A deuteration method for fluorinated aromatic rings

Abstract

The present invention discloses a method for deuterating fluorinated aromatic rings, belonging to the technical field of electrolytic preparation of carbocyclic hydrocarbons. The method comprises mixing a fluorinated aromatic ring, deuterated water, a first electrolyte, and a first organic solvent to obtain a solution and performing electrolysis to obtain a product of defluorination and aromatic ring deuteration reduction. The method can achieve full defluorination and aromatic ring deuteration reduction under hydrogen-free conditions at room temperature and pressure, and the deuterium source used is easily available. The method not only has low energy consumption and low pollution, but is also a very green and environmentally friendly reaction method. The method also has excellent substrate applicability, scalability, broad economic value, and application space, and has extremely outstanding innovation and advantages in the field of deuterated drug synthesis.

Description

Technical Field

[0001] The present invention relates to the technical field of electrolytic preparation of carbocyclic hydrocarbons, and in particular to a deuteration method for fluorinated aromatic rings. Background Art

[0002] Deuteration of existing drug backbones has been widely applied in small molecule drugs. Deuteration of key sites in bioactive drug molecules can also improve their absorption and metabolism properties at the kinetic level. Several potential deuterated drug molecules are currently under development. Furthermore, deuterated molecules also play a crucial role as markers in mass spectrometry research. Given these numerous applications, deuteration reactions and methods for synthesizing deuterated compounds have garnered significant attention from chemists. Developing novel, green deuteration reactions and implementing them in practical pharmaceutical applications is of great significance.

[0003] Reductive deuteration is one of the primary methods for synthesizing deuterated drugs, widely used due to its high site-specific deuteration rate. However, existing methods generally use expensive deuterium sources, and the reduction conditions are too harsh, requiring high temperatures and high pressures. These factors contribute to the high cost of synthesizing deuterated drugs, limiting both R&D and clinical applications. Summary of the Invention

[0004] The purpose of the present invention is to develop a new, green and environmentally friendly deuteration reduction method, aiming to reduce the research and development costs of deuterated drugs and expand the market for deuterated drugs.

[0005] In order to achieve the above object, the present invention provides a method for deuterating a fluorinated aromatic ring, comprising:

[0006] A fluorinated aromatic ring, deuterated water, a first electrolyte, and a first organic solvent are mixed to obtain a solution, and the solution is electrolyzed to obtain a product of defluorination and aromatic ring reduction deuteration.

[0007] Furthermore, the concentrations of the fluorinated aromatic ring and the electrolyte in the solution are 0.05-0.2 mol / L and 0.1-0.3 mol / L, respectively.

[0008] Furthermore, the first electrolyte includes at least one of tetrabutylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium tetrafluoroborate, sodium chloride, sodium fluoride, and sodium bromide.

[0009] Furthermore, the first organic solvent includes at least one of deuterated methanol, deuterated tert-butyl alcohol, deuterated ethanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylbenzamide, and dimethyl sulfoxide.

[0010] Furthermore, the electrolysis is carried out at a current density of 1-40 mA / cm 2 The condition lasts for 24-72 hours.

[0011] In the present invention, the anode material used in electrolysis does not need to be strictly limited and can be an inert material, such as one of platinum sheets, carbon sheets, carbon cloth, carbon felt, carbon rods, carbon paper, etc.; it can also be a sacrificial anode material, such as one of magnesium, aluminum, zinc, iron, copper, lead, etc.

[0012] Furthermore, the cathode material used in the electrolysis is nitrogen-doped carbon felt loaded with metal, and its preparation method includes:

[0013] The carbon felt, melamine and ethanol are mixed and refluxed to obtain pretreated carbon felt;

[0014] The pretreated carbon felt is immersed in a mixed solution of melamine and paraformaldehyde to carry out a polymerization reaction to obtain a polymer-coated carbon felt;

[0015] calcining the polymer-coated carbon felt under a protective gas atmosphere to obtain nitrogen-doped carbon felt;

[0016] Immersing the nitrogen-doped carbon felt in a metal salt solution for adsorption reaction to obtain nitrogen-doped carbon felt adsorbing the metal salt;

[0017] The nitrogen-doped carbon felt adsorbed with metal salt is used as a cathode to obtain a metal-loaded nitrogen-doped carbon felt electrode through electrodeposition.

[0018] Furthermore, the mass ratio of the carbon felt, melamine and ethanol is 1:1-3:20.

[0019] Furthermore, the mass ratio of the pretreated carbon felt, melamine, paraformaldehyde and the solvent in the mixed solution is 1:1-15:1-15:10-50.

