5-amino triazolopyrimidine derivatives and processes for their preparation

Abstract

The application discloses a 5-amino triazolopyrimidine derivative and a preparation method thereof. The preparation method comprises the following steps: reacting a compound shown in a formula (I), a compound shown in a formula (II) and a compound shown in a formula (III) in the presence of a metal salt catalyst and a solvent, so as to obtain the 5-amino triazolopyrimidine derivative. The structural formulae of the formula (I) to the formula (III) are shown in the following: wherein R 1 a substituted 4-14-membered carbocyclic compound or a heterocyclic compound; the R 1 is selected from H, halogen, cyano, C1-C6 alkyl and C1-C6 alkoxy; the R 2 is selected from H, C1-C6 alkyl or wherein R 21 a substituted 4-14-membered carbocyclic compound or a heterocyclic compound; the R 21 is selected from H, halogen, nitro, C1-C6 alkyl and C1-C6 alkoxy; the R 3 is selected from trimethylsilyl, substituted or unsubstituted phenylsulfonyl and alkylsulfonyl.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis, in particular to a 5-amino triazolopyrimidine derivative and a preparation method thereof. BACKGROUND

[0002] Molecules containing 5-amino triazolopyrimidine skeleton have a wide range of biological activities, for example, CGS 15943 binds to the aryl hydrocarbon receptor (AhR) receptor to activate AhR signaling and induce apoptosis of hepatocarcinoma and breast cancer cells; in ischemic stroke, CGS19543 competes with adenosine triphosphate (ATP) to bind to P2 receptors, inhibits the production of cytokines and chemokines by microglial cells, and relieves neuronal damage to improve post-stroke sequelae (Apoptosis. 2021, 26, 307-322.; Semin. Immunopathol. 2023, 45, 347-365); MRS1220 is an A3 antagonist, which has been proven to have anti-inflammatory effects and regulate tumor necrosis factor (Br. J. Pharmacol. 2010, 159, 1304-1311; J. Med. Chem. 1999, 42, 22, 4473-4478.). CGS21197 is an A2 antagonist, which has been confirmed to be a drug for treating anxiety asthma (EP263071A1). Therefore, it is of great significance to develop a synthetic method for constructing 5-amino triazolopyrimidine compounds.

[0003]

[0004] Although the synthesis of 5-amino triazolopyrimidine compounds has been reported (David et al., J. Med. Chem. 2014, 57, 7955-7970.; Amjad et al., WO 2022 / 020550 A1.; Steven et al., Steven et al., WO 2020 / 102506 A1.; Maes et al., Adv. Synth. Catal. 2014, 356, 1205-1209.; Olga et al., Chem. Pharm. Bull. 2007, 55, 372-375.; Sather et al., Org. Lett. 2022, 24, 6331-6334.). However, among the existing synthesis methods, most of the synthesis of 5-amino triazolopyrimidine compounds is linear synthesis. The report of Maes requires 2 steps, but uses-78℃ and noble metal palladium conditions; David, Olga requires 4 steps; Amjad requires 4 steps and each step reaction lasts for 16 hours; Sather requires 4 steps to prepare precursors, and the reaction requires-78℃ conditions, and the single reaction lasts for 1-7 days; Steven requires 5 steps. In summary, the above methods have the defects of long reaction time, difficult to obtain raw materials, low reaction temperature, and low yield caused by multiple reaction steps.

[0005] Therefore, in order to meet the needs of drug activity screening research and expand the diversity of compound structures, it is particularly important to develop a preparation method of 5-amino triazolopyrimidine compounds with mild reaction conditions, short reaction time, few reaction steps, high yield and easy-to-obtain raw materials. SUMMARY

[0006] The technical problem to be solved by the present application is to provide a 5-amino triazolopyrimidine derivative and a preparation method thereof, which can be obtained by a multi-component one-pot reaction, and the preparation method is simple and the reaction conditions are mild, which is conducive to wide production and application.

[0007] In order to solve the above technical problem, the first aspect of the present application provides a preparation method of a 5-amino triazolopyrimidine derivative, specifically, a compound represented by formula (I), a compound represented by formula (II) and a compound represented by formula (III) are reacted in the presence of a metal salt catalyst and a solvent to obtain the 5-amino triazolopyrimidine derivative.

[0008] The structural formula of the above-mentioned formula (I) to formula (III) is as follows:

[0009]

[0010] Among them, R is R 1 a substituted 4-14 membered carbocyclic compound or a heterocyclic compound; said R 1one of H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy;

[0011] R 2 one of H, C1-C6 alkyl or wherein, R 21 substituted 4-14 membered carbocyclic or heterocyclic compound; R 21 one of H, halogen, nitro, C1-C6 alkyl, C1-C6 alkoxy;

[0012] R 3 one of trimethylsilyl, substituted or unsubstituted phenylsulfonyl, alkylsulfonyl.

[0013] further, R 1 one of H, fluorine, bromine, chlorine, methoxy, methyl; R 2 one of H, methyl, thiophene, furan, pyridine, phenyl, chlorophenyl, nitrophenyl, methoxyphenyl, methylphenyl, p-tert-butylphenyl, fluorophenyl, bromophenyl, indolyl; R 3 one of trimethylsilyl, p-methylphenylsulfonyl, p-tert-butylphenylsulfonyl, p-nitrophenylsulfonyl.

