 10 minutes, the mixture was allowed to stand for stratification, and the mixture was extracted once. 5mL of a 14% by mass aqueous solution of potassium carbonate was added to the reaction solution to adjust its pH to 9. 5mL of water was added to the reaction solution, the mixture was stirred for 10 minutes, the mixture was allowed to stand for stratification, and the mixture was extracted once. 5mL of water was added to the reaction solution, the mixture was stirred for 10 minutes, the mixture was allowed to stand for stratification, and the mixture was extracted once. 5mL of water was added to the reaction solution, the mixture was stirred for 10 minutes, the mixture was allowed to stand for stratification, and the mixture was extracted once. The filtrate was concentrated under reduced pressure (50°C, -0.1MPa) to remove ethyl acetate, and a red liquid of 2-bromo-N-methyl-6-nitroaniline was obtained. The yield was 93%.The red liquid gradually turned into red crystals at room temperature.

[0079] Example 3

[0080] This embodiment is basically the same as embodiment 1, except that steps (1) and (2) are different. Steps (1) and (2) are specifically as follows:

[0081] (1) Preparation of 2-bromo-6-nitrophenyl trifluoromethanesulfonate

[0082] Dissolve 2-bromo-6-nitrophenol (2.14 g, 9.8 mmol) in a mixed solvent of pyridine and dichloromethane (the volume ratio of the two is 1:5, and the total volume is 6.4 mL) at room temperature. When the temperature is lowered to 15 °C, potassium carbonate (with a total addition of 4.07 g) is added in batches, the temperature is lowered to 0 °C, trifluoromethanesulfonic anhydride (2.78 g) is added, and then the reaction is stirred at -10 °C for 16 h. Sampling, adding water and ethyl acetate for extraction and TLC spotting, it is found that there is basically no raw material, and HPLC is used to judge that the content of the raw material 2-bromo-6-nitrophenol is less than 1% at 214 nm, indicating the end of the reaction.

[0083] Raise the reaction system to room temperature, add water (10 mL) and methyl tert-butyl ether (15 mL), stir for 10 minutes, let it stand for layering, and extract once; add methyl tert-butyl ether (10 mL) again, stir for 10 minutes, let it stand for layering, and extract for the second time. Combine the organic layers of the two times, dry with anhydrous sodium sulfate (0.5 g) (stir for 30 minutes), filter, and wash with methyl tert-butyl ether (0.5 mL). Concentrate the filtrate under reduced pressure (45 °C, -0.1 MPa) to remove methyl tert-butyl ether. Obtain 2-bromo-6-nitrophenyl trifluoromethanesulfonate as a pale yellow liquid The yield is 93%, and the purity is 92%. It becomes a pale yellow solid at room temperature.

[0084] (2) Preparation of 2-bromo-N-methyl-6-nitroaniline

[0085] Add 40% aqueous methylamine solution (the solution amount is 2.08 g) to a four-necked flask, start stirring, and then add 2-bromo-6-nitrophenyl trifluoromethanesulfonate (2.11 g). Raise the temperature to 80 °C and react for 18 h. Sampling and extracting with ethyl acetate, TLC spotting shows that part of 2-bromo-6-nitrophenol is generated, and the reaction is terminated. Cool the reaction system to 30 °C, add 15 mL of ethyl acetate and 10 mL of water, stir for 10 minutes and let it stand for layering, and extract once. Add 5 mL of 14% aqueous potassium carbonate solution to the reaction solution to adjust its pH to 9. Add 5 mL of water to the reaction solution, stir for 10 minutes and let it stand for layering, and extract once. Add 5 mL of water again, stir for 10 minutes and let it stand for layering, and extract again. Concentrate the filtrate under reduced pressure (50 °C, -0.1 MPa) to remove ethyl acetate. Obtain 2-bromo-N-methyl-6-nitroaniline as a red liquid The yield is 91%. The red liquid gradually becomes red crystals at room temperature.

[0086] The above embodiments are only for illustrating the technical concept and features of the present invention, and the purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly. However, the protection scope of the present invention cannot be limited thereby. Any equivalent changes or modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

[0087] In the ranges disclosed herein, endpoints and any values are not limited to the exact ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the endpoint values of each range, between the endpoint values of each range and a single point value, and between single point values, they can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein.

