A 1-N-substituted 1,2,3-triazole-4-carboxamide derivative and a preparation method thereof

Abstract

The invention discloses a 1-N-substituted 1,2,3-triazole-4-formamide derivative and a preparation method thereof, wherein the compound structural formula is: the R1 is a phenyl substituted with various substitutions; R2 is a heterocyclic aromatic group or an alkyl group; R3 is an alkyl group. The preparation method includes: dissolving an azidophenyl derivative and an amine compound in a two-phase solvent, adding a base and a phase transfer catalyst, then adding an α-trifluoromethyl propylene compound, stirring at a certain temperature until the raw material reaction is complete; extracting the obtained reaction system, the organic layer is concentrated under reduced pressure to obtain a residue, and the residue is subjected to silica gel column chromatography to obtain a 1-N-substituted 1,2,3-triazole-4-formamide derivative. The preparation method provided by the present invention has the advantages of simple operation, easy availability of raw materials, good tolerance of the functional groups of the reaction, excellent product yield and easy separation.

Description

Technical Field

[0001] The present invention relates to a synthesis method of a compound, and in particular to a 1-N-substituted 1,2,3-triazole-4-carboxamide derivative and a preparation method thereof. Background Art

[0002] 1,2,3-Triazole compounds are an important class of heterocyclic compounds with wide applications in synthesis, medicine and materials chemistry. 1-N-substituted 1,2,3-triazole-4-carboxamide derivatives are of great significance and are often used as the basic core skeleton of many biological and pharmaceutical active molecules. These molecules have a wide range of properties and can be used as Hsp90 inhibitors as well as anti-epileptic and antibacterial agents. The relevant structures are shown below:

[0003]

[0004] Currently, the most common route for the synthesis of 1-N-substituted 1,2,3-triazole-4-carboxamide derivatives is mainly achieved through a two-step process, including azide-olefin cyclization and amidation reaction. The existing synthesis methods of 1-N-substituted 1,2,3-triazole-4-carboxamide derivatives have low 1,4 / 1,5-dipolar selectivity and most require precious metal catalysis. Metal residues in the products are still a thorny problem, especially in the pharmaceutical industry. Summary of the invention

[0005] The purpose of the embodiments of the present application is to provide a 1-N-substituted 1,2,3-triazole-4-carboxamide derivative and a preparation method thereof in order to solve the problems existing in the prior art.

[0006] According to a first aspect of an embodiment of the present application, a 1-N-substituted 1,2,3-triazole-4-carboxamide derivative is provided, wherein the 1-N-substituted 1,2,3-triazole-4-carboxamide derivative has the structural formula:

[0007]

[0008] Where R 1 is various substituted phenyl groups, R 2 is a heterocyclic aromatic group or an alkyl group, R 3 It is an alkane group.

[0009] Further, the 1-N-substituted 1,2,3-triazole-4-carboxamide derivative is any one of the following:

[0010] (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone;

[0011] (1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone;

[0012] (1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone;

[0013] (1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone;

[0014] Piperidin-1-yl(1-(p-tolyl)-1H-1,2,3-triazol-4-yl)methanone;

[0015] (1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone;

[0016] Piperidin-1-yl(1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methanone;

[0017] (1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone;

[0018] Piperidin-1-yl(1-(m-tolyl)-1H-1,2,3-triazol-4-yl)methanone;

[0019] (1-(2-chlorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone;

[0020] Piperidin-1-yl(1-(o-tolyl)-1H-1,2,3-triazol-4-yl)methanone;

[0021] (1-(2-bromo-4-chlorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone;

[0022] (1-(2,4-dibromophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone;

[0023] (1-(2-bromo-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone;

[0024] (1-(2,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone;

[0025] (1-(2-chloro-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone;

[0026] (1-(3-chloro-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone;

[0027] (1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)(morpholinyl)methanone;

[0028] (1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)(pyrrolidin-1-yl)methanone;

[0029] 1-(4-Bromophenyl)-N,N-diethyl-1H-1,2,3-triazole-4-carboxamide;

[0030] 1-(4-Bromophenyl)-N-isopropyl-1H-1,2,3-triazole-4-carboxamide.

[0031] According to a second aspect of the embodiments of the present application, a method for preparing the 1-N-substituted 1,2,3-triazole-4-carboxamide derivative as described in the first aspect is provided, comprising the following steps:

[0032] Step (1), dissolving an azidophenyl derivative and an amine compound in a two-phase solvent, adding a base and a phase transfer catalyst, and then adding an α-trifluoromethylpropylene compound, and stirring at a certain temperature until the raw materials react completely;

[0033] The structural formula of the azidophenyl derivative is:

[0034]

[0035] Where R 1 is various substituted phenyl groups;

[0036] The structural formula of the amine compound is:

[0037]

[0038] Where R 2 is a heterocyclic aromatic group or an alkyl group, R 3 is an alkane group;

[0039] The structural formula of the α-trifluoromethyl propylene compound is:

[0040]

[0041] Step (2), extracting the reaction system obtained in step (1), concentrating the organic layer obtained by extraction under reduced pressure to obtain a residue, and subjecting the residue to silica gel column chromatography to obtain a 1-N-substituted 1,2,3-triazole-4-carboxamide derivative, wherein the structural formula of the 1-N-substituted 1,2,3-triazole-4-carboxamide derivative is:

[0042]

[0043] Furthermore, in the step (1), the molar ratio of the azidophenyl derivative to the amine compound is 1:5, the ratio of the azidophenyl derivative to the two-phase solvent is 1 mol:2L, the molar ratio of the azidophenyl derivative to the base is 1:3, and the ratio of the azidophenyl derivative to the α-trifluoromethylpropylene compound is 1 mol:2L.

