Preparation method of deuterated arylamine compound
Deuterated is achieved on the C-H bond of the arylamine compound through direct hydrogen-deuterium exchange reaction, and the use of cheap deuterium water and commercial catalysts, which solves the problems of multi-step synthesis and expensive deuterium source, and achieves efficient and low-cost preparation of deuterated arylamine compounds, which is applied in the pharmaceutical and optoelectronic fields.
Patent Information
- Application Number
- CN202410345403.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-03-25
- Publication Date
- 2025-08-12
AI Technical Summary
In the prior art, the synthesis of deuterated arylamine compounds requires multiple steps, and there are many by-products and low final yields, which is a problem of using expensive deuterium sources.
Deuterated is achieved on the C-H bond of the arylamine compound through direct hydrogen-deuterium exchange reaction under the atmosphere of an atmosphere of metal catalysts and reducing gas. Inexpensive deuterium water is used as the deuterium source, and commercially available catalysts such as palladium acetate, palladium carbon, and platinum carbon are selected to simplify the reaction steps.
The high conversion rate and high selectivity of deuterated arylamine compounds are achieved, the reaction steps are simplified, and the cost is reduced. The prepared deuterated arylamine compounds can be used for pharmaceutical intermediates, photoelectric intermediates and isotope labeling.
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Figure CN120463573A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of preparing deuterated chemicals by hydrogen-deuterium exchange, and particularly relates to a method for preparing a deuterated arylamine compound. Background Art
[0002] Hydrogen is the most abundant element in nature. Deuterium is an isotope of hydrogen that has one more neutron than hydrogen, hence its name, heavy hydrogen. Since the launch of the first deuterated drug, deutetrabenazine, deuteration technology and methods have become increasingly important. Deuterated organic compounds play a crucial role in biological protein analysis, pharmaceutical metabolism research, and the stability of organic materials. Many arylamine compounds are important intermediates for chemical dyes, photoelectric molecules, and pharmaceuticals. Developing methods for preparing deuterated arylamine compounds is a crucial challenge in the field of deuteration.
[0003] Traditional synthesis of deuterated arylamines requires a multi-step process, resulting in numerous byproducts and low final yields. However, the synthesis of deuterated chemicals by direct hydrogen-deuterium exchange on organic compounds offers advantages such as simple procedures, high target selectivity, and improved reaction economy. Therefore, it is desirable to develop a method for preparing deuterated arylamines via a one-step direct hydrogen-deuterium exchange process. Summary of the Invention
[0004] The first purpose of the present invention is to solve the problem that deuterated arylamine compounds require multiple steps to synthesize, and to provide a one-step direct hydrogen-deuterium exchange method for preparing deuterated arylamine compounds.
[0005] The second object of the present invention is to provide a deuterated arylamine compound prepared according to the above method.
[0006] The purpose of the present invention is specifically achieved through the following technical solutions:
[0007] A method for preparing a deuterated arylamine compound, wherein the C-H bond of the arylamine compound undergoes a direct hydrogen-deuterium exchange reaction with a deuterium source under the action of a metal catalyst and a reducing gas atmosphere to prepare the deuterated arylamine compound. The reaction formula of the reaction is as follows:
[0008]
[0009] In the reaction formula, R1 to R3 are a hydrogen atom or a substituent containing a benzene ring.
[0010] Preferably, the reaction temperature is 80-180°C.
[0011] Preferably, the metal catalyst contains at least one of a metal palladium catalyst and / or a metal platinum catalyst.
[0012] Further preferably, the metal palladium catalyst is selected from tetrakistriphenylphosphine palladium catalyst, palladium acetate catalyst, palladium carbon catalyst, and the metal platinum catalyst is selected from platinum carbon catalyst and platinum dioxide catalyst.
[0013] Preferably, the deuterium source is any one of deuterated water, deuterated methanol, deuterated ethanol or deuterated acetonitrile.
[0014] Preferably, the mass ratio of the arylamine compound to the deuterium source and the metal catalyst is 1:1-25:0.01-0.2.
[0015] Preferably, the reducing gas is any one of hydrogen, methane and ammonia.
[0016] Preferably, the reaction time is 6-24 hours.
[0017] A deuterated arylamine compound, prepared by any of the methods described above, having a structure shown in the following formula (1):
[0018]
[0019] Formula (1)
[0020] In formula (1), R1 to R3 are a hydrogen atom or a substituent containing a benzene ring.
[0021] Compared with the prior art, the present invention has the following advantages:
[0022] (1) Using cheap and readily available deuterium sources such as deuterated water instead of other expensive deuterium sources, a direct hydrogen-deuterium exchange reaction with high conversion rate of C-H bonds on the benzene ring of aromatic amine compounds was achieved under metal catalysts and reducing gases. The reaction steps are simpler, solving the problems of multi-step reaction and the use of expensive deuterium sources in existing deuteration schemes.
