Synthesis method of 2-aryl quinazoline compound

Abstract

The invention discloses a synthesis method of a 2-aryl quinazoline compound. The quinazoline compound has wide biological characteristics including tumor resistance, cancer resistance, microbe resistance, bacteria resistance, virus resistance, inflammation resistance, tuberculosis resistance and obesity resistance. The previous improvement of synthesis of quinazoline is generally started from the change of catalyst types, reaction conditions and raw material types, but most synthesis routes rarely involve a series reaction of five-membered ring opening and ring closing, so that on the basis, the invention develops a method for synthesizing quinazoline by using anammoic anhydride and benzylamine as raw materials. The quinazoline compound is synthesized by a one-pot method through a tandem cyclization reaction under an alkaline condition. The synthesis method comprises the following steps: taking ammine anhydride and a benzylamine compound as substrates, and carrying out a synthesis reaction in the presence of a solvent dimethyl sulfoxide. The method has the advantages of simple reaction operation, mild conditions, low cost and the like.

Description

Technical field:

[0001] The invention relates to the field of organic synthesis methodology, and in particular to a synthesis route of 2-arylquinazoline derivatives. Background technology:

[0002] Quinazolines and their derivatives are a special class of nitrogen-containing heterocyclic compounds that are commonly found in various natural products and synthetic chemicals. Their relatively simple synthetic routes, diverse functional groups, and flexible and controllable structural modifications increase their appeal in medicinal chemistry. Quinazolines, including nitrogen bicyclic heteroaromatics, are considered attractive target drugs, and chemists believe that these skeletons are the main components of bioactive molecules that can show antibacterial effects.

[0003] Many synthetic methods for quinazolines are based on ortho-functionalized nitrobenzene and benzene. In recent years, due to the wide application of quinazolines in biomedical materials, some synthetic methods have been developed in the past few decades. These classical methods are associated with harsh reaction conditions, complex synthetic routes, and the generation of auxiliary waste, which makes it difficult for conventional synthetic devices to meet the requirements. The resulting high cost makes it difficult to promote the development of industrialization. Therefore, the development of a low-cost and easy-to-implement synthetic route has practical significance for promoting the industrialization of quinazoline derivatives. Summary of the invention:

[0004] Based on the above problems, the present invention proposes a method for synthesizing a class of quinazoline derivatives, which does not require precious metal catalysts, has a short reaction time, mild reaction conditions, simple reaction operation, and good reaction universality and functional group compatibility.

[0005] In order to achieve the above object, the present invention provides a method for synthesizing a class of 2-arylquinazoline derivatives, characterized in that benzylamine and anthranilic anhydride are used as raw materials, copper acetate is used as a catalyst, and the reaction is carried out in a dimethyl sulfoxide solvent at 120°C for 3h under the action of cesium carbonate, and quinazoline is synthesized by a one-pot tandem cyclization. The reaction formula is:

[0006]

[0007] Among them, R 1 is selected from representing hydrogen, halogen, alkane, nitro or alkoxy;

[0008] R 2 is selected from hydrogen, halogen, alkane, trifluoromethyl, nitro, pyridine or alkoxy

[0009] The synthesis mechanism of the 2-arylquinazoline compound is as follows: anthracene anhydride is ring-opened under the catalysis of copper, the N atom coordinates with Cu, the O atom isomerizes with the double bond to form an aldehyde, and the aldehyde group then reacts with the amino group on the benzylamine to remove a molecule of water to form an intermediate. There are two synthetic routes:

[0010] Path A: Because N is negatively charged and C is positively charged, the N atom coordinated with Cu attacks the methylene group, then removes a molecule of water, and finally oxidizes the two imines to obtain the product.

[0011] Path B: The electron pair on the CN double bond is shared with the C of the methylene group. Because N is positively charged, the N atom coordinated with Cu attacks the methylene group, the CN double bond is retained, and finally the N coordinated with Cu is oxidized to obtain the product.

