Method for preparing deuterated aromatic hydrocarbons by Pt monatomic photocatalytic hydrogen-deuterium exchange and application thereof

Abstract

The application discloses a method for preparing deuterated aromatic hydrocarbons by Pt monatomic photocatalytic hydrogen-deuterium exchange and application thereof. The method comprises the following steps: in a protective atmosphere, taking an aromatic hydrocarbon compound as a substrate, taking an inorganic semiconductor nanomaterial loaded with metal monatomic Pt as a photocatalyst, adding a deuterium source, and performing a hydrogen-deuterium exchange reaction under the condition of room temperature and visible light irradiation to obtain deuterated aromatic hydrocarbons. The method can realize direct hydrogen-deuterium exchange reaction of a series of aromatic hydrocarbon molecules under the condition of room temperature and normal pressure by using relatively cheap D2O as the deuterium source and driving by visible light, avoids harsh reaction conditions of high temperature and high pressure and use of expensive deuterium sources, is simple and easy to implement, is safe to operate, is simple in product separation, and can be easily implemented in large-scale production, and provides possibility for large-scale production of deuterated chemicals.

Description

Technical Field

[0001] This invention relates to a method and application of Pt single-atom photocatalytic hydrogen-deuterium exchange for the preparation of deuterated aromatics, belonging to the field of photocatalytic organic conversion technology. Background Technology

[0002] Deuterated compounds have significant applications in numerous fields, such as reaction mechanism research, development of deuterated drug molecules, mass spectrometry analytical standards, and optoelectronic devices. In recent years, developing mild, efficient, and universal deuteration methods has become a hot topic in chemical research. In specific applications, the controllable selectivity of the deuteration site is particularly crucial. Currently, three deuteration methods have been reported: hydrogen-deuterium exchange, reductive deuteration, and dehalogenation. Among these three methods, hydrogen-deuterium exchange does not require pre-functionalization of the compound, directly achieving the conversion of CH bonds to CD bonds without substantially altering the compound's structure. It is the simplest, most direct, economical, and efficient deuteration strategy, attracting considerable research interest.

[0003] Aromatic hydrocarbons are a common component of many small molecule drugs, and the development of deuteration methods for aromatic hydrocarbons has broad prospects and challenges for drug application research. However, current aromatic hydrocarbon deuteration methods generally suffer from problems such as poor safety, harsh conditions (high temperature, high pressure, use of hydrogen, use of acid-base catalysts, etc.) and high cost (use of expensive deuterium sources such as D2, C6D6, CD3OD, DMSO-d6, etc.). Summary of the Invention

[0004] The main objective of this invention is to provide a method for preparing deuterated aromatic hydrocarbons by photocatalytic hydrogen-deuterium exchange of Pt single atoms and its application, thereby overcoming the shortcomings of the prior art.

[0005] To achieve the aforementioned objectives, the technical solution adopted by this invention includes:

[0006] The first aspect of this invention provides a method for preparing deuterated aromatic hydrocarbons by photocatalytic hydrogen-deuterium exchange of Pt single atoms, comprising: in a protective atmosphere, using an aromatic compound as a substrate, using an inorganic semiconductor nanomaterial loaded with metal single atoms Pt as a photocatalyst, adding a deuterium source, and carrying out a hydrogen-deuterium exchange reaction under room temperature and visible light irradiation conditions to obtain deuterated aromatic hydrocarbons.

[0007] A second aspect of the present invention provides the application of the aforementioned method in the field of deuterated drug preparation.

[0008] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0009] 1) This invention uses inorganic semiconductor nanomaterials loaded with metal single atoms Pt as photocatalysts, achieving nearly 100% metal atom utilization, providing high-density and uniform active sites, significantly improving catalytic efficiency and selectivity, and overcoming the defects of low metal utilization and non-uniform active sites in traditional nanoparticle catalysts.

[0010] 2) This invention uses inexpensive D2O as a deuterium source, and can realize the direct hydrogen-deuterium exchange reaction of aromatics under room temperature, normal pressure and visible light irradiation conditions. It avoids the use of high temperature, high pressure, expensive deuterium source and complex metal complex catalyst. It has the advantages of simple and easy method, mild conditions, safe operation and low cost, and has high economic value.

