CN109608379B - Preparation method of protein cross-linking agent maleimide-diethylene glycol-succinimidyl acrylate - Google Patents
Preparation method of protein cross-linking agent maleimide-diethylene glycol-succinimidyl acrylate Download PDFInfo
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- CN109608379B CN109608379B CN201811555928.0A CN201811555928A CN109608379B CN 109608379 B CN109608379 B CN 109608379B CN 201811555928 A CN201811555928 A CN 201811555928A CN 109608379 B CN109608379 B CN 109608379B
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- C07—ORGANIC CHEMISTRY
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
Abstract
The invention relates to the technical field of organic chemical synthesis, in particular to a preparation method of a protein cross-linking agent maleimide-diglycol-acrylic acid succinimide ester, which comprises the following steps; step one, synthesizing 3-maleimide propionyl chloride; step two, synthesizing maleimide-polyethylene glycol-acrylic acid; step three, synthesizing maleimide-polyethylene glycol-acryloyl chloride; step four, synthesizing maleimide-diglycol-acrylic acid succinimide ester; the method adopts acyl chloride reagent for esterification reaction, is cheaper than condensation reagent, can reduce cost, is convenient to purify, avoids removing by-products of the condensation reagent, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of organic chemical synthesis, in particular to a preparation method of a protein cross-linking agent maleimide-diethylene glycol-acrylic acid succinimide ester.
Background
The maleimide-diglycol-succinimidyl acrylate is a water-soluble heterobifunctional protein cross-linking agent, the heterobifunctional protein cross-linking agent is mainly used for modifying the traditional alkyl fatty chain and replacing the alkyl fatty chain with ethylene glycol chains with different lengths which are harmless to organisms, the alteration is mainly to enhance the water solubility of the drug molecules, to make them better dispersed in the blood, this avoids the drug clustering effect caused by the cross-linking of the traditional alkyl fatty chain and the fat-soluble cytotoxic drug molecule, thereby being beneficial to the quick absorption and the quick effect of the medicine, further reducing the toxicity caused by the decomposition of the medicine outside the cells, on the other hand, the system and the previous partial fat soluble heterobifunctional protein cross-linking agent system form a chemical trousers of the protein cross-linking agent together, which lays a good foundation for the research and development of new drugs and new cross-linking agents;
the traditional synthesis method of maleimide-diglycol-acrylic acid succinimide ester is mainly as shown in the reaction formula (I):
because condensation reagents are needed in the reaction between the two steps of the synthesis method and the HOSU, the production cost is greatly improved, and the synthesis method is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of a protein cross-linking agent maleimide-diglycol-succinimidyl acrylate, which aims to solve the problems of high production cost and unsuitability for industrial production in the background technology.
In order to achieve the purpose, the invention adopts the following technical scheme:
designing a preparation method of a protein cross-linking agent maleimide-diglycol-succinimidyl acrylate, which comprises the following steps;
step one, synthesizing 3-maleimide propionyl chloride;
adding oxalyl chloride into 3-maleimide propionic acid and catalyzing by DMF to synthesize 3-maleimide propionyl chloride;
step two, synthesizing maleimide-polyethylene glycol-acrylic acid;
dropwise adding the 3-maleimidopropionyl chloride solution into a diisopropylethylamine organic solution of aminodiglycol-carboxylic acid to react the aminodiglycol-carboxylic acid with the 3-maleimidopropionyl chloride under an alkaline condition to generate the maleimide-diglycol-acrylic acid;
step three, synthesizing maleimide-polyethylene glycol-acryloyl chloride;
adding oxalyl chloride into maleimide-polyethylene glycol-acrylic acid and catalyzing with DMF to synthesize maleimide-polyethylene glycol-acryloyl chloride;
step four, synthesizing maleimide-diglycol-acrylic acid succinimide ester;
and (3) dripping a maleimide-diethylene glycol-acryloyl chloride solution into a triethylamine solution of the N-hydroxysuccinimide to ensure that the N-hydroxysuccinimide and the maleimide-diethylene glycol-acryloyl chloride react under an alkaline condition to generate maleimide-diethylene glycol-acrylic acid succinimide ester.
Preferably, oxalyl chloride in the first step and the third step can be replaced by acylating agents such as sulfoxide chloride, phosphorus trichloride and phosphorus pentachloride.
Preferably, the base in the second step and the fourth step can be replaced by organic base such as triethylamine, diisopropylethylamine and the like.
Preferably, in the first step, the organic solvent used is one or more selected from tetrahydrofuran, dichloromethane and chloroform.
Preferably, in the first, second, third and fourth steps, the reaction temperature is 0-40 ℃ and the reaction time is 2-24 h.
Preferably, in the second step, the reaction solution after the reaction in the first step is concentrated and dried, excess oxalyl chloride is removed, and then the solution is prepared into a required solution, and the solution is filtered, concentrated and recrystallized to obtain the purified maleimide-polyethylene glycol-acrylic acid.
