CN111777556B - Method for preparing acridine 9-carboxylic acid by oxidation method - Google Patents
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- CN111777556B CN111777556B CN202010679602.XA CN202010679602A CN111777556B CN 111777556 B CN111777556 B CN 111777556B CN 202010679602 A CN202010679602 A CN 202010679602A CN 111777556 B CN111777556 B CN 111777556B
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- 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
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Abstract
The invention relates to the field of acridine derivatives, in particular to a method for preparing acridine 9-carboxylic acid by an oxidation method, which comprises the following steps of firstly, weighing 9-methylacridine, an oxidant, an oxidation catalyst and a solvent, wherein the molar ratio of the 9-methylacridine to the oxidant to the oxidation catalyst is 1: 4-8: 0.03-0.06, wherein the weight ratio of the 9-methylacridine to the solvent is 1: 3-8; putting 9-methylacridine, an oxidant, an oxidation catalyst and a solvent into a container, and reacting for 1-3 hours at the temperature of 80-120 ℃ to obtain a reaction liquid containing acridine 9-carboxylic acid; and step three, the acridine 9-carboxylic acid is separated from the reaction liquid to obtain the acridine 9-carboxylic acid, and the method is simple and easy to operate, simple in steps, environment-friendly, good in controllability of the reaction process, simple and convenient in post-treatment and good in industrial application value.
Description
Technical Field
The invention relates to the field of acridine derivatives, in particular to a method for preparing acridine 9-carboxylic acid by an oxidation method.
Background
Chemiluminescence immunoassay (CLIA) is a technique for detecting an antigen or an antibody by combining an immune reaction and a chemiluminescence reaction, and is widely used in the field of immunoassay due to high sensitivity and simple operation. With the rapid development of CLIA, a plurality of chemiluminescent substances have been developed abroad, and different chemiluminescent substances have different luminescent mechanisms and luminescent properties. Wherein the acridine ester acridine derivative is used as an immunoassay tracer without a catalyst, so that the reaction is simplified; the luminous reaction is rapid, the sufficiency of counting is increased, and the background noise is low; high specific activity, high reaction efficiency, short reaction time and other advantages. In addition, acridinium ester is used as an efficient chemiluminescent reagent, is widely applied to aspects such as clinical immunoassay which is very suitable for labeling a DNA chain to manufacture a chemiluminescent DNA probe, biological enzyme activity determination and the like, and acridinium 9-carboxylic acid is an important raw material for preparing the acridinium ester, but the preparation method or steps of documents are complicated or the used raw materials are polluted by the environment, most of the raw materials are in the research stage of laboratories, and the large-scale research and application is less, so that the research of the raw materials in the application field is limited, and therefore, the process for preparing the acridinium 9-carboxylic acid, which is environment-friendly, simple and convenient to operate and efficient, is urgently needed to be developed.
Acridine 9-carboxylic acid having the formula C 14 H 9 NO 2 The structural formula is as follows:
currently, there are two methods for synthesizing acridine 9-carboxylic acid, which are an oxidation method and a non-oxidation method: the non-oxidation method 1 is characterized in that acridine is used as a raw material, and is subjected to 9-site cyano substitution and then hydrolysis to obtain a product; the method 2 comprises the steps of taking diphenylamine as a raw material, and carrying out ring closure with oxalyl chloride to obtain a product; the oxidation method takes 9-methylacridine as a raw material to be oxidized to obtain a product.
The development of chemistry began with an oxidation reaction, established in 1777 by lavatin, which initiated a new era of chemistry from qualitative observations to quantitative studies. The oxidation reaction has been an important subject in organic synthesis research due to its relatively mild conditions and high atom economy. The acridine 9-carboxylic acid is synthesized by a non-oxidation method, and the defects of low atom utilization rate and environmental pollution exist in cyano-substituted and oxalyl chloride ring closure, so that the method selects 9-methylacridine as a raw material for oxidation, obtains a process with high atom utilization rate, relatively mild reaction conditions and environmental friendliness by screening oxidants, catalysts and other conditions.
The literature, "new synthesis route of acridine ester as chemiluminescent immunoassay reagent" (advanced chemical reports, 1998, 19(12): 1933-1936) reports that 9- β -hydroxyethylacridine is obtained by reacting 9-methylacridine as a raw material with formaldehyde, acridine 9-carboxylic acid is obtained by oxidizing with chromic acid, the formaldehyde and potassium dichromate used in the reaction cause environmental pollution, and the reaction requires two steps and is complicated.
