CN113277990A - Synthesis method of 1, 4-bis (p-toluenesulfonyl) triazacyclononane - Google Patents
Synthesis method of 1, 4-bis (p-toluenesulfonyl) triazacyclononane Download PDFInfo
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- CN113277990A CN113277990A CN202110690228.8A CN202110690228A CN113277990A CN 113277990 A CN113277990 A CN 113277990A CN 202110690228 A CN202110690228 A CN 202110690228A CN 113277990 A CN113277990 A CN 113277990A
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- C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
- C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention discloses a method for synthesizing 1, 4-bis (p-toluenesulfonyl) triazacyclononane, which comprises the following steps: the method adopts 1, 4-bis (p-toluenesulfonyl) -7-benzoyl triazacyclononane as a substrate, removes a protecting group of benzoyl under an alkaline condition, and obtains the 1, 4-bis (p-toluenesulfonyl) triazacyclononane without reacting two p-toluenesulfonyl groups. The reaction condition is reflux reaction, and the reaction time is 10-36 hours. Compared with the prior art, the invention has the following beneficial effects: the invention avoids using a large amount of inorganic acid and organic acid, and effectively guarantees the problems of safety, environmental protection and the like in nature; the reaction yield can reach more than 90 percent at most.
Description
Technical Field
The invention relates to a synthesis method of 1, 4-bis (p-toluenesulfonyl) triazacyclononane.
Background
1, 4-bis (p-toluenesulfonyl) triazacyclononane, the molecular structural formula of which is:
1, 4-bis (p-toluenesulfonyl) triazacyclononane, an important organic ligand intermediate. The molecular structure of the organic ligand compound has an unprotected amine group, and after a needed group is connected, the tosyl group is deprotected, and then other asymmetric groups are connected, so that the organic ligand compound with special purposes is obtained.
At present, the synthesis method of 1, 4-bis (p-toluenesulfonyl) triazacyclononane is disclosed and reported, which is to synthesize 1,4, 7-tris (p-toluenesulfonyl) triazacyclononane by a traditional method, and then remove one p-toluenesulfonyl group under the condition of hydrogen bromide or propionic acid to obtain 1, 4-bis (p-toluenesulfonyl) triazacyclononane. The synthetic route is as follows:
in the deprotection process, when hydrobromic acid is adopted, a large amount of glacial acetic acid and phenol are required to be used as catalysts, and the research of the Debresen university (SYNTHETIC COMMUNICATIONS, 31(20), 3141-3144 (2001)) shows that the conversion rate is only 30 percent; when propionic acid is used, propionic anhydride and concentrated sulfuric acid are required as catalysts, and PCT patent (WO 2012/003712a 1) discloses that 1, 4-bis (p-toluenesulfonyl) triazacyclononane with a purity of 90% is obtained in a yield of 78%, with an actual yield of 70%. Both methods require a large amount of inorganic acid and organic acid, resulting in a large amount of waste acid; the reaction yield is low, the production efficiency is low, and the method is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a method for synthesizing 1, 4-bis (p-toluenesulfonyl) triazacyclononane, which adopts 1, 4-bis (p-toluenesulfonyl) -7-benzoyl triazacyclononane as a substrate, removes a protective group of benzoyl under alkaline conditions, and obtains the 1, 4-bis (p-toluenesulfonyl) triazacyclononane without reacting two p-toluenesulfonyls.
The method has the advantages of mild reaction conditions, high yield, no use of organic acid and inorganic acid, less pollutant generation, high yield and greatly improved production efficiency.
The invention aims to realize the synthesis method of 1, 4-bis (p-toluenesulfonyl) -7-benzoyl triazacyclononane by the following technical scheme, and the molecular structural formula of the compound is as follows:
the synthesis method adopts 1, 4-bis (p-toluenesulfonyl) -7-benzoyl triazacyclononane as a substrate, uses a strong base reagent to carry out deprotection on benzoyl in an alcohol solvent, and has the reaction condition of reflux reaction for 10-36 hours. The strong alkali reagent comprises sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide and potassium tert-butoxide.
Compared with the prior art, the invention has the following beneficial effects: the invention avoids using a large amount of inorganic acid and organic acid, and effectively guarantees the problems of safety, environmental protection and the like in nature; the reaction yield can reach more than 90 percent, and the reaction product can reach more than 96 percent without refining, thereby completely meeting the synthesis requirements of various organic ligands; low production cost and simple process control, avoids various side reactions caused by using various raw materials and improves the atom interest rate. In conclusion, the process of the invention improves the intrinsic safety of the process, greatly reduces the types and the quantity of pollution factors in the process and represents the trend of clean production process.
Detailed Description
The invention is further illustrated by the following examples of embodiments.
A method for synthesizing 1, 4-bis (p-toluenesulfonyl) -7-benzoyl triazacyclononane is disclosed, the molecular structural formula of the compound is:
the synthesis method comprises the steps of taking 1, 4-bis (p-toluenesulfonyl) -7-benzoyl triazacyclononane as a substrate, carrying out deprotection on benzoyl in an alcohol solvent by using a strong base reagent, and filtering and drying after the reaction is finished to obtain the product.
Further, the reaction condition is reflux reaction, and the reaction time is 10-36 hours.
Further, the alcohol solvent includes methanol, ethanol, isopropanol, and tert-butanol.
Further, the strong alkali reagent used includes sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide.
