CN113549020B - Quinazoline derivatives, their preparation and use - Google Patents
Quinazoline derivatives, their preparation and use Download PDFInfo
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Abstract
The invention belongs to the field of organic synthesis, and particularly relates to a quinazoline derivative, and preparation and application thereof. The invention provides a synthetic method of a quinazoline derivative with more step economy, high atom economy, convenient post-treatment and high efficiency, the raw materials are cheap and easy to obtain, the conditions are simple and mild, the atom economy is high, the yield is excellent, and the method also has the advantages of wide substrate range and the like, the catalyst can be recycled and utilized in the amplification reaction, the catalytic activity is not obviously reduced, and a very green synthetic method is provided for the high-efficiency construction of a quinazoline framework; the quinazoline derivative has potential antibacterial activity.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a quinazoline derivative, and preparation and application thereof.
Background
Quinazoline derivatives are a class of nitrogen-containing heterocyclic compounds with important biological activities, widely occurring in natural products and bioactive molecules, such as the anti-cancer drugs Gefitinib and Erlotinib containing quinazoline backbone, which have been approved for the treatment of non-small cell lung cancer (NSCLC), (angelw chem. Int. Ed.2012,51, 8960) and human adenosine A3 receptor antagonist I, which have been successfully used in therapeutics. (Acc. Chem. Res.2015,48, 1832) therefore, there are many reports of strategies for constructing quinazoline compounds.
Although there have been several reports on the effective synthesis of the above compounds, these methods have disadvantages of requiring various additives, using expensive metal catalysts, complicated post-reaction treatment, and being incapable of recycling the catalysts, and are very inefficient in terms of step economy and atom economy. In the compounds, the synthesis efficiency is the most important part, and in addition, the aspects of simple operation, safety, economy, environmental protection and the like also need to be comprehensively considered, so that the requirement of a green organic synthesis concept is met.
Therefore, under mild conditions, starting from simple and easily available substrates, the method for efficiently constructing the novel quinazoline compound by the one-pot method is very attractive, does not use expensive metal catalysts in the synthesis process, is simple in post-reaction treatment, can recycle the catalysts, and has very important significance.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a quinazoline derivative and preparation and application thereof, the quinazoline derivative is constructed by simple raw materials in one step, the reaction condition is mild, the environment is friendly, the operation is simple, in addition, in the amplification amount of the reaction, the catalyst can be recycled, the obvious reduction of the catalytic activity is not found, a green synthesis method is provided for the efficient construction of a quinazoline framework, and the quinazoline derivative has the characteristic of antibacterial activity.
In a first aspect of the present invention, there is provided a quinazoline derivative having a structural formula as shown in formula (IV):
wherein R1 is selected from C1-C6 alkyl or C6-C18 aryl;
r2 is selected from C1-C6 alkyl or C6-C18 aryl;
r3 is selected from hydrogen, methyl, alkoxy, nitro or halogen.
Preferably, R3 is selected from hydrogen, methyl, methoxy, nitro, fluoro, chloro or bromo.
Further, when R1 is C6-C18 aryl, the C6-C18 aryl is selected from phenyl, thienyl, benzotetrahydrofuranyl, substituted phenyl, substituted thienyl or substituted benzotetrahydrofuranyl, and the substituents of the substituted phenyl, substituted thienyl and substituted benzotetrahydrofuranyl are each independently selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 fluoroalkyl, halogen or acetamido.
Further, C6 alkyl is straight chain alkyl or cycloalkyl.
Preferably, R1 is selected from cyclohexyl, thienyl, benzotetrahydrofuranyl or substituted phenyl, wherein the substituents on the substituted phenyl are selected from hydrogen, n-propyl, methoxy, methyl, acetylamino, trifluoromethyl, phenyl, nitro, cyano, fluoro, chloro or bromo.
Further, when R2 is C6-C18 aryl, the C6-C18 aryl is selected from phenyl, benzopyrrole, substituted phenyl or substituted benzopyrrole, and the substituents of the substituted phenyl and the substituted benzopyrrole are respectively and independently selected from C1-C5 alkyl, C1-C5 alkoxy, halogen or C1-C5 fluoroalkyl.
Preferably, R2 is selected from n-butyl, tryptamine or substituted phenyl, wherein the substituents on the substituted phenyl are selected from hydrogen, methyl, methoxy, ester, nitro, trifluoromethyl, fluoro, chloro or bromo.
A second aspect of the present invention provides a method for producing the above quinazoline derivative, comprising the steps of: reacting compounds of formula (I), formula (II) and formula (III) in an organic solvent under the action of a metal salt catalyst to obtain the quinazoline derivative; wherein the general formulas of the compounds of formula (I), formula (II) and formula (III) are respectively as follows:
the reaction route is as follows:
wherein R1 is selected from C1-C6 alkyl or C6-C18 aryl;
r2 is selected from C1-C6 alkyl or C6-C18 aryl;
r3 is selected from hydrogen, methyl, alkoxy, nitro or halogen.
Further, when R1 is C6-C18 aryl, the C6-C18 aryl is selected from phenyl, thienyl, benzotetrahydrofuranyl, substituted phenyl, substituted thienyl or substituted benzotetrahydrofuranyl, and the substituents of the substituted phenyl, substituted thienyl and substituted benzotetrahydrofuranyl are each independently selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 fluoroalkyl, halogen or acetamido.
