CN116478064A - 2-azido-2, 2-difluoro-N-aryl acetamide and synthesis method and application thereof - Google Patents

2-azido-2, 2-difluoro-N-aryl acetamide and synthesis method and application thereof Download PDF

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CN116478064A
CN116478064A CN202310433347.4A CN202310433347A CN116478064A CN 116478064 A CN116478064 A CN 116478064A CN 202310433347 A CN202310433347 A CN 202310433347A CN 116478064 A CN116478064 A CN 116478064A
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difluoro
azido
nmr
mmol
arylacetamide
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李玖零
齐金旭
魏凯
任牵会
郭佳康
徐宜福
杨玉洁
章晓敏
赵爽
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Pingdingshan University
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Pingdingshan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/12—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to 2-azido-2, 2-difluoro-N-aryl acetamide and a synthesis method and application thereof. A 2-azido-2, 2-difluoro-N-aryl acetamide having the structural formula:wherein R is 1 Is a hydrogen atom or benzyl; r is R 2 Is benzyl, phenyl, naphthyl. The synthesis method takes organic amine, bromodifluoroacetic acid ethyl ester and the like as raw materials, and obtains the 2-azido-2, 2-difluoro-N-aryl acetamide through simple operation and mild reaction conditions. And (3) carrying out application conversion on the synthesized 2-azido-2, 2-difluoro-N-aryl acetamide, and carrying out click chemistry on the obtained product and alkyne to obtain the triazole derivative. The synthesis method of the 2-azido-2, 2-difluoro-N-aryl acetamide has the advantages of cheap and easily obtained raw materials, mild reaction conditions,simple operation and the like, and can be subjected to click chemistry with alkyne to obtain the triazole derivative modified by the 2, 2-difluoro-N-aryl acetamide.

Description

2-azido-2, 2-difluoro-N-aryl acetamide and synthesis method and application thereof
Technical Field
The invention belongs to the fields of synthetic chemistry and reagent development, and mainly relates to a synthetic method and conversion application of 2-azido-2, 2-difluoro-N-aryl acetamide.
Background
Fluorine-containing drugs are of great medical importance. Fluorine is a very active element, and can form a strong chemical bond with other atoms in the drug design, so that the effect and stability of the drug are enhanced. For example, fluorine-containing compounds can enhance the pharmacokinetic properties of the drug, such as solubility, absorption, distribution, excretion, etc., thereby improving the therapeutic efficacy and safety of the drug. In addition, fluorine-containing drugs have a wide range of application fields, such as antiviral drugs, anticancer drugs, antipsychotics, etc., and are one of the important directions in the field of drug development. Difluoromethyl is taken as an important functional group, can be regarded as an isostere of carbonyl, amide, alcohol and hydroxamic acid, has good lipophilicity, can be taken as a carrier of hydrogen bonds, and is widely commonly found in drug molecules on the market. Such as Taflupirest for treating glaucoma, lubiprostone which is a specific drug for treating female constipation and Gemcitabine which is a broad-spectrum anticancer drug and is developed by Gift corporation, which are developed by the combination of the Japanese participating pharmaceutical and the moxadong corporation, have difluoromethyl functional groups. Development and application of a novel difluoromethyl reaction block are important ways for constructing difluoromethyl-containing drug molecules. Therefore, the construction of novel small organic molecules containing difluoromethyl fragments and the development and application of the small organic molecules are always research hotspots for organic synthesis and drug synthesis workers.
At present, although a synthetic method for constructing small organic molecules containing difluoromethyl fragments has been developed to a certain extent, the requirement of rapid development of the biomedical industry cannot be met, so that the development of novel reagents containing difluoromethyl fragments and the application of the reagents to the construction of gem-difluoromethyl structures with novel structures have important theoretical and practical significance.
Disclosure of Invention
The invention provides a new reactant-2-azido-2, 2-difluoro-N-aryl acetamide and a synthesis method thereof.
The synthesis method of the 2-azido-2, 2-difluoro-N-aryl acetamide has the advantages of mild reaction conditions, simple and convenient operation, low-cost and easily-obtained raw materials and the like;
the invention also discloses the conversion application of the synthesized 2-azido-2, 2-difluoro-N-aryl acetamide, which is used for constructing an organic molecule with a new structure, namely a 2, 2-difluoro-N-aryl acetamide modified triazole compound.
The invention adopts the technical scheme that:
the invention provides synthesis of 2-azido-2, 2-difluoro-N-aryl acetamide, which has a structure shown in the following formula (1):
（1），
wherein R is 1 Is a hydrogen atom or benzyl; r is R 2 Is benzyl, phenyl, tert-butyl substituted phenyl, halogen substituted phenyl, methyl substituted phenyl, ethoxy substituted phenyl or naphthyl.
