One-pot ultrasonic-assisted rapid synthesis method of 2-hydroxyacridone

Abstract

The present invention relates to a method for the rapid synthesis of 2-hydroxyacridone by an ultrasonic-assisted one-pot method. 2-Bromobenzoic acid is dissolved in DMF to form solution A, and p-methoxyaniline is dissolved in DMF to form solution B. Copper powder is added as a catalyst in a reaction vessel, and then solution A and solution B are added thereto. The resulting reaction mixture is placed in an ultrasonic reactor, and the reaction is assisted by ultrasound for 45-60 min. After cooling, distillation is carried out under reduced pressure, and then hot water is added to extract the product. The crude 2-hydroxyacridone obtained is purified by recrystallization with ethanol to obtain high-purity 2-hydroxyacridone. The present invention rapidly, efficiently and with high yield prepares the target product 2-hydroxyacridone by an ultrasonic-assisted one-pot method at a reaction temperature of about 50 °C. The process steps are simple, the operation is convenient, the reaction time is short, the reaction conditions are mild, the raw materials are easily available, the yield is high, the loss of raw materials is greatly reduced, the reaction time is shortened, and the reaction energy consumption is reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of the preparation and purification of organic compounds, and particularly relates to a method for rapidly synthesizing 2-hydroxyacridone by a one-pot ultrasonic-assisted method. Background Art

[0002] Acridone compounds are organic compounds based on the acridine skeleton and have a carbonyl group at the 9-position. Most acridone compounds are yellow flaky crystals, which are soluble in hot ethanol, hot acetic acid, and potassium hydroxide ethanol solution, insoluble in water, ether, benzene, and chloroform, and exhibit blue fluorescence in ethanol solution.

[0003] Acridone derivatives have been widely used in many fields such as pharmaceuticals and clinical diagnostics, chemical industry dyes, etc. Specifically as follows:

[0004] In the field of pharmaceuticals, many drugs synthesized from acridine and acridone compounds have been widely used in clinical research. For example, Acronycine has a strong broad-spectrum anti-tumor effect and is used as an anti-cancer drug clinically; Atabrine was widely used to prevent and treat malaria in the last century; Amsacrime is used clinically to treat acute leukemia; Rivanolum is used as a mid-term pregnancy induction drug. In addition, acridone derivatives have also been widely studied in many fields such as anti-virus, anti-parasite, anti-inflammatory, and improving memory.

[0005] In the field of clinical diagnostics, acridone derivatives, as enhanced fluorescence signal probes, have the characteristics of small sample volume, high sensitivity, low detection limit, rapid reaction, high stability, and convenient operation. In recent years, the related reports on them have been increasing day by day.

[0006] In the field of dyes, quinacridone pigments have the characteristics of bright and translucent colors, stability, remarkable heat resistance, solvent resistance, and light resistance, and are widely used in automotive and industrial coatings, plastics, inks, cosmetics, etc., and are a kind of pigment that is indispensable in our daily life.

[0007] 2-Hydroxyacridone is an intermediate in the synthesis of many drugs and pigments. Currently, there are few reports on the synthesis methods of hydroxyacridone, and most of them are synthesized by the Cu-catalyzed Ullmann reaction. The main reaction process is to first prepare o-(N-phenylamino)benzoic acid from o-chlorobenzoic acid and aniline under the action of copper powder, potassium carbonate and nitrobenzene, and then react at 100 °C for 2 h under the catalysis of phosphorus oxychloride to obtain acridone. The above synthesis methods all require two-step reactions to synthesize the target product, with complex reactions, many by-products, cumbersome operation steps, and relatively harsh requirements for the dosage of phosphorus oxychloride, because acridone is easily converted to 9-chloroacridine under the action of phosphorus oxychloride. Therefore, this method has many deficiencies both in terms of operation and yield. In addition, there are also literature reports that acridone is obtained by condensing diphenylamine with carboxylic acid compounds under the catalysis of ZnCl2. Although this method has relatively simple operation steps, the reaction time is extremely long, there are many by-products, and the experimental conditions are extremely strict. At the same time, it should be noted that diphenylamine is highly dangerous, and inhalation, ingestion and skin contact can all cause harm to the human body.

