Method for preparing drug intermediate chromene [4, 3-d] pyrimidone derivative and catalytic system

Abstract

The invention relates to the field of catalytic preparation of drug intermediates, and particularly discloses a method for preparing a drug intermediate chromene [4, 3-d] pyrimidone derivative and a catalytic system.The preparation method comprises the steps that aromatic aldehyde, urea or thiourea and 4-hydroxycoumarin serve as reaction raw materials; the chromene [4, 3-d] pyrimidone derivative is prepared through a one-step reaction in a catalytic system composed of an acidic ionic liquid and a deep eutectic solvent under a heating condition. According to the present invention, the recyclable and regenerated catalytic system using the acidic ionic liquid as the catalyst and the eutectic solvent as the reaction solvent is adopted, such that the generation of the large amount of the acid wastewater caused by the use of the inorganic or organic acid and the volatile organic solvent is avoided, the catalyst cost and the wastewater treatment cost are reduced, and the environmental burden is reduced; the method is not only a focus of wide attention in the medicine intermediate preparation industry, but also an urgent demand and an inevitable trend for establishing an environment-friendly society.

Description

Technical Field

[0001] The invention relates to a method for preparing a derivative, in particular to a method for preparing a drug intermediate chromeno[4,3-d]pyrimidinone derivative and a catalytic system, belonging to the field of catalytic preparation of drug intermediates. Background Art

[0002] Among anticancer drugs, there is a class of antimetabolites containing pyrimidine ring structures, such as fluorouracil, azacytidine, etc. In addition, chromene derivatives can strongly inhibit tubulin polymerization and show good inhibitory effects on a variety of cancer cells. Chromene [4, 3-d] pyrimidinone derivatives are compounds that contain pyrimidine ring-containing chromene structures at the same time, so they have a wide range of biological and pharmacological activities. At the same time, through the results of recent years, it has been found that compounds containing chromene [4, 3-d] pyrimidinone structures in the parent structure often have anticancer activity, and have a wide range of applications in the pharmaceutical industry, especially in antitumor drugs, and have become the focus of current anticancer drug research. Therefore, as a drug intermediate, the preparation of chromene [4, 3-d] pyrimidinone derivatives has become an important research topic for chemical drug synthesizers.

[0003] In recent years, foreign organic synthesis workers have found that chromeno[4,3-d]pyrimidinone derivatives can be prepared by a three-component one-pot process of aromatic aldehydes, urea or thiourea and 4-hydroxycoumarin under the catalysis of inorganic or organic acids. For example, in 2020, MMHeravi et al. used 12-tungstoboric acid as a catalyst to prepare a series of chromeno[4,3-d]pyrimidinone derivatives in refluxing water; in 2013, GMNazeruddin et al. used chlorosulfonic acid as a catalyst to prepare chromeno[4,3-d]pyrimidinone derivatives under ultrasonic-assisted, solvent-free conditions; in 2015, Hossein Mehrabi et al. used acetic acid as a catalyst to catalyze the three-component reaction of aromatic aldehydes, urea or thiourea, and 4-hydroxycoumarin in water containing sodium dodecyl sulfate to produce chromeno[4,3-d]pyrimidinone derivatives. However, since the acid catalyst in the above method cannot be recovered and recycled, a large amount of waste acid is generated during the preparation process, resulting in serious environmental pollution. In addition, the use of these acids also brings about the problem of difficulty in product separation. Usually, selecting a material with a relatively large specific surface area, porosity, and good stability as a carrier and loading an organic or inorganic acid on it to make a heterogeneous catalyst is an effective way to solve the above shortcomings. For example, in 2022, NegarJamasbi et al. used ultrasound-assisted technology to 3 O 4 @SiO 2 @(BuSO 3H) as a catalyst, chromeno[4,3-d]pyrimidinone derivatives can be prepared in water. However, the above method still has the disadvantages of complex preparation of the catalyst and high cost, and the catalytic system cannot be recycled and regenerated.

[0004] In order to solve the above problems, Lu Hua et al. used chloromethyl resin to graft -SO 3 H as a catalyst, ethanol-water-[C 4 DABCO]Br mixed solvent realizes the recycling and regeneration of the catalytic system and improves the utilization efficiency of raw materials. 3 H catalyst and reaction solvent [C 4 The preparation process of DABCO]Br is very complicated and the raw materials are relatively expensive. In addition, the preparation process of the entire chromeno[4,3-d]pyrimidinone derivative is also relatively cumbersome and requires three filtration operations. Summary of the invention

[0005] In order to solve the problems of complex and expensive catalyst preparation process, environmental pollution caused by volatile organic solvents and cumbersome preparation process, the present invention uses a catalyst system composed of an acidic ionic liquid as a catalyst and a low eutectic solvent as a reaction solvent, and uses aromatic aldehydes, urea or thiourea and 4-hydroxycoumarin as reaction raw materials to prepare chromeno[4,3-d]pyrimidinone derivatives by a one-pot reaction. The method has the advantages of high atom economy, strong product selectivity, easy recycling and regeneration of the catalyst, and easy separation and purification of the product.