Preferably, said R 2 Is any one of p-tert-butylphenyl, o-chlorophenyl, o-ethoxyphenyl, m-methylphenyl and 2-naphthyl.
The invention also provides a synthesis method of the 2-azido-2, 2-difluoro-N-aryl acetamide shown in the formula (1), which takes organic amine, bromodifluoroacetic acid ethyl ester and sodium azide as raw materials, and the 2-azido-2, 2-difluoro-N-aryl acetamide is obtained through two steps of simple reactions under mild reaction conditions:
the synthetic reaction process is shown in a reaction formula (I):
（I）
(1) Adding 10 mmol of organic amine and 14 mmol of bromodifluoroacetic acid ethyl ester as starting materials into a 50-ml round-bottom flask, reacting for 1-4 hours at room temperature under the catalysis of 5 mol% of lanthanum triflate (0.5 mmol) without adding a solvent, monitoring by TLC, stopping the reaction after the raw materials are completely consumed, and purifying by column chromatography (PE: EA=20:1-10:1) to obtain bromodifluoromethyl substituted amide derivatives;
(2) The bromodifluoromethyl substituted amide derivative (5 mmol) is dissolved in 10 ml of dimethyl sulfoxide, 1.4 equivalent of sodium azide is added, the mixture is stirred for 8 to 12 hours at room temperature, and the mixture is purified by column chromatography (PE: EA=10:1) to obtain the 2-azido-2, 2-difluoro-N-aryl acetamide compound.
The 2-azido-2, 2-difluoro-N-arylacetamide compound synthesized in the invention can also be applied to conversion application shown in a reaction formula (II):
（II）
to a 25 mL reaction flask was added 2.0 mmol of 2-azido-2, 2-difluoro-N-arylacetamide, 2.0 mmol of terminal alkyne, 2.0 mmol of triethylamine, and 4 mL of tetrahydrofuran as a solvent. And then adding 10 mol% of CuI as a catalyst into the reaction liquid, stirring for 2-4 hours at room temperature, monitoring by TLC, stopping the reaction after the consumption of the raw materials is complete, and purifying by column chromatography (PE: EA=10:1-5:1) to obtain the 2, 2-difluoro-N-aryl acetamide modified triazole compound.
The invention has the beneficial effects that:
1. the invention develops a new reaction route for the first time for constructing a new compound 2-azido-2, 2-difluoro-N-aryl acetamide. The synthesis method of the 2-azido-2, 2-difluoro-N-aryl acetamide can be carried out at room temperature without anhydrous and anaerobic operation, the required raw materials are common organic aromatic amine and bromodifluoroethyl acetate, the two-step reaction in the synthesis method is smoothly carried out in a solvent-free and common dimethyl sulfoxide solvent (other reagents can influence the reaction effect), and the synthesis method has the advantages of mild reaction condition, simple and convenient operation, low-cost and easily obtained raw materials and the like.
2. The 2-azido-2, 2-difluoro-N-aryl acetamide synthesized by the invention can be applied to synthesizing 2, 2-difluoro-N-aryl acetamide modified triazole compounds through a simple click chemistry reaction means, and the compounds have novel structures and potential biological activities, and have been researched and developed by Syngenta Crop Protection (Qianzon) company in Switzerland. Therefore, the synthesis and application of the 2-azido-2, 2-difluoro-N-aryl acetamide can provide powerful power for further constructing a difluoromethyl compound library with potential pharmaceutical activity.
