A 1,5-disubstituted 1,2,3-triazole derivative and a synthesis method thereof

Abstract

The invention discloses a 1,5-disubstituted 1,2,3-triazole derivative and a synthesis method thereof. A 1,5-disubstituted 1,2,3-triazole derivative synthesis method, using 2,2-difluoro-2-arylethane-1-amine as a raw material, acetic acid as a catalyst, and tert-butyl nitrite as an oxidant, dissolving the 2,2-difluoro-2-arylethane-1-amine in an organic solvent, then adding acetic acid and tert-butyl nitrite to the above solution, and reacting at 25 to 60 ° C to obtain the 1,5-disubstituted 1,2,3-triazole derivative. The present invention can realize the synthesis of 1,5-disubstituted 1,2,3-triazole derivatives without azide as a raw material. The synthesis method has the advantages of high atom economy, high regioselectivity, cheap and easy-to-obtain raw materials, mild reaction conditions, simple and safe operation, etc. The synthesized 1,5-disubstituted 1,2,3-triazole derivatives are widely present in natural products and drug molecules, have good biological activity, and are important pharmaceutical intermediates.

Description

Technical Field

[0001] The invention relates to the fields of synthetic chemistry and reagent development, and in particular to a 1,2,3-triazole derivative and a synthesis method thereof. Background Art

[0002] Among nitrogen-containing heterocyclic compounds, 1,2,3-triazole, as an important molecular skeleton, is widely present in many drugs and has many applications in drug discovery and materials science. Using 1,3 dipole azides and terminal alkynes as substrates, under copper catalysis, the [3+2] cycloaddition reaction is a general method for synthesizing this type of compound. The pioneer of this type of synthesis method, K. Barry Sharpless, also won the 2022 Nobel Prize in Chemistry for this reason. The advantages of this type of synthesis method are good functional group tolerance, mild reaction conditions and fine control of regioselectivity, but the above advantages are also the disadvantages that limit this synthesis method, so that it can only synthesize 1,4-disubstituted 1,2,3-triazole derivatives, but cannot synthesize 1,5-disubstituted 1,2,3-triazole derivatives with high regioselectivity.

[0003] At present, although the synthesis methods of 1,5-disubstituted 1,2,3-triazole derivatives have made some progress, such as Professor Valery V. Fokin of the United States in 2010 and Professor Eva Hevia of the United Kingdom in 2021, both realized the strategy of using azide and terminal alkyne as substrates to synthesize 1,5-disubstituted 1,2,3-triazole derivatives, the synthesis still relies on unstable organic azide as substrate, which still has obvious limitations and restrictions on the synthesis and application of 1,5-disubstituted 1,2,3-triazole derivatives. Therefore, it is of great theoretical and practical significance to develop a new synthesis method without the participation of azide for the construction of 1,5-disubstituted 1,2,3-triazole derivatives. Summary of the invention

[0004] The present invention aims at the deficiencies of the prior art and proposes a 1,5-disubstituted 1,2,3-triazole derivative and a synthesis method thereof. The synthesis method can realize the synthesis of 1,5-disubstituted 1,2,3-triazole derivatives without using azide as a raw material.

[0005] The technical solution adopted by the present invention is:

[0006] The present invention provides a 1,5-disubstituted 1,2,3-triazole derivative, the structure of which is shown in formula (1):

[0007] (1),

[0008] Wherein, Ar is phenyl, halogen-substituted phenyl, C1-C4 alkyl-substituted phenyl, alkoxy-substituted phenyl, naphthyl or thienyl. Preferably, Ar is p-chloro-substituted phenyl, p-bromo-substituted phenyl, p-ethyl-substituted phenyl, p-isopropyl-substituted phenyl, p-tert-butyl-substituted phenyl, m-methoxy-substituted phenyl, o-methyl-substituted phenyl, 1-naphthyl or 2-thienyl.

[0009] The present invention also provides a method for synthesizing the 1,5-disubstituted 1,2,3-triazole derivatives, using 2,2-difluoro-2-arylethane-1-amine as a raw material, acetic acid as a catalyst, and tert-butyl nitrite as an oxidant, and a one-step reaction at 25-60° C. to efficiently and quickly obtain the 1,2,3-triazole derivatives. The reaction process is shown in reaction formula (I):

[0010] (I).