[0020] Furthermore, the calcination is carried out at a temperature of 700-1000° C. for 0.5-2 h, and the protective gas may be at least one of a rare gas and nitrogen.

[0021] Furthermore, the mass ratio of the nitrogen-doped carbon felt, the metal salt, and the solvent in the metal salt solution is 1:0.05-0.5:40-60;

[0022] The metal element in the metal salt includes at least one of ruthenium, cerium, europium, gold, terbium, dysprosium, holmium, erbium, thulium, ytterbium, and lutetium.

[0023] Furthermore, the electrodeposition is carried out at a current density of 1-40 mA / cm 2 The electrolyte used in the cathode chamber and the anode chamber is prepared by the second electrolyte, the second organic solvent and water.

[0024] Wherein, the mass ratio of the second organic solvent to the water is 0-9:1;

[0025] The concentration of the second electrolyte is 0.05-0.2 mol / L;

[0026] The second electrolyte comprises at least one of sodium fluoride, tetrabutylammonium bromide, tetrabutylammonium chloride, and tetrabutylammonium iodide;

[0027] The second organic solvent includes at least one of tetrahydrofuran, 1,4-dioxane, methanol, ethanol, isopropanol, and tert-butanol;

[0028] The anode of the electrodeposition is made of an inert material.

[0029] The present invention also provides a perdeuterated cyclohexyl compound, which is obtained by the above method.

[0030] The present invention also provides the use of the above-mentioned perdeuterated cyclohexyl compound in synthesizing deuterium-labeled drugs.

[0031] The present invention has the following two significant features: First, it uses a self-made catalytic electrode, which has superior performance, long life, adjustable size, good electrical conductivity and catalytic activity, and has a very outstanding prospect for scale-up industrialization. Second, the electrochemical reaction system realizes the full defluorination reduction of aromatic rings at room temperature and pressure without hydrogen for the first time, and realizes the reaction of obtaining a perdeuterated cyclohexyl compound in one step for the first time. The reaction has good substrate applicability and scalability, and the deuterium sources are all relatively cheap deuterium sources such as deuterated water, deuterated methanol, deuterated ethanol, deuterated tert-butanol, etc., which has broad economic value and application space. The reaction can quickly and easily obtain drug molecule precursors containing perdeuterated cyclohexyl, and has extremely outstanding innovation and advantages in the field of deuterated drug synthesis.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] The method of the present invention can realize full defluorination reduction of aromatic rings to deuterate under conditions of hydrogen-free, normal temperature and normal pressure. At the same time, the deuterium source used is easily available. It not only has low energy consumption and low pollution, but is also a very green and environmentally friendly reaction method. It also has good substrate applicability, scalability, broad economic value and application space, and has extremely outstanding innovation and advantages in the field of deuterated drug synthesis. DETAILED DESCRIPTION

[0034] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to form one or more new numerical ranges, and these numerical ranges should be considered to be specifically disclosed in the present invention.

[0035] The following will be combined with specific embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described 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 making creative efforts are within the scope of protection of the present invention.

[0036] Example 1

[0037] A method for deuterating a fluorinated aromatic ring, comprising the following steps:

[0038] S1. Add 0.4 mmol pentafluorobenzamide, 0.8 mmol sodium chloride, 2.5 mL deuterated methanol, and 2.5 mL deuterated water to a dry 15 mL three-necked flask equipped with a magnet and stir to obtain a solution;

[0039] S2: Nitrogen-doped carbon felt and aluminum sheet loaded with ruthenium were inserted into the solution below the liquid surface as cathode and anode, respectively, to construct a reaction system. The reaction system was heated at room temperature and 5 mA / cm 2 The electrolysis reaction was stirred for 36 h;

[0040] S3. After the electrolysis reaction is completed, the reaction solution is extracted with ethyl acetate, and the organic phase is then spin-dried. The product is separated by dry-loading on 200-300 mesh silica gel and gradient eluting with petroleum ether and ethyl acetate.

[0041] The preparation method of ruthenium-loaded nitrogen-doped carbon felt is as follows:

[0042] 1) Carbon felt was refluxed in a melamine ethanol dispersion at 80° C. and dried to prepare a melamine-adsorbed carbon felt, wherein the mass ratio of the carbon felt, melamine, and ethanol was 1:1:20.

[0043] 2) Melamine and paraformaldehyde were dissolved in dimethyl sulfoxide to obtain a mixed solution, and then the melamine-adsorbed carbon felt was immersed in the mixed solution, wherein the mass ratio of the melamine-adsorbed carbon felt, melamine, paraformaldehyde and dimethyl sulfoxide was 1:2:1:30. The mixture was heated at 110°C for 1 hour, and then raised to 160°C and heated for 24 hours to prepare the melamine and paraformaldehyde polymer-coated carbon felt.

