A method for synthesizing quinazoline derivatives using a manganese-based catalyst

Abstract

This invention provides a method for synthesizing quinazoline derivatives using a manganese-based catalyst. The method uses o-aminobenzyl alcohol and amide compounds as raw materials, and synthesizes quinazoline derivatives under the catalysis of a manganese catalyst with a tridentate nitrogen-phosphine ligand. This method features stable and readily available reactants, an environmentally friendly reaction process, a wide range of applicable substrates, and high functional group compatibility. Because the tridentate nitrogen-phosphine ligand significantly enhances the catalytic activity of the central manganese metal, the reaction yield reaches over 90%. This invention provides a highly atom-economical, environmentally friendly, simple, and efficient method for synthesizing quinazoline derivatives, aligning with the current trend of green chemistry and possessing significant implications for organic synthesis, medicinal chemistry, and materials science.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, and relates to quinazoline derivatives, specifically a method for synthesizing quinazoline derivatives using a manganese-based catalyst. Background Technology

[0002] Quinazoline derivatives are a class of nitrogen-containing heterocyclic compounds widely found in natural products and other functional molecules. They possess important biological and pharmacological activities, such as anti-inflammatory, antibacterial, antimalarial, anticonvulsant, antituberculosis, antihypertensive, anticancer, antiviral, and herbicidal activities.

[0003] Existing methods for synthesizing quinazoline derivatives include: (1) using anthranilic acid as a raw material, reacting with formamide to form a cyclization ring to prepare a quinazoline ring; reacting with acid anhydrides and fatty amines to generate a quinazoline ring; cyclizing with thiocyanates to generate a quinazoline ring; (2) using anthranilic acid as a raw material, reacting with aldehydes under I2 / KI catalysis to prepare quinazoline compounds; cyclizing with diethyl oxalate to prepare quinazoline ketone compounds, but this method has a low yield; (3) using anthranilic acid ester as a raw material, reacting with guanidine or guanidine hydrochloride to form a cyclization ring to prepare quinazoline ketone compounds; reacting with isothiocyanate to form a cyclization ring to generate a quinazoline ring compound; (4) using anthranilic acid benzonitrile as a raw material, reacting with aminoguanidine or cyanoguanidine to form a cyclization ring to obtain quinazoline compounds. Compounds; react with carbon dioxide or formic acid to form a ring and prepare quinazoline compounds. This method has a narrow substrate range. (5) Using o-aminobenzophenone as a raw material, react with aldehydes and ammonium acetate to prepare quinazoline compounds. This method requires the raw material to have an electron-withdrawing group, and the structure is complex and difficult to prepare. React with benzylamine, with graphite oxide as a catalyst, and prepare quinazoline compounds under heating conditions. (6) Using o-aminobenzyl alcohol as a raw material, under the action of copper / cerium dual catalyst, react with aryl aldehydes in the presence of ammonium source, oxidant, and base to prepare quinazoline compounds. (7) Using o-aminobenzylamine as a raw material, under the action of iridium catalyst, react with aryl aldehydes to form a cyclization-dehydrogenation reaction to prepare quinazoline compounds. Under the action of visible light, Eosin Y is used as a photocatalyst to prepare quinazoline heterocyclic compounds by oxidation-cyclization-oxidation tandem reaction with alcohols; quinazoline heterocyclic compounds are prepared by reaction with aryl aldehydes and ammonium compounds in the presence of ligands, bases, and TEMPO under the action of copper / iron dual catalysts; quinazoline heterocyclic compounds are prepared by reaction with aryl nitriles using copper cinnamate as a catalyst; (8) quinazoline derivatives are obtained by cross-coupling of benzaldehyde with N-arylsulfonyloxyphthalimide under the action of ruthenium catalyst and ammonia reaction of the obtained intermediate with ammonia reagent; (9) quinazoline compounds are obtained by dehydrogenation reaction of tetrahydroquinazoline compounds under the action of copper catalyst, ligands and additives; (10) quinazoline derivatives are prepared by one-pot reaction using isonitriles, azides and amine derivatives as reaction raw materials.

[0004] Despite the development of various synthetic strategies, the aforementioned methods still suffer from numerous drawbacks, such as the need for expensive transition metal catalysts (Ir, Ru, Pd), ligands, and auxiliaries; difficulty in preparing reactants; the requirement for high temperatures or strong bases in the reaction conditions; long synthetic routes; limited substrate availability; and the need for large amounts of oxidants and condensing reagents, which does not meet the requirements of green and environmentally friendly practices. These limitations significantly restrict the application of quinazoline derivatives in drug synthesis. Summary of the Invention

[0005] In view of the defects and shortcomings of the existing technology, the purpose of this invention is to provide a method for synthesizing quinazoline derivatives using a manganese-based catalyst, thereby solving the technical problems in the prior art that require the use of expensive transition metal compounds, are difficult to obtain reaction raw materials, have relatively harsh reaction conditions, have complex process routes, and have significant substrate limitations when synthesizing quinazoline derivatives.

