A method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange

Abstract

The invention discloses a method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange, and relates to the technical field of organic synthesis. The invention provides a method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange, wherein heavy water is used as a deuterated reagent, and a hydrogen-deuterium exchange reaction of aldehydes occurs under the action of a catalyst and light in an inert reaction gas atmosphere to obtain deuterated aldehydes. Practice has proved that the method provided by the invention has the characteristics of simple process, few steps, high yield, and high deuteration rate, and the deuterium source and catalyst are cheap and easy to obtain, and the reaction conditions are mild, so that it is a green method for synthesizing deuterated aldehydes. Thanks to the high efficiency of the method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange and the simple and easy-to-operate reaction conditions, the method can also use a continuous flow reaction device for reaction, so that the reaction can achieve the preparation of deuterated aldehydes on a 100-gram scale in the laboratory.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange. Background Art

[0002] Deuterium is a stable isotope of hydrogen. Deuterated compounds are widely used in organic synthesis and medicinal chemistry. The weight of deuterium atoms in deuterated substances is larger than that of hydrogen atoms. The isotope effect can help researchers easily track the metabolic pathway of hydrogen in organic matter and determine the structure and reaction mechanism of organic compounds. On the other hand, due to the successive launch of deuterated new drugs, deuterated methodology has gradually become one of the hot areas of concern. It is reported that many pharmaceutical companies are using deuteration technology to prepare deuterated new drugs. These deuterated new drugs have better efficacy, metabolic stability and safety than traditional drugs. In addition, deuterated compounds can also be used to study drug metabolism and toxicity, predict the effects and detoxification of drugs, etc.

[0003] Aldehyde groups are at the core of drug synthesis and are important reaction units. They can undergo a variety of organic reactions, such as aldol condensation, Michael addition, Wittig reaction, Cannizzaro reaction, and reduction reaction. Among them, the aldol condensation reaction can be used to generate complex organic molecules with natural product structures, which have a wide range of applications in biological activity and drug activity; the Wittig reaction can be used to synthesize important drug molecules such as rifampicin; and the reduction reaction can be used to prepare many compounds, such as the diuretic hydrochlorothiazide. Correspondingly, deuterated aldehydes can be used as ideal deuterated synthesis units, which can efficiently synthesize deuterated drugs and their natural products, thereby accelerating the process of drug research and development. The increasing demand for deuterated drugs in the pharmaceutical industry has greatly promoted the rapid development of deuterated synthesis methodology. Therefore, the synthesis of deuterated aldehydes has important scientific research value and practical value.

[0004] The existing methods for synthesizing deuterated aldehydes mainly include functional group conversion method and hydrogen-deuterium exchange method.

[0005] Functional group conversion methods mainly convert other functional groups into deuterated aldehyde functional groups. Traditional methods include: esters are reduced under the action of lithium deuterated aluminum, and then oxidized under the action of an oxidant to synthesize deuterated aldehydes; zirconium deuterium reagent reduction method, tertiary amides are selectively reduced under the action of zirconium deuterium reagents to obtain deuterated aldehydes; Rosenmund reduction method, acid chlorides are catalytically hydrogenated and reduced in a deuterium atmosphere with palladium as a catalyst to synthesize deuterated aldehydes. These methods generally use a reaction dose or an over-reaction dose of deuterated reagents, and the deuterated reagents are expensive, dependent on imports, or have slow reaction rates. In recent years, some newer strategies for synthesizing deuterated aldehydes by functional group conversion methods have also been developed. For example, photocatalytic preparation of deuterated aldehydes from carboxylic acids (CN 109293484A), and preparation of deuterated aldehydes using halomethyl compounds as raw materials (CN 108383697 A). However, these two types of reactions have harsh reaction conditions, low substrate applicability, and require the use of additional complex activation reagents or additional reaction steps, resulting in low atom economy and low practicality.