[0044] 3) The carbon felt coated with melamine and paraformaldehyde was calcined at 800°C for 1 h under an argon atmosphere to prepare nitrogen-doped carbon felt.

[0045] 4) Immersing the nitrogen-doped carbon felt in a ruthenium trichloride aqueous solution, stirring at room temperature for 12 hours, and then removing and drying to obtain the nitrogen-doped carbon felt adsorbed with ruthenium salt, wherein the mass ratio of the nitrogen-doped carbon felt, ruthenium trichloride, and water is 1:0.05:50.

[0046] 5) Set up a separate electrolytic cell, where the electrolyte in the cathode chamber is prepared by 0.8 mmol tetrabutylammonium bromide, 5 mL tert-butyl alcohol and 5 mL water, and the electrolyte in the anode chamber is prepared by 0.8 mmol sodium fluoride and 10 mL water; insert the nitrogen-doped carbon felt adsorbed with ruthenium salt as the cathode into the cathode chamber, use a carbon rod as the anode, and connect the power supply at 5 mA / cm 2 The ruthenium-loaded nitrogen-doped carbon felt was obtained by deposition at a current density of 500 nm for 3 h.

[0047] The nuclear magnetic resonance data of the deuterated product obtained in this example are: 1 H NMR (400 MHz, DMSO- d 6) δ 7.14 (s, 0.98H), 6.63 (s, 1.00H), 2.01 (s, 0.05H), 1.62 (s, 0.14H), 1.53 (s, 0.03H), 1.13 (s, 0.07H), 1.06 (s, 0.03H); 13 C NMR (101 MHz, DMSO- d 6) δ 177.50, 42.93(m, labeled), 28.11 (m, labeled), 24.24 (m, labeled).

[0048] Example 2

[0049] A method for deuterating a fluorinated aromatic ring, comprising the following steps:

[0050] S1. Add 0.4 mmol N-ethylpentafluorobenzamide, 0.8 mmol sodium chloride, 2.5 mL deuterated methanol, and 2.5 mL deuterated water to a dry 15 mL three-necked flask equipped with a magnet and stir to obtain a solution;

[0051] S2: Nitrogen-doped carbon felt and aluminum sheet loaded with ruthenium were inserted into the solution below the liquid surface as cathode and anode, respectively, to construct a reaction system. The reaction system was heated at room temperature and 5 mA / cm 2 The electrolysis reaction was stirred for 36 h;

[0052] S3. After the electrolysis reaction is completed, the reaction solution is extracted with ethyl acetate, and the organic phase is then spin-dried. The product is separated by dry-loading on 200-300 mesh silica gel and gradient eluting with petroleum ether and ethyl acetate.

[0053] The preparation method of the ruthenium-loaded nitrogen-doped carbon felt is the same as that in Example 1.

[0054] The nuclear magnetic resonance data of the deuterated product obtained in this example are: 1H NMR (400 MHz, CDCl3) δ 5.52 (s,0.99H), 3.30-3.23 (m, 3.00H), 2.01 (s, 0.03H), 1.79 (s, 0.02H), 1.72 (s,0.05H), 1.60 (s, 0.02H), 1.37 (s, 0.04H), 1.19-1.18 (m, 0.05H), 1.12 (t, J =7.2 Hz, 2.99H); 13 C NMR (101 MHz, CDCl3) δ 176.30, 44.94 (m, labeled), 34.27, 28.76 (m, labeled), 24.59 (m, labeled), 15.08.

[0055] Example 3

[0056] A method for deuterating a fluorinated aromatic ring, comprising the following steps:

[0057] S1. Add 0.4 mmol of N-butylpentafluorobenzamide, 0.8 mmol of sodium chloride, 2.5 mL of deuterated methanol, and 2.5 mL of deuterated water to a dry 15 mL three-necked flask equipped with a magnet and stir to obtain a solution;

[0058] S2: Nitrogen-doped carbon felt and aluminum sheet loaded with ruthenium were inserted into the solution below the liquid surface as cathode and anode, respectively, to construct a reaction system. The reaction system was heated at room temperature and 5 mA / cm 2 The electrolysis reaction was stirred for 48 h;

[0059] S3. After the electrolysis reaction is completed, the reaction solution is extracted with ethyl acetate, and the organic phase is then spin-dried. The product is separated by dry-loading on 200-300 mesh silica gel and gradient eluting with petroleum ether and ethyl acetate.

[0060] The preparation method of the ruthenium-loaded nitrogen-doped carbon felt is the same as that in Example 1.