[0014] further, the compound shown in formula (I) is selected from one of 2-isocyano-benzonitrile (1), 2-isocyano-3-bromobenzonitrile (2), 2-isocyano-6-bromobenzonitrile (3), 2-isocyano-4-methylbenzonitrile (4), 2-isocyano-4-fluorobenzonitrile (5), 2-isocyano-4-methoxybenzonitrile (6), 2-isocyano-5-chlorobenzonitrile (7), 2-isocyano-cyclopenta-1-en-1-carbonitrile (8); the structural formula is shown as follows, respectively:

[0015]

[0016] further, the compound shown in formula (II) is selected from one of 4-chlorobenzhydrazide (9), benzhydrazide (10), 4-nitrobenzhydrazide (11), 4-methoxybenzhydrazide (12), 4-pyridinecarbohydrazide (13), 2-furan carbohydrazide (14), 2-thiophene carbohydrazide (15), 4-methylbenzhydrazide (16), 4-tert-butylbenzhydrazide (17), acethydrazide (18), 4-fluorobenzhydrazide (19), 4-bromobenzhydrazide (20), 3-indole carbohydrazide (21), formhydrazide (22); the structural formula is shown as follows, respectively:

[0017]

[0018] Further, the compound of formula (III) is selected from one of p-toluenesulfonyl azide (23), 4-tert-butylbenzenesulfonyl azide (24), p-nitrobenzenesulfonyl azide (25), and trimethylsilyl azide (26); the structures of which are shown below:

[0019]

[0020] Further, the metal salt catalyst is selected from one or more of acetylacetonatocobalt (III), acetylacetonatocobalt (II), cobalt acetate, and cobalt acetate tetrahydrate.

[0021] Further, the solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, 1,2-dichloroethane, and toluene.

[0022] Further, the molar ratio of the compound of formula (I), the compound of formula (II), and the compound of formula (III) is (0.1-20):10:(0.1-20); preferably (5-15):10:(10-20); more preferably 12:10:15.

[0023] Further, the molar ratio of the metal salt catalyst to the compound of formula (II) is (0.1-200):100; preferably (1-10):100; more preferably 5:100.

[0024] Further, the temperature of the reaction is 60-120°C; for example, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, and the like, including but not limited to the temperatures listed above; and the time of the reaction is 1h-12h, for example, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, and the like, including but not limited to the times listed above.

[0025] The reaction mechanism is as follows:

[0026]

[0027] First, the isonitrile II-1 coordinates with cobalt (III) to form a metal cobalt complex II-A, and the metal cobalt complex II-A reacts with the azide II-3 to form a complex II-B. The complex II-B loses N2, and forms a carbodiimide intermediate II-C with the isonitrile. The II-C is attacked by the primary amine of the hydrazide II-2 to form an intermediate II-D, and then a proton transfer occurs to obtain an intermediate II-E, i.e., the compound II-F. The amino group of the compound II-F attacks the cyano group nucleophilically to cyclize, and H2O is lost. When R 3 is aryl or arylsulfonyl, the compound II-4 is formed, and when R 3When R is trimethylsilyl, i.e. compound II-G, it can be further hydrolyzed to form compound II-5.

[0028] The second aspect of the present application provides the 5-amino triazolopyrimidine derivative prepared by the preparation method of the first aspect. Specifically, the structure of the 5-amino triazolopyrimidine derivative is shown in formula IV:

[0029]

[0030] wherein, R is R 1 a substituted 4-14 membered carbocyclic compound or a heterocyclic compound; R 1 is selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy;

[0031] R is R 2 is selected from H, C1-C6 alkyl or wherein, R is R 21 a substituted 4-14 membered carbocyclic compound or a heterocyclic compound; R 21 is selected from H, halogen, nitro, C1-C6 alkyl, C1-C6 alkoxy;

[0032] R is R 3 is selected from H, substituted or unsubstituted phenylsulfonyl, alkylsulfonyl.

[0033] R is R 1 is selected from H, fluorine, bromine, chlorine, methoxy, methyl; R 2 is selected from H, methyl, thiophene, furan, pyridine, phenyl, chlorophenyl, nitrophenyl, methoxyphenyl, methylphenyl, p-tert-butylphenyl, fluorophenyl, bromophenyl, indolyl; R 3 is selected from H, p-toluenesulfonyl, p-nitrobenzenesulfonyl, p-tert-butylbenzenesulfonyl.

[0034] Further, the 5-amino triazolopyrimidine derivative is selected from one of the structures shown in formulae IV-1 to IV-26:

[0035]

[0036] The beneficial effects of the present application are:

[0037] The present application uses isonitrile, hydrazide and azide compound as a reaction raw material, and a 5-amino triazolopyrimidine derivative is prepared by one-pot method. Compared with the prior art, the present application provides a 5-amino triazolopyrimidine derivative synthesis method which is more economical in steps, high in atom economy, convenient in post-treatment, fast and efficient. The method is constructed by simple raw materials in one step, has the advantages of cheap and easy-to-obtain raw materials, simple and mild conditions, high atom economy, excellent yield (as high as 97%), and wide substrate range, and provides a very green synthesis method for efficient construction of 5-amino triazolopyrimidine skeleton.

[0038] The present application provides a series of 5-amino triazolopyrimidine derivatives with potential biological activity, which can be used for preparing adenosine antagonists. BRIEF DESCRIPTION OF DRAWINGS

[0039] Figure 1 is the hydrogen spectrum of compound IV-24 in Example 1 of the present application.

[0040] Figure 2 is the carbon spectrum of compound IV-24 in Example 1 of the present application. DETAILED DESCRIPTION

[0041] The present application will be further described below in combination with the drawings and specific examples, so that those skilled in the art can better understand the present application and implement it, but the examples are not limiting to the present application.

[0042] Example 1: Synthesis of the compound shown in (IV-1)

[0043] 0.1 mmol of 4-chlorobenzoyl hydrazine (compound corresponding to number (9), 0.0171 g), 0.12 mmol of 2-isocyano benzonitrile (compound corresponding to number (1), 0.0154 g, 120 mol%), 33 μL of p-toluenesulfonyl azide (compound corresponding to number (23), 0.0296 g, 150 mol%), 0.005 mmol of Co(acac)3 (0.0018 g, 5 mol%) were weighed in a 25 mL reaction tube, 2 mL of 1,4-dioxane was added as a solvent, and stirring was carried out under air atmosphere at 120°C for 5 hours. After the reaction was completed, the reaction liquid was evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was dichloromethane (A) and methanol (B), and the mobile phase change program (A:B) was 30:1), and 0.036 g of reaction product was obtained.