[0012] According to the above scheme, the raw materials remain unchanged, the catalyst is copper powder, monovalent copper (CuI, CuCl), divalent copper (CuBr2, Cu(OAc)2), and the equivalent ratio of catalyst to anthracene anhydride is 0.2:1.

[0013] According to the above scheme, the raw materials remain unchanged, the base is cesium carbonate, sodium carbonate, DBU, DABCO, and the equivalent ratio of the base to the anthranilic anhydride is 1:1.

[0014] According to the above scheme, the solvent is one of dimethyl sulfoxide, dichloromethane, 1,4-dioxane, N,N-dimethylformamide, and acetonitrile, and the solvent volume is 5 mL / g.

[0015] After screening a large number of conditions as mentioned above, the optimal conditions were finally determined to be: using benzylamine and anthranilic anhydride as raw materials, copper acetate as catalyst, reacting at 120°C for 3 hours in DMSO solvent under the action of cesium carbonate, and synthesizing quinazoline by a one-pot tandem cyclization.

[0016] The specific path is as follows:

[0017]

[0018] Beneficial effects: The present invention proposes a method for synthesizing 2-arylquinazoline compounds by a one-pot tandem cyclization reaction, which provides a new idea for preparing such compounds. The method has the characteristics of low cost, easy availability of raw materials, simple operation, short reaction time, high yield, etc., and the functional group compatibility of the substrate is good, and quinazoline compounds with different substituents at different sites can be synthesized, which has certain application value. Description of the drawings:

[0019] Figure 1 is the compound prepared in Example 1 of the present invention 1 H-NMR nuclear magnetic resonance spectrum.

[0020] Figure 2 is the compound prepared in Example 1 of the present invention 13 C-NMR nuclear magnetic resonance spectrum.

[0021] Figure 3is the compound prepared in Example 2 of the present invention 1 H-NMR nuclear magnetic resonance spectrum.

[0022] Figure 4 is the compound prepared in Example 2 of the present invention 13 C-NMR nuclear magnetic resonance spectrum.

[0023] Figure 5 is the compound prepared in Example 3 of the present invention 1 H-NMR nuclear magnetic resonance spectrum.

[0024] Figure 6 is the compound prepared in Example 3 of the present invention 13 C-NMR nuclear magnetic resonance spectrum.

[0025] Figure 7 is the compound prepared in Example 4 of the present invention 1 H-NMR nuclear magnetic resonance spectrum.

[0026] Figure 8 is the compound prepared in Example 4 of the present invention 13 C-NMR nuclear magnetic resonance spectrum.

[0027] Fig. 9 is the compound prepared in Example 5 of the present invention 1 H-NMR nuclear magnetic resonance spectrum.

[0028] Fig.10 is the compound prepared in Example 5 of the present invention 13 C-NMR nuclear magnetic resonance spectrum.

[0029] Fig.11 is the compound prepared in Example 6 of the present invention 1 H-NMR nuclear magnetic resonance spectrum.

[0030] Fig.12 is the compound prepared in Example 6 of the present invention 13 C-NMR nuclear magnetic resonance spectrum.

[0031] Fig.13 is the compound prepared in Example 7 of the present invention 1 H-NMR nuclear magnetic resonance spectrum.

[0032] Fig.14 is the compound prepared in Example 7 of the present invention 13 C-NMR nuclear magnetic resonance spectrum.

[0033] Fig.15 is the compound prepared in Example 8 of the present invention 1H-NMR nuclear magnetic resonance spectrum.

[0034] Fig.16 is the compound prepared in Example 8 of the present invention 13 C-NMR nuclear magnetic resonance spectrum. Specific implementation method:

[0035] The following embodiments are further detailed descriptions of the technical solutions of the present invention. The described embodiments are only some embodiments of the present invention, rather than all embodiments.