[0011] 2,2-difluoro-2-arylethane-1-amine is dissolved in an organic solvent, and then acetic acid and tert-butyl nitrite are added to the solution to react under mild conditions to obtain a 1,5-disubstituted 1,2,3-triazole derivative as shown in formula (1).

[0012] The molar ratio of the reaction materials is 2,2-difluoro-2-arylethane-1-amine: acetic acid: tert-butyl nitrite = 1.0: (0.2-0.5): (1.2-1.5); the reaction temperature is 25-60° C.; the reaction temperature is 25° C., that is, it can be carried out at room temperature without heating.

[0013] The organic solvent includes any one or more of 1,2-dichloroethane, dichloromethane, and chloroform. Preferably, the organic solvent is dichloromethane, which has lower toxicity.

[0014] Beneficial effects of the invention:

[0015] 1. The method for synthesizing 1,5-disubstituted 1,2,3-triazole derivatives of the present invention can realize the synthesis of 1,5-disubstituted 1,2,3-triazole derivatives without using azide as a raw material. This makes the synthesis of 1,5-disubstituted 1,2,3-polysubstituted imidazole compounds more convenient and feasible, and strongly promotes the construction of a triazole compound library.

[0016] 2. The method for synthesizing 1,5-disubstituted 1,2,3-triazole derivatives of the present invention has the advantages of readily available raw materials, simple operation, mild reaction conditions, no need for metal catalysts, high yield, high atom economy, etc. 1,5-disubstituted 1,2,3-triazole compounds can be directly and efficiently synthesized using 2,2-difluoro-2-arylethane-1-amine as a raw material.

[0017] 3. The synthesis method developed by the present invention improves the dependence of traditional triazole synthesis on unstable reagents such as sodium azide, organic azide and organic diazo. 1,5-disubstituted 1,2,3-triazole derivatives are polysubstituted 1,2,3-triazole derivatives modified with difluoromethyl fragments, with novel structures, and no other methods can achieve synthesis. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1A, Figure 1B, and Figure 1C show the NMR spectra of 1,5-disubstituted 1,2,3-triazole compounds obtained in Example 1 1 H NMR (Figure 1A), 13 C NMR (Figure 1B), 19 F NMR ( Figure 1C ) spectrum;

[0019] Figures 2A, 2B and 2C show the NMR spectra of 1,5-disubstituted 1,2,3-triazole compounds obtained in Example 2. 1 H NMR (Figure 2A), 13 C NMR (Figure 2B), 19 F NMR ( Figure 2C ) spectrum;

[0020] FIG. 3A , FIG. 3B , and FIG. 3C show the NMR spectra of the 1,5-disubstituted 1,2,3-triazole compounds obtained in Example 3 1 H NMR (Figure 3A), 13 C NMR (Figure 3B), 19 F NMR ( Figure 3C ) spectrum;

[0021] FIG. 4A , FIG. 4B , and FIG. 4C show the NMR spectra of the 1,5-disubstituted 1,2,3-triazole compounds obtained in Example 4 1 H NMR (Figure 4A), 13 C NMR (Figure 4B), 19 F NMR ( Figure 4C ) spectrum;

[0022] FIG5A, FIG5B, and FIG5C show the NMR of the 1,5-disubstituted 1,2,3-triazole compound obtained in Example 5 1 H NMR (Figure 5A), 13 C NMR (Figure 5B), 19 F NMR ( Figure 5C ) spectrum;

[0023] FIG6A, FIG6B, and FIG6C show the NMR of the 1,5-disubstituted 1,2,3-triazole compound obtained in Example 6 1 H NMR (Figure 6A), 13 C NMR (Figure 6B),19 F NMR ( Figure 6C ) spectrum;

[0024] FIG. 7A , FIG. 7B , and FIG. 7C show the NMR images of the 1,5-disubstituted 1,2,3-triazole compounds obtained in Example 7 1 H NMR (Figure 7A), 13 C NMR (Figure 7B), 19 F NMR ( Figure 7C ) spectrum;

