Preparation method of a pharmaceutical intermediate pyrazoloquinolinone derivative and catalyst

Abstract

The present invention relates to the field of the preparation of pharmaceutical intermediates, and specifically discloses a preparation method and a catalyst for a pharmaceutical intermediate pyrazoloquinolinone derivative. The method uses an aromatic aldehyde, 1-phenyl-3-methyl-5-aminopyrazole and 1,3-cyclohexanedione compounds as reaction raw materials, an ethanol aqueous solution as a reaction solvent, and carries out a reaction for preparing a pyrazoloquinolinone derivative under the catalytic action of a catalyst. By adopting the catalytic system composed of the catalyst and the ethanol aqueous solution of the present invention, and optimizing the design of the ratio and usage amount of the catalyst and the ethanol aqueous solution and the reaction process parameters, the catalytic activity of the catalyst and the dual functions of the ethanol aqueous solution can be best exerted, thereby being beneficial to reducing the preparation and purification costs of the pyrazoloquinolinone derivative.

Description

Technical Field

[0001] The present invention relates to a preparation method of a derivative, in particular to a preparation method and a catalyst of a pyrazoloquinolinone derivative as a pharmaceutical intermediate, belonging to the field of pharmaceutical intermediate preparation. Background Art

[0002] Pyrazole compounds are a very important class of heterocyclic compounds. Due to their characteristics such as high efficiency, low toxicity, and multi-directional transformation of substituents on the pyrazole ring, they have good physiological and pharmacological activities and can be used as intermediates in the preparation of drugs such as antihypertensive, antibacterial, anti-inflammatory, and anticancer drugs. In addition, as an important class of quinolinone derivatives containing a quinoline ring structure, they widely exist in natural plants and are also the parent structures in the structures of many drugs. Recently, research data show that: the fused pyrazole compound pyrazoloquinolinone derivative has a variety of biological and pharmacological activities, such as bactericidal, anti-parasitic, antimalarial, vasodilating effects, etc. Therefore, the synthesis of this kind of derivative has always attracted the attention of drug synthesis workers.

[0003] Up to now, there are 2 synthesis routes for pyrazoloquinolinone derivatives: the first one uses o-aminobenzaldehyde and pyrazolone as reaction raw materials and an alkali as a catalyst to prepare through the Friedlander condensation reaction, but this method has disadvantages such as serious environmental pollution, low product yield and purity; the second one uses aromatic aldehyde, dimedone and aminopyrazole as reaction raw materials and triethylamine as a catalyst to prepare through the condensation reaction, but this method still has disadvantages such as relatively low product yield and serious pollution caused by the non-recyclable catalyst.

[0004] Taking advantage of the heating effect and catalytic effect of microwaves, synthetic chemists at home and abroad have applied them to the improvement of the synthetic methods of pyrazoloquinolinone derivatives. For example, in 2007, Valentin A. Chebanov et al. used 5-aminopyrazole, aromatic aldehyde, and 1,3-cyclohexanedione as reaction raw materials, and inorganic base as a catalyst to synthesize a series of pyrazoloquinolinone derivatives in ethanol as the reaction solvent with microwave assistance (One-pot, multicomponent route to pyrazoloquinolizinones[J], Organic Letters, 2007, 9(9): 1691~1694); in 2008, this research group improved the above work and used the organic base triethylamine as a catalyst (Tuning of chemo- and regioselectivities in multicomponent condensations of 5-aminopyrzoles, dimidone, and aldehydes[J], Journal of Organic Chemistry, 2008, 73: 5110~5118). However, in the above methods, an alkali is still used as a catalyst and this catalyst cannot be recycled, resulting in a large amount of waste alkali solution. Based on this, a catalyst-free preparation method was put on the agenda and has also been developed to a certain extent. For example, in 2011, the research group of Valentin A. Chebanov synthesized pyrazolo[3,4-b]quinolinone derivatives by reacting 5-aminopyrazole, aromatic aldehyde, and dimedone in water using microwaves (Green and efficient synthesis of pyrazolo[3,4-b]quinolin-5-ones derivatives by microwave-assisted multicomponent reaction in hot water medium[J], Journal of Heterocyclic Chemistry, 2011, 48: 365~367); in 2005, Tu Shujiang et al. used aromatic aldehyde, 1,3-cyclohexanedione or dimedone, and aminopyrazole as reaction raw materials, and ethylene glycol as an energy transfer agent to rapidly synthesize a series of pyrazolo[5,4-b]quinolinone derivatives (One-pot synthesis of 5-aryl-1,5,6,7,8,9-hexahydro-2H-pyrazolo[5,4-b]quinolin-6-one under microwave irradiation[J], Chinese Journal of Organic Chemistry, 2005, 25(12): 1610~1614).

