A process for the preparation of 2-bromo-5,6-dichloro-1H-benzimidazole

Abstract

A synthesis method of a maribavir intermediate 2-bromo-5,6-dichloro-1H-benzimidazole, which is prepared from 4,5-dichloro-2-nitroaniline as raw material through hydrogenation reduction, cyclization and nucleophilic substitution reaction to obtain the intermediate 2-bromo-5,6-dichloro-1H-benzimidazole. The reagent selected in the application has low price, mild reaction condition, simple operation, high process reproducibility, simple post-treatment, high product purity and yield, and has realized workshop industrial production.

Description

Technical Field

[0001] This article relates to the field of drug synthesis technology, specifically to a method for synthesizing 2-bromo-5,6-dichloro-1H-benzimidazole, an intermediate of maribavir. Background Technology

[0002] Maribavir, chemically known as 5,6-dichloro-2-(isopropylamino)-1-(β-L-furanoribosyl)-1H-benzimidazole, is a novel benzimidazole riboside inhibitor belonging to the pUL97 protein kinase inhibitor class. It possesses a unique mechanism of action against cytomegalovirus (CMV). Due to its high oral absorption rate and few adverse reactions, maribavir exhibits excellent clinical safety. Maribavir has been granted Orphan Drug Designation by the U.S. Food and Drug Administration and the European Commission for the treatment of severe cytomegalovirus viremia in high-risk patient groups and for the treatment of CMV infection in immunocompromised patients. In the United States, it has also been granted Breakthrough Therapy Designation for the treatment of CMV infection in transplant recipients. In China, maribavir received clinical trial approval in April 2020 and was included in the Breakthrough Therapy designation for the treatment of CMV infection.

[0003] The original developer, GlaxoSmithKline, disclosed the following synthetic route for maribavir in patent application CN1214049A:

[0004]

[0005] 2-Bromo-5,6-dichloro-1H-benzimidazole and tetraacetylribose are condensed in the presence of N,O-bis(trimethylsilylacetamide) to give intermediate 1. Intermediate 1 is then hydrolyzed with sodium carbonate to give intermediate 2. Finally, intermediate 2 reacts with isopropylamine to give maribavir. This route has mild process conditions, is simple to operate, and can be used for the industrial production of the active pharmaceutical ingredient maribavir.

[0006] The starting material 2-bromo-5,6-dichloro-1H-benzimidazole is an important intermediate in the synthesis of maribavir. The currently disclosed synthetic route for this intermediate is as follows:

[0007] Route 1:

[0008]

[0009] This process route uses 4,5-dichloro-2-nitroaniline as a raw material, which undergoes catalytic hydrogenation, cyclization, and substitution to obtain the intermediate 2-bromo-5,6-dichloro-1H-benzimidazole as shown in formula D. This process route has the following problems: (1) The catalytic hydrogenation reduction reaction uses Raney nickel as a catalyst, which is highly flammable, leading to complex post-processing and catalyst recovery; (2) The cyclization reaction uses cyanide bromide, a highly toxic reagent that also produces the byproduct hydrogen cyanide; (3) The substitution reaction uses nitrite, which produces the dangerous and explosive intermediate product diazonium salt. Therefore, this process route is complex, highly dangerous, and causes significant environmental pollution, making it unsuitable for industrial production.

[0010] Route 2:

[0011]

[0012] This process uses 4,5-dichloro-1,2-phenylenediamine as a raw material, which undergoes cyclization with urea and then substitution with phosphorus tribromooxy to obtain the intermediate 2-bromo-5,6-dichloro-1H-benzimidazole as shown in formula D. This process has the following problems: (1) Cyclocyclization with urea requires reflux reaction at 118°C with n-butanol, with a yield of approximately 30%; (2) The substitution reaction with phosphorus tribromooxy is dangerous and has high production costs. Therefore, this process is costly and dangerous, making it unsuitable for industrial production.

[0013] Route 3:

[0014]

[0015] This process route uses 4,5-dichloro-2-nitroaniline as raw material, and through catalytic hydrogenation, cyclization, and substitution, yields the intermediate 2-bromo-5,6-dichloro-1H-benzimidazole as shown in formula D. This process route has the following problems: (1) The catalytic hydrogenation reduction reaction uses Raney nickel as a catalyst, which is highly flammable, leading to complex post-processing and catalyst recovery processes; (2) The substitution reaction uses the hazardous reagent sodium hydride as a catalyst, resulting in high production costs and a final yield of approximately 10%. Therefore, this process route has complex post-processing, high production costs, and low yield, making it unsuitable for industrial production.

[0016] Route 4:

[0017]

[0018] This process route uses 4,5-dichloro-1,2-phenylenediamine as a raw material, and through a two-step reaction of cyclization and substitution, yields the intermediate 2-bromo-5,6-dichloro-1H-benzimidazole as shown in formula D. This process route has the following problems: (1) the cyclization reaction uses the highly toxic reagent cyanide bromide; (2) the substitution reaction uses nitrite, which will produce a dangerous and explosive intermediate diazonium salt. Therefore, this process route is not suitable for industrial production.

