Macrocyclic polyamine organic ligand molecule and synthesis method thereof
By directly using N,N’-dimethylethylenediamine and chloroacetyl chloride, 4,7,13,16-tetramethyl-1,10-ethyl-1,4,7,10,13,16-hexazazocyclooctadecane was synthesized through three-step reaction, which solved the problems of complex and high cost in the existing process and achieved a high-efficiency and low-cost synthesis process.
Patent Information
- Application Number
- CN202411475028.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-22
- Publication Date
- 2025-03-25
AI Technical Summary
The synthesis process of existing macrocyclic polyamine organic ligand molecules is complex, involving protection and deprotection unit reactions, resulting in low atomic utilization, high production costs, and is not suitable for large-scale production.
N,N’-dimethylethylenediamine and chloroacetyl chloride were used as raw materials, and through three steps of reaction: amidation reaction, substitution reaction and carbonyl reduction reaction, 4,7,13,16-tetramethyl-1,10-ethyl-1,4,7,10,13,16-hexazazocyclooctadecane was directly synthesized, avoiding protection and deprotection operations.
It has achieved efficient synthesis of macrocyclic polyamine organic ligand molecules, with high atomic utilization rate and low production cost, suitable for large-scale production, and simplified process flow.
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Abstract
Description
Technical Field
[0001] The invention relates to a macrocyclic polyamine organic ligand molecule and a synthesis method thereof. Background Art
[0002] Saturated macrocyclic polyamines, also called saturated allazacrown ethers, have similar functions to active substances such as porphyrins and biopolyamines in organisms. Compared with ordinary monodentate or polydentate ligands, the complexes formed by saturated macrocyclic polyamines containing multiple donor N atoms and transition metal ions have higher thermodynamic stability and kinetic inertness, which lays the foundation for their application in functional mimicry of metalloproteins and metalloenzymes and coordination catalysis. Therefore, the synthesis and property research of macrocyclic polyamine ligands and their complexes have become a hot area in organic chemistry research.
[0003] In recent years, the synthesis and properties of bridged bis(cyclic polyamines) have attracted people's attention. The most striking property of bridged bis(cyclic polyamines) is that they can form binuclear metal complexes with transition metals and heavy metal ions. At present, their binuclear metal complexes have been used in the study of multi-electron redox behavior, organic substrate receptors, and the simulation of active sites of metal proteins. At present, the most widely used in industry is the bridged bis(triazacyclononane) compound with the following structure I:
[0004]
[0005] Andrea E. Martin (J. Org. Chem., V47, No3, 1982. p412) of the University of Delaware mentioned another macrocyclic polyamine organic ligand molecule with a bicyclic ring that can also form a binuclear complex when synthesizing the above-mentioned bridged bis (nitrogen heterocyclic) compound, as shown in the following formula II:
[0006]
[0007] Structurally, this bicyclic macrocyclic polyamine organic ligand molecule can still provide three nitrogen atoms with lone pairs of electrons in each ring, and can also form binuclear metal complexes with transition metals and heavy metal ions. The synthesis and study of this type of bicyclic macrocyclic polyamine organic ligand molecule has great scientific and commercial significance.
[0008] 4,7,13,16-Tetramethyl-1,10-ethylene-1,4,7,10,13,16-hexaazacyclooctadecane is the most symmetrical one among the above-mentioned structures of formula II, and is also the most stable one. Summary of the invention
[0009] The purpose of the present invention is to provide a macrocyclic polyamine organic ligand molecule and a synthesis method thereof, namely a synthesis method of 4,7,13,16-tetramethyl-1,10-ethylene-1,4,7,10,13,16-hexaazacyclooctadecane. The chemical structural formula of 4,7,13,16-tetramethyl-1,10-ethylene-1,4,7,10,13,16-hexaazacyclooctadecane is as follows:
[0010]
[0011] The synthesis method of 4,7,13,16-tetramethyl-1,10-ethylene-1,4,7,10,13,16-hexaazacyclooctadecane provided by the invention is simple and efficient, does not involve protection and deprotection unit reactions, has the advantages of high atom utilization rate, low production cost, etc., and is a synthesis method suitable for large-scale production.
[0012] The objective of the present invention is achieved through the following technical scheme: a macrocyclic polyamine organic ligand molecule and a synthesis method thereof, using N,N'-dimethylethylenediamine and chloroacetyl chloride as raw materials, and reacting to obtain an intermediate a, namely N,N'-dimethyl-N,N'-di(2-chloroacetyl)ethylenediamine. Intermediate a then reacts with ethylenediamine to obtain a ring-closing intermediate b, and then reduces with borane to obtain a product. The chemical reaction formula of the three-step reaction is as follows:
[0013] first step:
[0014]
[0015] Step 2:
[0016]
[0017] Step 3:
[0018]
[0019] The existing public synthesis process of 1,4,7,10,13,16-hexaazacyclooctadecane derivatives is to obtain the product by ring-closing reaction of diethylenetriamine protected by p-toluenesulfonyl or benzoyl and ethylene glycol p-toluenesulfonate. The reaction formula is as follows:
[0020]
[0021] Compared with the above-mentioned existing process ideas, the present invention does not adopt complicated protection and deprotection operations, has the characteristics of high atom utilization, simple and efficient reaction, and is a clean production process that conforms to sustainable development.
