Nothing Special   »   [go: up one dir, main page]

CN110606839B - A kind of green synthesis method of polysubstituted quinazoline derivatives - Google Patents

A kind of green synthesis method of polysubstituted quinazoline derivatives Download PDF

Info

Publication number
CN110606839B
CN110606839B CN201910944039.1A CN201910944039A CN110606839B CN 110606839 B CN110606839 B CN 110606839B CN 201910944039 A CN201910944039 A CN 201910944039A CN 110606839 B CN110606839 B CN 110606839B
Authority
CN
China
Prior art keywords
quinazoline
aminobenzophenone
quinolin
phenyl
phenylquinazoline
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201910944039.1A
Other languages
Chinese (zh)
Other versions
CN110606839A (en
Inventor
唐晓冬
梁恩
吴银容
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Southern Medical University
Original Assignee
Southern Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Southern Medical University filed Critical Southern Medical University
Priority to CN201910944039.1A priority Critical patent/CN110606839B/en
Publication of CN110606839A publication Critical patent/CN110606839A/en
Application granted granted Critical
Publication of CN110606839B publication Critical patent/CN110606839B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

本发明公开了一种多取代喹唑啉衍生物的绿色合成方法。包括：以式Ⅱ化合物和甲基芳香氮杂环化合物为原料，在醋酸铵存在条件下，以铜盐为催化剂，氧气为氧化剂，有机酸为活化剂，混合并反应，即可制得目标产物。本发明所述合成方法避免了复杂底物和强氧化剂的使用，反应原料简单易得、反应过程环境友好、底物适用性好、官能团容忍性好，在优选条件下，分离产率高。

Figure DDA0002223696350000011
The invention discloses a green synthesis method of polysubstituted quinazoline derivatives. Including: taking the compound of formula II and methyl aromatic nitrogen heterocyclic compound as raw materials, in the presence of ammonium acetate, using copper salt as catalyst, oxygen as oxidant, organic acid as activator, mixing and reacting to obtain the target product . The synthesis method of the present invention avoids the use of complex substrates and strong oxidants, and has simple and easy-to-obtain reaction raw materials, friendly reaction process, good substrate applicability, good functional group tolerance, and high separation yield under optimal conditions.
Figure DDA0002223696350000011