[0005] Since the reaction assisted by microwave radiation is difficult to be applied on a large scale in industrial production, and it is difficult to control the pressure and temperature with poor reproducibility, domestic and foreign scholars have also been conducting research on the synthesis method of pyrazoloquinolinone derivatives by heating. For example, in 2001, Jairo Quiroga et al. used ethanol as the reaction solvent and prepared pyrazolo[3,4-b]quinolinone derivatives through the condensation reaction of 5-aminopyrazole, aromatic aldehyde and dimedone under heating reflux (Regioselective synthesis of 4,7,8,9-tetrahydro-2H-pyrazolo[3,4-b]-quinolin-5(6H)-ones. Mechanism and structural analysis[J], Tetrahedron, 2001, 57: 6947~6953). Since no catalyst was used in the reaction, the yield of the product was relatively low, and most yields were in the 60% range. Based on this, in order to improve the product yield and expand the range of reaction raw materials, in 2008, Shi Daqing et al. used aromatic aldehyde, 5-amino-3-methyl-1-phenylpyrazole, and 1,3-cyclohexanedione as reaction raw materials and sodium dodecyl sulfate as a phase transfer catalyst to synthesize 4-aryl-3-methyl-1-phenyl-4,5,6,7,8,9-hexahydropyrazolo[5,4-b]quinolin-5-one derivatives by a three-component one-pot reaction in an aqueous medium (Three-component one-pot synthesis of 4-aryl-3-methyl-1-phenyl-4,5,6,7,8,9-hexahydropyrazolo[5,4-b]quinolin-5-one derivatives in aqueous medium[J], Organic Chemistry, 2008, 28(2): 261~265). However, the above methods still have some disadvantages: 1. The selectivity of the phase transfer catalyst is poor and there are many by-products, resulting in a complex product purification process that requires column chromatography separation; 2. The catalyst and reaction solvent cannot be recycled, resulting in serious environmental pollution; 3. The catalytic ability of the catalyst is weak, the reaction time is long and it needs to be heated to a relatively high temperature, consuming a large amount of energy. Summary of the Invention

[0006] Aiming at the problems in the prior art, the purpose of the present invention is to overcome the deficiencies of the existing preparation process of pyrazoloquinolinone derivatives, such as low catalytic activity and selectivity of the catalyst, non-recyclability, complex preparation process, high cost, and easy environmental pollution, and provide a preparation method and catalyst for the pharmaceutical intermediate pyrazoloquinolinone derivatives. Using the method of the present invention can effectively overcome the above deficiencies, and has the characteristics of green pollution-free, high efficiency, simplicity, etc., which is convenient for large-scale industrial production.

[0007] The purpose of the present invention can be achieved through the following technical solutions:

[0008] A preparation method of a pyrazoloquinolinone derivative as a pharmaceutical intermediate. In this method, an aromatic aldehyde (I), 1-phenyl-3-methyl-5-aminopyrazole (II), and a 1,3-cyclohexanedione compound (III) are used as reaction raw materials, an ethanol aqueous solution is used as the reaction solvent, and a reaction for preparing the pyrazoloquinolinone derivative (IV) is carried out under the catalysis of a catalyst. The chemical reaction formula is as follows:

[0009]

[0010] The aromatic aldehyde in (I) is selected from any one of:

[0011]

[0012] ;

[0013] The 1,3-cyclohexanedione compound in (III) is 1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione.

[0014] Optionally, the preparation method includes the following steps:

[0015] Step 1: Add the aromatic aldehyde (I), 1-phenyl-3-methyl-5-aminopyrazole (II), 1,3-cyclohexanedione compound (III), and the catalyst into the ethanol aqueous solution respectively and mix them evenly. Under the protection of nitrogen or argon, heat the reaction solution to reflux and maintain the reflux reaction time for 36 - 69 min;

[0016] Step 2: After the reflux reaction in Step 1 ends, still under the protection of nitrogen or argon, cool the reaction solution to room temperature, crush the precipitated solid in the air, let it stand, filter by suction, and the filter residue is washed and dried under vacuum to obtain the pyrazoloquinolinone derivative (IV).

[0017] Optionally, in Step 1, the molar ratio of the aromatic aldehyde, 1,3-cyclohexanedione compound, and 1-phenyl-3-methyl-5-aminopyrazole is 1:1:1, and the mass of the catalyst in grams is 3 - 5% of the amount of substance of the aromatic aldehyde in millimoles.

[0018] Optionally, the volume ratio concentration of ethanol in the reaction solvent ethanol aqueous solution in Step 1 is 94 - 97%.

[0019] Optionally, the volume of the reaction solvent ethanol aqueous solution in milliliters in Step 1 is 6 - 9 times the molar amount of the aromatic aldehyde in millimoles.

[0020] Optionally, after Step 2, an ethanol aqueous solution with a volume ratio concentration of 94 - 97% is used as the filter residue washing solution to wash the filter residue obtained by suction filtration after the reaction 3 - 5 times.

[0021] Optionally, after the filtrate obtained by suction filtration is supplemented with the filter residue washing liquid, it can be directly added to the reaction raw materials without any treatment and then subjected to the next reaction, and can be reused at least 6 times.

[0022] A catalyst for a preparation method of a pharmaceutical intermediate pyrazoloquinolinone derivative, and the chemical structural formula of the catalyst is:

[0023]

[0024] Advantages of the present invention:

[0025] 1. For the preparation method and catalyst of a pharmaceutical intermediate pyrazoloquinolinone derivative of the present invention, when using this catalyst to prepare pyrazoloquinolinone derivative, the catalytic activity and selectivity are relatively high, and the catalyst can be recycled without any treatment.

