CN111718301B - Synthetic method of quinazolinone derivative - Google Patents

Synthetic method of quinazolinone derivative Download PDF

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CN111718301B
CN111718301B CN202010696816.8A CN202010696816A CN111718301B CN 111718301 B CN111718301 B CN 111718301B CN 202010696816 A CN202010696816 A CN 202010696816A CN 111718301 B CN111718301 B CN 111718301B
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CN111718301A (en
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谢峰
张向宇
李亦彪
陈晓勇
徐莹
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Shandong Holly Pharmaceutical Co ltd
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    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72Quinazolines; Hydrogenated quinazolines
    • C07D239/86Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07D239/70Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72Quinazolines; Hydrogenated quinazolines
    • C07D239/86Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The invention discloses a method for synthesizing quinazolinone derivatives, belonging to the technical field of organic synthesis. The method takes isatoic anhydride or derivatives thereof, aldehyde compounds and inert amide as raw materials, and the quinazolinone derivatives are obtained through one-step synthesis treatment, so that the method has the advantages of simple synthesis steps, non-toxic raw materials, low price and easy obtainment, good functional group compatibility and high atom economy, and has the potential to prepare the quinazolinone derivatives in a large scale by one step.

Description

Synthetic method of quinazolinone derivative
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of a quinazolinone derivative.
Background
Quinazolinone derivatives are core structures constituting many natural alkaloids and synthetic compounds, exhibiting interesting biological and pharmacological activities, such as antidepressant activity, antithrombotic activity, anti-inflammatory activity, anticancer activity and use as free radical scavengers. In addition, quinazolinone has high affinity and multi-site characteristics, which is helpful for the development of drug-related products. (org.Lett.2016,18, 5280-5283; Bioorg.Med.chem.2017,25, 4533-4552; ACS Med.chem.Lett.2014,5, 884-888; chem.Rev.2003,103, 893-930).
Quinazolinones are traditionally prepared by ring-closing condensation of anthranilamide with an aldehyde or an aldehyde substitute. In recent years, a series of new methods have been developed to construct quinazolinone backbone molecules, representative examples being mainly carbonylation cyclization reactions, formation of the corresponding carbon-nitrogen bond by 2-halobenzoic acid first followed by intramolecular cyclocondensation reactions, oxidative cyclization reactions of anthranilamide derivatives, oxidative ring-opening reactions of indoles and free radical-induced cascade reactions (org. Lett.2017,19, 6432-. In addition, the use of three components, benzyl chloride, arylamine and isatoic anhydride, in K has been reported2CO3With the catalyst of (1), the DSMO is used as a solvent to react to generate the quinazolinone derivative. Although these methods have been developed with significant utility, most of them suffer from one or more disadvantages, such as the use of environmentally unfriendlyThe oxidizing agent and the coupling agent of (a), require a multi-step preparation process to prepare reactants and catalysts that are difficult to reuse.
Disclosure of Invention
In order to solve the defects and shortcomings in the prior art, the invention aims to provide a method for obtaining a target quinazolinone derivative by using isatoic anhydride or a derivative thereof, an aldehyde compound and inert amide as raw materials and only performing one-step synthesis treatment, wherein the synthesis method has the advantages of simple synthesis steps, non-toxic and cheap and easily available raw materials, good functional group compatibility and high atom economy.
In order to achieve the purpose, the invention adopts the technical scheme that: a synthetic method of quinazolinone derivatives comprises the following steps: reacting a compound with a structure shown in a formula (1), a compound with a structure shown in a formula (2) and a compound with a structure shown in a formula (3) in a solvent in the presence of a catalyst to obtain the quinazolinone derivative;
Figure BDA0002590186760000021
wherein each R is1Independently represents alkyl, alkoxy, halogen or hydrogen, R2Represents an alkyl group, an aromatic group or hydrogen, R3Represents an aliphatic hydrocarbon group, an aromatic group, a heteroaromatic group or an aromatic group having a substituent, R4Represents alkyl or hydrogen, R5Represents alkyl or hydrogen, n represents 1, 2, 3 or 4;
when R is2When the quinazoline ketone derivative represents hydrogen, the quinazoline ketone derivative is a compound with a structure shown as a formula (4); when R is2When the derivative represents alkyl or benzyl, the quinazolinone derivative is a compound with a structure shown as a formula (5).
