A method for removing viscous impurities in the synthesis of hexahydro pyridazine
By removing viscous impurities in the synthesis of hexahydropyridazine through segmented reaction catalytic cyclization, extraction, and low-temperature crystallization, the problem of impurities caused by high-temperature distillation was solved, and the production of high-purity and high-yield hexahydropyridazine dihydrochloride was achieved, reducing energy consumption and environmental impact.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- HENAN YUCHEN PHARM CO LTD
- Filing Date
- 2023-09-25
- Publication Date
- 2026-05-29
AI Technical Summary
In the production process of hexahydropyridazine, the generation of viscous impurities affects product quality and yield. Existing high-temperature distillation methods cannot effectively remove them and also introduce new impurities.
A segmented reaction catalytic cyclization method was adopted, combined with high-temperature extraction, activated carbon dehydration and decolorization, and low-temperature crystallization. Impurities were removed by utilizing the difference in viscosity and solubility. Reaction conditions were controlled to reduce side reactions, and impurity generation was controlled during the alcoholysis of ethanol and hydrogen chloride to form salts.
It effectively removes viscous oily substances of different molecular weights, improves product purity and yield, reduces energy consumption and environmental pollution, is easy to operate, and the solvent can be recycled.
Smart Images
Figure CN117327021B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical synthesis technology, and in particular to a method for removing viscous impurities during the synthesis of hexahydropyridazine. Background Technology
[0002] Hexahydropyridazine dihydrochloride is an important organic chemical intermediate widely used in pharmaceuticals, pesticides, and organic chemicals. In particular, it is a key intermediate in pesticide synthesis, serving as a crucial step in the production of herbicides and insecticides such as fluthiamethoxam, and it itself possesses amoebic activity. In pharmaceuticals, it is primarily used in the synthesis of pyridazine-based drugs.
[0003] There are three main synthetic routes for the synthesis of hexahydropyridazines, depending on the starting materials: the 1,4-dihalobutane route; the 1,4-butanediol route; and the butadiene route. Among these, the method using 1,4-dihalobutane as a starting material is the mainstream industrial method due to its readily available raw materials, simple synthesis method, few side reactions, and easy product separation.
[0004] However, in the production of hexahydropyridazines, especially in the synthesis of the intermediate tetrahydropyridazine-1,2-dicarboxaldehyde, a large amount of viscous impurities are generated due to the complex chemical reactions during substitution, polymerization, and heating. If these impurities are not removed, they will significantly affect the quality and yield of the final product. The literature "Improvement of the Synthesis Method of Hexahydropyridazines" uses high-vacuum distillation to purify the intermediate tetrahydropyridazine-1,2-dicarboxaldehyde (bp 120℃-128℃ / 0.53kPa, 96℃-102℃ / 0.13kPa). However, the high-temperature distillation process continues to generate viscous impurities, affecting the product yield.
[0005] In view of this, the present invention proposes a process that can effectively remove viscous substances in the preparation of hexahydropyridazine without affecting the yield. Summary of the Invention
[0006] The purpose of this invention is to provide a method for removing viscous impurities in the synthesis of hexahydropyridazine. This method not only avoids the generation of new impurities during high-temperature distillation purification, but also effectively removes viscous oily substances of different molecular weights.
[0007] This invention provides a method for removing viscous impurities during the synthesis of hexahydropyridazine, comprising the following steps:
[0008] S1 and 1,2-dicarboxyhydrazide were reacted with 1,4-dichlorobutane in stages under alkaline and potassium bromide catalytic conditions. After the reaction was complete, the solution was filtered and distilled under reduced pressure to obtain a concentrated solution of tetrahydropyridazine-1,2-dicarboxaldehyde.
[0009] S2. The concentrated tetrahydropyridazine-1,2-dicarboxaldehyde solution was successively extracted with ethyl acetate, dehydrated and decolorized, cooled to remove impurities and distilled under reduced pressure to obtain purified tetrahydropyridazine-1,2-dicarboxaldehyde.
[0010] S3. The purified tetrahydropyridazine-1,2-dicarboxaldehyde was dissolved in anhydrous ethanol, and ethanol hydrogen chloride was added dropwise and kept at a constant temperature. After the reaction was complete, the product was crystallized, filtered, washed and dried to obtain hexahydropyridazine dihydrochloride.