Drawings
FIGS. 1A, 1B and 1C show nuclear magnetic resonance of 2-azido-2, 2-difluoro-N-arylacetamides obtained in example 1 1 H NMR (FIG. 1A), 13 C NMR (FIG. 1B), 19 F NMR (fig. 1C) spectrum;
FIGS. 2A, 2B and 2C show nuclear magnetic resonance of 2-azido-2, 2-difluoro-N-arylacetamides obtained in example 2 1 H NMR (FIG. 2A), 13 C NMR (FIG. 2B), 19 F NMR (fig. 2C) spectrum;
FIGS. 3A, 3B and 3C show nuclear magnetic resonance of 2-azido-2, 2-difluoro-N-arylacetamides obtained in example 3 1 H NMR (FIG. 3A), 13 C NMR (FIG. 3B), 19 F NMR (fig. 3C) spectrum;
FIGS. 4A, 4B and 4C show nuclear magnetic resonance of 2-azido-2, 2-difluoro-N-arylacetamides obtained in example 4 1 H NMR (FIG. 4A), 13 C NMR (FIG. 4B), 19 F NMR (fig. 4C) spectrum;
FIGS. 5A, 5B and 5C show nuclear magnetic resonance of 2-azido-2, 2-difluoro-N-arylacetamides obtained in example 5 1 H NMR (FIG. 5A), 13 C NMR (FIG. 5B), 19 F NMR (fig. 5C) spectrum;
FIGS. 6A, 6B and 6C show nuclear magnetic resonance of 2-azido-2, 2-difluoro-N-arylacetamides obtained in example 6 1 H NMR (FIG. 6A), 13 C NMR (FIG. 6B), 19 F NMR (fig. 6C) spectrum;
FIGS. 7A, 7B and 7C show nuclear magnetic resonance of 2-azido-2, 2-difluoro-N-arylacetamides obtained in example 7 1 H NMR (FIG. 7A), 13 C NMR (FIG. 7B), 19 F NMR (fig. 7C) spectrum;
FIGS. 8A, 8B and 8C show nuclear magnetic resonance of 2, 2-difluoro-N-arylacetamide-modified triazole obtained in example 8 1 H NMR (FIG. 8A), 13 C NMR (FIG. 8B), 19 F NMR (fig. 8C) spectrum;
FIGS. 9A, 9B and 9C show nuclear magnetic resonance of 2, 2-difluoro-N-arylacetamide-modified triazole obtained in example 9 1 H NMR (FIG. 9A), 13 C NMR (FIG. 9B), 19 F NMR (fig. 9C) spectrum;
FIGS. 10A, 10B and 10C show nuclear magnetic resonance of 2, 2-difluoro-N-arylacetamide-modified triazole obtained in example 10 1 H NMR (FIG. 10A), 13 C NMR (FIG. 10B), 19 F NMR (fig. 10C) spectrum;
description of the embodiments
The structure of the 2-azido-2, 2-difluoro-N-aryl acetamide provided by the invention is shown as the following formula (1):
（1）
wherein R is 1 Is a hydrogen atom or benzyl; r is R 2 Is benzyl, phenyl, naphthyl. Specifically, the R 2 Is tert-butyl-substituted phenyl, halogen-substituted phenyl, methyl-substituted phenyl, ethoxy-substituted phenyl, 2-naphthyl, o-chlorophenyl, o-ethoxyphenyl or m-methylphenyl.
The technical scheme of the invention is further described in detail below through specific embodiments and with reference to the accompanying drawings.
Examples
The structure of the 2-azido-2, 2-difluoro-N-arylacetamide of this example is represented by the following formula (3-1):
(3-1)
the synthesis method comprises the following steps:
(1) In a 50-ml round-bottom flask, adding 10 mmol of aniline and 14 mmol of bromodifluoroethyl acetate as starting materials, reacting for 2 hours at room temperature under the catalysis of 5 mol% of lanthanum triflate (0.5 mmol) without adding a solvent, monitoring by TLC, stopping the reaction after the consumption of the raw materials is complete, and purifying by column chromatography (PE: EA=20:1-10:1) to obtain bromodifluoromethyl substituted amide derivatives;
the specific reaction time depends on the reaction conditions, and the reaction time required for the substrate to be different is generally 1 to 4 hours.
(2) The bromodifluoromethyl substituted amide derivative (5 mmol) is dissolved in 10 ml of dimethyl sulfoxide, 1.4 equivalent of sodium azide is added, and the mixture is stirred at room temperature for 8 hours (the raw material can be completely treated after the overnight reaction, generally the raw material consumption is not more than 12 hours), and then the 2-azido-2, 2-difluoro-N-aryl acetamide compound is obtained after purification by column chromatography (PE: EA=10:1).
The overall yield of the synthesis method of this example was 87%.
Nuclear magnetic resonance of 2-azido-2, 2-difluoro-N-arylacetamide obtained in this example 1 H NMR (FIG. 1A), 13 C NMR (FIG. 1B), 19 F NMR (FIG. 1C) spectra are shown in FIG. 1A, FIG. 1B, and FIG. 1C, respectively, 1 H NMR(400 MHz, CDCl 3 ): δ 7.97 (s, 1H), 7.56 (dt,J= 8.8, 1.7 Hz, 2H), 7.43 – 7.34 (m, 2H), 7.26 – 7.20 (m, 1H) ppm; 13 C NMR(100 MHz, CDCl 3 ): δ 157.43 (t,J CF = 34.0 Hz), 135.27, 129.35, 126.22, 120.42, 113.51 (t,J CF = 268.5 Hz) ppm; 19 F NMR(376 MHz, CDCl 3 ): δ -82.84 ppm.
examples
The structure of the 2-azido-2, 2-difluoro-N-arylacetamide of this example is represented by the following formula (3-2):
(3-2)
the synthesis method comprises the following steps:
(1) In a 50-ml round-bottom flask, adding 10 mmol of p-tert-butylaniline and 14 mmol of bromodifluoroacetic acid ethyl ester as starting materials, reacting for 1 hour at room temperature under the catalysis of 5 mol% of lanthanum triflate (0.5 mmol) without adding a solvent, monitoring by TLC, stopping the reaction after the consumption of the raw materials is complete, and purifying by column chromatography (PE: EA=20:1-10:1) to obtain bromodifluoromethyl substituted amide derivatives;
(2) The bromodifluoromethyl substituted amide derivative (5 mmol) is dissolved in 10 ml of dimethyl sulfoxide, 1.4 equivalent of sodium azide is added, the mixture is stirred for 8 hours at room temperature, and the mixture is purified by column chromatography (PE: EA=10:1) to obtain the 2-azido-2, 2-difluoro-N-aryl acetamide compound.
