CN115181140B - Method for synthesizing On-DNA (deoxyribonucleic acid) dihydroquinazolinone compound by using carbonyl compound - Google Patents

Abstract

The invention belongs to the technical field of DNA coding compound libraries, and particularly relates to a synthesis method of an On-DNA dihydroquinazolinone compound and a DNA coding compound library. The method provided by the invention comprises the following steps: reacting the On-DNA compound with a carbonyl compound in a water phase system containing Lewis acid to obtain the On-DNA dihydroquinazolinone compound. The invention provides a new method for the On-DNA dihydroquinazolinone compound, the dihydroquinazolinone skeleton structure has important biological activity and medicinal value, the diversity of a DNA coding compound library can be obviously increased by synthesizing the compound, and the On-DNA dihydroquinazolinone compound prepared by the reaction method provided by the invention has the advantages of good reaction substrate universality, mild conditions, low cost, convenient operation and high yield.

Description

Method for synthesizing On-DNA (deoxyribonucleic acid) dihydroquinazolinone compound by using carbonyl compound

Technical Field

The invention belongs to the technical field of DNA coding compound libraries, and particularly relates to a synthesis method of an On-DNA dihydroquinazolinone compound and a DNA coding compound library.

Background

The DNA-Encoded Library of compounds (DEL for short) is an emerging technology for screening small-molecule drugs. It combines DNA technology with combinatorial chemistry, and can efficiently construct compound libraries containing hundred million levels of capacity; and in the screening process, the DEL can screen multiple conditions for multiple or the same target simultaneously. Compared with traditional high-throughput screening, DEL has great advantages in terms of compound library capacity, library construction difficulty, and time and cost for screening.

One of the major tasks in the DEL library field at present is the development of chemical reactions On DNA, called On-DNA chemistry for short. Because DNA must be kept stable in a certain aqueous phase, pH, temperature, metal ion concentration and inorganic salt concentration, the On-DNA chemical reaction which has small DNA damage, better recovery rate and wide substrate adaptability is required for the synthesis of a DNA coding compound library in a large scale. At present, on-DNA chemical reactions reported in public are hundreds of, including aqueous phase, solid phase and DNA template reactions, each reaction condition is one kind or more than ten kinds, so that under the same other conditions, the more kinds of On-DNA chemical reactions are, the more abundant the conditions are, the better the universality is, the more the selectivity is in the design of a DNA coding compound library, the higher the synthesis success rate of the final DNA coding compound library is, and the more the diversity of the obtained DNA coding compound library is.

The dihydro quinazolinone skeleton structure widely exists in natural products and drug molecules, and has important biological activity and medicinal value. In the reported synthetic methods, 2-aminobenzamide, isatoic anhydride derivatives, 2-aminobenzonitrile, 2-nitroaniline and the like are used as starting materials and are subjected to condensation reaction with carbonyl compounds under certain conditions to obtain the dihydro quinazolinone compounds. These methods not only have single reaction raw material, but also have some obvious disadvantages, and most of the reaction conditions are harsh, such as the need of dangerous organic solvents, higher temperature, strong acid, expensive catalyst, and complicated post-treatment process. In order to better screen the dihydroquinazolinone compounds and solve the problem of the limitation of the synthesis method of the On-DNA dihydroquinazolinone compounds in the construction of the DNA coding compound library, the development of a synthesis method which has the advantages of easily available raw materials, mild reaction conditions, high yield and good universality of reaction substrates is urgently needed, and the method can also increase the diversity of the DNA coding compound library.

Disclosure of Invention

In view of this, the present invention provides a method for synthesizing On-DNA dihydroquinazolinone compounds, which is applied to construct DNA coding compound libraries, thereby improving drug screening efficiency.