[0006] The purpose of the present invention can be achieved through the following technical solutions:

[0007] A method for preparing a drug intermediate chromeno[4,3-d]pyrimidinone derivative, the reaction formula of the preparation method is:

[0008]

[0009] The preparation method uses aromatic aldehyde, urea or thiourea and 4-hydroxycoumarin as reaction raw materials, and prepares chromeno[4,3-d]pyrimidinone derivatives by one-step reaction under a catalytic system consisting of an acidic ionic liquid and a low eutectic solvent and heating conditions.

[0010] Optionally, at room temperature, a preset amount of reaction raw materials are first added to a catalytic system consisting of a low eutectic solvent as a solvent and an acidic ionic liquid as a catalyst, and then mixed evenly to form a mixed solution → heated to a preset temperature → kept warm for a preset time until the reaction ends → naturally cooled to room temperature and then added with ethanol aqueous solution → allowed to stand, filtered, and the residue was vacuum dried to obtain a chromeno[4,3-d]pyrimidinone derivative.

[0011] Optionally, mixing uniformly to form a mixed solution: adding a preset amount of aromatic aldehyde, urea or thiourea and 4-hydroxycoumarin into a flask with a thermometer, a magnetic stirrer and a condenser containing a catalytic system consisting of a deep eutectic solvent as a solvent and an acidic ionic liquid as a catalyst, and mixing uniformly under magnetic stirring;

[0012] Heating to preset temperature: uniformly heating to 63-72°C under magnetic stirring;

[0013] Keep warm for the preset time until the reaction is finished: keep warm at 63-72℃ for 12-27min until the reaction is finished;

[0014] After cooling naturally to room temperature, add ethanol aqueous solution: after the heat preservation reaction is completed, the reaction solution is cooled naturally to room temperature and a preset amount of ethanol aqueous solution is added;

[0015] Standing, filtering, and vacuum drying the filter residue: After standing for 8 hours, filter and vacuum dry the filter residue at 85°C to constant weight.

[0016] Optionally, the aromatic aldehyde in the reaction raw material is any one of benzaldehyde, o-chlorobenzaldehyde, o-hydroxybenzaldehyde, o-nitrobenzaldehyde, m-chlorobenzaldehyde, m-nitrobenzaldehyde, m-hydroxybenzaldehyde, p-chlorobenzaldehyde, p-hydroxybenzaldehyde, p-tolualdehyde, p-methoxybenzaldehyde, p-nitrobenzaldehyde, and p-dimethylaminobenzaldehyde.

[0017] Optionally, the molar ratio of aromatic aldehyde, urea or thiourea and 4-hydroxycoumarin in the reaction raw materials is 1:1:1.

[0018] Optionally, the low eutectic solvent is obtained by mixing and heating choline chloride and oxalic acid in a molar ratio of 1:1.

[0019] Optionally, the volume usage of the deep eutectic solvent in milliliters is 9 to 16 times the amount of the aromatic aldehyde substance in millimoles.

[0020] Optionally, the acidic ionic liquid has the structural formula: The amount of the acidic ionic liquid used in the reaction is 8-12% of the amount of the aromatic aldehyde used.

[0021] Optionally, the volume usage of the ethanol aqueous solution in milliliters is 12 to 17 times the amount of the aromatic aldehyde substance in millimoles, and the volume ratio concentration of ethanol contained in the ethanol aqueous solution is 95 to 97%.

[0022] A catalytic system for preparing a drug intermediate chromeno[4,3-d]pyrimidinone derivative, wherein the catalytic system can be recycled or regenerated after the chromeno[4,3-d]pyrimidinone derivative is prepared;

[0023] The specific process of recycling the catalytic system is as follows:

[0024] After the filtrate is filtered, the ethanol aqueous solution is evaporated and then the aromatic aldehyde, urea or thiourea and 4-hydroxycoumarin are directly added for recycling. In consideration of the nature of the pharmaceutical intermediate industry and the economic requirements, when the HPLC purity of the chromeno[4,3-d]pyrimidinone derivative obtained in the recycling process is lower than 98% or the calculated yield is reduced by more than 5% compared with the initial use of the catalyst system, the recycling of the catalyst system is stopped;

[0025] The specific process of catalytic system regeneration is as follows:

[0026] After the filtrate which cannot be recycled is evaporated to remove the ethanol aqueous solution, ether is added for washing and liquid separation, and the lower layer of liquid is collected. Then, the same amount of ether is added to continue washing and liquid separation, and the lower layer of liquid is collected. Washing is performed 3 to 5 times in total. The lower layer of liquid collected after the last washing is vacuum dried at 85° C. to constant weight to obtain a regenerated catalytic system; the volume of ether used is 1.5 to 1.8 times the volume of the low eutectic solvent used.

