CN111808039B - Novel synthesis method of 1,4,7, 10-tetranitrogen cyclododecane - Google Patents
Novel synthesis method of 1,4,7, 10-tetranitrogen cyclododecane Download PDFInfo
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- CN111808039B CN111808039B CN202010811991.7A CN202010811991A CN111808039B CN 111808039 B CN111808039 B CN 111808039B CN 202010811991 A CN202010811991 A CN 202010811991A CN 111808039 B CN111808039 B CN 111808039B
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- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
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- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
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Abstract
The invention provides a novel method for synthesizing 1,4,7, 10-tetranitrogen cyclododecane. 1,4,7, 10-tetraazacyclododecane has important applications in the major areas of biomedicine and molecular science, molecular recognition, catalysis, enzymatic chemistry, supramolecular chemistry, hydrogen storage materials, and the like. The invention uses triethylene tetramine and urea as starting materials to react to generate ethylene bis-imidazolidinone (hereinafter referred to as bis-imidazolidinone); then carrying out condensation reaction with 1, 2-dihalogenated ethane to generate 1, 4-ketone-7, 10-ketone-1, 4,7, 10-tetranitrogen cyclododecane (diketone cyclododecane); then hydrolyzing to obtain the 1,4,7, 10-tetranitrogen cyclododecane. The invention can obtain the product with the gas chromatography content of more than 99 percent with the total yield of 74.97 percent. The method has the advantages of high atom utilization rate, few reaction steps, simplicity, easiness in control, high yield and the like, and is a novel process route representing clean and efficient production.
Description
Technical Field
The invention provides a novel method for synthesizing 1,4,7, 10-tetranitrogen cyclododecane.
Background
Polyamines present in organisms are closely related to cell growth and cancer and they can regulate the efficiency of in vitro transcription systems (e.g., have an effect on the in vitro transcription of T7RNA polymerase). 1,4,7, 10-tetrazacyclododecane, which has a structure similar to that of polyamine, can be covalently linked to a bioactive molecule (such as an antibody or antibody fragment) after complexing with a metal ion, and thus 1,4,7, 10-tetrazacyclododecane is becoming an important structural component of a new drug.
1,4,7, 10-tetraazacyclododecane is also the most common intermediate for lanthanide-specific chelators, primarily for compounds used in diagnostic and therapeutic drugs, such as lanthanide chelators for medical nuclear magnetic resonance. N-alkylation can also be carried out to prepare a variety of coordination compounds useful for molecular recognition. 1,4,7, 10-tetraazacyclododecane has important applications in the major areas of biomedicine and molecular science, molecular recognition, catalysis, enzymatic chemistry, supramolecular chemistry, hydrogen storage materials, and the like.
Many disclosures of 1,4,7, 10-tetraazacyclododecane have been reported, including the process of deprotection after protection of tosyl group (tetrahedron lett 1992.33. P5505-5508), the glyoxal method (US5589595), the dithiooxamide method (J.Org.chem.1997.62.P4548), and the like. The methods have the defects of large amount of concentrated sulfuric acid for deprotection, poor atom economy, high-risk reduction process and the like, and can not be applied to the industrial production of 1,4,7, 10-tetranitrogen cyclododecane.
The only processes currently most consistent with atomic economics and suitable for commercial production are the methods mentioned in US5587451 by dow chemistry, and the same processes are disclosed in j. org. chem., vol. 67, number 12, 2002. The method comprises the steps of methylating triethylene tetramine, cyclizing to generate a cyclic quaternary ammonium salt, carrying out multi-step molecular rearrangement and deacidification to obtain 1,4,7, 10-tetranitrogen cyclododecane-1, 4-ketone, and finally hydrolyzing to obtain the 1,4,7, 10-tetranitrogen cyclododecane. Although the method has good atom economy, the method has long process route, low total molar yield and high production cost.
Disclosure of Invention
The invention aims to provide a novel method for synthesizing 1,4,7, 10-tetranitrogen cyclododecane.
