Quinazolinone compounds synthesized from carbon dioxide and methods for preparing the same

Abstract

This application relates to the field of organic chemical synthesis, specifically to a method for synthesizing quinazolinone compounds from carbon dioxide and its preparation. The method uses carbon dioxide, 2-aminobenzamide compounds, and aryl halides as raw materials, and reacts under heating in the presence of a palladium metal catalyst, a ligand, a reducing agent, a base, and an organic solvent to generate quinazolinone compounds. The mechanism is as follows: carbon dioxide forms intermediate A under alkaline and reducing conditions; the aryl halide reacts with intermediate A under the action of a palladium metal catalyst to form a carbonyl metal compound B, which then reacts with the 2-aminobenzamide compound under the action of an alkaline and reducing agent to obtain the quinazolinone compound. This catalyst system is universally applicable to various types of 2-aminobenzamides and their derivatives, as well as aryl halides; the raw materials are widely available, inexpensive, and readily available; and the reaction process is simple and controllable.

Description

Technical Field

[0001] This application relates to the field of organic chemical synthesis, specifically to a quinazolinone compound synthesized from carbon dioxide and its preparation method. Background Technology

[0002] Quinazolinones are an important class of chemicals. Quinazolinone homologues and derivatives have wide applications in various fields, such as catalysis, pharmaceutical research and development, and functional materials, due to their high structural tunability, excellent biological activity, and superior functional properties.

[0003] Quinazolinones are precursors of over 200 naturally available quinazolidinone alkaloid derivatives isolated from natural sources such as animals, microorganisms, and plants. The preparation of quinazolinones mainly relies on the condensation pathway of 1,2-disubstituted aromatics and formamide derivatives. Although these well-known pathways can effectively promote the formation of the desired scaffold, they have significant limitations, such as high-temperature conditions and prolonged reaction times.

[0004] Carbonylation is a class of reactions with good atom economy and can efficiently synthesize high-value-added carbonyl compounds. The Niementowski reaction is a one-pot synthesis of 4(3H)-quinazolinone from o-aminobenzoic acid and formamide. This method has few steps, but the reaction temperature is high and difficult to control. Wu et al. (Chemistry-A European Journal 2013,19(38):12635-12638.) used Pd(OAc)2 as a catalyst to synthesize quinazolinone through a carbonylation cascade reaction of high-pressure carbon monoxide with 2-aminobenzoamide and aryl bromide. This reaction has a wide range of substrates, the product is easy to purify, and the raw materials are commercially available. Subsequently, heterogeneous Ru-cluster / cerium oxide-catalyzed synthesis of quinazolinones from olefins, carbon monoxide, and amines (Angew. Chem. Int. Ed. 2018, 57(38): 12308-12312) and heterogeneous MCM-41 supported bidentate phosphine palladium(II) complex-catalyzed carbonylation cyclization of 2-aminobenzamide with aryl iodine to quinazolinones (Journal of Organometallic Chemistry 2018, 875, 35-45) have the advantages of broad substrate range, good to excellent yields, simple product purification, and commercially available raw materials. However, the above methods all require the use of highly toxic and high-pressure carbon monoxide gas, and the reaction must be carried out at high temperature. This places certain requirements on the pressure resistance and operational safety of the reaction equipment, which limits their application scenarios and is not conducive to industrial production. Summary of the Invention

[0005] To address the aforementioned technical problems, this application provides a method for synthesizing quinazolinone compounds from carbon dioxide and the same. Carbon dioxide is an ideal carbon-1 synthon that is inexpensive, readily available, non-toxic, and renewable. The carbonylation reaction using carbon dioxide as a carbonyl source to synthesize quinazolinone compounds has significant economic and environmental value. Specifically, the method uses 2-aminobenzamide and its derivatives, aryl halides, and carbon dioxide as raw materials, employing a palladium metal catalyst and an organophosphorus ligand as a combined catalyst, to achieve a one-step carbonylation reaction to obtain quinazolinone homologues and derivatives. This preparation method uses inexpensive and readily available raw materials, exhibits high reaction selectivity and efficiency, and has a simple route. Only a 1% molar fraction of palladium catalyst is required in the reaction system, significantly reducing the synthesis cost and potentially enabling large-scale industrial production.

[0006] To achieve the above objectives, this scheme first provides a method for preparing quinazolinone compounds by synthesizing carbon dioxide, including the following steps:

[0007] Aryl halides of formula (I), 2-aminobenzamide compounds of formula (II), palladium metal catalyst, ligand, reducing agent, base and organic solvent are brought into contact with carbon dioxide and reacted at 80℃~120℃ for 6h~15h to generate quinazolinone compounds of formula (III).

[0008] , , ,

[0009] In formula (I), X is selected from halogens; R 1 Selected from any one of hydrogen, C1-C5 alkyl, C1-C5 alkoxy, halogen, ester group, trifluoromethyl, and aryl; R 2 Selected from hydrogen and C1-C5 alkyl groups; R 3 Selected from hydrogen, C1~C 10 Alkyl, C6~C 12 Any of the aryl groups.

[0010] As an example, the general formula for the synthesis of quinazolinone compounds from carbon dioxide is as follows:

[0011] .

[0012] As a preferred option, X in formula (I) is selected from any one of F, Br, and I.

[0013] As a preferred option, R 1 It is selected from any one of hydrogen, methyl, methoxy, tert-butyl, F, Cl, ester, trifluoromethyl and aryl.

[0014] As a preferred option, R 2It is selected from any one of hydrogen, methyl, n-propyl, isopropyl, and n-butyl.

[0015] As a preferred option, R 3 Selected from hydrogen, C1~C 10 Any one of alkyl, phenyl, and naphthyl groups.

