CN114181036B - Preparation method of total deuterated bromobenzene - Google Patents
Preparation method of total deuterated bromobenzene Download PDFInfo
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Abstract
The invention relates to a preparation method of full deuterium bromobenzene. According to the method, hexabromobenzene is used as a raw material, deuterated ethanol is used as a deuterium source, pyridine is used as a solvent, metal zinc powder is used as a catalyst, alkali is used as an additive, and the number of deuterium on dehalogenation is accurately controlled, so that the full deuterated bromobenzene is successfully prepared. The isotope is utilized efficiently, and the aim of using expensive metal as a catalyst is avoided. The method is low in cost, high in efficiency and pollution-free, and has wide industrial production prospect. The deuterated bromobenzene can be used in the fields of organic photoelectricity, medicines, pesticides and the like.
Description
Technical Field
The invention relates to a method for synthesizing full deuterated bromobenzene, belonging to the technical field of chemical synthesis.
Background
As early as 60 th century, there was a report of research on deuterated compounds, which have higher bond energy, shorter bond length and lower vibration energy of bonds than C-H bonds. Whereby the lower ground state energy compound is more stable. So the deuterated material can be used in the fields of medicine, material, mass spectrum detection, gene detection and the like.
In the field of medicine, after hydrogen in a medicine molecule is replaced by deuterium, the metabolism circulation of the medicine can be prolonged, the generation of harmful metabolites can be reduced, and the interaction between medicines can be inhibited under the condition that the targeting of the medicine molecule is not changed. The use of deuterated compounds in the pharmaceutical field includes the following aspects: optimizing pharmacokinetic characteristics, reducing drug toxicity, increasing drug bioactivity, enhancing the stability of the three-dimensional structure of the drug, and assisting in elucidating the mechanism of action of the drug. In 2017, the first example of the global deuterated drug, ausedo, was approved by the us Food and Drug Administration (FDA) for marketing, which marks the FDA's recognition that deuterium has a different role in drug design than the common hydrogen element.
Deuterium plays an indispensable role in the field of electroluminescence. Generally, the deuterium modified material is widely applied to light emitting devices such as Organic Light Emitting Diodes (OLED) and thermally excited delayed fluorescence (TADF), and the service life and power efficiency of the light emitting devices are improved to different degrees.
The halogen-containing aromatic ring is a core raw material for preparing a plurality of complex aromatic medicaments and materials, and is widely applied to industries such as medicines, pesticides, dyes, photoelectric materials, synthetic resins and the like. In introducing deuterated aromatic ring structures onto existing structures, coupling reaction introduction is typically performed using perdeuterated bromobenzene.
The synthesis of existing perdeuterated bromobenzene can be divided into three categories, exemplified below:
first, expensive deuterated benzene is used as a raw material, and halogen atoms are introduced into a benzene ring through a conventional halogenation reaction. However, this method requires the use of expensive deuterated materials such as deuterated benzene, and the use of expensive elements such as bromine instead of expensive elements such as deuterium, which is expensive to produce.
Second, a halogen is introduced on deuterated benzene through the conversion of a functional group, thereby obtaining deuterated bromobenzene. However, the starting materials for this process need to be deuterated functionalized aromatic compounds, such as deuterated anilines, which are extremely costly and disadvantageous for large-scale production.
The third method is that the p-bromobenzene is directly deuterated through H/D exchange reaction. However, the method often causes the problems of low isotope utilization rate, great waste of expensive deuterated reagents, rearrangement and isomerization of a carbon skeleton, incapability of obtaining products with high deuteration rate and the like.
The existing synthetic methods of the full deuterated bromobenzene all face the problems of high production cost and low isotope utilization rate. And all have the problems of expensive catalyst and difficult production and supply.
Therefore, the development of a synthesis method of deuterated bromobenzene with mild, high-efficiency, economical and universal deuterium incorporation at high level has very important value and application prospect.
Disclosure of Invention
The invention aims to provide a preparation method of deuterated bromobenzene. In the method, hexabromobenzene is used as a raw material, deuterium is directly obtained by controlling dehalogenation and deuterium reaction, and controlling the dehalogenation number in the process. Thus solving the problems of complex synthesis process and high production cost of the existing deuterated bromobenzene.
