CN111303044A - Synthetic method of sulfachloropyridazine sodium - Google Patents
Synthetic method of sulfachloropyridazine sodium Download PDFInfo
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- CN111303044A CN111303044A CN202010231817.5A CN202010231817A CN111303044A CN 111303044 A CN111303044 A CN 111303044A CN 202010231817 A CN202010231817 A CN 202010231817A CN 111303044 A CN111303044 A CN 111303044A
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- 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
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention relates to a synthesis method of sulfachlorpyridazine sodium, which is characterized by comprising the following steps: s1, adding sulfanilamide, 3, 6-dichloropyridazine and a high-boiling-point solvent into a reaction kettle in sequence, then adding a supported basic catalyst into the reaction kettle, and stirring the mixture for 10 to 16 hours at the temperature of between 100 and 160 ℃ under the pressure of between 0.3 and 1.2MPa to obtain a first mixed solution; step S2, removing the solvent from the first mixed solution prepared in step S1 by suction filtration; and then dissolving the product with the solvent removed in deionized water, adding sodium salt into the deionized water, stirring the mixture at the temperature of between 60 and 80 ℃ for reaction for 8 to 10 hours, filtering the mixture to remove insoluble substances, cooling the obtained solution for crystallization, and filtering the solution to obtain the sulfachlorpyridazine sodium. The synthesis method of sulfachlorpyridazine sodium disclosed by the invention is simple and feasible, and has the advantages of rich raw material sources, low price, high preparation efficiency, higher yield and lower production cost.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a synthesis method of sulfachlorpyridazine sodium.
Background
Sulfachloropyridazine sodium, known as 4-yl-N- (6-amino-3-pyridazinyl) benzenesulfonamide, of the formula: c10H8ClN4NaO2S, white solid, melting point 180-. Sulfachlorpyridazine sodium is a widely used sulfanilamide antibacterial agent, and is used for animals to resist digestive tract infection and coccidiosis caused by escherichia coli. Because it is easily dissolved in water, it can be taken with drinking water of livestock and poultry. The medicine has the characteristics of low price, easy production, stable character, convenient use, high drug effect selectivity and the like, and is always used as the antibody with the most research valueBacterial drugs are gaining importance.
With the increase of the market demand and the quality requirement of sulfachlorpyridazine sodium, a more appropriate synthesis method is required. In the prior art, the synthesis of sulfachlorpyridazine sodium generally adopts maleic anhydride and hydrazine hydrate to carry out ring expansion reaction to obtain 3, 6-dihydroxypyridazine, 3, 6-dichloropyridazine is obtained through chlorination, then condensation is carried out on the 3, 6-dichloropyridazine and sulfanilamide, and a target product is obtained through acid-base conversion. The chlorinating agent is generally phosphorus oxychloride, and the price is high, so that the production cost of the final product is high. In addition, because the post-treatment control of the chlorination reaction is difficult, the reaction liquid needs to flow in parallel with the ammonia water, the temperature and the acidity are strictly controlled, the precipitated chloride needs to be purified by melting and water separation, the operation is complicated, the product quality is not improved, and the environment protection is not facilitated.
The Chinese patent with the application number of 201010259346.5 discloses a preparation method of sulfachlorpyridazine sodium, belonging to the technical field of chemical synthesis. Carrying out chlorination reaction on 3, 6-dihydroxypyridazine and a chlorinating agent to generate 3, 6-dichloropyridazine; reacting the 3, 6-dichloropyridazine, sulfanilamide and potassium carbonate, adding hot water and activated carbon for decolorization, filtering to remove the activated carbon, layering the filtrate, adding dilute hydrochloric acid into the supernatant to make the pH value of the mixed solution be 4.0-5.0, filtering, taking a solid substance, and washing with water to obtain sulfachloropyridazine; and finally, reacting the sulfachloropyridazine with an aqueous solution of sodium hydroxide, cooling, crystallizing and filtering to obtain the sulfachloropyridazine sodium. The method has low production cost, does not take out the 3, 6-dichloropyridazine, does not need refining and purification, only needs HPLC to measure the content and then directly enters the next condensation reaction, simplifies the production operation process and has good practical value; wherein, the chlorinating agent is thionyl chloride, chlorine or phosphorus trichloride, and the technical defect that the post-treatment control of the chlorination reaction is difficult still exists.
Therefore, it is important to develop a synthetic method of sulfachlorpyridazine sodium with high yield and high production efficiency.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a synthesis method of sulfachlorpyridazine sodium, which is simple and easy to implement, rich in raw material source, low in price and high in preparation efficiency; by reasonably selecting raw materials and reaction conditions, the yield is higher and the production cost is lower.