[0061] The nuclear magnetic resonance data of the deuterated product obtained in this example are: 1 H NMR (400 MHz, CDCl3) δ 5.76 (s,0.75H), 3.22-3.17 (m, 1.94H), 2.00 (s, 0.04H), 1.75 (s, 0.03H), 1.68 (s,0.04H), 1.47-1.40 (m, 2.00H), 1.34-1.25 (m, 2.09H), 1.16 (s, 0.07H), 1.11 (s,0.04H), 0.88 (t,J = 7.6 Hz, 3.00H); 13 C NMR (101 MHz, CDCl3) δ 176.36, 44.90 (m, labeled), 39.11, 38.97, 31.91, 31.89, 28.86 (m, labeled), 24.73 (m, labeled), 20.19, 13.88.

[0062] Example 4

[0063] A method for deuterating a fluorinated aromatic ring, comprising the following steps:

[0064] S1. Add 0.4 mmol of N-tert-butyloxycarbonyl pentafluoroaniline, 0.8 mmol of sodium chloride, 2.5 mL of deuterated methanol, and 2.5 mL of deuterated water to a dry 15 mL three-necked flask equipped with a magnet and stir to obtain a solution;

[0065] S2: Nitrogen-doped carbon felt and aluminum sheet loaded with ruthenium were inserted into the solution below the liquid surface as cathode and anode, respectively, to construct a reaction system. The reaction system was heated at room temperature and 5 mA / cm 2 The electrolysis reaction was stirred for 36 h;

[0066] S3. After the electrolysis reaction is completed, the reaction solution is extracted with ethyl acetate, and the organic phase is then spin-dried. The product is separated by dry-loading on 200-300 mesh silica gel and gradient eluting with petroleum ether and ethyl acetate.

[0067] The preparation method of the ruthenium-loaded nitrogen-doped carbon felt is the same as that in Example 1.

[0068] The nuclear magnetic resonance data of the deuterated product obtained in this example are: 1 H NMR (400 MHz, CDCl3) δ 4.42 (s, 1.00H), 3.39 (s, 0.02H), 1.86 (s, 0.04H), 1.77 (s, 0.23H), 1.63 (s, 0.04H), 1.59 (s, 0.03H), 1.44 (s, 8.80H), 1.28 (s, 0.07H), 1.08 (s, 0.03H), 1.04 (s,0.06H); 13 C NMR (101 MHz, CDCl3) δ 155.42, 79.13, 48.96 (m, labeled), 32.48 (m, labeled), 28.63, 24.06 (m, labeled).

[0069] Example 5

[0070] A method for deuterating a fluorinated aromatic ring, comprising the following steps:

[0071] S1. Add 0.4 mmol of N-tert-butyloxycarbonyl-N-methylpentafluoroaniline, 0.8 mmol of sodium bromide, 2.5 mL of deuterated methanol, and 2.5 mL of deuterated water to a dry 15 mL three-necked flask equipped with a magnet and stir to obtain a solution;

[0072] S2: Nitrogen-doped carbon felt and aluminum sheet loaded with ruthenium were inserted into the solution below the liquid surface as cathode and anode, respectively, to construct a reaction system. The reaction system was heated at 60°C and 5 mA / cm 2 The electrolysis reaction was stirred for 36 h;

[0073] S3. After the electrolysis reaction is completed, the reaction solution is extracted with ethyl acetate, and the organic phase is then spin-dried. The product is separated by dry-loading on 200-300 mesh silica gel and gradient eluting with petroleum ether and ethyl acetate.

[0074] The preparation method of the ruthenium-loaded nitrogen-doped carbon felt is the same as that in Example 1.

[0075] The nuclear magnetic resonance data of the deuterated product obtained in this example are: 1 H NMR (400 MHz, CDCl3) δ 2.70 (s,3.00H), 2.05-1.98 (m, 0.05H), 1.81 (s, 0.12H), 1.72 (s, 0.03H), 1.45 (s,9.02H), 1.29 (s, 0.03H), 0.99 (s, 0.01H); 13 C NMR (101 MHz, CDCl3) δ 155.86,79.17, 29.87 (m, labeled), 29.65 (m, labeled), 29.48 (m, labeled), 28.68,28.35, 24.77 (m, labeled).

[0076] Example 6

[0077] A method for deuterating a fluorinated aromatic ring, comprising the following steps:

[0078] S1. Add 0.4 mmol of N-cyclobutylpentafluorobenzamide, 0.8 mmol of sodium chloride, 2.5 mL of deuterated methanol, and 2.5 mL of deuterated water to a dry 15 mL three-necked flask equipped with a magnet and stir to obtain a solution;

[0079] S2, the nitrogen-doped carbon felt and carbon felt loaded with ruthenium were inserted into the liquid surface of the solution as cathode and anode respectively to construct a reaction system, and the reaction system was heated at room temperature and 5 mA / cm2 The electrolysis reaction was stirred for 36 h;

[0080] S3. After the electrolysis reaction is completed, the reaction solution is extracted with ethyl acetate, and the organic phase is then spin-dried. The product is separated by dry-loading on 200-300 mesh silica gel and gradient eluting with petroleum ether and ethyl acetate.