[0026] 2. For the preparation method and catalyst of a pharmaceutical intermediate pyrazoloquinolinone derivative of the present invention, using aromatic aldehyde, 1,3 - cyclohexanedione compound and 1 - phenyl - 3 - methyl - 5 - aminopyrazole as reaction raw materials, adopting the catalytic system composed of the catalyst and ethanol aqueous solution of the present invention, and optimizing the ratio and usage amount of the catalyst and ethanol aqueous solution and reaction process parameters, so that the catalytic activity of the catalyst and the dual functions of the ethanol aqueous solution (reaction solvent function and recrystallization solvent function) can be best exerted, and thus it is beneficial to reduce the preparation and purification costs of pyrazoloquinolinone derivative.

[0027] 3. For the preparation method and catalyst of a pharmaceutical intermediate pyrazoloquinolinone derivative of the present invention, by using ethanol aqueous solution with a specific concentration as the reaction solvent, on the one hand, it is beneficial to improve the recycling performance of the catalyst and the utilization rate of raw materials, and on the other hand, this reaction solvent can also serve as a recrystallization solvent, combining the reaction process and the recrystallization process into one, which is simple and efficient and simplifies the purification operation of the product.

[0028] 4. For the preparation method and catalyst of a pharmaceutical intermediate pyrazoloquinolinone derivative of the present invention, the catalyst does not need to be treated before recycling, the operation is simple and convenient, the reaction solvent can also be recycled, and the raw materials that were not reacted in the previous time can also participate in the subsequent reaction, so as to ensure the full utilization of resources, reduce resource waste, and the utilization rate of raw materials is relatively high.

[0029] 5. For the preparation method and catalyst of a pharmaceutical intermediate pyrazoloquinolinone derivative of the present invention, the entire preparation process can be carried out in large - scale and continuous production, and has less harm to the environment, can meet the requirements of green, economic and efficient indicators, and is convenient for industrial popularization and application. Description of the Drawings

[0030] For the convenience of those skilled in the art to understand, the present invention will be further described below in conjunction with the accompanying drawings.

[0031] Figure 1 It is a schematic diagram of the test results of Example 13 of the present invention.

[0032] Figure 2 It is a schematic diagram of the test results of Example 14 of the present invention. Detailed implementation manners

[0033] Next, the technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

[0034] As Figure 1-2 shown, a preparation method of a pharmaceutical intermediate pyrazoloquinolinone derivative, which uses aromatic aldehyde (I), 1-phenyl-3-methyl-5-aminopyrazole (II) and 1,3-cyclohexanedione compound (III) as reaction raw materials, uses an ethanol aqueous solution as a reaction solvent, and carries out a reaction for preparing a pyrazoloquinolinone derivative (IV) under the catalytic action of a catalyst. The chemical reaction formula is:

[0035]

[0036] The aromatic aldehyde in (I) is selected from:

[0037]

[0038] any one of;

[0039] The 1,3-cyclohexanedione compound in (III) is 1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione.

[0040] As a technical optimization scheme of the present invention, the preparation method includes the following steps:

[0041] Step 1: Add the aromatic aldehyde (I), 1-phenyl-3-methyl-5-aminopyrazole (II), 1,3-cyclohexanedione compound (III) and the catalyst into the ethanol aqueous solution respectively and mix them evenly. Heat the reaction solution to reflux under the protection of nitrogen or argon and keep the reflux reaction time for 36-69 min;

[0042] Step 2: After the reflux reaction in Step 1 ends, still under the protection of nitrogen or argon, cool the reaction solution to room temperature, crush the precipitated solid in the air, let it stand, filter by suction, and the filter residue is washed and dried in vacuum to obtain the pyrazoloquinolinone derivative (IV).

[0043] As a technical optimization scheme of the present invention, the molar ratio of the aromatic aldehyde, 1,3 - cyclohexanedione compound, and 1 - phenyl - 3 - methyl - 5 - aminopyrazole in step one is 1:1:1, and the mass of the catalyst in grams is 3 - 5% of the amount of the aromatic aldehyde in millimoles.

[0044] As a technical optimization scheme of the present invention, the volume concentration of ethanol in the ethanol aqueous solution used as the reaction solvent in step one is 94 - 97%.

[0045] As a technical optimization scheme of the present invention, the volume of the ethanol aqueous solution used as the reaction solvent in step one in milliliters is 6 - 9 times the molar amount of the aromatic aldehyde in millimoles.

[0046] As a technical optimization scheme of the present invention, after step two, an ethanol aqueous solution with a volume concentration of 94 - 97% is used as the filter residue washing liquid to wash the filter residue obtained by suction filtration after the reaction 3 - 5 times.

[0047] As a technical optimization scheme of the present invention, after the filtrate obtained by suction filtration is made up with the filter residue washing liquid and without any treatment, the reaction raw materials are directly added for the next reaction, and it can be reused at least 6 times.

[0048] A catalyst for the preparation method of pyrazoloquinolinone derivatives as pharmaceutical intermediates, and the chemical structural formula of the catalyst is:

[0049]

[0050] The present invention will be further described below in conjunction with specific embodiments.