[0036] Example 1: The complete scheme for the synthesis of compound (2-arylquinazoline) is as follows:

[0037]

[0038] The specific synthesis steps of 2-arylquinazoline are:

[0039] Weigh 1mmol (119mg) of anthranilic anhydride, 1.4mmol (150mg) of benzylamine, 0.2mmol (36mg) of copper acetate, and 1mmol (326mg) of cesium carbonate in sequence, mix them in a 35mL pressure tube, add 5mL of dimethyl sulfoxide as a solvent, react at 120°C for 3h, and monitor in real time until the conversion is complete. Then add 20mL of saturated brine and extract twice with 20mL of ethyl acetate, take the upper solution, dry the extracted organic phase with anhydrous Na2SO4, and then concentrate by rotary evaporation to obtain a crude quinazoline product. The crude product is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to obtain a pure product.

[0040] The compound (2-arylquinazoline) synthesized in this example 1 H-NMR spectrum Figure 1 shown.

[0041] The compound (2-arylquinazoline) synthesized in this example 13 C-NMR spectrum Figure 2 shown.

[0042] Example 2: The complete scheme for the synthesis of compound (2-(m-methylphenyl)quinazoline) is as follows:

[0043]

[0044] The specific synthesis steps of 2-(m-methylphenyl)quinazoline are:

[0045] Weigh 1mmol (119mg) of anthranilic anhydride, 1.4mmol (170mg) of m-methylbenzylamine, 0.2mmol (36mg) of copper acetate, and 1mmol (326mg) of cesium carbonate in sequence, mix them in a 35mL pressure tube, add 5mL of dimethyl sulfoxide as a solvent, react at 120°C for 3h, and monitor in real time until the conversion is complete. Then add 20mL of saturated brine and extract twice with 20mL of ethyl acetate, take the upper solution, dry the extracted organic phase with anhydrous Na2SO4, and then concentrate by rotary evaporation to obtain a crude quinazoline product. The crude product is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to obtain a pure product.

[0046] The compound (2-(m-methylphenyl)quinazoline) synthesized in this example 1 H-NMR spectrum Figure 3 shown.

[0047] The compound (2-(m-methylphenyl)quinazoline) synthesized in this example 13 C-NMR spectrum Figure 4 shown.

[0048] Example 3: The complete scheme for the synthesis of compound (2-(p-methoxyphenyl)quinazoline) is as follows:

[0049]

[0050] The specific synthesis steps of 2-(p-methoxyphenyl)quinazoline are:

[0051] Weigh 1mmol (119mg) of anthranilic anhydride, 1.4mmol (192mg) of p-methoxybenzylamine, 0.2mmol (36mg) of copper acetate, and 1mmol (326mg) of cesium carbonate in sequence, mix them in a 35mL pressure tube, add 5mL of dimethyl sulfoxide as a solvent, react at 120°C for 3h, and monitor in real time until the conversion is complete. Then add 20mL of saturated brine and extract twice with 20mL of ethyl acetate, take the upper solution, dry the extracted organic phase with anhydrous Na2SO4, and then concentrate by rotary evaporation to obtain a crude quinazoline product. The crude product is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to obtain a pure product.

[0052] The compound (2-(p-methoxyphenyl)quinazoline) synthesized in this example 1 H-NMR spectrum Figure 5 shown.

[0053] The compound (2-(p-methoxyphenyl)quinazoline) synthesized in this example 13 C-NMR spectrum Figure 6 shown.

[0054] Example 4: The complete scheme for the synthesis of compound (2-(p-chlorophenyl)quinazoline) is as follows:

[0055]

[0056] The specific synthesis steps of 2-(p-chlorophenyl)quinazoline are:

[0057] Weigh 1mmol (119mg) of anthranilic anhydride, 1.4mmol (197mg) of p-chlorobenzylamine, 0.2mmol (36mg) of copper acetate, and 1mmol (326mg) of cesium carbonate in sequence, mix them in a 35mL pressure tube, add 5mL of dimethyl sulfoxide as a solvent, react at 120°C for 3h, and monitor in real time until the conversion is complete. Then add 20mL of saturated brine and extract twice with 20mL of ethyl acetate, take the upper solution, dry the organic phase after extraction with anhydrous Na2SO4, and then concentrate by rotary evaporation to obtain a crude quinazoline product. The crude product is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to obtain a pure product.