[0008] Therefore, it is necessary to study and design a synthesis method of acridone and its derivatives, which can quickly, conveniently, efficiently, environmentally friendly and low-cost complete the preparation of acridone and its derivatives, so as to reduce the production cost of acridone and its derivatives and expand their application scope. Summary of the Invention

[0009] The purpose of the present invention is to provide a one-pot ultrasonic-assisted rapid synthesis method of 2-hydroxyacridone. Using copper powder as a catalyst, under the condition of 50 °C, the target product 2-hydroxyacridone is rapidly, efficiently and with high yield prepared by the one-pot ultrasonic-assisted method. The process steps are simple, the operation is convenient, the reaction time is short, the reaction conditions are mild, the raw materials are easy to obtain, the yield is high, greatly reducing the loss of raw materials, shortening the reaction time, reducing the reaction energy consumption, avoiding waste, and reducing the process cost.

[0010] The present invention is specifically realized through the following technical solutions. A one-pot ultrasonic-assisted rapid synthesis method of 2-hydroxyacridone proposed according to the present invention includes the following steps:

[0011] (1) Take a certain amount of 2-bromobenzoic acid and place it in a beaker, add DMF solvent, and stir magnetically to dissolve 2-bromobenzoic acid to obtain solution A for standby;

[0012] (2) Take a certain amount of p-methoxyaniline and place it in a new beaker, add DMF solvent to it, and stir magnetically to dissolve p-methoxyaniline to obtain solution B for standby;

[0013] (3) Weigh a certain amount of copper powder and place it in a round-bottom flask. Slowly pour the solution A in step (1) and the solution B in step (2) into the round-bottom flask to obtain a mixed material for standby. Among them, the mass of the copper powder is 2-5% of the mass of 2-bromobenzoic acid.

[0014] (4) Place the round-bottom flask containing the mixed material in step (3) into an ultrasonic reactor, and use ultrasonic wave to assist the reaction. After the reaction is completed, naturally cool it to room temperature.

[0015] (5) Subject the material cooled in step (4) to vacuum distillation to recover the excessive p-methoxyaniline.

[0016] (6) Transfer the remaining liquid after vacuum distillation in step (5) to a separating funnel. Add hot water to the separating funnel and shake it well to transfer 2-hydroxyacridone fully into the hot water. Let the separating funnel stand still. After the liquid layers are separated, separate the layers, discard the organic layer, take the aqueous layer, let the obtained aqueous layer stand still and cool naturally, and then filter it by suction. The obtained filter residue is the crude product of 2-hydroxyacridone.

[0017] (7) Recrystallize the obtained crude 2-hydroxyacridone with ethanol to obtain high-purity 2-hydroxyacridone, and its structural formula is:

[0018]

[0019] The above one-pot ultrasonic-assisted rapid synthesis method of 2-hydroxyacridone, wherein the molar ratio of p-methoxyaniline to 2-bromobenzoic acid is (1-1.2):1, and the purity of 2-bromobenzoic acid and p-methoxyaniline is not less than 99%.

[0020] Preferably, in step (1), the mass ratio of 2-bromobenzoic acid to the volume of DMF is 1 g:(10-15) ml.

[0021] Preferably, in step (2), the mass ratio of p-methoxyaniline to the volume of DMF is 1 g:(20-25) ml.

[0022] Preferably, in step (4), the conditions of ultrasonic-assisted reaction are set as: ultrasonic frequency 60-65 KHz, power 400 W, reaction temperature 50 °C, and reaction time 45-60 min.

[0023] Preferably, the temperature of the hot water added to the separating funnel in step (5) is 50±5 °C, and the added volume of the hot water is 2-3 times the volume of DMF in step (1).