In order to achieve the purpose, the invention adopts the technical scheme that:
a synthetic method of sulfachlorpyridazine sodium is characterized by comprising the following steps:
s1, adding sulfanilamide, 3, 6-dichloropyridazine and a high-boiling-point solvent into a reaction kettle in sequence, then adding a supported basic catalyst into the reaction kettle, and stirring the mixture for 10 to 16 hours at the temperature of between 100 and 160 ℃ under the pressure of between 0.3 and 1.2MPa to obtain a first mixed solution, so that the reaction kettle is cooled to normal temperature and normal pressure;
step S2, removing the solvent from the first mixed solution prepared in the step S1 by suction filtration, and condensing and recycling the obtained solvent; and then dissolving the product with the solvent removed in deionized water, adding sodium salt into the deionized water, stirring the mixture at the temperature of between 60 and 80 ℃ for reaction for 8 to 10 hours, filtering the mixture to remove insoluble substances, cooling the obtained solution for crystallization, and filtering the solution to obtain the sulfachlorpyridazine sodium.
Preferably, the molar ratio of the sulfanilamide, the 3, 6-dichloropyridazine, the high-boiling-point solvent and the supported basic catalyst in the step S1 is 1:1 (6-10) to 2-4.
Preferably, the high boiling point solvent in step S1 is at least one of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, and N-methylpyrrolidone.
Preferably, the preparation method of the supported basic catalyst comprises the following steps: dispersing the loaded central body in an organic solvent, adding tetraethyl dimethyl (3-trimethoxysilylpropyl) ammonium, stirring and reacting for 3-5 hours at the temperature of 60-80 ℃, then removing the solvent by suction filtration, recovering the solvent, and obtaining a solid, namely the loaded alkaline catalyst by suction filtration.
Preferably, the loading central body is at least one of porous alumina, graphene, carbon fiber and carbon nanotube.
Preferably, the mass ratio of the supported central body, the organic solvent and the dimethyl tetraacetate (3-trimethoxysilylpropyl) ammonium is 1 (3-5) to (0.3-0.6).
Preferably, the organic solvent is any one of ethanol, dichloromethane and acetone.
Furthermore, the molar ratio of the product after the solvent is removed, the deionized water and the sodium salt in the step S2 is 1 (5-10) to 1.
Preferably, the sodium salt is at least one of sodium sulfate and sodium thiosulfate.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages: the synthesis method of sulfachlorpyridazine sodium provided by the invention is simple and feasible, rich in raw material source, low in price and high in preparation efficiency; through reasonable selection of raw materials and reaction conditions, the yield is higher, the production cost is lower, the process of preparing sulfachlorpyridazine in the prior art is omitted, and the yield is improved, the separation and purification are easier, the operation is simpler, and the cost is lower.
Detailed Description
A synthetic method of sulfachlorpyridazine sodium is characterized by comprising the following steps:
s1, adding sulfanilamide, 3, 6-dichloropyridazine and a high-boiling-point solvent into a reaction kettle in sequence, then adding a supported basic catalyst into the reaction kettle, and stirring the mixture for 10 to 16 hours at the temperature of between 100 and 160 ℃ under the pressure of between 0.3 and 1.2MPa to obtain a first mixed solution, so that the reaction kettle is cooled to normal temperature and normal pressure;
step S2, removing the solvent from the first mixed solution prepared in the step S1 by suction filtration, and condensing and recycling the obtained solvent; and then dissolving the product with the solvent removed in deionized water, adding sodium salt into the deionized water, stirring the mixture at the temperature of between 60 and 80 ℃ for reaction for 8 to 10 hours, filtering the mixture to remove insoluble substances, cooling the obtained solution for crystallization, and filtering the solution to obtain the sulfachlorpyridazine sodium.
Preferably, the molar ratio of the sulfanilamide, the 3, 6-dichloropyridazine, the high-boiling-point solvent and the supported basic catalyst in the step S1 is 1:1 (6-10) to 2-4; in step S1, the high boiling point solvent is at least one of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, and N-methylpyrrolidone.
Preferably, the preparation method of the supported basic catalyst comprises the following steps: dispersing the loaded central body in an organic solvent, adding tetraethyl dimethyl (3-trimethoxysilylpropyl) ammonium, stirring and reacting for 3-5 hours at the temperature of 60-80 ℃, then removing the solvent by suction filtration, recovering the solvent, and obtaining a solid, namely the loaded alkaline catalyst by suction filtration.