[0011] The synthetic route for hexahydropyridazine dihydrochloride of this invention is as follows:
[0012]
[0013] Specifically, under segmented temperature control, 1,2-dicarboxyhydrazide undergoes a cyclization reaction with 1,4-dichlorobutane under alkaline and potassium bromide catalytic conditions. This segmented catalytic cyclization method not only saves reaction time but also effectively reduces the occurrence of side reactions and the generation of viscous impurities during the high-temperature stage, thereby improving the conversion rate while ensuring the purity of the product.
[0014] Although this invention employs a segmented reaction catalytic cyclization method to reduce the occurrence of side reactions during the reaction process, the following side reactions are still unavoidable:
[0015]
[0016] Therefore, in the purification process of tetrahydropyridazine-1,2-dicarboxaldehyde concentrate, this invention first utilizes the difference in fluidity between the extractant and the viscous oil at high temperature to remove most of the viscous oil. Then, activated carbon and sodium sulfate are added for dehydration and decolorization, simultaneously removing a small portion of the viscous oil. Finally, the difference in solubility between the viscous oil and tetrahydropyridazine-1,2-dicarboxaldehyde at low temperature is used to further remove the remaining low-molecular-weight viscous oil. Thus, the purification process of tetrahydropyridazine-1,2-dicarboxaldehyde in this invention is primarily a physical method, which not only avoids the generation of new impurities during high-temperature distillation purification but also effectively removes viscous oils of different molecular weights.
[0017] Finally, in the alcoholysis salt formation process of tetrahydropyridazine-1,2-dicarboxaldehyde, this invention selects ethanol hydrogen chloride to react with tetrahydropyridazine-1,2-dicarboxaldehyde. By controlling the reaction concentration, reaction temperature, and crystallization temperature, the generation of viscous impurities during salt formation is reduced. Furthermore, the volatilization of solvent and hydrogen chloride is reduced, while effectively controlling the residual methanol solvent in the product.
[0018] As a preferred embodiment of this technical solution, step S1 specifically includes adding 1,2-dicarboxyhydrazide and N,N-dimethylformamide to a reaction vessel under nitrogen conditions, heating to 40-45°C, stirring to dissolve, adding anhydrous potassium carbonate and potassium bromide, heating to 70-80°C, and adding 1,4-dichlorobutane for staged reaction.
[0019] This invention uses N,N-dimethylformamide as a solvent, which not only increases the solubility of reactants, catalysts, and products, avoiding the use of phase transfer catalysts, but also improves the reaction rate and conversion rate. Furthermore, the use of staged heating and staged addition of reactants, solvents, and catalysts effectively avoids the occurrence of side reactions in the initial stage of the reaction.
[0020] In step S1, the present invention does not impose strict requirements on the molar ratio of 1,2-dicarboxyhydrazide, 1,4-dichlorobutane, anhydrous potassium carbonate and potassium bromide, and it is preferably 1:1:1:0.05.
[0021] As a preferred embodiment of this technical solution, in step S1, the segmented reaction is specifically controlled to react at 85-95℃ for 25-35 minutes, at 100-110℃ for 25-35 minutes, and at 110-120℃ for 1.5-2.5 hours, and preferably at 90℃ for 30 minutes, at 105℃ for 30 minutes, and at 110-120℃ for 2 hours.
[0022] As a preferred embodiment of this technical solution, in step S2, specifically, during the ethyl acetate extraction, ethyl acetate is added to the tetrahydropyridazine-1,2-dicarboxaldehyde concentrate at 35-50°C for multiple extractions to separate viscous oily impurities. The extracted organic layers are then combined and allowed to stand at this temperature for 1-3 hours to separate viscous oily impurities with larger molecular weights, resulting in a preliminarily purified organic layer.
[0023] As a preferred embodiment of this technical solution, in step S2, during the dehydration and decolorization, activated carbon and sodium sulfate are added to the purified organic layer for decolorization and drying for 1-3 hours, followed by filtration to obtain the dehydrated and decolorized organic layer.
[0024] In a preferred embodiment of this technical solution, during step S2, the dehydrated and decolorized organic layer is cooled to -10 to 0°C to separate viscous oily impurities with low solubility, and a filtrate is obtained.
