Method for photocatalytic synthesis of polydeuterium substituted amine

Abstract

The invention discloses a method for photocatalytic synthesis of polydeuterium substituted amine, and relates to the technical field of chemical synthesis. The method comprises the step of reacting a carbonyl compound with an amine compound in the presence of a deuterium-containing reagent, a mercaptan catalyst and a reducing agent under the conditions of a photocatalyst and illumination to obtain the polydeuterium substituted amine. According to the method disclosed by the invention, multiple introduction of deuterium atoms at alpha-carbon sites of a target amine product is realized through a series free radical mechanism initiated by photon-generated carriers, so that simple and easily available raw materials are directly converted into the polydeuterium substituted amine. According to the invention, the ubiquitous problems that only one deuterium atom can be introduced to a nitrogen alpha-site, the synthesis route is tedious, the operation steps are complicated and the existing deuterated amine synthesis technology depends on an expensive deuterium source or a metal catalyst are solved; the invention provides a novel polydeuterium substituted amine synthesis strategy which has the advantages of simple steps, mild conditions, high atom economy and easiness in large-scale production.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and in particular to a method for photocatalytic synthesis of polydeuterated amines. Background Technology

[0002] In drug development, the strategy of selectively introducing deuterium atoms at key metabolic sites, known as deuteration modification, has become an important research direction for improving the metabolic properties of drugs. The mechanism of this strategy is based on the fact that carbon-deuterium bonds have higher bond energies than carbon-hydrogen bonds and can produce a significant kinetic isotope effect (KIE), thereby slowing down the rate at which drug molecules are catalyzed and broken down in vivo by metabolic enzymes (such as cytochrome P450 oxidase).

[0003] Amine structures are widely found in drug molecules and are among the most common pharmacophores. In these structures, the carbon-hydrogen bond at the α-position of the nitrogen atom is prone to oxidative metabolic reactions, such as N-dealkylation, leading to loss of drug activity. Introducing a deuterium atom at this position can enhance the stability of this chemical bond, thereby delaying the related metabolic pathways.

[0004] Reductive amination is one of the important methods for amine synthesis. Statistics show that approximately one-quarter of carbon-nitrogen bonds (C–N) in the pharmaceutical industry are constructed through reductive amination, with deuterated reduced imines (C=N) being an effective route for precisely obtaining α-deuterated amines. However, existing methods are usually limited to introducing a single deuterium atom at the nitrogen α-position, making it difficult to introduce multiple deuterium atoms into the same molecule. This limits their application in situations requiring multiple deuterium substitutions to further regulate drug metabolism.

[0005] Therefore, there is an urgent need to develop a universal method for the efficient and highly selective synthesis of polydeuterated amines under mild conditions, in order to overcome the problems of single deuteration sites, complex synthesis steps, and high costs in existing technologies. Summary of the Invention

[0006] The technical problem to be solved by this invention is how to introduce multiple deuterium atoms into the same molecule to achieve the synthesis of polydeuterated amines.

[0007] To address the above problems, the present invention proposes the following technical solution: A method for photocatalytic synthesis of polydeuterated amines includes the following steps: under photocatalyst and light irradiation conditions, a carbonyl compound and an amine compound are reacted in the presence of a deuterium-containing reagent, a thiol catalyst, and a reducing agent to obtain a polydeuterated amine.

[0008] Understandably, the polydeuterium-substituted amines described in this invention refer to compounds in which at least one hydrogen atom at the carbon site (nitrogen α-position, β-position, etc.) connecting the amine group is replaced by a deuterium atom.

[0009] Preferably, the photocatalyst is selected from 4CzIPN, 4DPAIPN, 5CzBN, Poly-4CzIPN, or Poly-5CzBN. Compared with small molecule catalysts, the polymer framework can provide stable photoactive sites, effectively separate photogenerated charges, and its insolubility facilitates recovery and recycling after the reaction.

[0010] Preferably, the thiol catalyst is selected from thiophenol, alkyl thiol or mercaptoalkyl sulfonate.

