A method for preparing a quinazolinone compound

Abstract

The application discloses a preparation method of quinazolinone compounds, which comprises the following steps: in the presence of a solvent and an oxidant, a nitrogen cyanamide olefin compound and azidotrimethylsilane are reacted to prepare 3-(azidomethyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one compounds or 3-methylene-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one compounds; in the presence of a solvent, an oxidant and an additive, the nitrogen cyanamide olefin compound and the azidotrimethylsilane are reacted to prepare 3-(2-nitroethyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one compounds; the application has the advantages of high yield, convenient separation, high efficiency, mildness, low cost and economic efficiency, and has great industrial application value.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing 3-(azidomethyl)-2,3-dihydropyrrolo[2,1-b]quinazoline-9(1H)-one compounds, 3-methylene-2,3-dihydropyrrolo[2,1-b]quinazoline-9(1H)-one compounds, and 3-(2-nitroethyl)-2,3-dihydropyrrolo[2,1-b]quinazoline-9(1H)-one compounds. Background Technology

[0002] Nitrogen-containing compounds are widely found in natural organic compounds and have important applications in the chemical and pharmaceutical industries. Many bioactive molecules have nitrogen-containing groups at their core structure, most of which are nitrogen-containing heterocyclic skeletons. Among them, azides offer substantial benefits for the synthesis of nitrogen-containing compounds and have been recognized as multifunctional intermediates. This is not only because they are potential precursors to nitrogen-containing structural motifs, but also because they possess significant bioactivity in medicinal chemistry. Introducing azide groups into nitrogen-containing heterocyclic compounds, intermolecular azidoarylation of simple alkenes was achieved through a radical multicomponent tandem process. This allows for the mild, rapid, and stepwise economical acquisition of a wide range of azidoalkylated heteroaromatics. Considering the diversity of organic azide transformations and the pharmaceutical skeletons of heteroaromatics, the synthesized products can be further converted into abundant heterocyclic compounds containing amino, hydroxyl, or drug-specific skeletons such as triazoles, piperidines, oxazolines, and Schiff bases, demonstrating considerable synthetic potential and application value. Therefore, the construction of such nitrogen-containing heterocycles has attracted widespread attention from chemists.

[0003] Existing methods for synthesizing alkyl azides are based on multi-step transformations of functionalized alkanes. Direct azidation of alkyl azides from alkenes is still underdeveloped. The application of azido radicals in olefin functionalization provides a direct route for alkyl azidation reactions. Several methods have been reported, such as the cycloaddition of azido radicals to alkenes followed by the formation of carbon-heteroatom bonds. For example, in 2016, Yu's group reported the synthesis of quinazolinones via the radical cyclization of α-azidobenzamide (Org. Chem. Front. 2017, 4, 421-426), but this synthesis requires pre-functionalization of the substrate, limiting the diversity of the resulting skeleton. In 2017, Bi's group reported the C≡C bond hydrogenation azidation of biphenylacetylene catalyzed by silver (Org. Lett. 2017, 19(15), 4026-4029), but these methods still have many shortcomings, mainly limited substrate scope and low functional group tolerance.

[0004] Quinazoline molecules are widely found in natural products, among which functionalized quinazoline compounds possess bioactivity for treating tumors, inflammation, malaria, and nervous system diseases, making them promising skeletons for drug discovery (J. Org. Chem. 1963, 28, 445-448). Therefore, in order to further explore new methods for skeleton synthesis and the potential value of quinazoline derivatives, the synthesis of various polycyclic quinazoline derivatives is essential. Initially, conventional methods such as high temperature, metals, or toxic initiators were used to synthesize quinazoline structural units. Later, Liao's group described an electrochemical strategy for synthesizing trifluoromethylated cyclic N-sulfonamides using Langlois reagents (Angew. Chem., Int. Ed. 2020, 59(18), 7266-7270). Meanwhile, Yu and colleagues developed a visible light-promoted intramolecular radical cyclization method to construct guanidine compounds from cyanamides (J. Org. Chem. 2016, 81(16), 7276-7281). However, the use of azide reagents as synthetic starting materials is extremely rare. In recent years, some progress has been made in the construction of quinazolinone compounds through intermolecular and intramolecular cyclization of N-cyanamide alkenes via metal and organocatalysis, but many problems still exist.

[0005] Therefore, it is of great significance to develop simpler and more efficient synthetic methods to solve the practical problems faced in the synthesis of azaquinazolinone compounds, such as complex substrate synthesis, limited functionalization, insufficiently mild reaction conditions, and difficulty in industrialization. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides a simple and efficient method for preparing quinazoline ketone compounds. The method involves adding a cyanamide olefin compound (compound 1), trimethyl azidosilane (compound 2), a solvent, and an oxidant to a reactor. The reaction is carried out in an oil bath at 20–30°C or 40–50°C. Thin-layer chromatography is used to monitor the completeness of the reaction. The reaction product is concentrated, and the concentrate is purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain compounds 3 and 4, namely 3-(azidomethyl)-2,3-dihydropyrrolo[2,1-b]quinazoline-9(1H)-ketone compounds or 3-methylene-2,3-dihydropyrrolo[2,1-b]quinazoline-9(1H)-ketone compounds.

[0007] A cyanamide olefin compound and (compound 1), trimethyl azidosilane (compound 2), solvent, oxidant, and additives were added to a reactor and reacted under oil bath conditions at 20-30°C. The reaction was monitored by thin-layer chromatography until complete. The reaction product was concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain compound 5, 3-(2-nitroethyl)-2,3-dihydropyrrolo[2,1-b]quinazoline-9(1H)-one compounds.

[0008]

[0009] Wherein A is selected from substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, and the substituents of aryl or heteroaryl groups are selected from hydrogen, alkyl, trifluoromethyl, nitro, halogen, and phenyl; R is selected from hydrogen, methyl, and phenyl.