The overall yield of the synthesis method of this example was 83%.
FIG. 2A, FIG. 2B and FIG. 2C show the nuclear magnetic resonance of 2-azido-2, 2-difluoro-N-arylacetamides, respectively, prepared in this example 1 H NMR (FIG. 2A), 13 C NMR (FIG. 2B), 19 F NMR (fig. 2C) spectrum. 1 H NMR(400 MHz, CDCl 3 ): δ 7.96 (s, 1H), 7.48 (d,J= 8.7 Hz, 2H), 7.40 (d,J= 8.6 Hz, 2H), 1.32 (s, 9H) ppm; 13 C NMR(100 MHz, CDCl 3 ): δ157.36 (t,J CF = 34.0 Hz), 149.38, 132.63, 126.18, 120.20, 113.58 (t,J CF = 269.0 Hz), 34.57, 31.28 ppm; 19 F NMR(376 MHz, CDCl 3 ): δ -82.87 ppm.
Examples
The structure of the 2-azido-2, 2-difluoro-N-arylacetamide of this example is represented by the following formula (3-3):
(3-3)
the synthesis process is as follows:
(1) Adding 10 mmol of o-ethoxyaniline and 14 mmol of bromodifluoroacetic acid ethyl ester as starting materials into a 50-ml round-bottom flask, reacting for 1 hour at room temperature under the catalysis of 5 mol% of lanthanum triflate (0.5 mmol) without adding a solvent, monitoring by TLC, stopping the reaction after the consumption of the raw materials is complete, and purifying by column chromatography (PE: EA=20:1-10:1) to obtain bromodifluoromethyl substituted amide derivatives;
(2) The bromodifluoromethyl substituted amide derivative (5 mmol) is dissolved in 10 ml of dimethyl sulfoxide, 1.4 equivalent of sodium azide is added, the mixture is stirred for 12 hours at room temperature, and the mixture is purified by column chromatography (PE: EA=10:1) to obtain the 2-azido-2, 2-difluoro-N-aryl acetamide compound.
The overall yield of the synthesis method of this example was 81%.
FIG. 3A, FIG. 3B and FIG. 3C show the nuclear magnetic resonance of 2-azido-2, 2-difluoro-N-arylacetamides, respectively, prepared in this example 1 H NMR (FIG. 3A), 13 C NMR (FIG. 3B), 19 F NMR (fig. 3C) spectrum. As shown in the drawing, the liquid crystal display device, 1 H NMR(400 MHz, CDCl 3 ): δ 8.69 (s, 1H), 8.31 (dd,J= 8.0, 1.6 Hz, 1H), 7.17 – 7.11 (m, 1H), 6.99 (td,J= 7.8, 1.2 Hz, 1H), 6.91 (dd,J= 8.2, 1.2 Hz, 1H), 4.14 (q,J= 7.0 Hz, 2H), 1.47 (t,J= 7.0 Hz, 3H); 13 C NMR(100 MHz, CDCl 3 ): δ156.98 (t,J CF = 34.0 Hz), 147.71, 125.75, 125.28, 121.05, 120.01, 113.53 (t,J CF = 269.0 Hz), 111.15, 64.47, 14.71 ppm; 19 F NMR(376 MHz, CDCl 3 ): δ -83.24 ppm.
examples
The structure of the 2-azido-2, 2-difluoro-N-arylacetamide of this example is represented by the following formula (3-4):
(3-4)
the synthesis process comprises the following steps:
(1) Adding 10 mmol of o-chloroaniline and 14 mmol of bromodifluoroethyl acetate as starting materials into a 50-ml round-bottom flask, reacting for 4 hours at room temperature under the catalysis of 5 mol% of lanthanum triflate (0.5 mmol) without adding a solvent, monitoring by TLC, stopping the reaction after the consumption of the raw materials is complete, and purifying by column chromatography (PE: EA=20:1-10:1) to obtain bromodifluoromethyl substituted amide derivatives;
(2) The bromodifluoromethyl substituted amide derivative (5 mmol) is dissolved in 10 ml of dimethyl sulfoxide, 1.4 equivalent of sodium azide is added, the mixture is stirred for 12 hours at room temperature, and the mixture is purified by column chromatography (PE: EA=10:1) to obtain the 2-azido-2, 2-difluoro-N-aryl acetamide compound.