The technical scheme provided by the invention is as follows:

in a first aspect, the present invention provides a method for synthesizing an On-DNA dihydroquinazolinone compound, comprising the steps of:

providing an On-DNA compound shown as a general formula (I) and a carbonyl compound shown as a general formula (II);

（I）

（II）

reacting the On-DNA compound with the carbonyl compound in a water phase system containing Lewis acid to obtain an On-DNA dihydroquinazolinone compound shown as a general formula (III);

（III）

wherein n is 0 or 1;

r is selected from C ₁ ～C ₇ Alkyl or substituted C ₁ ～C ₇ Alkyl, said substituted C ₁ ～C ₇ The substituents of the alkyl groups being selected from C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ One of cycloalkyl, aryl methylene and substituted aryl;

R ¹ selected from hydrogen, C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ Cycloalkyl, alkoxy, trifluoromethyl, halogen, amino, amido, hydroxyl, cyano, nitro, aldehyde group, ester group, amido and aryl, wherein the substituent of the aryl is independently selected from hydrogen and C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ One or more of cycloalkyl, halogen, alkoxy, trifluoromethyl, amino, aldehyde group, ester group, amide group and cyano;

R ³ and R ⁴ Each independently selected from hydrogen,C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ One of cycloalkyl, benzyl, aryl methylene, aryl and substituted isatin, wherein the substituents of the benzyl, the aryl methylene, the aryl and the substituted isatin are respectively and independently selected from hydrogen and C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ One or more of cycloalkyl, halogen, hydroxyl, alkoxy, trifluoromethyl, amino, aldehyde group, boric acid group, carboxyl, ester group, amide group, nitro, phenyl and cyano; or, said R ³ And said R ⁴ Directly or indirectly linked to form a substituted isatinyl group, the substituted isatinyl group including:

，R ^a selected from hydrogen, C ₁ ～C ₆ One of alkyl, halogen, hydroxyl, alkoxy, trifluoromethoxy, trifluoromethyl, amino, amido, aldehyde group, carboxyl, ester group, nitro and cyano, R ^b Selected from hydrogen, C ₁ ～C ₆ One of alkyl, aryl and benzyl;

represents DNA.

The synthesis method provided by the invention takes a carbonyl compound and an On-DNA compound as reaction substrates, and the On-DNA dihydroquinazolinone compound is prepared by reaction in a Lewis acid aqueous phase system. In the reaction process, carbonyl of the carbonyl compound and amino of the On-DNA compound form Schiff base, and simultaneously, under the action of Lewis acid and water, the Schiff base and amide part On the anthranilamide compound form rings, so that the On-DNA dihydroquinazolinone compound is prepared.

In a second aspect, the invention also provides a DNA coding compound library, and the DNA coding compound library comprises the On-DNA dihydroquinazolinone compound prepared by the synthesis method.

The On-DNA dihydro quinazolinone compound prepared by the synthesis method can be used for constructing a DNA coding compound library, so that the diversity and the novelty of the DNA coding compound library are improved, the drug-like property of the DNA coding compound library is greatly improved, and the drug screening efficiency is favorably improved.

Drawings

FIG. 1 is a scheme of synthesis of example 1;

FIG. 2 is a synthetic scheme of example 2;

FIG. 3 is a synthetic scheme of example 3;

FIG. 4 is a drawing of a class of On-DNA dihydroquinazolinone compounds synthesized in example 3;

FIG. 5 is another class of On-DNA dihydroquinazolinone compounds synthesized in example 3;

FIG. 6 is yet another class of On-DNA dihydroquinazolinone compounds synthesized in example 3.

Detailed Description

The technical solutions of the present invention will be described clearly and completely with reference to the accompanying drawings, and it is to be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.