Description

Green synthesis method of polysubstituted quinazoline derivative
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a green synthesis method of a polysubstituted quinazoline derivative.
Background
Quinazoline derivatives are important components of nitrogen heterocyclic compounds, have wide biological activities, such as anticonvulsant activity, antibacterial activity, antidiabetic activity, anticancer activity, antihypertensive activity, anti-Alzheimer's disease and the like, and are important functional structures of a plurality of bioactive macromolecules and natural products. Because of the important application value of quinazoline derivatives, research on the synthesis methods thereof has been continuously conducted.
The synthetic methods reported to date are mainly: 1. carrying out Ullmann coupling reaction on aryl bromide and amidine compounds under the catalysis of copper; 2. oxidative coupling reaction of aniline derivatives with aldehydes or nitriles; 3. intramolecular cyclization of phenylamidine compounds (Wang, C.; Li, S.; Liu, H.; Jiang, Y.; Fu, H.J.J.Org.Chem.2010,75,7936, 7938; Han, B.; Yang, X.L.; Wang, C.; Bai, Y.W.; Pan, T.C.; Chen, X.; Yu, W.J.Org.Chem.2012,77,1136, 1142; Lv, Z.; Wang, B.; Hu Z.; Zhou, Y.; Yu U, W.Chang, J.Org.Chem.2016,81,9924, 9930).
However, the method still has some defects, such as the use of strong oxidant, limited range of reaction substrates, non-green reaction system, environmental pollution and the like. Therefore, the development of a new more green and efficient synthesis method of the quinazoline derivative has very important significance.
Disclosure of Invention
The invention aims to overcome the defects of narrow substrate application range, harsh reaction conditions, complicated reaction steps, need of using a strong oxidant, various side reactions, difficult product separation and the like in the conventional organic synthesis reaction of the polysubstituted quinazoline derivative, and provides a green synthesis method of the polysubstituted quinazoline derivative.
The above object of the present invention is achieved by the following scheme:
a green synthesis method of a polysubstituted quinazoline derivative is disclosed, wherein the structure of the polysubstituted quinazoline derivative is as shown in a formula I:
Figure BDA0002223696340000021
the preparation process comprises the following steps: taking a compound shown in a formula II and a methyl aromatic nitrogen heterocyclic compound as raw materials, mixing and reacting in an organic solvent in the presence of ammonium salt by taking copper salt as a catalyst, oxygen as an oxidant and organic acid as an activator to obtain a target product;
Figure BDA0002223696340000022
wherein R is hydrogen, halogen, C1～4Alkyl radical, C1～4Haloalkyl or C～4An alkoxy group; r1Is phenyl, substituted phenyl, benzyl or substituted benzyl; wherein the substituent in the substituted phenyl and the substituted benzyl is halogen and C1～4Alkyl radical, C1～4Haloalkyl, C～4Alkoxy, phenyl or benzyl; r2Is aromatic nitrogen heterocycle.
