CN117327021A - Method for removing sticky impurities in hexahydropyridazine synthesis - Google Patents
Method for removing sticky impurities in hexahydropyridazine synthesis Download PDFInfo
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- tetrahydropyridazine
- dicarboxaldehyde
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- 239000012535 impurity Substances 0.000 title claims abstract description 57
- 238000000034 method Methods 0.000 title claims abstract description 32
- HTFFABIIOAKIBH-UHFFFAOYSA-N diazinane Chemical compound C1CCNNC1 HTFFABIIOAKIBH-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 22
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 81
- 238000006243 chemical reaction Methods 0.000 claims abstract description 71
- BKWBJAMZEUGAIC-UHFFFAOYSA-N diazinane-1,2-dicarbaldehyde Chemical compound O=CN1CCCCN1C=O BKWBJAMZEUGAIC-UHFFFAOYSA-N 0.000 claims abstract description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000001914 filtration Methods 0.000 claims abstract description 18
- POVXOWVFLAAVBH-UHFFFAOYSA-N n-formamidoformamide Chemical compound O=CNNC=O POVXOWVFLAAVBH-UHFFFAOYSA-N 0.000 claims abstract description 18
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims abstract description 18
- KJDRSWPQXHESDQ-UHFFFAOYSA-N 1,4-dichlorobutane Chemical compound ClCCCCCl KJDRSWPQXHESDQ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000001816 cooling Methods 0.000 claims abstract description 14
- 238000004821 distillation Methods 0.000 claims abstract description 14
- 238000005406 washing Methods 0.000 claims abstract description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 11
- PJUZEZLTRTTWOK-UHFFFAOYSA-N diazinane;dihydrochloride Chemical compound Cl.Cl.C1CCNNC1 PJUZEZLTRTTWOK-UHFFFAOYSA-N 0.000 claims abstract description 10
- 235000019441 ethanol Nutrition 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 8
- 238000004321 preservation Methods 0.000 claims abstract description 7
- 238000000967 suction filtration Methods 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- 238000003756 stirring Methods 0.000 claims description 28
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- 239000012065 filter cake Substances 0.000 claims description 19
- 239000000706 filtrate Substances 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- 239000012044 organic layer Substances 0.000 claims description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 238000004042 decolorization Methods 0.000 claims description 6
- 230000018044 dehydration Effects 0.000 claims description 6
- 238000006297 dehydration reaction Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000011345 viscous material Substances 0.000 claims 7
- 238000004090 dissolution Methods 0.000 claims 1
- 238000003541 multi-stage reaction Methods 0.000 claims 1
- 238000007086 side reaction Methods 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 5
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 19
- 239000000126 substance Substances 0.000 description 17
- 239000002904 solvent Substances 0.000 description 14
- 238000004064 recycling Methods 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- VXGVACGQGLVRLX-UHFFFAOYSA-N diazinane;hydrochloride Chemical compound Cl.C1CCNNC1 VXGVACGQGLVRLX-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 229910017053 inorganic salt Inorganic materials 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 238000007363 ring formation reaction Methods 0.000 description 5
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- SEQRDAAUNCRFIT-UHFFFAOYSA-N 1,1-dichlorobutane Chemical compound CCCC(Cl)Cl SEQRDAAUNCRFIT-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000003912 environmental pollution Methods 0.000 description 3
- 239000000575 pesticide Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000002351 wastewater Substances 0.000 description 3
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 2
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical compound C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000006136 alcoholysis reaction Methods 0.000 description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000000053 physical method Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- HAGXAKAJNOVYAJ-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridazine;dihydrochloride Chemical compound Cl.Cl.C1CC=CNN1 HAGXAKAJNOVYAJ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 241000224489 Amoeba Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of medicine synthesis, in particular to a method for removing sticky impurities in hexahydropyridazine synthesis, which comprises the following steps: the 1, 2-diformyl hydrazine reacts with 1, 4-dichlorobutane in a segmented way under the catalysis of alkali and potassium bromide, and after the reaction is completed, the concentrated solution of the tetrahydropyridazine-1, 2-dicarboxaldehyde is obtained through suction filtration and reduced pressure distillation treatment; sequentially extracting the concentrated solution of the tetrahydropyridazine-1, 2-dicarboxaldehyde with ethyl acetate, dehydrating and decoloring, cooling and removing impurities and distilling under reduced pressure to obtain purified tetrahydropyridazine-1, 2-dicarboxaldehyde; dissolving the purified tetrahydropyridazine-1, 2-dicarboxaldehyde in absolute ethyl alcohol, dropwise adding ethanol and hydrogen chloride for heat preservation reaction, crystallizing, filtering, washing and drying after the reaction is completed, thus obtaining hexahydropyridazine dihydrochloride. The invention not only reduces and prevents side reaction, effectively removes sticky impurities, but also has low energy consumption, and improves the product yield and the product purity of the hexahydropyridazine dihydrochloride.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a method for removing sticky impurities in hexahydropyridazine synthesis.