[0016] Preferably, the ligand is selected from one or more monodentate phosphine ligands and multidentate phosphine ligands.

[0017] Preferably, the ligand is selected from one or more of bis(diphenylphosphine)methane, 1,2-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine)propane, 1,4-bis(diphenylphosphine)butane, 1,2-bis(diphenylphosphine)benzene, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 1,1'-bis(diphenylphosphine)ferrocene, bis(2-diphenylphosphine)ether, 4,6-bis(diphenylphosphine)-10H-phenoxazine, and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene.

[0018] Preferably, the palladium metal catalyst is selected from divalent palladium compounds or zero-valent palladium complexes.

[0019] Preferably, the divalent palladium compound is selected from one or more of palladium acetate, palladium dichloride, bis(triphenylphosphine)palladium dichloride, (1,5-cyclooctadiene)palladium dichloride, allyl palladium chloride, bis(acetonitrile)palladium dichloride, palladium trifluoroacetate, tetratriphenylphosphine palladium, bis(acetylacetone)palladium, bis(dibenzylacetone)palladium, or tri(dibenzylacetone)palladium.

[0020] Preferably, the reducing agent is selected from either hydrogen or silane.

[0021] Preferably, the silane is selected from phenylsilane, trimethoxysilane, polymethylhydrosiloxane, triethylsilane, diphenylsilane, or triisopropylsilane.

[0022] Preferably, the base is selected from any one of triethylamine, N-ethyldiisopropylamine, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,5,7-triazidobicyclo(4.4.0)dec-5-ene, ethylenediamine, isopropylamine, sodium carbonate, cesium carbonate, potassium hydroxide, potassium carbonate, potassium phosphate, and piperazine.

[0023] Preferably, the solvent is selected from any one of dichloromethane, dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, acetonitrile, methanol, ethanol, 1,4-dioxane, N-methylpyrrolidone, toluene, xylene, mesitylene, and chlorobenzene.

[0024] Preferably, the molar ratio of the 2-aminobenzamide compound to the palladium metal catalyst is (1~1000):1. More preferably, the molar ratio of the 2-aminobenzamide compound to the palladium metal catalyst is (100~1000):1. Even more preferably, the molar ratio of the 2-aminobenzamide compound to the palladium metal catalyst is (130~135):1.

[0025] Preferably, the molar ratio of the 2-aminobenzamide compound to the base is (0.1~10):1. More preferably, the molar ratio of the 2-aminobenzamide compound to the base is (0.4~0.6):1.

[0026] Preferably, the molar ratio of the 2-aminobenzamide compound to the reducing agent is (0.1~10):1. More preferably, the molar ratio of the 2-aminobenzamide compound to the reducing agent is (0.4~0.6):1.

[0027] Preferably, the molar ratio of the ligand to the palladium metal catalyst is (0.1 to 120):1.

[0028] More preferably, the molar ratio of the ligand to the palladium metal catalyst is (95~105):1.

[0029] Preferably, when the aryl halide of formula (I), the 2-aminobenzamide compound of formula (II), the palladium metal catalyst, the ligand, the reducing agent, the base, and the organic solvent are contacted with carbon dioxide, the carbon dioxide is selected from... 11 CO2, 12 CO2, 13 CO2, 14 Any type of CO2, wherein the pressure of the carbon dioxide is 1 bar to 30 bar. That is, in the reaction system for synthesizing quinazolinone compounds from carbon dioxide, the reaction pressure of the carbon dioxide is 1 bar to 30 bar.

[0030] Preferably, when the aryl halide of formula (I), the 2-aminobenzamide compound of formula (II), the palladium metal catalyst, the ligand, the reducing agent, the base, and the organic solvent are contacted with carbon dioxide, the amount of carbon dioxide added is 1 mL to 20 mL. When the amount of CO2 added is measured in mL, it refers to the volume under normal room temperature and pressure conditions.

[0031] In this application, room temperature refers to conditions of 20℃ to 25℃; atmospheric pressure refers to conditions of 101kPa to 102kPa.

[0032] Preferably, the following steps are included before contacting the aryl halide of formula (I), the 2-aminobenzamide compound of formula (II), the palladium metal catalyst, the ligand, the reducing agent, the base, and the organic solvent with carbon dioxide:

[0033] First, under a nitrogen atmosphere, the aryl halide of formula (I), the 2-aminobenzamide compound of formula (II), the palladium metal catalyst, the ligand, the reducing agent, the base and the organic solvent are added to the reactor. Then, the nitrogen gas in the reactor is discharged with carbon dioxide, and then carbon dioxide is introduced to the required pressure of the reaction system.

[0034] Based on a general inventive concept, this application also provides a quinazolinone compound obtained according to the above preparation method.

[0035] The catalytic mechanism of this synthesis scheme is as follows:

[0036] The reaction uses 2-aminobenzamide and its derivatives, aryl halides as reactants, and carbon dioxide as the carbonyl source. Under conditions of reducing agent and base, the carbonylation reaction, upon heating, yields quinazolinone compounds. The specific reaction principle is as follows:

[0037] .

[0038] Carbon dioxide reacts with methyl silicate intermediate A under the action of alkali and reducing agent. Aryl halides react with methyl silicate intermediate A under the action of metal catalyst to form carbonyl metal compound B. Finally, it reacts with 2-aminobenzamide and its derivatives to obtain quinazolinone compounds.

[0039] Compared with the prior art, this application has the following beneficial effects:

[0040] (1) This application uses palladium metal catalyst and organophosphorus ligand as catalyst system to catalyze the carbonylation reaction of aryl halides, 2-aminobenzamide and its derivatives with carbon dioxide to prepare quinazolinone compounds. The reaction conditions are mild, the reaction selectivity and efficiency are high, and the route is simple.