[0019] In summary, developing a synthetic method for 2-bromo-5,6-dichloro-1H-benzimidazole that uses low-cost reagents, has mild process conditions, simple post-processing procedures, and can obtain high yields and high purity is a technical problem that urgently needs to be solved. Summary of the Invention

[0020] To overcome the shortcomings of existing technologies, this application provides a method for synthesizing the maribavir intermediate 2-bromo-5,6-dichloro-1H-benzimidazole (as shown in Formula D). The problem to be solved is to overcome the drawbacks of existing methods for synthesizing the 2-bromo-5,6-dichloro-1H-benzimidazole intermediate, which include high production costs, low yields, complex post-processing, high risks, and are not conducive to industrial production. The synthesis method of this application has the advantages of low production costs, high yields, simple post-processing, and no use of hazardous reagents, making it more suitable for industrial production.

[0021] This application provides a method for preparing the maribavir intermediate 2-bromo-5,6-dichloro-1H-benzimidazole, the synthetic route of which is as follows:

[0022] S1): Compound A undergoes a hydrogenation-reduction reaction with hydrazine hydrate in the presence of a metal catalyst to yield compound B.

[0023]

[0024] S2): Compound B undergoes a cyclization reaction with carbon disulfide to yield compound C.

[0025]

[0026] S3): Compound C undergoes a substitution reaction with bromine to give 2-bromo-5,6-dichloro-1H-benzimidazole.

[0027]

[0028] In one exemplary embodiment, step S1) includes: compound A and hydrazine hydrate undergo a hydrogenation reduction reaction in a first solvent under the action of a metal catalyst to obtain compound B.

[0029] In one exemplary embodiment, step S2) includes: the compound B undergoes a cyclization reaction with carbon disulfide in a second solvent under the action of a phase transfer catalyst and an acid-binding agent to obtain compound C.

[0030]

[0031] In one exemplary embodiment, step S3) includes: the compound C reacts with bromine in a third solvent under the action of an initiator to give compound D, namely 2-bromo-5,6-dichloro-1H-benzimidazole.

[0032]

[0033] In one exemplary embodiment, the metal catalyst is platinum-carbon; preferably, the metal catalyst is platinum-carbon with a platinum mass fraction of 5%.

[0034] In one exemplary embodiment, the hydrazine hydrate is hydrazine hydrate with a mass fraction of 85%.

[0035] In one exemplary embodiment, the first solvent is selected from one or a combination of methanol, ethanol, isopropanol, acetone, tetrahydrofuran and water; preferably, the first solvent is ethanol; more preferably, the first solvent is 95% (v / v) ethanol.

[0036] In one exemplary embodiment, in step S1), the molar ratio of compound A: hydrazine hydrate: metal catalyst is 1:(1-3):(0.001-0.01).

[0037] In one exemplary embodiment, step S1) involves the following steps for the hydrogenation reduction reaction:

[0038] Compound A, the first solvent, and the metal catalyst were added to a reaction vessel and stirred. Hydrazine hydrate was slowly added dropwise. After the addition was complete, the mixture was heated and reacted. After the reaction was completed, the mixture was cooled and filtered while hot. The filtrate was collected, concentrated, and dried to obtain compound B.

[0039] Preferably, compound A, 95% (v / v) ethanol, and platinum carbon are added to a reaction vessel and stirred. The temperature is controlled to below 15°C, and hydrazine hydrate is slowly added dropwise. After the addition is complete, the temperature is raised to 30°C-40°C and stirred for 1 hour. The temperature is then raised to 60°C-70°C and stirred until the reaction is complete. The temperature is then lowered. The reaction solution temperature is controlled at 45°C-55°C. The mixture is filtered while hot, and the filtrate is collected, concentrated, and dried to obtain compound B.

[0040] In one exemplary embodiment, the phase transfer catalyst is a quaternary ammonium salt phase transfer catalyst. Preferably, the phase transfer catalyst is selected from one or a combination of several of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, and tetradecyltrimethylammonium chloride. More preferably, the phase transfer catalyst is tetrabutylammonium bromide.

[0041] In one exemplary embodiment, the acid-binding agent is selected from one or a combination of several of potassium carbonate, ammonium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate; preferably, the acid-binding agent is sodium carbonate.

[0042] In one exemplary embodiment, the second solvent is selected from one or a combination of methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, and water; preferably, the second solvent is ethanol; more preferably, the second solvent is 50% (v / v) ethanol.

[0043] In an exemplary embodiment, in step S2), the molar ratio of compound B: carbon disulfide: phase transfer catalyst: acid-binding agent is 1:(1-3):(0.5-1.5).

[0044] In one exemplary embodiment, step S2) involves the following steps for the cyclization reaction:

[0045] The acid-binding agent, the phase transfer catalyst, compound B, and the second solvent were added to a reaction vessel, and carbon disulfide was slowly added dropwise. After the addition was complete, the mixture was heated to reflux and reacted. After the reaction was completed, the reaction solution was concentrated and the temperature was controlled to below 25°C. The pH of the reaction solution was adjusted to neutral or weakly alkaline until a large amount of solid precipitated. The mixture was then filtered, dried, and the filter cake was collected to obtain compound C.