[0025] FIG8A, FIG8B, and FIG8C show the NMR of the 1,5-disubstituted 1,2,3-triazole compound obtained in Example 8 1 H NMR (Figure 8A), 13 C NMR (Figure 8B), 19 F NMR ( Figure 8C ) spectrum;

[0026] FIG9A, FIG9B, and FIG9C show the NMR of the 1,5-disubstituted 1,2,3-triazole compound obtained in Example 9 1 H NMR (Figure 9A), 13 C NMR (Figure 9B), 19 F NMR ( Figure 9C ) spectrum;

[0027] FIG. 10A , FIG. 10B , and FIG. 10C show the NMR of the 1,5-disubstituted 1,2,3-triazole compound obtained in Example 10 1 H NMR (Figure 10A), 13 C NMR (Figure 10B), 19 F NMR (Fig. 10C) spectrum. Implementation

[0028] In order to make the technical concept and advantages of the invention more clearly understood, the technical solution of the invention is further described in detail below in conjunction with the accompanying drawings.

[0029] The 1,5-disubstituted 1,2,3-triazole compound proposed in the present invention has a structure as shown in the following formula (1):

[0030] (1)

[0031] Wherein, Ar can be phenyl, p-chloro-substituted phenyl, p-bromo-substituted phenyl, p-ethyl-substituted phenyl, p-isopropyl-substituted phenyl, p-tert-butyl-substituted phenyl, m-methoxy-substituted phenyl, o-methyl-substituted phenyl, 1-naphthyl or 2-thienyl.

[0032] The technical solution of the present invention is further described in detail below through specific examples. It should be understood that the following examples are only used to explain and illustrate the preferred implementation of the present invention and should not constitute a limitation on the scope of patent protection required by the present invention. Example

[0033] The 1,5-disubstituted 1,2,3-triazole compound of this embodiment has a structure as shown in the following formula (1-1):

[0034] (1-1)

[0035] The synthesis method comprises the following steps:

[0036] In a 25 mL round-bottom flask, add 1 mmol of 2,2-difluoro-2-phenylethane-1-amine and 5 mL of dichloromethane, then add 0.2 mmol of acetic acid and 1.2 mmol of tert-butyl nitrite, react at 25 °C for 0.5 hour, monitor by TLC, stop the reaction after the raw material is completely consumed, and purify by column chromatography (PE:EA=10:1~5:1) to obtain a pure product with a yield of 90%.

[0037] The NMR of the 1,5-disubstituted 1,2,3-triazole compounds prepared in this example 1 H NMR (Figure 1A), 13 C NMR (Figure 1B), 19 The F NMR spectra (Figure 1C) are shown in Figure 1A, Figure 1B, and Figure 1C, respectively. 1 H NMR (400 MHz, CDCl3): δ 7.63 (s, 1H), 7.49 – 7.37 (m, 4H), 7.31 (t, J = 7.7 Hz, 2H), 7.17 (d, J = 7.6 Hz, 2H), 7.11 (dd, J = 7.8, 1.5 Hz, 2H), 4.91 (t, J = 12.4 Hz, 2H) ppm; 13 CNMR (101 MHz, CDCl3): δ 139.4, 133.5 (t, J = 25.2 Hz), 133.1, 130.7, 129.6,129.0, 128.9, 128.7, 126.4, 125.0 (t, J CF = 6.2 Hz), 118.9 (t, J CF= 248.1 Hz),53.4 (t, J CF = 34.3 Hz) ppm; 19 F NMR (376 MHz, CDCl3): δ -99.7 ppm. Example

[0038] The 1,5-disubstituted 1,2,3-triazole compound of this embodiment has a structure as shown in the following formula (1-2):

[0039] (1-2)

[0040] The synthesis method comprises the following steps:

[0041] In a 25 mL round-bottom flask, add 1 mmol of 2,2-difluoro-2-(4-chlorophenyl)ethane-1-amine and 5 mL of chloroform, then add 0.2 mmol of acetic acid and 1.2 mmol of tert-butyl nitrite. React at 25 °C for 0.5 hour and monitor by TLC. After the raw material is completely consumed, stop the reaction and purify by column chromatography (PE:EA=10:1~5:1) to obtain a pure product with a yield of 92%.