In the method, isatoic anhydride or derivatives thereof, aldehyde compounds and inert amide are used as raw materials to synthesize the quinazolinone derivatives in one step, and as shown in figure 1, amide bonds are broken in the reaction process. The method has the advantages of simple synthesis steps, non-toxic and cheap and easily-obtained raw materials, good functional group compatibility and high atom economy, and has the potential to prepare the quinazolinone derivative in a large scale in one step.
Wherein R is1Alkyl groups represented include straight chain alkyl, branched chain alkyl, and cycloalkyl groups such as methyl, ethyl, isopropyl, cyclopropyl, and the like;
R1examples of the alkoxy group include methoxy, ethoxy, isopropoxy and the like;
R1examples of the halogen include fluorine, chlorine, bromine, iodine, etc.;
R2alkyl groups represented include straight chain alkyl, branched chain alkyl, and cycloalkyl groups such as methyl, ethyl, isopropyl, cyclopropyl, and the like;
R2examples of the aromatic group include phenyl and benzyl;
R3examples of the aliphatic hydrocarbon group include hexyl group;
R3examples of the aromatic group include phenyl and benzyl;
R3examples of the heteroaryl group include a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group and the like;
R3examples of the substituted aromatic group include 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group and the like;
R4alkyl groups represented include straight chain alkyl, branched chain alkyl, and cycloalkyl groups such as methyl, ethyl, isopropyl, cyclopropyl, and the like;
R5alkyl groups represented include straight chain alkyl, branched chain alkyl, and cycloalkyl groups such as methyl, ethyl, isopropyl, cyclopropyl, and the like.
Preferably, said R is1Represents methyl, methoxy, fluorine or hydrogen, said R2Represents methyl, benzyl or hydrogen, said R3Represents hexyl, phenyl, benzyl, 4-chlorophenyl or 4-pyridyl, said R4Represents methyl or hydrogen, said R5Represents methyl, ethyl, cyclopropyl or hydrogen.
Preferably, the molar ratio of the compound with the structure shown in the formula (1) to the compound with the structure shown in the formula (2) is the compound with the structure shown in the formula (1): the structure of the compound is shown as a formula (2), wherein the compound is 1-10.
Preferably, the molar ratio of the compound with the structure shown in the formula (1) to the compound with the structure shown in the formula (3) is the compound with the structure shown in the formula (1): the structure of the compound is shown as a formula (3), wherein the compound is 1 (10-20).
Preferably, the molar ratio of the compound with the structure shown in the formula (1) to the catalyst is the compound with the structure shown in the formula (1): and (0.02-0.08) as a catalyst.
Preferably, the volume ratio of the compound with the structure shown in the formula (1) to the solvent is the compound with the structure shown in the formula (1): the solvent is 1 (1-2).
Preferably, the reaction temperature is 25-130 ℃, and the reaction time is 1-24 h.
Preferably, the catalyst is an acidic catalyst.
Preferably, the acidic catalyst comprises at least one of p-toluenesulfonic acid, trifluoroacetic acid, sodium triflate, ytterbium triflate, hydrochloric acid, phosphoric acid, pivalic acid, carrier-supported p-toluenesulfonic acid, carrier-supported trifluoroacetic acid, carrier-supported sodium triflate, carrier-supported ytterbium triflate, carrier-supported hydrochloric acid, carrier-supported phosphoric acid, carrier-supported pivalic acid. Preferably, a catalyst loaded by a carrier is adopted, so that the catalyst is easy to recover, the catalyst can be recycled, and the obtained quinazolinone derivative has no metal residue, such as p-toluenesulfonic acid loaded by activated carbon, p-toluenesulfonic acid loaded by diatomite, and p-toluenesulfonic acid loaded by polyaniline.
Preferably, the carrier adopted by the carrier-loaded p-toluenesulfonic acid, the carrier-loaded trifluoroacetic acid, the carrier-loaded sodium trifluoromethanesulfonate, the carrier-loaded ytterbium trifluoromethanesulfonate, the carrier-loaded hydrochloric acid, the carrier-loaded phosphoric acid and the carrier-loaded pivalic acid is at least one of activated carbon, diatomite and polyaniline.
