Synthetic method of drug intermediate pyrazolo [1, 2-b] phthalazine-5, 10-diketone derivative and catalytic system for synthesis

Abstract

The invention relates to the field of preparation of drug intermediates, and particularly discloses a synthetic method of a drug intermediate pyrazolo [1, 2-b] phthalazine-5, 10-diketone derivative and a catalytic system for synthesis. According to the synthetic method, aromatic aldehyde, phthalylhydrazine and malononitrile are used as reaction raw materials; the pyrazolo [1, 2-b] phthalazine-5, 10-diketone derivative is synthesized under the catalytic action of a catalytic system consisting of an alkaline eutectic solvent and absolute ethyl alcohol. The content of each component and reaction process parameters are optimally designed, so that the utilization rate of the reaction raw materials and the yield of the pyrazolo [1, 2-b] phthalazine-5, 10-diketone derivative can be remarkably increased, and the economical efficiency is relatively good; the catalytic system is high in catalytic activity, the usage amount in the catalytic process and the loss amount of the catalyst during recycling are small, the number of times of recycling is large, the catalytic system does not need to be treated before recycling, and operation is easy.

Description

Technical Field

[0001] This invention relates to a method for synthesizing a derivative, specifically to a method for synthesizing a pharmaceutical intermediate pyrazolo[1,2-b]phthalazine-5,10-dione derivative and a catalytic system for the synthesis, belonging to the field of pharmaceutical intermediate preparation. Background Technology

[0002] Phthalasinone compounds are a class of six-membered nitrogen-containing heterocycles with good biological activity. As a pharmaceutical intermediate, they occupy an important position in the research and development of medicines and pesticides. For example, in pesticides, phthalazinone compounds are widely used, such as insecticides, herbicides, plant growth regulators, and fungicides. In medicine, phthalazinone compounds can be used as cyclooxygenase inhibitors, calcium sensitizers, and phosphodiesterase inhibitors, and can be used to treat related diseases. In addition, compounds containing pyrazole ring structures are also compatible with the requirements of future drug development due to their good biological and pharmacological activities, becoming a direction for the development of chemical drugs. Using the principle of active splicing, introducing the pyrazole ring structure into phthalazinone derivatives to form pyrazolophthalazin dione derivatives with both pyrazole ring and phthalazinone structures has a wider range of applications. For example, the pyrazolo[1,2-b]phthalazin-5,10-dione molecular fragment has anti-inflammatory, antipyretic analgesic, and anti-hypoxic pharmacological effects. Therefore, the synthesis of pyrazolophthalazindione derivatives has become a hot topic of interest.

[0003] Three-component synthesis is the most important method for synthesizing pyrazolophthalazine dione derivatives in multi-component synthesis. It involves adding three raw materials to the reaction in a "one-pot" manner, directly obtaining compounds containing pyrazolophthalazine dione fragments without intermediate separation. Compared to traditional stepwise synthesis methods, it exhibits higher atom economy and selectivity, and therefore its application in the synthesis of pyrazolophthalazine dione derivatives is becoming increasingly widespread. For example, the synthesis of pyrazolo[1,2-b]phthalazine-5,10-dione derivatives often uses a three-component "one-pot" cyclocondensation reaction with phthalohydrazide, aromatic aldehyde, and malononitrile or ethyl cyanoacetate. Currently, commonly used catalysts for this reaction include triethylamine, metal salts (such as cerium ammonium nitrate, indium trichloride, zirconium tetrachloride), and oxides (oxidizing agents, lead oxide), but these catalysts cannot be recycled and generate large amounts of wastewater. Based on this, recyclable catalysts have been developed, such as the ionic liquid [Bmim]OH (1-butyl-3-methylimidazolium hydroxide) and acidic solid materials (sulfonated mesoporous molecular sieves, silica gel-supported tungstic acid, and 3-aminopropyl-triethoxysilane-modified magnetic nanomaterials). However, the preparation processes of these catalysts are relatively complex, and because they are heterogeneous catalysts, the reaction times are long, the reaction conditions are harsh, and the product yields are low. Finally, none of the above synthetic methods can regenerate the catalyst or catalytic system, resulting in low economic efficiency and low raw material utilization. In addition, the product purification process is relatively complex, often requiring column chromatography or recrystallization. Finally, the above synthetic methods are not easy to implement for large-scale continuous industrial production.

[0004] In recent years, eutectic solvents, as a type of eutectic mixture produced by the combined reaction of hydrogen bond acceptors (such as quaternary ammonium salts) and hydrogen bond donors (such as amides, carboxylic acids, and polyols) in a certain stoichiometric ratio at a specific temperature, have been widely used in many fields, such as extraction, separation, and catalysis, due to their green, inexpensive, and easy-to-prepare characteristics. Based on this consideration, this invention proposes to apply a catalytic system consisting of an alkaline eutectic solvent as a catalyst and anhydrous ethanol as a reaction solvent to the one-pot synthesis of pyrazolo[1,2-b]phthalazine-5,10-dione derivatives from aromatic aldehydes, phthalohydrazides, and malononitriles. The aim is to achieve a catalytic system that is recyclable and regenerable, with a simple product purification process, and suitable for large-scale continuous industrial production. Summary of the Invention

[0005] To address the problems in existing technologies, this invention provides a method for synthesizing the pharmaceutical intermediate pyrazolo[1,2-b]phthalazine-5,10-dione derivative and a catalytic system for the synthesis. The aim is to overcome the shortcomings of existing technologies, such as low catalyst activity, non-recyclable and non-renewable catalytic systems, and complex product purification, leading to long reaction times, low raw material utilization, low economic efficiency, severe environmental pollution, and difficulty in achieving large-scale continuous industrial production. The method of this invention can significantly improve the utilization rate of raw materials and the reaction rate, simplifies product purification, provides high catalyst activity, allows for multiple recycling of the catalytic system without any treatment, and enables the regeneration of the catalytic system.