[0044] Furthermore, the stirring temperature in step (1) is 50°C to 150°C, preferably 140°C.

[0045] Furthermore, in the step (1), the two-phase solvent is selected from one or more of water, acetone, tetrahydrofuran, toluene, N,N-dimethylformamide, anhydrous methanol, and acetonitrile, preferably a mixture of tetrahydrofuran and water. Furthermore, the two-phase solvent is a mixture of tetrahydrofuran and water in a volume ratio of 3:1.

[0046] Furthermore, the concentration of the two-phase solvent is 0.5 mmol / mL.

[0047] Furthermore, in the step (1), the base is selected from an inorganic base or an organic base, the inorganic base includes potassium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide; the organic base includes 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), N,N-dimethylaniline (DMA), N,N-diisopropylethylamine (DIPEA), triethylamine, 4-dimethylaminopyridine (DMAP), among which N,N-diisopropylethylamine is preferred.

[0048] Furthermore, in the step (1), the phase transfer catalyst is selected from DL-α-tocopherol methoxy polyethylene glycol succinate solution (TPGS-750-M), 18-crown ether-6, and tetrabutylammonium hydrogen sulfate (TBAHS), wherein 18-crown ether-6 is preferred.

[0049] The technical solution provided by the embodiments of the present application may have the following beneficial effects:

[0050] As can be seen from the above embodiments, the present application dissolves azidophenyl derivatives and amine compounds in a two-phase solvent, adds a base and a phase transfer catalyst, and then adds an α-trifluoromethylpropylene compound to construct a 1-N-substituted 1,2,3-triazole-4-carboxamide structure. The reaction temperature of the present invention is more selective than the conventional synthesis method, does not require the use of heavy / precious metals, is convenient for post-processing, and such compounds may have potential biological activity. The reaction yield is high and easy to purify, and the separation yield of most products is above 60%; the substrate has a wide range of applicability, and a variety of substrate structures can tolerate the reaction conditions.

[0051] It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the present application. DETAILED DESCRIPTION

[0052] Here, exemplary embodiments will be described in detail, and the implementations described in the following exemplary embodiments do not represent all implementations consistent with the present application.

[0053] The terms used in this application are for the purpose of describing specific embodiments only and are not intended to limit this application. The singular forms of "a", "said" and "the" used in this application and the appended claims are also intended to include plural forms unless the context clearly indicates other meanings. It should also be understood that the term "and / or" used herein refers to and includes any or all possible combinations of one or more associated listed items.

[0054] The present invention will be further described below by way of examples.

[0055] Example 1: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0056]

[0057] Dissolve phenylazide (1.0mmol, 1.0 equivalent) and piperidine (5.0mmol, 5.0 equivalent) in 2mL solvent (tetrahydrofuran: water = 3:1), add 18-crown ether-6 (1.0mmol, 1.0 equivalent), then add DIPEA (3.0mmol, 3.0 equivalent), and finally add 2mL (trans)-1-chloro-3,3,3,-trifluoropropene, and stir at 140°C until the raw material reaction is complete. After the reaction is complete, the reaction system is extracted, and the organic layer is concentrated under reduced pressure to obtain a residue. The residue is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:3) to obtain a white solid with a yield of 68%.

[0058] White solid, yield 68%. Melting point: 144.7-145.5℃. 1 H NMR (400 MHz, CDCl 3 ): δ8.48(s,1H),7.77–7.75(m,2H),7.57-7.53(m,2H),7.49-7.46(m,1H),4.19(d,J=5.2Hz,2H),3.75(t,J=4.8Hz,2H),1.72(s,6H); 13 C NMR (100 MHz, CDCl 3): δ159.6,145.30,136.6,129.9,129.2,126.0,120.7,48.0,44.0,26.8,25.8,24.7; HRMS calcd for C 14 H 16 N 4 O+H + :257.1397,found:257.1394.

[0059] Example 1 Comparison of yields under different reaction conditions

[0060]

[0061] sequence catalyst Alkali Temperature(℃) Yield [%] 1 / LiOH 50℃ Trace 2 / / 50℃ Trace 3 / DABCO 50℃ 9％ 4 / DBU 50℃ 3％ 5 / <![CDATA[Et 3 N]]> 50℃ 4％ 6 / DABCO 80℃ 13％ 7 TPGS-750-M DABCO 80℃ 16％ 8 TPGS-750-M DABCO 100℃ 33％ 9 18-Crown-6 DABCO 100℃ 36％ 10 TBAHS DABCO 100℃ 28％ 11 TPGS-750-M DABCO 120℃ 35％ 12 18-Crown-6 DABCO 120℃ 44％ 13 TBAHS DABCO 120℃ 38％ 14 18-Crown-6 DABCO 140℃ 46％ 15 18-Crown-6 DMAP 140℃ 38％ 16 18-Crown-6 DMA 140℃ 50％ 17 18-Crown-6 DIPEA 140℃ 68％

[0062] Comparative Example 1: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0063] Dissolve phenylazide (1.0 mmol, 1.0 equivalent) and piperidine (5.0 mmol, 5.0 equivalent) in 2 mL of solvent (tetrahydrofuran: water = 3:1), then add LiOH (3.0 mmol, 3.0 equivalent), and finally add 2 mL of (trans)-1-chloro-3,3,3,-trifluoropropene, and stir at 50°C until the reaction of the raw materials is complete. After the reaction is complete, there is almost no product.