[0010] In the preparation of 3-(azidomethyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one compounds, the oxidant is selected from phenyliodo(III)bis(trifluoroacetate), hydroxy(toluenesulfonyloxy)iodobenzene, iodobenzoylbenzene, 2-iodoacylbenzoic acid, and iodophenyldiacetic acid; the reaction is carried out at 20-30℃;

[0011] When preparing 3-methylene-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one compounds, the oxidant is selected from phenyliodo(III)bis(trifluoroacetate), hydroxy(toluenesulfonyloxy)iodobenzene, iodobenzoylbenzene, 2-iodoacylbenzoic acid, and iodophenyldiacetic acid; the reaction is carried out at 40-50℃; additives can also be added during the preparation process, and the additives are selected from 1,8-diazabicycloundec-7-ene, triethylamine, 1,4-diazabicyclo[2.2.2]octane, and 4-dimethylaminopyridine; the molar ratio of the cyanamide olefin compound to the additive is 1:0.1-1.

[0012] In the preparation of 3-(2-nitroethyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one compounds, the oxidant is iodobenzoylbenzene; the additives are selected from 1,8-diazabicycloundec-7-ene, triethylamine, 1,4-diazabicyclo[2.2.2]octane, and 4-dimethylaminopyridine; the molar ratio of the cyanamide olefin compound to the additive is 1:2 to 3, and the reaction is carried out at 20 to 30 °C.

[0013] In the above method, the solvent is selected from 1,4-dioxane, dimethyl sulfoxide, acetonitrile, toluene, acetone, ethyl acetate, and nitromethane; the molar ratio of the cyanamide olefin compound and azide trimethylsilane is 1:1 to 3.5, and the molar ratio of the cyanamide olefin compound to the oxidant is 1:1 to 2.5.

[0014] Compound 1 was prepared by conventional methods, for example, according to the method described in Xi JM, Sun YH, Li WC, Wu YH, Wei ZL, Liao W W. Radical Alkene-Trifluoromethylation-Triggered Nitrile Insertion Remote Functionalization Relay Processes: Diverse Synthesis of Trifluoromethylated Azaheterocycles Enabled by Copper Catalysis. Org. Lett, 2022, 24, 1110-1115.

[0015] Compared with the prior art, the present invention has the following advantages:

[0016] 1. The raw materials used in the method of this invention are widely available and simple to obtain, and the operation is safe and convenient;

[0017] 2. The synthesis method of the present invention is simple and efficient, the target product can be obtained in one step, the reaction conditions are mild, the operation is simple, the environment is friendly, and the yield is high. The gram-level reaction yield is good and has industrial production potential.

[0018] 3. The resulting target product compounds exhibit a wide variety of structures and are applicable to substrates with special structures. Detailed Implementation

[0019] The present invention will be further described in detail below through examples, but the scope of protection of the present invention is not limited to the content described. Unless otherwise specified, the reagents in the examples are all commercially available reagents or reagents prepared by conventional methods.

[0020] Example 1:

[0021] Compound 1N-(but-3-en-1-yl)-N-cyanobenzamide (0.2 mmol), TMSN3 (0.7 mmol), iodophenyl diacetic acid (0.5 mmol), and nitromethane (3 mL) were added to a 15 mL reaction tube. The mixture was heated to 25 °C with magnetic stirring, and the reaction was monitored by TLC. After the starting material spot completely disappeared, the reaction product was concentrated by rotary evaporation at 40 °C. The concentrate was loaded onto a silica gel column, and a petroleum ether-ethyl acetate mixture was used as the eluent. The eluent was collected and dried at 40 °C to give a yellow solid 3a, with a yield of 80%. The reaction is as follows:

[0022]

[0023] The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of product 3a are as follows:

[0024]

[0025] V 石油醚 / V 乙酸乙酯 =3:1,R f =0.2; Yellow solid: 39mg, yield 80%; Melting point = 83-84℃ 1 H NMR (600MHz, CDCl3) δ8.31-8.18(m,1H),7.79-7.67(m,1H),7.64(d,J=8.1Hz,1H),7.43(t,J=7.5Hz,1H),4.27(ddd,J=12.6,9.1,3 .8Hz,1H),4.00(m,J=12.1,8.1Hz,1H),3.85(d,J=5.0Hz,2H),3.55-3.40(m,1H),2.54-2.38(m,1H),2.15(dq,J=13.0,8.6Hz,1H). 13 C NMR(151MHz, CDCl3)δ160.7,158.3,148.8,134.1,127.0,126.5,126.3,120.6,52.2,44.7,43.8,23.8.HRMS(ESI):calc.for C 12 H 11 N5O[M+H] + ,242.1036;found,242.1041.

[0026] The preparation methods for the following examples are the same as those for Example 1;

[0027] Example 2: The difference is that compound 1 is N-(but-3-en-1-yl)-N-cyano-4-nitrobenzamide. The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the obtained product 3b are as follows;

[0028]

[0029] V 石油醚 / V 乙酸乙酯 =4:1,R f =0.2; Yellow solid: 52mg, yield 91%; Melting point = 63-64℃ 1H NMR(600MHz, CDCl3)δ8.50(d,J=1.7Hz,1H),8.47-8.36(m,1H),8.21(dd,J=6.5,4.5Hz,1H),4.43-4.29(m,1H),4 .15-4.03(m,1H),4.04-3.94(m,1H),3.95-3.82(m,1H),3.67-3.48(m,1H),2.66-2.45(m,1H),2.38-2.14(m,1H). 13 C NMR(151MHz, CDCl3)δ160.9,159.5,151.3,149.5,128.2,124.9,122.7,120.1,51.8,45.2,44.0,23.6.HRMS(ESI):calc.for C 12 H 10 N6O3[M+H] + ,287.0887;found,287.0882.