[0024] The above one-pot ultrasonic-assisted rapid synthesis method of 2-hydroxyacridone, the molar yield of the finally prepared high-purity 2-hydroxyacridone is greater than 85%.

[0025] The present invention has obvious advantages and beneficial effects compared with the prior art. By means of the above technical solution, the present invention can achieve quite high technological progressiveness and practicability, and has wide utilization value. It has at least the following advantages:

[0026] (1) The process steps of the present invention are simple, easy to operate, the reaction conditions are mild, the time is short, and the efficiency is high. Compared with the traditional two-step process for synthesizing 2-hydroxyacridone, the present invention uses 2-bromobenzoic acid and p-methoxyaniline as raw materials, and copper powder as a catalyst. Under the action of ultrasonic waves, the copper powder contacts the reactants more uniformly and has a larger contact area, enhancing the catalytic effect, reducing the activation energy of the reaction, and enabling the reaction to proceed efficiently at a lower temperature. The target product is synthesized in one step. More importantly, the process raw material of the present invention replaces the traditionally used 2-chlorobenzoic acid with 2-bromobenzoic acid. The carbon bond connected to bromine in 2-bromobenzoic acid has a weaker binding force and is more easily hydrolyzed, greatly reducing the loss of raw materials, increasing the yield, and avoiding waste.

[0027] (2) The present invention adopts the method of ultrasonic radiation-assisted reaction in the synthesis process. At a specific ultrasonic frequency and power, at a lower temperature (50 °C), through ultrasonic oscillation, the intermolecular contact of the raw materials is more uniform and sufficient, the contact area between the raw materials is larger, the reaction and bonding are faster, more sufficient and thorough, and the conversion rate of the target product is higher. Through experimental determination, the reaction rate of the process of the present invention is about 5 times faster than the traditional method, and the molar yield of the target compound 2-hydroxyacridone can reach more than 85%, greatly shortening the reaction time, improving the reaction efficiency, the purity and the yield of the finished compound. Description of the Drawings

[0028] Figure 1 It is the single crystal XRD pattern of the finished compound prepared in Example 1 of the present invention;

[0029] Figure 2 It is the diffraction peak pattern of the finished compound prepared in Example 1 of the present invention. Detailed Embodiments

[0030] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below in conjunction with specific embodiments. Obviously, the described embodiments are some but not all of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0031] A method for the one-pot ultrasonic-assisted rapid synthesis of acridone and its derivative - 2-hydroxyacridone provided by the present invention uses 2-bromobenzoic acid and p-methoxyaniline as raw materials. The purity of 2-bromobenzoic acid and p-methoxyaniline is not less than 99%. With the aid of ultrasonic wave radiation to assist the reaction, the rapid and efficient preparation of 2-hydroxyacridone is realized. The key points of the process method lie in the material ratio between the reaction raw materials, the setting of ultrasonic radiation frequency parameters, and the separation and purification method of the reaction products, etc. The specific process steps are as follows:

[0032] (1) Take a certain amount of 2-bromobenzoic acid and place it in a beaker. Add DMF solvent and stir magnetically until 2-bromobenzoic acid is completely dissolved to obtain solution A for standby;

[0033] (2) Take a certain amount of p-methoxyaniline and place it in a new beaker. Add DMF solvent and stir magnetically until p-methoxyaniline is completely dissolved to obtain solution B for standby;

[0034] (3) Take a certain amount of copper powder and place it in a round-bottom flask. Slowly pour solution A in step (1) and solution B in step (2) into the round-bottom flask to obtain a mixed material for standby;

[0035] (4) Place the round-bottom flask containing the mixed material in step (3) in an ultrasonic reactor. Set the ultrasonic frequency to 60 - 65 KHz, the power to 400 W, and the heating temperature to 50 °C. Carry out ultrasonic-assisted reaction for 45 - 60 min. After the reaction is completed, cool it naturally to room temperature;

[0036] The reaction equation for this step is:

[0037]

[0038] (5) Distill the material cooled in step (4) under reduced pressure and recover the excessive p-methoxyaniline;

[0039] (6) Add hot water with a temperature of 50 ± 5 °C to the remaining liquid after distillation under reduced pressure in step (5). Extract the product by hot water extraction. Let the water layer obtained after extraction stand, cool naturally, and filter by suction. The obtained filter residue is the crude 2-hydroxyacridone;

[0040] (7) Recrystallize the obtained crude 2-hydroxyacridone with ethanol to obtain the high-purity finished product 2-hydroxyacridone.

