CN103275085B - Quinazoline and quinazolinone compound, its synthesis method and application - Google Patents

Abstract

The invention relates to a quinazolinoquinazolinone compound, its synthesis method and application. The synthesis method uses a copper compound as a catalyst to react dihydroquinazolinone and amidine compounds in one step. The reaction conditions are mild, the product yield is high, and the aftertreatment is simple. In addition, it was unexpectedly found that the quinazolinoquinazolinone compound has significant fluorescence intensity changing characteristics, can be used in application fields such as fluorescence sensing, and has broad application prospects and research value.

Description

A kind of quinazolinoquinazolinone compound and its synthesis method and application

technical field

The invention relates to a nitrogen-containing heterocyclic compound, in particular to a quinazolinoquinazolinone compound and its synthesis method and application, belonging to the field of organic chemistry.

Background technique

Polycyclic nitrogen-containing heterocyclic compounds widely exist in nature, and some of them are used in drug research because of their certain biological activities. For example, it has been found that polycyclic compounds with quinazolinone as the skeleton exist in the In the core structure skeleton of a variety of natural products, such as active compounds such as deoxyvasicinone, Luotonin A, Circumdatins, Rutaecarpine and Tryptanthrin middle. Because polycyclic quinazolinone compounds have a variety of pharmaceutical activities, such as anti-tumor, anti-bacterial, anti-fungal, anti-depressant, anti-inflammatory, anti-rheumatic, anti-hypertensive, anti-spasmodic, anti-malarial, anti-infection and analgesic, etc. Pharmacological activity has been highly concerned and valued by drug researchers, and a variety of quinazolinone compounds and their chemical synthesis methods have been developed.

Li Shuyi ("Synthetic Research on Quinazolinone Derivatives", Master Thesis of Northwest University, 2009) discloses an organic synthesis method for preparing quinazolinone derivatives. The method is to use microwave-assisted synthesis to replace benzene Reaction of formic acid with formamide, as well as with 1,4-butynediol, L-glutamine and isatoic anhydride, yields a number of quinazolinone derivatives.

CN1845908A discloses a class of 5-substituted quinazolinones and a preparation method thereof. The quinazolinones can be used as alpha-1A/B adrenergic receptor antagonists.

CN101415688A discloses a class of quinazolinone derivatives, which have B-RAF inhibitory activity and can be used in human anticancer treatment.

CN1628104A discloses a class of quinazolinone derivatives, which can be used as CB agonists.

CN1538966A discloses a class of quinazolinone derivatives, which have M3 selective muscarinic receptor antagonism and rhythmic bladder contraction frequency inhibition, and can be used to treat urinary frequency or urinary incontinence.

CN101429166A discloses a quinazolinone derivative and its preparation method and application, which has a stronger PDES inhibitory activity than sildenafil, and has higher selectivity relative to PED6 distributed in the retina, thereby in Clinically demonstrated better safety and efficacy.

CN1683844A discloses a 4-quinazolinone derivative and its application in antitumor drugs, the derivative has antitumor activity.

CN1856485A discloses a derivative of benzimidazolone and quinazolinone, said compound can be used as an agonist of human ORL1 receptor, so as to treat diseases involving ORL1 receptor.

CN1845924A discloses a quinazolinone compound substituted by arylamine, which can treat diseases related to α-1A/B adrenoceptor activity.

CN1708306A discloses a quinazolinone compound, which can be used as a calcium blocker, thereby acting as a calcium receptor antagonist.

CN1980899A discloses a quinazolinone derivative, which can be used as a PARP inhibitor and can be used to treat various diseases involving PARP.

As mentioned above, although a variety of methods for the preparation of quinazolinones have been disclosed in the prior art, there are few reports on compounds containing quinazolinones and quinazoline fused skeletons at the same time, let alone their preparation method routes and methods. up.

In addition, so far, all studies involving quinazolinones have focused on their pharmaceutical activity, and a large number of studies have been carried out on the therapeutic mechanism and activity, but have never involved research on other uses other than pharmaceutical activity.

Therefore, finding its new use, and exploring new compounds of this type under the premise of the new use, and its brand-new preparation method are the key and difficult issues that exist at present, and are also the starting point for the completion and realization of the present invention.

Contents of the invention

In view of this, in order to seek new quinazolinoquinazolinone compounds, their preparation methods and their new applications, the inventors conducted in-depth research, and completed the present invention after paying a lot of creative work.

Specifically, the technical scheme and content of the present invention relate to three aspects: quinazolinoquinazolinone compounds, their preparation methods and their new uses.

In the first aspect, the present invention relates to a quinazolinoquinazolinone compound, the structural formula of which is shown in the following formula (I).

in:

R ¹ -R ⁴ are each the same or different, and are independently selected from H, C ₁ -C ₆ alkyl, halogen, C1-C6 alkoxy;

R is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl;

Provided that when R is methyl, R ¹ -R ⁴ are not H at the same time.

In the present invention, unless otherwise specified, throughout, the meaning of C ₁ -C ₆ alkyl refers to straight chain or branched chain alkyl having 1-6 carbon atoms, which includes C ₁ alkyl, C ₂ alkane C ₃ alkyl, C ₄ alkyl, C ₅ alkyl or C ₆ alkyl, non-limiting examples may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl , isobutyl, tert-butyl, n-pentyl, isopentyl or n-hexyl, etc.

In the present invention, unless otherwise specified, throughout, C ₁ -C ₆ alkoxy refers to a group in which the "C ₁ -C ₆ alkyl" defined above is linked to an O atom.

In the present invention, unless otherwise specified, throughout, the meaning of C ₃ -C ₆ cycloalkyl refers to a cyclic alkyl group with 3-6 carbon atoms, which includes C ₃ cycloalkyl, C ₄ cycloalkane Group, C ₅ cycloalkyl or C ₆ cycloalkyl, non-limiting examples may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In the present invention, unless otherwise specified, throughout, the meaning of halogen refers to halogen elements, such as F, Cl, Br or I without limitation.

