Synthesis method of 1, 4, 7, 10-tetraaza-2, 6-pyridine cyclophane

Abstract

The invention discloses a synthesis method of 1, 4, 7, 10-tetraaza-2, 6-pyridine cyclophane, and relates to the technical field of organic synthesis.The synthesis method comprises the steps that 2, 6-pyridine dimethanol which is low in price and easy to obtain serves as a starting raw material, and the 1, 4, 7, 10-tetraaza-2, 6-pyridine cyclophane is synthesized through a Mitsunobu reaction, a Staudinger reaction and a reductive amination ring closing reaction; the synthesis method has the characteristics of short route, simple operation, mild reaction conditions, high yield and the like, and is suitable for industrial production of 1, 4, 7, 10-tetraaza-2, 6-pyridine cyclophane.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for synthesizing 1,4,7,10-tetraaza-2,6-pyridine cycloaven. Background Technology

[0002] 1,4,7,10-Tetraaza-2,6-pyridine cyclophane is a key intermediate in the synthesis of various NMR imaging contrast agents and diagnostic reagents, possessing significant market application value. Specifically, 1,4,7,10-Tetraaza-2,6-pyridine cyclophane (often simply referred to as cyclophane) is a compound containing four nitrogen atoms, structurally belonging to the macrocyclic compound class. Due to their unique structure and chemical properties, these compounds are frequently used in medical and chemical research, particularly as ligands in the synthesis of metal complexes. These metal complexes have shown great potential in the development of diagnostics, therapeutics (such as radiolabeled compounds), chemical sensors, and catalysts.

[0003] Due to the difficulty in synthesizing 1,4,7,10-tetraaza-2,6-pyridine cyclovas and the environmental problems arising during the synthesis process, developing efficient and environmentally friendly preparation methods has become a research hotspot. Green preparation methods focus on improving reaction efficiency and yield while reducing the generation of harmful byproducts, making the process more suitable for industrial production. This is crucial for reducing costs, improving safety, and minimizing environmental impact. Furthermore, 1,4,7,10-tetraaza-2,6-pyridine cyclovas and their derivatives, due to their excellent coordination ability, can form stable complexes with different metal ions. These complexes have promising applications in medical imaging, drug delivery, and biosensoring. For example, these complexes bound to radioisotopes can be used in positron emission tomography (PET) imaging to help doctors diagnose diseases more accurately.

[0004] Currently, the synthesis of cycloflavins mainly involves cyclizing 2,6-bis(bromomethyl)pyridine and its triethylenetetramine derivative in a low-concentration solvent, followed by hydrolysis in concentrated sulfuric acid to obtain the sulfate of the target product. This method not only requires the use of large amounts of solvent but also necessitates high-temperature reactions under strong acid and strong base conditions, and the post-processing is extremely complex, posing challenges to the further industrialization of the product. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a method for synthesizing 1,4,7,10-tetraaza-2,6-pyridine cycloalumina, using 2,6-pyridinediethanol as the starting material, which has the advantages of fewer synthesis steps, simple operation, mild reaction conditions and high yield.

[0006] The technical problem to be solved by this invention is achieved by the following technical solution:

[0007] A method for synthesizing 1,4,7,10-tetraaza-2,6-pyridine cycloacon includes the following steps:

[0008] S1, 2,6-pyridinediethanol reacts with diphenyl azidophosphate via the Mitsunobu reaction to give 2,6-bis(azidomethyl)pyridine;

[0009] S2, 2,6-bis(azidomethyl)pyridine undergoes a Staudinger reaction to give 2,6-bis(aminomethyl)pyridine;

[0010] S3, 2,6-bis(aminomethyl)pyridine undergoes a reductive amination cyclization reaction with diacetaldehyde amine to give 1,4,7,10-tetraaza-2,6-pyridine cycloaffin.

[0011] The synthesis route is as follows:

[0012]

[0013] Furthermore, the reaction solvent for the Mitsunobu reaction is at least one of the following nonprotic organic solvents: ketone solvents, ester solvents, ether solvents, amide solvents, sulfoxide solvents, aromatic solvents, alkane solvents, halogenated hydrocarbon solvents, and nitrile solvents. The ketone solvent is at least one selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone; the ester solvent is at least one selected from ethyl acetate, butyl acetate, and isopropyl acetate; the ether solvent is at least one selected from tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, and ethylene glycol dimethyl ether; the amide solvent is at least one selected from N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; the sulfoxide solvent is dimethyl sulfoxide; the aromatic solvent is at least one selected from toluene, xylene, chlorobenzene, and bromobenzene; the alkane solvent is at least one selected from cyclohexane, n-hexane, and n-heptane; the haloalkanes solvent is at least one selected from dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; and the nitrile solvent is at least one selected from acetonitrile, propionitrile, and butyronitrile. Preferably, the reaction solvent for the Mitsunobu reaction is tetrahydrofuran or ethyl acetate.