[0041] (2) Compared with the prior art, the method disclosed in this application only uses carbon dioxide gas as the carbonyl source, avoids the use of multiple high-pressure gases, is simple to operate, shortens the multi-step reaction to a one-step reaction, and is easy to process.

[0042] (3) The catalyst system disclosed in this application is universally applicable to various types of aryl halides, 2-aminobenzamide and their derivatives, with a wide range of raw material sources that are inexpensive and readily available. The reaction process is simple and controllable, making it suitable for large-scale industrial production. Attached Figure Description

[0043] To more clearly illustrate the technical solutions of the embodiments of this application, the drawings used in the embodiments of this application will be briefly introduced below. Obviously, the drawings described below are only some implementation methods of this application. For those skilled in the art, other drawings can be obtained based on the drawings without creative effort.

[0044] Figure 1 The 1H NMR spectrum of compound 1 synthesized in Example 1;

[0045] Figure 2 The carbon NMR spectrum of compound 1 synthesized in Example 1;

[0046] Figure 3 The 1H NMR spectrum of compound 2 synthesized in Example 2;

[0047] Figure 4 The image shows the carbon NMR spectrum of compound 2 synthesized in Example 2. Detailed Implementation

[0048] The embodiments described in this specification are for illustrative purposes only and are not intended to limit the scope of this application.

[0049] For simplicity, this paper explicitly discloses certain numerical ranges. However, any lower limit can be combined with any upper limit to form an undefined range; and any lower limit can be combined with other lower limits to form an undefined range, just as any upper limit can be combined with any other upper limit to form an undefined range. Furthermore, although not explicitly stated, every point or individual value between the endpoints of a range is included within that range. Therefore, each point or individual value can serve as its own lower or upper limit and be combined with any other point or individual value, or with other lower or upper limits, to form an undefined range.

[0050] Those skilled in the art will understand that the order in which the steps are written in the various embodiments or examples does not imply a strict execution order and does not limit the implementation process in any way. The detailed execution order of each step should be determined by its function and possible internal logic. Unless otherwise specified, all steps of the present invention may be performed sequentially or randomly, but sequentially is preferred.

[0051] In this application, "alkyl" can mean straight-chain, branched, and / or cyclic alkyl. The number of carbon atoms in an alkyl group can be 1 to 50, 1 to 30, 1 to 20, 1 to 10, or 1 to 6. Phrases containing this term, such as "C1~C6", are also included. 10 "Alkyl" refers to an alkyl group containing 1 to 9 carbon atoms. Each time it appears, it can independently be C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, or C10 Alkyl groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, 2-ethylbutyl, 3,3-dimethylbutyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, cyclopentyl, 1-methylpentyl, 3-methylpentyl, 2-ethylpentyl, 4-methyl-2-pentyl, n-hexyl, 1-methylhexyl, 2-ethylhexyl, 2-butylhexyl, cyclohexyl, 4-methylcyclohexyl, 4-tert-butylcyclohexyl, n-heptyl, 1-methylheptyl, 2,2-dimethyl, hexyl, 2-ethylheptyl, 2-butylheptyl, n-octyl, tert-octyl, 2-ethyloctyl, 2-butyloctyl, 2-hexyloctyl, 3,7-dimethyloctyl, cyclooctyl, n-nonyl, n-decyl, adamantyl, 2- Ethyldecyl, 2-butyldecyl, 2-hexyldecyl, 2-octyldecyl, undecyl, dodecyl, 2-ethyldodecyl, 2-butyldodecyl, 2-hexyldodecyl, 2-octyldodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, 2-ethylhexadecyl, 2-butylhexadecyl, 2-hexylhexadecyl, 2-octylhexadecyl, heptadecanyl, octadecyl, nonadecanyl, eicosyl, 2-butyleicosyl, 2-octyleicosyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, triadecyl, adamantane, etc.

[0052] The term "alkoxy" refers to a group with the structure "-O-alkyl", that is, an alkyl group as defined above that is attached to other groups via an oxygen atom. Suitable examples of phrases containing this term include, but are not limited to: methoxy (-O-CH3 or -OMe), ethoxy (-O-CH2CH3 or -OEt), and tert-butoxy (-OC(CH3)3 or -OtBu).

[0053] The term "aryl" refers to a closed aromatic ring or ring system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthracene, biphenyl (including diphenyl and terphenyl), triphenylene, pyrene, spirobisfluorene, peryl, indene, azulene, and benzo[a]phenanthryl. In various embodiments, C6-C 30 Aryl groups can contain 6 to 30 carbon atoms for forming rings.

[0054] In this application, the abbreviations for substituents are: n-n-, sec-sec-, i-iso-, t-tert-, o-ortho-, m-me-, p-para-, Me-methyl, Et-ethyl, Pr-propyl, Bu-butyl, Am-pentyl, Hx-hexyl, Cy-cyclohexyl.

[0055] In this application, DMSO-d6 represents deuterated dimethyl sulfoxide; Chloroform-d represents deuterated chloroform.

[0056] "equiv." indicates an equivalent amount in a chemical reaction. "3equiv." means 3 equivalents.

[0057] The present application is further illustrated below with reference to embodiments. It should be understood that these embodiments are for illustrative purposes only, as various modifications and variations will be apparent to those skilled in the art within the scope of the disclosure of this application. Unless otherwise stated, all parts, percentages, and ratios reported in the following embodiments are based on mass, and all reagents used in the embodiments are commercially available or synthesized by conventional methods and can be used directly without further processing, and the instruments used in the embodiments are commercially available.

