CN114539172A - Method for continuously preparing sulfaquinoxaline without solvent - Google Patents
Method for continuously preparing sulfaquinoxaline without solvent Download PDFInfo
- Publication number
- CN114539172A CN114539172A CN202210299952.2A CN202210299952A CN114539172A CN 114539172 A CN114539172 A CN 114539172A CN 202210299952 A CN202210299952 A CN 202210299952A CN 114539172 A CN114539172 A CN 114539172A
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- CN
- China
- Prior art keywords
- sulfaquinoxaline
- extruder
- temperature
- continuously preparing
- screw
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- NHZLNPMOSADWGC-UHFFFAOYSA-N 4-amino-N-(2-quinoxalinyl)benzenesulfonamide Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CN=C(C=CC=C2)C2=N1 NHZLNPMOSADWGC-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 229960003097 sulfaquinoxaline Drugs 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 22
- 239000002904 solvent Substances 0.000 title claims abstract description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 28
- BYHVGQHIAFURIL-UHFFFAOYSA-N 2-chloroquinoxaline Chemical compound C1=CC=CC2=NC(Cl)=CN=C21 BYHVGQHIAFURIL-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000000463 material Substances 0.000 claims abstract description 17
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229940124530 sulfonamide Drugs 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 14
- 238000002156 mixing Methods 0.000 claims abstract description 13
- 239000007787 solid Substances 0.000 claims abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 11
- 239000003651 drinking water Substances 0.000 claims description 11
- 235000020188 drinking water Nutrition 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 11
- 239000012452 mother liquor Substances 0.000 claims description 10
- 230000020477 pH reduction Effects 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 238000004042 decolorization Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 230000006641 stabilisation Effects 0.000 claims description 2
- 238000011105 stabilization Methods 0.000 claims description 2
- 238000001125 extrusion Methods 0.000 abstract description 16
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 238000005516 engineering process Methods 0.000 abstract description 4
- 230000035484 reaction time Effects 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 239000000155 melt Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 22
- 239000013078 crystal Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 239000012621 metal-organic framework Substances 0.000 description 2
- 238000006452 multicomponent reaction Methods 0.000 description 2
- 238000000498 ball milling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for continuously preparing sulfaquinoxaline without solvent, which comprises the following steps: under the condition of room temperature, mixing 2-chloroquinoxaline, industrial sulfanilamide and potassium carbonate in a reaction kettle, and then putting the mixture into a melt extruder with a set temperature and a set rotating speed at a certain feeding speed; the materials react under the meshing action of the screws in the extruder, and the obtained product is extruded from the outlet in a semi-solid state. By adopting the technology, compared with the traditional kettle type reaction, the temperature is reduced, and the energy consumption of the extrusion reaction is obviously reduced; meanwhile, due to the continuity of the extrusion equipment, the sulfaquinoxaline product can be continuously obtained, the reaction time is shortened, the production efficiency is increased, the production cost is reduced, the technology has obvious technical advantages in the large-scale production of the sulfaquinoxaline, and the wide development prospect in the future can be realized.
Description
Technical Field
The invention relates to the technical field of pharmaceutical technology, in particular to a method for continuously preparing sulfaquinoxaline without solvent.
Background
The sulfaquinoxaline serving as a veterinary drug for 60 years still occupies a large share in the market at present, can be used together with a synergist such as trimethoprim and the like, can obviously enhance the killing effect on coccidium and the like, and therefore has a very wide application prospect, and the molecular formula of the sulfaquinoxaline is shown as follows:
the conventional preparation method of sulfaquinoxaline is to use 2-chloroquinoxaline and sulfanilamide as raw materials to carry out condensation reaction in the presence of a solvent or in the molten state of the solvent-free raw materials, and the conventional preparation method of sulfaquinoxaline has the problems of high reaction temperature, high production cost and intermittent production in the process, and the reaction equation and mechanism are as follows:
the reaction equation is as follows:
the reaction mechanism is as follows:
mechanochemistry (Mechanochemistry) can be used to perform chemical reactions while reducing or eliminating the use of solvents, resulting in less risk of chemical synthesis, improved production efficiency, reduced cost, and overall greater economy. This form of synthesis process has been currently improved from batch ball milling experiments to the use of Extrusion (Extrusion) continuous processing processes. And reactive extrusion was also selected by IUPAC in 2019 as one of ten major chemical innovations that will change the world.
