A preparation method of 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile

Abstract

The present invention provides a preparation method of 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile, which includes (1) adding a polymerization inhibitor after dissolving 3-amino-6-chloropyridazine in DMF-DMA in a reactor to react and obtain an intermediate; (2) adding an organic solvent to the reactor, and the intermediate and bromoacetonitrile undergo a ring-closing reaction; after the reaction is completed, the pH of the material in the reactor is adjusted to neutral, and a crude product is obtained by cooling and crystallizing; (3) the crude product is recrystallized to obtain the 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile pure product. The preparation method of the present invention adds a polymerization inhibitor in the chain extension stage to promote the full reaction of bromoacetonitrile, avoid the appearance of an oily substance after the ring-closing reaction, and obtain a high-purity 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile pure product. The preparation method has a simple process flow, high yield, and the quality of the obtained pure product is good, with significant economic value and industrial application value.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a method for preparing 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile. Background Art

[0002] As an important class of aromatic heterocyclic compounds, imidazopyridazine derivatives not only have high biological activities such as herbicides, insecticides, bactericides, plant growth regulators, antivirals, anticonvulsants, and anticancers, but also have good mesomorphic properties. Therefore, they are widely used in the fields of medicine, pesticides, and optoelectronic materials.

[0003] Imidazolo[1,2-b]pyridazines and their derivatives are a class of compounds with strong biological activity. They are important intermediates in the synthesis of the fourth-generation cephalosporin cefozopran and many other fine chemical products. Research on these compounds has both theoretical significance and practical application value. Imidazolo[1,2-b]pyridazines and their derivatives are widely used in the development of new drugs. Among them, 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile is an important intermediate in organic synthesis, primarily used as a pharmaceutical intermediate and organic synthesis, and is a key intermediate in the new anticancer drugs BMS-986260 and Ponatinib.

[0004] However, it should be noted that although 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile, as a novel pharmaceutical intermediate, has great medical value, there are currently few studies on the preparation method of 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile, and most of them are gram-scale syntheses. Not only is the synthesis difficult, the process steps are complicated, and the cost is high, but column chromatography or multi-solvent recrystallization is required during the preparation process to obtain a high-purity product, which is not suitable for industrial production. Therefore, there is a lack of high-quality, high-yield large-scale preparation methods for 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile. Summary of the Invention

[0005] In response to the above problems, the present invention provides a method for preparing 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile. The preparation method has a simple process flow and high yield. The obtained pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile is of good quality and has significant economic value and industrial application value.

[0006] Specifically, the preparation method of 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile of the present invention comprises the following steps:

[0007] (1) dissolving 3-amino-6-chloropyridazine in DMF-DMA in a reactor and then adding a polymerization inhibitor to react to obtain an intermediate;

[0008] (2) adding an organic solvent to the reactor, and the intermediate reacts with bromoacetonitrile to undergo a ring-closing reaction; after the reaction is completed, adjusting the pH value of the material in the reactor to neutral, and cooling and crystallizing to obtain a crude product;

[0009] (3) The crude product is recrystallized to obtain the pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile.

[0010] The reaction process of the above technical solution is as follows:

[0011]

[0012] The DMF-DMA mentioned in this article is the raw material N,N-dimethylformamide dimethyl acetal, DMSO is dimethyl sulfoxide, and DMF is N,N-dimethylformamide.

[0013] Patent CN112321592A proposes a step-by-step method for synthesizing 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile using N,N-dimethylformamide dimethyl acetal, 3-amino-6-chloropyridazine, and bromoacetonitrile as raw materials. The method is simple to operate and easy to control. However, when the research and development team of the present invention used this method to conduct exploratory experiments, they unexpectedly discovered that an oily substance appeared during the addition of alkaline solution to adjust the pH value, and a viscous solid mixture subsequently formed during the solid filtration process. This increased the difficulty of subsequent product purification and refining, reduced the yield of the overall process, and further affected the purity and quality of the prepared product.

