CN111170994A - Preparation method of acridine inner salt - Google Patents
Preparation method of acridine inner salt Download PDFInfo
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- CN111170994A CN111170994A CN202010145333.9A CN202010145333A CN111170994A CN 111170994 A CN111170994 A CN 111170994A CN 202010145333 A CN202010145333 A CN 202010145333A CN 111170994 A CN111170994 A CN 111170994A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
- C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
Abstract
The invention discloses a preparation method of acridine inner salt, which comprises the steps of taking a compound with a structure shown in a formula C as a raw material, adding an activating agent into acetonitrile solvent, activating for 1-4h at 20-40 ℃, adding N-hydroxysuccinimide into the acetonitrile solvent, reacting at 20-40 ℃, adding another solvent into a reactant after the reaction is completed, stirring and crystallizing, and carrying out post-treatment to obtain the product acridine inner salt, namely the compound shown in the formula D. The invention adopts the N-hydroxysuccinimide with relatively low price to replace the TSTU with high price to prepare the acridine inner salt compound which can be used as a chemiluminescence detection reagent, thereby reducing the cost.
Description
Technical Field
The invention belongs to the technical field of biological detection, relates to synthesis of a chemiluminescent agent, and particularly relates to a preparation method of acridine inner salt.
Background
In vitro diagnosis refers to products and services for determining diseases or body functions by detecting human body samples (blood, body fluids, interstitial fluids, etc.) to obtain clinical diagnosis information, outside the human body. According to the classification of the detection principle and the detection method, the in vitro diagnosis can be mainly classified into chemical diagnosis, immunological diagnosis, molecular diagnosis, instant diagnosis, microbial diagnosis, urine diagnosis, blood coagulation diagnosis, blood diagnosis and other diagnosis methods, wherein the immunological diagnosis is an important branch of the in vitro diagnosis. Immunodiagnosis is based on the principle of specific combination of antigen and antibody, and is mainly used for hepatitis, virus, blood source, tumor, medicine detection, etc. The development of immunodiagnostic techniques has gone through isotope Radioimmunoassay (RIA), colloidal gold, enzyme-linked immunosorbent assay (ELISA), time-resolved fluorescence (TRFIA), Chemiluminescence (CLIA), and the like. At present, the mainstream of immunodiagnosis technology in China is enzyme-linked immunosorbent assay and chemiluminescence, and the chemiluminescence is more sensitive, faster, more stable, more specific and more reproducible than the enzyme-linked immunosorbent assay, so that the chemiluminescence market scale is continuously enlarged every year, and the substitution of chemiluminescence for enzyme-linked immunosorbent assay is a great trend.
The chemiluminescence immunoassay technique comprises two parts of immunoreaction and chemiluminescence. Firstly, a luminescent substance or enzyme is marked on an antigen or an antibody, after the antigen or the antibody is specifically combined with a substance to be detected, an oxidant or a chemiluminescent substrate is added, after oxidation or reaction with the substrate, the chemiluminescent substance can form an intermediate in an excited state, and the intermediate returns to a ground state and emits photons to release energy. The content of the substance to be detected can be determined by detecting the chemiluminescence intensity of the system by using an instrument according to the principle that the concentration of the substance to be detected in a chemical detection system and the chemiluminescence intensity of the system are in a linear quantitative relationship under a certain condition.
Direct chemiluminescence immunoassay is one of the more common technical centers of chemiluminescence immunoassay, and specifically, chemiluminescent agents such as acridinium ester compounds are directly marked on antigens or antibodies. The chemical reaction of the marker is simple and rapid, does not need a catalyst, and has high marking efficiency. However, the acridine ester compound is expensive due to complex preparation route, high synthesis difficulty, low combination yield and serious pollution, thereby limiting the wide application of the acridine ester compound in chemiluminescence detection. Patent application No. CN201310250582.4 discloses a method for preparing acridine series chemiluminescence agent, but the method uses high-price TSTU in the process of preparing 9- [ [ [4- [ (2, 5-dioxo-1-pyrrolidinyl) oxy ] -4-oxobutyl ] [ (4-methylphenyl) sulfonyl ] amino ] carbonyl ] -10- (3-sulfopropyl) -acridine inner salt, which increases the production cost and has very low atom economic efficiency. More importantly, DMF is used as a solvent in the preparation step of the target product, and the product after the reaction is oily, so that the target product is difficult to analyze by a conventional method, and only a small amount of reactants can be purified by adopting a preparative chromatography, thereby limiting the application of the synthetic route in the mass production of the target product. DMF as a high boiling polar solvent has good solubility to both raw materials and products, so it is difficult to separate the product by conventional separation means, such as column chromatography, crystallization, etc., after the reaction is completed.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a preparation method of acridine inner salt, which comprises the following steps: a preparation method of acridine inner salt is disclosed, wherein the structure of the acridine inner salt is shown as a formula D, a compound with a structure of a formula C is used as a raw material, acetonitrile is used as a solvent, an activating agent is added to activate for 1-4h at 20-40 ℃, N-hydroxysuccinimide is added to react for 3-8h at 20-40 ℃, another solvent is added to the reactant after the reaction is completed, the mixture is stirred and crystallized, and the product of the acridine inner salt, namely the compound with the formula D, is obtained after post-treatment; the reaction proceeds as follows.
