CN110804021A - Synthesis method of 2-aryl-4-aminoquinazoline - Google Patents
Synthesis method of 2-aryl-4-aminoquinazoline Download PDFInfo
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Abstract
The invention relates to a synthetic method of 2-aryl-4-amido quinazoline, which comprises the following steps: under the protection of inert gas, mixing 2-chloro-4-aminoquinazoline, arylboronic acid, a catalyst N-heterocyclic carbene-palladium complex, an alkaline substance and a reaction solvent to obtain a mixed solution, stirring the mixed solution at room temperature to 80 ℃ to react for 12-48 h to obtain a reaction solution, and carrying out post-treatment on the reaction solution to obtain the 2-aryl-4-aminoquinazoline. The invention discloses a synthetic method of 2-aryl-4-amino quinazoline, which has the following beneficial effects: 1. a novel catalytic system is developed, the catalyst is stable and easy to obtain, and the reaction condition is mild; 2. simple reaction operation, high product yield and high purity.
Description
Technical Field
The invention relates to a synthetic method of 2-aryl-4-amino quinazoline, belonging to the field of organic chemical synthesis.
Background
Quinazoline compounds are rich sources of bioactive molecular entities, have wide pharmacological activity, have potential pharmaceutical activity and have great effects in the biomedical field.
The 2-aryl-4-amino quinazoline compound can inhibit the proliferation of human T lymphocytes, and quinazoline molecules show the remarkable capacity of inhibiting the proliferation of the T lymphocytes in a selective mode, have obvious selective action on the T lymphocytes and low activity on other types of cells, so that the compound is a potential inhibitor for transplant rejection and has very important action and significance on organ transplant immunology. For example, 2- (3,4, 5-trimethoxyphenyl) -4- (p-toluidino) quinazoline, among others, is an ideal drug for suppressing immune cell rejection in clinical transplantation and also has the potential to combat psoriasis and other inflammatory diseases. However, the literature reports that the method for synthesizing the compound is quite few, the catalyst dosage is large, the reaction condition is harsh, the post-treatment is complicated, and the large-scale operation is not easy to realize.
Based on the above reasons, the search for a stable, easily available and efficient catalyst, the development of a simple and convenient method with a low catalytic amount, and the synthesis of 2-aryl-4-aminoquinazoline under a mild condition still have a great research and development space, which are the foundation and the motivation for the completion of the invention.
Disclosure of Invention
In order to overcome the defects in the synthesis of the 2-aryl-4-amino quinazoline, the invention provides a novel catalytic system, which realizes the synthesis of the 2-aryl-4-amino quinazoline by using a stable and easily-obtained catalyst with low dosage under mild conditions.
The technical scheme is as follows: a synthetic method of 2-aryl-4-amino quinazoline comprises the following steps:
under the protection of inert gas, mixing 2-chloro-4-aminoquinazoline, arylboronic acid, a catalyst N-heterocyclic carbene-palladium complex, an alkaline substance and a reaction solvent to obtain a mixed solution, stirring the mixed solution at room temperature to 80 ℃ to react for 12-48 h to obtain a reaction solution, and carrying out post-treatment on the reaction solution to obtain the 2-aryl-4-aminoquinazoline, wherein:
the mass ratio of the 2-chloro-4-aminoquinazoline, the arylboronic acid, the catalyst N-heterocyclic carbene-palladium complex and the alkaline substance is 1: (1-3): (0.001-0.1): (2-5);
the volume dosage of the reaction solvent is 5-10 mL/g based on the mass of the 2-chloro-4-aminoquinazoline.
Further, the 2-chloro-4-aminoquinazoline is selected from one of compounds represented by the following formulas (1a) to (1 g):
further, the arylboronic acid is selected from one of the compounds represented by the following formulas (2a) to (2 d):
further, the 2-aryl-4-aminoquinazoline is selected from one of compounds represented by the following formulas (3a) to (3 g):
further, the ratio of the amount of the 2-chloro-4-aminoquinazoline, the arylboronic acid, the catalyst azacyclo-carbene-palladium complex, and the basic substance is 1: (1.5-2): (0.05-0.1): (2-3).
Further, the basic substance is selected from any one of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium hydroxide, potassium phosphate, sodium phosphate, potassium bicarbonate, and sodium bicarbonate.