[0051] Example 1

[0052] Preparation of 7,8 - dihydro - 3 - methyl - 1,4 - diphenyl - 1H - pyrazolo[3,4 - b]quinolin - 5(4H,6H,9H) - one

[0053]

[0054] 1 mmol of benzaldehyde, 1 mmol of 1-phenyl-3-methyl-5-aminopyrazole, 1 mmol of 1,3-cyclohexanedione and 0.04 g of catalyst were respectively added to a 50 mL three-necked flask equipped with a magnetic stirrer, a thermometer and a spherical condenser and containing 6 mL of 94% ethanol aqueous solution, and magnetically stirred and mixed evenly at room temperature. Then, under the protection of nitrogen, the reaction solution was heated to reflux (the vapor of the reaction solution did not exceed the second sphere of the spherical condenser) and the reflux reaction time was maintained for 58 min. Track by TLC (thin layer chromatography). When the raw material spot disappeared, the stirring was immediately stopped, and it was naturally cooled to room temperature under the protection of nitrogen. A large amount of white solid was precipitated. The precipitated solid was crushed, allowed to stand and age for 2 h, and then filtered to obtain the filter residue and the filtrate. The filter residue was washed with 94% ethanol aqueous solution (3 mL×3) and dried in vacuo at 80 °C for 24 h to obtain 0.31 g of 7,8-dihydro-3-methyl-1,4-diphenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one. 10 mg of the above product was ultrasonically dissolved in 5 mL of chromatographic methanol, then quantified with a 20 mL volumetric flask, filtered through a 0.45 μm organic membrane, and finally detected by high performance liquid chromatography. The purity of 7,8-dihydro-3-methyl-1,4-diphenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one was measured to be 99.1%, and its yield was calculated to be 86%.

[0055] After adding benzaldehyde, 1-phenyl-3-methyl-5-aminopyrazole and 1,3-cyclohexanedione directly to the filtrate after replenishing the washing liquid to 6 mL after washing the filter residue, it was reused.

[0056] The performance parameters of the 7,8-dihydro-3-methyl-1,4-diphenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one obtained in this example are: white solid; m.p. 205-207 °C; 1 H NMR (400 MHz, DMSO-d 6 ): δ = 1.74-1.92 (m, 2H, CH 2 ), 1.86 (s, 3H, CH 3 ), 2.08-2.17 (m, 2H, CH 2 ), 2.56-2.69 (m, 2H, CH 2), 4.95 (s, 1H, CH), 6.74 - 7.51 (m, 10H, ArH), 9.40 (s, 1H, NH); IR (KBr): ν = 3324, 3226, 3158, 3027, 2959, 1724, 1608, 1531, 1462, 1425, 1342, 1257, 1194, 1120, 1075, 1033, 1017, 952, 769, 698 cm -1 .

[0057] Examples 2 - 4

[0058] The reflux temperature of the reaction solution described in Example 1 was replaced with different reaction temperatures (shown in Table 1), and other conditions were the same as in Example 1. The experimental results are shown in Table 1.

[0059] Table 1 Effect of reaction temperature on the yield of 7,8 - dihydro - 3 - methyl - 1,4 - diphenyl - 1H - pyrazolo[3,4 - b]quinolin - 5(4H, 6H, 9H) - one

[0060] Example Reaction temperature / °C Yield / % Example 2 Room temperature (32 °C) 23 Example 3 45 47 Example 4 65 69

[0061] Examples 5 - 10

[0062] The 0.04 g of catalyst described in Example 1 was replaced with catalysts of different masses, and other conditions were the same as in Example 1. The experimental results are shown in Table 2.

[0063] Table 2 Effect of catalyst mass on the yield of 7,8 - dihydro - 3 - methyl - 1,4 - diphenyl - 1H - pyrazolo[3,4 - b]quinolin - 5(4H, 6H, 9H) - one

[0064] Example / Comparative example Mass of catalyst / g Yield / % Example 5 0 0 Example 6 0.01 14 Example 7 0.02 47 Example 8 0.03 71 Example 9 0.05 85 Example 10 0.06 83

[0065] Example 11

[0066] Preparation of 7,8 - dihydro - 3,7,7 - trimethyl - 1,4 - diphenyl - 1H - pyrazolo[3,4 - b]quinolin - 5(4H, 6H, 9H) - one

[0067]

[0068] 1 mmol of benzaldehyde, 1 mmol of 1-phenyl-3-methyl-5-aminopyrazole, 1 mmol of 5,5-dimethyl-1,3-cyclohexanedione and 0.03 g of catalyst were respectively added into a 50 mL three-necked flask equipped with a magnetic stirrer, a thermometer and a spherical condenser and containing 7 mL of 95% aqueous ethanol solution, and magnetically stirred and mixed evenly at room temperature. Then, under the protection of nitrogen, the reaction solution was heated to reflux (the vapor of the reaction solution did not exceed the second sphere of the spherical condenser) and the reflux reaction time was maintained for 63 min. Traced by TLC (thin layer chromatography), when the raw material spots disappeared, the stirring was immediately stopped, and it was continuously cooled to room temperature naturally under the protection of nitrogen. A large amount of white solid was precipitated. The precipitated solid was crushed, allowed to stand and age for 2 h, and then filtered by suction to obtain a filter residue and a filtrate. The filter residue was washed with 95% aqueous ethanol solution (3 mL×3) and vacuum dried at 80 °C for 24 h to obtain 0.36 g of 7,8-dihydro-3,7,7-trimethyl-1,4-diphenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one. 10 mg of the above product was ultrasonically dissolved in 5 mL of chromatographic methanol, then quantified with a 20 mL volumetric flask, filtered through a 0.45 μm organic membrane, and finally detected by high performance liquid chromatography. The purity of 7,8-dihydro-3,7,7-trimethyl-1,4-diphenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one was measured to be 99.3%, and its yield was calculated to be 92%.