As a preferred embodiment, R is C ₂ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, preferably ethyl or cyclopropyl.

As a preferred embodiment, ^R4 is H.

In a second aspect, the present invention relates to a synthesis method of a quinazolinoquinazolinone compound of formula (I).

The method comprises reacting formula (II) with (III) in an organic solvent in the presence of a copper source catalyst and a base to obtain a compound of formula (I).

Wherein, the definitions of R ¹ -R ⁴ and R are as above.

X is halogen and can be F, Cl, Br or I, for example.

In the synthesis method of the present invention, the copper source catalyst is inorganic copper, organic copper or a mixture of both.

The inorganic copper is selected from copper halide or cuprous halide, non-limitatively, for example, it can be any one or more of CuI, CuBr, CuCl, _CuCl2 , _CuBr2 , _CuI2 , that is, the copper source catalyst can be Any one or more of these specific substances.

The organic copper is selected from copper acetate [Cu(OAc) ₂ ], copper acetylacetonate [Cu(acac) ₂ ], Cu(PPh ₃ ) ₂ NO ₃ , copper(II) ethylacetoacetate, copper hexafluoroacetylacetonate Any one or more of them, that is, the copper source catalyst can be any one or more of these specific substances.

The copper source catalyst is preferably Cu(acac) ₂ , copper hexafluoroacetylacetonate, Cu(PPh ₃ ) ₂ NO ₃ , most preferably Cu(acac) ₂ .

In the synthesis method of the present invention, the base can be, for example, any one or more of alkali metal carbonates, phosphates, hydroxides, and alkoxides.

As an example, the base may be any one or more of potassium carbonate, potassium phosphate, lithium carbonate, lithium hydroxide, and cesium carbonate.

The base is preferably potassium phosphate, potassium carbonate, lithium hydroxide or cesium carbonate, most preferably cesium carbonate.

In the synthesis method of the present invention, the reaction solvent when the formula (II) reacts with (III) is not particularly limited, and can be any conventional organic solvent used in the field of organic synthesis, non-limitingly, for example, Benzene, toluene, xylene, chlorobenzene, acetone, 1,4-dioxane, 1,6-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, N,N-dimethylmethane Amide (DMF), Dimethyl Sulfoxide (DMSO), Dichloromethane, Chloroform, Carbon Tetrachloride, Dichloroethane, n-Hexane, Diethyl Ether, Methanol, Ethanol, n-Propanol, Isopropanol, Butyl One or more of alcohol, pentanol, hexanol, etc.

In the synthesis method of the present invention, the molar ratio of the compounds of formula (II) and (III) can be properly selected, for example, the molar ratio can be 1:1-4, and this range includes any subgroups thereof. The interval range, such as 1:1.4-3.6, 1:1.8-3.2 or 1:2.2-2.8, also includes any specific point value, for example, it can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5 or 1:4.

The molar ratio of the compounds of formula (II) to (III) is preferably 1:2-3, for example 1:2, 1:2.5 or 1:3.

In the synthesis method of the present invention, the amount of the catalyst is not particularly limited, for example, the molar ratio of the compound of formula (II) to the copper source catalyst can be 1:0.02-0.2, for example, it can be 1:0.02 , 1:0.05, 1:0.08, 1:0.11, 1:0.14, 1:0.17 or 1:0.2.

In the synthesis method of the present invention, the compound of formula (III) can also be in the form of a salt, for example, in the form of hydrochloride, sulfate, nitrate, phosphate or hydrogen phosphate, that is, the above formula ( III) Compounds in the form of salts obtained after the compound is salified with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. .

In the synthesis method of the present invention, the molar ratio of the compound of formula (II) to the base can be properly selected, for example, the molar ratio can be 1:2-6, and this range includes any subrange range therein , such as 1:2.4-5.6, 1:2.8-5.2, 1:3.2-4.8 or 1:3.6-4.4, also includes any specific point value, for example, it can be 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5 or 1:6.

The molar ratio of the compound of formula (II) to the base is preferably 1:3-5, for example 1:3, 1:3.5, 1:4, 1:4.5 or 1:5.

In the synthesis method of the present invention, the reaction temperature is 60-120°C, for example, non-limitingly, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C or 120°C.

The reaction temperature is preferably 80-100°C, such as 80°C, 90°C or 100°C.

In the synthesis method of the present invention, the reaction time is not particularly limited, for example, the appropriate reaction time can be determined by liquid chromatography to detect the residual percentage of the target product or raw material, which is usually 16-30 hours, non-limiting For example, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours or 30 hours.

The reaction time is preferably 20-26 hours, such as 20 hours, 22 hours, 24 hours or 26 hours.

In the synthetic method of the present invention, the aftertreatment after the reaction can adopt any known conventional treatment means in the field of organic synthesis, such as any treatment means in crystallization, recrystallization, column chromatography purification, extraction, etc. or A combination of various treatments. As an exemplary post-treatment method, for example, the mixture obtained after the reaction is poured into an organic medium such as esters, ethers or alcohol compounds, such as poured into ethyl acetate, and then saturated with Wash with _NaHCO3 aqueous solution and brine, extract the aqueous layer with a conventional organic medium such as ethyl acetate, benzene, chloroform or tetrahydrofuran, etc., combine the organic layers (that is, combine the washed organic layer and the organic layer obtained by extraction), and wash with anhydrous NaHSO ₄ or dried over anhydrous MgSO ₄ , evaporated under negative pressure to remove the solvent, and the residue was purified by flash column chromatography (for example, n-hexane/ethyl acetate as the eluent) to obtain the target product.

In the synthesis method of the present invention, the reaction of the present invention is preferably carried out under the protection of an inert gas, such as nitrogen.

In the synthesis method of the present invention, the compound of formula (II) as raw material can use the compound known in the prior art, or according to the following method, synthesized by anthranilamide and benzaldehyde:

wherein R ¹ -R ⁴ and X are as defined above.