[0006] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0007] A method for synthesizing quinazoline derivatives using a manganese-based catalyst, wherein the method uses o-aminobenzyl alcohol and amide compounds as raw materials and synthesizes quinazoline derivatives under the catalysis of a nitrogen-phosphine tridentate ligand manganese catalyst;

[0008] The chemical structure of the nitrogen-phosphine tridentate ligand manganese catalyst is shown in Formula I below:

[0009]

[0010] The chemical structure of the o-aminobenzyl alcohol is shown in Formula II below:

[0011]

[0012] The chemical structure of the amide compound is shown in Formula III below:

[0013]

[0014] The chemical structure of the quinazoline derivative is shown in Formula IV below:

[0015]

[0016] In the formula: R is selected from hydrogen, phenyl, halophenyl, heterocyclic phenyl, alkane-substituted phenyl with 1 to 8 carbon atoms, alkoxy-substituted phenyl with 1 to 8 carbon atoms, heterocyclic aryl, cycloalkane, straight-chain and branched alkane with 1 to 8 carbon atoms, and benzyl.

[0017] The present invention also has the following technical features:

[0018] Preferably, R is selected from phenyl, chlorophenyl, bromophenyl, fluorophenyl, alkoxy-substituted phenyl with 1 to 8 carbon atoms, azaaryl, cycloalkane with 5 to 8 carbon atoms, and alkane with 1 to 8 carbon atoms.

[0019] The optimal choice, R is selected from

[0020] Specifically, the amount of the nitrogen-phosphine tridentate ligand manganese catalyst used is 0.5-5% of the molar amount of o-aminobenzyl alcohol. Preferably, the amount of the nitrogen-phosphine tridentate ligand manganese catalyst used is 2-5% of the molar amount of o-aminobenzyl alcohol.

[0021] Specifically, the molar ratio of o-aminobenzyl alcohol to the amide compound is 1:(1 to 1.5).

[0022] Specifically, the method includes the following steps: adding o-aminobenzyl alcohol, an amide compound, a tridentate manganese catalyst with phosphine nitrogen, a base, and a solvent to a reaction vessel, and stirring the reaction at a temperature of 80–150°C for 8–16 h. Preferably, the reaction is stirred at a temperature of 110–125°C for 12 h.

[0023] Specifically, the solvent is selected from one or more of toluene, xylene, dioxane, tert-butanol, tert-amyl alcohol, and tetrahydrofuran.

[0024] Specifically, the alkali is one or more of potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, cesium carbonate, and potassium phosphate.

[0025] Specifically, the amount of alkali used is 10-100% of the molar amount of o-aminobenzyl alcohol. Preferably, the amount of alkali used is 10-50% of the molar amount of o-aminobenzyl alcohol.

[0026] Specifically, the method also includes the following steps: after the reaction is completed, the system is cooled to room temperature, water is added to quench the reaction, the aqueous phase is extracted with ethyl acetate, the organic phases are combined and back-extracted with saturated brine, anhydrous sodium sulfate is added to dry the organic phase, the organic phase is concentrated, and finally purified by column chromatography to obtain the pure product of the quinazoline derivative.

[0027] The beneficial technical effects of this invention compared to the prior art are as follows:

[0028] This invention utilizes inexpensive manganese metal complexes as catalysts to catalyze the reaction of o-aminobenzyl alcohol and amides to generate quinazoline. A one-step reaction is then carried out using a catalytic amount of base under heating conditions to obtain the quinazoline derivative. This method features stable and readily available reactants, an environmentally friendly reaction process, a wide range of applicable substrates, and high functional group compatibility. Due to the significant enhancement of the catalytic activity of the central manganese metal by the phosphine tridentate ligand, the reaction yield reaches over 90%. This invention provides a highly atom-economical, environmentally friendly, simple, and efficient method for synthesizing quinazoline derivatives, aligning with the current trend of green chemistry and holding significant importance for organic synthesis, medicinal chemistry, and materials science. Attached Figure Description

[0029] Figure 1 The 1H NMR spectrum of the nitrogen-phosphine tridentate ligand manganese catalyst is shown.

[0030] Figure 2 The carbon NMR spectrum of the nitrogen-phosphine tridentate ligand manganese catalyst.