Twin Screw Extrusion (TSE) is widely used in the mixing and processing of pharmaceutical, polymer, and food industries, and in scalable, continuous mechanochemical synthesis currently being explored, examples of products displayed include Metal Organic Frameworks (MOFs), deep eutectic solvents (DESS), metal complexes, condensation products, and applications in pharmaceutical chemistry such as chemoenzymatic oligomerization, fluorination, and multicomponent reactions (MCR).
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for continuously preparing sulfaquinoxaline in a solvent-free manner, which utilizes a double-screw extrusion technology and has obvious advantages in the aspects of reaction time, temperature and production cost.
The technical scheme adopted by the invention for solving the technical problem is as follows: a method for continuously preparing sulfaquinoxaline without solvent is characterized in that an extruder is used as reaction equipment, and the preparation method comprises the following steps:
1) uniformly mixing the raw materials 2-chloroquinoxaline, sulfanilamide and potassium carbonate for later use;
2) heating and preheating each reaction cylinder area in the extruder, and keeping the temperature after stabilization;
3) adjusting the rotating speed of a screw of the extruder, slowly adding the mixed material obtained in the step 1) into the extruder at a certain speed, and reacting in the rotating process of the screw;
4) and (3) carrying out alkali dissolution and acidification treatment on the product extruded by the extruder to obtain the sulfaquinoxaline product.
Further, the invention also defines the extruder as an intermeshing co-rotating twin screw extruder.
Further, the invention also defines the feeding molar ratio of the 2-chloroquinoxaline, the sulfanilamide and the potassium carbonate in the step 1) to be 1.0: 0.5-2.0: 0.5 to 2.5, preferably 1.0: 1.2: 1.3.
further, the invention also limits the temperature of three areas of the extruder in the step 2) to be 120-160 ℃, 140-180 ℃, 160-200 ℃, preferably 140 ℃, 155 ℃ and 170 ℃.
Further, the invention also limits the screw rotation speed in the step 3) to be 10-100 rrm/min, preferably 30-50rrm/min, and optimally 35 rrm/min.
Further, the invention also limits the adding speed of the mixed material in the step 3) to be 0.1-10.0 g/min, and preferably 1.2 g/min.
Furthermore, the invention also defines the alkali dissolution acidification treatment process in the step 4) as follows: dissolving the extruded material with drinking water, adding activated carbon for decolorization, dropwise adding hydrochloric acid at the temperature to adjust the pH value to 5-6, cooling to room temperature, separating crystalline solid and mother liquor, and drying the crystalline solid to obtain the sulfaquinoxaline dry product.
Compared with the prior art, the invention has the advantages that:
the invention adopts the extruder as the reaction equipment, is set to be in a step temperature rise reaction, and reacts in the screw rotation process, thereby effectively solving the problems of long reaction time, high temperature, stirring paddle loss possibly caused by product solidification and the like of the 2-chloroquinoxaline and the sulfanilamide in the condensation reaction process, greatly reducing the production cost while ensuring the yield and the purity, and having the development prospect of realizing industrial production and good application value.
Detailed Description
The invention is further described below with reference to examples, but the technical parameters involved in the schemes should not be construed as limiting the invention.
In the embodiment of the invention, a SJZS-7A miniature double-screw extruder is adopted for reaction.