Preferably, the solvent is at least one of acetonitrile, tetrahydrofuran, N-methylformamide, formamide, N-ethylformamide, tert-amyl alcohol, isopropanol, isobutanol, N-dimethylformamide, toluene, p-xylene, methanol, water.
Preferably, the synthesis method further comprises the steps of: and after the reaction is finished, removing the solvent of the reaction system or removing the solvent of the reaction system after cooling, and purifying by column chromatography to obtain the quinazolinone derivative.
Preferably, the stationary phase adopted by the column chromatography is silica gel, the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is petroleum ether: and (0.5-50) 1 for ethyl acetate.
Compared with the prior art, the invention has the following advantages: the method takes isatoic anhydride or derivatives thereof, aldehyde compounds and inert amide as raw materials, and the quinazolinone derivatives are obtained through one-step synthesis treatment, so that the method has the advantages of simple synthesis steps, non-toxic raw materials, low price and easy obtainment, good functional group compatibility and high atom economy, and has the potential to prepare the quinazolinone derivatives in a large scale by one step.
Drawings
FIG. 1 is a chemical reaction equation involved in the synthesis method of quinazolinone derivatives according to the present invention;
FIGS. 2 and 3 are a hydrogen spectrum and a carbon spectrum, respectively, of the product obtained in example 1;
FIGS. 4 and 5 are a hydrogen spectrum and a carbon spectrum, respectively, of the product obtained in example 2;
FIGS. 6 and 7 are a hydrogen spectrum and a carbon spectrum, respectively, of the product obtained in example 3;
FIGS. 8 and 9 are a hydrogen spectrum and a carbon spectrum, respectively, of the product obtained in example 4;
FIGS. 10 and 11 are a hydrogen spectrum and a carbon spectrum, respectively, of the product obtained in example 5;
FIGS. 12 and 13 are a hydrogen spectrum and a carbon spectrum, respectively, of the product obtained in example 6;
FIGS. 14 and 15 are a hydrogen spectrum and a carbon spectrum, respectively, of the product obtained in example 7;
FIGS. 16 and 17 are a hydrogen spectrum and a carbon spectrum, respectively, of the product obtained in example 8;
FIGS. 18 and 19 are a hydrogen spectrum and a carbon spectrum, respectively, of the product obtained in example 9;
FIGS. 20 and 21 are a hydrogen spectrum and a carbon spectrum, respectively, of the product obtained in example 10;
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
Example 1
This example is an embodiment of the method for synthesizing quinazolinone derivatives according to the present invention. The synthesis method of the quinazolinone derivative in the embodiment comprises the following steps: adding 0.25 mmol of isatoic anhydride, 0.375 mmol of benzaldehyde, 60 mg of activated carbon-supported p-toluenesulfonic acid catalyst and 1 ml of N-methylformamide into a schlenk tube (a schlenk tube), stirring and reacting for 12 hours at 120 ℃ under the condition of air, stopping heating and stirring, cooling to room temperature, performing reduced pressure rotary evaporation to remove the solvent, and performing column chromatography separation and purification to obtain the target product, wherein a stationary phase of the column chromatography is silica gel, an eluent is a mixed solvent of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate is 6:1, v/v), and the yield of the target product is 89%.
The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in fig. 2 and fig. 3, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3):δ8.37-8.30(m,1H),7.78–7.72(m,2H),7.60–7.56(m,2H),7.51(m,4H),3.50(s,3H);
13C NMR(126MHz,CDCl3):δ162.7,156.1,147.3,135.4,134.3,130.1,128.9,128.0,127.5,127.0,126.7,120.5,34.3;
IR(KBr):3053,1674,1556,1471,1345,763,695cm-1
MS(EI,m/z):236.10[M]+
the structure of the resulting product is deduced from the above data as shown in the following formula:
Figure BDA0002590186760000061
example 2
This example is an embodiment of the method for synthesizing quinazolinone derivatives according to the present invention. The synthesis method of the quinazolinone derivative in the embodiment comprises the following steps: 0.25 mmol of isatoic anhydride, 0.375 mmol of p-tolualdehyde, 60 mg of polyaniline-supported p-toluenesulfonic acid catalyst and 1 ml of N-methylformamide are added into a schlenk tube, the mixture is stirred and reacted for 16 hours at 100 ℃ under the condition of air, heating and stirring are stopped, the mixture is cooled to room temperature, the solvent is removed by rotary evaporation under reduced pressure, and the mixture is separated and purified by column chromatography, wherein the stationary phase of the column chromatography is silica gel, the eluent is a mixed solvent of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate ═ 5:1, v/v), and the yield of the target product is 84%.