The invention provides a method for preparing an On-DNA (deoxyribonucleic acid) dihydroquinazolinone compound, which comprises the following steps of:

s01, providing an On-DNA compound shown as a general formula (I) and a carbonyl compound shown as a general formula (II);

（I）

（II）

s02, reacting the On-DNA compound with the carbonyl compound in a water phase system containing Lewis acid to obtain an On-DNA dihydroquinazolinone compound shown in a general formula (III);

（III）

wherein n is 0 or 1;

r is selected from C ₁ ～C ₇ Alkyl or substituted C ₁ ～C ₇ Alkyl, said substituted C ₁ ～C ₇ The substituents of the alkyl groups being selected from C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ One of cycloalkyl, aryl methylene and substituted aryl;

R ¹ selected from hydrogen, C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ Cycloalkyl, alkoxy, trifluoromethyl, halogen, amino, hydroxyl, cyano, nitro, aldehyde group, ester group, amide group and aromatic group, wherein the substituent of the aromatic group is independently selected from hydrogen and C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ One or more of cycloalkyl, halogen, alkoxy, trifluoromethyl, amino, aldehyde group, ester group, amide group and cyano;

R ³ and R ⁴ Each independently selected from hydrogen and C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ One of cycloalkyl, benzyl, aryl methylene, aryl and substituted isatin, wherein the substituents on the benzyl, the aryl methylene, the aryl and the substituted isatin are respectively and independently selected from hydrogen and C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ One or more of cycloalkyl, halogen, hydroxyl, alkoxy, trifluoromethyl, amino, aldehyde group, boric acid group, carboxyl, ester group, amide group, nitro, phenyl and cyano; or, said R ³ And said R ⁴ Directly or indirectly linked to form a substituted isatinyl group, the substituted isatinyl group including:

，R ^a selected from hydrogen, C ₁ ～C ₆ Alkyl, halogen, hydroxy, alkoxy, trifluoromethoxy, trifluoromethyl, amino, aldehyde, carboxyl,One of ester group, nitro group and cyano group, R ^b Selected from hydrogen, C ₁ ～C ₆ One of alkyl, aryl and benzyl;

represents DNA.

In some embodiments, the On-DNA compound has the structure of formula (I) ₁ ) Or general formula (I) ₂ ) Shown in the figure:

（I ₁ ），

（I ₂ ）

in some embodiments, the On-DNA dihydroquinazolinone compounds have the structure of formula (III) ₁ ）、（III ₂ ) Or general formula (III) ₃ ) Shown in the specification:

（III ₁ ），

（III ₂ ），

（III ₃ ）；

wherein R is ² Selected from hydrogen, C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ One of cycloalkyl, aryl methylene and aryl, wherein substituents on aryl of the aryl methylene are independently selected from hydrogen and C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ One or more of cycloalkyl, halogen, alkoxy, trifluoromethyl, amino, aldehyde group, ester group, amide group and cyano, and the substituents of the aromatic group are independentSelected from hydrogen, C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ One or more of cycloalkyl, halogen, hydroxyl, alkoxy, trifluoromethyl, amino, aldehyde group, boric acid group, carboxyl, ester group, amide group, nitro, cyano and phenyl;

R ³ and R ⁴ Each independently selected from C ₁ ～C ₆ Alkyl or C ₁ ～C ₆ A cycloalkyl group; or, said R ³ And said R ⁴ Directly or indirectly linked to form said substituted isatin group.

In some embodiments, the aqueous system is comprised of water and an organic agent selected from at least one of acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, methanol, ethanol, t-butanol, isopropanol, tetrahydrofuran, and in a specific embodiment, methanol.

In some embodiments, the volume ratio of water to organic agent in the aqueous system is (1 to 9): 3. wherein the volume ratio of the organic solvent to water may be specifically 1: 3, 2: 3, 1, 4: 3, 5: 3, 2. In a specific embodiment, the volume ratio of the organic solvent to water is 2

In some embodiments, the lewis acid is selected from at least one of aluminum halide, zinc halide, magnesium halide, iron halide, zirconium halide, nickel halide, cobalt halide, manganese halide, titanium halide, copper halide, antimony halide, silver halide, gold halide, palladium halide, boron trifluoride, iron triflate, zinc triflate, copper triflate, silver triflate, scandium triflate, silver triflate, antimony trichloride, in a particular embodiment, the lewis acid is antimony trichloride.