[0044] The above reaction product was characterized, and the results were as follows:

[0045] 1H NMR (400 MHz, CDC13) δ 11.53 (s, 1H), 8.41 (d, J = 9.4 Hz, 1H), 8.28 (d, J = 13.6 Hz, 2H), 7.97 (d, J = 8.0 Hz, 2H), 7.76 (t, J = 17.1 Hz, 1H), 7.53 (t, J = 15.2 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 2.41 (s, 3H).

[0046] According to the characterization data, the prepared reaction product is a pure product (purity > 95%); the product yield is calculated, and the result is 80%.

[0047] Example 2: Synthesis of the compound shown in (IV-2)

[0048] 0.1 mmol of benzoyl hydrazine (corresponding to the compound of number (10), 0.0136 g), 0.12 mmol of 2-isocyano benzonitrile (corresponding to the compound of number (1), 0.0154 g, 120 mol%), 33 μL of p-toluenesulfonyl azide (corresponding to the compound of number (23), 0.0296 g, 150 mol%), 0.005 mmol of Co(acac)3(0.0018 g, 5 mol%) were weighed into a 25 mL reaction tube, 2 mL of 1,4-dioxane was added as solvent, and the reaction was stirred at 120°C under air atmosphere for 5 hours. After the reaction was completed, the reaction solution was evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is dichloromethane (A) and methanol (B), and the mobile phase variation program (A:B) is 30:1). 0.040 g of the reaction product was obtained.

[0049] The above reaction product was characterized, and the results were as follows:

[0050] 1 H NMR (400 MHz, CDC13) δ 11.53 (s, 1H), 8.41 (d, J = 9.4 Hz, 1H), 8.28 (d, J = 13.6 Hz, 2H), 7.97 (d, J = 8.0 Hz, 2H), 7.76 (t, J = 17.1 Hz, 1H), 7.53 (t, J = 15.2 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 2.41 (s, 3H).

[0051] According to the characterization data, the prepared reaction product is a pure product (purity > 95%); the product yield is calculated, and the result is 80%.

[0052] Example 3: Synthesis of the compound shown in (IV-3)

[0053] Example 3: Synthesis of the compound shown in (IV-3)

[0054] The reaction product was characterized, and the results were as follows:

[0055] 1 H NMR (400 MHz, CDC13) δ 11.56 (s, 1H), 8.53 (d, J = 9.0 Hz, 2H), 8.44 (d, J = 9.4 Hz, 1H), 8.34 (d, J = 8.9 Hz, 2H), 7.99 (d, J = 8.0 Hz, 2H), 7.79 (t, J = 16.6 Hz, 1H), 7.33-7.35 (m, J = 26.9 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 2.43 (s, 3H).

[0056] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the result was 91%.

[0057] Example 4: Synthesis of the compound shown in (IV-4)

[0058] Take 0.1 mmol 4-methoxybenzoyl hydrazine (compound corresponding to number (12), 0.0171 g), 0.12 mmol 2-isocyano benzonitrile (compound corresponding to number (1), 0.0154 g, 120 mol%), 33 μL p-toluenesulfonyl azide (compound corresponding to number (23), 0.0296 g, 150 mol%), 0.005 mmol Co(acac)3(0.0018 g, 5 mol%) in a 25 mL reaction tube, add 2 mL 1,4-dioxane as solvent, stir the reaction under air atmosphere at 120°C for 5 hours. After the reaction is completed, the reaction liquid is evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is dichloromethane (A) and methanol (B), the mobile phase variation program (A:B) is 30:1), to obtain 0.037 g of the reaction product.

[0059] The reaction product is characterized, and the results are as follows:

[0060] 1 H NMR (400 MHz, CDCl3) δ 11.48 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.18 (d, J = 8.1 Hz, 2H), 7.93 (s, 2H), 7.71 (t, 1H), 7.49-7.50 (m, J = 6.6 Hz, 2H), 7.28 (s, 2H), 7.24 (s, 2H), 2.38 (d, J = 8.8 Hz, 6H).

[0061] According to the characterization data, it is known that the prepared reaction product is a pure product (purity > 95%); the product yield is calculated, and the result is 83%.

[0062] Example 5: Synthesis of the compound shown in (IV-5)

[0063] Take 0.1 mmol 4-pyridine carbohydrazine (compound corresponding to number (13), 0.0137 g), 0.12 mmol 2-isocyano benzonitrile (compound corresponding to number (1), 0.0154 g, 120 mol%), 33 μL p-toluenesulfonyl azide (compound corresponding to number (23), 0.0296 g, 150 mol%), 0.005 mmol Co(acac)3(0.0018 g, 5 mol%) in a 25 mL reaction tube, add 2 mL 1,4-dioxane as solvent, stir the reaction under air atmosphere at 120°C for 5 hours. After the reaction is completed, the reaction liquid is evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is dichloromethane (A) and methanol (B), the mobile phase variation program (A:B) is 30:1), to obtain 0.041 g of the reaction product.

[0064] The reaction product was characterized, and the results were as follows:

[0065] 1 H NMR (400 MHz, CDCI3) δ 8.79 (d, 2H), 8.44 (t, 1H), 8.20 (d, 2H), 8.00 (d, 2H), 7.79 (t, 1H), 7.54 (d, J = 14.7 Hz, 2H), 7.34 (d, J = 7.2 Hz, 2H), 2.43 (s, 3H).

[0066] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the results were 99%.

[0067] Example 6: synthesis of the compound shown in (IV-6)

[0068] 0.1 mmol of 2-furancarboxylic hydrazine (corresponding to compound (14), 0.0126 g), 0.12 mmol of 2-isocyano benzonitrile (corresponding to compound (1), 0.0154 g, 120 mol%), 33 μL of p-toluenesulfonyl azide (corresponding to compound (23), 0.0296 g, 150 mol%), 0.005 mmol of Co(acac)3(0.0018 g, 5 mol%) were weighed into a 25 mL reaction tube, 2 mL of 1,4-dioxane was added as a solvent, and the reaction was stirred at 120°C under air atmosphere for 5 hours. After the reaction was completed, the reaction liquid was evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was dichloromethane (A) and methanol (B), and the mobile phase variation program (A:B) was 30:1). 0.036 g of the reaction product was obtained.