In order to solve the problems of environmental pollution and complex operation caused by chromic acid adopted in the existing preparation method, the invention further researches on the basis to obtain the preparation method for generating acridine 9-carboxylic acid by oxidation.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide the method for preparing the acridine 9-carboxylic acid by the oxidation method, which is simple and easy to operate, simple in steps, environment-friendly, good in controllability of the reaction process, simple and convenient in post-treatment and high in industrial application value.
The invention is realized by the following technical scheme: a method for preparing acridine 9-carboxylic acid by an oxidation method comprises the following steps,
weighing 9-methylacridine, an oxidant, an oxidation catalyst and a solvent, wherein the molar ratio of the 9-methylacridine to the oxidant to the oxidation catalyst is 1: 4-8: 0.03-0.06, wherein the weight ratio of the 9-methylacridine to the solvent is 1: 3-8;
putting 9-methylacridine, an oxidant, an oxidation catalyst and a solvent into a container, and reacting for 1-3 hours at the temperature of 80-120 ℃ to obtain a reaction liquid containing acridine 9-carboxylic acid;
and step three, separating the acridine 9-carboxylic acid from the reaction liquid to obtain the acridine 9-carboxylic acid.
Further, the oxidizing agent is tert-butyl hydroperoxide.
Further, the oxidation catalyst is vanadyl acetylacetonate.
Further, the solvent is chloroform.
Further, in the second step, the microwave heating is performed by 200-350W.
Further, the second step comprises the following steps,
a, dividing 9-methylacridine into three parts, putting the first part of 9-methylacridine, oxidant, oxidation catalyst and solvent into a container, heating to 80-90 ℃, and reacting for 0.5-1 h;
b, cooling to 30-40 ℃, adding a second part of 9-methylacridine into the container treated in the step a, heating to 90-100 ℃, and reacting for 0.5-1 h;
c, cooling to 30-40 ℃, adding a second part of 9-methylacridine into the container treated in the step b, heating to 120 ℃ and reacting for 0.3-0.5h to obtain a reaction solution containing acridine 9-carboxylic acid.
Further, in step a, 9-methylacridine was divided into three portions.
Further, the third step includes the following steps,
a, cooling the reaction liquid to room temperature, and filtering to obtain a crude product of acridine 9-carboxylic acid;
b, adding ethanol into the acridine 9-carboxylic acid crude product for recrystallization to obtain a mixed solution;
and C, filtering the mixed solution, and then drying to obtain yellow solid powder which is acridine 9-carboxylic acid.
The invention has the beneficial effects that: the method comprises the following steps of putting 9-methylacridine, an oxidant, an oxidation catalyst and a solvent into a solvent, and controlling the dosage of each material, the reaction temperature and the reaction time, wherein the method is simple and easy to operate, simple in step, environment-friendly, good in controllability of the reaction process, simple and convenient in post-treatment and good in industrial application value; the tert-butyl hydroperoxide replaces heavy metal or transition metal oxidant in the prior art, so that the introduction of metal ions is avoided, and the used oxidation catalyst ensures that the reaction is more thorough and the use amount is small, reduces the discharge of three wastes, is environment-friendly and meets the requirement of green chemistry; by using microwave heating, the reaction conversion rate and selectivity are improved, the reaction time is shortened, and the reaction rate is improved; the 9-methylacridine is added into the reaction system in three batches, so that the reaction is better controlled, the product conversion rate is improved, the generation of byproducts is reduced, and the yield and the purity of the product are improved.
Drawings
FIG. 1 is a NMR chart of acridine 9-carboxylic acid obtained in example 1.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to 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.
In each of the following examples,
the oxidant is tert-butyl hydroperoxide, and the tert-butyl hydroperoxide replaces heavy metal or transition metal oxidant in the prior art, so that the introduction of metal ions is avoided;
the oxidation catalyst is vanadyl acetylacetonate, so that the reaction is more thorough, the use amount is small, the discharge of three wastes is reduced, and the method is environment-friendly and meets the requirement of green chemistry;
the solvent is chloroform, the organic solvent does not participate in the reaction and can support the temperature of the reaction, and the acridine 9-carboxylic acid can be precipitated from the organic solvent;
in the second step, microwave heating is adopted, so that the reaction conversion rate and selectivity are improved, the reaction time is shortened, and the reaction rate is improved;
in the second step, 9-methylacridine is added into the reaction system in three batches, so that the reaction is better controlled, the product conversion rate is improved, the generation of byproducts is reduced, and the yield and the purity of the product are improved.
In the following examples, the stirring speed was 100rpm, and the reaction was more uniform.
The filter paper with 300 meshes is selected for the filtration in the third step.