Preferably, the compound of formula (I) is selected from 4-methylbenzenesulfonyl azide (I-1), benzenesulfonyl azide (I-2), 4-methoxybenzenesulfonyl azide (I-3), 4-fluorobenzenesulfonyl azide (I-4), 4-chlorobenzenesulfonyl azide (I-5), 4-bromobenzenesulfonyl azide (I-6), 4-trifluoromethylbenzenesulfonyl azide (I-7), 4-acetamidobenzenesulfonyl azide (I-8), 5-tetrahydrofuranesulfonyl azide (I-9), 2-thienylsulfonyl azide (I-10), cyclohexylsulfonyl azide (I-11) or n-propylsulfonyl azide (I-12). The specific structural formula of the compound of formula (I) corresponding to each number is as follows:
further, when R2 is C6-C18 aryl, the C6-C18 aryl is selected from phenyl, benzopyrrole, substituted phenyl or substituted benzopyrrole, and the substituents of the substituted phenyl and the substituted benzopyrrole are respectively and independently selected from C1-C5 alkyl, C1-C5 alkoxy, halogen or C1-C5 fluoroalkyl.
Preferably, the compound of formula (II) is selected from aniline (II-1), 4-methylaniline (II-2), 4-methoxyaniline (II-3), 4-fluoroaniline (II-4), 4-chloroaniline (II-5), 4-bromoaniline (II-6), 4-trifluoromethylaniline (II-7), 4-esteraniline (II-8), 4-nitroaniline (II-9), 2-methylaniline (II-10), 2-methoxyaniline (II-11), 2-chloroaniline (II-12), 2-bromoaniline (II-13), 2, 6-dimethylaniline (II-14), N-methylindol-5-amine (II-15), tryptamine (II-16) or N-butylamine (II-17). The specific structural formula of the compound of formula (II) corresponding to each number is as follows:
preferably, the compound of formula (III) is selected from the group consisting of o-cyanophenylisonitrile (III-1), 3-methyl-o-cyanophenylisonitrile (III-2), 3-methoxy-o-cyanophenylisonitrile (III-3), 3, 4-dimethoxy-o-cyanophenylisonitrile (III-4), 3-fluoro-o-cyanophenylisonitrile (III-5), 3-chloro-o-cyanophenylisonitrile (III-6), 3-bromo-o-cyanophenylisonitrile (III-7) and 3-nitro-o-cyanophenylisonitrile (III-8). The specific structural formula of the compound of formula (III) corresponding to each number is as follows:
preferably, the quinazoline derivative represented by the formula (IV) has a structural formula represented by any one of the formulae (IV-1) to (IV-35):
in the above structural formula, ts represents a p-toluenesulfonyl group.
Further, the metal salt catalyst is cobalt acetylacetonate (Co (acac) 3 ) One or more of cobalt chloride and cobaltous oxalate, preferably Co (acac) 3 。
Further, the molar ratio of the compound of formula (I), formula (II) and formula (III) to the metal salt catalyst is 1.0-1.5:1.0:1.0-1.2:0.025-0.075, preferably 1.5:1.0:1.2:0.05.
further, the organic solvent is selected from one or more of acetonitrile, 1, 4-dioxane, N-dimethylformamide and toluene.
Further, the reaction temperature is 40-100 ℃, preferably 80 ℃.
Further, the reaction time is 6-12h, and preferably 12h.
Further, the reaction was carried out in an air atmosphere.
Concretely, the raw materials are sulfonyl azide, aniline and o-cyanophenyl isonitrile, and the catalyst is Co (acac) 3 The reaction of (IV) in the preparation process of the quinazoline derivative of the present invention is as follows:
first, co (acac) 3 And the metal cobalt complex A is obtained by rapid ligand exchange with isonitrile. And reacting the metal complex A with sulfonyl azide to obtain a complex B. Removing N from complex B 2 Then obtaining the carbodiimide intermediate C. Then aniline is used for nucleophilic attack on C to obtain E, and intramolecular amino is used for nucleophilic attack cyclization on cyano to obtain the quinazoline compound 4a.
The third aspect of the invention provides the use of the above quinazoline derivatives in the manufacture of a medicament with antibacterial activity.
By the scheme, the invention at least has the following advantages:
the quinazoline derivative is prepared by using isonitrile, azide and an amine derivative as reaction raw materials through a one-pot method. Compared with the prior art, the invention provides a synthetic method of the quinazoline derivative, which has more step economy, high atom economy, convenient post-treatment and high efficiency. The method is constructed by utilizing simple raw materials in one step, has the advantages of cheap and easily obtained raw materials, simple and mild conditions, high atom economy, excellent yield which can reach 98 percent at most, wide substrate range and the like, can realize the recovery and utilization of the catalyst in the amplification reaction, does not show obvious reduction of the catalytic activity, and provides a very green synthetic method for the efficient construction of the quinazoline framework.
The invention provides a series of quinazoline derivatives with potential biological activity, wherein the quinazoline derivatives have potential antibacterial activity.
Detailed Description
The present invention is further described below with reference to specific examples so that those skilled in the art can better understand the present invention and can practice the present invention, but the examples are not intended to limit the present invention.
The following examples of the invention provide methods for the preparation of quinazoline derivatives of any one of the formulae (III-1) to (III-35) hereinbefore described. The numbering in the following materials corresponds to the numbering above.
Example 1: synthesis of Compound (IV-1)
1.1, 0.3mmol of p-toluenesulfonyl azide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of aniline (the compound corresponding to the accession number (II-1), 0.019 g), 0.24mmol of o-cyanophenylisocyanide (the compound corresponding to the accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction is finished, the reaction solution is subjected to vacuum evaporation and column chromatography separationAnd (5) performing separation (under the conditions of column chromatography separation, wherein the stationary phase is silica gel powder of 200-300 meshes, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change procedure (A: B) is 1), so as to obtain 0.0760g of a reaction product.