[0025] During the vacuum distillation, the filtrate after cooling and impurity removal is concentrated under reduced pressure to remove the solvent, yielding purified tetrahydropyridazine-1,2-dicarboxaldehyde, wherein the removed ethyl acetate can be recycled.
[0026] As a preferred embodiment of this technical solution, in step S3, ethanolic hydrogen chloride is added dropwise to an anhydrous ethanol solution of tetrahydropyridazine-1,2-dicarboxaldehyde at 20-30°C, and the reaction is maintained at this temperature for 2-6 hours.
[0027] As a preferred embodiment of this technical solution, in step S3, the mass ratio of tetrahydropyridazine-1,2-dicarboxaldehyde to ethanol hydrogen chloride is 1:(1.5-1.8), wherein the concentration of ethanol hydrogen chloride is 30-36% (i.e., 6.5-7.9M).
[0028] As a preferred embodiment of this technical solution, in step S3, during crystallization, the mixture is stirred at 0-10°C for 0.5-1.5 hours to further reduce impurities generated by the viscous substance; during washing, the filter cake is washed with ethanol; and during drying, it is vacuum dried at 45-55°C.
[0029] The method for removing viscous impurities during the synthesis of hexahydropyridazine according to the present invention has at least the following technical effects:
[0030] 1. This invention uses 1,2-dicarboxyhydrazide and dichlorobutane as the main raw materials and adopts a segmented reaction catalytic cyclization method, which not only saves reaction time, but also effectively reduces the occurrence of side reactions and the generation of viscous impurities in the high-temperature stage, improves the conversion rate and ensures the purity of the product.
[0031] 2. In the purification process of tetrahydropyridazine-1,2-dicarboxaldehyde concentrate, this invention first utilizes the difference in fluidity between the extractant and the viscous oil at high temperature to remove most of the viscous oil. Then, activated carbon and sodium sulfate are added for dehydration and decolorization, simultaneously removing a small portion of the viscous oil. Finally, the difference in solubility between the viscous oil and tetrahydropyridazine-1,2-dicarboxaldehyde at low temperature is used to further remove the remaining low-molecular-weight viscous oil. The purification process of tetrahydropyridazine-1,2-dicarboxaldehyde in this invention is primarily a physical method, which not only avoids the generation of new impurities during high-temperature distillation purification but also effectively removes viscous oils of different molecular weights.
[0032] 3. In the process of alcoholysis to salt formation of tetrahydropyridazine-1,2-dicarboxaldehyde, the reaction of ethanol and hydrogen chloride with tetrahydropyridazine-1,2-dicarboxaldehyde is selected. This not only increases the concentration of reactants and reduces the volatilization of solvent and hydrogen chloride, but also effectively avoids the residue of methanol solvent in the product. The appropriate crystallization temperature improves the purity and yield of the product.
[0033] 4. The preparation process of hexahydropyridazine dihydrochloride of the present invention is mild and easy to operate, which not only reduces and prevents the occurrence of side reactions, but also has low energy consumption, effectively improving the product yield and product purity of hexahydropyridazine dihydrochloride (purity ≥99.0%, residue on ignition ≤0.1%, unknown single impurities ≤0.5%). In addition, the solvent and filter cake can be recycled, with virtually no wastewater generated, resulting in minimal environmental pollution. Attached Figure Description
[0034] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.
[0035] Figure 1 This is a chromatogram of the concentrated tetrahydropyridazine-1,2-dicarboxaldehyde solution from Example 5 of the present invention;
[0036] Figure 2 This is the purified chromatogram of tetrahydropyridazine-1,2-dicarboxaldehyde from Example 5 of the present invention.
[0037] Figure 3 This is a chromatogram of the tetrahydropyridazine dihydrochloride product from Example 5 of the present invention; Detailed Implementation
[0038] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of this application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.
[0039] It should be noted that the terminology used herein is for the purpose of describing particular implementations only and is not intended to limit the exemplary implementations according to this application. As used herein, the singular form includes the plural form unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this description, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.
[0040] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. 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.