The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in fig. 4 and fig. 5, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3):δ8.35–8.29(m,1H),7.77–7.71(m,2H),7.53–7.45(m,3H),7.33(d,J=8.0Hz,2H),3.51(s,3H),2.44(s,3H);
13C NMR(126MHz,CDCl3):δ162.8,156.3,147.4,140.3,134.2,132.6,129.5,128.0,127.5,126.8,126.6,120.5,34.3,21.4;
IR(KBr):3741,3030,2317,1671,1465,1340,776cm-1
MS(EI,m/z):250.10[M]+
the structure of the resulting product is deduced from the above data as shown in the following formula:
Figure BDA0002590186760000062
example 3
This example is an embodiment of the method for synthesizing quinazolinone derivatives according to the present invention. The synthesis method of the quinazolinone derivative in the embodiment comprises the following steps: adding 0.25 mmol of isatoic anhydride, 0.375 mmol of p-chlorobenzaldehyde, 60 mg of trifluoroacetic acid and 1 ml of N-methylformamide into a schlenk tube, stirring and reacting at 110 ℃ under the condition of air for 10 hours, stopping heating and stirring, cooling to room temperature, decompressing and rotary evaporating to remove the solvent, and then separating and purifying by column chromatography to obtain the target product, wherein the stationary phase of the column chromatography is silica gel, the eluent is a mixed solvent of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 7:1, v/v), and the yield of the target product is 83%.
The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in fig. 6 and 7, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3):δ8.32(dd,J=8.0,1.0Hz,1H),7.79–7.70(m,2H),7.56–7.49(m,5H),3.50(s,3H);
13C NMR(126MHz,CDCl3):δ162.6,155.0,147.2,136.4,134.4,133.8,129.6,129.2,127.5,127.2,126.7,120.5,34.3;
IR(KBr):3064,2317,1674,1553,1345,1095,833cm-1
HRMS(ESI):270.0[M]+
the structure of the resulting product is deduced from the above data as shown in the following formula:
Figure BDA0002590186760000071
example 4
This example is an embodiment of the method for synthesizing quinazolinone derivatives according to the present invention. The synthesis method of the quinazolinone derivative in the embodiment comprises the following steps: adding 0.25 mmol of isatoic anhydride, 0.375 mmol of 3-pyridine benzaldehyde, 60 mg of trifluoroacetic acid and 1 ml of N-methylformamide into a schlenk tube, stirring at 120 ℃ under the air condition for 10 hours, stopping heating and stirring, cooling to room temperature, decompressing and rotary evaporating to remove the solvent, and then separating and purifying by column chromatography to obtain the target product, wherein the stationary phase of the column chromatography is silica gel, the eluent is a mixed solvent of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 3:1, v/v), and the yield of the target product is 87%.
The hydrogen spectrogram and the carbon spectrogram of the obtained product are respectively shown in fig. 8 and fig. 9, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3):δ8.87(d,J=1.5Hz,1H),8.75(dd,J 5.0,1.5Hz,1H),8.28(d,J=8.0Hz,1H),7.99–7.88(m,1H),7.77–7.65(m,2H),7.55–7.39(m,2H),3.49(s,3H);
13C NMR(126MHz,CDCl3):δ162.4,153.3,151.0,148.9,147.1,135.7,134.5,131.5,127.5,127.4,126.7,123.4,120.6,34.2;
IR(KBr):3740,2361,1673,1550,1463,1018,700cm-1
MS(EI,m/z):237.10[M]+
the structure of the resulting product is deduced from the above data as shown in the following formula:
Figure BDA0002590186760000081
example 5
This example is an embodiment of the method for synthesizing quinazolinone derivatives according to the present invention. The synthesis method of the quinazolinone derivative in the embodiment comprises the following steps: adding 0.25 mmol of isatoic anhydride, 0.375 mmol of N-heptanal, 60 mg of activated carbon-supported p-toluenesulfonic acid and 1 ml of N-methylformamide into a schlenk tube, stirring and reacting for 10 hours at 130 ℃ under the condition of air, stopping heating and stirring, cooling to room temperature, decompressing and rotary evaporating to remove the solvent, and then separating and purifying by column chromatography to obtain the target product, wherein a stationary phase of the column chromatography is silica gel, an eluent is a mixed solvent of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate ═ 8:1, v/v), and the yield of the target product is 65%.