The above reaction product was characterized and the results were:
1 H NMR(400MHz,CDCl 3 )δ8.2(d,J＝8.0Hz,1H),7.7–7.5(m,6H),7.3–7.3(m,1H),7.2–7.1(m,5H),2.4(s,3H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 98%.
1.2, on the basis of 1.1, the weighed amount of p-methyl benzenesulfonyl azide is changed to 0.2mmol,0.0373g, and the yield of the product is 89%.
1.3, the weighed amount of p-methyl benzenesulfonyl azide is changed to 0.24mmol and 0.0448g on the basis of 1.1, and the product yield is 91 percent.
1.4, the weighed amount of the o-cyanophenyl isonitrile is changed to 0.2mmol and 0.0258g on the basis of 1.2, and the product yield is 62%.
1.5, the amount of o-cyanophenylisonitrile weighed was changed to 0.3mmol,0.0388g based on 1.2, and the product yield was 89%.
1.6, on the basis of 1.1, weighing Co (acac) 3 The amounts were changed to 0.005mmol and 0.015mmol, respectively, and the product yields were 75% and 80%, respectively.
1.7, adding Co (acac) on the basis of 1.4 3 The cobalt chloride and the cobaltous oxalate are respectively replaced, and the product yield is 50 percent and 49 percent respectively.
1.8, the reaction temperature is changed to 40 ℃ and 100 ℃ respectively on the basis of 2.0, and the product yield is 23 percent and 62 percent respectively.
1.9, the reaction time is changed to 6h and 12h on the basis of 1.1, and the product yield is 96 percent and 98 percent respectively.
Example 2: synthesis of Compound represented by (IV-2)
0.3mmol of benzenesulfonylazide (the compound corresponding to accession number (I-2), 0.055g, 0.2mmol of aniline (the compound corresponding to accession number (II-1), 0.019 g), and 0.24mmol of o-cyanophenylisocyanide (the compound corresponding to accession number (I-2))(III-1) corresponding Compound, 0.031 g), 0.01mmol Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase was 200 to 300 mesh silica gel powder, mobile phase was ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) was 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,CDCl 3 )δ10.12(s,1H),8.20(d,J＝8.0Hz,1H),7.69(d,J＝7.8Hz,2H),7.65–7.43(m,5H),7.39(t,J＝7.7Hz,2H),7.26(t,J＝7.7Hz,1H),7.23–7.01(m,3H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 98%.
Example 3: synthesis of the Compound represented by (IV-3)
0.3mmol of p-methoxybenzenesulfonylazide (the compound corresponding to accession No. (I-3), 0.064 g), 0.2mmol of aniline (the compound corresponding to accession No. (II-1), 0.019 g), 0.24mmol of o-cyanophenylisonitrile (the compound corresponding to accession No. (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase is 200 to 300 mesh silica gel powder, mobile phase is ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) is 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,CDCl 3 )δ10.41(s,1H),8.20(d,J＝8.0Hz,1H),7.62(d,J＝8.9Hz,2H),7.59–7.45(m,4H),7.29–7.23(m,1H),7.15(d,J＝6.9Hz,2H),7.10(d,J＝8.1Hz,1H),6.86(d,J＝8.9Hz,2H),3.82(s,3H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 95%.
Example 4: synthesis of the Compound represented by (IV-4)
0.3mmol of p-fluorobenzenesulfonylazide (the compound corresponding to the accession number (I-4), 0.060 g), 0.2mmol of aniline (the compound corresponding to the accession number (II-1), 0.019 g), 0.24mmol of o-cyanophenylisonitrile (the compound corresponding to the accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase is 200 to 300 mesh silica gel powder, mobile phase is ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) is 1.
The above reaction product was characterized and the results were:
1 H NMR(400MHz,CDCl 3 )δ10.39(s,1H),8.21(d,J＝7.7Hz,1H),7.75–7.64(m,2H),7.62–7.47(m,4H),7.29(d,J＝7.7Hz,1H),7.22–7.10(m,3H),7.06(t,J＝8.6Hz,2H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 97%.
Example 5: synthesis of the Compound represented by (IV-5)
0.3mmol of p-chlorobenzenesulfonylazide (the compound corresponding to the accession number (I-5), 0.065 g), 0.2mmol of aniline (the compound corresponding to the accession number (II-1), 0.019 g), 0.24mmol of o-cyanophenylisocyanide (the compound corresponding to the accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase was 200 to 300 mesh silica gel powder, mobile phase was ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) was 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,CDCl 3 )δ10.37(s,1H),8.21(d,J＝8.0Hz,1H),7.65–7.57(m,3H),7.57–7.48(m,3H),7.35(d,J＝8.6Hz,2H),7.29(d,J＝7.7Hz,1H),7.19–7.06(m,3H).
according to the characterization data, the prepared reaction product is a pure product (the purity is more than 95 percent); the product yield was calculated to be 98%.
Example 6: synthesis of the Compound represented by (IV-6)
0.3mmol of p-bromobenzenesulfonylazide (the compound corresponding to accession No. (I-6), 0.078 g), 0.2mmol of aniline (the compound corresponding to accession No. (II-1), 0.019 g), 0.24mmol of o-cyanophenylisocyanide (the compound corresponding to accession No. (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) is 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,CDCl 3 )δ10.43(s,1H),8.20(d,J＝8.0Hz,1H),7.61–7.48(m,8H),7.34–7.26(m,1H),7.19–7.07(m,3H).
according to the characterization data, the prepared reaction product is a pure product (the purity is more than 95 percent); the product yield was calculated to be 98%.