[0081] The preparation method of the ruthenium-loaded nitrogen-doped carbon felt is the same as that in Example 1.

[0082] The nuclear magnetic resonance data of the deuterated product obtained in this example are: 1 H NMR (400 MHz, CDCl3) δ 5.77 (d, J =7.2 Hz, 0.74H), 4.43-4.32 (m, 0.91H), 2.34-2.27 (m, 2.00H), 2.00-1.97 (m,0.06H), 1.86-1.76 (m, 2.05H), 1.72-1.62 (m, 2.05H), 1.35 (s, 0.07H), 1.17 (s,0.05H), 1.13 (m, 0.02H); 13 C NMR (101 MHz, CDCl3) δ 175.44, 44.57, 44.44,31.51, 31.49, 28.67 (m, labeled), 24.65 (m, labeled), 15.16.

[0083] Example 7

[0084] A method for deuterating a fluorinated aromatic ring, comprising the following steps:

[0085] S1. Add 0.4 mmol of octafluoronaphthalene, 0.8 mmol of tetrabutylammonium iodide, 2.5 mL of deuterated methanol, and 2.5 mL of deuterated water to a dry 15 mL three-necked flask equipped with a magnet and stir to obtain a solution;

[0086] S2: Nitrogen-doped carbon felt and carbon paper loaded with ruthenium were inserted into the solution as cathode and anode respectively to construct a reaction system. The reaction system was heated at 60°C and 5 mA / cm 2 The electrolysis reaction was stirred for 36 h;

[0087] S3. After the electrolysis reaction is completed, the reaction solution is extracted with ethyl acetate, and the organic phase is then spin-dried. The product is separated by dry-loading on 200-300 mesh silica gel and gradient eluting with petroleum ether and ethyl acetate.

[0088] The preparation method of the ruthenium-loaded nitrogen-doped carbon felt is the same as that in Example 1.

[0089] The nuclear magnetic resonance data of the deuterated product obtained in this example are: 1 H NMR (400 MHz, CDCl3) δ 1.61 (s, 0.02H), 1.48 (s, 0.05H), 1.10-1.03 (m, 0.02H); 13 C NMR (101 MHz, CDCl3) δ 35.34(m, labeled), 33.21 (m, labeled), 29.59 (m, labeled).

[0090] Example 8

[0091] A method for deuterating a fluorinated aromatic ring, comprising the following steps:

[0092] S1. Add 0.4 mmol of 1-isobutylpentafluorobenzyl alcohol, 0.8 mmol of tetrabutylammonium iodide, 2.5 mL of deuterated methanol, and 2.5 mL of deuterated water to a dry 15 mL three-necked flask equipped with a magnet and stir to obtain a solution;

[0093] S2: Nitrogen-doped carbon felt and aluminum sheet loaded with ruthenium were inserted into the solution below the liquid surface as cathode and anode, respectively, to construct a reaction system. The reaction system was heated at 10°C and 5 mA / cm 2 The electrolysis reaction was stirred for 36 h;

[0094] S3. After the electrolysis reaction is completed, the reaction solution is extracted with ethyl acetate, and the organic phase is then spin-dried. The product is separated by dry-loading on 200-300 mesh silica gel and gradient eluting with petroleum ether and ethyl acetate.

[0095] The preparation method of the ruthenium-loaded nitrogen-doped carbon felt is the same as that in Example 1.

[0096] The nuclear magnetic resonance data of the deuterated product obtained in this example are: 1 H NMR (400 MHz, CDCl3) δ 3.39-3.31(m, 1.33H), 1.77-1.54 (m, 1.72H), 1.45-1.39 (m,1.52H), 1.32-1.13 (m,1.34H),0.97-0.82 (m, 4.84H); 13 C NMR (101 MHz, CDCl3) δ 73.43, 58.69, 43.10, 43.00,27.81 (m, labeled), 26.48 (m, labeled), 24.81 (m, labeled), 24.32, 23.93,23.58, 21.50, 19.50, 13.46.