Claims

1. A preparation method of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, characterized in that, The preparation method includes the following steps: 1) React the compound of formula I with methylamine to obtain 2-bromo-N-methyl-6-nitroaniline wherein, in formula I, group A is a mesyl group; 2) Carry out a reduction reaction on the 2-bromo-N-methyl-6-nitroaniline in the presence of a reducing agent to obtain 6-bromo-N1-methylbenzene-1,2-diamine The reducing agent is sodium dithionite; 3) React the 6-bromo-N1-methylbenzene-1,2-diamine with N,N'-dicarbonylimidazole in an organic solvent to obtain the 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one; The preparation method further includes: reacting 2-bromo-6-nitrophenol with methanesulfonyl chloride in an organic solvent under alkaline conditions to form the compound of formula I; In step 1), the molar ratio of the compound of formula I to methylamine is 1:1 - 2.

2. The preparation method of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one according to claim 1, characterized in that, In step 1), the methylamine exists in the form of an aqueous solution or an alcohol solution; and / or, in step 1), the temperature of the reaction is 50 - 100 °C; and / or, in step 1), the reaction time is 15 - 20 h; and / or, after the reaction in step 1) ends, the reaction system is extracted, the pH is adjusted by adding a base, and concentrated to obtain the 2-bromo-N-methyl-6-nitroaniline.

3. The preparation method of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one according to claim 1, characterized in that, In step 2), the molar ratio of the 2-bromo-N-methyl-6-nitroaniline to the reducing agent is 1:1 - 4; and / or, in step 2), the temperature of the reduction reaction is 20 - 30 °C; and / or, in step 2), the reaction time of the reduction reaction is 2 - 4 h; and / or, in step 2), the reduction reaction is carried out under alkaline conditions and in an organic solvent.

4. The preparation method of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one according to claim 1, characterized in that, In step 2), the reducing agent, the base, and the alcohol solvent are mixed in water to obtain a mixed solution, and the organic solution of 2-bromo-N-methyl-6-nitroaniline is added dropwise to the mixed solution to carry out the reduction reaction; and / or, after the reduction reaction in step 2) ends, an organic solvent is added to the reaction system for extraction, the pH is adjusted by adding a base, and concentrated to obtain the 6-bromo-N1-methylbenzene-1,2-diamine.

5. The preparation method of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one according to claim 1, characterized in that, In step 3), the molar ratio of the 6-bromo-N1-methylbenzene-1,2-diamine to N,N'-dicarbonylimidazole is 1:1 - 3; and / or, in step 3), the reaction is carried out at the reflux temperature; and / or, in step 3), the organic solvent is selected from one or more combinations of methanol, ethanol, isopropanol, n-butanol, tert-butanol, acetonitrile, and acetone.

6. The preparation method of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one according to claim 1, characterized in that, In step 3), at 0 - 10 °C, the N,N'-dicarbonylimidazole is added in batches to the organic solution of the 6-bromo-N1-methylbenzene-1,2-diamine, and then heated to the reflux temperature for reaction.

7. The preparation method of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one according to claim 1, characterized in that, In the step of generating the compound of formula I, the alkaline condition is formed by adding one or more bases selected from sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, and sodium carbonate; and / or, in the step of generating the compound of formula I, the organic solvent is selected from one or more combinations of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, pyridine, and dichloromethane.

8. The preparation method of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one according to claim 1, characterized in that, In the step of generating the compound of formula I, the temperature of the reaction is 20 - 80 °C; and / or, in the step of generating the compound of formula I, the reaction time is 14 - 16 h; and / or, in the step of generating the compound of formula I, 2-bromo-6-nitrophenol is dissolved in the organic solvent to obtain an organic solution, the temperature of the organic solution is lowered to 0 - 15 °C, an alkali solution is added dropwise to the organic solution, and then methanesulfonyl chloride is added to the organic solution, and the temperature is raised for reaction; and / or, after the reaction in the step of generating the compound of formula I ends, the reaction system is extracted, dried, filtered, and concentrated to obtain the compound of formula I.

9. The preparation method of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one according to claim 1, characterized in that, In the step of the generative I compound, 2-bromo-6-nitrophenol reacts with methanesulfonyl chloride, and the organic solvent is selected from one or a combination of more than one of N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

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