[0041] The structural formula of the obtained target product 2-hydroxyacridone is:

[0042]

[0043] The present invention will be described in detail below with specific embodiments. The experimental methods and detection methods described in the following embodiments are all conventional methods in the art unless otherwise specified; the experimental processes are carried out under normal temperature and pressure conditions unless otherwise specified; the reagents and materials can be obtained in the market unless otherwise specified. The calculation formula for the yield (molar yield) of the high-purity 2-hydroxyacridone in the embodiment is:

[0044]

[0045] Example 1

[0046] (1) Accurately weigh 2.01 g (0.01 mol) of 2-bromobenzoic acid and place it in a beaker. Add 20 ml of DMF solvent and stir magnetically to completely dissolve 2-bromobenzoic acid to obtain solution A for standby;

[0047] (2) Accurately weigh 1.48 g (0.012 mol) of p-methoxyaniline and place it in a new beaker. Add 30 ml of DMF solvent to it and stir magnetically to completely dissolve p-methoxyaniline to obtain solution B for standby;

[0048] (3) Take 0.06 g of copper powder and place it in a round-bottom flask. Slowly pour solution A in step (1) and solution B in step (2) into the round-bottom flask to obtain a mixed material for standby;

[0049] (4) Place the round-bottom flask containing the mixed material in step (3) in an ultrasonic reactor. Set the ultrasonic frequency to 60 KHz, the power to 400 W, and the heating temperature to 50 °C. Carry out ultrasonic-assisted reaction. After 60 min, stop the reaction and let the product cool naturally to room temperature;

[0050] (5) Transfer the product solution cooled in step (4) to a distillation device and carry out vacuum distillation to distill out p-methoxyaniline;

[0051] (6) Transfer the remaining liquid after vacuum distillation in step (5) to a separatory funnel. Add 50 ml of hot water at about 50 °C (50 ± 5 °C) to the separatory funnel, and immediately shake it well to fully transfer 2-hydroxyacridone to the added hot water solvent. Then let the separatory funnel stand. After the liquid layers are separated, carry out liquid separation again. Take the aqueous layer and discard the organic layer. Then let the aqueous layer stand and cool, and carry out suction filtration. The obtained filter residue is the crude 2-hydroxyacridone;

[0052] (7) Recrystallize the obtained crude 2-hydroxyacridone with ethanol. After crystals precipitate, carry out suction filtration to obtain high-purity 2-hydroxyacridone. After drying, weigh it and the mass of the high-purity 2-hydroxyacridone is 1.84 g. Calculate its yield according to the aforementioned yield formula, and the yield is 87.2%.

[0053] Elemental analysis was performed on the prepared high-purity 2-hydroxyacridone using a Perkin-Elmer 1400C elemental analyzer. The obtained data were as follows: C: 73.87% (theoretical value: 73.93%), H: 4.39% (theoretical value: 4.26%), N: 6.76% (theoretical value: 6.64%), O: 14.98% (theoretical value: 15.17%). The analytical values of the product were basically consistent with the theoretical values.

[0054] Single-crystal X-ray diffraction analysis was performed on the high-purity 2-hydroxyacridone prepared in this example. The obtained single-crystal XRD pattern was analyzed using Mercury software, and the single-crystal XRD pattern and diffraction peak pattern are shown respectively as Figure 1 and Figure 2 shown.

