CN108569999B - Preparation method of 3, 5-dibromopyridine - Google Patents
Preparation method of 3, 5-dibromopyridine Download PDFInfo
- Publication number
- CN108569999B CN108569999B CN201810595342.0A CN201810595342A CN108569999B CN 108569999 B CN108569999 B CN 108569999B CN 201810595342 A CN201810595342 A CN 201810595342A CN 108569999 B CN108569999 B CN 108569999B
- Authority
- CN
- China
- Prior art keywords
- dibromopyridine
- reaction
- sulfuric acid
- concentrated sulfuric
- pyridine
- Prior art date
- 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.)
- Active
Links
Images
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a preparation method of 3, 5-dibromopyridine, belonging to the technical field of chemical raw material synthesis. The preparation method provided by the invention has the advantages that the reaction catalyst is easy to obtain, the reaction condition is easy to control, the reaction byproducts are few, the use of catalysts such as nickel powder, copper powder and aluminum chloride is avoided, the discharge of three wastes is reduced, and the problems of serious pollution, low yield and the like in the prior art are solved.
Description
Technical Field
The invention belongs to the technical field of chemical raw material synthesis, and particularly relates to a preparation method of 3, 5-dibromopyridine.
Background
3, 5-dibromopyridine is an important medical intermediate and is an important raw material for preventing and treating central nervous system disorder TC-2559. Because the aromatic electrophilic reaction speed of pyridine is much slower than that of benzene, a violent reaction condition is often required, and only 3-position substitution reaction is generated, the existing literature reports that Englert and the like synthesize a mixture (38%) of 3, 5-dibromopyridine (36%) and 3-bromopyridine at a high temperature of 230-250 ℃, while Mallet and the like synthesize a mixture of 3, 5-dibromopyridine (25%), 3-bromopyridine (20%) and 4-bromopyridine (20%) under the action of n-butyllithium by using 3, 4-dibromopyridine at a temperature of-78 ℃, and the synthesis methods are harsh in reaction conditions, have single bromination byproducts, and cause low yield and difficult separation. 4-aminopyridine has special activation and positioning capabilities, so that 4-aminopyridine is used as a raw material to react to obtain 3, 5-dibromopyridine in subsequent researches.
For example, the synthesis of 3, 5-dibromopyridine, chemical reagent 2010, 32(3), 261-262, Linyangfei et al, studied a method of obtaining 3, 5-dibromopyridine by brominating 4-aminopyridine with bromine in glacial acetic acid at high yield and then carrying out an improved Sandmeyer diazotization reduction reaction, using 4-aminopyridine as a raw material. However, the reaction is carried out in multiple steps, the reaction conditions need to be controlled in each step, and the final yield is not high (36.8%), so that the industrial application is difficult. Aiming at the defects, the Chinese patent application No. 201610014465.1, 2016, 01, 11 discloses a synthesis method of 3, 5-dibromopyridine, which comprises the following steps: (1) bromination reaction: dissolving 4-aminopyridine and azodiisobutyronitrile in carbon tetrachloride, adding N-bromosuccinimide at 25 ℃, monitoring in a liquid phase until the reaction is complete, and treating to obtain 3, 5-dibromo-4-aminopyridine; (2) diazotization reaction: adding 3, 5-dibromo-4-aminopyridine into concentrated sulfuric acid, after completely dissolving, dropwise adding nitroso sulfuric acid at 48-55 ℃, and reacting for 1-1.5 h after dropwise adding is stopped when potassium iodide starch test paper turns blue and does not fade; (3) reduction reaction: and continuously adding nickel powder and an absolute ethyl alcohol solution into the solution, performing reflux reaction, cooling, adjusting the solution to be alkalescent by using a concentrated sodium hydroxide solution, and treating the solution to obtain the nickel-titanium dioxide composite material. The method disclosed in this patent is an improvement on the basis of the linyangfei, and conditions of bromination reaction and reduction reaction are optimized, but the reaction also has many steps, nickel powder is used as a reducing agent, and three wastes are difficult to treat after the reaction, which is not favorable for industrial application, and the cost is very high.
3, 5-dibromopyridine is used as an important medical intermediate, and the market demand is large, so that the significance of developing an environment-friendly, efficient and economic preparation method of 3, 5-dibromopyridine is great.