[0097] Example 9

[0098] A method for deuterating a fluorinated aromatic ring, comprising the following steps:

[0099] S1. In a dry 15 mL three-necked flask equipped with a magnet, add 0.4 mmol N,N-diethylpentafluorobenzamide, 0.8 mmol tetrabutylammonium tetrafluoroborate, 2.5 mL deuterated methanol, and 2.5 mL deuterated water, and stir to obtain a solution;

[0100] S2: Nitrogen-doped carbon felt and aluminum sheet loaded with ruthenium were inserted into the solution below the liquid surface as cathode and anode, respectively, to construct a reaction system. The reaction system was heated at room temperature and 5 mA / cm 2 The electrolysis reaction was stirred for 36 h;

[0101] S3. After the electrolysis reaction is completed, the reaction solution is extracted with ethyl acetate, and the organic phase is then spin-dried. The product is separated by dry-loading on 200-300 mesh silica gel and gradient eluting with petroleum ether and ethyl acetate.

[0102] The preparation method of the ruthenium-loaded nitrogen-doped carbon felt is the same as that in Example 1.

[0103] The nuclear magnetic resonance data of the deuterated product obtained in this example are: 1 H NMR (400 MHz, CDCl3) δ 3.43-3.33(m, 2.00H), 3.00 (s, 1.20H), 2.90 (s, 1.30H), 2.41 (s, 0.04H), 1.75 (s,0.04H), 1.64 (s, 0.06H), 1.51 (s, 0.05H), 1.46 (s, 0.05H), 1.18 (t, J = 7.0 Hz,1.50H), 1.15 (s, 0.05H), 1.13 (s, 0.04H), 1.08 (t, J = 7.2 Hz, 1.31H), 1.02 (t, J = 7.2 Hz, 0.06H), 0.88 (t, J = 6.6 Hz, 0.13H); 13 C NMR (101 MHz, CDCl3) δ 44.38, 42.48, 34.63, 33.07, 14.40, 12.53.

[0104] Example 10

[0105] A method for deuterating a fluorinated aromatic ring, comprising the following steps:

[0106] S1. Add 0.4 mmol of pentafluorophenol, 0.8 mmol of tetrabutylammonium tetrafluoroborate, 2.5 mL of deuterated isopropanol, and 2.5 mL of deuterated water to a dry 15 mL three-necked flask equipped with a magnet and stir to obtain a solution.

[0107] S2: Nitrogen-doped carbon felt and aluminum sheet loaded with ruthenium were inserted into the solution below the liquid surface as cathode and anode, respectively, to construct a reaction system. The reaction system was heated at 20°C and 10 mA / cm 2 The electrolysis reaction was stirred for 24 h;

[0108] S3. After the electrolysis reaction is completed, the reaction solution is extracted with ethyl acetate, and the organic phase is then spin-dried. The product is separated using 200-300 mesh silica gel dry loading and gradient elution with petroleum ether and ethyl acetate. The esterification reaction is then completed with benzoyl chloride to obtain the esterified product.

[0109] The preparation method of the ruthenium-loaded nitrogen-doped carbon felt is the same as that in Example 1.

[0110] The nuclear magnetic resonance data of the deuterated product obtained in this example are: 1 H NMR (400 MHz, DMSO- d 6) δ 7.98-7.95(m, 1.99H), 7.67-7.62 (m, 1.00H), 7.54-7.50 (m, 2.02H), 1.81 (s, 0.02H), 1.65(s, 0.03H), 1.49 (s, 0.03H), 1.45 (s, 0.01H), 1.34 (s, 0.11H), 1.25 (s, 0.02H); 13 C NMR (101 MHz, DMSO- d 6) δ 165.06, 133.19, 130.27, 129.08, 128.73,71.82 (m, labeled), 30.04 (m, labeled), 23.62 (m, labeled), 21.89 (m, labeled).

[0111] Example 11

[0112] A method for deuterating a fluorinated aromatic ring, comprising the following steps:

[0113] S1. Add 0.4 mmol of pentafluorobenzyl n-octyl ether, 0.8 mmol of tetrabutylammonium iodide, 2.5 mL of deuterated ethanol, and 2.5 mL of deuterated water to a dry 15 mL three-necked flask equipped with a magnet and stir to obtain a solution.

[0114] S2: Nitrogen-doped carbon felt and aluminum sheet loaded with ruthenium were inserted into the solution below the liquid surface as cathode and anode, respectively, to construct a reaction system. The reaction system was heated at room temperature and 15 mA / cm 2 The electrolysis reaction was stirred for 15 h;

[0115] S3. After the electrolysis reaction is completed, the reaction solution is extracted with ethyl acetate, and the organic phase is then spin-dried. The product is separated by dry-loading on 200-300 mesh silica gel and gradient eluting with petroleum ether and ethyl acetate.

[0116] The preparation method of the ruthenium-loaded nitrogen-doped carbon felt is the same as that in Example 1.