Example 7: synthesis of the Compound represented by (IV-7)
0.3mmol of p-trifluoromethylbenzenesulfonyl azide (the compound corresponding to No. (I-7), 0.075 g), 0.2mmol of aniline (the compound corresponding to No. (II-1), 0.019 g), 0.24mmol of o-cyanophenylisonitrile (the compound corresponding to No. (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) is 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ9.43(s,1H),8.22(d,J＝8.3Hz,1H),8.00(d,J＝8.0Hz,2H),7.76–7.52(m,7H)one-NH-is contained,7.38(d,J＝7.6Hz,2H),7.22(d,J＝8.4Hz,1H),7.15(t,J＝7.7Hz,1H).
according to the characterization data, the prepared reaction product is a pure product (the purity is more than 95 percent); the product yield was calculated to be 96%.
Example 8: synthesis of the Compound represented by (IV-8)
0.3mmol of p-acetamidobenzenesulfonyl azide (the compound corresponding to accession No. (I-8), 0.072 g), 0.2mmol of aniline (the compound corresponding to accession No. (II-1), 0.019 g), 0.24mmol of o-cyanophenylisonitrile (the compound corresponding to accession No. (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase is 200 to 300 mesh silica gel powder, mobile phase is ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) is 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ10.04(s,1H),9.37(s,1H),8.21(d,J＝8.3Hz,1H),7.80–7.46(m,9H),one-NH-is contained,7.35(d,J＝7.7Hz,2H),7.24(d,J＝8.5Hz,1H),7.14(t,J＝7.7Hz,1H),2.01(s,3H).
according to the characterization data, the prepared reaction product is a pure product (the purity is more than 95 percent); the product yield was calculated to be 75%.
Example 9: synthesis of the Compound represented by (IV-9)
0.3mmol of a benzotrifluoroalkylsulfonylazide (compound No. (I-9), 0.068 g), 0.2mmol of an aniline (compound No. (II-1), 0.019 g), 0.24mmol of an o-cyanophenylisonitrile (compound No. (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was addedAs a solvent, the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase is 200 to 300 mesh silica gel powder, mobile phase is ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) is 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,CDCl 3 )δ8.19(d,J＝8.0Hz,1H),7.66–7.40(m,6H),7.25(t,J＝7.4Hz,1H),7.21–7.13(m,2H),7.10(d,J＝8.1Hz,1H),6.72(d,J＝8.4Hz,1H),4.61(t,J＝8.8Hz,2H),3.17(t,J＝8.8Hz,2H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 96%.
Example 10: synthesis of the Compound represented by (IV-10)
0.3mmol of thienylsulfonyl azide (the compound corresponding to accession number (I-10), 0.057 g), 0.2mmol of aniline (the compound corresponding to accession number (II-1), 0.019 g), 0.24mmol of o-cyanophenylisocyanide (the compound corresponding to accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase was 200 to 300 mesh silica gel powder, mobile phase was ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) was 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ9.43(s,1H),8.25(d,J＝8.3Hz,1H),7.72(t,J＝7.7Hz,1H),7.67–7.46(m,6H)one-NH-is contained,7.42–7.30(m,3H),7.18(t,J＝7.6Hz,1H),6.91(t,J＝4.3Hz,1H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 96%.
Example 11: synthesis of the Compound represented by (IV-11)
0.3mmol of cyclohexylsulfonyl azide (compound corresponding to accession No. (I-11), 0.057 g), 0.2mmol of aniline (compound corresponding to accession No. (II-1), 0.019 g), 0.24mmol of o-cyanophenylisonitrile (compound corresponding to accession No. (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase is 200 to 300 mesh silica gel powder, mobile phase is ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) is 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,CDCl 3 )δ8.21(d,J＝8.0Hz,1H),7.66–7.44(m,4H),7.30–7.21(m,3H),7.05(d,J＝8.1Hz,1H),2.88–2.58(m,1H),2.07–1.99(m,2H),1.88–1.70(m,2H),1.64(d,J＝12.7Hz,1H),1.28–1.12(m,4H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 88%.
Example 12: synthesis of the Compound represented by (IV-12)
0.3mmol of n-propylsulfonyl azide (the compound corresponding to the accession number (I-12), 0.045 g), 0.2mmol of aniline (the compound corresponding to the accession number (II-1), 0.019 g), 0.24mmol of o-cyanophenylisocyanide (the compound corresponding to the accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction is finished, the reaction solution is subjected to vacuum evaporation and column chromatography separation (the column chromatography separation conditions are that the stationary phase is silica gel powder of 200-300 meshes, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A: B) is 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ9.40(s,1H),8.26(d,J＝8.2Hz,1H),7.71(t,J＝7.6Hz,1H),7.61(t,J＝7.5Hz,2H),7.54(d,J＝7.2Hz,1H),7.34(t,J＝8.6Hz,3H),7.18(t,J＝7.5Hz,1H),3.16–2.99(m,2H),1.57–1.43(m,2H),0.85(t,J＝7.4Hz,3H).
according to the characterization data, the prepared reaction product is a pure product (the purity is more than 95 percent); the product yield was calculated to be 70%.
Example 13: synthesis of the Compound represented by (IV-13)
0.3mmol of p-toluenesulfonyl azide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of p-methylaniline (the compound corresponding to the accession number (II-2), 0.021 g), 0.24mmol of o-cyanophenylisonitrile (the compound corresponding to the accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase was 200 to 300 mesh silica gel powder, mobile phase was ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) was 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,CDCl 3 )δ10.57(s,1H),8.18(d,J＝8.1Hz,1H),7.60(d,J＝8.1Hz,2H),7.57–7.49(m,J＝7.8,1.5Hz,1H),7.31(d,J＝7.9Hz,2H),7.26–7.16(m,3H),7.08(d,J＝8.1Hz,1H),7.01(d,J＝8.1Hz,2H),2.42(s,3H),2.36(s,3H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 97%.