As an example, the formula (II) compound can be prepared as follows: add 1 equivalent of the above formula 1 compound, 1.2 equivalents of the above formula 2 compound, 1.2 equivalents of citric acid and an appropriate amount of solvent such as ethanol or Ethers, etc., react at reflux temperature and stirring for 12-24 hours. After the reaction, dry with anhydrous MgSO ₄ or anhydrous sodium bisulfate, concentrate under reduced pressure to remove ethanol, and separate the residue with 300-400 mesh silica gel column chromatography to obtain the above target product (II).

In a third aspect, the present invention relates to the use of the quinazolinoquinazolinone compound of formula (I) in the field of fluorescence sensing of metal ions, for example, it can be used for labeling, displaying, detecting, fluorescence quenching, etc. of metal ions, In particular it relates to the use of said compounds as fluorescent probes for Fe ³⁺ . .

By immersing the quinazolinoquinazolinone compound of the present invention in the metal ion solution for a certain period of time, and then measuring its solid fluorescence data after suction filtration and drying, it is found that its fluorescence intensity has the characteristics of significant changes in certain wavelength ranges, It can be used in a variety of specific fluorescent sensing fields, and has good application prospects and research value in industrial applications.

In summary, the present invention obtains novel quinazolinoquinazolinone compounds in one step through the use of compounds of formula (II) and (III) as reaction substrates, through the synergistic effect of copper source catalyst and base Compound, simple reaction, easy operation, high yield, is a new synthetic method of quinazolinoquinazolinone compound, provides a new synthetic route for the preparation of this type of compound, and discovered the drug of this novel compound The new uses other than the application provide a research and theoretical basis for the expanded application of this type of compound.

Description of drawings

Fig. 1 is a schematic diagram of the fluorescence intensity of the quinazolinoquinazolinone compound of the present invention combined with different metal ions relative to the wavelength.

Detailed ways

The present invention will be described in detail below through specific examples, but the use and purpose of these exemplary embodiments are only used to exemplify the present invention, and do not constitute any form of any limitation to the actual protection scope of the present invention, nor will the present invention The scope of protection is limited to this.

Example 1

(A) Preparation of compound (II)

Add 10mmol of anthranilamide 1, 12mmol of 2-bromobenzaldehyde 2, 12mmol of citric acid and 10ml of ethanol into the reaction flask, and react under reflux and stirring at 80°C for 16 hours. After the reaction was finished, it was dried with anhydrous MgSO ₄ , concentrated under reduced pressure to remove ethanol, and the residue was separated by 400-mesh silica gel column chromatography to obtain the target product (II), with a yield of 81.7%.

(B) Preparation of compound (I)

In a reaction vessel equipped with a stirrer, a thermometer, and a feeding port, add 50ml of solvent THF, and then add compounds of the above formula (II), (III), Cu(acac) ₂ and Cs ₂ CO ₃ so that the molar ratio is 1 : 1: 0.02: 2, wherein the compound of formula (II) is 10 mmol. Nitrogen was replaced three times, and then reacted at 60° C. with stirring for 16 hours under the protection of continuous feeding of nitrogen. After the reaction was finished, the mixture was poured into ethyl acetate, washed with saturated _NaHCO3 aqueous solution and brine successively, and after the aqueous layer was extracted with ethyl acetate, the organic layer was combined (that is, the organic layer after washing and the organic layer obtained by extraction were combined). layer), dried with anhydrous Na ₂ SO ₄ , evaporated under negative pressure to remove the solvent, and the residue was purified by flash column chromatography (n-hexane/ethyl acetate) to obtain the target product (I) in the above formula. Yield 96.8%, purity 98.5% (HPLC).

Melting point: 203-205°C.

NMR: ¹ H NMR (500MHz, DMSO-d ₆ ) δ0.94(t, J=7.4Hz, 3H), 2.26(dq, J=14.8Hz, 7.4Hz, 1H), 2.59(dq, J=14.8 Hz, 7.4Hz, 1H), 6.18(d, J=1.4Hz, 1H), 7.21-7.18(m, 2H), 7.28-7.27(m, 1H), 7.40-7.37(m, 1H), 7.48-7.44 (m, 1H), 7.66-7.60(m, 2H), 7.96-7.94(m, 1H), 8.72(s, 1H);

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 10.3, 26.8, 64.1, 118.7, 124.3, 124.7, 125.1, 126.7, 126.8, 127.5, 127.6, 130.0, 132.3, 140.7, 141.3, 155.7, 162.2.

Example 2

(A) Preparation of compound (II)

Add 10mmol of 2-amino-5-methylbenzamide 1, 12mmol of 2-bromobenzaldehyde 2, 12mmol of citric acid and 10ml of ethanol into the reaction flask, and react under reflux and stirring at 80°C for 16 hours. After the reaction was finished, it was dried with anhydrous MgSO ₄ , concentrated under reduced pressure to remove ethanol, and the residue was separated by 350-mesh silica gel column chromatography to obtain the target product (II), with a yield of 86.3%.

(B) Preparation of compound (I)

In the reaction vessel equipped with stirrer, thermometer, feeding port, add 50ml solvent toluene, then add above formula compound (II), (III), Cu(acac) ₂ and Cs ₂ CO ₃ , make its molar ratio be 1 :2:0.05:3, wherein the compound of formula (II) is 10 mmol. Nitrogen was replaced three times, and then reacted at 80° C. with stirring for 20 hours under the protection of continuous feeding of nitrogen. After the reaction was finished, the mixture was poured into ethyl acetate, washed with saturated _NaHCO3 aqueous solution and brine successively, and after the aqueous layer was extracted with ethyl acetate, the organic layer was combined (that is, the organic layer after washing and the organic layer obtained by extraction were combined). layer), dried with anhydrous _MgSO4 , evaporated under negative pressure to remove the solvent, and the residue was purified by flash column chromatography (n-hexane/ethyl acetate) to obtain the target product (I) in the above formula. Yield 97.2%, purity 99.1% (HPLC).