[0022] The first step is an amidation reaction between N,N'-dimethylethylenediamine and chloroacetyl chloride. The present invention directly quotes the literature process (DOI: 10.1021 / ic051983+), uses anhydrous potassium carbonate as an acid-binding agent, chloroform as a solvent, changes the reaction temperature from 0 degrees to minus 10 degrees, reacts for 5 hours, and obtains intermediate a, namely N,N'-dimethyl-N,N'-di(2-chloroacetyl)ethylenediamine, with a molar yield of 80%.
[0023] The second step reaction is actually a substitution reaction of chlorinated hydrocarbon and fatty amine. Specifically for the reaction of the substrate of the present invention, the molar ratio of intermediate a to ethylenediamine is theoretically 2 / 1. When this molar ratio is less than 2, a chain polymerization side reaction as shown in the following formula will occur:
[0024]
[0025] From a mechanistic analysis, when the above molar ratio is greater than or equal to 2, an ethylene bicyclic ring with the following structure C will be generated:
[0026]
[0027] In fact, the original intention of the route design of the second step of the present invention is to synthesize the c-structured substance as shown in the above formula. However, no matter the molar ratio of intermediate a and ethylenediamine is 2 / 1, 3 / 1 or 4 / 1, no c-structured substance is obtained. The present invention has no side reaction of generating c-structured substance. Considering the cost of intermediate a, the molar ratio of intermediate a and ethylenediamine of the present invention is (2-2.2) / 1. The second step reaction of the present invention adopts acetonitrile as solvent, and the amount of acetonitrile is 20-100 times the mass of intermediate a. The second step reaction of the present invention adopts anhydrous sodium carbonate as acid binding agent, and the molar ratio of anhydrous sodium carbonate to intermediate a is (2.5-3.5) / 1. The second step reaction of the present invention adopts reflux reaction, and the reaction time is 8-20 hours.
[0028] The third step reaction is actually a reduction reaction of the carbonyl group. Considering the factors of convenient operation and safe production, the present invention uses 1M borane tetrahydrofuran complex solution as a reducing agent and tetrahydrofuran as a solvent. When actually feeding, the molar ratio of borane to intermediate b is (8-10) / 1, the mass of tetrahydrofuran is 20-50 times that of intermediate b, the reaction temperature is between 40-65°C, and the reaction time is 10-20 hours.
[0029] The test operation of the present invention is carried out in the following manner: ①, add measured N, N'-dimethylethylenediamine, anhydrous potassium carbonate, and chloroform to the reaction bottle, add measured chloroacetyl chloride at minus 10 degrees, and keep warm for reaction after the addition is completed. After the insulation is completed, add measured deionized water to the reaction bottle, stir thoroughly and let stand, and separate the organic layer. The organic layer is washed with water, dried, and concentrated to obtain a white solid intermediate a, that is, N, N'-dimethyl-N, N'-di(2-chloroacetyl)ethylenediamine; ②, add measured intermediate a, ethylenediamine, anhydrous sodium carbonate and acetonitrile to the reaction bottle, heat and reflux for reaction, and cool to room temperature after the reaction is completed. Filter out the salt, distill a part of the solvent in the filtrate under reduced pressure, cool the residual liquid to crystallize, and filter to obtain a white powder intermediate b; ③, add measured intermediate b and tetrahydrofuran to the reaction bottle, start dropping measured borane tetrahydrofuran complex solution under stirring at a specified temperature, and keep warm for reaction. After the reaction is completed, the system is cooled to 0 degrees, and a 60% aqueous solution of tetrahydrofuran, concentrated hydrochloric acid, deionized water, and a 40% sodium hydroxide solution are sequentially added dropwise into the system, and finally a measured amount of dichloromethane is added for extraction. The extract is concentrated to obtain a white powder, i.e., the product of the present invention, 4,7,13,16-tetramethyl-1,10-ethylene-1,4,7,10,13,16-hexaazacyclooctadecane.