[0041] Example 1
[0042] Under nitrogen atmosphere (S11), 200 kg (2.273 kmol) of 1,2-dicarboxyhydrazide and 1400 kg of DMF were added to the reactor. The mixture was heated to 40-45 °C and stirred to dissolve. Then, 304 kg (2.2 kmol) of anhydrous potassium carbonate and 13.5 kg (0.11 kmol) of 13.5 KBr were added. The mixture was heated to 70-80 °C and 289 kg (2.275 kmol) of 1,4-dichlorobutane were added. The reaction was carried out at 90 °C for 30 min, at 105 °C for 30 min, and at 110-120 °C for 2 h. The mixture was cooled to room temperature and filtered. The filter cake was a solid mixture of inorganic salts, which was collected, processed, and reused. The filtrate was distilled under reduced pressure to remove the solvent (recovering the DMF solvent for reuse) to obtain 380 kg of concentrated tetrahydropyridazine-1,2-dicarboxaldehyde solution.
[0043] S12. At 35-50℃, add 150kg of ethyl acetate to the concentrated tetrahydropyridazine-1,2-dicarboxaldehyde and stir for 30min. Separate the organic phase. Extract the oily substance twice with 500kg of ethyl acetate, and separate about 66kg of viscous oily impurities. Combine the organic phases and let stand at 35-45℃ for 2 hours. Separate about 10kg of the lower oily substance. Add 2kg of activated carbon and 5kg of anhydrous sodium sulfate to the organic phase and stir. Filter. Cool the filtrate to -5~0℃. Viscous oily impurities precipitate. Separate 5kg of viscous oily impurities. Concentrate the organic phase under reduced pressure with ethyl acetate to dryness (recover ethyl acetate for reuse) to obtain 297kg of purified tetrahydropyridazine-1,2-dicarboxaldehyde, with a yield of 92% and a purity of 98.7%.
[0044] S13. Dissolve 297 kg (2.09 kmol) of tetrahydropyridazine-1,2-dicarboxaldehyde and 240 kg of anhydrous ethanol by stirring. Add 490 kg of 30% ethanol-hydrogen chloride dropwise at 20-30 °C and maintain the temperature for 5 h. After the reaction is complete, stir at 5-10 °C for 1 h, filter, wash the filter cake with anhydrous ethanol, and dry it under vacuum at 50 °C to obtain 312 kg (1.96 kmol) of hexahydropyridazine hydrochloride, with a yield of 93.8%.
[0045] The product quality is as follows: purity 99.2%, residue on ignition 0.06%, unknown elemental content 0.03%.
[0046] Example 2
[0047] Under nitrogen atmosphere (S21), 200 kg (2.273 kmol) of 1,2-dicarboxyhydrazide and 1400 kg of DMF were added to the reactor. The mixture was heated to 40-45 °C and stirred to dissolve. Then, 304 kg (2.2 kmol) of anhydrous potassium carbonate and 13.5 kg (0.11 kmol) of 13.5 KBr were added. The mixture was heated to 70-80 °C and 289 kg (2.275 kmol) of 1,4-dichlorobutane were added. The reaction was carried out at 90 °C for 30 min, at 105 °C for 30 min, and at 110-120 °C for 2 h. The mixture was cooled to room temperature and filtered. The filter cake was a solid mixture of inorganic salts, which was collected, processed, and reused. The filtrate was distilled under reduced pressure to remove the solvent (recovering the DMF solvent for reuse) to obtain 380 kg of concentrated tetrahydropyridazine-1,2-dicarboxaldehyde solution.
[0048] S22. At 45-50℃, 150 kg of ethyl acetate was added to the concentrated tetrahydropyridazine-1,2-dicarboxaldehyde and stirred for 30 min. The organic phase was separated, and the oily substance was extracted twice with 500 kg of ethyl acetate. About 62 kg of viscous oily impurities were separated. The organic phases were combined and allowed to stand at 45-50℃ for 2 hours. About 8 kg of the lower oily substance was separated. 2 kg of activated carbon and 5 kg of anhydrous sodium sulfate were added to the organic phase and stirred. The mixture was filtered. The filtrate was cooled to -10 to -5℃, and viscous oily impurities precipitated. 6.6 kg of viscous oily impurities were separated. The organic phase was concentrated under reduced pressure with ethyl acetate to dryness (the ethyl acetate was recovered for reuse) to obtain 303.4 kg of purified tetrahydropyridazine-1,2-dicarboxaldehyde, with a yield of 94% and a purity of 98.5%.