Further, the alkaline substance is potassium hydroxide.
Further, the reaction solvent is one or a mixture of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, toluene, N-dimethylacetamide, N-dimethylformamide, acetonitrile, ethanol, methanol, propanol, isopropanol, butanol, acetone and water in any proportion.
Further, the reaction solvent is ethanol or isopropanol.
Further, the catalyst N-heterocyclic carbene-palladium complex is selected from one of the following formulas (4) to (23):
further, the post-treatment of the reaction solution after the completion of the reaction may include any one or a combination of a plurality of treatment means selected from crystallization, recrystallization, column chromatography and extraction.
Further, the post-treatment may be performed as follows: after the reaction is finished, naturally cooling the reaction liquid to 20-30 ℃, removing the reaction solvent in the reaction liquid by using a rotary evaporator, and then carrying out conventional column chromatography separation and purification on the residue, wherein 300-400-mesh silica gel is used as a column filler, and the volume ratio of petroleum ether to ethyl acetate is (1-8): eluting with eluent of the mixed solution of 1, tracking and monitoring by TLC during column chromatography, collecting eluent containing target compounds, and evaporating to remove solvent to obtain 2-aryl-4-amino quinazoline.
Has the advantages that: the invention discloses a synthetic method of 2-aryl-4-amino quinazoline, which has the following beneficial effects:
1. a novel catalytic system is developed, the catalyst is stable and easy to obtain, and the reaction condition is mild;
2. has the advantages of simple reaction operation, high product yield, high purity and the like, provides a new synthesis strategy for the synthesis of the 2-aryl-4-amino quinazoline, and has good research value and industrial application prospect.
The specific implementation mode is as follows:
the invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. In the synthesis method, the room temperature is 25 ℃.
Example 1
A synthetic method of 2-aryl-4-amino quinazoline comprises the following steps:
under the protection of argon, mixing 2-chloro-4-aminoquinazoline, arylboronic acid, a catalyst N-heterocyclic carbene-palladium complex, an alkaline substance and a reaction solvent to obtain a mixed solution, stirring the mixed solution at room temperature for reacting for 48 hours to obtain a reaction solution, and carrying out post-treatment on the reaction solution to obtain the 2-aryl-4-aminoquinazoline, wherein the 2-aryl-4-aminoquinazoline is a white solid, the yield is 89%, and the liquid phase purity is 99%, and the method comprises the following steps:
the mass ratio of the 2-chloro-4-aminoquinazoline, the arylboronic acid, the catalyst N-heterocyclic carbene-palladium complex and the alkaline substance is 1: 1: 0.001: 2;
the volume dosage of the reaction solvent is 5mL/g based on the mass of the 2-chloro-4-aminoquinazoline.
Further, the 2-chloro-4-aminoquinazoline is a compound represented by the formula (1 a):
further, the arylboronic acid is a compound represented by the formula (2 a):
further, the 2-aryl-4-amino quinazoline is a compound represented by the formula (3 a):
further, the alkaline substance is potassium tert-butoxide.
Further, the reaction solvent is tetrahydrofuran.
Further, the reaction time of the method of the present invention is not particularly limited, and for example, the reaction time may be suitably determined by detecting the amount of the residual raw material by liquid chromatography, chromatography-mass spectrometry, or TLC, and is usually 12 to 48 hours.
Further, the catalyst N-heterocyclic carbene-palladium complex is a compound shown as a formula (4):
further, the post-treatment of the reaction solution after the completion of the reaction may include any one or a combination of a plurality of treatment means selected from crystallization, recrystallization, column chromatography and extraction.
Further, the post-treatment may be performed as follows: after the reaction is finished, naturally cooling the reaction liquid to 20 ℃, removing the reaction solvent in the reaction liquid by using a rotary evaporator, and then carrying out conventional column chromatography separation and purification on the residue, wherein 300-mesh silica gel is used as a column filler, and the volume ratio of petroleum ether to ethyl acetate is 1: eluting with eluent of the mixed solution of 1, tracking and monitoring by TLC during column chromatography, collecting eluent containing target compounds, and evaporating to remove solvent to obtain 2-aryl-4-amino quinazoline.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,CDCl3,TMS)δ8.00(d,J＝8.0Hz,1H),7.91-7.88(m,5H),7.80(t,J＝7.5Hz,1H),7.54-7.51(m,2H),7.43(t,J＝7.5Hz,2H),7.19(t,J＝7.5Hz,1H),4.00(s,6H),3.93(s,3H).