The mechanism of the above reaction: the methyl aromatic nitrogen heterocyclic compound is isomerized under an acidic condition (TFA) to generate an enamine intermediate, the enamine intermediate combines copper ions and oxygen to generate an oxygen radical intermediate, and a copper oxygen intermediate is generated after rearrangement; the o-carbonylamine raw material (the compound shown in the formula II) reacts with ammonium salt under acidic conditions to generate an imine intermediate, the free amino group of the imine intermediate reacts with a copper oxide intermediate, and intramolecular dehydration, reoxidation and cyclization are carried out to generate a target product.
The reaction can take place as long as the aromatic nitrogen heterocycle contains a methyl group.
Preferably, said R is hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl or trifluoroethyl; r1Is phenyl, substituted phenyl, benzyl or substituted benzyl; wherein the substituent in the substituted phenyl and the substituted benzyl is fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, phenyl or benzyl.
Preferably, the methyl aromatic nitrogen heterocyclic compound is substituted or unsubstituted quinoline, pyridine, thiazole, benzothiazole, pyrazine or pyrimidine.
Preferably, the copper salt is one or more of cupric chloride, copper trifluoromethanesulfonate, cupric bromide, cupric acetate, cupric nitrate, cuprous chloride, cuprous bromide or cuprous iodide, and the like.
Preferably, the organic acid is diphenyl phosphate, trifluoroacetic acid, p-toluenesulfonic acid or benzoic acid.
Preferably, the ammonium salt is an ammonium salt commonly used in the art; more preferably, the ammonium salt is ammonium chloride, ammonium acetate, ammonium iodide or the like.
Preferably, the reaction molar ratio of the compound shown in the formula II, the methyl aromatic nitrogen heterocyclic compound and the ammonium acetate is 1: 1.5-3.
More preferably, the reaction molar ratio of the compound of formula II, the methyl aromatic nitrogen heterocyclic compound and the ammonium acetate is 1:2: 2.
Preferably, the reaction molar ratio of the compound of formula II, the copper salt and the organic acid is 0.2-0.5: 0.5-1: 1.
More preferably, the molar ratio of the reaction of the compound of formula II, the copper salt and the organic acid is 0.2:0.5: 1.
Preferably, the organic solvent is N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide or toluene.
Preferably, the reaction temperature is 100-130 ℃; more preferably, the temperature of the reaction is 120 ℃.
Preferably, after the reaction is finished, adding a sodium hydroxide aqueous solution into the reaction system, extracting with ethyl acetate, collecting an organic phase, concentrating, and performing column chromatography separation to obtain a pure target product.
Preferably, the mobile phase of the column chromatography is petroleum ether and ethyl acetate in a volume ratio of 2-5: 1 for elution.
More preferably, the mobile phase is petroleum ether and ethyl acetate in a volume ratio of 5: 1.
Compared with the prior art, the invention has the following beneficial effects:
the invention relates to a green synthesis method of a polysubstituted quinazoline derivative, which takes a methyl aromatic nitrogen heterocyclic compound, ammonium acetate and a substituted or unsubstituted 2-aminobenzophenone compound (a compound shown in a formula II) as raw materials, takes copper salt as a catalyst, oxygen as an oxidant and organic acid as an activator, and reacts in an organic solvent by a one-pot method to obtain the polysubstituted quinazoline derivative.