[0011] The sulfur radical generated by the oxidation of the thiol group (-SH) in mercaptoalkyl sulfonates is a key mediator that initiates hydrogen atom transfer (HAT), driving the formation of CO2 from reducing agents (such as formate). - Mercaptoalkyl sulfonates can also rapidly undergo hydrogen-deuterium exchange with deuterium-containing reagents to generate deuterated thiols (R-SD), serving as a direct deuterium source for subsequent deuterium atom transfer (DAT) reactions. Mercaptoalkylates, especially water-soluble mercaptoalkyl sulfonates or mercaptoalkyl carboxylates, significantly improve reaction efficiency due to their good solubility, which facilitates uniform dispersion in the reaction system and their compatibility with deuterium-containing reagents and polar solvents. The mercaptoalkylates described in this invention include, but are not limited to, mercaptoethanesulfonate and mercaptopropanesulfonate.

[0012] Preferably, the mercaptoalkyl sulfonate comprises sodium 2-mercaptoethanesulfonate.

[0013] Preferably, the reducing agent is a formate.

[0014] It should be noted that in the HAT reaction initiated by sulfur free radicals, formate (HCOO) - It loses a hydrogen atom and efficiently transforms into a carbon dioxide free radical anion (·CO2). - This free radical possesses a moderate reduction potential, enabling it to selectively reduce imine intermediates to generate the crucial α-amino carbon radical without over-reducing other functional groups or initiating side reactions. Formate salts (such as sodium formate and ammonium formate) are inexpensive, stable, and readily available, making them ideal reducing agents.

[0015] Preferably, the deuterium-containing reagent includes heavy water (D2O) and deuterated alcohol.

[0016] The deuterium-containing reagent provides deuterium atoms for the entire reaction system. Deuterium atoms are introduced into the thiol molecule via a hydrogen-deuterium exchange reaction catalyzed by a thiol catalyst (R-SH + D₂O ⇌ R-SD + HDO), thus forming an in-situ deuterium source (R-SD). Subsequently, the deuterium atoms are transferred to the target molecule via the DAT reaction. Using heavy water as the deuterium source has significant advantages such as relatively low cost, safe operation, high deuterium atom utilization, and simple post-treatment (easy separation of the aqueous phase). Other deuterated reagents that can effectively exchange deuterium with the thiol used and provide deuterium atoms, such as deuterated alcohols, can also achieve similar effects.

[0017] Preferably, the reaction is carried out under illumination with a wavelength range of 400-450 nm. This wavelength range matches the absorption spectrum of the photocatalyst, maximizing the efficiency of exciting the catalyst to generate active charges. Illumination is the essential energy source for initiating the entire photocatalytic cycle.

[0018] Furthermore, the reaction is carried out under an inert atmosphere (such as nitrogen or argon). An inert atmosphere eliminates interference from oxidizing gases such as oxygen, preventing the carbon radical intermediates generated during the reaction from being quenched by oxygen or undergoing unnecessary oxidation side reactions, thus ensuring the high efficiency and selectivity of the reaction. An inert atmosphere is an important condition for achieving high conversion rates, but it is not absolutely necessary for all substrates.

[0019] Preferably, the reaction further includes a solvent, and the amount of solvent used is the amount required for the reaction. The solvent is selected from one or more of the following: ethanol, methanol, cyclohexane, n-hexane, n-pentane, n-heptane, petroleum ether, diethyl ether, tetrahydrofuran, dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile.

[0020] A suitable solvent should be able to effectively dissolve the various key components in the reaction, including catalyst fragments, formates, mercaptoalkyl sulfonates, and ionic or polar intermediates generated during the reaction, while not interfering with the hydrogen / deuterium atom transfer process as a proton donor. This helps maintain the homogeneity of the reaction system and promotes effective contact and reaction between the components. Preferred solvents include, but are not limited to, dichloromethane (DCM), 1,4-dioxane, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), and acetonitrile (MeCN).

[0021] Preferably, the reaction is carried out at room temperature.

[0022] In some embodiments, room temperature is expressed as 0-50 °C.

[0023] In some embodiments, room temperature is defined as 20-40 °C.

[0024] In some embodiments, room temperature is defined as 25-35 °C.

[0025] Preferably, the carbonyl compound is an aldehyde or ketone with the structural formula shown in formula (1); the amine compound is a primary amine or a secondary amine with the structural formula shown in formula (2). (1) (2); In the formula, R1 and R3 are each independently aryl, substituted aryl, polycyclic aryl, heterocyclic aryl, substituted heterocyclic aryl, substituted polycyclic aryl, C 1-18 Alkyl, C 1-10 cycloalkyl; R2 and R4 are independently hydrogen and C, respectively. 1-18 Alkyl, C 1-10 Cycloalkyl.