The overall yield of the synthesis method of this example was 78%.
FIG. 4A, FIG. 4B and FIG. 4C show the nuclear magnetic resonance of 2-azido-2, 2-difluoro-N-arylacetamides, respectively, prepared in this example 1 H NMR (FIG. 4A), 13 C NMR (FIG. 4B), 19 F NMR (fig. 4C) spectrum. As shown in the drawing, the liquid crystal display device, 1 H NMR(400 MHz, CDCl 3 ): δ 7.97 (s, 1H), 7.52 (d,J= 7.0 Hz, 2H), 7.37 – 7.30 (m, 2H) ppm; 13 C NMR(100 MHz, CDCl 3 ): δ157.43 (t,J CF = 34.0 Hz), 133.86, 131.46, 129.45, 129.32, 121.67, 121.56, 113.41 (t,J CF = 269.0 Hz) ppm; 19 F NMR(376 MHz, CDCl 3 ): δ -83.36 ppm.
examples
The structure of the 2-azido-2, 2-difluoro-N-arylacetamide of this example is represented by the following formula (3-5):
（3-5）
the synthesis process is as follows:
(1) In a 50-ml round-bottom flask, 10 mmol of dibenzylamine and 14 mmol of bromodifluoroacetic acid ethyl ester are added as starting materials, a solvent is not required to be added, the reaction is carried out for 2 hours at room temperature under the catalysis of 5 mol% of lanthanum triflate (0.5 mmol), the reaction is stopped after the consumption of the raw materials is complete through TLC monitoring, and the bromodifluoromethyl substituted amide derivative is obtained through column chromatography purification (PE: EA=20:1-10:1);
(2) The bromodifluoromethyl substituted amide derivative (5 mmol) is dissolved in 10 ml of dimethyl sulfoxide, 1.4 equivalent of sodium azide is added, the mixture is stirred for 10 hours at room temperature, and the mixture is purified by column chromatography (PE: EA=10:1) to obtain the 2-azido-2, 2-difluoro-N-aryl acetamide compound.
The overall yield of the synthesis method of this example was 72%.
FIG. 5A, FIG. 5B and FIG. 5C show the nuclear magnetic resonance of 2-azido-2, 2-difluoro-N-arylacetamides, respectively, prepared in this example 1 H NMR (FIG. 5A), 13 C NMR (FIG. 5B), 19 F NMR (fig. 5C) spectrum. As shown in the drawing, the liquid crystal display device, 1 H NMR(400 MHz, CDCl 3 ): δ 9.27 (s, 1H), 7.82 (d,J= 9.0 Hz, 2H), 7.77 (d,J= 8.1 Hz, 2H), 7.37 (d,J= 8.1 Hz, 2H), 7.31 (t,J= 6.9 Hz, 1H), 6.96 (d,J= 9.0 Hz, 2H), 3.85 (s, 3H), 2.46 (s, 3H) ppm; 13 C NMR(100 MHz, CDCl 3 ): δ 163.93, 147.53, 131.76 (t,J CF = 26.0 Hz), 130.87, 130.25, 130.23, 128.84, 128.61, 117.10 (t,J CF = 285.0 Hz), 114.51, 55.72, 21.90 ppm; 19 F NMR(376 MHz, CDCl 3 ): δ -105.91 ppm.
examples
The structure of the 2-azido-2, 2-difluoro-N-arylacetamide of this example is represented by the following formula (3-6):
（3-6）
the synthesis process comprises the following steps:
(1) In a 50-ml round-bottom flask, adding 10 mmol of m-methylaniline and 14 mmol of bromodifluoroethyl acetate as starting materials, reacting for 2 hours at room temperature under the catalysis of 5 mol% of lanthanum triflate (0.5 mmol) without adding a solvent, monitoring by TLC, stopping the reaction after the consumption of the raw materials is complete, and purifying by column chromatography (PE: EA=20:1-10:1) to obtain bromodifluoromethyl substituted amide derivatives;
(2) The bromodifluoromethyl substituted amide derivative (5 mmol) is dissolved in 10 ml of dimethyl sulfoxide, 1.4 equivalent of sodium azide is added, the mixture is stirred for 10 hours at room temperature, and the mixture is purified by column chromatography (PE: EA=10:1) to obtain the 2-azido-2, 2-difluoro-N-aryl acetamide compound.
The overall yield of the synthesis method of this example was 86%.
