Synthesis method of deuterated aniline based on in-situ hydrogen activation atom catalysis

Abstract

The invention relates to a method for synthesizing deuterated aniline based on in-situ hydrogen activation atom catalysis, which comprises the following steps: adding aniline and heavy water into a reaction container, taking Rh / C and Ni as catalysts, controlling the inert atmosphere in the reactor, adding lithium aluminum deuteride, heating and stirring to react, cooling, and separating the product to obtain aniline-D5. Compared with the prior art, the deuterated aniline can be synthesized in a high-yield and high-abundance mode, the synthesis reaction yield reaches 98% or above, the product isotope abundance reaches 99% atom% D or above, and the method has the advantages that the isotope utilization rate is high, and the product isotope abundance is high.

Description

Technical Field

[0001] The present invention belongs to the technical field of deuterated aniline, and relates to a method for synthesizing deuterated aniline based on in-situ hydrogen activation atom catalysis. Background Art

[0002] Deuterium (D) is a stable isotope of hydrogen (H). Due to the mass effect, the C-D bond has a shorter bond length and higher bond energy than the C-H bond. Deuterated compounds are widely used in fields such as medicine, environmental analysis and detection, and new material development.

[0003] In recent years, deuterated aniline, as a basic raw material in the synthesis of stable isotope deuterium-labeled reagents and a small molecule building block for the synthesis of deuterated drugs and deuterated display materials, has been widely used in cutting-edge disciplinary fields such as clinical diagnosis, special materials, and food safety, with characteristics such as large demand, high requirements for abundance and purity. Currently, the synthesis processes of deuterated aniline mainly include synthesis methods and exchange methods. The synthesis of deuterium-labeled aniline reported in current patents and literature mainly uses the exchange method. Among them, patents CN106892790B, CN117402030B, and the literature Organic Letters, 2008, 10(19): 4351-4353 disclose an exchange preparation method of deuterated aniline catalyzed by acids and bases. Using deuterium water as the deuterium source, hydrochloric acid, sulfuric acid, organic acids, bases, etc. are used to catalyze the exchange of aniline and deuterium water to prepare deuterated aniline; in these acid- and base-catalyzed hydrogen-deuterium exchange methods, due to the introduction of H atoms in the acids and bases, the stable isotope D abundance of the system will be reduced, and some acids such as hydrochloric acid are prone to react with aniline to generate amine hydrochlorides, reducing the yield and introducing impurities.

[0004] Patents CN103664642A, CN110054541B, and the literature Tetrahedron letters, 2005, 46(41): 6995-6998, Bulletin of the Chemical Society of Japan, 2008, 81(2): 278-286, Synlett, 2016, 27(17): 2467-2472 disclose a method for synthesizing deuterated aniline compounds by catalytic hydrogen activation of aniline compounds and deuterium water under the catalysis of catalysts such as platinum and / or palladium supported on a carrier and Al2O3; in such H2-activated metal-catalyzed hydrogen-deuterium exchange methods, the aniline-D5 catalyzed by the H2-activated catalyst also causes abundance dilution due to the introduction of H, and products with a D abundance above 99 atom% cannot be prepared.

[0005] The Journal of the American Chemical Society, 1999, 121(18): 4385 - 4396 reported a method for preparing deuterated aniline compounds by the exchange of aniline compounds with deuterium water catalyzed by a composite catalyst. However, this method focused on the description of the catalyst, and the deuterium abundance of the deuterated aniline mentioned was only 97 atom% D. Organometallics, 2012, 31(5): 1943 - 1952 reported a method for preparing deuterated aniline compounds by the exchange of aniline compounds with deuterium water catalyzed by a composite catalyst. However, this method also focused on the description of the catalyst, and the deuterium incorporation rate on the deuterated aniline ring mentioned was only 49 atom% D. Angewandte Chemie International Edition, 2022, 61(27): e202202423 reported a method for preparing deuterated aniline compounds by the exchange of aniline compounds with deuterium water catalyzed by a composite catalyst. The catalyst used was Mn / MnOx, and a biological complex was required as a medium. Summary of the Invention

[0006] The purpose of the present invention is to provide a method for synthesizing deuterated aniline based on in - situ hydrogen activation atomic catalysis, in order to overcome the problems in the existing hydrogen - deuterium exchange processes, such as the high cost of the synthesis method and the inability of the exchange method to prepare aniline - D5 with a deuterium abundance above 99 atom%.

