Preparation method and application of deuterated aniline compound
By using a palladium catalyst and ligand-catalyzed deuterium-hydrogen exchange reaction, the complexity and high cost of synthesizing deuterated aniline compounds in existing technologies have been solved, enabling efficient and simple preparation of deuterated aniline compounds, which are suitable for the synthesis of optoelectronic functional materials and drugs.
Patent Information
- Application Number
- CN202510934885.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-08
- Publication Date
- 2025-10-21
AI Technical Summary
Existing methods for synthesizing deuterated aniline compounds suffer from problems such as harsh reaction conditions, long reaction times, high costs, complex operations, and difficulty in deuterating large sterically hindered groups.
The deuterium-hydrogen exchange reaction catalyzed by conventional palladium reagents and ligands uses deuterated reagents, palladium catalysts and ligands. The reaction conditions are mild, suitable for industrial scale-up, simplifying the steps and improving the deuteration rate.
The preparation of deuterated aniline compounds with high yield and high deuteration rate was achieved, simplifying the operation steps and reducing costs.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a deuterated aniline compound and application thereof. Background Art
[0002] Deuterated aniline compounds, which consist of aniline molecules with hydrogen atoms (H) replaced at specific positions with their stable isotope, deuterium (D), have shown unique application value in optoelectronic materials and biomedicine. In optoelectronic materials, deuterated materials obtained by replacing hydrogen atoms with deuterium can significantly alter their physical and chemical properties, particularly exhibiting improved chemical and optoelectronic stability. Deuterium atoms are more massive than hydrogen atoms, resulting in a lower vibration frequency of the CD bond than the CH bond. This property can effectively reduce non-radiative energy loss (such as intramolecular vibrational relaxation) in the material's high-energy excitation state, thereby improving the material's fluorescence quantum yield and stability. Therefore, deuterated aniline and its derivatives are widely used in the design of high-performance organic light-emitting diode (OLED) emitting layer materials, transport layer materials, and organic photovoltaic (OPV) materials, aiming to improve the device's luminous efficiency, color purity, operating life, and photoelectric conversion efficiency. In the biomedical field, deuterated aniline structural units serve as core pharmacophores or key intermediates for the construction of many important drug molecules. CD bonds are stronger and harder to break than CH bonds, which can slow down the metabolic rate of drug molecules containing this group in the body. This metabolic deceleration effect can prolong the half-life of drugs, reduce the frequency of dosing, improve bioavailability, and may reduce toxic metabolites produced by rapid metabolism, thereby optimizing the efficacy and safety of drugs. Deuterated drug molecules based on deuterated aniline have broad research and development prospects in the fields of neurological diseases and tumor treatment. In summary, deuterated aniline compounds, with their unique isotope effect, have become an important bridge connecting the development of advanced optoelectronic functional materials and innovative drug design, and their application prospects are worth looking forward to.
[0003] Aniline compounds are the most common molecular structures found in pharmaceuticals and organic materials. Therefore, developing an efficient method for synthesizing deuterated anilines that is compatible with a wide range of aniline compounds is crucial. Currently reported methods for synthesizing deuterated anilines suffer from the following drawbacks: 1. Harsh reaction conditions and time-consuming, high-temperature, and long-duration reactions: Traditional deuteration methods require long reactions (24 hours to several days) at high temperatures (e.g., 180°C). For example, aniline requires 24 hours of refluxing in hydrochloric acid and heavy water to complete deuteration, resulting in extremely low reaction efficiency. 2. Expensive deuteration reagents: Some methods require specialized reagents such as Bu3SnD (tributyltin deuteride) or LiAlD4 (lithium aluminum deuteride), further increasing costs. 3. Complex procedures and multi-step purification of byproducts: Post-synthesis requires tedious steps such as neutralization (e.g., pH adjustment with sodium bicarbonate), extraction, and column chromatography. For example, deuterated aniline requires multiple extractions with ethyl acetate and column chromatography purification, resulting in significant yield loss. Fourth, aromatic hydrogen atoms with large steric hindrance groups are difficult to be efficiently deuterated.
