Deuterated difluoromethyl compound as well as preparation method and application thereof
By using inexpensive and readily available deuterated methanol as a deuterium source, deuterated difluoromethyl compounds are synthesized through acid-base neutralization reactions. This solves the problems of high raw material costs and poor substrate adaptability in existing technologies, and achieves efficient and highly selective synthesis of deuterated difluoromethyl compounds, which are suitable for drug modification.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-07
- Publication Date
- 2026-04-03
AI Technical Summary
Existing methods for synthesizing deuterated difluoromethyl compounds suffer from high raw material costs, poor substrate adaptability, and a limited variety of synthesized deuterated difluoromethyl compounds, making it difficult to achieve efficient and highly selective synthesis.
Using inexpensive and readily available deuterated methanol as the deuterium source, hydrogen-deuterium exchange of difluoromethyl reagents is achieved through acid-base neutralization reaction to synthesize deuterated difluoromethyl compounds. The use of inexpensive and readily available deuterium sources and other reagents avoids the use of transition metals, making it suitable for the synthesis of drugs sensitive to heavy metal residues.
High yield and high deuteration rate of deuterated difluoromethyl compounds were achieved. The synthesis process is simple, the product yield is high, the functional groups have a wide range of applicability, it is suitable for the late-stage modification of drugs, and it is easy to graft it into the modification of existing drugs.
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Figure CN121779337A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the fields of organic synthetic chemistry, medicinal chemistry and organofluorine chemistry, and in particular to a deuterated difluoromethyl compound and its preparation method and application. Background Technology
[0002] CD bonds are more stable than CH bonds, so deuteration of CH bonds may greatly alter the metabolic and pharmacokinetic properties of candidate drugs. Deuteration can improve drug metabolic stability, prolong half-life, and reduce toxic side effects.
[0003] Difluoromethyl (-CF2H) is an important pharmacophore, and some molecules containing CF2H exhibit unique biological and pharmaceutical activities. Given the importance of deuteration and difluoromethyl groups in drug candidates, constructing CF2D-substituted molecules for drug development is highly valuable.
[0004] Conventional difluoromethylation methods (such as Ru / Cu catalysis and halodifluoromethyl reagents) are difficult to directly introduce deuterium or require complex reagent preparation, especially since nucleophilic deuterated difluoromethyl reagents are extremely scarce. Existing deuteration methods (such as deuterium reduction and isotope exchange) are inefficient and have poor selectivity for difluoromethyl systems. The lack of efficient and highly selective methods for synthesizing compounds containing -CF2D limits their application.
[0005] In summary, current methods for synthesizing deuterated difluoromethyl compounds generally require expensive reagents, have poor substrate adaptability, and yield a limited variety of deuterated difluoromethyl compounds. Summary of the Invention
[0006] To address the problems of high raw material costs, poor substrate adaptability, and limited variety of deuterated difluoromethyl compounds in the synthesis of deuterated difluoromethyl compounds using existing technologies, this invention provides a deuterated difluoromethyl compound, its preparation method, and its applications.
[0007] The preparation method provided by this invention uses deuterated methanol as the deuterium source, and the precursor reagents used are inexpensive and readily available. The resulting deuterated difluoromethyl compounds have a wide range of functional group adaptability in different types of reactions. It is a method for constructing a class of inexpensive, efficient and broad-spectrum deuterated difluoromethyl compounds.
