Isatoic anhydride compound and preparation method thereof

Abstract

The invention relates to the technical field of isatoic anhydride compounds, and discloses an isatoic anhydride compound and a preparation method thereof, and the isatoic anhydride compound comprises the following materials: 1g-2g of isatin, 1g-2g of phthalic anhydride, 0.1 g-0.5 g of a zinc chloride catalyst and 10ml-20ml of a dichloromethane solvent. According to the isatoic anhydride compound and the preparation method thereof, 1-2 g of isatin, 1-2 g of phthalic anhydride, 0.1-0.5 g of a zinc chloride catalyst and 10-20 ml of a dichloromethane solvent are weighed through a high-precision balance, it is ensured that all the raw materials are high in purity, and a reaction flask is pre-cleaned. The method has the advantages of simple operation process, low operation difficulty and safety risk, suitableness for large-scale production, selection of the catalyst and the solvent which are safer to the environment and operators, reduction of the generation of byproducts, improvement of the product purity, and reduction of environmental pollution and operation risk through selection of the solvent with low toxicity and low volatility.

Description

Technical Field

[0001] The invention relates to the technical field of isatinic anhydride compounds, in particular to isatinic anhydride compounds and preparation methods thereof. Background Art

[0002] Isatoic anhydride compounds are a class of compounds generated by the reaction of isatoxin and anhydride (such as phthalic anhydride or maleic anhydride). They have unique molecular structures and chemical properties and are widely used in dyes, pigments, medicines, and organic synthesis. These compounds have attracted attention due to their excellent stability, color development properties, and biological activity, and have potential application prospects in the development of antibacterial and anticancer drugs.

[0003] Authorization announcement number (CN 116768815 A) discloses isatoic anhydride compounds that are selective inhibitors of histone deacetylase 6 (HDAC6), and their use in the preparation of drugs for treating HDAC6-related diseases; specifically discloses compounds represented by formula (I) and pharmaceutically acceptable salts thereof. The inventive compound has high inhibitory activity and high HDAC enzyme subtype selectivity against HDAC6, and also has ideal pharmacokinetic characteristics, high blood-brain barrier permeability and good safety;

[0004] However, the above-mentioned technology may require higher temperature and pressure, which increases the complexity and safety risks of the reaction, has high requirements for equipment, and is not conducive to large-scale production. Due to improper control of reaction conditions or poor catalyst selection, more by-products may be produced in the reaction, resulting in low purity of the final product and requiring complex purification steps. At the same time, the above-mentioned technology may use some catalysts that are harmful to the environment and operators, such as strong acids or strong bases, which not only increases the danger of operation, but also brings about the problem of waste disposal. The solvents used may be toxic or volatile, increasing environmental pollution and operational risks, and the cost of solvent recovery and treatment is high.

[0005] Therefore, those skilled in the art provide isatoic anhydride compounds and preparation methods thereof to solve the problems raised in the above background technology. Summary of the invention

[0006] To achieve the above object, the present invention provides the following technical solutions.

[0007] Isatoic anhydride compounds, including the following materials:

[0008] Isatin 1g-2g, phthalate 1g-2g, zinc chloride catalyst 0.1g-0.5g and dichloromethane solvent 10ml-20ml.

[0009] Preparation method of isatinic anhydride compounds, S1, raw material preparation: use a high-precision balance to weigh 1g-2g of indigo, 1g-2g of phthalic anhydride, 0.1g-0.5g of zinc chloride catalyst, and 10ml-20ml of dichloromethane solvent, ensure that all raw materials are of high purity, and pre-clean the reaction bottle to ensure that the reaction bottle is clean and dry to prevent impurities from affecting the reaction effect;

[0010] S2, reaction mixing: the indigo carmine and phthalic anhydride weighed in step S1 are mixed in a reaction bottle at a molar ratio of 1:1-2, and then 0.1g-0.5g of catalyst is added to the reaction bottle, followed by 10ml-20ml of solvent, and the solution is continuously stirred using an agitator to ensure that the reaction proceeds uniformly. While stirring, the mixture is placed on a heating device for heating;