Example 1
A method for preparing acridine 9-carboxylic acid by an oxidation method comprises the following steps,
weighing 19.3g of 9-methylacridine, 36.0g of oxidant, 0.79g of oxidation catalyst and 57.9g of solvent;
step two, dividing 9-methylacridine into three parts, namely 6.4g of first part 9-methylacridine, 6.4g of second part 9-methylacridine and 6.5g of third part 9-methylacridine, putting an oxidant, an oxidation catalyst and a solvent into a container, stirring for 10min, then adding the first part 9-methylacridine under the stirring state, stirring for 50min, heating to 90 ℃ by 200w of microwaves, reacting for 1h under the stirring state,
then cooling to 30 ℃, adding a second part of 9-methylacridine under the stirring state, heating to 100 ℃ by 200w of microwave, reacting for 1h under the stirring state,
cooling to 30 ℃, adding a third part of 9-methylacridine under a stirring state, heating to 120 ℃ by 200w of microwave, and reacting for 0.5h under a stirring state to obtain a reaction solution containing acridine 9-carboxylic acid;
step three, cooling the reaction liquid to room temperature, filtering to obtain a crude product of acridine 9-carboxylic acid,
adding ethanol with the weight of 3-5 times of that of the crude acridine 9-carboxylic acid, heating and refluxing for 1.5-3h, then cooling to room temperature to complete recrystallization to obtain a mixed solution,
and filtering the mixed solution, and then drying at the temperature of 100 ℃ to obtain yellow solid powder which is acridine 9-carboxylic acid.
The results of the detection of acridine 9-carboxylic acid are shown in the attached Table 1.
Example 2
A method for preparing acridine 9-carboxylic acid by an oxidation method comprises the following steps,
weighing 96g of 9-methylacridine, 270g of oxidant, 6.65g of oxidation catalyst and 482.5g of solvent;
step two, dividing the 9-methylacridine into three parts, putting the oxidant, the oxidation catalyst and the solvent into a container, stirring for 10min, then adding the first part of 9-methylacridine under the stirring state, heating to 90 ℃ by 250w of microwave after stirring for 50min, reacting for 0.5h under the stirring state,
then cooling to 40 ℃, adding a second part of 9-methylacridine under the stirring state, heating to 95 ℃ by 250w of microwave, reacting for 0.8h under the stirring state,
cooling to 40 ℃, adding a third part of 9-methylacridine under stirring, heating to 110 ℃ by 250w of microwave, and reacting for 0.4h under stirring to obtain a reaction solution containing acridine 9-carboxylic acid;
step three, cooling the reaction liquid to room temperature, filtering to obtain a crude product of acridine 9-carboxylic acid,
adding ethanol with the weight of 3-5 times of that of the crude acridine 9-carboxylic acid, heating and refluxing for 1.5-3h, then cooling to room temperature to complete recrystallization to obtain a mixed solution,
and filtering the mixed solution, and then drying at the temperature of 100 ℃ to obtain yellow solid powder which is acridine 9-carboxylic acid.
The results of the detection of acridine 9-carboxylic acid are shown in the attached Table 1.
Example 3
A method for preparing acridine 9-carboxylic acid by an oxidation method comprises the following steps,
weighing 19.3g of 9-methylacridine, 72.1g of oxidant, 1.6g of oxidation catalyst and 154.4g of solvent;
step two, dividing 9-methylacridine into three parts, namely 6.4g of first part 9-methylacridine, 6.4g of second part 9-methylacridine and 6.5g of third part 9-methylacridine, putting an oxidant, an oxidation catalyst and a solvent into a container, stirring for 10min, then adding the first part 9-methylacridine under the stirring state, stirring for 30min, heating to 80 ℃ through 350w of microwaves, reacting for 1h under the stirring state,
then cooling to 40 ℃, adding a second part of 9-methylacridine under the stirring state, heating to 90 ℃ by 350w of microwave, reacting for 0.5h under the stirring state,
cooling to 40 ℃, adding a third part of 9-methylacridine under stirring, heating to 100 ℃ by 350w of microwave, and reacting for 0.3h under stirring to obtain a reaction solution containing acridine 9-carboxylic acid;
step three, cooling the reaction liquid to room temperature, filtering to obtain a crude product of acridine 9-carboxylic acid,
adding ethanol with the weight of 3-5 times of that of the crude acridine 9-carboxylic acid, heating and refluxing for 1.5-3h, then cooling to room temperature to complete recrystallization to obtain a mixed solution,
and filtering the mixed solution, and then drying at the temperature of 100 ℃ to obtain yellow solid powder which is acridine 9-carboxylic acid.