[0046] Preferably, sodium carbonate, tetrabutylammonium bromide, compound B, and 50% (v / v) ethanol are added to a reaction vessel, the temperature is controlled to below 25°C, and carbon disulfide is slowly added dropwise. After the addition is complete, the temperature is raised to 30°C-40°C and the reaction is stirred for 2 hours, then the temperature is raised to 85°C-95°C until the reaction is complete. The reaction solution is concentrated until no large amount of solvent evaporates, the temperature is controlled to below 25°C, and the pH of the reaction solution is adjusted to neutral or weakly alkaline until a large amount of solid precipitates. The solution is then filtered, dried, and the filter cake is collected to obtain compound C.

[0047] In one exemplary embodiment, the initiator is hydrogen bromide, a hydrobromic acid solution, or an aqueous solution of hydrogen bromide (with a hydrogen bromide content of 33 wt%); preferably, the initiator is a hydrobromic acid solution; more preferably, the initiator is a hydrobromic acid solution with a hydrogen bromide content of 33 wt%.

[0048] In one exemplary embodiment, the third solvent is selected from one or a combination of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, acetic acid, and N,N-dimethylformamide; preferably, the third solvent is a combination of N,N-dimethylformamide and acetic acid.

[0049] In one exemplary embodiment, the volume ratio of N,N-dimethylformamide to acetic acid in the third solvent is 1:1 to 1:5; preferably, the volume ratio of N,N-dimethylformamide to acetic acid in the third solvent is 1:1 or 1:5; more preferably, the volume ratio of N,N-dimethylformamide to acetic acid in the third solvent is 1:1.

[0050] In an exemplary embodiment, in step S3), the molar ratio of compound C: bromine: initiator is 1:(1-5):(0.5-3).

[0051] In one exemplary embodiment, the temperature of the substitution reaction is 50-60°C.

[0052] In one exemplary embodiment, step S3) involves the following reaction steps for the substitution reaction:

[0053] Compound C, the third solvent, and the initiator were added to a reaction vessel and stirred. Bromine was slowly added dropwise to the reaction vessel. After the addition was complete, the temperature was raised and the reaction was initiated. After the reaction was completed, the temperature was lowered and the reaction was quenched until a large amount of solid precipitated. The mixture was then filtered, dried, and the filter cake was collected to obtain compound D.

[0054] Preferably, compound C, a mixed solution of N,N-dimethylformamide and acetic acid in a volume ratio of 1:1, and a solution of hydrobromic acid are added to a reaction vessel, stirred, and the temperature is controlled below 25°C. Bromine is slowly added dropwise. After the addition is complete, the temperature is raised to 50°C-60°C and the reaction is stirred for 3 hours until the reaction is complete. The reaction solution is then cooled to below 25°C and quenched with water, resulting in the precipitation of a large amount of solid. The solid is filtered, dried, and the filter cake is collected to obtain compound D.

[0055] Compared with the prior art, this application has the following technical features and advantages:

[0056] First, in step S1), a platinum-carbon catalyst is used instead of the Raney nickel catalyst in the prior art. The platinum-carbon catalyst has relatively low activity, which avoids the hydrogenation reduction of the chlorine site in compound A, reduces the generation of intermediate by-products, and improves the conversion rate. At the same time, platinum-carbon does not have the characteristic of being extremely easy to spontaneously combust with Raney nickel catalyst, which simplifies the post-processing process and catalyst recovery process.

[0057] Second, in step S2), an acid-binding agent is added, along with a phase transfer catalyst, such as tetrabutylammonium bromide, as a catalyst. This not only avoids the generation of acidic byproducts but also improves the conversion rate.

[0058] Third, in step S3), N,N-dimethylformamide and acetic acid are used as the reaction solvent, and hydrobromic acid is used as the initiator of the nucleophilic substitution reaction to make the reaction more complete, thereby improving the conversion rate.

[0059] In summary, the synthesis method of this application has the following advantages: 1) no hazardous reagents are used and the process conditions are mild; 2) the conversion rate and product purity are improved; and 3) the post-processing procedure is simplified.

[0060] Other features and advantages of this application will be set forth in the following description, and will be apparent in part from the description, or may be learned by practicing the application. Other advantages of this application can be realized and obtained by means of the solutions described in the description and the accompanying drawings. Attached Figure Description

[0061] The accompanying drawings are used to provide an understanding of the technical solutions of this application and constitute a part of the specification. They are used together with the embodiments of this application to explain the technical solutions of this application and do not constitute a limitation on the technical solutions of this application.

[0062] Figure 1 The HPLC chromatogram for determining the purity of amines by high performance liquid chromatography in Example 1-1;

[0063] Figure 2 The HPLC chromatograms for determining the purity of cyclic compounds using high performance liquid chromatography in Examples 4-4 are shown.

[0064] Figure 3 The HPLC chromatogram for determining the purity of substituted compounds by high performance liquid chromatography in Example 5-1;

[0065] Figure 4 The HPLC chromatogram for detecting amine conversion rate by high performance liquid chromatography in Example 1-1;

[0066] Figure 5 The HPLC chromatograms for detecting the conversion rate of cyclic compounds by high performance liquid chromatography in Examples 4-4 are shown.