[0031] The specific content of the present invention will be further explained in detail below with reference to the embodiments. Detailed Implementation

[0032] The synthetic route of this invention is shown below:

[0033]

[0034] Among them, the NNP-Mn catalyst, namely the nitrogen-phosphine tridentate manganese catalyst, has the following characterization data: Figure 1 and Figure 2 As shown. The compound represented by Formula II is o-aminobenzyl alcohol; the compound represented by Formula III is an amide compound; the compound represented by Formula IV is a quinazoline derivative; in the formulas, R can be aryl, substituted aryl, alkane group, etc.

[0035] It should be noted that all reagents used in this invention, unless otherwise specified, are reagents known in the art. For example, the nitrogen-phosphine tridentate ligand manganese catalyst is a known catalyst in the prior art, described in Chinese Patent Application No. 202410220244.4.

[0036] Following the above technical solutions, specific embodiments of the present invention are given below. It should be noted that the present invention is not limited to the following specific embodiments, and all equivalent modifications made based on the technical solutions of this application fall within the protection scope of the present invention.

[0037] Example 1:

[0038] This embodiment provides a method for synthesizing 2-phenylquinazoline, and the reaction formula is shown below:

[0039]

[0040] The method specifically includes the following steps: 123.2 mg of o-aminobenzyl alcohol, 121.1 mg of benzamide, 11.5 mg of NNP-Mn catalyst, 56.1 mg of potassium tert-butoxide, and 2 mL of toluene are added to a dry 15 mL Shrek tube, and the mixture is stirred at 110 °C for 12 h. After the reaction is completed, the system is cooled to room temperature, 10 mL of water is added to quench the reaction, the aqueous phase is extracted twice with 10 mL of ethyl acetate, the organic phases are combined and back-extracted once with saturated brine, the organic phase is dried with anhydrous sodium sulfate for 30 minutes, the organic phase is then concentrated, and finally purified by column chromatography to obtain 187.6 mg of white solid product.

[0041] The above-mentioned white solid product was identified, and its NMR data are as follows: 1 H NMR (500MHz, CDCl3): δ9.48(s,1H),8.74-8.54(m,2H),8.28-8.08(m,1H),8.08-7.81(m,2H),7.69-7.59(m,1H),7.58-7.47(m,3H); 13 C NMR (125MHz, CDCl3): δ161.1,160.6,150.8,138.1,134.2,130.7,128.7,128.6,127.3,127.2,123.7ppm.

[0042] As shown by the above NMR data, this embodiment successfully synthesized the target product 2-phenylquinazoline with a yield of 91%.

[0043] Example 2:

[0044] This embodiment provides a method for synthesizing 2-(2-bromophenyl)quinazoline, and the reaction formula is shown below:

[0045]

[0046] The method specifically includes the following steps: 123.2 mg of o-aminobenzyl alcohol, 200 mg of 2-bromobenzamide, 11.5 mg of NNP-Mn catalyst, 56.1 mg of potassium tert-butoxide, and 2 mL of toluene are added to a dry 15 mL Shrek tube, and the mixture is stirred at 110 °C for 12 h. After the reaction is completed, the reaction system is cooled to room temperature, 10 mL of water is added to quench the reaction, 10 mL of ethyl acetate is used to extract the aqueous phase twice, the organic phases are combined and back-extracted once with saturated brine, anhydrous sodium sulfate is added to dry the organic phase for 30 minutes, the organic phase is then concentrated, and finally purified by column chromatography to obtain 222.3 mg of white solid product.

[0047] The above-mentioned white solid product was identified, and its NMR data are as follows:1 H NMR (500MHz, CDCl3): δ9.46 (s, 1H), 8.65-8.57 (m, 2H), 8.09 (d, J = 8.7Hz, 1H), 7.96-7.85 (m, 2H), 7.65-7.46 (m, 4H); 13 CNMR (125MHz, CDCl3): δ161.0,160.4,150.7,137.9,134.1,130.5,128.6,128.5,127.2,127.1,123.5ppm.

[0048] As shown by the above NMR data, this embodiment synthesized the target product 2-(2-bromophenyl)quinazoline with a yield of 78%.

[0049] Example 3:

[0050] This embodiment provides a method for synthesizing 2-(4-methoxyphenyl)quinazoline, the reaction formula of which is shown below:

[0051]

[0052] The method specifically includes the following steps: 123.2 mg of o-aminobenzyl alcohol, 151.2 mg of 4-methoxybenzamide, 11.5 mg of NNP-Mn catalyst, 56.1 mg of potassium tert-butoxide, and 2 mL of toluene are added to a dry 15 mL Shrek tube, and the mixture is stirred at 110 °C for 12 h. After the reaction is completed, the reaction system is cooled to room temperature, 10 mL of water is added to quench the reaction, the aqueous phase is extracted twice with 10 mL of ethyl acetate, the organic phases are combined and back-extracted once with saturated brine, the organic phase is dried with anhydrous sodium sulfate for 30 minutes, the organic phase is then concentrated, and finally purified by column chromatography to obtain 210.3 mg of white solid product.

