A method for synthesizing 2-arylquinazoline compounds
The one-pot tandem cyclization reaction for the synthesis of quinazolines solves the problems of harsh conditions and high costs in the synthesis of quinazolines in the existing technology, and realizes the low-cost and high-efficiency synthesis of quinazoline derivatives, which is applicable to quinazoline compounds with different substituent sites.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-08-31
- Publication Date
- 2026-04-03
AI Technical Summary
Existing methods for synthesizing quinazolines suffer from harsh reaction conditions, complex synthetic routes, and high costs, making it difficult to meet the needs of industrialization.
Using benzylamine and aminoanisidine as raw materials, and copper acetate as catalyst, quinazoline was synthesized by one-pot tandem cyclization in dimethyl sulfoxide solvent at 120°C for 3 hours in the presence of cesium carbonate. This method avoids the use of precious metal catalysts, and the reaction conditions are mild and the operation is simple.
This method enables the low-cost and efficient synthesis of quinazoline derivatives with short reaction times, high yields, and good substrate functional group compatibility, making it suitable for the synthesis of quinazoline compounds with substituents at different sites.
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Abstract
Description
Technical fields:
[0001] This invention relates to the field of organic synthesis methodology, specifically to a synthetic route for a class of 2-arylquinazoline derivatives. Background technology:
[0002] Quinazolines and their derivatives are a special class of nitrogen-containing heterocyclic compounds, widely 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-containing bicyclic heteroaromatics, are considered attractive target drugs; chemists believe these skeletons are key components of bioactive molecules and can exhibit antibacterial effects.
[0003] Many synthetic methods for quinazolines are based on ortho-functionalized nitrobenzene and benzene. In recent years, due to the widespread application of quinazolines in biomedical materials, several synthetic methods have been developed over the past few decades. These classic methods involve demanding reaction conditions, complex synthetic routes, and the generation of auxiliary waste, making conventional synthetic equipment insufficient and resulting in high costs that hinder industrialization. Therefore, developing a low-cost and easily implemented synthetic route is of practical significance for promoting the industrialization of quinazoline derivatives. Summary of the Invention:
[0004] Based on the above problems, this invention proposes a method for synthesizing a class of quinazoline derivatives that does not require a precious metal catalyst, has a short reaction time, mild reaction conditions, simple operation, broad reaction scope, and good functional group compatibility.
[0005] To achieve the above objectives, this invention provides a method for synthesizing a class of 2-arylquinazoline derivatives, characterized by: using benzylamine and aminoanisidine as raw materials, copper acetate as a catalyst, and reacting in dimethyl sulfoxide solvent at 120°C for 3 hours under the action of cesium carbonate, to synthesize quinazoline via a one-pot tandem cyclization process. The reaction formula is as follows:
[0006]
[0007] Among them, R 1 Selected from those representing hydrogen, halogens, alkanes, nitro groups, or alkoxy groups;
[0008] R 2 Selected from hydrogen, halogen, alkane, trifluoromethyl, nitro, pyridine, or alkoxy.
[0009] The synthetic mechanism of this 2-arylquinazoline compound is as follows: The anisidine undergoes ring-opening under copper catalysis; the nitrogen atom coordinates with Cu, and the oxygen atom isomerizes with the double bond to form an aldehyde. The aldehyde group then reacts with the amino group on benzylamine, removing one 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 loses one molecule of water, and finally oxidizes the two imine atoms to obtain the product.
[0011] Pathway B: The electron pair on the CN double bond is shared by the C atom 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 atom coordinated with Cu is oxidized to obtain the product.
[0012] According to the above scheme, the raw materials remain unchanged, and the catalyst is copper powder, monovalent copper (CuI, CuCl), and divalent copper (CuBr2, Cu(OAc)2). The equivalent ratio of the catalyst to the ammonia anhydride is 0.2:1.
[0013] According to the above scheme, the raw materials remain unchanged, and the alkali is cesium carbonate, sodium carbonate, DBU, or DABCO. The alkali equivalent to the equivalent ratio of amino 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 extensive screening of the above conditions, the optimal conditions were finally determined to be: using benzylamine and aminoaniline as raw materials, copper acetate as catalyst, and DMSO solvent in the presence of cesium carbonate, the reaction was carried out at 120°C for 3 hours to synthesize quinazoline in a one-pot tandem cyclization process.
[0016] The specific path is as follows:
[0017]
[0018] Beneficial Effects: This invention proposes a one-pot tandem cyclization reaction method for synthesizing 2-arylquinazoline compounds, providing a new approach for the preparation of this class of compounds. This method is characterized by low cost, readily available raw materials, simple operation, short reaction time, and high yield. Furthermore, it exhibits good substrate functional group compatibility, enabling the synthesis of quinazoline compounds with different substituents at different sites, thus possessing certain application value. Attached image description:
[0019] Figure 1 The compound prepared in Example 1 of this invention 1 H-NMR nuclear magnetic resonance spectrum.
[0020] Figure 2 The compound prepared in Example 1 of this invention 13 C-NMR nuclear magnetic resonance spectrum.
[0021] Figure 3The compound prepared in Example 2 of this invention 1 H-NMR nuclear magnetic resonance spectrum.
