Green synthesis method of triazole urea derivative

Abstract

The invention discloses a green synthesis method of a triazole urea derivative, which is characterized in that isocyanate generated by hydroxamic acid ester through Rosen rearrangement captures triazole amine and nitrogen anion intermediates generated by nitrile and azide under the promotion of alkali to prepare the triazole urea derivative. The preparation method comprises the following specific steps: adding alkali and hydroxamic acid ester into a reactor, then adding DMSO, nitrile and azide, and transferring the reactor to the temperature of 70 DEG C to react for 2 hours; after the reaction is finished, DCM is added for quenching, a product is poured into water, liquid separation, DCM extraction and merging are performed, and an organic phase is obtained; and drying the organic phase with Na2SO4, concentrating, and carrying out petroleum ether / acetone column chromatography to obtain the target product. According to the method, the nitrile, azide and hydroxamic acid ester multi-component one-pot cascade reaction is promoted through alkali, green and efficient synthesis of the triazole urea derivative is achieved, the reaction operation is simple and convenient, aftertreatment is easy, the substrate compatibility is wide, the target product yield is stable, and the yield is high.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthetic chemistry, and particularly to a green synthesis method of triazole urea derivatives. Background Art

[0002] Triazoles are a class of aromatic nitrogen-containing heterocyclic compounds with unique properties and are also important bioisosteres. Their unique chemical structure and biological activity make them have extremely wide application values in synthetic chemistry, medicinal chemistry, materials science, etc. Therefore, the development of efficient triazole synthesis methods has become the research focus of scientists, and the transition metal-catalyzed synthesis of triazoles has become a research hotspot in the field of triazole synthesis and has made great progress. Transition metal catalysts are widely used in various chemical reactions due to their strong coordination ability, high stability and excellent selectivity. However, since heavy metal ions will pollute the soil and water bodies after entering the environment, it will not only affect human health but also lead to damage to biodiversity. Therefore, in order to avoid the potential toxicity and pollution of transition metals, the development of triazole synthesis strategies without the participation of transition metals has attracted more and more attention.

[0003] Urea compounds have good stability, unique biological activity, high reactivity and strong coordination ability. The urea group can form multiple stable hydrogen bonds with proteins and receptor targets, which determines the unique biological activity and pharmacological functions of urea derivatives, and thus lays the core position of this structural fragment in drug development and design. And triazole urea derivatives, as a class of compounds containing both triazole ring and urea structural fragments, have great potential in pharmacodynamic functions and pharmacological activities. For example, the existing drugs cefatrizine and Rufinamide show good efficacy in antibacterial and anti-epileptic aspects respectively.

[0004] Although many triazole urea derivatives have long been used as clinical drugs in the actual treatment of many diseases, their synthesis still relies on the transition metal-catalyzed cycloaddition of alkynes and azides. There is still a blank in the green synthesis of triazole urea. Therefore, the development of a more green, novel and efficient synthesis strategy for triazole urea derivatives has become a research hotspot and an urgent problem to be solved in the field of organic synthesis. Summary of the Invention

[0005] The purpose of the present invention is to provide a green synthesis method of triazole urea derivatives, and a series of triazole urea derivatives are greenly and efficiently synthesized through an alkali-promoted one-pot tandem reaction of nitriles, azides and isohydroxamic acid esters.

[0006] The purpose of the present invention is achieved through the following technical solutions:

[0007] A green synthesis method of triazolylurea derivatives, wherein the synthesis method uses isocyanates generated by the rearrangement of hydroxamic acid esters to capture triazolamines and nitrogen anion intermediates generated by nitriles and azides under the promotion of a base to prepare triazolylurea derivatives.

[0008] Further, the synthesis method specifically includes the following steps:

[0009] S1. Add a base and a hydroxamic acid ester into a reactor, then add DMSO, a nitrile, and an azide, and transfer the reactor to 70 °C for reaction for 2 h;

[0010] S2. After the reaction is completed, add DCM to quench, pour the product into water, separate the liquid, extract with DCM, and combine to obtain an organic phase;

[0011] S3. Dry the organic phase with Na2SO4, concentrate, and obtain the target product by column chromatography with petroleum ether / acetone.

[0012] Further, the nitrile includes one of phenylacetonitrile, methylphenylacetonitrile, 4-methoxyphenylacetonitrile, p-fluorophenylacetonitrile, p-bromophenylacetonitrile, 4-cyanophenylacetonitrile, p-trifluoromethylphenylacetonitrile, o-bromophenylacetonitrile, 3-methylphenylacetonitrile, 2-naphthylacetonitrile, 3-pyridineacetonitrile, 2-thiopheneacetonitrile.

[0013] Further, the azide includes one of phenyl azide, p-tert-butylphenyl azide, 4-methoxyphenyl azide, 4-fluorophenyl azide, 4-cyanophenyl azide, m-chlorophenyl azide, benzyl azide.

[0014] Further, the base is KO t Bu.

[0015] Further, the molar ratio of the base, hydroxamic acid ester, nitrile, and azide is 30:15:10:12.

[0016] The present invention has the following advantages:

[0017] 1. Through the base-promoted multi-component one-pot tandem reaction of nitriles, azides, and hydroxamic acid esters, the green and efficient synthesis of a series of triazolylurea derivatives is realized.

[0018] 2. The reaction operation is simple and easy to post-treat, safe and environmentally friendly, has a wide substrate compatibility, the yield of the target product is stable, and the yield is relatively high. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 It is the synthesis method of the triazolylurea derivative of the present invention.

[0020] Figure 2 It is the synthesis route of the triazolylurea derivative of the present invention.

[0021] Figure 3 The types of nitrile compounds selected in the embodiments of the present invention.

[0022] Figure 4 The types of azide compounds selected in the embodiments of the present invention.

[0023] Figure 5 The types of hydroxamic acid ester compounds selected in the embodiments of the present invention. Detailed implementation manners

[0024] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. The components of the embodiments of the present invention usually described and illustrated in the accompanying drawings here can be arranged and designed in various different configurations.

[0025] Therefore, the following detailed description of the embodiments of the present invention provided in the accompanying drawings is not intended to limit the scope of the claimed present invention, but merely represents selected embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the scope of protection of the present invention.

[0026] It should be noted that, without conflict, the embodiments in the present invention and the features in the embodiments can be combined with each other.

[0027] It should be noted that similar reference numerals and letters denote similar items in the following drawings. Therefore, once an item is defined in one drawing, it does not need to be further defined and explained in subsequent drawings.