[0008] The objective of this invention can be achieved through the following technical solutions: This invention first provides a deuterated difluoromethyl compound (abbreviated as ArCF2D), with the structural formula shown in Formula I: (Formula I) In Formula I: Ar represents phenyl, substituted phenyl, aromatic heteroyl, or substituted aromatic heteroyl; the substituents in the substituted phenyl include alkoxy, aryloxy, halogen, borate ester, silyl, thioether, NH2-, amino, acylamino, furanyl, phenyl, substituted phenyl, or amide; the substituents in the substituted aromatic heteroyl include alkoxy, the alkyl group in the alkoxy is preferably a chain alkyl or cycloalkyl, the carbon number of the alkoxy is preferably 1 to 12, more preferably 3 to 10; the aryloxy is preferably phenoxy, substituted phenoxy, naphthoxy, heterocyclic alkyl, or substituted heterocyclic alkyl; the halogen is preferably F or Cl; The anion X- is selected from tetrafluoroborate anion, trifluoromethanesulfonate anion, or methyl sulfate anion; R 1 and R 2 Each of the following is independently an alkyl, alkenyl, alkynyl, cycloalkyl, or aryl group, wherein the alkyl group is a C1 to C12 alkyl group having one or more substituents; the alkenyl group is a C2 to C6 alkenyl group having one or more substituents; the alkynyl group is a C2 to C6 alkynyl group having one or more substituents; the cycloalkyl group is a C3 to C8 cycloalkyl group having one or more substituents; and the aryl group is a C6 to C10 aryl group having one or more substituents.
[0009] In one embodiment of the present invention, the deuterated difluoromethyl compound is selected from any one of the structures described in Formulas I-1 to I-3: (Formula I-1), (Formula I-2), (Formula I-3); In Equation I-1, R 1 R is an alkyl group. 2 For methyl, R 3 It is selected from one of phenyl, substituted phenyl, alkyl, naphthyl, benzyl, heterocyclic, substituted heterocyclic, alkenyl, ester, or amide groups; In Equation I-2: R 1 R is an alkyl group. 2 For methyl, R 3 and R 4 Ra and Rb are independently selected from H, amino, amide, halogen, nitrogen-containing heterocyclic group, silyl, borate ester, phenyl, substituted phenyl or -NRaRb, where Ra and Rb are independently alkyl or phenyl; In Equation I-3: R 1 R is an alkyl group. 2 For methyl, R 3 It is phenyl, substituted phenyl, or alkyl.
[0010] In one embodiment of the present invention, the deuterated difluoromethyl compound is selected from one of compound 2a, compound 2b, or compound 2c: , , .
[0011] The present invention further provides a method for preparing the deuterated difluoromethyl compound, comprising the following steps: Difluoromethylbenzimidazole salt and base were added to the reaction apparatus, and solvent was added to dissolve them completely. Then, a deuterium source was added and stirred until the reaction was complete. The solvent was removed by concentration under reduced pressure. The solid obtained was crude deuterated difluoromethyl compound. After recrystallization, pure deuterated difluoromethyl compound was obtained.
[0012] In one embodiment of the present invention, the alkali is selected from lithium hydroxide, sodium hydroxide, potassium bicarbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, or triethylamine.
[0013] In one embodiment of the present invention, the solvent is selected from one or more of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone or dichloroethane.
[0014] In one embodiment of the present invention, the deuterium source is selected from one or more of deuterated methanol, deuterated water, or deuterated dimethyl sulfoxide.
[0015] In one embodiment of the present invention, the molar ratio of difluoromethylbenzimidazole salt to deuterated reagent is 10-100:1.
[0016] In one embodiment of the present invention, the difluoromethylbenzimidazole salt is selected from benzimidazole difluoromethyltetrafluoroborate.
[0017] In one embodiment of the present invention, the reaction temperature is 30-100°C.
[0018] In one embodiment of the present invention, the stirring time ranges from 12 to 48 hours.
[0019] In one embodiment of the present invention, the solvent for recrystallization is selected from one or more of acetonitrile, water, acetone, dichloromethane, diethyl ether, methyl tert-butyl ether, or n-hexane.
[0020] The present invention further provides the application of the aforementioned deuterated difluoromethyl compound in the preparation of deuterated difluoromethyl drugs.
[0021] Compared with the prior art, the present invention has the following advantages and beneficial effects: This invention provides deuterated difluoromethyl compounds and their preparation methods. Based on the scheme provided in this application, a series of different deuterated difluoromethyl compounds can be constructed. This invention uses difluoromethyl compounds and deuterium source substances, including deuterated methanol, as raw materials, and realizes the hydrogen-deuterium exchange of difluoromethyl reagents through acid-base neutralization reaction, thereby achieving the synthesis of deuterated difluoromethyl compounds.
