CN113666876B - Production process of sulfachloropyridazine - Google Patents
Production process of sulfachloropyridazine Download PDFInfo
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- CN113666876B CN113666876B CN202110755815.0A CN202110755815A CN113666876B CN 113666876 B CN113666876 B CN 113666876B CN 202110755815 A CN202110755815 A CN 202110755815A CN 113666876 B CN113666876 B CN 113666876B
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- 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
- C07D237/06—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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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/86—Signal analysis
- G01N30/8624—Detection of slopes or peaks; baseline correction
- G01N30/8631—Peaks
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Abstract
The invention discloses a production process of sulfachloropyridazine, which comprises the following steps: s1, stirring and mixing 3, 6-dichloropyridazine, sulfanilamide, potassium carbonate and tri-n-propylamine, heating to 140-150 ℃, and then preserving heat for 4-5 hours; s2, detecting by a high performance liquid chromatography, and stopping condensation reaction when the mass content of the sulfanilamide in the material is less than 10 percent: s3, adding water and active carbon, controlling the temperature to 90-95 ℃ and preserving the temperature for 2 hours for decoloring, taking out materials, filtering, collecting filtrate, adjusting the pH value of the filtrate to 5-6 at 20-30 ℃ so as to precipitate crystals, and centrifugally drying to obtain a crude product; s4, adding water into the crude product, adjusting the pH value of the crude product to 13-14, adding active carbon, heating to 90-95 ℃, preserving heat for 2 hours for decoloring, taking out the material, filtering, and collecting filtrate; adjusting the pH value of the filtrate to 5-6 at 20-30 ℃ so as to separate out crystals, and centrifugally drying to obtain refined sulfachloropyridazine; s5, cooling the crude mother liquor to 0-5 ℃ to precipitate sulfonamide; the refining mother liquor recycling sleeve is used for mixing with water and active carbon in the step S3.
Description
Technical Field
The invention relates to the field of pharmaceutical technology, in particular to a production technology of sulfachloropyridazine.
Background
Sulfonamides are the earliest synthetic antibacterial agents, usually white or pale yellow crystalline powders. Since the application of the invention in the last 30 th century, sulfanilamide medicines have been widely paid attention to and studied as antibacterial medicines with the most research and use value because of the advantages of easy production, easy preservation, good efficacy, convenient use, low price and the like. The sulfa drugs have been 80 years old, more than 8500 sulfa drugs are synthesized successively, and more than 20 sulfa-pyrimidine, sulfamonomethoxine, sulfadimidine and the like are commonly used clinically. With the continuous discovery and development of various antibiotics, antibiotics and quinolones gradually replace sulfonamides, but the sulfonamides still have the unique advantages of broad antibacterial spectrum, stable property, convenient use, low price, no grain consumption in medicine production and mass production. The discovery of Trimethoprim (TMP), trimethoprim (DVD) and other antibacterial synergists leads the antibacterial spectrum to be enlarged and the antibacterial activity to be greatly enhanced after the sulfanilamide drug is combined with the antibacterial synergists, so the sulfanilamide drug is still one of important drugs in the anti-infection treatment of livestock and poultry.
Wherein sulfachloropyridazine is one of sulfanilamide medicines, is yellow powdery solid, and is composed of aniline and chloro heterocycle connected by sulfanilamide groups. It belongs to broad-spectrum antibacterial medicine, has the characteristics of low toxicity, easy absorption by oral administration and the like, and has antibacterial effect on a plurality of gram-positive bacteria and certain gram-negative bacteria.
At present, the synthesis process of sulfachloropyridazine is reported at home and abroad, and 3, 6-dichloropyridazine and sulfanilamide are generally condensed for 10-16 hours in the presence of potassium carbonate to prepare the product. Some of these processes add high boiling solvents to the condensation reaction such as: dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, o-dichlorobenzene and the like, or adding a catalyst such as: tetrabutylammonium bromide, tetrabutylammonium bisulfate, etc., so that the condensation reaction is quicker and more complete. However, the addition of the high-boiling solvent has a certain difficulty in subsequent treatment, and partial catalyst can darken the reactant, which is unfavorable for the production activity of enterprises.