[0049] S23. Dissolve 303.4 kg (2.14 kmol) of tetrahydropyridazine-1,2-dicarboxaldehyde and 240 kg of anhydrous ethanol by stirring. Add 490 kg of 30% ethanol-hydrogen chloride dropwise at 20-30 °C and keep the reaction at this temperature for 5 h. After the reaction is complete, stir at 5-10 °C for 1 h, filter, wash the filter cake with anhydrous ethanol, and dry it under vacuum at 50 °C to obtain 316 kg (1.99 kmol) of hexahydropyridazine hydrochloride, with a yield of 93%.
[0050] The product quality is as follows: purity 99.3%, residue on ignition 0.04%, unknown elemental content 0.05%.
[0051] Example 3
[0052] Under nitrogen atmosphere (S31), 200 kg (2.273 kmol) of 1,2-dicarboxyhydrazide and 1400 kg of DMF were added to the reactor. The mixture was heated to 40-45 °C and stirred to dissolve. Then, 304 kg (2.2 kmol) of anhydrous potassium carbonate and 13.5 kg (0.11 kmol) of 13.5 KBr were added. The mixture was heated to 70-80 °C and 289 kg (2.275 kmol) of 1,4-dichlorobutane were added. The reaction was carried out at 90 °C for 30 min, at 105 °C for 30 min, and at 110-120 °C for 2 h. The mixture was cooled to room temperature and filtered. The filter cake was a solid mixture of inorganic salts, which was collected, processed, and reused. The filtrate was distilled under reduced pressure to remove the solvent (recovering the DMF solvent for reuse) to obtain 380 kg of concentrated tetrahydropyridazine-1,2-dicarboxaldehyde solution.
[0053] S32. At 45-50℃, 150 kg of ethyl acetate was added to the concentrated tetrahydropyridazine-1,2-dicarboxaldehyde and stirred for 30 min. The organic phase was separated, and the oily substance was extracted twice with 500 kg of ethyl acetate. About 62 kg of viscous oily impurities were separated. The organic phases were combined and allowed to stand at 45-50℃ for 2 hours. About 4.4 kg of the lower oily substance was separated. 2 kg of activated carbon and 5 kg of anhydrous sodium sulfate were added to the organic phase and stirred. The mixture was then filtered. The filtrate was cooled to -10 to -5℃, and viscous oily impurities precipitated. 7 kg of viscous oily impurities were separated. The organic phase was concentrated under reduced pressure with ethyl acetate to dryness (the ethyl acetate was recovered for reuse) to obtain 305.6 kg of purified tetrahydropyridazine-1,2-dicarboxaldehyde, with a yield of 94.7% and a purity of 98.6%.
[0054] S33. Dissolve 305.6 kg (2.54 kmol) of tetrahydropyridazine-1,2-dicarboxaldehyde and 240 kg of anhydrous ethanol by stirring. Add 490 kg of 36% ethanol-hydrogen chloride dropwise at 20-30 °C and maintain the temperature for 8 h. After the reaction is complete, stir at 0-5 °C for 1 h, filter, wash the filter cake with anhydrous ethanol, and dry it under vacuum at 50 °C to obtain 319 kg (2.0 kmol) of hexahydropyridazine hydrochloride, with a yield of 93.2%.
[0055] The product quality is as follows: purity 99.3%, residue on ignition 0.04%, unknown elemental composition 0.02%.
[0056] Example 4
[0057] Under nitrogen atmosphere, 200 kg (2.273 kmol) of 1,2-dicarboxyhydrazide and 1400 kg of DMF were added to the reactor. The mixture was heated to 40-45 °C and stirred to dissolve. Then, 304 kg (2.2 kmol) of anhydrous potassium carbonate and 13.5 kg (0.11 kmol) of 13.5 KBr were added. The mixture was heated to 70-80 °C and 289 kg (2.275 kmol) of 1,4-dichlorobutane were added. The reaction was carried out at 90 °C for 30 min, at 105 °C for 30 min, and at 110-120 °C for 2.5 h. The mixture was cooled to room temperature and filtered. The filter cake was a solid mixture of inorganic salts, which was collected, processed, and reused. The filtrate was distilled under reduced pressure to remove the solvent (recovering the DMF solvent for reuse) to obtain 382 kg of concentrated tetrahydropyridazine-1,2-dicarboxaldehyde solution.