[0028] As Figure 1 shown, in the synthesis method of triazuron derivatives in the present application, isocyanates generated by the rearrangement of hydroxamic acid esters capture triazoleamines and nitrogen anion intermediates generated by nitriles and azides under the promotion of a base, thereby preparing triazuron derivatives.

[0029] Since the reaction mainly utilizes the electrophilic addition of isocyanates with amine compounds to form ureas, however, isocyanates pose various hazards to humans and the environment during production and use. Isocyanate vapors can cause various respiratory diseases. For the environment, isocyanates may cause secondary pollution to the environment. Moreover, isocyanates are prone to deterioration during storage, resulting in a low yield of the target product. Therefore, in this method, hydroxamic acid ester compounds are introduced into the reaction system as improved raw materials for isocyanates to participate in the reaction. The hydroxamic acid ester compounds can generate isocyanates in situ through the Lossen rearrangement under the conditions of heat or base. The isocyanates generated by this pathway can directly act as electrophilic reagents to undergo electrophilic addition with amine compounds to form ureas. Moreover, most hydroxamic acid ester compounds are solids, which are easy to synthesize and store, ensuring the safety, environmental friendliness, and convenience of the reaction, and the yield of the target product is higher and more stable. In terms of reaction control, by carrying out a one-pot tandem reaction of the raw materials in a reactor, the reaction operation is simple, without the need for operations such as separating and re-reacting intermediates, and the target product with a high yield can be obtained after simple post-treatment.

[0030] To determine the promoting effect of the base on the reaction and the reaction mechanism, this method also carried out a series of control experiments. Under the condition of not adding a base, triazoleamine and hydroxamic acid ester cannot produce the target compound. From this, it can be seen that the base directly affects the formation of isocyanates from hydroxamic acid esters through the Lossen rearrangement, and thus affects the subsequent addition with the intermediate. In addition, under standard conditions (alkali environment, DMSO, 70 °C), triazoleamine and hydroxamic acid ester react directly, and only 58% of the target product is formed, and a large amount of triazoleamine remains in the system. From this, it can be seen that part of the target product in the reaction system is generated through a three-component reaction. Therefore, the reaction mechanism of this method is as Figure 2 shown. In the reaction system, nitrile 1 and organic azide 2 undergo cycloaddition under the action of a base to form a nitrogen anion intermediate M 1 , M 1 undergoes aromatization to obtain a triazole nitrogen anion intermediate M 2 , M 2 and triazoleamine 5 can both be captured by the high-purity isocyanates generated by the Lossen rearrangement of hydroxamic acid esters to form triazole urea 4, thereby realizing the high-yield synthesis of the target product.

[0031] This application uses phenylacetonitrile 1a, phenyl azide 2a, and hydroxamic acid ester 3a as template substrates to determine the optimal reaction conditions. The screened reaction conditions are shown in the following table:

[0032]

[0033]

[0034] Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), 3a (0.3 mmol), KO tBu (0.6 mmol), DMSO (1 mL), 70 °C, react for 2 h.

[0035] Isolation yield: c KO t Bu (0.3 mmol). d KO t Bu (0.4 mmol). e KO t Bu (0.5 mmol). f KO t Bu (0.7 mmol).

[0036] From the yield analysis of the target product 4a and the by-product 5a in the above table, the optimal reaction conditions are determined as follows: the molar ratio of base, hydroxamic acid ester, nitrile, and azide is 30:15:10:12, the solvent is determined as DMSO, and the base is determined as KO t Bu, the reaction temperature is 70 °C. Under these reaction conditions, the yield of the target product 4 is stable and higher, and the yield corresponding to the by-product 5 is the lowest.

[0037] Refer to the types of materials used as shown in Figures 3 - 5 The specific examples are as follows:

[0038] Example 1

[0039] Take KO t Bu (0.6 mmol, 67.2 mg), hydroxamic acid ester 3a (0.3 mmol, 76.5 mg) into the reactor, then add DMSO (1 mL), phenylacetonitrile 1a (0.2 mmol, 23.4 mg), phenyl azide 2a (0.24 mmol, 28.6 mg), and transfer the reaction system to 70 °C for reaction for 2 h. After the reaction is completed, add 5 mL of DCM to quench, then pour it into 150 mL of water, separate the layers, extract with DCM (30 ml x 3), combine the organic phases, dry over Na2SO4, concentrate, and perform column chromatography with petroleum ether / acetone (3:1). The product is a white solid 4a (66.4 mg, 90%).

[0040] The structural characterization of the obtained compound 4a is as follows: 1 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.46 (s, 1H), 7.93 - 7.92 (m, 2H), 7.70 - 7.69 (m, 2H), 7.64 - 7.50 (m, 5H), 7.41 - 7.39 (m, 1H), 7.25 - 7.23 (m, 2H), 7.05 - 7.03 (m, 2H), 2.21 (s, 3H); 1313C NMR (125 MHz, DMSO-d6) δ 153.48, 141.33, 137.08, 135.96, 131.79, 130.78, 130.41, 129.98, 129.94, 129.57, 129.29, 128.60, 126.30, 124.76, 119.30, 20.79; HRMS exact mass calcd for (C 22 H 19 N5O + H + ) requires m / z 370.1662, found m / z 370.1680.

[0041] Example 2

[0042] Take KO t Bu (0.6 mmol, 67.2 mg), isohydroxamate 3a (0.3 mmol, 76.5 mg) in a reactor, then add DMSO (1 mL), p-methylphenylacetonitrile 1b (0.2 mmol, 26.2 mg), phenyl azide 2a (0.24 mmol, 28.6 mg), and transfer the reaction system to react at 70 °C for 2 h. After the reaction is completed, add 5 mL of DCM to quench, then pour it into 150 mL of water, separate the layers, extract with DCM (30 ml x 3), combine the organic phases, dry over Na2SO4, concentrate, and perform column chromatography with petroleum ether / acetone (3:1). The product is a white solid 4b (65.1 mg, 85%).

[0043] The structural characterization of the obtained compound 4b is as follows: 1 1H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.41 (s, 1H), 7.82 - 7.80 (m, 2H), 7.69 - 7.53 (m, 5H), 7.32 - 7.30 (m, 2H), 7.24 - 7.23 (m, 2H), 7.05 - 7.03 (m, 2H), 2.34 (s, 3H), 2.21 (s, 3H); 13 13C NMR (125 MHz, DMSO-d6) δ 153.47, 141.43, 137.98, 137.10, 135.99, 131.76, 130.03, 129.96, 129.88, 129.84, 129.56, 127.95, 126.22, 124.73, 119.28, 21.34, 20.79; HRMS exact mass calcd for (C 23 H 21 N5O + H +)requires m / z 384.1819,found m / z 384.1833.