[0067] Figure 6 The image shows the HPLC chromatogram for detecting the conversion rate of substituted compounds using high performance liquid chromatography in Example 5-1. Detailed Implementation

[0068] The present invention will be further described in detail below with reference to embodiments, but this is not intended to limit the present invention. Any equivalent substitutions made in accordance with the disclosure of the present invention shall fall within the protection scope of the present invention.

[0069] In the following specific embodiments, operations without specified conditions are performed under standard conditions or conditions recommended by the manufacturer. Raw materials without specified manufacturers and specifications are all commercially available products.

[0070] The conversion rate of the reaction in this application was determined by high performance liquid chromatography (HPLC). The HPLC chromatogram was determined using an HPLC instrument with an octadecylsilane-bonded silica gel column, a UV detector with a wavelength of 210 nm, mobile phase A being 20 nM potassium dihydrogen phosphate solution, and mobile phase B being acetonitrile. Gradient elution was used for the determination.

[0071] The specific testing conditions are as follows:

[0072] Column: YMC Triart C18, 4.6*150nm, 3μm

[0073] Detector: UV-210nm

[0074] Mobile phase A: 20 nM potassium dihydrogen phosphate solution

[0075] Mobile phase B: Acetonitrile

[0076] Column temperature: 30℃

[0077] Flow rate: 0.5 mL / min

[0078] Diluent: 80% acetonitrile aqueous solution

[0079] Sample concentration: 1.0 mg / mL

[0080] Injection volume: 1 μL

[0081] The elution procedure is as follows:

[0082] Time / min Mobile phase A (%) Mobile phase B (%) 0 50 50 4 50 50 5 25 75 12 25 75 12.5 50 50 15 50 50

[0083] Example 1

[0084] Example 1-1

[0085] Add 1.0 kg of 4,5-dichloro-2-nitroaniline and 8.0 L of 95% (v / v) ethanol to a 50 L glass reaction vessel. Weigh 30 g of 5% platinum carbon (platinum mass fraction 5%) and add it to the reaction vessel, stirring to react. Cool down, controlling the temperature of the reaction solution below 15 °C. Then weigh 0.80 kg of 85% hydrazine hydrate (hydrazine hydrate mass fraction 85%) and slowly add it dropwise to the reaction vessel. After the addition is complete, raise the temperature to 30 °C-40 °C and stir to react for 1 hour. Then raise the temperature to 60 °C-70 °C and stir to react for 4 hours. Take samples to monitor until the conversion rate is ≥99%. After the reaction was completed, the temperature was lowered and controlled at 45℃-55℃. The mixture was filtered while hot, and the filter cake was washed twice with 1L of hot 95% (v / v) ethanol. The filtrate was concentrated until no solvent evaporated. The concentrated product was then placed in an electric vacuum drying oven and dried under reduced pressure at 55℃-65℃. The intermediate amine 4,5-dichloro-1,2-phenylenediamine was obtained with a yield of 0.82kg, a yield of 95%, and a product purity of 99%.

[0086] Examples 1-2

[0087] Under controlled temperature conditions of 10℃-30℃, 10g of 4,5-dichloro-2-nitroaniline, 85mL of concentrated hydrochloric acid, and 100mL of 95% (v / v) ethanol were added to a 500mL reaction flask and stirred until dissolved. Then, 40g of zinc powder was added in batches. After the addition was complete, samples were taken and monitored until the reaction was finished. The reaction solution was filtered, and 5N sodium hydroxide was added to the filtrate to adjust the pH of the reaction solution to 9-10. The temperature was controlled at 50℃-60℃ and stirred for 15 minutes. The mixture was filtered while hot, and the filter cake was washed twice with 50mL of 95% (v / v) ethanol. The filtrate was concentrated to remove the ethanol, cooled, stirred to precipitate crystals, filtered and dried to obtain the intermediate amine 4,5-dichloro-1,2-phenylenediamine, with a yield of 12g and a yield of 140%. The product contained a large amount of sodium zinc hydroxide.

[0088] Examples 1-3

[0089] 100 g of 4,5-dichloro-2-nitroaniline and 800 mL of 95% (v / v) ethanol were added to a 2 L reaction flask and stirred. Then, 2 g of 10% palladium on carbon was added, followed by dropwise addition of 57 g of 85% hydrazine hydrate. After the addition was complete, the mixture was refluxed for 3 hours until no gas was produced. The reaction was monitored until the end of the reaction. The reaction solution was filtered while hot. The filter cake was washed twice with 100 mL of hot 95% (v / v) ethanol. After concentrating most of the filtrate, the remaining concentrate was mixed with 300 mL of water and stirred to form a slurry. The mixture was then filtered and the filter cake was vacuum dried for at least 4 hours to obtain the intermediate amination 4,5-dichloro-1,2-phenylenediamine, with a yield of 64 g and a yield of 74.8%.

[0090] Examples 1-4

[0091] In a 2L reaction flask, 100g of 4,5-dichloro-2-nitroaniline and 800mL of 95% (v / v) ethanol were added and stirred. Then, 2g of 5% platinum carbon was added, followed by dropwise addition of 57g of 85% hydrazine hydrate. After the addition was complete, the mixture was refluxed for 3 hours. Monitoring showed that the reaction was incomplete. 1g of 5% platinum carbon was then added, and the reaction was continued for another 2 hours with stirring. Monitoring showed that the starting materials had reacted completely.