[0014] Furthermore, the Mitsunobu reaction is carried out under the catalysis of an organophosphorus reagent and an azo reagent. Even further, the organophosphorus reagent is at least one of triarylphosphine and trialkylphosphine, preferably triarylphosphine, more preferably triphenylphosphine; the azo reagent is at least one of azodicarbonate and azodicarbonamide, preferably azodicarbonate, more preferably at least one of diethyl azodicarbonate (DEAD) and diisopropyl azodicarbonate (DIAD).

[0015] Furthermore, the temperature of the Mitsunobu reaction is 0–50°C, and the time is 0.5–24 h.

[0016] Furthermore, the molar ratio of 2,6-pyridinediethanol, organophosphorus reagent, azo reagent, and diphenyl azidophosphate (DPPA) is 1:(1-2):(1.5-3):(2-4).

[0017] Further, the Staudinger reaction comprises a two-step reaction involving the addition reaction of 2,6-bis(azidomethyl)pyridine with an organophosphorus reagent to form an intermediate, and the hydrolysis of the intermediate to obtain 2,6-bis(aminomethyl)pyridine. Even further, the organophosphorus reagent is at least one of triarylphosphine and trialkylphosphine, preferably triarylphosphine, more preferably triphenylphosphine; the molar ratio of 2,6-bis(azidomethyl)pyridine to the organophosphorus reagent is 1:(1-2).

[0018] Furthermore, the Staudinger reaction is carried out at a temperature of 20–50°C for a time of 0.5–24 h.

[0019] Further, the reductive amination cyclization reaction comprises a two-step reaction: an addition reaction of 2,6-bis(aminomethyl)pyridine with diacetaldehyde amine to form an intermediate, and a reduction reaction of the intermediate to obtain 1,4,7,10-tetraaza-2,6-pyridine cyclopane. More specifically, the catalyst for the addition reaction is at least one of benzotriazole and benzimidazole; the reducing agent for the reduction reaction is at least one of sodium borohydride, lithium aluminum hydride, hydrogen, hydrazine hydrate, ammonium formate, formic acid, and a triethylamine / formic acid azeotrope; and the molar ratio of 2,6-bis(aminomethyl)pyridine to diacetaldehyde amine, catalyst, and reducing agent is 1:(1-1.5):(2-5):(1-2).

[0020] Furthermore, the temperature of the reductive amination cyclization reaction is 0–30°C, and the time is 2–10 h.

[0021] Further, the reaction solvent for the reductive amination cyclization reaction is water and an organic solvent. More specifically, the organic solvent is at least one selected from alcohols, ethers, esters, nitriles, halogenated hydrocarbons, ketones, and aromatic hydrocarbons, preferably alcohols. Specifically, the alcohol solvent is at least one selected from ethanol, methanol, and isopropanol, preferably ethanol; the ether solvent is preferably methyl tert-butyl ether; the ester solvent is preferably at least one selected from ethyl acetate and isopropyl acetate; the nitrile solvent is preferably acetonitrile; the halogenated hydrocarbon solvent is preferably dichloromethane; the ketone solvent is preferably acetone; and the aromatic hydrocarbon solvent is preferably at least one selected from toluene and xylene.

[0022] The beneficial effects of this invention are as follows: Using readily available and inexpensive 2,6-pyridinediethanol as the starting material, this invention synthesizes 1,4,7,10-tetraaza-2,6-pyridine cyclopartites via the Mitsunobu reaction, Staudinger reaction, and reductive amination cyclization reaction. This synthetic method features a short route, simple operation, mild reaction conditions, and high yield, making it suitable for the industrial production of 1,4,7,10-tetraaza-2,6-pyridine cyclopartites. Specifically, using 2,6-pyridinediethanol to synthesize the intermediate 2,6-bis(aminomethyl)pyridine in a one-pot process not only simplifies the process but also reduces intermediate losses, thereby increasing the overall yield of 1,4,7,10-tetraaza-2,6-pyridine cyclopartites. Attached Figure Description

[0023] Figure 1 The NMR spectrum of the product 1,4,7,10-tetraaza-2,6-pyridine cyclophane is shown.