Preferably, in the fourth step, the reaction solution obtained after the reaction in the third step is concentrated and dried, excess oxalyl chloride is removed, and then the solution is prepared into a required solution, and the solution is filtered, concentrated and recrystallized to obtain the refined maleimide-diethylene glycol-succinimidyl acrylate.
The preparation method of the protein cross-linking agent maleimide-diglycol-acrylic acid succinimide ester provided by the invention has the beneficial effects that:
1. compared with the method using a condensation reagent, the method using the acyl chloride reagent for esterification reaction is cheaper, so that the cost can be reduced;
2. the invention has convenient purification, avoids the removal of by-products of condensation reagents and is suitable for industrial production.
Drawings
FIG. 1 is a diagram showing a scheme for preparing maleimide-diglycol-succinimidyl acrylate according to the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Referring to fig. 1, a method for preparing maleimide-diethylene glycol-succinimidyl acrylate, a protein cross-linking agent, comprises the following steps;
step one, synthesizing 3-maleimide propionyl chloride;
adding oxalyl chloride into 3-maleimide propionic acid and catalyzing by DMF to synthesize 3-maleimide propionyl chloride; oxalyl chloride can be replaced by acylating agents such as thionyl chloride, phosphorus trichloride and phosphorus pentachloride; the organic solvent is one or more selected from tetrahydrofuran, dichloromethane and chloroform;
the specific operation steps for synthesizing the 3-maleimidopropionyl chloride are as follows:
adding 3-maleimide propionic acid (845.6g, 5.0mol) and dichloromethane into a 10L three-neck flask, adding oxalyl chloride (759.3g, 6.0mol) and a catalytic amount of DMF, reacting in a solution system oil seal at room temperature for half an hour, refluxing until no bubbles emerge in the oil seal, cooling, concentrating, draining by an oil pump, and dissolving and clearing by dichloromethane to prepare a solution for later use;
step two, synthesizing maleimide-polyethylene glycol-acrylic acid;
dropwise adding the 3-maleimidopropionyl chloride solution into a diisopropylethylamine organic solution of aminodiglycol-carboxylic acid to react the aminodiglycol-carboxylic acid with the 3-maleimidopropionyl chloride under an alkaline condition to generate the maleimide-diglycol-acrylic acid; the alkali can be replaced by organic alkali such as triethylamine, diisopropylethylamine and the like; concentrating and drying the reaction solution reacted in the step one, removing excessive oxalyl chloride, preparing a required solution, and filtering, concentrating and recrystallizing to obtain refined maleimide-polyethylene glycol-acrylic acid;
the specific operation steps for synthesizing the maleimide-diglycol-acrylic acid are as follows:
adding aminodiglycol-carboxylic acid (1063g, 6.0mol), dichloromethane and diisopropylethylamine (775.5g, 6.0mol) into a 10L three-neck flask, stirring at room temperature until the mixture is clear, keeping the internal temperature not to exceed 25 ℃, starting to dropwise add the prepared acyl chloride solution, stirring at room temperature until the reaction is finished after the dropwise addition, performing post-treatment, extracting the reaction solution with water, drying, concentrating, and recrystallizing with absolute ethyl alcohol to obtain white powder (1300g, yield 79%);
step three, synthesizing maleimide-polyethylene glycol-acryloyl chloride;
adding oxalyl chloride into maleimide-polyethylene glycol-acrylic acid and catalyzing with DMF to synthesize maleimide-polyethylene glycol-acryloyl chloride; oxalyl chloride can be replaced by acylating agents such as thionyl chloride, phosphorus trichloride and phosphorus pentachloride;
the specific operation steps for synthesizing the maleimide-diglycol-acryloyl chloride are as follows:
adding maleimide-diglycol-acrylic acid (985g, 3.0mol) and dichloromethane into a 10L three-neck flask, adding oxalyl chloride (456g, 3.6mol) and a catalytic amount of DMF, reacting for half an hour at room temperature in a solution system oil seal, refluxing until no bubbles emerge in the oil seal, cooling, concentrating, draining by an oil pump, and dissolving and clearing by dichloromethane to prepare a solution for later use;
step four, synthesizing maleimide-diglycol-acrylic acid succinimide ester;
dripping a maleimide-diethylene glycol-acryloyl chloride solution into a triethylamine solution of N-hydroxysuccinimide to enable the N-hydroxysuccinimide to react with the maleimide-diethylene glycol-acryloyl chloride under an alkaline condition to generate maleimide-diethylene glycol-acrylic acid succinimide ester; the alkali can be replaced by organic alkali such as triethylamine, diisopropylethylamine and the like; in the fourth step, the reaction solution obtained after the reaction in the third step is concentrated and dried, excess oxalyl chloride is removed, and then the solution is prepared into a required solution, and the required solution is filtered, concentrated and recrystallized to obtain refined maleimide-diethylene glycol-succinimidyl acrylate;
the specific operation steps for synthesizing maleimide-diglycol-acrylic acid succinimide ester are as follows:
n-hydroxysuccinimide (414.4g, 3.6mol), methylene chloride and triethylamine (607g, 6.0mol) were added to a 10L three-necked flask, and stirred at room temperature until it became clear, the internal temperature was kept at 25 ℃ or less, the prepared acid chloride solution was started to be dropped, and after dropping, stirred at room temperature until the reaction was completed, the reaction solution was post-treated, extracted with water, dried, concentrated, and recrystallized with absolute ethanol to obtain a white powder (944g, yield 74%).