[0092] Examples 1-5

[0093] 10 g of 4,5-dichloro-2-nitroaniline and 80 mL of 95% (v / v) ethanol were added to a 500 mL reaction flask and stirred. Then, 0.3 g of 5% palladium on carbon was added, followed by dropwise addition of 4.3 g of 85% hydrazine hydrate. After the addition was complete, the mixture was refluxed for 3 hours. A sample was taken for monitoring, and the reaction was found to be incomplete. Another 4.3 g of 85% hydrazine hydrate was added, and the reaction was continued for another 2 hours. A sample was taken for monitoring, and the reaction was found to be complete. The reaction solution was filtered while hot. The filter cake was washed twice with 10 mL of hot 95% (v / v) ethanol. After concentrating most of the filtrate, the remaining concentrate was mixed with 30 mL of water and stirred to form a slurry. The mixture was then filtered, and the filter cake was vacuum dried for at least 4 hours to obtain the intermediate amination 4,5-dichloro-1,2-phenylenediamine, with a yield of 6.0 g and a yield of 88.2%.

[0094] The results of the above examples show that: 1) In Examples 1-3, palladium on carbon / hydrazine hydrate was used for hydrogenation reduction reaction. Because palladium on carbon has higher activity than platinum on carbon catalyst, the chlorine substituents in the starting material 4,5-dichloro-2-nitroaniline may also be reduced and removed, resulting in a decrease in conversion rate; 2) In Examples 1-2, zinc powder / concentrated hydrochloric acid was used for hydrogenation reduction reaction. The final product will contain a large amount of zinc hydroxide / sodium salt, and the post-processing process is complicated. Therefore, the hydrogenation reduction reaction using platinum carbon / hydrazine hydrate resulted in a higher yield and purity of the intermediate amination 4,5-dichloro-1,2-phenylenediamine; 3) In Examples 1-4, when the amount of platinum carbon added was insufficient, although the hydrogenation reaction could proceed, it could not be completed; when the content of platinum carbon was increased to 3%, the hydrogenation reaction was completed; 4) In Examples 1-5, when 1.5 equivalents of hydrazine hydrate (based on 4,5-dichloro-2-nitroaniline) were added, the reaction could not be completed; when 3 equivalents were added, the reaction was completed, but the residual solvent in the post-treatment resulted in a low yield.

[0095] Example 2

[0096] Example 2-1

[0097] Add 0.6 kg of sodium carbonate, 20 g of tetrabutylammonium bromide, and 5 kg of purified water to a 50 L glass reaction vessel, stir until dissolved, then add 1.0 kg of the intermediate amine 4,5-dichloro-1,2-phenylenediamine obtained in Example 1-1 and 5 L of 95% (v / v) ethanol. Maintain the reaction temperature below 25 °C. Weigh 0.8 kg of carbon disulfide and slowly add it dropwise to the reaction vessel. After the addition is complete, raise the temperature to 30 °C-40 °C and stir for 2 hours. Then raise the temperature to 85 °C-95 °C and react for 5 hours. Take samples for monitoring until the conversion rate reaches ≥99%. After the reaction was completed, the reaction solution was concentrated until no large amount of solvent evaporated. The temperature was controlled below 25℃, and 5% hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 6-8. A large amount of solid precipitated out. The solid was filtered, and the filter cake was washed twice with purified water. The filter cake was then placed in an electric vacuum drying oven and dried under reduced pressure at 65℃-75℃ to obtain the cyclic compound 5,6-dichlorobenzimidazole-2-thiol. The yield was 1.15 kg, the yield rate was 93%, and the product purity was 99%.

[0098] Example 2-2

[0099] In a 1L three-necked flask, 35.93g of sodium carbonate and 250mL of purified water were first added and stirred until dissolved. Then, 50g of the intermediate amine 4,5-dichloro-1,2-phenylenediamine obtained in Example 1-1 and 250mL of 95% (v / v) ethanol solution were added and stirred to disperse. The temperature was controlled below 25°C, and 32.2g of carbon disulfide was added dropwise. After the addition was complete, the mixture was heated under reflux for 2 hours, and samples were taken to monitor the reaction until it was finished. The reaction solution was cooled to below 20°C, and 5% hydrochloric acid solution was added dropwise while stirring to adjust the pH of the reaction solution to 8. The mixture was filtered, and the filter cake was washed twice with 200mL of purified water. Finally, it was dried by forced air to obtain the cyclic compound 5,6-dichlorobenzimidazole-2-thiol, with a yield of 48g, a yield rate of 77.5%, and a product purity of 54%. A large amount of the amine did not participate in the reaction.

