A method for preparing deuterated 1,2,3-triazole compounds using acetylene

Abstract

The present invention relates to a method for preparing a deuterated 1,2,3-triazole compound by using acetylene, comprising the following steps: #imgabs0# reacting an azide compound of formula I with acetylene in heavy water / solvent under the action of a catalyst to generate a compound of formula II; wherein Y is selected from H or D; and R is selected from a suitable substituent, preferably an optionally substituted aryl or alkyl group.

Description

Technical Field

[0001] The present invention belongs to the fields of pharmaceutical synthesis, organic chemical industry and the like, and particularly relates to a method for preparing a deuterated 1,2,3-triazole compound by utilizing acetylene. Background Art

[0002] Acetylene is an inexpensive and readily available industrial gas with important applications in organic chemistry, pharmaceuticals, and polymers. Utilizing acetylene as a resource and developing high-value-added industrial products is a crucial technology. In recent years, this resource utilization has led to numerous synthetic applications in organic synthetic chemistry. Furthermore, 1,2,3-triazole structures are unique structural fragments found in pharmaceutical and material molecules. Synthesis of 1,2,3-triazoles from acetylene has become a convenient method for this purpose. In 2009, Liang Yongmin et al. reported a method for synthesizing 1,2,3-triazoles from acetylene (Synlett, 2009, 1453-1456).

[0003] Deuterated compounds play an important role in pharmaceutical research and the study of organic chemical reaction mechanisms. Deuterated organic molecules have important applications in nuclear magnetic resonance, such as as deuterated solvents. In 2010, Novák et al. developed a method for preparing deuterium-labeled 4,5-dideuterium-labeled 1,2,3-triazole by reacting calcium carbide as an acetylene source with azide (Tetrahedron Lett. 2010, 51, 6275-6277). In 2021, Ananikov et al. achieved the in situ preparation of deuterated acetylene from calcium carbide using a double-branched reactor, thereby synthesizing double-deuterated 1,2,3-triazole (Eur. J. Org. Chem. 2021, 5640–5648). The double-branched reactor allows calcium carbide and other reactants to be stored in separate reactors, thus avoiding the adverse effects of reactions carried out in the same reactor. The above-mentioned reaction using calcium carbide as an acetylene substitute is essentially to generate deuterated acetylene in situ by reacting calcium carbide with heavy water, and ultimately to prepare deuterium-labeled 1,2,3-triazole, and the deuterated 1,2,3-triazole compound obtained is 4,5-dideuterium-labeled 1,2,3-triazole.

[0004] This invention provides a method for synthesizing deuterium-labeled 1,2,3-triazoles. Through a cycloaddition reaction of acetylene and an azide compound in the presence of a catalyst, and in a deuterated water environment, deuterium atoms can be labeled at the C4 and C5 positions of the 1,2,3-triazole ring. Furthermore, in this experiment, the deuterium substitution ratio at the C4 and C5 positions can be adjusted by controlling the catalyst, and even 1,2,3-triazole compounds with deuterium labeled C5 but undeuterated C4 can be produced. Summary of the Invention

[0005] The present invention provides a method for preparing a deuterium-labeled 1,2,3-triazole compound represented by Formula II, which is characterized by comprising the following steps:

[0006]

[0007] In heavy water / solvent, an azide compound of formula I reacts with acetylene in the presence of a catalyst to generate a compound of formula II; wherein Y is selected from H or D; and R is selected from a suitable substituent, preferably an optionally substituted aryl or alkyl group.

[0008] The catalyst is selected from a monovalent copper complex or a combination of a monovalent copper salt and a ligand; the amount of the catalyst used, calculated as copper salt, is such that the molar ratio of the copper salt to the azide compound of formula I is 0.05:1 to 0.2:1, preferably 0.05:1 to 0.1:1; the monovalent copper salt is preferably cuprous chloride, cuprous bromide, cuprous iodide, cuprous acetate, cuprous nitrate, or the like; the ligand is a nitrogen-containing ligand, preferably triethylamine, pyridine, diisopropylethylamine, triphenylphosphine and its substituents, 1,10-phenanthroline and its substituents, 2,2'-bipyridine, or the like. The above-mentioned monovalent copper complex can be prepared in advance and then added to the reaction, or it can be prepared in situ by adding the copper salt and ligand to the reactor. The pre-prepared catalyst may include but is not limited to tris(triphenylphosphine)copper(I) complex, dichloro(1,10-phenanthroline)copper, (1,10-phenanthroline)bis(triphenylphosphine)cuprous nitrate, bromo(1,10-phenanthroline)(triphenylphosphine)copper(I), and other corresponding complexes. 1,10-phenanthroline substituted compounds include but are not limited to 4,7-diphenyl-1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline, and 2,9-dimethyl-4,7-biphenyl-1,10-phenanthroline.