[0030] Example 3: The difference is that compound 1 is N-(but-3-en-1-yl)-N-cyano-4-methylbenzamide. The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the obtained product 3c are as follows;

[0031]

[0032] V 石油醚 / V 乙酸乙酯 =4:1,R f =0.2; Yellow solid: 35mg, yield 68%; Melting point = 86-87℃ 1 H NMR (600MHz, CDCl3) δ8.16(d,J=8.1Hz,1H),7.47(s,1H),7.28(d,J=8.0Hz,1H),4.29(ddd,J=12.6,9.1,3.8Hz,1H),4 .03(m,J=12.1,8.1Hz,1H),3.87(d,J=5.0Hz,2H),3.53-3.43(m,1H),2.53-2.41(m,4H),2.17(dq,J=13.0,8.6Hz,1H). 13 C NMR(151MHz, CDCl3)δ160.8,158.4,149.0,145.2,128.1,126.8,126.1,118.3,52.3,44.7,43.9,23.8,21.8.HRMS(ESI):calc.for C 13 H 13 N5O[M+H]+ ,256.1193; found,256.1195.

[0033] Example 4: The difference is that compound 1 is 3-bromo-N-(but-3-en-1-yl)-N-cyanobenzamide. The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the obtained product are as follows;

[0034]

[0035] V 石油醚 / V 乙酸乙酯 =3:1,R f =0.2; White solid: 43mg, yield 78%; Melting point = 91-92℃ 1 H NMR (600MHz, CDCl3) δ8.24(d,J=7.9Hz,1H),8.01(d,J=7.6Hz,1H),7.31(t,J=7.8Hz,1H),4.40-4.24(m,1H),4. 05(m,J=12.1,8.2Hz,1H),4.00-3.87(m,2H),3.69-3.51(m,1H),2.59-2.41(m,1H),2.21(m,J=12.9,8.7Hz,1H). 13 C NMR (151MHz, CDCl3) δ160.3,159.4,146.7,138.0,127.1,126.1,122.4,122.3,52.3,45.1,44.2,23.9.HRMS(ESI):calc.forC 12 H 10 BrN5O[M+H] + ,320.0141; found,320.0143.

[0036] Example 5: The difference is that compound 1 is N-(but-3-en-1-yl)-N-cyano-3-(trifluoromethyl)benzamide, and the structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the obtained product 3e are as follows;

[0037]

[0038] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.2; Yellow solid: 17mg, yield 28%; Melting point = 114-115℃ 1H NMR (600MHz, CDCl3) δ8.57(s,1H),7.93(dd,J=8.5,1.2Hz,1H),7.78(d,J=8.5Hz,1H),4.33(ddd,J=12.5,9.2,3.7Hz,1H),4.07(m,J=12.2, 8.2Hz,1H),3.94(dd,J=12.4,5.7Hz,1H),3.88(dd,J=12.4,3.9Hz,1H),3.60-3.46(m,1H),2.57-2.45(m,1H),2.22(dq,J=13.0,8.7Hz,1H). 13 C NMR(151MHz,CDCl3)δ159.6,159.0,150.0,129.36(q,J C-F =6.3,3.1Hz),127.41(q,J) C-F =33.4Hz), 127.0, 123.30(q,J) C-F =4.0Hz), 122.56(q,J C-F =272.2Hz),119.6,51.0,44.0,43.0,22.6.HRMS(ESI):calc.for C 13 H 10 F3N5O[M+H] + ,310.0910.1036; found,310.0910.

[0039] Example 6: The difference is that compound 1 is N-(but-3-en-1-yl)-N-cyano-3-(trifluoromethyl)benzamide. The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the obtained product 3f are as follows;

[0040]

[0041] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.2; Yellow solid: 36mg, yield 57%; Melting point = 121-122℃ 1H NMR (600MHz, CDCl3) δ8.47(d,J=7.9Hz,1H),8.04(d,J=7.4Hz,1H),7.51(t,J=7.7Hz,1H),4.34(ddd,J=12.3,9.2,3.1Hz,1H),4.03(m,J=12.2 ,8.4Hz,1H),3.95(dd,J=12.4,5.8Hz,1H),3.87(dd,J=12.4,3.7Hz,1H),3.62-3.49(m,1H),2.57-2.42(m,1H),2.22(dq,J=12.9,9.1Hz,1H). 13 C NMR (151MHz, CDCl3) δ160.7,160.1,151.1,130.5(q,J C-F =6.3,3.1Hz), 128.5(q,J) C-F =66.7,33.4Hz),128.1,124.4(q,J C-F =8.1,4.0Hz),123.6(q,J) C-F =544.5,272.2Hz),120.7,52.1,45.1,44.1,23.7.HRMS(ESI):calc.for C 13 H 10 F3N5O[M+H] + ,310.0910; found,310.0914.

[0042] Example 7: The difference is that compound 1 is N-cyano-N-(3-methylbut-3-en-1-yl)benzamide. The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the obtained product 3g are as follows;

[0043]

[0044] V 石油醚 / V 乙酸乙酯 =6:1,R f =0.2; colorless oil: 50mg, yield 98%. 1H NMR (600MHz, CDCl3) δ8.27(dd,J=7.9,0.8Hz,1H),7.75-7.64(m,2H),7.47-7.40(m,1H),4.21(ddd,J=12.3,9.0,4.7Hz,1H),4.13 -4.00(m,1H),3.83(d,J=12.1Hz,1H),3.53(d,J=12.1Hz,1H),2.48-2.31(m,1H),2.02(ddd,J=12.9,8.2,4.7Hz,1H),1.40(s,3H). 13 C NMR (151MHz, CDCl3) δ161.5,160.9,149.1,134.1,127.1,126.4,126.3,120.7,58.1,48.0,43.3,30.5,22.7.HRMS(ESI):calc.for C 13 H 13 N5O[M+H] + ,256.1193; found,256.1194.