[0006] The objective of this invention can be achieved through the following technical solutions:

[0007] A catalytic system for the formation of a pharmaceutical intermediate pyrazolo[1,2-b]phthalazine-5,10-dione derivative, comprising an alkaline eutectic solvent as a catalyst and anhydrous ethanol as a reaction solvent, wherein the alkaline eutectic solvent is prepared by mixing and heating choline chloride and ethanolamine, with a molar ratio of choline chloride to ethanolamine of 1:8.

[0008] A method for synthesizing a pharmaceutical intermediate, pyrazolo[1,2-b]phthalazine-5,10-dione derivative, is disclosed. This method uses aromatic aldehydes, phthaloyl hydrazide, and malononitrile as reactants, and synthesizes the pyrazolo[1,2-b]phthalazine-5,10-dione derivative under the catalysis of a basic eutectic solvent and anhydrous ethanol. The chemical reaction formula is as follows:

[0009]

[0010] In the above formula, Formula I is an aromatic aldehyde, Formula II is phthalamide, Formula III is malononitrile, and Formula IV is a synthetic pyrazolo[1,2-b]phthalazine-5,10-dione derivative.

[0011] Optionally, the specific steps of this synthesis method are as follows:

[0012] (1) Formation of catalytic system: Add a predetermined volume of anhydrous ethanol to a four-necked flask equipped with a magnetic stir bar, a spherical condenser and a thermometer, and add a predetermined amount of alkaline eutectic solvent while stirring at room temperature. Mix well to form a catalytic system.

[0013] (2) Weighing of raw materials: Weigh the aromatic aldehyde, phthalamide and malononitrile accurately according to the molar ratio of 1:1:(1.0~1.2);

[0014] (3) Catalytic reaction: The weighed reactants were added to the catalytic system and mixed evenly. Then, the mixture was heated under stirring and refluxed. The reflux temperature was maintained until the reactant spot disappeared (TLC detection). After the reaction was completed, stirring and heating were stopped immediately and the four-necked flask was removed from the oil bath and allowed to cool naturally to room temperature to obtain solid precipitates.

[0015] (4) Extraction of the product: The obtained solid precipitate was crushed and allowed to stand for 8 hours before being filtered under reduced pressure. The filter residue was washed with an ethanol aqueous solution containing 98% ethanol by volume and then dried under vacuum at 75°C to obtain the pyrazolo[1,2-b]phthalazine-5,10-dione derivative.

[0016] Optionally, the reflux reaction is carried out at an atmosphere, the reflux reaction time is 6 to 14 minutes, and the volume of anhydrous ethanol as the reaction solvent is 5 to 8 times the molar amount of the aromatic aldehyde in millimoles, and the amount of the alkaline eutectic solvent catalyst used is 7 to 11% of the amount of the aromatic aldehyde.

[0017] Optionally, the aromatic aldehyde is any one of benzaldehyde, o-chlorobenzaldehyde, o-bromobenzaldehyde, o-nitrobenzaldehyde, m-fluorobenzaldehyde, m-chlorobenzaldehyde, m-bromobenzaldehyde, m-nitrobenzaldehyde, m-methylbenzaldehyde, m-methoxybenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-nitrobenzaldehyde, p-methylbenzaldehyde, and p-methoxybenzaldehyde.

[0018] Optionally, the reflux temperature in step (3) refers to the reflux temperature being between 81 and 83°C, where the vapor of the reaction solution does not exceed the second sphere of the spherical condenser.

[0019] Optionally, the synthesis method also includes a step of recycling the catalytic system, the specific process of which is as follows:

[0020] The filtrate (mainly the catalytic system) generated in step (4) is added directly to the reaction raw materials without any treatment, and the catalytic system is recycled according to steps (3) and (4). When the liquid chromatography purity of the product pyrazolo[1,2-b]phthalazine-5,10-dione derivative is lower than 98% or its yield decreases by more than 5% compared with the first use of the catalytic system, the filtrate is no longer recycled.

[0021] Optionally, the synthesis method further includes a regeneration step of the catalytic system, the specific regeneration process of which is as follows:

[0022] The filtrate that has been taken out of circulation is first evaporated to remove ethanol, then a predetermined volume of diethyl ether is added, and the mixture is magnetically stirred for 10 minutes before separation. The same volume of diethyl ether is then added to the lower layer of the liquid, and the mixture is magnetically stirred for 10 minutes before separation. This process is repeated three times. Finally, the lower layer of the third reaction is vacuum dried at 50°C to constant weight to obtain the regenerated alkaline eutectic solvent catalyst. This regenerated catalyst is then added to a new solvent consisting of evaporated ethanol and anhydrous ethanol added to make up the required volume, and stirred until homogeneous to obtain the regenerated catalytic system.

[0023] Optionally, during the regeneration process, the filtrate that has been taken out of circulation is washed and regenerated using ether at a volume of 1 to 3 times that of anhydrous ethanol as the reaction solvent.

[0024] The beneficial effects of this invention are:

[0025] 1. This invention uses aromatic aldehydes, phthalamide, and malononitrile as reactants to synthesize pyrazolo[1,2-b]phthalazine-5,10-dione derivatives under the catalysis of an alkaline eutectic solvent and anhydrous ethanol. By using the catalytic system of this invention to synthesize pyrazolo[1,2-b]phthalazine-5,10-dione derivatives and optimizing the content of each component and reaction process parameters, the utilization rate of reactants and the yield of pyrazolo[1,2-b]phthalazine-5,10-dione derivatives can be significantly improved, with good atom economy. The catalytic system of this invention has high catalytic activity, low catalyst usage during catalysis and low catalyst loss during recycling, and can be recycled many times. It can still maintain high activity during recycling, and the catalytic system does not require any treatment before recycling, making the operation simple.

