CN113968812A - Preparation method of 2, 6-dichloropyridine - Google Patents
Preparation method of 2, 6-dichloropyridine Download PDFInfo
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- CN113968812A CN113968812A CN202111411424.3A CN202111411424A CN113968812A CN 113968812 A CN113968812 A CN 113968812A CN 202111411424 A CN202111411424 A CN 202111411424A CN 113968812 A CN113968812 A CN 113968812A
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- dichloropyridine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/61—Halogen atoms or nitro radicals
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Abstract
The invention discloses a preparation method of 2, 6-dichloropyridine, which comprises the following steps: dissolving 50.0g and 0.067mol of 2, 6-dichloropyridine in a mixture consisting of 150mL of trifluoroacetic acid and 25mL of 30% hydrogen peroxide, and irradiating for 20min and heating at 28-32 ℃ under 150-250W of microwave power; adding saturated sodium thiosulfate solution into the solution until the hydrogen peroxide is completely exhausted; after the mother liquor is desolventized to remove water and excessive trifluoroacetic acid, adding a proper amount of dichloromethane for extraction, liquid separation and desolventization to obtain the final product, namely the white-like solid 2, 6-dichloropyridine-N-oxide. The preparation method of the drug intermediate 2, 6-dichloropyridine has the advantages of reasonable design of the whole process flow, mild conditions, simple and convenient operation, easily obtained raw materials and high generation efficiency, and is very suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of intermediate synthesis, in particular to a preparation method of 2, 6-dichloropyridine.
Background
Pyridine N-oxides are an important class of pyridine derivatives, which are not only found in natural products, but are also important structural features of many biologically active compounds, and have many specific properties and chemical reactions. For example, nitration is relatively easy and the reaction occurs in the para position; reacting with chlorinating agent such as phosphorus oxychloride at 2-position or 4-position, and removing oxygen atom; the chlorine or nitro group at the 2-or 4-position is readily displaced by other affinity reagents. In addition, the oxygen atom of pyridine N-oxide is easy to remove by the action of 3-valent phosphorus reagent, so that the pyridine N-oxide is an important intermediate for synthesizing and converting a plurality of pyridine heterocyclic compounds. In recent years, pyridine N-oxide has excellent activity as a ligand of an oxygen atom transfer agent metal complex, and a C-H bond at a 2-position can be directly activated to participate in various coupling reactions.
At present, the oxidation preparation method of pyridine N-oxygen compound by pyridine compound is more, the most used method is hydrogen peroxide oxidation method without catalyst or with catalyst, and the second method is m-chloroperoxybenzoic acid oxidation method, the first method has high reaction condition, uses large amount of acid and hydrogen peroxide, generates a large amount of waste water after treatment, and the second method is that m-chloroperoxybenzoic acid raw material is expensive.
Disclosure of Invention
In view of the problems mentioned in the background, the present invention aims to provide a method for preparing 2, 6-dichloropyridine, so as to solve the problems mentioned in the background.
The technical purpose of the invention is realized by the following technical scheme:
a preparation method of 2, 6-dichloropyridine comprises the following steps: dissolving 50.0g and 0.067mol of 2, 6-dichloropyridine in a mixture consisting of 150mL of trifluoroacetic acid and 25mL of 30% hydrogen peroxide, and irradiating for 20min and heating at 28-32 ℃ under 150-250W of microwave power; adding saturated sodium thiosulfate solution into the solution until the hydrogen peroxide is completely exhausted; after the mother liquor is desolventized to remove water and excessive trifluoroacetic acid, adding a proper amount of dichloromethane for extraction, liquid separation and desolventization to obtain a final product, namely a white solid 2, 6-dichloropyridine-N-oxide, wherein the specific reaction is as follows:
preferably, 50.0g and 0.067mol of the 2, 6-dichloropyridine are dissolved in a mixture of 150mL of trifluoroacetic acid and 25mL of 30% hydrogen peroxide, and the mixture is irradiated at 30 ℃ for 20min and heated under 200W of microwave power.