[0023] (2) This method can directly use arylamine compounds as reaction raw materials and commercially available palladium acetate, palladium carbon, platinum carbon, etc. as catalysts to prepare deuterated arylamine compounds in one step;
[0024] (3) The deuterated arylamine compounds prepared by this method can be used in deuterated arylamine pharmaceutical intermediates, photoelectric intermediates, isotope labeling, etc. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] Figure 1 This is the H-NMR spectrum of deuterated triphenylamine, the product of Example 1.
[0026] Figure 2 is the C-NMR spectrum of deuterated triphenylamine, the product of Example 1.
[0027] Figure 3 This is the D-NMR spectrum of deuterated triphenylamine, the product of Example 1.
[0028] Figure 4 The following are Fourier transform infrared spectra of the raw material triphenylamine and the product deuterated triphenylamine in Example 1.
[0029] Figure 5 This is the H-NMR spectrum of deuterated p-phenylenediamine, the product of Example 2.
[0030] Figure 6 This is the C-NMR spectrum of deuterated p-phenylenediamine, the product of Example 2.
[0031] Figure 7 This is the Fourier transform infrared spectrum of the raw material p-phenylenediamine and the product deuterated p-phenylenediamine in Example 2.
[0032] Figure 8 This is the H-NMR spectrum of deuterated benzidine, the product of Example 3.
[0033] Figure 9 This is the C-NMR spectrum of deuterated benzidine, the product of Example 3.
[0034] Figure 10 This is the Fourier transform infrared spectrum of the raw material benzidine and the product deuterated benzidine in Example 3. DETAILED DESCRIPTION
[0035] The preferred embodiments of the present invention are described below. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.
[0036] The raw materials in the embodiments of the present invention are all commercially available products.
[0037] Example 1
[0038] Preparation of deuterated triphenylamine-d15
[0039] Weigh 67 mg of palladium acetate into an autoclave, add 490 mg of triphenylamine and 10 g of deuterated water. Replace the reaction system with hydrogen, heat to 180°C, and allow to react for 24 hours. After the reaction is complete, turn off the heat and cool to room temperature. Filter the reaction mixture to remove insoluble matter, extract the mixture with dichloromethane, evaporate the solvent, and purify by column chromatography to obtain the desired product in a 90% yield.
[0040] The structure of the obtained product was confirmed by H-NMR, C-NMR, D-NMR and FT-IR tests, and its deuteration rate was calculated by the integrated area of H-NMR adding internal standard. Figure 1 This is the H-NMR spectrum of the product deuterated triphenylamine. Figure 2 This is the C-NMR spectrum of the product deuterated triphenylamine. Figure 3 This is the D-NMR spectrum of the product deuterated triphenylamine. Figure 4 This is the Fourier infrared spectrum of the raw material triphenylamine and the product deuterated triphenylamine. From the H-NMR spectrum of deuterated triphenylamine ( Figure 1 ) It can be seen that with pyrazine as the internal standard, the three peak areas of the benzene ring region of deuterated triphenylamine are 0.49, 0.27, and 0.48, respectively, indicating that the deuteration rates of the three sites are 92%, 96%, and 84%, and the total deuteration rate is 92%. Figure 4 The Fourier infrared spectrum of the raw material triphenylamine and the product deuterated triphenylamine shows the deuterium signal peak of the product and the CD bond at 2250cm -1 Out of the peak, Figure 2 The C-NMR spectrum of the product deuterated triphenylamine further confirmed the absence of other by-products.
[0041] The deuterium substitution rate of the above reaction is shown below:
[0042]
[0043] Example 2
[0044] Preparation of deuterated p-phenylenediamine-d4
[0045] 20 mg of Pd / C (10%) and 20 mg of Pt / C (10%) were weighed into an autoclave, along with 1.08 g of p-phenylenediamine and 25 g of deuterated water. The reaction system was replaced with hydrogen, heated to 80°C, and allowed to react for 24 hours. After the reaction was complete, the heat was turned off and the mixture was cooled to room temperature. The reaction mixture was filtered to remove insoluble matter, extracted with dichloromethane, and the solvent evaporated to obtain the desired product in a 94% yield.
[0046] The structure of the obtained product was confirmed by H-NMR, C-NMR and FT-IR tests, and its deuteration rate was calculated by the integrated area of H-NMR. Figure 5 This is the H-NMR spectrum of the product deuterated p-phenylenediamine. Figure 6 This is the C-NMR spectrum of the product deuterated p-phenylenediamine. Figure 7 This is the Fourier infrared spectrum of the raw material p-phenylenediamine and the product deuterated p-phenylenediamine. From the H-NMR spectrum of deuterated p-phenylenediamine ( Figure 5 ) It can be seen that the peak area of the benzene ring region of deuterated p-phenylenediamine is 0.2, indicating that the deuteration rate of deuterated p-phenylenediamine is 92%. Figure 7 The Fourier infrared spectrum of the raw material p-phenylenediamine and the product deuterated p-phenylenediamine shows that the CD bond is at 2250cm -1 Out of the peak, Figure 6 The C-NMR spectrum of the product deuterated p-phenylenediamine further confirmed the absence of other by-products.