The invention aims to realize the technical proposal that a new method for synthesizing 1,4,7, 10-tetranitrogen cyclododecane,
the molecular structural formula is as follows:
the method is characterized by comprising three steps of reactions:
the first step is as follows: reacting triethylene tetramine with urea to generate ethylene bis-imidazolidinone (hereinafter referred to as bis-imidazolidinone);
the second step is that: carrying out condensation reaction on the bisimidazolidinone and 1, 2-dihalogenated ethane to generate 1, 4-keto-7, 10-keto-1, 4,7, 10-tetranitrogen cyclododecane (hereinafter referred to as diketone cyclododecane);
the third step: hydrolysis reaction of diketone cyclododecane to obtain 1,4,7, 10-tetranitrogen cyclododecane.
The chemical reaction formula of the synthesis method is as follows:
the first step is as follows:
the second step is that:
the third step:
in the first step of reaction, too little urea does not react completely, too much urea is produced, the materials are carbonized seriously, the color of the product is black, and the purification is difficult. The invention selects the mol ratio of triethylene tetramine and urea as 1 (2.0-2.2). The reaction temperature is selected to be between 130 ℃ and 200 ℃. In order to make the reaction by-product ammonia gas escape from the system in time, the invention selects the reaction to be carried out under the condition of no solvent. As the reaction proceeds, the system will gradually cure. The more complete the stirring, the more powdery the obtained crude product is; if the power of the stirring motor is small and the width of the stirring blade is narrow, the system material can be a large solid, the single impurity component is high, and the difficulty of material taking and refining is increased. The obtained crude product is recrystallized by 50 percent methanol aqueous solution, so that the high-purity bis-imidazolidinone can be obtained with high yield, and the highest molar yield can reach 93.94 percent.
The second reaction mechanism is as follows:
as can be seen from the above reaction mechanism, the condensation reaction is a nucleophilic substitution reaction, and the nitrogen atoms at the 1-position and the 10-position of the bisimidazolidinone are both linked to the carbonyl group, which is very nucleophilic. In the presence of an alkaline acid-binding agent, the target product is easily generated by ring closing through a substitution reaction with dihalogenated ethane. The reaction can be completed at low temperature.
Due to steric hindrance effects, when the reaction temperature is higher, or the bis-imidazolidinone is in excess, the reaction is more biased toward the formation of by-products according to the following formula:
even longer molecular chain polymerization reactions can occur:
in order to avoid the side reaction, the invention makes the dihalogenated ethane excessive, and selects the molar ratio (0.5-1) of the bisimidazolidinone to the dihalogenated ethane as 1; the invention selects the reaction temperature between minus 30 ℃ and 0 ℃ and the reaction time between 5 hours and 24 hours. Polar solvents may promote the reaction equilibrium to the right, but at the same time also increase the probability of the above-mentioned side reactions. The invention selects non-proton medium polarity ethyl acetate and toluene as reaction solvent, and selects anhydrous potassium carbonate, cesium carbonate and sodium carbonate as acid-binding agent.
The third step can be actually considered as a hydrolysis reaction of the amide under alkaline conditions. The reaction is facilitated by increasing the concentration of the base and the hydrolysis temperature. However, the target product 1,4,7, 10-tetraazacyclododecane is unstable under strong alkaline and high temperature conditions and is easily decomposed and ring-opened. In the process of the invention, the hydrolysis reaction and the ring-opening side reaction of the product are almost simultaneously carried out under most of inorganic strong alkali conditions, and the yield balance cannot be realized by changing conditions such as temperature, alkali concentration and the like.
The invention finally discovers that the diketone cyclododecane and hydrazine hydrate can make the reaction stay at the stage of the target product in the alcohol solvent without continuing the ring-opening decomposition. This is because the reaction of diketocyclododecane with hydrazine hydrate produces 1,4,7, 10-tetranitrogen cyclododecane and hydrazine carbonate as a by-product, and when the amount of alcohol used as a solvent exceeds a certain ratio, the hydrazine carbonate as a by-product is precipitated as a solid, thereby promoting the reaction equilibrium to move to the right, and the produced hydrazine carbonate does not catalyze the ring-opening decomposition of 1,4,7, 10-tetranitrogen cyclododecane any more.
