Preparation method of deuterated alkyl (hetero) aryl ether compound (deuterated drug)

Abstract

The invention discloses a preparation method of a deuterated alkyl (hetero) aryl ether compound (deuterated medicine), and belongs to the technical field of deuterated compound synthesis. The preparation method comprises the following steps: adding a (hetero) aryl halide, deuterated alcohol, a nickel catalyst, organic alkali and a silane reagent into an organic solvent, and reacting in an inert gas atmosphere to obtain the deuterated alkyl (hetero) aryl ether compound and the deuterated drug. The compound can be applied to later modification of drug molecules and synthesis of deuterated drugs such as agomelatine and phenacetin. The method has the advantages of mild reaction conditions, simple operation and low cost, and has good application prospects in the field of deuterated drug synthesis.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a preparation method of deuterated alkyl (hetero)aryl ether compound (deuterated drug). BACKGROUND

[0002] Because the bond energy between deuterium atom and carbon atom is higher than that between hydrogen atom and carbon atom, the deuterated drug usually has more stable chemical properties and longer metabolic half-life. Replacing hydrogen atom with deuterium atom at a specific site in a drug molecule can improve the pharmacokinetics of the drug or reduce the toxicity of the drug, and is highly valued in the pharmaceutical industry. Nature. Reviews. Drug. Discovery 2023, 22 , 562-584).

[0003] Alkyl (hetero)aryl ether compound is an important organic compound, which contains alkyl and (hetero)aryl in the molecular structure, and the two are connected by an ether bond. Such compounds have a wide range of biological activities and have important application value in the pharmaceutical field, and are often used as drug candidate molecules or important intermediates for drug synthesis, mainly for improving the metabolic stability and pharmacokinetic properties of drugs. For example, in 2017, the U.S. Food and Drug Administration approved the world's first deuterated drug, deutetrabenazine ( Nature Biotechnology, 2017 , 35 , 493-494), which is a vesicular monoamine transporter 2 inhibitor for treating Huntington's disease. Compared with the non-deuterated reference drug tetrabenazine, deutetrabenazine shows more excellent pharmacokinetic properties and better safety, so that the drug dosage and administration frequency are significantly reduced. Therefore, the synthesis of deuterated alkyl aryl ether compound has important research significance and shows broad application prospects in the field of drug synthesis.

[0004] Currently, the synthesis methods of deuterated alkyl aryl ether compounds mainly include the following: method one: using triazene as a precursor, reacting in the presence of carboxylic acid and alcohol to obtain deuterated methyl aryl ether compounds (Chemical Communications, 2011, 47, 9063-9065); method two: transition metal palladium catalyzes aryl halide to react with deuterated methanol to obtain deuterated methyl aryl ether compounds (Chemistry-A European Journal, 2012, 18, 2498-2502). Method four: using cheap metal cobalt as a catalyst, salicylaldehyde as a ligand, and deuterated methanol as a deuterium source, by introducing a bidentate directing group on the benzene ring, the deuterated methoxy group is effectively introduced into benzamide derivatives (Shandong Chemical Industry, 2023, 52, 48-52). The existing synthesis methods mainly rely on special substrates, noble metals, harsh reaction conditions, low yield, poor substrate applicability, etc., which are not easy to be scaled up, limiting its further application. Therefore, it is of important research significance and application value to develop deuterated methoxylation of (hetero) aryl halides under the condition of using abundant and cheap metal catalysts and simple and mild conditions. SUMMARY

[0005] In view of the technical status that the existing synthesis methods of deuterated alkyl aryl ether compounds have harsh reaction conditions, low yield, poor selectivity, limited substrate applicability, etc., which are difficult to meet the diversified needs of drug research and development for deuterated compounds, the present application aims to provide a preparation method of deuterated alkyl heteroaryl ether compounds, which uses abundant and cheap metal nickel as a catalyst, has mild reaction conditions, simple operation and wide substrate applicability.