[0064] Comparative Example 2: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0065] Dissolve phenylazide (1.0 mmol, 1.0 equivalent) and piperidine (5.0 mmol, 5.0 equivalent) in 2 mL of solvent (tetrahydrofuran: water = 3:1), and finally add 2 mL of (trans)-1-chloro-3,3,3,-trifluoropropene, and stir at 50°C until the raw materials react. After the reaction is completed, there is almost no product.

[0066] Comparative Example 3: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0067] Dissolve phenylazide (1.0 mmol, 1.0 equivalent) and piperidine (5.0 mmol, 5.0 equivalent) in 2 mL of solvent (tetrahydrofuran: water = 3:1), then add DABCO (3.0 mmol, 3.0 equivalent), and finally add 2 mL of (trans)-1-chloro-3,3,3,-trifluoropropene, and stir at 50°C until the reaction of the raw materials is complete. After the reaction is complete, the yield is calculated by HPLC analysis, and the yield is 9%.

[0068] Comparative Example 4: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0069] Dissolve phenylazide (1.0 mmol, 1.0 equivalent) and piperidine (5.0 mmol, 5.0 equivalent) in 2 mL of solvent (tetrahydrofuran: water = 3:1), then add DBU (3.0 mmol, 3.0 equivalent), and finally add 2 mL of (trans)-1-chloro-3,3,3,-trifluoropropene, and stir at 50°C until the reaction of the raw materials is complete. After the reaction is complete, the yield is calculated by HPLC analysis, and the yield is 3%.

[0070] Comparative Example 5: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0071] Azide benzene (1.0 mmol, 1.0 equivalent) and piperidine (5.0 mmol, 5.0 equivalent) were dissolved in 2 mL of solvent (tetrahydrofuran: water = 3:1), and then Et 3 N (3.0 mmol, 3.0 equivalents), and finally 2 mL of (trans)-1-chloro-3,3,3,-trifluoropropene was added and stirred at 50°C until the reaction of the raw materials was completed. After the reaction was completed, the yield was calculated by HPLC analysis, and the yield was 4%.

[0072] Comparative Example 6: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0073] Dissolve phenylazide (1.0 mmol, 1.0 equivalent) and piperidine (5.0 mmol, 5.0 equivalent) in 2 mL of solvent (tetrahydrofuran: water = 3:1), then add DABCO (3.0 mmol, 3.0 equivalent), and finally add 2 mL of (trans)-1-chloro-3,3,3,-trifluoropropene, and stir at 80°C until the reaction of the raw materials is complete. After the reaction is complete, the yield is calculated by HPLC analysis, and the yield is 13%.

[0074] Comparative Example 7: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0075] Dissolve phenylazide (1.0 mmol, 1.0 equivalent) and piperidine (5.0 mmol, 5.0 equivalent) in 2 mL of solvent (tetrahydrofuran: water = 3:1), add TPGS-750-M (1.0 mmol, 1.0 equivalent), then add DABCO (3.0 mmol, 3.0 equivalent), and finally add 2 mL of (trans)-1-chloro-3,3,3,-trifluoropropene, and stir at 80°C until the reaction of the raw materials is complete. After the reaction is complete, the yield is calculated by HPLC analysis, and the yield is 16%.

[0076] Comparative Example 8: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0077] Dissolve phenylazide (1.0 mmol, 1.0 equivalent) and piperidine (5.0 mmol, 5.0 equivalent) in 2 mL of solvent (tetrahydrofuran: water = 3:1), add TPGS-750-M (1.0 mmol, 1.0 equivalent), then add DABCO (3.0 mmol, 3.0 equivalent), and finally add 2 mL of (trans)-1-chloro-3,3,3,-trifluoropropene, and stir at 100°C until the reaction of the raw materials is complete. After the reaction is complete, the yield is calculated by HPLC analysis, and the yield is 33%.

[0078] Comparative Example 9: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0079] Dissolve phenylazide (1.0 mmol, 1.0 equivalent) and piperidine (5.0 mmol, 5.0 equivalent) in 2 mL of solvent (tetrahydrofuran: water = 3:1), add 18-crown-6 (1.0 mmol, 1.0 equivalent), then add DABCO (3.0 mmol, 3.0 equivalent), and finally add 2 mL of (trans)-1-chloro-3,3,3,-trifluoropropene, and stir at 100°C until the raw material reaction is complete. After the reaction is complete, the yield is calculated by HPLC analysis, and the yield is 36%.