[0044] Example 3

[0045] Take KO t Bu(0.6 mmol, 67.2 mg), isohydroxamic acid ester 3a(0.3 mmol, 76.5 mg) in a reactor, then add DMSO(1 mL), 4-methoxyphenylacetonitrile 1c(0.2 mmol, 30.0 mg), phenyl azide 2a(0.24 mmol, 28.6 mg), and then transfer the reaction system to react at 70 °C for 2 h. After the reaction is completed, add 5 mL of DCM to quench, then pour it into 150 mL of water, separate the layers, extract with DCM(30 ml x 3), combine the organic phases, dry over Na2SO4, concentrate, and perform column chromatography with petroleum ether / acetone(3:1). The product is a white solid 4c(72.6 mg, 91%).

[0046] The structural characterization of the obtained compound 4c is as follows: 1 H NMR(500 MHz, DMSO-d6)δ9.11(s, 1H), 8.40(s, 1H), 7.86 - 7.85(m, 2H), 7.70 - 7.53(m, 5H), 7.26 - 7.25(m, 2H), 7.09 - 7.04(m, 4H), 3.79(s, 3H), 2.21(s, 3H); 13 C NMR(125 MHz, DMSO-d6)δ159.67, 153.57, 141.43, 137.13, 136.03, 131.76, 129.95, 129.85, 129.56, 129.51, 127.68, 124.70, 123.22, 119.27, 114.76, 55.64, 20.79; HRMS exact mass calcd for(C 23 H 21 N5O2 + H + )requires m / z 400.1768, found m / z 400.1778.

[0047] Example 4

[0048] Take KO tBu (0.6 mmol, 67.2 mg), isohydroxamate 3a (0.3 mmol, 76.5 mg) were placed in a reactor, then DMSO (1 mL) was added, followed by 4-fluorobenzyl cyanide 1d (0.2 mmol, 27.2 mg) and phenyl azide 2a (0.24 mmol, 28.6 mg). The reaction system was then transferred to 70 °C for 2 h. After the reaction was completed, 5 mL of DCM was added to quench the reaction, and then the mixture was poured into 150 mL of water. The layers were separated, and the aqueous layer was extracted with DCM (30 mL × 3). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography on silica gel with petroleum ether / acetone (3:1) as the eluent to give the product as a white solid 4d (65.0 mg, 84%).

[0049] The structural characterization of the obtained compound 4d was as follows: 1 H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.44 (s, 1H), 7.95 - 7.92 (m, 2H), 7.68 - 7.55 (m, 5H), 7.37 - 7.34 (m, 2H), 7.23 - 7.21 (m, 2H), 7.04 - 7.02 (m, 2H), 2.20 (s, 3H); 13 C NMR (125 MHz, DMSO-d6) δ 163.40, 161.45, 153.42, 140.63, 137.04, 135.89, 131.82, 130.30, 130.00, 129.56, 128.41, 128.34, 127.31, 124.76, 119.31, 116.39, 116.22, 20.78; HRMS exact mass calcd for (C 22 H 18 FN5O + H + ) requires m / z 388.1568, found m / z 388.1582.

[0050] Example 5

[0051] Take KO t Bu (0.6 mmol, 67.2 mg), isohydroxamate 3a (0.3 mmol, 76.5 mg) were placed in a reactor, then DMSO (1 mL) was added, followed by 4-bromobenzyl cyanide 1e (0.2 mmol, 39.2 mg) and phenyl azide 2a (0.24 mmol, 28.6 mg). The reaction system was then transferred to 70 °C for 2 h. After the reaction was completed, 5 mL of DCM was added to quench the reaction, and then the mixture was poured into 150 mL of water. The layers were separated, and the aqueous layer was extracted with DCM (30 mL × 3). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography on silica gel with petroleum ether / acetone (3:1) as the eluent to give the product as a white solid 4e (73.3 mg, 82%).

[0052] The structural characterization of the obtained compound 4e is as follows: 1 H NMR(500MHz,DMSO-d6)δ9.14(s,1H),8.47(s,1H),7.86-7.84(m,2H),7.72-7.71(m,2H),7.67-7.60(m,4H),7.57-7.56(m,1H),7.22-7.20(m,2H),7.04-7.02(m,2H),2.21(s,3H); 13 C NMR(125MHz,DMSO-d6)δ153.25,140.30,136.98,135.80,132.32,131.84,130.70,130.04,130.01,129.56,128.18,124.77,121.86,119.32,20.79;HRMS exact mass calcd for(C 22 H 18 BrN5O+H + )requires m / z 448.0767,found m / z448.0783.

[0053] Example 6

[0054] Take KO t Bu(0.6mmol,67.2mg),isohydroxamic acid ester 3a(0.3mmol,76.5mg) into a reactor, then add DMSO(1mL), 4-cyanobenzyl cyanide 1f(0.2mmol,28.4mg), phenyl azide 2a(0.24mmol,28.6mg), and then transfer the reaction system to react at 70 °C for 2h. After the reaction is completed, add 5mL DCM to quench, then pour it into 150mL of water, separate the layers, extract with DCM(30ml x 3), combine the organic phases, dry over Na2SO4, concentrate, and perform column chromatography with petroleum ether / acetone(3:1). The product is a white solid 4f(70.1mg,89%).

[0055] The structural characterization of the obtained compound 4f is as follows: 1 H NMR(500MHz,DMSO-d6)δ9.19(s,1H),8.57(s,1H),8.11-8.09(m,2H),8.01-8.00(m,2H),7.70-7.59(m,5H),7.23-7.21(m,2H),7.06-7.04(m,2H),2.22(s,3H); 1313C NMR (125 MHz, DMSO-d6) δ 153.07, 139.55, 136.90, 135.63, 135.31, 133.38, 131.93, 131.83, 130.20, 130.06, 129.57, 126.64, 124.85, 119.33, 119.24, 110.93, 20.79; HRMS exact mass calcd for (C 23 H 18 N6O + H + ) requires m / z 395.1615, found m / z 395.1624.

[0056] Example 7

[0057] Take KO t Bu (0.6 mmol, 67.2 mg), isohydroxamic acid ester 3a (0.3 mmol, 76.5 mg) in a reactor, then add DMSO (1 mL), p-trifluoromethylphenylacetonitrile 1 g (0.2 mmol, 37.1 mg), phenyl azide 2a (0.24 mmol, 28.6 mg), and then transfer the reaction system to react at 70 °C for 2 h. After the reaction is completed, add 5 mL of DCM to quench, then pour it into 150 mL of water, separate the layers, extract with DCM (30 ml x 3), combine the organic phases, dry over Na2SO4, concentrate, and perform column chromatography with petroleum ether / acetone (3:1). The product is a white solid 4 g (68.2 mg, 78%).