[0011] 3) The Pt single-atom photocatalyst used in this invention has high selectivity, is easy to obtain, has good stability, can be reused, and the product separation is simple, without the need for complex column chromatography purification, and is easy to scale up for production, providing a feasible technical solution for the large-scale preparation of deuterated chemicals. Attached Figure Description

[0012] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0013] Figure 1 The X-ray diffraction data of the photocatalysts TiO2-h and Pt1 / TiO2-h in Example 1 of this invention are shown.

[0014] Figure 2 These are scanning electron microscope (SEM) images of the photocatalysts TiO2-h and Pt1 / TiO2-h in Example 1 of this invention. Figure 2 A is a scanning electron microscope image of TiO2-h. Figure 2 B is a scanning electron microscope image of Pt1 / TiO2-h;

[0015] Figure 3 These are transmission electron microscope and elemental analysis images of the photocatalyst Pt1 / TiO2-h in Example 1 of this invention;

[0016] Figure 4 The image shown is an aberration-corrected electron microscope image of the photocatalyst Pt1 / TiO2-h in Example 1 of this invention.

[0017] Figure 5 The image shows the performance of different photocatalysts (different noble metals and supports) in Example 2 of this invention.

[0018] Figure 6 The infrared spectra of phenol adsorbed by photocatalysts Pt1 / TiO2-h and Pd1 / TiO2-h in Example 2 of this invention are shown.

[0019] Figure 7 The graph shows the performance of the photocatalyst Pt1 / TiO2-h in Example 2 of this invention at different light wavelengths.

[0020] Figure 8 The graph shows the performance of the photocatalyst Pt1 / TiO2-h in Example 2 of this invention at different reaction times.

[0021] Figure 9 The graph shows the performance of the photocatalyst Pt1 / TiO2-h with different Pt loadings in Example 2 of this invention.

[0022] Figure 10 The 1H NMR spectrum of the raw material in Example 2 of this invention ( 1 H NMR);

[0023] Figure 11 The 1H NMR spectrum of the product in Example 2 of this invention ( 1 H NMR);

[0024] Figure 12 The 1H NMR spectrum of the raw material in Example 3 of this invention ( 1 H NMR);

[0025] Figure 13 The 1H NMR spectrum of the product in Example 3 of this invention ( 1 H NMR);

[0026] Figure 14 The 1H NMR spectrum of the raw material in Example 4 of this invention ( 1 H NMR);

[0027] Figure 15 The 1H NMR spectrum of the product in Example 4 of this invention ( 1 H NMR);

[0028] Figure 16 The 1H NMR spectrum of the raw material in Example 5 of this invention ( 1 H NMR);

[0029] Figure 17 The 1H NMR spectrum of the product in Example 5 of this invention ( 1 H NMR);

[0030] Figure 18 The 1H NMR spectrum of the raw material in Example 6 of this invention ( 1 H NMR);

[0031] Figure 19 The 1H NMR spectrum of the product in Example 6 of this invention ( 1 H NMR). Detailed Implementation

[0032] In recent years, the rise of single-atom catalysis has provided entirely new ideas for the design of deuteration reactions. In single-atom catalysts, metal atoms are dispersed in an isolated form on the surface of the support, achieving 100% metal atom utilization and forming uniform and tunable active centers. This structure not only far surpasses traditional nanoparticle catalysts in catalytic efficiency and selectivity, but also allows for precise regulation of reaction pathways by controlling metal-support interactions. Especially in the field of photocatalysis, single-atom photocatalysts possess the dual advantages of light absorption and atomic-level catalysis, enabling efficient separation and utilization of photogenerated electrons and holes, thereby driving a series of chemical transformation reactions under mild conditions, demonstrating enormous development potential.

[0033] To address the problems of harsh reaction conditions, high deuterium source costs, and low catalyst efficiency in existing technologies, the inventors of this invention, through long-term research and extensive practice, have proposed a technical solution. The main focus is a Pt single-atom photocatalytic method for preparing deuterated aromatics via hydrogen-deuterium exchange. This catalyst achieves nearly 100% metal atom utilization through its single-atom structure, providing a high density and uniformity of active sites, enabling the deuteration reaction to proceed efficiently at room temperature and in an inert atmosphere. This achieves efficient deuteration reactions using inexpensive deuterium sources at room temperature and atmospheric pressure. Using inexpensive D₂O as the deuterium source, this system can efficiently deuterate various aromatics and their derivatives, exhibiting excellent stability. It effectively overcomes the problems of low metal utilization and uneven distribution of active sites inherent in traditional metal nanoparticle catalysts, providing a safe, economical, and efficient new route for aromatic deuteration reactions.