In some embodiments, the step of reacting the carbonyl compound with the On-DNA compound in an aqueous system comprising a Lewis acid, the Lewis acid being present in a molar concentration of 10 to 300 mM. The molar concentration of the Lewis acid after dissolution in water may be 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100mM, 1100mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, 200 mM, 210 mM, 220 mM, 230 mM, 240 mM, 250 mM, 260 mM, 270 mM, 280 mM, 290 mM, or 300 mM. In one embodiment, the Lewis acid is dissolved in water at a molar concentration of 100 mM.

The concentration of the lewis acid may also be expressed by molar equivalents, and in some embodiments, in the step of reacting the On-DNA compound and the carbonyl compound in an aqueous phase system containing a lewis acid, the molar equivalent of the lewis acid is 500 to 5000, and may be specifically 500 equivalents, 1000 equivalents, 1500 equivalents, 2000 equivalents, 2500 equivalents, 3000 equivalents, 3500 equivalents, 4000 equivalents, 4500 equivalents, or 5000 equivalents. In one embodiment, the molar equivalent of the lewis acid is 1000 equivalents.

In some embodiments, in the step of reacting the carbonyl compound with the On-DNA compound in an aqueous system containing a Lewis acid, the molar concentration of the On-DNA compound is 10 to 300. Mu.M. The molar concentration of the On-DNA compound after dissolution in the aqueous system may be 10. Mu.M, 20. Mu.M, 30. Mu.M, 40. Mu.M, 50. Mu.M, 60. Mu.M, 70. Mu.M, 80. Mu.M, 90. Mu.M, 100. Mu.M, 110. Mu.M, 120. Mu.M, 130. Mu.M, 140. Mu.M, 150. Mu.M, 160. Mu.M, 170. Mu.M, 180. Mu.M, 190. Mu.M, 200. Mu.M, 210. Mu.M, 220. Mu.M, 230. Mu.M, 240. Mu.M, 250. Mu.M, 260. Mu.M, 270. Mu.M, 280. Mu.M, 290. Mu.M or 300. Mu.M. In one embodiment, the On-DNA compound is present at a molar concentration of 100. Mu.M.

In some embodiments, in the step of reacting the On-DNA compound and the carbonyl compound in an aqueous system containing a Lewis acid, the molar concentration of the carbonyl compound in the aqueous system containing a Lewis acid is 10 to 300 mM. Specifically, the molar concentration of the carbonyl compound after dissolution in an aqueous system may be 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100mM, 1100mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, 200 mM, 210 mM, 220 mM, 230 mM, 240 mM, 250 mM, 260 mM, 270 mM, 280 mM, 290 mM, or 300 mM. In one embodiment, the carbonyl compound is dissolved in the aqueous system at a molar concentration of 200 mM.

The concentration of the carbonyl compound can also be expressed by molar equivalent, and in some embodiments, in the step of reacting the On-DNA compound and the carbonyl compound in an aqueous system containing Lewis acid, the molar equivalent of the carbonyl compound is 1000 to 10000. Specifically, the molar equivalent of the carbonyl compound is specifically 1000 equivalents, 2000 equivalents, 3000 equivalents, 4000 equivalents, 5000 equivalents, 6000 equivalents, 7000 equivalents, 8000 equivalents, 9000 equivalents, or 10000 equivalents. In a specific embodiment, the molar equivalent of the carbonyl compound is 5000 equivalents.

In some embodiments, in the step of reacting the On-DNA compound and the carbonyl compound in a water phase system containing Lewis acid, the reaction temperature is 20-100 ℃, and the reaction time is 1-48h. In one embodiment, the reaction temperature is 25 ℃, and in some embodiments, the reaction time is 3 hours, 24 hours, or 40 hours.

