Direct continuous deuteration method of perdeuterated 9-bromoanthracene

Abstract

The invention relates to the field of organic synthesis, and discloses a continuous deuteration preparation method of perdeuterated 9-bromoanthracene. The method comprises the following steps: taking 9-bromoanthracene and a deuterium source as raw materials, reacting under the protection of inert gas and under the catalysis conditions of a solvent and a catalyst, collecting an effluent reaction solution, filtering, and recrystallizing to obtain the perdeuterium 9-bromoanthracene. According to the invention, through catalytic continuous fluid pipeline reaction, 9-bromoanthracene is taken as a raw material, through hydrogen-deuterium exchange with heavy water, the problems of high production cost and complex process in the synthesis of perdeuterated 9-bromoanthracene are solved, the reaction conditions are mild, continuous deuteration is completed at a high level by supplementing deuterium water for multiple times in the reaction process, and the yield of perdeuterated 9-bromoanthracene is increased. The conversion rate and the yield are greatly improved. The whole process is mild in reaction condition, relatively simple and convenient to operate and beneficial to industrial large-scale production.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and more particularly to a direct and continuous deuteration method for perdeuterated 9-bromoanthracene. Background Art

[0002] Since hydrogen atoms in biological molecules or material molecules are replaced by deuterium atoms, the physical and biological properties of the original molecules can be significantly changed. Therefore, deuterated compounds are widely used in pharmaceutical science, material science, biological science, organic identification and other fields. In the field of pharmaceutical design, studies have found that the activity of drug molecules remains basically unchanged when some hydrogen atoms in drug molecules are replaced by deuterium atoms. At the same time, replacing hydrogen with deuterium can reduce the drug metabolism rate, thereby achieving the advantages of reducing the dosage and frequency of taking drugs and reducing drug toxicity. In the field of material science, after hydrogen in organic electroluminescent element compounds is replaced by deuterium, carbon-deuterium bonds have significantly smaller stretching vibrations and bending vibrations than carbon-hydrogen bonds. These factors have significantly improved the parameters such as the element life and luminous efficiency of deuterated materials.

[0003] 9-Bromoanthracene is a key intermediate frequently used in drug development, chemical engineering and optoelectronic materials. It is one of the core building blocks of organic synthesis. A series of functional group derivatizations can be achieved through it. Therefore, a series of deuterated organic compounds can be further derived using fully deuterated 9-bromoanthracene as a substrate.

[0004] At present, the research on the deuteration of aromatic rings of aromatic derivatives is still in its infancy. There are not many reports on the synthesis methods of deuterated 9-bromoanthracene. Most of them are based on classical organic reactions, using perdeuterated anthracene as the parent and NBS as the bromine source for bromination (US2020 / 111965, WO2023 / 96387, etc.), and perdeuterated anthracene is expensive. It is mainly synthesized by exchanging hydrogen and deuterium with deuterated substances under high temperature and high pressure conditions. Werstiuk Nick Henry et al. first reported the synthesis of perdeuterated anthracene in the Canadian Journal of Chemistry in 1981. They used heavy water as the deuterium source and deuterated hydrochloric acid as the catalyzer, and achieved the synthesis of perdeuterated 9-bromoanthracene at 250°C for 50 hours. In 1999, Boix Carmen et al. published an article in Tetrahedron Letters, using heavy water as a deuterium source, polymer-supported sulfonic acid catalysis, 325°C and high pressure conditions, and reacting for 24 hours to achieve the deuterated synthesis from anthracene to perdeuterated anthracene. These reactions have high temperatures and harsh deuteration conditions. In 2023, Yun Seo Jin et al. developed a series of PzPyOH ligands for Pd-catalyzed perdeuteration of aromatics. In this system, the 2-pyridone moiety is used as an internal base to activate CH, even for challenging sp2 CH bonds, thereby achieving perdeuteration of aromatics. Although the system does not require particularly high temperatures (system deuteration temperature 120°C), the special ligands, expensive metal palladium catalysts, and deuterated acetic acid solvents still limit the promotion of its industrial production.