[0058] The compound (2-(p-chlorophenyl)quinazoline) synthesized in this example 1 H-NMR spectrum Figure 7 shown.

[0059] The compound (2-(p-chlorophenyl)quinazoline) synthesized in this example 13 C-NMR spectrum Figure 8 shown.

[0060] Example 5: The complete scheme for the synthesis of compound (2-(p-nitrophenyl)quinazoline) is as follows:

[0061]

[0062] The specific synthesis steps of 2-(p-nitrophenyl)quinazoline are:

[0063] Weigh 1mmol (119mg) of anthranilic anhydride, 1.4mmol (213mg) of p-nitrobenzylamine, 0.2mmol (36mg) of copper acetate, and 1mmol (326mg) of cesium carbonate in sequence, mix them in a 35mL pressure tube, add 5mL of dimethyl sulfoxide as a solvent, react at 120°C for 3h, and monitor in real time until the conversion is complete. Then add 20mL of saturated brine and extract twice with 20mL of ethyl acetate, take the upper solution, dry the extracted organic phase with anhydrous Na2SO4, and then concentrate by rotary evaporation to obtain a crude quinazoline product. The crude product is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to obtain a pure product.

[0064] The compound (2-(p-nitrophenyl)quinazoline) synthesized in this example 1 H-NMR spectrum Fig. 9 shown.

[0065] The compound (2-(p-nitrophenyl)quinazoline) synthesized in this example 13 C-NMR spectrum Fig.10 shown.

[0066] Example 6: The complete scheme for the synthesis of compound (2-(p-ethoxyphenyl)quinazoline) is as follows:

[0067]

[0068] The specific synthesis steps of 2-(p-ethoxyphenyl)quinazoline are:

[0069] Weigh 1mmol (119mg) of anthranilic anhydride, 1.4mmol (211mg) of p-ethoxybenzylamine, 0.2mmol (36mg) of copper acetate, and 1mmol (326mg) of cesium carbonate in sequence, mix them in a 35mL pressure tube, add 5mL of dimethyl sulfoxide as a solvent, react at 120°C for 3h, and monitor in real time until the conversion is complete. Then add 20mL of saturated brine and extract twice with 20mL of ethyl acetate, take the upper solution, dry the extracted organic phase with anhydrous Na2SO4, and then concentrate by rotary evaporation to obtain a crude quinazoline product. The crude product is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to obtain a pure product.

[0070] The compound (2-(p-ethoxyphenyl)quinazoline) synthesized in this example 1 H-NMR spectrum Fig.11 shown.

[0071] The compound (2-(p-ethoxyphenyl)quinazoline) synthesized in this example 13 C-NMR spectrum Fig.12 shown.

[0072] Example 7: The complete scheme for the synthesis of compound (2-(m-cyanophenyl)quinazoline) is as follows:

[0073]

[0074] The specific synthesis steps of 2-(m-cyanophenyl)quinazoline are:

[0075] Weigh 1mmol (119mg) of anthranilic anhydride, 1.4mmol (185mg) of m-cyanobenzylamine, 0.2mmol (36mg) of copper acetate, and 1mmol (326mg) of cesium carbonate in sequence, mix them in a 35mL pressure tube, add 5mL of dimethyl sulfoxide as a solvent, react at 120°C for 3h, and monitor in real time until the conversion is complete. Then add 20mL of saturated brine and extract twice with 20mL of ethyl acetate, take the upper solution, dry the extracted organic phase with anhydrous Na2SO4, and then concentrate by rotary evaporation to obtain a crude quinazoline product. The crude product is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to obtain a pure product.

[0076] The compound (2-(m-cyanophenyl)quinazoline) synthesized in this example 1 H-NMR spectrum Fig.13 shown.