[0026] The present invention also provides the application of the photocatalytic synthesis method for polydeuterated amines in the preparation of polydeuterated drug molecules or biomass derivatives.

[0027] The present invention also provides a method for synthesizing polydeuterated drug molecules or biomass derivatives, including the method for photocatalytic synthesis of polydeuterated amines.

[0028] Preferably, the method includes a step of deuterating the inherent or derived amine structure in the drug molecule or biomass derivative using the photocatalytic synthesis of polydeuterated amines described in this invention.

[0029] In this invention, a drug molecule refers to a compound that has pharmacological activity or serves as a drug intermediate, and whose structure contains an amine group that can be modified by the method of this invention.

[0030] In this invention, biomass derivatives refer to compounds derived from biomass (such as sugars, lignin, oils, etc.) and obtained through chemical transformation, whose structures contain amine groups that can be modified by the method of this invention.

[0031] Understandably, the amine group can be an amine group that is present in the target molecule itself, or an amine group that is introduced through a simple chemical step (such as amination) for deuteration modification.

[0032] See Figure 1 The method for photocatalytic synthesis of polydeuterated amines provided by this invention involves the oxidation of a thiol catalyst by photogenerated holes under photocatalysis, generating corresponding sulfur free radicals. These sulfur free radicals drive a hydrogen atom transfer reaction in a reducing agent, producing highly reducing carbon dioxide free radical anions (·CO2). -This free radical, acting as a key reduction intermediate, can reduce the imine generated by the in-situ condensation of carbonyl compounds and amines, producing a nitrogen-α-carbon radical intermediate. Subsequently, this carbon radical intermediate undergoes a deuterium atom transfer reaction with a deuterated thiol generated in the system through hydrogen-deuterium exchange with a deuterium-containing reagent and a thiol catalyst, forming a monodeuterated amine. This monodeuterated amine can be further oxidized by photogenerated holes, regenerating a nitrogen-α-carbon radical, and can undergo another deuterium atom transfer process, thereby introducing a second deuterium atom at the same carbon site. This cycle can be repeated to sequentially introduce multiple deuterium atoms at this site, ultimately leading to the efficient synthesis of polydeuterated amine products. The entire process achieves the synergistic effect of photo-driven reductive amination and hydrogen-deuterium exchange, realizing a one-step direct conversion from ordinary carbonyl compounds and amines to polydeuterated amines.

[0033] Compared with the prior art, the technical effects achieved by the present invention include: The method for photocatalytic synthesis of polydeuterated amines provided by this invention utilizes a reaction system consisting of a photocatalyst, a deuterated reagent, a thiol catalyst, and a reducing agent. Through the coupling of deuteration-reductive amination initiated by carbon dioxide free radical anions and hydrogen-deuterium exchange mediated by thiol, aldehydes / ketones and amines can be directly and efficiently converted into polydeuterated amines within the same reaction system. This method has been successfully applied to the deuteration modification of drug molecules and biomass derivatives.

[0034] The method of this invention achieves multiple introductions of deuterium atoms into the α-carbon site of the target amine product through a tandem radical mechanism initiated by photogenerated carriers, thereby directly converting readily available raw materials into polydeuterated amines. This invention solves the problems commonly found in existing deuterated amine synthesis techniques, such as the ability to introduce only one deuterium atom at the nitrogen α-position, lengthy synthetic routes, complex operational steps, and reliance on expensive deuterium sources or metal catalysts. It provides a novel strategy for the synthesis of polydeuterated amines that is simple in procedure, mild in conditions, highly atom-economical, and easily scalable. Attached Figure Description

[0035] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the following description of the embodiments will be briefly introduced. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0036] Figure 1 This is a schematic diagram illustrating the reaction principle of the photocatalytic synthesis of polydeuterated amines provided in this embodiment of the invention. Figure 2 This is a schematic diagram of a partial catalyst structure provided in an embodiment of the present invention; Figure 3 The carbon NMR spectrum of α,α-dideuterated N-benzylaniline prepared in Example 4; Figure 4 The carbon NMR spectrum of α-deuterated N-(4-chlorobenzyl)aniline prepared in Example 5; Figure 5 The carbon NMR spectrum of α-deuterated N-cyclohexyl p-methoxyaniline obtained in Example 6; Figure 6 This is a schematic diagram showing the test results of the recycling performance of the catalyst Poly-5CzBN (demonstrating the relationship between the number of cycles and the yield and deuteration rate). Figure 7 The results are for different polydeuterated amines prepared in the embodiments of the present invention. Detailed Implementation

[0037] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Similar component reference numerals in the drawings represent similar components. Obviously, the embodiments described below are only some embodiments of the present invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0038] It should be understood that, when used in this specification and the appended claims, the terms "comprising" and "including" indicate the presence of the described features, integrals, steps, operations, elements and / or components, but do not exclude the presence or addition of one or more other features, integrals, steps, operations, elements, components and / or collections thereof.