Further, after the reaction is completed, another solvent selected from ethyl acetate, petroleum ether, ethanol or tert-butyl methyl ether is added into the reactants.
Further, the activator is N, N' -carbonyldiimidazole; and/or the activation temperature is room temperature; and/or the temperature of the reaction with the N-hydroxysuccinimide is room temperature.
Further, the compound of formula C is prepared as follows: the compound of the formula B and 1, 3-propane sultone are heated and reacted in the absence of light in the presence of an aprotic polar solvent, the reaction is cooled to room temperature after the reaction is finished, the compound of the formula C 'is obtained after column chromatography, the compound of the formula C' is placed in an acid solution for acid hydrolysis reaction, the pH value is adjusted to be more than 7 after the reaction is completed, and then the compound of the formula C is obtained after post-treatment; the reaction proceeds as follows.
Further, the aprotic polar solvent is N-methyl pyrrolidone, and the temperature for reacting with 1, 3-propane sultone is 110-130 ℃; and/or, the acidic reagent is HCl; and/or, the post-treatment comprises the specific steps of extracting for at least 2 times by using an alkyl halide solvent, collecting a water phase, decompressing, rotatably removing the organic solvent, concentrating the solution, adjusting the pH to 1, carrying out suction filtration on the separated solid, washing a filter cake by using water, and drying to obtain the compound of the formula C.
Further, said methyl 4- [ (4-methylphenylsulfonyl) (9-acridinecarbonyl) amino ] -butyrate, i.e., the compound of formula B, is prepared as follows: 4- [ (4-methylphenyl) sulfonylamino ] methyl butyrate and 9-acridine acyl chloride hydrochloride react in the presence of an alkaline reagent by taking alkyl halide as a solvent, and then are subjected to post-treatment to obtain the compound.
Further, the alkaline reagent is NaH, the alkyl halide is dichloromethane, and/or the reaction temperature is room temperature, and the reaction time is 6-8 h; and/or the post-treatment comprises adding water for quenching, extracting, drying the organic phase, and performing column chromatography to obtain the product.
The invention has the beneficial effects that:
(1) according to the invention, through screening, acetonitrile is selected as a reaction solvent, the solubility of acetonitrile to a target product is low, the target product is favorably separated directly by adopting a crystallization reaction, the expandability of the reaction is greatly improved, the acetonitrile has low solubility to raw materials, so that the reaction is not facilitated, in order to improve the solubility of the raw materials, namely the compound of the formula C in the acetonitrile, the compound of the formula C is activated by adopting an activating agent N, N' -Carbonyldiimidazole (CDI), the solubility of the generated active intermediate in the acetonitrile is greatly improved, and the reaction is effectively promoted.
(2) The invention adopts the N-hydroxysuccinimide (NHS) with relatively low price to replace TSTU with high price to prepare the acridine inner salt compound which can be used as a chemiluminescence detection reagent, reduces the cost and improves the yield, and in addition, adopts NHS as a raw material to greatly improve the atom utilization efficiency of a synthesis route.
(3) The steps of the total synthesis route can be separated by a conventional separation means, so that the total synthesis route and the comprehensive efficiency are high, the process is simple, and the acridine inner salt is generated on a large scale.
Drawings
FIG. 1 shows a reaction formula of acridine inner salt in the present invention.
FIG. 2 is a reaction scheme of a compound of formula C in the present invention.
FIG. 3 is a reaction scheme of the compound of formula C' in the present invention.
FIG. 4 is a reaction scheme of a compound of formula B in the present invention.
FIG. 5 shows the reaction scheme of 9-acridine chloride hydrochloride in the present invention.
FIG. 6 shows a reaction scheme of methyl 4- [ (4-methylphenyl) sulfonylamino ] butanoate according to the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the description is intended to be exemplary only, and is not intended to limit the scope of the present invention.