[0024] Figure 2 The mass spectrum of the product 1,4,7,10-tetraaza-2,6-pyridine cyclophane is shown. Detailed Implementation

[0025] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below with reference to specific embodiments and illustrations.

[0026] Example 1

[0027] Synthesis of 2,6-bis(aminomethyl)pyridine:

[0028] Under nitrogen protection, 2,6-pyridinediethanol (10 g, 0.072 mol) and triphenylphosphine (37.8 g, 0.144 mol) were added to 100 mL of tetrahydrofuran. DIAD (30.5 g, 0.151 mol) was added dropwise at 0 °C, and the reaction was stirred at 0 °C for 0.5 h after the addition was complete. DPPA (39.6 g, 0.144 mol) was then added dropwise, and the reaction was stirred at 25 °C for 21 h after the addition was complete. Triphenylphosphine (37.8 g, 0.144 mol) was then added, and the reaction was stirred at 50 °C for 2 h. Water (5.2 g, 0.288 mol) was then added, and the reaction was stirred at 20 °C for 20 h. The solvent was removed by vacuum distillation, and the solution was obtained by column chromatography with a purity of 98% and a yield of 85%.

[0029] Synthesis of 1,4,7,10-tetraaza-2,6-pyridine cyclophane:

[0030] 2,6-bis(aminomethyl)pyridine (137 g, 1 mol) and benzotriazole (238 g, 2 mol) were added to 1600 mL of ethanol. Diacetaldehyde amine (106 g, 1.05 mol) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 3 h. Then, sodium borohydride (52 g, 1.37 mol) was added, and the mixture was stirred at 20 °C for 5 h. The mixture was filtered, and the filtrate was concentrated to remove ethanol. 600 mL of toluene was added, and the mixture was refluxed under normal pressure to remove water. After the water was completely removed, the mixture was cooled to 20 °C, filtered, and the filtrate was concentrated under reduced pressure until no obvious distillate was distilled off. Column chromatography was performed to obtain 1,4,7,10-tetraaza-2,6-pyridine cyclophosphide with a yield of 78% and a purity greater than 99%. 1 H NMR(400MHz,D2O)δ7.95(t,J=7.8Hz,1H),7.49(d,J=7.9Hz,2H),4.60(s,4H),3.45(d,J=19.7Hz,8H).MS(ESI)calcd for C 11 H 18 N4[M+H] + 207.29, found 207.1.

[0031] Example 2

[0032] Synthesis of 2,6-bis(aminomethyl)pyridine:

[0033] Under nitrogen protection, 2,6-pyridinediethanol (10 g, 0.072 mol) and triphenylphosphine (18.9 g, 0.072 mol) were added to 100 mL of ethyl acetate. DEAD (18.8 g, 0.108 mol) was added dropwise at 0 °C, and the reaction was stirred at 0 °C for 0.5 h after the addition was complete. DPPA (59.4 g, 0.216 mol) was then added dropwise, and the reaction was stirred at 35 °C for 12 h after the addition was complete. Triphenylphosphine (37.8 g, 0.144 mol) was then added, and the reaction was stirred at 50 °C for 2 h. Water (5.2 g, 0.288 mol) was then added, and the reaction was stirred at 50 °C for 8 h. The solvent was removed by vacuum distillation, and the solution was obtained by column chromatography with a purity of 98% and a yield of 83%.

[0034] Synthesis of 1,4,7,10-tetraaza-2,6-pyridine cyclophane:

[0035] 2,6-bis(aminomethyl)pyridine (137 g, 1 mol) and benzimidazole (473 g, 4 mol) were added to 1600 mL of acetonitrile. Diacetaldehyde amine (152 g, 1.5 mol) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 3 h. Then, lithium aluminum hydride (75.9 g, 2 mol) was added, and the mixture was stirred at 30 °C for 3 h. The mixture was filtered, and the filtrate was concentrated to remove acetonitrile. 600 mL of toluene was added, and the mixture was refluxed under normal pressure to remove water. After the water was completely removed, the mixture was cooled to 20 °C, filtered, and the filtrate was concentrated under reduced pressure until no obvious distillate was distilled off. Column chromatography was performed to obtain 1,4,7,10-tetraaza-2,6-pyridine cyclophosphide with a yield of 81% and a purity greater than 99%.