[0009] Another embodiment of the present invention provides a method for preparing the deuterium-labeled 1,2,3-triazole compound represented by the above formula II, characterized in that the reaction occurs in an environment containing heavy water, and the amount of heavy water used in the reaction is 10 to 120 times, preferably 30 to 60 times, the molar amount of the azide compound of formula I.

[0010] Another embodiment of the present invention provides a method for preparing the deuterium-labeled 1,2,3-triazole compound represented by Formula II, characterized in that other solvents may or may not be added to the reaction environment in addition to deuterated water. Such solvents used in conjunction with deuterated water include dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, hexamethylphosphoramide, dioxane, methyl tert-butyl ether, and 2-methylfuran.

[0011] One embodiment of the present invention provides a method for preparing the deuterium-labeled 1,2,3-triazole compound represented by the above formula II, characterized in that the deuterium label in formula II is at the C5 position; while the C4 position is not deuterated, is deuterated (the deuteration rate exceeds 70%), or is slightly deuterated (the deuteration rate does not exceed 20%).

[0012] Another embodiment of the present invention provides a method for preparing a deuterium-labeled 1,2,3-triazole compound shown in the above-mentioned formula II, characterized in that an azide compound, a catalyst, and heavy water / solvent are added to a reaction vessel, and after replacing the air in the instrument, acetylene gas is introduced into the reaction system. The reaction mixture is stirred at 0-50 degrees Celsius (preferably 10-40 degrees Celsius) for 3-24 hours. After the reaction is completed, the reaction mixture is separated by extraction, column chromatography, and other separation means to obtain the corresponding deuterium-labeled 1,2,3-triazole compound. The reaction can be carried out under pressure or at normal pressure.

[0013] An embodiment of the present invention provides a method for preparing the deuterium-labeled 1,2,3-triazole compound represented by the above formula II, characterized in that the reactant acetylene can be industrial acetylene gas or can be prepared by reacting calcium carbide with water.

[0014] The aryl group of the present invention is further preferably a C5-C10 aryl group optionally substituted with one or more C1-C6 alkyl groups, C1-C6 alkoxy groups, cyano groups, halogen groups, azido groups, nitro groups, hydroxyl groups and the like; the alkyl group is further preferably a C1-C12 alkyl group optionally substituted with one or more C1-C6 alkyl groups, C1-C6 alkoxy groups, cyano groups, halogen groups, azido groups, nitro groups, hydroxyl groups and the like; the aryl group of the present invention is preferably a C6-C10 aryl group or a C5-C6 heteroaryl group, and is further preferably a phenyl group, a naphthyl group, a pyridyl group, a thienyl group, a furyl group and the like.

[0015] Compared with the prior art, the advantages of the present invention are: (1) the present invention can introduce deuterium-labeled C4 and C5 on the 1,2,3-triazole ring to form a double-labeled compound, and can also selectively achieve deuterium labeling on C5 while C4 is rarely or even not deuterated; (2) the present invention uses acetylene prepared from industrial acetylene or calcium carbide as a raw material to achieve the synthesis of deuterated 1,2,3-triazole. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 The product of Example 1 1 H NMR spectrum;

[0017] Figure 2 The product of Example 1 13 C NMR spectrum;

[0018] Figure 3 The product of Example 21 H NMR spectrum;

[0019] Figure 4 The product of Example 2 13 C NMR spectrum;

[0020] Figure 5 The product of Example 3 1 H NMR spectrum;

[0021] Figure 6 The product of Example 3 13 C NMR spectrum;

[0022] Figure 7 The product of Example 4 1 H NMR spectrum;

[0023] Figure 8 The product of Example 4 13 C NMR spectrum;

[0024] Figure 9 The product of Example 5 1 H NMR spectrum;