example 2
A synthetic method of 2-aryl-4-amino quinazoline comprises the following steps:
under the protection of inert gas (helium), mixing 2-chloro-4-aminoquinazoline, arylboronic acid, a catalyst N-heterocyclic carbene-palladium complex, an alkaline substance and a reaction solvent to obtain a mixed solution, stirring the mixed solution at 80 ℃ to react for 12 hours to obtain a reaction solution, carrying out post-treatment on the reaction solution to obtain the 2-aryl-4-aminoquinazoline, which is a white solid, with the yield of 88% and the liquid phase purity of 98%, wherein:
the mass ratio of the 2-chloro-4-aminoquinazoline, the arylboronic acid, the catalyst N-heterocyclic carbene-palladium complex and the alkaline substance is 1: 3: 0.1: 5;
the volume dosage of the reaction solvent is 10mL/g based on the mass of the 2-chloro-4-aminoquinazoline.
Further, the 2-chloro-4-aminoquinazoline is a compound represented by the formula (1 b):
further, the arylboronic acid is a compound represented by the formula (2 a):
the 2-aryl-4-amino quinazoline is a compound shown as a formula (3 b):
further, the alkaline substance is sodium tert-butoxide.
Further, the reaction solvent is 2-methyltetrahydrofuran.
Further, the reaction time of the method of the present invention is not particularly limited, and for example, the reaction time may be suitably determined by detecting the amount of the residual raw material by liquid chromatography, chromatography-mass spectrometry, or TLC, and is usually 12 to 48 hours.
Further, the catalyst N-heterocyclic carbene-palladium complex is a compound shown as a formula (5):
further, the post-treatment of the reaction solution after the completion of the reaction may include any one or a combination of a plurality of treatment means selected from crystallization, recrystallization, column chromatography and extraction.
Further, the post-treatment may be performed as follows: after the reaction is finished, naturally cooling the reaction liquid to 30 ℃, removing the reaction solvent in the reaction liquid by using a rotary evaporator, and then carrying out conventional column chromatography separation and purification on the residue, wherein 400-mesh silica gel is used as a column filler, and the volume ratio of petroleum ether to ethyl acetate is 8: eluting with eluent of the mixed solution of 1, tracking and monitoring by TLC during column chromatography, collecting eluent containing target compounds, and evaporating to remove solvent to obtain 2-aryl-4-amino quinazoline.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(400MHz,CDCl3,TMS)δ7.94(d,J＝8.4Hz,1H),7.89-7.87(m,3H),7.71(t,J＝7.6Hz,1H),7.40(t,J＝7.6Hz,1H),4.02(s,6H),3.92(s,3H),3.80-3.79(m,4H),1.85-1.82(m,6H).
example 3
A synthetic method of 2-aryl-4-amino quinazoline comprises the following steps:
under the protection of inert gas (neon), mixing 2-chloro-4-amino quinazoline, aryl boric acid, a catalyst N-heterocyclic carbene-palladium complex, an alkaline substance and a reaction solvent to obtain a mixed solution, stirring the mixed solution at 50 ℃ for 24 hours to obtain a reaction solution, carrying out post-treatment on the reaction solution to obtain the 2-aryl-4-amino quinazoline, which is a white solid, with the yield of 96% and the liquid phase purity of 99%, wherein:
the mass ratio of the 2-chloro-4-aminoquinazoline, the arylboronic acid, the catalyst N-heterocyclic carbene-palladium complex and the alkaline substance is 1: 2: 0.05: 3;
the volume dosage of the reaction solvent is 7.5mL/g based on the mass of the 2-chloro-4-aminoquinazoline.
Further, the 2-chloro-4-aminoquinazoline is a compound represented by the formula (1 c):
further, the arylboronic acid is a compound represented by formula (2 a:
further, the 2-aryl-4-amino quinazoline is a compound represented by the formula (3 c):
further, the alkaline substance is potassium hydroxide.
Further, the reaction solvent is dioxane.