The hydrogen spectrum and the carbon spectrum of the obtained product are respectively shown in fig. 10 and fig. 11, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3):δ8.25(dd,J=8.0,1.0Hz,1H),7.73–7.67(m,1H),7.66–7.60(m,1H),7.46–7.39(m,1H),3.63(s,3H),2.86–2.79(m,2H),1.87–1.78(m,2H),1.51-1.48(m,2H),1.40–1.32(m,4H),0.91(t,J=7.0Hz,3H);
13C NMR(126MHz,CDCl3):δ162.6,157.3,147.3,134.0,126.8,126.7,126.3,120.2,35.8,31.6,30.5,29.1,26.9,22.5,14.0;
IR(KBr):3458,2917,2320,1668,1415,1139,770cm-1
HRMS(ESI):Calcd.for C15H21N2O[M+1]+245.1648; found 245.1641 (i.e., C)15H21N2O[M+1]+Calculated 245.1648, found 245.1641).
The structure of the resulting product is deduced from the above data as shown in the following formula:
Figure BDA0002590186760000082
example 6
This example is an embodiment of the method for synthesizing quinazolinone derivatives according to the present invention. The synthesis method of the quinazolinone derivative in the embodiment comprises the following steps: adding 0.25 mmol of 4-methylisatoic anhydride, 0.375 mmol of benzaldehyde, 60 mg of pivalic acid and 1 ml of N-methylformamide into a schlenk tube, stirring at 130 ℃ under the air condition for 12 hours, stopping heating and stirring, cooling to room temperature, decompressing and rotary evaporating to remove the solvent, and then separating and purifying by column chromatography to obtain the target product, wherein the stationary phase of the column chromatography is silica gel, the eluent is a mixed solvent of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 6:1, v/v), and the yield of the target product is 85%.
The hydrogen spectrum and the carbon spectrum of the obtained product are respectively shown in fig. 12 and 13, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3):δ8.21(d,J=8.5Hz,1H),7.59–7.51(m,6H),7.32(dd,J=8.5,1.5Hz,1H),3.49(s,3H),2.50(s,3H);
13C NMR(126MHz,CDCl3):δ162.6,156.2,147.4,145.2,135.5,130.0,128.9,128.6,128.0,127.2,126.5,118.2,34.2,21.9;
IR(KBr):3063,2360,1673,1576,1348,1033,781cm-1
MS(EI,m/z):250.10[M]+
the structure of the resulting product is deduced from the above data as shown in the following formula:
Figure BDA0002590186760000091
example 7
This example is an embodiment of the method for synthesizing quinazolinone derivatives according to the present invention. The synthesis method of the quinazolinone derivative in the embodiment comprises the following steps: 0.25 mmol of 5-fluoroisatoic anhydride, 0.375 mmol of benzaldehyde, 60 mg of activated carbon-supported p-toluenesulfonic acid and 1 ml of N-methylformamide are added into a schlenk tube, the mixture is stirred and reacted for 12 hours at 120 ℃ under the condition of air, heating and stirring are stopped, the mixture is cooled to room temperature, the solvent is removed by rotary evaporation under reduced pressure, and the mixture is separated and purified by column chromatography to obtain the target product, wherein the stationary phase of the column chromatography is silica gel, the eluent is a mixed solvent of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate ═ 6:1, v/v), and the yield of the target product is 68%.