In order to solve the technical problems, the technical scheme adopted by the invention is to provide a preparation method of full deuterated bromobenzene, which is characterized by comprising the following steps:
step one, adding hexabromobenzene, deuterated ethanol, pyridine and alkali into a reactor to obtain a mixed solution;
step two, preheating the mixed solution, adding a metal catalyst, heating and refluxing the mixed solution for reaction, and stirring for more than 8 hours;
step three, filtering the solution, collecting filtrate, and adding saturated ammonium chloride solution into the filtrate of the reactor for quenching;
and step four, adding a dichloromethane solvent into the reactor, and obtaining the full deuterated bromobenzene compound after extraction and rectification.
In one embodiment, the hexabromobenzene: deuterated ethanol: metal catalyst: pyridine: the molar ratio of the organic base is 1:5 (5-10): 24: (5-10).
In one embodiment, the metal catalyst is zinc metal.
In one embodiment, the metal catalyst is in the form of a powder of 200 to 500 mesh.
In an embodiment, the base is any one of potassium carbonate, cesium carbonate, potassium sulfate, potassium phosphate, DMAP, DBU, and tetramethyl diamine.
Advantageous effects
The application aims to develop a synthesis method of deuterated bromobenzene with mild, high-efficiency, economical and high-level deuterium incorporation.
Thus, the present application utilizes a metal zinc catalyzed dehalogenation reduction reaction to prepare perdeuterated bromobenzene by utilizing bromine/deuterium exchange by tightly controlling the dehalogenation degree. The deuterated ethanol is taken as a deuterium source, pyridine is taken as a solvent, zinc powder is taken as a catalyst, the deuteration rate of all products is above 98%, the use of expensive deuterium sources and expensive metal catalysts is avoided, the aim of economically and high-level deuterium incorporation is realized, the reaction can be completed in 80 ℃ for 8 hours, the reaction condition is simple, high-temperature and high-pressure experimental conditions are not needed in the reaction process, a toxic catalyst is not needed, and the method is suitable for industrial production.
Drawings
FIG. 1 is a nuclear magnetic characterization map of the perdeuterated bromobenzene compound prepared in example 1 of the present application.
FIG. 2 is a nuclear magnetic characterization map of the perdeuterated bromobenzene compound prepared in example 2 of the present application.
FIG. 3 is a nuclear magnetic characterization map of the perdeuterated bromobenzene compound prepared in example 3 of the present application.
FIG. 4 is a nuclear magnetic characterization map of the perdeuterated bromobenzene compound prepared in example 4 of the present application.
Detailed Description
The present invention is further illustrated below in conjunction with specific embodiments, it being understood that these embodiments are meant to be illustrative of the invention and not limiting the scope of the invention, and that modifications, equivalent to the various embodiments of the invention, will fall within the scope of the claims appended hereto, after reading the invention.
The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application. It will be apparent that the described embodiments are only some, but not all, of the embodiments of the present application. All other embodiments, which can be made by those skilled in the art based on the embodiments herein without making any inventive effort, are intended to be within the scope of the present application.
In one embodiment, a method for preparing perdeuterated bromobenzene is provided, wherein the synthesis reaction equation of the target compound in the reaction is as follows:
the method comprises the following steps:
step one, adding hexabromobenzene, deuterated ethanol, pyridine and alkali into a reactor to obtain a mixed solution;
step two, preheating the mixed solution, adding a metal catalyst, heating and refluxing the mixed solution for reaction, and stirring for more than 8 hours;
step three, filtering the solution, collecting filtrate, and adding saturated ammonium chloride solution into the filtrate of the reactor for quenching;
and step four, adding a dichloromethane solvent into the reactor, and obtaining the full deuterated bromobenzene compound after extraction and rectification.
In one embodiment, the hexabromobenzene: deuterated ethanol: metal catalyst: pyridine: the molar ratio of the organic base is 1:5 (5-10): 24: (5-10).
In one embodiment, the metal catalyst is zinc metal.
In one embodiment, the metal catalyst is in the form of a powder of 200 to 500 mesh.
In an embodiment, the base is any one of potassium carbonate, cesium carbonate, DMAP, DBU.