[0025] Figure 10 The product of Example 5 13 C NMR spectrum;

[0026] Figure 11 The product of Example 6 1 H NMR spectrum;

[0027] Figure 12 The product of Example 6 13 C NMR spectrum;

[0028] Figure 13 The product of Example 7 1 H NMR spectrum;

[0029] Figure 14 The product of Example 7 13 C NMR spectrum;

[0030] Figure 15 The product of Example 8 1 H NMR spectrum;

[0031] Figure 16 The product of Example 8 13 C NMR spectrum;

[0032] Figure 17 The product of Example 9 1 H NMR spectrum;

[0033] Figure 18The product of Example 9 13 C NMR spectrum;

[0034] Figure 19 The product of Example 10 1 H NMR spectrum;

[0035] Figure 20 The product of Example 10 13 C NMR spectrum;

[0036] Figure 21 The product of Example 11 1 H NMR spectrum;

[0037] Figure 22 The product of Example 11 13 C NMR spectrum;

[0038] Figure 23 The product of Example 12 1 H NMR spectrum;

[0039] Figure 24 The product of Example 12 13 C NMR spectrum;

[0040] Figure 25 The product of Example 13 1 H NMR spectrum;

[0041] Figure 26 The product of Example 13 13 C NMR spectrum;

[0042] Figure 27 The product of Example 14 1 H NMR spectrum;

[0043] Figure 28 The product of Example 14 13 C NMR spectrum. DETAILED DESCRIPTION

[0044] In order to facilitate further understanding of the present invention, the following examples are provided to illustrate it in more detail. However, these examples are only for better understanding of the invention and are not intended to limit the scope or implementation principles of the present invention. The implementation methods of the present invention are not limited to the following.

[0045] Example 1 Preparation of 4,5-dideuterio-1-phenyl-1,2,3-triazole

[0046] To a dry 10 mL flask, phenylazide (1.0 mmol, 1.0 equiv.), CuI (0.1 mmol, 10 mol%), triethylamine (0.4 mmol, 40 mol%), N,N-dimethylformamide (1.5 mL), and D2O (0.5 mL) were added sequentially. Acetylene gas was introduced into the reactor and the reaction was stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was extracted, washed, dried, and the solvent removed. Column chromatography was performed to obtain the corresponding product, 4,5-dideuterio-1-phenyl-1,2,3-triazole, in an 85% yield. The deuteration rate of C5 was 73%, and the deuteration rate of C4 was 80%.

[0047] 1 H NMR (400MHz, Chloroform-d) δ7.99 (s, 0.27H), 7.79 (s, 0.20H), 7.69 (d, J = 7.8Hz, 2H), 7.47 (t, J = 7.7Hz, 2H), 7.39 (t, J = 7.5Hz, 1H). 13 C NMR (100MHz, Chloroform-d) δ 136.98, 134.39 (d, J = 10.9Hz), 129.76, 128.77, 121.80 (d, J = 9.7Hz), 120.62 (d, J = 1.7Hz).

[0048] Example 2 Preparation of 4,5-dideuterio-1-phenyl-1,2,3-triazole

[0049] To a dry 10 mL flask, phenylazide (1.0 mmol, 1.0 equiv.), CuI (0.1 mmol, 10 mol%), triethylamine (0.2 mmol, 20 mol%), N-methylpyrrolidone (1.5 mL), and D2O (0.5 mL) were added sequentially. Acetylene gas was introduced into the reactor and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was extracted, washed, dried, and the solvent removed. Column chromatography was performed to obtain the corresponding product, 4,5-dideuterio-1-phenyl-1,2,3-triazole, in an 85% yield. The deuteration rate of C5 was 81%, and the deuteration rate of C4 was 71%.

[0050] 1 H NMR (400MHz, Chloroform-d) δ7.99 (s, 0.19), 7.76 (d, J = 10.9Hz, 0.29H), 7.68 (d, J = 7.5Hz, 2H), 7.45 (t, J = 8.2Hz, 2H), 7.37 (t, J = 7.3Hz, 1H). 13C NMR (100MHz, Chloroform-d) δ 136.98, 134.39 (d, J = 10.8Hz), 129.76, 128.77, 121.80 (d, J = 9.7Hz), 120.62 (d, J = 1.7Hz).

