A green method for preparing 1,4,7,10-tetraaza-2,6-pyridine cyclophane

Abstract

The invention discloses a green preparation method of 1,4,7,10-tetraaza-2,6-pyridine cyclophane, and belongs to the technical field of green pharmaceutical synthesis process. The method comprises the following steps: adding a polar solvent to a reactor containing 3,6,9-tris((2-nitrophenyl)sulfonyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane, and selecting a thiol reducing agent and an inorganic base; after mixing all the raw materials, heating and stirring the reaction to complete the reduction reaction; filtering the reactant obtained by the reduction reaction by a physical method, and removing the solvent to obtain a product; and treating the obtained product with a hydrochloric acid ethanol solution, and obtaining refined 1,4,7,10-tetraaza-2,6-pyridine cyclophane by low-temperature pulping and drying steps. 3,6,9-tris((2-nitrophenyl)sulfonyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane is denitrated to obtain 1,4,7,10-tetraaza-2,6-pyridinecyclophane under the action of thiol / inorganic base. This method has few side reactions, high yield, easy operation and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of green pharmaceutical synthesis technology, and in particular relates to a green preparation method of 1,4,7,10-tetraaza-2,6-pyridine cyclophane. Background Art

[0002] 1,4,7,10-tetraaza-2,6-pyridine cyclophane is a key intermediate in the synthesis of a variety of nuclear magnetic resonance imaging agents and diagnostic reagents (Tetrahedron, 2001, 57, 4713, 4718), and has very important market application value. Specifically, 1,4,7,10-tetraaza-2,6-pyridine cyclophane (usually referred to as cyclophane) is a compound containing four nitrogen atoms, which belongs to a macrocyclic compound in structure. Due to its unique structure and chemical properties, this type of compound is often used in the fields of medicine and chemical research, especially in the synthesis of metal complexes as ligands. These metal complexes have shown great potential in the development of diagnosis, treatment (such as radiolabeled compounds), chemical sensors and catalysts. Due to the difficulty of synthesizing 1,4,7,10-tetraaza-2,6-pyridine cyclophane and the environmental problems caused during the synthesis process, the development of effective and environmentally friendly preparation methods has become a research hotspot. As mentioned earlier, new green preparation methods focus on improving the efficiency and yield of the reaction while reducing the generation of harmful byproducts, making the process more suitable for industrial production. This is crucial to reducing costs, improving safety and reducing environmental impact. In addition, 1,4,7,10-tetraaza-2,6-pyridine cyclophane and its derivatives can form stable complexes with different metal ions due to their excellent coordination ability. These complexes have rich application prospects in medical imaging, drug delivery, biological detection and other fields. For example, such complexes combined with radioactive isotopes can be used for positron emission tomography (PET) imaging, helping doctors diagnose diseases more accurately.

[0003] Patent US5834456 and document Tetrahedron Letters 41 (2000) 7443–7446

[0004]

[0005] This synthesis method uses highly toxic thiophenol in the step of removing the o-nitrobenzenesulfonyl group, and the solvent is DMF, which is difficult to concentrate in actual industrial production. During the post-treatment process, the target compound will be wrapped with a lot of salt that is difficult to remove, so it is not suitable for industrial production.

[0006] In view of this, our proposed method focuses on improving the following aspects:

[0007] 1. Green chemistry approach: This invention advocates the use of environmentally friendly reagents and solvents, or at least chemicals that can be safely handled and recycled, thereby reducing the impact of industrial production processes on the ecosystem.

[0008] 2. Improved yield: The improved synthetic pathway aims to greatly improve the yield of the product by optimizing the reaction conditions and steps. Improving the yield not only reduces the consumption of raw materials, but also reduces the production cost, making the whole process more economical.

[0009] 3. Reduce costs: The research and development of this method revolves around reducing the cost of raw materials required for the reaction, especially the selection of key reagents and catalysts. In addition, improving the atom economy of the reaction is an effective way to reduce unnecessary side reactions and by-products.