[0006] In order to achieve the above purposes, the technical scheme adopted by the present application is as follows: The present application provides a preparation method of deuterated alkyl heteroaryl ether compounds (deuterated drugs), comprising: Inert gas atmosphere, compound 1 and compound 2 are used as reaction substrates, catalyst, ligand, reducing agent and organic base are added for reaction, after reaction, cooling to room temperature, extraction, evaporation concentration, column chromatography purification to obtain deuterated alkyl heteroaryl ether compounds;

[0007] The structural formula of the compound 1 is: Ar-X, wherein Ar is aryl or heteroaryl, substituted aryl or heteroaryl, the substituent is any 1-3 of C1-C5 alkyl, hydroxyl, C1-C5 alkoxy, amino, nitro, sulfonic acid group and carboxyl; X is Br or Cl; The structural formula of the compound 2 is: n D 2n+1OD, wherein n is 1 or 2; The catalyst is a divalent nickel salt; the reducing agent is a silicon-based reducing agent; and the ligand is selected from a bis-nitrogen ligand. The structural formula of the deuterated alkyl heteroaryl ether compound is: Ar-OC n D 2n+1 .

[0008] Further, the solvent used is selected from any one of N,N-dimethylformamide, 1,4-dioxane, toluene or acetonitrile.

[0009] The molar ratio of the compound 1 to the compound 2 is 1:2-3.

[0010] The molar ratio of the compound 1 to the catalyst is 1:0.04-0.06.

[0011] Further, the catalyst is selected from any one of nickel bromide, nickel chloride or nickel bromide trihydrate.

[0012] The molar ratio of the compound 1 to the ligand is 1:0.04-0.06.

[0013] Further, the ligand is selected from any one of 4,4-dimethyl-2,2-bipyridine, 4,4-dimethoxy-2,2-bipyridine or 4,4-di-tert-butyl-2,2-bipyridine.

[0014] The molar ratio of the compound 1 to the reducing agent is 1:0.1-0.3.

[0015] Further, the reducing agent is selected from any one of phenylsilane, diethylsilane or triphenylsilane.

[0016] The molar ratio of the compound 1 to the organic base is 1:1.4-1.6.

[0017] Further, the organic base is selected from any one of 1,8-diazobis-spiro[5.4.0]undec-7-ene, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene or tetramethylguanidine.

[0018] The reaction temperature is 80-120 DEG C, and the reaction time is 12-24h.

[0019] The column chromatography uses petroleum ether and ethyl acetate with a volume ratio of 70-90:1 as the mobile phase.

[0020] Further, the column chromatography uses petroleum ether and ethyl acetate with a volume ratio of 80:1 as the mobile phase.

[0021] Compared with the prior art, the present application has the following technical effects: The application provides a preparation method of a deuterated alkyl heteroaryl ether compound (deuterated drug), which uses cheap and readily available aryl or heteroaryl halides and deuterated alcohols as substrates, uses cheap and abundant nickel as a catalyst, has mild reaction conditions, is simple to operate, and has wide substrate applicability, effectively solves problems of harsh reaction conditions, low yield, poor selectivity, and limited substrate application range in existing synthesis methods, and meets diversified needs of drug research and development for deuterated compounds.

[0022] Further, the bidentate nitrogen ligand can form a stable complex with the nickel catalyst to improve catalytic activity, and the silicon-based reducing agent has the characteristics of strong reduction capacity and good selectivity, and by controlling the amount of the reducing agent, the reduction step in the reaction can be ensured to proceed smoothly, while over-reduction or under-reduction is avoided; the organic base can provide an alkaline environment required by the reaction and promote the progress of the reaction. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 The deuterated methoxy aryl ether compound (compound 1) prepared by the preparation method of the application has the following H NMR spectrum: 1 H NMR spectrum; Figure 2 The deuterated methoxy aryl ether compound (compound 1) prepared by the preparation method of the application has the following H NMR spectrum: 13 C NMR spectrum; Figure 3 The deuterated methoxy aryl ether compound (compound 2) prepared by the preparation method of the application has the following H NMR spectrum: 1 H NMR spectrum; Figure 4 The deuterated methoxy aryl ether compound (compound 2) prepared by the preparation method of the application has the following H NMR spectrum: 13 C NMR spectrum; Figure 5 The deuterated methoxy aryl ether compound (compound 3) prepared by the preparation method of the application has the following H NMR spectrum: 1 H NMR spectrum; Figure 6 The deuterated methoxy aryl ether compound (compound 3) prepared by the preparation method of the application has the following H NMR spectrum: 13 C NMR spectrum; Figure 7 The deuterated methoxy aryl ether compound (compound 4) prepared by the preparation method of the application has the following H NMR spectrum: 1 H NMR spectrum; Figure 8 The deuterated methoxy aryl ether compound (compound 4) prepared by the preparation method of the application has the following H NMR spectrum: 13 C NMR spectrum; Figure 9The deuterium derivative of Fenofibrate (Compound 5) prepared by the preparation method of the present application is 1 H NMR spectrum; Figure 10 The deuterium derivative of Fenofibrate (Compound 5) prepared by the preparation method of the present application is 13 C NMR spectrum; Figure 11 The deuterium derivative of Etoricoxib (Compound 6) prepared by the preparation method of the present application is 1 H NMR spectrum; Figure 12 The deuterium derivative of Etoricoxib (Compound 6) prepared by the preparation method of the present application is 13 C NMR spectrum; Figure 13 The deuterium derivative of Diazoxide (Compound 7) prepared by the preparation method of the present application is 1 H NMR spectrum; Figure 14 The deuterium derivative of Diazoxide (Compound 7) prepared by the preparation method of the present application is 13 C NMR spectrum; Figure 15 The deuterium derivative of Moxonidine (Compound 8) prepared by the preparation method of the present application is 1 H NMR spectrum; Figure 16 The deuterium derivative of Moxonidine (Compound 8) prepared by the preparation method of the present application is 13 C NMR spectrum; Figure 17 The deuterium derivative of Agomelatine (Compound 9) prepared by the preparation method of the present application is 1 H NMR spectrum; Figure 18 The deuterium derivative of Agomelatine (Compound 9) prepared by the preparation method of the present application is 13 C NMR spectrum; Figure 19 The deuterium derivative of Phenazopyridine (Compound 10) prepared by the preparation method of the present application is 1 H NMR spectrum; Figure 20 The deuterium derivative of Phenazopyridine (Compound 10) prepared by the preparation method of the present application is 13 C NMR spectrum. DETAILED DESCRIPTION