[0069] The reaction product was characterized, and the results were as follows:

[0070] 1 H NMR (400 MHz, CDCI3) δ 11.54 (s, 1H), 8.43 (d, J = 9.7 Hz, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.76 (d, J = 17.2 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 22.4 Hz, 2H), 7.30 (d, J = 8.7 Hz, 3H), 6.57 (s, 1H), 2.40 (s, 3H).

[0071] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the results were 89%.

[0072] Example 7: Synthesis of the compound shown in (IV-7)

[0073] Example 7: Synthesis of the compound shown in (IV-7)

[0074] The reaction product was characterized, and the results were as follows:

[0075] 1 H NMR (400 MHz, CDCI3) δ 11.51 (s, 1 H), 8.41 (d, J = 7.3 Hz, 1 H), 7.97 (s, 3 H), 7.75 (d, J = 15.2 Hz, 1 H), 7.51 (d, J = 19.9 Hz, 3 H), 7.30 (d, J = 8.1 Hz, 2 H), 7.16 (s, 1 H), 2.40 (s, 3 H).

[0076] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the results were 92%.

[0077] Example 8: Synthesis of the compound shown in (IV-8)

[0078] Example 1: Synthesis of the compound shown in (IV-1)

[0079] The reaction product was characterized, and the results were as follows:

[0080] 1 H NMR (400 MHz, CDCI3) δ 11.50 (s, 1 H), 8.40 (d, J = 7.9 Hz, 1 H), 8.25 (d, J = 8.9 Hz, 2 H), 7.94 (d, J = 8.7 Hz, 2 H), 7.74 (d, J = 17.1 Hz, 1 H), 7.51 (d, J = 15.0 Hz, 2 H), 7.28 (d, J = 8.1 Hz, 2 H), 6.97 (d, J = 8.9 Hz, 2 H), 3.86 (s, 3 H), 2.38 (s, 3 H).

[0081] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the results were 95%.

[0082] Example 9: Synthesis of the compound shown in (IV-9)

[0083] Example 1: Synthesis of the compound shown in (IV-1)

[0084] The reaction product was characterized, and the results were as follows:

[0085] 1 H NMR (400 MHz, CDC13) δ 11.21 (s, 1H), 8.39 (d, J = 8.3 Hz, 1H), 8.21 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 21.0 Hz, 3H), 7.22 (d, J = 8.1 Hz, 2H), 2.33 (s, 3H), 1.34 (s, 9H).

[0086] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the result was 89%.

[0087] Example 10: Synthesis of the compound shown in (IV-10)

[0088] Take 0.1 mmol of acetyl hydrazine (compound corresponding to number (18), 0.0074 g), 0.12 mmol of 2-isocyano benzonitrile (compound corresponding to number (1), 0.0154 g, 120 mol%), 33 μL of p-toluenesulfonyl azide (compound corresponding to number (23), 0.0296 g, 150 mol%), 0.005 mmol of Co(acac)3(0.0018 g, 5 mol%) in a 25 mL reaction tube, add 2 mL of 1,4-dioxane as solvent, stir the reaction under air atmosphere at 120°C for 5 hours. After the reaction is completed, the reaction liquid is evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is dichloromethane (A) and methanol (B), the mobile phase variation program (A:B) is 30:1), 0.021 g of reaction product is obtained.

[0089] The above reaction product is characterized, and the results are:

[0090] 1 H NMR (400 MHz, CDCI3) δ 8.26 (d, J = 7.9 Hz, 1 H), 7.90 (d, J = 8.4 Hz, 2 H), 7.70 (d, J = 17.1 Hz, 1 H), 7.47 (d, J = 21.3 Hz, 2 H), 7.24 (s, 2 H), 2.58 (s, 3 H), 2.35 (s, 3 H).

[0091] According to the characterization data, it is known that the prepared reaction product is a pure product (purity > 95%); the product yield is calculated, and the result is 60%.

[0092] Example 11: synthesis of the compound shown in (IV-11)

[0093] Take 0.1 mmol of 4-fluorobenzohydrazide (compound corresponding to number (19), 0.0154 g), 0.12 mmol of 2-isocyano benzonitrile (compound corresponding to number (1), 0.0154 g, 120 mol%), 33 μL of p-toluenesulfonyl azide (compound corresponding to number (23), 0.0296 g, 150 mol%), 0.005 mmol of Co(acac)3(0.0018 g, 5 mol%) in a 25 mL reaction tube, add 2 mL of 1,4-dioxane as solvent, stir the reaction under air atmosphere at 120°C for 5 hours. After the reaction is completed, the reaction liquid is evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is dichloromethane (A) and methanol (B), the mobile phase variation program (A:B) is 30:1), 0.040 g of reaction product is obtained.

[0094] The above reaction product is characterized, and the results are:

[0095] 1 H NMR (400 MHz, CDC13) δ 11.52 (s, 1H), 8.42 (d, J = 7.1 Hz, 1H), 8.33 (s, 2H), 7.98 (s, 2H), 7.76 (s, 1H), 7.53 (s, 2H), 7.32 (d, J = 7.1 Hz, 2H), 7.17 (s, 2H), 2.41 (s, 3H).

[0096] According to the characterization data, the prepared reaction product is a pure product (purity > 95%); the product yield is calculated, and the result is 92%.

