A process for the preparation of 6,8-dibromoimidazo[1,2-b]pyridazine

Abstract

The application discloses a preparation process of 6,8-dibromimidazo[1,2-b]pyridazine, which comprises the following steps: (1) dissolving 3-amino-6-bromopyridazine in a solvent, and then carrying out a bromination reaction with a bromination reagent to obtain a first mixture; (2) adding a catalyst and a cyclization reagent into the first mixture to carry out a reaction, and obtaining a second mixture; wherein the catalyst is a single or compounded lanthanide Lewis acid. The process is simple in operation, mild in reaction condition, short in reaction time, high in production efficiency, high in product quality, and high in product yield by more than 34%, and is suitable for industrialized scale production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of chemical industry, and particularly relates to a preparation process of 6,8-dibromoimidazo[1,2-b]pyridazine. BACKGROUND

[0002] Imidazopyridazine is also a typical nitrogen-containing heterocyclic compound imidazopyridazine derivative, which is widely used in the field of new drug research and development, including many anticancer drugs, tumor, neurological drugs, endocrine diseases, digestive system diseases, etc. At present, a variety of imidazopyrazine skeleton drugs have been applied in clinic. Imidazo[1,2-b]pyridazine is the 3-position side chain of cefozopran, which is an important intermediate for synthesizing cefozopran. The 6,8-dibromoimidazo[1,2-b]pyridazine compound is an important intermediate for organic synthesis, especially in the research and application of medicinal chemistry. Its multifunctional group or potential multifunctional group nature is used in various drugs for organic synthesis.

[0003] The existing technology of imidazo[1,2-b]pyridazine has a complicated synthesis route, long time consumption, and most of the products are obtained by recrystallization and column chromatography, which is not easy to realize large-scale production. For example, patent CN201510630627.X discloses a synthesis method of 6-chloro-8-bromoimidazo[1,2-b]pyridazine. The reaction temperature of the method is as high as 40-100℃, the reaction time is as long as 5-30h, and the yield and product purity are low. The target product with complex purity requirements needs to be obtained by recrystallization. Therefore, in order to meet the growing market demand, it is necessary to develop a preparation process of 6,8-dibromoimidazo[1,2-b]pyridazine which is simple to operate, has mild reaction conditions, low production cost, high yield and suitable for industrial production. SUMMARY

[0004] In view of the above problems, the application provides a preparation process of 6,8-dibromoimidazo[1,2-b]pyridazine. The bromination reaction and the ring-closing reaction of the process are carried out in the same reaction kettle, which is simple to operate, shortens the reaction time, has milder reaction conditions, and significantly improves the product yield.

[0005] Specifically, as shown in the following figure, the preparation process of 6,8-dibromoimidazo[1,2-b]pyridazine includes the following steps:

[0006]

[0007] (1) Dissolving 3-amino-6-bromopyridazine in a solvent and reacting with a bromination reagent to obtain a first mixture;

[0008] (2) adding a catalyst and a cyclization reagent to the first mixture to obtain a second mixture; wherein the catalyst is a single or compounded lanthanide Lewis acid.

[0009] In the above technical solution, the research and development team of the present application unexpectedly found that adding a catalyst, especially a single or compounded lanthanide Lewis acid, in the cyclization stage in the prior art route can significantly shorten the reaction time, and the applicable reaction conditions are milder, and more importantly, the purity and product state of the prepared 6,8-dibromoimidazo[1,2-b]pyridazine are better, that is, the product quality is better, and at the same time, the product yield is significantly improved. The product yield is increased by more than 34% after adding the lanthanide Lewis acid catalyst in the embodiments of the present application.

[0010] Based on the above findings, the research and development team carried out a large number of selectivity experiments of single or compounded lanthanide Lewis acid catalysts, and found that when the single lanthanide Lewis acid is lanthanum chloride, neodymium chloride or erbium chloride, and when the compounded lanthanide Lewis acid is one of the following compounds: compounded lanthanum chloride and rubidium chloride, lanthanum chloride and erbium chloride, and erbium chloride and rubidium chloride, the product purity and product yield of the preparation process are high, the side reactions are few, the reaction conditions are mild, and the reaction efficiency is high.

[0011] Further, the research and development team selected a single lanthanide Lewis acid catalyst to carry out a large number of exploratory experiments on the amount of catalyst added in the preparation process. Optionally, the amount of catalyst added is 3 ‰-10 ‰ of the molar amount of 3-amino-6-bromopyridazine, and within this range of catalyst addition, the purity of the prepared 6,8-dibromoimidazo[1,2-b]pyridazine product is high, and the yield reaches more than 70.2%, which is much higher than 45% in the comparative example; preferably, the amount of catalyst added is 5 ‰ of the molar amount of 3-amino-6-bromopyridazine.