[0039] It should also be understood that the terminology used in this specification of embodiments of the invention is for the purpose of describing particular embodiments only and is not intended to limit the embodiments of the invention. As used in this specification of embodiments of the invention and the appended claims, the singular forms “a,” “an,” and “the” are intended to include the plural forms unless the context clearly indicates otherwise.

[0040] The term "room temperature" means 0-50 °C; in some embodiments, room temperature means 20-40 °C, and in some embodiments, room temperature means 25-35 °C.

[0041] The amount of solvent required for the reaction as described in this invention is preferably sufficient to completely dissolve the reactants, and can be adapted to different reactants. In some embodiments, the amount of solvent required for the reaction may also be adapted to be more than the amount required to just dissolve the reactants.

[0042] This invention provides a method for photocatalytic synthesis of polydeuterium-substituted amines, comprising the following steps: under photocatalyst and light irradiation conditions, a carbonyl compound and an amine compound are reacted in the presence of a deuterium-containing reagent, a thiol catalyst, and a reducing agent to obtain a polydeuterium-substituted amine. The polydeuterium-substituted amine refers to an amine compound in which at least one hydrogen atom directly bonded to a carbon atom is replaced by a deuterium atom.

[0043] In the method of this invention, the molar ratio of the carbonyl compound to the amine compound is 1:1.0-2.0, preferably 1:1.5. The amount of the photocatalyst is 0.5-5.0 mol% of the molar amount of the amine compound, preferably 2.0 mol%. The amount of the thiol catalyst is 1.0-15.0 mol% of the molar amount of the amine compound, preferably 5.0 mol%. The amount of the reducing agent is 1.2 to 3.0 times the equivalent amount of the carbonyl compound, preferably 2.0 times. The deuterium-containing reagent can be used as the main solvent of the reaction or mixed with other polar aprotic solvents. The reaction effect is best when it is used as the sole solvent. If a co-solvent is required, the volume percentage of the polar aprotic solvent (such as acetonitrile, N,N-dimethylformamide) shall not exceed 50%. In the reaction system, the initial concentration of the amine compound is preferably 0.05-0.5 mmol / mL, more preferably 0.1 mmol / mL.

[0044] The method of this invention can efficiently and selectively synthesize polydeuterated amines with a degree of deuteration higher than 90% under mild conditions.

[0045] Example 1: Catalyst Screening The performance of different photocatalysts was investigated under standard reaction conditions (using sodium messodium as a thiol catalyst, sodium formate as a reducing agent, D2O as a deuterium source, DMSO as a solvent, 420 nm LED illumination, and reaction under a nitrogen atmosphere for 12 hours) according to the following reaction formula. The results are summarized in Table 1. Table 1. Reaction effects of different photocatalysts The structures of some catalysts are as follows: Figure 2 As shown in Table 1, the heterogeneous organic polymer catalyst Poly-5CzBN exhibits the best performance in both yield and deuteration rate, and is therefore selected as the catalyst for subsequent examples.

[0046] Example 2 Solvent Screening In this embodiment, Poly-5CzBN was used as the photocatalyst, and other conditions were the same as in Example 1. The reaction effects of different solvents were investigated, and the results are summarized in Table 2. Table 2 Reaction effects of different solvents Among the various solvent systems investigated, dimethyl sulfoxide (DMSO) yielded the best reaction yield and deuteration rate. This is presumably because DMSO exhibits good solubility for the reactants (such as mesna and sodium formate) and is miscible with water, which facilitates the homogenization of the reaction system and promotes efficient reaction.

[0047] Example 3 Screening of thiol catalysts In this embodiment, thiophenols, alkyl thiols, and diphenyl sulfides with different substituents were used as thiol catalysts, and other conditions were the same as in Example 1. Experimental results showed that the above-mentioned thiol catalysts all exhibited poor reaction performance, with yields between 10-30%. Only when messo was used as the sulfur source could the target deuterated product be prepared efficiently.

