Preparation method of pharmaceutical intermediate 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative

Abstract

The invention relates to the field of preparation of pharmaceutical intermediates, and specifically discloses a preparation method of a pharmaceutical intermediate 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-nitrile derivative, wherein the preparation method uses aromatic aldehyde, 6-aminoindazole and 3-(1H-indol-3-yl)-3-oxypropionitrile as reaction raw materials, uses magnetic Fe3O4-loaded polyamino nanomaterials as catalysts, and uses ethanol as a reaction solvent, and performs preparation under reflux conditions. The invention uses aromatic aldehyde, 6-aminoindazole and 3-(1H-indol-3-yl)-3-oxypropionitrile as reaction raw materials, selects magnetic Fe3O4-loaded polyamino nanomaterials as heterogeneous catalysts, and uses ethanol as a reaction solvent to form a catalytic system, wherein the system has high catalytic activity when preparing 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-nitrile derivatives, and can greatly reduce the time required for the reaction.

Description

Technical Field

[0001] The invention relates to a method for preparing a derivative, in particular to a method for preparing a pharmaceutical intermediate 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative, and belongs to the field of pharmaceutical intermediate preparation. Background Art

[0002] In recent years, quinoline derivatives have received considerable attention due to their unique antimalarial activity, such as chloroquine and promaloquine, which are clinical drugs for the treatment of malaria. In addition, pyrazole derivatives also adapt to the requirements of future drug development because they have good biological activity and pharmacological activity, and become a direction for the development of chemical drugs. And adopting the active splicing principle, the pyrazole ring structure is introduced into the quinoline derivatives to form pyrazoloquinoline derivatives with pyrazole ring and quinoline structure simultaneously, which has a wider application, such as pyrazole [4,3-c] quinoline compounds have anti-infection and analgesic effects, and are effective drugs for the treatment of herpes and anticancer. Therefore, as a very important pharmaceutical intermediate, the preparation of pyrazoloquinoline derivatives has attracted extensive attention from drug researchers.

[0003] 6,9-Dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivatives are widely used pyrazoloquinoline derivatives and can be prepared by a one-pot method using aromatic aldehydes, 6-aminoindazole and 3-(1H-indol-3-yl)-3-oxypropionitrile. For example, Wen-Ting Zhang et al. used triethylamine as a homogeneous catalyst, acetonitrile as a reaction solvent, and aromatic aldehydes, 6-aminoindazole and 3-(1H-indol-3-yl)-3-oxopropionitrile reacted at 80°C to prepare 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivatives (A convenient and efficient process for the synthesis of 9-aryl-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile and 1-aryl-1,4-dihydrobenzo[f]quinoline-2-carbonitrile derivatives[J], Journal of Heterocyclic Chemistry, 2022, 59: 543-554). Although this method has the advantages of mild reaction conditions, easy operation and high product yield, it also has the problem of environmental pollution caused by the inability to recycle the catalyst. Based on this, Hong-Lei Li et al. used ethanol as the reaction solvent and prepared a series of 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivatives by reacting aromatic aldehydes, 6-aminoindazole and 3-(1H-indol-3-yl)-3-oxopropionitrile under catalyst-free and reflux conditions (An efficient cascade synthesis of substituted 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile[J], Heterocycl Communications, 2018, 24(5): 279-283).

[0004] However, the above preparation method will produce many shortcomings in the process of industrial large-scale production, such as: 1) long reaction time, high energy consumption, and relatively low economic benefits; 2) due to improper catalyst selection or no catalyst, the reaction selectivity is not high, there are many by-products, and the reaction solvent cannot be recycled; 3) since the reaction solvent cannot be recycled, the utilization rate of the more expensive reaction raw materials is relatively low; 4) the yield of the product is low.

[0005] In view of this, it is necessary to provide a method for preparing a pharmaceutical intermediate 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative which is economical, efficient and suitable for industrial large-scale production. Summary of the invention

[0006] In view of the problems in the prior art, the present invention provides a method for preparing a pharmaceutical intermediate 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative.

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

[0008] A preparation method of a pharmaceutical intermediate 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative (IV), wherein the preparation method uses aromatic aldehyde (I), 6-aminoindazole (II) and 3-(1H-indol-3-yl)-3-oxypropionitrile (III) as reaction raw materials, uses magnetic Fe3O4-loaded polyamino nanomaterials as catalyst, and uses ethanol as reaction solvent, and the preparation is carried out under reflux conditions;

[0009] The chemical reaction formula involved in the preparation method of the pharmaceutical intermediate 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative (IV) is:

[0010]

[0011] The chemical structure of the magnetic Fe3O4-loaded multi-amino nanomaterial catalyst is:

[0012]

[0013] in: It is cyclodextrin;

[0014] The aromatic aldehyde in (I) is any one of benzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-tolualdehyde, p-methoxybenzaldehyde, p-nitrobenzaldehyde, p-cyanobenzaldehyde, m-chlorobenzaldehyde, m-bromobenzaldehyde, m-tolualdehyde, m-methoxybenzaldehyde, m-nitrobenzaldehyde, 3,4-dichlorobenzaldehyde and 3,4-dimethylbenzaldehyde.