[0080] Comparative Example 10: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0081] Dissolve phenylazide (1.0 mmol, 1.0 equivalent) and piperidine (5.0 mmol, 5.0 equivalent) in 2 mL of solvent (tetrahydrofuran: water = 3:1), add TBAHS (1.0 mmol, 1.0 equivalent), then add DABCO (3.0 mmol, 3.0 equivalent), and finally add 2 mL of (trans)-1-chloro-3,3,3,-trifluoropropene, and stir at 100°C until the raw material reaction is complete. After the reaction is complete, the yield is calculated by HPLC analysis, and the yield is 28%.

[0082] Comparative Example 11: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0083] Dissolve phenylazide (1.0 mmol, 1.0 equivalent) and piperidine (5.0 mmol, 5.0 equivalent) in 2 mL of solvent (tetrahydrofuran: water = 3:1), add TPGS-750-M (1.0 mmol, 1.0 equivalent), then add DABCO (3.0 mmol, 3.0 equivalent), and finally add 2 mL of (trans)-1-chloro-3,3,3,-trifluoropropene, and stir at 120°C until the reaction of the raw materials is complete. After the reaction is complete, the yield is calculated by HPLC analysis, and the yield is 35%.

[0084] Comparative Example 12: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0085] Dissolve phenylazide (1.0 mmol, 1.0 equivalent) and piperidine (5.0 mmol, 5.0 equivalent) in 2 mL of solvent (tetrahydrofuran: water = 3:1), add 18-crown-6 (1.0 mmol, 1.0 equivalent), then add DABCO (3.0 mmol, 3.0 equivalent), and finally add 2 mL of (trans)-1-chloro-3,3,3,-trifluoropropene, and stir at 120°C until the reaction of the raw materials is complete. After the reaction is complete, the yield is calculated by HPLC analysis, and the yield is 44%.

[0086] Comparative Example 13: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0087] Dissolve phenylazide (1.0 mmol, 1.0 equivalent) and piperidine (5.0 mmol, 5.0 equivalent) in 2 mL of solvent (tetrahydrofuran: water = 3:1), add TBAHS (1.0 mmol, 1.0 equivalent), then add DABCO (3.0 mmol, 3.0 equivalent), and finally add 2 mL of (trans)-1-chloro-3,3,3,-trifluoropropene, and stir at 120°C until the reaction of the raw materials is complete. After the reaction is complete, the yield is calculated by HPLC analysis, and the yield is 38%.

[0088] Comparative Example 14: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0089] Dissolve phenylazide (1.0 mmol, 1.0 equivalent) and piperidine (5.0 mmol, 5.0 equivalent) in 2 mL of solvent (tetrahydrofuran: water = 3:1), add 18-crown-6 (1.0 mmol, 1.0 equivalent), then add DABCO (3.0 mmol, 3.0 equivalent), and finally add 2 mL of (trans)-1-chloro-3,3,3,-trifluoropropene, and stir at 140°C until the reaction of the raw materials is complete. After the reaction is complete, the yield is calculated by HPLC analysis, and the yield is 46%.

[0090] Comparative Example 15: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0091] Dissolve phenylazide (1.0 mmol, 1.0 equivalent) and piperidine (5.0 mmol, 5.0 equivalent) in 2 mL of solvent (tetrahydrofuran: water = 3:1), add 18-crown-6 (1.0 mmol, 1.0 equivalent), then add DMAP (3.0 mmol, 3.0 equivalent), and finally add 2 mL of (trans)-1-chloro-3,3,3,-trifluoropropene, and stir at 140°C until the reaction of the raw materials is complete. After the reaction is complete, the yield is calculated by HPLC analysis, and the yield is 38%.

[0092] Comparative Example 16: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0093] Dissolve phenylazide (1.0 mmol, 1.0 equivalent) and piperidine (5.0 mmol, 5.0 equivalent) in 2 mL of solvent (tetrahydrofuran: water = 3:1), add 18-crown-6 (1.0 mmol, 1.0 equivalent), then add DMA (3.0 mmol, 3.0 equivalent), and finally add 2 mL of (trans)-1-chloro-3,3,3,-trifluoropropene, and stir at 140°C until the reaction of the raw materials is complete. After the reaction is complete, the yield is calculated by HPLC analysis, and the yield is 50%.

[0094] Comparative Example 17: (1-phenyl-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0095] Dissolve phenylazide (1.0 mmol, 1.0 equivalent) and piperidine (5.0 mmol, 5.0 equivalent) in 2 mL of solvent (tetrahydrofuran: water = 3:1), add 18-crown-6 (1.0 mmol, 1.0 equivalent), then add DIPEA (3.0 mmol, 3.0 equivalent), and finally add 2 mL of (trans)-1-chloro-3,3,3,-trifluoropropene, and stir at 140°C until the reaction of the raw materials is complete. After the reaction is complete, the yield is calculated by HPLC analysis, and the yield is 68%.

[0096] Example 2: (1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0097]

[0098] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced with 1-azido-4-chlorobenzene to obtain a white solid with a yield of 52%.