[0045] Example 8: The difference is that compound 1 is N-cyano-N-(1-phenylbut-3-en-1-yl)benzamide. The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the obtained product after 3 hours are as follows;

[0046]

[0047] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.2; Yellow solid: 31mg, yield 48%; Melting point = 88-89℃ 1 H NMR(600MHz, CDCl3) δ8.26(d,J=7.8Hz,1H),7.76(m,J=16.3,7.6Hz,2H),7.48(t,J =7.2Hz,1H),7.33(t,J=7.5Hz,2H),7.28(t,J=7.5Hz,1H),7.14(d,J=7.5Hz,2H),5. 81(d,J=8.8Hz,1H),3.96(dd,J=12.5,5.9Hz,1H),3.89(dd,J=12.5,3.9Hz,1H),3. 72-3.54(m,1H),2.66(ddd,J=20.3,11.2,9.2Hz,1H),2.41(dd,J=12.6,8.3Hz,1H). 13C NMR (151MHz, CDCl3) δ160.3,158.4,149.0,139.3,134.5,129.0,128.0,127.2,126.8,126.7,125.3,121.1,60.0,51.6,42.1,34.1.HRMS(ESI):calc.for C 18 H 15 N5O[M+H] + ,318.1349; found,318.1351.

[0048] Example 9: The difference is that compound 1 is N-(but-3-en-1-yl)-N-cyano-2-naphthylcarboxamide. The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the obtained product 3i are as follows;

[0049]

[0050] V 石油醚 / V 乙酸乙酯 =4:1,R f =0.2; White solid: 52mg, yield 90%; Melting point = 76-77℃; 1 H NMR (600MHz, CDCl3) δ9.02(d,J=7.7Hz,1H),8.20(d,J=8.7Hz,1H),7.90(d,J=7.6Hz,1H),7.81(d,J=8.7Hz,1H),7.75-7.61(m,2H),4. 44-4.33(m,1H),4.09(m,J=11.9,8.3Hz,1H),3.97(t,J=8.8Hz,2H),3.71-3.53(m,1H),2.52(m,J=11.3,5.9Hz,1H),2.30-2.12(m,1H). 13 C NMR (151MHz, CDCl3) δ161.0,158.5,147.8,136.1,129.8,129.2,127.8,126.8,125.1,121.6,117.1,52.4,45.1,44.3,24.1.HRMS(ESI):calc.for C 16 H 13 N5O[M+H] + ,292.1193; found,292.1189.

[0051] Example 10: The difference is that compound 1 is N-(but-3-en-1-yl)-N-cyanothiophene-2-carboxamide. The structure, morphology, melting point, and high-resolution mass spectrometry data of the obtained product 3j are as follows;

[0052]

[0053] V 石油醚 / V 乙酸乙酯 =4:1,R f =0.2; White solid: 16mg, yield 32%; Melting point = 75-76℃ 1 H NMR (600MHz, CDCl3) δ7.71(d,J=5.2Hz,1H),7.23(d,J=5.2Hz,1H),4.32-4.18(m,1H),3.99(m,J=12. 2,8.1Hz,1H),3.84-3.74(m,2H),3.51-3.39(m,1H),2.51-2.38(m,1H),2.16(dq,J=13.0,8.5Hz,1H). 13 C NMR(151MHz, CDCl3)δ160.3,158.0,157.0,134.2,124.7,121.8,52.2,44.8,43.6,24.2.HRMS(ESI):calc.for C 10 H9N5OS[M+H] + ,248.0601; found,248.0598.

[0054] Example 11: The difference is that compound 1 is N-cyano-N-(2-(prop-1-en-2-yl)phenyl)benzamide. The structure, morphology, melting point, and high-resolution mass spectrometry data of the obtained product 3k are as follows;

[0055]

[0056] V 石油醚 / V 乙酸乙酯 =4:1,R f =0.2; White solid: 58mg, yield 95%; Melting point = 104-105℃ 1 H NMR(600MHz, CDCl3) δ8.62(d,J=8.3Hz,1H),8.42(d,J=7.8Hz,1H),7.84-7.7 0(m,2H),7.59-7.46(m,3H),7.38(t,J=7.4Hz,1H),3.89(s,2H),1.65(s,3H). 13C NMR (151MHz, CDCl3) δ161.2,159.9,147.2,139.3,134.4,133.3,129.3,127.4,1 27.0,126.8,126.6,123.0,121.5,117.3,58.9,49.7,22.5.HRMS(ESI):calc.for C 17 H 13 N5O[M+H] + ,304.1193; found,304.1188.

[0057] Example 12: The difference is that compound 1 is N-(but-3-en-1-yl)-N-cyano-1,3-dimethyl-1H-pyrazole-4-carboxamide. The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the obtained product 3l are as follows;

[0058]

[0059] V 石油醚 / V 乙酸乙酯 =2:1,R f =0.2; White solid: 29mg, yield 55%; Melting point = 143-144℃ 1 H NMR (600MHz, CDCl3) δ4.33-4.18(m,4H),4.00(m,J=12.2,8.1Hz,1H),3.90-3.80(m ,2H),3.47(m,J=8.6,5.5Hz,1H),2.56-2.43(m,4H),2.20(dq,J=13.1,8.5Hz,1H). 13 C NMR(151MHz, CDCl3)δ156.2,153.2,141.4,139.1,124.9,52.6,44.3,43.2,38.2,24.7,10.6.HRMS(ESI):calc.for C 11 H 13 N7O[M+H] + ,260.1254;found,260.1251.