[0051] Example 3 Preparation of 5-deuterium-1-phenyl-1,2,3-triazole

[0052] To a dry 10 mL round-bottom flask were added phenylazide (1.0 mmol, 1.0 equiv.), CuI (0.1 mmol, 10 mol%), 1,10-phenanthroline (0.2 mmol, 20 mol%), N,N-dimethylformamide (1.5 mL), and D2O (0.5 mL). The air in the reactor was replaced with acetylene gas and the reaction was stirred at room temperature for 10 h. After completion of the reaction, the reaction solution was extracted, washed, dried, and the solvent removed. Column chromatography was performed to obtain the corresponding product, 5-deuterium-1-phenyl-1,2,3-triazole, in a 72% yield. The deuteration rate of C5 was 87%, and C4 was undeuterated. 1 H NMR (400MHz, Chloroform-d) δ7.97(d,J=1.1Hz,0.13H),7.71(s,1H),7.66–7.58(m,2H),7.38(t,J=7.6Hz,2H),7.29(t,J=7.4Hz,1H). 13 CNMR(100MHz,Chloroform-d)δ136.77,134.18,129.58,128.59,120.38.

[0053] Example 4 Preparation of 5-deuterium-1-phenyl-1,2,3-triazole

[0054] To a dry 10 mL round-bottom flask were added phenylazide (1.0 mmol, 1.0 equiv.), CuI (0.1 mmol, 10 mol%), 4,7-diphenyl-1,10-phenanthroline (0.2 mmol, 20 mol%), N,N-dimethylformamide (1.5 mL), and D2O (0.5 mL). The air in the reactor was replaced with acetylene gas and the reaction was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was extracted, washed, dried, and the solvent removed. Column chromatography was performed to obtain the corresponding product, 5-deuterium-1-phenyl-1,2,3-triazole, in a 77% yield. The deuteration rate of C5 was 93%, and the deuteration rate of C4 was 2%.

[0055] 1H NMR (400MHz, Chloroform-d) δ8.08 (d, J = 1.1Hz, 0.07H), 7.81 (s, 0.98H), 7.75–7.68 (m, 2H), 7.52–7.43 (m, 2H), 7.43–7.36 (m, 1H). 13 C NMR (100MHz, Chloroform-d) δ136.89,134.30,129.70,128.69,120.49.

[0056] Example 5 Preparation of 5-deuterium-1-phenyl-1,2,3-triazole

[0057] To a dry 10 mL round-bottom flask, phenylazide (1.0 mmol, 1.0 equiv.), CuI (0.1 mmol, 10 mol%), 3,4,7,8-tetramethyl-1,10-phenanthroline (0.2 mmol, 20 mol%), N,N-dimethylformamide (1.5 mL), and D2O (0.5 mL) were added sequentially. Acetylene gas was introduced under vacuum and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was extracted, washed, dried, and the solvent removed. Column chromatography was performed to obtain the corresponding product, 5-deuterium-1-phenyl-1,2,3-triazole, in a 45% yield. The deuteration rate of C5 was 91%, and the deuteration rate of C4 was 1%.

[0058] 1 H NMR (400MHz, Chloroform-d) δ8.08(d,J=1.1Hz,0.09H),7.81(s,0.99H),7.72(dd,J=8.5,1.3Hz,2H),7.48(t,J=7.7Hz,2H),7.40(t,J=7.4Hz,1H). 13 C NMR(100MHz,Chloroform-d)δ136.89,134.29,129.70,128.69,120.49.

[0059] Example 6 Preparation of 5-deuterium-1-phenyl-1,2,3-triazole

[0060] To a dry 10 mL round-bottom flask, phenylazide (1.0 mmol, 1.0 equiv.), [Cu(PPh3)2]NO3 (0.1 mmol, 10 mol%), N,N-dimethylformamide (1.5 mL), and D2O (0.5 mL) were added sequentially. The air in the reactor was replaced with acetylene gas, and the reaction was stirred at room temperature for 10 hours. After completion of the reaction, the reaction solution was extracted, washed, dried, and the solvent removed. Column chromatography was performed to obtain the corresponding product, 5-deuterium-1-phenyl-1,2,3-triazole, with an 85% yield, a 93% deuteration rate at C5, and a 16% deuteration rate at C4.