[0097] Example 12: Synthesis of the compound shown as (IV-12)

[0098] 0.1 mmol of 4-bromobenzohydrazide (corresponding to the compound of No. (20), 0.0214 g), 0.12 mmol of 2-isocyano-benzonitrile (corresponding to the compound of No. (1), 0.0154 g, 120 mol%), 33 μL of p-toluenesulfonyl azide (corresponding to the compound of No. (23), 0.0296 g, 150 mol%), 0.005 mmol of Co(acac)3(0.0018 g, 5 mol%) were weighed into a 25 mL reaction tube, 2 mL of 1,4-dioxane was added as a solvent, and the reaction was stirred at 120°C under air atmosphere for 5 hours. After the reaction was completed, the reaction solution was evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was dichloromethane (A) and methanol (B), and the mobile phase variation program (A:B) was 30:1). 0.021 g of the reaction product was obtained.

[0099] The above reaction product was characterized, and the results were as follows:

[0100] 1 H NMR (400 MHz, CDC13) δ 11.52 (s, 1H), 8.42 (d, J = 7.1 Hz, 1H), 8.33 (s, 2H), 7.98 (s, 2H), 7.76 (s, 1H), 7.53 (s, 2H), 7.32 (d, J = 7.1 Hz, 2H), 7.17 (s, 2H), 2.41 (s, 3H).

[0101] According to the characterization data, the prepared reaction product is a pure product (purity > 95%); the product yield is calculated, and the result is 92%.

[0102] Example 13: Synthesis of the compound shown as (IV-13)

[0103] Weigh 0.1 mmol of 3-indolecarboxylhydrazine (corresponding compound of No. (21), 0.0175 g), 0.12 mmol of 2-isocyano-benzonitrile (corresponding compound of No. (1), 0.0154 g, 120 mol%), 33 μL of p-toluenesulfonyl azide (corresponding compound of No. (23), 0.0296 g, 150 mol%), 0.005 mmol of Co(acac)3(0.0018 g, 5 mol%) into a 25 mL reaction tube, add 2 mL of 1,4-dioxane as solvent, and stir the reaction at 120°C under air atmosphere for 5 hours. After the reaction is completed, the reaction solution is evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: 200-300 mesh silica gel powder as stationary phase, dichloromethane (A) and methanol (B) as mobile phase, mobile phase variation program (A:B) is 30:1). 0.037 g of reaction product is obtained.

[0104] The reaction product is characterized, and the results are as follows:

[0105] 1 H NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 8.40 (s, 1H), 8.32 (d, J = 9.5 Hz, 1H), 8.21 (d, J = 2.9 Hz, 1H), 8.12 - 7.96 (m, 3H), 7.81 (d, J = 17.3 Hz, 1H), 7.57 (d, J = 16.1 Hz, 1H), 7.50 (d, J = 9.3 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 9.3 Hz, 2H), 2.39 (s, 3H).

[0106] According to the characterization data, it is known that the prepared reaction product is a pure product (purity > 95%); the product yield is calculated, and the result is 81%.

[0107] Example 14: Synthesis of the compound shown in (IV-14)

[0108] The reaction was carried out in a 25 mL reaction tube with 0.1 mmol of 4- chlorobenzoyl hydrazine (compound corresponding to No. (9), 0.0171 g), 0.12 mmol of 2- isocyancyclopent-l-en-l-cyanide (compound corresponding to No. (8), 0.0142 g, 120 mol%), 33 μL of p-toluenesulfonyl azide (compound corresponding to No. (23), 0.0296 g, 150 mol%), 0.005 mmol of Co(acac)3(0.0018 g, 5 mol%) as the catalyst, 2 mL of 1,4-dioxane as the solvent, and stirring at 120°C under an air atmosphere for 5 hours. After the reaction was completed, the reaction solution was evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: 200-300 mesh silica gel powder as the stationary phase, dichloromethane (A) and methanol (B) as the mobile phase, mobile phase variation program (A:B) 30:1). The reaction product was obtained in an amount of 0.018 g.

[0109] The reaction product was characterized, and the results were as follows:

[0110] 1 H NMR (400 MHz, DMSO) δ 11.98 (s, 1H), 8.17 (d, J = 8.6 Hz, 2H), 7.89 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 2.93 (d, J = 14.7 Hz, 2H), 2.86 (d, J = 15.9 Hz, 2H), 2.35 (s, 3H), 2.12 (d, J = 14.3 Hz, 2H).

[0111] According to the characterization data, it was known that the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the results were 40%.

[0112] Example 15: Synthesis of the compound shown in (IV-15)

[0113] Take 0.1 mmol 4-chlorobenzoyl hydrazine (compound corresponding to number (9), 0.0171 g), 0.12 mmol 2-isocyano-3-bromobenzonitrile (compound corresponding to number (2), 0.0247 g, 120 mol%), 33 μL p-toluenesulfonyl azide (compound corresponding to number (23), 0.0296 g, 150 mol%), 0.005 mmol Co(acac)3(0.0018 g, 5 mol%) in a 25 mL reaction tube, add 2 mL 1,4-dioxane as solvent, 120°C air atmosphere stirring reaction for 5 hours. After the reaction, the reaction liquid is evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is dichloromethane (A) and methanol (B), the mobile phase variation program (A:B) is 30:1), 0.045 g of reaction product is obtained.

[0114] The reaction product is characterized, and the results are as follows:

[0115] 1 H NMR (400 MHz, CDCl3) δ 12.09 (s, 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.25 (d, J = 8.2 Hz, 2H), 8.02 (s, 2H), 7.96 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.39 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 2.42 (s, 3H).

[0116] According to the characterization data, it is known that the prepared reaction product is a pure product (purity > 95%); the product yield is calculated, and the result is 93%.

[0117] Example 16: Synthesis of the compound shown in (IV-16)

[0118] Take 0.1 mmol 4-chlorobenzoyl hydrazine (compound corresponding to number (9), 0.0171 g), 0.12 mmol 2-isocyano-3-bromobenzonitrile (compound corresponding to number (2), 0.0247 g, 120 mol%), 33 μL p-toluenesulfonyl azide (compound corresponding to number (23), 0.0296 g, 150 mol%), 0.005 mmol Co(acac)3(0.0018 g, 5 mol%) in a 25 mL reaction tube, add 2 mL 1,4-dioxane as solvent, 120°C air atmosphere stirring reaction for 5 hours. After the reaction, the reaction liquid is evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is dichloromethane (A) and methanol (B), the mobile phase variation program (A:B) is 30:1), 0.045 g of reaction product is obtained.