Further, the reaction time of the method of the present invention is not particularly limited, and for example, the reaction time may be suitably determined by detecting the amount of the residual raw material by liquid chromatography, chromatography-mass spectrometry, or TLC, and is usually 12 to 48 hours.
Further, the catalyst N-heterocyclic carbene-palladium complex is a compound shown as a formula (6):
further, the post-treatment of the reaction solution after the completion of the reaction may include any one or a combination of a plurality of treatment means selected from crystallization, recrystallization, column chromatography and extraction.
Further, the post-treatment may be performed as follows: after the reaction is finished, naturally cooling the reaction liquid to 25 ℃, removing the reaction solvent in the reaction liquid by using a rotary evaporator, and then carrying out conventional column chromatography separation and purification on the residue, wherein 325-mesh silica gel is used as a column filler, and the volume ratio of petroleum ether to ethyl acetate is 4: eluting with eluent of the mixed solution of 1, tracking and monitoring by TLC during column chromatography, collecting eluent containing target compounds, and evaporating to remove solvent to obtain 2-aryl-4-amino quinazoline.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,CDCl3,TMS)δ7.92(t,J＝6.8Hz,2H),7.88(s,2H),7.69(t,J＝7.6Hz,1H),7.36(t,J＝7.6Hz,1H),4.01(s,6H),3.92(s,3H),3.82(q,J＝7.2Hz,4H),1.48(t,J＝7.2Hz,6H).
example 4
A synthetic method of 2-aryl-4-amino quinazoline comprises the following steps:
under the protection of inert gas (argon), mixing 2-chloro-4-aminoquinazoline, arylboronic acid, a catalyst N-heterocyclic carbene-palladium complex, an alkaline substance and a reaction solvent to obtain a mixed solution, stirring the mixed solution at 60 ℃ to react for 36 hours to obtain a reaction solution, carrying out post-treatment on the reaction solution to obtain the 2-aryl-4-aminoquinazoline, which is a white solid, has the yield of 99 percent and the liquid phase purity of 99 percent, wherein:
the mass ratio of the 2-chloro-4-aminoquinazoline, the arylboronic acid, the catalyst N-heterocyclic carbene-palladium complex and the alkaline substance is 1: 1.75: 0.05: 2.5;
the volume dosage of the reaction solvent is 8mL/g based on the mass of the 2-chloro-4-aminoquinazoline.
Further, the 2-chloro-4-aminoquinazoline is a compound represented by the formula (1 d):
further, the arylboronic acid is a compound represented by the formula (2 b):
further, the 2-aryl-4-amino quinazoline is a compound represented by the formula (3 d):
further, the alkaline substance is potassium hydroxide.
Further, the reaction solvent is ethanol.
Further, the reaction time of the method of the present invention is not particularly limited, and for example, the reaction time may be suitably determined by detecting the amount of the residual raw material by liquid chromatography, chromatography-mass spectrometry, or TLC, and is usually 12 to 48 hours.
Further, the catalyst N-heterocyclic carbene-palladium complex is a compound shown as a formula (7):
further, the post-treatment of the reaction solution after the completion of the reaction may include any one or a combination of a plurality of treatment means selected from crystallization, recrystallization, column chromatography and extraction.
Further, the post-treatment may be performed as follows: after the reaction is finished, naturally cooling the reaction liquid to 25 ℃, removing the reaction solvent in the reaction liquid by using a rotary evaporator, and then carrying out conventional column chromatography separation and purification on the residue, wherein 400-mesh silica gel is used as a column filler, and the volume ratio of petroleum ether to ethyl acetate is 7: eluting with eluent of the mixed solution of 1, tracking and monitoring by TLC during column chromatography, collecting eluent containing target compounds, and evaporating to remove solvent to obtain 2-aryl-4-amino quinazoline.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,CDCl3,TMS)δ8.32(d,J＝10.0Hz,1H),8.22(dq,J＝13.5,1.5Hz,1H),7.96(d,J＝9.5Hz,1H),7.87-7.83(m,3H),7.77(td,J＝10.5,1.5Hz,1H),7.56(br,1H),7.51-7.42(m,4H),7.21-7.13(m,2H).