[0022] In the method provided by this invention, the deuterium source and other reagents are inexpensive and readily available, and no transition metals are used, making it suitable for synthesizing drugs sensitive to heavy metal residues. The entire preparation process of the deuterated difluoromethyl compound in this invention is simple, easy to operate, and has a high product yield and high deuteration rate. The deuterated difluoromethyl compound provided by this invention has a wide range of functional groups applicable in the synthesis of other deuterated difluoromethylation reactions, making it suitable for the later modification of drugs and facilitating its integration into the modification of existing drugs.
[0023] The results of the examples show that the deuterated difluoromethyl compounds synthesized by the method of the present invention can achieve a yield of up to 90% and a deuteration rate of up to 98%.
[0024] In summary, the preparation process of the deuterated difluoromethyl compounds in this invention is simple and economical, structurally stable, and highly reactive, enabling the deuteration of different types of compounds. Attached Figure Description
[0025] Figure 1 The 1H spectrum of compound 2a; Figure 2 For compound 2a 19 F-spectrum; Figure 3 For compound 2a 13 C spectrum; Figure 4 The 1H spectrum of compound 2f; Figure 5 For compound 2f 19 F-spectrum; Figure 6 For compound 2f 13 C spectrum Figure 7 The 1H spectrum of compound 2i; Figure 8 For compound 2i 19 F-spectrum; Figure 9 For compound 2i 13 C-spectrum. Detailed Implementation
[0026] This invention provides a deuterated difluoromethyl compound (abbreviated as ArCF2D), with the structural formula shown in Formula I: (Formula I) In Formula I: Ar represents phenyl, substituted phenyl, aromatic heteroyl, or substituted aromatic heteroyl; the substituents in the substituted phenyl include alkoxy, aryloxy, halogen, borate ester, silyl, thioether, NH2-, amino, acylamino, furanyl, phenyl, substituted phenyl, or amide; the substituents in the substituted aromatic heteroyl include alkoxy, the alkyl group in the alkoxy is preferably a chain alkyl or cycloalkyl, the carbon number of the alkoxy is preferably 1 to 12, more preferably 3 to 10; the aryloxy is preferably phenoxy, substituted phenoxy, naphthoxy, heterocyclic alkyl, or substituted heterocyclic alkyl; the halogen is preferably F or Cl; The anion X- is selected from tetrafluoroborate anion, trifluoromethanesulfonate anion, or methyl sulfate anion; R 1 The group can be phenyl, substituted phenyl (the substituent on the substituted phenyl is preferably alkyl or halogen, and the halogen is preferably F or Cl), alkyl (preferably 1 to 12 carbon atoms), naphthyl, benzyl, heterocyclic (preferably nitrogen-containing heterocyclic), substituted heterocyclic, alkenyl (preferably 3 to 15 carbon atoms), ester, amide, R 2 Selected from alkyl groups.
[0027] In one embodiment of the present invention, the deuterated difluoromethyl compound is selected from any one of the structures described in Formulas I-1 to I-3: (Formula I-1), (Formula I-2), (Formula I-3); In Equation I-1, R 1 The group can be phenyl, substituted phenyl (the substituent on the substituted phenyl is preferably alkyl or halogen, and the halogen is preferably F or Cl), alkyl (preferably 1 to 12 carbon atoms), naphthyl, benzyl, heterocyclic (preferably nitrogen-containing heterocyclic), substituted heterocyclic, alkenyl (preferably 3 to 15 carbon atoms), ester, amide, R 2 R 3 Ra and Rb are independently H, amino, amide, halogen (preferably F or Cl), nitrogen-containing heterocyclic group, silyl, borate ester group, phenyl, substituted phenyl or -NRaRb, where Ra and Rb are independently alkyl (preferably 1 to 5 carbon atoms) or phenyl; In Equation I-2: R 1 R is an alkyl group. 2 For methyl, R 3 and R 4Ra and Rb are independently selected from H, amino, amide, halogen, nitrogen-containing heterocyclic group, silyl, borate ester, phenyl, substituted phenyl or -NRaRb, where Ra and Rb are independently alkyl or phenyl; In Equation I-3: R 1 R is an alkyl group. 2 For methyl, R 3 It is phenyl, substituted phenyl, or alkyl.