[0058] The structural characterization of the obtained compound 4g is as follows: 1 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.57 (s, 1H), 8.14 - 8.12 (m, 2H), 7.90 - 7.88 (m, 2H), 7.70 - 7.56 (m, 5H), 7.23 - 7.22 (m, 2H), 7.04 - 7.03 (m, 2H), 2.21 (s, 3H); 13 13C NMR (125 MHz, DMSO-d6) δ 153.20, 139.90, 136.96, 135.72, 134.81, 131.88, 131.52, 130.13, 130.04, 129.56, 128.87, 128.62, 126.72, 126.31, 126.28, 125.78, 124.84, 123.62, 119.34, 20.77; HRMS exact mass calcd for (C 23 H 18 F3N5O + H +)requires m / z 438.1536,found m / z 438.1551.

[0059] Example 8

[0060] Take KO t Bu(0.6 mmol, 67.2 mg), isohydroxamic acid ester 3a(0.3 mmol, 76.5 mg) in a reactor, then add DMSO(1 mL), o-bromobenzyl cyanide 1h(0.2 mmol, 39.2 mg), phenyl azide 2a(0.24 mmol, 28.6 mg), and then transfer the reaction system to react at 70 °C for 2 h. After the reaction is completed, add 5 mL of DCM to quench, then pour it into 150 mL of water, separate the layers, extract with DCM(30 ml x 3), combine the organic phases, dry over Na2SO4, concentrate, and perform column chromatography with petroleum ether / acetone(3:1). The product is a white solid 4h(73.3 mg, 82%).

[0061] The structural characterization of the obtained compound 4h is as follows: 1 H NMR(500 MHz, DMSO-d6)δ8.87(s, 1H), 8.43(s, 1H), 7.79 - 7.77(m, 1H), 7.73 - 7.71(m, 2H), 7.65 - 7.61(m, 2H), 7.57 - 7.49(m, 3H), 7.41 - 7.37(m, 1H), 7.16 - 7.14(m, 2H), 7.02 - 7.00(m, 2H), 2.20(s, 3H); 13 C NMR(125 MHz, DMSO-d6)δ152.88, 141.29, 136.89, 136.16, 133.52, 132.41, 131.72, 131.68, 131.05, 130.03, 129.85, 129.55, 128.21, 124.46, 123.35, 119.10, 20.77; HRMS exact mass calcd for(C 22 H 18 BrN5O + H + )requires m / z 448.0767,found m / z 448.0774.

[0062] Example 9

[0063] Take KO tBu(0.6 mmol, 67.2 mg), isohydroxamate 3a (0.3 mmol, 76.5 mg) were placed in a reactor. Subsequently, DMSO (1 mL), 3-methylphenylacetonitrile 1i (0.2 mmol, 24.7 mg), and phenyl azide 2a (0.24 mmol, 28.6 mg) were added. Then, the reaction system was transferred to 70 °C for reaction for 2 h. After the reaction was completed, 5 mL of DCM was added to quench the reaction, and then it was poured into 150 mL of water. The layers were separated, and the aqueous layer was extracted with DCM (30 mL × 3). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography using petroleum ether / acetone (3:1) to obtain the product as a white solid 4i (61.3 mg, 80%).

[0064] The structural characterization of the obtained compound 4i was as follows: 1 H NMR (500 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.45 (s, 1H), 7.76 (s, 1H), 7.70 - 7.68 (m, 3H), 7.64 - 7.54 (m, 3H), 7.40 - 7.37 (m, 1H), 7.24 - 7.20 (m, 3H), 7.05 - 7.04 (m, 2H), 2.37 (s, 3H), 2.21 (s, 3H); 13 C NMR (125 MHz, DMSO-d6) δ 153.54, 141.38, 138.33, 137.07, 135.97, 131.82, 130.68, 130.36, 129.96, 129.90, 129.56, 129.22, 129.16, 126.96, 124.72, 123.43, 119.38, 21.67, 20.79; HRMS exact mass calcd for (C 23 H 21 N5O + H + ) requires m / z 384.1819, found m / z 384.1834.

[0065] Example 10

[0066] Take KO tBu(0.6 mmol, 67.2 mg), isohydroxamic acid ester 3a (0.3 mmol, 76.5 mg) were placed in a reactor. Subsequently, DMSO (1 mL), 2-naphthonitrile 1j (0.2 mmol, 33.5 mg), and phenyl azide 2a (0.24 mmol, 28.6 mg) were added. Then the reaction system was transferred to react at 70 °C for 2 h. After the reaction was completed, 5 mL of DCM was added to quench the reaction, and then it was poured into 150 mL of water. After liquid separation, it was extracted with DCM (30 mL × 3). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography with petroleum ether / acetone (3:1). The product was a white solid 4j (70.4 mg, 84%).

[0067] The structural characterization of the obtained compound 4j was as follows: 1 H NMR (500 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.58 (s, 1H), 8.47 (s, 1H), 8.12 - 8.04 (m, 2H), 7.96 - 7.95 (m, 2H), 7.75 - 7.73 (m, 2H), 7.66 - 7.54 (m, 5H), 7.27 - 7.26 (m, 2H), 7.05 - 7.04 (m, 2H), 2.21 (s, 3H); 13 C NMR (125 MHz, DMSO-d6) δ 153.55, 141.20, 137.07, 135.97, 133.46, 132.99, 131.88, 130.81, 130.02, 129.99, 129.59, 128.86, 128.56, 128.32, 128.17, 127.15, 126.91, 125.04, 124.80, 124.27, 119.44, 20.80; HRMS exact mass calcd for (C 26 H 21 N5O + H + ) requires m / z 420.1819, found m / z 420.1832.

[0068] Example 11

[0069] Take KO tBu(0.6 mmol, 67.2 mg), isohydroxamic acid ester 3a (0.3 mmol, 76.5 mg) were placed in a reactor, then DMSO (1 mL), 3-pyridineacetonitrile 1k (0.2 mmol, 23.6 mg), and phenyl azide 2a (0.24 mmol, 28.6 mg) were added. Then the reaction system was transferred to 70 °C and reacted for 2 h. After the reaction was completed, 5 mL of DCM was added to quench the reaction, and then it was poured into 150 mL of water. The layers were separated, and the aqueous layer was extracted with DCM (30 mL × 3). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography on petroleum ether / acetone (3:1). The product was a white solid 4k (66.6 mg, 90%).