[0060] Example 13

[0061] Compound 1N-(but-3-en-1-yl)-N-cyanobenzamide (0.2 mmol), TMSN3 (0.7 mmol), iodophenyl diacetic acid (0.5 mmol), additive 1,8-diazabicycloundec-7-ene (0.1 mmol), and nitromethane (3 mL) were added to a 15 mL reaction tube. The mixture was heated to 50 °C with magnetic stirring, and the reaction was monitored by TLC. After the starting material spot completely disappeared, the mixture was concentrated by rotary evaporation at 40 °C. The concentrate was loaded onto a silica gel column and eluented with a mixture of petroleum ether and ethyl acetate. The eluent was collected and dried at 40 °C to give a white solid 4a, with a yield of 73%. The reaction equation is as follows:

[0062]

[0063] The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of product 4a are as follows:

[0064]

[0065] V 石油醚 / V 乙酸乙酯 =4:1,R f =0.2; White solid: 29 mg, yield 73%; Melting point = 124-125℃ 1 H NMR(600MHz, CDCl3)δ8.29(d,J=7.7Hz,1H),7.82-7.67(m,2H),7.46(ddd,J=8.1,6.1,2.1H z,1H),6.43(t,J=2.7Hz,1H),5.57(t,J=2.3Hz,1H),4.42-4.09(m,2H),3.12-2.92(m,2H). 13 C NMR(151MHz, CDCl3)δ161.2,153.9,149.4,140.3,134.2,127.5,126.5,126.3,120.9,116.2,43.4,25.5.HRMS(ESI):calc.for C 12 H 10 N₂O[M+H] + ,199.0866;found,199.0867.

[0066] The preparation methods for the following examples are the same as those for Example 13;

[0067] Example 14: The difference is that compound 1 is N-(but-3-en-1-yl)-N-cyano-4-iodobenzamide. The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the resulting product 4b are as follows:

[0068]

[0069] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.2; Yellow solid: 41 mg, yield 63%; Melting point = 122-123℃ 1 H NMR (600MHz, CDCl3) δ8.15(s,1H),7.96(d,J=8.4Hz,1H),7.75(d,J=8.4Hz,1H),6.43(s,1H),5.60(s,1H),4.17(t,J=7.4Hz,2H),3.03(t,J=7.2Hz,2H). 13 C NMR (151MHz, CDCl3) δ161.0,154.8,150.2,140.1,136.5,135.4,127.5,120.2,117.0,101.6,43.5,25.4.HRMS(ESI):calc.for C 12 H9IN2O[M+H] + ,324.9832;found,324.9832.

[0070] Example 15: The difference lies in that compound 1 is N-(but-3-en-1-yl)-N-cyano-[1,1'-biphenyl]-4-carboxamide. The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the obtained product 4c are as follows:

[0071]

[0072] V 石油醚 / V 乙酸乙酯 =6:1,R f =0.2; White solid: 33mg, yield 59%; Melting point = 111-112℃ 1 H NMR (600MHz, CDCl3) δ8.34(d,J=8.3Hz,1H),7.96(d,J=1.4Hz,1H),7.71(dd,J=7.8,3.0Hz,3H),7.54-7.45(m,2H),7. 42(t,J=7.4Hz,1H), 6.46(t,J=2.7Hz,1H), 5.59(t,J=2.3Hz,1H), 4.21(t,J=7.4Hz,2H), 3.05(dd,J=12.3,4.8Hz,2H). 13C NMR(151MHz, CDCl3)δ161.1,154.3,149.8,147.0,140.3,139.6,129.0,128.4,127.4,126.8,125.7,125.4,119.6,116.4,43.4,25.5.HRMS(ESI):calc.for C 18 H 14 N₂O[M+H] + ,275.1179; found,275.1181.

[0073] Example 16: The difference is that compound 1 is N-(but-3-en-1-yl)-N-cyano-4-nitrobenzamide. The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the obtained product after 4 days are as follows;

[0074]

[0075] V 石油醚 / V 乙酸乙酯 =4:1,R f =0.2; Yellow solid: 26mg, yield 53%; Melting point = 132-133℃ 1 H NMR (600MHz, CDCl3) δ8.56(d,J=2.0Hz,1H),8.44(d,J=8.7Hz,1H),8.20(dd,J=8.7,2.0Hz, 1H), 6.52 (t, J = 2.7Hz, 1H), 5.68 (d, J = 2.3Hz, 1H), 4.23 (t, J = 7.5Hz, 2H), 3.15-2.96 (m, 2H). 13 C NMR(151MHz, CDCl3)δ160.0,156.0,151.5,150.1,139.7,128.2,125.0,123.1,120.0,118.2,43.8,25.3.HRMS(ESI):calc.for C 12 H9N3O3[M+H] + ,244.0717; found,244.0719.

[0076] Example 17: The difference is that compound 1 is N-cyano-N-(1-phenylbut-3-en-1-yl)benzamide. The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the obtained product 4e are as follows;

[0077]

[0078] V 石油醚 / V 乙酸乙酯 =6:1,Rf =0.2; White solid: 23mg, yield 42%; Melting point = 42-43℃ 1 H NMR (600MHz, CDCl3) δ8.22(d,J=7.9Hz,1H),7.76(q,J=7.8Hz,2H),7.44(t,J=6.9Hz,1H),7.28(m,J=36.0 ,7.2Hz,5H),6.54(s,1H),5.74(d,J=9.0Hz,1H),5.62(s,1H),3.59-3.38(m,1H),2.96(d,J=16.8Hz,1H). 13 C NMR(151MHz, CDCl3)δ160.5,153.9,149.3,140.5,139.6,134.3,128.9,128.1,127.5,126.7,126.6,125.9,121.4,116.8,59.0,36.2.HRMS(ESI):calc.for C 18 H 14 N₂O[M+H] + ,275.1179;found,275.1179.