Background
Hexahydropyridazine dihydrochloride is an important intermediate of organic chemical industry and is widely applied to the fields of medicines, pesticides, organic chemical industry and the like. In particular to the synthesis of pesticides, which is a key intermediate for synthesizing herbicides such as fluorothiobac-sodium and the like and pesticides, and has the activity of killing amoeba; the method is mainly used for synthesizing pyridazine medicines in medicine.
For the synthesis of hexahydropyridazine, there are three main synthetic routes, depending on the starting materials: a 1, 4-dihalobutane route; 1, 4-butanediol route; a butadiene route. The hexahydropyridazine is prepared by taking 1, 4-dihalobutane as a raw material, the raw material is easy to obtain, the synthesis method is simple and convenient, the side reaction is less, and the product is easy to separate, thus being the main stream method of industrialization at present.
However, in the production and preparation of hexahydropyridazine, particularly in the synthesis of the intermediate tetrahydropyridazine-1, 2-dicarboxaldehyde, a large amount of sticky impurities are generated due to complex chemical reactions in the processes of substitution, polymerization and heating, and the quality and yield of the final product are greatly affected if the sticky impurities are not removed. The document "improvement of hexahydropyridazine synthesis method" adopts high vacuum distillation method to purify intermediate tetrahydropyridazine-1, 2-dicarboxaldehyde (b.p.120-128 ℃/0.53kPa, 96-102 ℃/0.13 kPa), but the high temperature distillation process can continue to cause the generation of sticky impurities, which affects the product yield.
In view of the above, the invention provides a process for effectively removing sticky matters in the preparation of hexahydropyridazine without affecting the yield.
Disclosure of Invention
The invention aims to provide a method for removing sticky impurities in the synthesis of hexahydropyridazine, which not only avoids the generation of new impurities in the high-temperature distillation purification process, but also effectively removes sticky oily matters with different molecular weights.
The invention provides a method for removing sticky impurities in hexahydropyridazine synthesis, which comprises the following steps:
s1, carrying out sectional reaction on 1, 2-diformylhydrazine and 1, 4-dichlorobutane under the catalysis of alkali and potassium bromide, and carrying out suction filtration and reduced pressure distillation treatment after the reaction is completed to obtain a tetrahydropyridazine-1, 2-dicarboxaldehyde concentrated solution;
s2, sequentially extracting the concentrated solution of the tetrahydropyridazine-1, 2-dicarboxaldehyde by ethyl acetate, dehydrating and decoloring, cooling and removing impurities and distilling under reduced pressure to obtain purified tetrahydropyridazine-1, 2-dicarboxaldehyde;
s3, dissolving the purified tetrahydropyridazine-1, 2-dicarboxaldehyde in absolute ethyl alcohol, dropwise adding ethanol and hydrogen chloride for heat preservation reaction, and crystallizing, suction filtering, washing and drying after the reaction is completed to obtain hexahydropyridazine dihydrochloride.
The synthetic route of the hexahydropyridazine dihydrochloride of the invention is as follows:
specifically, firstly, under the condition of sectional temperature control, the 1, 2-diformyl hydrazine and the 1, 4-dichlorobutane are subjected to cyclization reaction under the catalysis of alkali and potassium bromide, and the mode of catalyzing the cyclization by the sectional reaction not only saves the reaction time, but also effectively reduces the occurrence of side reaction and the generation of sticky impurities at the high temperature stage, improves the conversion rate and ensures the purity of the product.
Although the invention adopts a method of catalyzing cyclization by a sectional reaction to reduce the occurrence of side reactions in the reaction process, the following side reactions are inevitable:
therefore, in the purification process of the tetrahydropyridazine-1, 2-dicarboxaldehyde concentrated solution, most of viscous oil is removed by utilizing the difference of fluidity of an extractant and viscous oil at high temperature, then active carbon and anhydrous sodium sulfate are added for dehydration and decoloration, at the same time, less part of viscous oil is removed, and finally the residual low molecular weight viscous oil is further removed by utilizing the difference of solubility of the viscous oil and the tetrahydropyridazine-1, 2-dicarboxaldehyde at low temperature. Therefore, the purification process of the tetrahydropyridazine-1, 2-dicarboxaldehyde is mainly a physical method, so that the generation of new impurities in the high-temperature distillation purification process is avoided, and viscous oily matters with different molecular weights are effectively removed.