[0034] The technical solution of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0035] Specifically, as one aspect of the technical solution of this invention, a method for preparing deuterated aromatic hydrocarbons by photocatalytic hydrogen-deuterium exchange of Pt single atoms includes: in a protective atmosphere, using aromatic compounds as substrates, using inorganic semiconductor nanomaterials loaded with metal single atoms Pt as photocatalysts, adding a deuterium source, and carrying out a hydrogen-deuterium exchange reaction under room temperature and visible light irradiation conditions to obtain deuterated aromatic hydrocarbons.

[0036] The above-mentioned solution of the present invention uses inorganic semiconductor nanomaterials loaded with metal single atoms Pt as photocatalysts (i.e., single-atom Pt photocatalysts). By utilizing the nearly 100% metal atom utilization rate and high density of uniform active sites of single-atom catalysts, the efficient activation of aromatic CH bonds and hydrogen-deuterium exchange are achieved under visible light driving, avoiding harsh conditions such as high temperature and high pressure, significantly reducing reaction costs and improving safety.

[0037] The principle of this invention is as follows: First, the hydroxyl or amino group of an aromatic compound reacts with a single atom Pt. δ+ Coordination complexation occurs at the site. Subsequently, under visible light excitation, photogenerated electrons migrate from the semiconductor conduction band to the single-atom Pt center, modulating the charge state of the Pt-O coordination bond. The excited-state Pt-O site then promotes the activation of nearby aromatic C(sp²)–H bonds via electrophilic platinumization. Subsequently, the possible transition state species undergo an H / D exchange reaction with D₂O to generate HOD. Finally, the reaction yields deuterated aromatic hydrocarbons and releases Pt-O sites, which can be restored to the ground state by photogenerated holes or hydroxyl radicals.

[0038] In some embodiments, the aromatic compound has the structural formula shown in formula (I):

[0039] Equation (I)

[0040] Wherein, X includes one of -OH and -NH2, and R includes an alkyl or aryl group.

[0041] In some preferred embodiments, the aromatic compounds may include, but are not limited to, one or more of the following natural product molecules: phenol and / or phenol derivatives, aniline and / or aniline derivatives, catechin, phloretin, etc.

[0042] The above-mentioned scheme of the present invention, by selecting specific types of aromatic compounds and utilizing the coordination of specific functional groups in their molecular structure with single-atom Pt sites, achieves selective activation of CH bonds at specific positions, thereby improving the regioselectivity and yield of the deuteration reaction.

[0043] In some embodiments, the inorganic semiconductor nanomaterial is TiO2, and the Pt loading rate is 0.5 wt.%~2.0 wt.%, preferably 0.5 wt.%~1.0 wt.%. This catalyst exhibits high selectivity, is readily available, has good stability, and is reusable.

[0044] The above-mentioned solution of the present invention optimizes the light absorption performance and active site density of the photocatalyst by limiting the loading rate of inorganic semiconductor materials and Pt, thereby avoiding metal agglomeration while ensuring catalytic activity and realizing efficient separation and utilization of photogenerated carriers.

[0045] In some preferred embodiments, the inorganic semiconductor nanomaterial is prepared as follows: titanium tetrachloride is used as the titanium source and is slowly added dropwise to anhydrous ethanol, followed by ultrasonic oscillation to form a homogeneous solution. Subsequently, the solution is left to stand in a sealed environment for 24 hours, where it absorbs trace amounts of moisture from the air, initiating hydrolysis and condensation reactions to gradually form a transparent sol and eventually transform into a dry gel. This dry gel is then dried at 80°C and calcined at a slow heating rate of 300–500°C to obtain white TiO2-h nanopowder.

[0046] Furthermore, the volume ratio of titanium tetrachloride to anhydrous ethanol is 1:10.

[0047] Furthermore, the method for loading metal Pt is one of photodeposition reduction, chemical reduction, coprecipitation, impregnation, etc. For example, a certain amount of TiO2-h nanopowder is taken, H2PtCl6 and deionized water are added, and photodeposition loading is carried out under 410 nm visible light irradiation in an argon atmosphere, and then centrifuged and dried to obtain the photocatalyst Pt1 / TiO2-h.

