A method for deoxygenating and deuterating aromatic compounds by using a hydrophilic carbon supported catalyst

Abstract

The application discloses a method for preparing aryl deuterated methane compounds by deoxygenation and deuteration of a hydrophilic carbon loaded catalyst, and relates to the technical field of fine chemical synthesis. The method comprises the following steps: taking aromatic aldehyde or aromatic ketone compounds as raw materials, heavy water as a deuterium source, a hydrophilic carbon loaded noble metal as a catalyst, and a non-polar organic reagent as a solvent, and preparing aryl deuterated methane compounds by deoxygenation and deuteration under a hydrogen reaction atmosphere. Compared with traditional deoxygenation and deuteration technology, the method has the following advantages: the reaction is a heterogeneous catalytic reaction, the reaction condition is mild, the reaction substrate and the deuterium source are cheap and easy to obtain, the hydrophilic carbon loaded catalyst used can significantly improve the yield of the target product and the deuterium content in the methyl functional group compared with a conventional activated carbon loaded catalyst, and the polar surface of the carrier is beneficial to the removal of the non-polar aryl deuterated methane compound product, and the catalytic efficiency and product recovery can be improved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of fine chemical synthesis, and relates to a method for preparing aryl-deuterated methane compounds by deoxygenation and deuteration of a hydrophilic carbon-supported catalyst. BACKGROUND

[0002] Deuterium-labeled chemicals are widely used in different research fields, such as new drug development, reaction mechanism exploration, nuclear magnetic resonance spectroscopy and mass spectrometry analysis (Nat. Chem. 2022, 14, 334-341). Compared with C-H bonds, breaking C-D bonds requires more energy. Therefore, deuterium labeling of common functional groups in drugs can adjust the metabolic rate of drugs in the body, thereby prolonging the half-life of drugs, reducing the amount of drug used, and reducing toxic metabolites. In 2017, the U.S. Food and Drug Administration (FDA) approved the marketing of deuterated biperiden, and the introduction of the deuterated methane functional group effectively reduced the toxic side effects of non-deuterated biperiden. The successful marketing of the first deuterated drug has promoted the development of synthesis technology for deuterated drugs and deuterated drug intermediates.

[0003] According to statistics, about 80% of the best-selling drugs on the market contain methyl functional groups. Therefore, designing and developing intermediates containing deuterated methyl functional groups is crucial for promoting the research of deuterated drugs. Traditionally, the synthesis of deuterated methyl compounds relies on the use of deuterated alkylating agents, such as CD3I. These deuterated alkylating agents are not only expensive, but also may produce toxic byproducts during synthesis. Currently, reducing reagents such as NaBD4, LiAlD4, and D2 are used to reduce aromatic ester, carboxylic acid or nitrile functional groups, which is a feasible alternative technology. However, such strong reducing deuterium reagents often have poor tolerance to multiple functional groups, which to some extent limits their scope of application. In recent years, the use of aldehyde compounds has shown potential for the synthesis of deuterated methane compounds through metal-catalyzed deoxygenation and deuteration of aldehydes. This technology not only simplifies the reaction steps, but also avoids the use of toxic deuterium reagents, and is therefore considered as a promising deuterium labeling technology. For example, Su et al. found that a palladium-based molecular catalyst activated by D2 can selectively catalyze the deoxygenation and deuteration of aldehydes or ketones, achieving deuterium labeling of the methyl site in drug molecules (Angew. Chem. Int. Ed. 2021, 60, 6357-6361). At the same time, Min et al. developed a rhodium-based molecular catalyst that can selectively catalyze the deoxygenation and deuteration of aldehyde groups, achieving precise deuterium labeling on the benzene ring (J. Am. Chem. Soc. 2022, 144, 11081-11087). However, existing technologies still rely on expensive D2 and homogeneous molecular catalysts, which have problems such as difficult recovery of catalysts and high preparation cost, which to some extent restricts their industrial application. SUMMARY

[0004] To solve the above technical problems, the applicant has developed a catalyst system, and proposes a more economical, practical and high deuterium content synthesis method of aryl deuterated methane compounds. The method uses aromatic aldehyde or aromatic ketone compounds as raw materials, under the system of hydrogen, heavy water and non-polar organic reagent, the deoxy deuterium of aromatic aldehyde or ketone compounds is catalyzed by hydrophilic carbon loaded noble metal catalyst, so as to obtain the target deuterated product, which provides a new synthesis technology for the synthesis of aryl deuterated methane compounds.