[0053] The above-mentioned white solid product was identified, and its NMR data are as follows: 1 H NMR (500MHz, CDCl3): δ9.46-9.25(m,1H),8.60-8.41(m,2H),7.97(dd,J=0.8,8. 4Hz,1H),7.88-7.72(m,2H),7.59-7.40(m,1H),7.04-6.90(m,2H),3.83(s,3H); 13 C NMR (125MHz, CDCl3): δ161.8,160.8,160.4,150.8,134.0,130.7,130.2,128.4,127.1,126.8,123.3,114.0,55.4ppm.

[0054] As shown by the above NMR data, this embodiment synthesized the target product 2-(4-methoxyphenyl)quinazoline with a yield of 89%.

[0055] Example 4:

[0056] This embodiment provides a method for synthesizing 2-(4-pyridyl)quinazoline, the reaction formula of which is shown below:

[0057]

[0058] The method specifically includes the following steps: 123.2 mg of o-aminobenzyl alcohol, 122.1 mg of isonicotinamide, 11.5 mg of NNP-Mn catalyst, 56.1 mg of potassium tert-butoxide, and 2 mL of toluene are added to a dry 15 mL Shrek tube, and the mixture is stirred at 110 °C for 12 h. After the reaction is completed, the reaction system is cooled to room temperature, 10 mL of water is added to quench the reaction, 10 mL of ethyl acetate is used to extract the aqueous phase twice, the organic phases are combined and back-extracted once with saturated brine, anhydrous sodium sulfate is added to dry the organic phase for 30 minutes, the organic phase is then concentrated, and finally purified by column chromatography to obtain 167.8 mg of white solid product.

[0059] The above-mentioned white solid product was identified, and its NMR data are as follows: 1 H NMR (500MHz, CDCl3): δ9.35(s,1H),8.31-8.08(m,4H),7.86-7.73(m,2H),7.67-7.49(m,3H); 13 CNMR (125MHz, CDCl3): δ151.7,143.3,142.2,141.5,136.7,130.2,130.1,129.5,129.4,129.1,127.5ppm.

[0060] As shown by the above NMR data, this embodiment synthesized the target product 2-(4-pyridyl)quinazoline with a yield of 81%.

[0061] Example 5:

[0062] This embodiment provides a method for synthesizing 2-cyclohexylquinazoline, the reaction formula of which is shown below:

[0063]

[0064] The method specifically includes the following steps: 123.2 mg of o-aminobenzyl alcohol, 127.2 mg of cyclohexylamide, 11.5 mg of NNP-Mn catalyst, 56.1 mg of potassium tert-butoxide, and 2 mL of toluene are added to a dry 15 mL Shrek tube, and the mixture is stirred at 125 °C for 12 h. After the reaction is completed, the reaction system is cooled to room temperature, 10 mL of water is added to quench the reaction, the aqueous phase is extracted twice with 10 mL of ethyl acetate, the organic phases are combined and back-extracted once with saturated brine, the organic phase is dried with anhydrous sodium sulfate for 30 minutes, the organic phase is then concentrated, and finally purified by column chromatography to obtain 182.6 mg of white solid product.

[0065] The above-mentioned white solid product was identified, and its NMR data are as follows: 1 H NMR (500MHz, CDCl3): δ9.37(s,1H),8.00(d,J=8.5Hz,1H),7.89(t,J=7.9Hz,2H),7.60(t,J=7.3Hz,1H),3 .26-2.97(m,1H),2.11(d,J=12.82Hz,2H),1.92(d,J=12.82Hz,2H),1.87-1.73(m,3H),1.58-1.31(m,4H); 13 C NMR (125MHz, CDCl3): δ170.9,160.3,150.4,133.8,128.0,127.0,126.8,123.2,47.9,31.9,26.3,26.0ppm.

[0066] As shown by the above NMR data, this embodiment successfully synthesized the target product 2-cyclohexylquinazoline with a yield of 86%.