[0058] Example 1: Preparation of quinazolinone compound 1.

[0059] Under a nitrogen atmosphere, tris(dibenzylacetone)dipalladium (Pd2(dba)3, 0.003 mmol), 1,3-bis(diphenylphosphine)propane (DPPP, 0.006 mmol), and a magnetic flux were added to a 20 mL pressure-resistant tube. Then, starting material 1 (bromobenzene, 0.3 mmol), starting material 2 (2-amino-N-methylbenzamide, 0.4 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.9 mmol), phenylsilane (PhSiH3, 0.8 mmol), and acetonitrile (CH3CN, 1 mL) were added. The pressure-resistant tube was sealed, the air inside was removed, and 20 mL of carbon dioxide gas was introduced. After the addition was complete, the pressure-resistant tube was placed in a metal module preheated to 100°C and stirred for 15 hours. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. Separation was performed using a silica gel column chromatography to obtain compound 1 in 88% yield. The reaction formula is as follows:

[0060] .

[0061] The NMR data of compound 1 were measured using an NMR spectrometer. The hydrogen NMR spectrum of compound 1 is shown below. Figure 1 As shown, the carbon spectrum is as follows Figure 2 As shown, δ represents the chemical shift, with units of ppm. Specifically, the NMR data for compound 1 are as follows:

[0062] 1 H NMR (400 MHz, DMSO-d6) δ8.18 (dd, J=8.0, 1.7Hz, 1H), 7.83-7.80 (m, 1H), 7.70-7.67 (m, 3H), 7.59-7.51 (m, 4H), 3.36 (s, 3H).

[0063] 13 C NMR (100 MHz, DMSO-d6) δ 161.8, 156.24, 147.1, 135.4, 134.5, 129.9, 128.5, 128.3, 127.3, 127.0, 126.2, 120.2, 34.0.

[0064] Example 2 Preparation of quinazolinone compound 2.

[0065] Under a nitrogen atmosphere, PdCl2 (palladium chloride, 0.003 mmol), DPPM (bis(diphenylphosphine)methane, 0.006 mmol), and a magnetic flux were added to a 20 mL pressure-resistant tube. Then, starting material 3 (2-bromonaphthalene, 0.3 mmol), starting material 2 (2-amino-N-methylbenzamide, 0.4 mmol), triethylamine (0.9 mmol), styrene (0.8 mmol), and DMF (N,N-dimethylformamide, 1 mL) were added. The pressure-resistant tube was sealed, the air inside was removed, and 20 mL of carbon dioxide gas was introduced. After the addition was complete, the pressure-resistant tube was placed in a metal module preheated to 80°C and stirred for 10 hours. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. Separation was performed using a silica gel column chromatography to give compound 2 in 86% yield. The reaction formula is as follows:

[0066] .

[0067] The NMR data of compound 2 were measured using an NMR spectrometer. The hydrogen NMR spectrum of compound 2 is shown below. Figure 3 As shown, the carbon spectrum is as follows Figure 4 As shown. Specifically, the NMR data for compound 2 are as follows:

[0068] 1 H NMR (400 MHz, Chloroform-d) δ 8.36 (d, J=8.0 Hz, 1H), 8.10 (s, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.96–7.89 (m, 2H), 7.77 (d, J=3.8 Hz, 2H), 7.64–7.57 (m, 3H), 7.54–7.50 (m, 1H), 3.54 (s, 3H).

[0069] 13 C NMR (100 MHz, Chloroform-d )δ162.9, 156.3, 147.5, 134.5, 133.8, 133.0, 132.8, 128.9, 128.7, 128.3, 128.0, 127.7, 127.6, 127.2, 126.9, 124.9, 120.7, 34.5.

[0070] Example 3: Preparation of quinazolinone compound 3.

[0071] Under a nitrogen atmosphere, tetratetraphenylphosphine palladium (Pd(PPh3)4, 0.003 mmol), 1,1'-bis(diphenylphosphine)ferrocene (DPPF, 0.006 mmol), and a magnetic flux were added to a 20 mL glass tube. Then, starting material 4 (3,5-dimethylbromobenzene, 0.3 mmol), starting material 2 (2-amino-N-methylbenzamide, 0.4 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.9 mmol), phenylsilane (0.8 mmol), and N,N-dimethylformamide (DMF, 1 mL) were added. The glass tube was sealed and transferred to a reaction vessel. Air was removed from the reaction vessel, and CO2 (10 bar) and hydrogen (10 bar) were introduced. After the addition was complete, the reaction vessel was placed in a preheated metal module at 100°C and stirred for 15 hours. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. Compound 3 was separated by silica gel column chromatography in 89% yield. The reaction formula is as follows:

[0072] .

[0073] The NMR data of compound 3 were measured using an NMR spectrometer. Specifically, the NMR data of compound 3 are as follows:

[0074] 1 H NMR (400 MHz, DMSO-d6) δ8.33 (d, J=7.8 Hz, 1H), 7.78–7.73 (m, 2H), 7.53–7.47 (m, 1H), 7.15 (s, 3H), 3.49 (s, 3H), 2.39 (s, 7H).

[0075] 13 C NMR (100 MHz, DMSO-d6) δ 162.9, 156.7, 147.5, 138.8, 135.4, 134.4, 131.7, 127.6, 127.0, 126.8, 125.6, 120.6, 34.3, 21.5.

[0076] Example 4: Preparation of quinazolinone compound 4.