[0012] Further research found that under the condition that the amount of catalyst added is 5 ‰ of the molar amount of 3-amino-6-bromopyridazine, when the catalyst used is compounded lanthanum chloride and rubidium chloride, and the molar ratio of lanthanum chloride to rubidium chloride is 1:1, the quality and product yield of the prepared product are better.

[0013] In the above technical solution, the research and development team of the present application carried out a large number of selectivity experiments on the type of solvent used in step (1) and the amount of solvent added, as well as the preferences of the two. Optionally, the solvent is one of DMF (N,N-dimethylformamide), dichloromethane, ethanol or methanol. Optionally, the mass ratio of the solvent to 3-amino-6-bromopyridazine is 2-10:1, preferably 6-10:1, and further preferably 6:1. The preparation results of different types of solvents and different amounts of solvents are given in the embodiments of the present application.

[0014] In the above technical solution, the research and development team of the present application has carried out a large number of selective experiments on the type and amount of bromination reagent used in step (1) and the preferred scheme. Alternatively, the bromination reagent is one of NBS (N-bromosuccinimide) or dibromohydantoin (DBDMH). Alternatively, when the bromination reagent is NBS, the molar ratio of bromination reagent to 3-amino-6-bromopyridazine is 1.1-1.8:1, preferably 1.3-1.5:1; when the bromination reagent is dibromohydantoin, the molar ratio of bromination reagent to 3-amino-6-bromopyridazine is 0.6-1.1:1, preferably 0.7-0.9:1. The preparation results of different types of bromination reagents and different amounts of bromination reagents are given in the examples of the present application.

[0015] In the above technical solution, the research and development team of the present application has carried out a large number of selective experiments on the type and amount of ring-closing reagent used in step (2) and the related preferred scheme. Alternatively, the ring-closing reagent is chloroacetaldehyde or bromoacetaldehyde dimethyl acetal, preferably chloroacetaldehyde. Alternatively, the molar ratio of the ring-closing reagent to 3-amino-6-bromopyridazine is 1.1-2.5:1, preferably 1.1-1.5:1. The preparation results of different types of ring-closing reagents and different amounts of ring-closing reagents are given in the examples of the present application.

[0016] In the above technical solution, the reaction temperature of step (1) is 0-5℃, and the reaction time is 3-5h.

[0017] In the above technical solution, the research and development team of the present application has carried out a large number of selective experiments on the type and amount of ring-closing reagent used in step (2) and the related preferred scheme. Alternatively, the ring-closing reagent is chloroacetaldehyde or bromoacetaldehyde dimethyl acetal, preferably chloroacetaldehyde. Alternatively, the molar ratio of the ring-closing reagent to 3-amino-6-bromopyridazine is 1.1-2.5:1, preferably 1.1-1.5:1. The preparation results of different types of ring-closing reagents and different amounts of ring-closing reagents are given in the examples of the present application.

[0018] It is worth noting that the first mixture in the above technical solution mainly includes the intermediate 3-amino-4,6-dibromopyridazine. In actual operation, when the starting material 3-amino-6-bromopyridazine in the first mixture is detected by HPLC to be <0.5%, it indicates that the bromination reaction is complete. The second mixture in the above technical solution mainly includes the target product 6,8-dibromoimidazo[1,2-b]pyridazine, and when the intermediate 3-amino-4,6-dibromopyridazine is detected by HPLC to be <0.5%, it indicates that the ring-closing reaction is complete.

[0019] Further, the technical solution above also includes step (3): adjusting the pH value of the second mixture to 7-8, and then extracting the 6,8-dibromoimidazo[1,2-b]pyridazine product. After adjusting the pH value of the second mixture, the product is only extracted into an organic solvent, and then the solvent is concentrated to obtain a product with high purity, avoiding the subsequent processing mode of column chromatography and recrystallization in the prior art, so that the process flow of the present application is more simplified and suitable for industrial production. Further, the step (3) also includes rotary evaporation of the organic phase after extraction; and further, the solvent obtained by extraction is washed with water and / or saturated brine before rotary evaporation.

[0020] In the above technical solution, the alkali solution used for adjusting the pH value in step (3) is explored and optimized by the R&D team of the present application. Optionally, sodium bicarbonate, sodium carbonate or sodium hydroxide solution can be used to adjust the pH value of the second mixture. The preparation results of the alkali solution for adjusting the pH value of the second mixture are given in the examples.

[0021] In the above technical solution, the extractant used in step (3) is explored and optimized by the R&D team of the present application. Optionally, the solvent used for extraction is one of dichloromethane, dichloroethane and ethyl acetate, and dichloromethane is preferred. The preparation results of extraction using different extractants are given in the examples.