[0026] 2. By optimizing and controlling the type, content, and reaction process parameters of the catalyst, this invention can effectively control the reaction direction, reduce the generation of side reactions and reaction impurities, and improve the synthetic purity of pyrazolo[1,2-b]phthalazine-5,10-dione derivatives, thereby effectively ensuring their quality and performance.

[0027] 3. By selecting a suitable reaction solvent and optimizing its usage, this invention can significantly improve the solubility of the reaction raw materials, ensuring their full dissolution and further improving the utilization rate of the reaction raw materials. Moreover, the reaction solvent can be recycled, resulting in minimal environmental impact.

[0028] 4. The reflux reaction pressure of this invention is one atmosphere, and the reflux reaction time is 6 to 14 minutes. The reaction conditions are relatively mild, which is convenient for actual operation. The reactants do not need to be added in batches, making it highly operable. Moreover, the purification process of the product is simple, which facilitates industrial-scale production.

[0029] 5. The catalytic system that cannot be recycled in this invention can be regenerated through a simple washing method, and the catalytic efficiency of the regenerated catalytic system is reduced by a small margin. This improves production efficiency while also enhancing the environmental and social benefits of the entire synthesis process. Attached Figure Description

[0030] To facilitate understanding by those skilled in the art, the present invention will be further described below with reference to the accompanying drawings.

[0031] Figure 1 The product 3-amino-1-(2-chlorophenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile in Example 2 1 H NMR;

[0032] Figure 2 The product 3-amino-1-(2-chlorophenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile in Example 2 13 C NMR. Detailed Implementation

[0033] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0034] A catalytic system for the formation of a pharmaceutical intermediate pyrazolo[1,2-b]phthalazine-5,10-dione derivative, comprising an alkaline eutectic solvent as a catalyst and anhydrous ethanol as a reaction solvent, wherein the alkaline eutectic solvent is prepared by mixing and heating choline chloride and ethanolamine, with a molar ratio of choline chloride to ethanolamine of 1:8.

[0035] A method for synthesizing a pharmaceutical intermediate, pyrazolo[1,2-b]phthalazine-5,10-dione derivative, is disclosed. This method uses aromatic aldehydes, phthaloyl hydrazide, and malononitrile as reactants, and synthesizes the pyrazolo[1,2-b]phthalazine-5,10-dione derivative under the catalysis of a basic eutectic solvent and anhydrous ethanol. The chemical reaction formula is as follows:

[0036]

[0037] In the above formula, Formula I is an aromatic aldehyde, Formula II is phthalamide, Formula III is malononitrile, and Formula IV is a synthetic pyrazolo[1,2-b]phthalazine-5,10-dione derivative.

[0038] As a technical optimization of the present invention, the specific steps of the synthesis method are as follows:

[0039] (1) Formation of catalytic system: Add a predetermined volume of anhydrous ethanol to a four-necked flask equipped with a magnetic stir bar, a spherical condenser and a thermometer, and add a predetermined amount of alkaline eutectic solvent while stirring at room temperature. Mix well to form a catalytic system.

[0040] (2) Weighing of raw materials: Weigh the aromatic aldehyde, phthalamide and malononitrile accurately according to the molar ratio of 1:1:(1.0~1.2);

[0041] (3) Catalytic reaction: The weighed reactants were added to the catalytic system and mixed evenly. Then, the mixture was heated under stirring and refluxed. The reflux temperature was maintained until the reactant spot disappeared (TLC detection). After the reaction was completed, stirring and heating were stopped immediately and the four-necked flask was removed from the oil bath and allowed to cool naturally to room temperature to obtain solid precipitates.

[0042] (4) Extraction of the product: The obtained solid precipitate was crushed and allowed to stand for 8 hours before being filtered under reduced pressure. The filter residue was washed with an ethanol aqueous solution containing 98% ethanol by volume and then dried under vacuum at 75°C to obtain the pyrazolo[1,2-b]phthalazine-5,10-dione derivative.

[0043] As a technical optimization of the present invention, the reaction pressure of the reflux reaction is one atmosphere, the reflux reaction time is 6 to 14 minutes, and the volume of the reaction solvent anhydrous ethanol in milliliters is 5 to 8 times the molar amount of the aromatic aldehyde in millimoles, and the amount of the alkaline eutectic solvent catalyst used is 7 to 11% of the amount of the aromatic aldehyde.

[0044] As a technical optimization of the present invention, the aromatic aldehyde is any one of benzaldehyde, o-chlorobenzaldehyde, o-bromobenzaldehyde, o-nitrobenzaldehyde, m-fluorobenzaldehyde, m-chlorobenzaldehyde, m-bromobenzaldehyde, m-nitrobenzaldehyde, m-methylbenzaldehyde, m-methoxybenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-nitrobenzaldehyde, p-methylbenzaldehyde, and p-methoxybenzaldehyde.

[0045] As a technical optimization of the present invention, the reflux temperature in step (3) refers to the reflux temperature being between 81 and 83°C, where the vapor of the reaction solution does not exceed the second sphere of the spherical condenser.

[0046] As an optimized technical solution of the present invention, the synthesis method further includes a step of recycling the catalytic system, the specific process of which is as follows:

[0047] The filtrate (mainly the catalytic system) generated in step (4) is added directly to the reaction raw materials without any treatment, and the catalytic system is recycled according to steps (3) and (4). When the liquid chromatography purity of the product pyrazolo[1,2-b]phthalazine-5,10-dione derivative is lower than 98% or its yield decreases by more than 5% compared with the first use of the catalytic system, the filtrate is no longer recycled.

[0048] As an optimized technical solution of the present invention, the synthesis method further includes a regeneration step of the catalytic system, the specific regeneration process of which is as follows:

[0049] The filtrate that has been taken out of circulation is first evaporated to remove ethanol, then a predetermined volume of diethyl ether is added, and the mixture is magnetically stirred for 10 minutes before separation. The same volume of diethyl ether is then added to the lower layer of the liquid, and the mixture is magnetically stirred for 10 minutes before separation. This process is repeated three times. Finally, the lower layer of the third reaction is vacuum dried at 50°C to constant weight to obtain the regenerated alkaline eutectic solvent catalyst. This regenerated catalyst is then added to a new solvent consisting of evaporated ethanol and anhydrous ethanol added to make up the required volume, and stirred until homogeneous to obtain the regenerated catalytic system.