Example 1:
referring to the chemical reaction formula shown in the attached FIG. 1, the preparation of 9- [ [ [4- [ (2, 5-dioxo-1-pyrrolidinyl) oxy ] is performed from 10- (3-sulfopropyl) -N-p-toluenesulfonyl-N- (3-carboxypropyl) acridine-9-carboxamide, a compound of formula C]-4-oxobutyl group][ (4-methylphenyl) sulfonyl]Amino group]Carbonyl radical]-10- (3-sulfopropyl) -acridine inner salt, i.e. a compound of formula D: dissolving 200 mg of compound C in acetonitrile, and reactingThe reaction solution was not dissolved and 150 mg of N, N' -carbonyldiimidazole, N was added2Wrapping with tin foil paper after air pumping, activating at room temperature for 2h, gradually dissolving and cleaning reaction liquid, adding 194 mg of N-hydroxysuccinimide, reacting at room temperature for 6h to separate out yellow solid, HPLC tracking to show that the raw material reaction is complete, adding tert-butyl methyl ether 6 times of acetonitrile volume, stirring, crystallizing, filtering, washing filter cake with a small amount of tert-butyl methyl ether, collecting solid, pumping to dry to obtain 213 mg of yellow solid, and HPLC>98%, yield: 92%, and storing in shade at-20 deg.C.
The reaction was scaled up to 100g with >98% HPLC and 86% yield. The synthetic route of the invention has good amplification effect and better industrialization potential.
Comparative example 1:
the above experiment was repeated using tetrahydrofuran as the solvent, and the other experimental conditions were unchanged, the final yield was only 23%, HPLC was only 84%, and the crystallization reaction could not be performed.
Example 2:
see the reaction formula of the compound C shown in the attached figure 2 prepared by the ester compound C': adding 750 mg of the compound of formula C' into 3N HCl solution, wrapping with tinfoil paper, and coating with N2Pumping gas for several times, reacting at 80 deg.C for 16 hr to obtain yellow solid, cooling to room temperature, adding NaHCO3Adjusting the pH of the solid to be alkaline, dissolving the yellow solid, extracting with dichloromethane for 3 times, collecting the water phase, performing reduced pressure spinning on the organic solvent remained in the water phase, adjusting the pH of the water phase to be 1 by using HCl, separating out the yellow solid, performing suction filtration, washing the filter cake with water, and drying at 50 ℃. This gave 652 mg of a yellow solid, i.e. the compound of the formula C, HPLC>99%, yield: 89 percent.
Example 3:
see the reaction scheme for the preparation of compounds of formula C' from compounds of formula B shown in figure 3: taking 0.99 g of the compound of the formula B, adding 0.77 g of 1, 3-propane sultone and 5 mL of N-methylpyrrolidone, adopting N2Pumping gas for several times, shading, heating in oil bath at 125 deg.C for reaction for 26 hr, stopping heating, cooling to room temperature, performing column chromatography to obtain yellow powder 1.11g, i.e. compound of formula C',HPLC: 91.5%, yield: 88 percent.
Example 4:
referring now to FIG. 4, there is shown a reaction scheme for the preparation of a substituted 4- [ (4-methylphenyl) sulfonylamino group]Preparation of 4- [ (4-methylphenylsulfonyl) (9-acridinocarbonyl) amino by reaction of methyl butyrate, a compound of formula A1, and 9-acridinoyl chloride hydrochloride, a compound of formula A2]-methyl butyrate, i.e. a compound of formula B: 2.0 g of Compound A2, 2.35 g of Compound A1, 0.7 g of NaH are placed in a three-necked flask, 30 mL of dry methylene chloride are added, and N is used2Extracting with air for several times, reacting at room temperature for 7 hr, adding water, quenching, extracting with ethyl acetate, drying organic phase, performing column chromatography to obtain 3.04g product, and performing HPLC>98%, yield: 86 percent.
Example 5:
referring to FIG. 5, preparation of 9-acridinoyl chloride hydrochloride from 9-acridinecarboxylic acid: 1.11g of 9-acridinecarboxylic acid are added to 30 ml of SOCl2The solution is refluxed until the reaction solution is completely clear, and a bright yellow solid is obtained. Directly carrying out rotary evaporation on the reaction liquid to obtain the 9-acridine acyl chloride hydrochloride, and arranging a NaOH tail gas absorption device between a rotary evaporator and a water pump.
Example 6:
referring to FIG. 6, methyl 4- [ (4-methylphenyl) sulfonylamino ] butanoate, the compound of formula A1, is prepared from methyl 4-aminobutanoate hydrochloride: 0.77 g of methyl 4-aminobutyric acid hydrochloride is dissolved in 30 ml of dichloromethane, 1.01 g of triethylamine (2 equivalents) is added, the mixture is stirred for 1 h at room temperature to be dissociated, 1 equivalent of triethylamine is added, 1.05 g of TsCl is subsequently added, the reaction is carried out at room temperature, after the TLC tracking reaction is completed, the reaction is quenched by water, the pH of the reaction solution is adjusted to 3 by using dilute hydrochloric acid, then ethyl acetate is used for extraction for three times, organic phases are combined, a crude product is obtained by rotary evaporation after drying, and the product, namely methyl 4- [ (4-methylphenyl) sulfonylamino ] butyrate, is obtained by column chromatography, wherein 1.27 g of LCMS is correct, the purity is more than 98 percent, and the yield is 93.7 percent.