[0014] The reasons for the appearance of oily substances in organic synthesis reactions are very complicated. Through comprehensive analysis of experimental data, the research and development team of the present invention speculates that the appearance of oily substances in the process route may be due to the formamidine intermediate. The formamidine intermediate generates a new carbon-nitrogen double bond, and the carbon-nitrogen double bond undergoes polymerization during the ring closing process, or it appears in a polymerization state with bromoacetonitrile at a high temperature, thereby producing a compound with a large molecular weight in the reaction system but it is not easy to manifest. When alkaline solution is added to adjust the acidity and base, the tar-like polymer cannot be dissolved in the system and begins to precipitate, thus appearing an oily compound with a large molecular weight.

[0015] Based on the above speculation, the research and development team of the present invention further conducted a large number of exploratory pilot experiments to investigate the composition and cause of the oily substance. By repeatedly adding small amounts of polymerization inhibitor to the pilot experiments, they surprisingly found that adding small amounts of polymerization inhibitor reduced the amount of black oil. The pilot examples of the present invention illustrate this exploratory process.

[0016] It is noteworthy that the polymerization inhibitor used in the pilot experiment of the present invention is a phenolic polymerization inhibitor, rather than an organic salt polymerization inhibitor. This is because the present invention's research and development team, based on the above speculation, considers that the formamidine intermediate contains a double bond in the reaction system, and there are also double bonds and triple bonds in the synthesis reaction process, and the double bond electron cloud is large and easily polymerized, so it is necessary to select a suitable type of polymerization inhibitor. Inorganic salt polymerization inhibitors inhibit polymerization by charge transfer, while phenols in phenolic polymerization inhibitors are oxidized to corresponding quinones and combine with chain free radicals to inhibit polymerization. Therefore, the research and development team speculates that in the presence of phenolic polymerization inhibitors, free radicals can be quickly terminated. Therefore, in the pilot experiment, 4-dimethylaminophenol was tried as a polymerization inhibitor, which unexpectedly achieved an unexpected effect.

[0017] The research and development team of the present invention further discovered through a large number of exploratory experiments that the technical effects of adding a polymerization inhibitor at different stages of the preparation of 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile are different. The experimental results of adding the polymerization inhibitor at different time points, such as step (1), step (2), and after the reaction system is quenched, are shown in the pilot test examples of the present invention. By comprehensively considering various factors such as the appearance of oily substances and reaction time, the research and development team of the present invention proposed the above technical solution, namely, in step (1), after 3-amino-6-chloropyridazine is dissolved in DMF-DMA, a polymerization inhibitor is added, and then a chain extension reaction and a subsequent ring-closing reaction are carried out to prepare 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile.

[0018] The above technical solution (1) can avoid the appearance of oily substances after the ring-closing reaction, and no sticky solid will appear when the crude product is subsequently extracted, thereby greatly reducing the difficulty of subsequent purification operations and reducing pollution; in addition, it was verified by HPLC that the addition of the inhibitor not only did not affect the product quality, but further improved the product purity and quality; (2) the research and development team also found that the use of the inhibitor can promote the precipitation of more crude products during the cooling and crystallization operation. In other words, more target products can be collected and the yield is improved; in addition, (3) through experimental exploration and analysis, the research and development team also unexpectedly found that the technical solution of the present invention can significantly shorten the reaction time and improve the overall process production efficiency; in addition, the amount of DMF-DMA required for the production of unit mass of pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile is significantly reduced, so the technical solution of the present invention can also reduce production costs. These advantages will effectively improve economic benefits in large-scale industrial production. Considering the huge demand for 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile both at home and abroad, improving the new industrial synthesis route of 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile has broad application prospects.

[0019] In the above technical solution, the research and development team of the present invention explored and optimized the ratio of raw materials in the preparation method. Specifically, the mass ratio of 3-amino-6-chloropyridazine to DMF-DMA can be selected from 1:2 to 1:4, and further selected from 1:2 to 1:3. The molar ratio of 3-amino-6-chloropyridazine to bromoacetonitrile can be selected from 1:1 to 1:1.5, and further selected from 1:1.3.