[0007] The purpose of the present invention can be achieved by the following technical solutions:

[0008] A method for synthesizing deuterated aniline based on in - situ hydrogen activation atomic catalysis. Add aniline and heavy water into a reaction vessel, use Rh / C and Ni as catalysts, control the inside of the reactor to be an inert atmosphere, then add lithium aluminum deuteride, heat and stir the reaction, cool, and separate the product to obtain aniline - D5.

[0009] Further, the mass ratio of aniline to heavy water is 1:6 - 1:240, more preferably 1:16 - 1:120. Exemplarily, it can be 1:16, 1:60, 1:120, etc.

[0010] Further, the addition amount of the catalyst is 0.1 - 3 eq based on the addition amount of aniline, preferably 0.2 - 2 eq. Exemplarily, it can be 0.2 eq, 0.3 eq, 0.5 eq, 1 eq, etc.

[0011] Further, in the catalyst, the mass ratio of Rh / C to Ni is 1:2 - 2:1. Exemplarily, it can be 1:2, 1:1, or 2:1, etc.

[0012] Further, the addition amount of lithium aluminum deuteride is 1 - 6 eq based on aniline.

[0013] Furthermore, the temperature of the heating and stirring reaction is 60 - 140°C, and can be optionally 60°C, 80°C, 100°C, 120°C or 140°C, etc.

[0014] Furthermore, the pressure of the heating and stirring reaction is normal pressure.

[0015] Furthermore, the time of the heating and stirring reaction is 8 - 36 h.

[0016] Furthermore, the inert atmosphere is nitrogen or argon.

[0017] Furthermore, the process of separating the product is as follows:

[0018] Filter to remove the catalyst, extract with dichloromethane, dry the organic phase with anhydrous magnesium sulfate, then continue to filter and concentrate under vacuum to obtain the target product aniline-D5.

[0019] Furthermore, the number of times of extraction with dichloromethane is one or several times.

[0020] Compared with the prior art, in the present invention, by using lithium aluminum hydride rich in active deuterium, deuterium atoms are in-situ generated on the surface of the metal catalyst, so that the metal catalyst is fully activated. At the same time, by screening and combining and optimizing the metal catalyst, the catalytic effect is more thorough, and the utilization rate of deuterium isotope atoms is improved. Using Rh / C and Ni as the combined catalyst and lithium aluminum hydride as the catalyst activation hydrogen donor, the generated deuterium atoms promote the dehydrogenation of aniline on the surface of Rh / C and Ni, so that the deuterium atoms generated from the deuterium source heavy water are fully exchanged with the hydrogen atoms after aniline dehydrogenation. By controlling the addition amount of the deuterium source heavy water, the hydrogen-deuterium exchange equilibrium reaction proceeds as a forward reaction, and the deuterium atom abundance of the product is increased as much as possible, so that the reaction yield can reach more than 98% at most, and the deuterium atom abundance reaches 99 atom% D. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is the synthesis reaction diagram of the deuterated aniline of the present invention;

[0022] Figures 2 to 4 They are the isotope mass spectra of deuterium-labeled aniline obtained in Example 2, Example 3 and Example 4 respectively;

[0023] Figure 5 It is the isotope mass spectrum of deuterium-labeled aniline obtained in Comparative Example 1;

[0024] Figure 6 It is the isotope mass spectrum of deuterium-labeled aniline obtained in Comparative Example 2;

[0025] Figure 7 It is the isotope mass spectrum of deuterium-labeled aniline obtained in Comparative Example 3;

[0026] Figure 8 Isotope mass spectrum of deuterium-labeled aniline obtained in Comparative Example 4;

[0027] Figure 9 Isotope mass spectrum of deuterium-labeled aniline obtained in Comparative Example 5. Specific Embodiments

[0028] The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments. These embodiments are implemented on the premise of the technical solution of the present invention, and detailed implementation manners and specific operation processes are given. However, the protection scope of the present invention is not limited to the following embodiments.