[0006] The hydrogen-deuterium exchange method does not require pre-functionalization. Aldehyde hydrogen can directly exchange hydrogen and deuterium with a deuterated reagent under the action of a catalyst to generate a deuterated aldehyde. In terms of practicality, the hydrogen-deuterium exchange method has more obvious advantages. At present, the synthesis of deuterated aldehydes by hydrogen-deuterium exchange mainly includes: 1. Transition metal catalysis method (Angew. Chem. Int. Ed. 2017, 56, 7808–7812), 2. Nitrogen heterocyclic carbene catalysis method (CN 111039767 A), 3. Visible light and organic small molecules synergistic catalysis (CN 114075108 A) to form aldehyde deuteration reaction. For the transition metal catalysis method, it is impossible to achieve hydrogen-deuterium exchange of fatty aldehydes, and the aromatic ring will also be partially deuterated. Therefore, this method has low substrate applicability and the deuteration site is not precise. In the nitrogen heterocyclic carbene catalysis method, triazole carbene catalysts need to be prepared additionally, and the preparation conditions are harsh. On the other hand, the reaction requires the use of stoichiometric bases, and the reaction is violent. In the synergistic catalysis of visible light and organic small molecules, organic cyanocarbazole catalysts need to be prepared additionally, and the silicon-based mercaptan used is very expensive. The above-mentioned shortcomings limit the practical application of this deuteration method. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a deuterated aldehyde synthesis method which is simple, inexpensive, highly versatile, accurately deuterated and easy to scale up for production.

[0008] In order to solve the above problems, the present invention proposes the following technical solutions:

[0009] The present invention provides a method for synthesizing deuterated aldehyde by photocatalytic hydrogen-deuterium exchange, which is characterized by comprising: using heavy water as a deuterated reagent, in an inert reaction gas atmosphere, a catalyst and light to cause a hydrogen-deuterium exchange reaction of the aldehyde to obtain the deuterated aldehyde;

[0010] The aldehyde is a compound represented by formula (1), and the deuterated aldehyde obtained by hydrogen-deuterium exchange of the aldehyde is represented by formula (2);

[0011]

[0012] Wherein, R is an aryl, an arylalkyl, a heteroaryl, a heteroarylalkyl, a fused cyclic group, a fused cyclic alkyl, a bridged cyclic group, a bridged cyclic alkyl, a spirocyclic group or a spirocyclic alkyl; and the aryl, arylalkyl, heteroaryl, heteroarylalkyl, fused cyclic group, fused cyclic alkyl, a bridged cyclic group, a bridged cyclic alkyl, a spirocyclic group or a spirocyclic alkyl may be arbitrarily substituted with one or more substituents selected from hydroxyl, cyano, nitro and halogen.

[0013] Its further technical solution is that R is C 6-20 Aryl, C 6-20 Aryl C 1-20 Alkyl, C 2-20 Heteroaryl, C 2-20 Heteroaryl C 1-20 Alkyl, C 5-20 Condensed ring group, C 5-20 Condensed ring group C 1-20 Alkyl, C 5-20 Bridged ring group, C 5-20 Bridged ring group C 1-20 Alkyl, C 5-20 Spirocyclyl or C 5-20 Spirocyclyl C 1-20 alkyl;

[0014] Among them, C 6-20 Aryl, C 6-20 Aryl C 1-20 Alkyl, C 2-20 Heteroaryl, C 2-20 Heteroaryl C 1-20 Alkyl, C 5-20 Condensed ring group, C 5-20 Condensed ring group C 1-20 Alkyl, C 5-20 Bridged ring group, C 5-20 Bridged ring group C 1-20 Alkyl, C 5-20 Spirocyclyl or C 5-20 Spirocyclyl C 1-20 The alkyl group may be optionally substituted by one or more substituents selected from hydroxy, cyano, nitro and halogen.

[0015] A further technical solution is that the aldehyde is one of the following structures:

[0016]

[0017] A further technical solution is that the catalyst includes a photocatalyst and a phase transfer catalyst.

[0018] A further technical solution is that the molar ratio of the aldehyde, the photocatalyst and the phase transfer catalyst is 1:(0.01-0.1):(0.01-0.1).

[0019] A further technical solution is that the phase transfer catalyst is selected from tetrabutylammonium chloride; the photocatalyst is selected from chlorine-containing iron salts or chlorine-containing cerium salts; for example, ferric chloride and cerium chloride.

[0020] A further technical solution is that the hydrogen-deuterium exchange reaction is carried out at room temperature.

[0021] In other embodiments, room temperature means 0-50°C.

[0022] In other embodiments, room temperature means 20-40°C.

[0023] In other embodiments, room temperature means 25-35°C.

[0024] In other embodiments, the method for synthesizing aryl deuterated methane is carried out at 0-50°C.