[0020] In the above technical solution, the research and development team of the present invention explored the type and amount of polymerization inhibitor used. Specifically, the polymerization inhibitor can be selected from phenolic polymerization inhibitors, quinone polymerization inhibitors, or aromatic nitro compound polymerization inhibitors, and further selected from p-phenol, p-methylphenol, and 4-dimethylaminophenol bromide.

[0021] The feed mass of the polymerization inhibitor can be selected to be 1%-7% of the mass of the 3-amino-6-chloropyridazine. Based on the analysis of the purity and process yield of the obtained 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile pure product, the feed mass of the polymerization inhibitor can be further selected to be 3.5%-5% of the mass of the 3-amino-6-chloropyridazine.

[0022] In the above technical solution, the reaction temperature of step (1) can be selected to be 75-85°C, and the reaction time can be selected to be 2-10h.

[0023] It should be noted that the present invention does not limit the operation of promoting the dissolution of 3-amino-6-chloropyridazine in DMF-DMA in step (1), and stirring can be used to promote the dissolution.

[0024] In the above technical solution, the type of organic solvent used is not limited, and DMF, methanol or DMSO can be selected. Ordinary technicians in this field can select other organic solvents through non-creative work, and the technical solutions thus formed are all within the scope of protection of the present invention.

[0025] In the above technical solution, the temperature of the ring-closing reaction can be selected to be 60-85° C., and the reaction time can be selected to be 5-6 h.

[0026] It should be noted that the present invention does not limit the reagent used to adjust the pH value of the material after the ring-closing reaction in step (2). A saturated sodium bicarbonate solution or a potassium bicarbonate solution can be selected. Ordinary technicians in this field can select other alkaline solutions for step (2) to adjust the pH value through non-creative work, and the technical solutions thus formed are all within the scope of protection of the present invention.

[0027] It should be noted that the present invention does not limit the extraction operation of the crude product after cooling and crystallization in step (2), and the solid phase can be obtained by solid-liquid separation, such as suction filtration, filtration, etc. In addition, ordinary technicians in this field can also use water washing and other operations to improve the purity of the crude product through non-creative labor.

[0028] In the above technical solution, the solvent used for recrystallization is not limited. The crude product can be recrystallized using n-hexane, methanol, or a mixed solvent of ethyl acetate and n-hexane to obtain pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile. Ordinary technicians in this field can select other solvents for recrystallization through non-creative work, and the technical solutions thus formed are all within the scope of protection of the present invention.

[0029] Compared with the prior art, the present invention uses 3-amino-6-chloropyridazine as a raw material, reacts with DMF-DMA for chain extension, and then forms a ring with bromoacetonitrile to prepare 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile. A polymerization inhibitor is added during the chain extension stage to promote the full reaction of bromoacetonitrile, avoiding the formation of an oily substance after the ring-closure reaction, thereby producing a high-purity, high-yield pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile. The present invention simplifies the process flow, reduces the difficulty of subsequent purification operations, and further improves product purity. The process yield is increased by reducing the formation of oily polymers and promoting solid precipitation during subsequent cooling and crystallization operations. The preparation method of the present invention significantly shortens the reaction time and reduces the amount of raw materials input, thereby improving production efficiency and saving production costs. Therefore, the preparation method of the present invention is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following is a brief introduction to the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative labor.

[0031] Figure 1 This is a high performance liquid chromatogram of the crude product of Example 1 of the present invention;

[0032] Figure 2 This is a high performance liquid chromatogram of the pure product of Example 1 of the present invention;

[0033] Figure 3 This is a high performance liquid chromatogram of the crude product of Example 3 of the present invention;

[0034] Figure 4 This is a high performance liquid chromatogram of the pure product of Example 3 of the present invention;

[0035] Figure 5 This is the HPLC chromatogram of the pure product of Example 6 of the present invention;

[0036] Figure 6 This is a state diagram of the materials after adjusting the pH value of Comparative Example 1 and Example 5 of the present invention. DETAILED DESCRIPTION

[0037] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts shall fall within the scope of protection of the present invention.