[0042] The NMR of the 1,5-disubstituted 1,2,3-triazole compounds prepared in this example 1 H NMR (Figure 1A), 13 C NMR (Figure 1B), 19 The F NMR spectra (Figure 1C) are shown in Figure 1A, Figure 1B, and Figure 1C, respectively. 1 H NMR (400 MHz, CDCl3): δ 7.64 (s, 1H), 7.48 – 7.41 (m, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.14 –7.05 (m, 4H), 4.93 (t, J = 12.0 Hz, 2H) ppm; 13 C NMR (101 MHz, CDCl3) δ 138.2,137.2 (t, J CF = 1.6 Hz), 136.1, 133.3, 131.8 (t, J CF = 25.8 Hz), 130.0, 129.4,129.0, 126.6 (t, J CF= 5.7 Hz), 124.7, 118.5 (t, J CF = 248.6 Hz), 53.3 (t, J CF = 35.0Hz) ppm; 19 F NMR (376 MHz, CDCl3): δ -99.36 ppm. Example

[0043] The 1,5-disubstituted 1,2,3-triazole compound of this embodiment has a structure as shown in the following formula (1-3):

[0044] (1-3)

[0045] The synthesis method comprises the following steps:

[0046] In a 25 mL round-bottom flask, add 1 mmol of 2,2-difluoro-2-(4-bromophenyl)ethane-1-amine and 5 mL of dichloromethane, then add 0.3 mmol of acetic acid and 1.3 mmol of tert-butyl nitrite, react at 25 °C for 0.5 hour, monitor by TLC, stop the reaction after the raw material is completely consumed, and purify by column chromatography (PE:EA=10:1~5:1) to obtain a pure product with a yield of 91%.

[0047] The NMR of the 1,5-disubstituted 1,2,3-triazole compounds prepared in this example 1 H NMR (Figure 1A), 13 C NMR (Figure 1B), 19 The F NMR spectra (Figure 1C) are shown in Figure 1A, Figure 1B, and Figure 1C, respectively. 1 H NMR (400 MHz, CDCl3): δ 7.56 (s, 1H), 7.53 – 7.48 (m, 2H), 7.36 (d, J = 8.6 Hz, 2H), 7.00 –6.88 (m, 4H), 4.87 (t, J = 12.0 Hz, 2H) ppm; 13 C NMR (101 MHz, CDCl3): δ 138.3,133.1, 132.3, 132.1, 131.9, 130.2, 126.7, 125.4, 125.0, 124.3, 118.5 (t, J CF =248.6 Hz), 53.2 (t, J= 34.9 Hz) ppm; 19 F NMR (376 MHz, CDCl3): δ -99.58 ppm. Example

[0048] The 1,5-disubstituted 1,2,3-triazole compound of this embodiment has a structure as shown in the following formula (1-4):

[0049] (1-4)

[0050] The synthesis method comprises the following steps:

[0051] In a 25 mL round-bottom flask, add 1 mmol of 2,2-difluoro-2-(4-ethylphenyl)ethane-1-amine and 5 mL of 1,2-dichloroethane, then add 0.2 mmol of acetic acid and 1.2 mmol of tert-butyl nitrite, react at 60 ° C for 0.5 hour, monitor by TLC, stop the reaction after the raw material is completely consumed, and purify by column chromatography (PE: EA = 10:1~5:1) to obtain a pure product with a yield of 88%.