The above-described embodiments are merely preferred embodiments of the present invention, and should not be construed as limiting the present invention, and the scope of the present invention is defined by the claims, and the equivalents of the technical features included in the claims are included in the scope of the present invention.
Claims (7)
1. A preparation method of acridine inner salt is characterized in that the structure of the acridine inner salt is shown as a formula D, a compound with the structure of the formula C is used as a raw material, acetonitrile is used as a reaction solvent, an activating agent is added to activate for 1-4h at 20-40 ℃, N-hydroxysuccinimide is added to react at 20-40 ℃, another solvent is added to a reactant after the reaction is completed, the mixture is stirred and crystallized, and the product of the acridine inner salt, namely the compound with the formula D, is obtained after post-treatment;
2. the method according to claim 1, wherein another solvent selected from ethyl acetate, petroleum ether, ethanol and t-butyl methyl ether is added to the reaction mixture after the reaction is completed.
3. The preparation method according to claim 1, wherein the activating agent is N, N' -carbonyldiimidazole, and the activating temperature is room temperature; and/or the temperature of the reaction with the N-hydroxysuccinimide is room temperature.
4. The process according to any one of claims 1 to 3, wherein the compound of formula C is prepared as follows: the compound of the formula B and 1, 3-propane sultone are heated and reacted in the absence of light in the presence of an aprotic polar solvent, the reaction is cooled to room temperature after the reaction is finished, the compound of the formula C 'is obtained after column chromatography, the compound of the formula C' is placed in an acid solution for acid hydrolysis reaction, the pH value is adjusted to be more than 7 after the reaction is completed, and then the compound of the formula C is obtained after post-treatment;
5. the method according to claim 4, wherein the aprotic polar solvent is N-methylpyrrolidone, and the reaction temperature with 1, 3-propane sultone is 110 to 130 ℃;
and/or, the acid solution is an HCl solution;
and/or, the post-treatment step comprises the steps of extracting the reaction liquid with the pH value adjusted to be more than 7 for several times by using an organic solvent, collecting a water phase, decompressing and rotatably removing the organic solvent, adjusting the pH value to be acidic, separating out solids, carrying out suction filtration on the separated solids, washing a filter cake with water, and drying to obtain the compound of the formula C.
6. The process of claim 4, wherein the compound of formula B is prepared as follows: 4- [ (4-methylphenyl) sulfonylamino ] methyl butyrate and 9-acridine acyl chloride hydrochloride react in the presence of an alkaline reagent by taking alkyl halide as a solvent, and then are subjected to post-treatment to obtain the compound.
7. The method according to claim 5, wherein the alkaline agent is NaH;
and/or the reaction temperature is room temperature, and the reaction time is 6-8 h;
and/or the post-treatment comprises adding water for quenching, extracting, drying the organic phase, and performing column chromatography to obtain the product.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112255224A (en) * | 2020-11-30 | 2021-01-22 | 郑州原理生物科技有限公司 | Method for detecting signal impurity sulfate ion in acridine compound |
| CN113773299A (en) * | 2021-08-18 | 2021-12-10 | 上海敏韬医药科技有限公司 | Acridine salt derivative and synthesis method and application thereof |
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| WO2019126734A1 (en) * | 2017-12-22 | 2019-06-27 | Pacific Biosciences Of California, Inc. | Modified biotin-binding proteins for immobilization |
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| CN103288802A (en) * | 2013-06-21 | 2013-09-11 | 深圳市美凯特科技有限公司 | Preparation method for a series of acridine chemiluminescence agents |
| WO2019126734A1 (en) * | 2017-12-22 | 2019-06-27 | Pacific Biosciences Of California, Inc. | Modified biotin-binding proteins for immobilization |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112255224A (en) * | 2020-11-30 | 2021-01-22 | 郑州原理生物科技有限公司 | Method for detecting signal impurity sulfate ion in acridine compound |
| CN112255224B (en) * | 2020-11-30 | 2022-08-09 | 郑州原理生物科技有限公司 | Method for detecting signal impurity sulfate ion in acridine compound |
| CN113773299A (en) * | 2021-08-18 | 2021-12-10 | 上海敏韬医药科技有限公司 | Acridine salt derivative and synthesis method and application thereof |
| CN113773299B (en) * | 2021-08-18 | 2023-10-20 | 上海敏韬医药科技有限公司 | Acridine salt derivative and synthesis method and application thereof |
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