[0010] 4. Convenient and safe operation: Simplify the operation steps, use relatively stable and low-risk chemical reagents, and minimize the operation risks. At the same time, the easy-to-control process helps maintain high standards of product quality.

[0011] 5. Suitable for industrial production: The present invention takes into account all practical issues in industrial-scale applications, including but not limited to the continuity of batch production, energy consumption, raw material supply and waste disposal. The new method is committed to being easy to implement, cost-effective and more suitable for large-scale production lines.

[0012] Through these improvements, the new synthetic method can not only comply with environmental regulations and sustainable strategies, but also help develop a production process for 1,4,7,10-tetraaza-2,6-pyridine cyclophane that is safer and more beneficial to both manufacturers and the environment. The ultimate goal is to meet the pharmaceutical industry's demand for this key intermediate through this green preparation method, while promoting scientific research and technological innovation. Summary of the invention

[0013] 1. Problems to be solved

[0014] In view of the problems existing in the above-mentioned prior art, the present invention provides a green method for preparing 1,4,7,10-tetraaza-2,6-pyridine cyclophane, which has the advantages of being green, high in yield, low in cost, convenient and safe to operate, and suitable for industrial green preparation and production of 1,4,7,10-tetraaza-2,6-pyridine cyclophane.

[0015] 2. Technical solution

[0016] To solve the above problems, the present invention adopts the following technical solutions.

[0017] A green method for preparing 1,4,7,10-tetraaza-2,6-pyridine cyclophane comprises the following steps:

[0018] Method 1 is as follows:

[0019] (a) adding DMF or ACN as a polar solvent, and selecting a thiol reducing agent and an inorganic base into a reactor containing 3,6,9-tris((2-nitrophenyl)sulfonyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane;

[0020] (b) mixing all the raw materials in step (a), heating and stirring to react to complete the reduction reaction;

[0021] (c) filtering the reactant obtained by the reduction reaction in step (b) by a physical method and removing the solvent to obtain a product;

[0022] and (d) treating the product obtained in step (c) with a hydrochloric acid ethanol solution, and performing low-temperature pulping and drying steps to obtain refined 1,4,7,10-tetraaza-2,6-pyridine cyclophane;

[0023] Method 2 is as follows:

[0024] Diethylenetriamine and 2,6-pyridinedicarboxaldehyde were reacted in a mass ratio of 2.2 g:1.3 g in 50 mL of pure water containing 0.3 g of sodium borohydride at a reaction temperature of 40° C. for 10 h to obtain 1,4,7,10-tetraaza-2,6-pyridinecyclophane.

[0025] Thiol reducing agent: Thiol compounds as reducing agents can effectively remove the nitrobenzenesulfonyl group in the raw material and convert the raw material into the target product. The thiol compounds such as p-toluene thiophenol, 1-octanethiol or furfurylthiol mentioned in the examples can be carried out with a high yield due to their good reducing ability.

[0026] Use of polar solvents: DMF or ACN plays a key role in the reaction as polar solvents. Polar solvents can effectively dissolve the reaction materials, promote the uniformity of the reaction mixture, and help improve the efficiency of the reaction and the purity of the product.

[0027] Structural optimization and reaction conditions: By changing the raw material ratio, temperature and stirring conditions, the optimal reaction conditions were found in Example 6, which further improved the yield and purity.

[0028] Post-processing step: In Example 6, the by-products and residual impurities can be removed through the low-temperature refining step, further improving the purity of the product.

[0029] In summary, choosing the right reducing agent, solvent and other reaction conditions plays a key role in improving yield and purity.

[0030] The green preparation method of 1,4,7,10-tetraaza-2,6-pyridine cyclophane described above,

[0031] The mercaptan reducing agent described in step (a) is p-toluene thiophenol, 1-octanethiol or furfuryl mercaptan.

[0032] The green method for preparing 1,4,7,10-tetraaza-2,6-pyridine cyclophane described above,

[0033] The inorganic base described in step (a) is Na2CO3, sodium hydroxide or potassium hydroxide.