[0052] The NMR of the 1,5-disubstituted 1,2,3-triazole compounds prepared in this example 1 H NMR (Figure 1A), 13 C NMR (Figure 1B), 19 The F NMR spectra (Figure 1C) are shown in Figure 1A, Figure 1B, and Figure 1C, respectively. 1 H NMR (400 MHz, CDCl3): δ 7.60 (s, 1H), 7.23 (d, J = 8.2 Hz, 2H), 7.11 (q, J = 8.4 Hz, 4H), 7.04– 7.00 (m, 2H), 4.89 (t, J = 12.4 Hz, 2H), 2.70 (dd, J = 15.3, 7.7 Hz, 2H), 2.64(dd, J = 15.4, 7.8 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H), 1.22 (t, J = 7.6 Hz, 3H); 13 CNMR (101 MHz, CDCl3): δ 147.03, 145.96, 139.48, 133.04, 130.90 (t, JCF = 25.4Hz), 128.82, 128.44, 128.12, 125.06 (t, J CF = 5.9 Hz), 123.67, 119.05 (t, J CF =247.8 Hz), 53.38 (t, J CF = 34.7 Hz), 28.68, 28.64, 15.42, 15.38 ppm; 19 F NMR (376MHz, CDCl3): δ -99.01 ppm. Example

[0053] The 1,5-disubstituted 1,2,3-triazole compound of this embodiment has a structure as shown in the following formula (1-5):

[0054] (1-5)

[0055] The synthesis method comprises the following steps:

[0056] In a 25 mL round-bottom flask, add 1 mmol of 2,2-difluoro-2-(4-isopropylphenyl)ethane-1-amine and 5 mL of dichloromethane, then add 0.5 mmol of acetic acid and 1.5 mmol of tert-butyl nitrite, react at 35 °C for 0.5 hour, monitor by TLC, stop the reaction after the raw material is completely consumed, and purify by column chromatography (PE:EA=10:1~5:1) to obtain the pure product with a yield of 89%.

[0057] The NMR of the 1,5-disubstituted 1,2,3-triazole compounds prepared in this example 1 H NMR (Figure 1A), 13 C NMR (Figure 1B), 19 The F NMR spectra (Figure 1C) are shown in Figure 1A, Figure 1B, and Figure 1C, respectively. 1 H NMR (400 MHz, CDCl3): δ 7.62 (s, 1H), 7.27 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 7.11(d, J = 8.3 Hz, 2H), 7.06 – 7.00 (m, 2H), 4.92 (t, J = 12.4 Hz, 2H), 2.95 (ddt,J =20.9, 13.8, 6.9 Hz, 2H), 1.31 (s, 3H), 1.29 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H) ppm; 13 C NMR (101 MHz, CDCl3): δ 151.6, 150.5, 139.5, 133.0, 131.0 (t, J CF =25.4 Hz), 128.8, 127.0, 125.1 (t, J CF = 5.9 Hz), 125.0, 123.8, 119.0 (t, J CF =247.9 Hz), 53.3 (t, J = 34.6 Hz), 34.0, 23.9, 23.8 ppm; 19 F NMR (376 MHz, CDCl3): δ -98.90 ppm. Example

[0058] The 1,5-disubstituted 1,2,3-triazole compound of this embodiment has a structure as shown in the following formula (1-6):

[0059] (1-6)

[0060] The synthesis method comprises the following steps:

[0061] In a 25 mL round-bottom flask, add 1 mmol of 2,2-difluoro-2-(4-tert-butylphenyl)ethane-1-amine and 5 mL of chloroform, then add 0.2 mmol of acetic acid and 1.2 mmol of tert-butyl nitrite, react at 60 ° C for 0.5 hour, monitor by TLC, stop the reaction after the raw material is completely consumed, and purify by column chromatography (PE: EA = 10:1~5:1) to obtain a pure product with a yield of 86%.

[0062] The NMR of the 1,5-disubstituted 1,2,3-triazole compounds prepared in this example 1 H NMR (Figure 1A), 13 C NMR (Figure 1B), 19 The F NMR spectra (Figure 1C) are shown in Figure 1A, Figure 1B, and Figure 1C, respectively. 1 H NMR (400 MHz, CDCl3): δ 7.61 (s, 1H), 7.41 (d, J= 8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 7.11(d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.3 Hz, 2H), 4.91 (t, J = 12.4 Hz, 2H), 1.35 (s,9H), 1.31 (s, 9H) ppm; 13 C NMR (101 MHz, CDCl3): δ 153.87, 152.83, 139.45,133.04, 130.70 (t, J CF = 25.4 Hz), 128.55, 125.89, 125.58, 124.83 (t, J CF = 5.4Hz), 123.44, 119.01 (t, J CF = 247.7 Hz), 53.31 (t, J CF = 34.5 Hz), 34.80, 31.24,31.21 ppm; 19 F NMR (376 MHz, CDCl3): δ -98.93 ppm. Example