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which this application belongs. The terms used in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0030] The term "and / or", "or / and", "and / or" used herein includes any one of two or more related listed items, and also includes any and all combinations of the related listed items. The said any and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least two conjunctions selected from "and / or", "or / and", "and / or" are used to connect at least three items, it should be understood that in this application, this technical solution undoubtedly includes the technical solution connected by "logical AND", and also undoubtedly includes the technical solution connected by "logical OR".

[0031] In this application, among the technical features described in an open-ended manner, it includes a closed technical solution composed of the listed features, and also includes an open technical solution containing the listed features.

[0032] In this application, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are considered continuous and include the minimum and maximum values of this range, as well as each value between such minimum and maximum values. Further, when the range refers to an integer, it includes each integer between the minimum and maximum values of this range. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0033] This document specifically discloses only some numerical ranges. However, any lower limit can be combined with any upper limit to form a range not explicitly recited; and any lower limit can be combined with other lower limits to form a range not explicitly recited, and similarly any upper limit can be combined with any other upper limit to form a range not explicitly recited. In addition, each individually disclosed point or single numerical value itself can serve as a lower limit or upper limit and be combined with any other point or single numerical value or with other lower limits or upper limits to form a range not explicitly recited.

[0034] In this application, the temperature parameter, unless otherwise specifically defined, allows both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuations within ranges such as ±5°C, ±4°C, ±3°C, ±2°C, ±1°C are allowed.

[0035] In this document, the "suitable combination method", "suitable method", "any suitable method", etc., the "suitable" mentioned therein is subject to being able to implement the technical solution of this application, solve the technical problems of this application, and achieve the expected technical effects of this application.

[0036] In this application, "further", "even further", "especially", etc. are used for descriptive purposes and indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0037] In this application, "optionally", "optional", "option", mean optional, that is, it refers to any one of the two alternative schemes of "yes" or "no". If "optional" appears multiple times in a technical solution, unless otherwise specifically stated and there are no contradictions or mutual restrictions, each "optional" is independent.

[0038] In the description of the application, the meaning of "a variety of" is at least two, such as two, three, etc., unless otherwise specifically and clearly defined.

[0039] Unless otherwise specified, all formulations and tests occur in an environment of 25°C in this document.

[0040] In this document, "comprises", "includes", "contains", "has" or other variants are intended to cover non-closed inclusion, and no distinction is made between these terms. The term "contains" means that other steps and components can be added without affecting the final result. The compositions and methods / processes of the present invention contain, consist of, and consist essentially of the essential elements and limitations described herein and any additional or optional components, ingredients, steps, or limitations described herein. In this document, no distinction is made between the terms "efficacy", "performance", "effect", "efficiency".

[0041] Unless otherwise specified, all embodiments and optional embodiments of this application can be combined with each other to form new technical solutions. Unless otherwise specified, all technical features and optional technical features of this application can be combined with each other to form new technical solutions.

[0042] Unless otherwise specified, all steps of this application can be carried out sequentially or randomly, and preferably sequentially.

[0043] In the following examples, the Rh / C used was directly purchased from Shanghai Titan Scientific Co., Ltd.; the Ni used was nickel metal powder with a mesh number of 800, purchased from Shanghai Titan Scientific Co., Ltd.

[0044] For the remaining raw materials or processing techniques without special instructions, it indicates that they are all conventional commercially available raw materials or conventional processing techniques in the art.