[0038] Sources of reagents in the following examples:

[0039] 3-Amino-6-chloropyridazineShanghai Jizhi Biochemical Technology Co., Ltd.

[0040] DMF-DMA Tianjin Yongda Chemical Reagent Co., Ltd.

[0041] Sodium Bicarbonate Henan Jindadi Chemical Co., Ltd.

[0042] Dimethyl Sulfoxide Hubei Xingfa Chemical Group Co., Ltd.

[0043] n-Hexane Tianjin Damao Chemical Reagent

[0044] Ethyl acetate Tianjin Damao Chemical Reagent

[0045] Methanol Shaanxi Changqing Energy Chemical Co., Ltd.

[0046] 4-Dimethylaminophenol (also known as p-dimethylaminophenol)

[0047] Phenol, p-cresol MACKLIN / McClint

[0048] 4-Dimethylaminophenol bromide (also known as p-dimethylaminophenol bromide)

[0049] In a specific embodiment, product purity was determined using HPLC. HPLC testing conditions included: chromatographic column model: Luna C18, 5 μm, 250 x 4.6; column temperature: 25°C; mobile phase: methanol:water = 70:30; flow rate: 1 ml / min; absorption wavelength: 254 nm; injection volume: 0.2 μl. Product yield was calculated as the molar ratio of the dried weight to the raw material.

[0050] The present invention will be further described below with reference to the embodiments.

[0051] Small test embodiment

[0052] During the preparation of 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile using the method proposed in patent CN112321592A, the research and development team of the present invention unexpectedly discovered the appearance of an oily substance when adding alkali solution. In view of this condition, the research and development team speculated that the cause of the oily substance may be the appearance of a new carbon-nitrogen double bond on the formamidine intermediate, which polymerized during the ring closing process, or polymerized with bromoacetonitrile at high temperatures, generating compounds with large molecular weights that are difficult to manifest. These compounds precipitated as tar after the addition of alkali solution. Based on this speculation, in this small-scale test example, the composition and cause of the oily substance were explored and verified by selecting a suitable polymerization inhibitor, and the time of adding the polymerization inhibitor was further explored and optimized.

[0053] Specifically, the pilot test includes: (1) adding 200g (1.54mol) of 3-amino-6-chloropyridazine as a raw material to a reactor, dissolving it in 400g of N-dimethylformamide dimethyl acetal, and reacting to obtain the intermediate formamidine; during this operation, the liquid phase detection of the raw material 3-amino-6-chloropyridazine is less than 0.5%, and the reaction is complete to obtain the N,N-dimethyl-N'-3-(6-chloro-pyridazine)-formamidine intermediate; (2) adding 600mL of DMF to the reactor and adding bromoacetonitrile (270g, 2.31mol) dropwise to react, and the liquid phase detection of the formamidine intermediate is less than 0.5% to complete the reaction. The reaction is cooled to room temperature, and an appropriate amount of saturated sodium bicarbonate solution is added to adjust the pH to about 7.5 to observe whether an oily substance appears. During the pilot test, 12g of 4-dimethylaminophenol as an inhibitor is added at different time points. The specific parameters and test results are shown in Table 1.

[0054] Table 1

[0055]

[0056] Table 1 verifies that adding a polymerization inhibitor at an appropriate stage in the preparation of 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile using N,N-dimethylformamide dimethyl acetal, 3-amino-6-chloropyridazine, and bromoacetonitrile as raw materials can indeed prevent the appearance of an oily substance when an alkali solution is subsequently added, thereby reducing the difficulty of product processing and improving the yield. In both small-scale tests 1 and 2, in which the polymerization inhibitor was added in steps (1) and (2), no oily substance appeared, and subsequent processing was easy to operate. Further consideration of the required reaction time confirms that the technical solution of the present invention preferably adds a polymerization inhibitor in step (1).