[0099] White solid, yield 52%. Melting point: 215.9-216.5℃. 1 H NMR (400 MHz, CDCl 3 ): δ8.47(s,1H),7.71(d,J=8.8Hz,2H),7.52(d,J=8.8Hz,2H),4.17(s,2H),3.74(s,2H),1.71(s,6H); 13 C NMR (100 MHz, CDCl 3 ): δ159.4,145.5,135.1,135.1,130.1,126.0,121.8,48.0,44.0,26.8,25.8,24.7; HRMS calcd for C 14 H 15 C1N 4 O+H +:291.1007,found:291.1005.

[0100] Example 3: (1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0101]

[0102] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced with 1-azido-4-bromobenzene to obtain a white solid with a yield of 72%.

[0103] White solid, yield 72%. Melting point: 223.0-223.6℃. 1 H NMR (400 MHz, CDCl 3 ): δ8.47(s,1H),7.70–7.67(m,2H),7.66–7.64(m,2H),4.17(d,J=5.6Hz,2H),3.74(t,J=4.8Hz,2H),1.71(s,6H); 13 C NMR (100 MHz, CDCl 3 ): δ159.4,145.6,135.6,133.1,125.9,123.0,122.0,48.0,44.0,26.8,25.8,24.7; HRMS calcd for C 14 H 15 Bn 4 O+H + :335.0502,found:335.0505.

[0104] Example 4: (1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0105]

[0106] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced with 1-azido-4-fluorobenzene to obtain a white solid with a yield of 51%.

[0107] White solid, yield 51%. Melting point: 128.6-129.4℃. 1 H NMR (500 MHz, CDCl 3 ): δ8.44(s,1H),7.75-7.72(m,2H),7.26-7.23(m,2H),4.18(d,J=4.5Hz,2H),3.75(d,J=5.5Hz,2H),1.71(s,6H); 13 C NMR (126 MHz, CDCl3 ): δ163.7,161.7,159.5,145.5,126.2,122.7(122.72,122.65,d,J=8.8H z),116.9(117.0,116.8,d,J=22.5Hz),48.0,44.0,26.8,25.8,24.7; HRMS calcd for C 14 H 15 FN 4 O+H + :275.1303,found:275.1306.

[0108] Example 5: Piperidin-1-yl (1-(p-tolyl)-1H-1,2,3-triazol-4-yl)methanone

[0109]

[0110] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced with 1-azido-4-methylbenzene to obtain a white solid with a yield of 35%.

[0111] White solid, yield 35%. Melting point: 184.3-184.9℃. 1 H NMR (400 MHz, CDCl 3 ): δ8.43(s,1H),7.62(d,J=8.4Hz,2H),7.33(d,J=8.0Hz,2H),4.19(d,J=5.2Hz,2H),3.75(d,J=5.2Hz,2H),2.43(s,3H),1.71(s,6H); 13 C NMR (100 MHz, CDCl 3 ): δ159.7,145.2,139.4,134.3,130.4,126.0,120.6,48.0,43.9,26.8,25.8,24.7,21.1; HRMS calcd for C 15 H 18 N 4 O+H + :271.1553,found:271.1557.

[0112] Example 6: (1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0113]

[0114] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced with 1-azido-4-methoxybenzene to obtain a white solid with a yield of 33%.

[0115] White solid, yield 33%. Melting point: 171.6-172.3℃. 1 H NMR (500 MHz, CDCl 3 ): δ8.39(s,1H),7.65(d,J=9.0Hz,2H),7.04(d,J=9.0Hz,2H),4.19(s,2H),3.88(s,3H),3.75(d,J=5.0Hz,2H),1.72(s,6H); 13 C NMR (125 MHz, CDCl 3 ): δ160.2,147.7,145.1,130.0,126.1,122.3,115.0,55.7,48.0,44.0,26.8,25.8,24.7; HRMS calcd for C 15 H 18 N 4 O2+H + :287.1503,found:287.1501.

[0116] Example 7: Piperidin-1-yl(1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methanone

[0117]

[0118] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced with 1-azido-4-(trifluoromethyl)benzene to obtain a white solid with a yield of 54%.

[0119] White solid, yield 54%. Melting point: 213.1-213.7℃. 1 H NMR (500 MHz, CDCl 3 ): δ8.56(s,1H),7.93(d,J=8.5Hz,2H),7.83(d,J=8.5Hz,2H),4.18(d,J=5.5Hz,2H),3.75(d,J=5.0Hz,2H),1.72(s,6H); 13 C NMR (125 MHz, CDCl 3): δ159.3,145.8,139.0,131.4,131.2,127.3(127.33,127.30,127.27,127.2 4,q,J=3.8Hz),126.0,124.5,122.4,120.7,48.0,44.0,26.8,25.8,24.6; HRMS calcd for C 15 H 15 F 3 N 4 O+H + :325.1271,found:325.1274.

[0120] Example 8: (1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0121]

[0122] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced with 1-azido-3-chlorobenzene to obtain a white solid with a yield of 43%.