[0025] In other embodiments, the method for synthesizing the aryl deuterated methane is carried out at 20-40°C.

[0026] In other embodiments, the method for synthesizing the aryl deuterated methane is carried out at 25-35°C.

[0027] A further technical solution is that the wavelength of the light is 390nm.

[0028] A further technical solution is that when no additional reaction solvent is added in the method for synthesizing deuterated aldehyde by photocatalytic hydrogen-deuterium exchange, the amount of heavy water is the amount of solvent required for the reaction;

[0029] When the method for synthesizing deuterated aldehyde by photocatalytic hydrogen-deuterium exchange further includes adding an inert reaction solvent, the volume ratio of the inert reaction solvent to heavy water is greater than or equal to 0.8.

[0030] In other embodiments, the volume ratio of the inert reaction solvent to heavy water is 0.8:1.

[0031] In other embodiments, the volume ratio of the inert reaction solvent to heavy water is 1:1.

[0032] In other embodiments, the volume ratio of the inert reaction solvent to heavy water is 2:1.

[0033] In other embodiments, the volume ratio of the inert reaction solvent to heavy water is 4:1.

[0034] In other embodiments, the volume ratio of the inert reaction solvent to heavy water is 5:1.

[0035] A further technical solution is that the inert reaction solvent is selected from one or more of ethanol, methanol, cyclohexane, n-hexane, n-pentane, n-heptane, petroleum ether, ethyl ether, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile.

[0036] A further technical solution is that the inert reaction gas is selected from at least one of nitrogen, helium, neon, argon, krypton, xenon and radon.

[0037] The reaction time is more than 8 hours, for example 12 hours, 40 hours, 72 hours, etc.

[0038] The present invention also provides a method for preparing deuterated aldehydes in a continuous flow scale, and the method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange is performed in a continuous flow reaction device.

[0039] Compared with the prior art, the technical effects achieved by the present invention include:

[0040] The method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange provided by the present invention has been proved in practice to have the characteristics of simple process, few steps, high yield and high deuteration rate, and the deuterium source and catalyst are cheap and easy to obtain, and the reaction conditions are mild. It is a green method for synthesizing deuterated aldehydes.

[0041] The method for preparing deuterated aldehydes on a large scale by continuous flow provided by the present invention benefits from the high efficiency of the method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange and the simple and easy-to-operate reaction conditions. By using a continuous flow reaction device, the reaction can achieve the preparation of deuterated aldehydes on a scale of 100 grams in the laboratory.

[0042] In summary, the method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange provided by the present invention has high practical application value for preparing deuterated aldehydes.

[0043] Terms and Definitions

[0044] It should be understood that when used in this specification and the appended claims, the terms "include" and "comprises" indicate the presence of described features, integers, steps, operations, elements and / or components, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components and / or combinations thereof.

[0045] Any structural formula given herein is also intended to represent non-isotopically enriched forms of these compounds as well as isotopically enriched forms. Isotopically enriched compounds have structures depicted by the general formula given herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 Oh, 18 Oh, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0046] The term "substituent" used in the present invention can be, but is not limited to, hydroxy, amino, halogen, cyano, nitro, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, and the like.

[0047] The term "alkyl" used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group. In some embodiments, the alkyl group is C 1-20 Alkyl, or alkyl is C 1-10 Alkyl, or alkyl is C 1-8 Alkyl, or alkyl is C 1-6 Alkyl, or alkyl is C 1-4 Alkyl, or alkyl is C 1-3 Alkyl, wherein the alkyl group may be independently and optionally substituted with one or more substituents described herein.

[0048] The term "heteroalkyl" as used herein means that one or more carbon atoms in the alkyl group described herein are replaced by heteroatoms. 2-20 Heteroalkyl, or heteroalkyl is C 2-10 Heteroalkyl, or heteroalkyl is C 2-8 Heteroalkyl, or heteroalkyl is C 2-6 Heteroalkyl, or heteroalkyl is C 2-4 Heteroalkyl, or heteroalkyl is C 2-3 Heteroalkyl. The heteroalkyl may be independently and optionally substituted with one or more substituents described herein.

[0049] The term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic carbon ring system. In some embodiments, the cycloalkyl is C 3-20 In some embodiments, the cycloalkyl group is C 3-10 Cycloalkyl.