[0015] Optionally, the preparation method comprises the following steps:

[0016] Step 1: First, add ethanol to a three-necked flask equipped with a magnetic stir bar, a thermometer and a spherical condenser, then add aromatic aldehyde, 6-aminoindazole and 3-(1H-indol-3-yl)-3-oxypropionitrile, mix well at room temperature, and then add a magnetic Fe3O4-supported multi-amino nanomaterial catalyst under continuous magnetic stirring to form a suspended reaction solution;

[0017] Step 2: The suspended reaction liquid formed in step 1 is uniformly heated in an oil bath to reflux, with the solvent vapor not exceeding the second ball of the spherical condenser, and then the reaction is maintained at this temperature until the raw material point disappears. When the reaction is completed, stirring and heating are immediately stopped, and the catalyst is adsorbed by a magnet while it is hot;

[0018] Step 3: The reaction solution from which the catalyst is adsorbed in step 2 is naturally cooled to room temperature, a solid is precipitated, and the solid is crushed, allowed to stand, and filtered to obtain a filtrate and a filter residue, and the filter residue is washed with ethanol and then vacuum dried at 80° C. for 12 h to obtain a 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative;

[0019] Step 4: The catalyst adsorbed in step 2 is placed into the filtrate formed in step 3 without any treatment and the volume is made up with washing liquid, and then the reaction raw materials aromatic aldehyde, 6-aminoindazole and 3-(1H-indol-3-yl)-3-oxypropionitrile prepared in the same step are directly added, and the next round of cyclic reaction is carried out according to steps 2 and 3.

[0020] Optionally, in step 1, the molar ratio of the aromatic aldehyde, 6-aminoindazole and 3-(1H-indol-3-yl)-3-oxypropionitrile is (1.0-1.2):1:1.

[0021] Optionally, the volume of ethanol in milliliters in step 1 is 8 to 12 times the amount of 6-aminoindazole substance in millimoles.

[0022] Optionally, in step 1, the mass of the magnetic Fe3O4-supported polyamino nanomaterial catalyst in grams is 7 to 13% of the mass of the 6-aminoindazole in millimoles used.

[0023] Optionally, the reaction time of maintaining reflux in step 2 is 1.2 to 1.8 hours.

[0024] Beneficial effects of the present invention:

[0025] 1. The present invention uses aromatic aldehydes, 6-aminoindazole and 3-(1H-indol-3-yl)-3-oxypropionitrile as reaction raw materials, selects magnetic Fe3O4-loaded polyamino nanomaterials as heterogeneous catalysts, and uses ethanol as a reaction solvent to form a catalytic system. The system has high catalytic activity when preparing 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivatives, and can greatly reduce the time required for the reaction.

[0026] 2. The present invention has a high shape selectivity due to the catalytic system composed of the magnetic Fe3O4-loaded multi-amino nanomaterial catalyst and ethanol, which can effectively inhibit the generation of by-products, thereby ensuring that the obtained 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative has a high yield and purity. In addition, the ethanol reaction solvent can be recycled without any treatment after use.

[0027] 3. The present invention uses magnetic Fe3O4 loaded with polyamino nanomaterials as heterogeneous catalysts, which can keep their own structure unchanged and lose less in the reaction, so the catalyst can be recycled for many times without any treatment. In addition, after being recycled for many times, it can be regenerated by reflux washing in an organic solvent, and the regenerated catalyst still has high catalytic activity and shape selectivity.

[0028] 4. The present invention uses ethanol as the reaction solvent and recrystallization solvent. After being recycled for many times, it can be regenerated by rotary evaporation, and the lost part can be supplemented by washing liquid. DETAILED DESCRIPTION

[0029] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0030] A preparation method of a pharmaceutical intermediate 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative, wherein the preparation method uses aromatic aldehyde (I), 6-aminoindazole (II) and 3-(1H-indol-3-yl)-3-oxypropionitrile (III) as reaction raw materials, uses a magnetic Fe3O4-loaded polyamino nanomaterial as a catalyst, uses ethanol as a reaction solvent, and performs the preparation under reflux conditions;

[0031] The chemical reaction formula involved in the preparation method of the pharmaceutical intermediate 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative (IV) is:

[0032]

[0033] The chemical structure of the magnetic Fe3O4-loaded multi-amino nanomaterial catalyst is:

[0034]

[0035] in: It is cyclodextrin;

[0036] The aromatic aldehyde in (I) is any one of benzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-tolualdehyde, p-methoxybenzaldehyde, p-nitrobenzaldehyde, p-cyanobenzaldehyde, m-chlorobenzaldehyde, m-bromobenzaldehyde, m-tolualdehyde, m-methoxybenzaldehyde, m-nitrobenzaldehyde, 3,4-dichlorobenzaldehyde and 3,4-dimethylbenzaldehyde.

[0037] For the preparation of magnetic Fe3O4-loaded polyamino nanomaterial catalysts, please refer to relevant literature (Design, preparation, and characterization of Fe3O4 nanoparticles encapsulating β-cyclodextrin-bearing guanidine as a highly efficient and reusable heterogeneous base catalyst for synthesis of 3, 4-dihydropyrano[3, 2-c]chromenes[J], Applied Organometallic Chemistry, 2020, 34: e5862).

[0038] As a technical optimization solution of the present invention, the preparation method comprises the following steps:

[0039] Step 1: First, add ethanol to a three-necked flask equipped with a magnetic stir bar, a thermometer and a spherical condenser, then add aromatic aldehyde, 6-aminoindazole and 3-(1H-indol-3-yl)-3-oxypropionitrile, mix well at room temperature, and then add a magnetic Fe3O4-supported multi-amino nanomaterial catalyst under continuous magnetic stirring to form a suspended reaction solution;

[0040] Step 2: The suspended reaction liquid formed in step 1 is uniformly heated in an oil bath to reflux, with the solvent vapor not exceeding the second ball of the spherical condenser, and then the reaction is maintained at this temperature until the raw material point disappears. When the reaction is completed, stirring and heating are immediately stopped, and the catalyst is adsorbed by a magnet while it is hot;

[0041] Step 3: The reaction solution from which the catalyst is adsorbed in step 2 is naturally cooled to room temperature, a solid is precipitated, and the solid is crushed, allowed to stand, and filtered to obtain a filtrate and a filter residue, and the filter residue is washed with ethanol and then vacuum dried at 80° C. for 12 h to obtain a 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative;

[0042] Step 4: The catalyst adsorbed in step 2 is placed into the filtrate formed in step 3 without any treatment and the volume is made up with washing liquid, and then the reaction raw materials aromatic aldehyde, 6-aminoindazole and 3-(1H-indol-3-yl)-3-oxypropionitrile prepared in the same step are directly added, and the next round of cyclic reaction is carried out according to steps 2 and 3.