The molar ratio of diketone cyclododecane to hydrazine selected by the invention is 1: (4-5).
The invention selects anhydrous methanol and anhydrous ethanol as the reaction solvent, and the dosage of the alcohol is 20-50 times of the mass of the diketone cyclododecane. The reaction temperature is 40-70 ℃ and the reaction time is 6-24 hours.
After the analysis of the mechanism of the invention is carried out, and proper reaction temperature, time, molar ratio and acid binding agent are selected, the invention obtains the product with the gas chromatography content of more than 99 percent with the yield of 74.97 percent at most. The method has the advantages of high atom utilization rate, few reaction steps, simplicity, easiness in control, high yield and the like, and is a novel process route representing clean and efficient production.
Detailed Description
Firstly, putting metered triethylene tetramine and urea into a reaction bottle with a high-power motor for stirring, and connecting a tail gas treatment device. Heating to a certain temperature, and then preserving the temperature for a certain period of time. After the reaction is finished, a certain amount of 50% methanol aqueous solution is added after cooling, and the mixture is heated until the solution is clear. Then put into a refrigerator for refrigeration overnight. Filtering, and drying the filter cake to obtain the light yellow diimidazolone.
Secondly, metered dihaloethane, a solvent and an acid-binding agent are added into a flask which is provided with a dry ice cold bath, a thermometer, a dropping funnel and stirring, and when the temperature is reduced to a certain temperature, a solution containing the bis-imidazolidinone is dropped. After the dropwise addition, the mixture is subjected to heat preservation for a certain time and then filtered. And concentrating, crystallizing, filtering and drying the filtrate to obtain white powdery diketone cyclododecane.
Finally, the measured amount of diketocyclododecane and solvent are added to a flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, and the measured amount of hydrazine hydrate is slowly dropped from the dropping funnel into the flask. The dropping speed is controlled to ensure that the temperature of the system does not exceed 30 ℃. After the dropwise addition is finished, heating for reaction and preserving heat. And after the heat preservation is finished, filtering, and distilling the filtrate to obtain the final product.
Synthesis example of bis-imidazolidinones:
in the examples 1-1, the following examples were used,
146g triethylene tetramine (native Japanese east Cao) (1mol) and 120g urea (2mol) were put into a 2000ml reaction flask equipped with a 300W motor for stirring, a thermometer was inserted, and an exhaust gas treatment device was connected to the outlet. After stirring is started, the temperature is raised by an electric heating sleeve. When the temperature reached 130 ℃, the contents suddenly expanded with a large amount of ammonia escaping. The temperature is continuously increased and kept at 150 ℃ for half an hour. With the heat preservation, the materials in the bottle gradually become dry powder, and the escaping gas is gradually reduced until no gas escapes. The electric heating jacket is removed, and the temperature is reduced to room temperature by stirring.
Adding 1000ml of 50% methanol aqueous solution into a bottle, connecting a tail gas port to a reflux condenser, heating by a water bath under stirring until boiling and refluxing, wherein the reflux temperature is 64 ℃. After refluxing for 10 minutes, the material was completely dissolved and the system became a clear and transparent solution. The reaction solution was poured into a beaker and placed in a refrigerator for refrigeration overnight. The next day pale yellow needle crystals precipitated out of the beaker. Filtering, leaching a filter cake by using a small amount of 50% methanol water solution, and drying the filter cake to obtain 186g of light yellow bis-imidazolidinone. The content of the product is 99.91 percent by gas chromatography detection, and the molar yield is 93.94 percent.