[0079] Example 18

[0080] In a 15 mL reaction tube, 1N-(but-3-en-1-yl)-N-cyanobenzamide (0.2 mmol), TMSN3 (0.7 mmol), iodobenzoylbenzene (0.5 mmol), additive 1,8-diazabicycloundec-7-ene (0.54 mmol), and nitromethane (3 mL) were added. The mixture was heated to 25 °C with magnetic stirring and the reaction was monitored by TLC. After the starting material spot completely disappeared, the reaction product was concentrated by rotary evaporation at 40 °C. The concentrate was loaded onto a silica gel column and eluented with a mixture of petroleum ether and ethyl acetate. The eluent was collected and dried at 40 °C to give a yellow solid 5a, with a yield of 68%. The reaction equation is as follows:

[0081]

[0082] The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of product 5a are as follows:

[0083]

[0084] V 石油醚 / V 乙酸乙酯 =3:1,R f =0.2; White solid: 35mg, yield 68%; Melting point = 105-106℃; 1H NMR (600MHz, CDCl3) δ8.22(d,J=6.9Hz,1H),7.65(dd,J=48.3,6.5Hz,2H),7.42(s,1H),4.94-4.72(m,2H ),4.37-4.22(m,1H),3.94(d,J=9.2Hz,1H),3.31(d,J=6.7Hz,1H),2.70-2.26(m,3H),2.00-1.82(m,1H). 13 C NMR (151MHz, CDCl3) δ160.6,159.6,148.7,134.1,127.1,126.5,126.2,120.6,73.0,44.4,40.5,29.4,26.7.HRMS(ESI):calc.for C 13 H 13 N3O3[M+H] + ,260.1030;found,260.1034.

[0085] The preparation methods for the following examples are the same as those for Example 18;

[0086] Example 19: The difference is that compound 1 is N-(but-3-en-1-yl)-4-chloro-N-cyanobenzamide. The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the obtained product 5b are as follows;

[0087]

[0088] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.2; Yellow solid: 30mg, yield 51%; Melting point = 152-153℃ 1 H NMR (600MHz, CDCl3) δ8.15(d,J=8.5Hz,1H),7.62(s,1H),7.38(d,J=8.3Hz,1H),4.89(m,J=13.8,7.0Hz,1H),4.85-4.77(m,1H),4.30(dd,J=15.2, 5.5Hz,1H),4.02-3.88(m,1H),3.39-3.24(m,1H),2.63(m,J=13.9,6.7Hz ,1H),2.58-2.49(m,1H),2.40(m,J=13.7,6.6Hz,1H),2.02-1.84(m,1H). 13C NMR (151MHz, CDCl3) δ161.1,160.1,149.9,140.4,127.8,127.2,126.8,119.3,73.1,44.7,40.7,29.5,26.9.HRMS(ESI):calc.for C 13 H 12 ClN3O3[M+H] + ,294.0640; found,294.0644.

[0089] Example 20: The difference is that compound 1 is N-(but-3-en-1-yl)-4-tert-butyl-N-cyanobenzamide. The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the obtained product 5c are as follows;

[0090]

[0091] V 石油醚 / V 乙酸乙酯 =4:1,R f =0.2; Yellow solid: 36mg, yield 57%; Melting point = 73-74℃ 1 H NMR (600MHz, CDCl3) δ8.20(d,J=8.4Hz,1H),7.65(s,1H),7.53(dd,J=8.4,1.1Hz,1H),4.88(m,J=27.3,13.6,6.9Hz,2H),4.43-4.19(m,1H),4.08-3. 87(m,1H),3.38-3.25(m,1H),2.68(m,J=14.2,7.0Hz,1H),2.59-2.47(m,1 H), 2.42 (m, J=14.0, 7.0Hz, 1H), 1.94 (m, J=18.6, 9.2Hz, 1H), 1.39 (s, 9H). 13 C NMR (151MHz, CDCl3) δ160.6,159.6,158.3,148.9,125.9,124.7,123.3,118.2,73.1,44.4,40.6,35.3,31.0,29.5,26.8.HRMS(ESI):calc.forC 17 H 21 N3O3[M+H] + ,316.1656;found,316.1657.

[0092] Example 21: The difference is that compound 1 is N-(but-3-en-1-yl)-N-cyano-2-naphthylcarboxamide. The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the obtained product after 5 days are as follows;

[0093]

[0094] V 石油醚 / V 乙酸乙酯 =4:1,R f =0.2; Yellow solid: 52mg, yield 66%; Melting point = 133-134℃ 1 H NMR (600MHz, CDCl3) δ8.88-8.76(m,1H),8.15-8.04(m,1H),7.90-7.80(m,1H),7.79-7.69(m,1H),7.70-7.56(m,2H),5.10-4.80 (m,2H),4.32(dd,J=20.9,10.0Hz,1H),4.08-3.90(m,1H),3.35(d,J=6.5Hz,1H),2.75-2.31(m,3H),1.93(m,J=19.3,9.5Hz,1H). 13 C NMR (151MHz, CDCl3) δ160.6,159.8,147.4,135.9,129.5,129.1,127.7,126.8, 126.7,124.8,121.3,116.8,73.1,44.7,40.5,29.6,26.8.HRMS(ESI):calc.for C 17 H 15 N3O3[M+H] + ,310.1186;found,310.1184.

[0095] Example 22: The difference is that compound 1 is N-cyano-N-(1-phenylbut-3-en-1-yl)benzamide. The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the obtained product 5e are as follows;

[0096]

[0097] V 石油醚 / V 乙酸乙酯 =6:1,R f =0.2; Yellow solid: 17mg, yield 25%; Melting point = 106-107℃ 1H NMR(600MHz, CDCl3)δ8.26(dd,J=7.9,0.8Hz,1H),7.82-7.67(m,2H),7.48(t,J=7.1Hz,1H),7.31(m,J=28.5,7.3Hz,3H),7.11 (d,J=7.3Hz,2H),5.81(d,J=8.4Hz,1H),5.03-4.76(m,2H),3.68-3.28(m,1H),2.72(m,J=14.1,6.9Hz,1H),2.56-2.29(m,3H). 13 C NMR (151MHz, CDCl3) δ160.1,159.8,148.9,138.7,134.4,129.0,128.1,127.3, 126.7,126.7,125.2,121.0,73.1,59.7,38.4,36.7,29.3.HRMS(ESI):calc.for C 19 H 17 N3O3[M+H] + ,336.1343;found,336.1342.