[0069] After adding benzaldehyde, 1-phenyl-3-methyl-5-aminopyrazole and 5,5-dimethyl-1,3-cyclohexanedione directly to the filtrate after replenishing the washing liquid to 7 mL with the washing liquid for washing the filter residue, it was reused.

[0070] The performance parameters of 7,8-dihydro-3,7,7-trimethyl-1,4-diphenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one obtained in this example are: white solid; m.p. 217-219 °C; 1 H NMR (400 MHz, DMSO-d 6 ): δ = 0.91 (s, 3H, CH 3 ), 1.00 (s, 3H, CH 3 ), 1.85 (s, 3H, CH 3 ), 1.94-2.12 (m, 2H, CH 2 ), 2.49 (s, 2H, CH 2), 4.96 (s, 1H, CH), 7.03 - 7.48 (m, 10H, ArH), 9.35 (s, 1H, NH); IR (KBr): ν = 3417, 3235, 3157, 2952, 1614, 1523, 1462, 1395, 1236, 1147, 1115, 1036, 756, 688, 560 cm -1 。

[0071] Example 12

[0072] Preparation of 4-(4-chlorophenyl)-7,8-dihydro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H, 6H, 9H)-one

[0073]

[0074] 1 mmol of 4-chlorobenzaldehyde, 1 mmol of 1-phenyl-3-methyl-5-aminopyrazole, 1 mmol of 1,3-cyclohexanedione and 0.04 g of catalyst were respectively added into a 50 mL three-necked flask equipped with a magnetic stirrer, a thermometer and a spherical condenser and containing 6 mL of 95% ethanol aqueous solution, and magnetically stirred and mixed evenly at room temperature. Then, under the protection of nitrogen, the reaction solution was heated to reflux (not exceeding the second sphere of the spherical condenser) and the reflux reaction time was maintained for 53 min. Track by TLC (thin layer chromatography). When the raw material spot disappeared, the stirring was immediately stopped. Continuing to cool naturally to room temperature under the protection of nitrogen, a large amount of yellow solid was precipitated. The precipitated solid was crushed and allowed to stand for 2 h. The filtrate and the residue were obtained by suction filtration. The residue was washed with 95% ethanol aqueous solution (4 mL×3) and vacuum dried at 80 °C for 24 h to obtain 0.35 g of 4-(4-chlorophenyl)-7,8-dihydro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H, 6H, 9H)-one. 10 mg of the above product was ultrasonically dissolved in 5 mL of chromatographic methanol, then quantified with a 20 mL volumetric flask, filtered through a 0.45 μm organic membrane, and finally detected by high performance liquid chromatography. The purity of 4-(4-chlorophenyl)-7,8-dihydro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H, 6H, 9H)-one was measured to be 99.4%, and its yield was calculated to be 89%.

[0075] After making up the filtrate to 6 mL with the washing solution for washing the residue, 4-chlorobenzaldehyde, 1-phenyl-3-methyl-5-aminopyrazole and 1,3-cyclohexanedione were directly added for reuse.

[0076] The performance parameters of 4-(4-chlorophenyl)-7,8-dihydro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one obtained in this example are: yellow solid; m.p. 191 - 193 °C; 1 H NMR(400MHz, DMSO-d 6 ): δ = 1.75 - 1.88(m, 2H, CH 2 ), 1.92(s, 3H, CH 3 ), 2.13 - 2.20(m, 2H, CH 2 ), 2.50 - 2.66(m, 2H, CH 2 ), 5.01(s, 1H, CH), 6.83 - 7.54(m, 9H, ArH), 9.49(s, 1H, NH); IR(KBr): ν = 3418, 3234, 3156, 3053, 2952, 1607, 1525, 1466, 1423, 1363, 1342, 1253, 1191, 1168, 1124, 1084, 1069, 1050, 1012, 789, 760cm -1 .

[0077] Example 13

[0078] Preparation of 4-(4-chlorophenyl)-7,8-dihydro-3,7,7-trimethyl-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one

[0079]

[0080] 1 mmol of 4-chlorobenzaldehyde, 1 mmol of 1-phenyl-3-methyl-5-aminopyrazole, 1 mmol of 5,5-dimethyl-1,3-cyclohexanedione and 0.03 g of catalyst were respectively added to a 50 mL three-necked flask equipped with a magnetic stirrer, a thermometer and a spherical condenser and containing 7 mL of 96% ethanol aqueous solution, and magnetically stirred and mixed evenly at room temperature. Then, under the protection of nitrogen, the reaction solution was heated to reflux (not exceeding the second sphere of the spherical condenser) and the reflux reaction time was maintained for 39 min. Traced by TLC (thin layer chromatography), when the raw material spots disappeared, the stirring was immediately stopped, and it was naturally cooled to room temperature under the protection of nitrogen. A large amount of white solid was precipitated, the precipitated solid was crushed, allowed to stand and age for 2 h, filtered by suction to obtain the filter residue and the filtrate. The filter residue was washed with 96% ethanol aqueous solution (3 mL×5) and vacuum dried at 80 °C for 24 h to obtain 0.40 g of 4-(4-chlorophenyl)-7,8-dihydro-3,7,7-trimethyl-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one. 10 mg of the above product was ultrasonically dissolved in 5 mL of chromatographic methanol, then quantitatively transferred to a 20 mL volumetric flask, filtered through a 0.45 μm organic membrane, and finally detected by high performance liquid chromatography. The purity of 4-(4-chlorophenyl)-7,8-dihydro-3,7,7-trimethyl-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one was measured to be 99.6%, and its yield was calculated to be 95%.