[0036] Example 3

[0037] Synthesis of 2,6-bis(aminomethyl)pyridine:

[0038] Under nitrogen protection, 2,6-pyridinediethanol (10 g, 0.072 mol) and tributylphosphine (29.1 g, 0.144 mol) were added to 100 mL of tetrahydrofuran. DIAD (30.5 g, 0.151 mol) was added dropwise at 0 °C, and the reaction was stirred at 0 °C for 0.5 h after the addition was complete. DPPA (39.6 g, 0.144 mol) was then added dropwise, and the reaction was stirred at 50 °C for 8 h after the addition was complete. Tributylphosphine (29.1 g, 0.144 mol) was then added, and the reaction was stirred at 40 °C for 3 h. Water (5.2 g, 0.288 mol) was then added, and the reaction was stirred at 30 °C for 12 h. The solvent was removed by vacuum distillation, and the solution was obtained by column chromatography with a purity of 98% and a yield of 81%.

[0039] Synthesis of 1,4,7,10-tetraaza-2,6-pyridine cyclophane:

[0040] 2,6-bis(aminomethyl)pyridine (137 g, 1 mol), benzotriazole (238 g, 2 mol), and benzimidazole (118 g, 1 mol) were added to 1600 mL of acetone. Diacetaldehyde amine (152 g, 1.5 mol) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 2 h. Then, sodium borohydride (37.8 g, 1 mol) was added, and the mixture was stirred at 20 °C for 5 h. The mixture was filtered, and the filtrate was concentrated to remove acetone. 600 mL of toluene was added, and the mixture was refluxed under normal pressure to remove water. After the water was completely removed, the mixture was cooled to 20 °C, filtered, and the filtrate was concentrated under reduced pressure until no obvious distillate was distilled off. Column chromatography was performed to obtain 1,4,7,10-tetraaza-2,6-pyridine cyclophosphide with a yield of 75% and a purity greater than 99%.

[0041] Comparative Example 1

[0042] Synthesis of 1,4,7,10-tetraaza-2,6-pyridine cyclophane:

[0043] 137 g of 2,6-bis(aminomethyl)pyridine (1 mol) was added to 1600 mL of ethanol, and diacetaldehyde amine (106 g, 1.05 mol) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 3 h. Then, sodium borohydride (52 g, 1.37 mol) was added, and the mixture was stirred at 20 °C for 5 h. The mixture was filtered, and the filtrate was concentrated to remove the ethanol. 600 mL of toluene was added, and the mixture was refluxed under normal pressure to remove water. After the water was completely removed, the mixture was cooled to 20 °C, filtered, and the filtrate was concentrated under reduced pressure until no obvious distillate was distilled off. Column chromatography was performed to obtain 1,4,7,10-tetraaza-2,6-pyridine cyclophosphide with a yield of 10% and a purity of 98%.

[0044] Comparative Example 2

[0045] Synthesis of 1,4,7,10-tetraaza-2,6-pyridine cyclophane:

[0046] 2,6-bis(aminomethyl)pyridine (137 g, 1 mol) was added to 1600 mL of acetonitrile, and diacetaldehyde amine (152 g, 1.5 mol) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 3 h. Then, lithium aluminum hydride (75.9 g, 2 mol) was added, and the mixture was stirred at 30 °C for 3 h. The mixture was filtered, and the filtrate was concentrated to remove acetonitrile. Then, 600 mL of toluene was added, and the mixture was refluxed under normal pressure to remove water. After the water was completely removed, the mixture was cooled to 20 °C, filtered, and the filtrate was concentrated under reduced pressure until no obvious distillate was distilled off. Column chromatography was performed to obtain 1,4,7,10-tetraaza-2,6-pyridine cyclophosphide with a yield of 13% and a purity of 98%.