[0027] Beneficial effects of the present invention:

[0028] In the present invention, a catalytic system composed of a recyclable and regenerable acidic ionic liquid as a catalyst and a deep eutectic solvent as a reaction solvent is used to avoid the large-scale generation of acid waste water caused by the use of inorganic or organic acids and volatile organic solvents, reduce the catalyst cost and wastewater treatment cost, and reduce the environmental burden. This is not only the focus of extensive attention in the pharmaceutical intermediate preparation industry, but also an urgent need and inevitable trend for building an environmentally friendly society. In addition, the purification process of the product chromeno[4,3-d]pyrimidinone derivative is relatively simple, and does not require processes such as recrystallization or column chromatography, which saves time and effort. While improving economic benefits, it is also convenient for the pharmaceutical intermediate chromeno[4,3-d]pyrimidinone derivative to achieve industrial large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to facilitate understanding by those skilled in the art, the present invention is further described below with reference to the accompanying drawings.

[0030] Figure 1 The 4-phenyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione prepared in Example 1 of the present invention 1 H NMR.

[0031] Figure 2 The 4-phenyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione prepared in Example 1 of the present invention 13 C NMR.

[0032] Figure 3 The 4-(4-dimethylaminophenyl)-2-thio-3,4-dihydro-1H-chromeno[4,3-d]pyrimidin-5-one prepared in Example 6 of the present invention is 1 H NMR.

[0033] Figure 4 The 4-(4-dimethylaminophenyl)-2-thio-3,4-dihydro-1H-chromeno[4,3-d]pyrimidin-5-one prepared in Example 6 of the present invention is 13 C NMR.

[0034] Figure 5 The catalytic system in Examples 9 to 13 of the present invention was used a total of 7 times, and the yield and purity of the product 4-phenyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione were measured each time.

[0035] Figure 6 The catalytic system in Examples 15 to 19 of the present invention was used a total of 5 times, and the yield and purity of the product 4-phenyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione were measured each time. DETAILED DESCRIPTION

[0036] 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.

[0037] The structural characterization of the reaction product chromeno[4,3-d]pyrimidinone derivatives in the following examples was performed using an AVANCE III HD 500 MHz nuclear magnetic resonance spectrometer from Bruker, Germany.

[0038] The purity of the reaction product chromeno[4,3-d]pyrimidinone derivative was characterized by using a high performance liquid chromatograph, model Water 2695, from Waters Corporation, USA.

[0039] The deep eutectic solvent used in the present invention is prepared by mixing and heating choline chloride and oxalic acid according to relevant reference materials (Deepeutectic solvents formed between choline chloride and carboxylic acids: versatile alternatives to ionic liquids [J], Journal of the American Chemical Society, 2004, 126 (29): 9142-9147).

[0040] The acidic ionic liquid used in the present invention is obtained by reacting ethanolamine with chlorosulfonic acid in a low temperature step according to relevant reference materials (Novel multiple-acidicionic liquids: catalysts for environmentally friendly benign synthesis of trans-β-nitrostyrenes under solvent-free conditions [J], Industrial & Engineering Chemistry Research, 2014, 53 (2): 547-552).

[0041] The following is a specific embodiment and the attached Figure 1-6 The present invention is further described.

[0042] Example 1

[0043]

[0044] At room temperature, 9 ml of low eutectic solvent and 0.08 mmol of acidic ionic liquid were added to a 50 ml four-necked reaction flask with a magnetic stirrer and a thermometer, and stirred to form a relatively viscous solution. Then, 1.0 mmol of benzaldehyde (0.11 g), 1.0 mmol of urea (0.06 g) and 1.0 mmol of 4-hydroxycoumarin (0.16 g) were added under stirring to form a turbid reaction system. Then, the reaction system was slowly heated in an oil bath until it was clear, and the temperature was continued to be evenly heated to 63 ° C. The reaction was stirred at this temperature for 12 minutes, and the TLC monitoring was performed until the raw material point just disappeared. Immediately stop heating and remove the oil bath pot, and continue to stir until the reaction solution cools to room temperature. Then, 12 ml of 95% ethanol aqueous solution was added to the reaction solution, stirred evenly and then allowed to stand, and solids began to precipitate. After 8 hours, the filter was suction filtered, and the filter residue was vacuum dried at 85 ° C to constant weight, and 0.28 g of off-white solid was weighed. The solid was detected by high performance liquid chromatography, and the purity of the main product was 99.2%. The solid was analyzed by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and the solid was found to be 4-phenyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione. The yield of 4-phenyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione calculated based on the high performance liquid chromatography purity was 96%.

[0045] After the ethanol aqueous solution is evaporated, the filtrate can be directly added with benzaldehyde, urea and 4-hydroxycoumarin for recycling.

[0046] The structural characterization data of the product 4-phenyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione obtained in this example are as follows: 1 H NMR (500 MHz, DMSO-d 6 ): δ6.36 (s, 1H, -CH), 7.09~7.39 (m, 9H, ArH), 7.60 (s, 1H, NH), 7.90 (s, 1H, NH); 13 C NMR (125 MHz, DMSO-d 6 ): 36(C-1), 103(C-2), 115(C-13), 116(C-17), 121(C-14), 122(C-15), 124(C-16), 125(C-6and C-10), 126(C-8), 126(C-7), 128(C-9), 131(C-5), 140(C-12), 152(C-3), 164(C-4), 165(C-11).