[0022] Compared with the prior art, the present application carries out bromination reaction and cyclization reaction in the same reaction kettle to prepare 6,8-dibromoimidazo[1,2-b]pyridazine, which is simple in operation, mild in reaction condition, shortens the reaction time, improves the production efficiency, and has better product quality, and the product yield is increased by more than 34%, which is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0023] The drawings accompanying the specification of this application form a part thereof, serve to provide further understanding of the present application, and together with the description of the exemplary embodiments of the present application and their description serve to explain the present application, and do not constitute improper limitations on the present application. In the drawings:

[0024] Figure 1 The liquid chromatogram of the 6,8-dibromoimidazo[1,2-b]pyridazine product prepared in Example 1 is shown in the following figure:

[0025] Figure 2 The state diagram of the second mixture in Example 1 is shown in the following figure:

[0026] Figure 3 The liquid chromatogram of the 6,8-dibromoimidazo[1,2-b]pyridazine product prepared in Comparative Example 1 is shown in the following figure:

[0027] Figure 4 The state diagram of the second mixture in Comparative Example 1 is shown in the following figure. Detailed Implementation

[0028] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0029] To facilitate understanding of the present invention, a more comprehensive description will be provided below, along with preferred embodiments. However, it should be understood that these embodiments are merely for more detailed explanation and should not be construed as limiting the invention in any way, i.e., not intended to limit the scope of protection of the invention.

[0030] It should be noted that, unless otherwise defined, the technical terms used in the following embodiments have the same meaning as commonly understood by those skilled in the art to which this invention pertains. In this embodiment, relational terms such as "first" and "second" are merely used to distinguish one component from another with the same name, and do not necessarily require or imply any such actual relationship or order between these components. Features defined with "first," "second," etc., may explicitly or implicitly include one or more of those features.

[0031] The reagents in the following examples were sourced from:

[0032] 3-Amino-6-bromopyridazine: Homemade

[0033] Catalyst support: Jiangxi Huihua Technology Co., Ltd.

[0034] Catalyst: Shandong Desheng New Materials Co., Ltd.

[0035] Chloroacetaldehyde: Jiangsu Raine Environmental Protection Technology Co., Ltd.

[0036] Ethanol: Zibo Qixing Chemical Technology Co., Ltd.

[0037] Dichloromethane: Shandong Huasheng New Materials Co., Ltd.

[0038] HPLC detection conditions: Column type: Luna C18, 5µm, 250*4.6; Column temperature: 25℃; Mobile phase: Acetonitrile:Water = 80:20; Flow rate: 1ml / min; Absorption wavelength: 254nm; Injection volume: 0.2µl;

[0039] This invention uses HPLC to detect product purity; the product yield is the molar ratio of the dried product (converted to moles) to the raw material.

[0040] Example 1

[0041] This embodiment shows a preparation process of 6,8-dibromoimidazo[l,2-b]pyridazine under a certain condition, which comprises the following steps:

[0042] (1) Put 1.74 kg of 3-amino-6-bromopyridazine (10 mol, 1 eq) into a reaction kettle, add 17 kg of DMF and stir for 30 min, dissolve under stirring, and then add 2.67 kg of NBS (15 mol, 1.5 eq) in batches while keeping the temperature unchanged, and stir the reaction for 3-5 h; (2) HPLC detection shows that the residual 3-amino-6-bromopyridazine in the reaction is <0.5%, which is considered as complete reaction, then add a catalyst 0.25 kg of lanthanum chloride (0.1 mol, 10 ‰) into the reaction, slowly drop 2.56 kg of chloroacetaldehyde (40% aqueous solution, 13 mol, 1.3 eq) into the reaction kettle, and then raise the temperature to 30-40 °C, and stir the reaction for 2-3 h; (3) HPLC detection shows that the 3-amino-4,6-dibromopyridazine is completely reacted (<0.5%), cool to room temperature, and then neutralize the second mixture with saturated sodium bicarbonate to pH 7-8, directly add dichloromethane 50 L*3 for extraction, wash with water, and then wash with saturated brine, and then spin to combine the solids to obtain light brown 6,8-dibromoimidazo[l,2-b]pyridazine product 2.08 kg, with a purity of 99.3% and a yield of 74.8%; the liquid chromatogram of the product is shown in Figure 1 ; the state of the second mixture after the complete reaction of step (2) is shown in Figure 2 It can be seen that the second mixture is clear, indicating that it contains less impurities, which further confirms that the 6,8-dibromoimidazo[l,2-b]pyridazine product prepared in this embodiment has high purity.