[0050] The term "heterocycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system, and at least one of the ring systems contains one or more heteroatoms, wherein the heteroatoms have the meanings described herein; in some embodiments, the heterocycloalkyl is C 2-20 In some embodiments, the heterocycloalkane is C 2-10 Heteroalkyl.

[0051] The term "fused ring group" refers to a polycyclic organic compound formed by two or more carbon rings or heterocyclic rings with a common ring edge. In some embodiments, the fused ring group is C 5-20 The fused ring group may optionally have 1 or more heteroatoms. 5-12 The fused ring group may optionally have 1 or more heteroatoms.

[0052] The term "bridged ring group" refers to a ring group in which any two rings in the group share two carbon atoms or heteroatoms that are not directly connected. According to the number of constituent rings, it is classified into bicyclic, tricyclic, tetracyclic, etc. In some embodiments, the bridged ring group is C 5-20 The bridged ring group optionally has 1 or more heteroatoms. In some embodiments, the bridged ring group is C 5-12 The bridged ring group may optionally have 1 or more heteroatoms.

[0053] The term "spirocyclyl" refers to a polycyclic group in which two monocyclic rings share a carbon atom, wherein the two rings may be carbocyclic or may contain one or more heteroatoms. 5-20 Spirocyclyl, optionally with 1 or more heteroatoms. In some embodiments, the spirocyclyl is C 5-12 The spirocyclic group may optionally have 1 or more heteroatoms.

[0054] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbon ring system, wherein at least one ring system is aromatic; in some embodiments, aryl is C 6-20 In some embodiments, the aryl group is C 6-12 Aryl. The term "aryl" may include phenyl, naphthyl and anthracenyl.

[0055] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein the heteroatoms have the meanings described herein; in some embodiments, heteroaryl is C 2-20 In some embodiments, the heteroaryl group is C 2-12 Heteroaryl.

[0056] The term "halogen" refers to F, Cl, Br or I.

[0057] The term "heteroatom" refers to one or more O, S, N, P and Si atoms, including N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring in which hydrogen is substituted.

[0058] When a term used in the present invention is a combination of two groups, the former group serves as a substituent of the latter group and is connected to the parent molecule through the latter group, wherein the two groups have the definitions described in the present invention, such as cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, condensed ring alkyl, bridged ring alkyl and spirocyclic alkyl, which respectively represent cycloalkyl, heterocycloalkyl, aryl, heteroaryl, condensed ring, bridged ring and spirocyclic groups as substituents of alkyl and are connected to the parent molecule through the alkyl group, while cycloalkyl, heterocycloalkyl, aryl, heteroaryl, condensed ring, bridged ring, spirocyclic group and alkyl have the definitions described in the present invention.

[0059] 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.

[0060] The "amount of solvent required for the reaction" used in the present invention is preferably sufficient to completely dissolve the reactants, and can be adaptively changed depending on the reactants. In some embodiments, the amount of solvent required for the reaction can also be adaptively greater than the amount required to just dissolve the reactants.

[0061] The "inert reaction solvent" used in the present invention has the commonly used explanation in the art, and specifically refers to a solvent that is not easy to react with the reactants and does not affect the reaction process.

[0062] General synthesis process

[0063] Generally, the compounds of the present invention can be prepared by the methods described in the present invention. The following reaction schemes and examples are provided to further illustrate the present invention.

[0064] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.

[0065] In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company, and Alfa Chemical Company and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

[0066] The solvents used in the present invention, such as ethanol, methanol, cyclohexane, n-hexane, n-pentane, n-heptane, petroleum ether, ether, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, are dried in advance by a drying method suitable for the field.

[0067] The chromatographic column used was a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. The nuclear magnetic resonance spectrum was CDC13, d 6 -DMSO, CD3OD or d 6 - Acetone is the solvent (reported in ppm), TMS (0 ppm) or chloroform (7.25 ppm) is used as the reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

[0068] Gas chromatography (GC) is a chromatographic separation and analysis method that uses gas as a mobile phase. The vaporized sample is carried into the chromatographic column by the carrier gas (mobile phase). The stationary phase in the column has different forces with the molecules of each component in the sample. Each component flows out of the chromatographic column at different times, and the components are separated from each other. Using an appropriate identification and recording system, a chromatogram is produced to mark the time and concentration of each component flowing out of the chromatographic column. According to the peak time and sequence shown in the figure, the compound can be qualitatively analyzed; according to the height and area of ​​the peak, the compound can be quantitatively analyzed. It has the characteristics of high efficiency, high sensitivity, strong selectivity, fast analysis speed, wide application, and simple operation. It is suitable for qualitative and quantitative analysis of volatile organic compounds. For non-volatile liquids and solid substances, they can be analyzed after high-temperature cracking and gasification.