[0028] The present invention further provides a method for preparing the deuterated difluoromethyl compound, comprising the following steps: Difluoromethylbenzimidazole salt and base were added to the reaction apparatus, and solvent was added to dissolve them completely. Then, a deuterium source was added and stirred until the reaction was complete. The solvent was removed by concentration under reduced pressure. The solid obtained was crude deuterated difluoromethyl compound. After recrystallization, pure deuterated difluoromethyl compound was obtained.
[0029] In one embodiment of the present invention, the base is selected from lithium hydroxide, sodium hydroxide, potassium bicarbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, or triethylamine. The solvent is selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone, or dichloroethane, or more than one or more of these. The deuterium source is selected from deuterated methanol, deuterated water, or deuterated dimethyl sulfoxide, or more than one or more of these. The molar ratio of difluoromethylbenzimidazole salt to the deuterating reagent is 10-100:1. The difluoromethylbenzimidazole salt is selected from benzimidazole difluoromethyltetrafluoroborate. The reaction temperature is 30-100°C, and the stirring time is 12-48 h. The solvent for recrystallization is selected from acetonitrile, water, acetone, dichloromethane, diethyl ether, methyl tert-butyl ether, or n-hexane, or more than one or more of these.
[0030] The present invention further provides the application of the aforementioned deuterated difluoromethyl compound in the preparation of deuterated difluoromethyl drugs.
[0031] The ArCF2D synthesis process of this invention is as follows: The present invention does not have any special requirements on the source of the raw materials for the preparation of the deuterated difluoromethyl compound; commercially available compounds or methods known to those skilled in the art can be used for synthesis.
[0032] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. The various aryltrifluoromethyl compounds used in the following embodiments were purchased from Bailingwei, Inokai, Bid reagent, or synthesized in-house.
[0033] Example 1 A method for preparing a deuterated difluoromethyl compound is provided. The raw material used is compound 1a, and the product is compound 2a. The reaction formula is as follows: Under a nitrogen atmosphere, 40 mg of sodium hydroxide and 2.84 g of aryldifluoromethyl reagent 1a were dissolved in 20 mL of anhydrous acetonitrile in a 100 mL reaction flask. 10 mL of deuterated methanol was slowly added while stirring, and the mixture was stirred for 12 h at room temperature. After the reaction was complete, the reaction solution was concentrated, and the solid was recrystallized from acetonitrile and diethyl ether to give 2.5 g of white solid 2a, with a yield of 90%.
[0034] 1 H NMR (600 MHz, DMSO- d 6) δ 8.20 – 8.13 (m, 2H), 7.85 – 7.79 (m, 2H), 4.22 (s, 6H). 19 F NMR (565 MHz, DMSO- d 6) δ -120.03 – -120.11 (t, J =5.6 Hz), -148.39 (d, J = 4.7 Hz). 13 C NMR (151 MHz, DMSO- d 6) δ 141.08 (t, J = 28.9 Hz),132.11, 128.44, 114.41, 33.39 (t, J = 2.3 Hz). Example 2 The raw material used is compound 1b, and the product is compound 2b. The reaction formula is as follows: Under a nitrogen atmosphere, 40 mg of sodium hydroxide and 3.51 g of aryldifluoromethyl reagent 1b were dissolved in 20 mL of anhydrous acetonitrile in a 100 mL reaction flask. 10 mL of deuterated methanol was slowly added while stirring, and the reaction was continued at room temperature for 12 h. After the reaction was complete, the reaction solution was concentrated, and the solid was recrystallized from acetonitrile and n-hexane to give 2.6 g of white solid 2b, with a yield of 75%.