[0043] As a technical optimization scheme of the present invention, the molar ratio of the aromatic aldehyde, 6-aminoindazole and 3-(1H-indol-3-yl)-3-oxypropionitrile in step 1 is (1.0-1.2):1:1.

[0044] As a technical optimization scheme of the present invention, the volume of ethanol in milliliters in step 1 is 8 to 12 times the amount of 6-aminoindazole substance in millimoles.

[0045] As a technical optimization scheme of the present invention, in step 1, the mass of the magnetic Fe3O4-supported polyamino nanomaterial catalyst in grams is 7-13% of the mass of the 6-aminoindazole in millimoles.

[0046] As a technical optimization solution of the present invention, the reaction time of maintaining reflux in step 2 is 1.2 to 1.8 hours.

[0047] The present invention is further described below in conjunction with specific embodiments.

[0048] Example 1

[0049] Preparation of 7-(1H-indol-3-yl)-9-phenyl-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile

[0050]

[0051] Add 1.0mmol benzaldehyde, 1.0mmol 6-aminoindazole and 1.0mmol 3-(1H-indol-3-yl)-3-oxypropionitrile to a 50mL three-necked flask with a magnetic stirrer, a thermometer and a spherical condenser containing 8mL ethanol, stir and mix evenly under magnetic stirring at room temperature, then add 0.08g of magnetic Fe3O4-supported multi-amino nanomaterial catalyst under stirring to form a suspended reaction liquid. Heat evenly in an oil bath to reflux (the vapor of the reaction liquid does not exceed the second ball of the spherical condenser), keep this temperature and reflux for 79min, and detect by TLC (thin plate chromatography, developing solvent: ethyl acetate: methanol = 5:1). When the raw material point disappears, stop stirring immediately and adsorb the catalyst with a magnet while it is hot. The reaction solution from which the catalyst was adsorbed was naturally cooled to room temperature, and a large amount of white solid was precipitated. The solid was crushed and allowed to stand for 2 hours, and then filtered to obtain a filter residue and a filtrate. The filter residue was washed with ethanol (5 mL × 3) and then vacuum dried at 80° C. for 12 hours to obtain 0.36 g of 7-(1H-indol-3-yl)-9-phenyl-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile. 10 mg of the above product was taken into a beaker, ultrasonically dissolved with 5 mL of chromatographic methanol, then quantitatively used with a 20 mL volumetric flask, and filtered with a 0.45 um organic membrane, and finally detected by high performance liquid chromatography. The purity of 7-(1H-indol-3-yl)-9-phenyl-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile was measured to be 99.6%, and the yield was calculated to be 92%.

[0052] The characterization data of the product 7-(1H-indol-3-yl)-9-phenyl-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile obtained in this example are as follows:

[0053] White solid; mp 273~275℃; 1H NMR (400MHz, DMSO-d6): δ (ppm) = 5.27 (s, 1H), 7.02 (d, J = 8.2Hz, 1H), 7.11 (t, J = 7.4Hz, 1H), 7.18 (t, J = 7. 4Hz, 2H), 7.26 (t, J=7.6Hz, 2H), 7.49 (dd, J=17.2, 8.2Hz, 4H), 7.56 (d, J=8.2Hz, 1H), 7.79 (d, J=1.2Hz, 1H ), 7.95 (s, 1H), 9.83 (s, 1H), 11.73 (s, 1H), 12.84 (s, 1H); IR (KBr): ν = 3418, 2920, 2217, 1630, 1598, 1503 , 1481, 1472, 1415, 1334, 1297, 1250, 1227, 1152, 1076, 1019, 934, 886, 862, 824, 744, 702, 667, 649, 574cm -1 .

[0054] Example 2

[0055] Reusability of the catalytic system

[0056] After the filtrate was supplemented to 8 mL with ethanol used to wash the filter residue, the adsorbed catalyst was put back into it, and then 1.0 mmol of benzaldehyde, 1.0 mmol of 6-aminoindazole and 1.0 mmol of 3-(1H-indol-3-yl)-3-oxypropionitrile were added. The next cycle reaction was carried out according to the reaction conditions and operating steps of Example 1. A total of 7 times were used. The purity and yield changes of the product 7-(1H-indol-3-yl)-9-phenyl-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile are shown in Table 1.

[0057] Table 1 Effect of the number of times the catalytic system is used on the purity and yield of the product 7-(1H-indol-3-yl)-9-phenyl-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile

[0058] Number of times the catalytic system is used purity / % Yield / % 1 99.6 92 2 99.4 92 3 99.3 91 4 98.2 90 5 99.0 90 6 98.8 90 7 98.4 88

[0059] It can be seen from the data in Table 1 that the catalytic system consisting of the magnetic Fe3O4-loaded multi-amino nanomaterial catalyst and the ethanol reaction solvent can still maintain a high purity and yield of the product after being used 7 times.