[0077] Under a nitrogen atmosphere, tetratetraphenylphosphine palladium (Pd(PPh3)4, 0.003 mmol), bis(2-diphenylphosphine) ether (DPEPhos, 0.006 mmol), and a magnetic induction device were added to a 20 mL pressure-resistant tube. Then, starting material 5 (p-bromotoluene, 0.3 mmol), starting material 2 (2-amino-N-methylbenzamide, 0.4 mmol), phenylsilane (0.8 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.9 mmol), and N-methylpyrrolidone (NMP, 1 mL) were added. The pressure-resistant tube was sealed, the air inside was removed, and 15 mL of carbon dioxide gas was introduced. After the addition was complete, the glass pressure-resistant tube was placed in a metal module preheated to 100°C, and the mixture was stirred for 15 hours. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. Separation was performed using a silica gel column chromatography to obtain compound 4 in 93% yield. The reaction formula is as follows:

[0078] .

[0079] The NMR data of compound 4 were measured using an NMR spectrometer. Specifically, the NMR data of compound 4 are as follows:

[0080] 1 H NMR (400 MHz, DMSO-d6) δ 8.34–8.32 (m, 1H), 7.80–7.68 (m, 2H), 7.53–7.45 (m, 3H), 7.32 (d, J=7.8 Hz, 2H), 3.50 (s, 3H), 2.44 (s, 3H).

[0081] 13 C NMR (100 MHz, DMSO-d6) δ 163.0, 156.4, 147.6, 140.4, 134.4, 132.7, 129.6, 128.1, 127.0, 126.8, 120.6, 34.4, 21.6.

[0082] Example 5: Preparation of quinazolinone compound 5.

[0083] Under a nitrogen atmosphere, tris(dibenzylacetone)palladium (Pd2(dba)3, 0.003 mmol), 4,6-bis(diphenylphosphine)phenazine (Nixantphos, 0.006 mmol), and a magnetic flux were added to a 20 mL reaction flask. Then, starting material 6 (4-bromoanisole, 0.3 mmol), starting material 2 (2-amino-N-methylbenzamide, 0.4 mmol), styrene (0.8 mmol), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN, 0.9 mmol), and acetonitrile (1 mL) were added. The pressure-resistant tube was sealed, the air inside was removed, and 15 mL of carbon dioxide gas was introduced. After the addition was complete, the glass pressure-resistant tube was placed in a metal module preheated to 100°C, and the mixture was stirred for 15 hours. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. The mixture was separated by silica gel column chromatography to give compound 5 in 90% yield. The reaction formula is as follows:

[0084] .

[0085] The NMR data of compound 5 were measured using a nuclear magnetic resonance spectrometer. Specifically, the NMR data of compound 5 are as follows:

[0086] 1 H NMR (400 MHz, DMSO-d6) δ8.34–8.26 (m, 1H), 7.75–7.69 (m, 2H), 7.52 (d, J=8.8Hz, 2H), 7.48–7.45 (m, 1H), 7.01 (d, J=8.8 Hz, 2H), 3.86 (s, 3H), 3.52 (s, 3H).

[0087] 13 C NMR (100 MHz, DMSO-d6) δ 163.0, 161.0, 156.1, 147.5, 134.3, 129.8, 127.8, 127.5, 126.9, 126.7, 120.4, 114.3, 55.5, 34.5.

[0088] Example 6: Preparation of quinazolinone compound 6.

[0089] Under a nitrogen atmosphere, 0.003 mmol of bis(acetonitrile)palladium dichloride, 0.006 mmol of Xantphos (4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene), and a magnetic flux were added to a 20 mL glass pressure-resistant tube. Then, starting material 7 (p-bromofluorobenzene, 0.3 mmol), starting material 2 (2-amino-N-methylbenzamide, 0.4 mmol), polymethylhydrosiloxane (PMHS, 0.8 mmol), 0.9 mmol of DBN (1,5-diazabicyclo[4.3.0]non-5-ene), and 1 mL of acetonitrile were added. The pressure-resistant tube was sealed, the air inside was removed, and 10 mL of carbon dioxide gas was introduced. After the addition was complete, the glass pressure-resistant tube was placed in a metal module preheated to 100°C and stirred for 15 hours. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. Compound 6 was obtained by silica gel column chromatography in 88% yield, as shown in the following reaction formula:

[0090] .

[0091] The NMR data of compound 6 were measured using an NMR spectrometer. Specifically, the NMR data of compound 6 are as follows:

[0092] 1 H NMR (400 MHz, DMSO-d6) δ8.33 (dd, J=8.0, 1.4 Hz, 1H), 7.81–7.70 (m, 2H), 7.63–7.56 (m, 2H), 7.53–7.50 (m, 1H), 7.25–7.21 (m, 2H), 3.50 (s, 3H).

[0093] 13 C NMR (100 MHz, DMSO-d6) δ163.9 (d, J=247.3 Hz), 162.5, 155.3, 147.3, 134.5, 131.4 (d, J=4.1 Hz), 130.4 (d, J=8.6 Hz), 127.4 (d, J=32.9 Hz), 126.86, 120.63, 116.2 (d, J=21.8 Hz), 34.43.

[0094] Example 7 Preparation of quinazolinone compound 7.

[0095] Under a nitrogen atmosphere, tris(dibenzylacetone)dipalladium (Pd2(dba)3, 0.003 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (Xantphos, 0.006 mmol), and a magnetic flux were added to a 20 mL pressure-resistant tube. Then, starting material 8 (4-bromochlorobenzene, 0.3 mmol), starting material 2 (2-amino-N-methylbenzamide, 0.4 mmol), triisopropylsilane (0.8 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.9 mmol), and toluene (1 mL) were added. The pressure-resistant tube was sealed, the air inside was removed, and 15 mL of carbon dioxide gas was introduced. After the addition was complete, the glass pressure-resistant tube was placed in a metal module preheated to 100°C, and the mixture was stirred for 15 hours. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. Separation was performed using a silica gel column chromatography to obtain compound 7 in 85% yield. The reaction formula is as follows:

[0096] .