[0047] As can be seen from Examples 1-3 and Comparative Examples 1-2, the use of catalyst in the reductive amination ring-closing reaction is a key factor affecting the yield of 1,4,7,10-tetraaza-2,6-pyridine cyclopartite. However, in Examples 1-3 using benzotriazole or benzimidazole as catalysts, the yield of 1,4,7,10-tetraaza-2,6-pyridine cyclopartite was not high, with an average yield of less than 80%. Further catalyst screening is needed to improve the yield of 1,4,7,10-tetraaza-2,6-pyridine cyclopartite. The inventors used organic bases such as triethylamine, ethylenediamine, pyridine, and sodium tert-butoxide, as well as transition metal salts or complexes such as copper, zinc, iron, cobalt, vanadium, and nickel as catalysts. From these, tetraphenylporphyrin copper was selected as having excellent catalytic activity, which can substantially improve the yield of 1,4,7,10-tetraaza-2,6-pyridine cyclopartite, reduce the amount of catalyst used, and control catalyst costs through recycling. The reductive amination cyclization reaction described in this invention comprises a two-step reaction: an addition reaction of 2,6-bis(aminomethyl)pyridine with diacetaldehyde amine to form an intermediate, followed by a reduction reaction of the intermediate to yield 1,4,7,10-tetraaza-2,6-pyridine cyclopane. Furthermore, the catalyst for the addition reaction is tetraphenylporphyrin copper; the reducing agent for the reduction reaction is at least one selected from sodium borohydride, lithium aluminum hydride, hydrogen, hydrazine hydrate, ammonium formate, formic acid, and a triethylamine / formic acid azeotrope; and the molar ratio of 2,6-bis(aminomethyl)pyridine to diacetaldehyde amine, catalyst, and reducing agent is 1:(1–1.5):(0.1–0.3):(1–2).

[0048] Example 4

[0049] Synthesis of 1,4,7,10-tetraaza-2,6-pyridine cyclophane:

[0050] 2,6-bis(aminomethyl)pyridine (137 g, 1 mol) and tetraphenylporphyrin copper (68 g, 0.1 mol) were added to 1600 mL of ethanol. Diacetaldehyde amine (106 g, 1.05 mol) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 3 h. Then, sodium borohydride (52 g, 1.37 mol) was added, and the mixture was stirred at 20 °C for 5 h. The mixture was filtered, and the filtrate was concentrated to remove ethanol. 600 mL of toluene was added, and the mixture was refluxed under normal pressure to remove water. After the water was completely removed, the mixture was cooled to 20 °C, filtered, and the filtrate was concentrated under reduced pressure until no obvious distillate was distilled off. Column chromatography was performed to obtain 1,4,7,10-tetraaza-2,6-pyridine cyclophosphide with a yield of 85% and a purity greater than 99%.

[0051] Example 5

[0052] Synthesis of 1,4,7,10-tetraaza-2,6-pyridine cyclophane:

[0053] 2,6-bis(aminomethyl)pyridine (137 g, 1 mol) and tetraphenylporphyrin copper (135 g, 0.2 mol) were added to 1600 mL of acetonitrile. Diacetaldehyde amine (152 g, 1.5 mol) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 3 h. Then, lithium aluminum hydride (75.9 g, 2 mol) was added, and the mixture was stirred at 30 °C for 3 h. The mixture was filtered, and the filtrate was concentrated to remove acetonitrile. 600 mL of toluene was added, and the mixture was refluxed under normal pressure to remove water. After the water was completely removed, the mixture was cooled to 20 °C, filtered, and the filtrate was concentrated under reduced pressure until no obvious distillate was distilled off. Column chromatography was performed to obtain 1,4,7,10-tetraaza-2,6-pyridine cyclophosphide with a yield of 90% and a purity greater than 99%.

[0054] Example 6

[0055] Synthesis of 1,4,7,10-tetraaza-2,6-pyridine cyclophane:

[0056] 2,6-bis(aminomethyl)pyridine (137 g, 1 mol), tetraphenylporphyrin copper (203 g, 0.3 mol), and benzimidazole (118 g, 1 mol) were added to 1600 mL of acetone. Diacetaldehyde amine (152 g, 1.5 mol) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 2 h. Then, sodium borohydride (37.8 g, 1 mol) was added, and the mixture was stirred at 20 °C for 5 h. The mixture was filtered, and the filtrate was concentrated to remove acetone. 600 mL of toluene was added, and the mixture was refluxed under normal pressure to remove water. After the water was completely removed, the mixture was cooled to 20 °C, filtered, and the filtrate was concentrated under reduced pressure until no obvious distillate was distilled off. Column chromatography was performed to obtain 1,4,7,10-tetraaza-2,6-pyridine cyclophosphide with a yield of 93% and a purity greater than 99%.

[0057] As can be seen from Examples 1 to 6, using tetraphenylporphyrin copper instead of benzotriazole and benzimidazole as the catalyst for the reductive amination cyclization reaction described in this invention can increase the yield of 1,4,7,10-tetraaza-2,6-pyridinecyclobisene while reducing the amount of catalyst used, making it suitable for the industrial production of 1,4,7,10-tetraaza-2,6-pyridinecyclobisene.