[0060] Example 3

[0061] Regeneration of the catalyst system

[0062] The catalyst adsorbed by the magnet after recycling 7 times in Example 2 is placed in the catalytic system formed by the filtrate for vacuum distillation, and the fraction is collected. Then 5 mL of petroleum ether (boiling range is 60-90° C.) is added to the residue after distillation, refluxed for 30 minutes, and then filtered with suction, and then 5 mL of petroleum ether (boiling range is 60-90° C.) is added to the filter residue, refluxed for 30 minutes, and filtered with suction, and a total of 3 times, and finally the obtained filter residue is vacuum dried at 85° C. for 12 hours to obtain the regenerated catalyst. The washing liquid of the washing product is used to supplement the fraction to 8 mL, and the regenerated catalyst is added to form a new catalytic system.

[0063] Example 4

[0064] Reusability of the regenerated catalyst system

[0065] Directly add 1.0mmol benzaldehyde, 1.0mmol 6-aminoindazole and 1.0mmol 3-(1H-indol-3-yl)-3-oxypropionitrile to the new catalyst system composed of Example 3, react according to the reaction conditions and operation steps of Example 1, and then recycle the catalyst system according to the step of Example 2. Use it 6 times. The purity and yield of its product 7-(1H-indol-3-yl)-9-phenyl-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile change are shown in Table 2.

[0066] Table 2 Effect of the number of times the regenerated catalyst system is used on the purity and yield of the product 7-(1H-indol-3-yl)-9-phenyl-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile

[0067] Number of times the catalyst system was used purity / % Yield / % 1 99.5 92 2 99.4 90 3 99.3 91 4 99.1 90 5 99.0 90 6 98.8 88

[0068] It can be seen from the data in Table 2 that the regenerated catalytic system can still be reused and maintain a high purity and yield of the product 7-(1H-indol-3-yl)-9-phenyl-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile.

[0069] Example 5

[0070] Preparation of 9-(4-chlorophenyl)-7-(1H-indol-2-yl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile

[0071]

[0072] Add 1.0mmol p-chlorobenzaldehyde, 1.0mmol 6-aminoindazole and 1.0mmol 3-(1H-indol-3-yl)-3-oxypropionitrile to a 50mL three-necked flask with a magnetic stirrer, a thermometer and a spherical condenser containing 9mL ethanol, stir and mix evenly under magnetic stirring at room temperature, then add 0.09g of magnetic Fe3O4-supported multi-amino nanomaterial catalyst under stirring to form a suspended reaction liquid. Heat evenly in an oil bath to reflux (the vapor of the reaction liquid does not exceed the second ball of the spherical condenser), keep this temperature and reflux for 83min, and detect by TLC (thin plate chromatography, developing solvent: ethyl acetate: methanol = 5:1). When the raw material point disappears, stop stirring immediately and adsorb the catalyst with a magnet while it is hot. The reaction solution from which the catalyst was adsorbed was naturally cooled to room temperature, and a large amount of white solid was precipitated. The solid was crushed and allowed to stand for 2 hours, and then filtered to obtain a filter residue and a filtrate. The filter residue was washed with ethanol (5 mL × 3) and then vacuum dried at 80°C for 12 hours to obtain 0.38 g of 9-(4-chlorophenyl)-7-(1H-indol-2-yl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile. 10 mg of the above product was taken into a beaker, ultrasonically dissolved with 5 mL of chromatographic methanol, then quantitatively used in a 20 mL volumetric flask, and filtered with a 0.45 um organic membrane, and finally detected by high performance liquid chromatography. The purity of 9-(4-chlorophenyl)-7-(1H-indol-2-yl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile was measured to be 99.1%, and the yield was calculated to be 90%.

[0073] The characterization data of the product 9-(4-chlorophenyl)-7-(1H-indol-2-yl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile obtained in this example are as follows:

[0074] White solid; mp>300℃; 1 H NMR (400MHz, DMSO-d6): δ (ppm) = 5.29 (s, 1H), 7.04 (d, J = 8.2Hz, 1H), 7.13 (t, J = 7.4Hz, 1H), 7.1 9 (t, J=7.4Hz, 1H), 7.38 (d, J=8.2Hz, 2H), 7.45 (s, 1H), 7.47~7.51 (m, 3H), 7.56 (d, J=8.6Hz, 1H) , 7.80 (d, J=2.2Hz, 1H), 7.96 (s, 1H), 9.84 (s, 1H), 11.71 (s, 1H), 12.85 (s, 1H); IR (KBr): ν=3407 , 3278, 2190, 1673, 1641, 1613, 1527, 1493, 1461, 1452, 1344, 1239, 1086, 1068, 1019, 936, 749cm-1 .

[0075] Example 6

[0076] Preparation of 7-(1H-indol-3-yl)-9-(4-methoxyphenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile

[0077]

[0078] Add 1.1mmol p-methoxybenzaldehyde, 1.0mmol 6-aminoindazole and 1.0mmol 3-(1H-indol-3-yl)-3-oxypropionitrile to a 50mL three-necked flask with a magnetic stirrer, a thermometer and a spherical condenser containing 12mL ethanol, stir and mix evenly under magnetic stirring at room temperature, then add 0.13g of magnetic Fe3O4-supported multi-amino nanomaterial catalyst under stirring to form a suspended reaction liquid. Heat evenly in an oil bath to reflux (the reaction liquid vapor does not exceed the second ball of the spherical condenser), keep this temperature and reflux for 97min, and detect by TLC (thin plate chromatography, developing solvent: ethyl acetate: methanol = 5:1). When the raw material point disappears, stop stirring immediately and adsorb the catalyst with a magnet while it is hot. The reaction solution from which the catalyst was adsorbed was naturally cooled to room temperature, and a large amount of white solid was precipitated. The solid was crushed and allowed to stand for 2 hours, and then filtered to obtain a filter residue and a filtrate. The filter residue was washed with ethanol (5 mL×5) and then vacuum dried at 80°C for 12 hours to obtain 0.36 g of 7-(1H-indol-3-yl)-9-(4-methoxyphenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile. 10 mg of the above product was put into a beaker, ultrasonically dissolved with 5 mL of chromatographic methanol, then quantitatively used with a 20 mL volumetric flask, and filtered with a 0.45 um organic membrane, and finally detected by high performance liquid chromatography. The purity of 7-(1H-indol-3-yl)-9-(4-methoxyphenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile was measured to be 99.4%, and the yield was calculated to be 86%.