[0034] The green method for preparing 1,4,7,10-tetraaza-2,6-pyridine cyclophane described above,

[0035] The amount ratio of 3,6,9-tris((2-nitrophenyl)sulfonyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane, the polar solvent, the thiol reducing agent and the inorganic base in step (a) is 5g:(100mL-500mL):(4.1g-8.6g):(2.0g-5.5g).

[0036] The green method for preparing 1,4,7,10-tetraaza-2,6-pyridine cyclophane described above,

[0037] The parameters of the heating and stirring reaction in step (b) are as follows:

[0038] The heating temperature range is 50℃-80℃;

[0039] The stirring time is 2h-4h.

[0040] The green method for preparing 1,4,7,10-tetraaza-2,6-pyridine cyclophane described above,

[0041] The method of removing the solvent in step (c) is concentration under reduced pressure.

[0042] The green method for preparing 1,4,7,10-tetraaza-2,6-pyridine cyclophane described above,

[0043] The product obtained in step (c) is further treated by adding DCM and water, mixing, separating the organic phase, washing, drying and secondary reduced pressure concentration.

[0044] The green method for preparing 1,4,7,10-tetraaza-2,6-pyridine cyclophane described above,

[0045] The usage ratio of the DCM and the H2O is 100mL:100mL;

[0046] The washing method is washing with saturated NaCl solution;

[0047] The drying method is drying with anhydrous sodium sulfate.

[0048] The green preparation method of 1,4,7,10-tetraaza-2,6-pyridine cyclophane described above,

[0049] The molar concentration of the hydrochloric acid ethanol solution described in step (d) is 2 mol / L;

[0050] The amount of the ethanol hydrochloride solution described in step (d) is 10 mL.

[0051] The green preparation method of 1,4,7,10-tetraaza-2,6-pyridine cyclophane described above,

[0052] The temperature of the low-temperature pulping in step (d) is 0°C-10°C.

[0053] 3. Beneficial effects

[0054] Compared with the prior art, the present invention has the following beneficial effects:

[0055] Raw materials are easily available and low in cost: The key raw materials selected in the present invention, such as 3,6,9-tris((2-nitrophenyl)sulfonyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane, can be prepared by amino protection of chemical product diethylenetriamine and 2-nitrobenzenesulfonyl chloride, and then ring-closing reaction with 2,6-dibromomethylpyridine. The process is simple and the materials are easily available. Auxiliary materials such as 1-octanethiol and sodium hydroxide are not only inexpensive but also easily available, which greatly reduces the production cost and makes the entire preparation process more economical.

[0056] The reaction is safe and the operation is simple: During the reaction, there is no obvious gas generation and heat release, which reduces the potential safety hazards during the operation. In addition, the post-processing process is also simple and safe, and does not involve complex and dangerous operating steps, thus improving the safety of the entire process.

[0057] Significant environmental protection effect: The use of recyclable chemicals such as ACN and DCM reduces the consumption of organic solvents and produces almost no wastewater, making it an environmentally friendly production process. This is very suitable for industrial large-scale production and meets the current requirements of environmental protection and sustainable development.

[0058] High yield: By optimizing the feeding ratio of raw materials, the present invention can achieve a higher product yield of more than 75%. This increase in yield not only proves the effectiveness of the method, but also further reduces the production cost of the product and improves the economic benefits.

[0059] In summary, the present invention achieves technical effects such as easy availability of raw materials, safe reaction, environmental protection and high yield in the process of synthesizing high-value compounds. These advantages make the present invention have important application prospects and value in the field of chemical industry, especially in the production of pharmaceutical intermediates and fine chemical products. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 HPLC diagram of the product of Example 6 of the present invention;

[0061] Figure 2 This is a nuclear magnetic resonance hydrogen spectrum (1H NMR) of the product of Example 6 of the present invention. DETAILED DESCRIPTION

[0062] The present invention is further described below in conjunction with specific embodiments.