[0061] 1 H NMR (400MHz, Chloroform-d) δ7.99(d,J=1.0Hz,0.07H),7.76(d,J=0.9Hz,0.84H),7.69–7.63(m,2H),7.43(ddd,J=7.9,6.9,1.1Hz,2H),7.39–7.32(m,1H). 13 C NMR (100MHz, Chloroform-d) δ136.87,134.24,129.66,128.66,120.48.

[0062] Example 7 Preparation of 5-deuterium-1-phenyl-1,2,3-triazole

[0063] To a dry 10 mL round-bottom flask, phenylazide (1.0 mmol, 1.0 equiv.), [Cu(phen)(PPh3)2]NO3 (0.1 mmol, 10 mol%), N,N-dimethylformamide (1.5 mL), and D2O (0.5 mL) were added sequentially. The air in the reactor was replaced with acetylene gas, and the reaction was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was extracted, washed, dried, and the solvent was removed. Column chromatography was then performed to obtain the corresponding product, 5-deuterium-1-phenyl-1,2,3-triazole, with an 85% yield, a 93% deuteration rate at C5, and a 3% deuteration rate at C4. 1 H NMR (400MHz, Chloroform-d) δ7.98(d,J=1.1Hz,0.07H),7.72(s,0.97H),7.62(d,J=7.5Hz,2H),7.38(t,J=8.0Hz,2H),7.30(t,J=7.4Hz,1H). 13 CNMR(100MHz,Chloroform-d)δ136.74,134.13,129.54,128.53,121.29,120.33.

[0064] Example 8 Preparation of 5-deuterium-1-(4-methylphenyl)-1,2,3-triazole

[0065] To a dry 10 mL round-bottom flask, 4-azidotoluene (1.0 mmol, 1.0 equiv.), [Cu(phen)(PPh3)2]NO3 (0.05 mmol, 5 mol%), triethylamine (0.2 mmol, 20 mol%), N,N-dimethylformamide (1.5 mL), and D2O (0.5 mL) were added sequentially. The air in the reactor was replaced with acetylene gas, and the reaction was stirred at room temperature for 10 h. After completion of the reaction, the reaction solution was extracted, washed, dried, and the solvent was removed. Column chromatography was performed to obtain the corresponding product, 5-deuterated-1-(4-methylphenyl)-1,2,3-triazole, with an 82% yield, a 93% C5 deuteration rate, and a 3% C4 deuteration rate.

[0066] 1 H NMR (400MHz, Chloroform-d) δ7.93 (d, J=1.1Hz, 0.07H), 7.71 (s, 0.97H), 7.55–7.44 (m, 2H), 7.18 (d, J=8.2Hz, 2H), 2.29 (s, 3H). 13 C NMR (100MHz, Chloroform-d) δ138.63,134.50,134.00,130.04,120.26,20.85.

[0067] Example 9 Preparation of 5-deuterium-1-(4-chlorophenyl)-1,2,3-triazole

[0068] To a dry 10 mL round-bottom flask, 4-azidochlorobenzene (1.0 mmol, 1.0 equiv.), [Cu(phen)(PPh3)2]NO3 (0.1 mmol, 10 mol%), N,N-dimethylformamide (1.5 mL), and D2O (0.5 mL) were added sequentially. The air in the reactor was replaced with acetylene gas, and the reaction was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was extracted, washed, dried, and the solvent was removed. Column chromatography was performed to obtain the corresponding product, 5-deuterated-1-(4-chlorophenyl)-1,2,3-triazole, with a yield of 68%, a C5 deuteration rate of 93%, and a C4 deuteration rate of 5%.

[0069] 1 H NMR (400MHz, Chloroform-d) δ7.99 (d, J=1.1Hz, 0.07H), 7.76 (d, J=0.9Hz, 0.95H), 7.62 (d, J=8.8Hz, 2H), 7.40 (dd, J=9.0, 1.1Hz, 2H).13 C NMR (100MHz, Chloroform-d) δ135.36,134.44,134.35,129.81,121.66.

