Method for preparing deuterated phenol-D5 by adopting hydrogen-deuterium exchange method

Abstract

The invention belongs to the technical field of fine chemical engineering, and particularly relates to a method for preparing deuterated phenol-D5 by adopting a hydrogen-deuterium exchange method, which comprises the following steps: mixing phenol, heavy water and a catalyst in a closed reaction kettle, carrying out multiple rounds of hydrogen-deuterium exchange under the protection of inert atmosphere to obtain a crude product, and further purifying to obtain the deuterated phenol-D5; wherein the catalyst is aluminum oxide loaded platinum. The preparation method has the advantages of mild reaction conditions, less heavy water consumption, no need of additional solvents, and convenient and fast purification, and the deuteration rate and purity of the prepared deuterated phenol-D5 are both 98% or above, reaching the quality level of commercially available deuterated phenol-D5.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemicals, and particularly relates to a method for preparing deuterated phenol-D5 by adopting a hydrogen-deuterium exchange method. Background Art

[0002] Deuterated phenol is not only of great significance in laboratory research but also has extensive applications in industrial production. For example, it can be used as an internal standard in gas chromatography-mass spectrometry analysis, helping to improve the accuracy and reliability of analyses. Furthermore, deuterated phenol's stability and unique chemical properties make it crucial in fields such as materials science, pharmaceutical research, and environmental analysis.

[0003] In the prior art, deuterated phenols are typically prepared by replacing hydrogen atoms in phenol with deuterium atoms in heavy water. For example, in the method reported by Yamamoto et al. in "PLATINUM CATALYZED H-DEXCHANGE REACTION OF VARIOUS AROMATIC COMPPOUNDS UNDER HYDROTHERMAL CONDITION," phenol is reacted with heavy water at 250°C and 4 MPa under the catalysis of platinum oxide to produce deuterated phenol. However, this method requires high temperature and high pressure, making the reaction conditions relatively harsh.

[0004] Chinese patent CN113979822A provides a method for preparing deuterated phenol, which uses phenol (23.53 mg) as a raw material, heavy water (3 ml) as a deuterium source, and 10% platinum on carbon (11.3 mg) as a catalyst. In a solution of isopropanol (0.1 ml) and cyclohexane (0.9 ml), the air in the reaction system is replaced with argon, and the temperature is then raised to 70°C for 12 hours to finally obtain deuterated phenol with a yield of 78%. However, the method requires a large amount of heavy water as a deuterium source, as well as isopropanol and cyclohexane as solvents, which is costly. Summary of the Invention

[0005] The present invention aims to provide a method for preparing deuterated phenol-D5 by using a hydrogen-deuterium exchange method, which has mild reaction conditions, uses a small amount of heavy water, does not require the addition of additional solvents, and is convenient and quick to purify.

[0006] Specifically, the present invention provides the following technical solutions:

[0007] A method for preparing deuterated phenol-D5 by a hydrogen-deuterium exchange method comprises the following steps:

[0008] Phenol, heavy water and a catalyst are mixed in a sealed reactor and subjected to multiple rounds of hydrogen-deuterium exchange under an inert atmosphere to obtain a crude product, which is further purified to obtain deuterated phenol-D5;

[0009] Wherein, the catalyst is alumina-supported platinum.

[0010] The reaction formula is:

[0011]

[0012] Preferably, the platinum loading in the catalyst is 4 to 6 wt%;

[0013] In each round of hydrogen-deuterium exchange, the mass ratio of phenol to catalyst is 10:(6-10).

[0014] Preferably, in each round of hydrogen-deuterium exchange, the mass ratio of phenol to heavy water is 10:(60-120).

[0015] Preferably, the reaction temperature of each round of hydrogen-deuterium exchange is 170-190° C., and the reaction pressure is 1-2 MPa.

[0016] Preferably, the multiple rounds of hydrogen-deuterium exchange comprise the following steps:

[0017] (1) Phenol, heavy water, and catalyst were mixed in a closed reactor and the first round of hydrogen-deuterium exchange was performed under inert atmosphere.

[0018] (2) After the first round of hydrogen-deuterium exchange is completed, the reactor is cooled to room temperature, the catalyst is removed from the reaction system by filtration, and then an organic solvent is added, the layers are extracted, and the upper organic phase is collected and concentrated to obtain the first round of hydrogen-deuterium exchange product;

[0019] (3) The product of the first round of hydrogen-deuterium exchange, heavy water, and catalyst are mixed in a closed reactor, and a second round of hydrogen-deuterium exchange is carried out under inert atmosphere.