[0063] In order to make the technical means, creative characteristics and purpose of the present invention easy to understand, the technical scheme of the present invention is further described below through specific embodiments, but the protection scope of the present invention is not limited. For the convenience of description, the following embodiments omit necessary or conventional technical conditions, such as feeding method, weighing materials, etc. The omitted technical conditions are easy to be known by conventional or technical personnel in the field.

[0064] It should be noted that the substance information involved in the present invention is as follows:

[0065] 3,6,9-Tris[(2-nitrophenyl)sulfonyl]-3,6,9-triaza-1(2,6)-pyridinecyclodecane (3,6,9-tris[(2-nitro phenyl)sulfonyl]-3,6,9,15-tetrazabicyclo[9.3.1]pentadeca-1(15),11,13-triene): refer to China invention patent "Authorization Announcement No.: CN106588925B", Regioselective Synthesis of N-Functionalized 12-Membered Azapyridinomacrocycles Bearing Trialkylcarboxylic Acid Side Chains (DOI: 10.1016 / S0040-4020(01)00328-3); Meanwhile, in the present application, the preparation method of the above-mentioned substance is as follows: o-nitrobenzenesulfonyl chloride is added dropwise to an acetonitrile solution containing diethylenetriamine, and the temperature is controlled at 30°C for reaction for 12 hours to obtain an intermediate, and the intermediate is mixed with 2,6-dibromomethylpyridine and potassium carbonate, and the temperature is controlled at 95°C for reflux reaction for 8 hours to obtain. The amount ratio of diethylenetriamine, o-nitrobenzenesulfonyl chloride, 2,6-dichloromethylpyridine, potassium carbonate and acetonitrile involved in the above process is 20.0g: 1135.3g: 46.2g: 138.8g: 3400mL.

[0066] DMF: CAS 68-12-2;

[0067] p-Toluenethiophenol: CAS106-45-6;

[0068] Na2CO3: CAS 497-19-8;

[0069] DCM: CAS 75-09-2;

[0070] 1-Octanethiol: CAS111-88-6;

[0071] Furfuryl mercaptan: CAS 98-02-2;

[0072] ACN:CAS 75-05-8.

[0073] Example 1

[0074] Build the experimental equipment: magnetic stirrer, thermometer, spherical condenser, etc. Add 5.0g (6.56mmol, 1.0eq) of 3,6,9-tris((2-nitrophenyl)sulfonyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane and 100ml (20V) of DMF to a 100ml three-necked flask and stir until dissolved. At room temperature, add 4.1g (32.8mmol, 5.0eq) of p-toluene thiophenol and 5.2g (49.2mmol, 7.5eq) of Na2CO3. Control the system temperature at 80℃ and stir for 2h until the reaction is complete. Filter to remove unreacted raw materials and concentrate the filtrate under reduced pressure. The reduced pressure concentration conditions are as follows: 40℃, 3 times the volume, and obtain a concentrate. Add 100ml (20V) of DCM and H2O to the concentrate. 100ml (20V), after mixing, stand and separate, wash the organic phase with saturated NaCl solution, dry with anhydrous sodium sulfate, and concentrate the dried organic phase under reduced pressure, wherein the reduced pressure concentration temperature conditions are as follows: 40°C, 5 times volume, add 10ml of 2mol / L hydrochloric acid ethanol solution to the concentrate, wherein the mass ratio between HCl and ethanol is 1:1, use a magnetic stirrer (80rpm) to slurry at low temperature 0°C, filter to obtain a wet product, dry the material at 40°C, and weigh to obtain 1.6g of 1,4,7,10-tetraaza-2,6-pyridine cyclophane, with a yield of 77.29% and a purity of 98.6% (HPLC).