[0011] S3, reaction termination: when the required reaction time is reached, the heating device is turned off, and the reaction bottle loaded with the mixture is carefully removed from the reaction bottle, and the reaction bottle is placed in a well-ventilated place, and naturally cooled to room temperature, while monitoring the temperature change to ensure that the entire mixture is cooled slowly and evenly to obtain a reaction mixture A. After cooling, the reaction mixture A is ready for the next step of separation and purification;

[0012] S4, separation and purification: the reaction mixture A after cooling in step S3 is filtered through a Buchner funnel to separate the solid product, then the filtered solid product is dissolved in a dichloromethane solvent, and the solution is slowly cooled to room temperature to allow the product to crystallize, and the crystals are filtered again using a Buchner funnel to collect the purified solid product B;

[0013] S5. Product drying: evenly place the solid product B purified in step S4 on the tray of the vacuum drying oven to avoid excessive accumulation and ensure uniform drying. Then start the vacuum pump to reduce the pressure in the drying oven to the required vacuum degree, dry the solid product B to remove residual solvent and moisture in the product, check the pressure and temperature regularly during the process to ensure stable operation. After the drying time is reached, gradually vent to normal pressure to prevent sudden venting from causing disturbance and loss of the product. Then open the drying oven, take out the dried product, and store it in a dryer or a sealed container to prevent moisture absorption, thereby obtaining a final isatin anhydride compound with higher purity.

[0014] Preferably, in step S2, the heating device is an oil bath heater, the heating temperature should be controlled between 80° C. and 100° C., the stirrer is a magnetic stirrer, and the mixing reaction time is 6 h to 12 h.

[0015] Preferably, the natural cooling temperature in step S3 should be controlled at 25-30° C. During this process, sudden cooling should be avoided to prevent over-saturation or crystallization of some components in the reaction mixture, thereby preventing the generation of by-products or impurities, which are difficult to remove and thus affect the purity and yield of the final product.

[0016] Preferably, the drying temperature in step S5 does not exceed 60° C. to prevent product decomposition caused by high temperature, and the drying is carried out under vacuum conditions for 6-8 hours, with the pressure reduced to 10 mbar-20 mbar.

[0017] Compared with the prior art, the present invention provides isatoic anhydride compounds and preparation methods thereof, which have the following beneficial effects:

[0018] 1. The isatoic anhydride compound and the preparation method thereof adopt milder reaction conditions, reduce the difficulty of operation and safety risks, are suitable for large-scale production, and select catalysts and solvents that are safer for the environment and operators, reduce the generation of by-products, and improve the purity of the product. In addition, by selecting low-toxicity and low-volatility solvents, environmental pollution and operation risks are reduced, while the cost of solvent recovery and treatment is reduced, the purification steps are simplified, and the use of hazardous substances and waste disposal problems are reduced.

[0019] 2. The isatoic anhydride compound and the preparation method thereof can provide a uniform heating effect by adopting an oil bath heater. The high specific heat capacity and uniform heat transfer performance of the oil help to stabilize the temperature and reduce the risk of overheating or local supercooling. By adopting a magnetic stirrer, contactless stirring can be achieved in a closed container, which is easy to operate and reduces the risk of contamination. It is suitable for stirring small volumes of liquids with precisely controlled temperature. DETAILED DESCRIPTION

[0020] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0021] Embodiment 1

[0022] Embodiments of isatinic anhydride compounds and preparation methods thereof

[0023] Isatoic anhydride compounds, including the following materials:

[0024] 1g of isatin, 1g of phthalate, 0.1g of zinc chloride catalyst and 10ml of dichloromethane solvent.