example 5
A synthetic method of 2-aryl-4-amino quinazoline comprises the following steps:
under the protection of inert gas (krypton), mixing 2-chloro-4-aminoquinazoline, aryl boric acid, a catalyst N-heterocyclic carbene-palladium complex, an alkaline substance and a reaction solvent to obtain a mixed solution, stirring the mixed solution at 75 ℃ to react for 40 hours to obtain a reaction solution, carrying out post-treatment on the reaction solution to obtain the 2-aryl-4-aminoquinazoline, which is a white solid, with the yield of 96% and the liquid phase purity of 99%, wherein:
the mass ratio of the 2-chloro-4-aminoquinazoline, the arylboronic acid, the catalyst N-heterocyclic carbene-palladium complex and the alkaline substance is 1: 1.5: 0.08: 3;
the volume dosage of the reaction solvent is 6mL/g based on the mass of the 2-chloro-4-aminoquinazoline.
Further, the 2-chloro-4-aminoquinazoline is a compound represented by the formula (1 e):
further, the arylboronic acid is a compound represented by the formula (2 c):
further, the 2-aryl-4-amino quinazoline is a compound represented by the formula (3 e):
further, the alkaline substance is potassium hydroxide.
Further, the reaction solvent is isopropanol.
Further, the reaction time of the method of the present invention is not particularly limited, and for example, the reaction time may be suitably determined by detecting the amount of the residual raw material by liquid chromatography, chromatography-mass spectrometry, or TLC, and is usually 12 to 48 hours.
Further, the catalyst N-heterocyclic carbene-palladium complex is a compound shown as a formula (8):
further, the post-treatment of the reaction solution after the completion of the reaction may include any one or a combination of a plurality of treatment means selected from crystallization, recrystallization, column chromatography and extraction.
Further, the post-treatment may be performed as follows: after the reaction is finished, naturally cooling the reaction liquid to 30 ℃, removing the reaction solvent in the reaction liquid by using a rotary evaporator, and then carrying out conventional column chromatography separation and purification on the residue, wherein 300-mesh silica gel is used as a column filler, and the volume ratio of petroleum ether to ethyl acetate is 8: eluting with eluent of the mixed solution of 1, tracking and monitoring by TLC during column chromatography, collecting eluent containing target compounds, and evaporating to remove solvent to obtain 2-aryl-4-amino quinazoline.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,CDCl3,TMS)δ8.55(d,J＝6.5Hz,2H),8.00(d,J＝8.5Hz,1H),7.91-7.87(m,3H),7.80(t,J＝7.5Hz,1H),7.54-7.46(m,7H),7.20(t,J＝7.5Hz,1H).
example 6
A synthetic method of 2-aryl-4-amino quinazoline comprises the following steps:
under the protection of inert gas (xenon), mixing 2-chloro-4-aminoquinazoline, arylboronic acid, a catalyst N-heterocyclic carbene-palladium complex, an alkaline substance and a reaction solvent to obtain a mixed solution, stirring the mixed solution at 30 ℃ for reaction for 24 hours to obtain a reaction solution, carrying out post-treatment on the reaction solution to obtain the 2-aryl-4-aminoquinazoline, which is a white solid, has the yield of 86% and the liquid phase purity of 98%, wherein:
the mass ratio of the 2-chloro-4-aminoquinazoline, the arylboronic acid, the catalyst N-heterocyclic carbene-palladium complex and the alkaline substance is 1: 1: 0.1: 2;
the volume dosage of the reaction solvent is 5mL/g based on the mass of the 2-chloro-4-aminoquinazoline.
Further, the 2-chloro-4-aminoquinazoline is a compound represented by the formula (1 f):
further, the arylboronic acid is a compound represented by the formula (2 d):
further, the 2-aryl-4-amino quinazoline is a compound represented by the formula (3 f):
further, the alkaline substance is potassium tert-butoxide.
Further, the reaction solvent is toluene.
Further, the reaction time of the method of the present invention is not particularly limited, and for example, the reaction time may be suitably determined by detecting the amount of the residual raw material by liquid chromatography, chromatography-mass spectrometry, or TLC, and is usually 12 to 48 hours.
Further, the catalyst N-heterocyclic carbene-palladium complex is a compound shown as a formula (9):
further, the post-treatment of the reaction solution after the completion of the reaction may include any one or a combination of a plurality of treatment means selected from crystallization, recrystallization, column chromatography and extraction.