[0117] The nuclear magnetic resonance data of the deuterated product obtained in this example are: 1 H NMR (400 MHz, CDCl3) δ 3.37 (t, J =6.8 Hz, 2.00H), 3.23-3.17 (m, 0.97H), 1.82-1.75 (m, 0.10H), 1.70 (s, 0.06H), 1.65 (s, 0.07H), 1.59-1.52 (m, 1.97H), 1.34-1.26 (m, 10.07H), 1.18-1.08 (m,0.18H), 0.89-0.86 (m, 3.13H); 13 C NMR (101 MHz, CDCl3) δ 76.96, 76.54 (m,labeled), 71.35, 71.31, 71.28, 37.20 (m, labeled), 32.05, 29.96, 29.68,29.49, 26.40, 25.17 (m, labeled), 22.86, 14.27.

[0118] Example 12

[0119] A method for deuterating a fluorinated aromatic ring, comprising the following steps:

[0120] S1. Add 0.4 mmol of pentafluorobenzamide, 0.8 mmol of tetrabutylammonium tetrafluoroborate, 2.5 mL of deuterated methanol, and 2.5 mL of deuterated water to a dry 15 mL three-necked flask equipped with a magnet and stir to obtain a solution;

[0121] S2: Insert the nitrogen-doped carbon felt and aluminum sheet loaded with gold as cathode and anode below the liquid surface of the solution to construct a reaction system. 2 The electrolysis reaction was stirred for 36 h;

[0122] S3. After the electrolysis reaction is completed, the reaction solution is extracted with ethyl acetate, and the organic phase is then spin-dried. The product is separated by dry-loading on 200-300 mesh silica gel and gradient eluting with petroleum ether and ethyl acetate.

[0123] The preparation method of the gold-loaded nitrogen-doped carbon felt can refer to Example 1, except that chloroauric acid is used instead of ruthenium trichloride.

[0124] The deuterated small molecule obtained in the example can be synthesized into a drug molecule through a reaction reported in the literature. The product obtained in Example 4 can be used for subsequent synthesis to obtain drug molecule 1 glipizide and drug molecule 3 bromhexine. The product obtained in Example 1 can be used for subsequent synthesis to obtain drug molecule 2 praziquantel.

[0125] Example 13

[0126] A method for deuterating a fluorinated aromatic ring, comprising the following steps:

[0127] S1. In a dry 15 mL three-necked flask equipped with a magnet, 0.4 mmol of 2-hydroxy-3,4,5,6-tetrafluoropyridine, 0.8 mmol of tetrabutylammonium tetrafluoroborate, 2.5 mL of deuterated isopropanol, and 2.5 mL of deuterated water were added and stirred to obtain a solution;

[0128] S2: Nitrogen-doped carbon felt and aluminum sheet loaded with ruthenium were inserted into the solution below the liquid surface as cathode and anode, respectively, to construct a reaction system. The reaction system was heated at 20°C and 10 mA / cm 2 The electrolysis reaction was stirred for 24 h;

[0129] S3. After the electrolysis reaction is completed, the reaction solution is extracted with ethyl acetate, and the organic phase is then spin-dried. The product is separated using 200-300 mesh silica gel dry method loading and gradient elution with dichloromethane and methanol.

[0130] The preparation method of the ruthenium-loaded nitrogen-doped carbon felt is the same as that in Example 1.

[0131] The nuclear magnetic resonance data of the deuterated product obtained in this example are: 1 H NMR (400 MHz, CDCl3) δ 6.52 (s, 1.00H), 3.39-3.26 (m, 0.12H), 2.44-2.31 (m, 0.32H), 1.85-1.73 (s, 0.32H); 13 CNMR (101 MHz, CDCl3) δ 172.41, 41.15 (m, labeled), 31.55 (m, labeled), 22.42 (m, labeled), 21.14 (m, labeled).

[0132] The fluorinated aromatic rings, deuterated products, yields and deuteration rates of the above examples and comparative examples are summarized in Table 1.

[0133] Table 1

[0134]

[0135]

[0136] The results in Table 1 indicate that the examples of the present invention can produce deuterated products with a high yield. However, compared to Examples 1 and 12, under otherwise identical reaction conditions, the yield of the deuterated product in Example 12, using a gold electrode, was only 9%. These results also demonstrate that the ruthenium-loaded nitrogen-doped carbon felt reaction system constructed in the present invention can effectively achieve full defluorination and reductive deuteration of aromatic rings.

[0137] Example 14

[0138] The perdeuterated cyclohexyl compound prepared in Example 1 It is applied to the synthesis of deuterated drug molecules, as shown in the following formulas 1 and 2.

[0139] .