[0020] (4) After the second round of hydrogen-deuterium exchange is completed, the reactor is cooled to room temperature, the catalyst is removed from the reaction system by filtration, and then an organic solvent is added, the layers are extracted, and the upper organic phase is collected and concentrated to obtain a crude product.

[0021] Preferably, the purification comprises the following steps:

[0022] The crude product is subjected to vacuum distillation to obtain deuterated phenol-D5.

[0023] The beneficial effects of the present invention are at least:

[0024] 1) The method for preparing deuterated phenol-D5 using a hydrogen-deuterium exchange method provided by the present invention has mild reaction conditions, is less likely to cause safety issues, uses less heavy water, and reduces costs;

[0025] 2) The method for preparing deuterated phenol-D5 using a hydrogen-deuterium exchange method provided by the present invention uses heavy water as both a deuterium source and a solvent, eliminating the need for adding additional solvents and simplifying purification.

[0026] 3) The method provided by the present invention for preparing deuterated phenol-D5 using a hydrogen-deuterium exchange method has a deuteration rate and purity of the prepared deuterated phenol-D5 of more than 98%, which is comparable to the deuteration rate and purity of deuterated phenol-D5 commercially available at home and abroad. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the gas chromatography spectrum of the deuterated phenol-D5 product prepared in Example 5;

[0028] Figure 2 This is the NMR spectrum of the deuterated phenol-D5 product prepared in Example 5. DETAILED DESCRIPTION

[0029] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention are clearly and completely described below. The following examples are used to illustrate the present invention but are not intended to limit the scope of the present invention. If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions shall be followed.

[0030] In the following examples, the Pt / Al2O3 catalyst is sourced from Xi'an Kaili New Materials Co., Ltd.

[0031] Example 1

[0032] In a 500ml autoclave, 10g of phenol, 8g of Pt / Al2O3 (5%) catalyst and 60g of heavy water were added, and the mixture was heated to 180°C under a nitrogen atmosphere for 24h at a reaction pressure of 1-2MPa. After cooling to room temperature, the autoclave was opened, and the reaction solution was filtered to remove the catalyst to obtain a mixture of heavy water and a crude product. 50ml of dichloromethane was added to the mixture, and the layers were separated by extraction. The organic phase was collected and concentrated (the concentration described in the embodiment is to remove dichloromethane by distillation under reduced pressure). After concentration, a second hydrogen-deuterium exchange was performed. The above operation was repeated, i.e., 8g of Pt / Al2O3 (5%) catalyst and 60g of heavy water were added, and the mixture was heated to 180°C under a nitrogen atmosphere for 24h at a reaction pressure of 1-2MPa. After cooling to room temperature, the autoclave was opened, and the reaction solution was filtered to remove the catalyst to obtain a mixture of heavy water and a crude product. 50ml of dichloromethane was added to the mixture, and the layers were separated by extraction. The organic phase was collected and concentrated.

[0033] Finally, a crude phenol-D5 product with a deuteration rate of 93.5% is obtained, and deuterated phenol-D5 product is obtained by vacuum distillation (purity and yield are not considered before the deuteration rate is less than 98%).

[0034] Example 2

[0035] In a 500ml autoclave, 10g of phenol, 8g of a Pt / Al2O3 (0.5%) catalyst, and 60g of heavy water were added. The mixture was heated to 180°C under a nitrogen atmosphere and reacted for 24 hours at a pressure of 1-2 MPa. After cooling to room temperature, the autoclave was opened and the catalyst was removed by filtration to obtain a mixture of heavy water and a crude product. 50ml of dichloromethane was added to the mixture, and the layers were extracted. The organic phase was collected and concentrated, and then a second hydrogen-deuterium exchange was performed. The above process was repeated to obtain a crude phenol-D5 product with a deuteration rate of 91.6%. The deuterated phenol-D5 product was obtained by vacuum distillation.

[0036] Example 3

[0037] In a 500ml autoclave, 10g of phenol, 8g of a Pt / Al2O3 (5%) catalyst, and 80g of heavy water were added. The mixture was heated to 180°C under a nitrogen atmosphere and reacted for 24 hours at a pressure of 1-2 MPa. After cooling to room temperature, the autoclave was opened and the catalyst was removed by filtration to obtain a mixture of heavy water and a crude product. 50ml of dichloromethane was added to the mixture, and the layers were extracted. The organic phase was collected and concentrated, and then a second hydrogen-deuterium exchange was performed. The above process was repeated to obtain a crude phenol-D5 product with a deuteration rate of 95.3%. The deuterated phenol-D5 product was obtained by vacuum distillation.