[0057] Example 1

[0058] 2 kg (15.4 mol) of 3-amino-6-chloropyridazine was used as the reaction raw material and was stirred with 4 kg of N-dimethylformamide dimethyl acetal at 60°C for half an hour. 60 g of p-phenol was added and the temperature was raised to 85°C for 2 hours. The reaction was completed. Liquid chromatography detection showed that the raw material 3-amino-6-chloropyridazine was less than 0.5%. The reaction was completed to obtain N,N-dimethyl-N'-3-(6-chloro-pyridazine)-formamidine intermediate. DMF 6L was added dropwise and bromoacetonitrile (2.7 kg, 23.1 mol) was added. The reaction was continued at 85°C for 5 hours. The reaction was completed after liquid chromatography detection showed that the formamidine intermediate was less than 0.5%. The reaction was cooled to room temperature, an appropriate amount of saturated sodium bicarbonate solution was added, the pH was adjusted to about 7.5, the temperature was lowered to 0-5°C and the reaction was allowed to stand for two hours. The solid precipitated, filtered, washed three times with water, and the crude product was recrystallized from n-hexane to obtain 2.15 kg of pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile. Purity 99.2%, yield 80.2%. Figure 1 shows the HPLC chromatogram of the crude 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile prepared in this example; Figure 2 The high performance liquid chromatogram of the pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile prepared in this example is shown.

[0059] Example 2

[0060] 2 kg (15.4 mol) of 3-amino-6-chloropyridazine was used as the reaction raw material and was stirred with 4 kg of N-dimethylformamide dimethyl acetal at 60°C for half an hour. 50 g of p-methylphenol was added and the temperature was raised to 85°C for 2 hours. The reaction was completed. Liquid chromatography detection showed that the raw material 3-amino-6-chloropyridazine was less than 0.5%. The reaction was completed to obtain N,N-dimethyl-N'-3-(6-chloro-pyridazine)-formamidine intermediate. DMF 6L was added dropwise and bromoacetonitrile (2.7 kg, 23.1 mol) was added. The reaction was completed at 85°C for 5 hours. The liquid chromatography detection showed that the formamidine intermediate was less than 0.5%. The reaction was completed. The reaction was cooled to room temperature, an appropriate amount of saturated sodium bicarbonate solution was added, the pH was adjusted to about 7.4, the temperature was lowered to 0-5°C and the reaction was allowed to stand for two hours. The solid precipitated, filtered, washed three times with water, and the crude product was recrystallized from methanol to obtain 2.28 kg of pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile. Purity 98.9%, yield 82.9%.

[0061] Example 3

[0062] 2 kg (15.4 mol) of 3-amino-6-chloropyridazine was used as the reaction raw material. It was mixed with 4 kg of N-dimethylformamide dimethyl acetal and stirred at 60°C for half an hour. 30 g of 4-dimethylaminophenol bromide was added and the temperature was raised to 85°C. The reaction was completed for 2 hours. The liquid chromatography detection of the raw material 3-amino-6-chloropyridazine was less than 0.5%. The reaction was completed to obtain N,N-dimethyl-N'-3-(6-chloro-pyridazine)-formamidine intermediate. 6 L of DMF was added dropwise with bromoacetonitrile (2.7 kg, 23.1 mol) l), react at 85°C for 5 hours. The reaction was complete when the formamidine intermediate content was <0.5% by liquid chromatography. The mixture was cooled to room temperature, and an appropriate amount of saturated sodium bicarbonate solution was added to adjust the pH to approximately 7.4. The mixture was cooled to 0-5°C and allowed to stand for two hours to precipitate a solid. The solid was filtered and washed three times with water. The crude product was recrystallized from n-hexane and ethyl acetate to obtain 2.34 kg of pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile. The purity was 99.2%, and the yield was 85.1%. Figure 3 shows the HPLC chromatogram of the crude 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile prepared in this example; Figure 4 The high performance liquid chromatogram of the pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile prepared in this example is shown.