[0030] The three-step reaction conditions of the present invention are mild, simple and easy to operate, with high atomic utilization, avoiding the protection and deprotection processes and the large amount of concentrated sulfuric acid required. The molar yield of the second step reaction can reach up to 87%, the molar yield of the third step reaction can reach up to 96%, and the total molar conversion rate of the three-step reaction can reach more than 66%. DETAILED DESCRIPTION
[0031] Example 1, synthesis of intermediate a, i.e. N,N'-dimethyl-N,N'-di(2-chloroacetyl)ethylenediamine:
[0032] In a 10L double-layer reaction bottle equipped with a mechanical stirrer, a dropping funnel, a circulating refrigeration unit and a thermometer, add 120g (1.36mol) N, N'-dimethylethylenediamine, 375g (2.72mol) anhydrous potassium carbonate, and 3200ml chloroform, start stirring, and pass the freezing liquid into the jacket. When the system temperature is below minus 10 degrees, use a dropping funnel to drop 310g (2.743mol) chloroacetyl chloride into the bottle. After 5 hours of heat preservation reaction, add 4000ml deionized water into the bottle, stir thoroughly, and after all the white solid in the system is dissolved, stand and separate. Wash the lower organic layer with deionized water until it is neutral, dry it with anhydrous sodium sulfate, and distill it at normal pressure until the volume is about 1000ml and stop distilling. Transfer the residual liquid to the freezer of the refrigerator overnight for crystallization.
[0033] Filter and dry the filter cake to obtain 265g of white powder with a melting point of 125-127°C and a gas phase content of 99.3%. The molar yield (based on N,N'-dimethylethylenediamine) is 80.85%
[0034] Example 2, synthesis of intermediate b:
[0035] In a 1000ml four-necked flask equipped with a mechanical stirrer, an electric heating jacket, a reflux condenser and a thermometer, 20g of the intermediate a (0.083mol) obtained in Example 1, 26g (0.25mol) of anhydrous sodium carbonate, 400ml of acetonitrile and 2.4g (0.04mol) of ethylenediamine were added, stirring was started and heating was performed until the system refluxed, and the reaction was carried out for 20 hours.
[0036] After the reaction liquid is cooled to room temperature, it is filtered. The filtrate is evaporated by a water pump, and the distillation is stopped when the volume in the distillation flask is evaporated to about 1 / 3 of the volume before distillation. The residual liquid in the distillation flask is placed in the refrigerator overnight to crystallize.
[0037] The next day, the filter cake was filtered and washed with anhydrous ethanol and dried to obtain 9.35 g of white powder with a melting point of 258-270°C and a content of 89.11% as determined by gas chromatography. The molar yield (based on ethylenediamine) was 52.5%.
[0038] Example 3, Synthesis of Intermediate b:
[0039] In a 2000ml four-necked flask equipped with a mechanical stirrer, an electric heating jacket, a dropping funnel, a reflux condenser and a thermometer, add 20g of the intermediate a (0.083mol) obtained in Example 1, 26g (0.25mol) of anhydrous sodium carbonate, and 1000ml of acetonitrile, and start stirring and heating. When the temperature in the system is 70°C, add a mixed solution of 2.4g (0.04mol) of ethylenediamine and 100ml of acetonitrile from the dropping funnel to the system, control the heating amount and the dropping speed, so that the temperature in the system is between 70-75°C during the dropping process, and the dropping is completed in about 1 hour. Then increase the heating amount, heat to reflux the system, and react for 10 hours.
[0040] After the reaction liquid is cooled to room temperature, it is filtered. The filtrate is evaporated by oil pump to dry the solvent, and 100 ml of anhydrous ethanol is added to the rotary evaporator and heated until it is completely dissolved. Then it is taken out and cooled, and crystallized in the refrigerator overnight.
[0041] The next day, the filter cake was filtered and washed with anhydrous ethanol and dried to obtain 13.9 g of white powder with a melting point of 267-269° C. and a content of 99.52% as determined by gas chromatography. The molar yield (based on ethylenediamine) was 87.75%.
[0042] Example 4, Synthesis of Intermediate b:
[0043] Take 20 g of the intermediate a (0.083 mol) obtained in Example 1 and add it to 1000 ml of acetonitrile, stir until dissolved, and set aside.
[0044] In a 2000ml four-necked flask equipped with a mechanical stirrer, an electric heating jacket, a dropping funnel, a reflux condenser and a thermometer, add 2.4g (0.04mol) of ethylenediamine, 26g (0.25mol) of anhydrous sodium carbonate, and 250ml of acetonitrile, and start stirring and heating. When the temperature in the system is 70°C, add the above-mentioned acetonitrile solution of the intermediate a to the system from the dropping funnel, control the heating amount and the dropping speed, so that the temperature in the system is between 70-75°C during the dropping process, and the dropping is completed in about 5 hours. Then increase the heating amount, heat to reflux the system, and react for 8 hours.