[0005] In order to achieve the above purpose, the technical scheme adopted by the present application is:

[0006] A method for preparing aryl deuterated methane compounds by deoxy deuterium of hydrophilic carbon loaded catalyst, comprising using aromatic aldehyde or aromatic ketone compounds as raw material, heavy water as deuterium source, using hydrophilic carbon loaded noble metal as catalyst, using non-polar organic reagent as solvent, and carrying out deoxy deuterium reaction under hydrogen reaction atmosphere to obtain aryl deuterated methane compounds; wherein the hydrophilic carbon has a water vapor adsorption capacity of ≥10mmol·g -1 at 298K and ≤20RH% relative humidity; the noble metal is one or more of palladium, ruthenium, platinum and rhodium, and the mass percentage of noble metal in the catalyst is 5-8wt.%;

[0007] The aromatic aldehyde compound includes one or more of the compounds shown in formula (1), the aromatic ketone compound includes one or more of the compounds shown in formula (2), and the aryl deuterated methane compound includes one or more of the compounds shown in formula (3):

[0008]

[0009] Wherein, R represents one of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, nitro, hydroxyl, aldehyde group, cyano and halogenated hydrocarbon; R' represents one of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl and halogenated hydrocarbon.

[0010] Specifically includes the following steps:

[0011] S1 aromatic aldehyde or aromatic ketone compound, heavy water and catalyst are added to non-polar organic reagent, and ultrasonic treatment is carried out until uniform;

[0012] S2 after inert atmosphere is replaced for several times, hydrogen is introduced, heating and stirring are carried out, and reaction is carried out; after reaction, cooling to room temperature, filtering and separating catalyst, the filtrate is a mixed solution of non-polar organic reagent and heavy water which dissolves aryl deuterated methane compounds;

[0013] S3 adding extractant to the mixed solution, after dropping, standing and separating, removing heavy water, collecting organic solution;

[0014] S4 removing non-polar organic reagent and extractant by rotary evaporation under reduced pressure to obtain target deuterated product.

[0015] The hydrophilic carbon is a N / O atom doped porous carbon carrier, wherein the N atom doping content is 10-20%, the O atom doping content is 10-20%, the specific surface area is 300-1000 m 2 g -1 , the pore size distribution is in the range of 0.5-20 nm, and the water contact angle test is < 35°.

[0016] The preparation method of the hydrophilic carbon comprises the following steps:

[0017] S01 respectively dissolving copper salt and iron salt in deionized water, and dissolving nitrogen-containing organic ligand in organic solvent;

[0018] S02 adding organic ligand solution and copper salt aqueous solution to iron salt aqueous solution in sequence, fully stirring to mix into a uniform solution, and obtaining carbon precursor through standing, centrifugation and drying;

[0019] S03 pyrolyzing the precursor under inert atmosphere at a carbonization temperature of 400-600℃, and then obtaining hydrophilic carbon material through acid washing, suction filtration and drying;

[0020] The mass ratio of ligand to copper salt in the uniform solution is 0.5-3:1, the mass ratio of ligand to iron salt is 0.5-3:1, and the volume ratio of water to organic solvent is 5-20:1.

[0021] The molar amount of noble metal in the catalyst is 2%-5% of the molar amount of aromatic aldehyde or aromatic ketone compound.

[0022] The molar amount of aromatic aldehyde or aromatic ketone compound is 1:10-20 of the volume amount of heavy water (mmol / mL).

[0023] The non-polar organic reagent is one of n-hexane, cyclohexane, toluene, xylene and dichloromethane, and the volume ratio of non-polar organic reagent to heavy water is 1:2-5.

[0024] The number of inert gas replacement in S2 is greater than or equal to two.

[0025] The reaction is carried out under a hydrogen atmosphere of 0.1-0.5 MPa.

[0026] The reaction temperature is 90-130℃, and the reaction time is 1-12h.

[0027] The stirring rate in S2 is 600-1000 rpm.

[0028] The extraction reagent in S3 is 5-10 times the volume of heavy water. The extraction reagent is ethyl acetate.

[0029] The deoxy-deuteration reaction principle of the aromatic aldehyde compound and the aromatic ketone compound in the present application is the same. Taking the aromatic aldehyde compound as an example, the reaction principle is shown in Figure 1

[0030] The beneficial effects of the present application are as follows:

[0031] The present application uses heavy water as a deuterium source, aromatic aldehyde or ketone compounds as a reaction substrate, uses a hydrophilic carbon-supported noble metal as a catalyst in a hydrogen atmosphere, and generates aryl-deuterated methane compounds by catalyzing aldehyde or ketone deoxy-deuteration. In this process, hydrogen acts as an activator of the metal site, promoting oxidative addition and reductive elimination. Under the catalytic action of the metal active site, first hydrogen isotope exchange is carried out with heavy water to generate deuterium in situ, and then deoxy-deuteration is carried out to generate aryl-deuterated methane compounds. The synthesis method of the above-mentioned aryl-deuterated methane compounds designed by the present application is simple and efficient, the reaction operation is simple, the yield of the target product synthesized by deoxy-deuteration is high, and the deuterium content in the methyl functional group is > 95%. The hydrophilic carbon-supported catalyst is easy to mass-produce, easy to separate from the deuterated product, and after five cycles of use, its deuterium substitution performance does not significantly decline, which meets the needs of practical research and application. The present application uses cheap heavy water as a deuterium source, and synthesizes aryl-deuterated methane compounds through heterogeneous catalysis, which provides a new technical approach for the research and application of deuterium-labeled compounds.