[0025] Preparation method of isatinic anhydride compounds, S1, raw material preparation: use a high-precision balance to weigh 1g of indigo, 1g of phthalic anhydride, 0.1g of zinc chloride catalyst, and 10ml of dichloromethane solvent, ensure that all raw materials are of high purity, and pre-clean the reaction bottle to ensure that the reaction bottle is clean and dry to prevent impurities from affecting the reaction effect;

[0026] S2, reaction mixing: the indigo carmine and phthalic anhydride weighed in step S1 are mixed in a reaction bottle at a molar ratio of 1:1, then 0.1 g of catalyst is added to the reaction bottle, followed by 10 ml of solvent, and the solution is continuously stirred using a stirrer to ensure that the reaction proceeds uniformly. While stirring, the mixture is placed on a heating device for heating;

[0027] S3, reaction termination: when the required reaction time is reached, the heating device is turned off, and the reaction bottle loaded with the mixture is carefully removed from the reaction bottle, and the reaction bottle is placed in a well-ventilated place, and naturally cooled to room temperature, while monitoring the temperature change to ensure that the entire mixture is cooled slowly and evenly to obtain a reaction mixture A. After cooling, the reaction mixture A is ready for the next step of separation and purification;

[0028] S4, separation and purification: the reaction mixture A after cooling in step S3 is filtered through a Buchner funnel to separate the solid product, then the filtered solid product is dissolved in a dichloromethane solvent, and the solution is slowly cooled to room temperature to allow the product to crystallize, and the crystals are filtered again using a Buchner funnel to collect the purified solid product B;

[0029] S5. Product drying: evenly place the solid product B purified in step S4 on the tray of the vacuum drying oven to avoid excessive accumulation and ensure uniform drying. Then start the vacuum pump to reduce the pressure in the drying oven to the required vacuum degree, dry the solid product B to remove residual solvent and moisture in the product, check the pressure and temperature regularly during the process to ensure stable operation. After the drying time is reached, gradually vent to normal pressure to prevent sudden venting from causing disturbance and loss of the product. Then open the drying oven, take out the dried product, and store it in a dryer or a sealed container to prevent moisture absorption, thereby obtaining a final isatin anhydride compound with higher purity.

[0030] Embodiment 2

[0031] Embodiments of isatinic anhydride compounds and preparation methods thereof

[0032] Isatoic anhydride compounds, including the following materials:

[0033] 2g of isatin, 2g of phthalate, 0.5g of zinc chloride catalyst and 20ml of dichloromethane solvent.

[0034] Preparation method of isatinic anhydride compounds, S1, raw material preparation: use a high-precision balance to weigh 2g of indigo, 2g of phthalic anhydride, 0.5g of zinc chloride catalyst, and 20ml of dichloromethane solvent, ensure that all raw materials are of high purity, and pre-clean the reaction bottle to ensure that the reaction bottle is clean and dry to prevent impurities from affecting the reaction effect;

[0035] S2, reaction mixing: the indigo carmine and phthalic anhydride weighed in step S1 are mixed in a reaction bottle at a molar ratio of 1:2, and then 0.5 g of catalyst is added to the reaction bottle, followed by 20 ml of solvent, and the solution is continuously stirred using a stirrer to ensure that the reaction proceeds uniformly. While stirring, the mixture is placed on a heating device for heating;

[0036] S3, reaction termination: when the required reaction time is reached, the heating device is turned off, and the reaction bottle loaded with the mixture is carefully removed from the reaction bottle, and the reaction bottle is placed in a well-ventilated place, and naturally cooled to room temperature, while monitoring the temperature change to ensure that the entire mixture is cooled slowly and evenly to obtain a reaction mixture A. After cooling, the reaction mixture A is ready for the next step of separation and purification;

[0037] S4, separation and purification: the reaction mixture A after cooling in step S3 is filtered through a Buchner funnel to separate the solid product, then the filtered solid product is dissolved in a dichloromethane solvent, and the solution is slowly cooled to room temperature to allow the product to crystallize, and the crystals are filtered again using a Buchner funnel to collect the purified solid product B;

[0038] S5. Product drying: evenly place the solid product B purified in step S4 on the tray of the vacuum drying oven to avoid excessive accumulation and ensure uniform drying. Then start the vacuum pump to reduce the pressure in the drying oven to the required vacuum degree, dry the solid product B to remove residual solvent and moisture in the product, check the pressure and temperature regularly during the process to ensure stable operation. After the drying time is reached, gradually vent to normal pressure to prevent sudden venting from causing disturbance and loss of the product. Then open the drying oven, take out the dried product, and store it in a dryer or a sealed container to prevent moisture absorption, thereby obtaining a final isatin anhydride compound with higher purity.