[0045] Example 1:

[0046] Into a three-necked flask equipped with a stirring device and a reflux device, 1 g of aniline, 0.1 g of Rh / C, 0.1 g of Ni, and 16 g of heavy water were added in sequence. After evacuating, the gas in the reaction flask was replaced with nitrogen, and then 2 g of lithium aluminum deuteride was added. The mixture was stirred and reacted at 80 °C for 12 h, cooled to room temperature, the catalyst was filtered off, the organic phase was extracted three times with 10 mL of dichloromethane, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to obtain the product aniline-D5. After detection by isotope mass spectrometry, the abundance was 99.2 atom% D and the yield was 98.1%.

[0047] Example 2:

[0048] Compared with Example 1, most of them were the same, except that the amounts of Rh / C and Ni added were 0.1 g and 0.2 g respectively, and 0.89 g of deuterium-labeled aniline was prepared. After detection by isotope mass spectrometry, the abundance was 99.1 atom% D and the calculated yield was 84.5%.

[0049] Example 3:

[0050] Compared with Example 1, most of them were the same, except that the amounts of Rh / C and Ni added were 0.2 g and 0.1 g respectively, and 0.92 g of deuterium-labeled aniline was prepared. After detection by isotope mass spectrometry, the abundance was 99.2 atom% D and the calculated yield was 87.3%.

[0051] Example 4:

[0052] Compared with Example 1, most of them were the same, except that 3 g of lithium aluminum deuteride was added, and 0.96 g of deuterium-labeled aniline was prepared. After detection by isotope mass spectrometry, the abundance was 99.2 atom% D and the calculated yield was 91.1%.

[0053] Example 5:

[0054] Compared with Example 1, most of them are the same, except that the reaction temperature is 100 °C, 0.92 g of deuterium-labeled aniline is prepared, and the abundance is 99.0 atom% D after detection by isotope mass spectrometry, and the yield is calculated to be 87.3%.

[0055] Example 6:

[0056] Compared with Example 1, most of them are the same, except that the mass of heavy water added is 50 g, 0.85 g of deuterium-labeled aniline is prepared, and the abundance is 99.1 atom% D after detection by isotope mass spectrometry, and the yield is calculated to be 80.7%.

[0057] Example 7:

[0058] Compared with Example 1, most of them are the same, except that the mass of heavy water added is 100 g, 0.83 g of deuterium-labeled aniline is prepared, and the abundance is 99.2 atom% D after detection by isotope mass spectrometry, and the yield is calculated to be 78.8%.

[0059] Example 8:

[0060] Compared with Example 1, most of them are the same, except that the mass of heavy water added is 150 g, 0.81 g of deuterium-labeled aniline is prepared, and the abundance is 99.4 atom% D after detection by isotope mass spectrometry, and the yield is calculated to be 76.9%.

[0061] Example 9:

[0062] Compared with Example 1, most of them are the same, except that the reaction time is 24 h, 0.96 g of deuterium-labeled aniline is prepared, and the abundance is 99.1 atom% D after detection by isotope mass spectrometry, and the yield is calculated to be 91.1%.

[0063] Comparative Example 1:

[0064] Compared with Example 1, most of them are the same, except that the addition of lithium aluminum deuteride is omitted, and the abundance of the prepared deuterium-labeled aniline is 3.4 atom% D after detection by isotope mass spectrometry.

[0065] Comparative Example 2:

[0066] Compared with Example 1, most of them are the same, except that the catalyst is changed to the same mass of Ni, and the abundance of the prepared deuterium-labeled aniline is 78.71 atom% D after detection by isotope mass spectrometry.

[0067] Comparative Example 3:

[0068] Compared with Example 1, most of them are the same, except that the catalyst is changed to Rh / C with the same mass. After the deuterium-labeled aniline is prepared and detected by isotope mass spectrometry, the abundance is 84.64 atom%D.