Melting point: 278-280°C;

NMR: ¹ H NMR (500MHz, DMSO-d ₆ ) δ2.10(s, 3H), 2.40(s, 3H), 6.17(s, 1H), 7.15-7.19(m, 2H), 7.27-7.28( m, 1H), 7.38-7.51(m, 3H), 7.75(s, 1H), 8.66(s, 1H);

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 20.5, 22.3, 63.9, 118.6, 123.9, 124.4, 124.9, 126.2, 127.5, 127.7, 129.9, 132.8, 136.1, 138.9, 140.7, 152.4, 162.2.

Example 3

(A) Preparation of compound (II)

Add 10mmol of 2-amino-5-chlorobenzamide 1, 12mmol of 2-bromobenzaldehyde 2, 12mmol of citric acid and 10ml of ethanol into the reaction flask, and react under reflux and stirring at 80°C for 16 hours. After the reaction was finished, it was dried with anhydrous MgSO ₄ , concentrated under reduced pressure to remove ethanol, and the residue was separated by 400-mesh silica gel column chromatography to obtain the target product (II), with a yield of 82.5%.

(B) Preparation of compound (I)

In a reaction vessel equipped with a stirrer, a thermometer, and a feeding port, add 50ml of solvent methylene chloride, then add compounds of the above formula (II), (III), Cu(acac) ₂ and Cs ₂ CO ₃ to make the molar ratio It is 1:3:0.08:4, wherein the compound of formula (II) is 10 mmol. Nitrogen was replaced three times, and then reacted at 90° C. with stirring for 24 hours under the protection of continuous feeding of nitrogen. After the reaction was finished, the mixture was poured into ethyl acetate, washed with saturated _NaHCO3 aqueous solution and brine successively, and after the aqueous layer was extracted with ethyl acetate, the organic layer was combined (that is, the organic layer after washing and the organic layer obtained by extraction were combined). layer), dried with _anhydrous MgSO , evaporated under negative pressure to remove the solvent, and the residue was purified by flash column chromatography (n-hexane/ethyl acetate) to obtain the target product (I) in the above formula. Yield 98.5%, purity 99.2% (HPLC).

Melting point: 106-108°C.

NMR: ¹ H NMR (500MHz, DMSO-d ₆ ) δ2.12(s, 3H), 6.23(d, J=1.4Hz, 1H), 7.20-7.16(m, 1H), 7.23-7.21(m, 1H), 7.28-7.27(m, 1H), 7.41-7.37(m, 1H), 7.72-7.68(m, 2H), 7.88(d, J=1.3Hz, 1H), 8.89(s, 1H);

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 22.2, 63.8, 118.4, 124.1, 125.2, 126.7, 126.9, 127.5, 128.0, 130.0, 130.9, 132.0, 140.2, 140.6, 151.9, 161.0.

Example 4

(A) Preparation of compound (II)

Add 10mmol of 2-amino-5-bromobenzamide 1, 12mmol of 2-iodobenzaldehyde 2, 12mmol of citric acid and 10ml of ethanol into the reaction flask, and react under reflux and stirring at 80°C for 16 hours. After the reaction was finished, it was dried with anhydrous MgSO ₄ , concentrated under reduced pressure to remove ethanol, and the residue was separated by 400-mesh silica gel column chromatography to obtain the target product (II), with a yield of 83.7%.

(B) Preparation of compound (I)

In the reaction vessel equipped with stirrer, thermometer, feed port, add 50ml solvent n-hexane, then add above formula compound (II), (III), Cu(acac) ₂ and Cs ₂ CO ₃ , make its molar ratio be 1:4:0.12:5, wherein the compound of formula (II) is 10 mmol. Nitrogen was replaced three times, and then reacted at 110° C. with stirring for 27 hours under the protection of continuous feeding of nitrogen. After the reaction was finished, the mixture was poured into ethyl acetate, washed with saturated _NaHCO3 aqueous solution and brine successively, and after the aqueous layer was extracted with ethyl acetate, the organic layer was combined (that is, the organic layer after washing and the organic layer obtained by extraction were combined). layer), dried with anhydrous Na ₂ SO ₄ , evaporated under negative pressure to remove the solvent, and the residue was purified by flash column chromatography (n-hexane/ethyl acetate) to obtain the target product (I) in the above formula. Yield 97.3%, purity 98.7% (HPLC).

Melting point: 235-236°C.

NMR: ¹ H NMR (500MHz, DMSO-d ₆ ) δ2.12(s, 3H), 6.23(d, J=1.3Hz, 1H), 7.18-7.16(m, 1H), 7.23-7.19(m, 1H), 7.29-7.27(m, 1H), 7.40-7.37(m, 1H), 7.63-7.62(m, 1H), 7.84-7.82(m, 1H), 8.01(d, J=2.4Hz, 1H) , 8.89(s, 1H);

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 22.3, 63.8, 118.4, 119.0, 124.1, 125.2, 127.0, 127.5, 128.3, 129.9, 130.0, 134.9, 140.5, 141.6, 151.8, 160.9.

Example 5

(A) Preparation of compound (II)

Add 10mmol anthranilamide 1, 12mmol 2-bromo-5-fluorobenzaldehyde 2, 12mmol citric acid and 10ml ethanol into the reaction flask, and react under reflux and stirring at 80°C for 20 hours. After the reaction was finished, it was dried with anhydrous MgSO ₄ , concentrated under reduced pressure to remove ethanol, and the residue was separated by 350-mesh silica gel column chromatography to obtain the target product (II), with a yield of 84.8%.