[0032] Compared with the traditional technical path of using deuterated alkylating reagents as a deuterium source and synthesizing through multiple steps of chemistry, the present application has the following advantages: the reaction steps are simplified, the reaction conditions are mild, no toxic, volatile and expensive deuterated alkylating reagents are needed, the reaction raw materials are cheap and easy to obtain; the reaction product has high purity, high yield and high deuteration rate. To some extent, the problems of catalyst deactivation, product yield reduction and separation and purification cost caused by difficult product detachment are avoided. In addition, the catalyst can be recycled after simple reduction treatment, further reducing the catalyst cost of deuterium substitution reaction. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 The reaction principle diagram of the aromatic aldehyde compound.

[0034] Figure 2 The mass spectrum (MS) diagram of the deuterated 2-methylnaphthalene obtained in Example 1.

[0035] Figure 3 The nuclear magnetic resonance hydrogen spectrum (​1 H NMR) chart.

[0036] Figure 4 H NMR) chart of deuterated 2-methylnaphthalene obtained from Example 1. 2 H NMR) chart.

[0037] Figure 5 (a) and (b) are the actual photos of the state of existence of the hydrophilic carbon supported palladium-based catalyst in heavy water and the deuterated 2-methylnaphthalene product obtained from Example 1.

[0038] Figure 6 (a) and (b) are the actual photos of the state of existence of the hydrophilic carbon supported palladium-based catalyst in heavy water and the deuterated 2-methylnaphthalene product obtained from Example 1. DETAILED DESCRIPTION

[0039] The application will be further described in conjunction with the examples below, but the examples described are not a limitation on the scope of protection of the application.

[0040] The preparation steps of the hydrophilic carbon in the examples are as follows: first, 40 mL of 0.1 mol L -1 aqueous copper chloride solution, 700 mL of 0.005 mol L -1 aqueous iron nitrate solution and 100 mL of 0.05 mol L -1 bipyridyl ethanol solution are prepared respectively. Subsequently, the bipyridyl ethanol solution and the aqueous copper salt solution are sequentially added to the aqueous iron salt solution, mixed uniformly, and left to stand for 24 h. Then, the carbon precursor is obtained by centrifugal separation and water washing, and dried in an oven at 50°C overnight. Then, it is heated to 500°C in a tube furnace under the protection of argon atmosphere for 1 h and naturally cooled to room temperature. Subsequently, the obtained black solid is soaked in nitric acid for 24 h to remove the precipitated copper metal, and then filtered, washed with water and dried to obtain the hydrophilic carbon material as the catalyst carrier. The N atom doping content of the obtained hydrophilic carbon material is 13.4%, the O atom doping content is 16.2%, the water vapor adsorption amount is 10 mmol·g -1 at 298 K and relative humidity ≤20 RH%, the specific surface area is 900 m 2 ·g -1 , the pore size range is between 0.5-1.5 nm, and the water contact angle test is completely wet.

[0041] The preparation steps of the hydrophilic carbon supported noble metal catalyst are as follows: first, a noble metal aqueous solution with a certain concentration is prepared, and the noble metal salt is loaded onto the hydrophilic carbon material as the carrier by the impregnation method. The mass percentage of the noble metal (Ru / Pt / Pd) is 5-8 wt.%. Subsequently, it is heated to 250°C in a tube furnace under the atmosphere of 5% H2 / 95% mixed gas for 2 h, and naturally cooled to room temperature to obtain the hydrophilic carbon supported noble metal catalyst.

[0042] Synthesis of deuterated 2-methylnaphthalene (4)

[0043]

[0044] Example 1

[0045] A 25 mL Schlenk tube was charged with 0.2 mmol (31.2 mg) of 2-naphthaldehyde, 1 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 10 mg of 5 wt.% hydrophilic carbon supported palladium catalyst, the reaction tube was evacuated and purged with argon (99.999%) twice to remove residual air in the system, and finally 0.1 MPa of hydrogen (99.999%) was introduced, then the reaction tube was placed in a preheated 100 °C oil bath, and after stirring at 800 rpm for 3 h, it was cooled to room temperature, the catalyst was removed by a filter, and a mixed solution of heavy water, cyclohexane and crude product was obtained. The product was extracted by adding ethyl acetate three times, 10 mL each time, and the organic layer and heavy water layer were separated, and the upper organic liquid was collected. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove residual heavy water. Finally, the organic solution was rotary evaporated at 40 °C under reduced pressure to remove the extractant and organic solvent, and 24.6 mg of the target deuterated product was obtained, with a yield of 78.8% and a methylene deuterium substitution rate of 97%. The MS spectrum of deuterated 2-methylnaphthalene is shown in Figure 2 , 1 The HNMR spectrum is shown in Figure 3 , 2 The H NMR spectrum is shown in Figure 4 . As shown in Figure 5 a, after the reaction stopped, the catalyst was dispersed in the lower heavy water layer, and the upper layer was the organic solvent layer; Figure 5 b shows a real photo of a gram-scale deuterated product. The catalyst was washed twice with ethanol and dried in a 60 °C reduced pressure oven for 8 h. Then, it was used again after reduction at 250 °C for 2 h in a mixed gas atmosphere (5% H2 / 95% Ar), and its cycle stability is shown in Figure 6 .