[0048] Furthermore, this invention replicated the operation of Example 3 under controlled experiments, respectively, without the addition of a photocatalyst (Poly-5CzBN), a thiol catalyst (mesna), or a reducing agent (sodium formate). The experimental results showed that the photocatalyst, thiol catalyst, and reducing agent are all indispensable; the absence of any one of these conditions resulted in the reaction failing or yielding extremely low yields (<5%), thus confirming the necessity of the photocatalyst, thiol catalyst, and reducing agent in the reaction system of this invention.

[0049] The screening results of the above embodiments show that the optimal reaction conditions for the method for preparing polydeuterated amines provided by the present invention, under room temperature and a nitrogen protective atmosphere, using heavy water (D2O) as the deuterating agent and irradiated with 420 nm visible light, are as follows: a deuteration-reductive amination reaction initiated by carbon dioxide radical anions using Poly-5CzBN as the photocatalyst, DMSO as the solvent, and messo as the thiol catalyst, coupled with a thiol-mediated hydrogen-deuterium exchange reaction. This allows for the direct and efficient conversion of aldehydes / ketones and amines into the corresponding polydeuterated amine products within the same reaction system, exhibiting optimal reaction efficiency and deuteration effect. The following examples demonstrate the preparation of compounds under the optimal reaction conditions obtained through screening.

[0050] Example 4: Preparation of α,α-dideuterated N-benzylaniline The reaction formula is as follows: .

[0051] Poly-5CzIPN (10 mg, 0.02 mmol), sodium formate (68 mg, 1 mmol), sodium mercaptoethanol (15.6 mg, 0.2 mmol), and imine (36 mg, 0.2 mmol) were added sequentially to a 25 mL Srank tube. The atmosphere in the reaction system was purged by vacuum and backfilled with nitrogen (this process was repeated three times). Under a nitrogen atmosphere, D2O (0.50 mL, 27.8 mmol, 22.2 equivalents) and DMSO (2.5 mL) were added using a syringe. The resulting mixture was stirred for 12 hours under 420 nm LED illumination. After the reaction was complete, the reaction solution was filtered, the organic layer was washed with water, and then extracted twice with dichloromethane (10 mL each time). The organic phase was dried over anhydrous Na2SO4 and the solvent was removed by rotary evaporation. The sample was loaded onto an automated column (eluent: petroleum ether-ethyl acetate, 1%-5% ethyl acetate, v / v) to obtain deuterated benzylaniline product (30.7 mg, yield 83%). The 1C NMR spectrum is shown below. Figure 3 The average number of deuterium atoms per molecule is 1.82D.

[0052] 1 H NMR (600 MHz, CDCl3) δ 7.40-7.26 (m, 5H), 7.19-7.16 (m, 2H), 6.74-6.71 (tt, J = 7.2, 1.2 Hz, 1H), 6.65 (dd, J = 8.8, 1.2 Hz, 2H), 4.31 (s, 0.18H), 4.19 (s, 1H) ppm; 13 C NMR (151 MHz, CDCl3) δ 148.3, 139.4, 129.4,128.8, 127.7, 127.4, 117.7, 113.0, 47.9 ppm. Example 5 Preparation of α-deuterated N-(4-chlorobenzyl)aniline The reaction formula is as follows: .

[0053] Poly-5CzIPN (10 mg, 0.02 mmol), sodium formate (68 mg, 1 mmol), sodium mercaptoethoxide (15.6 mg, 0.2 mmol), and p-chlorobenzaldehyde (28 mg, 0.2 mmol) were added sequentially to a 25 mL Srank tube. The atmosphere in the reaction system was purged by vacuum and backfilled with nitrogen (this process was repeated three times). Under a nitrogen atmosphere, aniline (18 μL, 0.2 mmol), D₂O (0.50 mL, 27.8 mmol, 22.2 equivalents), and DMSO (2.5 mL) were added using a syringe. The resulting mixture was stirred for 12 hours under 420 nm LED illumination. After the reaction was complete, the reaction solution was filtered, the organic layer was washed with water, and then extracted twice with dichloromethane (10 mL each time). The organic phase was dried over anhydrous Na₂SO₄ and the solvent was removed by rotary evaporation. The sample was loaded onto a dry column and purified by an automated column chromatography system (eluent: petroleum ether-ethyl acetate, 1%-5% ethyl acetate, v / v) to obtain the deuterated amine product (28.5 mg, 65% yield). The carbon NMR spectrum is shown below. Figure 4 The average number of deuterium atoms per molecule is 1.90D.