[0055] Example 2

[0056] (1) Accurately weigh 4.02 g (0.02 mol) of 2-bromobenzoic acid and place it in a beaker. Add 50 ml of DMF solvent and stir magnetically to completely dissolve 2-bromobenzoic acid to obtain solution A for standby.

[0057] (2) Accurately weigh 2.71 g (0.022 mol) of p-methoxyaniline and place it in a new beaker. Add 60 ml of DMF solvent and stir magnetically to completely dissolve p-methoxyaniline to obtain solution B for standby.

[0058] (3) Take 0.12 g of copper powder and place it in a round-bottom flask. Slowly pour solution A in step (1) and solution B in step (2) into the round-bottom flask to obtain a mixed material for standby.

[0059] (4) Place the round-bottom flask containing the mixed material in step (3) in an ultrasonic reactor. Set the ultrasonic frequency to 65 KHz, the power to 400 W, and the heating temperature to 50 °C for ultrasonic-assisted reaction. After 45 min, stop the reaction and let the product cool naturally to room temperature.

[0060] (5) Transfer the cooled product solution in step (4) to a distillation device and perform vacuum distillation to distill off p-methoxyaniline.

[0061] (6) Transfer the remaining liquid after vacuum distillation in step (5) to a separatory funnel. Add 100 ml of hot water at about 50 °C (50 ± 5 °C) to the separatory funnel and immediately shake it well to fully transfer 2-hydroxyacridone to the added hot water solvent. Then let the separatory funnel stand. After the liquid layers separate, perform liquid separation, take the aqueous layer, discard the organic layer, then let the aqueous layer stand, cool it, filter it by suction, and the obtained filter residue is the crude 2-hydroxyacridone.

[0062] (7) The obtained crude 2-hydroxyacridone was recrystallized with ethanol. After the crystals precipitated, suction filtration was carried out to obtain high-purity 2-hydroxyacridone. After drying, the weight of the high-purity 2-hydroxyacridone was 3.78 g, and its yield was calculated to be 89.6% according to the aforementioned yield formula.

[0063] Example 3

[0064] (1) Accurately weigh 4.02 g (0.02 mol) of 2-bromobenzoic acid and place it in a beaker. Add 50 ml of DMF solvent and stir magnetically to completely dissolve 2-bromobenzoic acid to obtain solution A for later use.

[0065] (2) Accurately weigh 2.46 g (0.02 mol) of p-methoxyaniline and place it in a new beaker. Add 60 ml of DMF solvent to it and stir magnetically to completely dissolve p-methoxyaniline to obtain solution B for later use.

[0066] (3) Take 0.12 g of copper powder and place it in a round-bottom flask. Slowly pour solution A in step (1) and solution B in step (2) into the round-bottom flask to obtain a mixed material for later use.

[0067] (4) Place the round-bottom flask containing the mixed material in step (3) in an ultrasonic reactor. Set the ultrasonic frequency to 60 KHz, the power to 400 W, and the heating temperature to 50 °C. Carry out ultrasonic-assisted reaction. After 50 min, stop the reaction, and let the product cool naturally to room temperature.

[0068] (5) Transfer the product solution cooled in step (4) to a distillation device and carry out vacuum distillation to distill out p-methoxyaniline.

[0069] (6) Transfer the remaining liquid after vacuum distillation in step (5) to a separatory funnel. Add 100 ml of hot water at about 50 °C (50 ± 5 °C) to the separatory funnel, and immediately shake it well to fully transfer 2-hydroxyacridone into the added hot water solvent. Then let the separatory funnel stand. After the liquid layers separate, carry out liquid separation, take the aqueous layer, discard the organic layer, then let the aqueous layer stand, cool it, and carry out suction filtration. The obtained filter residue is the crude 2-hydroxyacridone.

[0070] (7) The obtained crude 2-hydroxyacridone was recrystallized with ethanol. After the crystals precipitated, suction filtration was carried out to obtain high-purity 2-hydroxyacridone. After drying, the weight of the high-purity 2-hydroxyacridone was 3.80 g, and its yield was calculated to be 90.1% according to the aforementioned yield formula.