Further, the post-treatment may be performed as follows: after the reaction is finished, naturally cooling the reaction liquid to 30 ℃, removing the reaction solvent in the reaction liquid by using a rotary evaporator, and then carrying out conventional column chromatography separation and purification on the residue, wherein 400-mesh silica gel is used as a column filler, and the volume ratio of petroleum ether to ethyl acetate is 4: eluting with eluent of the mixed solution of 1, tracking and monitoring by TLC during column chromatography, collecting eluent containing target compounds, and evaporating to remove solvent to obtain 2-aryl-4-amino quinazoline.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(400MHz,CDCl3,TMS)δ7.93(d,J＝8.0Hz,1H),7.86-7.84(m,1H),7.77-7.70(m,2H),7.46-7.25(m,9H),5.99(br,1H),4.92(d,J＝5.6Hz,2H),2.56(s,3H).
example 7
A synthetic method of 2-aryl-4-amino quinazoline comprises the following steps:
under the protection of argon, mixing 2-chloro-4-aminoquinazoline, arylboronic acid, a catalyst N-heterocyclic carbene-palladium complex, an alkaline substance and a reaction solvent to obtain a mixed solution, stirring the mixed solution at room temperature for reacting for 48 hours to obtain a reaction solution, and carrying out post-treatment on the reaction solution to obtain the 2-aryl-4-aminoquinazoline, wherein the 2-aryl-4-aminoquinazoline is a white solid, the yield is 82%, and the liquid phase purity is 99%, and the method comprises the following steps:
the mass ratio of the 2-chloro-4-aminoquinazoline, the arylboronic acid, the catalyst N-heterocyclic carbene-palladium complex and the alkaline substance is 1: 3: 0.001: 5;
the volume dosage of the reaction solvent is 10mL/g based on the mass of the 2-chloro-4-aminoquinazoline.
Further, the 2-chloro-4-aminoquinazoline is a compound represented by the formula (1 g):
further, the arylboronic acid is a compound represented by the formula (2 c):
further, the 2-aryl-4-aminoquinazoline is a compound represented by the formula (3 g):
further, the alkaline substance is potassium carbonate.
Further, the reaction solvent is N, N-dimethylacetamide.
Further, the reaction time of the method of the present invention is not particularly limited, and for example, the reaction time may be suitably determined by detecting the amount of the residual raw material by liquid chromatography, chromatography-mass spectrometry, or TLC, and is usually 12 to 48 hours.
Further, the catalyst N-heterocyclic carbene-palladium complex is a compound shown as a formula (10):
further, the post-treatment of the reaction solution after the completion of the reaction may include any one or a combination of a plurality of treatment means selected from crystallization, recrystallization, column chromatography and extraction.
Further, the post-treatment may be performed as follows: after the reaction is finished, naturally cooling the reaction liquid to 30 ℃, removing the reaction solvent in the reaction liquid by using a rotary evaporator, and then carrying out conventional column chromatography separation and purification on the residue, wherein 400-mesh silica gel is used as a column filler, and the volume ratio of petroleum ether to ethyl acetate is 8: eluting with eluent of the mixed solution of 1, tracking and monitoring by TLC during column chromatography, collecting eluent containing target compounds, and evaporating to remove solvent to obtain 2-aryl-4-amino quinazoline.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,CDCl3,TMS)δ8.56(dd,J＝7.2,1.6Hz,2H),7.97(d,J＝8.4Hz,1H),7.94(d,J＝8.4Hz,1H),7.69(t,J＝7.6Hz,1H),7.50-7.40(m,7H),7.36-7.28(m,2H),5.07(s,2H),3.38(s,3H).
examples 8 to 17
The same as example 1, except for the basic substance, is as shown in the following table:
examples 18 to 29
The reaction was carried out in the same manner as in example 2, except that the reaction solvent was different, as shown in the following table:
examples 30 to 42
The catalyst was substantially the same as example 3, except that the azacyclo-carbene-palladium complex was different, as shown in the following table:
comparative example
2-chloro-4- (p-toluidino) quinazoline of the formula (1a) (3.76g,0.014mol), ethylene glycol dimethyl ether-water (1L/120mL), 3,4, 5-trimethoxyphenylboronic acid of the formula (2a) (2.714g,0.014mol) and sodium carbonate (3.6g) were treated under argon for 15 minutes. Further adding Pd (dppf) Cl2(0.84g), the mixture was refluxed overnight. After the reaction was completed, the mixture was cooled to room temperature, and methylene chloride CH was added2Cl2(1L) and H2O (500 mL). The organic phase was separated off and the aqueous phase was extracted with dichloromethane (2X500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure and the crude product was purified by recrystallization from methanol to give the pure product of formula (3a) (3.15g, 56%).