Example 14: synthesis of the Compound represented by (IV-14)
0.3mmol of p-toluenesulfonylazide (compound corresponding to No. (I-1), 0.056 g), 0.2mmol of p-anisidine (compound corresponding to No. (II-3), 0.025 g), 0.24mmol of o-cyanophenylisonitrile (compound corresponding to No. III-1, 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction is finished, the reaction liquid is subjected to vacuum evaporation and column chromatography separation (the column chromatography separation condition is that the stationary phase is silica gel powder with 200-300 meshes and the mobile phase isFor ethyl acetate (a) and petroleum ether (B), the flow phase change procedure (a: B) was 1.
The above reaction product was characterized and the results were:
1 H NMR(400MHz,CDCl 3 )δ8.23(d,J＝8.0Hz,1H),7.68–7.55(m,3H),7.33–7.26(m,1H),7.23(d,J＝8.0Hz,2H),7.12(d,J＝8.1Hz,1H),7.10–7.03(m,4H),3.90(s,3H),2.40(s,3H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 94%.
Example 15: synthesis of the Compound represented by (IV-15)
0.3mmol of p-toluenesulfonyl azide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of p-fluoroaniline (the compound corresponding to the accession number (II-4), 0.022 g), 0.24mmol of o-cyanophenylisonitrile (the compound corresponding to the accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase is 200 to 300 mesh silica gel powder, mobile phase is ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) is 1.
The above reaction product was characterized and the results were:
1 H NMR(400MHz,CDCl 3 )δ8.16(d,J＝8.0Hz,1H),7.65–7.52(m,3H),7.31–7.26(m,1H),7.25–7.18(m,4H),7.18–7.03(m,3H),2.38(s,3H).
according to the characterization data, the prepared reaction product is a pure product (the purity is more than 95 percent); the product yield was calculated to be 90%.
Example 16: synthesis of the Compound represented by (IV-16)
0.3mmol of p-toluenesulfonyl azide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of p-chloroaniline (the compound corresponding to the accession number (II-5), 0.025 g), 0.24mmol of o-cyanophenylisonitrile (the compound corresponding to the accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase is 200 to 300 mesh silica gel powder, mobile phase is ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) is 1.
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ9.42(s,1H),8.22(d,J＝8.3Hz,1H),7.91–7.62(m,6H)one-NH-is contained,7.48–7.39(m,2H),7.25(d,J＝8.4Hz,1H),7.18(d,J＝7.8Hz,3H),2.29(s,3H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 86%.
Example 17: synthesis of the Compound represented by (IV-17)
0.3mmol of p-toluenesulfonyl azide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of p-bromoaniline (the compound corresponding to the accession number (II-6), 0.034 g), 0.24mmol of o-cyanophenylisonitrile (the compound corresponding to the accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase was 200 to 300 mesh silica gel powder, mobile phase was ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) was 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ9.43(s,1H),8.22(d,J＝8.3Hz,1H),8.02–7.57(m,6H)one-NH-is contained,7.37(d,J＝8.2Hz,2H),7.25(d,J＝8.4Hz,1H),7.18(d,J＝7.8Hz,3H),2.29(s,3H).
according to the characterization data, the prepared reaction product is a pure product (the purity is more than 95 percent); the product yield was calculated to be 88%.
Example 18: synthesis of the Compound represented by (IV-18)
0.3mmol of p-toluenesulfonyl azide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of p-trifluoromethylaniline (the compound corresponding to the accession number (II-7), 0.032 g), 0.24mmol of o-cyanophenylisocyanide (the compound corresponding to the accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) is 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ9.45(s,1H),8.25(d,J＝8.3Hz,1H),8.02(d,J＝8.1Hz,2H),7.88(s,1H),7.79–7.59(m,5H),7.29(d,J＝8.5Hz,1H),7.24–7.06(m,3H),2.29(s,3H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 60%.
Example 19: synthesis of the Compound represented by (IV-19)
0.3mmol of p-toluenesulfonyl azide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of p-esteranilide (the compound corresponding to the accession number (II-8), 0.033 g), 0.24mmol of o-cyanophenylisonitrile (the compound corresponding to the accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase was 200 to 300 mesh silica gel powder, mobile phase was ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) was 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ9.44(s,1H),8.28–8.14(m,3H),7.91–7.62(m,4H)one-NH-is contained,7.56(d,J＝8.1Hz,2H),7.26(d,J＝8.5Hz,1H),7.17(d,J＝7.9Hz,3H),4.41(q,J＝7.1Hz,2H),2.29(s,3H),1.37(t,J＝7.1Hz,3H).
according to the characterization data, the prepared reaction product is a pure product (the purity is more than 95 percent); the product yield was calculated to be 73%.
Example 20: synthesis of Compound represented by (IV-20)
0.3mmol of p-toluenesulfonyl azide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of p-nitroaniline (the compound corresponding to the accession number (II-9), 0.028 g), 0.24mmol of o-cyanophenylisonitrile (the compound corresponding to the accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase was 200 to 300 mesh silica gel powder, mobile phase was ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) was 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ9.49(s,1H),8.49(d,J＝8.5Hz,2H),8.23(d,J＝8.3Hz,1H),8.12–7.80(m,1H),7.80–7.64(m,5H),7.29(d,J＝8.4Hz,1H),7.24–7.07(m,3H),2.28(s,3H).
according to the characterization data, the prepared reaction product is a pure product (the purity is more than 95 percent); the product yield was calculated to be 52%.