The synthesis method avoids the use of complex substrates and strong oxidants, has the advantages of simple and easily-obtained reaction raw materials, environment-friendly reaction process, good substrate applicability, good functional group tolerance and high separation yield under the optimal condition.
Detailed Description
The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
Example 1 investigation of reaction conditions
2-aminobenzophenone, ammonium acetate and 2-methylquinoline are taken as reaction raw materials, and the influence of the types of adopted catalysts, solvents and organic acids on the reaction and the yield of the prepared reaction product under different conditions are researched.
The specific process is as follows: adding 0.3mmol of 2-aminobenzophenone, 0.6mmol of ammonium acetate, 0.6mmol of 2-methylquinoline and 2mL of organic solvent into a 25mL reaction tube, reacting at 120 ℃ under an oxygen environment for 24 hours, cooling to room temperature, adding an aqueous solution of sodium hydroxide, extracting for three times by using ethyl acetate, drying by using anhydrous magnesium sulfate, carrying out reduced pressure rotary evaporation to remove the solvent, and carrying out column chromatography separation and purification to obtain a product, wherein a column chromatography eluent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of (2-5): 1.
The specific reaction conditions are preferably as shown in Table 1.
TABLE 1 different reaction conditions and yields of products
Figure BDA0002223696340000041
As can be seen from table 1, when the organic acid is pivalic acid or glacial acetic acid, the yield of the reaction product is low; when the acid is any one of diphenyl phosphoric acid, trifluoroacetic acid, p-toluenesulfonic acid or benzoic acid, the yield of the reaction product is better; when the copper salt is any one of copper chloride, copper trifluoromethanesulfonate, copper bromide, copper acetate, copper nitrate, cuprous chloride, cuprous bromide or cuprous iodide, the yield of the reaction product is better; when only copper salt or organic acid is added, the reaction is not carried out, and the target product cannot be obtained; the reaction solvent has less influence on the reaction.
As a result of screening the above conditions, it is found that the optimum reaction condition is the condition in which the yield of the product is highest when the copper salt is copper chloride, the organic acid is trifluoroacetic acid, and the solvent is N, N-dimethylformamide.
Examples 2 to 21
The optimum conditions obtained by screening in the example 1 are used for replacing different reaction raw materials to carry out the reaction, and the specific process is as follows:
adding 0.3mmol of 2-aminobenzophenone compound, 0.6mmol of ammonium acetate, 0.6mmol of methyl aromatic nitrogen heterocyclic compound, 0.15mmol of trifluoroacetic acid, 0.06mmol of copper chloride and 2mL of N, N-dimethylformamide into a 25mL reaction tube, stirring and reacting for 24 hours at 120 ℃ in an oxygen environment, stopping heating and stirring, cooling to room temperature, adding an aqueous solution of sodium hydroxide, extracting for three times with ethyl acetate, drying with anhydrous magnesium sulfate, concentrating under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of (2-5): 1.
The kinds of the raw materials used and the yields of the products are shown in Table 2.
Table 2 types of starting materials and yields of products