[0058] S42. At 35-45℃, 150 kg of ethyl acetate was added to the concentrated tetrahydropyridazine-1,2-dicarboxaldehyde and stirred for 30 min. The organic phase was separated, and the oily substance was extracted twice with 500 kg of ethyl acetate. About 66 kg of viscous oily impurities were separated. The organic phases were combined and allowed to stand at 35-45℃ for 2 hours. About 7.6 kg of the lower oily substance was separated. 2 kg of activated carbon and 5 kg of anhydrous sodium sulfate were added to the organic phase and stirred. The mixture was then filtered. The filtrate was cooled to -10 to -5℃, and viscous oily impurities precipitated. 6 kg of viscous oily impurities were separated. The organic phase was concentrated under reduced pressure with ethyl acetate to dryness (the ethyl acetate was recovered for reuse) to obtain 302.4 kg of purified tetrahydropyridazine-1,2-dicarboxaldehyde, with a yield of 94% and a purity of 98.6%.
[0059] S43. Dissolve 3023.4 kg (2.34 kmol) of tetrahydropyridazine-1,2-dicarboxaldehyde in 240 kg of anhydrous ethanol by stirring. Add 490 kg of 36% ethanol-hydrogen chloride dropwise at 20-30 °C and keep the reaction at this temperature for 6 h. After the reaction is complete, stir at 0-5 °C for 1 h, filter, wash the filter cake with anhydrous ethanol, and dry it under vacuum at 50 °C to obtain 315 kg (1.98 kmol) of hexahydropyridazine hydrochloride, with a yield of 93%.
[0060] The product quality is as follows: purity 99.3%, residue on ignition 0.06%, unknown elemental content 0.08%.
[0061] Example 5
[0062] Under nitrogen atmosphere, 200 kg (2.273 kmol) of 1,2-dicarboxyhydrazide and 1400 kg of DMF were added to a reactor. The mixture was heated to 40-45 °C and stirred until dissolved. Then, 304 kg (2.2 kmol) of anhydrous potassium carbonate and 13.5 kg (0.11 kmol) of 13.5 KBr were added. The mixture was heated to 70-80 °C and 289 kg (2.275 kmol) of 1,4-dichlorobutane were added. The reaction was carried out at 90 °C for 30 min, at 105 °C for 30 min, and at 110-120 °C for 2 h. The mixture was cooled to room temperature and filtered. The filter cake was a solid mixture of inorganic salts, which was collected, processed, and reused. The filtrate was distilled under reduced pressure to remove the solvent (recovering the DMF solvent for reuse) to obtain 380 kg of concentrated tetrahydropyridazine-1,2-dicarboxaldehyde solution.
[0063] S52. At 35-45℃, 150 kg of ethyl acetate was added to the concentrated tetrahydropyridazine-1,2-dicarboxaldehyde and stirred for 30 min. The organic phase was separated, and the oily substance was extracted twice with 500 kg of ethyl acetate. About 66 kg of viscous oily impurities were separated. The organic phases were combined and allowed to stand at 35-45℃ for 2 hours. About 8 kg of the lower oily substance was separated. 2 kg of activated carbon and 6 kg of anhydrous sodium sulfate were added to the organic phase and stirred. The mixture was filtered. The filtrate was cooled to -10 to -5℃, and viscous oily impurities precipitated. 10 kg of viscous oily impurities were separated. The organic phase was concentrated under reduced pressure with ethyl acetate to dryness (the ethyl acetate was recovered for reuse) to obtain 300 kg of purified tetrahydropyridazine-1,2-dicarboxaldehyde, with a yield of 93% and a purity of 98.9%.
[0064] S53. Dissolve 300 kg (2.11 kmol) of tetrahydropyridazine-1,2-dicarboxaldehyde and 240 kg of anhydrous ethanol by stirring. Add 490 kg of 36% ethanol-hydrogen chloride dropwise at 20-30 °C and maintain the temperature for 6 h. After the reaction is complete, stir at 0-10 °C for 1 h, filter, wash the filter cake with anhydrous ethanol, and dry it under vacuum at 50 °C to obtain 317 kg (1.99 kmol) of hexahydropyridazine hydrochloride, with a yield of 94.3%.
[0065] The product quality is as follows: purity 99.3%, residue on ignition 0.04%, unknown elemental content 0.05%.