FIG. 6A, FIG. 6B and FIG. 6C show the nuclear magnetic resonance of 2-azido-2, 2-difluoro-N-arylacetamides, respectively, prepared in this example 1 H NMR (FIG. 6A), 13 C NMR (FIG. 6B), 19 F NMR (fig. 6C) spectrum. As shown in the drawing, the liquid crystal display device, 1 H NMR(400 MHz, CDCl 3 ): δ 8.05 (s, 1H), 7.33 (dd,J= 50.1, 18.0 Hz, 3H), 7.05 (s, 1H), 2.38 (s, 3H) ppm; 13 C NMR(100 MHz, CDCl 3 ): δ 157.46 (t,J CF = 34.0 Hz), 139.43, 135.24, 129.13, 126.99, 121.07, 117.56, 113.56 (t,J CF = 268.0 Hz), 21.43 ppm; 19 F NMR(376 MHz, CDCl 3 ): δ -83.23 ppm.
examples
The structure of the 2-azido-2, 2-difluoro-N-arylacetamide of this example is represented by the following formula (3-7):
（3-7）
the synthesis process is as follows:
(1) In a 50-ml round-bottom flask, adding 10 mmol of 2-naphthylamine and 14 mmol of bromodifluoroethyl acetate as starting materials, reacting for 3 hours at room temperature under the catalysis of 5 mol% of lanthanum triflate (0.5 mmol) without adding a solvent, monitoring by TLC, stopping the reaction after the consumption of the materials is complete, and purifying by column chromatography (PE: EA=20:1-10:1) to obtain bromodifluoromethyl substituted amide derivatives;
(2) The bromodifluoromethyl substituted amide derivative (5 mmol) is dissolved in 10 ml of dimethyl sulfoxide, 1.4 equivalent of sodium azide is added, the mixture is stirred for 9 hours at room temperature, and the mixture is purified by column chromatography (PE: EA=10:1) to obtain the 2-azido-2, 2-difluoro-N-aryl acetamide compound.
The overall yield of the synthesis method of this example was 80%.
FIGS. 7A, 7B and 7C illustrate nuclear magnetic resonance of 2-azido-2, 2-difluoro-N-arylacetamides, respectively, prepared in accordance with the present examples 1 H NMR (FIG. 7A), 13 C NMR (FIG. 7B), 19 F NMR (fig. 7C) spectrum. As shown in the drawing, the liquid crystal display device, 1 H NMR(400 MHz, CDCl 3 ): δ 8.05 (s, 1H), 7.33 (dd,J= 50.1, 18.0 Hz, 3H), 7.05 (s, 1H), 2.38 (s, 3H) ppm; 13 C NMR(100 MHz, CDCl 3 ): δ 157.46 (t,J CF = 34.0 Hz), 139.43, 135.24, 129.13, 126.99, 121.07, 117.56, 113.56 (t,J CF = 268.0 Hz), 21.43 ppm; 19 F NMR(376 MHz, CDCl 3 ): δ -83.23 ppm.
the following examples are the conversion applications of the 2-azido-2, 2-difluoro-N-aryl acetamide of the present invention, and the triazole derivative is obtained by click chemistry with alkyne, and the structure of the triazole derivative is shown in the following formula (2):
（2）。
examples
The triazole derivative of the embodiment has the structure shown in the following formula (5-1):
（5-1）
the conversion application process is as follows:
1) 2.0 mmol of 2-azido-2, 2-difluoro-N-arylacetamide, 2.0 mmol of terminal alkyne, 2.0 mmol of triethylamine and 4 ml of tetrahydrofuran are added as solvent in a 25 ml reaction flask;
2) And adding 10 mol% of CuI serving as a catalyst into the reaction liquid, stirring for 3 hours at room temperature, monitoring by TLC, stopping the reaction after the consumption of the raw materials is complete, and purifying by column chromatography (PE: EA=10:1-5:1) to obtain the 2, 2-difluoro-N-aryl acetamide modified triazole compound.
In this example, the overall yield of the triazole-based compound was 95%.
FIGS. 8A, B and 8C illustrate the NMR of 2, 2-difluoro-N-arylacetamide-modified triazole obtained in this example 1 H NMR (FIG. 8A), 13 C NMR (FIG. 8B), 19 F NMR (fig. 8C) spectrum. As shown in the drawing, the liquid crystal display device, 1 H NMR(400 MHz, CDCl 3 ): δ 8.77 (s, 1H), 8.14 (s, 1H), 7.60 (d,J= 7.8 Hz, 2H), 7.37 (t,J= 7.9 Hz, 2H), 7.34 – 7.30 (m, 2H), 7.23 (t,J= 7.4 Hz, 1H), 7.00 (dd,J= 13.5, 7.6 Hz, 3H), 5.23 (s, 2H) ppm; 13 C NMR(100 MHz, CDCl 3 ): δ 157.91, 155.79 (t,J CF = 31.0 Hz), 145.16, 135.28, 129.70, 129.33, 126.42, 121.66, 121.59, 120.76, 114.69, 110.35 (t,J CF = 270.0 Hz), 61.41 ppm; 19 F NMR (376 MHz, CDCl 3 ): δ -87.82 ppm.