[0050] As a technical optimization of the present invention, the filtrate that has been discontinued is washed and regenerated using 1 to 3 times the volume of anhydrous ethanol as a reaction solvent during the regeneration process.

[0051] To further understand the content of the present invention, the present invention will now be described in detail with reference to the embodiments.

[0052] The preparation method of the alkaline eutectic solvent catalyst used in this invention is based on relevant materials (Optimization of eutectic solvent pretreatment to improve the enzymatic hydrolysis effect of licorice residue [J], Chemical Industry and Engineering Progress, 2022, 41(3): 1349-1356).

[0053] The type of catalyst and reaction solvent, as well as the reaction process parameters, have a significant impact on the quality and performance of the final synthesized substance. Since different substances have different properties, their requirements for the type of catalyst and reaction solvent, as well as the reaction process parameters, also vary. Based on the properties of pyrazolo[1,2-b]phthalazine-5,10-dione derivatives, the inventors, through extensive theoretical analysis and experimental research, ultimately selected the catalytic system of this invention, composed of an alkaline eutectic solvent catalyst and anhydrous ethanol reaction solvent, for the catalytic synthesis of pyrazolo[1,2-b]phthalazine-5,10-dione derivatives. The inventors optimized the content of each component and the reaction process parameters, thereby significantly improving the utilization rate of the reaction raw materials and the yield of pyrazolo[1,2-b]phthalazine-5,10-dione derivatives. The system exhibits good atom economy, and its catalytic activity is maximized. It has high catalytic activity, with minimal usage and loss during recycling, allowing for a high number of recycling cycles. The catalytic system maintains high activity even during recycling, and requires no pretreatment before recycling, making the operation simple. In addition, catalytic systems that cannot be recycled can be regenerated through simple washing.

[0054] This invention, through optimized control of the type and content of catalysts and reaction solvents, as well as reaction process parameters, can effectively control the reaction direction, reduce the generation of side reactions and reaction impurities, and improve the synthetic purity of pyrazolo[1,2-b]phthalazine-5,10-dione derivatives, thereby effectively ensuring their quality and performance.

[0055] Through extensive experimental research, the inventors ultimately chose anhydrous ethanol as the reaction solvent, which can significantly improve the solubility of the reaction raw materials, ensure their full dissolution, and further improve the utilization rate of the reaction raw materials. Moreover, the above-mentioned reaction solvent can be recycled, with minimal environmental impact.

[0056] The essential features and significant effects of this invention can be seen from the following embodiments, but they do not limit the invention in any way. Any non-essential improvements and adjustments made by those skilled in the art based on the content of this invention are within the scope of protection of this invention. The invention will be further described below through specific embodiments, wherein the reaction products in the embodiments were tested and characterized using an AVANCE 400MHz nuclear magnetic resonance spectrometer from Bruker GmbH, Germany; the melting point was determined using the capillary method.

[0057] Example 1

[0058] Add 5 ml of anhydrous ethanol to a four-necked flask equipped with a magnetic stirrer, a spherical condenser, and a thermometer. Add 0.08 mmol of an alkaline eutectic solvent while stirring at room temperature, and mix thoroughly to form a catalytic system. Then add 1 mmol of benzaldehyde, 1 mmol of phthalamide, and 1 mmol of malononitrile, and mix thoroughly to form a reaction system. Heat the reaction system uniformly in a methyl silicone oil bath until the reaction system is refluxed (the vapor from the reaction solution should not exceed the second sphere of the spherical condenser). Maintain reflux for 8 minutes. When the starting material spot disappears as detected by TLC (thin-plate chromatography), immediately stop heating, stop magnetic stirring, and remove the four-necked flask from the oil bath. Allow to cool naturally to room temperature. A large amount of pale yellow solid precipitates. Crush the solid, let it stand for 8 hours, and then filter under reduced pressure. Wash the filter residue three times with an aqueous solution containing 98% ethanol (volume percentage) and dry it under vacuum at 75°C to constant weight. The weight is 0.30 g. Nuclear magnetic resonance (NMR) and infrared spectral analysis revealed that it was 3-amino-1-phenyl-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile; high performance liquid chromatography (HPLC) showed that its purity was 99.1%, and the yield was calculated to be 94%.

[0059] The performance parameters of the 3-amino-1-phenyl-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile obtained in this embodiment are as follows:

[0060]

[0061] mp278~280℃; 1 H NMR (400MHz, DMSO-d6): δ=6.12 (s, 1H), 7.25~7.38 (m, 3H), 7.41~7.45 (m, 2H), 7.93 (s, 2H), 8.08 (s, 3H), 8.24 (s, 1H); 13 CNMR (100MHz, DMSO-d6): δ=157.05, 154.07, 151.06, 138.89, 135.11, 134.17, 1 29.24, 129.07, 128.98, 128.73, 127.72, 127.23, 127.11, 116.52, 63.41, 61.86.

[0062] Example 2

[0063] Add 6 ml of anhydrous ethanol to a four-necked flask equipped with a magnetic stirrer, a spherical condenser, and a thermometer. Then, add 0.08 mmol of an alkaline eutectic solvent while stirring at room temperature, and mix thoroughly to form a catalytic system. Next, add 1 mmol of o-chlorobenzaldehyde, 1 mmol of phthalamide, and 1.1 mmol of malononitrile, and mix thoroughly to form a reaction system. Heat the reaction system uniformly in a methyl silicone oil bath until the reaction mixture is refluxed (the vapor from the reaction solution should not exceed the second sphere of the spherical condenser). Maintain reflux for 9 min. Once the starting material spot disappears as detected by TLC (thin-plate chromatography), immediately stop heating, stop the magnetic stirring, and remove the four-necked flask from the oil bath. Allow it to cool naturally to room temperature. A large amount of yellow solid precipitates. Crush the solid, let it stand for 8 h, and then filter under reduced pressure. Wash the residue three times with an aqueous solution containing 98% ethanol (v / v) and dry it under vacuum at 75°C to constant weight. The weight of the residue is 0.32 g. Nuclear magnetic resonance (NMR) and infrared spectral analysis revealed its structure to be 3-amino-1-(2-chlorophenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile; high performance liquid chromatography (HPLC) determined its purity to be 99.3%, and the calculated yield was 92%.