Figure BDA0002223696340000051
Figure BDA0002223696340000061
Figure BDA0002223696340000071
Figure BDA0002223696340000081
The characterization data for the compounds of examples 2 to 21 are as follows:
example 2:1H NMR(400MHz,CDCl3)δ8.86(d,J＝8.6Hz,1H),8.43(dd,J＝17.6,8.5Hz,2H),8.34(d,J＝8.6Hz,1H),8.18(d,J＝8.4Hz,1H),7.94(t,J＝6.9Hz,3H),7.87(d,J＝7.4Hz,1H),7.76(t,J＝7.7Hz,1H),7.66–7.55(m,5H).13C NMR(100MHz,CDCl3)δ168.9,159.2,155.4,152.0,148.3,137.3,136.9,133.7,130.9,130.3,130.0,129.5,128.5,128.5,128.0,127.4,127.3,126.9,122.2,121.5.
example 3:1H NMR(400MHz,CDCl3)δ8.85(d,J＝8.5Hz,1H),8.44(dd,J＝18.6,8.4Hz,2H),8.35(d,J＝8.3Hz,1H),8.15(d,J＝8.1Hz,1H),7.96(s,3H),7.88(d,J＝7.7Hz,1H),7.77(t,J＝7.4Hz,1H),7.66-7.58(m,2H),7.31(t,J＝8.3Hz,2H).13C NMR(100MHz,CDCl3)δ167.6,163.9(d,J＝248.9Hz),159.0,155.1,151.9,148.2,136.8,133.7,133.3,132.3,132.2,130.7,129.9,129.5,128.4,128.1,127.3,126.5,121.9,121.3,115.6(d,J＝21.5Hz).
example 4:1H NMR(400MHz,CDCl3)δ8.83(d,J＝8.6Hz,1H),8.45-8.39(m,2H),8.33(d,J＝8.5Hz,1H),8.12(d,J＝8.4Hz,1H),7.95(t,J＝7.6Hz,1H),7.87(t,J＝7.3Hz,3H),7.76(t,J＝7.5Hz,1H),7.65-7.58(m,4H).13C NMR(100MHz,CDCl3)δ167.5,159.0,155.1,152.0,148.2,136.9,136.4,135.6,133.8,131.5,130.7,130.0,129.5,128.8,128.4,128.2,127.3,126.4,121.9,121.3.
example 5:1H NMR(400MHz,CDCl3)δ8.84(d,J＝8.5Hz,1H),8.49–8.39(m,2H),8.35(d,J＝8.5Hz,1H),8.12(d,J＝8.7Hz,1H),7.96(t,J＝7.5Hz,1H),7.88(d,J＝7.8Hz,1H),7.85–7.74(m,5H),7.66-7.59(m,2H).13C NMR(101MHz,CDCl3)δ167.8,159.1,155.1,152.1,148.3,137.4,137.0,136.2,133.9,131.8,130.8,130.2,129.6,128.5,128.3,127.4,127.4,126.5,124.8,122.0,121.4.
example 6:1H NMR(400MHz,CDCl3)δ8.17(d,J＝8.6Hz,2H),8.12(d,J＝8.5Hz,2H),7.95(s,2H),7.85–7.79(m,4H),7.73(ddd,J＝8.4,6.9,1.4Hz,2H),7.56–7.49(m,2H).13C NMR(100MHz,CDCl3)δ167.5,159.4,155.1,152.1,148.3,140.8,137.1,134.1,130.9,130.6,130.3,129.7,128.6,128.5,127.5,127.4,126.4,125.6(q,J＝3.7Hz),122.1,121.4.
example 7:1H NMR(400MHz,CDCl3)δ8.84(d,J＝8.6Hz,1H),8.45(d,J＝8.5Hz,1H),8.30(d,J＝8.5Hz,2H),7.91(d,J＝6.1Hz,3H),7.84(d,J＝8.1Hz,1H),7.74(t,J＝7.9Hz,2H),7.63–7.52(m,4H),2.50(s,3H).13C NMR(100MHz,CDCl3)δ168.0,158.6,155.5,150.6,148.2,138.3,137.5,136.8,135.9,130.8,130.1,129.8,129.7,129.4,128.4,127.3,127.1,125.4,122.1,121.4,21.9.
example 8:1H NMR(400MHz,CDCl3)δ8.86(d,J＝8.6Hz,1H),8.48(d,J＝8.5Hz,1H),8.35(d,J＝8.6Hz,1H),8.06(d,J＝9.2Hz,1H),7.96–7.86(m,3H),7.81–7.71(m,2H),7.64–7.59(m,4H),7.23(d,J＝2.5Hz,1H),4.03(s,3H).13C NMR(100MHz,CDCl3)δ167.7,163.9,159.7,155.5,154.6,148.2,137.5,137.0,130.8,130.2,129.9,129.6,128.5,128.3,127.4,127.3,121.5,121.4,117.7,107.6,55.9.
example 9:1H NMR(400MHz,CDCl3)δ8.78(d,J＝8.6Hz,1H),8.43(d,J＝8.5Hz,1H),8.36(t,J＝10.2Hz,2H),7.88(d,J＝8.6Hz,2H),7.77(t,J＝7.6Hz,1H),7.68(s,1H),7.63–7.50(m,5H).13C NMR(100MHz,CDCl3)δ166.9,159.7,154.9,150.0,148.3,137.1,135.6,135.2,134.0,132.9,131.6,131.2,131.0,130.9,130.1,129.7,128.6,127.5,127.4,127.1,125.5,123.4,121.6.
example 10:1H NMR(400MHz,CDCl3)δ8.87(d,J＝8.2Hz,1H),8.44(s,1H),8.39(d,J＝8.0Hz,1H),8.27(d,J＝8.2Hz,1H),8.17(d,J＝7.8Hz,1H),7.92(s,3H),7.65–7.41(m,6H).13C NMR(10MHz,CDCl3)δ169.0,161.1(d,J＝264.6Hz),159.0,154.9,152.0,145.4,137.3,136.3,136.2,133.8,133.4(d,J＝9.3Hz),130.3,130.1,130.0,129.2(d,J＝10.1Hz),128.6,128.1,127.0,122.3,119.9(d,J＝25.9Hz),110.4(d,J＝21.5Hz).
example 11:1H NMR(400MHz,CDCl3)δ8.86(d,J＝8.5Hz,1H),8.46(s,1H),8.40(d,J＝8.4Hz,1H),8.32(d,J＝8.5Hz,1H),8.19(d,J＝8.3Hz,1H),7.99–7.92(m,3H),7.81(d,J＝8.6Hz,1H),7.68–7.60(m,4H),7.54(d,J＝8.6Hz,1H).13C NMR(100MHz,CDCl3)δ169.0,158.9,156.4,152.0,148.6,137.2,136.8,135.4,133.9,130.3,130.1,130.0,129.6,128.6,128.4,128.2,127.0,126.8,122.3,121.7.