(B) Preparation of compound (I)

In a reaction vessel equipped with a stirrer, a thermometer, and a feeding port, add 50ml of solvent methanol, then add compounds of the above formula (II), (III), Cu(acac) ₂ and Cs ₂ CO ₃ so that the molar ratio is 1 : 1.5: 0.16: 6, wherein the compound of formula (II) is 10 mmol. Nitrogen was replaced three times, and then reacted at 120° C. with stirring for 30 hours under the protection of continuous feeding of nitrogen. After the reaction was finished, the mixture was poured into ethyl acetate, washed with saturated _NaHCO3 aqueous solution and brine successively, and after the aqueous layer was extracted with ethyl acetate, the organic layer was combined (that is, the organic layer after washing and the organic layer obtained by extraction were combined). layer), dried with anhydrous Na ₂ SO ₄ , evaporated under negative pressure to remove the solvent, and the residue was purified by flash column chromatography (n-hexane/ethyl acetate) to obtain the target product (I) in the above formula. Yield 96.9%, purity 98.6% (HPLC).

Melting point: 217-218°C.

NMR: ¹ H NMR (500MHz, DMSO-d ₆ ) δ2.10(s, 3H), 6.22(s, 1H), 7.17-7.15(m, 1H), 7.25-7.19(m, 2H), 7.48- 7.45(m, 1H), 7.67-7.62(m, 2H), 7.95(d, J=7.5Hz, 1H), 8.79(s, 1H);

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 22.3, 63.6, 113.9, 114.1, 116.8, 117.0, 119.9, 124.7, 126.4, 126.7, 127.6, 132.4, 141.2, 151.8, 159.0, 162.1.

Example 6

(A) Preparation of compound (II)

Add 10mmol of anthranilamide 1, 12mmol of 2-bromo-5-methoxybenzaldehyde 2, 12mmol of citric acid and 10ml of ethanol into the reaction flask, and react under reflux and stirring at 80°C for 16 hours. After the reaction was finished, it was dried with _anhydrous MgSO, concentrated under reduced pressure to remove ethanol, and the residue was separated by 300 mesh silica gel column chromatography to obtain the target product (II), with a yield of 85.1%.

(B) Preparation of compound (I)

In a reaction vessel equipped with a stirrer, a thermometer, and a feeding port, add 50ml of solvent 1,6-dioxane, and then add compounds of the above formula (II), (III), Cu(acac) ₂ and Cs ₂ CO ₃ , so that the molar ratio is 1:2.5:0.2:3, wherein the compound of formula (II) is 10 mmol. Nitrogen was replaced three times, and then reacted at 70° C. with stirring for 18 hours under the protection of continuous feeding of nitrogen. After the reaction was finished, the mixture was poured into ethyl acetate, washed with saturated _NaHCO3 aqueous solution and brine successively, and after the aqueous layer was extracted with ethyl acetate, the organic layer was combined (that is, the organic layer after washing and the organic layer obtained by extraction were combined). layer), dried with anhydrous _MgSO4 , evaporated under negative pressure to remove the solvent, and the residue was purified by flash column chromatography (n-hexane/ethyl acetate) to obtain the target product (I) in the above formula. Yield 98.1%, purity 98.9% (HPLC).

Melting point: 264-266°C;

Nuclear Magnetic Resonance ¹ H NMR (500MHz, DMSO-d ₆ ) δ2.08(s, 3H), 3.76(s, 3H), 6.15(s, 1H), 6.88-6.87(m, 1H), 6.97-6.95(m , 1H), 7.12-7.11(m, 1H), 7.46-7.43(m, 1H), 7.65-7.60(m, 2H), 7.94(d, J=7.5Hz, 1H), 8.69(s, 1H);

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 22.2, 55.4, 64.1, 112.1, 115.9, 119.4, 124.7, 125.3, 126.3, 126.4, 127.6, 132.3, 134.3, 141.5, 150.0, 156.6, 162.2.

Example 7

(A) Preparation of compound (II)

Add 10mmol of anthranilamide 1, 12mmol of 2-iodo-4-methylbenzaldehyde 2, 12mmol of citric acid and 10ml of ethanol into the reaction flask, and react under reflux and stirring at 80°C for 12 hours. After the reaction was finished, it was dried with anhydrous MgSO ₄ , concentrated under reduced pressure to remove ethanol, and the residue was separated by 400-mesh silica gel column chromatography to obtain the target product (II), with a yield of 84.9%.

(B) Preparation of compound (I)

In a reaction vessel equipped with a stirrer, a thermometer, and a feeding port, add 50ml of solvent DMF, and then add compounds of the above formula (II), (III), Cu(acac) ₂ and Cs ₂ CO ₃ so that the molar ratio is 1 : 3.5: 0.05: 2, wherein the compound of formula (II) is 10 mmol. Nitrogen was replaced three times, and then reacted at 80° C. for 30 hours under the protection of continuous feeding of nitrogen. After the reaction was finished, the mixture was poured into ethyl acetate, washed with saturated _NaHCO3 aqueous solution and brine successively, and after the aqueous layer was extracted with ethyl acetate, the organic layer was combined (that is, the organic layer after washing and the organic layer obtained by extraction were combined). layer), dried with anhydrous _MgSO4 , evaporated under negative pressure to remove the solvent, and the residue was purified by flash column chromatography (n-hexane/ethyl acetate) to obtain the target product (I) in the above formula. Yield 96.8%, purity 99.5% (HPLC).

Melting point: 270-272°C;

NMR: ¹ H NMR (500MHz, DMSO-d ₆ ) δ2.10(s, 3H), 3.32(s, 3H), 6.16(d, J=1.3Hz, 1H), 7.02-6.99(m, 2H) , 7.16-7.15(m, 1H), 7.46-7.43(m, 1H), 7.65-7.60(m, 2H), 7.95-7.93(m, 1H), 8.64(s, 1H);

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 22.4, 30.6, 63.8, 114.0, 115.8, 124.4, 125.8, 126.4, 127.2, 125.5, 127.6, 132.2, 139.3, 140.6, 141.5, 152.0, 162.1.

Example 8

(A) Preparation of compound (II)

Add 10mmol of anthranilamide 1, 12mmol of 2-bromo-4,5-dimethoxybenzaldehyde 2, 12mmol of citric acid and 10ml of ethanol into the reaction flask, and react under reflux and stirring at 80°C for 24 hours. After the reaction was finished, it was dried with anhydrous MgSO ₄ , concentrated under reduced pressure to remove ethanol, and the residue was separated by 350-mesh silica gel column chromatography to obtain the target product (II), with a yield of 85.0%.