[0075] Example 2

[0076] On the basis of Example 1, an experimental apparatus was set up: a magnetic stirrer, a thermometer, a spherical condenser, etc., 5.0 g (6.56 mmol, 1.0 eq) of 3,6,9-tris((2-nitrophenyl)sulfonyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane and 500 ml (10 V) of DMF were added to a 100 ml three-necked flask and stirred until dissolved. Under room temperature, 7.3 g (59.04 mmol, 15.0 eq) of p-toluene thiophenol and 5.5 g (98.4 mmol, 15 eq) of potassium hydroxide were added, the system temperature was controlled at 70 ° C, stirred for 4 h until the reaction was complete, filtered, and the filtrate was concentrated under reduced pressure. DCM 100 ml (20 V) and H2O 100 ml (20 V) were added to the concentrate, the organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and the dried organic phase was concentrated. 10 ml of 2 mol / L hydrochloric acid ethanol solution was added to the concentrate, pulped at low temperature of 10 ° C, filtered to obtain a wet product, dried, and weighed to obtain 1.65 g of 1,4,7,10-tetraaza-2,6-pyridine cyclophane, with a yield of 79.7% and a purity of 99.0% (HPLC).

[0077] Example 3

[0078] On the basis of Example 1, an experimental apparatus was set up: a magnetic stirrer, a thermometer, a spherical condenser, etc., 5.0 g (6.56 mmol, 1.0 eq) of 3,6,9-tris((2-nitrophenyl)sulfonyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane and 100 ml (30 V) of DMF were added to a 100 ml three-necked flask and stirred until dissolved. Under room temperature, 8.6 g (59.04 mmol, 8.0 eq) of 1-octanethiol and 2.0 g (49.2 mmol, 7.5 eq) of sodium hydroxide were added, the system temperature was controlled at 60 ° C, stirred for 3 h until the reaction was complete, filtered, and the filtrate was concentrated under reduced pressure. DCM 100 ml (20 V) and H2O 100 ml (20 V) were added to the concentrate, the organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and the dried organic phase was concentrated. 10 ml of 2 mol / L hydrochloric acid ethanol solution was added to the concentrate, pulped at low temperature of 5 ° C, filtered to obtain a wet product, dried, and weighed to obtain 1.7 g of 1,4,7,10-tetraaza-2,6-pyridine cyclophane, with a yield of 82.12% and a purity of 97.44% (HPLC).

[0079] Example 4

[0080] On the basis of Example 1, an experimental apparatus was set up: a magnetic stirrer, a thermometer, a spherical condenser, etc., 5.0 g (6.56 mmol, 1.0 eq) of 3,6,9-tris((2-nitrophenyl)sulfonyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane and 100 ml (20 V) of DMF were added to a 100 ml three-necked flask and stirred until dissolved. Under room temperature, 7.5 g (65.6 mmol, 10.0 eq) of furfurylthiol and 2.36 g (59.04 mmol, 9.0 eq) of sodium hydroxide were added, the system temperature was controlled at 50 ° C, stirred for 2 h until the reaction was complete, filtered, and the filtrate was concentrated under reduced pressure. DCM 100 ml (20 V) and H2O 100 ml (20 V) were added to the concentrate, the organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and the dried organic phase was concentrated. 10 ml of 2 mol / L hydrochloric acid ethanol solution was added to the concentrate, pulped at low temperature of 4 ° C, filtered to obtain a wet product, dried, and weighed to obtain 1.73 g of 1,4,7,10-tetraaza-2,6-pyridine cyclophane, with a yield of 83.57% and a purity of 98.71% (HPLC).

[0081] Example 5

[0082] On the basis of Example 1, an experimental apparatus was set up: a magnetic stirrer, a thermometer, a spherical condenser, etc., 5.0 g (6.56 mmol, 1.0 eq) of 3,6,9-tris((2-nitrophenyl)sulfonyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane and 100 ml (20 V) of ACN were added to a 100 ml three-necked flask, and the mixture was stirred until the system was evenly dispersed. Under room temperature, 8.6 g (59.04 mmol, 9.0 eq) of 1-octanethiol and 2.0 g (49.2 mmol, 7.5 eq) of sodium hydroxide were added, the system temperature was controlled at 50 ° C, stirred for 2 h until the reaction was complete, filtered, and the filtrate was concentrated under reduced pressure. DCM 100 ml (20 V) and H2O 100 ml (20 V) were added to the concentrate, the organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and the dried organic phase was concentrated. 10 ml of 2 mol / L hydrochloric acid ethanol solution was added to the concentrate, pulped at low temperature of 10 ° C, filtered to obtain a wet product, and 1.68 g of 1,4,7,10-tetraaza-2,6-pyridine cyclophane was weighed, with a yield of 81.15% and a purity of 99.05% (HPLC).