[0070] The structural characterization of the obtained compound 4k was as follows: 1 H NMR (500 MHz, DMSO-d6) δ 9.18 (s, 1H), 9.09 (s, 1H), 8.61 - 8.55 (m, 2H), 8.26 - 8.24 (m, 1H), 7.69 - 7.54 (m, 6H), 7.23 - 7.22 (m, 2H), 7.05 - 7.03 (m, 2H), 2.21 (s, 3H); 13 C NMR (125 MHz, DMSO-d6) δ 153.27, 149.55, 147.11, 138.93, 136.94, 135.74, 133.56, 131.90, 131.24, 130.11, 130.05, 129.58, 126.84, 124.79, 124.46, 119.31, 20.78; HRMS exact mass calcd for (C 21 H 18 N6O + H + ) requires m / z 371.1615, found m / z 371.1617.

[0071] Example 12

[0072] Take KO t Bu(0.6 mmol, 67.2 mg), isohydroxamic acid ester 3a (0.3 mmol, 76.5 mg) were placed in a reactor, then DMSO (1 mL), 2-thiopheneacetonitrile 1l (0.2 mmol, 24.7 mg), and phenyl azide 2a (0.24 mmol, 28.6 mg) were added. Then the reaction system was transferred to 70 °C and reacted for 2 h. After the reaction was completed, 5 mL of DCM was added to quench the reaction, and then it was poured into 150 mL of water. The layers were separated, and the aqueous layer was extracted with DCM (30 mL × 3). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography on petroleum ether / acetone (3:1). The product was a white solid 4l (68.3 mg, 91%).

[0073] The structural characterization of the obtained compound 4l was as follows: 1H NMR (500 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.44 (s, 1H), 7.69 - 7.68 (m, 2H), 7.64 - 7.56 (m, 4H), 7.50 - 7.49 (m, 1H), 7.28 - 7.26 (m, 2H), 7.20 - 7.18 (m, 1H), 7.06 - 7.05 (m, 2H), 2.22 (s, 3H); 13 13C NMR (125 MHz, DMSO-d6) δ 153.28, 138.21, 137.06, 135.77, 132.18, 131.84, 130.03, 129.58, 129.31, 128.33, 126.63, 124.71, 124.61, 119.33, 20.81; HRMS exact mass calcd for (C 20 H 17 N5OS + H + ) requires m / z 376.1227, found m / z 376.1241.

[0074] Example 13

[0075] Take KO t Bu (0.6 mmol, 67.2 mg), isohydroxamic acid ester 3a (0.3 mmol, 76.5 mg) in a reactor, then add DMSO (1 mL), phenylacetonitrile 1a (0.2 mmol, 23.4 mg), p-tert-butylphenyl azide 2b (0.24 mmol, 42.0 mg), and then transfer the reaction system to react at 70 °C for 2 h. After the reaction is completed, add 5 mL of DCM to quench, then pour it into 150 mL of water, separate the layers, extract with DCM (30 ml x 3), combine the organic phases, dry over Na2SO4, concentrate, and perform column chromatography with petroleum ether / acetone (3:1). The product is a white solid 4m (79.9 mg, 94%).

[0076] The structural characterization of the obtained compound 4m was as follows: 1 1H NMR (500 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.44 (s, 1H), 7.93 - 7.91 (m, 2H), 7.65 - 7.60 (m, 4H), 7.52 - 7.49 (m, 2H), 7.41 - 7.38 (m, 1H), 7.27 - 7.25 (m, 2H), 7.06 - 7.04 (m, 2H), 2.22 (s, 3H), 1.33 (s, 9H); 1313C NMR(125MHz,DMSO-d6)δ153.60,152.61,141.30,137.12,133.48,131.79,130.85,130.33,129.55,129.26,128.54,126.77,126.25,124.36,119.35,35.08,31.48,20.79;HRMS exact mass calcd for(C 26 H 27 N5O+H + requires m / z 426.2288,found m / z 426.2305.

[0077] Example 14

[0078] Take KO t Bu(0.6 mmol,67.2 mg),isohydroxamate 3a(0.3 mmol,76.5 mg)in a reactor.Subsequently,add DMSO(1 mL),phenylacetonitrile 1a(0.2 mmol,23.4 mg),4-methoxyphenyl azide 2c(0.24 mmol,35.8 mg),and then transfer the reaction system to react at 70 °C for 2 h.After the reaction is completed,add 5 mL of DCM to quench it,then pour it into 150 mL of water,separate the layers,extract with DCM(30 ml x 3),combine the organic phases,dry over Na2SO4,concentrate,and perform column chromatography with petroleum ether / acetone(3:1).The product is white solid 4n(57.5 mg,72%).

[0079] The structural characterization of the obtained compound 4n is as follows: 1 1H NMR(500 MHz,DMSO-d6)δ9.11(s,1H),8.39(s,1H),7.90 - 7.89(m,2H),7.59 - 7.56(m,2H),7.51 - 7.48(m,2H),7.39 - 7.36(m,1H),7.25 - 7.23(m,2H),7.16 - 7.14(m,2H),7.05 - 7.03(m,2H),3.82(s,3H),2.21(s,3H); 13 13C NMR(125 MHz,DMSO-d6)δ160.33,153.51,141.11,137.12,131.73,130.88,130.40,129.56,129.26,128.78,128.52,126.38,126.22,119.23,115.04,56.03,20.79;HRMS exact mass calcd for(C 23 H21 N5O2 + H + ) requires m / z 400.1768, found m / z 400.1780.

[0080] Example 15

[0081] Take KO t Bu (0.6 mmol, 67.2 mg), isohydroxamic acid ester 3a (0.3 mmol, 76.5 mg) in a reactor, then add DMSO (1 mL), phenylacetonitrile 1a (0.2 mmol, 23.4 mg), 4-fluorophenyl azide 2d (0.24 mmol, 32.9 mg), and then transfer the reaction system to react at 70 °C for 2 h. After the reaction is completed, add 5 mL of DCM to quench, then pour it into 150 mL of water, separate the layers, extract with DCM (30 ml x 3), combine the organic phases, dry over Na2SO4, concentrate, and perform column chromatography with petroleum ether / acetone (3:1). The product is a white solid 4o (65.0 mg, 84%).