[0064] The performance parameters of the 3-amino-1-(2-chlorophenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile obtained in this embodiment are as follows:

[0065]

[0066] mp276~278℃; 1 H NMR (400MHz, DMSO-d6): δ=6.46 (s, 1H), 7.26~7.40 (m, 2H), 7.42~7.55 (m, 3H), 7.60 (dd, J=7.2, 2.2 Hz, 1H), 7.94~8.04 (m, 2H), 8.09 (dt, J=6.8, 3.1Hz, 1H), 8.15 (s, 2H), 8.28 (dt, J=5.4, 3.0Hz, 1H); 13 C NMR (100MHz, DMSO-d6): δ=157.15, 154.02, 151.65, 135.80, 135.24, 134.36, 131.75, 130.39, 130.23, 129.28, 128.86, 128.31, 127.84, 127.19, 116.14, 61.15, 60.26. Details are as follows: Figure 1 and Figure 2 As shown.

[0067] Example 3

[0068] Add 6 ml of anhydrous ethanol to a four-necked flask equipped with a magnetic stirrer, a spherical condenser, and a thermometer. Add 0.07 mmol of an alkaline eutectic solvent while stirring at room temperature, and mix thoroughly to form a catalytic system. Then add 1 mmol of o-nitrobenzaldehyde, 1 mmol of phthalamide, and 1 mmol of malononitrile, and mix thoroughly to form a reaction system. Heat the reaction system uniformly in a methyl silicone oil bath until the reaction system is refluxed (the vapor from the reaction solution does not exceed the second sphere of the spherical condenser). Maintain reflux for 7 min. When the starting material spot disappears as detected by TLC (thin-plate chromatography), immediately stop heating, stop magnetic stirring, and remove the four-necked flask from the oil bath. Allow to cool naturally to room temperature. A large amount of yellow solid precipitates. Crush the solid, let it stand for 8 h, and then filter under reduced pressure. Wash the filter residue three times with an ethanol aqueous solution containing 98% ethanol (v / v) and dry it under vacuum at 75°C to constant weight. The weight is 0.35 g. Nuclear magnetic resonance (NMR) and infrared spectral analysis revealed that it was 3-amino-1-(2-nitrophenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile; high performance liquid chromatography (HPLC) showed that its purity was 99.5%, and the yield was calculated to be 96%.

[0069] The performance parameters of the 3-amino-1-(2-nitrophenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile obtained in this embodiment are as follows:

[0070]

[0071] mp266~268℃; 1 H NMR (400MHz, DMSO-d6): δ=6.58 (s, 1H), 7.54~7.60 (m, 1H), 7.69 (td, J=7.7, 1.1Hz, 1H), 7.83 (dd, J =7.9, 1.2Hz, 1H), 7.92~7.99(m, 2H), 8.01~8.06(m, 2H), 8.16(s, 2H), 8.25(dt, J=5.5, 3.1Hz, 1H); 13 C NMR (100MHz, DMSO-d6): δ=157.08, 154.27, 152.09, 148.74, 135.16, 134.38, 133.6 7, 130.11, 129.43, 129.31, 128.74, 127.79, 127.13, 124.75, 116.16, 60.03, 58.62.

[0072] Example 4

[0073] 7 ml of anhydrous ethanol was added to a four-necked flask equipped with a magnetic stirrer, a spherical condenser, and a thermometer. 0.07 mmol of an alkaline eutectic solvent was then added with stirring at room temperature, and the mixture was thoroughly mixed to form a catalytic system. Next, 1 mmol of m-nitrobenzaldehyde, 1 mmol of phthalamide, and 1 mmol of malononitrile were added, and the mixture was thoroughly mixed to form a reaction system. The reaction system was uniformly heated in a methyl silicone oil bath until reflux was achieved (the vapor from the reaction solution did not exceed the second sphere of the spherical condenser). The reflux was maintained for 6 minutes. Once the starting material spot disappeared as detected by TLC (thin-plate chromatography), heating was immediately stopped, magnetic stirring was resumed, and the four-necked flask was removed from the oil bath. The mixture was allowed to cool naturally to room temperature, resulting in the precipitation of a large amount of yellow solid. This solid was crushed, allowed to stand for 8 hours, and then filtered under reduced pressure. The filter residue was washed three times with an aqueous solution containing 98% ethanol (volume percentage) and dried under vacuum at 75°C to constant weight, yielding a mass of 0.35 g. Nuclear magnetic resonance (NMR) and infrared spectral analysis revealed that it was 3-amino-1-(3-nitrophenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile; high performance liquid chromatography (HPLC) showed that its purity was 99.2%, and the yield was calculated to be 97%.

[0074] The performance parameters of the 3-amino-1-(3-nitrophenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile obtained in this embodiment are as follows:

[0075]

[0076] mp271~273℃; 1 H NMR (400MHz, DMSO-d6): δ=6.35 (s, 1H), 7.69 (t, J=8.0Hz, 1H), 7.93~8.03 (m, 3H) , 8.05~8.12(m, 1H), 8.15~8.23(m, 3H), 8.24~8.30(m, 1H), 8.43(t, J=1.9Hz, 1H); 13 C NMR (100MHz, DMSO-d6): δ=157.26, 154.38, 151.55, 148.47, 141.28, 135.07, 13 4.30, 130.65, 129.55, 128.96, 127.16, 123.84, 122.40, 116.39, 62.59, 60.79.