[0048] In some embodiments, the mass ratio of the photocatalyst to the deuterium source is greater than 1:40. This invention ensures a sufficient supply of deuterium source in the reaction system by controlling the ratio of catalyst to deuterium source, while avoiding catalyst waste, thus improving deuteration efficiency and economy. When the mass ratio of catalyst to D2O is less than 1:40, the relatively insufficient deuterium source limits the full progress of the hydrogen-deuterium exchange reaction.

[0049] In the implementation scheme, the deuterium source is D2O. Using inexpensive and readily available D2O as the deuterium source replaces expensive deuterium gas or deuterated organic solvents, significantly reducing the raw material cost of the deuteration reaction and making the operation safer and more convenient.

[0050] In the implementation scheme, the light source used for illumination has a wavelength of 365-600 nm, preferably 365-450 nm. For example, the light source wavelength used for illumination can be 410 nm or 450 nm. This invention effectively excites the semiconductor photocatalyst by selecting visible light of a specific wavelength, driving the subsequent hydrogen-deuterium exchange reaction.

[0051] In the implementation scheme, for substrates with poor solubility, one of the organic solvents such as acetone, isopropanol, and acetonitrile can be added as a co-solvent to accelerate the reaction. This invention improves the dispersibility of poorly soluble substrates in the reaction system by adding a co-solvent, increasing the probability of contact between the substrate and the catalyst, thereby accelerating the reaction rate and improving the conversion rate.

[0052] In a similar embodiment, the hydrogen-deuterium exchange reaction takes 1 to 12 hours, preferably more than 3 hours, and particularly preferably more than 6 hours.

[0053] The above scheme optimizes the reaction time, ensuring a high deuteration rate while avoiding unnecessary energy consumption and time waste.

[0054] Furthermore, the method also includes: centrifuging directly after the synthesis reaction is completed, and then rotary evaporating the supernatant to remove the solvent to obtain deuterated aromatic hydrocarbons, without the need for column chromatography separation and purification.

[0055] In some more specific embodiments, a method for preparing deuterated aromatics by Pt single-atom photocatalytic hydrogen-deuterium exchange includes the following steps: using aromatic compounds as substrates, using inorganic semiconductor nanomaterials supported on metal Pt as single-atom photocatalysts, adding a deuterium source, introducing argon gas for protection, and stirring the reaction under room temperature and visible light irradiation conditions to synthesize deuterated aromatics, as shown in the following reaction formula:

[0056] As another aspect of the technical solution of the present invention, it also relates to the application of the aforementioned method in the field of deuterated drug preparation.

[0057] Using the above technical solution, the method of the present invention is the first example of Pt single-atom photocatalysis for direct hydrogen-deuterium exchange of aromatics, which is more innovative than metal nanoparticle photocatalysis. This deuteration method is carried out at room temperature and atmospheric pressure, which solves the defects of existing deuteration reactions that require high temperature, high pressure, expensive deuterium sources and complex metal complex catalysts. The method is simple and easy to implement, the conditions are mild, the operation is safe, and the product separation is simple, which provides the possibility for the large-scale production of deuterated chemicals.

[0058] The present invention is further illustrated below by way of examples, but is not intended to limit the invention. Specific materials used in the embodiments of the present invention and their sources are provided below. However, it should be understood that these are merely exemplary and not intended to limit the invention. Materials of the same or similar type, model, quality, properties, or function as the reagents and instruments described below can be used to implement the present invention. Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials, reagents, etc., used in the following examples are commercially available.

[0059] Example 1: Preparation of photocatalyst

[0060] 1. Preparation of TiO2-h:

[0061] (1) Using titanium tetrachloride as the titanium source, it was slowly added dropwise to anhydrous ethanol (the volume ratio of titanium tetrachloride to anhydrous ethanol was 1:10), and a homogeneous solution was formed by ultrasonic vibration for 3 h.

[0062] (2) The solution obtained in step (1) was left to stand at room temperature for 24 h in a closed environment. It gradually formed a transparent sol and eventually turned into a dry gel by absorbing trace amounts of water vapor in the air to initiate hydrolysis and condensation reactions.