[0035] Example 3 The raw material used is compound 1c, and the product is compound 2c. The reaction formula is as follows: Under a nitrogen atmosphere, 40 mg of sodium hydroxide and 3.12 g of aryldifluoromethyl reagent 1c were dissolved in 20 mL of anhydrous acetonitrile in a 100 mL reaction flask. 10 mL of deuterated methanol was slowly added while stirring. The reaction was continued at room temperature for 12 h. After the reaction was complete, the reaction solution was concentrated, and the solid was recrystallized from acetonitrile and diethyl ether to give 2.53 g of white solid 2a, with a yield of 81%.
[0036] Regarding the application value of the reagent ArCF2D, it has been used in various substrates to obtain the corresponding deuterated difluoromethylated products. These products contain the unique physicochemical properties of "fluorine" and "deuterium", which have important potential value in pharmaceutical applications. Example 4 The starting material used is compound 1f, and the product is compound 2f. The reaction formula is as follows: Under a nitrogen atmosphere, 56 mg of compound 1f and 128 mg of deuterated difluoromethyl reagent 2a were dissolved in 5 mL of toluene in a 25 mL reaction flask. 0.1 mL of triethylamine was slowly added dropwise to the above solution, and the reaction was continued at 60 °C for 12 h. After the reaction was complete, the reaction solution was concentrated and column chromatography was performed to obtain 44 mg of difluorodeuterated methyl product 2f, with a yield of 61% and a deuteration rate of 98%.
[0037] 1 H NMR (600 MHz, Chloroform- d ) δ 7.80 (d, J = 1.8 Hz, 1H), 7.74 (dd, J = 12.4, 8.7 Hz, 2H), 7.46 (dd, J = 8.5, 1.8 Hz, 1H), 7.17 (dd, J = 8.8, 2.5Hz, 1H), 7.13 (d, J = 2.6 Hz, 1H), 4.96 – 4.91 (m, 1H), 3.92 (s, 3H), 2.60(d, J = 3.7 Hz, 1H). 19 F NMR (565 MHz, Chloroform- d ) δ -127.40 (q, J = 9.0Hz), -127.90 (q, J= 8.6 Hz), -128.01 – -128.10 (m), -128.51 – -128.60 (m). 13 C NMR (151 MHz, Chloroform- d ) δ 158.21, 134.86, 130.99, 129.66, 128.60,127.39, 126.50, 124.94, 119.41, 105.69, 73.76 (t, J = 24.6 Hz), 55.38. Example 5 The raw material used is 1g of compound, and the product is 2g of compound. The reaction formula is as follows: Under a nitrogen atmosphere, 119 mg of compound 1 g and 128 mg of deuterated difluoromethyl reagent 2a were dissolved in 5 mL of toluene in a 25 mL reaction flask. 10 mg of potassium hydroxide was slowly added to the above solution, and the reaction was continued at 60 °C for 12 h. After the reaction was complete, the reaction solution was concentrated and column chromatography was performed to obtain 69 mg of difluorodeuterated methyl product 2 g, with a yield of 51% and a deuteration rate of 96%.
[0038] 1 H NMR (600 MHz, Chloroform- d ) δ 7.98 (s, 1H), 7.92 – 7.85 (m, 3H), 7.76 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.54 – 7.48 (m, 3H), 6.98(d, J = 8.4 Hz, 1H), 4.97 (t, J = 9.9 Hz, 1H), 3.89 (s, 3H), 2.18 (s, 3H), 2.10 (s, 1H), 1.80 (s, 4H). 19 F NMR (565 MHz, Chloroform- d ) δ -127.31 (q, J =8.6 Hz), -127.81 (q, J = 8.6 Hz), -127.98 (q, J = 9.4 Hz), -128.48 (q, J=9.3 Hz). 13 C NMR (151 MHz, Chloroform- d ) δ 158.76, 139.78, 138.99, 133.98,132.90, 131.91, 128.72, 128.53, 126.43, 126.38, 125.95, 125.68, 124.84,124.69, 112.16, 73.82 (t, J = 24.5 Hz), 55.23, 40.67, 37.25, 37.19, 29.18. Example 6 The raw material used is compound 1h, and the product is compound 2h. The reaction formula is as follows: Under a nitrogen atmosphere, 54 mg of compound 1h and 255 mg of deuterated difluoromethyl reagent 2a were dissolved in 8 mL of anhydrous acetonitrile in a 25 mL reaction flask. 0.1 mL of triethylamine was slowly added dropwise to the above solution. The reaction was carried out at 50 °C for 12 hours until the reaction was complete. The reaction solution was concentrated and column chromatography was performed to obtain 60 mg of difluorodeuterated methyl product 2h, with a yield of 71% and a deuteration rate of 98%.