[0004] Therefore, how to provide a simple, high-yield, and low-cost method for preparing deuterated aniline has become an urgent problem to be solved. Summary of the Invention
[0005] In view of the shortcomings of the prior art, the present invention aims to provide a method for preparing deuterated aniline compounds and their application. The method provided by the present invention has mild conditions, is easy to scale up industrially, has simple reaction steps, high yield, and high deuteration rate.
[0006] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:
[0007] In a first aspect, the present invention provides a method for preparing a deuterated aniline compound, the preparation method comprising the following steps:
[0008] Mixing an aniline compound with a deuterated reagent, a palladium catalyst, and a ligand to react to obtain the deuterated aniline compound;
[0009] The reaction formula is as follows:
[0010]
[0011] Wherein, R1 is selected from H or R2 is selected from H or
[0012] Alkyl- indicates that there are 0-4 C1-C12 alkyl groups or hydroxyl groups independently on the benzene ring;
[0013] D- indicates the presence of 1 to 5 deuterium atoms on the benzene ring;
[0014] R1 and R2 are not connected to the benzene ring or are connected to form a five-membered ring or a six-membered ring.
[0015] The above method utilizes conventional palladium reagents and ligand catalysis to generate a deuterium-hydrogen exchange reaction. The reaction conditions are mild, and the deuteration of aromatic hydrogens containing large steric groups can be achieved. The method is easy to scale up industrially, has simple reaction steps, high yield, and high deuteration rate.
[0016] Preferably, the deuterated reagent includes deuterated water and / or deuterated dimethyl sulfoxide.
[0017] Preferably, the molar ratio of the aniline compound to the deuterated reagent is 1:(100-150), for example, 1:100, 1:110, 1:120, 1:130, 1:140 or 1:150, etc., but is not limited to the above values. Other values not listed within the above numerical range are also applicable.
[0018] Preferably, the palladium catalyst comprises any one of palladium dichloride, palladium acetate, bis(dibenzylideneacetone)palladium or tetrakis(triphenylphosphine)palladium, or a combination of at least two thereof, preferably palladium acetate.
[0019] Preferably, the amount of the palladium catalyst is 0.1-5% of the molar amount of the aniline compound, for example, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5%, etc., but is not limited to the values listed above. Other values not listed within the above numerical range are also applicable.
[0020] Preferably, the ligand is a pyridine ligand, including any one or a combination of at least two of the following structural compounds:
[0021]
[0022] Preferably, the ligand is selected from and / or
[0023] Preferably, the amount of the ligand is 0.2-10% of the molar amount of the aniline compound, for example 0.2%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%, etc., but is not limited to the values listed above. Other values not listed within the above numerical range are also applicable.
[0024] Preferably, the reaction temperature is 80-120°C, and the reaction time is 18-24h, wherein the temperature can be 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C or 120°C, etc., and the reaction time can be 18h, 19h, 20h, 21h, 22h, 23h or 24h, etc., but are not limited to the values listed above. Other values not listed within the above numerical range are also applicable.
[0025] The above-mentioned specific reagents can further increase the reaction yield and deuteration rate, thereby improving the preparation effect.
[0026] Preferably, the reaction is carried out under an inert atmosphere or hydrogen.
[0027] Preferably, the material is washed with water after the reaction.
[0028] Preferably, the structure of the deuterated aniline compound is as follows:
[0029]
[0030]
[0031] In a second aspect, the present invention provides the use of the above-mentioned method for preparing deuterated aniline compounds in the preparation of drugs containing deuterated aniline.
[0032] In a third aspect, the present invention further provides the use of the above-mentioned method for preparing deuterated aniline compounds in the preparation of optoelectronic functional materials containing deuterated aniline.