[0047] Example 2

[0048]

[0049] At room temperature, 9 ml of low eutectic solvent and 0.09 mmol of acidic ionic liquid were added to a 50 ml four-necked reaction flask with a magnetic stirrer and a thermometer, and stirred to form a relatively viscous solution. Then, 1.0 mmol of benzaldehyde (0.11 g), 1.0 mmol of thiourea (0.08 g) and 1.0 mmol of 4-hydroxycoumarin (0.16 g) were added under stirring to form a turbid reaction system. Then, the reaction system was slowly heated in an oil bath until it was clear, and the temperature was continued to be evenly heated to 66 ° C. The reaction was stirred at this temperature for 17 minutes, and the TLC monitoring was performed until the raw material point just disappeared. Immediately stop heating and remove the oil bath pot, and continue to stir until the reaction solution cools to room temperature. Then, 12 ml of 95% ethanol aqueous solution was added to the reaction solution, stirred evenly and then allowed to stand, and solids began to precipitate. After 8 hours, the filter residue was vacuum dried at 85 ° C to constant weight, and 0.29 g of off-white solid was weighed. The solid was detected by high performance liquid chromatography, and the purity of the main product was 99.1%. The solid was analyzed by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and the solid was found to be 4-phenyl-2-sulfanyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidin-5-one. The yield of 4-phenyl-2-sulfanyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidin-5-one was calculated to be 93% based on the high performance liquid chromatography purity.

[0050] After the ethanol aqueous solution is evaporated, the filtrate can be directly added with benzaldehyde, thiourea and 4-hydroxycoumarin for recycling.

[0051] The structural characterization data of the product 4-phenyl-2-sulfanyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidin-5-one obtained in this example are as follows: 1 H NMR (500 MHz, DMSO-d 6 ): δ6.36 (s, 1H, -CH), 7.28~7.41 (m, 9H, ArH), 7.84 (s, 1H, -NH), 8.12 (s, 1H, -NH); 13 C NMR (125 MHz, DMSO-d 6 ): 37(C-1), 102(C-2), 113(C-13), 118(C-17), 125(C-14), 125(C-15), 126(C-16), 129(C-5), 134(C-6and C-10), 135(C-7and C-9), 147(C-8), 151(C-12), 154(C-3), 164(C-4), 167(C-11).

[0052] Example 3

[0053]

[0054] At room temperature, 14 ml of a low eutectic solvent and 0.12 mmol of an acidic ionic liquid were added to a 50 ml four-necked reaction flask with a magnetic stirrer and a thermometer, and stirred to form a relatively viscous solution. Then, 1.0 mmol of p-chlorobenzaldehyde (0.14 g), 1.0 mmol of urea (0.06 g) and 1.0 mmol of 4-hydroxycoumarin (0.16 g) were added under stirring to form a turbid reaction system. Then, the reaction system was slowly heated in an oil bath until it was clear, and the temperature was continued to be evenly heated to 70 ° C. The reaction was stirred at this temperature for 24 minutes, and the TLC monitoring was performed until the raw material point just disappeared. Immediately stop heating and remove the oil bath pot, and continue stirring until the reaction solution drops to room temperature. Then, 17 ml of 97% ethanol aqueous solution was added to the reaction solution, stirred evenly and then allowed to stand, and solids began to precipitate. After 8 hours, the filter residue was vacuum dried at 85 ° C to constant weight, and 0.28 g of off-white solid was obtained by weighing. The solid was detected by high performance liquid chromatography, and the purity of the main product was 99.4%. The solid was analyzed by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and the solid was found to be 4-(4-chlorophenyl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione. The yield of 4-(4-chlorophenyl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione was calculated to be 85% based on the high performance liquid chromatography purity.

[0055] After the ethanol aqueous solution is evaporated, the filtrate can be directly added with p-chlorobenzaldehyde, urea and 4-hydroxycoumarin for recycling.

[0056] The structural characterization data of the product 4-(4-chlorophenyl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione obtained in this example are as follows: 1 H NMR (500 MHz, DMSO-d 6 ): δ6.32 (s, 1H, -CH), 7.16 (d, J=8.7Hz, 2H, ArH), 7.37~7.55 (m, 6H, ArH), 7.58 (s, 1H, NH), 7.86 (s, 1H, NH); 13 C NMR (125 MHz, DMSO-d 6 ): 34(C-1), 102(C-2), 116(C-13), 119(C-17), 125(C-14), 129(C-15), 129(C-16), 129(C-7 ), 131(C-9), 132(C-10), 134(C-5), 138(C-8), 140(C-12), 153(C-3), 165(C-4), 167(C-11).

