A kind of preparation method of inner salt of acridine

An acridine and compound technology, which is applied in the synthesis of chemiluminescent agents and the preparation of acridine inner salts, can solve the problems of low atomic economic efficiency, high synthesis difficulty, low combined yield, etc. The effect of improving the expandability and solubility

Active Publication Date: 2021-01-15
合肥华纳生物医药科技有限公司
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  • Claims
  • Application Information

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Problems solved by technology

However, due to the complicated preparation route, high synthesis difficulty, low combined yield and serious pollution of acridine ester compounds, their price is expensive, which limits their wide application in chemiluminescence detection.
The patent application whose application number is CN201310250582.4 discloses a preparation method of acridine series chemiluminescence agent, but it is used in the preparation of 9-[[[4-[(2,5-dioxo-1-pyrrolidinyl )oxy]-4-oxobutyl][(4-methylphenyl)sulfonyl]amino]carbonyl]-10-(3-sulfopropyl)-acridine inner salt High TSTU, pushing up the production cost, and the atomic economic efficiency is also very low
More importantly, due to the use of DMF as a solvent in the preparation step of the target product, the product after the reaction is oily, it is difficult to analyze the target product by conventional methods, and only a small amount of reactant can be purified by preparative chromatography, which limits the Synthetic routes for mass production of target products

Method used

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  • A kind of preparation method of inner salt of acridine
  • A kind of preparation method of inner salt of acridine
  • A kind of preparation method of inner salt of acridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] See attached figure 1 The shown chemical reaction formula is prepared from 10-(3-sulfopropyl)-N-p-toluenesulfonyl-N-(3-carboxypropyl)acridine-9-carboxamide, i.e. formula C compound 9-[ [[4-[(2,5-dioxo-1-pyrrolidinyl)oxy]-4-oxobutyl][(4-methylphenyl)sulfonyl]amino]carbonyl]-10- (3-sulfopropyl)-acridine inner salt, that is, the compound of formula D: after dissolving 200 mg of compound C in acetonitrile, the reaction solution was not dissolved, and 150 mg of N,N'-carbonyldiimidazole was added, N 2 After ventilation, wrap it in tinfoil paper, activate it at room temperature for 2 hours, and gradually dissolve the reaction solution, then add 194 mg of N-hydroxysuccinimide, react at room temperature for 6 hours, and a yellow solid precipitates out. HPLC tracking shows that the reaction of the raw materials is complete. Add 6 tert-butyl methyl ether twice the volume of acetonitrile was stirred and crystallized, suction filtered, the filter cake was washed with a small amount...

Embodiment 2

[0031] See attached figure 2 The reaction formula for the preparation of the shown C compound from its ester compound C': take 750 mg of the formula C' compound and add it to the HCl solution with a concentration of 3N, wrap it in tin foil, and use N 2 Pump and change air several times, react at 80°C for 16h, a yellow solid precipitates out of the reaction liquid, after the reaction is complete, cool down to room temperature, add NaHCO 3 Adjust the pH of the solid to alkaline, dissolve the yellow solid, extract it with dichloromethane three times, collect the water phase, spin off the remaining organic solvent in the water phase under reduced pressure, use HCl to adjust the pH of the water phase to 1, and the yellow solid precipitates , filtered with suction, washed the filter cake with water, and dried at 50°C. Obtained 652 mg of yellow solid, namely the compound of formula C, HPLC > 99%, yield: 89%.

Embodiment 3

[0033] See attached image 3 The reaction formula for preparing the compound of formula C' from the compound of formula B as shown: take 0.99 gram of compound of formula B, add 0.77 gram of 1,3-propane sultone, add 5 mL of N-methylpyrrolidone, and use N 2 Air exchange several times, shading, heating reaction in an oil bath at 125°C, reaction for 26 hours, stop heating, cool to room temperature, and direct column chromatography to obtain 1.11g of yellow powder, which is the compound of formula C', HPLC: 91.5%, yield: 88%.

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Abstract

The invention discloses a preparation method of acridine inner salt. The method specifically comprises the following steps: by taking a compound with a structure as shown in a formula C as a raw material, adding an activating agent into an acetonitrile solvent, activating at 20-40 DEG C for 1-4 hours, adding N-hydroxysuccinimide, reacting at 20-40 DEG C, adding another solvent into a reactant after the reaction is completed, stirring for crystallization, and carrying out after-treatment to obtain the product acridine inner salt, namely a compound as shown in a formula D. According to the invention, N-hydroxysuccinimide with relatively low price is used for replacing expensive TSTU to prepare the acridine inner salt compound which can be used as a chemiluminescence detection reagent, and the cost is reduced; and meanwhile, the final product can be separated out through crystallization side reaction by screening the reaction solvent and the activating agent, so that the production process is greatly simplified.

Description

technical field [0001] The invention belongs to the technical field of biological detection and relates to the synthesis of chemiluminescent agents, in particular to a preparation method of acridine inner salt. Background technique [0002] In vitro diagnosis refers to products and services that obtain clinical diagnostic information by testing human samples (blood, body fluids, tissue fluids, etc.) outside the human body, and then determine diseases or body functions. According to the classification of detection principles and detection methods, in vitro diagnosis can be mainly divided into biochemical diagnosis, immunodiagnosis, molecular diagnosis, instant diagnosis, microbial diagnosis, urine diagnosis, coagulation diagnosis, blood diagnosis and other diagnostic methods, among which immunodiagnosis is an in vitro diagnosis important branch. Immunodiagnosis is based on the principle of specific combination of antigen and antibody, and is mainly used in hepatitis, virus, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07D219/04
CPCC07D219/04C07D401/12
Inventor 王闪雷吴义进鲍彦沈文静王忠
Owner 合肥华纳生物医药科技有限公司
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