[0081] After making up the filtrate to 7 mL with the washing solution for washing the filter residue, 4-chlorobenzaldehyde, 1-phenyl-3-methyl-5-aminopyrazole and 5,5-dimethyl-1,3-cyclohexanedione were directly added and reused.

[0082] The performance parameters of the 4-(4-chlorophenyl)-7,8-dihydro-3,7,7-trimethyl-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one obtained in this example are: white solid; m.p. 219 - 221 °C; 1 H NMR (400 MHz, DMSO-d 6 ): δ = 0.95 (s, 3H, CH 3 ), 1.06 (s, 3H, CH 3 ), 1.92 (s, 3H, CH 3 ), 2.04 - 2.17 (m, 2H, CH 2 ), 2.55 (s, 2H, CH 2), 5.06 (s, 1H, CH), 7.23~7.55 (m, 9H, ArH), 9.47 (s, 1H, NH); IR (KBr): ν = 3415, 3223, 3151, 2952, 1610, 1525, 1482, 1461, 1388, 1364, 1270, 1167, 1149, 1118, 1065, 1008, 832, 789, 762, 690, 671, 585 cm -1 .

[0083] Under the reaction conditions of Example 13, the influence of the number of uses of the catalytic system composed of the catalyst and the reaction solvent on the yield and purity of 4-(4-chlorophenyl)-7,8-dihydro-3,7,7-trimethyl-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H, 6H, 9H)-one was investigated. The experimental results are shown in Figure 1 .

[0084] Example 14

[0085] Preparation of 4-(2,4-dichlorophenyl)-7,8-dihydro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H, 6H, 9H)-one

[0086]

[0087] 1 mmol of 2,4-dichlorobenzaldehyde, 1 mmol of 1-phenyl-3-methyl-5-aminopyrazole, 1 mmol of 1,3-cyclohexanedione and 0.05 g of catalyst were respectively added into a 50 mL three-necked flask equipped with a magnetic stirrer, a thermometer and a spherical condenser and containing 9 mL of 97% ethanol aqueous solution. The mixture was magnetically stirred and mixed evenly at room temperature. Then, under the protection of argon, the reaction solution was heated to reflux (not exceeding the second sphere of the spherical condenser) and the reflux reaction time was maintained for 69 min. TLC (thin layer chromatography) was used for tracking. When the raw material spots disappeared, the stirring was immediately stopped. The reaction solution was continuously cooled to room temperature naturally under the protection of argon, and a large amount of white solid was precipitated. The precipitated solid was crushed, allowed to stand for aging for 2 h, filtered by suction to obtain the filter residue and the filtrate. The filter residue was washed with 97% ethanol aqueous solution (4 mL×5) and dried in vacuo at 80 °C for 24 h to obtain 0.36 g of 4-(2,4-dichlorophenyl)-7,8-dihydro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one. 10 mg of the above product was ultrasonically dissolved in 5 mL of chromatographic methanol, then quantitatively transferred to a 20 mL volumetric flask, filtered through a 0.45 μm organic membrane, and finally detected by high performance liquid chromatography. The purity of 4-(2,4-dichlorophenyl)-7,8-dihydro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one was measured to be 99.5%, and its yield was calculated to be 84%.

[0088] After making up the filtrate to 9 mL with the washing solution for washing the filter residue, 2,4-dichlorobenzaldehyde, 1-phenyl-3-methyl-5-aminopyrazole and 1,3-cyclohexanedione were directly added and then reused.

[0089] The performance parameters of 4-(2,4-dichlorophenyl)-7,8-dihydro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one obtained in this example are as follows: white solid; m.p. 278 - 280 °C; 1 H NMR (400 MHz, DMSO-d 6 ): δ = 1.92 (s, 3H, CH 3 ), 1.94 - 1.99 (m, 2H, CH 2 ), 2.17 - 2.25 (m, 2H, CH 2 ), 2.59 - 2.74 (m, 2H, CH 2),5.44 (s, 1H, CH), 7.23~7.57 (m, 8H, ArH), 9.62 (s, 1H, NH); IR(KBr): ν=3405, 3248, 3151, 2949, 1609, 1524, 1460, 1425, 1388, 1360, 1335, 1253, 1192, 1167, 1117, 1091, 1068, 1035, 1013, 756 cm -1 。

[0090] Under the reaction conditions of Example 14, the effects of the number of times of using the catalyst on the yield and purity of 4-(2,4-dichlorophenyl)-7,8-dihydro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H, 6H, 9H)-one were investigated. The experimental results are shown in Figure 2 。

[0091] Example 15

[0092] Preparation of 7,8-dihydro-3-methyl-4(3-nitrophenyl)-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H, 6H, 9H)-one

[0093]