[0098] Example 23: The difference is that compound 1 is N-(but-3-en-1-yl)-N-cyano-2-methylnicotinamide. The structure, morphology, melting point, NMR, and high-resolution mass spectrometry data of the obtained product 5f are as follows;

[0099]

[0100] V 石油醚 / V 乙酸乙酯 =1:3,R f =0.2; Yellow solid: 31 mg, yield 56%; Melting point = 116-117℃ 1 H NMR (600MHz, CDCl3) δ8.72(d,J=4.5Hz,1H),7.18(d,J=4.5Hz,1H),4.89(m,J=57.1,13.4,6.6Hz,2H),4.32(t,J=10.6Hz,1H),4.01-3.91 (m,1H),3.49-3.38(m,1H),2.90(s,3H),2.76(dd,J=14.1,7.0Hz,1H),2.62-2.55(m,1H),2.43(m,J=14.1,7.0Hz,1H),2.01-1.92(m,1H). 13C NMR(151MHz,CDCl3)δ163.0,161.4,160.2,154.4,152.6,124.8,115.1,73.2,44.8,41.0,29.3,26.6,22.5.HRMS(ESI):calc.for C 13 H 14 N4O3[M+H] + ,275.1139;found,275.1139。

Claims

1. A method for preparing a quinazolinone compound, characterized in that: Under the presence of solvent, oxidant and additive, cyanamide olefin compound 1 and trimethyl azidosilane 2 reacted. Thin-layer chromatography was used to monitor the completeness of the reaction. The reaction product was concentrated and the concentrate was separated and purified by silica gel column chromatography to obtain 3-methylene-2,3-dihydropyrrolo[2,1-b]quinazoline-9(1H)-one compound 4. ； Where A is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and the substituent of aryl or heteroaryl is selected from hydrogen, alkyl, trifluoromethyl, nitro, halogen, or phenyl; R is selected from hydrogen, methyl, or phenyl. The oxidant is iodophenyl diacetic acid, the additive is 1,8-diazabicycloundec-7-ene; the solvent is nitromethane; the molar ratio of the cyanamide olefin compound to the additive is 1:0.1~1, and the reaction is carried out at 40~50℃; The molar ratio of cyanamide olefin compound to trimethyl azidosilane is 1:1 to 3.5, and the molar ratio of cyanamide olefin compound to oxidant is 1:1 to 2.

5.

2. A method for preparing a quinazolinone compound, characterized in that: Under the presence of solvent, oxidant and additive, cyanamide olefin compound 1 and trimethyl azidosilane 2 reacted. Thin-layer chromatography was used to monitor the completeness of the reaction. The reaction product was concentrated and the concentrate was separated and purified by silica gel column chromatography to obtain 3-(2-nitroethyl)-2,3-dihydropyrrolo[2,1-b]quinazoline-9(1H)-one compound 5. ； Where A is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and the substituent of aryl or heteroaryl is selected from hydrogen, alkyl, trifluoromethyl, nitro, halogen, or phenyl; R is selected from hydrogen, methyl, or phenyl. The oxidant is iodobenzoylbenzene; the additive is 1,8-diazabicycloundec-7-ene; the solvent is nitromethane; the molar ratio of the cyanamide olefin compound to the additive is 1:2~3, and the reaction is carried out at 20~30℃; The molar ratio of cyanamide olefin compound to trimethyl azidosilane is 1:1 to 3.5, and the molar ratio of cyanamide olefin compound to oxidant is 1:1 to 2.

5.

3. A method for preparing a quinazolinone compound, characterized in that: In a 15 mL reaction tube, 0.2 mmol of N-(but-3-en-1-yl)-N-cyanobenzamide, 0.7 mmol of TMSN3, 0.5 mmol of iodophenyl diacetic acid, and 3 mL of nitromethane were added. The mixture was heated to 25 °C with magnetic stirring, and the reaction was monitored by TLC. After the starting material spot completely disappeared, the reaction product was concentrated by rotary evaporation at 40 °C. The concentrate was loaded onto a silica gel column, using a petroleum ether-ethyl acetate mixture as the eluent. 石油醚 / V 乙酸乙酯 = 3:1, R f = 0.2, collect the eluent and dry it at 40℃ to obtain a yellow solid product. .

4. A method for preparing a quinazolinone compound, characterized in that: In a 15 mL reaction tube, 0.2 mmol of N-(but-3-en-1-yl)-N-cyano-4-nitrobenzamide, 0.7 mmol of TMSN3, 0.5 mmol of iodophenyl diacetic acid, and 3 mL of nitromethane were added. The mixture was heated to 25 °C with magnetic stirring, and the reaction was monitored by TLC. After the starting material spot completely disappeared, the reaction product was concentrated by rotary evaporation at 40 °C. The concentrate was loaded onto a silica gel column, using a petroleum ether-ethyl acetate mixture as the eluent. 石油醚 / V 乙酸乙酯 =4:1, R f = 0.2, collect the eluent and dry it at 40℃ to obtain a yellow solid product. .

5. A method for preparing a quinazolinone compound, characterized in that: In a 15 mL reaction tube, 0.2 mmol of N-(but-3-en-1-yl)-N-cyano-4-methylbenzamide, 0.7 mmol of TMSN3, 0.5 mmol of iodophenyl diacetic acid, and 3 mL of nitromethane were added. The mixture was heated to 25 °C with magnetic stirring, and the reaction was monitored by TLC. After the starting material spot completely disappeared, the reaction product was concentrated by rotary evaporation at 40 °C. The concentrate was loaded onto a silica gel column, using a petroleum ether-ethyl acetate mixture as the eluent. 石油醚 / V 乙酸乙酯 =4:1, R f = 0.2, collect the eluent and dry it at 40℃ to obtain a yellow solid product. .