[0119] The reaction product was characterized, and the results were as follows:

[0120] 1 H NMR (400 MHz, CDCI3) δ 8.30 (d, J = 8.0 Hz, 2H), 8.00 (s, 2H), 7.79 (d, J = 7.0 Hz, 2H), 7.55 (s, 1H), 7.46 (d, J = 7.9 Hz, 2H), 7.33 (d, J = 7.4 Hz, 2H), 2.42 (s, 3H).

[0121] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the results were 87%.

[0122] Example 17: synthesis of the compound shown in (IV-17)

[0123] 0.1 mmol of 4-chlorobenzoyl hydrazine (compound corresponding to number (9), 0.0171 g), 0.12 mmol of 2-isocyano-4-methylbenzonitrile (compound corresponding to number (4), 0.0170 g, 120 mol%), 33 μL of p-toluenesulfonyl azide (compound corresponding to number (23), 0.0296 g, 150 mol%), 0.005 mmol of Co(acac)3(0.0018 g, 5 mol%) were weighed into a 25 mL reaction tube, 2 mL of 1,4-dioxane was added as solvent, and the reaction was stirred at 120°C under air atmosphere for 5 hours. After the reaction was completed, the reaction liquid was evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: 200-300 mesh silica gel powder as stationary phase, dichloromethane (A) and methanol (B) as mobile phase, mobile phase variation program (A:B) 30:1). 0.042 g of reaction product was obtained.

[0124] The reaction product was characterized, and the results were as follows:

[0125] 1 H NMR (400 MHz, CDCI3) δ 11.48 (s, 1H), 8.27 (d, J = 12.5 Hz, 3H), 7.97 (d, J = 7.7 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 31.2 Hz, 4H), 2.56 (s, 3H), 2.42 (s, 3H).

[0126] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the results were 91%.

[0127] Example 18: synthesis of the compound shown in (IV-18)

[0128] To a 25 mL reaction tube was added 0.1 mmol of 4-chlorobenzoyl hydrazine (the compound corresponding to No. (9), 0.0171 g), 0.12 mmol of 2-isocyano-4- fluorobenzonitrile (the compound corresponding to No. (5), 0.0175 g, 120 mol%), 33 μL of p-toluenesulfonyl azide (the compound corresponding to No. (23), 0.0296 g, 150 mol%), 0.005 mmol of Co(acac)3(0.0018 g, 5 mol%) as a solvent of 2 mL of 1,4-dioxane, and the mixture was stirred at 120°C under an air atmosphere for 5 hours. After the reaction was completed, the reaction solution was evaporated in vacuo and separated by column chromatography (column chromatography separation conditions: stationary phase was 200-300 mesh silica gel powder, mobile phase was dichloromethane (A) and methanol (B), mobile phase variation program (A:B) was 30:1) to obtain 0.040 g of the reaction product.

[0129] The reaction product was characterized, and the results were as follows:

[0130] 1 H NMR (400 MHz, CDC13) δ 11.63 (s, 1H), 8.26 (d, J = 8.7 Hz, 2H), 8.18 (d, J = 7.0 Hz, 1H), 8.04 (s, 2H), 7.50 (d, J = 39.9 Hz, 5H), 7.34 (d, J = 8.4 Hz, 2H), 2.42 (s, 3H).

[0131] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the results were 85%.

[0132] Example 19: Synthesis of the compound shown in (IV-19)

[0133] To a 25 mL reaction tube was added 0.1 mmol of 4-chlorobenzoyl hydrazine (the compound corresponding to No. (9), 0.0171 g), 0.12 mmol of 2-isocyano-4- fluorobenzonitrile (the compound corresponding to No. (5), 0.0175 g, 120 mol%), 33 μL of p-toluenesulfonyl azide (the compound corresponding to No. (23), 0.0296 g, 150 mol%), 0.005 mmol of Co(acac)3(0.0018 g, 5 mol%) as a solvent of 2 mL of 1,4-dioxane, and the mixture was stirred at 120°C under an air atmosphere for 5 hours. After the reaction was completed, the reaction solution was evaporated in vacuo and separated by column chromatography (column chromatography separation conditions: stationary phase was 200-300 mesh silica gel powder, mobile phase was dichloromethane (A) and methanol (B), mobile phase variation program (A:B) was 30:1) to obtain 0.040 g of the reaction product.

[0134] The reaction product was characterized, and the results were as follows:

[0135] 1 H NMR (400 MHz, CDCI3) δ 11.50 (s, 1 H), 8.27 (dd, J = 11.5, 8.8 Hz, 3 H), 7.96 (d, J = 8.6 Hz, 2 H), 7.45 (d, J = 8.6 Hz, 2 H), 7.32 (d, J = 8.2 Hz, 2 H), 7.08 (d, J = 10.3 Hz, 1 H), 6.90 (s, 1 H), 3.97 (s, 3 H), 2.41 (s, 3 H).

[0136] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the results were 83%.

[0137] Example 20: Synthesis of the compound shown in (IV-20)

[0138] 0.1 mmol of 4-chlorobenzoyl hydrazine (compound corresponding to number (9), 0.0171 g), 0.12 mmol of 2-isocyano-5-chlorobenzonitrile (compound corresponding to number (7), 0.0194 g, 120 mol%), 33 μL of p-toluenesulfonyl azide (compound corresponding to number (23), 0.0296 g, 150 mol%), 0.005 mmol of Co(acac)3(0.0018 g, 5 mol%) were weighed into a 25 mL reaction tube, 2 mL of 1,4-dioxane was added as solvent, and the reaction was stirred at 120°C under air atmosphere for 5 hours. After the reaction was completed, the reaction liquid was evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was dichloromethane (A) and methanol (B), and the mobile phase variation program (A:B) was 30:1). 0.035 g of the reaction product was obtained.