[0079] The characterization data of the product 7-(1H-indol-3-yl)-9-(4-methoxyphenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile obtained in this example are as follows:

[0080] White solid; mp 271~273℃; 1H NMR (400MHz, DMSO-d6): δ (ppm) = 3.67 (s, 3H), 5.16 (s, 1H), 6.83 (s, 1H), 6.85 (s, 1H), 6.98 (d, J = 8.2Hz, 1H) , 7.10 (t, J=7.4Hz, 1H), 7.16 (t, J=7.4Hz, 2H), 7.34 (d, J=8.2Hz, 2H), 7.44~7.52 (m, 4H), 7.76 (d, J=2.2Hz, 1H), 9.72 (s, 1H), 11.69 (s, 1H), 12.77 (s, 1H); IR (KBr): ν = 3449, 2934, 2198, 1638, 1611, 1601, 1564, 1512, 1497, 1462, 1427, 1391, 1343, 1309, 1279, 1240, 1179, 1136, 1114, 1072, 1033, 942, 835, 764, 748, 671, 653cm -1 .

[0081] Example 7

[0082] Preparation of 7-(1H-indol-3-yl)-9-(4-nitrophenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile

[0083]

[0084] Add 1.1mmol p-nitrobenzaldehyde, 1.0mmol 6-aminoindazole and 1.0mmol 3-(1H-indol-3-yl)-3-oxypropionitrile to a 50mL three-necked flask with a magnetic stirrer, a thermometer and a spherical condenser containing 10mL ethanol, stir and mix evenly under magnetic stirring at room temperature, then add 0.11g of magnetic Fe3O4-supported multi-amino nanomaterial catalyst under stirring to form a suspended reaction liquid. Heat evenly in an oil bath to reflux (the reaction liquid vapor does not exceed the second ball of the spherical condenser), keep this temperature and reflux for 82min, and detect by TLC (thin plate chromatography, developing solvent: ethyl acetate: methanol = 5:1). When the raw material point disappears, stop stirring immediately and adsorb the catalyst with a magnet while it is hot. The reaction solution from which the catalyst was adsorbed was naturally cooled to room temperature, and a large amount of yellow solid was precipitated. The solid was crushed and allowed to stand for 2 hours, and then filtered to obtain a filter residue and a filtrate. The filter residue was washed with ethanol (5 mL × 3) and then vacuum dried at 80°C for 12 hours to obtain 0.39 g of 7-(1H-indol-3-yl)-9-(4-nitrophenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile. 10 mg of the above product was taken into a beaker, ultrasonically dissolved with 5 mL of chromatographic methanol, then quantitatively used with a 20 mL volumetric flask, and filtered with a 0.45 um organic membrane, and finally detected by high performance liquid chromatography. The purity of 7-(1H-indol-3-yl)-9-(4-nitrophenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile was measured to be 99.2%, and its yield was 89% by calculation.

[0085] The characterization data of the product 7-(1H-indol-3-yl)-9-(4-nitrophenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile obtained in this example are as follows:

[0086] Yellow solid; mp>300℃; 1 H NMR (400MHz, DMSO-d6): δ (ppm) = 5.49 (s, 1H), 7.07 ~ 7.14 (m, 2H), 7.18 ~ 7.22 (m, 1H) , 7.48~7.53 (m, 2H), 7.61 (d, J=8.4Hz, 1H), 7.69 (d, J=8.6Hz, 2H), 7.84 (t, J=2.6Hz , 1H), 7.96 (s, 1H), 8.22 (d, J=8.6Hz, 2H), 9.96 (s, 1H), 11.75 (s, 1H), 12.91 (s, 1H) ; IR (KBr): ν=3406, 3223, 2194, 1634, 1600, 1536, 1489, 1445, 1337, 1229, 930, 746cm -1 .

[0087] Example 8

[0088] Preparation of 9-(3-bromophenyl)-7-(1H-indol-3-yl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile

[0089]

[0090] Add 1.2mmol m-bromobenzaldehyde, 1.0mmol 6-aminoindazole and 1.0mmol 3-(1H-indol-3-yl)-3-oxypropionitrile to a 50mL three-necked flask with a magnetic stirrer, a thermometer and a spherical condenser containing 9mL ethanol, stir and mix evenly under magnetic stirring at room temperature, then add 0.12g of magnetic Fe3O4-supported multi-amino nanomaterial catalyst under stirring to form a suspended reaction liquid. Heat evenly in an oil bath to reflux (the vapor of the reaction liquid does not exceed the second ball of the spherical condenser), keep this temperature and reflux for 103min, and detect by TLC (thin plate chromatography, developing solvent: ethyl acetate: methanol = 5:1). When the raw material point disappears, stop stirring immediately and adsorb the catalyst with a magnet while it is hot. The reaction solution from which the catalyst was adsorbed was naturally cooled to room temperature, and a large amount of white solid was precipitated. The solid was crushed and allowed to stand for 2 hours, and then filtered to obtain a filter residue and a filtrate. The filter residue was washed with ethanol (5 mL × 3) and then vacuum dried at 80°C for 12 hours to obtain 0.40 g of 9-(3-bromophenyl)-7-(1H-indol-3-yl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile. 10 mg of the above product was taken into a beaker, ultrasonically dissolved with 5 mL of chromatographic methanol, then quantitatively used with a 20 mL volumetric flask, and filtered with a 0.45 um organic membrane, and finally detected by high performance liquid chromatography. The purity of 9-(3-bromophenyl)-7-(1H-indol-3-yl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile was measured to be 99.3%, and the yield was calculated to be 86%.