The results of the detection of acridine 9-carboxylic acid are shown in the attached Table 1.
Attached table 1
The method of calculating the yield in the above table is as follows,
yield = (molar amount of acridine 9-carboxylic acid obtained. purity%)/(molar amount of raw material 9-methylacridine). 100%, the weight in attached table 1 is the weight of acridine 9-carboxylic acid obtained.
The comparative example is a data value obtained by a preparation route of the acridine 9-carboxylic acid disclosed in a document 'a new synthesis route of a chemiluminescent immunoassay reagent acridine ester', and the preparation process of the acridine 9-carboxylic acid provided by the application can greatly improve the yield and reduce the reaction time.
In the production process, the third step can also be completed by cooling the reaction liquid to room temperature, filtering to obtain a crude acridine 9-carboxylic acid product,
adding 3-5 times of ethanol into the crude acridine 9-carboxylic acid product, pulping, filtering, and drying at 100 ℃ to obtain yellow solid powder which is acridine 9-carboxylic acid, wherein the steps are simpler and are suitable for industrial production.
Experimental example 1
The acridine 9-carboxylic acid obtained in example 1 of the present invention was subjected to a hydrogen nuclear magnetic resonance spectroscopy and the results are shown in FIG. 1.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still make modifications to the technical solutions described in the foregoing embodiments, or make equivalent substitutions and improvements to part of the technical features of the foregoing embodiments, and any modifications, equivalent substitutions and improvements made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (3)
1. The method for preparing acridine 9-carboxylic acid by an oxidation method is characterized by comprising the following steps of firstly, weighing 9-methylacridine, an oxidant, an oxidation catalyst and a solvent, wherein the molar ratio of the 9-methylacridine to the oxidant to the oxidation catalyst is 1: 4-8: 0.03-0.06, wherein the weight ratio of the 9-methylacridine to the solvent is 1: 3-8;
putting 9-methylacridine, an oxidant, an oxidation catalyst and a solvent into a container, and reacting for 1-3 hours at the temperature of 80-120 ℃ to obtain a reaction liquid containing acridine 9-carboxylic acid;
step three, separating the acridine 9-carboxylic acid from the reaction liquid to obtain the acridine 9-carboxylic acid,
the oxidant is tert-butyl hydroperoxide, the oxidation catalyst is vanadyl acetylacetonate, the solvent is chloroform,
in the second step, through 200-350W microwave heating,
the second step comprises the following steps of,
a, dividing 9-methylacridine into three parts, putting the first part of 9-methylacridine, oxidant, oxidation catalyst and solvent into a container, heating to 80-90 ℃, and reacting for 0.5-1 h;
b, cooling to 30-40 ℃, adding a second part of 9-methylacridine into the container treated in the step a, heating to 90-100 ℃, and reacting for 0.5-1 h;
c, cooling to 30-40 ℃, adding a third part of 9-methylacridine into the container treated in the step b, heating to 120 ℃ and reacting for 0.3-0.5h to obtain a reaction solution containing acridine 9-carboxylic acid.
2. The method for producing acridine 9-carboxylic acid according to claim 1, wherein in step a, 9-methylacridine is divided into three portions.
3. The oxidation method for producing acridine 9-carboxylic acid according to claim 1, wherein step three comprises the steps of,
a, cooling the reaction liquid to room temperature, and filtering to obtain a crude product of acridine 9-carboxylic acid;
b, adding ethanol into the acridine 9-carboxylic acid crude product for recrystallization to obtain a mixed solution;
and C, filtering the mixed solution, and then drying to obtain yellow solid powder which is acridine 9-carboxylic acid.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101423469A (en) * | 2007-10-31 | 2009-05-06 | 香港浸会大学 | Oxidation process for aromatic compound |
| CN102491960A (en) * | 2011-11-16 | 2012-06-13 | 福建广生堂药业股份有限公司 | Intermediate compound for synthesis of entecavir, and preparation method and application of intermediate compound |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101423469A (en) * | 2007-10-31 | 2009-05-06 | 香港浸会大学 | Oxidation process for aromatic compound |
| CN102491960A (en) * | 2011-11-16 | 2012-06-13 | 福建广生堂药业股份有限公司 | Intermediate compound for synthesis of entecavir, and preparation method and application of intermediate compound |
Non-Patent Citations (1)
| Title |
|---|
| Ordered mesoporous V2O5/WO3 composite catalysts for efficient oxidation of aryl alcohols;Euaggelia Skliri et al.;《The Royal Society of Chemistry》;20140911;第4卷;第46170-46178页 * |
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