[0043] Comparative Example 1

[0044] The operation conditions and process parameters of the preparation process of 6,8-dibromoimidazo[l,2-b]pyridazine shown in Comparative Example 1 are the same as those shown in Example 1, but no catalyst is added in step (2); specifically, the comparative example comprises the following steps:

[0045] (1) In a reaction kettle, 1.74 kg of 3-amino-6-bromopyridazine (10 mol, 1 eq) was added, 17 kg of DMF was added and stirred for 30 min, and the temperature was reduced to 5-10 °C. 2.67 kg of NBS (15 mol, 1.5 eq) was added in batches while keeping the temperature unchanged, and the reaction was stirred for 3-5 h; (2) HPLC detection showed that the residual 3-amino-6-bromopyridazine in the reaction was <0.5%, which was considered to be complete. 2.56 kg of chloroacetaldehyde (40% aqueous solution, 13 mol, 1.3 eq) was slowly added into the reaction kettle, and the temperature was increased to 30-40 °C. The reaction was stirred for 6-8 h. HPLC detection showed that the unreacted 3-amino-4,6-dibromopyridazine in the reaction was not completely reacted, and the temperature was increased to 85-100 °C. The reaction was carried out for 5 h; (3) HPLC detection showed that there was no residual 3-amino-4,6-dibromopyridazine, which was considered to be complete. The reaction system was a red-brown oil. The solution was neutralized with saturated sodium bicarbonate, and the reaction solution was directly added into 50 L of dichloromethane for extraction, washed with water, and then washed with saturated brine. The combined solid was obtained by rotary evaporation, which was a light brown product with a purity of 93.8% and a yield of 45.0%. The liquid chromatogram of the product is shown in Figure 3 The state of the second mixture after the completion of step (2) is shown in Figure 4 It can be seen that the second mixture prepared in the present comparative example is relatively turbid, indicating that it contains a certain amount of impurities.

[0046] Subsequently, the reaction conditions and product parameters of Example 1 and Comparative Example 1 were compared, and the results are shown in Table 1.

[0047] Table 1

[0048] Comparison Reaction temperature Reaction time Yield (%) Purity (%) Example 1 30-40℃ 2-3h 78.7 99.3 Comparative Example 1 85-100℃ 5-8h 45.0 93.8

[0049] As can be seen from Table 1, the reaction without catalyst in Comparative Example 1 reduces the purity of the product, and the state of the second mixture after the completion of the reaction changes from clear light brown to red-brown oil, indicating that the byproduct increases in Comparative Example 1, and the obtained product needs to be further purified; thus, the overall product quality is improved in the preparation process of Example 1. In addition, the product yield of Example 1 is increased by 66% compared with Comparative Example 1. It is worth noting that the overall reaction time and reaction temperature of Example 1 with catalyst are lower than those of Comparative Example 1, which can improve the production efficiency and save energy consumption.

[0050] Example 2

[0051] A process for preparing 6,8-dibromoimidazo[1,2-b]pyridazine, specifically: (1) in a reaction kettle, 1.74 kg of 3-amino-6-bromopyridazine (10 mol, 1 eq) is added, 17 kg of different solvents are added and stirred for 30 min, the temperature is reduced to 5-10 °C, 2.67 kg of NBS (15 mol, 1.5 eq) is added in batches, and the temperature is kept constant. (2) Stir the reaction for a period of time, detect the remaining 3-amino-6-bromopyridazine in the reaction <0.5%, and detect the completion of the reaction, first add a catalyst 0.25 kg of lanthanum chloride (0.1 mol, 10 ‰), directly slowly drop 2.56 kg of chloroacetaldehyde (40% aqueous solution, 13 mol, 1.3 eq) into the reaction kettle, after the drop is completed, the temperature is raised to 30-40 °C, and the reaction is stirred for 2-3 hours; (3) detect the completion of the reaction of the intermediate 3-amino-4,6-dibromopyridazine in the raw material <0.5%, cool to room temperature, neutralize the second mixture with saturated sodium bicarbonate to pH 7-8, directly extract with dichloromethane 50L*3, wash with water, then wash with saturated brine, and spin to combine the solids to obtain light brown 6,8-dibromoimidazo[1,2-b]pyridazine product.

[0052] The other conditions and parameters are determined to be unchanged, the only variable is the solvent used in step (1), the specific process parameters and conditions of examples 2.1-2.4, and the product parameters are as shown in Table 2.

[0053] Table 2

[0054]

[0055]

[0056] As can be verified in Table 2, the solvent used in step (1) can be selected from one of DMF, dichloromethane, ethanol or methanol. The research and development team found that when other process conditions and parameters are the same, the reaction time is shorter when DMF is used as the reaction solvent, in addition, the yield and purity obtained by example 1 using DMF as the reaction solvent are the best, the product yield is about 20% higher than using other solvents. It should be noted that even when the solvent used in step (1) is methanol, the product yield is also higher than the yield of 34% in comparative example 1, which is 45% in comparative example 1.