[0082] The structural characterization of the obtained compound 4o is as follows: 1 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.44 (s, 1H), 7.92 - 7.90 (m, 2H), 7.75 - 7.72 (m, 2H), 7.52 - 7.47 (m, 4H), 7.41 - 7.38 (m, 1H), 7.24 - 7.22 (m, 2H), 7.05 - 7.03 (m, 2H), 2.22 (s, 3H); 13 13C NMR (125 MHz, DMSO-d6) δ 163.68, 161.72, 153.41, 141.17, 137.02, 132.33, 131.83, 130.67, 130.59, 129.57, 129.30, 128.64, 127.22, 127.15, 126.27, 119.29, 117.05, 116.87, 20.78; HRMS exact mass calcd for (C 22 H 18 FN5O + H + ) requires m / z 388.1568, found m / z 388.1583.

[0083] Example 16

[0084] Take KO tBu(0.6 mmol, 67.2 mg), isohydroxamate 3a (0.3 mmol, 76.5 mg) were placed in a reactor, then DMSO (1 mL), phenylacetonitrile 1a (0.2 mmol, 23.4 mg), 4-cyanophenyl azide 2e (0.24 mmol, 34.6 mg) were added. Then the reaction system was transferred to react at 70 °C for 2 h. After the reaction was completed, 5 mL of DCM was added to quench the reaction, and then it was poured into 150 mL of water. After liquid separation, it was extracted with DCM (30 mL × 3). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography with petroleum ether / acetone (3:1). The product was a white solid 4p (35.5 mg, 45%).

[0085] The structural characterization of the obtained compound 4p was as follows: 1 H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.56 (s, 1H), 8.15 - 8.13 (m, 2H), 7.95 - 7.91 (m, 4H), 7.54 - 7.50 (m, 2H), 7.43 - 7.41 (m, 1H), 7.22 - 7.20 (m, 2H), 7.05 - 7.03 (m, 2H), 2.21 (s, 3H); 13 C NMR (125 MHz, DMSO-d6) δ 153.20, 141.48, 139.45, 136.90, 134.38, 131.95, 130.64, 130.34, 129.59, 129.37, 128.83, 126.38, 125.02, 119.32, 118.50, 112.49, 20.79; HRMS exact mass calcd for (C 23 H 18 N6O + H + ) requires m / z 395.1615, found m / z 395.1629.

[0086] Example 17

[0087] Take KO tBu (0.6 mmol, 67.2 mg), isohydroxamate 3a (0.3 mmol, 76.5 mg) were placed in a reactor, followed by the addition of DMSO (1 mL), phenylacetonitrile 1a (0.2 mmol, 23.4 mg), m-chlorophenyl azide 2f (0.24 mmol, 37.0 mg). Then the reaction system was transferred to 70 °C for reaction for 2 h. After the reaction was completed, 5 mL of DCM was added to quench the reaction, and then it was poured into 150 mL of water. After liquid separation, it was extracted with DCM (30 mL × 3). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography with petroleum ether / acetone (3:1). The product was a white solid 4q (56.4 mg, 70%).

[0088] The structural characterization of the obtained compound 4q was as follows: 1 H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.50 (s, 1H), 7.92 - 7.91 (m, 2H), 7.82 (s, 1H), 7.70 - 7.64 (m, 3H), 7.53 - 7.50 (m, 2H), 7.42 - 7.39 (m, 1H), 7.23 - 7.22 (m, 2H), 7.05 - 7.04 (m, 2H), 2.21 (s, 3H); 13 C NMR (125 MHz, DMSO-d6) δ 153.39, 141.35, 137.05, 136.94, 134.11, 131.93, 131.76, 130.55, 130.51, 129.91, 129.59, 129.34, 128.74, 126.32, 124.47, 123.43, 119.40, 20.79; HRMS exact mass calcd for (C 22 H 18 ClN5O + H + ) requires m / z 404.1273, found m / z 404.1284.

[0089] Example 18

[0090] Take KO tBu(0.6 mmol, 67.2 mg), isohydroxamic acid ester 3a (0.3 mmol, 76.5 mg) were placed in a reactor. Subsequently, DMSO (1 mL), phenylacetonitrile 1a (0.2 mmol, 23.4 mg), and benzyl azide 2g (0.24 mmol, 32.0 mg) were added. Then, the reaction system was transferred to 70 °C for reaction for 2 h. After the reaction was completed, 5 mL of DCM was added to quench the reaction, and then it was poured into 150 mL of water. After liquid separation, extraction was carried out with DCM (30 mL × 3). After the organic phases were combined, they were dried over Na2SO4, concentrated, and purified by column chromatography with petroleum ether / acetone (3:1). The product was a white solid 4r (57.5 mg, 75%).

[0091] The structural characterization of the obtained compound 4r was as follows: 1 1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.49 (s, 1H), 7.86 - 7.84 (m, 2H), 7.47 - 7.44 (m, 2H), 7.38 - 7.32 (m, 8H), 7.10 - 7.08 (m, 2H), 5.49 (s, 2H), 2.24 (s, 3H); 13 13C NMR (125 MHz, DMSO-d6) δ 153.28, 140.18, 137.14, 135.97, 131.79, 131.06, 130.26, 129.62, 129.19, 129.09, 128.39, 128.31, 126.07, 119.32, 50.80, 20.83; HRMS exact mass calcd for (C 23 H 21 N5O + H + ) requires m / z 384.1819, found m / z 384.1836.

[0092] Example 19

[0093] Take KO t Bu(0.6 mmol, 67.2 mg), isohydroxamic acid ester 3b (0.3 mmol, 72.6 mg) were placed in a reactor. Subsequently, DMSO (1 mL), phenylacetonitrile 1a (0.2 mmol, 23.4 mg), and phenyl azide 2a (0.24 mmol, 28.6 mg) were added. Then, the reaction system was transferred to 70 °C for reaction for 2 h. After the reaction was completed, 5 mL of DCM was added to quench the reaction, and then it was poured into 150 mL of water. After liquid separation, extraction was carried out with DCM (30 mL × 3). After the organic phases were combined, they were dried over Na2SO4, concentrated, and purified by column chromatography with petroleum ether / acetone (3:1). The product was a white solid 4s (61.1 mg, 86%).

[0094] The structural characterization of the obtained compound 4s is as follows: 1 H NMR(500MHz,DMSO-d6)δ9.25(s,1H),8.52(s,1H),7.93-7.91(m,2H),7.70-7.69(m,2H),7.64-7.49(m,5H),7.41-7.35(m,3H),7.25-7.22(m,2H),6.98-6.95(m,1H); 13 C NMR(125MHz,DMSO-d6)δ153.47,141.39,139.68,135.96,130.77,130.34,130.00,129.96,129.31,129.21,128.63,126.32,124.76,122.89,119.14;HRMS exact mass calcd for(C 21 H 17 N5O+H + )requires m / z 356.1506,found m / z356.1460.