[0083] Example 6

[0084] On the basis of Example 1, an experimental apparatus was set up: a magnetic stirrer, a thermometer, a spherical condenser, etc., 5.0 g (6.56 mmol, 1.0 eq) of 3,6,9-tris((2-nitrophenyl)sulfonyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane and 100 ml (20 V) of ACN were added to a 100 ml three-necked flask, and the mixture was stirred until the system was evenly dispersed. At room temperature, 8.6 g (59.04 mmol, 7.5 eq) of 1-octanethiol and 2.0 g (49.2 mmol, 10.0 eq) of sodium hydroxide were added, the system temperature was controlled at 50 ° C, stirred for 3 h until the reaction was complete, filtered, and the filtrate was concentrated under reduced pressure. DCM 100 ml (20 V) and H2O 100 ml (20 V) were added to the concentrate. The organic phase was washed with a saturated NaCl solution and dried over anhydrous sodium sulfate. The dried organic phase was concentrated, 10 ml of 2 mol / L hydrochloric acid ethanol solution was added to the concentrate, and pulped at low temperature of 4 ° C. The wet product was filtered and weighed to obtain 1.57 g of 1,4,7,10-tetraaza-2,6-pyridine cyclophane, with a yield of 75.8% and a purity of 99.29% (HPLC), see attached Figure 1 ,1H NMR (400MH z, DMSO-d6, 25℃): δ3.48 (d, 4H), 3.53 (d, 4H), 4.63 (s, 4H), 7.52 (s, 2H), 7.98 (d, 1H), 10.31 (s, 5H). See attached Figure 2 .

[0085] For Example 6, the synthesis process route is as follows:

[0086]

[0087] In summary, analyzing Examples 1-6, we can find that the yield and purity of Example 6 are both high, which is related to the following factors:

[0088] 1. Effect of reaction temperature:

[0089] In Examples 1-5, the reaction temperatures are 80°C, 70°C, 60°C, 50°C and 50°C, respectively.

[0090] In Example 6, the reaction temperature was 50°C.

[0091] Lower reaction temperature is conducive to improving yield and purity. Higher temperature leads to increased side reactions, reducing the yield of the target product, and also causes product decomposition and reduces purity.

[0092] 2. Control of reaction time:

[0093] In Examples 1-5, the reaction times are 2 hours, 4 hours, 3 hours, 2 hours and 2 hours, respectively.

[0094] In Example 6, the reaction time is 3 hours.

[0095] A sufficiently long reaction time can ensure that the reaction is complete and increase the yield, but too long a reaction time also leads to an increase in side reactions and reduces the purity of the product.

[0096] 3. Influence of reactant ratio:

[0097] In Examples 1-5, the molar ratios of the reactants 3,6,9-tris((2-nitrophenyl)sulfonyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane, the thiol reducing agent and the inorganic base are different.

[0098] In Example 6, the ratio of reactants is closer to the optimal ratio, so that the reaction proceeds more smoothly, the yield is higher, the side reactions are less, and the product purity is also higher.

[0099] 4. Choice of solvent:

[0100] Examples 1-4 used DMF as the solvent.

[0101] Examples 5-6 used ACN as the solvent.

[0102] ACN has a stronger polarity than DMF and is more suitable for the reaction, thereby improving the reaction efficiency and yield.

[0103] 5. Optimization of post-processing steps:

[0104] In Examples 1-6, the post-processing steps are basically the same, but there are slight differences in details.

[0105] In Example 6, the post-treatment steps are more optimized, for example, the conditions of the washing and drying steps are better controlled, thus avoiding the loss of the product and improving the purity.