[0039] The above technical solution reduces the difficulty of operation and safety risks by adopting milder reaction conditions, and is suitable for large-scale production. At the same time, it selects catalysts and solvents that are safer for the environment and operators, reduces the generation of by-products, and improves product purity. In addition, it reduces environmental pollution and operational risks by selecting solvents with low toxicity and low volatility, while reducing solvent recovery and processing costs, simplifying the purification steps, and reducing the use of hazardous substances and waste disposal problems.

[0040] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. An isatoic anhydride compound, characterized in that: The compound includes the following materials: Isatin 1g-2g, phthalate 1g-2g, zinc chloride catalyst 0.1g-0.5g and dichloromethane solvent 10ml-20ml.

2. The method for preparing an isatoic anhydride compound according to claim 1, wherein: S1. Raw material preparation: Use a high-precision balance to weigh 1g-2g of indigo carmine, 1g-2g of phthalic anhydride, 0.1g-0.5g of zinc chloride catalyst, and 10ml-20ml of dichloromethane solvent, ensuring that all raw materials are of high purity, and pre-clean the reaction bottle to ensure that the reaction bottle is clean and dry to prevent impurities from affecting the reaction effect; S2, reaction mixing: the indigo carmine and phthalic anhydride weighed in step S1 are mixed in a reaction bottle at a molar ratio of 1:1-2, and then 0.1g-0.5g of catalyst is added to the reaction bottle, followed by 10ml-20ml of solvent, and the solution is continuously stirred using an agitator to ensure that the reaction proceeds uniformly. While stirring, the mixture is placed on a heating device for heating; S3, reaction termination: when the required reaction time is reached, the heating device is turned off, and the reaction bottle loaded with the mixture is carefully removed from the reaction bottle, and the reaction bottle is placed in a well-ventilated place, and naturally cooled to room temperature, while monitoring the temperature change to ensure that the entire mixture is cooled slowly and evenly to obtain a reaction mixture A. After cooling, the reaction mixture A is ready for the next step of separation and purification; S4, separation and purification: the reaction mixture A after cooling in step S3 is filtered through a Buchner funnel to separate the solid product, then the filtered solid product is dissolved in a dichloromethane solvent, and the solution is slowly cooled to room temperature to allow the product to crystallize, and the crystals are filtered again using a Buchner funnel to collect the purified solid product B; S5. Product drying: evenly place the solid product B purified in step S4 on the tray of the vacuum drying oven to avoid excessive accumulation and ensure uniform drying. Then start the vacuum pump to reduce the pressure in the drying oven to the required vacuum degree, dry the solid product B to remove residual solvent and moisture in the product, check the pressure and temperature regularly during the process to ensure stable operation. After the drying time is reached, gradually vent to normal pressure to prevent sudden venting from causing disturbance and loss of the product. Then open the drying oven, take out the dried product, and store it in a dryer or a sealed container to prevent moisture absorption, thereby obtaining a final isatin anhydride compound with higher purity.

3. The method for preparing the isatoic anhydride compound according to claim 2, characterized in that In step S2, the heating device is an oil bath heater, the heating temperature should be controlled between 80°C and 100°C, the stirrer is a magnetic stirrer, and the mixing reaction time is 6h-12h.

4. The method for preparing the isatoic anhydride compound according to claim 2, characterized in that : The natural cooling temperature in step S3 should be controlled at 25-30°C. During this process, sudden cooling should be avoided to prevent some components in the reaction mixture from being oversaturated or crystallized, thereby producing by-products or impurities. These by-products are difficult to remove, thereby affecting the purity and yield of the final product.

5. The method for preparing the isatoic anhydride compound according to claim 2, characterized in that : In step S5, the drying temperature does not exceed 60° C. to prevent product decomposition caused by high temperature, and the product is dried under vacuum conditions for 6-8 hours until the pressure drops to 10 mbar-20 mbar.