Disclosure of Invention
1. Problems to be solved
Aiming at the problems of high requirement on conditions, complicated steps, more three-waste pollution, low yield and the like of the existing preparation method of the 3, 5-dibromopyridine, the invention provides the preparation method of the 3, 5-dibromopyridine, bromine is added under the high temperature condition for reaction, and the use of a catalyst is avoided, so that the three wastes after the reaction are less, the method provided by the invention has less reaction steps, high reaction yield, the purity of the product can reach about 99 percent, and the reaction yield is improved to 82 percent from 50 percent in the prior art.
2. Technical scheme
In order to solve the problems, the technical scheme adopted by the invention is as follows:
a preparation method of 3, 5-dibromopyridine takes pyridine as a raw material, concentrated sulfuric acid and thionyl chloride as catalysts, and bromine is dropwise added under the condition of high temperature to react to obtain the pyridine bromide.
As a further technical solution of the present invention, the high temperature means a temperature of 125-138 ℃.
A preparation method of 3, 5-dibromopyridine comprises the following steps:
(1) adding pyridine into concentrated sulfuric acid and thionyl chloride, and heating and refluxing;
(2) dropwise adding bromine under a reflux state, and heating to 125-138 ℃ for reaction;
(3) and (3) carrying out steam distillation on the reaction liquid, and separating out a crude product of the 3, 5-dibromopyridine in water.
As a further technical scheme of the invention, the mass ratio of the pyridine to the concentrated sulfuric acid and the thionyl chloride in the step (1) is 1:1 (2.5-3), and the mass fraction of the concentrated sulfuric acid is more than 98%.
As a further technical scheme of the invention, the addition amount of bromine in the step (2) is 5-7 times, preferably 5-6 times of the mass of pyridine.
As a further technical scheme of the invention, the bromine in the step (2) is added dropwise within 10-12 hours.
As a further technical proposal of the invention, the reflux temperature in the step (2) is controlled at 130 ℃.
As a further technical scheme of the invention, the crude product of the 3, 5-dibromopyridine in the step (3) is recrystallized and purified by using an alcohol solution.
As a further technical scheme of the invention, the alcohol solution is methanol or ethanol solution.
The application of the mixed solution of concentrated sulfuric acid and thionyl chloride as a catalyst in the field of preparation of 3, 5-dibromopyridine is realized, wherein the mass ratio of the concentrated sulfuric acid to the thionyl chloride is 1: 2.
3. Advantageous effects
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention provides a preparation method of 3, 5-dibromo pyridine, which takes concentrated sulfuric acid and thionyl chloride as catalysts, performs bromine adding reaction on pyridine under the condition of high temperature to obtain the 3, 5-dibromo pyridine, and finally separates out a product through steam distillation, wherein the reaction steps are simple and easy to control, catalysts such as nickel powder, copper powder, aluminum chloride and the like are not needed, the discharge of three wastes is reduced, and the purity and the quality of the product are improved;
(2) the method can overcome the problems that pyridine is not easy to generate aromatic electrophilic reaction and generate monobromo by-products in the prior art, and the reaction conditions provided by the invention only enable 1-2% of the pyridine to generate monobromo reaction, and can remove the monobromo products in subsequent refining;
(3) the preparation method of the 3, 5-dibromopyridine provided by the invention has the advantages of mild reaction conditions, easy control, good reaction effect, easy separation of products and high reaction yield up to 82%;
(4) according to the preparation method of the 3, 5-dibromopyridine, after a crude product separated out by distillation is refined by using methanol or ethanol, the purity can reach more than 99%;
(5) the preparation method of the 3, 5-dibromopyridine provided by the invention has the advantages of few reaction byproducts, low cost of reaction raw materials and no need of expensive catalysts and solvents.
Drawings
FIG. 1 is a schematic diagram of a synthetic scheme of the present invention;
FIG. 2 is a gas chromatogram of the product of the present invention.
Detailed Description
The invention is further described with reference to specific examples.
Example 1
As shown in figure 1, the invention provides a simple and easy preparation method of 3, 5-dibromopyridine, which takes pyridine as a raw material, concentrated sulfuric acid and thionyl chloride as catalysts, and bromine is dropwise added under the high temperature condition (the high temperature refers to the temperature of 125-138 ℃). The specific reaction steps are as follows:
(1) adding 100g of pyridine into 100g of concentrated sulfuric acid and 300g of thionyl chloride, and heating and refluxing, wherein the mass fraction of the concentrated sulfuric acid is 98%;
(2) dripping 550g of bromine under the reflux state (dripping is finished within 10 hours), heating to 130 ℃ for reaction, and observing whether reddish brown gas exists in a reaction test tube to judge whether the reaction is complete;
(3) and (3) carrying out steam distillation on the reaction solution, wherein a product separated out from water is a crude product of the 3, 5-dibromopyridine, drying is not needed, and then dissolving the crude product of the 3, 5-dibromopyridine into methanol for recrystallization and purification to obtain a pure product of the 3, 5-dibromopyridine with the yield of about 82%.