Based On the above examples, some examples react the On-DNA compound with a molar concentration of 10 to 300. Mu.M with 1000 to 10000 molar equivalents of the carbonyl compound under the action of 500 to 5000 molar equivalents of Lewis acid at 20 to 100 ℃ for 1 to 48 hours.

In some embodiments, the method of synthesizing the On-DNA compound comprises: will be provided with

And

the condensation reaction is carried out in a buffer solution containing a condensing agent.

In some embodiments, the method of synthesizing the On-DNA compound comprises: will be provided with

And

dehydrating and condensing, removing Fmoc in piperidine-containing aqueous solution, and reacting with

The condensation reaction is carried out in a buffer solution containing a condensing agent.

In some embodiments, the buffer solution has a pH of 7-14 or 8-12. In a specific embodiment, the pH of the buffer solution =9.4.

In some embodiments, the condensing agent is selected from at least one of HATU/DIEA, HBTU/NMM, HATU/NMM, TBTU/DIEA, TBTU/NMM, pyBOP/DIEA, DCC, DIC, edc.

In some embodiments, the buffer solution is selected from at least one of BBS, HEPES, MOPS, tricine, TEA, tris-hcl.

The embodiment of the invention provides a new method for synthesizing the On-DNA dihydroquinazolinone compound in the construction of the DNA coding compound library, and the diversity and novelty of the DNA coding compound library can be improved by using the cheap and easily obtained small molecular substrates with various reagent types, so that the drug-like property of the DNA coding compound library is greatly improved.

The practice of the present invention is illustrated by the following examples.

Example 1

In this example, an On-DNA anthranilamide compound 1 was synthesized by the synthetic route shown in FIG. 1, and the specific steps were as follows:

reacting the DNA with NH ₂ Dissolved in BBS buffer (250 mM, pH 9.4) to prepare DNA-NH at a concentration of 20 mM ₂ Subpackaging the solution into EP tubes; a DMA solution of the isatoic acid anhydride compound 9 at a concentration of 200 mM was added to the EP tube so that the concentration of the isatoic acid anhydride compound 9 in the mixed solution was 40 mM. DNA-NH ₂ Performing ring-opening reaction with the isatin acid anhydride compound 9 to prepare the corresponding On-DNA anthranilamide compound 1, performing ethanol precipitation after the reaction is finished, concentrating and drying, purifying by HPLC, freezing the obtained filtrate at-80 ℃ overnight, and freeze-drying by a freeze dryer to obtain the product.

Example 2

This example synthesizes the synthesis of an On-DNA anthranilamide compound 1' with reference to the synthetic route shown in FIG. 2: the method comprises the following specific steps:

reacting DNA-NH ₂ Dissolved in BBS buffer (250 mM, pH 9.4) to prepare DNA-NH at a concentration of 20 mM ₂ Subpackaging the solution into 96-well plate, reacting with Fmoc-amino acid-OH (Fmoc-AA-OH) by using HATU/DIEA as condensing agent to obtain corresponding On-DNA-AA-NH ₂ Fmoc, ethanol precipitation after completion of the reaction. After LCMS detection, 10% piperidine aqueous solution is added to remove Fmoc, ethanol precipitation is carried out after the reaction is finished, purification is carried out by HPLC after concentration and drying, the obtained filtrate is frozen at minus 80 ℃ overnight, and freeze-drying is carried out by a freeze dryer to obtain DNA-AA-NH ₂ 。

DNA-AA-NH ₂ The solution was dissolved in 250 mM BBS buffer solution at pH 9.4 to prepare a 20 mM solution, which was dispensed into 96-well plates, and 200 mM DMA solution of an isatoic anhydride compound was added to prepare a 40 mM solution. DNA-AA-NH ₂ And performing ring-opening reaction with the isatoic anhydride compound to obtain corresponding On-DNA anthranilamide 1', performing ethanol precipitation after the reaction is completed, concentrating and drying, purifying by HPLC, freezing the obtained filtrate at-80 ℃ overnight, and freeze-drying by a freeze dryer to obtain the product.