[0033] Compared with the prior art, the present invention has the following beneficial effects:
[0034] The present invention provides a preparation method of deuterated aniline compounds. The deuterium-hydrogen exchange reaction occurs by utilizing a conventional palladium reagent and a ligand for catalysis. The reaction conditions are mild, and the deuteration of aryl hydrogen containing a large sterically hindered group can be achieved. The method is easy to prepare on an industrial scale, has simple reaction steps, high yield, and high deuteration rate. BRIEF DESCRIPTION OF THE DRAWINGS
[0035] Figure 1 This is the NMR spectrum of 3,5-di-tert-butylaniline-2,4,6-d3 prepared in Example 6. DETAILED DESCRIPTION
[0036] The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the embodiments are merely to help understand the present invention and should not be regarded as specific limitations of the present invention.
[0037] Example 1: Preparation of Aniline-2,3,4,5,6-d5
[0038] To a 100 mL three-necked flask, bis(dibenzylideneacetone)palladium (183 mg, 0.2 mmol), 3-nitro-5-(trifluoromethyl)pyridin-2-ol (71.2 mg, 0.4 mmol), aniline (930 mg, 10 mmol), deuterated dimethyl sulfoxide (5 mL), and deuterated water (5 mL) were added sequentially. The atmosphere was replaced with high-purity nitrogen three times. After reacting at 100°C for 24 hours, the mixture was extracted with dichloromethane. The organic phases were combined, the organic solvent was concentrated, and the product was further purified by column chromatography to obtain aniline-2,3,4,5,6-d5 in a 96% yield. The deuteration rate was >98% (the target compound and deuteration rate were confirmed by gas chromatography-mass spectrometry).
[0039] Example 2: Preparation of 3,5-dimethylaniline-2,4,6-d3
[0040] To a 100 mL three-necked flask were added bis(dibenzylideneacetone)palladium (183 mg, 0.2 mmol), 3-nitro-5-(trifluoromethyl)pyridin-2-ol (71.2 mg, 0.4 mmol), 3,5-dimethylaniline (1210 mg, 10 mmol), deuterated dimethyl sulfoxide (5 mL), and deuterated water (5 mL). The atmosphere was replaced with high-purity nitrogen three times. After reacting at 100°C for 24 hours, the mixture was extracted with dichloromethane. The organic phases were combined, the solvent was concentrated, and the product was further purified by column chromatography to obtain 3,5-dimethylaniline-2,4,6-d3 in a 97% yield. The deuteration rate was >98% (the target compound and the deuteration rate were confirmed by gas chromatography-mass spectrometry).
[0041] Example 3: Preparation of 2,4,6-trimethylaniline-3,5-d2
[0042] To a 100 mL three-necked flask were added bis(dibenzylideneacetone)palladium (183 mg, 0.2 mmol), 3-nitro-5-(trifluoromethyl)pyridin-2-ol (71.2 mg, 0.4 mmol), 2,4,6-trimethylaniline (1350 mg, 10 mmol), deuterated dimethyl sulfoxide (5 mL), and deuterated water (5 mL). The atmosphere was replaced with high-purity nitrogen three times. After reacting at 100°C for 24 hours, the mixture was extracted with dichloromethane. The organic phases were combined, the organic solvent was concentrated, and the product was further purified by column chromatography to obtain 2,4,6-trimethylaniline-3,5-d2 in a 92% yield. The deuteration rate was >99% (the target compound and the deuteration rate were confirmed by gas chromatography-mass spectrometry).
[0043] Example 4: Preparation of 4-(tert-butyl)aniline-2,3,5,6-d4
[0044] To a 100 mL three-necked flask, bis(dibenzylideneacetone)palladium (183 mg, 0.2 mmol), 3-nitro-5-(trifluoromethyl)pyridin-2-ol (71.2 mg, 0.4 mmol), 4-(tert-butyl)aniline (1490 mg, 10 mmol), deuterated dimethyl sulfoxide (5 mL), and deuterated water (5 mL) were added sequentially. The atmosphere was replaced with high-purity nitrogen three times. After reacting at 100°C for 24 hours, the mixture was extracted with dichloromethane. The organic phases were combined, the solvent was concentrated, and the product was further purified by column chromatography to obtain 4-(tert-butyl)aniline-2,3,5,6-d4 in a 90% yield. The deuteration rate was >97% (the target compound and deuteration rate were confirmed by gas chromatography-mass spectrometry).