[0054] 1 H NMR (600 MHz, CDCl3) d 7.31 (s, 4H), 7.19-7.16 (m, 2H), 7.18 (dd, J= 8.8, 7.2 Hz, 2H), 6.73 (tt, J = 7.5, 1.1 Hz, 1H), 6.62 (dd, J = 8.7, 1.0Hz, 2H), 4.30 (s, 0.18H), 4.04 (s, 1H) ppm; 13 C NMR (151 MHz, CDCl3) d 147.8,137.9, 132.9, 129.3, 128.8, 128.8, 117.8, 112.9, 47.0 ppm. Example 6: Preparation of α-deuterated N-cyclohexyl-p-methoxyaniline The reaction formula is as follows: .

[0055] Poly-5CzIPN (10 mg, 0.02 mmol), sodium formate (68 mg, 1 mmol), sodium mercaptoethanol (15.6 mg, 0.2 mmol), and p-methoxyaniline (25 mg, 0.2 mmol) were added sequentially to a 25 mL Srank tube. The atmosphere in the reaction system was purged by vacuum and backfilled with nitrogen (this process was repeated three times). Under a nitrogen atmosphere, cyclohexanone (21 μL, 0.2 mmol), D2O (0.50 mL, 27.8 mmol, 22.2 equivalents), and DMSO (2.5 mL) were added using a syringe. The resulting mixture was stirred for 12 hours under 420 nm LED illumination. After the reaction was complete, the reaction solution was filtered, the organic layer was washed with water, and then extracted twice with dichloromethane (10 mL each time). The organic phase was dried over anhydrous Na₂SO₄ and the solvent was removed by rotary evaporation. The sample was loaded onto an automated column (eluent: petroleum ether-ethyl acetate, v / v 10%-30% ethyl acetate) to obtain deuterated benzylaniline product (23 mg, yield 54%). The carbon NMR spectrum is shown below. Figure 5 The average number of deuterium atoms per molecule at the first carbon position is 0.85D, and the average number of deuterium atoms per molecule at the second carbon position is 1.50D.

[0056] 1 H NMR (600 MHz, CDCl3) δ 6.76 (d, J = 9.0 Hz, 2H), 6.57 (J = 9.0 Hz,2H), 3.74 (s, 3H), 3.18-3.14 (m, 0.13H), 2.06-2.00 (m, 1.50H), 1.78-1.71 (m,2H), 1.68 -1.61(m, 1H), 1.40 – 1.00 (m, 5H) ppm; 13 C NMR (151 MHz, CDCl3) δ 152.1, 141.9, 115.1, 115.0, 56.0, 53.0, 33.9, 26.3, 25.4 ppm. Example 7: Cyclic performance test of catalyst Poly-5CzBN To evaluate the stability and economy of the catalyst, a catalyst recovery and recycling experiment was conducted on the reaction system of Example 4. After each reaction, the solid catalyst Poly-5CzBN was recovered by filtration, thoroughly washed with DMSO and diethyl ether, vacuum dried, and then directly added to the next round of reaction (replenishing with fresh reactants, reagents, and solvents).

[0057] The results are as follows Figure 6 As shown, after five consecutive reuses, the reaction yield remained above 80%, the average number of deuterium atoms in the product remained above 1.8, and the activity did not decrease significantly. This indicates that the heterogeneous polymer photocatalyst used in this invention has good stability and recyclability.

[0058] To further illustrate the universality of the photocatalytic synthesis method for polydeuterated amines provided by this invention, Figure 7 The polydeuterated amines in this study were prepared at room temperature under a nitrogen protective atmosphere, using heavy water (D₂O) as the deuterating agent, with the reaction system irradiated by 420 nm visible light, Poly-5CzBN and DMSO as solvents, messodium as a thiol catalyst, and sodium formate as a reducing agent. Specific experimental procedures are not detailed here. The general reaction formula is as follows: .