The product of the reaction was analyzed by the following analyzer: linghua GC 9890B;
the instrument conditions were as follows:
column temperature: 140 ℃; a detector: 280 ℃; sample injector temperature: 280 ℃; sensitivity: 3.
hydrogen gas: 0.1 Mpa; air: 0.1 Mpa; carrier gas (nitrogen): 0.08 MPa.
Temperature programming:
keeping at 140 deg.C for 1min, heating to 280 deg.C at 20 deg.C/min, and keeping for 5min
Sample treatment:
taking 0.3g of sample, adding 10mL of ethyl acetate to completely dissolve, injecting 0.02uL of sample by using a 10uL sample injector, sampling for 10min, measuring the content by an area normalization method, wherein a chromatogram is shown in figure 2, specific information of each peak in the figure is shown in the following table, the purity of the product is as high as 99.85 percent, the purity is very high, the preparation method is convenient and economic compared with the prior art, the three-waste pollution is small, the byproducts are few, and the catalyst is easy to obtain.
TABLE 1 chromatographic Peak area of the product
The invention provides a method for easily preparing 3, 5-dibromopyridine, which comprises the steps of carrying out substitution under the high-temperature condition, adding concentrated sulfuric acid and thionyl chloride to activate hydrogen, and actually utilizing bromine to generate thionyl bromide under the action of the concentrated sulfuric acid to substitute the hydrogen; when the temperature is low, the reaction stops at the monobrominated product, and when the temperature is high, the dibromo product exists.
Example 2
As shown in figure 1, the invention provides a simple and easy preparation method of 3, 5-dibromopyridine, which takes pyridine as a raw material, concentrated sulfuric acid and thionyl chloride as catalysts, and bromine is dropwise added under the high temperature condition (the high temperature refers to the temperature of 125-138 ℃). The specific reaction steps are as follows:
(1) adding 100g of pyridine into 100g of concentrated sulfuric acid and 250g of thionyl chloride, and heating and refluxing, wherein the mass fraction of the concentrated sulfuric acid is 99%;
(2) dropwise adding 500g of bromine under a reflux state (after dropwise adding within 12 hours), heating to about 125 ℃ for reaction, and observing whether reddish brown gas exists in a reaction test tube to judge whether the reaction is complete;
(3) and (3) carrying out steam distillation on the reaction solution, separating out a product in water, namely a crude product of the 3, 5-dibromopyridine, and then dissolving the crude product of the 3, 5-dibromopyridine into methanol for recrystallization and purification to obtain a pure product of the 3, 5-dibromopyridine with the yield of about 80%.
The product of the reaction was analyzed by the following analyzer: linghua GC 9890B;
the instrument conditions were as follows:
column temperature: 140 ℃; a detector: 280 ℃; sample injector temperature: 280 ℃; sensitivity: 3.
hydrogen gas: 0.1 Mpa; air: 0.1 Mpa; carrier gas (nitrogen): 0.08 MPa.
Temperature programming:
keeping at 140 deg.C for 1min, heating to 280 deg.C at 20 deg.C/min, and keeping for 5min
Sample treatment:
taking 0.3g of sample, adding 10mL of ethyl acetate to completely dissolve, injecting 0.02uL of sample by using a 10uL sample injector, sampling for 10min, and measuring the content by an area normalization method, wherein the purity of the product is up to 99.78 percent, the purity is very high, the preparation method is convenient and economic compared with the prior art, the three-waste pollution is small, the byproducts are few, and the catalyst is easy to obtain.