[0063] (3) After drying the dry gel obtained in step (2) at 80°C, it is calcined at 300~500°C for 4 h at a heating rate of 1°C / min to obtain white TiO2-h nanopowder.

[0064] 2. Preparation of Pt1 / TiO2-h:

[0065] Take 500 mg of TiO2-h prepared in the above steps, add H2PtCl6 and deionized water, and perform photodeposition loading by irradiating the reaction solution with 410 nm visible light at room temperature and in an argon atmosphere for 10 h. After the reaction solution turns grayish-brown, centrifuge and dry to obtain the photocatalyst Pt1 / TiO2-h. The prepared TiO2-h and Pt1 / TiO2-h were characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, and spherical aberration electron microscopy. The results are as follows: Figures 1-4 As shown. Specifically, the X-ray diffraction data of TiO2-h and Pt1 / TiO2-h are as follows: Figure 1 As shown, the sample loaded with Pt did not exhibit characteristic diffraction peaks of metallic Pt or Pt oxide, indicating that the Pt species were highly dispersed on the support surface and did not form nanoparticle aggregates. Scanning electron microscopy (SEM) images of TiO2-h and Pt1 / TiO2-h are shown below. Figure 2 As shown, the support exhibits a uniform morphology of spherical particle aggregation, and the morphology did not change significantly after loading Pt. Transmission electron microscopy (TEM) and elemental analysis of Pt1 / TiO2-h are shown below. Figure 3 As shown, the uniform distribution of Pt on the TiO2 support is confirmed. The spherical aberration electron microscopy (HAADF-STEM) image of Pt1 / TiO2-h is shown below. Figure 4 As shown, numerous isolated bright spots were clearly observed, corresponding to individual Pt atoms, proving that Pt is dispersed on the support surface in a single-atom form, rather than in clusters or nanoparticles. This single-atom dispersion feature enables nearly 100% utilization of metal atoms, providing a high density and uniformity of active sites, laying the structural foundation for the subsequent efficient driving of hydrogen-deuterium exchange reactions under mild conditions.

[0066] Photocatalysts containing different noble metals and supports were also prepared by the photodeposition method described in Example 1.

[0067] Example 2 Preparation of deuterated 4-methoxyphenol (4-Methoxyphenol-d2)

[0068]

[0069] In a vial equipped with a magnetic stirrer, add 0.1 mmol (12.4 mg) of 4-methoxyphenol, 50 mg of photocatalyst (0.7 wt.% Pt1 / TiO2-h), and 2 mL of D2O. Place the vial in a stainless steel reactor with a glass lens on top, rinse with argon gas 3-5 times, and then stir the reaction under an LED lamp with a wavelength of 450 nm for 6 h. Transfer the reaction solution to a 10 mL centrifuge tube, centrifuge to obtain the supernatant, and perform NMR detection directly. The deuteration rate of the ortho-CH bond of the hydroxyl group was found to be 95%.

[0070] The proton NMR spectrum of the raw material is as follows Figure 10 As shown: 1 H NMR (400 MHz, D2O) δ 6.90 – 6.86 (m, 2H), 6.85 – 6.81 (m, 2H), 3.75 (s, 3H).

[0071] The 1H NMR spectrum of the product is as follows Figure 11 As shown: 1 H NMR (400 MHz, DO) δ 6.93 (s, 1.67H), 6.88 (d, J = 8 Hz, 0.10H), 3.80 (s, 3H).

[0072] Using Example 2 as a model reaction, different noble metals (Pt) were changed while keeping other conditions constant. n (e.g., Pd1, Rh, Ir, Au), or changing the inorganic semiconductor nanocarrier (rutile TiO2, Nb2O5, SrTiO3, In2O3, C3N4, BiVO4, BiOCl) under otherwise unchanged conditions, its deuteration rate is as follows: Figure 5 As shown in the figure. The results show that only the Pt1 / TiO2-h catalyst exhibits deuteration performance. This is mainly because, when noble metals are supported on TiO2-h or other semiconductor supports are used, the metal components do not exist in single-atom form. Notably, even when Pd is supported on TiO2-h in single-atom form, it does not exhibit deuteration performance. We found this through infrared characterization (see reference). Figure 6Byproducts were generated on the Pd1 / TiO2 surface, which hindered the deuteration reaction of phenol and D2O.