[0059] In the formula, R1 and R3 are independently aryl, substituted aryl, polycyclic aryl, heterocyclic aryl, substituted heterocyclic aryl, substituted polycyclic aryl, and C. 1-18 Alkyl, C 1-10 Cycloalkyl; R2 and R4 are each independently hydrogen and C. 1-18 Alkyl, C 1-10 Cycloalkyl.

[0060] Combination Figure 7 The results show that deuterated fentanyl was successfully synthesized using the photocatalytic iterative deuteration reaction of the present invention in the fentanyl skeleton method. The deuteration efficiencies were 1.72 D for the α-benzylic position and 1.56 D for the amide α-position, with a yield of 65%.

[0061] The method of this invention also successfully prepared the deuterated cinacalcet (Cinacalcet-D5), achieving deuterium labeling at three metabolically sensitive sites. The deuteration efficiencies were: 1.68 D at the α-position of the naphthalene ring, 1.56 D at the α-methyl position of the side chain, and 0.97 D at the β-position of the side chain, with a yield of 75%.

[0062] The method of the present invention can deuterate modify the inherent or derived amine structure in drug molecules or biomass derivatives, and has universality.

[0063] In summary, the method for preparing polydeuterium-substituted amines provided by this invention is applicable to a variety of carbonyl compounds, including aromatic aldehydes, aliphatic aldehydes, and ketones, and can react smoothly with primary and secondary amines. Even when the carbonyl base contains halogen or alkoxy functional groups, the system exhibits good compatibility and wide applicability. In all examples, the target polydeuterium-substituted amines were obtained with good to excellent separation yields (75%-92%), demonstrating the high efficiency and reliability of this method. Furthermore, the method of this invention can selectively introduce more than 1.5 deuterium atoms / molecules at the α-position of the carbonyl group (i.e., the carbon atom adjacent to the newly formed CN bond), achieving efficient and precise deuterium labeling.

[0064] In the above embodiments, the descriptions of each embodiment have different focuses. For parts that are not described in detail in a certain embodiment, please refer to the relevant descriptions in other embodiments.

[0065] The above description describes specific embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any person skilled in the art can easily conceive of various equivalent modifications or substitutions within the technical scope disclosed in the present invention, and these modifications or substitutions should all be covered 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 photocatalytic synthesis of polydeuterated amines, characterized in that, Includes the following steps: Under photocatalyst and light irradiation conditions, carbonyl compounds and amine compounds are reacted in the presence of deuterium-containing reagents, thiol catalysts and reducing agents to obtain polydeuterium-substituted amines.

2. The method according to claim 1, characterized in that, The photocatalyst is selected from 4CzIPN, 4DPAIPN, 5CzBN, Poly-4CzIPN or Poly-5CzBN.

3. The method according to claim 1, characterized in that, The thiol catalyst is selected from thiophenols, alkyl thiols, or mercaptoalkyl sulfonates.

4. The method according to claim 3, characterized in that, The mercaptoalkyl sulfonate is sodium 2-mercaptoethanesulfonate.

5. The method according to claim 1, characterized in that, The reducing agent is a formate, and the deuterium-containing reagent is heavy water or a deuterated alcohol.

6. The method according to claim 1, characterized in that, The reaction is carried out under illumination with a wavelength range of 400-450 nm; and / or, the reaction is carried out under an inert atmosphere.

7. The method according to claim 1, characterized in that, The reaction further includes a solvent selected from one or more of the following: ethanol, methanol, cyclohexane, n-hexane, n-pentane, n-heptane, petroleum ether, diethyl ether, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile.

8. The method according to claim 1, characterized in that, The carbonyl compound is an aldehyde or ketone, with the structural formula shown in formula (1); the amine compound is a primary amine or a secondary amine, with the structural formula shown in formula (2). （1）、 （2）； In the formula, R1 and R3 are each independently aryl, substituted aryl, polycyclic aryl, heterocyclic aryl, substituted heterocyclic aryl, substituted polycyclic aryl, C 1-18 Alkyl chain, C 1-10 cycloalkyl; R2 and R4 are independently hydrogen and C, respectively. 1-18 Alkyl chain, C 1-10 Cycloalkyl.

9. The application of the photocatalytic synthesis method for polydeuterated amines as described in any one of claims 1-8 in the preparation of polydeuterated drug molecules or biomass derivatives.

10. A method for synthesizing a multi-deuterium-substituted drug molecule or biomass derivative, characterized in that, The deuteration reaction is carried out using the method described in any one of claims 1-8.

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