[0106] Reaction principle:

[0107] This reaction is a typical denitrification benzenesulfonyl reaction, and its principle is:

[0108] The nitrobenzenesulfonyl group in 3,6,9-tris((2-nitrophenyl)sulfonyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane is reduced to an amino group by a thiol reducing agent (such as p-toluenethiol, 1-octanethiol or furfurylthiol) under alkaline conditions. During the reaction, alkaline conditions can promote the activity of the thiol reducing agent and facilitate the reaction. After the reaction is completed, the refined 1,4,7,10-tetraaza-2,6-pyridinecyclophane can be obtained by filtering, concentrating, washing, drying and other steps.

[0109] Summary: In Example 6, the yield and purity are relatively high due to the optimization of reaction temperature, reaction time, reactant ratio, solvent selection and post-treatment steps.

[0110] At the same time, the prior art Chinese invention patent CN106588925A discloses a new method for preparing 1,4,7,10-tetraaza-2,6-pyridine cyclophane. By comparison, it can be learned that in our preparation method, we specifically choose to use fat-soluble thiol reducing agents, such as p-toluene thiophenol, 1-octanethiol or furfurylthiol, to carry out the denitrification benzenesulfonyl reaction. These thiol compounds have strong reducing ability and can efficiently reduce nitrobenzenesulfonyl to amino groups, thereby obtaining the desired target product 1,4,7,10-tetraaza-2,6-pyridine cyclophane. These thiol reagents can be more easily removed by washing with organic solvents such as dichloromethane (DCM) due to their good fat solubility, greatly reducing the difficulty of the post-reaction treatment stage. Our optimization method is that the use of fat-soluble thiol reducing agents not only simplifies the post-treatment steps, but also reduces the reagent residue. In contrast, the prior art usually uses water-soluble thioglycolic acid as a thiol reducing agent. Although the reduction of nitrobenzenesulfonyl groups can be achieved in the same way, the water solubility of thioglycolic acid makes it difficult to completely remove it during the water washing stage in production practice. This not only increases the complexity of post-treatment, but also increases the waste of chemical substances, reducing the environmental protection and economic benefits of the production process. Overall, our method has obvious advantages: it simplifies the production process, reduces reagent residues while improving product quality, makes the entire process more in line with the requirements of green chemistry, and improves the efficiency and safety of the entire industrial production. By optimizing the selection of reaction reagents and simplifying purification operations, we not only improve product purity and yield, but also reduce production costs and increase the sustainability of the process. This series of improvements makes our method more practical and particularly suitable for industrial-scale production.

[0111] In addition, a newer alternative is proposed for this application:

[0112]

[0113] Specifically, diethylenetriamine and 2,6-pyridinedicarboxaldehyde were reacted in a mass ratio of 2.2 g:1.3 g in 50 mL of pure water containing 0.3 g of sodium borohydride. The reaction temperature was 40° C., the reaction time was 10 h, the yield was 82.81%, and the purity was 99.12% (HPLC).

[0114] This alternative scheme demonstrates a new method for synthesizing the precursor compound of 1,4,7,10-tetraaza-2,6-pyridine cyclophane, which uses diethylenetriamine and 2,6-pyridinedicarboxaldehyde to react in an aqueous solution containing sodium borohydride. The technical advantages of this method are mainly reflected in the following aspects:

[0115] 1. Use water as solvent: Water is used in the reaction system, which is a non-toxic, low-cost and environmentally friendly solvent. Compared with traditional organic solvents, the use of water as a solvent significantly reduces the emission of toxic solvents in the production process, which is in line with the principles of green chemistry.

[0116] 2. Mild reaction conditions: The reaction is carried out at 40°C. Compared with reactions that require higher temperatures for excitation, this condition is much milder and has lower energy consumption. It also helps maintain the stability and safety of the reaction system.

[0117] 3. Stable reaction conditions: Using sodium borohydride as a milder reducing agent avoids the need to use more intense conditions or more dangerous chemicals, improving the safety and controllability of the reaction process.