Preferably, the loading central body is at least one of porous alumina, graphene, carbon fiber and carbon nanotube; the mass ratio of the load central body, the organic solvent and the tetraacetic acid dimethyl (3-trimethoxysilylpropyl) ammonium is 1 (3-5) to 0.3-0.6; the organic solvent is any one of ethanol, dichloromethane and acetone.
Further, the molar ratio of the product after the solvent is removed, the deionized water and the sodium salt in the step S2 is 1 (5-10) to 1;
preferably, the sodium salt is at least one of sodium sulfate and sodium thiosulfate.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages: the synthesis method of sulfachlorpyridazine sodium provided by the invention is simple and feasible, rich in raw material source, low in price and high in preparation efficiency; through reasonable selection of raw materials and reaction conditions, the yield is higher, the production cost is lower, the process of preparing sulfachlorpyridazine in the prior art is omitted, and the yield is improved, the separation and purification are easier, the operation is simpler, and the cost is lower.
The invention will be further described with reference to specific examples, but the scope of protection of the invention is not limited thereto:
example 1
Embodiment 1 provides a method for synthesizing sulfachlorpyridazine sodium, which is characterized by comprising the following steps:
step S1, adding sulfanilamide, 3, 6-dichloropyridazine and dimethyl sulfoxide into a reaction kettle in sequence, then adding a supported basic catalyst into the reaction kettle, stirring the mixture for 10 hours at 100 ℃ under 0.3MPa to obtain a first mixed solution, and reducing the temperature of the reaction kettle to normal temperature and pressure;
step S2, removing the solvent from the first mixed solution prepared in the step S1 by suction filtration, and condensing and recycling the obtained solvent; and then dissolving the product with the solvent removed in deionized water, adding sodium salt into the deionized water, stirring the mixture at the temperature of 60 ℃ for reaction for 8 hours, filtering the mixture to remove insoluble substances, cooling the obtained solution for crystallization, and filtering the solution to obtain sulfachlorpyridazine sodium.
In the step S1, the molar ratio of the sulfanilamide, the 3, 6-dichloropyridazine, the dimethyl sulfoxide and the supported basic catalyst is 1:1:6: 2.
The preparation method of the supported basic catalyst comprises the following steps: dispersing the loaded central body in ethanol, adding dimethyl (3-trimethoxysilylpropyl) ammonium tetraacetate into the ethanol, stirring the mixture at the temperature of 60 ℃ for reaction for 3 hours, then carrying out suction filtration to remove the solvent, recovering the solvent, and obtaining solid which is the loaded alkaline catalyst after suction filtration; the load central body is porous alumina; the mass ratio of the loaded central body to the ethanol to the dimethyl (3-trimethoxysilylpropyl) ammonium tetraacetate is 1:3: 0.3.
The molar ratio of the product after the solvent is removed, the deionized water and the sodium salt in the step S2 is 1:5: 1; the sodium salt is sodium sulfate.
Example 2
Example 2 provides a method for synthesizing sulfachloropyridazine sodium, which is essentially the same as example 1, except that the molar ratio of the sulfanilamide, 3, 6-dichloropyridazine, N-dimethylformamide and supported basic catalyst in step S1 is 1:1:7: 2.5; the loading central body is graphene; the mass ratio of the supported central body to the dichloromethane to the tetraethyl dimethyl (3-trimethoxysilylpropyl) ammonium is 1:3.5: 0.4.
Example 3
Example 3 provides a method for synthesizing sulfachlorpyridazine sodium, which is essentially the same as example 1, except that the molar ratio of the sulfanilamide, 3, 6-dichloropyridazine, N-dimethylacetamide and the supported basic catalyst in step S1 is 1:1:8: 3; the load central body is at least one of porous alumina, graphene, carbon fiber and carbon nano tube; the mass ratio of the supported central body to the dichloromethane to the tetraethyl dimethyl (3-trimethoxysilylpropyl) ammonium is 1:4: 0.45.
Example 4
Example 2 provides a synthesis method of sulfachloropyridazine sodium, which is essentially the same as example 1 except that the molar ratio of the sulfanilamide, 3, 6-dichloropyridazine, N-methylpyrrolidone and the supported basic catalyst in step S1 is 1:1:9: 3.5; the loading central body is carbon fiber; the mass ratio of the supported central body to the acetone to the dimethyl (3-trimethoxysilylpropyl) ammonium tetraacetate is 1:4.5: 0.55.