[0097] The NMR data of compound 7 were measured using an NMR spectrometer. Specifically, the NMR data of compound 7 are as follows:

[0098] 1 H NMR (400 MHz, DMSO-d6) δ8.30 (dd, J=8.0, 1.6 Hz, 1H), 7.75–7.69 (m, 2H), 7.55–7.46 (m, 5H), 3.48 (s, 3H).

[0099] 13 C NMR (100 MHz, DMSO-d6) δ 162.7, 155.1, 147.2, 136.4, 134.5, 133.8, 129.6, 129.2, 127.6, 127.3, 126.8, 120.6, 34.3.

[0100] Example 8: Preparation of quinazolinone compound 8.

[0101] Under a nitrogen atmosphere, palladium acetate (Pa(OAc)2, 0.003 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (Xantphos, 0.006 mmol), and a magnetic flux were added to a 20 mL glass pressure-resistant tube. Then, starting material 9 (p-bromotrifluorotoluene, 0.3 mmol), starting material 2 (2-amino-N-methylbenzamide, 0.4 mmol), diphenylsilane (0.8 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.9 mmol), and DMF (1 mL) were added. The pressure-resistant tube was sealed, the air inside was removed, and 10 mL of carbon dioxide gas was introduced. After the addition was complete, the glass pressure-resistant tube was placed in a metal module preheated to 100°C and stirred for 15 hours. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. Separation was performed using a silica gel column chromatography to give compound 8 in 73% yield. The reaction formula is as follows:

[0102] .

[0103] The NMR data of compound 8 were measured using a nuclear magnetic resonance spectrometer. Specifically, the NMR data of compound 8 are as follows:

[0104] 1 H NMR (400 MHz, DMSO-d6) δ8.34 (dd, J=8.0, 1.4 Hz, 1H), 7.87–7.76 (m, 3H), 7.73–7.71 (m, 3H), 7.55–7.51 (m, 1H), 3.49 (s, 3H).

[0105] 13 C NMR (100 MHz, DMSO-d6) δ162.6, 154.8, 147.2, 138.9, 134.6, 132.4 (q, J C-F =32.0 Hz), 128.8, 127.6 (d, J C-F =10.6 Hz), 126.9, 126.2, 126.1 (q, J C-F =3.0 Hz), 126.1, 123.8 (d, J C-F =270.6 Hz), 120.75, 34.28.

[0106] Example 9: Preparation of quinazolinone compound 9.

[0107] Under a nitrogen atmosphere, allyl palladium chloride (0.003 mmol), 4,6-bis(diphenylphosphine)-10H-phenoxazine (0.006 mmol), and a magnetic flux were added to a 20 mL glass pressure-resistant tube. Then, starting material 1 (bromobenzene, 0.3 mmol), starting material 10 (2-amino-5-fluorobenzamide, 0.4 mmol), styrene (0.8 mmol), potassium hydroxide (0.9 mmol), and N,N-dimethylacetamide (DMAc, 1 mL) were added. The pressure-resistant tube was sealed, the air inside was removed, and 10 mL of carbon dioxide gas was introduced. After the addition was complete, the glass pressure-resistant tube was placed in a metal module preheated to 100°C, and the mixture was stirred for 15 hours. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. The mixture was separated by silica gel column chromatography to give compound 9 in 86% yield. The reaction formula is as follows:

[0108] .

[0109] The NMR data of compound 9 were measured using an NMR spectrometer. Specifically, the NMR data of compound 9 are as follows:

[0110] 1 H NMR (400 MHz, DMSO-d6) δ12.66 (s, 1H), 8.15 (d, J=7.1 Hz, 2H), 7.85–7.78 (m, 2H), 7.74–7.69 (m, 1H), 7.61–7.53 (m, 3H).

[0111] 13 C NMR (100 MHz, DMSO-d6) δ 161.8, 161.3, 158.9, 152.0, 145.7, 132.6, 131.5, 130.3, 128.7, 127.8, 123.3, 123.1, 122.3, 122.2, 110.7, 110.5.

[0112] Example 10: Preparation of quinazolinone compound 10.

[0113] Under a nitrogen atmosphere, (1,5-cyclooctadiene)palladium dichloride (0.003 mmol), 1,1'-bis(diphenylphosphine)ferrocene (DPPF, 0.006 mmol), and a magnetic flux were added to a 20 mL glass pressure-resistant tube. Then, starting material 1 (bromobenzene, 0.3 mmol), starting material 11 (2-amino-5-chlorobenzamide, 0.4 mmol), diphenylsilane (0.8 mmol), cesium carbonate (0.9 mmol), and N-methylpyrrolidone (NMP, 1 mL) were added. The pressure-resistant tube was sealed, the air inside was removed, and 10 mL of carbon dioxide gas was introduced. After the addition was complete, the glass pressure-resistant tube was placed in a metal module preheated to 100°C, and the mixture was stirred for 15 hours. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. The mixture was separated by silica gel column chromatography to give compound 10 in 81% yield. The reaction formula is as follows:

[0114] .

[0115] The NMR data of compound 10 were measured using a nuclear magnetic resonance spectrometer. Specifically, the NMR data of compound 10 are as follows:

[0116] 1 H NMR (400 MHz, DMSO-d6) δ12.70 (s, 1H), 8.41–8.02 (m, 3H), 7.94–7.69 (m, 2H), 7.66–7.53 (m, 3H).

[0117] 13 C NMR (100 MHz, DMSO-d6) δ 161.4, 147.5, 134.7, 132.5, 131.6, 130.8, 129.7, 128.7, 127.9, 124.9, 122.2.