[0123] White solid, yield 43%. Melting point: 132.0-132.6℃. 1 H NMR (400 MHz, CDCl 3 ): δ8.48(s,1H),7.83(t,J=2.0Hz,1H),7.65(dt,J=7.2,1.8Hz,1H),7.51-7.44(m,2H),4.17(d,J=5.2Hz,2H),3.74(t,J=1.2Hz,2H),1.72(s,6H); 13 C NMR (100 MHz, CDCl 3 ): δ159.4,145.6,137.5,135.8,131.0,129.3,126.0,121.0,118.6,48.0,44.0,26.8,25.8,24.7; HRMS calcdfor C 14 H 15 C1N 4 O+H + :291.1007,found:291.1005.

[0124] Example 9: Piperidin-1-yl (1-(m-tolyl)-1H-1,2,3-triazol-4-yl)methanone

[0125]

[0126] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced with 1-azido-3-methylbenzene to obtain a white solid with a yield of 17%.

[0127] White solid, yield 17%. Melting point: 119.7-121.1℃. 1 H NMR (500 MHz, CDCl 3 ): δ8.45(s,1H),7.58(s,1H),7.52(d,J=8.0Hz,1H),7.41(t,J=8.0Hz,1H),7.28(d,J =7.5Hz,1H),4.19(d,J=5.0Hz,2H),3.74(d,J=5.0Hz,2H),2.46(s,3H),1.72(s,6H); 13 C NMR (125 MHz, CDCl 3 ): δ159.7,145.2,140.2,136.6,130.0,129.7,126.1,121.3,117.7,48.0,43.9,26.8,25.8,24.7,21.4; HRMS calcd for C 15 H 18 N 4 O+H + :271.1553,found:271.1557.

[0128] Example 10: (1-(2-chlorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0129]

[0130] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced with 1-azido-2-chlorobenzene to obtain a white solid with a yield of 25%.

[0131] White solid, yield 25%. Melting point: 114.5-115.2℃. 1 H NMR (400 MHz, CDCl 3 ): δ8.46(s,1H),7.63-7.59(m,2H),7.51–7.44(m,2H),4.20(s,2H),3.75(t,J=4.8Hz,2H),1.72(s,6H); 13 C NMR (125 MHz, CDCl 3): δ159.5,144.5,134.5,131.1,130.9,130.0,128.9,128.0,127.7,48.0,44.0,26.8,25.8,24.7; HRMS calcd for C 14 H 15 C1N 4 O+H + :291.1007,found:291.1005.

[0132] Example 11: Piperidin-1-yl (1-(o-tolyl)-1H-1,2,3-triazol-4-yl)methanone

[0133]

[0134] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced with 1-azido-2-methylbenzene to obtain a white solid with a yield of 19%.

[0135] White solid, yield 19%. Melting point: 111.3-112.0℃. 1 H NMR (500 MHz, CDCl 3 ): δ8.24(s,1H),7.45–7.42(m,1H),7.39(d,J=7.5Hz,1H),7.35–7.33(m,2H),4.24(s,2H),3.75(t,J=5.0Hz,2H),2.24(s,3H),1.73(s,6H); 13 C NMR (125 MHz, CDCl 3 ): δ159.7,144.6,136.0,133.7,131.6,130.2,129.6,127.0,125.9,48.0,44.0,26.8,25.8,24.7,17.9; HRMS calcdfor C 15 H 18 N 4 O+H + :271.1553,found:271.1557.

[0136] Example 12: (1-(2-bromo-4-chlorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0137]

[0138] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced with 1-azido-2-bromo-4-chlorobenzene to obtain a white solid with a yield of 79%.

[0139] White solid, yield 79%. Melting point: 114.8-115.3℃. 1 H NMR (400 MHz, CDCl 3 ): δ8.42(s,1H),7.79(t,J=1.2Hz,1H),7.50(d,J=1.2Hz,2H),4.20(d,J=4.8Hz,2H),3.75(t,J=5.0Hz,2H),1.73(s,6H); 13 C NMR (100 MHz, CDCl 3 ): δ159.4,144.7,137.0,134.8,133.7,130.0,128.9,128.7,119.3,48.0,44.0,26.8,25.8,24.7; HRMS calcd for C 14 H 14 BrClN 4 O+H + :369.0112,found:369.0114.

[0140] Example 13: (1-(2,4-dibromobenzene)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0141]

[0142] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced with 1-azido-2,4-dibromobenzene to obtain a white solid with a yield of 77%.

[0143] White solid, yield 77%. Melting point: 130.2-131.0℃. 1 H NMR (400 MHz, CDCl 3 ): δ8.42(s,1H),7.94(d,J=2.4Hz,1H),7.64(dd,J=8.4,2.0Hz,1H),7.43(d,J=8.4Hz,1H),4.19(s,2H),3.74(t,J=4.8Hz,2H),1.72(s,6H); 13 C NMR (100 MHz, CDCl 3 ): δ159.3,144.7,136.5,135.2,131.9,130.0,129.0,124.8,119.4,48.0,44.0,26.8,25.8,24.7; HRMS calcd forC 14 H 14 Br 2 N 4O+H + :412.9607,found:412.9609.