(B) Preparation of compound (I)

In a reaction vessel equipped with a stirrer, a thermometer, and a feeding port, add 50ml of solvent DMSO, and then add compounds of the above formula (II), (III), Cu(acac) ₂ and Cs ₂ CO ₃ so that the molar ratio is 1 : 1: 0.1: 5, wherein the compound of formula (II) is 10 mmol. Nitrogen was replaced three times, and then reacted at 90° C. with stirring for 28 hours under the protection of continuous feeding of nitrogen. After the reaction was finished, the mixture was poured into ethyl acetate, washed with saturated _NaHCO3 aqueous solution and brine successively, and after the aqueous layer was extracted with ethyl acetate, the organic layer was combined (that is, the organic layer after washing and the organic layer obtained by extraction were combined). layer), dried with anhydrous _MgSO4 , evaporated under negative pressure to remove the solvent, and the residue was purified by flash column chromatography (n-hexane/ethyl acetate) to obtain the target product (I) in the above formula. Yield 97.5%, purity 99.0% (HPLC).

Melting point: 270-272°C;

NMR: ¹ H NMR (500MHz, DMSO-d ₆ ) δ 2.09(s, 3H), 3.75(s, 3H), 3.78(s, 3H), 6.12(d, J=1.2Hz, 1H), 6.77 (s, 1H), 6.88 (s, 1H), 7.46-7.42 (m, 1H), 7.64-7.61 (m, 2H), 7.95-7.93 (m, 1H), 8.62 (s, 1H);

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 22.2, 55.5, 55.8, 64.1, 107.6, 110.0, 110.4, 124.7, 126.2, 126.4, 127.5, 128.8, 132.2, 141.5, 146.4, 149.9, 150.2, 162.1.

Example 9

In a reaction vessel equipped with a stirrer, a thermometer, and a feeding port, add 50ml of solvent carbon tetrachloride, then add the above formula compound (II), (III), Cu(acac) ₂ and Cs ₂ CO ₃ to make the mole The ratio is 1:2:0.2:2, wherein the compound of formula (II) is 10 mmol. Nitrogen was replaced three times, and then reacted at 100° C. with stirring for 25 hours under the protection of continuous feeding of nitrogen. After the reaction was finished, the mixture was poured into ethyl acetate, washed with saturated _NaHCO3 aqueous solution and brine successively, and after the aqueous layer was extracted with ethyl acetate, the organic layer was combined (that is, the organic layer after washing and the organic layer obtained by extraction were combined). layer), dried with anhydrous Na ₂ SO ₄ , evaporated under negative pressure to remove the solvent, and the residue was purified by flash column chromatography (n-hexane/ethyl acetate) to obtain the target product (I) in the above formula. Yield 97.1%, purity 99.2% (HPLC).

Melting point: 243-245°C;

NMR: ¹ H NMR (500MHz, DMSO-d ₆ ) δ0.94(t, J=7.4Hz, 3H), 2.24(dq, J=14.8Hz, 7.4Hz, 1H), 2.40(s, 3H), 2.56(dq, J=14.8Hz, 7.4Hz, 1H), 6.13(d, J=1.5Hz, 1H), 7.21-7.18(m, 2H), 7.28-7.26(m, 1H), 7.40-7.36(m , 1H), 7.45-7.43(m, 1H), 7.49-7.48(m, 1H), 7.76-7.75(m, 1H), 8.65(s, 1H);

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 10.3, 20.5, 26.7, 64.1, 118.7, 124.2, 124.4, 125.0, 126.6, 127.4, 127.7, 129.8, 132.8, 136.2, 138.8, 140.8, 155.9, 162.2.

Example 10

In a reaction vessel equipped with a stirrer, a thermometer, and a feeding port, add 50ml of solvent n-butanol, and then add compounds of the above formula (II), (III), Cu(acac) ₂ and Cs ₂ CO ₃ to make the molar ratio It is 1:1.2:0.05:2.5, wherein the compound of formula (II) is 10 mmol. Nitrogen was replaced three times, and then reacted at 90° C. with stirring for 20 hours under the protection of continuous feeding of nitrogen. After the reaction was finished, the mixture was poured into ethyl acetate, washed with saturated _NaHCO3 aqueous solution and brine successively, and after the aqueous layer was extracted with ethyl acetate, the organic layer was combined (that is, the organic layer after washing and the organic layer obtained by extraction were combined). layer), dried with anhydrous _MgSO4 , evaporated under negative pressure to remove the solvent, and the residue was purified by flash column chromatography (n-hexane/ethyl acetate) to obtain the target product (I) in the above formula. Yield 96.8%, purity 98.4% (HPLC).

Melting point: 175-176°C;

NMR: ¹ H NMR (500MHz, DMSO-d ₆ ) δ0.92(t, J=7.4Hz, 3H), 2.22(dq, J=14.8Hz, 7.4Hz, 1H), 2.57(dq, J=14.8 Hz, 7.4Hz, 1H), 3.76(s, 3H), 6.12(d, J=1.4Hz, 1H), 6.88-6.87(m, 1H), 6.98-6.95(m, 1H), 7.15-7.14(m , 1H), 7.47-7.43(m, 1H), 7.65-7.59(m, 2H), 7.95-7.94(m, 1H), 8.67(s, 1H);

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 10.3, 26.7, 55.4, 64.3, 112.7, 115.8, 119.5, 124.7, 125.5, 126.5, 126.7, 127.5, 132.2, 134.3, 141.4, 153.5, 156.6, 162.2.