Example 1:
55g of hexabromobenzene, 26g of deuterated ethanol, 200mL of pyridine, 110g of potassium carbonate are added to a 1000mL four-necked flask at dry room temperature. The solution is stirred and heated to an internal temperature of 40 ℃, 33 g of 325 mesh zinc metal catalyst is slowly added, during the adding process, the reaction releases heat, and the feeding speed is controlled so that the internal temperature is not more than 60 ℃. After the metallic zinc catalyst was added, the reaction system was warmed to 80 ℃. The reaction was carried out for 8 hours. After the reaction was completed, the system was cooled to room temperature under stirring. Saturated ammonium chloride solution is added for quenching, diatomite is used for filtering, 100ml of dichloromethane is added for extraction, an organic phase is taken, the temperature of the solution is increased at a temperature increasing rate of 5 ℃ per minute, 13 g of full deuterated benzene is obtained, the product yield is 80%, and the deuteration rate is 99.22%. The nuclear magnetic characterization result of the prepared compound is shown in figure 1.
Example 2:
55g of hexabromobenzene, 26g of deuterated ethanol, 200mL of pyridine, 163g of cesium carbonate are added to a 1000mL four-necked flask at dry room temperature. The solution is stirred and heated to an internal temperature of 40 ℃, 33 g of 325 mesh zinc metal catalyst is slowly added, during the adding process, the reaction releases heat, and the feeding speed is controlled so that the internal temperature is not more than 60 ℃. After the metallic zinc catalyst was added, the reaction system was warmed to 80 ℃. The reaction was carried out for 8 hours. After the reaction was completed, the system was cooled to room temperature under stirring. Saturated ammonium chloride solution is added for quenching, diatomite is used for filtering, 100ml of dichloromethane is added for extraction, an organic phase is taken, the temperature of the solution is increased at a temperature increasing rate of 5 ℃ per minute, 13.8 g of full deuterated benzene is obtained, the product yield is 85%, and the deuteration rate is 99.50%. The nuclear magnetic characterization result of the prepared compound is shown in fig. 2.
Example 3:
55g of hexabromobenzene, 26g of deuterated ethanol, 100mL of pyridine, 122g of DMAP are added to a 1000mL four-necked flask at dry room temperature. The solution is stirred and heated to an internal temperature of 40 ℃, 33 g of 325 mesh zinc metal catalyst is slowly added, during the adding process, the reaction releases heat, and the feeding speed is controlled so that the internal temperature is not more than 60 ℃. After the metallic zinc catalyst was added, the reaction system was warmed to 80 ℃. The reaction was carried out for 8 hours. After the reaction was completed, the system was cooled to room temperature under stirring. Saturated ammonium chloride solution is added for quenching, diatomite is used for filtering, 100ml of dichloromethane is added for extraction, an organic phase is taken, the temperature of the solution is increased at a temperature increasing rate of 5 ℃ per minute, 14 g of full deuterated benzene is obtained, the product yield is 86%, and the deuteration rate is 99.44%. The nuclear magnetic characterization result of the prepared compound is shown in fig. 3.
Example 4:
55g of hexabromobenzene, 26g of deuterated ethanol, 100mL of pyridine, 152g of DBU are added to a 1000mL four-necked flask at dry room temperature. The solution is stirred and heated to an internal temperature of 40 ℃, 33 g of 325 mesh zinc metal catalyst is slowly added, during the adding process, the reaction releases heat, and the feeding speed is controlled so that the internal temperature is not more than 60 ℃. After the metallic zinc catalyst was added, the reaction system was warmed to 80 ℃. The reaction was carried out for 8 hours. After the reaction was completed, the system was cooled to room temperature under stirring. Adding saturated ammonium chloride solution for quenching, filtering by using diatomite, adding 100ml of dichloromethane into filtrate for extraction, taking an organic phase, heating the solution at a heating rate of 5 ℃ per minute, and taking a third fraction to obtain 12 g of total deuterated benzene, wherein the yield of the product is 74%, and the deuteration rate is 99.74%. The nuclear magnetic characterization result of the prepared compound is shown in fig. 4.
In the foregoing embodiments, the descriptions of the embodiments are emphasized, and for parts of one embodiment that are not described in detail, reference may be made to related descriptions of other embodiments.
