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Synthesis of acridinium ester chemiluminescent substrate DMAE.NHS

A technology of chemiluminescence and chemiluminescent reagents, which is applied in the field of synthesis of acridine ester chemiluminescent substrates DMAE·NHS chemiluminescent reagents, can solve the problems of complex synthesis, many steps, and potential toxicity, and achieve simple reaction steps, The effect of mild reaction conditions and high overall yield

Inactive Publication Date: 2017-05-31
HUNAN NORMAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

However, the synthesis of such luminescent substrates is relatively complicated, resulting in high cost of synthesis and analysis and detection, which limits its general application.
Among the methods reported in current literature and patents, there is a synthesis method using ionic liquids as solvents, such as Chinese patent CN 104411688 A, but ionic liquids are not only expensive, but also have potential toxicity, and they need to be reacted under the protection of an inert gas if necessary. , These all directly lead to high production costs, easy to cause environmental pollution, etc.; there are also strategies using protective groups (Qin Wenling, Synthesis and application research of several acridinium esters, Chongqing University, 2010 (D)), these methods not only There are many steps, complex post-processing, and low yield; when it comes to the synthesis of acridinium ester DMAE NHS, a protecting group strategy (such as Chinese patent CN 101121710 A, European patent EP263657A2) is used to synthesize DMAE in seven steps NHS is currently the most widely used process (Chinese patent CN 101121710 A), but the steps in the synthesis process are long and need further improvement

Method used

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  • Synthesis of acridinium ester chemiluminescent substrate DMAE.NHS

Examples

Experimental program
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Effect test

Embodiment 1

[0010] Example 1: Synthesis of 1-((4-hydroxyl-3,5-dimethylbenzoyl)oxy)-2,5-pyrrolidinedione

[0011] Dissolve 1.38 g (12 mmol) of N-hydroxysuccinimide and 2.44 g (11.07 mmol) of dicyclohexylcarbodiimide in anhydrous DMF, cool to about 0 °C, and dissolve 1.53 g (9.22 mmol) of 3, 5-Dimethylbenzoic acid was dissolved in 20mL DMF and placed in a constant pressure dropping funnel, slowly added dropwise, the temperature of the reaction system was controlled not to be higher than 5°C, after the dropwise addition was completed, the reaction was continued and the temperature was slowly raised to room temperature. After the reaction was complete, a certain amount of water was added, a large amount of white solids were precipitated, suction filtered, the filter cake was washed with ethyl acetate, the filtrate was extracted 3 times with ethyl acetate, washed once with water, dried, and spin-dried to obtain a crude product, all The solid was recrystallized from ethyl acetate to obtain 2.1 ...

specific Embodiment 2

[0012] Specific Example 2: Preparation of 2', 6'-dimethyl-4'-(N-succinimidyl) phenyl-acridine-9-carboxylate

[0013] 11 g (49.38 mmol) acridine-9-carbonyl chloride, 10 g (37.99 mmol) 1-((4-hydroxy-3,5-dimethylbenzoyl)oxy)-2,5-pyrrolidine Diketone and 7.24 g (37.99 mmol) p-toluenesulfonyl chloride were dissolved in 200 mL of anhydrous pyridine; under a nitrogen atmosphere, heated to 100 ° C. After the reaction is complete, the solvent is spin-dried, and after spin-drying, add 50mL of 1N hydrochloric acid (1N means that 1mL of concentrated hydrochloric acid is diluted with water to form a 12mL solution), 200mL of saturated sodium chloride solution, and 50mL of 1% sodium hydroxide solution. Ethyl acetate was extracted three times, the organic phase was washed three times with water, dried and spin-dried to obtain 7.2 g of crude product, and the obtained solid was purified by column chromatography to obtain 5 g of product. The yield was 28.1%.

Embodiment 3

[0014] Embodiment 3: the preparation of acridinium ester DMAE NHS

[0015] Add 1 g (2.13 mmol) of 2',6'-dimethyl-4'-(N-succinimidyl)phenyl-acridine-9-carboxylate into 20 mL of anhydrous toluene, heat to 110°C It was completely dissolved in toluene and cooled to room temperature. After cooling slightly, 11 mL of dry redistilled dimethyl sulfate was added. Under the protection of nitrogen atmosphere, the reaction was stirred at 110°C for 20 hours, and the solution was cooled to room temperature, followed by 4 Continue to stir the reaction at ℃ for 1 hour; filter the obtained mixture, wash the solid twice with toluene, then dissolve the yellow solid in 60 mL of dichloromethane, heat to boiling, keep for 2-3 minutes, and filter hot, the obtained filtrate Concentrate to about 40 mL, cool to room temperature to obtain yellow crystals, wash with ether three times, and obtain 500 mg of yellow solids after vacuum drying with a yield of 39.4%.

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Abstract

The invention aims to provide a synthesis method of a chemiluminescent substrate namely acridinium ester 9-((4-(((2,5-dioxo-1-pyrrolidinyl)oxy)carbonyl)-2,6-dimethylphenoxyl)carbonyl)-10-methyl acridine onium methyl sulfate (DAME.NHS). The chemical structure of DMAE.NHS is represented in the description. According to the synthesis method, 3,5-dimethyl-4-hydroxyl benzoic acid, N-hydroxyl succinimide, and acridine-9-carbonyl chloride are taken as the raw materials, and after two steps of esterification reactions, the reaction product is subjected to methylation to obtain the target compound. Compared with other synthesis method, the provided synthesis method has the advantages that the steps are few, the method does not need any pricy reagent or solvent, the reaction conditions are mild, the product yield and purity are high, and the synthesis method is suitable for massive production.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, and in particular relates to the synthesis of acridinium ester chemiluminescence substrate DMAE·NHS chemiluminescence reagent. Background technique [0002] Chemiluminescence analysis has been widely used in environmental monitoring, clinical analysis, biochemistry and other important fields due to its high sensitivity, relatively simple equipment, avoiding the influence of astigmatism without light source, and high reproducibility. As a current commercial chemiluminescent substrate, compared with other types of luminescent substrates, it has high luminous intensity, high efficiency, low background interference, no catalyst and enhancer, high signal-to-noise ratio and stable label binding It is favored by analysts due to its advantages, and the structural modification of acridine compounds to make chemiluminescent probes is not only suitable for labeling small molecules, but also for bi...

Claims

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Application Information

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IPC IPC(8): C07D401/12G01N21/76
CPCC07D401/12G01N21/76
Inventor 尹鹏谢朝龙夏开富尹国兴喻婷
Owner HUNAN NORMAL UNIVERSITY
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