[0045] Example 5: Preparation of 4-(tert-butyl)-2,6-dimethylaniline-3,5-d2
[0046] To a 100 mL three-necked flask were added palladium acetate (449 mg, 0.2 mmol), 4-(trifluoromethyl)pyridin-2-ol (70.8 mg, 0.4 mmol), 4-(tert-butyl)-2,6-dimethylaniline (1772 mg, 10 mmol), deuterated dimethyl sulfoxide (5 mL), and deuterated water (5 mL). The mixture was replaced with high-purity hydrogen three times and reacted at 80°C for 18 hours. The mixture was extracted with dichloromethane, and the organic phases were combined, the organic solvent was concentrated, and the product was further purified by column chromatography to obtain 4-(tert-butyl)-2,6-dimethylaniline-3,5-d2 in a 91% yield. The deuteration rate was >98% (the target compound and the deuteration rate were confirmed by gas chromatography-mass spectrometry).
[0047] Example 6: Preparation of 3,5-di-tert-butylaniline-2,4,6-d3
[0048] To a 100 mL three-necked flask were added palladium acetate (449 mg, 0.2 mmol), 4-(trifluoromethyl)pyridin-2-ol (70.8 mg, 0.4 mmol), 4-(tert-butyl)-2,6-dimethylaniline (2050 mg, 10 mmol), deuterated dimethyl sulfoxide (5 mL), and deuterated water (5 mL). The mixture was replaced with high-purity hydrogen three times and reacted at 80°C for 18 hours. The mixture was then extracted with dichloromethane, and the organic phases were combined, the solvent was concentrated, and the product was further purified by column chromatography to obtain 3,5-di-tert-butylaniline-2,4,6-d3 in a 95% yield. The deuteration rate was >96% (the target compound and the deuteration rate were confirmed by gas chromatography-mass spectrometry).
[0049] The reaction was scaled up to a 10-liter vessel, with palladium acetate (44.9 g, 10 mmol), 4-(trifluoromethyl)pyridin-2-ol (7.08 g, 40 mmol), 4-(tert-butyl)-2,6-dimethylaniline (820 g, 40 mmol), deuterated dimethyl sulfoxide (2 L), and deuterated water (2 L) added sequentially. The atmosphere was replaced with high-purity hydrogen three times, and the reaction was continued at 90°C for 24 hours. The mixture was then extracted with dichloromethane, the organic phases combined, the organic solvent concentrated, and the product further purified by vacuum distillation to obtain 3,5-di-tert-butylaniline-2,4,6-d3 in a 98% yield. The deuteration rate was >95%.
[0050] Product NMR Figure 1 As shown, from Figure 1 It can be observed that the deuteration rates of 3,5-di-tert-butylaniline-2,4,6-d3 are 98% and 96.5%, respectively.
[0051] Example 7: Preparation of 3,5-di-tert-butyl-4-methylaniline-2,6-d2
[0052] To a 100 mL three-necked flask were added palladium acetate (449 mg, 0.2 mmol), 5-nitro-3-(trifluoromethyl)pyridin-2-ol (83.2 mg, 0.4 mmol), 3,5-di-tert-butyl-4-methylaniline (2190 mg, 10 mmol), deuterated dimethyl sulfoxide (5 mL), and deuterated water (5 mL). The mixture was replaced with high-purity hydrogen three times and reacted at 80°C for 18 hours. The mixture was then extracted with dichloromethane, the organic phases were combined, the solvent was concentrated, and the product was further purified by column chromatography to obtain 3,5-di-tert-butyl-4-methylaniline-2,6-d2 in a 90% yield. The deuteration rate was >97% (the target compound and the deuteration rate were confirmed by gas chromatography-mass spectrometry).