Example 1: preparation of sulfaquinoxaline
Uniformly mixing 20.5g of 2-chloroquinoxaline, 25.8g of industrial sulfanilamide and 22.4g of potassium carbonate to obtain a material for standby, setting the temperature of three areas of a screw to be 120 ℃, 140 ℃ and 160 ℃, keeping the temperature, adjusting the rotating speed of the screw to be 30rrm/min, adding the material into an extruder at the speed of 0.8g/min, adding an extrusion product into 60 ℃ drinking water for dissolving, decoloring the activated carbon for half an hour, dropwise adding hydrochloric acid at the temperature, adjusting the pH value to be 5-6, cooling to the room temperature, separating crystals and a mother solution, and drying to obtain a dry sulfaquinoxaline product, wherein the yield is 81.51%, and the purity is 96.42%.
Example 2: preparation of sulfaquinoxaline
Uniformly mixing 20.5g of 2-chloroquinoxaline, 27.9g of industrial sulfanilamide and 22.4g of potassium carbonate for later use, setting the temperature of three areas of a screw to be 140 ℃, 160 ℃ and 180 ℃, keeping the temperature, adjusting the rotating speed of the screw to be 40rrm/min, adding the materials into an extruder at the speed of 1.2g/min, adding an extrusion product into 60 ℃ drinking water for dissolving, decoloring the activated carbon for half an hour, dropwise adding hydrochloric acid at the temperature, adjusting the pH to be 5-6, cooling to the room temperature, separating crystals and mother liquor, and drying to obtain a dry sulfaquinoxaline product, wherein the yield is 88.45% and the purity is 95.41%.
Example 3: preparation of 2-chloroquinoxaline
Uniformly mixing 20.5g of 2-chloroquinoxaline, 27.9g of industrial sulfanilamide and 24.1g of potassium carbonate for later use, setting the temperature of three regions of a screw to 130 ℃, 155 ℃ and 180 ℃, keeping the temperature, adjusting the rotating speed of the screw to 50rrm/min, adding the materials into an extruder at the speed of 1.0g/min, adding an extrusion product into 60 ℃ drinking water for dissolving, decoloring the activated carbon for half an hour, dropwise adding hydrochloric acid at the temperature, adjusting the pH to 5-6, cooling to room temperature, separating crystals and mother liquor, and drying to obtain a dry sulfaquinoxaline product with the yield of 85.78% and the purity of 94.55%.
Example 4: preparation of 2-chloroquinoxaline
Uniformly mixing 20.5g of 2-chloroquinoxaline, 25.8g of industrial sulfanilamide and 24.1g of potassium carbonate for later use, setting the temperature of three regions of a screw to be 140 ℃, 155 ℃ and 170 ℃, keeping the temperature, adjusting the rotating speed of the screw to be 35rrm/min, adding the materials into an extruder at the speed of 1.2g/min, adding an extrusion product into 60 ℃ drinking water for dissolving, decoloring the activated carbon for half an hour, dropwise adding hydrochloric acid at the temperature, adjusting the pH to be 5-6, cooling to the room temperature, separating crystals and mother liquor, and drying to obtain a dry sulfaquinoxaline product, wherein the yield is 89.52 percent, and the purity is 96.88 percent.
Example 5: preparation of 2-chloroquinoxaline
Uniformly mixing 20.5g of 2-chloroquinoxaline, 25.8g of industrial sulfanilamide and 22.4g of potassium carbonate for later use, setting the temperature of three regions of a screw to 130 ℃, 145 ℃ and 160 ℃, keeping the temperature, adjusting the rotating speed of the screw to 50rrm/min, adding the materials into an extruder at the speed of 1.0g/min, adding an extrusion product into 60 ℃ drinking water for dissolving, decoloring the activated carbon for half an hour, dropwise adding hydrochloric acid at the temperature, adjusting the pH to 5-6, cooling to room temperature, separating crystals and mother liquor, and drying to obtain a dry sulfaquinoxaline product with the yield of 80.22% and the purity of 96.32%.