[0077] Example 5

[0078] 7 ml of anhydrous ethanol was added to a four-necked flask equipped with a magnetic stirrer, a spherical condenser, and a thermometer. 0.10 mmol of an alkaline eutectic solvent was then added under stirring at room temperature, and the mixture was thoroughly mixed to form a catalytic system. Next, 1 mmol of m-fluorobenzaldehyde, 1 mmol of phthalamide, and 1.2 mmol of malononitrile were added, and the mixture was thoroughly mixed to form a reaction system. The reaction system was uniformly heated in a methyl silicone oil bath until reflux was achieved (the vapor from the reaction solution did not exceed the second sphere of the spherical condenser). The reflux was maintained for 12 min. Once the starting material spot disappeared according to TLC (thin-plate chromatography), heating was immediately stopped, the magnetic stirring was stopped, and the four-necked flask was removed from the oil bath. The mixture was allowed to cool naturally to room temperature, resulting in the precipitation of a large amount of yellow solid. This solid was crushed, allowed to stand for 8 h, and then filtered under reduced pressure. The filter residue was washed three times with an aqueous solution containing 98% ethanol (v / v) and dried under vacuum at 75°C to constant weight, yielding a mass of 0.29 g. Nuclear magnetic resonance (NMR) and infrared spectral analysis revealed that it was 3-amino-1-(3-fluorophenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile; high performance liquid chromatography (HPLC) showed that its purity was 99.0%, and the yield was calculated to be 87%.

[0079] The performance parameters of the 3-amino-1-(3-fluorophenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile obtained in this embodiment are as follows:

[0080]

[0081] mp256~258℃; 1 H NMR (400MHz, DMSO-d6): δ=6.13 (s, 3H), 7.14 (dd, J=11.8, 5.1Hz, 1H), 7.30 (d, J=7.7Hz, 1H), 7. 38 (dd, J=13.6, 8.1Hz, 2H), 7.91~7.99 (m, 2H), 8.03~8.12 (m, 3H), 8.22 (dd, J=6.0, 3.0Hz, 1H); 13 CNMR (100MHz, DMSO-d6): δ=164.05, 161.62, 157.21, 154.19, 151.20, 141.95, 135.05, 134.19, 130.9 6, 129.43, 129.02, 127.68, 127.15, 123.30, 116.41, 115.65, 115.43, 114.13, 113.91, 62.82, 61.40.

[0082] Example 6

[0083] 7 ml of anhydrous ethanol was added to a four-necked flask equipped with a magnetic stirrer, a spherical condenser, and a thermometer. 0.09 mmol of an alkaline eutectic solvent was then added with stirring at room temperature, and the mixture was thoroughly mixed to form a catalytic system. Next, 1 mmol of p-bromobenzaldehyde, 1 mmol of phthalamide, and 1 mmol of malononitrile were added, and the mixture was thoroughly mixed to form a reaction system. The reaction system was uniformly heated in a methyl silicone oil bath until reflux was achieved (the vapor from the reaction solution did not exceed the second sphere of the spherical condenser). The reflux was maintained for 8 minutes. Once the starting material spot disappeared as detected by TLC (thin-plate chromatography), heating was immediately stopped, magnetic stirring was resumed, and the four-necked flask was removed from the oil bath. The mixture was allowed to cool naturally to room temperature, resulting in the precipitation of a large amount of yellow solid. This solid was crushed, allowed to stand for 8 hours, and then filtered under reduced pressure. The filter residue was washed three times with an aqueous solution containing 98% ethanol (volume percentage) and dried under vacuum at 75°C to constant weight, yielding a mass of 0.38 g. Nuclear magnetic resonance (NMR) and infrared spectral analysis revealed that it was 3-amino-1-(4-bromophenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile; high performance liquid chromatography (HPLC) showed that its purity was 99.2%, and the yield was calculated to be 96%.

[0084] The performance parameters of the 3-amino-1-(4-bromophenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile obtained in this embodiment are as follows:

[0085]

[0086] mp270~272℃; 1 H NMR (400MHz, DMSO-d6): δ = 6.14 (s, 1H), 7.46 (d, J = 8.4Hz, 2H), 7.57 (d, J = 8.4Hz, 2H), 7.97 (d d, J=5.3, 3.8Hz, 2H), 8.09 (dd, J=6.0, 3.0Hz, 1H), 8.14 (s, 2H), 8.26 (dd, J=6.1, 3.0Hz, 1H); 13 C NMR (400MHz, DMSO-d6): δ=157.12, 154.15, 151.21, 138.37, 135.12, 134.24, 13 1.92, 129.64, 129.33, 129.00, 127.75, 127.14, 121.95, 116.46, 62.85, 61.34.

[0087] Example 7

[0088] 8 ml of anhydrous ethanol was added to a four-necked flask equipped with a magnetic stirrer, a spherical condenser, and a thermometer. 0.11 mmol of an alkaline eutectic solvent was then added with stirring at room temperature, and the mixture was thoroughly mixed to form a catalytic system. Next, 1 mmol of p-methoxybenzaldehyde, 1 mmol of phthalamide, and 1.2 mmol of malononitrile were added, and the mixture was thoroughly mixed to form a reaction system. The reaction system was uniformly heated in a methyl silicone oil bath until reflux was achieved (the vapor from the reaction solution did not exceed the second sphere of the spherical condenser). The reflux reaction was maintained for 14 min. Once the starting material spot disappeared as detected by TLC (thin-plate chromatography), heating was immediately stopped, magnetic stirring was resumed, and the four-necked flask was removed from the oil bath. The mixture was allowed to cool naturally to room temperature, resulting in the precipitation of a large amount of yellow solid. This solid was crushed, allowed to stand for 8 h, and then filtered under reduced pressure. The filter residue was washed three times with an aqueous solution containing 98% ethanol (volume percentage) and dried under vacuum at 75°C to constant weight, yielding a mass of 0.32 g. Nuclear magnetic resonance (NMR) and infrared spectral analysis revealed that it was 3-amino-1-(4-methoxyphenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile; high performance liquid chromatography (HPLC) showed that its purity was 99.4%, and the yield was calculated to be 91%.