[0045] After the reaction liquid is cooled to room temperature, it is filtered. The filtrate is evaporated by oil pump to dry the solvent, and 100 ml of anhydrous ethanol is added to the rotary evaporator bottle and heated until it is completely dissolved. Then take it out and cool it, and store it in the refrigerator overnight. There are two layers in the bottle. The upper layer is colorless liquid, which is ethanol, and the lower layer is a yellow viscous colloid.
[0046] A small amount of colloid was taken and tested by gas chromatography. The content of intermediate b was 16.81% by gas chromatography.
[0047] Example 5, Synthesis of 4,7,13,16-tetramethyl-1,10-ethylene-1,4,7,10,13,16-hexaazacyclooctadecane:
[0048] Add 10g of the intermediate b (0.0253mol) obtained in Example 3 and 300ml of tetrahydrofuran to a 2000ml four-necked flask equipped with a mechanical stirrer, a water bath, a dropping funnel, a reflux condenser and a thermometer; then add 220ml of a 1M borane tetrahydrofuran complex solution (0.22mol) to the dropping funnel; replace the air in the system with a nitrogen balloon and protect with nitrogen. Start the dropping after stirring. With the addition of the borane tetrahydrofuran solution, the temperature in the system rises. Control the dropping speed so that the temperature in the system is less than 50°C.
[0049] After the addition was completed, the temperature was raised to 64-65°C with a water bath to slight reflux, and the reaction was kept warm for 11 hours.
[0050] Then remove the water bath, lower the system temperature to below 0°C with an ice-water bath, and drop 180g of 60% tetrahydrofuran aqueous solution. Control the drop rate to ensure that the system temperature does not exceed 5°C; then drop 516g of 18.5% hydrochloric acid into the system, control the drop rate to ensure that the system temperature does not exceed 5°C; then add 90g of flake caustic soda in batches into the system, control the caustic soda addition rate to ensure that the system temperature does not exceed 5°C; then adjust the pH of the system to 11 with 40% sodium hydroxide solution.
[0051] The material in the system was filtered, and the filtrate was rotary evaporated (water bath temperature set at 50° C., water circulating vacuum pump) to evaporate most of the tetrahydrofuran.
[0052] Then, the mixture was extracted with 6 x 50 ml of dichloromethane, and the organic layers of the six extractions were combined, washed with water until neutral, dried over anhydrous sodium sulfate, and dichloromethane was evaporated under reduced pressure to obtain 8.27 grams of a white solid. The melting point was 226-228°C. The content of the solid was 99.07% as determined by gas chromatography, and the molar yield (based on intermediate b) was 96.05%.
Claims
1. A macrocyclic polyamine organic ligand molecule and a method for synthesizing the same, characterized in that: The macrocyclic polyamine organic ligand molecule is 4,7,13,16-tetramethyl-1,10-ethylene-1,4,7,10,13,16-hexaazacyclooctadecane, and the molecular structure is: The synthesis method of 4,7,13,16-tetramethyl-1,10-ethylene-1,4,7,10,13,16-hexaazacyclooctadecane comprises the following three steps: ① N,N'-dimethylethylenediamine and chloroacetyl chloride are used as raw materials to obtain N,N'-dimethyl-N,N'-di(2-chloroacetyl)ethylenediamine through reaction; ②N,N'-dimethyl-N,N'-di(2-chloroacetyl)ethylenediamine reacts with ethylenediamine to obtain intermediate b; ③ The intermediate b is then subjected to a reduction reaction with borane to obtain the product, namely 4,7,13,16-tetramethyl-1,10-ethylene-1,4,7,10,13,16-hexaazacyclooctadecane. The chemical reaction formulas of the three steps of the synthesis method are as follows: first step: Step 2: Step 3:
2. The method for synthesizing 4,7,13,16-tetramethyl-1,10-ethylene-1,4,7,10,13,16-hexaazacyclooctadecane according to claim 1, characterized in that: In the step ②, the molar ratio of N,N'-dimethyl-N,N'-di(2-chloroacetyl)ethylenediamine to ethylenediamine is (2-2.2) / 1, and the reaction time is 8-20 hours.
3. The method for synthesizing 4,7,13,16-tetramethyl-1,10-ethylene-1,4,7,10,13,16-hexaazacyclooctadecane according to claim 1, characterized in that: In the second step, acetonitrile is used as a solvent, and the amount of acetonitrile used is 20-100 times the mass of N,N'-dimethyl-N,N'-di(2-chloroacetyl)ethylenediamine. Anhydrous sodium carbonate is used as an acid binding agent, and the molar ratio of anhydrous sodium carbonate to N,N'-dimethyl-N,N'-di(2-chloroacetyl)ethylenediamine is (2.5-3.5) / 1.
4. The method for synthesizing 4,7,13,16-tetramethyl-1,10-ethylene-1,4,7,10,13,16-hexaazacyclooctadecane according to claim 1, characterized in that: The borane described in step ③ is a 1M borane tetrahydrofuran complex solution.