6. A method for preparing a quinazolinone compound, characterized in that: Add 0.2 mmol of 3-bromo-N-(but-3-en-1-yl)-N-cyanobenzamide, 0.7 mmol of TMSN3, 0.5 mmol of iodophenylacetic acid, and 3 mL of nitromethane to a 15 mL reaction tube. Heat to 25 °C with magnetic stirring and monitor the reaction by TLC. After the starting material spot completely disappears, concentrate the reaction product by rotary evaporation at 40 °C. Column chromatography is performed on silica gel, using a petroleum ether-ethyl acetate mixture as the eluent. 石油醚 / V 乙酸乙酯 =3:1,R f = 0.2, collect the eluent and dry at 40℃ to obtain a white solid product. .

7. A method for preparing a quinazolinone compound, characterized in that: In a 15 mL reaction tube, 0.2 mmol of N-(but-3-en-1-yl)-N-cyano-3-(trifluoromethyl)benzamide, 0.7 mmol of TMSN3, 0.5 mmol of iodophenyl diacetic acid, and 3 mL of nitromethane were added. The mixture was heated to 25 °C with magnetic stirring, and the reaction was monitored by TLC. After the starting material spot completely disappeared, the reaction product was concentrated by rotary evaporation at 40 °C. The concentrate was loaded onto a silica gel column, using a petroleum ether-ethyl acetate mixture as the eluent. 石油醚 / V 乙酸乙酯 =5:1, R f = 0.2, collect the eluent and dry it at 40℃ to obtain a yellow solid product. .

8. A method for preparing a quinazolinone compound, characterized in that: In a 15 mL reaction tube, 0.2 mmol of N-cyano-N-(3-methylbut-3-en-1-yl)benzamide, 0.7 mmol of TMSN3, 0.5 mmol of iodophenyl diacetic acid, and 3 mL of nitromethane were added. The mixture was heated to 25 °C with magnetic stirring, and the reaction was monitored by TLC. After the starting material spot completely disappeared, the reaction product was concentrated by rotary evaporation at 40 °C. The concentrate was loaded onto a silica gel column, using a petroleum ether-ethyl acetate mixture as the eluent. 石油醚 / V 乙酸乙酯 =6:1, R f = 0.2, collect the eluent and dry at 40℃ to obtain a colorless oily product. .

9. A method for preparing a quinazolinone compound, characterized in that: In a 15 mL reaction tube, 0.2 mmol of N-cyano-N-(1-phenylbut-3-en-1-yl)benzamide, 0.7 mmol of TMSN3, 0.5 mmol of iodophenyldiacetic acid, and 3 mL of nitromethane were added. The mixture was heated to 25 °C with magnetic stirring, and the reaction was monitored by TLC. After the starting material spot completely disappeared, the reaction product was concentrated by rotary evaporation at 40 °C. The concentrate was loaded onto a silica gel column, using a petroleum ether-ethyl acetate mixture as the eluent. 石油醚 / V 乙酸乙酯 =5:1, R f = 0.2, collect the eluent and dry it at 40℃ to obtain a yellow solid product. .

10. A method for preparing a quinazolinone compound, characterized in that: In a 15 mL reaction tube, 0.2 mmol of N-(but-3-en-1-yl)-N-cyano-2-naphthylcarboxamide, 0.7 mmol of TMSN3, 0.5 mmol of iodophenyl diacetic acid, and 3 mL of nitromethane were added. The mixture was heated to 25 °C with magnetic stirring, and the reaction was monitored by TLC. After the starting material spot completely disappeared, the reaction product was concentrated by rotary evaporation at 40 °C. The concentrate was loaded onto a silica gel column, using a petroleum ether-ethyl acetate mixture as the eluent. 石油醚 / V 乙酸乙酯 =4:1, R f = 0.2, collect the eluent and dry at 40℃ to obtain a white solid product. .

11. A method for preparing a quinazolinone compound, characterized in that: In a 15 mL reaction tube, 0.2 mmol of N-(but-3-en-1-yl)-N-cyanothiophene-2-carboxamide, 0.7 mmol of TMSN3, 0.5 mmol of iodophenyl diacetic acid, and 3 mL of nitromethane were added. The mixture was heated to 25 °C with magnetic stirring, and the reaction was monitored by TLC. After the starting material spot completely disappeared, the reaction product was concentrated by rotary evaporation at 40 °C. The concentrate was loaded onto a silica gel column, using a petroleum ether-ethyl acetate mixture as the eluent. 石油醚 / V 乙酸乙酯 =4:1, R f = 0.2, collect the eluent and dry at 40℃ to obtain a white solid product. .

12. A method for preparing a quinazolinone compound, characterized in that: Add 0.2 mmol of N-cyano-N-(2-(prop-1-en-2-yl)phenyl)benzamide, 0.7 mmol of TMSN3, 0.5 mmol of iodophenyldiacetic acid, and 3 mL of nitromethane to a 15 mL reaction tube. Heat to 25 °C with magnetic stirring and monitor the reaction by TLC. After the starting material spot completely disappears, concentrate the reaction product by rotary evaporation at 40 °C. Column chromatography of the concentrate is performed on a silica gel column using a petroleum ether-ethyl acetate mixture as the eluent. 石油醚 / V 乙酸乙酯 =4:1, R f = 0.2, collect the eluent and dry at 40℃ to obtain a white solid product. .

13. A method for preparing a quinazolinone compound, characterized in that: In a 15 mL reaction tube, 0.2 mmol of N-(but-3-en-1-yl)-N-cyano-1,3-dimethyl-1H-pyrazole-4-carboxamide, 0.7 mmol of TMSN3, 0.5 mmol of iodophenyl diacetic acid, and 3 mL of nitromethane were added. The mixture was heated to 25 °C with magnetic stirring, and the reaction was monitored by TLC. After the starting material spot completely disappeared, the reaction product was concentrated by rotary evaporation at 40 °C. The concentrate was loaded onto a silica gel column, using a petroleum ether-ethyl acetate mixture as the eluent. 石油醚 / V 乙酸乙酯 =2:1, R f = 0.2, collect the eluent and dry at 40℃ to obtain a white solid product. .

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