[0073] When using Example 2 as a model reaction, and changing different light wavelengths (365-600nm) while keeping other conditions constant, the deuteration rate is as follows: Figure 7 As shown in the figure, the catalyst exhibits high deuteration activity in the wavelength range of 365–450 nm, with particularly significant effects at 410 nm and 450 nm. This is mainly because the light absorption capacity of the Pt1 / TiO2-h photocatalyst is limited; when the wavelength exceeds 500 nm, Pt1 / TiO2-h does not exhibit deuteration activity.

[0074] When using Example 2 as a model reaction, and changing different reaction times (0-7h) while keeping other conditions constant, the deuteration rate is as follows: Figure 8 As shown, the preferred reaction time is 3 hours or more, at which point the deuteration rate can reach over 84%, and a more preferred reaction time is 6 hours or more, at which point the deuteration rate can reach over 95%. The deuteration rate shows an increasing trend with reaction time, rising to 84% within 3 hours. Subsequently, from 3 hours to 7 hours, the deuteration rate slows down (from 84% to 96% deuteration rate) because most reactants have been deuterated by this time, and the probability of collision between the photocatalyst active sites and undeuterated molecules is significantly reduced.

[0075] When using Example 2 as a model reaction, and changing different Pt loadings (0-1.0 wt.%) while keeping other conditions constant, the deuteration rate is as follows: Figure 9 As shown in the figure, the experimental results indicate that the deuteration rate increases significantly when the loading increases from 0 to 0.7 wt.%, which is attributed to the increase in the number of active sites in the photocatalyst; when the loading reaches approximately 0.7 wt.%, the deuteration rate reaches 95%; when the loading is further increased to above 1.0 wt.%, the increase in deuteration rate tends to level off. This suggests that in 1 wt.% Pt1 / TiO2-h with a higher loading, some Pt ​​species may exist in the form of clusters or nanoparticles.

[0076] Example 3: Preparation of deuterated 4-methylaniline (p-Toluidine-d2)

[0077]

[0078] In a stainless steel reactor with a glass lens on top, add 0.1 mmol (10.7 mg) of 4-methylaniline, 50 mg of photocatalyst (0.7 wt.% Pt1 / TiO2-h), and 2 mL of D2O; rinse with argon gas 3-5 times, and heat to 60°C. oC. The reaction was stirred for 6 h under LED light with a wavelength of 410 nm. The reaction solution was then transferred to a 10 mL centrifuge tube and centrifuged to obtain the supernatant, which could be directly subjected to NMR detection. The deuteration rate of the ortho-CH bond of the amino group was found to be 94%.

[0079] The proton NMR spectrum of the raw material is as follows Figure 12 As shown: 1 H NMR (400 MHz, D2O) δ 7.09 (d, J = 8 Hz, 2H), 6.79 (d, J = 8 Hz, 2H), 2.23 (s, 3H).

[0080] The 1H NMR spectrum of the product is as follows Figure 13 As shown: 1 H NMR (400 MHz, DO) δ 7.09 (s, 1.80H), 6.78 (d, J = 8 Hz, 0.10H), 2.23 (s, 3H).

[0081] Example 4 Preparation of deuterated 3-(4-morpholinyl)aniline (3-(4-Morpholinyl)aniline-d3)

[0082]

[0083] In a stainless steel reactor with a glass lens on top, add 0.1 mmol (17.8 mg) of 3-(4-morpholino)aniline, 50 mg of photocatalyst (0.7 wt.% Pt1 / TiO2-h), 1.6 mL of D2O, and 0.4 mL of acetone; rinse with argon gas 3-5 times, and heat to 60°C. o C. The reaction was stirred for 12 h under LED light at a wavelength of 410 nm. The reaction solution was then transferred to a 10 mL centrifuge tube and centrifuged to obtain the supernatant. The supernatant was then rotary evaporated to obtain the solid product. After dissolving it in CDCl3, NMR was performed, and the deuteration rate of the ortho- and para-CH bonds of the amino group was found to be 87%.

[0084] The proton NMR spectrum of the raw material is as follows Figure 14 As shown: 1 H NMR (400 MHz, CDCl3) δ 6.80 (d, J = 8 Hz, 2H), 6.66 (d, J = 8 Hz, 2H), 3.85 (t, J = 4 Hz, 4H), 3.44 (s, 2H), 3.02 (t, J = 4 Hz, 4H).