[0069] GC-MS refers to gas chromatography-mass spectrometry, which is an analytical instrument that measures the charge-to-mass ratio of ions.

[0070] Thin layer chromatography (TLC) is a method of coating a suitable stationary phase on a glass plate, plastic or aluminum substrate to form a uniform thin layer. After the sample is spotted and developed, the relative shift value (Rf) is compared with the relative shift value (Rf) of the chromatogram obtained by the same method with a suitable reference substance to identify the drug, check for impurities or determine the content. Thin layer chromatography is a very important experimental technique for rapid separation and qualitative analysis of small amounts of substances, and is also used to track the progress of reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Figure 1 is the product spectrum of Example 1;

[0072] Figure 2 is the product spectrum of Example 2;

[0073] Figure 3 This is a schematic diagram of the reaction process of Example 18. DETAILED DESCRIPTION

[0074] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments. Obviously, the embodiments described below are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0075] Example 1

[0076] Synthesis of aromatic deuterated aldehydes:

[0077] The reaction process is as follows:

[0078]

[0079] Dissolve p-chlorobenzaldehyde (140 mg, 1.0 mmol) in 5 ml acetonitrile / heavy water (volume ratio 4:1) solution, then add tetrabutylammonium chloride (14 mg, 0.05 mmol) and ferric chloride (8 mg, 0.05 mmol), evacuate the air three times through the vacuum pipeline, change the reaction to argon atmosphere, and then stir the reaction at room temperature for 24 hours under 390 nm wavelength lamp irradiation. After the reaction, extract with ethyl acetate three times, each extraction amount is 10 mL; the organic phase is dried over anhydrous Na2SO4 and the solvent is removed by rotary evaporation, the sample is dry loaded, and the column is passed through an automatic column machine (eluent: petroleum ether-ethyl acetate, volume ratio 1%-5% ethyl acetate) to obtain the deuterated p-chlorobenzaldehyde product (134 mg, yield 95%), see Figure 1 , the deuterium substitution rate is 97%.

[0080] The NMR data are: 1 H NMR (600MHz, CDCl3): δ9.96 (s, 0.04H), 7.81 (d, J = 8.6Hz, 2H), 7.49 (d, J = 8.6Hz, 2H); 13 C NMR (600MHz, CDCl3)190.6,141.0,134.7,131.0,129.5ppm.

[0081] Example 2

[0082] Synthesis of fatty deuterated aldehydes:

[0083] The reaction process is as follows:

[0084]

[0085] Dissolve trifluoromethylbenzylpropionaldehyde (202mg, 1.0mmol) in 5ml acetonitrile / heavy water (volume ratio 4:1) solution, then add tetrabutylammonium chloride (14mg, 0.05mmol) and ferric chloride (8mg, 0.05mmol), evacuate the air three times through the vacuum pipeline, change the reaction to argon atmosphere, and then stir the reaction at room temperature for 24 hours under 390nm wavelength lamp irradiation. After the reaction, use ethyl acetate to extract 3 times, each extraction amount is 10mL; the organic phase is dried over anhydrous Na2SO4 and then evaporated to remove the solvent, dry sample is loaded, and the column is passed through an automatic column machine (eluent: petroleum ether-ethyl acetate, volume ratio 1%-5% ethyl acetate) to obtain the deuterated fatty aldehyde product (189mg, yield 93%), see Figure 2 , the deuterium substitution rate is 95%.

[0086] The NMR data are: 1H NMR (600MHz, CDCl3): δ10.02(t,J=2.3Hz,0.05H),7.54-7.44(m,4H),3.06(t,J=15.2Hz,2H),2.76(t,J=7.9Hz,2H)ppm; 13 C NMR (600MHz, CDCl3)178.8,141.1,131.8,131.0,130.8,129.1,125.2,123.4,35.3,30.3ppm.