[0039] 1 H NMR (600 MHz, Chloroform- d ) δ 7.62 – 7.55 (m, 4H), 7.45 (t, J =7.7 Hz, 2H), 7.39 – 7.32 (m, 3H), 3.33 (dddd, J = 18.4, 13.7, 10.0, 5.0 Hz,1H), 2.55 – 2.45 (m, 1H), 2.34 (dddd, J = 24.5, 14.5, 11.4, 10.0 Hz, 1H). 19 FNMR (565 MHz, Chloroform- d ) δ -116.78 (dt, J = 17.3, 8.9 Hz), -117.28 (dt, J = 16.3, 8.4 Hz), -117.64 (ddt, J = 22.7, 15.2, 8.6 Hz), -118.15 (ddt, J=22.7, 14.6, 8.5 Hz), -118.66 (dt, J = 15.3, 8.5 Hz), -119.16 (dt, J = 15.1,8.4 Hz), -124.48 – -124.61 (m), -125.04 (dt, J = 18.2, 8.7 Hz). 13 C NMR (151MHz, Chloroform- d ) δ 141.36, 140.34, 133.93, 129.09, 128.91, 127.84, 127.64,127.13, 44.01, 44.01, 33.01. Example 7 The raw material used is compound 1i, and the product is compound 2i. The reaction formula is as follows: Under a nitrogen atmosphere, 102 mg of compound 1i and 255 mg of deuterated difluoromethyl reagent 2a were dissolved in 8 mL of anhydrous acetonitrile in a 25 mL reaction flask. 0.1 mL of triethylamine was slowly added dropwise to the above solution. The reaction was carried out at 50 °C for 12 hours until the reaction was complete. The reaction solution was concentrated and column chromatography was performed to obtain 76 mg of difluorodeuterated methyl product 2a, with a yield of 58% and a deuteration rate of 98%.
[0040] 1 H NMR (600 MHz, Chloroform- d ) δ 8.16 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.60 (td, J = 7.4, 1.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.45 (dd, J = 8.4, 2.4 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.07 (d, J = 8.4 Hz,1H), 5.22 (s, 2H), 4.16 (t, J = 6.3 Hz, 2H), 3.68 (s, 2H), 2.18 – 2.05 (m,2H), 1.88 (qd, J= 15.0, 14.4, 4.5 Hz, 1H), 1.82 – 1.71 (m, 3H), 1.66 (ddt, J = 16.3, 11.0, 5.6 Hz, 1H), 1.53 – 1.42 (m, 1H). 19 F NMR (565 MHz, Chloroform- d ) δ -114.34 (q, J = 16.7, 15.7 Hz), -114.78 – -114.93 (m), -116.74 (td, J =19.8, 18.7, 9.5 Hz), -117.22 (tt, J = 22.8, 11.6 Hz), -122.13 (q, J = 11.5, 10.7 Hz), -122.63 (q, J = 10.9, 10.5 Hz), -124.96 – -125.11 (m), -125.46 – -125.61 (m). 13 C NMR (151 MHz, Chloroform- d ) δ 190.85, 171.37, 160.54, 140.43,136.31, 135.60, 132.85, 132.41, 129.50, 129.30, 127.86, 127.77, 125.21,121.13, 73.65, 64.37, 40.28, 36.74, 36.64, 36.61, 36.48, 32.25, 32.13, 32.10,32.08, 31.96, 25.75, 24.87, 24.85, 24.83, 24.80. The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.