[0005] In 2022, Ningbo Cuiying Chemical Technology Co., Ltd. published a patent (CN114853557), which uses aromatic compounds as raw materials and heavy water as a deuterium source. Under the action of polyfluoroanhydride, the preparation of deuterated products of aromatic compounds is achieved at 100°C–250°C. Perdeuterated anthracene and perdeuterated 9-bromoanthracene are prepared under this condition, requiring a high temperature of 220°C and 5 deuterations to achieve a better deuteration. The deuteration temperature under this condition is high and the reaction time is long. In order to achieve a better deuteration effect, the deuteration needs to be repeated several times. Therefore, the development of a new synthesis method for perdeuterated 9-bromoanthracene is of great significance to the industrial production of perdeuterated 9-bromoanthracene. Summary of the invention

[0006] In order to solve the above technical problems, the present invention overcomes the shortcomings of the prior art, independently develops, designs and manufactures automated synthesis control equipment, and provides a continuous deuterated preparation method for fully deuterated 9-bromoanthracene, which has relatively mild reaction conditions, simple operation, high deuteration degree and high product yield.

[0007] To realize the present invention, the synthetic route of fully deuterated 9-bromoanthracene is:

[0008]

[0009] The perdeuterated 9-bromoanthracene obtained by the invention is a light yellow solid, with a yield greater than 91% and a deuteration degree greater than 99%.

[0010] The present application provides a fully automated synthesis control device, which specifically adopts the following scheme:

[0011] A fully automatic synthesis control device, comprising:

[0012] Injector;

[0013] A circulating heating device, connected to the pipeline reactor, comprising a heater and a circulating pump, for heating the reaction;

[0014] The pipeline reactor is connected to the sample injector and comprises 10 pipeline reaction units connected in series. The front ends of the catalyst units from the second to the last of the continuous pipeline reaction units are connected to the deuterium source supplement pipeline.

[0015] The present application provides a method for preparing perdeuterated 9-bromoanthracene by continuous deuteration, comprising the following steps:

[0016] 9-bromoanthracene and a deuterium source are used as raw materials, and a reaction is carried out under the catalytic conditions of a solvent and a catalyst. The reaction liquid flowing out is collected, filtered, and recrystallized to obtain fully deuterated 9-bromoanthracene. The reaction route is as follows:

[0017]

[0018] Further optionally, the method specifically comprises the following steps:

[0019] The metal catalyst is loaded into the reactor, and in an inert gas atmosphere, circulating heating is started to preheat the reactor to the reaction temperature;

[0020] Mix 9-bromoanthracene, deuterium source and solvent evenly, and pump them into the preheated reactor at a certain flow rate for reaction, while slowly pumping the deuterium source into the reaction system;

[0021] The reaction solution was collected, filtered, and recrystallized to obtain fully deuterated 9-bromoanthracene.

[0022] Optionally, the metal catalyst can be any one or two of Fe, Ni, Co, Pt, Pd, Ir, Mo, and Cu, or a nano alloy of any two of them, or any one or two of the metal salts supported by a carrier.

[0023] Optionally, the inert gas is nitrogen or argon.

[0024] Optionally, the reaction temperature is 60-120°C, preferably 70-90°C.

[0025] Optionally, the initial mixing ratio (molar ratio) of the 9-bromoanthracene, the deuterium source and the solvent is 1:(5-10):(5-10).

[0026] Optionally, the organic solvent may be any one or more of 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide.

[0027] Optionally, the reaction flow rate is 0.5-10 mL / min, preferably 1-5 mL / min.

[0028] Optionally, the deuterium supplement source is pumped in at a flow rate of 0.1-5 mL / min, preferably 0.2-1 mL / min.

[0029] Optionally, the deuterium source reagent is selected from one or two of heavy water, deuterated methanol, deuterated ethanol, deuterated isopropanol, and deuterated benzene.