Finally, in the alcoholysis and salification process of the tetrahydropyridazine-1, 2-dicarboxaldehyde, ethanol hydrogen chloride is selected to react with the tetrahydropyridazine-1, 2-dicarboxaldehyde, and the generation of sticky impurities in the salification process is reduced by controlling the reaction concentration, the reaction temperature and the crystallization temperature. And the volatilization of the solvent and hydrogen chloride is reduced, and the residue of the methanol solvent in the product is effectively controlled.
As the technical scheme, the step S1 specifically comprises the steps of adding 1, 2-diformyl hydrazine and N, N-dimethylformamide into a reaction kettle under the condition of nitrogen, heating to 40-45 ℃, stirring and dissolving, adding anhydrous potassium carbonate and potassium bromide, heating to 70-80 ℃, and adding 1, 4-dichlorobutane for sectional reaction.
The invention selects N, N-dimethylformamide as solvent, which not only increases the solubility of reactants, catalysts and products, avoids the use of phase transfer catalysts, but also improves the reaction rate and conversion rate. In addition, in the process of adding reactants, solvent and catalyst, the method of sectional heating and sectional adding is adopted, so that side reactions in the initial stage of the reaction can be effectively avoided.
In step S1, the molar ratio of 1, 2-diformylhydrazine, 1, 4-dichlorobutane, anhydrous potassium carbonate and potassium bromide is not critical, and the molar ratio of the anhydrous potassium carbonate to the potassium bromide is preferably 1:1:1:0.05.
in the step S1, preferably, the step is performed by controlling the temperature of 85-95 ℃ for 25-35min, the temperature of 100-110 ℃ for 25-35min, the temperature of 110-120 ℃ for 1.5-2.5h, and preferably 90 ℃ for 30min,105 ℃ for 30min, and the temperature of 110-120 ℃ for 2h.
In step S2, in particular, ethyl acetate is added to the concentrated solution of tetrahydropyridazine-1, 2-dicarboxaldehyde at 35-50 ℃ for multiple times to extract viscous oily impurities, the extracted organic layers are combined and kept stand for 1-3h at the temperature to separate viscous oily impurities with larger molecular weight, and the initially purified organic layer is obtained.
In the step S2, preferably, activated carbon and anhydrous sodium sulfate are added to the purified organic layer for decolorization and drying for 1-3 hours, and the organic layer after dehydration and decolorization is obtained after filtration.
In the step S2, the organic layer after dehydration and decolorization is cooled to-10-0 ℃ to separate out viscous oily impurities with lower solubility, so as to obtain filtrate;
and in the reduced pressure distillation, the filtrate after the temperature reduction and impurity removal is subjected to reduced pressure concentration to remove the solvent, so that the purified tetrahydropyridazine-1, 2-dicarboxaldehyde is obtained, wherein the removed ethyl acetate can be recycled.
As a preferred scheme, in the step S3, ethanol hydrogen chloride is dropwise added into an absolute ethanol solution of the tetrahydropyridazine-1, 2-dicarboxaldehyde at 20-30 ℃, and the reaction is kept at the temperature for 2-6 hours.
In the present technical solution, preferably, in step S3, the mass ratio of the tetrahydropyridazine-1, 2-dicarboxaldehyde to the 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).
Preferably, in the step S3, stirring is performed at 0-10 ℃ for 0.5-1.5 hours to further reduce impurities generated by the sticky matters; during the washing, ethanol is used for washing filter cakes; the drying is performed under vacuum at 45-55deg.C.
The method for removing the sticky impurities in the synthesis of the hexahydropyridazine has at least the following technical effects:
1. the invention takes 1, 2-diformyl hydrazine and dichlorobutane as main raw materials, adopts a mode of catalyzing cyclization by a sectional reaction, thereby saving the reaction time, effectively reducing the occurrence of side reaction and the generation of sticky impurities at a high temperature stage, improving the conversion rate and simultaneously ensuring the purity of the product;
2. in the process of purifying the tetrahydropyridazine-1, 2-dicarboxaldehyde concentrated solution, most of viscous oily matters are removed by utilizing the difference of flowability of an extractant and the viscous oily matters at high temperature, then, active carbon and anhydrous sodium sulfate are added for dehydration and decoloration, at the same time, less part of viscous oily matters are removed, and finally, the residual low-molecular-weight viscous oily matters are further removed by utilizing the difference of solubility of the viscous oily matters and the tetrahydropyridazine-1, 2-dicarboxaldehyde at low temperature. The purification process of the tetrahydropyridazine-1, 2-dicarboxaldehyde is mainly a physical method, so that not only is the generation of new impurities avoided in the high-temperature distillation purification process avoided, but also viscous oily matters with different molecular weights are effectively removed;
3. in the alcoholysis and salification process of the tetrahydropyridazine-1, 2-dicarboxaldehyde, ethanol hydrogen chloride is selected to react with the tetrahydropyridazine-1, 2-dicarboxaldehyde, so that the concentration of a reactant is increased, the volatilization of a solvent and the hydrogen chloride is reduced, and the residue of a methanol solvent in a product is effectively avoided; the proper crystallization temperature can improve the purity and yield of the product.