[0100] Example 2-3

[0101] In a 1L three-necked flask, first add 36g of sodium carbonate, 0.8g of tetrabutylammonium bromide, and 250mL of purified water, stirring until dissolved. Then add 50g of the intermediate amine 4,5-dichloro-1,2-phenylenediamine obtained in Example 1-1 and 250mL of 95% (v / v) ethanol solution, stirring to disperse. Maintain the temperature below 25°C, and add 21.5g of carbon disulfide dropwise. After the addition is complete, heat under reflux for 2 hours, and monitor the conversion rate at 85%. Cool the reaction solution to below 25°C, add 10.7g of carbon disulfide, and heat under reflux for 2 hours, monitoring the conversion rate until the reaction is complete. Cool the reaction solution to below 20°C, and while stirring, add 5% hydrochloric acid solution dropwise to adjust the pH to 8. After filtration, the filter cake was washed twice with 200 mL of purified water and then dried by forced air to obtain the cyclic compound 5,6-dichlorobenzimidazole-2-thiol, with a yield of 58.8 g, a yield of 94.7%, and a product purity of 98%.

[0102] From the above examples, it can be seen that: 1) Compared with the preparation method of Example 2-2, the addition of tetrabutylammonium bromide as a catalyst in Example 2-1 to participate in the cyclization reaction improved the conversion rate of the amine and also improved the purity of the cyclization product 5,6-dichlorobenzimidazole-2-thiol; 2) In Example 2-3, the initial addition of 1.0 equivalent of carbon disulfide (based on 4,5-dichloro-1,2-phenylenediamine) could not complete the reaction, but the subsequent addition of 0.5 equivalent of carbon disulfide could complete the reaction.

[0103] Example 3

[0104] Using different acid-binding agents and solvents in step S2), the results shown in Table 1 below were obtained:

[0105] Table 1

[0106]

[0107] As can be seen from Example 3: 1) In step S2), the methanol / water system was used as the reaction solvent and the compound shown in formula C was not obtained; 2) In step S2), the strong base potassium hydroxide was used as the acid-binding agent and the product yield was low, but the weak base carbonate was used as the acid-binding agent and the product yield was high. Finally, it was determined that the lower cost weak base sodium carbonate was selected as the acid-binding agent, and ethanol / water was selected as the solvent system.

[0108] Example 4

[0109] Example 4-1

[0110] In a 250 ml three-necked flask, 7.2 g of sodium carbonate, 0.1 g of tetrabutylammonium bromide, and 35 ml of purified water were first added and stirred until dissolved. Then, 10 g of the intermediate amine 4,5-dichloro-1,2-phenylenediamine obtained in Example 1-1 and 70 ml of ethanol were added and stirred to disperse. The mixture was kept below 25°C, and 5.3 g of carbon disulfide was added dropwise. After the addition was complete, the mixture was heated to reflux for 2 hours. The reaction was monitored, and 17.6% of the amine remained unreacted.

[0111] Example 4-2

[0112] In a 1L three-necked flask, 7.2g of sodium carbonate and 0.1g of tetrabutylammonium bromide were added first, followed by 10g of the intermediate amine 4,5-dichloro-1,2-phenylenediamine obtained in Example 1-1 and 100ml of ethanol. The mixture was stirred and dispersed, and kept below 25°C. 5.3g of carbon disulfide was then added dropwise. After the addition was complete, the mixture was heated to reflux for 2 hours. The reaction was monitored, and 36% of the amine remained unreacted.

[0113] Example 4-3

[0114] In a 1L three-necked flask, 7.2g of sodium carbonate and 0.1g of tetrabutylammonium bromide were added first, followed by 10g of the intermediate amine 4,5-dichloro-1,2-phenylenediamine obtained in Example 1-1 and 100ml of purified water. The mixture was stirred and dispersed, and kept below 25°C. 5.3g of carbon disulfide was then added dropwise. After the addition was complete, the mixture was heated to reflux for 2 hours. The reaction was monitored, and 26% of the amine remained unreacted.

[0115] Example 4-4

[0116] In a 2L three-necked flask, first add 46g of sodium carbonate, 0.6g of tetrabutylammonium bromide, and 300ml of purified water, stirring until dissolved. Then add 64g of the intermediate amine 4,5-dichloro-1,2-phenylenediamine obtained in Example 1-1 and 300ml of ethanol, stirring to disperse. Maintain the temperature below 25°C, and then add 41.3g of carbon disulfide dropwise. After the addition is complete, heat to reflux for 2 hours. Monitor the reaction until complete.

[0117] Examples 4-5

[0118] In a 2L three-necked flask, 49g of sodium carbonate, 0.6g of tetrabutylammonium bromide, and 800ml of purified water were first added and stirred until dissolved. Then, 68g of the intermediate amine 4,5-dichloro-1,2-phenylenediamine obtained in Example 1-1 and 200ml of ethanol were added and stirred to disperse. The mixture was kept below 25°C, and 43.9g of carbon disulfide was added dropwise. After the addition was complete, the mixture was heated to reflux for 2 hours. The reaction was monitored, and 9% of the amine remained unreacted.

[0119] As can be seen from the above examples, in step S2), adding 50% (v / v) ethanol as a reaction solvent results in the highest conversion rate of the amine.