[0046] Example 2

[0047] In a 25 mL Schlenk tube, 0.2 mmol (31.2 mg) of 2-naphthaldehyde, 1 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 10 mg of 5 wt.% hydrophilic carbon-supported ruthenium catalyst were added. After the reaction tube was evacuated and purged with argon (99.999%) twice to remove residual air in the reaction system, 0.1 MPa of hydrogen (99.999%) was finally introduced. Then the reaction tube was placed in a preheated 100°C oil bath, and after 3h of reaction at a stirring rate of 800 rpm, it was cooled to room temperature. The catalyst was removed by a filter tip to obtain a mixed solution of heavy water, cyclohexane and crude product. The product was extracted by adding ethyl acetate in three portions of 10 mL each. The organic layer and the heavy water layer were separated, and the upper organic liquid was collected. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove residual heavy water. Finally, the organic solution was rotary evaporated at 40°C under reduced pressure to remove the extractant and organic solvent, and 19.8 mg of the target deuterated product was obtained, with a yield of 63.4% and a methyl deuterium substitution rate of 81%.

[0048] Example 3

[0049] In a 25 mL Schlenk tube, 0.2 mmol (31.2 mg) of 2-naphthaldehyde, 1 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 15 mg of 5 wt.% hydrophilic carbon-supported platinum catalyst were added. After the reaction tube was evacuated and purged with argon (99.999%) twice to remove residual air in the reaction system, 0.1 MPa of hydrogen (99.999%) was finally introduced. Then the reaction tube was placed in a preheated 100°C oil bath, and after 3h of reaction at a stirring rate of 800 rpm, it was cooled to room temperature. The catalyst was removed by a filter tip to obtain a mixed solution of heavy water, cyclohexane and crude product. The product was extracted by adding ethyl acetate in three portions of 10 mL each. The organic layer and the heavy water layer were separated, and the upper organic liquid was collected. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove residual heavy water. Finally, the organic solution was rotary evaporated at 40°C under reduced pressure to remove the extractant and organic solvent, and 21.7 mg of the target deuterated product was obtained, with a yield of 69.6% and a methyl deuterium substitution rate of 84%.

[0050] Example 4

[0051] In a 25 mL Schlenk tube, 0.2 mmol (31.2 mg) of 2-naphthaldehyde, 1 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 20 mg of 5 wt.% hydrophilic carbon-supported palladium catalyst were added. After the reaction tube was evacuated and purged with argon (99.999%) twice to remove residual air in the reaction system, 0.1 MPa of hydrogen (99.999%) was finally introduced. Then the reaction tube was placed in a preheated 100°C oil bath, and after 3h of reaction at a stirring rate of 800 rpm, it was cooled to room temperature. The catalyst was removed by a filter tip to obtain a mixed solution of heavy water, cyclohexane and crude product. The product was extracted by adding ethyl acetate in three portions of 10 mL each. The organic layer and the heavy water layer were separated, and the upper organic liquid was collected. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove residual heavy water. Finally, the organic solution was rotary evaporated at 40°C under reduced pressure to remove the extractant and organic solvent, and 19.3 mg of the target deuterated product was obtained with a yield of 61.9% and a methy deuterium substitution rate of 98%.

[0052] Example 5

[0053] In a 25 mL Schlenk tube, 0.2 mmol (31.2 mg) of 2-naphthaldehyde, 1 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 20 mg of 5 wt.% hydrophilic carbon-supported palladium catalyst were added. After the reaction tube was evacuated and purged with argon (99.999%) twice to remove residual air in the reaction system, 0.1 MPa of hydrogen (99.999%) was finally introduced. Then the reaction tube was placed in a preheated 100°C oil bath, and after 3h of reaction at a stirring rate of 800 rpm, it was cooled to room temperature. The catalyst was removed by a filter tip to obtain a mixed solution of heavy water, cyclohexane and crude product. The product was extracted by adding ethyl acetate in three portions of 10 mL each. The organic layer and the heavy water layer were separated, and the upper organic liquid was collected. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove residual heavy water. Finally, the organic solution was rotary evaporated at 40°C under reduced pressure to remove the extractant and organic solvent, and 19.3 mg of the target deuterated product was obtained with a yield of 61.9% and a methy deuterium substitution rate of 98%.