[0030] In summary, this application has the following beneficial effects:

[0031] The present invention uses 9-bromoanthracene as a raw material through a catalytic continuous fluid pipeline reaction, and solves the problems of high production cost and complicated process of fully deuterated 9-bromoanthracene synthesis by hydrogen-deuterium exchange with heavy water. In addition, the reaction conditions are mild, and deuterated water is supplemented repeatedly during the reaction process for continuous deuteration, so that deuteration is completed at a high level, and both the conversion rate and the yield are greatly improved. The reaction conditions of the whole process are mild, the operation is relatively simple, and it is conducive to realizing industrial large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 : Schematic diagram of the reaction process and device of the embodiment of the present application. DETAILED DESCRIPTION

[0033] The structure and effect of the present application are further described in detail below in conjunction with the embodiments. It is to be understood that the specific embodiments described herein are only used to explain the invention, rather than to limit the invention. It is also necessary to explain that, for ease of description, only the parts related to the invention rather than the entire structure are shown in the accompanying drawings.

[0034] Example 1

[0035] This embodiment discloses a fully automated synthesis control device, referring to Figure 1 , the fully automated synthesis control equipment comprises:

[0036] Injector;

[0037] A circulating heating device, connected to the pipeline reactor, comprising a heater and a circulating pump, for heating the reaction;

[0038] The pipeline reactor is connected to the sample injector and comprises 10 pipeline reaction units connected in series. The front ends of the catalyst units from the second to the last of the continuous pipeline reaction units are connected to the deuterium source supplement pipeline.

[0039] Example 2

[0040] This embodiment discloses a method for preparing perdeuterated 9-bromoanthracene by continuous deuteration, comprising the following steps:

[0041] 9-bromoanthracene and a deuterium source are used as raw materials, and a reaction is carried out under the catalytic conditions of a solvent and a catalyst. The reaction liquid flowing out is collected, filtered, and recrystallized to obtain fully deuterated 9-bromoanthracene. The reaction route is as follows:

[0042]

[0043] The method specifically comprises the following steps:

[0044] The iron powder loaded with molecular sieve is filled in the catalyst unit of the pipeline reactor, and the circulating heating device is started under a nitrogen atmosphere to preheat the pipeline to 80°C. During the preheating period, 9-bromoanthracene (100.0g, 0.39mol, 1 equivalent), heavy water (38.9g, 1.9mol, 5 equivalents) and dimethyl sulfoxide (152g, 1.9mol, 5 equivalents) are stirred and mixed evenly. After the pipeline temperature is reached, the reaction material is pumped into the continuous pipeline reactor through the injector at a flow rate of 3mL / min, and heavy water is supplemented and pumped into the pipeline system at a flow rate of 0.5mL / min. The reaction solution flowing out is collected at the outlet of the continuous reactor, cooled, filtered, and the filter cake is recrystallized to obtain 95g of fully deuterated 9-bromoanthracene, and low-purity deuterated water can be recovered. The yield of fully deuterated 9-bromoanthracene is 91.8%, and the degree of deuteration is 99.15%.

[0045] Example 3

[0046] This embodiment discloses a method for preparing perdeuterated 9-bromoanthracene by continuous deuteration, comprising the following steps:

[0047] 9-bromoanthracene and a deuterium source are used as raw materials, and a reaction is carried out under the catalytic conditions of a solvent and a catalyst. The reaction liquid flowing out is collected, filtered, and recrystallized to obtain fully deuterated 9-bromoanthracene. The reaction route is as follows:

[0048]

[0049] The method specifically comprises the following steps:

[0050] The iron powder loaded with molecular sieve is filled in the catalyst unit of the pipeline reactor, and the circulating heating device is started under a nitrogen atmosphere to preheat the pipeline to 80°C. During the preheating period, 9-bromoanthracene (100.0g, 0.39mol, 1 equivalent), heavy water (62.2g, 3.04mol, 8 equivalents) and dimethyl sulfoxide (243.2g, 3.04mol, 8 equivalents) are stirred and mixed evenly. After the pipeline temperature is reached, the reaction material is pumped into the continuous pipeline reactor through the injector at a flow rate of 3mL / min, and heavy water is supplemented and pumped into the pipeline system at a flow rate of 0.5mL / min. The reaction solution flowing out is collected at the outlet of the continuous reactor, cooled, filtered, and the filter cake is recrystallized to obtain 95.2g of fully deuterated 9-bromoanthracene, and low-purity deuterated water can be recovered. The yield of fully deuterated 9-bromoanthracene is 92%, and the degree of deuteration is 99.22%.