4. The preparation process of the hexahydropyridazine dihydrochloride has mild conditions and convenient operation, not only reduces and prevents side reactions, but also has low energy consumption, effectively improves the product yield and the product purity (the purity is more than or equal to 99.0 percent, the burning residue is less than or equal to 0.1 percent, and the unknown single impurity is less than or equal to 0.5 percent), and the solvent and the filter cake can be recycled, so that no waste water is generated basically and the environmental pollution is small.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is a diagram of a concentrate of tetrahydropyridazine-1, 2-dicarboxaldehyde according to example 5 of the present invention;
FIG. 2 is a graph showing the purified tetrahydropyridazine-1, 2-dicarboxaldehyde as purified in example 5 of the present invention;
FIG. 3 is a chart of the tetrahydropyridazine dihydrochloride product according to example 5 of the present invention;
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. Unless defined otherwise, 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 belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments in accordance with the present application. As used herein, the singular forms also include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
The technical solutions of the present invention will be clearly and completely described in connection with the embodiments, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
S11, under the condition of nitrogen, 200kg (2.273 kmol) of 1, 2-diformylhydrazine and 1400kg of DMF are added into a reaction kettle, the temperature is raised to 40-45 ℃, 304kg (2.2 kmol) of anhydrous potassium carbonate and 13.5KBr kg (0.11 kmol) are added into the reaction kettle for stirring and dissolving, the temperature is raised to 70-80 ℃, 289kg (2.275 kmol) of 1, 4-dichlorobutane is added into the reaction kettle for reaction at 90 ℃ for 30min, the temperature is raised for 30min at 105 ℃ for reaction at 110-120 ℃ for 2h. Cooling to room temperature, suction filtering, collecting and treating a filter cake which is solid mixed inorganic salt, and then reusing the filter cake, and carrying out reduced pressure distillation and desolventizing on the filtrate (recycling DMF solvent for reuse) to obtain 380kg of tetrahydropyridazine-1, 2-dicarboxaldehyde concentrated solution;
s12, adding 150kg of ethyl acetate into the concentrated solution of the tetrahydropyridazine-1, 2-dicarboxaldehyde at the temperature of 35-50 ℃ and stirring for 30min, separating an organic phase, extracting the oily substance with 500kg of ethyl acetate for 2 times, separating out about 66kg of viscous oily impurities, combining the organic phases, standing at the temperature of 35-45 ℃ for 2 hours, and separating out about 10kg of oily substance at the lower layer; adding 2kg of active carbon and 5kg of anhydrous sodium sulfate into the organic phase, stirring, and filtering; cooling the filtrate to-5-0 ℃, separating out viscous oil impurities, separating out 5kg of the viscous oil impurities, concentrating the ethyl acetate in a reduced pressure way to dryness (recycling the ethyl acetate for reuse) to obtain 297kg of purified tetrahydropyridazine-1, 2-dicarboxaldehyde, wherein the yield is 92% and the content is 98.7%;
s13, taking 297kg (2.09 kmol) of tetrahydropyridazine-1, 2-dicarboxaldehyde and 240kg of absolute ethyl alcohol, stirring and dissolving, dropwise adding 490kg of 30% ethyl alcohol hydrogen chloride at 20-30 ℃, carrying out heat preservation reaction for 5 hours, stirring for 1 hour at 5-10 ℃ after the reaction is finished, carrying out suction filtration, washing a filter cake by using absolute ethyl alcohol, and carrying out vacuum drying at 50 ℃ to obtain 312kg (1.96 kmol) of hexahydropyridazine hydrochloride, wherein the yield is 93.8%.
The product quality is as follows: purity 99.2%, burning residue 0.06%, unknown simple substance 0.03%.