[0057] Further, examples 2.5-2.9 are set up with DMF as the solvent to verify the effect of the amount of solvent used in step (1) on the preparation process, and the specific process parameters and product parameters of examples 2.5-2.9 are as shown in Table 3.

[0058] Table 3

[0059]

[0060] As can be verified from Table 3, the amount of DMF added in step (1) can be selected as 2-10:1, further selected as 6-10:1, and more further selected as 6:1, in terms of the mass ratio of the raw material 3-amino-6-bromopyridazine. Table 3 demonstrates that when the amount of DMF used in step (1) is too small, the product yield and purity are affected, and when the amount of DMF is increased to a certain amount, the product yield will not be improved any more, but the amount of wastewater will be increased if the amount of solvent is large, which is not conducive to the later treatment.

[0061] Example 3

[0062] A preparation process of 6,8-dibromoimidazo[1,2-b]pyridazine, comprising the following steps: (1) 1.74 kg of 3-amino-6-bromopyridazine (10 mol, 1 eq) is put into a reaction kettle, 10.5 kg of DMF is added and stirred for 30 min, and then stirred to dissolve, and then different amounts of NBS (11 mol, 1.1 eq; 13 mol, 1.3 eq; 15 mol, 1.5 eq; 18 mol, 1.8 eq) or dibromohydantoin (6 mol, 0.6 eq; 7 mol, 0.7 eq; 9 mol, 0.9 eq; 11 mol, 1.1 eq) are added in batches respectively for bromination reaction, the temperature is kept unchanged, and stirring is performed for 3-5 h; (2) when the residual 3-amino-6-bromopyridazine in the reaction is less than 0.5%, it is detected that the reaction is complete, a catalyst 0.25 kg of lanthanum chloride (0.1 mol, 10 ‰) is added first, and then 2.56 kg of chloroacetaldehyde (40% aqueous solution, 13 mol, 1.3 eq) is slowly added dropwise into the reaction kettle, the temperature is increased to 30-40 °C after the dropwise addition is completed, and stirring is performed for 2-3 h; (3) when the intermediate 3-amino-4,6-dibromopyridazine in the reaction is less than 0.5%, it is detected that the reaction is complete, the second mixture is cooled to room temperature, neutralized with saturated sodium bicarbonate to pH 7-8, directly extracted with 50 L*3 of dichloromethane, washed with water, and then washed with saturated brine, and then the combined solids are obtained by rotary evaporation to obtain light brown 6,8-dibromoimidazo[1,2-b]pyridazine product. The bromination reagents and the addition amounts of Example 3.1-Example 3.8, and the product parameters are shown in Table 4.

[0063] Table 4

[0064]

[0065] As can be verified from Table 4, when the bromination reagent is NBS, the molar ratio of the bromination reagent to 3-amino-6-bromopyridazine can be selected as 1.1-1.8:1, further selected as 1.3-1.5:1, and more further selected as 1.3:1; when the bromination reagent is dibromohydantoin, the molar ratio of the bromination reagent to 3-amino-6-bromopyridazine can be selected as 0.6-1.1:1, further selected as 0.7-0.9:1.

[0066] Example 4

[0067] A process for preparing 6,8-dibromoimidazo[l,2-b]pyridazine, the process comprising the steps of: (1) putting 1.74 kg of 3-amino-6-bromopyridazine (10 mol, 1 eq) into a reaction kettle, adding 10.5 kg of DMF and stirring for 30 min, dissolving, and reducing the temperature to 5-10 °C, adding 2.31 kg of NBS (13 mol, 1.3 eq) in batches while keeping the temperature unchanged, and stirring the reaction for 3-5 h; (2) detecting that the 3-amino-6-bromopyridazine in the reaction is <0.5% of the remaining raw material, detecting that the reaction is complete, adding a catalyst, 0.25 kg of lanthanum chloride (0.1 mol, 10 ‰), directly into the reaction kettle, slowly dropping chloroacetaldehyde (40% aqueous solution, 11 mol, 1.1 eq; 13 mol, 1.3 eq; 15 mol, 1.5 eq; etc.) or bromoacetaldehyde dimethyl acetal (11 mol, 1.1 eq; 13 mol, 1.3 eq; 15 mol, 1.5 eq; etc.) into the reaction kettle, and raising the temperature to 30-40 °C after the dropping is complete, and stirring the reaction for 2-3 h; (3) detecting that the intermediate 3-amino-4,6-dibromopyridazine in the reaction is <0.5% of the remaining raw material, cooling to room temperature, neutralizing the second mixture with saturated sodium bicarbonate to a pH of 7-8, directly adding dichloromethane 50 L*3 for extraction, washing with water, then saturated brine, and rotary evaporating to obtain light brown 6,8-dibromoimidazo[l,2-b]pyridazine product. The ring-closing reagent and the amount of addition in this example, and the product parameters are shown in Table 5.