Example 5
Example 2 provides a method for synthesizing sulfachlorpyridazine sodium, which is essentially the same as example 1, except that the molar ratio of the sulfanilamide, 3, 6-dichloropyridazine, N-dimethylacetamide and the supported basic catalyst in step S1 is 1:1:10: 4; the load central body is at least one of porous alumina, graphene, carbon fiber and carbon nano tube; the mass ratio of the supported central body to the dichloromethane to the tetraethyl dimethyl (3-trimethoxysilylpropyl) ammonium is 1:5: 0.6.
Comparative example 1
Comparative example 1 provides a synthesis method of sulfachloropyridazine sodium, which is substantially the same as example 1 except that potassium carbonate is used instead of the supported basic catalyst.
Comparative example 2
Comparative example 2 provides a synthesis method of sulfachlorpyridazine sodium, which is the same as the embodiment of the Chinese invention patent CN 101914064B.
In order to further illustrate the beneficial technical effects of the examples, statistical techniques were carried out on the yield and the product purity of the method for synthesizing sulfachloropyridazine sodium in each of examples 1-5 and comparative examples 1-2, and the results are shown in Table 1.
TABLE 1
| Test items | Yield of | Purity of the product |
| Unit of | ％ | ％ |
| Example 1 | 98.3 | 99.2 |
| Example 2 | 98.6 | 99.4 |
| Example 3 | 98.8 | 99.5 |
| Example 4 | 99.2 | 99.5 |
| Example 5 | 99.5 | 99.7 |
| Comparative example 1 | 96.8 | 98.3 |
| Comparative example 2 | 96.5 | 96.0 |
As can be seen from Table 1, the synthesis of sulfachloropyridazine sodium in examples 1-5 has a significantly better yield and product purity than the comparative example.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (9)
1. A synthetic method of sulfachlorpyridazine sodium is characterized by comprising the following steps:
s1, adding sulfanilamide, 3, 6-dichloropyridazine and a high-boiling-point solvent into a reaction kettle in sequence, then adding a supported basic catalyst into the reaction kettle, and stirring the mixture for 10 to 16 hours at the temperature of between 100 and 160 ℃ under the pressure of between 0.3 and 1.2MPa to obtain a first mixed solution, so that the reaction kettle is cooled to normal temperature and normal pressure;
step S2, removing the solvent from the first mixed solution prepared in the step S1 by suction filtration, and condensing and recycling the obtained solvent; and then dissolving the product with the solvent removed in deionized water, adding sodium salt into the deionized water, stirring the mixture at the temperature of between 60 and 80 ℃ for reaction for 8 to 10 hours, filtering the mixture to remove insoluble substances, cooling the obtained solution for crystallization, and filtering the solution to obtain the sulfachlorpyridazine sodium.
2. The method for synthesizing sulfachlorpyridazine sodium as claimed in claim 1, wherein the molar ratio of the sulfanilamide, the 3, 6-dichloropyridazine, the high boiling point solvent and the supported basic catalyst in step S1 is 1:1 (6-10): 2-4.
3. The method for synthesizing sulfachloropyridazine sodium according to claim 1, characterized in that, the high boiling point solvent in step S1 is at least one of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.
4. The synthesis method of sulfachlorpyridazine sodium according to claim 1, characterized in that the preparation method of the supported alkaline catalyst comprises the following steps: dispersing the loaded central body in an organic solvent, adding tetraethyl dimethyl (3-trimethoxysilylpropyl) ammonium, stirring and reacting for 3-5 hours at the temperature of 60-80 ℃, then removing the solvent by suction filtration, recovering the solvent, and obtaining a solid, namely the loaded alkaline catalyst by suction filtration.
5. The method for synthesizing sulfachloropyridazine sodium according to claim 4, characterized in that the supporting central body is at least one of porous alumina, graphene, carbon fiber, carbon nanotube.
6. The method for synthesizing sulfachloropyridazine sodium according to claim 4, characterized in that the mass ratio of the supported central body, the organic solvent and the ammonium dimethyl tetraacetate (3-trimethoxysilylpropyl) is 1 (3-5) to (0.3-0.6).
7. The method for synthesizing sulfachlorpyridazine sodium according to claim 4, characterized in that the organic solvent is any one of ethanol, dichloromethane and acetone.
8. The method for synthesizing sulfachloropyridazine sodium as claimed in claim 1, wherein the molar ratio of the product after solvent removal, deionized water and sodium salt in step S2 is 1 (5-10): 1.
9. The method for synthesizing sulfachloropyridazine sodium according to claim 1, characterized in that the sodium salt is at least one of sodium sulfate and sodium thiosulfate.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113666876A (en) * | 2021-07-05 | 2021-11-19 | 佛山市南海北沙制药有限公司 | Production process of sulfachlorpyridazine |
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Application publication date: 20200619 |