[0063] The 1,5-disubstituted 1,2,3-triazole compound of this embodiment has a structure as shown in the following formula (1-7):

[0064] (1-7)

[0065] The synthesis method comprises the following steps:

[0066] In a 25 mL round-bottom flask, add 1 mmol of 2,2-difluoro-2-(3-methoxyphenyl)ethane-1-amine and 5 mL of chloroform, then add 0.5 mmol of acetic acid and 1.5 mmol of tert-butyl nitrite, react at 60 ° C for 0.5 hour, monitor by TLC, stop the reaction after the raw material is completely consumed, and purify by column chromatography (PE: EA = 10:1~5:1) to obtain a pure product with a yield of 87%.

[0067] The NMR of the 1,5-disubstituted 1,2,3-triazole compounds prepared in this example 1 H NMR (Figure 1A), 13C NMR (Figure 1B), 19 The F NMR spectra (Figure 1C) are shown in Figure 1A, Figure 1B, and Figure 1C, respectively. 1 H NMR (400 MHz, CDCl3): δ 7.61 (s, 1H), 7.35 – 7.28 (m, 1H), 7.19 (t, J = 8.0 Hz, 1H), 6.96(ddd, J = 8.4, 2.6, 0.8 Hz, 1H), 6.91 (dd, J = 8.3, 2.3 Hz, 1H), 6.73 (d, J = 7.8Hz, 1H), 6.71 – 6.66 (m, 1H), 6.65 – 6.61 (m, 1H), 6.58 (dd, J = 2.3, 1.7 Hz,1H), 4.92 (t, J = 12.3 Hz, 2H), 3.80 (s, 3H), 3.69 (s, 3H) ppm; 13 C NMR (101 MHz, CDCl3): δ 159.79, 159.65, 139.30, 134.79 (t, J CF = 25.2 Hz), 133.02, 130.07,129.83, 127.56, 120.90, 118.72 (t, J CF = 249.5 Hz), 117.18 (t, J CF = 5.3 Hz),116.69, 115.00, 114.61, 110.13, 55.40, 55.29, 53.37 (t, J CF = 34.6 Hz) ppm; 19 FNMR (376 MHz, CDCl3): δ -99.44 ppm. Example

[0068] The 1,5-disubstituted 1,2,3-triazole compound of this embodiment has a structure as shown in the following formula (1-8):

[0069] (1-8)

[0070] The synthesis method comprises the following steps:

[0071] In a 25 ml round-bottom flask, add 1 mmol of 2,2-difluoro-2-(2-methylphenyl)ethane-1-amine and 5 mL of dichloromethane, then add 0.3 mmol of acetic acid and 1.3 mmol of tert-butyl nitrite, react at 25 ° C for 0.5 hours, monitor by TLC, stop the reaction after the raw material is completely consumed, and purify by column chromatography (PE: EA = 10: 1 ~ 5: 1) to obtain a pure product with a yield of 85%. The NMR of the 1,5-disubstituted 1,2,3-triazole compound prepared in this example 1 H NMR (Figure 1A), 13 C NMR (Figure 1B), 19 The F NMR spectra (Figure 1C) are shown in Figure 1A, Figure 1B, and Figure 1C, respectively. 1 H NMR (400 MHz, CDCl3): δ 7.62 (s, 1H), 7.38 (td, J = 7.6, 1.3 Hz, 1H), 7.29 (d, J = 7.6 Hz, 2H),7.26 – 7.21 (m, 2H), 7.15 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 7.2 Hz, 1H), 4.77 (t, J = 13.4 Hz, 2H), 2.03 (s, 3H), 1.95 (t, J = 2.2 Hz, 3H)ppm; 13 C NMR (101 MHz, CDCl3): δ 138.09, 137.85, 135.72 (t, J CF = 2.8 Hz), 133.44,132.23, 131.43 (t, J CF = 23.2 Hz), 130.67, 130.59, 130.48 (t, J CF = 22.2 Hz),130.39, 130.04, 126.22, 126.13, 125.85, 119.49 (t, J CF = 248.8 Hz), 52.09 (t, J CF= 31.7 Hz), 19.65, 19.34 ppm; 19 F NMR (376 MHz, CDCl3): δ -97.52 ppm. Example