Preferably, when a saturated solution of sodium thiosulfate is added to the solution, potassium iodide-starch test paper is used to check whether the hydrogen peroxide is completely consumed.
Preferably, when a proper amount of dichloromethane is added into the mother liquor for extraction, a solvent recovery tower is adopted for treatment, 2, 6-dichloropyridine-N-oxide is extracted in the solvent recovery tower, and desolventization is carried out after liquid separation.
Preferably, the yield of the 2, 6-dichloropyridine-N-oxide of the final product off-white solid is 91%.
Preferably, the structure of the 2, 6-dichloropyridine-N-oxide is characterized by 1H NMR.
In summary, the invention mainly has the following beneficial effects:
the preparation method of the drug intermediate 2, 6-dichloropyridine has the advantages of reasonable design of the whole process flow, mild conditions, simple and convenient operation, easily obtained raw materials and high generation efficiency, and is very suitable for large-scale industrial production; according to the invention, potassium carbonate is added in the cyanidation reaction, so that the reaction is carried out at normal temperature, side reactions are hardly generated, and the reaction yield is high; the invention adopts a microwave synthesis method, and reduces the dosage of acid and oxidant.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A preparation method of 2, 6-dichloropyridine comprises the following steps: dissolving 50.0g and 0.067mol of 2, 6-dichloropyridine in a mixture consisting of 150mL of trifluoroacetic acid and 25mL of 30% hydrogen peroxide, and irradiating for 20min and heating at 28-32 ℃ under 150-250W of microwave power; adding saturated sodium thiosulfate solution into the solution until the hydrogen peroxide is completely exhausted; after the mother liquor is desolventized to remove water and excessive trifluoroacetic acid, adding a proper amount of dichloromethane for extraction, liquid separation and desolventization to obtain a final product, namely a white solid 2, 6-dichloropyridine-N-oxide, wherein the specific reaction is as follows:
wherein 50.0g and 0.067mol of the 2, 6-dichloropyridine are dissolved in a mixture consisting of 150mL of trifluoroacetic acid and 25mL of 30% hydrogen peroxide, and the mixture is irradiated for 20min and heated at 30 ℃ under 200W of microwave power.
Wherein, when the saturated sodium thiosulfate solution is added to the solution, potassium iodide-starch test paper is used to check whether hydrogen peroxide is completely exhausted.
When a proper amount of dichloromethane is added into the mother liquor for extraction, a solvent recovery tower is adopted for treatment, 2, 6-dichloropyridine-N-oxide is extracted in the solvent recovery tower, and desolventization is carried out after liquid separation.
Wherein the yield of the 2, 6-dichloropyridine-N-oxide of the final product off-white solid is 91%.
Wherein the structure of the 2, 6-dichloropyridine-N-oxide is characterized by 1H NMR.
The preparation method of the drug intermediate 2, 6-dichloropyridine has the advantages of reasonable design of the whole process flow, mild conditions, simple and convenient operation, easily obtained raw materials and high generation efficiency, and is very suitable for large-scale industrial production; according to the invention, potassium carbonate is added in the cyanidation reaction, so that the reaction is carried out at normal temperature, side reactions are hardly generated, and the reaction yield is high; the invention adopts a microwave synthesis method, and reduces the dosage of acid and oxidant.
Example 2
A preparation method of 2, 6-dichloropyridine comprises the following steps: dissolving 50.0g and 0.067mol of 2, 6-dichloropyridine in a mixture consisting of 150mL of trifluoroacetic acid and 25mL of 30% hydrogen peroxide, and irradiating for 20min and heating at 28-32 ℃ under 150-250W of microwave power; adding saturated sodium thiosulfate solution into the solution until the hydrogen peroxide is completely exhausted; after the mother liquor is desolventized to remove water and excessive trifluoroacetic acid, adding a proper amount of dichloromethane for extraction, liquid separation and desolventization to obtain a final product, namely a white solid 2, 6-dichloropyridine-N-oxide, wherein the specific reaction is as follows:
wherein 50.0g and 0.067mol of the 2, 6-dichloropyridine are dissolved in a mixture consisting of 150mL of trifluoroacetic acid and 25mL of 30% hydrogen peroxide, and the mixture is irradiated for 20min and heated at 32 ℃ under the microwave power of 210W.