[0094] 1 mmol of m-nitrobenzaldehyde, 1 mmol of 1-phenyl-3-methyl-5-aminopyrazole, 1 mmol of 1,3-cyclohexanedione and 0.04 g of the catalyst were respectively added to a 50 mL three-necked flask equipped with a magnetic stirrer, a thermometer and a spherical condenser and containing 8 mL of 96% aqueous ethanol solution, and magnetically stirred and mixed evenly at room temperature. Then, under the protection of argon, the reaction solution was heated to reflux (not exceeding the second sphere of the spherical condenser) and the reflux reaction time was maintained for 61 min. TLC (thin layer chromatography) was used for tracking. When the raw material spot disappeared, the stirring was immediately stopped, and it was naturally cooled to room temperature under the protection of argon. A large amount of yellow solid was precipitated. The precipitated solid was crushed and allowed to stand for 2 h. The filtrate and the filter residue were obtained by suction filtration. The filter residue was washed with 96% aqueous ethanol solution (4 mL×3) and vacuum dried at 80 °C for 24 h to obtain 0.34 g of 7,8-dihydro-3-methyl-4(3-nitrophenyl)-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H, 6H, 9H)-one. 10 mg of the above product was ultrasonically dissolved in 5 mL of chromatographic methanol, then quantified with a 20 mL volumetric flask, filtered through a 0.45 μm organic membrane, and finally detected by high performance liquid chromatography. The purity of 7,8-dihydro-3-methyl-4(3-nitrophenyl)-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H, 6H, 9H)-one was measured to be 99.2%, and its yield was calculated to be 85% through calculation.

[0095] After making up the filtrate to 8 mL with the washing liquid after washing the filter residue, m-nitrobenzaldehyde, 1-phenyl-3-methyl-5-aminopyrazole and 1,3-cyclohexanedione were directly added and then it was reused.

[0096] The performance parameters of 7,8-dihydro-3-methyl-4-(3-nitrophenyl)-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one obtained in this example are: yellow solid; m.p. 218-220 °C; 1 H NMR(400 MHz, DMSO-d 6 ): δ = 1.74-1.90 (m, 2H, CH 2 ), 1.85 (s, 3H, CH 3 ), 2.14-2.19 (m, 2H, CH 2 ), 2.56-2.71 (m, 2H, CH 2 ), 5.01 (s, 1H, CH), 7.13-7.52 (m, 9H, ArH), 9.50 (s, 1H, NH); IR(KBr): ν = 3417, 3221, 3150, 2956, 2828, 1725, 1604, 1527, 1389, 1352, 1316, 1232, 1174, 1118, 1042, 1033, 1017, 951, 770, 698 cm -1 .

[0097] Example 16

[0098] Preparation of 7,8-dihydro-3,7,7-trimethyl-4-(3-nitrophenyl)-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one

[0099]

[0100] 1 mmol of m-nitrobenzaldehyde, 1 mmol of 1-phenyl-3-methyl-5-aminopyrazole, 1 mmol of 5,5-dimethyl-1,3-cyclohexanedione and 0.04 g of catalyst were respectively added into a 50 mL three-necked flask equipped with a magnetic stirrer, a thermometer and a spherical condenser and containing 8 mL of 96% ethanol aqueous solution, and magnetically stirred and mixed evenly at room temperature. Then, under the protection of argon, the reaction solution was heated to reflux (not exceeding the second sphere of the spherical condenser) and the reflux reaction time was maintained for 51 min. Traced by TLC (thin layer chromatography), when the raw material spots disappeared, the stirring was immediately stopped, and it was continuously cooled to room temperature naturally under the protection of argon. A large amount of yellow solid was precipitated, the precipitated solid was crushed, allowed to stand and age for 2 h, and then filtered to obtain a filter residue and a filtrate. The filter residue was washed with 96% ethanol aqueous solution (4 mL×3) and vacuum dried at 80 °C for 24 h to obtain 0.38 g of 7,8-dihydro-3,7,7-trimethyl-4-(3-nitrophenyl)-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one. 10 mg of the above product was ultrasonically dissolved in 5 mL of chromatographic methanol, then quantitatively transferred to a 20 mL volumetric flask, filtered through a 0.45 μm organic membrane, and finally detected by high performance liquid chromatography. The purity of 7,8-dihydro-3,7,7-trimethyl-4-(3-nitrophenyl)-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one was measured to be 99.2%, and its yield was calculated to be 87%.

[0101] After making up the filtrate to 8 mL with the washing solution for washing the filter residue, m-nitrobenzaldehyde, 1-phenyl-3-methyl-5-aminopyrazole and 5,5-dimethyl-1,3-cyclohexanedione were directly added and then reused.

[0102] The performance parameters of 7,8-dihydro-3,7,7-trimethyl-4-(3-nitrophenyl)-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(4H,6H,9H)-one obtained in this example are: yellow solid; m.p. 222~224 °C; 1 H NMR(400MHz, DMSO-d 6 ): δ=0.91(s, 3H, CH 3 ), 0.98(s, 3H, CH 3 ), 1.86(s, 3H, CH 3 ), 1.90~2.18(m, 2H, CH 2 ), 2.52(s, 2H, CH 2), 5.16 (s, 1H, CH), 7.37 - 8.03 (m, 9H, ArH), 9.55 (s, 1H, NH); IR (KBr): ν = 3422, 3236, 3165, 2960, 1617, 1528, 1472, 1377, 1351, 1240, 1183, 1157, 1122, 1070, 766, 734, 720, 692, 654, 607 cm -1 .

[0103] The present invention uses a polymer containing multiple amino groups as a catalyst and an ethanol aqueous solution as a reaction solvent to prepare pyrazoloquinolinone derivatives. The catalytic activity and selectivity of this catalyst are relatively high, thus overcoming the disadvantages existing in the existing preparation process of pyrazoloquinolinone derivatives, such as low product yield and purity, complex purification operation process, and low raw material utilization rate. At the same time, this method also has the characteristics that the catalyst can be reused, and basically no waste liquid is generated during the whole preparation process, and it is economical and efficient, thus facilitating large-scale industrial production.