Example 2
Under the condition of S21 and nitrogen, 200kg (2.273 kmol) of 1, 2-diformylhydrazine and 1400kg of DMF are added into a reaction kettle, the temperature is raised to 40-45 ℃, 304kg (2.2 kmol) of anhydrous potassium carbonate and 13.5KBr kg (0.11 kmol) are added into the reaction kettle for stirring and dissolving, the temperature is raised to 70-80 ℃, 289kg (2.275 kmol) of 1, 4-dichlorobutane is added into the reaction kettle for reaction at 90 ℃ for 30min, the temperature is raised for 30min at 105 ℃ for reaction at 110-120 ℃ for 2h. Cooling to room temperature, suction filtering, collecting and treating a filter cake which is solid mixed inorganic salt, and then reusing the filter cake, and carrying out reduced pressure distillation and desolventizing on the filtrate (recycling DMF solvent for reuse) to obtain 380kg of tetrahydropyridazine-1, 2-dicarboxaldehyde concentrated solution;
s22, adding 150kg of ethyl acetate into the concentrated solution of the tetrahydropyridazine-1, 2-dicarboxaldehyde at 45-50 ℃ and stirring for 30min, separating an organic phase, extracting the oily substance with 500kg of ethyl acetate for 2 times, separating about 62kg of viscous oily impurities, combining the organic phases, standing at 45-50 ℃ for 2 hours, and separating about 8kg of oily substance at the lower layer; adding 2kg of active carbon and 5kg of anhydrous sodium sulfate into the organic phase, stirring, and filtering; cooling the filtrate to-10 to-5 ℃, separating out viscous oil impurities, separating out 6.6kg of viscous oil impurities, concentrating ethyl acetate in an organic phase under reduced pressure until the ethyl acetate is dried (recycling the ethyl acetate to be reused), and obtaining 303.4kg of purified tetrahydropyridazine-1, 2-dicarboxaldehyde, wherein the yield is 94%, and the content is 98.5%;
s23, taking 303.4kg (2.14 kmol) of tetrahydropyridazine-1, 2-dicarboxaldehyde and 240kg of absolute ethyl alcohol, stirring and dissolving, dropwise adding 490kg of 30% ethyl alcohol hydrogen chloride at 20-30 ℃, carrying out heat preservation reaction for 5 hours, stirring for 1 hour at 5-10 ℃ after the reaction is completed, carrying out suction filtration, washing a filter cake by using absolute ethyl alcohol, and carrying out vacuum drying at 50 ℃ to obtain 316kg (1.99 kmol) of hexahydropyridazine hydrochloride, wherein the yield is 93%.
The product quality is as follows: purity 99.3%, burning residue 0.04%, unknown simple substance 0.05%.
Example 3
Under the condition of S31 and nitrogen, 200kg (2.273 kmol) of 1, 2-diformylhydrazine and 1400kg of DMF are added into a reaction kettle, the temperature is raised to 40-45 ℃, 304kg (2.2 kmol) of anhydrous potassium carbonate and 13.5KBr kg (0.11 kmol) are added into the reaction kettle for stirring and dissolving, the temperature is raised to 70-80 ℃, 289kg (2.275 kmol) of 1, 4-dichlorobutane is added into the reaction kettle for reaction at 90 ℃ for 30min, the temperature is raised for 30min at 105 ℃ for reaction at 110-120 ℃ for 2h. Cooling to room temperature, suction filtering, collecting and treating a filter cake which is solid mixed inorganic salt, and then reusing the filter cake, and carrying out reduced pressure distillation and desolventizing on the filtrate (recycling DMF solvent for reuse) to obtain 380kg of tetrahydropyridazine-1, 2-dicarboxaldehyde concentrated solution;
s32, adding 150kg of ethyl acetate into the concentrated solution of the tetrahydropyridazine-1, 2-dicarboxaldehyde at 45-50 ℃ and stirring for 30min, separating an organic phase, extracting the oily substance with 500kg of ethyl acetate for 2 times, separating about 62kg of viscous oily impurities, combining the organic phases, standing at 45-50 ℃ for 2 hours, and separating about 4.4kg of oily substance at the lower layer; adding 2kg of active carbon and 5kg of anhydrous sodium sulfate into the organic phase, stirring, and filtering; cooling the filtrate to-10 to-5 ℃, separating out viscous oil impurities, separating out 7kg of viscous oil impurities, concentrating the ethyl acetate in a reduced pressure way to dryness (recycling the ethyl acetate for reuse) by an organic phase to obtain 305.6kg of purified tetrahydropyridazine-1, 2-dicarboxaldehyde, wherein the yield is 94.7%, and the content is 98.6%;
s33, taking 305.6kg (2.54 kmol) of tetrahydropyridazine-1, 2-dicarboxaldehyde and 240kg of absolute ethyl alcohol, stirring and dissolving, dropwise adding 490kg of 36% ethyl alcohol hydrogen chloride at 20-30 ℃, carrying out heat preservation reaction for 8 hours, stirring at 0-5 ℃ for 1 hour after the reaction is completed, carrying out suction filtration, washing a filter cake by the absolute ethyl alcohol, and carrying out vacuum drying at 50 ℃ to obtain 319kg (2.0 kmol) of hexahydropyridazine hydrochloride, wherein the yield is 93.2%.