[0058] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing 1,4,7,10-tetraaza-2,6-pyridine cycloaven, characterized in that, Includes the following steps: S1, 2,6-pyridinediethanol reacts with diphenyl azidophosphate via the Mitsunobu reaction to give 2,6-bis(azidomethyl)pyridine; S2, 2,6-bis(azidomethyl)pyridine undergoes a Staudinger reaction to give 2,6-bis(aminomethyl)pyridine; S3, 2,6-bis(aminomethyl)pyridine undergoes a reductive amination cyclization reaction with diacetaldehyde amine to give 1,4,7,10-tetraaza-2,6-pyridine cyclophosphide; The synthesis route is as follows:

2. The method for synthesizing 1,4,7,10-tetraaza-2,6-pyridine cycloaven according to claim 1, characterized in that: The reaction solvent for the Mitsunobu reaction is at least one of the following: ketone solvents, ester solvents, ether solvents, amide solvents, sulfoxide solvents, aromatic solvents, alkane solvents, halogenated hydrocarbon solvents, and nitrile solvents.

3. The method for synthesizing 1,4,7,10-tetraaza-2,6-pyridine cycloaven according to claim 1, characterized in that: The Mitsunobu reaction is carried out under the catalysis of organophosphorus reagents and azo reagents; Preferably, the organophosphorus reagent is at least one of triarylphosphine and trialkylphosphine; Preferably, the azo reagent is at least one of azodicarbonate and azodicarbonamide.

4. The method for synthesizing 1,4,7,10-tetraaza-2,6-pyridine cycloaven according to claim 1, characterized in that: The Mitsunobu reaction was carried out at a temperature of 0–50 °C for a time of 0.5–24 h.

5. The method for synthesizing 1,4,7,10-tetraaza-2,6-pyridine cycloaven according to claim 1, characterized in that: The molar ratio of 2,6-pyridinediethanol, organophosphoric reagent, azo reagent, and diphenyl azidophosphate is 1:(1-2):(1.5-3):(2-4).

6. The method for synthesizing 1,4,7,10-tetraaza-2,6-pyridine cycloaven according to claim 1, characterized in that: The Staudinger reaction comprises two steps: an addition reaction of 2,6-bis(azidomethyl)pyridine with an organophosphorus reagent to form an intermediate, and a hydrolysis reaction of the intermediate to obtain 2,6-bis(aminomethyl)pyridine. Preferably, the organophosphorus reagent is at least one of triarylphosphine and trialkylphosphine; Preferably, the molar ratio of 2,6-bis(azidomethyl)pyridine to organophosphorus reagent is 1:(1-2).

7. The method for synthesizing 1,4,7,10-tetraaza-2,6-pyridine cycloaven according to claim 1, characterized in that: The Staudinger reaction was carried out at a temperature of 20–50 °C for a time of 0.5–24 h.

8. The method for synthesizing 1,4,7,10-tetraaza-2,6-pyridine cyclophane according to claim 1, characterized in that: The reductive amination cyclization reaction comprises a two-step reaction: an addition reaction of 2,6-bis(aminomethyl)pyridine with diacetaldehyde amine to form an intermediate, and a reduction reaction of the intermediate to obtain 1,4,7,10-tetraaza-2,6-pyridine cyclopane. Preferably, the catalyst for the addition reaction is at least one of benzotriazole and benzimidazole; Preferably, the reducing agent in the reduction reaction is at least one of sodium borohydride, lithium aluminum hydride, hydrogen, hydrazine hydrate, ammonium formate, formic acid, and triethylamine / formic acid azeotrope; Preferably, the molar ratio of 2,6-bis(aminomethyl)pyridine to diacetaldehyde amine, catalyst, and reducing agent is 1:(1-1.5):(2-5):(1-2).

9. The method for synthesizing 1,4,7,10-tetraaza-2,6-pyridine cycloaven according to claim 1, characterized in that: The reductive amination cyclization reaction is carried out at a temperature of 0–30 °C for 2–10 h.

10. The method for synthesizing 1,4,7,10-tetraaza-2,6-pyridine cycloaven according to claim 1, characterized in that: The reaction solvents for the reductive amination cyclization reaction are water and organic solvents; Preferably, the organic solvent is at least one of alcohol solvents, ether solvents, ester solvents, nitrile solvents, halogenated hydrocarbon solvents, ketone solvents, and aromatic hydrocarbon solvents.

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