Example 6: preparation of 2-chloroquinoxaline
Uniformly mixing 20.5g of 2-chloroquinoxaline, 23.6g of industrial sulfanilamide and 19.0g of potassium carbonate for later use, setting the temperature of three areas of a screw to be 120 ℃, 145 ℃ and 200 ℃, keeping the temperature, adjusting the rotating speed of the screw to be 40rm/min, adding the materials into an extruder at the speed of 0.8g/min, adding an extrusion product into 60 ℃ drinking water for dissolving, decoloring the activated carbon for half an hour, dropwise adding hydrochloric acid at the temperature, adjusting the pH to be 5-6, cooling to the room temperature, separating crystals and mother liquor, and drying to obtain a dry sulfaquinoxaline product, wherein the yield is 79.98 percent, and the purity is 95.44 percent.
Example 7: preparation of 2-chloroquinoxaline
Uniformly mixing 20.5g of 2-chloroquinoxaline, 25.8g of industrial sulfanilamide and 22.4g of potassium carbonate for later use, setting the temperature of three areas of a screw to 130 ℃, 145 ℃ and 170 ℃, keeping the temperature, adjusting the rotating speed of the screw to 35rrm/min, adding the materials into an extruder at the speed of 1.2g/min, adding an extrusion product into 60 ℃ drinking water for dissolving, decoloring the activated carbon for half an hour, dropwise adding hydrochloric acid at the temperature, adjusting the pH to 5-6, cooling to room temperature, separating crystals and mother liquor, and drying to obtain a dry sulfaquinoxaline product with the yield of 83.54% and the purity of 97.48%.
Example 8: preparation of 2-chloroquinoxaline
Uniformly mixing 20.5g of 2-chloroquinoxaline, 23.6g of industrial sulfanilamide and 24.1g of potassium carbonate for later use, setting the temperature of three areas of a screw to 145 ℃, 165 ℃ and 185 ℃, keeping the temperature, adjusting the rotating speed of the screw to 50rrm/min, adding the materials into an extruder at the speed of 1.0g/min, adding an extrusion product into 60 ℃ drinking water for dissolving, decoloring the activated carbon for half an hour, dropwise adding hydrochloric acid at the temperature, adjusting the pH to 5-6, cooling to room temperature, separating crystals and mother liquor, and drying to obtain a dry sulfaquinoxaline product, wherein the yield is 76.68 percent, and the purity is 96.67 percent.
Example 9: preparation of 2-chloroquinoxaline
Uniformly mixing 20.5g of 2-chloroquinoxaline, 23.6g of industrial sulfanilamide and 24.1g of potassium carbonate for later use, setting the temperature of three regions of a screw to be 120 ℃, 145 ℃ and 200 ℃, keeping the temperature, adjusting the rotating speed of the screw to be 50rrm/min, adding the materials into an extruder at the speed of 1.0g/min, adding an extrusion product into 60 ℃ drinking water for dissolving, decoloring the activated carbon for half an hour, dropwise adding hydrochloric acid at the temperature, adjusting the pH to be 5-6, cooling to the room temperature, separating crystals and mother liquor, and drying to obtain a dry sulfaquinoxaline product, wherein the yield is 82.63%, and the purity is 96.35%.
Claims (7)
1. A method for continuously preparing sulfaquinoxaline without solvent is characterized in that an extruder is used as reaction equipment, and the preparation method comprises the following steps:
1) uniformly mixing the raw materials 2-chloroquinoxaline, sulfanilamide and potassium carbonate for later use;
2) heating and preheating each reaction cylinder area in the extruder, and keeping the temperature after stabilization;
3) adjusting the rotating speed of a screw of the extruder, slowly adding the mixed material obtained in the step 1) into the extruder at a certain speed, and reacting in the rotating process of the screw;
4) and (3) carrying out alkali dissolution and acidification treatment on the product extruded by the extruder to obtain the sulfaquinoxaline product.