[0063] Example 4

[0064] 2 kg (15.4 mol) of 3-amino-6-chloropyridazine was used as the reaction raw material. It was mixed with 6 kg of N-dimethylformamide dimethyl acetal and stirred at 60°C for half an hour. 100 g of p-methylphenol was added and the temperature was raised to 85°C. The reaction was completed for 2 hours. The liquid chromatography detection showed that the raw material 3-amino-6-chloropyridazine was less than 0.5%. The reaction was completed to obtain N,N-dimethyl-N'-3-(6-chloro-pyridazine)-formamidine intermediate. 8 L of DMF was added dropwise with bromoacetonitrile (2.6 kg, 20.2 mol) l), reacted at 85°C for 5.5 hours. The reaction was complete when the formamidine intermediate content was <0.5% by liquid chromatography. The mixture was cooled to room temperature, an appropriate amount of saturated sodium bicarbonate solution was added, the pH was adjusted to approximately 7.0, and the temperature was lowered to 0-5°C and allowed to stand for two hours. A solid precipitated, which was filtered and washed three times with water. The crude product was recrystallized from ethyl acetate and n-hexane in a ratio of 1:2 to obtain 2.41 kg of pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile. The purity was 99.3%, and the yield was 87.6%.

[0065] Example 5

[0066] 2 kg (15.4 mol) of 3-amino-6-chloropyridazine was used as the reaction raw material, and 6 kg of N-dimethylformamide dimethyl acetal were stirred at 60 ° C for half an hour, 70 g of 4-dimethylaminophenol was added, and the temperature was raised to 85 ° C for 2 hours to complete the reaction. The liquid chromatography detection of the raw material 3-amino-6-chloropyridazine was less than 0.5%, and the reaction was completed to obtain N, N-dimethyl-N'-3-(6-chloro-pyridazine)-formamidine intermediate. 8 L of DMF was added dropwise with bromoacetonitrile (2.6 kg, 20.2 mol) l), reacted at 85°C for 6 hours. The reaction was complete when the formamidine intermediate was <0.5% by liquid chromatography. The mixture was cooled to room temperature, an appropriate amount of saturated sodium bicarbonate solution was added, the pH was adjusted to approximately 7.0, the temperature was lowered to 0-5°C, and the mixture was allowed to stand for two hours to precipitate a solid. The solid was filtered and washed three times with water. The crude product was recrystallized from ethyl acetate and n-hexane in a ratio of 1:2 to obtain 2.54 kg of pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile. The purity was 99.2%, and the yield was 92.4%.

[0067] Example 6

[0068] 2 kg (15.4 mol) of 3-amino-6-chloropyridazine was used as the reaction raw material. It was mixed with 6 kg of N-dimethylformamide dimethyl acetal and stirred at 60°C for half an hour. 100 g of 4-dimethylaminophenol bromide was added and the temperature was raised to 85°C. The reaction was completed for 2 hours. The liquid chromatography detection of the raw material 3-amino-6-chloropyridazine was less than 0.5%. The reaction was completed to obtain N,N-dimethyl-N'-3-(6-chloro-pyridazine)-formamidine intermediate. 8 L of DMF was added dropwise with bromoacetonitrile (2.6 kg, 20.2 mol) l), reacted at 85°C for 6 hours. The reaction was complete when the formamidine intermediate content was <0.5% by liquid chromatography. The mixture was cooled to room temperature, an appropriate amount of saturated sodium bicarbonate solution was added, the pH was adjusted to approximately 7.0, and the temperature was lowered to 0-5°C and allowed to stand for two hours. A solid precipitated, which was filtered and washed three times with water. The crude product was recrystallized from ethyl acetate and n-hexane in a ratio of 1:2 to obtain 2.58 kg of pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile. The purity was 99.1%, and the yield was 93.8%. Figure 5 The high performance liquid chromatogram of the pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile prepared in this example is shown.