[0066] Compare with Example 1
[0067] Example 1 of Chinese invention patent with publication number CN110483410 A is used as the comparative example.
[0068] Specifically, the following steps are included:
[0069] (1) Add 280 mL of toluene and 56 g of formic acid to a three-necked reaction flask equipped with a stirrer; add 31.9 g of hydrazine hydrate dropwise at 0 °C; after the addition is complete, react at 90 °C for 8 hours; cool to room temperature, filter, collect the solid and dry to obtain 37.5 g of N,N'-diformylhydrazine white solid, with a yield of 84% and a purity of 96%.
[0070] MRI results: 1 H NMR (400MHz, d6-DMSO): δ9.98(2H), 8.12(2H).
[0071] (2) Add 180 mL of acetonitrile and 18.0 g of N,N'-dicarboxyhydrazide to a three-necked reaction flask equipped with a stirrer and mix well; then add 55.2 g of potassium carbonate, 0.66 g of tetrabutylammonium bromide, 0.34 g of potassium iodide and 45.2 g of 1,4-dibromobutane in sequence, and react at 70 °C for 5 hours; cool to room temperature, filter, and concentrate the filtrate to obtain 15.7 g of brown oily tetrahydropyridazine-1,2-dicarboxaldehyde, with a yield of 79% and a purity of 95%.
[0072] MRI results: 1 H NMR (400MHz, d6-DMSO): δ 8.66 (2H), 3.02 (4H), 1.97 (4H).
[0073] (3) Add 100 mL of 3M hydrochloric acid methanol solution and 15.0 g of tetrahydropyridazine-1,2-dicarboxaldehyde to a three-necked reaction flask equipped with a stirrer, and react at 30 °C for 2 hours; filter, collect the solid and dry to obtain 15.1 g of hexahydropyridazine dihydrochloride white solid, with a yield of 90% and a purity of 97%.
[0074] MRI results: 1 H NMR (400MHz, d6-DMSO): 9.86(4H), 2.98(4H), 1.67(4H).
[0075] Compare with Example 2
[0076] The method disclosed in the literature "Improvement of the Synthesis Method of Hexahydropyridazine" is used as a comparative example in this study.
[0077] The reaction of dichlorobutane and dicarboxyhydrazide in DMF was carried out with the addition of a small amount of KI as a catalyst. The reaction was monitored by gas chromatography. It was found that the cyclization reaction was completed within 5 hours, and the selectivity of 1,2-dicarboxyhexahydropyridazine reached 98%, with a separation yield of 87%.
[0078] Dissolve 1,2-dicarboxyhexahydropyridazine in anhydrous methanol, purge with dry HCl gas until saturated, and then react at room temperature for 1 hour to complete the reaction. Concentrate the reaction solution to remove most of the HCl, then neutralize with sodium methoxide solution, filter, remove solvent from the filtrate under normal pressure, and then distill under reduced pressure to obtain 88% hexahydropyridazine dihydrochloride.
[0079] Table 1 Product Yield and Purity
[0080]
[0081] Combined with Table 1 and Figure 1-2 Comparing Examples 1-5 of the present invention with Comparative Example 1, it can be seen that the present invention uses 1,4-dichlorobutane as a raw material, which, compared with 1,4-dibromobutane in Comparative Example 1, does not produce wastewater, waste liquid or waste salt containing bromine or iodine that is highly polluting to the environment, and can achieve green industrialization; moreover, the segmented reaction method effectively saves reaction time, reduces the occurrence of side reactions and the formation of viscous oily substances during long reaction times, and significantly improves the conversion rate and purity of tetrahydropyridazine-1,2-dicarboxaldehyde.
[0082] Comparing Examples 1-5 of the present invention with Comparative Example 2, it can be seen that although Comparative Example 2 used dichlorobutane and dicarboxyhydrazide to react in DMF, the reaction time was long and the purity of the product tetrahydropyridazine-1,2-dicarboxaldehyde was low, which seriously affected the yield of hexahydropyridazine hydrochloride.
[0083] In summary, the preparation process of hexahydropyridazine dihydrochloride of the present invention is mild and easy to operate, which not only reduces and prevents the occurrence of side reactions, but also has low energy consumption, effectively improving the product yield and purity of hexahydropyridazine dihydrochloride (purity ≥99.0%, residue on ignition ≤0.1%, unknown single impurities ≤0.5%), and the solvent and filter cake can be recycled, with virtually no wastewater generated and minimal environmental pollution.
