A quinazolinone compound and its preparation method

Abstract

The present invention relates to the field of chemical synthesis technology, and specifically discloses a quinazolinone compound and a preparation method thereof. The quinazolinone compound provided by the present invention has a structure as shown in formula (I): #imgabs0# R1, R2, R3, and R4 are each independently selected from H, halogen, nitro, methyl, or methoxy, wherein at least two of R1, R2, R3, and R4 are H. The present invention provides a quinazolinone compound with a novel structure, enriching the variety of quinazolinone compounds and providing a new class of compounds for the development of antibacterial, antitumor, anti-allergic, antidiabetic, anti-human immunodeficiency virus (HIV), and anticonvulsant drugs. This is of great significance for studying the activity of such compounds and expanding the application of quinazolinone compounds in the medical field and industrial production, and provides a basis for the research of new drugs with unique physiological activities.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a quinazolinone compound and a preparation method thereof. Background Art

[0002] Nitrogen-containing heterocyclic compounds hold broad application prospects in both pharmaceuticals and pesticides, particularly quinazolines and quinazolinones, which are widely found in nature. Quinazolinones, a typical class of quinazoline derivatives, possess multiple pharmacological and biological activities, including significant antibacterial, antitumor, antiallergic, antidiabetic, anti-human immunodeficiency virus (HIV) and anticonvulsant effects. Due to their broad application prospects in both medicine and industrial production, the design and synthesis of quinazolinone compounds have attracted increasing attention from researchers.

[0003] Currently, the preparation of quinazolinone compounds usually uses o-aminobenzoic acid, o-aminobenzamide, o-amino aromatic ketone or o-halo aromatic ketone, or o-aminobenzylamine as substrates for reaction. This reaction process has many problems, such as complex reaction steps, the need to carry out the reaction at high temperature, poor substrate adaptability, the need for strong oxidants to participate in the reaction, and when some reagents are highly toxic, special post-treatment is required, which limits their scope of application. Therefore, it is of great significance to develop a new quinazolinone compound and its preparation method. Summary of the Invention

[0004] In order to enrich the types of quinazolinone compounds and solve the problem that the methods for synthesizing quinazolinone compounds in the prior art are relatively complicated, the present invention provides a quinazolinone compound and a preparation method thereof.

[0005] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0006] The present invention provides a quinazolinone compound, the structure of which is shown in formula (I):

[0007]

[0008] R1, R2, R3 and R4 are each independently selected from H, halogen, nitro, methyl or methoxy, wherein at least two of R1, R2, R3 and R4 are H;

[0009] R5 is selected from H, halogen, methoxy or methyl; R6 is selected from methyl, phenyl, p-methoxyphenyl, p-tolyl or p-hydroxyphenyl.

[0010] Compared with the prior art, the present invention provides a quinazolinone compound with a novel structure, enriching the types of quinazolinone compounds and providing a new class of compounds for the development of antibacterial, antitumor, anti-allergic, anti-diabetic, anti-human immunodeficiency virus (HIV) and anticonvulsant drugs. This is of great significance for studying the activity of this class of compounds and expanding the application of quinazolinone compounds in the medical field and industrial production, and provides a basis for studying new drugs with unique physiological activities.

[0011] The present invention also provides a method for preparing the above-mentioned quinazolinone compound, comprising the following steps:

[0012] Under an inert atmosphere, a 4-hydroxyquinazoline compound represented by formula (II) and an active benzyl alcohol compound represented by formula (III) undergo a substitution reaction in an organic solvent to obtain a quinazolinone compound;

[0013]

[0014] R1, R2, R3 and R4 are each independently selected from H, halogen, nitro, methyl or methoxy, wherein at least two of R1, R2, R3 and R4 are H;

[0015] R5 is selected from H, halogen, methoxy or methyl; R6 is selected from methyl, phenyl, p-methoxyphenyl, p-tolyl or p-hydroxyphenyl;

[0016] Wherein, the organic solvent is toluene, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, 1,4-dioxane or hexafluoroisopropanol.

[0017] Currently, there are many reports on the preparation of quinazolinone compounds, but there are no reports on the synthesis of quinazolinone compounds using 4-hydroxyquinazoline compounds and benzyl alcohol compounds as raw materials through a one-step process. The present invention uses 4-hydroxyquinazoline compounds and active benzyl alcohol compounds as reaction substrates to generate novel quinazolinone compounds through a one-step reaction, achieving structural diversification of the target compounds and having important value in expanding the application of quinazolinone compounds in the fields of medicine and industrial production.

[0018] The present invention utilizes a 4-hydroxyquinazoline compound with a specific structure and an active benzyl alcohol compound as reaction substrates, and can initiate a substitution reaction in a specific organic solvent. While ensuring the purity of the target product, the yield is greatly improved, the steps of separating and purifying the intermediate are reduced, the operation is convenient, the atom economy is high, the substrate has a wide range of applicability, the production cost is low, and industrial production is easily realized.

[0019] Preferably, the organic solvent is hexafluoroisopropanol.

[0020] In the present invention, hexafluoroisopropanol can be used not only as an organic solvent but also as a catalyst. The coordinated hydrogen bond between the alcoholic hydroxyl group in hexafluoroisopropanol and the substrate weakens the nucleophilicity of oxygen, improves the regioselectivity, thereby increasing the reaction rate, allowing the reaction substrate to fully react, and further improving the purity and yield of the target product.

[0021] Preferably, the inert atmosphere is provided by an inert gas commonly used in the art, such as nitrogen, argon, etc.

[0022] Preferably, the molar ratio of the 4-hydroxyquinazoline compound to the active benzyl alcohol compound is 1-3:1.

[0023] Preferably, the molar ratio of the 4-hydroxyquinazoline compound to the active benzyl alcohol compound is 2:1.

[0024] The preferred ratio can ensure that the reaction proceeds in the forward direction and increase the yield of the target product under the condition of a smaller dosage.

[0025] Preferably, the molar volume ratio of the 4-hydroxyquinazoline compound to the organic solvent is 1:1-3, wherein the unit of mole is mmol and the unit of volume is mL.

[0026] Preferably, the molar volume ratio of the 4-hydroxyquinazoline compound to the organic solvent is 1:1.5, wherein the unit of mole is mmol and the unit of volume is mL.

[0027] The preferred amount of organic solvent used ensures that the raw materials are fully dissolved, allowing them to fully react and increasing the yield of the target product.

[0028] Preferably, the temperature of the substitution reaction is 80°C-130°C.

[0029] Preferably, the temperature of the substitution reaction is 120°C.

[0030] The preferred substitution reaction temperature can reduce the occurrence of side reactions and improve the purity and yield of the target product.

[0031] Preferably, thin layer chromatography is used to detect the reaction progress during the substitution reaction to determine the reaction completion time.

[0032] Preferably, the preparation method of the quinazolinone compound further comprises a purification step: adding anhydrous ethanol to the reaction product for extraction, adding a saturated sodium chloride solution to the extract for washing, dehydrating with anhydrous sodium sulfate, concentrating, and separating and purifying by silica gel column chromatography to obtain the quinazolinone compound.

[0033] Preferably, the developing solvent in the silica gel column chromatography is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 5-8:1. DETAILED DESCRIPTION

[0034] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0035] In order to better illustrate the present invention, further examples are given below.

[0036] The purity of the target products prepared in the examples of the present invention was determined by TLC point-half detection.

[0037] Example 1

[0038] Preparation of 3-(bis(4-methoxyphenyl)methyl)quinazolin-4(3H)one:

[0039] 4-Hydroxyquinazoline (1 mmol) and 4,4'-dimethoxybenzhydrol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol. The air in the flask was replaced with argon. The reaction mixture was stirred at 120°C and the reaction process was monitored by thin layer chromatography. After the reaction was completed, it was quenched with water (15 mL).

[0040] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, and filtered. The filtrate was concentrated and chromatographed on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 5:1) to obtain 170 mg of the product with a purity of 94% and a yield of 91%.

[0041] The reaction equation is as follows:

[0042]

[0043] The obtained product was subjected to nuclear magnetic resonance detection. 1 The detection results of H NMR (500MHz, CDCl3) were: δ8.36 (dd, J=8.1, 1.5Hz, 1H), 8.02 (s, 1H), 7.79 (ddd, J=8.4, 7.0, 1.5Hz, 1H), 7.74 (d, J=8.1Hz, 1H), 7.54 (ddd, J=8.2, 7.0, 1.3Hz, 1H), 7.37 (s, 1H), 7.18 (d, J=1.8Hz, 4H), 6.96-6.90 (m, 4H), 3.84 (s, 6H).

[0044] 13C NMR (126MHz, CDCl3) detection results: δ160.93, 159.49, 147.64, 145.50, 134.38, 130.31, 129.75, 127.46, 127.34, 127.15, 114.44, 60.04, 55.39.

[0045] Example 2

[0046] Preparation of 3-(bis(4-methoxyphenyl)methyl)-6-fluoroquinazolin-4(3H)one:

[0047] 6-Fluoro-4-hydroxyquinazoline (1 mmol) and 4,4'-dimethoxybenzhydrol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol. The air in the flask was replaced with argon. The reaction mixture was stirred at 120°C and the reaction process was monitored by thin layer chromatography. After the reaction was completed, it was quenched with water (15 mL).

[0048] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, and filtered. The filtrate was concentrated and chromatographed on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 5:1) to obtain 180 mg of the product with a purity of 95% and a yield of 92%.

[0049] The reaction equation is as follows:

[0050]

[0051] The obtained product was subjected to nuclear magnetic resonance detection. 1 The detection results of H NMR (400 MHz, CDCl3) were: δ7.97-7.92 (m, 2H), 7.70 (dd, J = 8.9, 4.8 Hz, 1H), 7.47 (td, J = 8.5, 3.0 Hz, 1H), 7.31 (s, 1H), 7.15-7.09 (m, 4H), 6.93-6.87 (m, 4H), 3.80 (s, 6H).

[0052] 13 C NMR (101MHz, CDCl3) detection results: δ159.50, 144.75, 144.73, 130.04, 129.70, 123.03, 122.79, 114.43, 112.08, 111.84, 60.20, 55.35.

[0053] Example 3

[0054] Preparation of 3-(bis(4-methoxyphenyl)methyl)-5-chloroquinazolin-4(3H)one:

[0055] 5-Chloro-4-hydroxyquinazoline (1 mmol) and 4,4'-dimethoxybenzhydrol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol. The air in the flask was replaced with argon. The reaction mixture was stirred at 120°C and the reaction process was monitored by thin layer chromatography. After completion of the reaction, the reaction was quenched with water (15 mL).

[0056] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, and filtered. The filtrate was concentrated and separated by chromatography on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 6:1) to obtain 175 mg of the product with a purity of 96% and a yield of 86%.

[0057] The reaction equation is as follows:

[0058]

[0059] The obtained product was subjected to nuclear magnetic resonance detection. 1 The detection results of H NMR (400 MHz, CDCl3) were: δ7.97 (s, 1H), 7.62-7.57 (m, 2H), 7.50 (dd, J=5.3, 3.7 Hz, 1H), 7.28 (s, 1H), 7.17-7.11 (m, 4H), 6.93-6.87 (m, 4H), 3.80 (s, 6H).

[0060] 13 C NMR (101MHz, CDCl3) detection results: δ159.49, 150.07, 146.12, 134.48, 133.70, 130.13, 130.10, 129.73, 126.81, 119.09, 114.44, 60.04, 55.36.

[0061] Example 4

[0062] Preparation of 3-(bis(4-methoxyphenyl)methyl)-8-chloroquinazoline-4(3H)one:

[0063] 8-Chloro-4-hydroxyquinazoline (1 mmol) and 4,4'-dimethoxybenzhydrol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol. The air in the flask was replaced with argon. The reaction mixture was stirred at 120°C and the reaction process was monitored by thin layer chromatography. After completion of the reaction, the reaction was quenched with water (15 mL).

[0064] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, filtered, and the filtrate was concentrated and separated by chromatography on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 5:1) to obtain 169 mg of the product with a purity of 93% and a yield of 83%.

[0065] The reaction equation is as follows:

[0066]

[0067] The obtained product was subjected to nuclear magnetic resonance detection. 1 The detection results of H NMR (400 MHz, CDCl3) were: δ8.25 (dd, J=8.0, 1.4 Hz, 1H), 8.11 (s, 1H), 7.84 (dd, J=7.8, 1.5 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.28 (s, 1H), 7.15-7.11 (m, 4H), 6.91-6.87 (m, 4H), 3.80 (s, 6H).

[0068] 13 C NMR (101MHz, CDCl3) detection results: δ159.58, 146.30, 134.60, 131.81, 129.85, 129.68, 127.38, 125.98, 123.45, 114.47, 113.47, 60.51, 55.37.

[0069] Example 5

[0070] Preparation of 3-(bis(4-methoxyphenyl)methyl)-6-iodoquinazolin-4(3H)one:

[0071] 6-iodo-4-hydroxyquinazoline (1 mmol) and 4,4'-dimethoxybenzhydrol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol. The air in the flask was replaced with argon. The reaction mixture was stirred at 120° C. The reaction process was monitored by thin layer chromatography. After completion of the reaction, the reaction was quenched with water (15 mL).

[0072] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, and filtered. The filtrate was concentrated and chromatographed on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 6:1) to obtain 225 mg of the product with a purity of 96% and a yield of 90%.

[0073] The reaction equation is as follows:

[0074]

[0075] The obtained product was subjected to nuclear magnetic resonance detection. 1 The detection results of H NMR (400MHz, CDCl3) were: δ8.65 (d, J=2.0Hz, 1H), 8.01 (dd, J=8.6, 2.1Hz, 1H), 7.97 (s, 1H), 7.42 (d, J=8.5Hz, 1H), 7.29 (s, 1H), 7.14-7.09 (m, 4H), 6.92-6.87 (m, 4H), 3.80 (s, 6H).

[0076] 13 C NMR (101MHz, CDCl3) detection results: δ159.52, 145.95, 143.11, 135.97, 129.94, 129.69, 129.24, 123.45, 114.44, 60.26, 55.36, 55.36.

[0077] Example 6

[0078] Preparation of 3-(bis(4-methoxyphenyl)methyl)-6-chloroquinazolin-4(3H)one:

[0079] 6-Chloro-4-hydroxyquinazoline (1 mmol) and 4,4'-dimethoxybenzhydrol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol. The air in the flask was replaced with argon. The reaction mixture was stirred at 120° C. The reaction process was monitored by thin layer chromatography. After completion of the reaction, the reaction was quenched with water (15 mL).

[0080] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, filtered, and the filtrate was concentrated and separated by chromatography on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 5:1) to obtain 184 mg of the product with a purity of 96% and a yield of 90%.

[0081] The reaction equation is as follows:

[0082]

[0083] The obtained product was subjected to nuclear magnetic resonance detection. 1The detection results of H NMR (400 MHz, CDCl3) were: δ8.28 (d, J=2.3 Hz, 1H), 7.96 (s, 1H), 7.72-7.61 (m, 2H), 7.30 (s, 1H), 7.15-7.10 (m, 4H), 6.92-6.87 (m, 4H), 3.80 (s, 6H).

[0084] 13 C NMR (101MHz, CDCl3) detection results: δ159.92, 159.52, 145.61, 134.75, 133.12, 129.97, 129.69, 129.12, 126.45, 114.44, 60.24, 55.36.

[0085] Example 7

[0086] Preparation of 3-(bis(4-methoxyphenyl)methyl)-6,7-difluoroquinazolin-4(3H)one:

[0087] 6,7-Difluoro-4-hydroxyquinazoline (1 mmol) and 4,4'-dimethoxybenzhydrol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol. The air in the flask was replaced with argon. The reaction mixture was stirred at 120°C and the reaction process was monitored by thin layer chromatography. After the reaction was completed, the reaction was quenched with water (15 mL).

[0088] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, and filtered. The filtrate was concentrated and chromatographed on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 5:1) to obtain 180 mg of the product with a purity of 90% and a yield of 88%.

[0089] The reaction equation is as follows:

[0090]

[0091] The obtained product was subjected to nuclear magnetic resonance detection. 1 The detection results of H NMR (500 MHz, CDCl3) were: δ8.10 (dd, J=10.0, 8.4 Hz, 1H), 7.99 (s, 1H), 7.51 (dd, J=10.5, 7.0 Hz, 1H), 7.31 (s, 1H), 7.16 (s, 4H), 6.96-6.91 (m, 4H), 3.84 (s, 6H).

[0092] 13C NMR (126MHz, CDCl3) detection results: δ159.62, 146.10, 129.83, 129.71, 115.35, 115.20, 114.53, 114.48, 113.49, 60.44, 55.40.

[0093] Example 8

[0094] Preparation of 3-(bis(4-methoxyphenyl)methyl)-7-bromoquinazolin-4(3H)one:

[0095] 7-Bromo-4-hydroxyquinazoline (1 mmol) and 4,4'-dimethoxybenzhydrol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol. The air in the flask was replaced with argon. The reaction mixture was stirred at 120°C and the reaction process was monitored by thin layer chromatography. After completion of the reaction, the reaction was quenched with water (15 mL).

[0096] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, and filtered. The filtrate was concentrated and chromatographed on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 8:1) to obtain 172 mg of the product with a purity of 95% and a yield of 76%.

[0097] The reaction equation is as follows:

[0098]

[0099] The obtained product was subjected to nuclear magnetic resonance detection. 1 The detection results of H NMR (400MHz, CDCl3) were: δ8.16 (d, J=8.5Hz, 1H), 7.97 (s, 1H), 7.87 (d, J=1.8Hz, 1H), 7.60 (dd, J=8.5, 1.9Hz, 1H), 7.28 (s, 1H), 7.15-7.09 (m, 4H), 6.93-6.87 (m, 4H), 3.80 (s, 6H).

[0100] 13 C NMR (101MHz, CDCl3) detection results: δ160.45, 159.52, 148.68, 146.57, 130.66, 130.20, 129.97, 129.68, 128.57, 120.70, 114.45, 60.21, 55.36.

[0101] Example 9

[0102] Preparation of 3-(bis(4-methoxyphenyl)methyl)-7-chloro-6-nitroquinazolin-4(3H)one:

[0103] 7-Chloro-6-nitro-4-hydroxyquinazoline (1 mmol) and 4,4'-dimethoxybenzhydrol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol. The air in the flask was replaced with argon. The reaction mixture was stirred at 120° C. The reaction process was monitored by thin layer chromatography. After completion of the reaction, the reaction was quenched with water (15 mL).

[0104] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, filtered, and the filtrate was concentrated and separated by chromatography on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 6:1) to obtain 193 mg of the product with a purity of 96% and a yield of 85%.

[0105] The reaction equation is as follows:

[0106]

[0107] The obtained product was subjected to nuclear magnetic resonance detection. 1 The detection results of H NMR (400MHz, CDCl3) were: δ8.80(s,1H),8.07(s,1H),7.86(s,1H),7.25(s,1H),7.14-7.09(m,4H),6.94-6.89(m,4H),3.81(s,6H).

[0108] 13 C NMR (101MHz, CDCl3) detection results: δ159.73, 159.14, 150.19, 149.09, 146.04, 132.47, 130.74, 129.66, 129.24, 125.31, 120.63, 114.60, 60.84, 55.39.

[0109] Example 10

[0110] Preparation of 3-(bis(4-methoxyphenyl)methyl)-6-methylquinazolin-4(3H)one:

[0111] 6-Methyl-4-hydroxyquinazoline (1 mmol) and 4,4'-dimethoxybenzhydrol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol. The air in the flask was replaced with argon. The reaction mixture was stirred at 120°C and the reaction process was monitored by thin layer chromatography. After completion of the reaction, the reaction was quenched with water (15 mL).

[0112] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, and filtered. The filtrate was concentrated and separated by chromatography on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 5:1) to obtain 168 mg of the product with a purity of 94% and a yield of 87%.

[0113] The reaction equation is as follows:

[0114]

[0115] The obtained product was subjected to nuclear magnetic resonance detection. 1 The detection results of H NMR (400MHz, CDCl3) were: δ8.11 (dt, J=1.8, 0.9Hz, 1H), 7.93 (s, 1H), 7.63-7.54 (m, 2H), 7.34 (s, 1H), 7.14 (d, J=1.9Hz, 2H), 7.12 (d, J=2.2Hz, 2H), 6.90 (d, J=2.2Hz, 2H), 6.88 (d, J=2.0Hz, 2H), 3.80 (s, 6H), 2.49 (s, 3H).

[0116] 13 C NMR (101MHz, CDCl3) detection results: δ159.41, 145.60, 144.69, 137.55, 135.78, 130.39, 129.70, 127.21, 126.51, 121.58, 114.36, 59.88, 55.34, 21.37.

[0117] Example 11

[0118] Preparation of 3-(bis(4-methoxyphenyl)methyl)-6-methoxyquinazolin-4(3H)one:

[0119] 6-Methoxy-4-hydroxyquinazoline (1 mmol) and 4,4'-dimethoxybenzhydrol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol. The air in the flask was replaced with argon. The reaction mixture was stirred at 120°C and the reaction process was monitored by thin layer chromatography. After completion of the reaction, the reaction was quenched with water (15 mL).

[0120] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, filtered, and the filtrate was concentrated and separated by chromatography on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 5:1) to obtain 179 mg of the product with a purity of 95% and a yield of 89%.

[0121] The reaction equation is as follows:

[0122]

[0123] The obtained product was subjected to nuclear magnetic resonance detection. 1 The detection results of H NMR (400 MHz, CDCl3) were: δ7.89 (s, 1H), 7.69 (d, J = 2.9 Hz, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.38-7.33 (m, 2H), 7.16-7.11 (m, 4H), 6.92-6.86 (m, 4H), 3.91 (s, 3H), 3.80 (s, 6H).

[0124] 13 C NMR (101MHz, CDCl3) detection results: δ159.42, 158.76, 143.29, 142.19, 130.31, 129.72, 128.97, 124.65, 114.37, 106.38, 60.09, 55.83, 55.35.

[0125] Example 12

[0126] Preparation of 3-(bis(4-methoxyphenyl)methyl)-8-methylquinazolin-4(3H)one:

[0127] 8-Methyl-4-hydroxyquinazoline (1 mmol) and 4,4'-dimethoxybenzhydrol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol. The air in the flask was replaced with argon. The reaction mixture was stirred at 120°C and the reaction process was monitored by thin layer chromatography. After completion of the reaction, the reaction was quenched with water (15 mL).

[0128] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, filtered, and the filtrate was concentrated and separated by chromatography on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 5:1) to obtain 174 mg of the product with a purity of 95% and a yield of 90%.

[0129] The reaction equation is as follows:

[0130]

[0131] The obtained product was subjected to nuclear magnetic resonance detection. 1The detection results of H NMR (400MHz, CDCl3) were: δ8.21-8.16 (m, 1H), 8.02 (s, 1H), 7.61 (dt, J = 7.3, 1.1 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.32 (s, 1H), 7.14 (d, J = 2.1 Hz, 2H), 7.13 (d, J = 2.2 Hz, 2H), 6.90 (d, J = 2.1 Hz, 2H), 6.88 (d, J = 2.1 Hz, 2H), 3.80 (s, 6H), 2.59 (s, 3H).

[0132] 13 C NMR (101MHz, CDCl3) detection results: δ161.21, 159.43, 146.19, 144.33, 135.77, 134.99, 130.38, 129.71, 126.89, 124.82, 121.84, 114.38, 59.98, 55.35, 17.28.

[0133] Example 13

[0134] Preparation of 3-benzoylquinazolin-4(3H)one:

[0135] 4-Hydroxyquinazoline (1 mmol) and benzhydrol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 120° C. and the reaction process was monitored by thin layer chromatography. After the reaction was completed, it was quenched with water (15 mL).

[0136] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, filtered, and the filtrate was concentrated and separated by chromatography on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 8:1) to obtain 113 mg of the product with a purity of 93% and a yield of 72%.

[0137] The reaction equation is as follows:

[0138]

[0139] The obtained product was subjected to nuclear magnetic resonance detection. 1The detection results of H NMR (500MHz, CDCl3) were: δ8.38 (dd, J=8.1, 1.5Hz, 1H), 8.02 (s, 1H), 7.81 (td, J=7.6, 7.0, 1.6Hz, 1H), 7.75 (d, J=7.5Hz, 1H), 7.59-7.53 (m, 1H), 7.50 (s, 1H), 7.44-7.36 (m, 6H), 7.28-7.24 (m, 4H).

[0140] 13 C NMR (126MHz, CDCl3) detection results: δ160.93, 145.49, 138.05, 134.50, 129.12, 128.62, 128.43, 127.50, 127.46, 127.20, 60.82.

[0141] Example 14

[0142] Preparation of 3-(di-p-tolylmethyl)quinazolin-4(3H)-one:

[0143] 4-Hydroxyquinazoline (1 mmol) and 4,4'-dimethylbenzhydrol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol. The air in the flask was replaced with argon. The reaction mixture was stirred at 120°C and the reaction process was monitored by thin layer chromatography. After the reaction was completed, the reaction was quenched with water (15 mL).

[0144] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, filtered, and the filtrate was concentrated and separated by chromatography on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 6:1) to obtain 141 mg of the product with a purity of 94% and a yield of 83%.

[0145] The reaction equation is as follows:

[0146]

[0147] The obtained product was subjected to nuclear magnetic resonance detection. 1 The detection results of H NMR (400MHz, CDCl3) were: δ8.37 (dd, J=8.0,1.4Hz,1H),8.01(s,1H),7.83-7.71(m,2H),7.58-7.51(m,1H),7.40(s,1H),7.21(d, J=8.0Hz,4H),7.14(d, J=8.0Hz,4H),2.39(s,6H).

[0148] 13C NMR (101MHz, CDCl3) detection results: δ147.68, 145.60, 138.18, 135.23, 134.39, 129.74, 128.49, 127.48, 127.34, 127.18, 121.92, 60.49, 21.17.

[0149] Example 15

[0150] Preparation of 3-((4-chlorophenyl)(4-hydroxyphenyl)methyl)quinazolin-4(3H)one:

[0151] 4-Hydroxyquinazoline (1 mmol) and 4-((4-chlorophenyl)(hydroxy)methyl)phenol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 120° C. and the reaction process was monitored by thin layer chromatography. After completion of the reaction, the reaction was quenched with water (15 mL).

[0152] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, and filtered. The filtrate was concentrated and chromatographed on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 5:1) to obtain 151 mg of the product with a purity of 90% and a yield of 83%.

[0153] The reaction equation is as follows:

[0154]

[0155] The obtained product was subjected to nuclear magnetic resonance detection. 1 The detection results of H NMR (500MHz, CDCl3) were: δ8.46-8.28 (m, 2H), 7.96 (s, 1H), 7.84-7.71 (m, 2H), 7.59-7.51 (m, 1H), 7.38-7.27 (m, 3H), 7.12 (d, J = 8.4 Hz, 2H), 7.01-6.94 (m, 2H), 6.80-6.70 (m, 2H).

[0156] 13 C NMR (126MHz, CDCl3) detection results: δ160.92, 157.12, 146.88, 145.51, 136.68, 134.98, 134.30, 130.30, 129.37, 129.26, 128.27, 127.98, 127.27, 127.00, 121.58, 116.31, 60.47.

[0157] Example 16

[0158] Preparation of 3-(1-(4-methoxyphenyl)ethyl)quinazolin-4(3H)one:

[0159] 4-Hydroxyquinazoline (1 mmol) and 1-(4-methoxyphenyl)ethanol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 120 ° C. The reaction process was monitored by thin layer chromatography. After the reaction was completed, it was quenched with water (15 mL).

[0160] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, filtered, and the filtrate was concentrated and separated by chromatography on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 6:1) to obtain 124 mg of the product with a purity of 92% and a yield of 89%.

[0161] The reaction equation is as follows:

[0162]

[0163] The obtained product was subjected to nuclear magnetic resonance detection. 1 The detection results of H NMR (500MHz, CDCl3) were: δ8.35 (dd, J=8.1, 1.5Hz, 1H), 7.94 (s, 1H), 7.94 (s, 1H), 7.78-7.63 (m, 2H), 7.53-7.45 (m, 1H), 7.31 (d, J=8.6Hz, 2H), 6.95–6.86 (m, 2H), 6.32 (q, J=7.1Hz, 1H), 3.78 (s, 3H), 1.81 (d, J=7.2Hz, 3H).

[0164] 13 C NMR (126MHz, CDCl3) detection results: δ160.83, 159.52, 147.64, 144.59, 134.23, 131.40, 128.67, 127.43, 127.25, 126.99, 121.92, 114.40, 114.10, 113.92, 55.35, 51.44, 19.37.

[0165] Example 17

[0166] Preparation of 3-(bis(4-methoxyphenyl)methyl)-5-methylquinazolin-4(3H)one:

[0167] 5-Methyl-4-hydroxyquinazoline (1 mmol) and 4,4'-dimethoxybenzhydrol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol. The air in the flask was replaced with argon. The reaction mixture was stirred at 120° C. The reaction process was monitored by thin layer chromatography. After completion of the reaction, the reaction was quenched with water (15 mL).

[0168] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, filtered, and the filtrate was concentrated and separated by chromatography on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 5:1) to obtain 153 mg of the product with a purity of 95% and a yield of 79%.

[0169] The reaction equation is as follows:

[0170]

[0171] The obtained product was subjected to nuclear magnetic resonance detection. 1 The detection results of H NMR (400MHz, CDCl3) were: δ7.92 (s, 1H), 7.54 (ddd, J = 14.4, 8.2, 6.9 Hz, 2H), 7.29 (s, 1H), 7.24-7.21 (m, 1H), 7.14 (d, J = 2.2 Hz, 2H), 7.12 (d, J = 2.2 Hz, 2H), 6.89 (d, J = 2.2 Hz, 2H), 6.88 (d, J = 2.1 Hz, 2H), 3.78 (s, 6H), 2.88 (s, 3H).

[0172] 13 C NMR (101MHz, CDCl3) detection results: δ161.37, 159.39, 149.24, 145.33, 141.51, 133.45, 130.60, 129.96, 129.70, 125.69, 114.38, 59.58, 55.33, 23.36.

[0173] Example 18

[0174] Preparation of 3-(phenyl(m-tolyl)methyl)quinazolin-4(3H)one:

[0175] 4-Hydroxyquinazoline (1 mmol) and phenyl (m-tolyl) methanol (0.5 mmol) were added to a single-necked flask containing 1.5 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 120 ° C. The reaction process was monitored by thin layer chromatography. After the reaction was completed, it was quenched with water (15 mL).

[0176] The reaction product was extracted with ethyl acetate (3×20 mL), washed with saturated brine (20 mL), dehydrated with anhydrous Na2SO4, filtered, and the filtrate was concentrated and separated by chromatography on a silica gel column (200-300 mesh, developing solvent: petroleum ether / ethyl acetate = 5:1) to obtain 129 mg of the product with a purity of 94% and a yield of 79%.

[0177] The reaction equation is as follows:

[0178]

[0179] The obtained product was subjected to nuclear magnetic resonance detection. 1 The detection results of H NMR (400MHz, CDCl3) were: δ8.39 (dd, J=8.0,1.6Hz,1H),8.05 (s,1H),7.83-7.72 (m,2H),7.54 (td, J=7.5,6.7,1.6Hz,1H),7.48 (s,1H),7.45-7.34 (m,3H),7.31 (d, J=7.6Hz,1H),7.28 (s,1H),7.26 (s,1H),7.19 (d, J=7.7Hz,1H),7.10 (s,1H),7.05 (d, J=7.8Hz,1H),2.35 (s,3H).

[0180] 13 C NMR (101MHz, CDCl3) detection results: δ147.69, 145.60, 138.94, 138.22, 138.03, 134.47, 129.34, 129.23, 129.09, 128.99, 128.62, 128.36, 127.55, 127.41, 127.20, 125.71, 60.81, 21.55.

[0181] Comparative Example 1

[0182] This comparative example is compared with Example 1, except that hexafluoroisopropanol is replaced by an equal amount of dichloromethane, and 0.1 mmol of trifluoromethanesulfonic acid is added as a reaction catalyst, to obtain 56 mg of product with a yield of 30%.

[0183] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing a quinazolinone compound, characterized in that: The steps include: Under an inert atmosphere, a 4-hydroxyquinazoline compound represented by formula (II) and an active benzyl alcohol compound represented by formula (III) undergo a substitution reaction in an organic solvent to obtain a quinazolinone compound represented by formula (I); R1, R2, R3 and R4 are each independently selected from H, halogen, nitro, methyl or methoxy, wherein at least two of R1, R2, R3 and R4 are H; R5 is selected from H, halogen, methoxy or methyl; R6 is selected from methyl, phenyl, p-methoxyphenyl, p-tolyl or p-hydroxyphenyl; Wherein, the organic solvent is hexafluoroisopropanol.

2. The method for preparing a quinazolinone compound according to claim 1, wherein The molar ratio of the 4-hydroxyquinazoline compound to the active benzyl alcohol compound is 1-3:

1.

3. The method for preparing a quinazolinone compound according to claim 2, wherein The molar ratio of the 4-hydroxyquinazoline compound to the active benzyl alcohol compound is 2:

1.

4. The method for preparing the quinazolinone compound according to claim 1, wherein The molar volume ratio of the 4-hydroxyquinazoline compound to the organic solvent is 1:1-3, wherein the unit of mole is mmol and the unit of volume is mL.

5. The method for preparing the quinazolinone compound according to claim 4, wherein The molar volume ratio of the 4-hydroxyquinazoline compound to the organic solvent is 1:1.5, wherein the unit of mole is mmol and the unit of volume is mL.

6. The method for preparing the quinazolinone compound according to claim 1, wherein The temperature of the substitution reaction is 80°C-130°C.

7. The method for preparing the quinazolinone compound according to claim 6, wherein The temperature of the substitution reaction is 120°C.

Images