[0139] The reaction product was characterized, and the results were as follows:

[0140] 1 H NMR (400 MHz, CDCI3) δ 8.39 (s, 1 H), 8.25 (d, J = 8.3 Hz, 2 H), 7.99 (s, 2 H), 7.81 (d, J = 7.7 Hz, 1 H), 7.70 (d, J = 7.0 Hz, 1 H), 7.46 (d, J = 8.3 Hz, 2 H), 7.33 (d, J = 7.8 Hz, 2 H), 2.43 (s, 3 H).

[0141] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the results were 72%.

[0142] Example 21: Synthesis of the compound shown in (IV-21)

[0143] Example 21: Synthesis of the compound shown in (IV-21)

[0144] The reaction product was characterized, and the results were as follows:

[0145] 1 H NMR (400 MHz, CDC13) δ 10.69 (s, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.45 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 16.6 Hz, 1H), 7.16 (d, J = 16.8 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H), 1.31 (s, 9H).

[0146] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the results were 44%.

[0147] Example 22: Synthesis of the compound shown in (IV-22)

[0148] Take 0.1 mmol 4-chlorobenzoyl hydrazine (compound corresponding to number (9), 0.0171 g), 0.12 mmol 2-isocyano benzyl nitrile (compound corresponding to number (1), 0.0154 g, 120 mol%), 0.15 mmol 4-nitrobenzenesulfonyl azide (compound corresponding to number (25), 0.0342 g, 150 mol%), 0.005 mmol Co(acac)3(0.0018 g, 5 mol%) in a 25 mL reaction tube, add 2 mL 1,4-dioxane as solvent, stir at 120°C under air atmosphere for 5 hours. After the reaction is completed, the reaction liquid is evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is dichloromethane (A) and methanol (B), the mobile phase variation program (A:B) is 30:1), to obtain 0.017 g of the reaction product.

[0149] The reaction product is characterized, and the results are as follows:

[0150] 1 H NMR (400 MHz, CDCl3) δ 10.55 (s, 1H), 8.28 (d, J = 8.9 Hz, 2H), 8.09 (d, J = 6.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 15.9 Hz, 3H), 7.29 (d, J = 7.7 Hz, 1H), 7.19 (s, 1H), 7.07 (d, J = 7.6 Hz, 1H).

[0151] According to the characterization data, it is known that the prepared reaction product is a pure product (purity > 95%); the product yield is calculated, and the result is 36%.

[0152] Example 23: Synthesis of the compound shown in (IV-23)

[0153] Take 0.1 mmol 4-chlorobenzoyl hydrazine (compound corresponding to number (9), 0.0171 g), 0.12 mmol 2-isocyano benzyl nitrile (compound corresponding to number (1), 0.0154 g, 120 mol%), 20 μL azidomethyl trimethylsilane (compound corresponding to number (26), 0.0296 g, 150 mol%), 0.005 mmol Co(acac)3(0.0018 g, 5 mol%) in a 25 mL reaction tube, add 2 mL 1,4-dioxane as solvent, stir at 120°C under air atmosphere for 5 hours. After the reaction is completed, the reaction liquid is evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is dichloromethane (A) and methanol (B), the mobile phase variation program (A:B) is 30:1), to obtain 0.023 g of the reaction product.

[0154] The reaction product was characterized, and the results were as follows:

[0155] 1 H NMR (400 MHz, CDCI3) δ 8.36 (d, J = 7.6 Hz, 1 H), 8.23 (d, J = 8.7 Hz, 2 H), 7.64 (d, J = 25.4 Hz, 2 H), 7.41 (d, J = 26.5 Hz, 3 H), 5.80 (s, 2 H).

[0156] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the results were 79%.

[0157] Example 24: synthesis of the compound shown in (IV-24)

[0158] 0.1 mmol of 2-furancarboxylic hydrazine (corresponding to compound (14), 0.0126 g), 0.12 mmol of 2-isocyano-5-chloro-benzonitrile (corresponding to compound (7), 0.0194 g, 120 mol%), 20 μL of azidotrimethylsilane (corresponding to compound (26), 0.0296 g, 150 mol%), 0.005 mmol of Co(acac)3(0.0018 g, 5 mol%) were weighed into a 25 mL reaction tube, 2 mL of 1,4-dioxane was added as solvent, and the reaction was stirred at 120°C under air atmosphere for 5 hours. After the reaction was completed, the reaction liquid was evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was dichloromethane (A) and methanol (B), and the mobile phase variation program (A:B) was 30:1). 0.020 g of the reaction product was obtained.

[0159] The reaction product was characterized, and the results were as follows:

[0160] 1 H NMR (400 MHz, DMSO) δ 8.15 (d, J = 2.4 Hz, 1 H), 7.98 (d, J = 11.0 Hz, 3 H), 7.69 (d, J = 11.4 Hz, 1 H), 7.56 (d, J = 8.8 Hz, 1 H), 7.25 (d, J = 4.3 Hz, 1 H), 6.74 (d, J = 5.3 Hz, 1 H).

[0161] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the results were 71%.

[0162] Example 25: synthesis of the compound shown in (IV-25)

[0163] Take 0.1 mmol of 2-furancarboxylic hydrazine (corresponding compound of No. (14), 0.0126 g), 0.12 mmol of 2-isocyano-5-chloro-benzonitrile (corresponding compound of No. (7), 0.0194 g, 120 mol%), 33 μL of p-toluenesulfonyl azide (corresponding compound of No. (23), 0.0296 g, 150 mol%), 0.005 mmol of Co(acac)3(0.0018 g, 5 mol%) in a 25 mL reaction tube, add 2 mL of 1,4-dioxane as solvent, stir the reaction under air atmosphere at 120°C for 5 hours. After the reaction is completed, the reaction liquid is evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is dichloromethane (A) and methanol (B), the mobile phase variation program (A:B) is 30:1), to obtain 0.031 g of the reaction product.