[0118] Example 11 Preparation of quinazolinone compound 11.

[0119] Under a nitrogen atmosphere, tris(dibenzylacetone)dipalladium (0.003 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (Xantphos, 0.006 mmol), and a magnetic flux were added to a 20 mL glass pressure-resistant tube. Then, starting material 1 (bromobenzene, 0.3 mmol), starting material 12 (2-amino-4-methylbenzamide, 0.4 mmol), trimethoxysilane (0.8 mmol), potassium phosphate (0.9 mmol), and chlorobenzene (1 mL) were added. The pressure-resistant tube was sealed, the air inside was removed, and 10 mL of carbon dioxide gas was introduced. After the addition was complete, the glass pressure-resistant tube was placed in a metal module preheated to 100°C, and stirred for 15 hours. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. Separation was performed using a silica gel column chromatography to give compound 11 in 84% yield. The reaction formula is as follows:

[0120] .

[0121] The NMR data of compound 11 were measured using an NMR spectrometer. Specifically, the NMR data of compound 11 are as follows:

[0122] 1 H NMR (400 MHz, DMSO-d6) δ12.39 (s, 1H), 8.16–8.14 (m, 2H), 8.03 (d, J=8.0 Hz, 1H), 7.64–7.48 (m, 4H), 7.33 (d, J=8.0 Hz, 1H), 2.46 (s, 3H).

[0123] 13 C NMR (100 MHz, DMSO-d6) δ162.3, 152.5, 148.9, 145.2, 132.9, 131.4, 128.7, 128.1, 127.8, 127.1, 125.8, 118.6, 21.4.

[0124] Example 12 Preparation of quinazolinone compound 12.

[0125] Under a nitrogen atmosphere, tris(dibenzylacetone)dipalladium (Pd2(dba)3, 0.003 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (BINAP, 0.006 mmol), and a magnetic flux were added to a 20 mL pressure-resistant tube. Then, starting material 1 (bromobenzene, 0.3 mmol), starting material 13 (2-aminobenzamide, 0.4 mmol), triethylamine (0.9 mmol), polymethylhydrosiloxane (PMHS, 0.8 mmol), and toluene (1 mL) were added. The pressure-resistant tube was sealed, the air inside was removed, and 20 mL of C13-labeled carbon dioxide was introduced. After the addition was complete, the glass pressure-resistant tube was placed in a metal module preheated to 100°C, and the mixture was stirred for 15 hours. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. Separation was performed using a silica gel column chromatography to give compound 12 in 85% yield. The reaction formula is as follows:

[0126] .

[0127] The NMR data of compound 12 were measured using a nuclear magnetic resonance spectrometer. Specifically, the NMR data of compound 12 are as follows:

[0128] 1 H NMR (400 MHz, DMSO-d6) δ12.53 (s, 1H), 8.23–8.13 (m, 3H), 7.86–7.83 (m, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.63–7.49 (m, 4H).

[0129] 13 C NMR (100 MHz, DMSO-d6) δ 162.4, 152.4, 148.7, 134.6, 132.8, 131.4, 128.6, 127.8, 127.4, 126.6, 125.9, 121.0.

[0130] Example 13 Preparation of quinazolinone compound 13.

[0131] Under a nitrogen atmosphere, bis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2, 0.003 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (Xantphos, 0.006 mmol), and a magnetic flux were added to a 20 mL pressure-resistant tube. Then, starting material 5 (p-bromotoluene, 0.3 mmol), starting material 13 (2-aminobenzamide, 0.4 mmol), polymethylhydrosiloxane (PMHS, 0.8 mmol), triethylamine (0.9 mmol), and dichloroethane (1 mL) were added. The pressure-resistant tube was sealed, the air inside was removed, and 20 mL of C11-labeled carbon dioxide was introduced. After the addition was complete, the glass pressure-resistant tube was placed in a metal module preheated to 100°C, and the mixture was stirred for 15 hours. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. Separation was performed using a silica gel column chromatography to obtain compound 13 in 89% yield. The reaction formula is as follows:

[0132] .

[0133] The NMR data of compound 13 were measured using an NMR spectrometer. Specifically, the NMR data of compound 13 are as follows:

[0134] 1 H NMR (400 MHz, DMSO-d6) δ12.48 (s, 1H), 8.16–8.14 (m, 1H), 8.10 (d, J=8.2 Hz, 2H), 7.86–7.82 (m, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.53–7.50 (m, 1H), 7.36 (d, J=8.0 Hz, 2H), 2.40 (s, 3H).

[0135] 13 C NMR (100 MHz, DMSO-d6) δ 162.4, 152.3, 141.5, 134.6, 129.9, 129.2, 127.7, 126.4, 125.9, 120.9, 21.0.

[0136] Example 14 Preparation of quinazolinone compound 14.

[0137] Under a nitrogen atmosphere, palladium acetate (Pd(OAc)2, 0.003 mmol), 1,2-bis(diphenylphosphino)benzene (DPPBE, 0.006 mmol), and a magnetic flux were added to a 20 mL pressure-resistant tube. Then, starting material 14 (4-tert-butylbromobenzene, 0.3 mmol), starting material 13 (2-aminobenzamide, 0.4 mmol), diphenylsilane (0.8 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.9 mmol), and N,N-dimethylformamide (DMF, 1 mL) were added. The pressure-resistant tube was sealed, the air inside was removed, and 20 mL of C14-labeled carbon dioxide was introduced. After the addition was complete, the glass pressure-resistant tube was placed in a metal module preheated to 120°C, and the mixture was stirred for 6 hours. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. The mixture was separated by silica gel column chromatography to give compound 14 in 91% yield. The reaction formula is as follows:

[0138] .