[0140] Example 15

[0141] The perdeuterated cyclohexyl compound prepared in Example 5 It is applied to the synthesis of deuterated drug molecules, as shown in Formula 3 below.

[0142] .

[0143] Example 16

[0144] The perdeuterated cyclohexyl compound prepared in Example 4 It is applied to the synthesis of deuterated drug molecules, as shown in Formula 4 below.

[0145] .

[0146] Example 17

[0147] The perdeuterated cyclopentanolactam prepared in Example 13 was applied to the synthesis of deuterated drug molecules, as shown in Formula 5 below.

[0148] .

[0149] It can be seen that the fully deuterated cyclohexyl compound obtained by the present invention can be conveniently applied to the synthesis of deuterated drug molecules. d 11After 2-3 steps of transformation, deuterium-labeled glipizide (Formula 1) and deuterium-labeled praziquantel (Formula 2) can be synthesized. d 11 After two steps of transformation, deuterium-labeled bromhexine (Formula 3) can be obtained. d 11 Deuterium-labeled cilostazol (Formula 4) can be obtained through multiple transformation steps. Deuterium-labeled apixaban (Formula 5) can be obtained through two-step transformation steps from perdeuterated cyclopentanolactam.

[0150] The deuterated drug molecules synthesized by the present invention have a high deuteration rate and a large number of deuterium labels, and are of great help to the transformation and innovation of drugs.

[0151] Finally, it should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for deuterating a fluorinated aromatic ring compound, characterized in that: include, Mixing a fluorinated aromatic ring, deuterated water, a first electrolyte, and a first organic solvent to obtain a solution and electrolyzing the solution to obtain a product of defluorination and aromatic ring reduction deuteration; The cathode material used in the electrolysis is nitrogen-doped carbon felt loaded with metal, and the preparation method thereof includes: The carbon felt, melamine and ethanol are mixed and refluxed to obtain pretreated carbon felt; The pretreated carbon felt is immersed in a mixed solution of melamine and paraformaldehyde to carry out a polymerization reaction to obtain a polymer-coated carbon felt; calcining the polymer-coated carbon felt under a protective gas atmosphere to obtain nitrogen-doped carbon felt; Immersing the nitrogen-doped carbon felt in a metal salt solution for adsorption reaction to obtain nitrogen-doped carbon felt adsorbing the metal salt, wherein the metal salt is a ruthenium salt; The nitrogen-doped carbon felt adsorbed with metal salts is used as a cathode to obtain a metal-loaded nitrogen-doped carbon felt electrode by electrodeposition; The current density during electrolysis is 5, 10, and 15 mA / cm 2 .

2. The deuteration method of a fluorinated aromatic ring compound according to claim 1, characterized in that: The concentrations of the fluorinated aromatic ring and the first electrolyte in the solution are 0.05-0.2 mol / L and 0.1-0.3 mol / L, respectively.

3. The deuteration method of a fluorinated aromatic ring compound according to claim 1, characterized in that: The first electrolyte comprises at least one of tetrabutylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium tetrafluoroborate, sodium chloride, sodium fluoride, and sodium bromide; The first organic solvent includes at least one of deuterated methanol, deuterated tert-butyl alcohol, deuterated ethanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylbenzamide, and dimethyl sulfoxide.

4. The deuteration method of a fluorinated aromatic ring compound according to claim 1, characterized in that: The mass ratio of the carbon felt, melamine and ethanol is 1:1-3:

20.

5. The deuteration method of a fluorinated aromatic ring compound according to claim 1, characterized in that: The mass ratio of the pretreated carbon felt, melamine, paraformaldehyde and the solvent in the mixed solution is 1:1-15:1-15:10-50.

6. The deuteration method of a fluorinated aromatic ring compound according to claim 1, characterized in that: The mass ratio of the nitrogen-doped carbon felt, the metal salt, and the solvent in the metal salt solution is 1:0.05-0.5:40-60.

7. The deuteration method of a fluorinated aromatic ring compound according to claim 1, characterized in that: The electrodeposition is carried out at a current density of 1-40 mA / cm 2 The electrolyte used in the cathode chamber is prepared by the second electrolyte, the second organic solvent and water, and the electrolyte used in the anode chamber is prepared by the second electrolyte and water; Wherein, the mass ratio of the second organic solvent to the water is 0-9:1; The concentration of the second electrolyte is 0.05-0.2 mol / L; The second electrolyte comprises at least one of sodium fluoride, tetrabutylammonium bromide, tetrabutylammonium chloride, and tetrabutylammonium iodide; The second organic solvent includes at least one of tetrahydrofuran, 1,4-dioxane, methanol, ethanol, isopropanol, and tert-butanol; The anode of the electrodeposition is made of an inert material.

Images