[0054] Example 6

[0055] In a 25 mL Schlenk tube, 0.2 mmol (31.2 mg) of 2-naphthaldehyde, 2 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 10 mg of 5 wt.% hydrophilic carbon-supported palladium catalyst were added. After the reaction tube was evacuated and purged with argon (99.999%) twice to remove residual air in the reaction system, 0.1 MPa of hydrogen (99.999%) was finally introduced. Then the reaction tube was placed in a preheated 100°C oil bath, and after 3h of reaction at a stirring rate of 800 rpm, it was cooled to room temperature. The catalyst was removed by a filter tip to obtain a mixed solution of heavy water, cyclohexane and crude product. The product was extracted by adding ethyl acetate in three portions of 10 mL each. The organic layer and the heavy water layer were separated, and the upper organic liquid was collected. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove residual heavy water. Finally, the organic solution was rotary evaporated at 40°C under reduced pressure to remove the extractant and organic solvent, and the target deuterated product 25.3 mg was obtained with a yield of 81.0% and a methyl deuterium substitution rate of 97%.

[0056] Example 7

[0057] In a 25 mL Schlenk tube, 0.2 mmol (31.2 mg) of 2-naphthaldehyde, 2 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 10 mg of 5 wt.% hydrophilic carbon-supported palladium catalyst were added. After the reaction tube was evacuated and purged with argon (99.999%) twice to remove residual air in the reaction system, 0.1 MPa of hydrogen (99.999%) was finally introduced. Then the reaction tube was placed in a preheated 100°C oil bath, and after 3h of reaction at a stirring rate of 800 rpm, it was cooled to room temperature. The catalyst was removed by a filter tip to obtain a mixed solution of heavy water, cyclohexane and crude product. The product was extracted by adding ethyl acetate in three portions of 10 mL each. The organic layer and the heavy water layer were separated, and the upper organic liquid was collected. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove residual heavy water. Finally, the organic solution was rotary evaporated at 40°C under reduced pressure to remove the extractant and organic solvent, and the target deuterated product 25.3 mg was obtained with a yield of 81.0% and a methyl deuterium substitution rate of 97%.

[0058] Example 8

[0059] A 25 mL Schlenk tube was charged with 0.2 mmol (31.2 mg) of 2-naphthaldehyde, 1 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 10 mg of 5 wt.% hydrophilic carbon supported palladium catalyst, the reaction tube was evacuated and purged twice with argon (99.999%) to remove the residual air in the reaction system, and finally 0.1 MPa of hydrogen (99.999%) was introduced. The reaction tube was then placed in a preheated 120 °C oil bath, stirred at a speed of 800 rpm for 3 h, and then cooled to room temperature. The catalyst was removed by a filter, and a mixed solution of heavy water, cyclohexane and crude product was obtained. The product was extracted by adding ethyl acetate three times, 10 mL each time. The organic layer and heavy water layer were separated, and the upper organic liquid was collected. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove the residual heavy water. Finally, the organic solution was rotary evaporated at 40 °C under reduced pressure to remove the extractant and organic solvent, and 24.1 mg of the target deuterated product was obtained, with a yield of 77.2% and a methyl deuterium substitution rate of 95%.

[0060] Example 9

[0061] A 25 mL Schlenk tube was charged with 0.2 mmol (31.2 mg) of 2-naphthaldehyde, 1 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 10 mg of 5 wt.% hydrophilic carbon supported palladium catalyst, the reaction tube was evacuated and purged twice with argon (99.999%) to remove the residual air in the reaction system, and finally 0.1 MPa of hydrogen (99.999%) was introduced. The reaction tube was then placed in a preheated 120 °C oil bath, stirred at a speed of 800 rpm for 3 h, and then cooled to room temperature. The catalyst was removed by a filter, and a mixed solution of heavy water, cyclohexane and crude product was obtained. The product was extracted by adding ethyl acetate three times, 10 mL each time. The organic layer and heavy water layer were separated, and the upper organic liquid was collected. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove the residual heavy water. Finally, the organic solution was rotary evaporated at 40 °C under reduced pressure to remove the extractant and organic solvent, and 24.1 mg of the target deuterated product was obtained, with a yield of 77.2% and a methyl deuterium substitution rate of 95%.

[0062] Synthesis of deuterated 3-methoxytoluene (5)

[0063]

[0064] Example 10

[0065] In a 25 mL Schlenk tube, 0.2 mmol (27.2 mg) of 3-methoxybenzaldehyde, 1 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 10 mg of 5 wt.% hydrophilic carbon-supported palladium catalyst were added. After the reaction tube was evacuated and purged with argon (99.999%) twice to remove the residual air in the reaction system, 0.1 MPa of hydrogen (99.999%) was finally introduced. Then the reaction tube was placed in a preheated 100°C oil bath, and after 3h of reaction at a stirring rate of 800 rpm, it was cooled to room temperature. The catalyst was removed by a filter, and a mixed solution of heavy water, cyclohexane and crude product was obtained. The product was extracted by adding ethyl acetate three times, 10 mL each time. The organic layer and heavy water layer were separated, and the upper organic liquid was collected. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove the residual heavy water. Finally, the organic solution was rotary evaporated at 40°C under reduced pressure to remove the extractant and organic solvent, and 23.0 mg of the target deuterated product was obtained, with a yield of 85.6% and a methylene deuterium substitution rate of 95%.