[0068] Table 5

[0069]

[0070] As can be verified from Table 5, the ring-closing reagent can be chloroacetaldehyde or bromoacetaldehyde dimethyl acetal, and further can be chloroacetaldehyde. In addition, by comparing the purity and product yield of the obtained 6,8-dibromoimidazo[l,2-b]pyridazine product, it can be proved that the molar ratio of the ring-closing reagent to 3-amino-6-bromopyridazine can be 1.1-2.5:1, further can be 1.1-1.5:1, and further can be 1.3:1.

[0071] Example 5

[0072] A process for preparing a compound 6,8-dibromoimidazo(1.2b)pyridazine, the process comprising the following steps: (1) in a reaction kettle, 1.74 kg of 3-amino-6-bromopyridazine (10 mol, 1 eq) is added, 10.5 kg of DMF is added and stirred for 30 min, dissolved by stirring, the temperature is reduced to 5-10°C, 2.31 kg of NBS (13 mol, 1.3 eq) is added in batches, the temperature is kept constant, and the reaction is stirred for 3-5 h; (2) when the residual 3-amino-6-bromopyridazine in the reaction is detected to be less than 0.5%, the reaction is determined to be complete, different amounts of different catalysts (0.03 mol, 3‰; 0.05 mol, 5‰; 0.07 mol, 7‰; 0.010 mol, 10‰) are added to the reaction, chloroacetaldehyde (40%, 13 mol, 1.3 eq) is slowly added into the reaction kettle, the temperature is raised to 30-40°C after the addition is completed, and the reaction is stirred for 2-3 h; (3) when the intermediate 3-amino-4,6-dibromopyridazine in the reaction is detected to be less than 0.5%, the reaction is determined to be complete, the second mixture is cooled to room temperature, neutralized with saturated sodium bicarbonate to a pH of 7-8, directly added with 50 L*3 of dichloromethane, washed with water, then washed with saturated brine, and the combined solids are obtained by rotary evaporation to obtain a light brown 6,8-dibromoimidazo[1,2-b]pyridazine product.

[0073] In this example, other conditions and parameters are determined to be unchanged, the variable is the amount of catalyst added in step (2), and the type of catalyst is the variable, the type and amount of catalyst, and the product parameters are shown in Table 6.

[0074] Table 6

[0075]

[0076]

[0077] As can be verified from Table 6, examples 5.11-5.14, examples 5.21-5.24, examples 5.31-5.34, the single lanthanide Lewis acid can be selected from lanthanum chloride, neodymium chloride and erbium chloride, and further can be selected from lanthanum chloride; by comparing the purity and yield of the obtained 6,8-dibromoimidazo[1,2-b]pyridazine product, it can be proved that when a single lanthanide Lewis acid is used as a catalyst, the amount of catalyst can be selected from 3-10‰ of the molar amount of 3-amino-6-bromopyridazine, and further can be selected from 5‰.

[0078] In addition, the present embodiment is under the condition that the catalyst dosage is 5‰ of the molar amount of 3-amino-6-bromopyridazine, further verifies the influence of different kinds of complex lanthanide Lewis acids on the product purity and yield. As can be verified from Examples 5.4-5.6, the complex lanthanide Lewis acid can be selected from complex lanthanum chloride and rubidium chloride, lanthanum chloride and erbium chloride, erbium chloride and rubidium chloride; by comparing the product purity and product yield data of the present embodiment, it can be further known that the catalyst used in the present application can be further selected from complex lanthanum chloride and rubidium chloride, wherein the molar ratio of lanthanum chloride and rubidium chloride is 1:1.