[0047] The deuterium substitution rate of the above reaction is shown below:
[0048]
[0049] Example 3
[0050] Preparation of deuterated benzidine-d8
[0051] 65 mg of Pd / C (10%) and 65 mg of Pt / C (10%) were weighed into an autoclave, along with 644 mg of benzidine and 15 g of deuterated water. The reaction system was replaced with hydrogen, heated to 180°C, and allowed to react for 24 hours. After the reaction was complete, the heat was turned off and the mixture was cooled to room temperature. The reaction mixture was filtered to remove insoluble matter, extracted with dichloromethane, and the solvent was evaporated. The desired product was then purified by column chromatography in an 85% yield.
[0052] The structure of the obtained product was confirmed by H-NMR, C-NMR and FT-IR tests, and its deuteration rate was calculated by the integrated area of H-NMR. Figure 8 This is the H-NMR spectrum of the product deuterated benzidine. Figure 9 This is the C-NMR spectrum of the product deuterated benzidine. Figure 10 This is the Fourier infrared spectrum of the raw material benzidine and the product deuterated benzidine. From the H-NMR spectrum of deuterated benzidine ( Figure 8 ) It can be seen that, with pyrazine as the internal standard, the two peak areas of the benzene ring region of deuterated benzidine are 0.2 and 0.16, respectively, indicating that the deuteration rates of the three sites are 95% and 96%, and the total deuteration rate is 95.5%. Figure 10 The Fourier infrared spectrum of the raw material benzidine and the product deuterated benzidine shows that the CD bond is at 2250cm -1 Out of the peak, Figure 9 The C-NMR spectrum of the product deuterated benzidine further confirmed the absence of other by-products.
[0053] The deuterium substitution rate of the above reaction is shown below:
[0054]
[0055] The present invention uses cheap and readily available deuterium water instead of other expensive deuterium sources, and realizes a direct hydrogen-deuterium exchange reaction with high conversion rate of C-H bonds on the benzene ring of an arylamine compound under a metal catalyst and a reducing gas. The reaction steps are simpler, and the problems of multi-step reaction and use of expensive deuterium sources in existing deuteration schemes are solved. The method can directly use the arylamine compound as a reaction raw material and use commercially available palladium acetate, palladium carbon, platinum carbon, etc. as a catalyst to prepare a deuterated arylamine compound in one step. The prepared deuterated arylamine compound can be used in deuterated arylamine pharmaceutical intermediates, photoelectric intermediates, isotope labeling, etc.
[0056] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art will be able to modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein with equivalents. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.
Claims
1. A method for preparing a deuterated arylamine compound, characterized in that: The CH bond of the arylamine compound undergoes a direct hydrogen-deuterium exchange reaction with a deuterium source under the action of a metal catalyst and a reducing gas atmosphere to produce a deuterated arylamine compound. The reaction formula of the reaction is as follows: In the reaction formula, R1 to R3 are a hydrogen atom or a substituent containing a benzene ring.
2. The method for preparing a deuterated arylamine compound according to claim 1, wherein: The reaction temperature is 80-180°C.
3. The method for preparing a deuterated arylamine compound according to claim 1, wherein: The metal catalyst contains at least one of a metal palladium catalyst and / or a metal platinum catalyst.
4. The method for preparing a deuterated arylamine compound according to claim 3, wherein: The metal palladium catalyst is selected from tetrakistriphenylphosphine palladium catalyst, palladium acetate catalyst, palladium carbon catalyst, and the metal platinum catalyst is selected from platinum carbon catalyst and platinum dioxide catalyst.
5. The method for preparing a deuterated arylamine compound according to claim 1, wherein: The deuterium source is any one of deuterated water, deuterated methanol, deuterated ethanol or deuterated acetonitrile.
6. The method for preparing a deuterated arylamine compound according to claim 1, wherein: The mass ratio of the arylamine compound to the deuterium source and the metal catalyst is 1:1-25:0.01-0.
2.
7. The method for preparing a deuterated arylamine compound according to claim 1, wherein: The reducing gas is any one of hydrogen, methane and ammonia.
8. The method for preparing a deuterated arylamine compound according to claim 1, wherein: The reaction time is 6-24h.
9. A deuterated arylamine compound, characterized in that The compound is prepared by the method according to any one of claims 1 to 8, and has a structure shown in the following formula (1): In formula (1), R1 to R3 are a hydrogen atom or a substituent containing a benzene ring.