[0069] Example 7

[0070] 2 kg (15.4 mol) of 3-amino-6-chloropyridazine was used as the reaction raw material and 6 kg of N-dimethylformamide dimethyl acetal were stirred at 60 ° C for half an hour. Different polymerization inhibitors were added and the temperature was raised to 85 ° C for 2 hours. The reaction was completed. The liquid phase detection of the raw material 3-amino-6-chloropyridazine was <0.5%. The reaction was completed to obtain N,N-dimethyl-N'-3-(6-chloro-pyridazine)-formamidine intermediate. DMF8L was added dropwise and bromoacetonitrile (2.6 kg, 20.2 mol) was added. The reaction was carried out at 85 ° C for 6 hours. The liquid phase detection of the formamidine intermediate was <0.5% and the reaction was completed. The reaction was cooled to room temperature, an appropriate amount of saturated sodium bicarbonate solution was added, the pH was adjusted to about 7.0, the temperature was lowered to 0-5 ° C and allowed to stand for two hours. The solid was precipitated, filtered, washed three times with water, and the crude product was recrystallized from ethyl acetate and n-hexane in a ratio of 1:2 to obtain pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile.

[0071] In this embodiment, other conditions and parameters are determined to be unchanged, and the variable is the type and amount of the polymerization inhibitor added in step (1). The specific amount and related parameters are shown in Table 2.

[0072] Table 2

[0073]

[0074] It can be verified from Examples 7.11-7.14, 7.21-7.24, 7.31-7.34 and 7.41-7.44 in Table 2 above that the feeding mass of the polymerization inhibitor can be selected as 1%-7% of the mass of 3-amino-6-chloropyridazine; by comparing the purity and product yield of the obtained target product 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile, it can be confirmed that when the polymerization inhibitor is used in an amount of 3.5%-7% of the mass of 3-amino-6-chloropyridazine, the yield is above 90% and the purity is 99%+. When the amount is too much, the yield and purity will not increase. Therefore, it can be seen that the optional polymerization inhibitor mass is 3.5%-7% of the mass of 3-amino-6-chloropyridazine, and can be further selected as 3.5%-5%.

[0075] Comparative Example 1

[0076] 2 kg (15.4 mol) of 3-amino-6-chloropyridazine was used as the reaction raw material, and 16 kg of N-dimethylformamide dimethyl acetal were stirred at 60 ° C for half an hour, and the temperature was raised to 85 ° C for 10 hours. The liquid chromatography detection of the raw material 3-amino-6-chloropyridazine was less than 0.5%, and the reaction was completed to obtain N, N-dimethyl-N'-3-(6-chloro-pyridazine)-formamidine intermediate. 8 L of DMF was added dropwise and bromoacetonitrile (2.6 kg, 20.2 mol) was added. l), react at 85°C for 8 hours. The reaction was complete when the formamidine intermediate was <0.5% by liquid chromatography. The mixture was cooled to room temperature, an appropriate amount of saturated sodium bicarbonate solution was added, the pH was adjusted to approximately 7.0, the temperature was lowered to 0-5°C, and the mixture was allowed to stand for two hours to precipitate a solid. The solid was filtered. If the filtration became viscous, it was filtered in batches. The solid was washed three times with water. The crude product was recrystallized from ethyl acetate and n-hexane in a ratio of 1:2 to obtain 2.07 kg of pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile. The purity was 97.5%, and the yield was 75.5%.

[0077] Comparative Example 2

[0078] 2 kg (15.4 mol) of 3-amino-6-chloropyridazine was used as the reaction raw material, and 16 kg of N-dimethylformamide dimethyl acetal were stirred at 60 ° C for half an hour, and the temperature was raised to 85 ° C for 10 hours. The liquid chromatography detection of the raw material 3-amino-6-chloropyridazine was less than 0.5%, and the reaction was completed to obtain N, N-dimethyl-N'-3-(6-chloro-pyridazine)-formamidine intermediate. 8 L of DMF was added dropwise and bromoacetonitrile (2.6 kg, 20.2 mol) was added. l), reacted at 85°C for 9 hours. The reaction was complete when the formamidine intermediate was <0.5% by liquid chromatography. The mixture was cooled to room temperature, an appropriate amount of saturated sodium bicarbonate solution was added, the pH was adjusted to approximately 7.0, and the temperature was lowered to 0-5°C and allowed to stand for two hours to precipitate a solid. The solid was filtered. If the filtration became viscous, it was filtered in batches. The solid was washed three times with water. The crude product was recrystallized from ethyl acetate and n-hexane in a ratio of 1:2 to obtain 2.02 kg of pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile. The purity was 97.1%, and the yield was 73.5%.