The preparation method of the full deuterated bromobenzene provided by the embodiment of the application is described in detail, and specific examples are applied to illustrate the principle and the implementation mode of the application, and the description of the above examples is only used for helping to understand the technical scheme and the core idea of the application; those of ordinary skill in the art will appreciate that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the technical solutions of the embodiments of the present application
The foregoing is merely a preferred embodiment of the invention, and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (3)
1. The preparation method of the full deuterated bromobenzene is characterized by comprising the following steps:
step one, adding hexabromobenzene, deuterated ethanol, pyridine and any one of alkali of potassium carbonate, cesium carbonate, DMAP and DBU into a reactor to obtain a mixed solution;
step two, preheating the mixed solution, adding a metal catalyst, heating and refluxing the mixed solution for reaction, and stirring for more than 8 hours;
step three, filtering the solution, collecting filtrate, and adding saturated ammonium chloride solution into the filtrate of the reactor for quenching;
step four, adding a dichloromethane solvent into the reactor, and obtaining the full deuterated bromobenzene compound after extraction and rectification: wherein the metal catalyst is metallic zinc.
2. The method of manufacturing according to claim 1, characterized in that: the molar ratio of any one of hexabromobenzene, deuterated ethanol, metal catalyst, pyridine, potassium carbonate, cesium carbonate, DMAP and DBU is 1:5 (5-10): 24: (5-10).
3. The method of manufacturing according to claim 1, characterized in that: the metal catalyst is in a powder form with 200-500 meshes.
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| CN117510295B (en) * | 2024-01-08 | 2024-05-03 | 宁波萃英化学技术有限公司 | Preparation method of bromobenzene-d 5 |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB822617A (en) * | 1955-07-29 | 1959-10-28 | Ca Nat Research Council | Synthesis of deuterated and tritiated organic compounds |
| CN109180411A (en) * | 2018-10-08 | 2019-01-11 | 深圳大学 | A kind of photocatalysis fixed point deuterate new method of unsaturated carbon carbon bond |
| CN110054541A (en) * | 2019-05-16 | 2019-07-26 | 安徽秀朗新材料科技有限公司 | A kind of preparation method of deuterated aromatic compound |
| CN111592442A (en) * | 2020-05-19 | 2020-08-28 | 北京理工大学 | Preparation method of benzene-d 6 |
| CN111606774A (en) * | 2020-07-01 | 2020-09-01 | 云南民族大学 | Method for efficiently preparing styrene and deuterated styrene compounds |
| CN111635300A (en) * | 2020-07-01 | 2020-09-08 | 云南民族大学 | Method for preparing deuterated benzoin by using deuterium source as deuterium source |
| CN111646903A (en) * | 2020-06-19 | 2020-09-11 | 北京理工大学 | Fully deuterated 2, 4-dinitroanisole and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7863274B2 (en) * | 2005-07-29 | 2011-01-04 | Concert Pharmaceuticals Inc. | Deuterium enriched analogues of tadalafil as PDE5 inhibitors |
| CN102190616B (en) * | 2010-03-18 | 2015-07-29 | 苏州泽璟生物制药有限公司 | A kind of deuterated synthesis of ω-diphenyl urea and the Method and process of production |
| GB201316050D0 (en) * | 2013-09-10 | 2013-10-23 | Univ Swansea | Deuterated compounds |
-
2021
- 2021-12-17 CN CN202111549866.4A patent/CN114181036B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB822617A (en) * | 1955-07-29 | 1959-10-28 | Ca Nat Research Council | Synthesis of deuterated and tritiated organic compounds |
| CN109180411A (en) * | 2018-10-08 | 2019-01-11 | 深圳大学 | A kind of photocatalysis fixed point deuterate new method of unsaturated carbon carbon bond |
| CN110054541A (en) * | 2019-05-16 | 2019-07-26 | 安徽秀朗新材料科技有限公司 | A kind of preparation method of deuterated aromatic compound |
| CN111592442A (en) * | 2020-05-19 | 2020-08-28 | 北京理工大学 | Preparation method of benzene-d 6 |
| CN111646903A (en) * | 2020-06-19 | 2020-09-11 | 北京理工大学 | Fully deuterated 2, 4-dinitroanisole and preparation method thereof |
| CN111606774A (en) * | 2020-07-01 | 2020-09-01 | 云南民族大学 | Method for efficiently preparing styrene and deuterated styrene compounds |
| CN111635300A (en) * | 2020-07-01 | 2020-09-08 | 云南民族大学 | Method for preparing deuterated benzoin by using deuterium source as deuterium source |
Non-Patent Citations (1)
| Title |
|---|
| 新法氘代溴苯-d_5的合成与表征;张林等;《化学世界》(第02期);第19-22页 * |
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