The results reported in the literature show that the reaction temperature is high, the solvent dosage is large, and the reaction yield is low; the solvent used for the treatment after the reaction has high toxicity and serious harm to the environment. The post-reaction treatment is complex and needs to combine the steps of extraction, drying and the like.
The embodiments of the present invention have been described in detail. However, the present invention is not limited to the above-described embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the spirit of the present invention.
Claims (10)
1. A synthetic method of 2-aryl-4-amino quinazoline is characterized by comprising the following steps:
under the protection of inert gas, mixing 2-chloro-4-aminoquinazoline, arylboronic acid, a catalyst N-heterocyclic carbene-palladium complex, an alkaline substance and a reaction solvent to obtain a mixed solution, stirring the mixed solution at room temperature to 80 ℃ to react for 12-48 h to obtain a reaction solution, and carrying out post-treatment on the reaction solution to obtain the 2-aryl-4-aminoquinazoline, wherein:
the mass ratio of the 2-chloro-4-aminoquinazoline, the arylboronic acid, the catalyst N-heterocyclic carbene-palladium complex and the alkaline substance is 1: (1-3): (0.001-0.1): (2-5);
the volume dosage of the reaction solvent is 5-10 mL/g based on the mass of the 2-chloro-4-aminoquinazoline.
2. The method for synthesizing a 2-aryl-4-aminoquinazoline according to claim 1, wherein the 2-chloro-4-aminoquinazoline is selected from one of compounds represented by the following formulae (1a) to (1 g):
3. the method for synthesizing a 2-aryl-4-aminoquinazoline according to claim 1, wherein the arylboronic acid is selected from one of compounds represented by the following formulae (2a) to (2 d):
4. the method for synthesizing a 2-aryl-4-aminoquinazoline according to claim 1, wherein the 2-aryl-4-aminoquinazoline is selected from one of compounds represented by the following formulae (3a) to (3 g):
5. the method for synthesizing 2-aryl-4-aminoquinazoline according to claim 1, wherein the ratio of the amount of the 2-chloro-4-aminoquinazoline, the arylboronic acid, the catalyst azacyclo-carbene-palladium complex, and the alkaline substance is 1: (1.5-2): (0.05-0.1): (2-3).
6. The method for synthesizing 2-aryl-4-aminoquinazoline as claimed in claim 1, wherein said basic substance is selected from any one of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium hydroxide, potassium phosphate, sodium phosphate, potassium bicarbonate, sodium bicarbonate, preferably potassium hydroxide.
7. The method for synthesizing 2-aryl-4-aminoquinazoline according to claim 1, wherein the reaction solvent is one or a mixture of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, toluene, N-dimethylacetamide, N-dimethylformamide, acetonitrile, ethanol, methanol, propanol, isopropanol, butanol, acetone and water, preferably ethanol or isopropanol.
8. The method of claim 1, wherein the catalyst azacyclocarbene-palladium complex is selected from one of the following formulas (4) to (23):
9. the method for synthesizing 2-aryl-4-aminoquinazoline as claimed in claim 1, wherein the post-treatment of the reaction solution after the reaction is completed comprises any one treatment means or combination of a plurality of treatment means selected from crystallization, recrystallization, column chromatography and extraction.
10. A process for the synthesis of 2-aryl-4-aminoquinazoline as claimed in claim 1, which is worked up as follows: after the reaction is finished, naturally cooling the reaction liquid to 20-30 ℃, removing the reaction solvent in the reaction liquid by using a rotary evaporator, and then carrying out conventional column chromatography separation and purification on the residue, wherein 300-400-mesh silica gel is used as a column filler, and the volume ratio of petroleum ether to ethyl acetate is (1-8): eluting with eluent of the mixed solution of 1, tracking and monitoring by TLC during column chromatography, collecting eluent containing target compounds, and evaporating to remove solvent to obtain 2-aryl-4-amino quinazoline.
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