[0144] Example 14: (1-(2-bromo-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0145]

[0146] The synthesis steps are the same as those in Example 1, except that azidobenzene is replaced by 1-azido-2-bromo-4-fluorobenzene to obtain a white solid with a yield of 86%. White solid with a yield of 86%. Melting point: 97.5-98.0°C. 1 H NMR (500 MHz, CDCl 3 ): δ8.38(s,1H),7.56–7.51(m,2H),7.25–7.21(m,1H),4.20(s,2H),3.77–3.75(t,J=5.0Hz,2H),1.73(s,6H); 13 C NMR (125 MHz, CDCl 3 ): δ163.9,161.8,159.4,144.6,130.2,129.4(129.39,129.31,d,J=10.0Hz), 121.3(121.41,121.21,d,J=25.0Hz), 119.8 (119.84, 119.76, d, J = 10.0Hz), 115.9 (115.95, 115.77, d, J = 22.5Hz), 48.0, 44.0, 26.8, 25.8, 24.7; HRMScalcd for C 14 H 14 BrFN 4 O+H + :353.0408,found:353.0406.

[0147] Example 15: (1-(2,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0148]

[0149] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced with 1-azido-2,4-dichlorobenzene to obtain a white solid with a yield of 62%.

[0150] White solid, yield 62%. Melting point: 135.8-136.3℃. 1 H NMR (400 MHz, CDCl 3): δ8.45(s,1H),7.62(d,J=2.0Hz,1H),7.57(d,J=8.4Hz,1H),7.45(dd,J=8.4,2.4Hz,1H),4.18(s,2H),3.75(t,J=4.6Hz,2H),1.73(s,6H); 13 C NMR (100 MHz, CDCl 3 ): δ159.3,144.7,136.7,133.1,130.8,129.9,129.6,128.4,100.0,48.0,44.0,26.8,25.8,24.7; HRMS calcd forC 14 H 14 Cl 2 N 4 O+H + :325.0617,found:325.0618.

[0151] Example 16: (1-(2-chloro-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0152]

[0153] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced with 1-azido-2-chloro-4-fluorobenzene to obtain a white solid with a yield of 78%.

[0154] White solid, yield 78%. Melting point: 141.3-141.8℃. 1 H NMR (400 MHz, CDCl 3 ): δ8.42(s,1H),7.60(dd,J=8.8,5.2Hz,1H),7.35(dd,J=8.0,2.8Hz,1H),7.21 -7.16(m,1H),4.19(s,2H),3.74(t,J=4.6Hz,2H),1.72(s,6H); 13 C NMR (100 MHz, CDCl 3 ): δ164.1,161.6,159.4,144.7,130.4(130.46,130.35,d,J=11.0Hz),130.1,129.1(129.13,129.04,d,J=9.0Hz ), 118.4 (118.40, 118.14, d, J = 26.0Hz), 115.4 (115.52, 115.29, d, J = 23.0Hz), 48.0, 44.0, 26.8, 25.8, 24.7; HRMS calcd for C14 H 14 CIF 4 O+H + :309.0913,found:309.0911.

[0155] Example 17: (1-(3-chloro-4-fluorophenyl)-1H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone

[0156]

[0157] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced with 4-azido-2-chloro-1-fluorobenzene to obtain a white solid with a yield of 95%.

[0158] White solid, yield 95%. Melting point: 163.4-164.1℃. 1 H NMR (500 MHz, CDCl 3 ): δ8.45(s,1H),7.89(dd,J=6.5,3.0Hz,1H),7.65–7.62(m,1H),7.33(t,J=8. 5Hz, 1H), 4.17 (d, J = 5.0Hz, 2H), 3.74 (t, J = 5.0Hz, 2H), 1.72 (t, J = 8.5Hz, 6H); 13 C NMR (125 MHz, CDCl 3 ): δ159.3, 157.3, 145.7, 133.1, 126.1, 123.3, 122.8 (122.91, 122.76, d, J = 18.8Hz), 120.4 (120. 43,120.37,d,J=7.5Hz),117.8(117.91,117.72,d,J=23.8Hz),48.0,44.0,26.8,25.8,24.6; HRMS calcd for C 14 H 14 CIF 4 O+H + :309.0913,found:309.0911.

[0159] Example 18: (1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)(morpholinyl)methanone

[0160]

[0161] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced by 1-azido-4-bromobenzene and piperidine was replaced by morpholine to obtain a white solid with a yield of 71%.

[0162] White solid, yield 71%. Melting point: 213.4-214.1℃. 1 H NMR (400 MHz, CDCl 3 ): δ8.52(s,1H),7.71–7.68(m,2H),7.66–7.64(m,2H),4.40–4.38(m,2H),3.81(d,J=8.8Hz,6H); 13 CNMR (100MHz, CDCl 3 ): δ159.4,145.1,135.4,133.2,126.4,123.2,122.1 67.3,66.9,47.4,43.2; HRMS calcd for C 13 H 13 Bn 4 O 2 +H + :337.0295,found:337.0294.

[0163] Example 19: (1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)(pyrrolidin-1-yl)methanone

[0164]

[0165] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced by 1-azido-4-bromobenzene and piperidine was replaced by pyrrolidine to obtain a white solid with a yield of 51%.