The product quality is as follows: purity 99.3%, burning residue 0.04%, unknown simple substance 0.02%.
Example 4
Under the condition of S41 and nitrogen, 200kg (2.273 kmol) of 1, 2-diformylhydrazine and 1400kg of DMF are added into a reaction kettle, the temperature is raised to 40-45 ℃, 304kg (2.2 kmol) of anhydrous potassium carbonate and 13.5KBr kg (0.11 kmol) are added into the reaction kettle for stirring and dissolving, the temperature is raised to 70-80 ℃, 289kg (2.275 kmol) of 1, 4-dichlorobutane is added into the reaction kettle for reaction at 90 ℃ for 30min, the temperature is raised for 30min at 105 ℃ for reaction at 110-120 ℃ for 2.5h. Cooling to room temperature, suction filtering, collecting and treating a filter cake which is solid mixed inorganic salt, and then reusing the filter cake, and carrying out reduced pressure distillation and desolventizing on the filtrate (recycling DMF solvent for reuse) to obtain 382kg of tetrahydropyridazine-1, 2-dicarboxaldehyde concentrated solution;
s42, adding 150kg of ethyl acetate into the concentrated solution of the tetrahydropyridazine-1, 2-dicarboxaldehyde at the temperature of 35-45 ℃ and stirring for 30min, separating an organic phase, extracting the oily substance with 500kg of ethyl acetate for 2 times, separating about 66kg of viscous oily impurities, combining the organic phases, standing at the temperature of 35-45 ℃ for 2 hours, and separating about 7.6kg of oily substance at the lower layer; adding 2kg of active carbon and 5kg of anhydrous sodium sulfate into the organic phase, stirring, and filtering; cooling the filtrate to-10 to-5 ℃, separating out viscous oil impurities, separating out 6kg of viscous oil impurities, concentrating the ethyl acetate in a reduced pressure way to dryness (recycling the ethyl acetate for reuse) by an organic phase to obtain 302.4kg of purified tetrahydropyridazine-1, 2-dicarboxaldehyde, wherein the yield is 94 percent and the content is 98.6 percent;
s43, taking 3023.4kg (2.34 kmol) of tetrahydropyridazine-1, 2-dicarboxaldehyde and 240kg of absolute ethyl alcohol, stirring and dissolving, dropwise adding 490kg of 36% ethyl alcohol hydrogen chloride at 20-30 ℃, carrying out heat preservation reaction for 6 hours, stirring for 1 hour at 0-5 ℃ after the reaction is finished, carrying out suction filtration, washing a filter cake by the absolute ethyl alcohol, and carrying out vacuum drying at 50 ℃ to obtain 315kg (1.98 kmol) of hexahydropyridazine hydrochloride with the yield of 93%.
The product quality is as follows: purity 99.3%, burning residue 0.06%, unknown simple substance 0.08%.
Example 5
Under the condition of S51 and nitrogen, 200kg (2.273 kmol) of 1, 2-diformylhydrazine and 1400kg of DMF are added into a reaction kettle, the temperature is raised to 40-45 ℃, 304kg (2.2 kmol) of anhydrous potassium carbonate and 13.5KBr kg (0.11 kmol) are added into the reaction kettle for stirring and dissolving, the temperature is raised to 70-80 ℃, 289kg (2.275 kmol) of 1, 4-dichlorobutane is added into the reaction kettle for reaction at 90 ℃ for 30min, the temperature is raised for 30min at 105 ℃ for reaction at 110-120 ℃ for 2h. Cooling to room temperature, suction filtering, collecting and treating a filter cake which is solid mixed inorganic salt, and then reusing the filter cake, and carrying out reduced pressure distillation and desolventizing on the filtrate (recycling DMF solvent for reuse) to obtain 380kg of tetrahydropyridazine-1, 2-dicarboxaldehyde concentrated solution;
s52, adding 150kg of ethyl acetate into the concentrated solution of the tetrahydropyridazine-1, 2-dicarboxaldehyde at the temperature of 35-45 ℃ and stirring for 30min, separating an organic phase, extracting the oily substance with 500kg of ethyl acetate for 2 times, separating out about 66kg of viscous oily impurities, combining the organic phases, standing at the temperature of 35-45 ℃ for 2 hours, and separating out about 8kg of oily substance at the lower layer; adding 2kg of active carbon and 6kg of anhydrous sodium sulfate into the organic phase, stirring, and filtering; cooling the filtrate to-10 to-5 ℃, separating out viscous oil impurities, separating out 10kg of viscous oil impurities, concentrating the ethyl acetate in a reduced pressure way to dryness (recycling the ethyl acetate for reuse) by an organic phase to obtain 300kg of purified tetrahydropyridazine-1, 2-dicarboxaldehyde, wherein the yield is 93%, and the content is 98.9%;
s53, taking 300kg (2.11 kmol) of tetrahydropyridazine-1, 2-dicarboxaldehyde and 240kg of absolute ethyl alcohol, stirring and dissolving, dropwise adding 490kg of 36% ethanol hydrogen chloride at 20-30 ℃, reacting for 6 hours at a temperature of between 0 and 10 ℃, stirring for 1 hour at the temperature of between 0 and 10 ℃ after the reaction is finished, filtering, washing a filter cake with absolute ethyl alcohol, and drying in vacuum at the temperature of 50 ℃ to obtain 317kg (1.99 kmol) of hexahydropyridazine hydrochloride with the yield of 94.3%.