Example 3
As shown in figure 1, the invention provides a simple and easy preparation method of 3, 5-dibromopyridine, which takes pyridine as a raw material, concentrated sulfuric acid and thionyl chloride as catalysts, and bromine is dropwise added under the high temperature condition (the high temperature refers to the temperature of 125-138 ℃). The specific reaction steps are as follows:
(1) adding 100g of pyridine into 100g of concentrated sulfuric acid and 300g of thionyl chloride, and heating and refluxing, wherein the mass fraction of the concentrated sulfuric acid is 99.5%;
(2) dropwise adding 700g of bromine under a reflux state (after dropwise adding within 10 hours), heating to 138 ℃ for reaction, and observing whether reddish brown gas exists in a reaction test tube to judge whether the reaction is complete;
(3) and (3) carrying out steam distillation on the reaction solution, separating out a product in water, namely a crude product of the 3, 5-dibromopyridine, and then dissolving the crude product of the 3, 5-dibromopyridine into methanol for recrystallization and purification to obtain a pure product of the 3, 5-dibromopyridine with the yield of 82.
The product of the reaction was analyzed by the following analyzer: linghua GC 9890B;
the instrument conditions were as follows:
column temperature: 140 ℃; a detector: 280 ℃; sample injector temperature: 280 ℃; sensitivity: 3.
hydrogen gas: 0.1 Mpa; air: 0.1 Mpa; carrier gas (nitrogen): 0.08 MPa.
Temperature programming:
keeping at 140 deg.C for 1min, heating to 280 deg.C at 20 deg.C/min, and keeping for 5min
Sample treatment:
taking 0.3g of sample, adding 10mL of ethyl acetate to completely dissolve, injecting 0.02uL of sample by using a 10uL sample injector, sampling for 10min, and measuring the content by an area normalization method, wherein the purity of the product is up to 99.80 percent, the purity is very high, the preparation method is convenient and economic compared with the prior art, the three-waste pollution is small, the byproducts are few, and the catalyst is easy to obtain.
Example 4
As shown in figure 1, the invention provides a simple and easy preparation method of 3, 5-dibromopyridine, which takes pyridine as a raw material, concentrated sulfuric acid and thionyl chloride as catalysts, and bromine is dropwise added under the high temperature condition (the high temperature refers to the temperature of 125-138 ℃). The specific reaction steps are as follows:
(1) adding 100g of pyridine into 100g of concentrated sulfuric acid and 250g of thionyl chloride, and heating and refluxing, wherein the mass fraction of the concentrated sulfuric acid is 98.5%;
(2) dropwise adding 600g of bromine under a reflux state (after dropwise adding within 10 hours), heating to 130 ℃ for reaction, and observing whether reddish brown gas exists in a reaction test tube to judge whether the reaction is complete;
(3) and (3) carrying out steam distillation on the reaction solution, separating out a product in water, namely a crude product of the 3, 5-dibromopyridine, and then dissolving the crude product of the 3, 5-dibromopyridine into methanol for recrystallization and purification to obtain a pure product of the 3, 5-dibromopyridine with the yield of about 81%.
The product of the reaction was analyzed by the following analyzer: linghua GC 9890B;
the instrument conditions were as follows:
column temperature: 140 ℃; a detector: 280 ℃; sample injector temperature: 280 ℃; sensitivity: 3.
hydrogen gas: 0.1 Mpa; air: 0.1 Mpa; carrier gas (nitrogen): 0.08 MPa.
Temperature programming:
keeping at 140 deg.C for 1min, heating to 280 deg.C at 20 deg.C/min, and keeping for 5min
Sample treatment:
taking 0.3g of sample, adding 10mL of ethyl acetate to completely dissolve, injecting 0.02uL of sample by using a 10uL sample injector, sampling for 10min, and measuring the content by an area normalization method, wherein the purity of the product is up to 99.88 percent, the purity is very high, the preparation method is convenient and economic compared with the prior art, the three-waste pollution is small, the byproducts are few, and the catalyst is easy to obtain.
Claims (7)
1. A preparation method of 3, 5-dibromopyridine is characterized by comprising the following steps: pyridine is used as a raw material, concentrated sulfuric acid and thionyl chloride are used as catalysts, bromine is dropwise added under the high-temperature condition for reaction, and the method is obtained by the following specific steps:
(1) adding pyridine into concentrated sulfuric acid and thionyl chloride, and heating and refluxing;
(2) dropwise adding bromine under a reflux state, and heating to 125-138 ℃ for reaction;
(3) and (3) carrying out steam distillation on the reaction liquid, and separating out a crude product of the 3, 5-dibromopyridine in water.