Example 21: synthesis of Compound (IV-21)
0.3mmol of p-methylbenzenesulfonylazide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of o-methylbenzylamine (the compound corresponding to the accession number (II-10), 0.021 g), 0.24mmol of o-cyanophenylisocyanide (the compound corresponding to the accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction is finished, the reaction solution is subjected to vacuum evaporation and column chromatography separation (the column chromatography separation condition is that the stationary phase is silica gel powder with 200-300 meshes, and the mobile phase is ethyl acetate (A) and stoneOil ether (B), mobile phase transition procedure (A: B) 1), 0.0660g of reaction product are obtained.
The above reaction product was characterized and the results were:
1 H NMR(400MHz,CDCl 3 )δ10.67(s,1H),8.22(d,J＝7.8Hz,1H),7.62–7.54(m,3H),7.43–7.32(m,3H),7.30–7.25(m,1H),7.18(d,J＝8.1Hz,2H),7.14–7.10(m,1H),7.08–7.03(m,1H),2.37(s,3H),1.97(s,3H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 82%.
Example 22: synthesis of the Compound represented by (IV-22)
0.3mmol of p-methylbenzenesulfonylazide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of o-anisidine (the compound corresponding to the accession number (II-11), 0.025 g), 0.24mmol of o-cyanophenylisonitrile (the compound corresponding to the accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase is 200 to 300 mesh silica gel powder, mobile phase is ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) is 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,CDCl 3 )δ10.71(s,1H),8.23(d,J＝8.0Hz,1H),7.70–7.54(m,3H),7.52–7.45(m,1H),7.34–7.27(m,1H),7.22(d,J＝8.0Hz,2H),7.18–7.05(m,3H),7.01(d,J＝8.3Hz,1H),3.54(s,3H),2.39(s,3H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 95%.
Example 23: synthesis of the Compound represented by (IV-23)
0.3mmol of p-toluenesulfonylazide (the compound corresponding to the reference numeral (I-1), 0.056 g), 0.2mmol of o-chloroaniline (the compound corresponding to the reference numeral (II-12), 0.026 g), and 0.24mmol of o-cyano groupPhenylisonitrile (Compound No. (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase was 200 to 300 mesh silica gel powder, mobile phase was ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) was 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ9.51(s,1H),8.24(d,J＝8.3Hz,1H),8.01(s,1H),7.77(dd,J＝5.8,3.5Hz,1H),7.74–7.65(m,3H),7.65–7.62(m,3H),7.24(d,J＝8.4Hz,1H),7.18(d,J＝7.9Hz,3H),2.29(s,3H).
according to the characterization data, the prepared reaction product is a pure product (the purity is more than 95 percent); the product yield was calculated to be 82%.
Example 24: synthesis of the Compound represented by (IV-24)
0.3mmol of p-toluenesulfonyl azide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of o-bromoaniline (the compound corresponding to the accession number (II-13), 0.034 g), 0.24mmol of o-cyanophenylisonitrile (the compound corresponding to the accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) is 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ9.50(s,1H),8.24(d,J＝8.3Hz,1H),7.97(s,1H),7.91(d,J＝8.0Hz,1H),7.79–7.61(m,4H),7.61–7.49(m,2H),7.33–7.06(m,4H),2.29(s,3H).
according to the characterization data, the prepared reaction product is a pure product (the purity is more than 95 percent); the product yield was calculated to be 72%.
Example 25: synthesis of the Compound represented by (IV-25)
0.3mmol of p-toluenesulfonyl azide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of 2, 6-dimethylaniline (the compound corresponding to the accession number (II-14), 0.024 g), 0.24mmol of o-cyanophenylisocyanide (the compound corresponding to the accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase was 200 to 300 mesh silica gel powder, mobile phase was ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) was 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,CDCl 3 )δ10.71(s,1H),8.24(d,J＝7.7Hz,1H),7.59(d,J＝7.9Hz,3H),7.28(dd,J＝7.7,4.8Hz,2H),7.22–7.12(m,5H),2.37(s,3H),1.95(s,6H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 83%.
Example 26: synthesis of the Compound represented by (IV-26)
0.3mmol of p-toluenesulfonyl azide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of N-methylindol-5-amine (the compound corresponding to the accession number (II-15), 0.030 g), 0.24mmol of o-cyanophenylisocyanide (the compound corresponding to the accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase was 200 to 300 mesh silica gel powder, mobile phase was ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) was 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ9.37(s,1H),8.21(d,J＝8.3Hz,1H),7.67(dd,J＝15.0,8.0Hz,4H),7.58–7.40(m,3H)one-NH-is contained,7.22(d,J＝8.4Hz,1H),7.13(d,J＝7.9Hz,3H),7.02(d,J＝8.6Hz,1H),6.56(d,J＝3.3Hz,1H),3.86(s,3H),2.26(s,3H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 72%.
Example 27: synthesis of Compound represented by (IV-27)
0.3mmol of p-toluenesulfonylazide (compound corresponding to accession number (I-1), 0.056 g), 0.2mmol of tryptamine (compound corresponding to accession number (II-16), 0.032 g), 0.24mmol of o-cyanophenylisonitrile (compound corresponding to accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase is 200 to 300 mesh silica gel powder, mobile phase is ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) is 1.
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ10.82(s,1H),9.09(s,1H),8.97(s,1H),8.09(d,J＝8.3Hz,1H),7.94–7.81(m,3H),7.59(t,J＝7.7Hz,1H),7.30(d,J＝8.1Hz,1H),7.26–7.13(m,4H),7.10(t,J＝7.7Hz,1H),7.03(t,J＝7.5Hz,1H),6.90(t,J＝7.4Hz,1H),4.50(s,2H),3.02(t,J＝8.2Hz,2H),2.25(s,3H).
according to the characterization data, the prepared reaction product is a pure product (the purity is more than 95 percent); the product yield was calculated to be 81%.