The product quality is as follows: purity 99.3%, burning residue 0.04%, unknown simple substance 0.05%.
Comparative example 1
Example 1 of chinese invention patent publication No. CN110483410 a is taken as the present control.
The method specifically comprises the following steps:
(1) 280 ml of toluene and 56 g of formic acid are added into a three-port reaction bottle with a stirrer; at 0 ℃, 31.9 g of hydrazine hydrate is added dropwise; after the dripping, reacting for 8 hours at 90 ℃; cooled to room temperature, filtered, the solid was collected and dried to give 37.5 g of N, N' -diformylhydrazine as a white solid in 84% yield and 96% purity.
Nuclear magnetic detection results: 1 H NMR(400MHz，d 6 -DMSO)：δ9.98(2H)，8.12(2H)。
(2) 180 ml of acetonitrile and 18.0 g of N, N' -diformylhydrazine are added into a three-port reaction bottle with a stirrer and uniformly mixed; then 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 are added in sequence to react for 5 hours at 70 ℃; cooled to room temperature, filtered, and the filtrate was concentrated to give 15.7 g of tetrahydropyridazine-1, 2-dicarboxaldehyde as a brown oil in 79% yield and 95% purity.
Nuclear magnetic detection results: 1 H NMR(400MHz，d 6 -DMSO)：δ8.66(2H)，3.02(4H)，1.97(4H)。
(3) 100 ml of 3M hydrochloric acid methanol solution and 15.0 g of tetrahydropyridazine-1, 2-dicarboxaldehyde are added into a three-port reaction bottle with a stirrer, and the mixture is reacted for 2 hours at the temperature of 30 ℃; the solid was collected by filtration and dried to give 15.1 g of hexahydropyridazine dihydrochloride as a white solid in 90% yield and 97% purity.
Nuclear magnetic detection results: 1 H NMR(400MHz，d 6 -DMSO)：9.86(4H)，2.98(4H)，1.67(4H)。
comparative example 2
The method disclosed in the literature "improvement of the synthetic method of hexahydropyridazine" was used as the present control.
The dichlorobutane and the diformylhydrazine are adopted to react in DMF, a small amount of KI is added as a catalyst, gas chromatography is used for tracking the reaction, the cyclization reaction is found to be complete within 5 hours, the selectivity of the 1, 2-diformylhexahydropyridazine reaches 98%, and the separation yield reaches 87%.
Dissolving 1, 2-diformyl hexahydropyridazine in anhydrous methanol, introducing dry HCl gas to saturation, then reacting for 1h at room temperature to obtain the complete reaction, concentrating the reaction liquid to remove most of HCl, neutralizing with sodium methoxide solution, filtering, removing the solution from the filtrate at normal pressure, and distilling under reduced pressure to obtain 88% hexahydropyridazine dihydrochloride.
TABLE 1 product yield and purity
As can be seen from the comparison of examples 1 to 5 of the present invention with comparative example 1 in combination with Table 1 and FIGS. 1 to 2, 1, 4-dichlorobutane of the present invention is used as a raw material, and no wastewater, waste liquid or waste salt containing bromine or iodine, which is large in environmental pollution, is produced as compared with 1, 4-dibromobutane of comparative example 1, thereby realizing green industrialization; the method of the sectional reaction effectively saves the reaction time, reduces the occurrence of side reactions and the generation of viscous oil in longer reaction time, and obviously improves the conversion rate and purity of the tetrahydropyridazine-1, 2-dicarboxaldehyde.
As is clear from comparison of examples 1-5 of the present invention with comparative example 2, comparative example 2 uses a reaction of dichlorobutane and diformylhydrazine in DMF, but the reaction time is long, the purity of the product tetrahydropyridazine-1, 2-dicarboxaldehyde is low, and the yield of hexahydropyridazine hydrochloride is seriously affected.