[0072] The 1,5-disubstituted 1,2,3-triazole compound of this embodiment has a structure as shown in the following formula (1-9):

[0073] (1-9)

[0074] The synthesis method comprises the following steps:

[0075] In a 25 mL round-bottom flask, add 1 mmol of 2,2-difluoro-2-(1-naphthyl)ethane-1-amine and 5 mL of chloroform, then add 0.4 mmol of acetic acid and 1.4 mmol of tert-butyl nitrite, react at 25 °C for 0.5 hour, monitor by TLC, stop the reaction after the raw material is completely consumed, and purify by column chromatography (PE:EA=10:1~5:1) to obtain a pure product with a yield of 89%.

[0076] The NMR of the 1,5-disubstituted 1,2,3-triazole compounds prepared in this example 1 H NMR (Figure 1A), 13 C NMR (Figure 1B), 19 The F NMR spectra (Figure 1C) are shown in Figure 1A, Figure 1B, and Figure 1C, respectively. 1 H NMR (400 MHz, CDCl3): δ 7.91 (dd, J = 7.9, 7.2 Hz, 2H), 7.78 (d, J = 7.7 Hz, 2H), 7.73 – 7.69(m, 1H), 7.53 – 7.48 (m, 2H), 7.40 (ddd, J = 14.1, 7.6, 1.3 Hz, 2H), 7.32 (ddd, J = 19.2, 10.2, 4.3 Hz, 3H), 7.12 – 7.06 (m, 2H), 7.04 – 6.98 (m, 1H), 5.40 –4.69 (m, 2H) ppm; 13C NMR (101 MHz, CDCl3): δ 137.4, 134.4, 133.8, 133.4,131.9, 131.5, 130.3, 129.0, 128.9, 128.8, 128.6, 127.5, 127.1, 126.7, 126.0,125.1, 125.0, 124.9, 124.5, 124.3, 123.4, 122.9, 119.3 (t, J CF = 249.1 Hz), 53.2(t, J CF = 31.0 Hz) ppm; 19 F NMR (376 MHz, CDCl3): δ -98.06 ppm. Example

[0077] The triazole derivative of this embodiment has a structure as shown in the following formula (1-10):

[0078] (1-10)

[0079] The synthesis method comprises the following steps:

[0080] In a 25 mL round-bottom flask, add 1 mmol of 2,2-difluoro-2-(2-thienyl)ethane-1-amine and 5 mL of dichloromethane, then add 0.2 mmol of acetic acid and 1.2 mmol of tert-butyl nitrite, react at 25 °C for 0.5 hour, monitor by TLC, stop the reaction after the raw material is completely consumed, and purify by column chromatography (PE:EA=10:1~5:1) to obtain a pure product with a yield of 86%.

[0081] The NMR of the 1,5-disubstituted 1,2,3-triazole compounds prepared in this example 1 H NMR (Figure 1A), 13 C NMR (Figure 1B), 19 The F NMR spectra (Figure 1C) are shown in Figure 1A, Figure 1B, and Figure 1C, respectively. 1 H NMR (400 MHz, CDCl3): δ 7.76 (s, 1H), 7.49 (dd, J = 5.1, 1.2 Hz, 1H), 7.41 (dd, J = 5.0, 1.2Hz, 1H), 7.16 – 7.11 (m, 2H), 7.10 (dd, J= 3.6, 1.2 Hz, 1H), 7.04 – 6.99 (m,1H), 5.08 (t, J = 12.4 Hz, 2H) ppm; 13 C NMR (101 MHz, CDCl3): δ 134.9 (t, J CF = 30.1Hz), 129.1, 128.6, 128.5, 128.1, 128.1, 127.6, 127.4, 127.4, 125.8, 117.4 (t, J CF = 246.4 Hz), 53.6 (t, J CF = 33.2 Hz) ppm; 19 F NMR (376 MHz, CDCl3): δ -88.36ppm.