[0051] Example 4

[0052] This embodiment discloses a method for preparing perdeuterated 9-bromoanthracene by continuous deuteration, comprising the following steps:

[0053] 9-bromoanthracene and a deuterium source are used as raw materials, and a reaction is carried out under the catalytic conditions of a solvent and a catalyst. The reaction liquid flowing out is collected, filtered, and recrystallized to obtain fully deuterated 9-bromoanthracene. The reaction route is as follows:

[0054]

[0055] The method specifically comprises the following steps:

[0056] The iron powder loaded with molecular sieve is filled in the catalyst unit of the pipeline reactor. Under nitrogen atmosphere, the circulating heating device is started to preheat the pipeline to 80°C. During the preheating period, 9-bromoanthracene (100.0g, 0.39mol, 1 equivalent), heavy water (77.8g, 3.8mol, 10 equivalents) and dimethyl sulfoxide (304g, 3.8mol, 10 equivalents) are stirred and mixed evenly. After the pipeline temperature is reached, the reaction material is pumped into the continuous pipeline reactor through the injector at a flow rate of 3mL / min, and heavy water is supplemented and pumped into the pipeline system at a flow rate of 0.5mL / min. The reaction solution flowing out is collected at the outlet of the continuous reactor, cooled, filtered, and the filter cake is recrystallized to obtain 94.3g of fully deuterated 9-bromoanthracene, and low-purity deuterated water can be recovered. The yield of fully deuterated 9-bromoanthracene is 91.1%, and the degree of deuteration is 99.25%.

[0057] Example 5

[0058] This embodiment discloses a method for preparing perdeuterated 9-bromoanthracene by continuous deuteration, comprising the following steps:

[0059] 9-bromoanthracene and a deuterium source are used as raw materials, and a reaction is carried out under the catalytic conditions of a solvent and a catalyst. The reaction liquid flowing out is collected, filtered, and recrystallized to obtain fully deuterated 9-bromoanthracene. The reaction route is as follows:

[0060]

[0061] The method specifically comprises the following steps:

[0062] The iron powder loaded with molecular sieve is filled in the catalyst unit of the pipeline reactor, and the circulating heating device is started under a nitrogen atmosphere to preheat the pipeline to 70°C. During the preheating period, 9-bromoanthracene (100.0g, 0.39mol, 1 equivalent), heavy water (38.9g, 1.9mol, 5 equivalents) and dimethyl sulfoxide (152g, 1.9mol, 5 equivalents) are stirred and mixed evenly. After the pipeline temperature is reached, the reaction material is pumped into the continuous pipeline reactor through the injector at a flow rate of 1mL / min, and heavy water is supplemented and pumped into the pipeline system at a flow rate of 0.2mL / min. The reaction solution flowing out is collected at the outlet of the continuous reactor, cooled, filtered, and the filter cake is recrystallized to obtain 94.2g of fully deuterated 9-bromoanthracene, and low-purity deuterated water can be recovered. The yield of fully deuterated 9-bromoanthracene is 91%, and the degree of deuteration is 98.3%.