2. The process according to claim 1 for preparing 3, 5-dibromopyridine, which is characterized in that: in the step (1), the mass ratio of the pyridine to the concentrated sulfuric acid to the thionyl chloride is 1:1 (2.5-3), and the mass fraction of the concentrated sulfuric acid is more than 98%.
3. The process according to claim 1 for preparing 3, 5-dibromopyridine, which is characterized in that: in the step (2), the dropping amount of bromine is 5-7 times of the mass of pyridine.
4. A process for producing 3, 5-dibromopyridine according to claim 1 or 3, characterized in that: and (3) dropwise adding bromine in the step (2) within 10-12 hours.
5. The process according to claim 4 for preparing 3, 5-dibromopyridine, which is characterized in that: the reflux temperature in step (2) was controlled at 130 ℃.
6. The process according to claim 1 for preparing 3, 5-dibromopyridine, which is characterized in that: and (4) recrystallizing and purifying the crude product of the 3, 5-dibromopyridine in the step (3) by using an alcoholic solution.
7. The process according to claim 6, wherein the reaction is carried out in the presence of a solvent selected from the group consisting of: the alcohol solution is methanol or ethanol solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810595342.0A CN108569999B (en) | 2018-06-11 | 2018-06-11 | Preparation method of 3, 5-dibromopyridine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810595342.0A CN108569999B (en) | 2018-06-11 | 2018-06-11 | Preparation method of 3, 5-dibromopyridine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108569999A CN108569999A (en) | 2018-09-25 |
| CN108569999B true CN108569999B (en) | 2020-05-05 |
Family
ID=63573123
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810595342.0A Active CN108569999B (en) | 2018-06-11 | 2018-06-11 | Preparation method of 3, 5-dibromopyridine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108569999B (en) |
-
2018
- 2018-06-11 CN CN201810595342.0A patent/CN108569999B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| Facile bromination of pyridine-type heterocycles at the b-position;Edward E. Garcia,等;《Journal of the American Chemical Society》;19600820;第82卷;第4430-4431页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108569999A (en) | 2018-09-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106905388B (en) | Method for synthesizing gastrodin | |
| TW201336806A (en) | Method for producing p-xylene and/or p-tolu aldehyde | |
| CN106588758A (en) | Synthetic process for 2-hydrazinylpyridine derivative | |
| CN114349674B (en) | Thiourea compound and preparation method thereof | |
| CN109232212B (en) | Method for synthesizing methyl heptenone from isopentenol | |
| CN108569999B (en) | Preparation method of 3, 5-dibromopyridine | |
| Hosokawa et al. | The first total synthesis and structural determination of TMC-66 | |
| CN106995362A (en) | The preparation method of seven fluorine cyclopentene | |
| CN102001934B (en) | Method for preparing 7-hydroxydehydroabietic acid | |
| CN110698352A (en) | Synthetic method of 3-bromo-5-aminocatechol dimethyl ether | |
| CN113354599B (en) | Preparation method of nintedanib key intermediate | |
| CN108675955B (en) | Preparation method of 2-amino-5 chloropyridine | |
| CN104059015A (en) | Method for synthesizing carbazole by fixed bed process | |
| CN103787908A (en) | Preparation method of para aminoacet anilide | |
| CN110028409B (en) | Polysubstituted naphthalene derivative and preparation method thereof | |
| CN109503473B (en) | Synthesis method of 2-methoxy-3-amino-5-pyridine boronic acid pinacol ester and intermediate thereof | |
| CN108191754B (en) | Preparation method of ortho-deuterated benzoic acid compound | |
| CN101797519B (en) | Application of fluoro-diphenyl sulfimide as nitrogen heterocyclic Diels-Alder reaction catalyst | |
| CN111302947A (en) | Synthetic method of 3, 5-dimethylaniline | |
| Ram et al. | Temperature and solvent dependent catalytic transfer hydrogenolysis in aromatic aldehydes and ketones via ammonium formate | |
| CN114315507B (en) | Process for preparing 1-chloro-3, 3, 3-trifluoropropene and/or Z-1, 3-dichloro-3, 3-difluoropropene | |
| CN105367396B (en) | A kind of synthetic method of naphthane ketone compounds | |
| CN110483388A (en) | A kind of preparation method of nicotinic acid derivates | |
| CN110002930B (en) | Method for hydrogenation reduction of alkenyl aromatic halogenated derivatives | |
| CN106316825A (en) | Preparing method for trans- 4- hydroxycyclohexanecarboxylic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |