Preparation method and application of 2-substituted quinazoline derivative

Abstract

The invention discloses a preparation method of a 2-substituted quinazoline derivative, which comprises the following step: heating and stirring three components, namely an ammonium salt, a benzyl alcohol compound and a 2, 1-benzisoxazole compound in an organic solvent to obtain the 2-substituted quinazoline derivative. According to the method, ammonium iodide which is low in price and easy to obtain is used as a nitrogen source and an oxidizing agent, benzyl alcohol is used as a carbon source, and efficient construction from a 2, 1-benzisoxazole skeleton to a 2-substituted quinazoline skeleton is achieved through a carbon-nitrogen diatom inserted ring expansion reaction under the mild conditions of no metal and no additive. The synthetic method developed by the invention has a good application prospect in the industrial fields of biological medicines, pesticides and the like, and is particularly suitable for efficiently preparing the quinazoline compound with biological activity under simple and convenient conditions. The synthetic method developed by the invention has a good application prospect in the industrial fields of biological medicines, pesticides and the like, and a theoretical basis is provided for commercialized application of the derivatives in the field of medicines.

Description

A method for preparing and applying a 2-substituted quinazoline derivative Technical Field

[0001] This invention belongs to the field of organic synthesis, and specifically relates to a novel method for preparing 2-substituted quinazoline derivatives. Background Technology

[0002] Quinazolines and their derivatives, as an important class of nitrogen-containing heterocyclic compounds, are widely found in natural products and synthetic chemicals. These compounds are characterized by simple synthetic routes, high functional group diversity, and flexible and controllable structural modifications, thus attracting considerable attention in the field of medicinal chemistry. Quinazoline structures (especially nitrogen-containing bicyclic heteroaromatic systems) are considered promising drug design frameworks; their chemical structures are often regarded as core units for constructing bioactive molecules. Chemists believe that these frameworks are the main components of bioactive molecules and can exhibit antibacterial effects.

[0003] Currently, the synthesis of quinazolines is mainly based on the cyclization / oxidation reaction of 2-aminobenzylamine. This not only involves prefunctionalized substrates and stoichiometric strong oxidants, but also makes it difficult to achieve the later modification of complex molecules. In recent years, due to the widespread application of quinazolines in biomedical materials, several synthetic methods have been developed over the past few decades. These classic methods often rely on complex nitrogen reagent precursors (Org. Lett., 2020, 22, 6756), noble metal catalysis (J.Org. Chem., 2022, 87, 11253), complex synthetic routes, and the generation of auxiliary waste (Org. Lett., 2016, 18, 4990), making it difficult for conventional synthetic equipment to meet the requirements. The resulting high costs hinder the industrialization of quinazoline derivatives. Therefore, developing a low-cost and simple synthetic route is of practical significance for promoting the industrialization of quinazoline derivatives. Summary of the Invention

[0004] To address the problems existing in the prior art, this invention provides a novel method for preparing 2-substituted quinazoline and its derivatives, which has the advantages of simple reaction conditions, convenient operation, high yield, and low cost.

[0005] To achieve the above objectives, the technical solution of the present invention is as follows: A method for preparing 2-substituted quinazoline and its derivatives, comprising heating and stirring an ammonium salt, a benzyl alcohol compound, and a 2,1-benzisoxazole compound in an organic solvent, wherein the reaction formula is as follows:

[0006] Ar is selected from benzene rings or substituted benzene rings; R is selected from substituted phenyl groups; R1 is selected from one of halogens, alkyl groups, alkoxy groups, and trifluoromethyl groups.

[0007] The substituents of the substituted benzene ring are selected from halogens or methoxy groups.

[0008] The substituents of the substituted phenyl group are selected from methyl groups.

[0009] The ammonium salt is one or more of NH4I, NH4OAc, NH4Cl, and NH4Br.

[0010] The organic solvent includes one or more of toluene, chlorobenzene, o-dichlorobenzene, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, and 1,4-dioxane.

[0011] The molar ratio of the 2,1-benzisoxazole compound to the benzyl alcohol compound and the ammonium salt is 1.0:0.5-2.0.

[0012] The molar ratio of the 2,1-benzisoxazole compound to the ammonium salt is 1.0:0.5-2.0.

[0013] The reaction temperature is 100-120℃.

[0014] The gaseous atmosphere of the reaction is one of air, oxygen, or nitrogen.

[0015] The reaction time is 2-12 h.

[0016] This invention provides a simple and efficient method for preparing 2-substituted quinazoline derivatives. The method uses inexpensive and readily available ammonium iodide as the nitrogen source and oxidant, and benzyl alcohol as the carbon source. Under mild conditions without metals or additives, a ring-expansion reaction involving carbon-nitrogen diatomic insertion is conducted to achieve efficient construction from the 2,1-benzisoxazole skeleton to the 2-substituted quinazoline skeleton.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention adopts a "one-pot method" to realize the three-component reaction of 2,1-benzisoxazole compounds, benzyl alcohol compounds and ammonium iodide in chlorobenzene solution. Through an oxidative coupling process of [4+1+1] cyclization addition, a ring expansion reaction of carbon-nitrogen diatomic insertion is realized, thus obtaining a technical solution for preparing 2-substituted quinazoline derivatives.

[0018] This invention utilizes readily available and inexpensive ammonium iodide as both the nitrogen source and oxidant, avoiding the use of precious metals as dehydrogenation reagents and complex nitrogen reagents as nitrogen precursors. This effectively addresses the high cost associated with preparing 2-substituted quinazoline derivatives. The method features a simple reaction system, requires no metal catalysts or additional additives, has a wide range of raw material sources, broad substrate applicability, and high atom economy. It also involves the functionalization of multiple CO / NO bonds and the construction of multiple CN bonds. Furthermore, the synthetic method developed in this invention shows promising application prospects in the biopharmaceutical and pesticide industries, providing a theoretical basis for the commercial application of such derivatives in the pharmaceutical field. Attached Figure Description

[0019] Figure 1 shows the chemical reaction formula of the present invention; Figure 2 shows the proton spectrum of the product of Example 2; Figure 3 shows the carbon spectrum of the product of Example 2; Figure 4 shows the proton spectrum of the product of Example 3; Figure 5 shows the carbon spectrum of the product of Example 3; Figure 6 shows the proton spectrum of the product of Example 5; Figure 7 shows the carbon spectrum of the product of Example 5; Figure 8 shows the proton spectrum of the product of Example 8; Figure 9 shows the carbon spectrum of the product of Example 8. Detailed Implementation

[0020] The synthetic route of this invention is as follows:

[0021] Examples 1-17 include the following steps: (1) adding 0.2 mmol of 2,1-benzisoxazole compound, benzyl alcohol compound, ammonium iodide, and organic solvent to a reaction vessel; (2) stirring the reactants evenly and then reacting them in an oil bath at 100-120 °C under a suitable gas atmosphere for 10-12 h; (3) according to the method shown in step (1), the benzyl alcohol compound has the general formula of Formula II:

[0022] Wherein: R1 is selected from various groups such as halogen, alkyl, alkoxy, and trifluoromethyl groups.

[0023] The molar mass of the benzyl alcohol compound is 0.3 mmol.

[0024] (4) According to the method shown in step (1), the general formula of the 2,1-benzisoxazole compound is III:

[0025] Wherein: Ar is selected from benzene ring or substituted benzene ring; the substituents of the substituted benzene ring are selected from: halogen, methoxy.

[0026] The molar mass of the 2,1-benzisoxazole compound is 0.2 mmol.

[0027] (5) According to the method shown in step (1), the ammonium salt is one or more of NH4I, NH4OAc, NH4Cl, and NH4Br, preferably NH4I as the nitrogen source and oxidant, and the molar mass of NH4I is further preferably 0.3 mmol.

[0028] (6) According to the method shown in step (1), the organic solvent is selected from one or two of toluene, chlorobenzene, o-dichlorobenzene, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, and 1,4-dioxane, and the preferred non-polar solvent chlorobenzene (PhCl) is the organic solvent for the reaction. A further preferred amount of the solvent is 1.0 mL.

[0029] (7) According to the method shown in step (1), the reaction temperature is 100-120 °C, preferably 120 °C. o C.

[0030] (8) According to the method shown in step (1), the reaction time is 10-12 h, and the optimal reaction temperature is 12 h.

[0031] (9) According to the method shown in step (1), the suitable gas atmosphere for the reaction is a nitrogen atmosphere, an oxygen atmosphere and an air atmosphere, and the preferred suitable gas atmosphere is an air atmosphere.

[0032] 2,1-Benzisoxazole compounds, benzyl alcohol compounds, ammonium iodide, reaction conditions, reaction products and yields are shown in Table 1: Table 1 Reactants and reaction conditions in Examples 1-17 The NMR data of the product in the example are as follows: The NMR data of the product in Example 1 are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 8.62 (dd,J= 8.0, 1.8 Hz,2H), 8.09 (d,J= 8.5 Hz, 1H), 7.89 (t,J= 7.9 Hz, 2H), 7.63 – 7.47 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 161.1, 160.5, 150.8, 138.1, 134.2, 130.7, 128.7, 128.7, 128.6, 127.3, 127.2, 123.6.

[0033] The NMR data of the product from Example 2 are as follows: 1H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 8.57 (d,J= 7.2 Hz, 2H), 7.97(d,J= 9.2 Hz, 1H), 7.56 – 7.47 (m, 4H), 7.09 (d,J= 2.6 Hz, 1H), 3.92 (s,3H). 13 C NMR (100 MHz, CDCl3) δ 159.42, 158.88, 158.28, 147.03, 138.25,130.27, 130.17, 128.69, 128.26, 127.27, 124.51, 103.92, 55.78.

[0034] The NMR data of the product in Example 3 are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.43 (s, 1H), 8.59 (dd,J= 7.8, 1.8 Hz,2H), 8.10 (dd,J= 9.2, 5.0 Hz, 1H), 7.67 (td,J= 8.9, 2.8 Hz, 1H), 7.57 –7.50 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 160.85, 160.53 (d,J= 251.1 Hz), 160.82, 159.96, 159.91, 148.06, 137.83, 131.51 (d,J= 8.6 Hz), 130.83, 128.82, 128.58, 124.67 (d,J= 25.8 Hz), 124.03 (d,J= 9.3 Hz), 110.28 (d,J= 21.9 Hz).

[0035] The NMR data of the product in Example 4 are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 8.59 (dd,J= 7.4, 2.0 Hz,2H), 8.03 (d,J= 9.0 Hz, 1H), 7.90 (d,J= 2.1 Hz, 1H), 7.82 (dd,J= 9.0,2.3 Hz, 1H), 7.57 – 7.51 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 161.41, 159.65, 149.37, 137.71, 135.23, 132.91, 131.02, 130.51, 128.83, 128.70, 125.96, 124.10.

[0036] The NMR data of the product in Example 5 are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.37 (s, 1H), 8.59 (dd,J= 7.3, 2.5 Hz,2H), 8.06 (s, 1H), 7.94 (d, 2H), 7.56 – 7.50 (m, 3H). 13 C NMR (100 MHz, CDCl3)δ 161.40, 159.50, 149.52, 137.71, 131.03, 130.55, 129.34, 128.82, 128.71,124.57, 121.36, 120.84.

[0037] The NMR data of the product in Example 6 are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 8.57 (d,J= 7.2 Hz, 2H), 7.97(d,J= 9.2 Hz, 1H), 7.56 – 7.47 (m, 4H), 7.09 (d,J= 2.6 Hz, 1H), 3.92 (s,3H). 13 C NMR (100 MHz, CDCl3) δ 159.44, 158.86, 158.25, 147.02, 138.23,130.27, 130.17, 128.69, 128.26, 127.26, 124.54, 103.92, 55.83.

[0038] The NMR data of the product in Example 7 are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 8.59 (dd,J= 6.6, 3.2 Hz,2H), 8.05 (s, 1H), 7.81 (d,J= 8.6 Hz, 1H), 7.57 – 7.49 (m, 4H). 13C NMR (100MHz, CDCl3) δ 161.90, 160.23, 151.33, 140.40, 137.63, 131.08, 128.77, 128.49, 128.46, 127.82, 121.97. The NMR data of the product of Example 8 are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 8.59 (dd,J= 6.6, 3.2 Hz,2H), 8.27 (s, 1H), 7.76 (d,J= 8.6 Hz, 1H), 7.67 (dd,J= 8.6, 1.8 Hz, 1H),7.57 – 7.52 (m, 3H). 13 C NMR (100 MHz, CDCl3) δ 161.86, 160.42, 151.47, 137.64, 131.22, 131.11, 131.05, 129.03, 128.80, 128.79, 128.41.

[0039] The NMR data of the product from Example 9 are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.71 (dd,J= 8.0, 1.5 Hz, 2H), 8.16 (d,J=9.5 Hz, 2H), 7.88 (t,J= 8.3 Hz, 1H), 7.81 (d,J= 8.0 Hz, 2H), 7.57 – 7.49(m, 4H), 7.41 (d,J= 7.8 Hz, 2H), 2.50 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 168.41, 160.33, 152.09, 140.29, 138.39, 134.98, 133.56, 130.57, 130.32, 129.37, 129.23, 128.78, 128.63, 127.21, 127.00, 121.82, 21.61. The NMR data of the product in Example 10 are as follows: 1H NMR (400 MHz, CDCl3) δ 9.43 (s, 1H), 8.51 (d,J= 8.4 Hz, 2H), 8.06(d,J= 8.4 Hz, 1H), 7.88 (t,J= 8.1 Hz, 2H), 7.58 (t,J= 7.4 Hz, 1H), 7.34(d,J= 7.9 Hz, 2H), 2.44 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 161.2, 160.5, 150.8, 140.9, 135.3, 134.08, 129.5, 128.6, 127.2, 127.1, 123.5, 21.6.

[0040] The NMR data of the product of Example 11 are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 8.53 (d,J= 8.4 Hz, 2H), 8.08(d,J= 8.9 Hz, 1H), 7.94 – 7.85 (m, 2H), 7.59 (t,J= 7.4 Hz, 1H), 7.40 (d,J= 8.2 Hz, 2H), 3.08 – 2.93 (m, 1H), 1.32 (s, 3H), 1.31 (s, 3H). 13 C NMR (100MHz, CDCl3) δ 161.2, 160.5, 151.8, 150.8, 135.7, 134.1, 128.7, 128.6, 127.2, 127.1, 126.8, 123.5, 34.2, 23.9.

[0041] The NMR data of the product in Example 12 are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.38 (s, 1H), 8.57 (d,J= 8.9 Hz, 2H), 8.02(d,J= 8.8 Hz, 1H), 7.88 – 7.80 (m, 2H), 7.53 (t,J= 7.4 Hz, 1H), 7.04 (d,J= 8.9 Hz, 2H), 3.88 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.8, 160.8, 160.4,150.8, 134.1, 130.7, 130.2, 128.4, 127.2, 126.8, 123.3, 113.9, 55.4.

[0042] The NMR data of the product in Example 13 are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.43 (s, 1H), 8.39 (s, 1H), 8.35 (d,J= 8.6Hz, 1H), 8.07 (d,J= 8.7 Hz, 1H), 7.87 (t,J= 7.3 Hz, 2H), 7.56 (t,J= 7.5Hz, 1H), 7.30 (d,J= 7.8 Hz, 1H), 2.40 (s, 3H), 2.35 (s, 3H). 13 C NMR (100MHz, CDCl3) δ 161.3, 160.4, 150.8, 139.7, 136.9, 135.7, 134.1, 130.1, 129.6,128.5, 127.2, 127.0, 126.2, 123.5, 20.0, 19.9.

[0043] The NMR data of the product in Example 14 are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.43 (s, 1H), 8.66 – 8.58 (m, 2H), 8.05 (d,J= 8.5 Hz, 1H), 7.90 (t,J= 7.8 Hz, 2H), 7.60 (t,J= 7.4 Hz, 1H), 7.20 (t,J= 8.7 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 164.7 (d,J= 250.4 Hz), 160.5,160.1, 150.7, 134.2, 134.2, 133.8, 130.7 (d,J= 8.7 Hz), 128.6, 127.3,127.2, 124.3 (d,J= 3.9 Hz), 115.6 (d,J= 21.7 Hz).

[0044] The NMR data of the product in Example 15 are as follows: 1H NMR (400 MHz, CDCl3) δ 9.48 (s, 1H), 8.73 (d,J= 8.1 Hz, 2H), 8.10 (d,J= 8.5 Hz, 1H), 7.96 (d,J= 7.8 Hz, 2H), 7.80 (t,J= 8.1 Hz, 2H), 7.68(t,J= 7.5 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 160.7, 159.1, 150.6, 142.1, 134.6, 132.4, 129.0, 128.8, 128.2, 127.3, 123.9, 118.9, 113.8.

[0045] The NMR data of the product in Example 16 are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 8.74 (d,J= 8.1 Hz, 2H), 8.11(d,J= 8.5 Hz, 1H), 7.96 (t,J= 7.7 Hz, 2H), 7.78 (d,J= 8.2 Hz, 2H), 7.66(t,J= 7.4 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 160.7, 159.6, 150.7, 141.3,134.4, 132.1 (q,J= 32.1 Hz), 128.8, 128.7 (q,J= 1.8 Hz), 127.9, 127.2,125.5 (q,J= 3.8 Hz), 124.2 (q,J= 273.8 Hz), 123.9.

[0046] The NMR data of the product in Example 17 are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 8.62 (s, 1H), 8.50 (d,J= 5.4Hz, 1H), 8.07 (d,J= 8.8 Hz, 1H), 7.91 (t,J= 7.3 Hz, 2H), 7.62 (t,J= 7.4Hz, 1H), 7.50 – 7.41 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 160.6, 159.7, 150.7, 139.9, 134.8, 134.3, 130.6, 129.9, 128.7, 128.6, 127.7, 127.2, 126.7, 123.8. Example

[0047] Taking compound 1 as an example, the optimized structural formula of ammonium salt compound 1 is as follows: The parallel synthesis steps are as follows: (1) Add 0.2 mmol of 2,1-benzisoxazole to the reaction vessel. Benzyl alcohol (0.3 mmol) (1) Add 1.0 mL of PhCl organic solvent; (2) Add 0.3 mmol of ammonium salts NH4I, NH4OAc, NH4Cl and NH4Br to the parallel reaction vessels above; (3) After stirring the reactants evenly, place them in an oil bath at 120 °C and react them in air atmosphere for 12 h to obtain the products.

[0048] The yields of different ammonium salts NH4I, NH4OAc, NH4Cl, and NH4Br were 73%, 25%, 15%, and 10%, respectively. NH4I was preferred as the optimal nitrogen source. Example

[0049] Taking compound 1 as an example, the optimized structural formula of the reaction solvent compound 1 is as follows: The parallel synthesis steps are as follows: (1) Add 0.2 mmol of 2,1-benzisoxazole to the reaction vessel. Benzyl alcohol (0.3 mmol) (1) Add NH4I (0.3 mmol); (2) Add 1.0 mL of solvent toluene, chlorobenzene, o-dichlorobenzene, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, and 1,4-dioxane to the parallel reaction vessels above; (3) After stirring the reactants evenly, place them in an oil bath at 120 °C and react for 12 h in air atmosphere to obtain the product.

[0050] The yields of toluene, chlorobenzene, o-dichlorobenzene, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, and 1,4-dioxane in different solvents were 62%, 73%, 70%, 25%, 42%, 10%, and 12%, respectively. It is evident that toluene, chlorobenzene, and o-dichlorobenzene yielded better results, with PhCl being the optimal solvent. Example

[0051] Taking compound 1 as an example, the optimized reaction temperature and structural formula of compound 1 are as follows: The parallel synthesis steps are as follows: (1) Add 0.2 mmol of 2,1-benzisoxazole to the reaction vessel. Benzyl alcohol (0.3 mmol) (1) NH4I (0.3 mmol) and organic solvent PhCl (1.0 mL); (2) After stirring the reactants evenly, they were placed in oil baths at 100, 110 and 120 °C and reacted in air for 12 h to obtain the product.