[0120] Example 5

[0121] Example 5-1

[0122] Add 1.0 kg of the cyclic compound 5,6-dichlorobenzimidazole-2-thiol obtained in Example 2-1, 5 L of N,N-dimethylformamide, 5 L of acetic acid, and 1.2 kg of hydrobromic acid-acetic acid solution to a 50 L glass reaction vessel. Stir and maintain the temperature below 25 °C. Weigh 3 kg of bromine and slowly add it dropwise to the reaction vessel. After the addition is complete, raise the temperature to 50 °C-60 °C and stir for 3 hours. Sampling and monitoring until the conversion rate reaches ≥99%. Cool the reaction solution to below 25 °C and then quench it with water, resulting in the precipitation of a large amount of solid. Filter the solid, wash the filter cake twice with hot water at 50 °C-60 °C, and then dry the filter cake under reduced pressure in an electric vacuum drying oven at 55 °C-65 °C to obtain 2-bromo-5,6-dichloro-1H-benzimidazole with a yield of 1.1 kg, a yield rate of 90.7%, and a product purity of 99%.

[0123] Example 5-2

[0124] In a 2L three-necked flask, 50g of the cyclic compound 5,6-dichlorobenzimidazole-2-thiol obtained in Example 2-1, 79g of a 33wt% aqueous solution of hydrobromic acid, and 300mL of acetic acid were added. The mixture was stirred and dispersed, and the temperature was controlled below 20°C. 109.3g of bromine was added dropwise. After the addition was complete, the temperature was raised to 50°C-60°C and the reaction was stirred for 3 hours. Samples were taken and monitored until the reaction was completed. The temperature was lowered to below 20°C, and purified water was added. A large amount of solid precipitated out. The solid was filtered, and the filter cake was washed twice with purified water and dried by forced air to obtain 2-bromo-5,6-dichloro-1H-benzimidazole. The yield was 35g, the yield rate was 57.7%, and the product purity was 74%. A large amount of the cyclic compound did not participate in the reaction.

[0125] Example 5-3

[0126] Add 30g of the cyclic compound 5,6-dichlorobenzimidazole-2-thiol obtained in Example 2-1, 150ml of N,N-dimethylformamide, 150ml of acetic acid, and 36g of hydrobromic acid-acetic acid solution to a 1L three-necked flask. Stir and maintain the temperature below 25°C. Weigh 40g of bromine and slowly add it dropwise to the reaction flask. After the addition is complete, raise the temperature to 50°C-60°C and stir for 3 hours. Sampling and monitoring show that the conversion is not complete. Add 20g of bromine and continue stirring for 2 hours, monitoring until the reaction is complete. Cool to below 20°C and add purified water. A large amount of solid precipitates out. Filter, wash the filter cake twice with purified water, and dry it with a forced air to obtain 2-bromo-5,6-dichloro-1H-benzimidazole. The yield is 21.7g, the yield rate is 59.6%, and the product purity is 56.4%. A large amount of the cyclic compound did not participate in the reaction.

[0127] Example 5-4

[0128] Add 30g of the cyclic compound 5,6-dichlorobenzimidazole-2-thiol obtained in Example 2-1, 50ml of N,N-dimethylformamide, 250ml of acetic acid, and 36g of hydrobromic acid-acetic acid solution to a 1L three-necked flask. Stir and maintain the temperature below 25°C. Weigh 60g of bromine and slowly add it dropwise to the reaction flask. After the addition is complete, raise the temperature to 50°C-60°C and stir the reaction for 3 hours. Sampling and monitoring are performed until the reaction is complete. Cool down to below 20°C, add purified water, and a large amount of solid precipitates. Filter, wash the filter cake twice with purified water, and dry it with a forced air to obtain 2-bromo-5,6-dichloro-1H-benzimidazole. The yield is 30.2g, the yield rate is 83.0%, and the product purity is 98.0%.

[0129] From the above examples, it can be seen that: 1) Compared with Example 5-2, Example 5-1 added the organic solvent N,N-dimethylformamide / acetic acid during the reaction, and simultaneously added hydrobromic acid-acetic acid solution as an initiator for the substitution reaction, thereby improving the conversion rate of the cyclized product and also improving the purity of the product 2-bromo-5,6-dichloro-1H-benzimidazole; 2) In Example 5-3, when the amount of bromine added in the initial reaction was insufficient, subsequent addition of bromine did not promote the complete reaction; 3) In Example 5-4, when the ratio of solvent N,N-dimethylformamide to acetic acid was not 1:1, the yield of the reaction decreased.

[0130] This application describes several embodiments, but these descriptions are exemplary and not restrictive, and it will be apparent to those skilled in the art that there are many more embodiments and implementations within the scope of the embodiments described herein.

Claims

1. A method for preparing the maribavir intermediate 2-bromo-5,6-dichloro-1H-benzimidazole, the method comprising the following steps: S1): Compound A undergoes a hydrogenation-reduction reaction with hydrazine hydrate in the presence of a metal catalyst to yield compound B. S2): Compound B undergoes a cyclization reaction with carbon disulfide in a second solvent under the action of a phase transfer catalyst and an acid-binding agent to obtain compound C. S3): Compound C undergoes a substitution reaction with bromine to yield compound D, namely 2-bromo-5,6-dichloro-1H-benzimidazole. ； The metal catalyst is platinum-carbon; The phase transfer catalyst is selected from one or a combination of tetrabutylammonium bromide and tetrabutylammonium chloride; The acid-binding agent is selected from one or more of potassium carbonate and sodium carbonate; The second solvent is 50% ethanol.