[0084] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.
Claims
1. A method for removing viscous impurities during the synthesis of hexahydropyridazine, characterized in that, Includes the following steps: S1 and 1,2-dicarboxyhydrazide were reacted with 1,4-dichlorobutane in stages under alkaline and potassium bromide catalysis. After the reaction was complete, the solution was filtered and distilled under reduced pressure to obtain a concentrated solution of tetrahydropyridazine-1,2-dicarboxaldehyde. S2. The concentrated tetrahydropyridazine-1,2-dicarboxaldehyde solution was successively extracted with ethyl acetate, dehydrated and decolorized, cooled to remove impurities and then distilled under reduced pressure to obtain purified tetrahydropyridazine-1,2-dicarboxaldehyde. S3. The purified tetrahydropyridazine-1,2-dicarboxaldehyde was dissolved in anhydrous ethanol, and ethanol hydrogen chloride was added dropwise and kept at a constant temperature. After the reaction was complete, the product was crystallized, filtered, washed and dried to obtain hexahydropyridazine dihydrochloride. During the segmented reaction, the reaction temperature is controlled at 85-95℃ for 25-35 minutes, at 100-110℃ for 25-35 minutes, and at 110-120℃ for 1.5-2.5 hours. In step S2, during the ethyl acetate extraction, ethyl acetate is added to the tetrahydropyridazine-1,2-dicarboxaldehyde concentrate at 35-50°C for multiple extractions to separate viscous oily impurities. The extracted organic layers are combined and allowed to stand at this temperature for 1-3 hours to separate viscous oily impurities, thus obtaining the purified organic layer.
2. The method for removing viscous impurities during the synthesis of hexahydropyridazine according to claim 1, characterized in that, Step S1 specifically includes adding 1,2-dicarboxyhydrazide and N,N-dimethylformamide to a reaction vessel under nitrogen atmosphere, heating to 40-45°C, stirring to dissolve, adding anhydrous potassium carbonate and potassium bromide, heating to 70-80°C, and adding 1,4-dichlorobutane for staged reaction.
3. The method for removing viscous impurities during the synthesis of hexahydropyridazine according to claim 2, characterized in that, In step S1, the molar ratio of 1,2-dicarboxyhydrazide, 1,4-dichlorobutane, anhydrous potassium carbonate, and potassium bromide is 1:1:1:0.
05.
4. The method for removing viscous impurities during the synthesis of hexahydropyridazine according to claim 1, characterized in that, In step S2, during the dehydration and decolorization, activated carbon and sodium sulfate are added to the purified organic layer for decolorization and drying for 1-3 hours, followed by filtration to obtain the dehydrated and decolorized organic layer.
5. The method for removing viscous impurities during the synthesis of hexahydropyridazine according to claim 4, characterized in that, In step S2, during the cooling and impurity removal process, the dehydrated and decolorized organic layer is cooled to -10~0℃ to separate viscous oily impurities and obtain filtrate. During the vacuum distillation, the filtrate after cooling and impurity removal is concentrated and desolventized under reduced pressure to obtain purified tetrahydropyridazine-1,2-dicarboxaldehyde.
6. The method for removing viscous impurities during the synthesis of hexahydropyridazine according to claim 1, characterized in that, In step S3, ethanolic hydrogen chloride is added dropwise to an anhydrous ethanol solution of tetrahydropyridazine-1,2-dicarboxaldehyde at 20-35℃, and the reaction is maintained at this temperature for 2-6 hours.
7. The method for removing viscous impurities during the synthesis of hexahydropyridazine according to claim 6, characterized in that, In step S3, the mass ratio of tetrahydropyridazine-1,2-dicarboxaldehyde to ethanol hydrogen chloride is 1:(1.5-1.8), wherein the concentration of ethanol hydrogen chloride is 30-36%.
8. The method for removing viscous impurities during the synthesis of hexahydropyridazine according to claim 1, characterized in that, In step S3, during crystallization, the mixture is stirred at 0-10°C for 0.5-1.5 hours. During the washing process, the filter cake is washed with ethanol. The drying process involves vacuum drying at 45-55°C.