examples
The triazole derivative of the embodiment has the structure shown in the following formula (5-2):
（5-2）
the conversion application process is as follows:
1) 2.0 mmol of 2-azido-2, 2-difluoro-N-arylacetamide, 2.0 mmol of terminal alkyne, 2.0 mmol of triethylamine and 4 ml of tetrahydrofuran are added as solvent in a 25 ml reaction flask;
2) And adding 10 mol% of CuI serving as a catalyst into the reaction liquid, stirring for 2 hours at room temperature, monitoring by TLC, stopping the reaction after the consumption of the raw materials is complete, and purifying by column chromatography (PE: EA=10:1-5:1) to obtain the 2, 2-difluoro-N-aryl acetamide modified triazole compound.
In this example, the overall yield of the triazole-based compound was 91%.
FIGS. 9A, 9B and 9C illustrate the NMR of 2, 2-difluoro-N-arylacetamide-modified triazole obtained in this example 1 H NMR (FIG. 9A), 13 C NMR (FIG. 9B), 19 F NMR (fig. 9C) spectrum. As shown in the drawing, the liquid crystal display device, 1 H NMR(400 MHz, CDCl 3 ): δ 8.72 (s, 1H), 8.15 (s, 1H), 7.55 – 7.51 (m, 2H), 7.41 – 7.37 (m, 2H), 7.31 (ddd,J= 9.8, 4.8, 2.2 Hz, 2H), 7.04 – 6.97 (m, 3H), 5.24 (s, 2H), 1.32 (s, 9H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ 157.92, 155.70 (t,J CF = 31.0 Hz), 149.55, 145.12, 132.66, 129.68, 126.18, 121.63, 121.59, 120.46, 114.69, 110.40 (t,J CF = 270.0 Hz), 61.43, 34.59, 31.30 ppm; 19 F NMR(376 MHz, CDCl 3 ): δ -87.87 ppm.
examples
The triazole derivative of the embodiment has the structure shown in the following formula (5-3):
（5-3）
the conversion application process is as follows:
1) 2.0 mmol of 2-azido-2, 2-difluoro-N-arylacetamide, 2.0 mmol of terminal alkyne, 2.0 mmol of triethylamine and 4 ml of tetrahydrofuran are added as solvent in a 25 ml reaction flask;
2) And adding 10 mol% of CuI serving as a catalyst into the reaction liquid, stirring for 4 hours at room temperature, monitoring by TLC, stopping the reaction after the consumption of the raw materials is complete, and purifying by column chromatography (PE: EA=10:1-5:1) to obtain the 2, 2-difluoro-N-aryl acetamide modified triazole compound.
In this example, the overall yield of the triazole-based compound was 89%.
FIGS. 10A, 10B and 10C illustrate the NMR of 2, 2-difluoro-N-arylacetamide-modified triazole obtained in the present example, respectively 1 H NMR (FIG. 10A), 13 C NMR (FIG. 10B), 19 F NMR (fig. 10C) spectrum. As shown in the drawing, the liquid crystal display device, 1 H NMR(400 MHz, CDCl 3 ): δ 8.18 (s, 1H), 7.42-7.32 (m, 10H), 7.26-7.24 (m, 2H), 7.08-7.03 (m, 3H), 5.32 (s, 2H), 4.71 (s, 2H), 4.52 (s, 2H) ppm; 13 C NMR(100 MHz, CDCl 3 ): δ 158.58 (t,J CF = 31.0 Hz), 157.91, 145.76, 134.89, 134.50, 129.70, 129.02, 128.88, 128.35, 128.23, 127.99, 127.37, 121.66, 120.77, 114.69, 109.88 (t,J CF = 269.0 Hz), 61.57, 50.30, 49.15 ppm; 19 F NMR(376 MHz, CDCl 3 ): δ -87.32 ppm.
the method synthesizes the 2-azido-2, 2-difluoro-N-aryl acetamide for the first time through cheap and easily available raw materials, simple, convenient and safe experimental operation and mild reaction conditions, and realizes the conversion application of the 2-azido-2, 2-difluoro-N-aryl acetamide and alkyne in the click chemistry efficient synthesis of the triazole derivative. The synthesis and application of the 2-azido-2, 2-difluoro-N-aryl acetamide can provide powerful power for further constructing a difluoromethyl compound library with potential pharmaceutical activity.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention. Other modifications of the practice of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention without the need for inventive faculty, and any modification or substitution of equivalents which fall within the spirit and principles of the invention, or which are obvious to those skilled in the art, are intended to be encompassed within the scope of the invention.

Claims (9)

1. 2-azido-2, 2-difluoro-N-aryl acetamide is characterized in that the structure is shown as formula (1):
（1），
wherein R is 1 Is a hydrogen atom or benzyl; r is R 2 Is benzyl, phenyl, naphthyl.