[0066] Synthesis of deuterated p-chlorotoluene formula (6)

[0067]

[0068] Example 11

[0069] In a 25 mL Schlenk tube, 0.2 mmol (28.1 mg) of p-chlorobenzaldehyde, 1 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 10 mg of 5 wt.% hydrophilic carbon-supported palladium catalyst were added. After the reaction tube was evacuated and purged with argon (99.999%) twice to remove the residual air in the reaction system, 0.1 MPa of hydrogen (99.999%) was finally introduced. Then the reaction tube was placed in a preheated 100°C oil bath, and after 3h of reaction at a stirring rate of 800 rpm, it was cooled to room temperature. The catalyst was removed by a filter, and a mixed solution of heavy water, cyclohexane and crude product was obtained. The product was extracted by adding ethyl acetate three times, 10 mL each time. The organic layer and heavy water layer were separated, and the upper organic liquid was collected. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove the residual heavy water. Finally, the organic solution was rotary evaporated at 40°C under reduced pressure to remove the extractant and organic solvent, and 17.6 mg of the target deuterated product was obtained, with a yield of 63% and a methylene deuterium substitution rate of 73%.

[0070] Synthesis of deuterated 3-methylindole formula (7)

[0071]

[0072] Example 12

[0073] In a 25 mL Schlenk tube, 0.2 mmol (29.0 mg) of indole-3-carboxaldehyde, 1 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 10 mg of 5 wt.% hydrophilic carbon-supported palladium catalyst were added. After the reaction tube was evacuated and purged with argon (99.999%) twice to remove the residual air in the reaction system, 0.1 MPa of hydrogen (99.999%) was finally introduced. Then the reaction tube was placed in a preheated 100 °C oil bath, and after 3 h of reaction at a stirring rate of 800 rpm, it was cooled to room temperature. The catalyst was removed by a filter, and a mixed solution of heavy water, cyclohexane and crude product was obtained. The product was extracted by adding ethyl acetate three times, 10 mL each time. The organic layer and heavy water layer were separated, and the upper organic liquid was collected. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove the residual heavy water. Finally, the organic solution was rotary evaporated at 40 °C under reduced pressure to remove the extractant and organic solvent, and 13.7 mg of the target deuterated product was obtained, with a yield of 47.2% and a methylene deuterium substitution rate of 92%.

[0074] Synthesis of deuterated 2,6-di-tert-butyltoluene (8)

[0075]

[0076] Example 13

[0077] In a 25 mL Schlenk tube, 0.2 mmol (43.7 mg) of 3,5-bis(tert-butyl)benzaldehyde, 1 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 20 mg of 5 wt.% hydrophilic carbon-supported palladium catalyst were added. After the reaction tube was evacuated and purged with argon (99.999%) twice to remove the residual air in the reaction system, 0.1 MPa of hydrogen (99.999%) was finally introduced. Then the reaction tube was placed in a preheated 120 °C oil bath, and after 3 h of reaction at a stirring rate of 800 rpm, it was cooled to room temperature. The catalyst was removed by a filter, and a mixed solution of heavy water, cyclohexane and crude product was obtained. The product was extracted by adding ethyl acetate three times, 10 mL each time. The organic layer and heavy water layer were separated, and the upper organic liquid was collected. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove the residual heavy water. Finally, the organic solution was rotary evaporated at 40 °C under reduced pressure to remove the extractant and organic solvent, and 31.0 mg of the target deuterated product was obtained, with a yield of 72% and a methylene deuterium substitution rate of 87%.

[0078] Synthesis of deuterated p-xylene (9)

[0079]

[0080] Example 14

[0081] In a 25 mL Schlenk tube, 0.2 mmol (26.8 mg) of p-xylylene glycol, 1 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 20 mg of 5 wt.% hydrophilic carbon-supported palladium (4.7 mol%) catalyst were added. After the reaction tube was evacuated and purged with argon (99.999%) twice to remove residual air in the reaction system, 0.1 MPa of hydrogen (99.999%) was finally introduced. Then the reaction tube was placed in a preheated 120 °C oil bath, and after 3 h of reaction at a stirring rate of 800 rpm, it was cooled to room temperature. The catalyst was removed by a filter, and a mixed solution of heavy water, cyclohexane and crude product was obtained. The product was extracted by adding ethyl acetate three times, 10 mL each time. The organic layer and heavy water layer were separated, and the upper organic liquid was collected. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove residual heavy water. Finally, the organic solution was rotary evaporated at 40 °C under reduced pressure to remove the extractant and organic solvent, and 18.4 mg of the target deuterated product was obtained, with a yield of 68% and a methyl deuterium substitution rate of 75%.