Wherein, when the saturated sodium thiosulfate solution is added to the solution, potassium iodide-starch test paper is used to check whether hydrogen peroxide is completely exhausted.
When a proper amount of dichloromethane is added into the mother liquor for extraction, a solvent recovery tower is adopted for treatment, 2, 6-dichloropyridine-N-oxide is extracted in the solvent recovery tower, and desolventization is carried out after liquid separation.
Wherein the yield of the 2, 6-dichloropyridine-N-oxide of the final product off-white solid is 91%.
Wherein the structure of the 2, 6-dichloropyridine-N-oxide is characterized by 1H NMR.
The preparation method of the drug intermediate 2, 6-dichloropyridine has the advantages of reasonable design of the whole process flow, mild conditions, simple and convenient operation, easily obtained raw materials and high generation efficiency, and is very suitable for large-scale industrial production; according to the invention, potassium carbonate is added in the cyanidation reaction, so that the reaction is carried out at normal temperature, side reactions are hardly generated, and the reaction yield is high; the invention adopts a microwave synthesis method, and reduces the dosage of acid and oxidant.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (6)
1. A preparation method of 2, 6-dichloropyridine is characterized by comprising the following steps: the method comprises the following steps: dissolving 50.0g and 0.067mol of 2, 6-dichloropyridine in a mixture consisting of 150mL of trifluoroacetic acid and 25mL of 30% hydrogen peroxide, and irradiating for 20min and heating at 28-32 ℃ under 150-250W of microwave power; adding saturated sodium thiosulfate solution into the solution until the hydrogen peroxide is completely exhausted; after the mother liquor is desolventized to remove water and excessive trifluoroacetic acid, adding a proper amount of dichloromethane for extraction, liquid separation and desolventization to obtain a final product, namely a white solid 2, 6-dichloropyridine-N-oxide, wherein the specific reaction is as follows:
2. the process according to claim 1, wherein the reaction is carried out in the presence of a solvent selected from the group consisting of: 50.0g and 0.067mol of the 2, 6-dichloropyridine are dissolved in a mixture consisting of 150mL of trifluoroacetic acid and 25mL of 30% hydrogen peroxide, and the mixture is irradiated for 20min and heated at 30 ℃ under 200W of microwave power.
3. The process according to claim 1, wherein the reaction is carried out in the presence of a solvent selected from the group consisting of: when the saturated sodium thiosulfate solution was added to the solution, it was checked whether the hydrogen peroxide was completely consumed using a potassium iodide-starch test paper.
4. The process according to claim 1, wherein the reaction is carried out in the presence of a solvent selected from the group consisting of: when a proper amount of dichloromethane is added into the mother liquor for extraction, a solvent recovery tower is adopted for treatment, 2, 6-dichloropyridine-N-oxide is extracted in the solvent recovery tower, and desolventization is carried out after liquid separation.
5. The process according to claim 1, wherein the reaction is carried out in the presence of a solvent selected from the group consisting of: the yield of the 2, 6-dichloropyridine-N-oxide of the final product was 91% as an off-white solid.
6. The process according to claim 1, wherein the reaction is carried out in the presence of a solvent selected from the group consisting of: the structure of the 2, 6-dichloropyridine-N-oxide was characterized by 1H NMR.
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| CN202111411424.3A CN113968812A (en) | 2021-11-25 | 2021-11-25 | Preparation method of 2, 6-dichloropyridine |
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| CN202111411424.3A CN113968812A (en) | 2021-11-25 | 2021-11-25 | Preparation method of 2, 6-dichloropyridine |
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