[0082] The above examples fully illustrate the synthesis method of the 1,5-disubstituted 1,2,3-triazole derivatives of the present invention, which can use 2,2-difluoro-2-arylethane-1-amine as a raw material and an organic reagent as a solvent to obtain the 1,5-disubstituted 1,2,3-triazole derivatives at room temperature. The raw materials involved in the synthesis method are cheap and easy to obtain, the reaction conditions are mild, and the operation is simple and safe.

[0083] The synthesized 1,5-disubstituted 1,2,3-triazole derivatives are widely present in natural products and drug molecules, have good biological activity, and are important pharmaceutical intermediates.

[0084] The above description is only a preferred embodiment of the present invention and does not constitute a limitation of the present invention. Under the guidance of the prior art, those skilled in the art can make other modifications to the implementation of the present invention without creative work. Any modification made within the spirit and principle of the present invention or simple replacement or equivalent substitution using conventional technical means in the field should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 1,5-disubstituted 1,2,3-triazole derivatives, characterized in that: Using 2,2-difluoro-2-arylethane-1-amine as a raw material, acetic acid as a catalyst, and tert-butyl nitrite as an oxidant, the 2,2-difluoro-2-arylethane-1-amine is dissolved in an organic solvent, and then acetic acid and tert-butyl nitrite are added to the above solution, and the reaction is carried out according to the following reaction formula (I): （I） The 1,5-disubstituted 1,2,3-triazole derivative is prepared by reaction under mild conditions; Wherein, Ar is any one of phenyl, halogen-substituted phenyl, C1-C4 alkyl-substituted phenyl, alkoxy-substituted phenyl, naphthyl and thienyl.

2. The method for synthesizing 1,5-disubstituted 1,2,3-triazole derivatives according to claim 1, characterized in that: The molar ratio of the reaction materials is 2,2-difluoro-2-arylethane-1-amine: acetic acid: tert-butyl nitrite = 1.0: (0.2-0.5): (1.2-1.5), and the reaction temperature is 25-60°C.

3. The method for synthesizing 1,5-disubstituted 1,2,3-triazole derivatives according to claim 2, characterized in that: The molar ratio of the reaction materials is 2,2-difluoro-2-arylethane-1-amine: acetic acid: tert-butyl nitrite = 1.0: 0.2: 1.

2.

4. The method for synthesizing 1,5-disubstituted 1,2,3-triazole derivatives according to claim 2, characterized in that: The molar ratio of the reaction materials is 2,2-difluoro-2-arylethane-1-amine: acetic acid: tert-butyl nitrite = 1.0:0.5:1.

5.

5. The method for synthesizing 1,5-disubstituted 1,2,3-triazole derivatives according to claim 2, characterized in that: The molar ratio of the reaction materials is 2,2-difluoro-2-arylethane-1-amine: acetic acid: tert-butyl nitrite = 1.0: 0.2: 1.

5.

6. The method for synthesizing 1,5-disubstituted 1,2,3-triazole derivatives according to claim 2, characterized in that: The molar ratio of the reaction materials is 2,2-difluoro-2-arylethane-1-amine: acetic acid: tert-butyl nitrite = 1.0: 0.3: 1.

3.

7. The method for synthesizing 1,5-disubstituted 1,2,3-triazole derivatives according to claim 2, characterized in that: The molar ratio of the reaction materials is 2,2-difluoro-2-arylethane-1-amine: acetic acid: tert-butyl nitrite = 1.0: 0.4: 1.

4.

8. The method for synthesizing a 1,5-disubstituted 1,2,3-triazole derivative according to any one of claims 1 to 7, characterized in that: The organic solvent is 1,2-dichloroethane, dichloromethane or chloroform.

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