[0077] The compound (2-(m-cyanophenyl)quinazoline) synthesized in this example 13 C-NMR spectrum Fig.14 shown.

[0078] Example 8: The complete scheme for the synthesis of compound (6-methoxy-2-phenylquinazoline) is as follows:

[0079]

[0080] The specific synthesis steps of 6-methoxy-2-phenylquinazoline are:

[0081] Weigh 1mmol (149mg) of 5-methoxybenzisoxazole, 1.4mmol (150mg) of benzylamine, 0.2mmol (36mg) of copper acetate, and 1mmol (326mg) of cesium carbonate in sequence, mix them in a 35mL pressure tube, add 5mL of dimethyl sulfoxide as a solvent, react at 120°C for 3h, and monitor in real time until the conversion is complete. Then add 20mL of saturated brine and extract twice with 20mL of ethyl acetate, take the upper solution, dry the extracted organic phase with anhydrous Na2SO4, and then concentrate by rotary evaporation to obtain a crude quinazoline product. The crude product is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to obtain a pure product.

[0082] The compound (6-methoxy-2-phenylquinazoline) synthesized in this example 1 H-NMR spectrum Fig.15 shown.

[0083] The compound (6-methoxy-2-phenylquinazoline) synthesized in this example 13 C-NMR spectrum Fig.16 shown.

[0084] The above-mentioned embodiments are only preferred technical solutions of the present invention and should not be regarded as limitations of the present invention. The embodiments and features in the embodiments of the present application can be arbitrarily combined with each other without conflict. The protection scope of the present invention shall be the technical solutions recorded in the claims, including the equivalent replacement solutions of the technical features in the technical solutions recorded in the claims. That is, equivalent replacement improvements within this scope are also within the protection scope of the present invention.

Claims

1. A synthetic method for a quinazoline derivative, the reaction equation being: in, R 1 is selected from hydrogen, halogen, alkane, nitro or alkoxy; R 2 is selected from the group representing hydrogen, halogen, alkane, trifluoromethyl, nitro, pyridine or alkoxy.

2. A method for preparing quinazoline derivatives based on tandem cyclization reaction according to claim 1, characterized in that: The steps of the method are as follows: Step 1, adding anthranilic anhydride, benzylamine, a metallic copper catalyst and a base into a reaction container, and adding DMSO as a reaction solvent; Step 2, the reaction vessel is sealed and reacted at a reaction temperature of 120° C. for 3 hours; Step 3, after the TLC detection of the disappearance of the substrate and the completion of the reaction, the reaction vessel is cooled to room temperature, then extracted with saturated brine, the organic phase is retained, and an equal volume of ethyl acetate is added to the aqueous phase for back extraction to separate the organic phase and the aqueous phase; Step 4, the organic phase is dried over anhydrous sodium sulfate, filtered, spin-dried, and separated by column chromatography to obtain a quinazoline derivative.

3. A method for synthesizing a quinazoline derivative according to claim 1 or 2, characterized in that: The ratio of the amount of anthranilic anhydride, benzylamine, metal copper catalyst and alkali is 1:1.4:0-0.25:0-1.

4. The method for synthesizing a quinazoline derivative according to claim 3, characterized in that: R is one of the substituted phenyl groups, wherein the substituent on the benzene ring of the substituted phenyl group is one of the alkyl group, the alkoxy group and the nitro group.

5. The method for synthesizing a quinazoline derivative according to claim 3, characterized in that: The metallic copper catalyst is one of monovalent copper and divalent copper.

6. The method for synthesizing a quinazoline derivative according to claim 3, characterized in that: The base is one of an organic base and an inorganic base.

7. The method for synthesizing a quinazoline derivative according to claim 3, characterized in that: The reaction solvent is one of tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol and acetonitrile.

8. A method for synthesizing a quinazoline derivative according to any one of claims 4 to 7, characterized in that: The metal copper catalyst is Cu(OAc)2; the base is cesium carbonate; the reaction solvent is dimethyl sulfoxide; and the reaction temperature is 120°C.

Images