In conclusion, the preparation process of the hexahydropyridazine dihydrochloride has mild conditions, convenient operation, reduced and prevented side reaction, low energy consumption, effective improvement of the product yield and the product purity (the purity is more than or equal to 99.0 percent, the burning residue is less than or equal to 0.1 percent, and the unknown single impurity is less than or equal to 0.5 percent), recycling of the solvent and the filter cake, no waste water generation basically, and little environmental pollution.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (10)
1. A method for removing impurities from a dope in a hexahydropyridazine synthesis, comprising the steps of:
s1, carrying out sectional reaction on 1, 2-diformylhydrazine and 1, 4-dichlorobutane under the catalysis of alkali and potassium bromide, and carrying out suction filtration and reduced pressure distillation treatment after the reaction is completed to obtain a tetrahydropyridazine-1, 2-dicarboxaldehyde concentrated solution;
s2, sequentially extracting the concentrated solution of the tetrahydropyridazine-1, 2-dicarboxaldehyde by ethyl acetate, dehydrating and decoloring, cooling and removing impurities and distilling under reduced pressure to obtain purified tetrahydropyridazine-1, 2-dicarboxaldehyde;
s3, dissolving the purified tetrahydropyridazine-1, 2-dicarboxaldehyde in absolute ethyl alcohol, dropwise adding ethanol and hydrogen chloride for heat preservation reaction, and crystallizing, suction filtering, washing and drying after the reaction is completed to obtain hexahydropyridazine dihydrochloride.
2. The method for removing impurities from a viscous material in the synthesis of hexahydropyridazine according to claim 1, wherein step S1 specifically comprises adding 1, 2-diformylhydrazine and N, N-dimethylformamide into a reaction kettle under nitrogen, heating to 40-45 ℃, stirring for dissolution, adding anhydrous potassium carbonate and potassium bromide, heating to 70-80 ℃, and adding 1, 4-dichlorobutane for staged reaction.
3. The method for removing a sticky impurity in the synthesis of hexahydropyridazine according to claim 2, wherein in step S1, the molar ratio of 1, 2-diformylhydrazine, 1, 4-dichlorobutane, anhydrous potassium carbonate and potassium bromide is 1:1:1:0.05.
4. the method for removing impurities from a viscous material in a hexahydropyridazine synthesis according to claim 2, wherein in step S1, the stepwise reaction is controlled to be performed at 85-95 ℃ for 25-35min,100-110 ℃ for 25-35min, and 110-120 ℃ for 1.5-2.5h.
5. The method for removing sticky impurities in the synthesis of hexahydropyridazine according to claim 1, wherein in step S2, ethyl acetate is added to the concentrated solution of tetrahydropyridazine-1, 2-dicarboxaldehyde at 35-50 ℃ for multiple times to extract sticky oily impurities, the extracted organic layers are combined, and the mixture is allowed to stand at the temperature for 1-3 hours to separate the sticky oily impurities, thereby obtaining a purified organic layer.
6. The method for removing impurities from a viscous material in a hexahydropyridazine synthesis according to claim 5, wherein in step S2, activated carbon and anhydrous sodium sulfate are added to the purified organic layer for decolorization and drying for 1-3 hours, and the organic layer after dehydration and decolorization is obtained by filtration.
7. The method for removing impurities from a viscous material in the synthesis of hexahydropyridazine according to claim 6, wherein in step S2, the organic layer after dehydration and decolorization is cooled to-10-0 ℃ during the cooling and impurity removal, and viscous oily impurities are separated out to obtain a filtrate;
and in the reduced pressure distillation, the filtrate after the temperature reduction and impurity removal is subjected to reduced pressure concentration and desolventizing to obtain the purified tetrahydropyridazine-1, 2-dicarboxaldehyde.
8. The method for removing impurities from a viscous material in the synthesis of hexahydropyridazine according to claim 1, wherein in step S3, ethanol hydrogen chloride is added dropwise to an absolute ethanol solution of tetrahydropyridazine-1, 2-dicarboxaldehyde at 20-35 ℃ and the reaction is carried out at this temperature for 2-6 hours.
9. The method for removing impurities from a viscous material in the synthesis of hexahydropyridazine according to claim 8, wherein in step S3, the mass ratio of the tetrahydropyridazine-1, 2-dicarboxaldehyde to the ethanol hydrogen chloride is 1: (1.5-1.8), wherein the concentration of ethanol hydrogen chloride is 30-36%.
10. The method for removing impurities from a viscous material in the synthesis of hexahydropyridazine according to claim 1, wherein in step S3, the mixture is stirred at 0-10 ℃ for 0.5-1.5h during crystallization;
during the washing, ethanol is used for washing filter cakes;
the drying is performed under vacuum at 45-55deg.C.
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