example 12:1H NMR(400MHz,CDCl3)δ8.89(d,J＝8.6Hz,1H),8.40(d,J＝8.4Hz,1H),8.31(d,J＝8.9Hz,1H),8.25(d,J＝8.6Hz,1H),8.19(d,J＝8.3Hz,1H),8.04(s,1H),7.98–7.90(m,3H),7.83(d,J＝8.9Hz,1H),7.67–7.60(m,4H).13C NMR(100MHz,CDCl3)δ168.9,159.0,156.2,152.1,144.7,137.4,137.3,134.7,133.8,130.37,130.1,130.0,129.9,129.8,128.5,128.2,127.2,126.9,126.6,122.3,122.2.
example 13:1H NMR(400MHz,CDCl3)δ8.85(d,J＝8.6Hz,1H),8.41(dd,J＝13.0,8.7Hz,2H),8.27(d,J＝8.6Hz,1H),8.19(d,J＝8.2Hz,1H),7.99–7.92(m,3H),7.67–7.60(m,6H),2.57(s,3H).13C NMR(101MHz,CDCl3)δ168.9,159.2,154.5,152.1,146.7,137.6,137.4,136.5,133.7,132.0,130.5,130.3,130.2,130.1,128.7,128.6,128.0,127.0,126.3,122.3,121.6,21.7.
example 14:1H NMR(400MHz,CDCl3)δ8.85(d,J＝8.5Hz,1H),8.39(dd,J＝15.5,8.9Hz,2H),8.24(d,J＝8.4Hz,1H),8.18(d,J＝7.8Hz,1H),7.95(s,3H),7.61(s,4H),7.42(d,J＝8.9Hz,1H),7.14(s,1H),3.97(s,3H).13C NMR(101MHz,CDCl3)δ168.9,158.6,153.0,152.1,144.3,137.5,135.7,133.7,132.3,131.3,130.3,130.1,129.8,128.6,127.9,127.0,122.6,122.2,121.9,104.8,55.6.
example 15:1H NMR(400MHz,CDCl3)δ8.75(d,J＝5.2Hz,1H),8.52(d,J＝8.5Hz,1H),8.30(d,J＝8.4Hz,1H),8.22(d,J＝8.3Hz,1H),7.96(t,J＝7.6Hz,1H),7.89(d,J＝5.5Hz,3H),7.77(d,J＝5.1Hz,1H),7.70-7.64(m,2H),7.60-7.55(m,4H).13C NMR(100MHz,CDCl3)δ168.8,160.9,156.7,151.5,142.3,137.1,137.0,133.9,130.1,130.0,130.0,129.4,128.5,128.1,127.6,127.3,127.0,126.9,126.9,121.9,121.7.
example 16:1H NMR(400MHz,CDCl3)δ8.91(s,1H),8.75(d,J＝7.9Hz,1H),8.36(d,J＝8.4Hz,1H),8.13(d,J＝8.3Hz,1H),7.97–7.84(m,4H),7.60–7.57(m,4H),7.43–7.38(m,1H).13C NMR(100MHz,CDCl3)δ168.8,159.0,155.3,152.0,150.2,137.3,136.9,133.7,130.1,129.9,129.9,128.5,127.8,126.9,124.6,124.3,122.2.
example 17:1H NMR(400MHz,CDCl3)δ8.81(s,2H),8.54(d,J＝5.8Hz,2H),8.19(t,J＝8.3Hz,2H),7.95(dd,J＝11.2,4.2Hz,2H),7.91–7.86(m,2H),7.63(dd,J＝9.9,6.4Hz,4H).13C NMR(100MHz,CDCl3)δ168.8,158.1,151.8,150.3,145.7,137.2,133.9,130.2,130.2,129.4,128.6,128.1,127.1,122.5,122.3.
example 18:1H NMR(400MHz,CDCl3)δ8.38(d,J＝8.3Hz,1H),8.32(d,J＝7.9Hz,1H),8.20(d,J＝8.3Hz,1H),8.00-7.92(m,4H),7.70–7.60(m,4H),7.54(t,J＝7.5Hz,1H),7.47(t,J＝7.3Hz,1H).13C NMR(100MHz,CDCl3)δ169.2,168.0,155.2,154.6,151.8,136.9,136.7,134.3,130.3,129.9,128.7,128.6,127.3,126.4,126.2,124.9,122.8,121.8.
example 19:1H NMR(400MHz,CDCl3)δ8.27(d,J＝8.3Hz,1H),8.13(d,J＝8.4Hz,1H),8.09(d,J＝3.1Hz,1H),7.93–7.84(m,3H),7.62–7.51(m,5H).13C NMR(100MHz,CDCl3)δ169.1,167.7,155.1,151.7,145.2,136.7,134.1,130.2,129.6,128.5,128.0,127.1,122.9,122.5.
example 20:1H NMR(400MHz,CDCl3)δ9.96(s,1H),8.86(s,1H),8.71(s,1H),8.37(d,J＝8.5Hz,1H),8.20(d,J＝8.4Hz,1H),7.97(t,J＝7.7Hz,1H),7.91–7.87(m,2H),7.69–7.59(m,4H).13C NMR(100MHz,CDCl3)δ169.2,157.5,151.8,150.7,146.0,145.2,144.6,137.0,134.1,130.2,130.2,129.7,128.6,128.4,127.1,122.4.
example 21:1H NMR(400MHz,CDCl3)δ9.50(s,1H),8.94(d,J＝5.0Hz,1H),8.65(d,J＝5.1Hz,1H),8.35(d,J＝8.5Hz,1H),8.16(d,J＝5.5Hz,1H),7.94(t,J＝7.7Hz,1H),7.87–7.82(m,2H),7.64(t,J＝7.7Hz,1H),7.59–7.56(m,3H).13C NMR(100MHz,CDCl3)δ169.1,162.1,159.5,158.3,157.3,151.7,136.9,134.1,130.2,130.1,129.9,128.8,128.6,127.0,122.7,120.4.
referring to the synthesis method, when the reaction raw materials replace different methyl aromatic nitrogen heterocyclic compounds or 2-aminobenzophenone compounds, the reaction can be carried out, the yield of the product is good, and the product is easy to separate and purify.
It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.