[0164] The reaction product is characterized, and the results are as follows:

[0165] 1 H NMR (400 MHz, DMSO) δ 8.12 (s, 1H), 7.94 (d, J = 8.3 Hz, 3H), 7.71 (s, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 3.3 Hz, 1H), 6.72 (d, J = 5.3 Hz, 1H), 2.34 (s, 3H).

[0166] According to the characterization data, it can be known that the prepared reaction product is a pure product (purity > 95%); the product yield is calculated, and the result is 71%.

[0167] Example 26: Synthesis of the compound shown in (IV-26)

[0168] Take 0.1 mmol of formylhydrazine (corresponding compound of No. (22), 0.0060 g), 0.12 mmol of 2-isocyano-benzonitrile (corresponding compound of No. (1), 0.0154 g, 120 mol%), 33 μL of p-toluenesulfonyl azide (corresponding compound of No. (23), 0.0296 g, 150 mol%), 0.005 mmol of Co(acac)3(0.0018 g, 5 mol%) in a 25 mL reaction tube, add 2 mL of 1,4-dioxane as solvent, stir the reaction under air atmosphere at 120°C for 5 hours. After the reaction is completed, the reaction liquid is evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is dichloromethane (A) and methanol (B), the mobile phase variation program (A:B) is 30:1), to obtain 0.014 g of the reaction product.

[0169] The reaction product was characterized, and the results were as follows:

[0170] 1 H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 8.08 (d, J = 9.5 Hz, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 13.8 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 18.1 Hz, 3H), 2.30 (s, 3H).

[0171] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the results were 40%.

[0172] Example 27: Biological activity test

[0173] According to the relevant reference (Chem. Pharm. Bull. 2007, 55, 372-375.), the compounds prepared in the above examples were randomly selected, and the biological activity was compared with compound IV-24 (CGS15943). Taking IV-24 (CGS15943) as a reference standard, the affinity of the compounds to human adenosine receptors A 2A and A 2B was determined by competitive binding assay.

[0174] Table 1

[0175]

[0176] The numerical values represent the average values ± standard errors of three independent detections.

[0177] The results shown in Table 1 are the affinity (percentage of displacement at 1 mM and pKi) of the prepared compounds to human adenosine A 2A and A 2B receptors; the results show that the prepared compounds can be well combined with adenosine receptors A 2A and A 2B , and can be used to prepare adenosine antagonists, and then as drugs for treating diseases.

[0178] The above examples are only preferred examples for fully illustrating the present application, and the protection scope of the present application is not limited thereto. The equivalent substitutions or transformations made by the person skilled in the art on the basis of the present application are within the protection scope of the present application. The protection scope of the present application is subject to the claims.

Claims

1. A method for preparing a 5-aminotriazolidine derivative, characterized in that, The compounds shown in formula (I), formula (II), and formula (III) are reacted in the presence of a metal salt catalyst and a solvent to obtain the 5-aminotriazolidine derivative; the metal salt catalyst is selected from one or more of cobalt acetylacetonate (III), cobalt acetylacetonate (II), cobalt acetate, and cobalt acetate tetrahydrate. The structural formulas of equations (I) to (III) above are shown below: ； The structural formula of the 5-aminotriazolidine derivative is shown in IV: ； Among them, R 2 Selected from H, C1-C6 alkyl or ; For R 21 Substituted 4-14 membered carbocyclic compounds or heterocyclic compounds; R 21 Selected from one of H, halogen, nitro, C1-C6 alkyl, and C1-C6 alkoxy; R 3 Selected from one of H, p-toluenesulfonyl, p-nitrobenzenesulfonyl, and p-tert-butylbenzenesulfonyl; The compound represented by formula (I) is selected from one of 2-isocyanobenzonitrile, 2-isocyano-3-bromobenzonitrile, 2-isocyano-6-bromobenzonitrile, 2-isocyano-4-methylbenzonitrile, 2-isocyano-4-fluorobenzonitrile, 2-isocyano-4-methoxybenzonitrile, 2-isocyano-5-chlorobenzonitrile, and 2-isocyanocyclopent-1-ene-1-carboxynitrile.

2. The preparation method according to claim 1, characterized in that, The compound represented by formula (II) is selected from one of 4-chlorobenzoylhydrazine, benzoylhydrazine, 4-nitrobenzoylhydrazine, 4-methoxybenzoylhydrazine, 4-pyridinecarboxylhydrazine, 2-furancarboxylhydrazine, 2-thiophenecarboxylhydrazine, 4-methylbenzoylhydrazine, 4-tert-butylbenzoylhydrazine, acetylhydrazine, 4-fluorobenzoylhydrazine, 4-bromobenzoylhydrazine, 3-indolecarboxylhydrazine, and formylhydrazine; The compound represented by formula (III) is selected from one of p-toluenesulfonyl azide, 4-tert-butylbenzenesulfonyl azide, p-nitrobenzenesulfonyl azide, and azide-trimethylsilane.

3. The preparation method according to claim 1, characterized in that, The solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, 1,2-dichloroethane, and toluene.

4. The preparation method according to claim 1, characterized in that, The molar ratio of the compound shown in formula (I), the compound shown in formula (II), and the compound shown in formula (III) is (0.1-20):10:(0.1-20); the molar ratio of the metal salt catalyst to the compound shown in formula (II) is (0.1-200):

100.

5. The preparation method according to claim 1, characterized in that, The reaction temperature is 60-120°C. o C; The reaction time is 1 h to 12 h.

6. The preparation method according to claim 1, characterized in that, R 2 It is selected from one of H, methyl, thiophene, furan, pyridine, phenyl, chlorophenyl, nitrophenyl, methoxyphenyl, methylphenyl, p-tert-butylphenyl, fluorophenyl, bromophenyl, and indole.

7. The preparation method according to claim 1, characterized in that, The 5-aminotriazolopyrimidine derivative is selected from one of the structures shown in formulas IV-1 to IV-26: 。

Images