The hydrogen spectrum and the carbon spectrum of the obtained product are respectively shown in fig. 14 and fig. 15, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3):δ7.95(dd,J=8.5,3.0Hz,1H),7.75(q,J=5.0Hz,1H),7.56-7.53(m,5H),7.50–7.44(m,1H),3.50(s,3H);
13C NMR(126MHz,CDCl3):δ162.0(d,J=3.5Hz),161.0(d,J=248.9Hz),155.47(d,J=2.0Hz),144.0(d,J=1.6Hz),135.1,130.2,130.0(d,J=7.6Hz),128.9,128.0,123.0(d,J=24.4Hz),121.8(d,J=8.8Hz),111.5(d,J=23.8Hz),34.37;
IR(KBr):2315,1680,1554,1484,1346,832,696cm-1
HRMS(ESI):Calcd.for C15H12FN2O[M+1]+:255.0928;found:255.0920。
the structure of the resulting product is deduced from the above data as shown in the following formula:
Figure BDA0002590186760000101
example 8
This example is an embodiment of the method for synthesizing quinazolinone derivatives according to the present invention. The synthesis method of the quinazolinone derivative in the embodiment comprises the following steps: 0.25 mmol of N-methylisatoic anhydride, 0.375 mmol of benzaldehyde, 60 mg of activated carbon-supported p-toluenesulfonic acid and 1.2 ml of N-methylformamide are added into a schlenk tube, the mixture is stirred and reacted for 12 hours at 120 ℃ under the condition of air, heating and stirring are stopped, the mixture is cooled to room temperature, the solvent is removed by rotary evaporation under reduced pressure, and the mixture is separated and purified by column chromatography to obtain the target product, wherein the stationary phase of the column chromatography is silica gel, the eluent is a mixed solvent of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate is 4:1, v/v), and the yield of the target product is 72%.
The hydrogen spectrum and the carbon spectrum of the obtained product are respectively shown in fig. 16 and 17, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3):δ8.03(dd,J=7.5,1.5Hz,1H),7.38–7.28(m,4H),7.23(dd,J=8.0,1.5Hz,2H),6.89–6.83(m,1H),6.50(d,J=8.0Hz,1H),5.43(s,1H),3.01(s,3H),2.81(s,3H)。
13C NMR(126MHz,CDCl3):δ162.5,146.2,136.9,133.8,129.3,128.9,128.5,126.3,118.0,116.0,111.4,81.0,35.4,32.4。
IR(KBr):2924,1647,1495,1449,1388,752,699cm-1
MS(EI,m/z):252.10[M]+
the structure of the resulting product is deduced from the above data as shown in the following formula:
Figure BDA0002590186760000111
example 9
This example is an embodiment of the method for synthesizing quinazolinone derivatives according to the present invention. The synthesis method of the quinazolinone derivative in the embodiment comprises the following steps: 0.25 mmol of isatoic anhydride, 0.375 mmol of benzaldehyde, 60 mg of diatomite-supported p-toluenesulfonic acid and 1.2 ml of formamide are added into a schlenk tube, the mixture is stirred and reacted for 12 hours at 120 ℃ under the condition of air, heating and stirring are stopped, the mixture is cooled to room temperature, the solvent is removed by rotary evaporation under reduced pressure, and the mixture is separated and purified by column chromatography, wherein the stationary phase of the column chromatography is silica gel, the eluent is a mixed solvent of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 4:1, v/v), and the yield of the target product is 67%.
The hydrogen spectrum and the carbon spectrum of the obtained product are respectively shown in fig. 18 and fig. 19, and the structural characterization data are as follows:
1H NMR(500MHz,DMSO):δ12.56(s,1H),8.29–8.10(m,3H),7.87–7.80(m,1H),7.75(d,J=8.0Hz,1H),7.64–7.47(m,4H);
13C NMR(126MHz,DMSO):δ162.7,152.8,149.2,135.1,133.2,131.9,129.1,128.2,128.0,127.1,126.3,121.5;
IR(KBr):2979,2317,1675,1570,1379,1067,771cm-1
MS(EI,m/z):222.10[M]+
the structure of the resulting product is deduced from the above data as shown in the following formula:
Figure BDA0002590186760000112
example 10
This example is an embodiment of the method for synthesizing quinazolinone derivatives according to the present invention. The synthesis method of the quinazolinone derivative in the embodiment comprises the following steps: adding 0.25 mmol of isatoic anhydride, 0.375 mmol of benzaldehyde, 60 mg of diatomite-supported p-toluenesulfonic acid and 1 ml of N-ethylformamide into a schlenk tube, stirring and reacting at 120 ℃ under the air condition for 12 hours, stopping heating and stirring, cooling to room temperature, decompressing and rotary evaporating to remove the solvent, and then carrying out column chromatography separation and purification to obtain the target product, wherein a stationary phase of the column chromatography is silica gel, an eluent is a mixed solvent of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate ═ 6:1, v/v), and the yield of the target product is 62%.