2. The 2-azido-2, 2-difluoro-N-arylacetamide according to claim 1, wherein R 2 Is tert-butyl substituted phenyl, halogen substituted phenyl, methyl substituted phenyl, ethoxy substituted phenyl, 2-naphthyl.
3. The 2-azido-2, 2-difluoro-N-arylacetamide according to claim 1, wherein R 2 Is p-tert-butylphenyl, o-chlorophenyl, o-ethoxyphenyl and m-methylphenyl.
4. A process for the synthesis of 2-azido-2, 2-difluoro-N-arylacetamides according to claim 1, characterized in that: the method comprises the following steps:
1) Preparing a bromodifluoromethyl substituted amide derivative by taking organic amine and bromodifluoroethyl acetate as raw materials;
2) Dissolving the amide derivative prepared in the step 1) by using dimethyl sulfoxide, then adding sodium azide, stirring, and performing chromatographic purification to prepare the 2-azido-2, 2-difluoro-N-aryl acetamide;
the synthetic route is as follows:
。
5. the method for synthesizing 2-azido-2, 2-difluoro-N-arylacetamide according to claim 4, wherein in step 1), the preparation process of bromodifluoromethyl-substituted amide derivative is as follows:
in a 50-ml round-bottom flask, 10 mmol of organic amine and 14 mmol of bromodifluoro ethyl acetate are added as starting materials, a solvent is not required to be added, the reaction is carried out for 1 to 4 hours at room temperature under the catalysis of 0.5 mmol of 5 mol% of lanthanum triflate, the reaction is stopped after the consumption of the raw materials is complete through TLC monitoring, and the bromodifluoro methyl substituted amide derivative is obtained through column chromatography purification.
6. The method for synthesizing 2-azido-2, 2-difluoro-N-arylacetamide according to claim 4 or 5, wherein in step 2), 5 mmol of bromodifluoromethyl-substituted amide derivative is dissolved in 10 ml of dimethyl sulfoxide, 1.4 equivalent of sodium azide is added, and the mixture is stirred at room temperature for 8 to 12 hours and purified by column chromatography to obtain the 2-azido-2, 2-difluoro-N-arylacetamide compound.
7. Use of a 2-azido-2, 2-difluoro-N-arylacetamide compound synthesized according to claim 1 or claim 4 for preparing a 2, 2-difluoro-N-arylacetamide-modified triazole compound.
8. The use of a 2-azido-2, 2-difluoro-N-arylacetamide compound according to claim 7 for the preparation of a 2, 2-difluoro-N-arylacetamide-modified triazole compound, wherein the transformation route is as follows:
。
9. use of a 2-azido-2, 2-difluoro-N-arylacetamides according to claim 7 or 8 for the preparation of 2, 2-difluoro-N-arylacetamides modified triazoles, characterized in that the conversion process is as follows:
1) 2.0 mmol of 2-azido-2, 2-difluoro-N-arylacetamide, 2.0 mmol of terminal alkyne, 2.0 mmol of triethylamine and 4 ml of tetrahydrofuran are added as solvent in a 25 ml reaction flask;
2) Then adding 10 mol% of CuI as a catalyst into the reaction bottle, stirring for 2-4 hours at room temperature, monitoring by TLC, and stopping the reaction after the raw materials are completely consumed;
3) Purifying by column chromatography to obtain the 2, 2-difluoro-N-aryl acetamide modified triazole compound.
CN202310433347.4A 2023-04-21 2023-04-21 2-azido-2, 2-difluoro-N-aryl acetamide and synthesis method and application thereof Pending CN116478064A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008156580A1 (en) * 2007-06-13 2008-12-24 Merck & Co., Inc. Triazole derivatives for treating alzheimer's disease and related conditions
CN106588693A (en) * 2016-11-11 2017-04-26 河南师范大学 Synthesis method for aryl azide compound
CN106588788A (en) * 2016-11-11 2017-04-26 河南师范大学 Method for synthesizing 1,2,3-triazole compound through one-pot two-step method
CN113121462A (en) * 2021-03-19 2021-07-16 浙江理工大学 Preparation method of 5-trifluoromethyl substituted 1,2, 3-triazole compound

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008156580A1 (en) * 2007-06-13 2008-12-24 Merck & Co., Inc. Triazole derivatives for treating alzheimer's disease and related conditions
CN106588693A (en) * 2016-11-11 2017-04-26 河南师范大学 Synthesis method for aryl azide compound
CN106588788A (en) * 2016-11-11 2017-04-26 河南师范大学 Method for synthesizing 1,2,3-triazole compound through one-pot two-step method
CN113121462A (en) * 2021-03-19 2021-07-16 浙江理工大学 Preparation method of 5-trifluoromethyl substituted 1,2, 3-triazole compound

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