[0057] Example 4

[0058]

[0059] At room temperature, 16 ml of low eutectic solvent and 0.12 mmol of acidic ionic liquid were added to a 50 ml four-necked reaction flask with a magnetic stirrer and a thermometer, and stirred to form a relatively viscous solution. Then, 1.0 mmol of p-chlorobenzaldehyde (0.14 g), 1.0 mmol of thiourea (0.08 g) and 1.0 mmol of 4-hydroxycoumarin (0.16 g) were added under stirring to form a turbid reaction system. Then, the reaction system was slowly heated in an oil bath until it was clear, and the temperature was continued to be evenly heated to 72 ° C. The reaction was stirred at this temperature for 27 minutes, and the TLC monitoring was performed until the raw material point just disappeared. Immediately stop heating and remove the oil bath pot, and continue to stir until the reaction solution cools to room temperature. Then, 17 ml of 97% ethanol aqueous solution was added to the reaction solution, stirred evenly and then allowed to stand, and solids began to precipitate. After 8 hours, the filter residue was vacuum dried at 85 ° C to constant weight, and 0.29 g of gray-white solid was weighed. The solid was detected by high performance liquid chromatography, and the purity of the main product was 99.1%. The solid was analyzed by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and the solid was found to be 4-(4-chlorophenyl)-2-sulfanyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidin-5-one. The yield of 4-(4-chlorophenyl)-2-sulfanyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidin-5-one was calculated to be 83% based on the high performance liquid chromatography purity.

[0060] After the ethanol aqueous solution is evaporated, the filtrate can be directly added with p-chlorobenzaldehyde, thiourea and 4-hydroxycoumarin for recycling.

[0061] The structural characterization data of the product 4-(4-chlorophenyl)-2-sulfanyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidin-5-one obtained in this example are as follows: 1 H NMR (500 MHz, DMSO-d 6 ): δ6.27 (s, 1H, -CH), 7.11 (d, 1H, J=7.7Hz, ArH), 7.22~7.33 (m, 5H, ArH), 7.52~7.58 (m, 2H, ArH), 7.88 (s, 1H, -NH), 7.91 (s, 1H, -NH); 13 C NMR (125 MHz, DMSO-d 6 ): 35(C-1), 103(C-2), 116(C-13), 117(C-17), 124(C-14), 127(C-15), 129(C-16), 130(C-5), 132(C-6and C-10), 133(C-7and C-9), 138(C-8), 139(C-12), 151(C-3), 165(C-4), 167(C-11).

[0062] Example 5

[0063]

[0064] At room temperature, 12 ml of low eutectic solvent and 0.10 mmol of acidic ionic liquid were added to a 50 ml four-necked reaction flask with a magnetic stirrer and a thermometer, and stirred to form a relatively viscous solution. Then, 1.0 mmol of p-dimethylaminobenzaldehyde (0.15 g), 1.0 mmol of urea (0.06 g) and 1.0 mmol of 4-hydroxycoumarin (0.16 g) were added under stirring to form a turbid reaction system. Then, the reaction system was slowly heated in an oil bath until it was clear, and the temperature was continued to be evenly heated to 65 ° C. The reaction was stirred at this temperature for 16 minutes, and the TLC monitoring was performed until the raw material point just disappeared. Immediately stop heating and remove the oil bath pot, and continue to stir until the reaction solution cools to room temperature. Then, 14 ml of 96% ethanol aqueous solution was added to the reaction solution, stirred evenly and then allowed to stand, and solids began to precipitate. After 8 hours, the filter residue was vacuum dried at 85 ° C to constant weight, and 0.30 g of gray-white solid was weighed. The solid was detected by high performance liquid chromatography, and the purity of the main product was 99.4%. The solid was analyzed by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and the solid was found to be 4-(4-dimethylaminophenyl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione. The yield of 4-(4-dimethylaminophenyl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione was calculated to be 88% based on the high performance liquid chromatography purity.

[0065] After the ethanol aqueous solution is evaporated, the filtrate can be directly added with p-dimethylaminobenzaldehyde, urea and 4-hydroxycoumarin for recycling.

[0066] The structural characterization data of the product 4-(4-dimethylaminophenyl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione obtained in this example are as follows: 1 H NMR (500 MHz, DMSO-d 6 ): δ 3.09 (s, 6H, N (CH 3 ), 6.26 (s, 1H, -CH), 7.19~7.25 (m, 8H, ArH), 7.49 (s, 1H, NH), 7.77 (s, 1H, NH); 13 C NMR (125 MHz, DMSO-d 6 ): 35(C-1), 46(N(CH 3 ) 2), 104(C-2), 113(C-13), 117(C-17), 120(C-14), 123(C-15and C-16), 125(C-8and C-5), 129(C-7and C-9), 132(C-6and C-10), 132(C-12), 154(C-3), 162(C-4), 168(C-11).