[0166] White solid, yield 51%. Melting point: 218.6-219.3℃. 1 H NMR (500 MHz, CDCl 3 ): δ8.55(s,1H),7.70 -7.65(m,4H),4.16(t,J=7.0Hz,2H),3.70(t,J=7.0Hz,2H),2.04(p,J=6.5Hz,2H),1.94(p,J=6.5Hz,2H); 13 C NMR (125 MHz, CDCl 3 ): δ159.1,146.0,135.6,133.1,125.5,123.0,122.0,48.8,47.1,26.6,23.8; HRMS calcd for C 13 H 13 Bn 4 O+H + :321.0346,found:321.0348.

[0167] Example 20: 1-(4-bromophenyl)-N,N-diethyl-1H-1,2,3-triazole-4-carboxamide

[0168]

[0169] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced by 1-azido-4-bromobenzene and piperidine was replaced by diethylamine to obtain a white solid with a yield of 51%.

[0170] White solid, yield 51%. Melting point: 182.2-183.0℃. 1 H NMR (500 MHz, CDCl 3 ): δ8.51(s,1H),7.69-7.64(m,4H),4.01(q,J=7.0Hz,2H),3.57(q,J=7.0Hz,2H),1.35(t,J=7.0Hz,3H),1.26(t,J=7.0Hz,3H); 13 C NMR (125 MHz, CDCl 3 ): δ160.1,145.9,135.6,133.1,126.0,123.0,122.0,43.1,41.4,14.8,12.8; HRMS calcd for C 13 H 15 Bn 4 O+H + :323.0502,found:323.0505.

[0171] Example 21: 1-(4-bromophenyl)-N-isopropyl-1H-1,2,3-triazole-4-carboxamide

[0172]

[0173] The synthesis steps were the same as those in Example 1, except that azidobenzene was replaced by 1-azido-4-bromobenzene and piperidine was replaced by isopropylamine to obtain a white solid with a yield of 25%.

[0174] White solid, yield 25%. Melting point: 217.6-218.1℃. 1 H NMR (500 MHz, CDCl 3 ): δ8.48(s,1H),7.70–7.68(m,2H),7.65–7.63(m,2H),7.03(d,J=7.0Hz,1H),4.34–4.27(m,1H),1.30(d,J=6.5Hz,6H); 13 C NMR (125 MHz, CDCl 3): δ158.8,144.4,135.6,133.1,126.4,123.2,122.1,41.4,22.8; HRMS calcd for C 12 H 13 Bn 4 O+H + :309.0346,found:309.0343.

[0175] It should be noted that in the above embodiments, the solvent is a mixture of tetrahydrofuran and water in a volume ratio of 3:1, which is a preferred solution. The solvent here can be selected from one or more of water, acetone, tetrahydrofuran, toluene, N,N-dimethylformamide (DMF), anhydrous methanol, and acetonitrile, preferably a mixture of tetrahydrofuran and water.

[0176] It is a preferred embodiment that the base is selected from N,N-diisopropylethylamine (DIPEA), and the base can be selected from potassium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), N,N-dimethylaniline (DMA), N,N-diisopropylethylamine (DIPEA), triethylamine, and 4-dimethylaminopyridine (DMAP).

[0177] It should be understood that the present application is not limited to what has been described above, and that various modifications and changes may be made without departing from its scope. The scope of the present application is limited only by the appended claims.

Claims

1. A method for preparing a 1-N-substituted 1,2,3-triazole-4-carboxamide derivative, characterized in that: The following steps are involved: Step (1), dissolving an azidophenyl derivative and an amine compound in a two-phase solvent, adding a base and a phase transfer catalyst, and then adding an α-trifluoromethylpropylene compound, stirring at a certain temperature until the raw materials react, wherein the two-phase solvent is a mixture of tetrahydrofuran and water in a volume ratio of 3:1; The structural formula of the azidophenyl derivative is: ， Wherein R1 is various substituted phenyl groups; The structural formula of the amine compound is: ， Wherein R2 is a heterocyclic aromatic group or an alkyl group, and R3 is an alkyl group; The structural formula of the α-trifluoromethyl propylene compound is: ， Step (2), extracting the reaction system obtained in step (1), concentrating the organic layer obtained by extraction under reduced pressure to obtain a residue, and subjecting the residue to silica gel column chromatography to obtain a 1-N-substituted 1,2,3-triazole-4-carboxamide derivative, wherein the structural formula of the 1-N-substituted 1,2,3-triazole-4-carboxamide derivative is: 。 2. The preparation method according to claim 1, characterized in that: In the step (1), the molar ratio of the azidophenyl derivative to the amine compound is 1:5, the ratio of the azidophenyl derivative to the two-phase solvent is 1 mol:2L, the molar ratio of the azidophenyl derivative to the base is 1:3, and the ratio of the azidophenyl derivative to the α-trifluoromethylpropylene compound is 1 mol:2L.

3. The preparation method according to claim 1, characterized in that: The stirring temperature in the step (1) is 50°C to 150°C.

4. The preparation method according to claim 1, characterized in that: In the step (1), the base is selected from an inorganic base or an organic base, the inorganic base is selected from potassium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide; the organic base is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, N,N-dimethylaniline, N,N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine.

5. The preparation method according to claim 1, characterized in that: In the step (1), the phase transfer catalyst is selected from DL-α-tocopherol methoxy polyethylene glycol succinate solution, 18-crown ether-6, and tetrabutylammonium hydrogen sulfate.

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