In the examples 1-2, the following examples were used,
146g triethylene tetramine (native Japanese east Cao) (1mol) and 132g urea (2.2mol) were put into a 2000ml reaction flask equipped with a 300W motor for stirring, a thermometer was inserted, and an exhaust gas treatment device was connected to the outlet. After stirring is started, the temperature is raised by an electric heating sleeve. When the temperature reached 130 ℃, the contents suddenly expanded with a large amount of ammonia escaping. The temperature was further raised and maintained at 200 ℃ for 10 minutes. With the heat preservation, the materials in the bottle gradually become dry powder, and the escaping gas is gradually reduced until no gas escapes. The electric heating jacket is removed, and the temperature is reduced to room temperature by stirring.
Adding 1000ml of 50% methanol aqueous solution into a bottle, connecting a tail gas port to a reflux condenser, heating by a water bath under stirring until boiling and refluxing, wherein the reflux temperature is 64 ℃. The solution was not completely dissolved after 30 minutes of reflux, filtered while hot, and the filtrate was poured into a beaker and refrigerated in a refrigerator overnight. Yellow needle crystals were precipitated in the next day beaker. Filtering, leaching a filter cake by using a small amount of 50% methanol water solution, and drying the filter cake to obtain 157g of yellow bis-imidazolone. The content of the product is 97.55 percent by gas chromatography detection, and the molar yield is 79.29 percent.
Example of synthesis of diketocyclododecane:
in the case of example 2-1,
20g of the bisimidazolidinone (0.1mol) obtained in example 1-1 were weighed out and added to 200ml of ethyl acetate, and the mixture was dissolved with stirring and used.
15g of 1, 2-dichloroethane (0.15mol), 107g of cesium carbonate (0.33 mol) and 800ml of ethyl acetate were introduced into a 2000ml flask equipped with a thermometer, dropping funnel and stirring, and cooled with a dry ice acetone bath. When the temperature drops to minus 30 ℃, the dropwise addition of the prepared ethyl acetate solution of the bis-imidazolidinone is started. The dropping speed is adjusted so that the temperature of the system does not exceed minus 10 ℃. After the dropwise addition, the mixture is kept at-10 ℃ to 0 ℃ for 5 hours.
After the completion of the heat preservation, the reaction solution was poured out and filtered, the filtrate was concentrated under reduced pressure to a volume of 100ml, and the concentrate was frozen in a refrigerator overnight. And precipitating flaky crystals the next day, filtering, washing a filter cake with petroleum ether, and drying to obtain 15g of white powdery diketone cyclododecane, wherein the content is 98.21% by gas chromatography detection, and the molar yield is 66.96%.
In the case of example 2-2,
20g of the bisimidazolidinone (0.1mol) obtained in example 1-1 were weighed out into 100ml of toluene and dissolved with stirring until ready for use.
21g of 1, 2-dibromoethane (0.11mol), 107g of cesium carbonate (0.33 mol) and 800ml of toluene were charged into a 2000ml flask equipped with a thermometer, dropping funnel and stirring, and cooled by a dry ice acetone cold bath. When the temperature is reduced to minus 30 ℃, the dropwise addition of the prepared bis-imidazolidinone toluene solution is started. The dropping speed is adjusted so that the temperature of the system does not exceed minus 10 ℃. After the dropwise addition, the mixture is kept at-10 ℃ to 0 ℃ for 24 hours.
After the completion of the heat preservation, the reaction solution was poured out and filtered, the filtrate was concentrated under reduced pressure to a volume of 100ml, and the concentrate was frozen in a refrigerator overnight. The next day, flaky crystals are separated out, filtered, and filter cakes are dried after being washed by petroleum ether to obtain 20.5g of white powdery diketone cyclododecane with the content of 98.83 percent and the molar yield of 91.52 percent by gas chromatography detection.
1,4,7, 10-tetraazacyclododecane:
in the case of example 3-1,
into a 1000ml four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were charged 13g of the diketocyclododecane (0.058mol) obtained in example 2-1 and 500ml of methanol, and 15g of hydrazine hydrate (0.24mol) having a content of 80% by mass was slowly dropped from the dropping funnel into the flask. The dropping speed is controlled so that the temperature of the system does not exceed 30 ℃. After the end of the dropwise addition, the mixture was stirred at room temperature for 30 minutes and then heated to reflux. And (3) refluxing and reacting for 20 hours, and filtering to obtain a filter cake which is hydrazine carbonate. Collecting the filtrate, distilling off methanol under normal pressure, performing high vacuum fractionation by using an oil pump, and cooling the distillate to obtain 8.7 white solids. The nuclear magnetism is consistent with that of a 1,4,7, 10-tetranitrogen cyclododecane standard product, the content is 98.47 percent by GC detection, the melting point is 111.2-112.7 percent by a melting point instrument, and the molar yield is 87.21 percent.