2. The method for the continuous preparation of sulfaquinoxaline without solvent according to claim 1, wherein the extruder is a twin screw extruder with intermeshing co-rotating shafts.
3. The method for continuously preparing sulfaquinoxaline without solvent according to claim 1, wherein the feeding molar ratio of the 2-chloroquinoxaline, the sulfanilamide and the potassium carbonate in the step 1) is 1.0: 0.5-2.0: 0.5 to 2.5, preferably 1.0: 1.2: 1.3.
4. the method for continuously preparing sulfaquinoxaline without solvent according to claim 1, wherein the temperature of the three zones of the extruder in the step 2) is 120-160 ℃, 140-180 ℃, 160-200 ℃, preferably 140 ℃, 155 ℃ and 170 ℃ in sequence.
5. The method for continuously preparing sulfaquinoxaline without solvent according to claim 1, wherein the screw rotation speed in the step 3) is 10-100 rrm/min, preferably 30-50rrm/min, and most preferably 35 rrm/min.
6. The method for continuously preparing sulfaquinoxaline without solvent according to claim 1, wherein the adding speed of the mixed material in the step 3) is 0.1-10.0 g/min, preferably 1.2 g/min.
7. The method for continuously preparing sulfaquinoxaline without solvent according to claim 1, wherein the alkali-dissolving acidification treatment process in the step 4) is as follows: dissolving the extruded material with drinking water, adding activated carbon for decolorization, dropwise adding hydrochloric acid at the temperature to adjust the pH value to 5-6, cooling to room temperature, separating crystalline solid and mother liquor, and drying the crystalline solid to obtain the sulfaquinoxaline product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210299952.2A CN114539172A (en) | 2022-03-25 | 2022-03-25 | Method for continuously preparing sulfaquinoxaline without solvent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210299952.2A CN114539172A (en) | 2022-03-25 | 2022-03-25 | Method for continuously preparing sulfaquinoxaline without solvent |
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| CN114539172A true CN114539172A (en) | 2022-05-27 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210299952.2A Pending CN114539172A (en) | 2022-03-25 | 2022-03-25 | Method for continuously preparing sulfaquinoxaline without solvent |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL208167A1 (en) * | 1978-07-03 | 1980-03-10 | Starogardzkie Zakl Farma | |
| CN1557854A (en) * | 2004-01-16 | 2004-12-29 | 成都新柯力化工科技有限公司 | Process for preparing poly-lacti acid |
| CN106565876A (en) * | 2016-11-01 | 2017-04-19 | 珠海澳圣聚合物材料有限公司 | Continuous preparation method of controlled-molecular-weight brominated polystyrene |
| CN111153861A (en) * | 2019-12-31 | 2020-05-15 | 佛山市南海北沙制药有限公司 | Preparation method of high-purity sulfaquinoxaline |
| CN112209889A (en) * | 2020-04-28 | 2021-01-12 | 佛山市南海北沙制药有限公司 | Method for preparing sulfaquinoxaline without solvent |
-
2022
- 2022-03-25 CN CN202210299952.2A patent/CN114539172A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL208167A1 (en) * | 1978-07-03 | 1980-03-10 | Starogardzkie Zakl Farma | |
| CN1557854A (en) * | 2004-01-16 | 2004-12-29 | 成都新柯力化工科技有限公司 | Process for preparing poly-lacti acid |
| CN106565876A (en) * | 2016-11-01 | 2017-04-19 | 珠海澳圣聚合物材料有限公司 | Continuous preparation method of controlled-molecular-weight brominated polystyrene |
| CN111153861A (en) * | 2019-12-31 | 2020-05-15 | 佛山市南海北沙制药有限公司 | Preparation method of high-purity sulfaquinoxaline |
| CN112209889A (en) * | 2020-04-28 | 2021-01-12 | 佛山市南海北沙制药有限公司 | Method for preparing sulfaquinoxaline without solvent |
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