[0082] Synthesis of deuterated p-methyl deuterated toluene (10)

[0083]

[0084] Example 15

[0085] In a 25 mL Schlenk tube, 0.2 mmol (24.0 mg) of p-methyl benzaldehyde, 1 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 10 mg of 5 wt.% hydrophilic carbon-supported palladium catalyst were added. After the reaction tube was evacuated and purged with argon (99.999%) twice to remove residual air in the reaction system, 0.1 MPa of hydrogen (99.999%) was finally introduced. Then the reaction tube was placed in a preheated 100 °C oil bath, and after 3 h of reaction at a stirring rate of 800 rpm, it was cooled to room temperature. The catalyst was removed by a filter, and a mixed solution of heavy water, cyclohexane and crude product was obtained. The product was extracted by adding ethyl acetate three times, 10 mL each time. The organic layer and heavy water layer were separated, and the upper organic liquid was collected. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove residual heavy water. Finally, the organic solution was rotary evaporated at 40 °C under reduced pressure to remove the extractant and organic solvent, and 18.5 mg of the target deuterated product was obtained, with a yield of 77% and a methyl deuterium substitution rate of 80%.

[0086] Synthesis of deuterated diphenylmethane (11)

[0087]

[0088] Example 16

[0089] In a 25 mL Schlenk tube, 0.2 mmol (31.2 mg) of 2-naphthaldehyde, 2 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 10 mg of 5 wt.% commercial carbon YP50 supported palladium catalyst were added. The reaction tube was evacuated and purged twice with argon (99.999%) to remove the residual air in the system, and finally 0.1 MPa of hydrogen (99.999%) was introduced. The reaction tube was then placed in a preheated 100 °C oil bath, and after 3 h of reaction at a stirring rate of 800 rpm, it was allowed to cool to room temperature. The catalyst was removed by a filter tip, and a mixture of heavy water, cyclohexane and crude product was obtained. The product was extracted by adding ethyl acetate three times, 10 mL each time, and the organic layer and the heavy water layer were separated, collecting the upper organic liquid. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove the residual heavy water. Finally, the organic solution was rotary evaporated at 40 °C under reduced pressure to remove the extractant and organic solvent, and 24.1 mg of the target deuterated product was obtained, with a yield of 83.5% and a methy deuterium substitution rate of 62%.

[0090] Comparative Example 1

[0091] In a 25 mL Schlenk tube, 0.2 mmol (31.2 mg) of 2-naphthaldehyde, 2 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 10 mg of 5 wt.% commercial carbon YP50 supported palladium catalyst were added. The reaction tube was evacuated and purged twice with argon (99.999%) to remove the residual air in the system, and finally 0.1 MPa of hydrogen (99.999%) was introduced. The reaction tube was then placed in a preheated 100 °C oil bath, and after 3 h of reaction at a stirring rate of 800 rpm, it was allowed to cool to room temperature. The catalyst was removed by a filter tip, and a mixture of heavy water, cyclohexane and crude product was obtained. The product was extracted by adding ethyl acetate three times, 10 mL each time, and the organic layer and the heavy water layer were separated, collecting the upper organic liquid. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove the residual heavy water. Finally, the organic solution was rotary evaporated at 40 °C under reduced pressure to remove the extractant and organic solvent, and 24.1 mg of the target deuterated product was obtained, with a yield of 83.5% and a methy deuterium substitution rate of 62%.

[0092] Comparative Example 2

[0093] A 25 mL Schlenk tube was charged with 0.2 mmol (31.2 mg) of 2-naphthaldehyde, 2 mL of heavy water (99.9%), 1 mL of cyclohexane solution (99.9%), 10 mg of 5 wt.% hydrophilic carbon supported palladium catalyst, the reaction tube was evacuated and purged twice with argon (99.999%) to remove residual air from the system, and finally purged with 0.1 MPa of argon (99.999%), then the reaction tube was placed in a preheated 100 °C oil bath, after 3 h of reaction at a stirring rate of 800 rpm, it was cooled to room temperature, the catalyst was removed by a filter tip, and a mixture of heavy water, cyclohexane and crude product was obtained. The product was extracted by adding ethyl acetate in three portions of 10 mL each, the organic layer and the heavy water layer were separated, and the upper organic liquid was collected. Subsequently, 10 mg of anhydrous magnesium sulfate was added as a drying agent to remove residual heavy water. Finally, the organic solution was rotary evaporated at 40 °C under reduced pressure to remove the extractant and organic solvents, and the target deuterated product was not collected.