[0085] The 1H NMR spectrum of the product is as follows Figure 15 As shown: 1H NMR (400 MHz, CDCl3) δ 6.80 (s, 1.90H), 6.66 (t, J = 4 Hz, 0.30H), 3.85 (t, J = 4 Hz, 4H), 3.35 (s, 0.92H), 3.02 (t,J = 4 Hz, 4H).

[0086] Example 5: Preparation of deuterated catechin (Cianidanol-d2)

[0087]

[0088] In a vial equipped with a magnetic stirrer, add 0.1 mmol (29.1 mg) of catechin, 50 mg of photocatalyst (0.7 wt.% Pt1 / TiO2-h), and 2 mL of D2O. Place the vial in a stainless steel reactor with a glass lens on top, rinse with argon gas 3-5 times, and then stir the reaction under an LED lamp with a wavelength of 410 nm for 6 h. Transfer the reaction solution to a 10 mL centrifuge tube, centrifuge to obtain the supernatant, and perform NMR detection directly. The deuteration rate of the ortho-CH bond of the hydroxyl group was found to be 99%.

[0089] The proton NMR spectrum of the raw material is as follows Figure 16 As shown: 1 H NMR (400 MHz, D2O) δ 6.95 (d, J = 12 Hz,2H), 6.87 (d, J = 8 Hz, 1H), 6.11 (s, 1H), 6.02 (s, 1H), 4.74 (d, J = 4 Hz,1H), 4.19 (q, J = 16, 8 Hz, 1H), 2.88 (dd, J = 16, 8 Hz, 1H), 2.54 (dd, J =16, 8 Hz, 1H).

[0090] The 1H NMR spectrum of the product is as follows Figure 17 As shown: 1 H NMR (400 MHz, D2O) δ 6.93 (d, J = 12 Hz, 2H), 6.85 (d, J = 8 Hz, 1H), 6.09 (s, 0.01H), 6.00 (s, 0.02H), 4.68 (d, J = 8Hz, 1H), 4.15 (q, J = 12, 8 Hz, 1H), 2.87 (dd, J = 16, 4 Hz, 1H), 2.51 (dd, J= 16, 8 Hz, 1H).

[0091] Example 6 Preparation of deuterated phloretin (Phloretin-d4)

[0092]

[0093] In a vial equipped with a magnetic stirrer, 0.1 mmol (27.4 mg) of phlorizin, 50 mg of photocatalyst (0.7 wt.% Pt1 / TiO2-h), 1.6 mL of D2O, and 0.4 mL of acetone were added. The vial was placed in a stainless steel reactor with a glass lens on top, rinsed with argon gas 3-5 times, and then stirred for 6 h under LED light at a wavelength of 410 nm. The reaction solution was transferred to a 10 mL centrifuge tube, centrifuged to obtain the supernatant, and the supernatant was rotary evaporated to obtain the solid product. After dissolving in DMSO-d6, NMR was performed, and the deuteration rates of the ortho-CH hydroxyl group were found to be 94% and 92%, respectively.

[0094] The proton NMR spectrum of the raw material is as follows Figure 18 As shown: 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 2H), 10.36 (s, 1H), 9.15 (s, 1H), 7.01 (d, J = 8 Hz, 2H), 6.66 (d, J = 8 Hz, 2H), 5.80 (s, 2H), 3.21 (t, J = 8 Hz, 2H), 2.76 (t, J = 8 Hz, 2H).

[0095] The 1H NMR spectrum of the product is as follows Figure 19 As shown: 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (d, J = 8Hz, 1.16H), 10.36 (s, 0.58H), 9.14 (s, 0.60H), 7.02 (s, 2H), 6.66 (d, J = 8Hz, 0.13H), 5.82 (s, 0.16H), 3.24 – 3.16 (m, 1.46H), 2.77 (t, J = 8 Hz, 2H).

[0096] As demonstrated in Examples 5 and 6, the method provided by this invention is not only applicable to simple small molecules such as phenol or aniline, but also exhibits excellent catalytic effects on natural product molecules with more complex structures and multiple active sites. This indicates that single-atom photocatalysts can accurately identify and activate specific CH bonds in natural product molecules, achieving efficient and highly selective hydrogen-deuterium exchange.