[0070] Example 10 Preparation of 5-deuterium-1-(4-bromophenyl)-1,2,3-triazole

[0071] A round-bottom flask was charged with 4-azidobromobenzene (1.0 mmol, 1.0 equiv.), CuI (0.1 mmol, 10 mol%), 1,10-phenanthroline (0.2 mmol, 20 mol%), and D2O (0.5 mL). Calcium carbide (4.0 mmol, 4.0 equiv.) was placed in a separate, dry reactor. Water was slowly added to the calcium carbide reactor through a glass tube or double-ended needle. Both reactors were stirred at room temperature for 24 hours. After the reaction, the reaction solution was extracted, washed, dried, and the solvent removed. Column chromatography was performed to obtain the corresponding product, 5-deuterated-1-(4-bromophenyl)-1,2,3-triazole, in a 71% yield, with a C5 deuteration rate of 94% and a C4 deuteration rate of 3%.

[0072] 1 H NMR (400MHz, Chloroform-d) δ7.99 (d, J = 1.1Hz, 0.06H), 7.80 (s, 0.97H), 7.65–7.53 (m, 4H). 13 C NMR (100MHz, Chloroform-d) δ135.96,134.57,132.91,122.39,122.02.

[0073] Example 11 Preparation of 5-deuterium-1-(3-bromophenyl)-1,2,3-triazole

[0074] To a dry 10 mL round-bottom flask were added 1-azido-3-bromobenzene (1.0 mmol, 1.0 equiv.), CuI (0.1 mmol, 10 mol%), 1,10-phenanthroline (0.1 mmol, 10 mol%), triphenylphosphine (0.2 mmol, 20 mol%), N,N-dimethylformamide (1.5 mL), and D2O (0.5 mL). The air in the reactor was replaced with acetylene gas, and the reaction was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was extracted, washed, dried, and the solvent removed. Column chromatography was performed to obtain the corresponding product, 5-deuterated-1-(3-bromophenyl)-1,2,3-triazole, in a 77% yield, with a C5 deuteration rate of 91% and a C4 deuteration rate of 3%.

[0075] 1H NMR(400MHz,Chloroform-d)δ8.02(d,J=1.1Hz,0.09H),7.85(d,J=1.8Hz,0.97H),7.76(d ,J=1.4Hz,1H),7.60(d,J=8.1Hz,1H),7.45(d,J=8.0Hz,1H),7.29(td,J=8.1,1.4Hz,1H). 13 C NMR (100MHz, Chloroform-d) δ137.70,134.44,131.58,130.99,123.46,123.11,118.87.

[0076] Example 12 Preparation of 5-deuterium-1-(2-methoxyphenyl)-1,2,3-triazole

[0077] To a dry 10 mL round-bottom flask, 2-azidoanisole (1.0 mmol, 1.0 equiv.), CuBr (0.1 mmol, 10 mol%), 4,7-dimethoxy-1,10-phenanthroline (0.2 mmol, 20 mol%), dimethyl sulfoxide (1.5 mL), and D2O (0.5 mL) were added sequentially. The air in the reactor was replaced with acetylene gas, and the reaction was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was extracted, washed, dried, and the solvent removed. Column chromatography was performed to obtain the corresponding product, 5-deuterated-1-(2-methoxyphenyl)-1,2,3-triazole, with an 83% yield, a 93% deuteration rate at C5, and no deuteration at C4.

[0078] 1 H NMR (400MHz, Chloroform-d) δ8.14(d,J=1.1Hz,0.07H),7.78(s,1H),7.73(dd,J=8.2,1.7Hz,1H),7.43–7.34(m,1H),7.09–7.03(m,2H),3.83(s,3H). 13 CNMR(100MHz,Chloroform-d)δ150.87,132.87(d,J=11.5Hz),129.90,125.86,125.07,120.83,112.11,55.69.

[0079] Example 13 Preparation of 5-deuterium-1-(4-methoxyphenyl)-1,2,3-triazole

[0080] To a dry 10 mL round-bottom flask, 4-azidoanisole (1.0 mmol, 1.0 equiv.), CuBr (0.1 mmol, 10 mol%), 3,4,7,8-tetramethyl-1,10-phenanthroline (0.2 mmol, 20 mol%), tetrahydrofuran (1.5 mL), and D2O (0.5 mL) were added sequentially. The air in the reactor was replaced with acetylene gas, and the reaction was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was extracted, washed, dried, and the solvent removed. Column chromatography was performed to obtain the corresponding product, 5-deuterated-1-(4-methoxyphenyl)-1,2,3-triazole, with a yield of 72%, a C5 deuteration rate of 92%, and a C4 deuteration rate of 5%.