[0024] In order to make the purposes, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below in conjunction with the embodiments of the present application. Obviously, the described embodiments are some but not all of the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative effort belong to the scope of protection of the present application.

[0025] The test materials and reagents used in the following examples, and the like, can be obtained from commercial channels unless otherwise specified.

[0026] If a specific technique or condition is not specified in the examples, the technique or condition described in the literature in the art or according to the product manual can be used.

[0027] The raw materials 2-bromonaphthalene, 6-bromo-2-methylquinoline, 6-bromoquinoxaline, fenofibrate, deuterated methanol, 4,4-di-tert-butyl-2,2-bipyridine, etoricoxib, procaine, and the like used in the present application are purchased from Anjie Chemical Reagent, Leyan Reagent, and Bidai Pharmaceutical Reagent Company.

[0028] Example 1 The present embodiment provides a preparation method of a deuterated alkyl heteroaryl ether compound (deuterated drug), and the specific steps are as follows: In a glove box under nitrogen atmosphere, 2-bromonaphthalene (0.5 mmol, C 10 H7Br), deuterated methanol (1.0 mmol, CD3OD), 4,4-di-tert-butyl-2,2-bipyridine (0.025 mmol), nickel bromide trihydrate (0.025 mmol), 1,8-diazabicycloundec-7-ene (DBU, 0.75 mmol), phenylsilane (0.10 mmol, phSiH3), toluene (1.0 mL), and a magnetic stirrer were added into a reaction tube, the reaction tube was sealed and taken out of the glove box, and then quickly placed into an oil bath preheated to 120°C. After stirring in the 120°C oil bath for 24 hours, the reaction tube was taken out of the oil bath and cooled to room temperature. The reaction mixture was transferred into a separatory funnel, extracted (2-3 times, with water and ethyl acetate as the extractant), evaporated and concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase PE / EA = 80:1) to obtain 78.1 mg of the target product 1, with a yield of 97%. The structure of the target product 1 was identified by 1 H NMR, 13 C NMR and HRMS, and the specific identification data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.77 (dd,J = 12.0, 8.0 Hz, 3H), 7.48– 7.44 (m, 1H), 7.37-7.33 (m, 1H), 7.19 – 7.15 (m, 2H). 13 C NMR (100 MHz, Chloroform- d ) δ 157.9, 134.8, 129.7, 129.2, 127.9,127.0, 126.6, 123.8, 119.0, 106.0. HRMS (ESI) m / z C 11 H8D3O [M+H] + : Theoretical value 162.0993, measured value 162.0995.

[0029] through 1 H NMR, 13 C NMR and HRMS confirmed that the structural formula of the deuterated methoxy aryl ether compound is: (Compound 1).