Example 28: synthesis of the Compound represented by (IV-28)
0.3mmol of p-toluenesulfonyl azide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of n-butylamine (the compound corresponding to the accession number (II-17), 0.015 g), 0.24mmol of o-cyanophenylisonitrile (the compound corresponding to the accession number (III-1), 0.031 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the mixture was stirred at 80 deg.CThe reaction was carried out for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase is 200 to 300 mesh silica gel powder, mobile phase is ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) is 1.
The above reaction product was characterized and the results were:
1 H NMR(400MHz,CDCl 3 )δ10.67(s,1H),8.29(s,1H),7.84(d,J＝8.0Hz,2H),7.81–7.65(m,1H),7.53(t,J＝7.7Hz,1H),7.27(t,J＝8.2Hz,3H),7.07(d,J＝8.1Hz,1H),4.20(t,J＝7.6Hz,2H),2.41(s,3H),1.57(p,J＝7.7Hz,2H),1.31(h,J＝7.5Hz,2H),0.86(t,J＝7.3Hz,3H).
according to the characterization data, the prepared reaction product is a pure product (the purity is more than 95 percent); the product yield was calculated to be 77%.
Example 29: synthesis of the Compound represented by (IV-29)
0.3mmol of p-methylbenzenesulfonylazide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of aniline (the compound corresponding to the accession number (II-1), 0.019 g), 0.24mmol of 3-methyl-o-cyanophenylisocyanide (the compound corresponding to the accession number (III-2), 0.034 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase is 200 to 300 mesh silica gel powder, mobile phase is ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) is 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,CDCl 3 )δ8.05(d,J＝8.1Hz,1H),7.61–7.45(m,5H),7.16(dd,J＝16.9,7.6Hz,4H),7.07(d,J＝8.2Hz,1H),6.91(s,1H),2.43(s,3H),2.37(s,3H).
according to the characterization data, the prepared reaction product is a pure product (the purity is more than 95 percent); the product yield was calculated to be 88%.
Example 30: synthesis of Compound represented by (IV-30)
0.3mmol of p-toluenesulfonyl azide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of aniline (the compound corresponding to the accession number (II-1), 0.019 g), 0.24mmol of 3-methoxy-o-cyanophenylisocyanide (the compound corresponding to the accession number (III-3), 0.038 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase is 200 to 300 mesh silica gel powder, mobile phase is ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) is 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ9.13(s,1H),8.14(d,J＝9.1Hz,1H),7.62(dd,J＝15.8,7.7Hz,4H),7.54(t,J＝7.3Hz,1H),7.32(d,J＝7.8Hz,3H)one-NH-is contained,7.14(d,J＝7.8Hz,2H),6.77(dd,J＝9.1,2.6Hz,1H),6.63(s,1H),3.86(s,3H),2.26(s,3H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 84%.
Example 31: synthesis of the Compound represented by (IV-31)
0.3mmol of p-methylbenzenesulfonylazide (the compound corresponding to accession No. (I-1), 0.056 g), 0.2mmol of aniline (the compound corresponding to accession No. (II-1), 0.019 g), 0.24mmol of 3, 4-dimethoxyo-cyanophenylisocyanide (the compound corresponding to accession No. (III-4), 0.045 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase is 200 to 300 mesh silica gel powder, mobile phase is ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) is 1.
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ7.69(s,1H),7.68–7.48(m,5H),7.33(d,J＝7.6Hz,2H),7.15(d,J＝7.9Hz,2H),6.68(s,1H),3.90(s,3H),3.80(s,3H),2.28(s,3H).
according to the characterization data, the prepared reaction product is a pure product (the purity is more than 95 percent); the product yield was calculated to be 80%.
Example 32: synthesis of Compound represented by (IV-32)
0.3mmol of p-toluenesulfonyl azide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of aniline (the compound corresponding to the accession number (II-1), 0.019 g), 0.24mmol of 3-fluorophthalocyanophenyl isonitrile (the compound corresponding to the accession number (III-5), 0.035 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase was 200-300 mesh silica gel powder, mobile phase was ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) was 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ9.37(s,1H),8.29(dd,J＝9.2,6.0Hz,1H),7.81–7.43(m,6H)one-NH-is contained,7.33(d,J＝7.6Hz,2H),7.13(d,J＝7.9Hz,2H),7.02(td,J＝8.8,2.7Hz,1H),6.92(d,J＝10.0Hz,1H),2.24(s,3H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 71%.
Example 33: synthesis of Compound represented by (IV-33)
0.3mmol of p-toluenesulfonyl azide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of aniline (the compound corresponding to the accession number (II-1), 0.019 g), 0.24mmol of 3-chloro-o-cyanophenylisocyanide (the compound corresponding to the accession number (III-6), 0.039 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction is finished, the reaction liquid is subjected to vacuum evaporation and column chromatography separation (the column chromatography separation condition is that the stationary phase is silica gel powder with 200-300 meshes, and the mobile phase is ethyl acetate (A) and stoneOil ether (B), flow phase change procedure (a: B) 1.
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ9.47(s,1H),8.26(d,J＝8.8Hz,1H),7.96–7.44(m,6H)one-NH-is contained,7.38(d,J＝7.4Hz,2H),7.25(s,1H),7.23–7.11(m,3H),2.30(s,3H).
according to the characterization data, the prepared reaction product is a pure product (the purity is more than 95 percent); the product yield was calculated to be 78%.