[0069] Comparative Example 4:

[0070] Compared with Example 1, most of them are the same, except that the catalyst is changed to Pd / C and Ni with the same mass. After the deuterium-labeled aniline is prepared and detected by isotope mass spectrometry, the abundance is 64.54 atom%D.

[0071] Comparative Example 5:

[0072] Compared with Example 1, most of them are the same, except that the catalysts Rh / C and Ni are replaced with the conventional composite catalyst Mn / MnO2. After the deuterium-labeled aniline is prepared and detected by isotope mass spectrometry, the abundance is 26.03 atom%D.

[0073] Comparative Example 6:

[0074] Compared with Example 1, most of them are the same, except that lithium aluminum deuteride is changed to lithium aluminum hydride with an equimolar amount. At this time, due to the incorporation of hydrogen atoms in lithium aluminum hydride, the deuterium abundance of the whole system is diluted, resulting in a decrease in the final abundance of the product deuterated aniline.

[0075] Combined with the above content, it can be seen that the in-situ hydrogen production activation exchange process based on lithium aluminum deuteride rich in active deuterium provided by the present invention can synthesize deuterated aniline with high yield and high abundance. The yield of the synthesis reaction reaches more than 98%, and the isotope abundance of the product reaches more than 99 atom%D, having the advantages of high isotope utilization rate and high isotope abundance of the product.

[0076] The above description of the embodiments is for those of ordinary skill in the art to understand and use the invention. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative labor. Therefore, the present invention is not limited to the above embodiments, and the improvements and modifications made by those skilled in the art without departing from the scope of the present invention should be within the protection scope of the present invention.

Claims

1. A method for synthesizing deuterated aniline based on in-situ hydrogen-activated atom catalysis, characterized in that, Aniline and heavy water are added into a reaction vessel. Using Rh / C and Ni as catalysts, an inert atmosphere is maintained in the reactor, and then lithium aluminum deuteride is added. The reaction is carried out with heating and stirring, cooled, and the product is separated to obtain aniline-D5.

2. The synthesis method of deuterated aniline based on in-situ hydrogen activation atomic catalysis according to claim 1, wherein The mass ratio of aniline to heavy water is 1:6 to 1:

240.

3. The synthesis method of deuterated aniline based on in-situ hydrogen-activated atom catalysis according to claim 1, wherein The addition amount of the catalyst is 0.1 to 3 eq based on the addition amount of aniline.

4. The synthesis method of deuterated aniline based on in-situ hydrogen-activated atom catalysis according to claim 1, characterized in that, In the catalyst, the mass ratio of Rh / C to Ni is 1:2 to 2:

1.

5. The synthesis method of deuterated aniline based on in-situ hydrogen-activated atom catalysis according to claim 1, wherein, The addition amount of lithium aluminum deuteride is 1 to 6 eq based on aniline.

6. The synthesis method of deuterated aniline based on in-situ hydrogen activation atom catalysis according to claim 1, wherein The temperature for the reaction with heating and stirring is 60 to 140 °C.

7. The synthesis method of deuterated aniline based on in-situ hydrogen activation atom catalysis according to claim 1, wherein The time for the reaction with heating and stirring is 8 to 36 h.

8. A method for synthesizing deuterated aniline based on in-situ hydrogen-activated atomic catalysis according to claim 1, characterized in that, The inert atmosphere is nitrogen or argon.

9. The synthesis method of deuterated aniline based on in-situ hydrogen-activated atom catalysis according to claim 1, characterized in that The process for separating the product is as follows: The catalyst is removed by filtration, the organic phase is extracted with dichloromethane, and the organic phase is dried with anhydrous magnesium sulfate. Then, filtration and vacuum concentration are continued to obtain the target product aniline-D5.

10. A method for synthesizing deuterated aniline based on in-situ hydrogen-activated atom catalysis according to claim 9, characterized in that, The number of times of extraction with dichloromethane is one or several times.

Images