Therefore, development of a green chemical reaction is particularly important in a production process which is beneficial to environmental protection, accelerates the reaction, reduces energy consumption and improves yield.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a production process of sulfachloropyridazine, which has the advantages of novel technology, high recovery rate, less emission, high efficiency and environmental protection.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a production process of sulfachloropyridazine, which comprises the following steps:
s1, condensation reaction: stirring and mixing 3, 6-dichloropyridazine, sulfanilamide and potassium carbonate, heating to 140-150 ℃ and then preserving heat for 4-5 hours;
s2, central control detection: taking out the materials and detecting by high performance liquid chromatography, and stopping condensation reaction when the mass content of the sulfanilamide in the materials is less than 10 percent:
s3, crude products are obtained: adding water and active carbon, controlling the temperature to 90-95 ℃ and preserving heat for 2 hours for decoloring, taking out the materials, filtering and collecting filtrate, adjusting the pH value of the filtrate to 5-6 at 20-30 ℃ to precipitate crystals, and centrifugally drying the crystals to obtain crude products;
s4, refining: adding water into the crude product, adjusting the pH value of the crude product to 13-14, adding active carbon, heating to 90-95 ℃, preserving heat for 2 hours for decoloring, taking out the material, filtering, and collecting filtrate; adjusting the pH value of the filtrate to 5-6 at 20-30 ℃ so as to separate out crystals, and centrifugally drying the crystals to obtain refined sulfachloropyridazine;
s5, recycling: cooling the crude mother liquor to 0-5 ℃ to precipitate sulfanilamide, and filtering and recycling; the refining mother liquor recovery sleeve is used in the step S3.
Preferably, in the steps S3 and S4, the pH is adjusted by dropwise adding hydrochloric acid and sodium hydroxide.
Preferably, in the step S2, the method for performing HPLC detection includes the following steps:
a. taking mass of m Feed device Putting the material of (2) as a sample into a volumetric flask, adding acetonitrile or mobile phase for dissolution, and fixing the volume to V Feed device Preparing a test solution;
weighing mass of m For a pair of Sulfanilamide is placed in a volumetric flask, acetonitrile or mobile phase is added for dissolution and volume is fixed to volume V For a pair of Preparing a control solution;
b. taking the volume L Feed device Is L in volume For a pair of Is used for the control liquid of (2)The high performance liquid chromatograph detects the test liquid and the control liquid respectively, and chromatograms of the test liquid and the control liquid are obtained respectively;
c. comparing chromatograms of the test solution and the control solution, finding out an absorption peak corresponding to the sulfonamide, and respectively calculating the absorption peak areas A of the sulfonamide in the chromatograms of the test solution and the control solution Feed device And A For a pair of ；
d. Calculating the content of sulfanilamide in the material according to the following formula: .
Preferably, the parameters at the time of high performance liquid chromatography detection are as follows: the chromatographic column is a C18 reversed phase chromatographic column; the column temperature is 30 ℃; the sample injection amount is 5ul; the flow rate is 1.0ml/min; the detection wavelength is UV 258nm; and c, the time is 15-20 min, and the mobile phase is the same as that in the step a.
Preferably, the mobile phase comprises a mass ratio of 1: the liquid A and the liquid B are 0.05% trifluoroacetic acid aqueous solution by mass percent; the solution B is acetonitrile water solution with the mass percentage of 0.05 percent.
Preferably, in the step S1, the molar ratio of 3, 6-dichloropyridazine, sulfanilamide, potassium carbonate and tri-n-propylamine is 3, 6-dichloropyridazine: sulfonamide: potassium carbonate: tri-n-propylamine=1.0 to 1.4:1.0 to 1.4:2.0 to 2.4:0.01.
the beneficial effects of the invention are as follows: the production process adopted by the invention is solvent-free reaction, does not need to add high-boiling solvent, and is environment-friendly. Meanwhile, the production process adopts normal pressure reaction, does not need to pressurize or rely on a high-pressure container, and has mild reaction, simple equipment and high safety. The condensation reaction adopts potassium carbonate as a catalyst to accelerate the reaction, the reaction time is about 4-5 hours and is far less than the traditional 10-16 hours, and the enterprise cost is reduced. The water for refining and the sulfonamide residue can be recycled, so that the enterprise cost is reduced and the sewage is reduced.
Detailed Description
The technical scheme claimed in the invention is further described in detail with reference to specific embodiments.