Example 3

In this example 3, an On- DNA dihydroquinazolinone compound 6 or 7 was synthesized according to the synthetic route shown in fig. 3, and the specific steps were as follows:

1 or 1' was dissolved in water to prepare an aqueous solution having a concentration of 100. Mu.M. To an EP tube were added 1 or 1' (2. Mu.L, 100. Mu.M aqueous solution), compound 2 (5. Mu.L, 200 mM methanol solution) or Compound 3 (5. Mu.L, 200 mM methanol solution), sbCl in that order ₃ (2. Mu.L, 100mM methanol solution) supplemented with 8. Mu.L of H ₂ O, 3. Mu.L MeOH, vortexed uniformly and reacted at 25 ℃ for 3h, 24h, or 40h.

Antimony removal: after the reaction was completed, a sodium diethyldithiocarbamate solution (20. Mu.L, 2000 nmol,100 mM aqueous solution, 10 eq.) was added to the EP tube, centrifuged to let the solution settle, vortexed and mixed, centrifuged again, reacted at 60 ℃ for 30 minutes in a metal bath to produce a large amount of precipitate, centrifuged at 13500 rpm for 10 minutes, and the supernatant was transferred to a new EP tube.

Ethanol precipitation: adding a 5M sodium chloride solution with the volume of 10% of that of the reaction solution into an EP tube, shaking and uniformly mixing, adding absolute ethyl alcohol with the volume 3 times that of the reaction solution at the temperature of-20 ℃, freezing at the temperature of-80 ℃ overnight, centrifuging at the rotating speed of 13500 rpm for 30 minutes, sucking and removing supernatant, dissolving a precipitate with water, and performing vacuum freeze-drying at the temperature of-80 ℃ to obtain a product.

FIG. 4 shows an embodiment of the reaction of the same On-DNA compound with different carbonyl compounds, and the mass spectrum data and conversion statistics of the products are shown in Table 1.

TABLE 1

FIG. 5 shows an embodiment of the reaction of the same On-DNA compound with different carbonyl compounds, and the mass spectrum data and the conversion statistics of the products are shown in Table 2.

TABLE 2

FIG. 6 shows a specific embodiment of the reaction of different on-DNA compounds with p-methoxybenzaldehyde, and the mass spectral data and conversion statistics for each product are shown in Table 3.

TABLE 3

The above embodiments and drawings are only representative of the present invention and are not intended to limit the scope of the present invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims (6)

1. A method for synthesizing an On-DNA dihydroquinazolinone compound is characterized by comprising the following steps:

providing an On-DNA compound shown as a general formula (I) and a carbonyl compound shown as a general formula (II);

（I）

（II）

reacting the On-DNA compound with the carbonyl compound in a water phase system containing Lewis acid to obtain an On-DNA dihydroquinazolinone compound shown as a general formula (III);

（III）

wherein n is 0 or 1;

r is selected from C ₁ ～C ₇ Alkyl or substituted C ₁ ～C ₇ Alkyl, said substituted C ₁ ～C ₇ The substituents of the alkyl groups being selected from C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ One of cycloalkyl, aryl methylene and substituted aryl;

R ¹ selected from hydrogen, C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ Cycloalkyl, alkoxy, trifluoromethyl, halogen, amino, hydroxyl, cyano, nitro, aldehyde group, ester group, amide group and aromatic group, wherein the substituent of the aromatic group is independently selected from hydrogen and C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ Cycloalkyl, halogen, alkoxyOne or more of trifluoromethyl, amino, aldehyde group, ester group, amide group and cyano;