[0089] The performance parameters of the 3-amino-1-(4-methoxyphenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile obtained in this embodiment are as follows:

[0090]

[0091] mp240~242℃; 1 H NMR (400MHz, DMSO-d6): δ=3.72 (s, 3H), 6.06 (s, 1H), 6.88 (d, J=8.7Hz, 2H), 7.37 (d, J=8 .7Hz, 2H), 7.94 (dd, J=5.9, 3.3Hz, 2H), 8.07~8.12 (m, 3H), 8.23 ​​(dd, J=5.9, 3.2Hz, 1H); 13 C NMR (100MHz, DMSO-d6): δ=159.71, 157.05, 154.02, 151.01, 135.09, 134.12, 1 30.56, 129.17, 128.93, 127.70, 127.08, 116.59, 114.27, 63.09, 61.85, 55.58.

[0092] Example 8

[0093] Add 8 ml of anhydrous ethanol to a four-necked flask equipped with a magnetic stirrer, a spherical condenser, and a thermometer. Add 0.10 mmol of an alkaline eutectic solvent while stirring at room temperature, and mix thoroughly to form a catalytic system. Then add 1 mmol of p-methylbenzaldehyde, 1 mmol of phthalamide, and 1 mmol of malononitrile, and mix thoroughly to form a reaction system. Heat the reaction system uniformly in a methyl silicone oil bath until the reaction system is refluxed (the vapor from the reaction solution should not exceed the second sphere of the spherical condenser). Maintain reflux for 12 min. When the starting material spot disappears as detected by TLC (thin-plate chromatography), immediately stop heating, stop magnetic stirring, and remove the four-necked flask from the oil bath. Allow to cool naturally to room temperature. A large amount of pale yellow solid precipitates. Crush the solid, let it stand for 8 h, and then filter under reduced pressure. Wash the filter residue three times with an ethanol aqueous solution containing 98% ethanol (v / v) and dry it under vacuum at 75°C to constant weight. The weight is 0.31 g. Nuclear magnetic resonance (NMR) and infrared spectral analysis revealed that it was 3-amino-1-(4-methylphenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile; high performance liquid chromatography (HPLC) showed that its purity was 99.2%, and the yield was calculated to be 93%.

[0094] The performance parameters of the 3-amino-1-(4-methylphenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile obtained in this embodiment are as follows:

[0095]

[0096] mp251~253℃; 1 H NMR (400MHz, DMSO-d6): δ=2.29(s, 3H), 6.09(s, 1H), 7.17(d, J=8.0Hz, 2H), 7.33(d , J=8.0Hz, 2H), 7.89~8.02(m, 2H), 8.09(dd, J=5.5, 3.3Hz, 3H), 8.21~8.32(m, 1H); 13 C NMR (100MHz, DMSO-d6): δ=157.09, 154.05, 151.05, 138.14, 135.86, 135.15, 134.2 0, 129.55, 129.20, 129.14, 127.75, 127.30, 127.13, 116.54, 63.31, 61.89, 21.19.

[0097] Example 9

[0098] Using the reaction described in Example 1 as a probe reaction, an activity repeatability test was conducted on the catalytic system consisting of an alkaline eutectic solvent catalyst and anhydrous ethanol reaction solvent. 1 mmol benzaldehyde, 1 mmol phthalamide, and 1 mmol malononitrile were directly added to the filtrate obtained in Example 1. The catalytic system was used repeatedly according to the reaction conditions and operating steps of Example 1. The catalytic system was used a total of 6 times. The changes in purity and yield of the product 3-amino-1-phenyl-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile each time are shown in Table 1.

[0099] Table 1. Results of repeatability tests on the catalytic system in the synthesis of 3-amino-1-phenyl-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile.

[0100]

[0101] Considering the characteristics of pharmaceutical intermediates and economic aspects of production, the catalytic system should be discontinued when the liquid chromatography purity of 3-amino-1-phenyl-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-onitrile is below 98% or its yield decreases by more than 5% compared to the first use of the catalytic system. As shown in Table 1, the optimal number of uses for the catalytic system is 5.

[0102] Example 10

[0103] Using the reaction described in Example 1 as a probe reaction, a regeneration experiment was conducted on the catalytic system composed of an alkaline eutectic solvent catalyst and anhydrous ethanol as the reaction solvent. The filtrate obtained after six uses in Example 9 was first rotary evaporated to remove ethanol, then 10 ml of diethyl ether was added, and the mixture was magnetically stirred for 10 minutes before separation. Then, another 10 ml of diethyl ether was added to the lower layer, and the mixture was magnetically stirred for 10 minutes before separation again. This process was repeated three times. Finally, the lower layer obtained in the third step was vacuum dried at 50°C to constant weight to obtain the regenerated alkaline eutectic solvent catalyst. This was then added to a new solvent composed of rotary evaporated ethanol (4.2 ml) and newly added anhydrous ethanol (0.8 ml) to make up 5 ml of ethanol. The mixture was stirred until homogeneous to obtain the regenerated catalytic system.

[0104] Example 11

[0105] Using the reaction involved in Example 1 as a probe reaction, a regenerated catalytic system consisting of an alkaline eutectic solvent catalyst and anhydrous ethanol reaction solvent was tested: 1 mmol benzaldehyde, 1 mmol phthalamide and 1 mmol malononitrile were added to the regenerated catalytic system produced in Example 10. The system was used for the first time according to the reaction conditions and operating steps of Example 1 and for repeated use according to the operating steps of Example 9. The catalytic system was used a total of 5 times. The changes in purity and yield of the product 3-amino-1-phenyl-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile each time are shown in Table 2.