[0071] The present invention does not limit that the reaction vessel must be a beaker, and other reaction vessels can be used. It is preferably to use a glass reaction vessel. The vessels used in the reactions and separations in the foregoing examples should not be construed as a limitation to the present invention.

[0072] The above are only embodiments of the present invention, and do not impose any form of limitation on the present invention. The present invention may also have other forms of embodiments based on the above structure and function, which will not be listed one by one. Therefore, any person skilled in the relevant art, without departing from the scope of the technical solution of the present invention, any simple modification, equivalent change and modification made to the above embodiments based on the technical essence of the present invention shall still fall within the scope of the technical solution of the present invention.

Claims

1. A method for the rapid synthesis of 2-hydroxyacridone by one-pot ultrasonic-assisted method, characterized in that It includes the following steps: (1) Take a certain amount of 2-bromobenzoic acid and place it in a beaker. Add DMF solvent and stir magnetically to dissolve 2-bromobenzoic acid to obtain solution A for standby; (2) Take a certain amount of p-methoxyaniline and place it in a new beaker. Add DMF solvent to it and stir magnetically to dissolve p-methoxyaniline to obtain solution B for standby; (3) Take a certain amount of copper powder and place it in a round-bottom flask. Slowly pour solution A in step (1) and solution B in step (2) into the round-bottom flask to obtain a mixed material for standby; wherein, the mass of the copper powder is 2-5% of the mass of 2-bromobenzoic acid; (4) Place the round-bottom flask containing the mixed material in step (3) in an ultrasonic reactor and carry out ultrasonic-assisted reaction. After the reaction is completed, naturally cool it to room temperature; (5) Distill the material cooled in step (4) under reduced pressure and recover the excessive p-methoxyaniline; (6) Transfer the remaining liquid after distillation under reduced pressure in step (5) to a separatory funnel. Add hot water to the separatory funnel and shake it well to transfer 2-hydroxyacridone fully into the hot water. Let the separatory funnel stand. After the liquid layers are separated, carry out liquid separation, discard the organic layer, take the aqueous layer, let the obtained aqueous layer stand and naturally cool, and then carry out suction filtration. The obtained filter residue is the crude 2-hydroxyacridone; (7) Recrystallize the obtained crude 2-hydroxyacridone with ethanol to obtain high-purity 2-hydroxyacridone.

2. The method for the one-pot ultrasonic-assisted rapid synthesis of 2-hydroxyacridone according to claim 1, characterized in that The molar ratio of p-methoxyaniline to 2-bromobenzoic acid is (1~1.2):

1.

3. The method for one-pot ultrasonic-assisted rapid synthesis of 2-hydroxyacridone according to claim 1, characterized in that In step (1), the mass-volume ratio of 2-bromobenzoic acid to DMF is 1 g:(10~15) ml.

4. The method for one-pot ultrasonic-assisted rapid synthesis of 2-hydroxyacridone according to claim 1, characterized in that In step (2), the mass-volume ratio of p-methoxyaniline to DMF is 1 g:(20~25) ml.

5. The method for one-pot ultrasonic-assisted rapid synthesis of 2-hydroxyacridone according to any one of claims 1-4, characterized in that In step (4), the conditions of the ultrasonic-assisted reaction are set as follows: ultrasonic frequency 60 - 65 KHz, power 400 W, reaction temperature 50 °C, and reaction time 45 - 60 min.

6. The method for one-pot ultrasonic-assisted rapid synthesis of 2-hydroxyacridone according to claim 1 or 3, characterized in that In step (6), the temperature of the hot water added to the separatory funnel is 50 ± 5 °C, and the added volume of the hot water is 2 - 3 times the volume of DMF in step (1).

7. The method for one-pot ultrasonic-assisted rapid synthesis of 2-hydroxyacridone according to claim 1, wherein The molar yield of the finally prepared high-purity 2-hydroxyacridone is greater than 85%.

Images