[0053] Example 8: Preparation of bis(4-(tert-butyl)phenyl-2,3,5,6-d4)amine
[0054] To a 100 mL three-necked flask were added palladium acetate (449 mg, 0.2 mmol), 5-nitro-3-(trifluoromethyl)pyridin-2-ol (83.2 mg, 0.4 mmol), bis(4-tert-butylphenyl)amine (2814 mg, 10 mmol), deuterated dimethyl sulfoxide (5 mL), and deuterated water (5 mL). The mixture was replaced with high-purity hydrogen three times and reacted at 80°C for 18 hours. The mixture was extracted with dichloromethane, and the organic phases were combined, the organic solvent was concentrated, and the product was further purified by column chromatography to obtain bis(4-(tert-butyl)phenyl-2,3,5,6-d4)amine in a 92% yield. The deuteration rate was >96% (the target compound and the deuteration rate were confirmed by gas chromatography-mass spectrometry).
[0055] Example 9: Preparation of 3-(tert-butyl)-5-methylaniline-2,4,6-d3
[0056] To a 100 mL three-necked flask were added palladium chloride (354 mg, 0.2 mmol), 5-nitro-3-(trifluoromethyl)pyridin-2-ol (83.2 mg, 0.4 mmol), 3-(tert-butyl)-5-methylaniline (1632 mg, 10 mmol), deuterated dimethyl sulfoxide (5 mL), and deuterated water (5 mL). The mixture was replaced with high-purity hydrogen three times and reacted at 80°C for 18 hours. The mixture was extracted with dichloromethane, and the organic phases were combined, the organic solvent was concentrated, and the product was further purified by column chromatography to obtain 3-(tert-butyl)-5-methylaniline-2,4,6-d3 in a 97% yield. The deuteration rate was >98% (the target compound and the deuteration rate were confirmed by gas chromatography-mass spectrometry).
[0057] Example 10: Preparation of p-phenylenediamine-d4
[0058] To a 100 mL three-necked flask were added palladium chloride (354 mg, 0.2 mmol), 5-nitro-3-(trifluoromethyl)pyridin-2-ol (83.2 mg, 0.4 mmol), p-phenylenediamine (1081 mg, 10 mmol), deuterated dimethyl sulfoxide (5 mL), and deuterated water (5 mL). The mixture was replaced with high-purity hydrogen three times and reacted at 80°C for 18 hours. The mixture was extracted with dichloromethane, the organic phases were combined, the organic solvent was concentrated, and the product was further purified by column chromatography to obtain p-phenylenediamine-d4 in a 92% yield. The deuteration rate was >97% (the target compound and the deuteration rate were confirmed by gas chromatography-mass spectrometry).
[0059] Example 11: 3-amino-2,4,5,6-d4-phenol
[0060] To a 100 mL three-necked flask were added palladium chloride (354 mg, 0.2 mmol), 5-nitro-3-(trifluoromethyl)pyridin-2-ol (83.2 mg, 0.4 mmol), 3-amino-phenol (1.09 g, 10 mmol), deuterated dimethyl sulfoxide (5 mL), and deuterated water (5 mL). The mixture was replaced with high-purity hydrogen three times and reacted at 80°C for 18 hours. The mixture was then extracted with dichloromethane, the organic phases were combined, the organic solvent was concentrated, and the product was further purified by column chromatography to obtain 3-amino-2,4,5,6-d4-phenol in a 98% yield. The deuteration rate was >99% (the target compound and the deuteration rate were confirmed by gas chromatography-mass spectrometry).
[0061] Example 12
[0062] This embodiment provides a method for preparing 3,5-di-tert-butylaniline-2,4,6-d3, which is consistent with Example 6 except that palladium acetate is replaced by an equimolar amount of palladium dichloride.