[0067] Example 6

[0068]

[0069] At room temperature, 12 ml of low eutectic solvent and 0.11 mmol of acidic ionic liquid were added to a 50 ml four-necked reaction flask with a magnetic stirrer and a thermometer, and stirred to form a relatively viscous solution. Then, 1.0 mmol of p-dimethylaminobenzaldehyde (0.15 g), 1.0 mmol of thiourea (0.08 g) and 1.0 mmol of 4-hydroxycoumarin (0.16 g) were added under stirring to form a turbid reaction system. Then, the reaction system was slowly heated in an oil bath until it was clear, and the temperature was continued to be evenly heated to 70 ° C. The reaction was stirred at this temperature for 23 minutes, and the TLC monitoring was performed until the raw material point just disappeared. Immediately stop heating and remove the oil bath pot, and continue to stir until the reaction solution cools to room temperature. Then, 15 ml of 96% ethanol aqueous solution was added to the reaction solution, stirred evenly and then allowed to stand, and solids began to precipitate. After 8 hours, the filter residue was vacuum dried at 85 ° C to constant weight, and 0.30 g of gray-white solid was weighed. The solid was detected by high performance liquid chromatography, and the purity of the main product was 99.3%. The solid was analyzed by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and the solid was found to be 4-(4-dimethylaminophenyl)-2-sulfanyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidin-5-one. The yield of 4-(4-dimethylaminophenyl)-2-sulfanyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidin-5-one was calculated to be 85% based on the high performance liquid chromatography purity.

[0070] After the ethanol aqueous solution is evaporated, the filtrate can be directly added with p-dimethylaminobenzaldehyde, thiourea and 4-hydroxycoumarin for recycling.

[0071] The structural characterization data of the product 4-(4-dimethylaminophenyl)-2-sulfanyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidin-5-one obtained in this example are as follows: 1 H NMR (500 MHz, DMSO-d 6 ): δ 3.11 (s, 6H, N (CH 3 ) 2), 6.26 (s, 1H, -CH), 7.17~7.28 (m, 4H, ArH), 7.49~7.56 (m, 4H, ArH), 7.69 (s, 1H, -NH), 7.80 (s, 1H, -NH); 13 C NMR (125 MHz, DMSO-d 6 ): 36(C-1), 45(N(CH 3 ) 2 ), 103(C-2), 111(C-13), 115(C-17), 119(C-14), 123(C-15), 123(C-16), 124(C-7and C-9), 124(C-6and C-10), 128(C-5and C-8), 131(C-12), 153(C-3), 164(C-4), 167(C-11).

[0072] Example 7

[0073]

[0074] At room temperature, 10 ml of a low eutectic solvent and 0.10 mmol of an acidic ionic liquid were added to a 50 ml four-necked reaction flask with a magnetic stirrer and a thermometer, and stirred to form a relatively viscous solution. Then, 1.0 mmol of m-nitrobenzaldehyde (0.15 g), 1.0 mmol of urea (0.06 g) and 1.0 mmol of 4-hydroxycoumarin (0.16 g) were added under stirring to form a turbid reaction system. Then, the reaction system was slowly heated in an oil bath until it was clear, and the temperature was continued to be evenly heated to 65 ° C. The reaction was stirred at this temperature for 18 minutes, and the TLC monitoring was performed until the raw material point just disappeared. Immediately stop heating and remove the oil bath pot, and continue stirring until the reaction solution cools to room temperature. Then, 15 ml of 96% ethanol aqueous solution was added to the reaction solution, stirred evenly and allowed to stand, and solids began to precipitate. After 8 hours, the filter was suction filtered, and the filter residue was vacuum dried at 85 ° C to constant weight, and 0.32 g of off-white solid was weighed. The solid was detected by high performance liquid chromatography, and the purity of the main product was 99.1%. The solid was analyzed by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and the solid was found to be 4-(3-nitrophenyl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione. The yield of 4-(3-nitrophenyl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione was calculated based on the high performance liquid chromatography purity and was 93%.

[0075] After the ethanol aqueous solution is evaporated, the filtrate can be directly added with m-nitrobenzaldehyde, urea and 4-hydroxycoumarin for recycling.

[0076] The structural characterization data of the product 4-(3-nitrophenyl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione obtained in this example are as follows: 1 H NMR (500 MHz, DMSO-d 6 ): δ6.34 (s, 1H, CH), 7.25~7.30 (m, 4H, ArH), 7.39 (d, J=8.5Hz, 2H, ArH), 7.53 (t, J=8.0Hz, 2H, ArH), 7.81 (s, 1H, NH), 8.07 (s, 1H, NH); 13 CNMR (125 MHz, DMSO-d 6 ): 36(C-1), 102(C-2), 113(C-13), 117(C-17), 123(C-14), 123(C-15), 124(C-16), 124(C-5), 128(C-6), 129(C-10), 131(C-7and C-9), 144(C-8), 150(C-12), 153(C-3), 164(C-4), 166(C-11).