[0030] Example 2 This example is based on Example 1, and an equal amount of 6-bromo-2-methylquinoline (0.5 mmol, C 10 H8BrN) to replace 2-bromonaphthalene in Example 1, and the other steps were the same as in Example 1 to obtain 82.8 mg of the target product 2 with the following structural formula and a yield of 94%. 1 H NMR, 13 C NMR and HRMS identification, the specific identification data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.91 (dd, J = 8.7, 4.1 Hz, 2H), 7.32(dd, J = 9.2, 2.9 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 2.8 Hz, 1H), 2.69(s, 3H). 13 C NMR (100 MHz, Chloroform- d) δ 157.2, 156.4, 144.0, 135.1, 130.2,127.4, 122.3, 122.0, 105.3, 25.1. HRMS (ESI) m / z C 11 H9D3NO [M+H] + : Calcd 177.1102, Found 177.1102.

[0031] The structure of the deuterated methoxy aryl ether compound was confirmed by 1 H NMR, 13 C NMR and HRMS. (Compound 2).

[0032] Example 3 This example was based on Example 1, using equimolar 6-bromoquinoxaline (0.5 mmol, C8H5BrN2) to replace 2-bromonaphthalene in Example 1, and other steps were the same as Example 1, to obtain 39.2 mg of target product 3 with a yield of 48 %, and the structure of target product 3 was identified by 1 H NMR, 13 C NMR and HRMS, and the specific identification data were as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.74 (d, J = 1.9 Hz, 1H), 8.68 (d, J =2.0 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.41 (dd, J = 9.2, 2.8 Hz, 1H), 7.35 (d, J =2.8 Hz, 1H). 13 C NMR (100 MHz, Chloroform- d ) δ 161.0, 145.2, 144.9, 142.7, 139.5,130.7, 123.7, 106.9. HRMS (ESI) m / z C9H6D3N2O [M+H] + : Calcd 164.0898, Found 164.0885.

[0033] The structure of the deuterated methoxy aryl ether compound was confirmed by 1H NMR, 13 C NMR and HRMS confirmed the structure of the deuterated methoxy aryl ether compound as: (Compound 3).

[0034] Example 4 This example is based on Example 1, using equimolar 6-chloroisoquinoline (0.5 mmol, C9H6ClN) to replace 2-bromonaphthalene in Example 1, and other steps are the same as Example 1, to obtain 55.1 mg of target product 4 with a yield of 68 %, and the structure of target product 4 is identified by 1 H NMR, 13 C NMR and HRMS identified, and the specific identification data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 9.09 (s, 1H), 8.43 (d, J = 5.8 Hz,1H), 7.84 (d, J = 9.0 Hz, 1H), 7.53 (d, J = 5.3 Hz, 1H), 7.22 (dd, J = 9.0, 2.2 Hz,1H), 7.04 (s, 1H). 13 C NMR (100 MHz, Chloroform- d ) δ 161.0, 151.7, 143.6, 137.9, 129.5,124.6, 120.5, 119.9, 104.1. HRMS (ESI) m / z C 10 H7D3NO [M+H] + : Theoretical value 163.0945, found value 163.0945.

[0035] After 1 H NMR, 13 C NMR and HRMS confirmed the structure of the deuterated methoxy aryl ether compound as: (Compound 4).

[0036] Example 5 This example is based on Example 1, using equimolar Fenofibrate (0.5 mmol, C 20 H 21ClO4) instead of 2-bromonaphthalene in Example 1, and other steps are the same as Example 1, to obtain 115.2 mg of target product 5 with a yield of 64 %, and the structure of target product 5 is identified by1H NMR, 1 H NMR, 13 C NMR and HRMS, and the specific identification data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.78 (d, J = 8.7 Hz, 2H), 7.72 (d, J =8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.12 – 5.06 (m,1H), 1.65 (s, 6H), 1.20 (d, J = 6.3 Hz, 6H). 13 C NMR (100 MHz, Chloroform- d ) δ 194.6, 173.4, 163.0, 159.2, 132.4,131.9, 131.4, 130.7, 117.3, 113.6, 79.4, 69.4, 25.5, 21.7. HRMS (ESI) m / z C 21 H 22 D3O5[M+H] + : theoretical value 360.1885, measured value 360.1880.

[0037] The structure of the fenofibrate deuterium derivative is confirmed by1H NMR, 1 H NMR, 13 C NMR and HRMS, and the specific identification data are as follows: (Compound 5).