Example 34: synthesis of the Compound represented by (IV-34)
0.3mmol of p-toluenesulfonylazide (compound corresponding to accession number (I-1), 0.056 g), 0.2mmol of aniline (compound corresponding to accession number (II-1), 0.019 g), 0.24mmol of 3-bromoo-cyanophenylisonitrile (compound corresponding to accession number (III-7), 0.049 g), 0.01mmol of Co (acac) 3 (0.00360 g) in a 20mL test tube reaction tube, 2mL toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase was 200-300 mesh silica gel powder, mobile phase was ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) was 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ9.49(s,1H),8.18(d,J＝8.8Hz,1H),7.92–7.50(m,6H)one-NH-is contained,7.47–7.35(m,3H),7.32(dd,J＝8.8,2.0Hz,1H),7.19(d,J＝7.9Hz,2H),2.30(s,3H).
according to the characterization data, the prepared reaction product is a pure product (the purity is more than 95 percent); the product yield was calculated to be 70%.
Example 35: synthesis of the Compound represented by (IV-35)
0.3mmol of p-toluenesulfonyl azide (the compound corresponding to the accession number (I-1), 0.056 g), 0.2mmol of aniline (the compound corresponding to the accession number (II-1), 0.019 g), 0.24mmol of 3-nitro-o-cyanophenylisocyanide (the compound corresponding to the accession number (III-8), 0.049 g), 0 were weighed.01mmol Co(acac) 3 (0.00420 g) in a 20mL test tube reaction tube, 2mL of toluene was added as a solvent, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction, the reaction solution was subjected to vacuum evaporation and column chromatography (column chromatography conditions: stationary phase was 200 to 300 mesh silica gel powder, mobile phase was ethyl acetate (a) and petroleum ether (B), mobile phase change procedure (a: B) was 1).
The above reaction product was characterized and the results were:
1 H NMR(400MHz,DMSO-d 6 )δ9.44(s,1H),8.52(s,1H),7.94–7.52(m,7H)one-NH-is contained,7.37(d,J＝7.6Hz,2H),7.16(d,J＝7.8Hz,3H),2.29(s,3H).
according to the characterization data, the prepared reaction product is pure (purity is more than 95%); the product yield was calculated to be 42%.
Detection example 1: biological activity assay
The present inventors selected 9 compounds prepared in the above examples and tested four fungi for antibacterial activity using MIC method according to the related references (bioorg.med.chem.lett.2013, 23, 4968;), and the results of the antibacterial activity of these different quinazoline derivatives against staphylococcus aureus (MSSA), staphylococcus aureus (MRSA), enterococcus faecalis (VSE) and enterococcus faecalis (VRE) are shown in table 1, and compared with oxacillin, vancomycin, erythromycin, tetracycline and clindamycin. The results showed that formulas IV-1 and IV-6 did not exhibit significant antibacterial activity against S.aureus or E.faecalis. The antibacterial activity of the compounds represented by the formulae IV-9, IV-16, IV-18 and IV-20 is remarkably increased. It is noted that the quinazoline compounds IV-26, IV-27, IV-30 did result in a significant increase in antibacterial activity due to the change in substituents.
TABLE 1 antimicrobial Activity (MIC, μ g/mL) test results for various compounds
The results show that the quinazoline derivative synthesized by the invention has the characteristic of antibacterial activity and can be prepared into antibacterial drugs.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Various other modifications and alterations will occur to those skilled in the art upon reading the foregoing description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications of the invention may be made without departing from the spirit or scope of the invention.
Claims (6)
1. A quinazoline derivative is characterized in that the structural formula is shown as a formula (IV):
wherein R1 is selected from C6-C18 aryl;
r2 is selected from C6-C18 aryl;
r3 is selected from hydrogen, methyl, nitro or halogen;
when R1 is C6-C18 aryl, the C6-C18 aryl is selected from benzotetrahydrofuranyl, substituted phenyl or substituted benzotetrahydrofuranyl, and the substituents of the substituted phenyl and the substituted benzotetrahydrofuranyl are respectively and independently selected from C1-C5 alkoxy, C1-C5 fluoroalkyl, halogen or acetamido;
when R2 is C6-C18 aryl, the C6-C18 aryl is selected from phenyl, benzopyrrole, substituted phenyl or substituted benzopyrrole, and the substituents of the substituted phenyl and the substituted benzopyrrole are respectively and independently selected from C1-C5 alkyl, C1-C5 alkoxy, halogen or C1-C5 fluoroalkyl.
2. A process for the preparation of a quinazoline derivative according to claim 1, comprising the steps of: reacting compounds of formula (I), formula (II) and formula (III) in an organic solvent at 40-100 ℃ under the action of a metal salt catalyst to obtain the quinazoline derivative; wherein the general formulas of the compounds of formula (I), formula (II) and formula (III) are respectively as follows:
wherein R1, R2 and R3 are as defined in claim 1;
the metal salt catalyst is one or more of cobalt acetylacetonate, cobalt chloride and cobaltous oxalate.
3. The method of claim 2, wherein the molar ratio of the compound of formula (I), formula (II), and formula (III) to the metal salt catalyst is from 1.0 to 1.5:1.0:1.0-1.2:0.025-0.075.
4. The method according to claim 2, wherein the organic solvent is one or more selected from the group consisting of acetonitrile, 1, 4-dioxane, N-dimethylformamide, and toluene.
5. The method of claim 2, wherein the reaction time is 6 to 12 hours.
6. Use of a quinazoline derivative according to claim 1 in the manufacture of a medicament with antibacterial activity.
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