Example 11

In a reaction vessel equipped with a stirrer, a thermometer, and a feeding port, add 50ml of solvent diethyl ether, and then add compounds of the above formula (II), (III), Cu(acac) ₂ and Cs ₂ CO ₃ so that the molar ratio is 1 : 2: 0.15: 4.5, wherein the compound of formula (II) is 10 mmol. Nitrogen was replaced three times, and then reacted at 80° C. with stirring for 28 hours under the protection of continuous feeding of nitrogen. After the reaction was finished, the mixture was poured into ethyl acetate, washed with saturated _NaHCO3 aqueous solution and brine successively, and after the aqueous layer was extracted with ethyl acetate, the organic layer was combined (that is, the organic layer after washing and the organic layer obtained by extraction were combined). layer), dried with anhydrous _MgSO4 , evaporated under negative pressure to remove the solvent, and the residue was purified by flash column chromatography (n-hexane/ethyl acetate) to obtain the target product (I) in the above formula. Yield 96.9%, purity 98.9% (HPLC).

Melting point: 215-217°C;

NMR: ¹ H NMR (500MHz, DMSO-d ₆ ) δ0.71-0.65(m, 1H), 0.98-0.91(m, 2H), 1.22-1.17(m, 1H), 1.59-1.54(m, 1H) , 6.24(d, J=1.5Hz, 1H), 7.09-7.07(m, 1H), 7.17-7.14(m, 1H), 7.27-7.26(m, 1H), 7.36-7.33(m, 1H), 7.48 -7.45(m, 1H), 7.67-7.62(m, 2H), 7.98-7.96(m, 1H), 8.78(s, 1H);

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ7.3, 10.6, 12.9, 64.3, 118.3, 124.1, 124.7, 124.8, 126.5, 126.7, 127.5, 127.8, 129.9, 132.1, 140.7, 141.2, 155.3, 162.3.

Example 12

In the reaction vessel equipped with stirrer, thermometer, feeding port, add 50ml of solvent acetone, then add above formula compound (II), (III), Cu(acac) ₂ and Cs ₂ CO ₃ , make its molar ratio be 1 : 1.2: 0.2: 2, wherein the compound of formula (II) is 10 mmol. Nitrogen was replaced three times, and then reacted at 70° C. with stirring for 17 hours under the protection of continuous feeding of nitrogen. After the reaction was finished, the mixture was poured into ethyl acetate, washed with saturated _NaHCO3 aqueous solution and brine successively, and after the aqueous layer was extracted with ethyl acetate, the organic layer was combined (that is, the organic layer after washing and the organic layer obtained by extraction were combined). layer), dried with anhydrous _MgSO4 , evaporated under negative pressure to remove the solvent, and the residue was purified by flash column chromatography (n-hexane/ethyl acetate) to obtain the target product (I) in the above formula. Yield 96.3%, purity 99.4% (HPLC).

Melting point: 214-216°C;

NMR: ¹ H NMR (500MHz, DMSO-d ₆ ) δ0.67-0.61(m, 1H), 0.95-0.85(m, 2H), 1.16-1.11(m, 1H), 1.56-1.51(m, 1H) , 3.75(s, 3H), 6.18(d, J=1.5Hz, 1H), 6.87-6.86(m, 1H), 6.94-6.92(m, 1H), 7.05-7.03(m, 1H), 7.47-7.43 (m, 1H), 7.67-7.62(m, 2H), 7.98-7.96(m, 1H), 8.71(s, 1H);

¹³ C NMR (125MHz, DMSO-d ₆ ) δ7.0, 10.3, 12.9, 55.3, 64.5, 112.09, 115.8, 119.0, 124.8, 125.3, 126.3, 126.5, 127.7, 132.1, 134.3, 141.3, 153.1, 156.4, 16 .

Example 13

In the reaction vessel equipped with stirrer, thermometer, feeding port, add 50ml solvent chlorobenzene, then add above formula compound (II), (III), Cu(acac) ₂ and Cs ₂ CO ₃ , make its molar ratio be 1 : 3.8: 0.04: 3.7, wherein the compound of formula (II) is 10 mmol. Nitrogen was replaced three times, and then reacted at 60° C. with stirring for 30 hours under the protection of continuous feeding of nitrogen. After the reaction was finished, the mixture was poured into ethyl acetate, washed with saturated _NaHCO3 aqueous solution and brine successively, and after the aqueous layer was extracted with ethyl acetate, the organic layer was combined (that is, the organic layer after washing and the organic layer obtained by extraction were combined). layer), dried with anhydrous _MgSO4 , evaporated under negative pressure to remove the solvent, and the residue was purified by flash column chromatography (n-hexane/ethyl acetate) to obtain the target product (I) in the above formula. Yield 94.1%, purity 98.5% (HPLC).

Melting point: 232-233°C;

NMR: ¹ H NMR (500MHz, DMSO-d ₆ ) δ0.73 (d, J=6.8Hz, 3H), 1.24 (d, J=6.6Hz, 3H), 3.01-2.93 (m, 1H), 6.17 (d, J=1.6Hz, 1H), 7.20-7.18(m, 2H), 7.28-7.26(m, 1H), 7.40-7.37(m, 1H), 7.49-7.46(m, 1H), 7.56-7.55 (m, 1H), 7.67-7.63(m, 1H), 7.96-7.95(m, 1H), 8.77(s, 1H);

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 19.8, 20.2, 29.2, 64.2, 118.4, 124.3, 124.6, 125.1, 126.7, 127.2, 127.5, 127.6, 129.9, 132.2, 140.7, 141.2, 159.1, 162.3.

It can be seen from the above Examples 1-13 that when the method of the present invention is adopted, quinazolinoquinazolinone compounds can be obtained with high yield and high purity.

Examples 14-26

Except that Cu(acac) therein is _replaced by following copper compound, implemented respectively embodiment 14-26 in the same manner as embodiment 1-13, its copper source catalyst, embodiment corresponding relation and corresponding product The yields are shown in the table below.

As can be seen from the above table, when other copper source catalysts are used, corresponding yields can be obtained, but the product yield is significantly lower than _that of using Cu(acac) as the catalyst.