[0095] Example 20

[0096] Take KO t Bu(0.6mmol,67.2mg),isohydroxamic acid ester 3c(0.3mmol,81.3mg) in a reactor,subsequently add DMSO(1mL),phenylacetonitrile 1a(0.2mmol,23.4mg),phenyl azide 2a(0.24mmol,28.6mg),and then transfer the reaction system to react at 70°C for 2h.After the reaction is completed,add 5mL DCM to quench,and then pour it into 150mL of water,separate the layers,extract with DCM(30mlx 3),combine the organic phases,dry over Na2SO4,concentrate,and perform column chromatography with petroleum ether / acetone(3:1).The product is a white solid 4t(65.5mg,87%).

[0097] The structural characterization of the obtained compound 4t is as follows: 1 H NMR(500MHz,DMSO-d6)δ9.03(s,1H),8.43(s,1H),7.93-7.92(m,2H),7.70-7.69(m,2H),7.64-7.49(m,5H),7.41-7.38(m,1H),7.25-7.24(m,2H),6.83-6.82(m,2H),3.68(s,3H); 1313C NMR(125 MHz, DMSO-d6) δ 155.37, 153.63, 141.31, 135.96, 132.61, 130.79, 130.49, 129.97, 129.93, 129.28, 128.59, 126.29, 124.75, 121.15, 114.38, 55.64; HRMS exact mass calcd for (C 22 H 19 N5O2 + H + ) requires m / z 386.1612, found m / z 386.1625.

[0098] Example 21

[0099] Take KO t Bu (0.6 mmol, 67.2 mg), isohydroxamic acid ester 3d (0.3 mmol, 83.0 mg) in a reactor, then add DMSO (1 mL), phenylacetonitrile 1a (0.2 mmol, 23.4 mg), phenyl azide 2a (0.24 mmol, 28.6 mg), and transfer the reaction system to react at 70 °C for 2 h. After the reaction is completed, add 5 mL of DCM to quench, then pour it into 150 mL of water, separate the layers, extract with DCM (30 ml x 3), combine the organic phases, dry over Na2SO4, concentrate, and perform column chromatography with petroleum ether / acetone (3:1). The product is a white solid 4u (59.9 mg, 77%).

[0100] The structural characterization of the obtained compound 4u is as follows: 1 1H NMR (500 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.60 (s, 1H), 7.93 - 7.91 (m, 2H), 7.70 - 7.68 (m, 2H), 7.64 - 7.61 (m, 2H), 7.57 - 7.49 (m, 3H), 7.41 - 7.38 (m, 3H), 7.29 - 7.28 (m, 2H); 13 13C NMR (125 MHz, DMSO-d6) δ 153.37, 141.38, 138.68, 135.88, 130.68, 130.16, 130.02, 129.32, 129.05, 128.66, 126.47, 126.30, 124.74, 120.66; HRMS exact mass calcd for (C 21 H 16 ClN5O + H + ) requires m / z 390.1116, found m / z 390.1131.

[0101] Example 22

[0102] Take KO t Bu (0.6 mmol, 67.2 mg), isohydroxamic acid ester 3e (0.3 mmol, 76.5 mg) in a reactor, then add DMSO (1 mL), phenylacetonitrile 1a (0.2 mmol, 23.4 mg), phenyl azide 2a (0.24 mmol, 28.6 mg), and then transfer the reaction system to react at 70 °C for 2 h. After the reaction is completed, add 5 mL of DCM to quench, then pour it into 150 mL of water, separate the layers, extract with DCM (30 ml x 3), combine the organic phases, dry over Na2SO4, concentrate, and perform column chromatography with petroleum ether / acetone (3:1). The product is a white solid 4v (59.0 mg, 80%).

[0103] The structural characterization of the obtained compound 4v is as follows: 1 1H NMR (500 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.48 (s, 1H), 7.94 - 7.92 (m, 2H), 7.71 - 7.69 (m, 2H), 7.64 - 7.50 (m, 5H), 7.41 - 7.38 (m, 1H), 7.21 - 7.10 (m, 3H), 6.79 - 6.78 (m, 1H), 2.23 (s, 3H); 13 13C NMR (125 MHz, DMSO-d6) δ 153.43, 141.37, 139.59, 138.41, 135.94, 130.76, 130.34, 130.00, 129.95, 129.31, 129.04, 128.62, 126.29, 124.76, 123.59, 119.63, 116.32, 21.62; HRMS exact mass calcd for (C 22 H 19 N5O + H + ) requires m / z 370.1662, found m / z 370.1676.

[0104] Example 23

[0105] Take KO tBu (0.6 mmol, 67.2 mg), isohydroxamate 3f (0.3 mmol, 87.3 mg) were placed in a reactor. Subsequently, DMSO (1 mL), phenylacetonitrile 1a (0.2 mmol, 23.4 mg), and phenyl azide 2a (0.24 mmol, 28.6 mg) were added. Then the reaction system was transferred to 70 °C for reaction for 2 h. After the reaction was completed, 5 mL of DCM was added to quench the reaction, and then it was poured into 150 mL of water. The layers were separated, and the aqueous layer was extracted with DCM (30 mL × 3). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography using petroleum ether / acetone (3:1) to give the product as a white solid 4w (67.2 mg, 83%).

[0106] The structural characterization of the obtained compound 4w was as follows: 1 1H NMR (500 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.62 (s, 1H), 7.98 - 7.95 (m, 3H), 7.82 - 7.79 (m, 2H), 7.74 - 7.73 (m, 3H), 7.65 - 7.62 (m, 2H), 7.57 - 7.50 (m, 3H), 7.46 - 7.33 (m, 4H); 13 13C NMR (125 MHz, DMSO-d6) δ 153.58, 141.41, 137.33, 135.94, 133.95, 130.75, 130.30, 130.03, 129.99, 129.79, 129.33, 128.85, 128.65, 127.89, 127.48, 126.87, 126.32, 124.79, 124.73, 120.30, 114.67; HRMS exact mass calcd for (C 25 H 19 N5O + H + ) requires m / z 406.1662, found m / z 406.1669.