[0063] Example 6

[0064] This embodiment discloses a method for preparing perdeuterated 9-bromoanthracene by continuous deuteration, comprising the following steps:

[0065] 9-bromoanthracene and a deuterium source are used as raw materials, and a reaction is carried out under the catalytic conditions of a solvent and a catalyst. The reaction liquid flowing out is collected, filtered, and recrystallized to obtain fully deuterated 9-bromoanthracene. The reaction route is as follows:

[0066]

[0067] The method specifically comprises the following steps:

[0068] The iron powder loaded with molecular sieve is filled in the catalyst unit of the pipeline reactor. Under nitrogen atmosphere, the circulating heating device is started to preheat the pipeline to 90°C. During the preheating period, 9-bromoanthracene (100.0g, 0.39mol, 1 equivalent), heavy water (38.9g, 1.9mol, 5 equivalents) and dimethyl sulfoxide (152g, 1.9mol, 5 equivalents) are stirred and mixed evenly. After the pipeline temperature is reached, the reaction material is pumped into the continuous pipeline reactor through the injector at a flow rate of 5mL / min, and heavy water is supplemented and pumped into the pipeline system at a flow rate of 1mL / min. The reaction solution flowing out is collected at the outlet of the continuous reactor, cooled, filtered, and the filter cake is recrystallized to obtain 94.3g of fully deuterated 9-bromoanthracene, and low-purity deuterated water can be recovered. The yield of fully deuterated 9-bromoanthracene is 91.1%, and the degree of deuteration is 99.1%.

[0069] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. A method for preparing perdeuterated 9-bromoanthracene by continuous deuteration, characterized in that: The following steps are involved: 9-bromoanthracene and a deuterium source are used as raw materials, and a reaction is carried out under an inert gas atmosphere and under the catalytic conditions of a solvent and a catalyst. The reaction liquid flowing out is collected, filtered, and recrystallized to obtain fully deuterated 9-bromoanthracene. The reaction route is as follows:

2. The method for preparing the perdeuterated 9-bromoanthracene according to claim 1, characterized in that: The method specifically comprises the following steps: Load the metal catalyst into the reactor, start the circulating heating, and preheat the reactor to the reaction temperature; Mix 9-bromoanthracene, deuterium source and solvent evenly, and pump them into the preheated reactor at a certain flow rate for reaction, while slowly pumping the deuterium source into the reaction system; The reaction solution was collected, filtered, and recrystallized to obtain fully deuterated 9-bromoanthracene.

3. The method for preparing the perdeuterated 9-bromoanthracene according to claim 1 by continuous deuteration according to claim 2, characterized in that: The metal catalyst can be any one or two of Fe, Ni, Co, Pt, Pd, Ir, Mo, and Cu, or a nano alloy of any two of them, or any one or two of the metal salts supported by a carrier.

4. The method for preparing the perdeuterated 9-bromoanthracene according to claim 1 by continuous deuteration according to claim 2, characterized in that: The inert gas is nitrogen or argon.

5. The method for preparing the perdeuterated 9-bromoanthracene according to claim 2, characterized in that: The reaction temperature is 60-120°C, preferably 70-90°C.

6. The method for preparing the perdeuterated 9-bromoanthracene according to claim 1 by continuous deuteration according to claim 2, characterized in that: The initial mixing ratio (molar ratio) of the 9-bromoanthracene, the deuterium source and the solvent is 1:(5-10):(5-10).

7. The method for preparing the perdeuterated 9-bromoanthracene according to claim 1 by continuous deuteration according to claim 2, characterized in that: The organic solvent may be any one or more of 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide.

8. The method for preparing the perdeuterated 9-bromoanthracene according to claim 1 by continuous deuteration according to claim 2, characterized in that: The reaction flow rate is 0.5-10 mL / min, preferably 1-5 mL / min.

9. The method for preparing the perdeuterated 9-bromoanthracene according to claim 1 by continuous deuteration according to claim 2, characterized in that: The pumping flow rate of the supplementary deuterium source is 0.1-5 mL / min, preferably 0.2-1 mL / min.

10. The method for preparing the perdeuterated 9-bromoanthracene according to claim 1 by continuous deuteration according to claim 2, characterized in that: The deuterium source reagent is selected from one or two of heavy water, deuterated methanol, deuterated ethanol, deuterated isopropanol, and deuterated benzene.

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