[0091] The characterization data of the product 9-(3-bromophenyl)-7-(1H-indol-3-yl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile obtained in this example are as follows:

[0092] White solid; mp>300℃; 1H NMR (400MHz, DMSO-d6): δ (ppm) = 5.35 (s, 1H), 7.09 (d, J = 8.6Hz, 1H), 7.18 (d, J = 7.4Hz, 1H), 7.24 (t, J=7.4Hz, 1H), 7.35 (d, J=7.4Hz, 1H), 7.34~7.40 (m, 2H), 7.49~7.56 (m, 3H), 7.64 (d, J=8.6Hz, 1H), 7.89 (d, J=2.2Hz, 1H), 8.04 (s, 1H), 9.96 (s, 1H), 11.79 (s, 1H), 12.96 (s, 1H); IR (KBr): ν=34 01, 3240, 2203, 1632, 1604, 1538, 1519, 1487, 1469, 1452, 1418, 1334, 1229, 1060, 932, 746, 735cm -1 .

[0093] Example 9

[0094] Preparation of 7-(1H-indol-3-yl)-9-(3-methylphenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile

[0095]

[0096] Add 1.1mmol m-methylbenzaldehyde, 1.0mmol 6-aminoindazole and 1.0mmol 3-(1H-indol-3-yl)-3-oxypropionitrile to a 50mL three-necked flask with a magnetic stirrer, a thermometer and a spherical condenser containing 10mL ethanol, stir and mix evenly under magnetic stirring at room temperature, then add 0.09g of magnetic Fe3O4-supported multi-amino nanomaterial catalyst under stirring to form a suspended reaction liquid. Heat evenly in an oil bath to reflux (the reaction liquid vapor does not exceed the second ball of the spherical condenser), keep this temperature and reflux for 87min, and detect by TLC (thin plate chromatography, developing solvent: ethyl acetate: methanol = 5:1). When the raw material point disappears, stop stirring immediately and adsorb the catalyst with a magnet while it is hot. The reaction solution from which the catalyst was adsorbed was naturally cooled to room temperature, and a large amount of white solid was precipitated. The solid was crushed and allowed to stand for 2 hours, and then filtered to obtain a filter residue and a filtrate. The filter residue was washed with ethanol (5 mL×5) and then vacuum dried at 80°C for 12 hours to obtain 0.37 g of 7-(1H-indol-3-yl)-9-(3-methylphenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile. 10 mg of the above product was put into a beaker, ultrasonically dissolved with 5 mL of chromatographic methanol, then quantitatively used with a 20 mL volumetric flask, and filtered with a 0.45 um organic membrane, and finally detected by high performance liquid chromatography. The purity of 7-(1H-indol-3-yl)-9-(3-methylphenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile was measured to be 99.6%, and the yield was calculated to be 91%.

[0097] The characterization data of the product 7-(1H-indol-3-yl)-9-(3-methylphenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile obtained in this example are as follows:

[0098] White solid; mp252~254℃; 1 H NMR (400MHz, DMSO-d6): δ (ppm) = 2.24 (s, 3H), 5.19 (s, 1H), 6.98 (t, J = 6.8Hz, 2H), 7.10 (t , J=7.2Hz, 1H), 7.17 (t, J=7.2Hz, 2H), 7.23 (d, J=7.6Hz, 1H), 7.31 (s, 1H), 7.42~7.58 (m, 3 H), 7.80 (s, 1H), 7.92 (s, 1H), 9.78 (s, 1H), 11.70 (s, 1H), 12.81 (s, 1H); IR (KBr): ν = 3407 , 3259, 2194, 1658, 1637, 1609, 1563, 1494, 1461, 1345, 1236, 1139, 1118, 1068, 941, 747cm -1.

[0099] Example 10

[0100] Reusability of the catalytic system

[0101] After the filtrate was supplemented to 10 mL with ethanol used to wash the filter residue, the adsorbed catalyst was put back into it, and then 1.1 mmol of m-methylbenzaldehyde, 1.0 mmol of 6-aminoindazole and 1.0 mmol of 3-(1H-indol-3-yl)-3-oxypropionitrile were added. The next cycle reaction was carried out according to the reaction conditions and operating steps of Example 9. A total of 6 times were used. The purity and yield changes of the product 7-(1H-indol-3-yl)-9-(3-methylphenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile are shown in Table 3.

[0102] Table 3 Effect of the number of times the catalytic system is used on the purity and yield of the product 7-(1H-indol-3-yl)-9-(3-methylphenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile

[0103]

[0104]

[0105] It can be seen from the data in Table 3 that the catalytic system consisting of the magnetic Fe3O4-loaded multi-amino nanomaterial catalyst and the ethanol reaction solvent can still maintain a high purity and yield of the product after being used 6 times.

[0106] Embodiment 11

[0107] Regeneration of the catalyst system

[0108] The catalyst adsorbed by the magnet after being recycled for 6 times in Example 10 was placed in the catalytic system formed by the filtrate for vacuum distillation, and the fraction was collected. Then, 5 mL of petroleum ether (boiling range of 60-90° C.) was added to the residue after distillation, refluxed for 30 minutes, and then filtered with suction, and then 5 mL of petroleum ether (boiling range of 60-90° C.) was added to the filter residue, refluxed for 30 minutes, and filtered with suction, and a total of 3 times, and finally the obtained filter residue was vacuum dried at 85° C. for 12 hours to obtain the regenerated catalyst. The fraction was supplemented to 10 mL with the washing liquid of the washing product, and the regenerated catalyst was added to form a new catalytic system.