R ³ and R ⁴ Each independently selected from hydrogen, C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ One of cycloalkyl, aryl methylene, aryl and substituted isatin, wherein the substituents on the aryl methylene, the aryl and the substituted isatin are respectively and independently selected from hydrogen and C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ One or more of cycloalkyl, halogen, hydroxyl, alkoxy, trifluoromethyl, amino, aldehyde group, boric acid group, carboxyl, ester group, amide group, nitro, phenyl and cyano; or, said R ³ And said R ⁴ Directly or indirectly linked to form a substituted isatin group, said substituted isatin group being:

，R ^a selected from hydrogen, C ₁ ～C ₆ One of alkyl, halogen, hydroxyl, alkoxy, trifluoromethoxy, trifluoromethyl, amino, aldehyde group, carboxyl, ester group, nitro and cyano, R ^b Selected from hydrogen, C ₁ ～C ₆ One of alkyl, aryl and benzyl;

represents DNA;

the water phase system consists of water and an organic reagent, the organic reagent is selected from at least one of acetonitrile, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, methanol, ethanol and isopropanol, the Lewis acid is selected from at least one of zinc halide, iron halide, zirconium halide, nickel halide, cobalt halide and antimony halide, and the volume ratio of the water to the organic reagent is (1-9): 3.

2. The synthetic method of claim 1 wherein the On-DNA dihydroquinazolinone compound has the structure of formula (III) ₁ ）、（III ₂ ) Or general formula (III) ₃ ) Shown in the specification:

（III ₁ ），

（III ₂ ），

（III ₃ ）；

wherein R is ² Selected from hydrogen, C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ One of cycloalkyl, aryl methylene and aryl, wherein substituents on aryl of the aryl methylene are independently selected from hydrogen and C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ One or more of cycloalkyl, halogen, alkoxy, trifluoromethyl, amino, aldehyde group, ester group, amide group and cyano, and the substituent of the aromatic group is independently selected from hydrogen and C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ One or more of cycloalkyl, halogen, hydroxyl, alkoxy, trifluoromethyl, amino, aldehyde group, boric acid group, carboxyl, ester group, amide group, nitro, cyano and phenyl;

R ³ and R ⁴ Each independently selected from C ₁ ～C ₆ Alkyl or C ₁ ～C ₆ A cycloalkyl group; or, said R ³ And said R ⁴ Directly or indirectly linked to form the substituted isatin group.

3. The method of synthesis according to claim 1, wherein in the step of reacting said On-DNA compound and said carbonyl compound in an aqueous system containing a lewis acid, the molar concentration of said lewis acid is 10 to 300 mM;

and in the step of reacting the On-DNA compound with the carbonyl compound in a water phase system containing Lewis acid, the reaction temperature is 20-100 ℃, and the reaction time is 1-48 hours.

4. The method of synthesis according to claim 1, wherein in the step of reacting the On-DNA compound and the carbonyl compound in an aqueous system containing a lewis acid, the molar concentration of the On-DNA compound in the aqueous system is 10 to 300 μ Μ;

in the step of reacting the On-DNA compound with the carbonyl compound in an aqueous system containing a Lewis acid, the molar concentration of the carbonyl compound in the aqueous system containing a Lewis acid is 10 to 300 mM.

5. The synthesis method according to any one of claims 1 to 3, characterized in that the On-DNA compound with a molar concentration of 10 to 300. Mu.M is reacted with 1000 to 10000 molar equivalents of the carbonyl compound under the action of 500 to 5000 molar equivalents of Lewis acid at 20 to 100 ℃ for 1 to 48 hours.

6. The method of synthesis according to any one of claims 1 to 4, wherein the method of synthesis of the On-DNA compound comprises: will be provided with

And with

Carrying out condensation reaction in a buffer solution containing a condensing agent; or

The method for synthesizing the On-DNA compound comprises the following steps: will be provided with

And

dehydrating and condensing, removing Fmoc in piperidine-containing aqueous solution, and reacting with

The condensation reaction is carried out in a buffer solution containing a condensing agent.

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