[0097] In the field of drug development, deuteration has become an important drug modification strategy. Replacing specific hydrogen atoms in a drug molecule with deuterium atoms, utilizing the deuterium isotope effect, can significantly improve the pharmacokinetic properties of drugs, such as prolonging half-life and reducing the formation of toxic metabolites. However, traditional deuterated drug synthesis methods often face problems such as complex synthetic routes, expensive deuterium sources, and harsh reaction conditions, limiting the widespread development of deuterated drugs. The method provided by this invention offers a new technical approach to overcome the above-mentioned technical bottlenecks.

[0098] Specifically, the method described in this invention has significant advantages in the field of deuterated drug preparation. This invention utilizes a Pt single-atom photocatalyst as its core to construct a novel, efficient, safe, and economical aromatic hydrocarbon deuteration system. First, this method uses relatively inexpensive and readily available D₂O as the deuterium source, replacing expensive deuteration reagents such as D₂ and C₆D₆ commonly used in traditional processes, significantly reducing the production cost of deuterated drug intermediates and enabling large-scale preparation of deuterated drugs. Second, this method not only achieves highly selective hydrogen-deuterium exchange reactions under room temperature and mild conditions but also significantly improves the utilization rate of precious metal atoms, reducing reaction costs. Compared with traditional deuteration strategies, the method of this invention exhibits significant advantages in reactivity, versatility, and sustainability, providing a new technical approach and theoretical basis for the green synthesis of deuterated aromatics and the development of deuterated drugs. Furthermore, as shown in Examples 5 and 6, this method has excellent deuteration effects on complex natural product molecules such as catechins and phloretin, demonstrating its universality for complex drug molecule structures and enabling the efficient synthesis of deuterated drug intermediates that are difficult to prepare using traditional methods.

[0099] It should be understood that the applications described in this invention are not limited to the direct synthesis of the final deuterated drug molecule, but also include the synthesis of deuterated drug intermediates. The deuterated aromatic hydrocarbons prepared by the method of this invention can serve as key intermediates, further used to construct more complex drug molecule structures through reactions such as coupling and condensation. For example, in the synthesis of antitumor drugs, antiviral drugs, or nervous system drugs, introducing deuterium atoms using the method of this invention can effectively improve the metabolic stability of the drugs. Furthermore, the high selectivity of this method (such as the ortho-selectivity shown in Example 2) allows medicinal chemists to precisely introduce deuterium atoms at specific metabolic sites of the molecule, thereby more accurately regulating the metabolic behavior of the drug and providing a powerful tool for the development of deuterated drugs.

[0100] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for preparing deuterated aromatic hydrocarbons by Pt single-atom photocatalytic hydrogen-deuterium exchange, characterized in that, include: In a protective atmosphere, using aromatic compounds as substrates and inorganic semiconductor nanomaterials loaded with single-atom metal Pt as photocatalysts, a deuterium source is added, and a hydrogen-deuterium exchange reaction is carried out under room temperature and visible light irradiation to obtain deuterated aromatics.

2. The method according to claim 1, characterized in that: The structural formula of the aromatic compounds is shown in formula (Ⅰ): ， Equation (I) Wherein, X includes one of -OH and -NH2, and R includes an alkyl or aryl group.

3. The method according to claim 1, characterized in that: The aromatic compounds include one or more combinations of phenol and / or phenol derivatives, aniline and / or aniline derivatives, catechins, and phloretin.

4. The method according to claim 1, characterized in that: The inorganic semiconductor nanomaterial is TiO2, and the Pt loading rate is 0.5 wt.% ~ 2.0 wt.%, preferably 0.5 wt.% ~ 1.0 wt.%.

5. The method according to claim 1, characterized in that: The mass ratio of the photocatalyst to the deuterium source is greater than 1:

40.

6. The method according to claim 1, characterized in that: The deuterium source is D2O.

7. The method according to claim 1, characterized in that: The wavelength of the light source used for illumination is 365~600nm, preferably 365~450nm.

8. The method according to claim 1, characterized in that, include: A co-solvent is also added, which includes one of acetone, isopropanol, and acetonitrile.

9. The method according to claim 1, characterized in that: The hydrogen-deuterium exchange reaction takes 1 to 12 hours, preferably more than 3 hours, and especially more than 6 hours.

10. The application of the method according to any one of claims 1 to 9 in the field of deuterated drug preparation.

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