The production process of sulfachloropyridazine in the embodiment comprises the following steps:
and (3) adding 750g of 3, 6-dichloropyridazine, 860g of sulfanilamide, 1382g of potassium carbonate and 7.2g of tri-n-propylamine into a 10L reaction kettle, starting stirring, heating to 140-150 ℃ and carrying out thermal insulation reaction for 4-5 hours to carry out condensation reaction. And (3) sampling the reaction kettle for a plurality of times in the condensation reaction process, taking out the sample, detecting by using high performance liquid chromatography, and stopping the condensation reaction when the mass content of the sulfanilamide in the material is less than 10%. In other examples, the specific amounts of the various materials may be adjusted in combination with the actual use, and the molar ratios of the various materials are required to meet the requirements of 3, 6-dichloropyridazine: sulfonamide: potassium carbonate: tri-n-propylamine=1.0 to 1.4:1.0 to 1.4:2.0 to 2.4:0.01.
the specific procedure for the high performance liquid chromatography detection in this example is as follows:
a. preparing a mobile phase: the mobile phase comprises the following components in percentage by mass: the liquid A and the liquid B are 0.05% trifluoroacetic acid aqueous solution by mass percent; the solution B is acetonitrile water solution with the mass percentage of 0.05 percent. The preparation process of the solution A comprises the following steps: dissolving 0.5ml of trifluoroacetic acid in 1000ml of water, uniformly mixing, filtering with a 0.45um membrane, and performing ultrasonic degassing to obtain the final product; the preparation process of the solution B comprises the following steps: the preparation process of the solution B is as follows: 0.5ml of trifluoroacetic acid is taken and dissolved in 1000ml of acetonitrile, and the solution is filtered by a membrane of 0.45um, and is prepared after ultrasonic degassing.
Preparing a test solution: taking mass of m Feed device Putting the material of (2) as a sample into a volumetric flask, adding acetonitrile or mobile phase for dissolution, and fixing the volume to V Feed device The test solution was prepared.
Preparing a control solution: weighing mass of m For a pair of Sulfanilamide is placed in a volumetric flask, acetonitrile or mobile phase is added for dissolution and volume is fixed to volume V For a pair of The control solution was prepared.
b. Taking the volume L Feed device Is L in volume For a pair of And (3) detecting the test liquid and the control liquid by using a high performance liquid chromatograph respectively to obtain chromatograms of the test liquid and the control liquid respectively. In this example, the parameters at the time of high performance liquid chromatography detection were as follows: the chromatographic column is a C18 reversed phase chromatographic column; the column temperature is 30 ℃; the sample injection amount is 5ul; the flow rate is 1.0ml/min; the detection wavelength is UV 258nm; and c, the time is 15-20 min, and the mobile phase is the same as that in the step a.
c. Comparing chromatograms of the test solution and the control solution, finding out an absorption peak corresponding to the sulfonamide, and respectively calculating the absorption peak areas A of the sulfonamide in the chromatograms of the test solution and the control solution Feed device And A For a pair of 。
d. Calculating the content of sulfanilamide in the material according to the following formula: .
After the condensation reaction is finished, 6000mL of water, 40g of active carbon, which is at 90-95 ℃ and is kept for 2 hours, is added into the reaction kettle for decolorization, and then the materials are taken out for filtration and the filtrate is collected. And (3) dropwise adding hydrochloric acid into the filtrate at the temperature of 20-30 ℃, adjusting the pH value to be 5-6, separating out crystals, centrifuging and drying the crystals to obtain about 2108g of crude product, wherein the molar yield of the crude product is 92.3%. And cooling the crude mother solution (namely the filtrate of the precipitated crystals) to 0-5 ℃ to precipitate sulfanilamide, and filtering and recycling.
And (3) adding 8000mL of water into the crude product, dropwise adding 30% sodium hydroxide until the pH value is=13-14, adding 40g of active carbon, controlling the temperature to be 90-95 ℃ and preserving the temperature for 2 hours for decoloring, and then taking out the material, filtering and collecting filtrate. And (3) regulating the pH value of the filtrate to be 5-6 by using hydrochloric acid, so as to precipitate crystals, and drying the crystals to obtain about 2002g of refined sulfachloropyridazine, wherein the refining yield is 95%. The refined mother liquor (i.e. the filtrate for separating out the fine crystals in the steps) is recycled and reused in the next batch of production to be mixed with water and active carbon.
The above-described embodiments are merely preferred embodiments of the present invention, and are not intended to limit the present invention in any way. Any person skilled in the art can make many more possible variations and modifications of the technical solution of the present invention or modify equivalent embodiments without departing from the scope of the technical solution of the present invention by using the technical content disclosed above. Therefore, all equivalent changes according to the inventive concept are covered by the protection scope of the invention without departing from the technical scheme of the invention.