[0104] In addition to the selection of the catalyst type, the amount of the catalyst used, the control of specific reaction process parameters, and the type and concentration of the reaction solvent are also key factors to effectively ensure the above effects of the present invention. Among them, the amount of the catalyst used and the control of the reaction temperature mainly have a greater impact on the catalytic activity of the catalyst and the yield and purity of the obtained product. When the amount of the catalyst used is small, the yield of the obtained product is relatively low. As the amount of the catalyst used increases, the yield of the product increases accordingly. However, when the amount of the catalyst used is too large, it will instead inhibit the normal progress of the reaction, resulting in a decrease in the product yield and increasing the preparation cost to a certain extent. When the reaction temperature is low, the activity of the catalyst is low, but when the temperature is too high, it will instead inhibit the normal progress of the reaction, resulting in a decrease in the product yield, and at the same time, it will also promote the occurrence of side reactions, increasing the amount of by-products and significantly decreasing the purity of the product. The selection of the solvent type and its concentration in the present invention is also crucial. In addition to affecting the catalytic activity of the catalyst, it will also affect the recycling performance of the catalyst.

[0105] Therefore, how to coordinate the relationship among the yield and purity of the obtained product, the activity of the catalyst, and the recycling performance is the key and difficulty of the present invention. Through a large number of experiments, on the basis of using the catalyst of the present invention, the inventors also optimize and control the dosage of the catalyst, the reaction temperature, and the type and concentration of the reaction solvent through a large number of experiments, so as to effectively ensure the yield and purity of the obtained product, reduce the occurrence of side reactions and the recycling loss of the catalyst, and significantly improve the recycling performance of the catalyst. In addition, by selecting an aqueous ethanol solution with a specific concentration as the reaction solvent, in addition to being beneficial to improving the recycling performance of the catalyst and the utilization rate of raw materials, this reaction solvent can also serve as a recrystallization solvent, combining the reaction process and the recrystallization process into one, which is simple and efficient and simplifies the purification operation of the product.

[0106] In the examples, the nuclear magnetic resonance characterization of the reaction product was performed using a nuclear magnetic resonance spectrometer of model AVANCE 400MHz from Bruker, Germany; the infrared spectrum was measured using an infrared spectrometer of model Nicolet 6700 from Thermo Fisher Scientific, USA (KBr pellet); the purity was determined by high performance liquid chromatography using a rapid high performance liquid chromatography instrument of model UFLC 2010PLUS from Shimadzu, Japan; the melting point of the reaction product was measured using a capillary melting point apparatus from Shanghai Jiahang Instrumentation Co., Ltd. All reagents or instruments not specified by the manufacturer can be obtained as conventional products through commercial purchase.

[0107] The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific embodiments described. Obviously, many modifications and variations can be made according to the content of this specification. These embodiments are selected and specifically described in this specification to better explain the principle and practical application of the present invention, so that those skilled in the art can understand and utilize the present invention well. The present invention is only limited by the claims and their full scope and equivalents.

Claims

1. A preparation method of a pyrazoloquinolinone derivative as a pharmaceutical intermediate, characterized in that, this method uses aromatic aldehyde (I), 1-phenyl-3-methyl-5-aminopyrazole (II) and 1,3-cyclohexanedione compound (III) as reaction raw materials, uses an ethanol aqueous solution as a reaction solvent, and carries out the reaction for preparing the pyrazoloquinolinone derivative (IV) under the catalytic action of a catalyst. The chemical reaction formula is: The aromatic aldehyde in (I) is selected from: any one of; the 1,3-cyclohexanedione compound in (III) is 1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione; this preparation method comprises the following steps: Step 1: Add the aromatic aldehyde (I), 1-phenyl-3-methyl-5-aminopyrazole (II), 1,3-cyclohexanedione compound (III) and the catalyst into the ethanol aqueous solution respectively and mix evenly. Heat the reaction solution to reflux under the protection of nitrogen or argon and keep the reflux reaction time for 36 - 69 min; Step 2: After the reflux reaction in Step 1 ends, still under the protection of nitrogen or argon, cool the reaction solution to room temperature, crush the precipitated solid in the air, stand still, filter by suction, and the filter residue is washed and dried in vacuo to obtain the pyrazoloquinolinone derivative (IV); in Step 1, the volume ratio concentration of ethanol in the reaction solvent ethanol aqueous solution is 94 - 97%; in Step 1, the volume amount of the reaction solvent ethanol aqueous solution in milliliters is 6 - 9 times the molar amount of the aromatic aldehyde in millimoles; after Step 2 ends, use an ethanol aqueous solution with a volume ratio concentration of 94 - 97% as the filter residue washing solution to wash the filter residue obtained after suction filtration of the reaction 3 - 5 times; after making up the filtrate obtained by suction filtration with the filter residue washing solution without any treatment, directly add the reaction raw materials and carry out the next reaction; in Step 1, the molar ratio of the aromatic aldehyde, 1,3-cyclohexanedione compound, and 1-phenyl-3-methyl-5-aminopyrazole is 1:1:1, and the mass of the catalyst in grams is 3 - 5% of the molar amount of the aromatic aldehyde used in millimoles; the chemical structural formula of the catalyst is:

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