Claims (1)

1. A green synthesis method of polysubstituted quinazoline derivatives is characterized in that the preparation process is as follows:
in a 25mL reaction tube, 0.3mmol of 2-aminobenzophenone compound, 0.6mmol of ammonium acetate, 0.6mmol of a methyl aromatic nitrogen heterocyclic compound, 0.15mmol of trifluoroacetic acid, 0.06mmol of copper chloride and 2mL of the compound were addedN,N-dimethylformamide, stirring and reacting for 24 hours at 120 ℃ under an oxygen environment, stopping heating and stirring, cooling to room temperature, adding a sodium hydroxide aqueous solution, extracting for three times by using ethyl acetate, drying by using anhydrous magnesium sulfate, concentrating under reduced pressure to remove a solvent, and separating and purifying by using column chromatography to obtain a target product, wherein a used column chromatography eluent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of (2-5) to 1;
wherein the 2-aminobenzophenone compound is 2-aminobenzophenone, 4' -fluoro-2-aminobenzophenone, 4' -chloro-2-aminobenzophenone, 4' -bromo-2-aminobenzophenone, 4' -trifluoromethyl-2-aminobenzophenone, 5-methyl-2-aminobenzophenone, 5-methoxy-2-aminobenzophenone, 2', 5-dichloro-2-aminobenzophenone or 2-aminobenzophenone;
the methyl aromatic nitrogen heterocyclic compound is 2-methylquinoline, 6-fluoro-2-methylquinoline, 7-chloro-2-methylquinoline, 6-bromo-2-methylquinoline, 2, 6-dimethylquinoline, 6-methoxy-2-methylquinoline, 1-methylisoquinoline, 2-methylpyridine, 4-methylpyridine, 2-methylbenzothiazole, 2-methylthiazole, 2-methylpyrazine and 2-methylpyrimidine;
the polysubstituted quinazoline derivatives prepared are 4-phenyl-2- (quinolin-2-yl) quinazoline, 4- (4-fluorophenyl) -2- (quinolin-2-yl) quinazoline, 4- (4-chlorophenyl) -2- (quinolin-2-yl) quinazoline, 4- (4-bromophenyl) -2- (quinolin-2-yl) quinazoline, 4- (4-trifluoromethylphenyl) -2- (quinolin-2-yl) quinazoline, 6-methyl-4-phenyl-2- (quinolin-2-yl) quinazoline, 6-methoxy-4-phenyl-2- (quinolin-2-yl) quinazoline, a, 6-chloro-4- (2-chlorophenyl) -2- (quinolin-2-yl) quinazoline, 2- (6-fluoroquinolin-2-yl) -4-phenylquinazoline, 2- (7-chloroquinolin-2-yl) -4-phenylquinazoline, 2- (6-bromoquinolin-2-yl) -4-phenylquinazoline, 2- (6-methylquinolin-2-yl) -4-phenylquinazoline, 2- (6-methoxyquinolin-2-yl) -4-phenylquinazoline, 2- (isoquinolin-1-yl) -4-phenylquinazoline, 4-phenyl-2- (pyridin-2-yl) quinazoline, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof, 4-phenyl-2- (pyridin-4-yl) quinazoline, 2- (4-phenylquinazolin-2-yl) benzo [ d ] thiazole, 2- (4-phenylquinazolin-2-yl) thiazole, 4-phenyl-2- (pyrazin-2-yl) quinazoline, or 4-phenyl-2- (pyrimidin-4-yl) quinazoline.
CN201910944039.1A 2019-09-30 2019-09-30 A kind of green synthesis method of polysubstituted quinazoline derivatives Expired - Fee Related CN110606839B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910944039.1A CN110606839B (en) 2019-09-30 2019-09-30 A kind of green synthesis method of polysubstituted quinazoline derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910944039.1A CN110606839B (en) 2019-09-30 2019-09-30 A kind of green synthesis method of polysubstituted quinazoline derivatives