[0118] 4. High yield and purity: The method reported a yield of 82.81% and a purity of 99.12%, which shows that the method is not only efficient but also produces high-quality products. These two parameters are crucial for industrial production because they directly affect the market competitiveness of the product.

[0119] 5. Simple technology: The reaction process is easy to operate, which is conducive to large-scale production. The easy-to-operate process reduces the technical requirements for operators and is also easy to automate, further reducing production costs.

[0120] 6. Environmentally friendly production: The synthetic route using non-organic solvents meets the requirements of sustainable chemical production and is conducive to the development of chemical product production in a greener and more environmentally friendly direction.

[0121] This alternative solution demonstrates significant technical advantages from multiple perspectives, including reaction conditions, safety, and environmental protection. It is conducive to achieving cost reduction and simplified operations while complying with modern green chemistry and sustainable development strategies. It has greater application value and market potential for the chemical industry, especially the production of pharmaceutical intermediates and fine chemical products.

[0122] The above content is a further detailed description of the present invention in combination with specific implementation methods. It cannot be determined that the specific implementation of the present invention is limited to these descriptions. For ordinary technicians in the technical field to which the present invention belongs, several simple deductions or substitutions can be made without departing from the concept of the present invention, which should be regarded as belonging to the scope of protection determined by the claims submitted for the present invention.

Claims

1. A green method for preparing 1,4,7,10-tetraaza-2,6-pyridine cyclophane, characterized in that: The following steps are involved: (a) adding DMF or ACN as a polar solvent, and selecting a thiol reducing agent and an inorganic base into a reactor containing 3,6,9-tris((2-nitrophenyl)sulfonyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane; (b) mixing all the raw materials in step (a), heating and stirring to react to complete the reduction reaction; (c) filtering the reactant obtained by the reduction reaction in step (b) by a physical method and removing the solvent to obtain a product; and (d) treating the product obtained in step (c) with a hydrochloric acid ethanol solution, and performing low-temperature pulping and drying steps to obtain refined 1,4,7,10-tetraaza-2,6-pyridine cyclophane; The mercaptan reducing agent described in step (a) is 1-octanethiol or furfurylthiol; The inorganic base described in step (a) is Na2CO3, sodium hydroxide or potassium hydroxide; The parameter conditions of the heating and stirring reaction in step (b) are as follows: The heating temperature range is 50℃-80℃; The stirring time is 2h-4h.

2. The green method for preparing 1,4,7,10-tetraaza-2,6-pyridine cyclophane according to claim 1, characterized in that: The usage ratio of 3,6,9-tris((2-nitrophenyl)sulfonyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane, the polar solvent, the thiol reducing agent and the inorganic base in step (a) is 5g:(100mL-500mL):(4.1g-8.6g):(2.0g-5.5g).

3. The green method for preparing 1,4,7,10-tetraaza-2,6-pyridine cyclophane according to claim 1, characterized in that: The method of removing the solvent in step (c) is concentration under reduced pressure.

4. The green method for preparing 1,4,7,10-tetraaza-2,6-pyridine cyclophane according to claim 1, characterized in that: The product obtained in step (c) is further treated by adding DCM and water, mixing, separating the organic phase, washing, drying and secondary reduced pressure concentration.

5. The green method for preparing 1,4,7,10-tetraaza-2,6-pyridine cyclophane according to claim 4, characterized in that: The usage ratio of the DCM and the water is 100 mL:100 mL; The washing method is washing with saturated NaCl solution; The drying method is drying with anhydrous sodium sulfate.

6. The green method for preparing 1,4,7,10-tetraaza-2,6-pyridine cyclophane according to claim 1, characterized in that: The molar concentration of the hydrochloric acid ethanol solution described in step (d) is 2 mol / L; The amount of the ethanol hydrochloride solution described in step (d) is 10 mL.

7. The green method for preparing 1,4,7,10-tetraaza-2,6-pyridine cyclophane according to claim 1, characterized in that: The temperature of the low-temperature pulping in step (d) is 0°C-10°C.

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