[0038] Example 6 This example is based on Example 1, and equimolar 5-chloro-6'-methyl-3-[4- (methylsulfonyl) phenyl] -2, 3'-bipyridine (etoricoxib, 0.5 mmol) is used instead of 2-bromonaphthalene in Example 1, and other steps are the same as Example 1, to obtain 121.5 mg of target product 6 with a yield of 68 %, and the structure of target product 6 is identified by1H NMR, 1 H NMR, 13C NMR and HRMS identification, the specific identification data as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.46 (d, J = 2.8 Hz, 1H), 8.34 (d, J =2.3 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.54 (dd, J = 8.0, 2.4 Hz, 1H), 7.41 (d, J =8.4 Hz, 2H), 7.21 (d, J = 2.8 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 3.08 (s, 3H),2.52 (s, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 157.7, 155.1, 150.0, 146.7, 145.3,139.9, 137.6, 137.4, 135.0, 132.2, 130.6, 127.9, 122.9, 122.8, 44.7, 24.3. HRMS (ESI) m / z C 19 H 16 D3N2O3S [M+H] + : theoretical value 358.1299, found 358.1298.

[0039] confirmed by 1 H NMR, 13 C NMR and HRMS, the structure of the etoricoxib deuterium derivative is as follows: (compound 6).

[0040] Example 7 This example is based on example 1, using equimolar of diazene (C8H7ClN2O2S, 0.5 mol) to replace 2-bromonaphthalene in example 1, and other steps are the same as example 1, to obtain 91.7 mg of target product 7, the yield is 80 %, the structure of target product 7 is confirmed by 1 H NMR, 13 C NMR and HRMS identification, the specific identification data as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 11.94 (s, 1H), 7.26 (s, 2H), 7.20 (s, 1H),2.27 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6) δ 156.9, 156.4, 128.8, 121.7, 121.4, 119.1,104.9, 22.4. HRMS (ESI) m / z C9H8D3N2O3S [M+H] + : Found: 230.0675.

[0041] The structure of the diazine deuterium derivative was confirmed by 1 H NMR, 13 C NMR and HRMS, and the structure of the diazine deuterium derivative was confirmed, and the specific identification data are as follows: (compound 7).

[0042] Example 8 This example is based on Example 1, using equimolar 4-chloro-N-[2-(4- morpholinylethyl)]benzamide (moclobemide, C 13 H 17 ClN2O2, 0.5 mol) instead of 2-bromonaphthalene in Example 1, and the other steps are the same as Example 1, to obtain 127.1 mg of target product 8, with a yield of 95 %, and the structure of target product 8 is identified by 1 H NMR, 13 C NMR and HRMS, and the specific identification data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.74 (d, J = 8.8 Hz, 2H), 6.93 (d, J =8.8 Hz, 2H), 6.70 (s, 1H), 3.73 (t, J = 4.5 Hz, 4H), 3.54 (q, J = 5.6 Hz, 2H),2.60 (t, J = 6.0 Hz, 2H), 2.51 (t, J = 4.6 Hz, 4H). 13C NMR (100 MHz, Chloroform- d ) δ 167.1, 162.2, 128.8, 127.0, 113.9,67.2, 57.3, 53.6, 36.2. HRMS (ESI) m / z C 14 H 18 D3N2O3[M+H] + : Calcd: 268.1735, Found: 268.1730.

[0043] The structure of the deuterium derivative of moxonidine was confirmed by 1 H NMR, 13 C NMR and HRMS as follows: (Compound 8).

[0044] Example 9 This example was based on Example 1, using equimolar of bromoagomelatine (N-[2-(7-bromonaphthalen-1-yl)ethyl]acetamide, C 14 H 14 BrNO, 0.5 mol) instead of 2-bromonaphthalene in Example 1, and other steps were the same as Example 1, to obtain 83.0 mg of target product 9 with a yield of 90 %, and the structure of target product 9 was identified by 1 H NMR, 13 C NMR and HRMS as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.81 – 7.72 (m, 1H), 7.70 – 7.65 (m,1H), 7.51 – 7.46 (m, 1H), 7.30 – 7.25 (m, 2H), 7.23 – 7.12 (m, 1H), 5.80 –5.73 (m, 1H), 3.60 – 3.55 (m, 2H), 3.28 – 3.20 (m, 2H), 1.97 – 1.90 (m, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 170.4, 158.0, 133.7, 133.3, 130.3,129.4, 127.14, 127.10, 123.2, 118.4, 102.5, 40.2, 33.3, 23.4. HRMS (ESI) m / z C 15 H 15 D3NO2[M+H] + : Calcd 247.1520, Found 247.1521.