[0109] Example 12

[0110] Reusability of the regenerated catalyst system

[0111] Directly add 1.1mmol m-tolualdehyde, 1.0mmol 6-aminoindazole and 1.0mmol 3-(1H-indol-3-yl)-3-oxypropionitrile to the new catalyst system composed of Example 11, react according to the reaction conditions and operation steps of Example 9, and then recycle the catalyst system according to the steps of Example 10. The product 7-(1H-indol-3-yl)-9-(3-methylphenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile is used 6 times. The purity and yield changes of the product 7-(1H-indol-3-yl)-9-(3-methylphenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile are shown in Table 4.

[0112] Table 4 Effect of the number of times the regenerated catalyst system is used on the purity and yield of the product 7-(1H-indol-3-yl)-9-(3-methylphenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile

[0113] Number of times the catalytic system is used purity / % Yield / % 1 99.4 90 2 99.3 90 3 99.1 90 4 99.0 88 5 98.9 89 6 98.6 86

[0114] It can be seen from the data in Table 4 that the regenerated catalytic system can still be reused and maintain a high purity and yield of the product 7-(1H-indol-3-yl)-9-(3-methylphenyl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile.

[0115] Embodiment 13

[0116] Preparation of 9-(3,4-dichlorophenyl)-7-(1H-indol-3-yl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile

[0117]

[0118] 1.0 mmol 3,4-dichlorobenzaldehyde, 1.0 mmol 6-aminoindazole and 1.0 mmol 3-(1H-indol-3-yl)-3-oxypropionitrile were added to a 50 mL three-necked flask with a magnetic stirrer, a thermometer and a spherical condenser containing 11 mL ethanol, and mixed evenly by magnetic stirring at room temperature, and then 0.07 g of magnetic Fe3O4-supported multi-amino nanomaterial catalyst was added under stirring to form a suspended reaction liquid. The temperature was raised to reflux (the vapor of the reaction liquid did not exceed the second ball of the spherical condenser) by uniform heating in an oil bath, and the temperature was kept at reflux for 72 minutes. TLC (thin plate chromatography, developing solvent: ethyl acetate: methanol = 5:1) was used for detection. When the raw material point disappeared, the stirring was stopped immediately, and the catalyst was adsorbed by a magnet while it was hot. The reaction solution from which the catalyst was adsorbed was naturally cooled to room temperature, and a large amount of white solid was precipitated. The solid was crushed and allowed to stand for 2 hours, and then filtered to obtain a filter residue and a filtrate. The filter residue was washed with ethanol (5 mL × 3) and then vacuum dried at 80°C for 12 hours to obtain 0.43 g of 9-(3,4-dichlorophenyl)-7-(1H-indol-3-yl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile. 10 mg of the above product was put into a beaker, ultrasonically dissolved with 5 mL of chromatographic methanol, then quantitatively used with a 20 mL volumetric flask, and filtered with a 0.45 um organic membrane, and finally detected by high performance liquid chromatography. The purity of 9-(3,4-dichlorophenyl)-7-(1H-indol-3-yl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile was measured to be 99.2%, and the yield was calculated to be 93%.

[0119] The characterization data of the product 9-(3,4-dichlorophenyl)-7-(1H-indol-3-yl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile obtained in this example are as follows:

[0120] White solid; mp 277~279℃; 1H NMR (400MHz, DMSO-d6): δ (ppm) = 5.29 (s, 1H), 7.02 (d, J = 8.6Hz, 1H), 7.12 (t, J = 7.4Hz, 1H), 7.19 (t, J = 7.4Hz, 1H) , 7.35 (dd, J=8.2, 2.0Hz, 1H), 7.52 (d, J=3.4Hz, 1H), 7.55 (d, J=3.4Hz, 1H), 7.60 (s, 1H), 7.68 (s, 1H), 7.74 (d, J=2 .0Hz, 1H), 7.89 (d, J=2.8Hz, 1H), 8.03 (s, 1H), 9.96 (s, 1H), 11.81 (d, J=1.4Hz, 1H), 12.89 (s, 1H); IR (KBr): ν=34 02, 3279, 2198, 1699, 1633, 1665, 1542, 1518, 1487, 1460, 1343, 1318, 1231, 1129, 1060, 1025, 930, 851, 747, 664cm -1 .

[0121] Comparative Example 1

[0122] Add 1.0mmol 3,4-dichlorobenzaldehyde, 1.0mmol 6-aminoindazole and 1.0mmol 3-(1H-indol-3-yl)-3-oxypropionitrile to a 50mL three-necked flask with a magnetic stirrer, a thermometer and a spherical condenser containing 11mL ethanol, stir magnetically at room temperature to mix evenly, and then add 0.07g of magnetic Fe3O4-loaded multi-amino nanomaterial catalyst to form a suspended reaction liquid. React at room temperature for 72min, and TLC (thin plate chromatography, developing solvent: ethyl acetate: methanol = 5:1) detection shows that many reaction raw materials still fail to participate in the reaction. Stop stirring and use a magnet to adsorb the catalyst while hot. The reaction liquid with the adsorbed catalyst is naturally cooled to room temperature, and no solid is precipitated. The reaction solution was subjected to HPLC detection, and the purity of 9-(3,4-dichlorophenyl)-7-(1H-indol-3-yl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile was found to be 34.1%. The yield was calculated to be 24%.