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (1)
1. Protein cross-linking agent
The preparation method is characterized by comprising the following steps:
step one, synthesizing 3-maleimide propionyl chloride;
the specific operation steps for synthesizing the 3-maleimidopropionyl chloride are as follows: adding 845.6g of 3-maleimide propionic acid and dichloromethane into a 10L three-neck flask, adding 759.3g of oxalyl chloride and DMF with a catalytic amount, carrying out oil seal reaction on a solution system at room temperature for half an hour, refluxing until no bubbles emerge in the oil seal, cooling, concentrating, draining by an oil pump, and dissolving and cleaning by dichloromethane to prepare a solution for later use;
step two, synthesis
Synthesis of
The method comprises the following specific operation steps: adding 1063g of aminodiglycol-carboxylic acid, 775.5g of dichloromethane and diisopropylethylamine into a 10L three-neck flask, stirring at room temperature until the mixture is clear, keeping the internal temperature not to exceed 25 ℃, starting to dropwise add the acyl chloride solution obtained in the step one, stirring at room temperature until the reaction is finished after the dropwise addition, performing post-treatment, extracting the reaction solution with water, drying, concentrating, and recrystallizing with absolute ethyl alcohol to obtain 1300g of white powder;
step three, synthesis
Synthesis of
The method comprises the following specific operation steps: adding into a 10L three-neck flask
And dichloromethane are added, 456g of oxalyl chloride and catalytic amount of DMF are added, the solution system oil seal is reacted for half an hour at room temperature, then the reaction is refluxed until no air bubble emerges in the oil seal, the solution is cooled and concentrated, and the solution is prepared by dissolving and cleaning with dichloromethane after an oil pump is drained;
step four, synthesis
Synthesis of
The method comprises the following specific operation steps: adding 414.4g of N-hydroxysuccinimide, dichloromethane and 607g of triethylamine into a 10L three-neck flask, stirring at room temperature until the mixture is clear, keeping the internal temperature not to exceed 25 ℃, starting to dropwise add the acyl chloride solution obtained in the third step, stirring at room temperature until the reaction is finished after the dropwise addition, performing post-treatment, extracting the reaction liquid with water, drying, concentrating, and recrystallizing with absolute ethyl alcohol to obtain 944g of white powder.
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| CN102145176A (en) * | 2011-04-11 | 2011-08-10 | 中国药科大学 | Targeting protein-polyethylene glycol-anticancer medicament junctional complex |
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| CN106243127A (en) * | 2015-06-09 | 2016-12-21 | 凯惠科技发展(上海)有限公司 | Antibody drug conjugates, intermediate, preparation method, pharmaceutical composition and application |
| CN108892631A (en) * | 2018-08-09 | 2018-11-27 | 广州臻莱迈新材料科技有限公司 | A kind of heat stabilizer and its synthetic method for PVC |
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- 2018-12-19 CN CN201811555928.0A patent/CN109608379B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102675385A (en) * | 2011-03-08 | 2012-09-19 | 斯涛利科技发展(天津)有限公司 | Preparation method for doxorubicin13-position hydrazone derivative |
| CN102145176A (en) * | 2011-04-11 | 2011-08-10 | 中国药科大学 | Targeting protein-polyethylene glycol-anticancer medicament junctional complex |
| CN106243127A (en) * | 2015-06-09 | 2016-12-21 | 凯惠科技发展(上海)有限公司 | Antibody drug conjugates, intermediate, preparation method, pharmaceutical composition and application |
| CN105037237A (en) * | 2015-06-12 | 2015-11-11 | 苏州昊帆生物科技有限公司 | Method for synthesizing N-maleimidoalkyl acid and succinimido ester thereof |
| CN106220843A (en) * | 2016-07-29 | 2016-12-14 | 中国科学院过程工程研究所 | A kind of containing Lin Ben diquines functional group polyethyleneglycol modified dose and its production and use |
| CN108892631A (en) * | 2018-08-09 | 2018-11-27 | 广州臻莱迈新材料科技有限公司 | A kind of heat stabilizer and its synthetic method for PVC |
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