[0038] Example 4

[0039] In a 500ml autoclave, 10g of phenol, 8g of Pt / Al2O3 (5%) catalyst, and 100g of heavy water were added. The mixture was heated to 180°C under a nitrogen atmosphere for 24 hours at a pressure of 1-2 MPa. After cooling to room temperature, the autoclave was opened and the catalyst was removed by filtration to obtain a mixture of heavy water and a crude product. 50ml of dichloromethane was added to the mixture, and the layers were extracted. The organic phase was collected and concentrated, and then a second hydrogen-deuterium exchange was performed. The above steps were repeated to obtain a crude phenol-D5 product with a deuteration rate of 96.9%. The deuterated phenol-D5 product was obtained by vacuum distillation.

[0040] Example 5

[0041] In a 500ml autoclave, 10g of phenol, 8g of a Pt / Al2O3 (5%) catalyst, and 120g of heavy water were added. The mixture was heated to 180°C under a nitrogen atmosphere and reacted for 24h at a pressure of 1-2MPa. After cooling to room temperature, the autoclave was opened and the catalyst was removed by filtration to obtain a mixture of heavy water and a crude product. 50ml of dichloromethane was added to the mixture, and the layers were extracted. The organic phase was collected and concentrated. After concentration, a second hydrogen-deuterium exchange was performed. The above operation was repeated to obtain a crude phenol-D5 product with a deuteration rate of 98.6%. After vacuum distillation, a deuterated phenol-D5 product with a purity of 98.34% was obtained in a yield of 54.8%.

[0042] Figure 1 This is the gas chromatography spectrum of the deuterated phenol-D5 product prepared in Example 5.

[0043] Figure 2 This is the NMR spectrum of the deuterated phenol-D5 product prepared in Example 5.

[0044] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A method for preparing deuterated phenol-D5 by hydrogen-deuterium exchange method, characterized in that: The following steps are involved: Phenol, heavy water and a catalyst are mixed in a sealed reactor and subjected to multiple rounds of hydrogen-deuterium exchange under an inert atmosphere to obtain a crude product, which is further purified to obtain deuterated phenol-D5; Wherein, the catalyst is alumina-supported platinum.

2. The method for preparing deuterated phenol-D5 by hydrogen-deuterium exchange according to claim 1, wherein: The platinum loading in the catalyst is 4 to 6 wt%; In each round of hydrogen-deuterium exchange, the mass ratio of phenol to catalyst is 10:(6-10).

3. The method for preparing deuterated phenol-D5 by hydrogen-deuterium exchange according to claim 1 or 2, wherein: In each round of hydrogen-deuterium exchange, the mass ratio of phenol to heavy water is 10:(60-120).

4. The method for preparing deuterated phenol-D5 by hydrogen-deuterium exchange method according to claim 1 or 2, wherein: The reaction temperature of each round of hydrogen-deuterium exchange is 170-190° C., and the reaction pressure is 1-2 MPa.

5. The method for preparing deuterated phenol-D5 by hydrogen-deuterium exchange method according to claim 1 or 2, characterized in that: The multiple rounds of hydrogen-deuterium exchange include the following steps: (1) Phenol, heavy water, and catalyst were mixed in a closed reactor and the first round of hydrogen-deuterium exchange was performed under inert atmosphere. (2) After the first round of hydrogen-deuterium exchange is completed, the reactor is cooled to room temperature, the catalyst is removed from the reaction system by filtration, and then an organic solvent is added, the layers are extracted, and the upper organic phase is collected and concentrated to obtain the first round of hydrogen-deuterium exchange product; (3) The product of the first round of hydrogen-deuterium exchange, heavy water, and catalyst are mixed in a closed reactor, and a second round of hydrogen-deuterium exchange is carried out under inert atmosphere. (4) After the second round of hydrogen-deuterium exchange is completed, the reactor is cooled to room temperature, the catalyst is removed from the reaction system by filtration, and then an organic solvent is added, the layers are extracted, and the upper organic phase is collected and concentrated to obtain a crude product.

6. The method for preparing deuterated phenol-D5 by hydrogen-deuterium exchange method according to claim 1 or 2, wherein: The purification comprises the following steps: The crude product is subjected to vacuum distillation to obtain deuterated phenol-D5.

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