[0077] Example 8

[0078]

[0079] At room temperature, 12 ml of a low eutectic solvent and 0.10 mmol of an acidic ionic liquid were added to a 50 ml four-necked reaction flask with a magnetic stirrer and a thermometer, and stirred to form a relatively viscous solution. Then, 1.0 mmol of o-hydroxybenzaldehyde (0.12 g), 1.0 mmol of urea (0.06 g) and 1.0 mmol of 4-hydroxycoumarin (0.16 g) were added under stirring to form a turbid reaction system. Then, the reaction system was slowly heated in an oil bath until it was clear, and the temperature was continued to be evenly heated to 68 ° C. The reaction was stirred at this temperature for 17 minutes, and the TLC monitoring was performed until the raw material point just disappeared. Immediately stop heating and remove the oil bath pot, and continue stirring until the reaction solution cools to room temperature. Then, 16 ml of 97% ethanol aqueous solution was added to the reaction solution, stirred evenly and then allowed to stand, and solids began to precipitate. After 8 hours, the filter was suction filtered, and the filter residue was vacuum dried at 85 ° C to constant weight, and 0.28 g of off-white solid was weighed. The solid was detected by high performance liquid chromatography, and the purity of the main product was 99.2%. The solid was analyzed by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and the solid was found to be 4-(2-hydroxyphenyl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione. The yield of 4-(2-hydroxyphenyl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione was calculated to be 90% based on the high performance liquid chromatography purity.

[0080] After the ethanol aqueous solution is evaporated, the filtrate can be directly added with o-hydroxybenzaldehyde, urea and 4-hydroxycoumarin for recycling.

[0081] The structural characterization data of the product 4-(2-hydroxyphenyl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione obtained in this example are as follows: 1 H NMR (500 MHz, DMSO-d 6 ): δ6.25 (s, 1H, CH), 6.49~6.56 (m, 2H, ArH), 6.79 (d, J=8.0Hz, 2H, ArH), 6.98 (t, J=7.5Hz, 1H, ArH), 7 .28~7.34 (m, 2H, ArH), 7.56 (t, J=7.0Hz, 1H, ArH), 7.67 (s, 1H, NH), 7.88 (s, 1H, NH), 9.66 (s, 1H, OH); 13 C NMR (125 MHz, DMSO-d 6 ): 35(C-1), 104(C-2), 111(C-13), 112(C-17), 113(C-14), 115(C-15), 117(C-16), 117(C-7), 123 (C-8), 129(C-9), 131(C-10), 141(C-5), 152(C-6), 154(C-12), 157(C-3), 164(C-4), 165(C-11).

[0082] Examples 9 to 13

[0083] Feasibility of recycling catalytic system composed of deep eutectic solvent and acidic ionic liquid

[0084] Taking the catalytic system of Example 1 as an example, the feasibility of recycling the catalytic system was investigated: 1.0 mmol benzaldehyde (0.11 g), 1.0 mmol urea (0.06 g) and 1.0 mmol 4-hydroxycoumarin were added to the filtrate produced in Example 1, and then the catalytic system was recycled according to the operating steps and reaction conditions of Example 1. The catalytic system was used 7 times in total, and the yield and purity of the product 4-phenyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione each time were as follows: Figure 5 .

[0085] When the HPLC purity of the product is lower than 98% or the calculated yield decreases by more than 5% compared with the initial use of the catalyst system, the recycling of the catalyst system is stopped. Figure 5 It can be seen that the catalytic system can be used 5 times.

[0086] Embodiment 14

[0087] Feasibility of regeneration of catalytic system composed of deep eutectic solvent and acidic ionic liquid

[0088] Taking the catalytic system of Example 13 which has been used 7 times as an example, the feasibility of regenerating the catalytic system was investigated: the filtrate produced in Example 13 was evaporated to remove the ethanol aqueous solution, and then 15 ml of ether was added for washing and liquid separation, and the lower layer of liquid was collected, and then 15 ml of ether was added to continue washing and liquid separation, and the lower layer of liquid was collected, and washing was performed 3 times in total. Finally, the lower layer of liquid collected after the third washing was vacuum dried at 85° C. to constant weight.

[0089] Embodiments 15 to 19

[0090] Feasibility of recycling the catalytic system composed of deep eutectic solvent and acidic ionic liquid after regeneration

[0091] Taking the catalyst system of Example 1 as an example, the feasibility of recycling the catalyst system after regeneration was investigated: 1.0 mmol benzaldehyde (0.11 g), 1.0 mmol urea (0.06 g) and 1.0 mmol 4-hydroxycoumarin were added to the regenerated catalyst system produced in Example 14, and then the catalyst system was recycled according to the operating steps and reaction conditions of Example 1. The catalyst system was used 5 times in total, and the yield and purity of the product 4-phenyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione each time were as follows: Figure 6 .

[0092] When the HPLC purity of the product is lower than 98% or the calculated yield is lower than that of the first use of the regenerated catalyst system by more than 5%, the recycling of the regenerated catalyst system is stopped. Figure 6 It can be seen that the regenerated catalytic system can be used three times.

[0093] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific implementation methods 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 drug intermediate chromeno[4,3-d]pyrimidinone derivative, characterized in that: The reaction formula of the preparation method is: The preparation method uses aromatic aldehyde, urea or thiourea and 4-hydroxycoumarin as reaction raw materials, and prepares chromeno[4,3-d]pyrimidinone derivatives by one-step reaction under a catalytic system consisting of an acidic ionic liquid and a low eutectic solvent and heating conditions.