[0079] Example 6

[0080] A preparation process of a compound 6,8-dibromoimidazo[1,2-b]pyridazine, comprising the following steps:

[0081] (1) Put 1.74 kg of 3-amino-6-bromopyridazine (10 mol, 1 eq) into a reaction kettle, add 10.5 kg of DMF and stir for 30 min, dissolve under stirring, and then add 2.31 kg of NBS (13 mol, 1.3 eq) in batches while keeping the temperature unchanged, and stir for 3-5 h; (2) After detecting that the residual 3-amino-6-bromopyridazine in the reaction is less than 0.5%, the reaction is complete, and the reaction is carried out by first adding a catalyst 123 g of lanthanum chloride (0.05 mol, 5‰) and then slowly dropping chloroacetaldehyde (40%, 13 mol, 1.3 eq) into the reaction kettle, and after the dropping is completed, the reaction liquid is warmed to four temperature gradients 20-30°C, 30-40°C, 40-50°C and 50-60°C, and the reaction is stirred for 2-3 hours; (3) After detecting that the intermediate 3-amino-4,6-dibromopyridazine in the reaction is completely reacted and the residual amount is less than 0.5%, the reaction is cooled to room temperature, and then the second mixture is neutralized to pH 7-8 with saturated sodium bicarbonate, directly extracted with 50 L*3 of dichloromethane, washed with water, and then washed with saturated brine, and then the combined solid is rotary evaporated to obtain a light brown 6,8-dibromoimidazo[1,2-b]pyridazine product. As shown in Table 7, Examples 6.1-6.4 show the influence of the reaction temperature in step (2) on the process.

[0082] Table 7

[0083]

[0084] As can be verified from Table 7, the reaction temperature in step (2) can be selected as 20-60°C. In addition, when the reaction temperature in (2) is lower, such as 20-30°C, it can result in slow reaction, long reaction period and further result in lower yield. When the reaction temperature in step (2) is increased to 30-40°C, the purity and yield of the product are better, and compared with the operation condition at higher temperature, it does not need to consume more energy for additional heating or to additionally treat the by-product. When the reaction temperature in step (2) is increased to a higher temperature, such as 40-50°C or a higher temperature of 50-60°C, a small amount of oily by-product can be generated. Therefore, the reaction temperature in step (2) can be further selected as 30-40°C.

[0085] Example 7

[0086] A preparation process of 6,8-dibromoimidazo[1,2-b]pyridazine, which comprises the following steps: (1) 1.74 kg of 3-amino-6-bromopyridazine (10 mol, 1 eq) is put into a reaction kettle, 10.5 kg of DMF is added and stirred for 30 min, dissolved by stirring, the temperature is reduced to 5-10°C, 2.31 kg of NBS (13 mol, 1.3 eq) is added in batches, and the temperature is kept unchanged, and the reaction is stirred for 3-5 h; (2) when the residual 3-amino-6-bromopyridazine in the reaction is less than 0.5%, the reaction is detected to be complete, a catalyst 123 g of lanthanum chloride (0.05 mol, 5 ‰) is first added, and chloroacetaldehyde (40%, 13 mol, 1.3 eq) is slowly added into the reaction kettle, then the temperature is increased to 30-40°C, and the reaction is stirred for 2-3 h; (3) when the intermediate 3-amino-4,6-dibromopyridazine in the reaction is less than 0.5%, the reaction is detected to be complete, the second mixture is cooled to room temperature, neutralized to pH 7-8 with different alkali solutions, extracted with 50 L*3 of dichloromethane, washed with water, then washed with saturated brine, and the combined solids are rotary evaporated to obtain light brown 6,8-dibromoimidazo[1,2-b]pyridazine product. Table 8 shows the influence of different alkali solutions on the process in step (3).

[0087] Table 8

[0088] Example Base Purity Yield Remarks 5.12 Sodium bicarbonate 99.5 84.2 Low solubility 7.2 Sodium hydroxide 98.2 75.6 Not easy to control 7.3 Sodium carbonate 98.3 76.2 Low solubility

[0089] As can be verified from Table 8, sodium bicarbonate, sodium carbonate or sodium hydroxide solution can be used to adjust the pH value of the second mixture, and sodium bicarbonate solution can be further selected to adjust the pH value of the second mixture.

[0090] Example 8

[0091] A preparation process of a compound 6,8-dibromoimidazo[1,2-b]pyridazine, the process comprising the following steps: (1) in a reaction kettle, 1.74 kg of 3-amino-6-bromopyridazine (10 mol, 1 eq) is put in, 10.5 kg of DMF is added and stirred for 30 min, dissolved by stirring, the temperature is reduced to 5-10°C, 2.31 kg of NBS (13 mol, 1.3 eq) is added in batches respectively, the temperature is kept unchanged, and the reaction is stirred for 3-5 h; (2) when the residual 3-amino-6-bromopyridazine in the reaction is less than 0.5%, the reaction is detected to be complete, a catalyst 123 g of lanthanum chloride (0.05 mol, 5 ‰) is first added in the reaction, and chloroacetaldehyde (40%, 13 mol, 1.3 eq) is slowly added dropwise into the reaction kettle, after the dropwise addition is completed, the temperature is increased to 30-40°C, and the reaction is stirred for 2-3 h; (3) when the intermediate 3-amino-4,6-dibromopyridazine in the reaction is less than 0.5%, the reaction is detected to be complete, the solution is cooled to room temperature, neutralized to pH 7-8 with sodium bicarbonate, directly added with different extraction solvents 50 L*3, extracted, washed with water, then washed with saturated brine, and then the combined solids are rotary evaporated to obtain light brown 6,8-dibromoimidazo[1,2-b]pyridazine product. Table 9 shows the influence of different extractants in step (3) on the process.