[0107] Example 24

[0108] Take KO tBu(0.6 mmol, 67.2 mg), isohydroxamic acid ester 3 g (0.3 mmol, 80.1 mg) were placed in a reactor. Subsequently, DMSO (1 mL), phenylacetonitrile 1a (0.2 mmol, 23.4 mg), and phenyl azide 2a (0.24 mmol, 28.6 mg) were added. Then, the reaction system was transferred to react at 70 °C for 2 h. After the reaction was completed, 5 mL of DCM was added to quench the reaction, and then it was poured into 150 mL of water. After liquid separation, it was extracted with DCM (30 mL × 3). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography with petroleum ether / acetone (3:1). The product was a white solid 4x (45.8 mg, 60%).

[0109] The structural characterization of the obtained compound 4x was as follows: 1 1H NMR (500 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.77 (s, 1H), 7.90 - 7.88 (m, 2H), 7.67 - 7.62 (m, 4H), 7.59 - 7.50 (m, 3H), 7.42 - 7.39 (m, 1H), 7.28 - 7.21 (m, 5H), 7.11 - 7.08 (m, 1H), 6.05 - 6.02 (m, 1H); 13 13C NMR (125 MHz, DMSO-d6) δ 153.10, 141.46, 137.23, 135.79, 130.60, 130.06, 129.36, 129.08, 128.71, 128.07, 126.29, 126.16, 125.27, 125.22, 124.73, 109.79; HRMS exact mass calcd for (C 23 H 19 N5O + H + ) requires m / z 382.1662, found m / z 382.1678.

[0110] Example 25

[0111] Take KO tBu (0.6 mmol, 67.2 mg), isohydroxamate 3h (0.3 mmol, 66.3 mg) were placed in a reactor, and then DMSO (1 mL), phenylacetonitrile 1a (0.2 mmol, 23.4 mg), and phenyl azide 2a (0.24 mmol, 28.6 mg) were added. Then the reaction system was transferred to react at 70 °C for 2 h. After the reaction was completed, 5 mL of DCM was added to quench the reaction, and then it was poured into 150 mL of water. After liquid separation, it was extracted with DCM (30 mL × 3). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography with petroleum ether / acetone (3:1). The product was a white solid 4y (57.1 mg, 85%).

[0112] The structural characterization of the obtained compound 4y was as follows: 1 1H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.89 - 7.89 (m, 2H), 7.66 - 7.60 (m, 4H), 7.57 - 7.56 (m, 1H), 7.51 - 7.48 (m, 2H), 7.41 - 7.38 (m, 1H), 6.47 (s, 1H), 1.19 (s, 9H); 13 13C NMR (125 MHz, DMSO-d6) δ 155.03, 140.88, 136.10, 131.04, 130.95, 129.82, 129.72, 129.15, 128.41, 126.26, 124.65, 50.23, 29.27; HRMS exact mass calcd for (C 19 H 21 N5O + H + ) requires m / z 336.1819, found m / z 336.1838.

[0113] Under the optimal reaction conditions, it can be seen from the above examples that:

[0114] Nitriles containing electron-donating groups such as p-methylphenylacetonitrile and p-methoxyphenylacetonitrile are all well compatible with the reaction conditions. Nitriles containing halogens such as p-fluorophenylacetonitrile and p-bromophenylacetonitrile can also obtain the target compounds 4d and 4e in relatively high yields, and the isolated yields are 84% and 82% respectively. Nitriles containing strong electron-withdrawing groups such as cyano and trifluoromethyl can also react smoothly and obtain the target products 4f and 4g with isolated yields of 89% and 78% respectively. Moreover, the steric effect has no obvious influence on this reaction. Nitriles with substituents in the ortho and meta positions such as o-bromophenylacetonitrile and m-methylphenylacetonitrile can also be isolated to obtain the target compounds 4h and 4i in moderate yields. This reaction also has good compatibility with heteroaromatic nitriles such as 3-pyridineacetonitrile and thiophene-2-acetonitrile, and the isolated yields of their target products 4k and 4l are 90% and 91% respectively.

[0115] Azides containing electron-donating groups, such as p-tert-butylphenyl azide and p-methoxyphenyl azide, can both give the target compounds 4m and 4n in high yields. Azides containing halogens, such as p-fluorophenyl azide and m-chlorophenyl azide, can all smoothly participate in the reaction. In addition, alkyl azides, such as benzyl azide, also have good compatibility with this reaction and can give the target compound 4q in a separated yield of 75%.

[0116] Both aryl and alkyl hydroxamic acid esters can well be compatible with this reaction system. Naphthyl-substituted hydroxamic acid ester and cinnamyl-substituted hydroxamic acid ester are separately obtained the target compounds 4w and 4x in separated yields of 83% and 60%. Among them, alkyl hydroxamic acid esters, such as tert-butyl-substituted hydroxamic acid ester, can give the target compound 4y in a separated yield of 87%.

[0117] Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments, or perform equivalent substitution on some of the technical features. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A green synthesis method of triazole urea derivatives, characterized in that: The synthesis method prepares triazole urea derivatives by capturing the triazole amine and nitrogen anion intermediate generated from nitriles and azides under the promotion of a base with the isocyanate generated by the rearrangement of hydroxamic acid ester through the Lossen rearrangement.

2. The green synthesis method of a triazole urea derivative according to claim 1, characterized in that: The synthesis method includes the following steps: S1. Add a base and a hydroxamic acid ester into a reactor, then add DMSO, nitriles, and azides, and transfer the reactor to 70 °C for reaction for 2 h; S2. After the reaction is completed, add DCM to quench, pour the product into water, separate the layers, extract with DCM, and combine to obtain the organic phase; S3. Dry the organic phase with Na2SO4, concentrate, and obtain the target product through column chromatography of petroleum ether / acetone.

3. A green synthesis method of a triazole urea derivative according to claim 1, characterized in that: The nitriles include one of phenylacetonitrile, methylphenylacetonitrile, 4-methoxyphenylacetonitrile, p-fluorophenylacetonitrile, p-bromophenylacetonitrile, 4-cyanophenylacetonitrile, p-trifluoromethylphenylacetonitrile, o-bromophenylacetonitrile, 3-methylphenylacetonitrile, 2-naphthylacetonitrile, 3-pyridineacetonitrile, 2-thiopheneacetonitrile.

4. A green synthesis method of a triazole urea derivative according to claim 1, characterized in that: The azides include one of phenyl azide, p-tert-butylphenyl azide, 4-methoxyphenyl azide, 4-fluorophenyl azide, 4-cyanophenyl azide, m-chlorophenyl azide, benzyl azide.

5. A green synthesis method of a triazole urea derivative according to claim 1, characterized in that: The base is KO t Bu.

6. The green synthesis method of a triazole urea derivative according to claim 1, characterized in that: The molar ratio of the base, hydroxamic acid ester, nitriles, and azides is 30:15:10:12.

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