[0067] Example 6:

[0068] This embodiment provides a method for synthesizing 2-pentylquinazoline, and the reaction formula is shown below:

[0069]

[0070] The method specifically includes the following steps: 123.2 mg of o-aminobenzyl alcohol, 115.2 mg of hexamethylenetetramine, 11.5 mg of NNP-Mn catalyst, 56.1 mg of potassium tert-butoxide, and 2 mL of toluene are added to a dry 15 mL Shrek tube, and the mixture is stirred at 125 °C for 12 h. After the reaction is completed, the reaction system is cooled to room temperature, 10 mL of water is added to quench the reaction, the aqueous phase is extracted twice with 10 mL of ethyl acetate, the organic phases are combined and back-extracted once with saturated brine, the organic phase is dried with anhydrous sodium sulfate for 30 minutes, the organic phase is then concentrated, and finally purified by column chromatography to obtain 160.2 mg of yellow solid product.

[0071] The above-mentioned yellow solid product was identified, and its NMR data are as follows: 1 H NMR (500MHz, CDCl3): δ9.35 (s, 1H), 7.95-8.06 (m, 1H), 7.81-7.94 (m, 2H), 7.59 (td, J = 7.5 ,1.0Hz,1H),3.05-3.20(m,2H),1.84-2.00(m,3H),1.31-1.49(m,4H),0.84-0.98(m,3H); 13 CNMR (125MHz, CDCl3): δ167.9,160.4,150.4,134.0,127.9,127.1,126.9,123.1,40.0,31.8,28.8,22.6,14.1ppm.

[0072] As can be seen from the above NMR data, the target product 2-pentylquinazoline was synthesized in this embodiment with a yield of 80%.

[0073] Example 7:

[0074] This embodiment provides a method for synthesizing 2-isopropylquinazoline, the reaction formula of which is shown below:

[0075]

[0076] The method specifically includes the following steps: 123.2 mg of o-aminobenzyl alcohol, 115.2 mg of isobutyramide, 11.5 mg of NNP-Mn catalyst, 56.1 mg of potassium tert-butoxide, and 2 mL of toluene are added to a dry 15 mL Shrek tube, and the mixture is stirred at 125 °C for 12 h. After the reaction is completed, the reaction system is cooled to room temperature, 10 mL of water is added to quench the reaction, the aqueous phase is extracted twice with 10 mL of ethyl acetate, the organic phases are combined and back-extracted once with saturated brine, the organic phase is dried with anhydrous sodium sulfate for 30 minutes, the organic phase is then concentrated, and finally purified by column chromatography to obtain 142.9 mg of colorless liquid product.

[0077] The above-mentioned colorless liquid product was identified, and its NMR data are as follows: 1 H NMR (500MHz, CDCl3): δ9.37 (s, 1H), 7.99 (dd, J = 8.3, 0.7Hz, 1H), 7.82-7.94 (m, 2 H),7.59(td,J=7.5,1.0Hz,1H),3.39(quin,J=6.9Hz,1H),1.45(d,J=6.9Hz,6H); 13C NMR (125MHz, CDCl3): δ171.7,160.5,150.3,133.8,128.0,127.0,126.8,123.2,38.0,21.8ppm.

[0078] As shown by the above NMR data, this embodiment successfully synthesized the target product 2-isopropylquinazoline with a yield of 83%.

Claims

1. A method for synthesizing quinazoline derivatives using a manganese-based catalyst, characterized in that, The method includes the following steps: adding o-aminobenzyl alcohol, an amide compound, a tridentate nitrogen-phosphine ligand manganese catalyst, a base, and a solvent to a reaction vessel, and stirring the reaction at a temperature of 80–150 °C for 12 h; After the reaction was completed, the system was cooled to room temperature, water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and back-extracted with saturated brine, anhydrous sodium sulfate was added to dry the organic phase, the organic phase was concentrated, and finally purified by column chromatography to obtain the pure quinazoline derivative. The chemical structure of the nitrogen-phosphine tridentate ligand manganese catalyst is shown in Formula I below: ； The chemical structure of the o-aminobenzyl alcohol is shown in Formula II below: ； The chemical structure of the amide compound is shown in Formula III below: ； The chemical structure of the quinazoline derivative is shown in Formula IV below: ； In the formula: R is selected from , , , , , or ; The amount of the nitrogen-phosphine tridentate ligand manganese catalyst used is 0.5-5% of the molar amount of o-aminobenzyl alcohol; The molar ratio of o-aminobenzyl alcohol to the amide compound is 1:(1-1.5). The solvent is selected from one or more of toluene, xylene, dioxane, tert-butanol, tert-amyl alcohol, and tetrahydrofuran; The alkali is one or more selected from potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, cesium carbonate, and potassium phosphate. The amount of alkali used is 10 to 100% of the molar amount of o-aminobenzyl alcohol.

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