Publications (2)

Publication Number Publication Date
CN110606839A CN110606839A (en) 2019-12-24
CN110606839B true CN110606839B (en) 2021-10-08

Family

ID=68894053

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910944039.1A Expired - Fee Related CN110606839B (en) 2019-09-30 2019-09-30 A kind of green synthesis method of polysubstituted quinazoline derivatives

Country Status (1)

Country Link
CN (1) CN110606839B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111700894B (en) * 2020-05-12 2023-07-28 南方医科大学 Application of 2-position azaarene substituted quinazoline compounds in the preparation of antitumor drugs

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103275016A (en) * 2013-06-04 2013-09-04 温州医学院附属第二医院 Synthetic method of 2-subsituted quinazoline compounds

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007510642A (en) * 2003-11-03 2007-04-26 ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー Novel norepinephrine reuptake inhibitors for the treatment of central nervous system disorders

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103275016A (en) * 2013-06-04 2013-09-04 温州医学院附属第二医院 Synthetic method of 2-subsituted quinazoline compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Copper-Catalyzed Aerobic Oxidative Amination of sp3C-H Bonds: Efficient Synthesis of 2-Hetarylquinazolin-4(3H)-ones;Qiang Li et al.;《Organic Letters》;20140630;第16卷;3672-3675 *
I2-Catalyzed three-component protocol for the synthesis of quinazolines;Sumit Kumar Panja et al.;《Tetrahedron Letters》;20120809;第53卷;6167-6172 *

Also Published As

Publication number Publication date
CN110606839A (en) 2019-12-24

Similar Documents

Publication Publication Date Title
JP2002338516A (en) Method for producing 2-halogenated benzoic acids
CN111675662B (en) A kind of preparation method of quinazolinone compound substituted by 2-trifluoromethyl
CN103435558B (en) Synthetic method of quinazoline derivative
CN110183378A (en) A kind of derivative and its process for catalytic synthesis of niacinamide
CN110606839B (en) A kind of green synthesis method of polysubstituted quinazoline derivatives
CN108884047B (en) Intermediates for the synthesis of aryl or heteroaryl substituted 5-hydroxy-1, 7-naphthyridine compounds and methods for their preparation
CN110483387B (en) A kind of method for synthesizing nicotinamide derivatives in one pot
CN112209876A (en) Preparation method of 3-trifluoromethyl isoquinolinone derivative
CN111349039A (en) Preparation method of indole-2-formic acid derivative
CN103992325B (en) A kind of synthetic method of N-phenylindazol[3,2-b]quinazolin-7(5H)-one derivative
CN105384697A (en) 2-subsituted quinazoline preparation method
CN112480112B (en) A kind of method for synthesizing substituted dihydrophenanthroline compounds
CN106336378B (en) Preparation method of quinoline-2-formic ether series
TWI725710B (en) SYNTHESIS OF 3-BROMO-5- (2-ETHYLIMIDAZO [1,2a] PYRIDINE-3-CARBONYL) -2-HYDROXYBENZONITRILE
CN112047879B (en) Method for selectively synthesizing halogenated arylamine by copper catalysis
CN108794396B (en) Oxidation method of 4-oxo-2,3-dihydroquinoline compounds
CN110483391B (en) Five-component synthesis method of nicotinamide amide derivative
CN107673994A (en) A kind of preparation method of arylmethane class compound
CN103172564B (en) The preparation method of Aripiprazole
CN113698358A (en) Method for synthesizing quinazolinone compound under induction of visible light
CN113214162A (en) Preparation method of benzimidazole derivative
CN108218758B (en) A kind of preparation method of 2,4-disubstituted pyrrole derivatives
CN106220554B (en) A kind of preparation method of arylpyridine and derivative thereof
CN111057058B (en) A kind of method for preparing 1H-[1,2,3]-triazolo[4,5-c]quinoline compounds
JP3315219B2 (en) Substituted 2,3-dicarboxypyridinium nitrate

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20211008