[0087] Example 3-17

[0088] According to the operation shown in Example 1, according to the following reaction process, deuterated aldehydes were synthesized with different aldehyde raw materials. The results are shown in Table 1:

[0089]

[0090] Table 1:

[0091]

[0092]

[0093]

[0094] The method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange provided by the present invention can deuterate aromatic aldehydes, aliphatic aldehydes, etc. at room temperature, and the deuteration sites are precise, the yield is high, and the deuteration rate is above 89%.

[0095] Embodiment 18

[0096] according to Figure 3 The reaction process shown in the figure uses a continuous flow reaction device to prepare deuterated p-chlorobenzaldehyde on a scale of 100 grams. The specific operation is as follows:

[0097] Dissolve p-chlorobenzaldehyde (100 g, 714 mmol) in 3000 ml acetonitrile / heavy water (volume ratio 4:1) solution, then add tetrabutylammonium chloride (9730 mg, 35 mmol) and ferric chloride (5670 mg, 35 mmol). Pump the reaction mixture into a continuous flow reactor (the retention volume of the microchannel reactor is 30 mL) at a rate of 250 microliters per minute. After the mobile phase reaction is balanced for two hours, the reaction liquid flowing out of the reactor is collected and collected for 200 hours. Finally, the collected reaction liquid is mixed, acetonitrile and most of the water are removed by rotary evaporation, and deuterated p-chlorobenzaldehyde (91 g, yield 91%) is obtained by slurrying with petroleum ether. The deuterated rate is 94% as determined by nuclear magnetic resonance.

[0098] The method for preparing deuterated aldehydes in a continuous flow scale provided by the present invention is to perform the method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange in a continuous flow reaction device. Benefiting from the advantages of mild conditions and simple synthesis process of the method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange, the reaction can be prepared on a 100-gram scale in a laboratory by using flow chemistry technology. Therefore, the method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange provided by the present invention has high practical application value and is suitable for industrial production.

[0099] In the above embodiments, the description of each embodiment has its own emphasis. For parts that are not described in detail in a certain embodiment, reference can be made to the relevant descriptions of other embodiments.

[0100] The above is a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can easily think of various equivalent modifications or replacements within the technical scope disclosed by the present invention, and these modifications or replacements should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention shall be based on the protection scope of the claims.

Claims

1. A method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange, characterized in that: include: Using heavy water as a deuterated reagent, in an inert reaction gas atmosphere, a catalyst and light irradiation, a hydrogen-deuterium exchange reaction of the aldehyde occurs to obtain a deuterated aldehyde; The aldehyde is a compound represented by formula (1), and the deuterated aldehyde obtained by hydrogen-deuterium exchange of the aldehyde is represented by formula (2); Formula (1); Formula (2); The catalyst is tetrabutylammonium chloride and ferric chloride; The compound of formula (1) is specifically one of the following structures: ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； 。 2. The method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange according to claim 1, characterized in that: The molar ratio of the aldehyde, ferric chloride and tetrabutylammonium chloride is 1: (0.01-0.1): (0.01-0.1).

3. The method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange according to claim 1, characterized in that: The hydrogen-deuterium exchange reaction is carried out at room temperature.

4. The method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange according to claim 1, characterized in that: The wavelength of the light was 390 nm.

5. The method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange according to claim 1, characterized in that: When no additional reaction solvent is added in the method for synthesizing deuterated aldehyde by photocatalytic hydrogen-deuterium exchange, the amount of heavy water is the amount of solvent required for the reaction; When the method for synthesizing deuterated aldehyde by photocatalytic hydrogen-deuterium exchange further includes adding an inert reaction solvent, the volume ratio of the inert reaction solvent to heavy water is greater than or equal to 0.

8.

6. The method for synthesizing deuterated aldehydes by photocatalytic hydrogen-deuterium exchange according to claim 5, characterized in that: The inert reaction solvent is selected from one or more of ethanol, methanol, cyclohexane, n-hexane, n-pentane, n-heptane, petroleum ether, ethyl ether, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile.

7. A method for preparing deuterated aldehydes in a continuous flow scale, characterized in that: The method for synthesizing deuterated aldehyde by photocatalytic hydrogen-deuterium exchange as claimed in any one of claims 1 to 6 is performed in a continuous flow reaction device.

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