Claims (3)
1. The production process of sulfachloropyridazine is characterized by comprising the following steps of:
s1, condensation reaction: stirring and mixing 3, 6-dichloropyridazine, sulfanilamide, potassium carbonate and tri-n-propylamine, heating to 140-150 ℃, and then preserving heat for 4-5 hours;
s2, central control detection: taking out the materials and detecting by high performance liquid chromatography, and stopping condensation reaction when the mass content of the sulfanilamide in the materials is less than 10 percent:
s3, crude products are obtained: adding water and active carbon, controlling the temperature to 90-95 ℃ and preserving heat for 2 hours for decoloring, taking out the materials, filtering and collecting filtrate, adjusting the pH value of the filtrate to 5-6 at 20-30 ℃ to precipitate crystals, and centrifugally drying the crystals to obtain crude products;
s4, refining: adding water into the crude product, adjusting the pH value of the crude product to 13-14, adding active carbon, heating to 90-95 ℃, preserving heat for 2 hours for decoloring, taking out the material, filtering, and collecting filtrate; the filtrate is 20-20%
Adjusting the pH value to 5-6 at 30 ℃ so as to separate out crystals, and centrifugally drying the crystals to obtain refined sulfachloropyridazine;
s5, recycling and mechanically applying: cooling the crude mother liquor to 0-5 ℃ to precipitate sulfanilamide, and filtering and recycling; the refining mother liquor recovery sleeve is used in the step S3.
2. The production process of sulfachloropyridazine according to claim 1, which is characterized in that: in the steps S3 and S4, the pH value is regulated by dropwise adding hydrochloric acid and sodium hydroxide.
3. The production process of sulfachloropyridazine according to claim 1, which is characterized in that: in the step S1, the molar ratio of 3, 6-dichloropyridazine, sulfanilamide, potassium carbonate and tri-n-propylamine is 3, 6-dichloropyridazine: sulfonamide: potassium carbonate: tri-n-propylamine=1.0 to 1.4:1.0 to 1.4:2.0 to 2.4:0.01.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0169484A2 (en) * | 1984-07-24 | 1986-01-29 | Ishihara Sangyo Kaisha, Ltd. | N-benzoyl-N'-pyridazinyloxyphenyl urea compounds, and antitumorous compositions containing them, and process for their preparation |
| CN101890027A (en) * | 2010-08-13 | 2010-11-24 | 中国农业科学院上海兽医研究所 | Application of Sulfaclozine and its derivatives |
| CN101914064A (en) * | 2010-08-17 | 2010-12-15 | 扬州天和药业有限公司 | Method for preparing sulfachlororyridazine sodium |
| WO2014019338A1 (en) * | 2012-07-30 | 2014-02-06 | Astar Biotech Llc | Protein kinase inhibitors |
| WO2014074761A2 (en) * | 2012-11-09 | 2014-05-15 | Glaxosmithkline Llc | Novel compounds as diacylglycerol acyltransferase inhibitors |
| CN111217760A (en) * | 2020-03-27 | 2020-06-02 | 湖南吴赣药业有限公司 | Synthetic method of sulfachloropyrazine sodium |
| CN111303044A (en) * | 2020-03-27 | 2020-06-19 | 湖南吴赣药业有限公司 | Synthetic method of sulfachloropyridazine sodium |
-
2021
- 2021-07-05 CN CN202110755815.0A patent/CN113666876B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0169484A2 (en) * | 1984-07-24 | 1986-01-29 | Ishihara Sangyo Kaisha, Ltd. | N-benzoyl-N'-pyridazinyloxyphenyl urea compounds, and antitumorous compositions containing them, and process for their preparation |
| CN101890027A (en) * | 2010-08-13 | 2010-11-24 | 中国农业科学院上海兽医研究所 | Application of Sulfaclozine and its derivatives |
| CN101914064A (en) * | 2010-08-17 | 2010-12-15 | 扬州天和药业有限公司 | Method for preparing sulfachlororyridazine sodium |
| WO2014019338A1 (en) * | 2012-07-30 | 2014-02-06 | Astar Biotech Llc | Protein kinase inhibitors |
| WO2014074761A2 (en) * | 2012-11-09 | 2014-05-15 | Glaxosmithkline Llc | Novel compounds as diacylglycerol acyltransferase inhibitors |
| CN111217760A (en) * | 2020-03-27 | 2020-06-02 | 湖南吴赣药业有限公司 | Synthetic method of sulfachloropyrazine sodium |
| CN111303044A (en) * | 2020-03-27 | 2020-06-19 | 湖南吴赣药业有限公司 | Synthetic method of sulfachloropyridazine sodium |
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