[0045] The structure of the deuterated agomelatine was confirmed by 1 H NMR, 13 C NMR and HRMS as follows: (compound 9).

[0046] Example 10 This example was based on Example 1, using equimolar of bromo-phenazyl (C9H 10 BrNO2, 0.5 mol) to replace 2-bromonaphthalene in Example 1, equimolar of deuterated ethanol to replace deuterated methanol, and other steps were the same as Example 1, to obtain 28.0 mg of target product 10 with a yield of 30 %, and the structure of target product 10 was identified by 1 H NMR, 13 C NMR and HRMS, and the specific identification data were as follows: 1 H NMR (600 MHz, Chloroform- d ) δ 7.37 (d, J = 5.9 Hz, 2H), 7.14 (s,1H), 6.84 (d, J = 5.9 Hz, 2H), 2.14 (s, 3H). 13 C NMR (151 MHz, Chloroform- d ) δ 168.3, 156.0, 130.9, 122.0, 114.9,24.5. HRMS (ESI) m / z C 10 H9D5NO2[M+H] + : Calcd 185.1333, Found 185.1333.

[0047] The structure of the deuterated phenazyl was confirmed by 1 H NMR, 13 C NMR and HRMS as follows: (compound 10).

[0048] The above merely illustrates the technical idea of the present application, and cannot limit the protection scope of the present application. Any modification made according to the technical idea of the present application on the basis of the technical scheme falls within the protection scope of the present application.

Claims

1. A method for preparing a deuterated alkyl heteroaryl ether compound, characterized in that: include: In an inert gas atmosphere, compound 1 and compound 2 are used as reaction substrates, and a catalyst, a ligand, a reducing agent, and an organic base are added to react. After the reaction, the mixture is cooled to room temperature, extracted, concentrated by evaporation, and purified by column chromatography to obtain a deuterated alkyl heteroaryl ether compound; The structural formula of the compound 1 is: Ar-X, wherein Ar is an aryl or heteroaryl group, a substituted aryl or heteroaryl group, and the substituent is any one to three of a C1-C5 alkyl group, a hydroxyl group, a C1-C5 alkoxy group, an amino group, a nitro group, a sulfonic acid group, and a carboxyl group; X is Br or Cl; The structural formula of the compound 2 is: n D 2n+1 OD, where n is 1 or 2; The catalyst is a divalent nickel salt; the reducing agent is a silicon-based reducing agent; and the ligand is selected from a dinitrogen ligand; The general structural formula of the deuterated alkyl (hetero) aryl ether compound is: Ar-OC n D 2n+1 .

2. The method for preparing a deuterated alkyl heteroaryl ether compound according to claim 1, wherein: The molar ratio of compound 1 to compound 2 is 1:2-3.

3. The method for preparing a deuterated alkyl heteroaryl ether compound according to claim 1, wherein: The molar ratio of the compound 1 to the catalyst is 1:0.04-0.

06.

4. The method for preparing a deuterated alkyl heteroaryl ether compound according to claim 3, wherein: The catalyst is selected from any one of nickel bromide, nickel chloride or nickel bromide trihydrate.

5. The method for preparing a deuterated alkyl heteroaryl ether compound according to claim 1, wherein: The molar ratio of the compound 1 to the ligand is 1:0.04-0.

06.

6. The method for preparing a deuterated alkyl heteroaryl ether compound according to claim 5, characterized in that: The ligand is selected from any one of 4,4-dimethyl-2,2-bipyridine, 4,4-dimethoxy-2,2-bipyridine or 4,4-di-tert-butyl-2,2-bipyridine.

7. The method for preparing a deuterated alkyl heteroaryl ether compound according to claim 1, characterized in that: The molar ratio of the compound 1 to the reducing agent is 1:0.1-0.

3.

8. The method for preparing a deuterated alkyl heteroaryl ether compound according to claim 1, characterized in that: The molar ratio of the compound 1 to the organic base is 1:1.4-1.

6.

9. The method for preparing a deuterated alkyl heteroaryl ether compound according to claim 1, wherein: The reaction temperature is 80-120° C., and the reaction time is 12-24 hours.

10. The method for preparing a deuterated alkyl heteroaryl ether compound according to claim 1, characterized in that: The column chromatography uses petroleum ether and ethyl acetate in a volume ratio of 70-90:1 as the mobile phase.

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