[0052] The yields at temperatures of 100, 110, and 120 °C were 45%, 66%, and 73%, respectively. Therefore, the yield at 120 °C was the best, indicating it was the optimal reaction temperature. Example

[0053] Taking compound 1 as an example, the optimized reaction temperature and structural formula of compound 1 are as follows: The parallel synthesis steps are as follows: (1) Add 0.2 mmol of 2,1-benzisoxazole to the reaction vessel. Benzyl alcohol (0.3 mmol) (1) NH4I (0.3 mmol) and organic solvent PhCl (1.0 mL); (2) After stirring the reactants evenly, they were placed in an oil bath at 120 °C and reacted in air for 6, 8, 10 and 12 h respectively to obtain the product.

[0054] The yields after 6, 8, 10, and 12 hours of reaction were 34%, 42%, 62%, and 73%, respectively. This indicates that the yield was better after 10-12 hours of reaction, with 12 hours being the optimal reaction time. Example

[0055] Taking compound 1 as an example, the optimized reaction temperature and structural formula of compound 1 are as follows: The parallel synthesis steps are as follows: (1) Add 0.2 mmol of 2,1-benzisoxazole to the reaction vessel. Benzyl alcohol (0.3 mmol) (1) NH4I (0.3 mmol) and organic solvent PhCl (1.0 mL); (2) After stirring the reactants evenly, they were placed in an oil bath at 120 °C and reacted for 12 h under nitrogen, air and oxygen atmospheres respectively to obtain the product.

[0056] The yields of the reaction under nitrogen, air, and oxygen atmospheres were <10%, 73%, and 72%, respectively. It can be seen that the yields of the reaction under air and oxygen atmospheres are better. Considering the simplicity of experimental operation, air is the best choice.

[0057] The above description is merely a preferred embodiment of this application and does not constitute any limitation on this application. Although this application discloses preferred embodiments as described above, it is not intended to limit this application. Any modifications or alterations made by those skilled in the art without departing from the scope of the technical solution of this application using the disclosed technical content are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A method for preparing 2-substituted quinazoline and its derivatives, characterized in that: The reaction is prepared by heating and stirring an organic solvent with three components: an ammonium salt, a benzyl alcohol compound, and a 2,1-benzisoxazole compound. The general reaction formula is as follows: Ar is selected from benzene rings or substituted benzene rings; R is selected from substituted phenyl groups; R1 is selected from one of halogens, alkyl groups, alkoxy groups, and trifluoromethyl groups.

2. The method for preparing 2-substituted quinazoline and its derivatives according to claim 1, characterized in that: The substituents of the substituted benzene ring are selected from halogens or methoxy groups; the substituents of the substituted phenyl group are selected from methyl groups.

3. The method for preparing 2-substituted quinazoline and its derivatives according to claim 2, characterized in that: The ammonium salt is one or more of NH4I, NH4OAc, NH4Cl, and NH4Br.

4. The method for preparing 2-substituted quinazoline and its derivatives according to claim 3, characterized in that: The organic solvent includes one or more of toluene, chlorobenzene, o-dichlorobenzene, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, and 1,4-dioxane.

5. The method for preparing 2-substituted quinazoline and its derivatives according to claim 4, characterized in that: The molar ratio of the 2,1-benzisoxazole compound to the benzyl alcohol compound and the ammonium salt is 1.0:0.5-2.

0.

6. The method for preparing 2-substituted quinazoline and its derivatives according to claim 5, characterized in that: The molar ratio of the 2,1-benzisoxazole compound to the ammonium salt is 1.0:0.5-2.

0.

7. The method for preparing 2-substituted quinazoline and its derivatives according to claim 6, characterized in that: The gaseous atmosphere of the reaction is one of air, oxygen, or nitrogen.

8. The method for preparing 2-substituted quinazoline and its derivatives according to claim 7, characterized in that: The reaction time is 2-12 h; the reaction temperature is 100-120℃.

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