[0123] Comparative Example 2

[0124] Add 1.0mmol 3,4-dichlorobenzaldehyde, 1.0mmol 6-aminoindazole and 1.0mmol 3-(1H-indol-3-yl)-3-oxypropionitrile to a 50mL three-necked flask with a magnetic stirrer, a thermometer and a spherical condenser containing 11mL ethanol, stir and mix evenly under magnetic stirring at room temperature, then add 0.07g magnetic Fe3O4-loaded multi-amino nanomaterial catalyst under stirring to form a suspended reaction liquid. Heat the mixture evenly to 50℃ in an oil bath, keep the reaction at this temperature for 72min, and detect by TLC (thin plate chromatography, developing solvent: ethyl acetate: methanol = 5:1). A small amount of reaction raw materials still fail to participate in the reaction. Stop stirring and use a magnet to adsorb the catalyst while it is hot. The reaction liquid with the adsorbed catalyst is cooled naturally to room temperature, and a small amount of white solid precipitates. The solid was crushed and allowed to stand for 2 hours, and then filtered to obtain a filter residue and a filtrate. The filter residue was washed with ethanol (5 mL × 3) and then vacuum dried at 80°C for 12 hours to obtain 0.36 g of 9-(3,4-dichlorophenyl)-7-(1H-indol-3-yl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile. 10 mg of the above product was put into a beaker, ultrasonically dissolved with 5 mL of chromatographic methanol, then quantitatively used with a 20 mL volumetric flask, and filtered with a 0.45 um organic membrane. Finally, high performance liquid chromatography was performed to detect the purity of 9-(3,4-dichlorophenyl)-7-(1H-indol-3-yl)-6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile, which was 99.0%. The yield was calculated to be 79%.

[0125] In the above specific embodiments, the hydrogen spectrum nuclear magnetic resonance characterization of the reaction product adopts the nuclear magnetic resonance instrument of model AVANCE III HD 400MHz of Bruker, Germany; the infrared spectrum characterization adopts the Fourier infrared spectrometer of model NEXUS 870 of Nicolet, USA; the HPLC purity determination adopts the HPLC of model Agilent Technologies 1260Infinity IIC of Agilent, USA; the melting point of the reaction product is determined by capillary method. The reagents or instruments used without indicating the manufacturer are all conventional products that can be purchased commercially.

[0126] 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 changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A method for preparing a pharmaceutical intermediate 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative, characterized in that: The preparation method uses aromatic aldehyde (I), 6-aminoindazole (II) and 3-(1H-indol-3-yl)-3-oxypropionitrile (III) as reaction raw materials, uses magnetic Fe3O4-loaded polyamino nanomaterials as catalyst, and uses ethanol as reaction solvent under reflux conditions. The chemical reaction formula involved in the preparation method of the pharmaceutical intermediate 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative (IV) is: The chemical structure of the magnetic Fe3O4-loaded multi-amino nanomaterial catalyst is: in: It is cyclodextrin; (I) wherein the aromatic aldehyde is any one of benzaldehyde, p-chlorobenzaldehyde, p-methoxybenzaldehyde, p-nitrobenzaldehyde, m-bromobenzaldehyde, m-tolualdehyde, and 3,4-dichlorobenzaldehyde; The preparation method comprises the following steps: Step 1: First, add ethanol to a three-necked flask equipped with a magnetic stir bar, a thermometer and a spherical condenser, then add aromatic aldehyde, 6-aminoindazole and 3-(1H-indol-3-yl)-3-oxypropionitrile, mix well at room temperature, and then add a magnetic Fe3O4-supported multi-amino nanomaterial catalyst under continuous magnetic stirring to form a suspended reaction solution; Step 2: The suspended reaction liquid formed in step 1 is uniformly heated in an oil bath to reflux, with the solvent vapor not exceeding the second ball of the spherical condenser, and then the reaction is maintained at this temperature until the raw material point disappears. When the reaction is completed, stirring and heating are immediately stopped, and the catalyst is adsorbed by a magnet while it is hot; Step 3: The reaction solution from which the catalyst is adsorbed in step 2 is naturally cooled to room temperature, a solid is precipitated, and the solid is crushed, allowed to stand, and filtered to obtain a filtrate and a filter residue, and the filter residue is washed with ethanol and then vacuum dried at 80° C. for 12 h to obtain a 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative; Step 4: The catalyst adsorbed in step 2 is placed into the filtrate formed in step 3 without any treatment and the volume is made up with washing liquid, and then the reaction raw materials aromatic aldehyde, 6-aminoindazole and 3-(1H-indol-3-yl)-3-oxypropionitrile prepared in the same step are directly added, and the next round of cyclic reaction is carried out according to steps 2 and 3.

2. The method for preparing the pharmaceutical intermediate 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative according to claim 1, characterized in that: In step 1, the molar ratio of the aromatic aldehyde, 6-aminoindazole and 3-(1H-indol-3-yl)-3-oxypropionitrile is (1.0-1.2):1:

1.

3. The method for preparing the pharmaceutical intermediate 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative according to claim 2, characterized in that: In step 1, the volume of ethanol in milliliters is 8 to 12 times the amount of 6-aminoindazole in millimoles.

4. The method for preparing the pharmaceutical intermediate 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative according to claim 3, characterized in that: In step 1, the mass of the magnetic Fe3O4-supported polyamino nanomaterial catalyst in grams is 7 to 13% of the mass of the 6-aminoindazole in millimoles.

5. The method for preparing the pharmaceutical intermediate 6,9-dihydro-1H-pyrazolo[3,4-f]quinoline-8-carbonitrile derivative according to claim 4, characterized in that: The reaction time of maintaining reflux in step 2 is 1.2 to 1.8 hours.

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