The hydrogen spectrum and the carbon spectrum of the obtained product are respectively shown in fig. 20 and 21, and the structural characterization data are as follows:
1H NMR(500MHz,CDCl3):δ8.36(d,J=7.5Hz,1H),7.79–7.74(m,2H),7.61–7.47(m,6H),4.06(q,J=7.0Hz,2H),1.23(t,J=7.0Hz,3H);
13C NMR(126MHz,CDCl3):δ162.0,156.2,147.2,135.6,134.3,129.8,128.8,127.7,127.5,127.0,126.7,121.0,41.2,14.1。
IR(KBr):3354,2317,1664,1605,1288,765,686cm-1
MS(EI,m/z):250.10[M]+.
the structure of the resulting product is deduced from the above data as shown in the following formula:
Figure BDA0002590186760000121
finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.

Claims (7)

1. A synthetic method of a quinazolinone derivative is characterized by comprising the following steps: reacting a compound with a structure shown in a formula (1), a compound with a structure shown in a formula (2) and a compound with a structure shown in a formula (3) in a solvent in the presence of a catalyst to obtain the quinazolinone derivative;
Figure FDA0003164762850000011
wherein each R is1Independently represents alkyl, alkoxy, halogen or hydrogen, R2Represents alkyl, aryl, benzyl or hydrogen, R3Represents an aliphatic hydrocarbon group, an aromatic group, a heteroaromatic group, a benzyl group or an aromatic group having a substituent, R4Represents alkyl or hydrogen, R5Represents alkyl or hydrogen, n represents 1, 2, 3 or 4;
when R is2When the quinazoline ketone derivative represents hydrogen, the quinazoline ketone derivative is a compound with a structure shown as a formula (4); when R is2When the quinazoline derivative represents alkyl, aryl or benzyl, the quinazoline ketone derivative is a compound with a structure shown as a formula (5);
wherein the solvent is N-methylformamide, formamide or N-ethylformamide; the catalyst is trifluoroacetic acid, pivalic acid, p-toluenesulfonic acid, carrier-supported trifluoroacetic acid, carrier-supported pivalic acid or carrier-supported p-toluenesulfonic acid.
2. The method of synthesis of claim 1, wherein R is1Represents methyl, methoxy, fluorine or hydrogen, said R2Represents methyl, benzyl or hydrogen, said R3Represents hexyl, phenyl, benzyl, 4-chlorophenyl or 4-pyridyl, said R4Represents methyl or hydrogen, said R5Represents methyl, ethyl, cyclopropyl or hydrogen.
3. The synthesis method according to claim 1 or 2, wherein the molar ratio of the compound having the structure shown in formula (1) to the compound having the structure shown in formula (2) is the compound having the structure shown in formula (1): the structure of the compound is shown as a formula (2), wherein the compound is 1-10.
4. The synthesis method according to claim 1 or 2, wherein the reaction temperature is 25-130 ℃, and the reaction time is 1-24 h.
5. The method of synthesis according to claim 1, wherein the support is activated carbon, diatomaceous earth or polyaniline.
6. The synthesis method according to claim 1 or 2, characterized in that it further comprises the following steps: and after the reaction is finished, removing the solvent of the reaction system or removing the solvent of the reaction system after cooling, and purifying by column chromatography to obtain the quinazolinone derivative.
7. The synthetic method according to claim 6, wherein the stationary phase adopted by the column chromatography is silica gel, the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is petroleum ether: and (0.5-50) 1 for ethyl acetate.
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