In the case of example 3-2,
in a 1000ml four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, 18g of the diketocyclododecane (0.08mol) obtained in example 2-2 and 600ml of anhydrous ethanol were charged, and 25g of hydrazine hydrate (0.4mol) having a content of 80% by mass was slowly dropped from the dropping funnel into the flask. The dropping speed is controlled so that the temperature of the system does not exceed 30 ℃. After the dropwise addition, stirring is carried out for 30 minutes at room temperature, the temperature is raised to 60 ℃ in a water bath, the temperature is kept for 6 hours, and after the completion, filtration is carried out, wherein a filter cake is hydrazine carbonate. Collecting the filtrate, distilling off ethanol under normal pressure, performing high vacuum fractionation by using an oil pump, and cooling the distillate to obtain 11.2 white solids. The nuclear magnetism is consistent with that of a 1,4,7, 10-tetranitrogen cyclododecane standard product, the content is 98.98 percent by GC detection, the melting point is 110.8-112.1 percent by a melting point apparatus, and the molar yield is 81.39 percent.
Combining examples 1-1, 2-2 and 3-1, 4,7, 10-tetraazacyclododecane can be obtained in a three-step molar overall yield of 74.97%.
Claims (5)
- The synthesis process of 1,4,7, 10-tetranitrogen cyclododecane has the molecular structure as follows:
the method is characterized by comprising three steps of reactions:the first step is as follows: reacting triethylene tetramine with urea to generate bis-imidazolidinone;the second step is that: carrying out condensation reaction on the bisimidazolidinone and the 1, 2-dihalogenated ethane to generate diketone cyclododecane; wherein the 1, 2-dihaloethane comprises 1, 2-dichloroethane or 1, 2-dibromoethane;the third step: hydrolysis reaction of diketone cyclododecane to obtain 1,4,7, 10-tetranitrogen cyclododecane.The chemical reaction formula of the synthesis method is as follows:the first step is as follows:
the second step is that:
the third step:。
- 2. the method for synthesizing 1,4,7, 10-tetraazacyclododecane according to claim 1, wherein the molar ratio of triethylene tetramine to urea in the first reaction step is 1 (2.0-2.2). The reaction temperature is selected to be between 130 ℃ and 200 ℃.
- 3. The process for the synthesis of 1,4,7, 10-tetraazacyclododecane according to claim 1, wherein in the first reaction step, the reaction is carried out by a solvent-free method.
- 4. The process for the synthesis of 1,4,7, 10-tetraazacyclododecane according to claim 1, characterized in that in the second reaction step, the molar ratio of bisimidazolidinone to dihaloethane (0.5-1): 1; the reaction temperature is between-30 ℃ and 0 ℃; the reaction time is 5-24 hours; the reaction solvent is ethyl acetate or toluene; the acid-binding agent is anhydrous potassium carbonate or cesium carbonate or sodium carbonate.
- 5. The process for the synthesis of 1,4,7, 10-tetraazacyclododecane according to claim 1, wherein in the third reaction step, the molar ratio of diketocyclododecane to hydrazine is 1: (4-5); anhydrous methanol or anhydrous ethanol is used as a reaction solvent in the step, and the dosage of the alcohol is 20-50 times of the mass of the diketone cyclododecane; the reaction temperature is between 40 and 70 ℃; the reaction time is 6-24 hours.
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| CN1616434A (en) * | 2004-10-01 | 2005-05-18 | 建德市新化化工有限责任公司 | Method for producing 1,3-dimethyl -2-imidazolinone |
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