[0063] The final product yield was 92% and the deuteration rate was >95%.
[0064] Example 13
[0065] This embodiment provides a method for preparing 3,5-di-tert-butylaniline-2,4,6-d3, which is consistent with Example 6 except that palladium acetate is replaced by an equimolar amount of bis(dibenzylideneacetone)palladium.
[0066] The final product yield was 90% and the deuteration rate was >95%.
[0067] Example 14
[0068] This example provides a method for preparing aniline-2,3,4,5,6-d5, which is consistent with Example 1 except that 3-nitro-5-(trifluoromethyl)pyridin-2-ol is replaced by an equimolar amount of 4-(trifluoromethyl)pyridin-2-ol.
[0069] The final product yield was 93% and the deuteration rate was >97%.
[0070] From the above data, it can be found that the method provided by the present invention has mild reaction conditions, simple reaction steps, high yield and high deuteration rate; by adopting specific palladium catalysts and ligands, the preparation yield and deuteration rate are further improved.
[0071] The applicant declares that while the above-described embodiments illustrate the preparation methods and applications of deuterated aniline compounds, the present invention is not limited to these embodiments. This does not necessarily mean that the present invention must rely on these embodiments for implementation. Those skilled in the art will appreciate that any improvements to the present invention, equivalent substitutions for raw materials in the products of the present invention, additions of auxiliary ingredients, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present invention.
[0072] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.
[0073] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.
Claims
1. A method for preparing deuterated aniline compounds, characterized in that: The preparation method comprises the following steps: Mixing an aniline compound with a deuterated reagent, a palladium catalyst, and a ligand to react to obtain the deuterated aniline compound; The reaction formula is as follows: Wherein, R1 is selected from H or R2 is selected from H or Alkyl- indicates that there are 0-4 C1-C12 alkyl groups or hydroxyl groups independently on the benzene ring; D- indicates the presence of 1 to 5 deuterium atoms on the benzene ring; R1 and R2 are not connected to the benzene ring or are connected to form a five-membered ring or a six-membered ring.
2. The method for preparing deuterated aniline compounds according to claim 1, wherein The deuterated reagent includes deuterated water and / or deuterated dimethyl sulfoxide; Preferably, the molar ratio of the aniline compound to the deuterated reagent is 1:(100-150).
3. The method for preparing deuterated aniline compounds according to claim 1 or 2, characterized in that: The palladium catalyst includes any one of palladium dichloride, palladium acetate, bis(dibenzylideneacetone)palladium or tetrakis(triphenylphosphine)palladium or a combination of at least two thereof, preferably palladium acetate.
4. The method for preparing a deuterated aniline compound according to any one of claims 1 to 3, characterized in that: The amount of the palladium catalyst used is 0.1-5% of the molar amount of the aniline compound.
5. The method for preparing the deuterated aniline compound according to any one of claims 1 to 4, characterized in that: The ligand is a pyridine ligand, including any one or a combination of at least two of the following structural compounds: Preferably, the ligand is selected from and / or Preferably, the amount of the ligand used is 0.2-10% of the molar amount of the aniline compound.
6. The method for preparing the deuterated aniline compound according to any one of claims 1 to 5, characterized in that: The reaction temperature is 80-120°C and the reaction time is 18-24h; Preferably, the reaction is carried out under an inert atmosphere or hydrogen.
7. The method for preparing a deuterated aniline compound according to any one of claims 1 to 6, characterized in that: After the reaction, the material is washed with water.
8. The method for preparing the deuterated aniline compound according to any one of claims 1 to 7, characterized in that: The structure of the deuterated aniline compound is shown below:
9. Use of the method for preparing a deuterated aniline compound according to any one of claims 1 to 8 in the preparation of a medicament containing deuterated aniline.
10. Use of the preparation method of the deuterated aniline compound according to any one of claims 1 to 8 in the preparation of a photoelectric functional material containing deuterated aniline.