Further, the molar ratio of the strong base used to 1, 4-bis (p-toluenesulfonyl) -7-benzoyltriazacyclononane was (1-5): 1.
The reaction equation is as follows:
during the specific operation, the metered 1, 4-bis (p-toluenesulfonyl) -7-benzoyl triazacyclononane, the solvent and the strong base reagent are added into a reactor, stirred and heated to reflux. After reflux reaction for a certain time, cooling, filtering, washing a filter cake to be neutral by water, and drying to obtain white solid powder, namely the 1, 4-bis (p-toluenesulfonyl) triazacyclononane.
Example 1
10g (0.018mol) of 1, 4-bis (p-toluenesulfonyl) -7-benzoyltriazacyclononane, 5g (0.045mol) of potassium tert-butoxide and 300ml of tert-butanol were placed in a 500ml four-necked flask equipped with an electric stirrer, a thermometer, a reflux condenser and an oil bath heating pan, and after the addition of the above materials, the temperature was raised by stirring.
And when the system flows back, timing and preserving heat for reaction, cooling to room temperature after preserving heat for reaction for 36 hours, filtering, washing a filter cake with a large amount of water, and washing until the pH value is neutral. The filter cake was dried to 7.11 g. The content by liquid chromatography was 96.75%, and the molar yield based on 1, 4-bis (p-toluenesulfonyl) -7-benzoyltriazacyclononane was 90.39%.
Example 2
10g (0.018mol) of 1, 4-bis (p-toluenesulfonyl) -7-benzoyltriazacyclononane, 3g (0.031mol) of sodium tert-butoxide and 300ml of tert-butanol were charged into a 500ml four-necked flask equipped with an electric stirrer, a thermometer, a reflux condenser and an oil bath heating pan, and after the above materials were charged, stirring and temperature rise were started.
And when the system flows back, timing and preserving heat for reaction, cooling to room temperature after preserving heat for reaction for 36 hours, filtering, washing a filter cake with a large amount of water, and washing until the pH value is neutral. The filter cake was dried to 6.6 g. The content by liquid chromatography was 95.17%, and the molar yield based on 1, 4-bis (p-toluenesulfonyl) -7-benzoyltriazacyclononane was 83.91%.
Example 3
10g (0.018mol) of 1, 4-bis (p-toluenesulfonyl) -7-benzoyltriazacyclononane, 20g (0.088mol) of a 30% ethanol solution of sodium ethoxide and 300ml of ethanol were placed in a 500ml four-neck flask equipped with an electric stirrer, a thermometer, a reflux condenser and an oil bath heating pan, and after the completion of the addition of the above materials, the stirring and temperature rise were started.
And when the system flows back, timing and preserving heat for reaction, cooling to room temperature after preserving heat for reaction for 12 hours, filtering, washing a filter cake with a large amount of water, and washing until the pH value is neutral. The filter cake was dried to give 3.2 g. The content by liquid chromatography was 88.55%, and the molar yield based on 1, 4-bis (p-toluenesulfonyl) -7-benzoyltriazacyclononane was 40.68%.
Example 4
10g (0.018mol) of 1, 4-bis (p-toluenesulfonyl) -7-benzoyltriazacyclononane, 4.5g (0.080mol) of potassium hydroxide flake (96% content), and 350ml of ethanol were charged into a 500ml four-necked flask equipped with an electric stirrer, a thermometer, a reflux condenser, and an oil bath heating pan, and after the completion of the charge, the temperature was raised by stirring.
And when the system flows back, timing and preserving heat for reaction, cooling to room temperature after preserving heat for reaction for 36 hours, filtering, washing a filter cake with a large amount of water, and washing until the pH value is neutral. The filter cake was dried to give 4.9 g. The liquid chromatography content was 91.26%, the molar yield based on 1, 4-bis (p-toluenesulfonyl) -7-benzoyltriazacyclononane was 62.29%.
Claims (5)
1. A method for synthesizing 1, 4-bis (p-toluenesulfonyl) triazacyclononane is disclosed, the molecular structural formula of the compound is:
the method is characterized in that 1, 4-bis (p-toluenesulfonyl) -7-benzoyl triazacyclononane is adopted as a substrate, and deprotection of benzoyl is carried out in an alcohol solvent by using a strong base reagent to obtain 1, 4-bis (p-toluenesulfonyl) triazacyclononane;
the reaction equation of the synthesis method is as follows:
2. the method for synthesizing 1, 4-bis (p-toluenesulfonyl) triazacyclononane according to claim 1, wherein the alcohol solvent comprises methanol, ethanol, isopropanol, and tert-butanol.
3. The method for synthesizing 1, 4-bis (p-toluenesulfonyl) triazacyclononane according to claim 1, wherein the strong alkaline reagent comprises sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.
4. The method for synthesizing 1, 4-bis (p-toluenesulfonyl) triazacyclononane according to claim 1, wherein the molar ratio of the strong base used to 1, 4-bis (p-toluenesulfonyl) -7-benzoyltriazacyclononane is (1-5): 1.
5. The method for synthesizing 1, 4-bis (p-toluenesulfonyl) triazacyclononane according to claim 1, wherein the reaction conditions are reflux reaction and the reaction time is 10-36 hours.
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Inventor after: Zou Congwei Inventor after: Zhang Yan Inventor after: Dai Jiukun Inventor after: Zhou Fen Inventor before: Zhang Yan Inventor before: Zou Congwei Inventor before: Dai Jiukun Inventor before: Zhou Fen |