[0081] 1 H NMR (400MHz, Chloroform-d) δ7.97(d,J=1.1Hz,0.08H),7.80(s,0.95H),7.66–7.56(m,2H),6.99(d,J=9.0Hz,2H),3.83(s,3H). 13 C NMR (100MHz, Chloroform-d) δ159.63,133.99,130.25,122.04,114.62,55.46.

[0082] Example 14 Preparation of 5-deuterium-1-(4-cyanophenyl)-1,2,3-triazole

[0083] To a dry 10 mL round-bottom flask, 4-azidobenzonitrile (1.0 mmol, 1.0 equiv.), [Cu(phen)(PPh3)2]NO3 (0.1 mmol, 10 mol%), dioxane (1.5 mL), and D2O (0.5 mL) were added sequentially. The air in the reactor was replaced with acetylene gas, and the reaction was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was extracted, washed, dried, and the solvent removed. Column chromatography was performed to obtain the corresponding product, 5-deuterated-1-(4-cyanophenyl)-1,2,3-triazole, in a 61% yield, with a C4 deuteration rate of 91% and a C5 deuteration rate of 4%. 1 H NMR (400MHz, Chloroform-d) δ8.10 (d, J = 1.2Hz, 0.09H), 7.96–7.91 (m, 2H), 7.89 (s, 0.96H), 7.86–7.82 (m, 2H). 13 C NMR (100MHz, Chloroform-d) δ 139.90, 135.11, 134.07, 120.82, 117.79, 112.56.

Claims

1. A method for preparing a deuterium-labeled 1,2,3-triazole compound represented by formula II, characterized in that The steps include: In heavy water / solvent, an azide compound of formula I reacts with acetylene in the presence of a catalyst to produce a compound of formula II; wherein Y is selected from H or D; and R is selected from an optionally substituted aryl or alkyl group; The catalyst is selected from a monovalent copper complex, or a combination of a monovalent copper salt and a ligand; The monovalent copper complex is selected from tris(triphenylphosphine)copper(I) complex, dichloro(1,10-phenanthroline)copper, (1,10-phenanthroline)bis(triphenylphosphine)cuprous nitrate, and bromo(1,10-phenanthroline)(triphenylphosphine)copper(I); The monovalent copper salt is selected from cuprous chloride, cuprous bromide, cuprous iodide, cuprous acetate, and cuprous nitrate; the ligand is triethylamine, pyridine, diisopropylethylamine, triphenylphosphine, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline, 2,9-dimethyl-4,7-biphenyl-1,10-phenanthroline, and 2,2'-bipyridine; The solvent used together with heavy water is selected from dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, hexamethylphosphoramide, dioxane, methyl tert-butyl ether, and 2-methylfuran.

2. The preparation method according to claim 1, characterized in that The amount of the catalyst used, calculated as copper salt, is such that the molar ratio of copper salt to the azide compound of formula I is 0.05:1 to 0.2:

1.

3. The preparation method according to claim 2, characterized in that The molar ratio of the copper salt to the azide compound of formula I is 0.05:1 to 0.1:

1.

4. The preparation method according to claim 1, characterized in that The reaction takes place in an environment containing heavy water, and the amount of heavy water used in the reaction is 10 to 120 times the molar amount of the azide compound of formula I.

5. The preparation method according to claim 1, characterized in that In Formula II, the deuterium label is at the C5 position.

6. The preparation method according to claim 5, characterized in that At the same time, the C4 position is either not deuterated or is deuterated.

7. The preparation method according to claim 1, characterized in that An azide compound of formula I, a catalyst, and heavy water / solvent are added to a reaction vessel. After the air in the reaction vessel is replaced, acetylene gas is introduced into the reaction system. The reaction mixture is stirred at 0-50 degrees Celsius for 3-24 hours. After the reaction is completed, the reaction mixture is separated by extraction and column chromatography to obtain the corresponding deuterium-labeled 1,2,3-triazole compound.

8. The preparation method according to any one of claims 1 to 7, characterized in that The reactant acetylene is selected from industrial acetylene gas, or is prepared by reacting calcium carbide with water.

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