Examples 27-39

Except that the cesium carbonate wherein is replaced by following organic base or inorganic base, implement embodiment 27-39 respectively in the same manner as embodiment 1-12 respectively, the corresponding relationship of used base, embodiment and the collection of corresponding product The rates are shown in the table below.

*: DABCO is 1,4-diazabicyclo[2.2.2]octane

NR: No reaction. the

As can be seen from the above table, unexpectedly, when other bases including organic bases except cesium carbonate are used, the yield of the product is greatly reduced, or even no reaction occurs at all. At the same time, it can be seen that even if cesium sulfate, which is also a cesium salt, is used, the reaction can hardly proceed [see Example 36]. This demonstrates the specific specificity of cesium carbonate for this reaction.

Fluorescence test effect

The quinazolinoquinazolinone compound (marked as 13I) obtained in Example 13 of the present invention was respectively immersed in Ni(NO ₃ ) ₂ , Co(NO ₃ ) ₂ and Fe(NO 3 ) 2 with a molar concentration of 0.1 mol/L. ₃ ) In the aqueous solution of ₃ , after soaking for 20 minutes, suction filtration, and drying in an oven at 80°C for 1 hour, together with the untreated quinazolinoquinazolinone compounds obtained in Example 13, were named 13I, 13I+Ni ²⁺ , 13I+Co ²⁺ and 13I+Fe ³⁺ .

The solid fluorescence of the above four samples was measured at different long wavelengths with a Shimadzu RF-5301PC fluorescence spectrophotometer, and the results are shown in Figure 1.

As can be clearly seen from Fig. 1, within the wavelength range of 400-500nm, the fluorescence intensity of the quinazolinoquinazolinone compound of the present invention and the metal ion has a significant change, especially near 425nm, its fluorescence intensity is the same as that of 13I The fluorescence intensity of 13I has the largest change, especially for 13I+Fe ³⁺ , its fluorescence intensity is only about 50% of 13I, which means that it can be used in specific applications such as fluorescence quenching and Fe ion detection, because it is compatible with Fe ³⁺ produces excellent fluorescence quenching performance, which can be used as a fluorescent probe for Fe ³⁺ and other specific applications. Therefore, based on such a strong fluorescence intensity difference, the quinazoline and quinazolinone compounds of the present invention can be used in various specific fluorescent sensing fields, such as metal ion recognition, display, detection, fluorescence quenching, etc., Especially as a fluorescent probe for Fe ³⁺ , it has good application prospects and research value in industrial applications.

When using other embodiments except embodiment 13, i.e. the quinazoline and quinazolinone compound obtained in embodiment 1-12 and Ni ²⁺ , Co ²⁺ and Fe ³⁺ to carry out the same measurement, with accompanying drawing 1 Having highly similar fluorescence changing characteristics also means that these compounds can also be used in the field of fluorescence sensing, etc.

In summary, it can be clearly seen from all the above examples that when the method of the present invention is adopted, not only can the reaction of dihydroquinazolinone and amidine compound be successfully realized, but also can be obtained with high yield and high purity. The target product is a brand-new synthetic method with great industrial application prospects, and provides a brand-new synthetic route for the efficient and rapid synthesis of quinazolinoquinazolinone compounds. In addition, a new application of the quinazolinoquinazolinone compound in the present invention in the field of fluorescence sensing has also been discovered, which provides a theoretical basis and exploratory research for the expansion of its application field.

It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the protection scope of the present invention. In addition, it should also be understood that after reading the technical content of the present invention, those skilled in the art can make various changes, modifications and/or variations to the present invention, and all these equivalent forms also fall within the appended claims of the present application. within the defined scope of protection.

Claims (9)

1. a quinazo quinazolinones, its structural formula is as shown in the formula shown in (I):

Wherein:

R ¹-R ⁴identical or different separately, and independently selected from H, C ₁-C ₆alkyl, halogen, C ₁-C ₆alkoxyl group;

R is selected from C ₁-C ₆alkyl, C ₁-C ₆alkoxyl group, C ₃-C ₆cycloalkyl;

Condition is when R is methyl, R ¹-R ⁴be asynchronously H.

2. quinazo quinazolinones as claimed in claim 1, is characterized in that: R is C ₂-C ₆alkyl or C ₃-C ₆cycloalkyl.

3. quinazo quinazolinones as claimed in claim 2, is characterized in that: R is ethyl or cyclopropyl.

4. the quinazo quinazolinones as described in any one of claim 1-3, is characterized in that: R ⁴for H.

5. the synthetic method of quinazo quinazolinones as claimed in claim 1, it is characterized in that: described method makes formula (II) and (III) react and obtain formula (I) compound under being included in copper source catalyzer and alkali existence in organic solvent.

Wherein, R ¹-R ⁴, R definition as described in the appended claim 1;

X is halogen;

Described copper source catalyzer is CuI, CuBr, CuCl, CuCl ₂, CuBr ₂, CuI ₂in any one or multiple; Or be venus crystals, Cu (acac) ₂, Cu (PPh ₃) ₂nO ₃, ethyl acetoacetic acid copper (II), in hexafluoroacetylacetone copper any one or multiple;

Described alkali be in salt of wormwood, potassiumphosphate, Quilonum Retard, lithium hydroxide, cesium carbonate any one or multiple.

6. synthetic method as claimed in claim 5, is characterized in that: described formula (II) is 1: 1-4 with the mol ratio of (III) compound; The mol ratio of described formula (II) compound and copper source catalyzer is 1: 0.02-0.2; The mol ratio of described formula (II) compound and alkali is 1: 2-6.

7. the synthetic method as described in claim 5 or 6, is characterized in that: described copper source catalyzer is Cu (acac) ₂, described alkali is cesium carbonate.

8. the synthetic method as described in claim 5 or 6, is characterized in that: temperature of reaction is 60-120 DEG C, and the reaction times is 16-30 hour.

9. the quinazo quinazolinones as described in any one of claim 1-4 is used for the purposes in fluorescence sense field.