2. The preparation method according to claim 1, wherein, Step S1) includes: Compound A undergoes a hydrogenation reduction reaction with hydrazine hydrate in a first solvent under the action of a metal catalyst to obtain compound B; and / or Step S3) includes: Compound C reacts with bromine in a third solvent under the action of an initiator to give compound D, namely 2-bromo-5,6-dichloro-1H-benzimidazole. 。 3. The preparation method according to claim 2, wherein, The first solvent is selected from one or a combination of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, and water; and / or The phase transfer catalyst is tetrabutylammonium bromide; and / or The acid-binding agent is sodium carbonate; and / or The initiator is hydrogen bromide, a hydrobromic acid solution, or an aqueous solution of hydrogen bromide; and / or The third solvent is selected from one or a combination of several of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, acetic acid, and N,N-dimethylformamide.

4. The preparation method according to claim 3, wherein, The first solvent is ethanol; and / or The initiator is a solution of hydrobromoacetic acid; and / or The third solvent is a combination of N,N-dimethylformamide and acetic acid.

5. The preparation method according to claim 4, wherein, The first solvent is 95% ethanol.

6. The preparation method according to claim 4, wherein, The volume ratio of N,N-dimethylformamide to acetic acid in the third solvent is 1:1 to 1:

5.

7. The preparation method according to claim 6, wherein, The volume ratio of N,N-dimethylformamide to acetic acid in the third solvent is 1:1 or 1:

5.

8. The preparation method according to claim 7, wherein, The volume ratio of N,N-dimethylformamide to acetic acid in the third solvent is 1:

1.

9. The preparation method according to any one of claims 1 to 8, wherein, In step S1), the molar ratio of compound A: hydrazine hydrate: metal catalyst is 1:(1-3):(0.001-0.01).

10. The preparation method according to any one of claims 2 to 8, wherein, In step S1), the hydrogenation reduction reaction includes: adding the compound A, the first solvent, and the metal catalyst into a reaction vessel and stirring, and slowly adding the hydrazine hydrate dropwise; after the addition is complete, heating and reacting; after the reaction is complete, cooling and filtering while hot, collecting the filtrate and concentrating and drying to obtain the compound B.

11. The preparation method according to claim 10, wherein, Compound A, 95% ethanol, and platinum carbon were added to a reaction vessel and stirred. The temperature was controlled to be below 15°C, and hydrazine hydrate was slowly added dropwise. After the addition was complete, the temperature was raised to 30°C-40°C and stirred for 1 hour. The temperature was then raised to 60°C-70°C and stirred until the reaction was complete. The temperature was then lowered. The reaction solution temperature was controlled at 45°C-55°C. The mixture was filtered while hot, and the filtrate was collected, concentrated, and dried to obtain compound B.

12. The preparation method according to any one of claims 2 to 8, wherein, In step S2), the cyclization reaction includes: adding the acid-binding agent, the phase transfer catalyst, the compound B, and the second solvent to a reaction vessel, and slowly adding carbon disulfide dropwise; after the addition is complete, heating to reflux and reacting; after the reaction is complete, concentrating the reaction solution and controlling the temperature to below 25°C, adjusting the pH of the reaction solution to neutral or weakly alkaline until a large amount of solid precipitates, filtering, drying, and collecting the filter cake to obtain the compound C.

13. The preparation method according to claim 12, wherein, Sodium carbonate, tetrabutylammonium bromide, compound B, and 50% ethanol were added to a reaction vessel, and the temperature was controlled below 25°C. Carbon disulfide was slowly added dropwise. After the addition was complete, the temperature was raised to 30°C-40°C and the mixture was stirred for 2 hours. Then the temperature was raised to 85°C-95°C until the reaction was complete. The reaction solution was concentrated until no large amount of solvent evaporated. The temperature was controlled below 25°C, and the pH of the reaction solution was adjusted to neutral or weakly alkaline until a large amount of solid precipitated. The solution was filtered, dried, and the filter cake was collected to obtain compound C.

14. In the preparation method according to any one of claims 2 to 8, in step S3), the molar ratio of compound C: bromine: initiator is 1:(1-5):(0.5-3).

15. The preparation method according to any one of claims 1 to 8, wherein, The temperature for the substitution reaction is 50-60℃.

16. The preparation method according to any one of claims 2 to 8, wherein, In step S3), the substitution reaction step includes: adding the compound C, the third solvent, and the initiator into a reaction vessel and stirring; slowly adding bromine dropwise into the reaction vessel; after the dropwise addition is complete, heating and reacting; after the reaction is complete, cooling and quenching the reaction until a large amount of solid precipitates; filtering, drying, and collecting the filter cake to obtain the compound D.

17. The preparation method according to claim 16, wherein, Compound C, a mixed solution of N,N-dimethylformamide and acetic acid in a weight ratio of 1:1, and a solution of hydrobromic acid were added to a reaction vessel. The mixture was stirred and the temperature was controlled below 25°C. Bromine was slowly added dropwise. After the addition was complete, the temperature was raised to 50°C-60°C and the mixture was stirred for 3 hours to complete the reaction. The reaction solution was cooled to below 25°C and quenched with water. A large amount of solid precipitated out. The solid was filtered, dried, and the filter cake was collected to obtain compound D.

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