[0139] The NMR data of compound 14 were measured using an NMR spectrometer. Specifically, the NMR data of compound 14 are as follows:

[0140] 1 H NMR (400 MHz, DMSO-d6) δ12.50 (s, 1H), 8.16–8.12 (m, 3H), 7.83–7.79 (m, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.58–7.46 (m, 3H), 1.30 (s, 9H).

[0141] 13 C NMR (100 MHz, DMSO-d6) δ 162.4, 154.3, 152.3, 148.8, 134.6, 130.0, 127.6, 127.4, 126.4, 125.9, 125.4, 120.9, 34.7, 30.9.

[0142] The above description is merely a specific embodiment of this application, but the scope of protection of this application is not limited thereto. Any person skilled in the art can easily conceive of various equivalent modifications or substitutions within the technical scope disclosed in this application, and these modifications or substitutions should all be covered within the scope of protection of this application. Therefore, the scope of protection of this application should be determined by the scope of the claims.

Claims

1. A method for preparing quinazolinone compounds by synthesizing carbon dioxide, characterized in that, Includes the following steps: Aryl halides of formula (I), 2-aminobenzamide compounds of formula (II), palladium metal catalyst, ligand, reducing agent, base and organic solvent are brought into contact with carbon dioxide and reacted at 80℃~120℃ for 6h~15h to generate quinazolinone compounds of formula (III). 、 、 ， Wherein, X is selected from halogens; R 1 Selected from any one of hydrogen, C1-C5 alkyl, C1-C5 alkoxy, halogen, trifluoromethyl, and aryl; R 2 Selected from hydrogen and C1-C5 alkyl groups; R 3 Selected from hydrogen, C1~C 10 Alkyl, C6~C 12 Any of the aryl groups; The ligand is selected from one or more monodentate phosphine ligands and multidentate phosphine ligands; the reducing agent is silane.

2. The preparation method according to claim 1, characterized in that, The preparation method satisfies at least one of the following conditions: (1) X in formula (I) is selected from any one of F, Br, and I; (2) R 1 It is selected from any one of hydrogen, methyl, methoxy, tert-butyl, F, Cl, trifluoromethyl and aryl; (3) R 2 It is selected from any one of hydrogen, methyl, n-propyl, isopropyl, and n-butyl; (4) R 3 Selected from hydrogen, C1~C 10 Any one of alkyl, phenyl, and naphthyl groups.

3. The preparation method according to claim 2, characterized in that, The ligand is selected from one or more of bis(diphenylphosphine)methane, 1,2-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine)propane, 1,4-bis(diphenylphosphine)butane, 1,2-bis(diphenylphosphine)benzene, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 1,1'-bis(diphenylphosphine)ferrocene, bis(2-diphenylphosphine) ether, 4,6-bis(diphenylphosphine)-10H-phenoxazine, and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene.

4. The preparation method according to claim 1, characterized in that, The palladium metal catalyst is selected from divalent palladium compounds or zero-valent palladium complexes.

5. The preparation method according to claim 4, characterized in that, The palladium metal catalyst is selected from one or more of palladium acetate, palladium dichloride, bis(triphenylphosphine)palladium dichloride, (1,5-cyclooctadiene)palladium dichloride, allyl palladium chloride, bis(acetonitrile)palladium dichloride, palladium trifluoroacetate, tetra(triphenylphosphine)palladium, bis(acetylacetone)palladium, bis(dibenzylacetone)palladium, or tri(dibenzylacetone)palladium.

6. The preparation method according to claim 1, characterized in that, The preparation method satisfies at least one of the following conditions: (1) The base is selected from any one of triethylamine, N-ethyldiisopropylamine, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,5,7-triazidobicyclo[4.4.0]dec-5-ene, ethylenediamine, isopropylamine, sodium carbonate, cesium carbonate, potassium hydroxide, potassium carbonate, potassium phosphate, and piperazine; (2) The solvent is selected from any one of dichloromethane, dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, acetonitrile, methanol, ethanol, 1,4-dioxane, N-methylpyrrolidone, toluene, xylene, mesitylene and chlorobenzene.

7. The preparation method according to claim 1, characterized in that, The molar ratio of the 2-aminobenzamide compound to the palladium metal catalyst is (1~1000):1; The molar ratio of the 2-aminobenzamide compound to the base is (0.1~10):1; The molar ratio of the 2-aminobenzamide compound to the reducing agent is (0.1~10):1; The molar ratio of the ligand to the palladium metal catalyst is (0.1–100):

1.

8. The preparation method according to claim 1, characterized in that, When an aryl halide of formula (I), a 2-aminobenzamide compound of formula (II), a palladium metal catalyst, a ligand, a reducing agent, a base, and an organic solvent are contacted with carbon dioxide, the carbon dioxide being selected from... 12 CO2 and 13 Any of the following CO2 types, wherein the pressure of the carbon dioxide is 1 bar to 30 bar; or, the amount of carbon dioxide added is 1 mL to 20 mL.

9. The preparation method according to claim 1, characterized in that, Before contacting the aryl halide of formula (I), the 2-aminobenzamide compound of formula (II), the palladium metal catalyst, the ligand, the reducing agent, the base, and the organic solvent with carbon dioxide, the following steps are included: First, under a nitrogen atmosphere, the aryl halide of formula (I), the 2-aminobenzamide compound of formula (II), the palladium metal catalyst, the ligand, the reducing agent, the base and the organic solvent are added to the reactor. Then, the nitrogen gas in the reactor is discharged with carbon dioxide, and then carbon dioxide is introduced to the pressure required for the reaction system.

Images