Claims
1. A deuterated difluoromethyl compound, characterized in that, The structural formula is shown in Formula I: (Formula I) In Formula I: Ar represents phenyl, substituted phenyl, aromatic heteroyl, or substituted aromatic heteroyl; the substituents in the substituted phenyl include alkoxy, aryloxy, halogen, borate ester, silyl, thioether, NH2-, amino, acylamino, furanyl, phenyl, substituted phenyl, or amide; the substituents in the substituted aromatic heteroyl include alkoxy, the alkyl group in the alkoxy is preferably a chain alkyl or cycloalkyl, the carbon number of the alkoxy is preferably 1 to 12, more preferably 3 to 10; the aryloxy is preferably phenoxy, substituted phenoxy, naphthoxy, heterocyclic alkyl, or substituted heterocyclic alkyl; the halogen is preferably F or Cl; The anion X- is selected from tetrafluoroborate anion, trifluoromethanesulfonate anion, or methyl sulfate anion; R 1 and R 2 Each of the following is independently an alkyl, alkenyl, alkynyl, cycloalkyl, or aryl group, wherein the alkyl group is a C1 to C12 alkyl group having one or more substituents; the alkenyl group is a C2 to C6 alkenyl group having one or more substituents; the alkynyl group is a C2 to C6 alkynyl group having one or more substituents; the cycloalkyl group is a C3 to C8 cycloalkyl group having one or more substituents; and the aryl group is a C6 to C10 aryl group having one or more substituents.
2. The deuterated difluoromethyl compound according to claim 1, characterized in that, The deuterated difluoromethyl compound is selected from any one of the structures described in Formula I-1 to Formula I-3: (Equation I-1), (Equation I-2), (Formula I-3); In Equation I-1, R 1 It is an alkyl group, R 2 For methyl, R 3 It is selected from one of phenyl, substituted phenyl, alkyl, naphthyl, benzyl, heterocyclic, substituted heterocyclic, alkenyl, ester, or amide groups; In Equation I-2: R 1 It is an alkyl group, R 2 For methyl, R 3 and R 4 Ra and Rb are independently selected from H, amino, amide, halogen, nitrogen-containing heterocyclic group, silyl, borate ester group, phenyl, substituted phenyl or -NRaRb, where Ra and Rb are independently alkyl or phenyl; In Equation I-3: R 1 It is an alkyl group, R 2 For methyl, R 3 It is phenyl, substituted phenyl, or alkyl.
3. The deuterated difluoromethyl compound according to claim 1, characterized in that, The deuterated difluoromethyl compound is selected from one of compound 2a, compound 2b, or compound 2c: 、 、 。 4. The method for preparing the deuterated difluoromethyl compound according to any one of claims 1-3, characterized in that, Includes the following steps: Difluoromethylbenzimidazole salt and base were added to the reaction apparatus, and solvent was added to dissolve them completely. Then, a deuterium source was added and stirred until the reaction was complete. The solvent was removed by concentration under reduced pressure. The solid obtained was crude deuterated difluoromethyl compound. After recrystallization, pure deuterated difluoromethyl compound was obtained.
5. The method for preparing the deuterated difluoromethyl compound according to claim 4, characterized in that, The alkali is selected from one of lithium hydroxide, sodium hydroxide, potassium bicarbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, or triethylamine; The solvent is selected from one or more of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone or dichloroethane.
6. The method for preparing the deuterated difluoromethyl compound according to claim 4, characterized in that, The deuterium source is selected from one or more of deuterated methanol, deuterated water, or deuterated dimethyl sulfoxide.
7. The method for preparing the deuterated difluoromethyl compound according to claim 4, characterized in that, The molar ratio of difluoromethylbenzimidazole salt to deuterated reagent is 10-100:
1.
8. The method for preparing the deuterated difluoromethyl compound according to claim 4, characterized in that, The reaction temperature is 30-100℃; the stirring time is 12-48h.
9. The method for preparing the deuterated difluoromethyl compound according to claim 4, characterized in that, The solvent for recrystallization is selected from one or more of acetonitrile, water, acetone, dichloromethane, diethyl ether, methyl tert-butyl ether, or n-hexane.
10. The use of the deuterated difluoromethyl compound according to any one of claims 1-3 in the preparation of deuterated difluoromethyl pharmaceuticals.