Claims

1. A method for deoxygenating a hydrophilic carbon supported catalyst to prepare an aromatic deuterated methane compound, characterized in that: The method comprises the following steps: taking aromatic aldehyde compounds as raw materials, heavy water as a deuterium source, hydrophilic carbon supported noble metal as a catalyst, non-polar organic reagent as a solvent, and carrying out deoxygenation and deuteration reaction in a hydrogen reaction atmosphere to obtain aromatic deuterated methane compounds; the hydrophilic carbon has a water vapor adsorption capacity of 10 mmol·g -1 -1 at 298 K and relative humidity of 20 RH% or less; the noble metal is one or more of palladium, ruthenium, platinum and rhodium, and the mass percentage of the noble metal in the catalyst is 5-8 wt.%; and the non-polar organic reagent is one of n-hexane, cyclohexane, toluene, xylene and dichloromethane. The aromatic aldehyde compound is one or more of compounds shown in formula (1), or is one of 2-naphthaldehyde, p-chlorobenzaldehyde, indole-3-carboxaldehyde, p-phenylenedimethylaldehyde and p-methylbenzaldehyde; R is selected from one of hydrogen, 3-methoxy, 3,5-di-tert-butyl, nitro, hydroxyl and cyano; The aromatic group deuterated methane compound is one or more of compounds shown in formula (2), or is one of formula (3), formula (4), formula (5), formula (6) and formula (7): ； R is selected from one of hydrogen, 3-methoxy, 3,5-di-tert-butyl, nitro, hydroxyl and cyano; The hydrophilic carbon is a N / O heteroatom-doped porous carbon carrier, wherein the N atom doping content is 10-20%, the O atom doping content is 10-20%, the specific surface area is 300-1000 m 2 g -1 Between, the pore size distribution is in the range of 0.5-20 nm, and the water contact angle test is <35°.

2. The method for deoxygenating and deuterating aromatic compounds to prepare aryl-deuterated methane compounds by using a hydrophilic carbon-supported catalyst according to claim 1, characterized in that: Specifically comprising: S1 adding the aromatic aldehyde compound, heavy water and catalyst into a non-polar organic reagent, and ultrasonic treatment until uniform; S2 after multiple replacement of inert atmosphere, hydrogen is introduced, and the reaction is carried out by heating and stirring; after the reaction is completed, the temperature is cooled to room temperature, the catalyst is separated by filtration, and the filtrate is a mixed solution of the non-polar organic reagent and the heavy water in which the aromatic group deuterated methane compound is dissolved; S3 adding an extractant to the mixed solution, and after the dropwise addition is completed, the heavy water is removed by static layer separation, and the organic solution is collected; S4 removing the non-polar organic reagent and the extractant by rotary evaporation under reduced pressure to obtain the target deuterated product.

3. The method for deoxygenating and deuterating aromatic compounds to prepare aryl-deuterated methane compounds by using the hydrophilic carbon-supported catalyst according to claim 1 or 2, characterized in that: The preparation method of the hydrophilic carbon comprises the following steps: S01 configuring a copper salt aqueous solution and an iron salt aqueous solution, dissolving a nitrogen-containing organic ligand in an organic solvent to obtain a nitrogen-containing organic ligand solution; S02 adding the nitrogen-containing organic ligand solution and the copper salt aqueous solution into the iron salt aqueous solution in sequence, fully stirring and mixing to form a uniform solution, and then obtaining a carbon precursor through standing, centrifugation, water washing and drying; wherein the molar ratio of the ligand and the copper salt in the uniform solution is 0.5-3:1; the mass ratio of the ligand to the iron salt is 0.5-3:1; and the volume ratio of water to the organic solvent is 5-20:1; S03 pyrolyzing the carbon precursor at a carbonization temperature of 400-600 ℃ in an inert atmosphere, and then obtaining the hydrophilic carbon material through acid washing, water washing and drying.

4. The method for deoxygenating and deuterating aromatic compounds to prepare aryl-deuterated methane compounds by using the hydrophilic carbon-supported catalyst according to claim 1 or 2, characterized in that: The molar amount of the noble metal in the catalyst is 2%-5% of the molar amount of the aromatic aldehyde compound.

5. The method for deoxygenating and deuterating aromatic compounds to prepare aryl-deuterated methane compounds by using the hydrophilic carbon-supported catalyst according to claim 1 or 2, characterized in that: The molar amount of the aromatic aldehyde compound is 1:10-20 mmol / mL of the volume amount of the heavy water.

6. The method for deoxygenating and deuterating aromatic compounds to prepare aryl-deuterated methane compounds by using the hydrophilic carbon-supported catalyst according to claim 1 or 2, characterized in that: The volume ratio of the non-polar organic reagent to the heavy water is 1:2-5.

7. The method for deoxygenating and deuterating aromatic compounds to prepare aryl-deuterated methane compounds by using the hydrophilic carbon-supported catalyst according to claim 1 or 2, characterized in that: The reaction pressure is 0.1-0.5 MP.

8. The method for deoxygenating and deuterating aromatic compounds to prepare aryl-deuterated methane compounds by using the hydrophilic carbon-supported catalyst according to claim 1 or 2, characterized in that: The reaction temperature is 90-130 ℃.

9. The method for preparing aromatic deuterated methane compounds by deoxygenation using a hydrophilic carbon-supported catalyst as described in claim 2, characterized in that: The stirring rate in S2 is 600-1000 rpm.

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