[0106] Table 2. Results of the regenerated catalyst system in the synthesis of 3-amino-1-phenyl-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-nitrile, including its use and recycling.

[0107]

[0108] As can be seen from the data in Table 2, the regenerated catalytic system can still be used and can be recycled up to 3 times.

[0109] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims

1. A catalytic system for the synthesis of a pharmaceutical intermediate, pyrazolo[1,2-b]phthalazine-5,10-dione derivative, characterized in that, The catalytic system comprises a basic deep eutectic solvent as a catalyst and anhydrous ethanol as a reaction solvent, wherein the basic deep eutectic solvent is prepared by mixing and heating choline chloride and ethanolamine, and the molar ratio of choline chloride to ethanolamine is 1:

8.

2. A method for the synthesis of a pharmaceutical intermediate pyrazolo[l,2-b]phthalazine-5,10-dione derivative, characterized by, The synthesis method synthesizes pyrazolo[1,2-b]phthalazine-5,10-dione derivatives from aromatic aldehyde, phthalhydrazide and malononitrile under the catalysis of a catalytic system composed of a basic deep eutectic solvent and anhydrous ethanol, and the chemical reaction formula is as follows: In the formula, formula I is aromatic aldehyde, formula II is phthalhydrazide, formula III is malononitrile, and formula IV is the synthesized pyrazolo[1,2-b]phthalazine-5,10-dione derivative.

3. A process for the synthesis of a pharmaceutical intermediate pyrazolo[l,2-b]phthalazine-5,10-dione derivative according to claim 2, characterized by, The specific steps of the synthesis method are as follows: (1) A flask with a magnetic stirrer, a spherical condenser and a thermometer is added with a preset volume of anhydrous ethanol, and a preset amount of a basic deep eutectic solvent is added under stirring at room temperature, and then mixed uniformly to form a catalytic system; (2) The reaction raw materials, aromatic aldehyde, phthalhydrazide and malononitrile, are weighed according to a molar ratio of 1:1:(1.0-1.2); (3) The weighed reaction raw materials are added to the catalytic system for mixing and stirring, and then heated for reflux reaction under stirring, the reflux temperature is maintained until the raw material point disappears, the reaction is completed, the stirring and heating are immediately stopped, the flask is removed from the oil bath, and the flask is naturally cooled to room temperature to obtain a solid precipitate; (4) The obtained solid precipitate is first crushed, and then subjected to vacuum filtration after standing for 8 hours, and then the filter residue is washed with an ethanol aqueous solution with a volume percentage concentration of 98% ethanol, and then vacuum dried at 75°C to obtain the pyrazolo[1,2-b]phthalazine-5,10-dione derivative.

4. The process for the synthesis of a pharmaceutical intermediate pyrazolo[l,2-b]phthalazine-5,10-dione derivative according to claim 3, characterized by, The reaction pressure of the reflux reaction is one atmosphere, the reflux reaction time is 6-14 min, the volume of the reaction solvent anhydrous ethanol in milliliters is 5-8 times the molar amount of the aromatic aldehyde in millimoles, and the amount of the basic deep eutectic solvent catalyst used is 7-11% of the amount of the aromatic aldehyde.

5. The process for the synthesis of a pharmaceutical intermediate pyrazolo[l,2-b]phthalazine-5,10-dione derivative according to claim 2, characterized by, The aromatic aldehyde is any one of benzaldehyde, o-chlorobenzaldehyde, o-bromobenzaldehyde, o-nitrobenzaldehyde, m-fluorobenzaldehyde, m-chlorobenzaldehyde, m-bromobenzaldehyde, m-nitrobenzaldehyde, m-methylbenzaldehyde, m-methoxybenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-nitrobenzaldehyde, p-methylbenzaldehyde and p-methoxybenzaldehyde.

6. The process for the synthesis of a pharmaceutical intermediate pyrazolo[l,2-b]phthalazine-5,10-dione derivative according to claim 3, characterized by, The reflux temperature in step (3) is 81-83°C.

7. The process for the synthesis of a pharmaceutical intermediate pyrazolo[l,2-b]phthalazine-5,10-dione derivative according to claim 3, characterized by, The synthesis method further comprises a recycling step of the catalytic system, and the specific process of recycling is as follows: The filtrate produced in step (4) is directly added to the reaction raw materials without any treatment, and the recycling of the catalytic system is carried out according to steps (3) and (4); when the liquid chromatography purity of the product pyrazolo[1,2-b]phthalazine-5,10-dione derivative is less than 98% or the yield decreases by more than 5% compared with the first use of the catalytic system, the recycling of the filtrate is stopped.

8. The process for the synthesis of a pharmaceutical intermediate pyrazolo[l,2-b]phthalazine-5,10-dione derivative according to claim 7, characterized by, The synthesis method further comprises a regeneration step of the catalytic system, and the specific process of regeneration is as follows: The filtrate of the stopped cycle is first rotary evaporated to remove ethanol, then a preset volume of ether is added, and after magnetic stirring for 10 minutes, the liquid is separated. Then the same volume of ether is added to the lower liquid, and after magnetic stirring for 10 minutes, the liquid is separated again. The process is repeated for 3 times. Finally, the lower liquid obtained in the third time is vacuum dried at 50℃ until the weight is constant, to obtain the regenerated basic eutectic solvent catalyst. Then the catalyst is added to a new solvent composed of the rotary evaporated ethanol and the newly added anhydrous ethanol to make up the required volume, and the mixture is stirred uniformly to obtain the regenerated catalyst system.

9. A process for the synthesis of a pharmaceutical intermediate pyrazolo[l,2-b]phthalazine-5,10-dione derivative according to claim 8, characterized by, In the regeneration process, the stopped cycle filtrate is washed with 1-3 times the volume of ether of the reaction solvent anhydrous ethanol.

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