[0092] Table 9

[0093] Example Extraction solvent Purity (%) Yield (%) 8.1 Methylene chloride 99.6 84.5 5.12 Dichloroethane 99.5 84.2 8.3 Ethyl acetate 98.7 79.8

[0094] As can be verified from Table 9, the solvent for extraction in step (3) can be one of dichloromethane, dichloroethane and ethyl acetate.

[0095] It should be noted that the above is a further detailed description of the present application in combination with specific embodiments, and the specific implementation of the present application cannot be limited to these descriptions; the size data in the embodiments does not limit the technical solution, but only shows one specific working condition. For ordinary skilled persons in the technical field to which the present application belongs, some simple improvements and refinements can be made without departing from the concept of the present application, and all of them should be regarded as falling within the scope of protection of the present application.

Claims

1. A preparation process for 6,8-dibromoimidazolo[1,2-b]pyridazine, characterized in that, Includes the following steps: (1) 3-Amino-6-bromopyridazine is dissolved in a solvent and then reacted with a brominating reagent to obtain a first mixture; the solvent is DMF; the mass ratio of the solvent to 3-amino-6-bromopyridazine is 6-10:1; (2) Add a catalyst and a cyclizing agent to the first mixture to react and obtain a second mixture; wherein, the reaction temperature of step (2) is 30-60℃ and the reaction time is 2-3h; the catalyst is a single or compound lanthanide Lewis acid; the single lanthanide Lewis acid is selected from lanthanum chloride, neodymium chloride or erbium chloride; the compound lanthanide Lewis acid is selected from one of the following: compound lanthanum chloride and rubidium chloride, lanthanum chloride and erbium chloride, erbium chloride and rubidium chloride; the amount of catalyst added is 3‰-10‰ of the molar amount of 3-amino-6-bromopyridazine.

2. The preparation process according to claim 1, characterized in that, The lanthanide Lewis acid in the compound is a compound of lanthanum chloride and rubidium chloride.

3. The preparation process according to claim 2, characterized in that, The molar ratio of lanthanum chloride to rubidium chloride in the compounded lanthanum chloride and rubidium chloride is 1:

1.

4. The preparation process according to any one of claims 1, characterized in that, The catalyst is added at 5‰ of the molar amount of 3-amino-6-bromopyridazine.

5. The preparation process according to claim 1, characterized in that, The mass ratio of the solvent to 3-amino-6-bromopyridazine is 6:

1.

6. The preparation process according to claim 1, characterized in that, The brominating agent is either NBS or dibromohydantoin.

7. The preparation process according to claim 6, characterized in that, When the brominating agent is NBS, the molar ratio of the brominating agent to 3-amino-6-bromopyridazine is 1.1-1.8:1; when the brominating agent is dibromohydantoin, the molar ratio of the brominating agent to 3-amino-6-bromopyridazine is 0.6-1.1:

1.

8. The preparation process according to claim 7, characterized in that, When the brominating agent is NBS, the molar ratio of the brominating agent to 3-amino-6-bromopyridazine is 1.3-1.5:

1.

9. The preparation process according to claim 6, characterized in that, When the brominating agent is dibromohydantoin, the molar ratio of the brominating agent to 3-amino-6-bromopyridazine is 0.7-0.9:

1.

10. The preparation process according to claim 1, characterized in that, The cyclizing reagent is chloroacetaldehyde or bromoacetaldehyde dimethyl acetal.

11. The preparation process according to claim 10, characterized in that, The cyclizing reagent is chloroacetaldehyde.

12. The preparation process according to claim 1, characterized in that, The molar ratio of the cyclizing agent to 3-amino-6-bromopyridazine is 1.1-2.5:

1.

13. The preparation process according to claim 12, characterized in that, The molar ratio of the cyclizing agent to 3-amino-6-bromopyridazine is 1.1-1.5:

1.

14. The preparation process according to claim 1, characterized in that, The reaction temperature in step (1) is 0-5℃ and the reaction time is 3-5h.

15. The preparation process according to claim 1, characterized in that, The preparation process further includes step (3): adjusting the pH value of the second mixture to 7-8, and then extracting it to obtain the 6,8-dibromoimidazole[1,2-b]pyridazine product.

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