[0079] It can be confirmed from Examples 1 to 7 that the mass ratio of the 3-amino-6-chloropyridazine to DMF-DMA can be selected from 1:2 to 1:4, and can further be selected from 1:2 to 1:3; the molar ratio of the 3-amino-6-chloropyridazine to bromoacetonitrile can be selected from 1:1 to 1:1.5, and can further be selected from 1:1.3.

[0080] By comparing Example 5 and Example 6 with Comparative Example 1 and Comparative Example 2, it can be verified that: (1) the amount of DMF-DMA in the examples is much less than the amount of DMF-DMA in the comparative examples, so the preparation method of 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile of the present invention can save raw material input and increase the yield by more than 22%; (2) the overall reaction time of Comparative Example 1 and Comparative Example 2 is more than twice the time required for the experimental example, so the preparation method of the present invention can significantly improve production efficiency and is more suitable for industrial production; (3) Figure 6 The state of the materials after adjusting the pH value in Example 5 and Comparative Example 1 is shown. It is not difficult to see that a black oily substance appears in Comparative Example 1, which will lead to the appearance of a viscous crude solid in the subsequent cooling and crystallization operation, which is not conducive to the separation and collection of the crude product, and will further affect the purity and process yield of the subsequent product; while no oily substance appears in Example 5, which greatly reduces the difficulty of subsequent cooling crystallization, separation, recrystallization and other operations. The prepared product has high purity and high process yield, and is suitable for large-scale industrial production.

[0081] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A method for preparing 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile, characterized in that: The following steps are involved: (1) dissolving 3-amino-6-chloropyridazine in DMF-DMA in a reactor and then adding a polymerization inhibitor to react to obtain an intermediate; (2) adding an organic solvent to the reactor, and the intermediate and bromoacetonitrile undergo a ring-closing reaction; After the reaction is completed, the pH value of the material in the reactor is adjusted to neutral, and the crude product is obtained by cooling and crystallization; (3) the crude product is recrystallized to obtain the pure 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile; The mass of the polymerization inhibitor is 1%-7% of the mass of the 3-amino-6-chloropyridazine; the polymerization inhibitor is phenol, p-methylphenol, 4-dimethylaminophenol or 4-dimethylaminophenol bromide.

2. The method for preparing 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile according to claim 1, wherein The mass ratio of the 3-amino-6-chloropyridazine to DMF-DMA is 1:2-1:

4.

3. The method for preparing 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile according to claim 1, wherein The mass of the polymerization inhibitor is 3.5%-5% of the mass of the 3-amino-6-chloropyridazine.

4. The method for preparing 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile according to claim 1, wherein The reaction temperature of step (1) is 75-85° C., and the reaction time is 2-10 h.

5. The method for preparing 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile according to claim 1, wherein The organic solvent is DMF, methanol or DMSO.

6. The method for preparing 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile according to claim 1, wherein The molar ratio of the 3-amino-6-chloropyridazine to bromoacetonitrile is 1:1-1:1.

5.

7. The method for preparing 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile according to claim 6, wherein The molar ratio of the 3-amino-6-chloropyridazine to bromoacetonitrile is 1:1.

3.

8. The method for preparing 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile according to claim 1, wherein The temperature of the ring-closing reaction is 60-85° C., and the reaction time is 5-6 hours.

9. The method for preparing 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile according to claim 1, wherein The solvent used for recrystallization in step (3) is selected from n-hexane, methanol, or a composite solvent of ethyl acetate and n-hexane.

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