2. A method for preparing a pharmaceutical intermediate chromeno[4,3-d]pyrimidinone derivative according to claim 1, characterized in that: At room temperature, a preset amount of reaction raw materials is first added to a catalytic system consisting of a low eutectic solvent as a solvent and an acidic ionic liquid as a catalyst, and then mixed evenly to form a mixed solution → heated to a preset temperature → kept warm for a preset time until the reaction is completed → naturally cooled to room temperature and then an ethanol aqueous solution is added → allowed to stand, filtered, and the residue is vacuum dried to obtain a chromeno[4,3-d]pyrimidinone derivative.

3. A method for preparing a pharmaceutical intermediate chromeno[4,3-d]pyrimidinone derivative according to claim 2, characterized in that: Mixing uniformly to form a mixed solution: adding a preset amount of aromatic aldehyde, urea or thiourea and 4-hydroxycoumarin into a flask equipped with a thermometer, a magnetic stirrer and a condenser containing a catalytic system consisting of a deep eutectic solvent as a solvent and an acidic ionic liquid as a catalyst, and mixing uniformly under magnetic stirring; Heating to preset temperature: uniformly heating to 63-72°C under magnetic stirring; Keep warm for the preset time until the reaction is finished: keep warm at 63-72℃ for 12-27min until the reaction is finished; After cooling naturally to room temperature, add ethanol aqueous solution: after the heat preservation reaction is completed, the reaction solution is cooled naturally to room temperature and a preset amount of ethanol aqueous solution is added; Standing, filtering, and vacuum drying the filter residue: After standing for 8 hours, filter and vacuum dry the filter residue at 85°C to constant weight.

4. A method for preparing a pharmaceutical intermediate chromeno[4,3-d]pyrimidinone derivative according to claim 1, characterized in that: The aromatic aldehyde in the reaction raw material is any one of benzaldehyde, o-chlorobenzaldehyde, o-hydroxybenzaldehyde, o-nitrobenzaldehyde, m-chlorobenzaldehyde, m-nitrobenzaldehyde, m-hydroxybenzaldehyde, p-chlorobenzaldehyde, p-hydroxybenzaldehyde, p-tolualdehyde, p-methoxybenzaldehyde, p-nitrobenzaldehyde and p-dimethylaminobenzaldehyde.

5. A method for preparing a pharmaceutical intermediate chromeno[4,3-d]pyrimidinone derivative according to claim 4, characterized in that: The molar ratio of the aromatic aldehyde, urea or thiourea and 4-hydroxycoumarin in the reaction raw materials is 1:1:

1.

6. A method for preparing a pharmaceutical intermediate chromeno[4,3-d]pyrimidinone derivative according to claim 5, characterized in that: The low eutectic solvent is obtained by mixing and heating choline chloride and oxalic acid in a molar ratio of 1:

1.

7. A method for preparing a pharmaceutical intermediate chromeno[4,3-d]pyrimidinone derivative according to claim 6, characterized in that: The volume of the deep eutectic solvent in milliliters is 9 to 16 times the amount of the aromatic aldehyde substance in millimoles.

8. A method for preparing a pharmaceutical intermediate chromeno[4,3-d]pyrimidinone derivative according to claim 7, characterized in that: The structural formula of the acidic ionic liquid is: The amount of the acidic ionic liquid used in the reaction is 8-12% of the amount of the aromatic aldehyde used.

9. A method for preparing a pharmaceutical intermediate chromeno[4,3-d]pyrimidinone derivative according to claim 8, characterized in that: The volume usage of the ethanol aqueous solution in milliliters is 12 to 17 times the amount of the aromatic aldehyde substance in millimoles, and the volume ratio concentration of ethanol contained in the ethanol aqueous solution is 95 to 97%.

10. A catalytic system for preparing a drug intermediate chromeno[4,3-d]pyrimidinone derivative, characterized in that: The catalytic system according to any one of claims 1 to 9 can be recycled or regenerated after the preparation of the chromeno[4,3-d]pyrimidinone derivative; The specific process of recycling the catalytic system is as follows: After the filtrate is filtered, the ethanol aqueous solution is evaporated and then the aromatic aldehyde, urea or thiourea and 4-hydroxycoumarin are directly added to the filtrate for recycling. When the HPLC purity of the chromeno[4,3-d]pyrimidinone derivative obtained in the recycling process is lower than 98% or the calculated yield is reduced by more than 5% compared with the initial use of the catalyst system, the recycling of the catalyst system is stopped; The specific process of catalytic system regeneration is as follows: After the filtrate that cannot be recycled is evaporated to remove the ethanol aqueous solution, ether is added for washing and liquid separation, and the lower layer of liquid is collected. Then, the same amount of ether is added to continue washing and liquid separation, and the lower layer of liquid is collected. Washing is performed 3 to 5 times in total. The lower layer of liquid collected after the last washing is vacuum dried at 85° C. to constant weight, thereby obtaining a regenerated catalyst system; The volume of ether used is 1.5 to 1.8 times that of the deep eutectic solvent.

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