[0022] Figure 4 The compound prepared in Example 2 of this invention 13 C-NMR nuclear magnetic resonance spectrum.
[0023] Figure 5 The compound prepared in Example 3 of this invention 1 H-NMR nuclear magnetic resonance spectrum.
[0024] Figure 6 The compound prepared in Example 3 of this invention 13 C-NMR nuclear magnetic resonance spectrum.
[0025] Figure 7 The compound prepared in Example 4 of this invention 1 H-NMR nuclear magnetic resonance spectrum.
[0026] Figure 8 The compound prepared in Example 4 of this invention 13 C-NMR nuclear magnetic resonance spectrum.
[0027] Figure 9 The compound prepared in Example 5 of this invention 1 H-NMR nuclear magnetic resonance spectrum.
[0028] Figure 10 The compound prepared in Example 5 of this invention 13 C-NMR nuclear magnetic resonance spectrum.
[0029] Figure 11 The compound prepared in Example 6 of this invention 1 H-NMR nuclear magnetic resonance spectrum.
[0030] Figure 12 The compound prepared in Example 6 of this invention 13 C-NMR nuclear magnetic resonance spectrum.
[0031] Figure 13 The compound prepared in Example 7 of this invention 1 H-NMR nuclear magnetic resonance spectrum.
[0032] Figure 14 The compound prepared in Example 7 of this invention 13 C-NMR nuclear magnetic resonance spectrum.
[0033] Figure 15 The compound prepared in Example 8 of this invention 1H-NMR nuclear magnetic resonance spectrum.
[0034] Figure 16 The compound prepared in Example 8 of this invention 13 C-NMR nuclear magnetic resonance spectrum. Detailed implementation method:
[0035] The following embodiments are a further detailed description of the technical solutions of the present invention. The described embodiments are only some embodiments of the present invention, and not all embodiments.
[0036] Example 1: The complete scheme for synthesizing the compound (2-arylquinazoline) is as follows:
[0037]
[0038] The specific synthetic steps for 2-arylquinazoline are as follows:
[0039] 1 mmol (119 mg) of aminoanisidine, 1.4 mmol (150 mg) of benzylamine, 0.2 mmol (36 mg) of copper acetate, and 1 mmol (326 mg) of cesium carbonate were weighed sequentially and mixed in a 35 mL pressure-resistant tube. 5 mL of dimethyl sulfoxide was added as a solvent, and the mixture was reacted at 120 °C for 3 h, monitored in real time, until complete conversion. Then, 20 mL of saturated brine was added, and the mixture was extracted twice with 20 mL of ethyl acetate. The supernatant was collected, and the organic phase was dried over anhydrous Na₂SO₄. The solution was then concentrated by rotary evaporation to obtain the crude quinazoline product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to obtain the pure product.
[0040] The compound (2-arylquinazoline) synthesized in this embodiment 1 H-NMR spectrum as follows Figure 1 As shown.
[0041] The compound (2-arylquinazoline) synthesized in this embodiment 13 C-NMR spectra as follows Figure 2 As shown.
[0042] Example 2: The complete scheme for synthesizing compound (2-(m-methylphenyl)quinazoline) is as follows:
[0043]
[0044] The specific synthetic steps for 2-(m-methylphenyl)quinazoline are as follows:
[0045] 1 mmol (119 mg) of aminoanisidine, 1.4 mmol (170 mg) of m-methylbenzylamine, 0.2 mmol (36 mg) of copper acetate, and 1 mmol (326 mg) of cesium carbonate were weighed sequentially and mixed in a 35 mL pressure-resistant tube. 5 mL of dimethyl sulfoxide was added as a solvent, and the mixture was reacted at 120 °C for 3 h, monitored in real time, until complete conversion. Then, 20 mL of saturated brine was added, and the mixture was extracted twice with 20 mL of ethyl acetate. The supernatant was collected, and the organic phase was dried over anhydrous Na₂SO₄. The solution was then concentrated by rotary evaporation to obtain the crude quinazoline product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to obtain the pure product.
[0046] The compound (2-(m-methylphenyl)quinazoline) synthesized in this embodiment 1 H-NMR spectrum as follows Figure 3 As shown.
[0047] The compound (2-(m-methylphenyl)quinazoline) synthesized in this embodiment 13 C-NMR spectra as follows Figure 4 As shown.
[0048] Example 3: The complete scheme for synthesizing the compound (2-(p-methoxyphenyl)quinazoline) is as follows:
[0049]
[0050] The specific synthetic steps for 2-(p-methoxyphenyl)quinazoline are as follows:
[0051] 1 mmol (119 mg) of aminoanisidine, 1.4 mmol (192 mg) of p-methoxybenzylamine, 0.2 mmol (36 mg) of copper acetate, and 1 mmol (326 mg) of cesium carbonate were weighed sequentially and mixed in a 35 mL pressure-resistant tube. 5 mL of dimethyl sulfoxide was added as a solvent, and the mixture was reacted at 120 °C for 3 h, monitored in real time, until complete conversion. Then, 20 mL of saturated brine was added, and the mixture was extracted twice with 20 mL of ethyl acetate. The supernatant was collected, and the organic phase was dried over anhydrous Na₂SO₄. The solution was then concentrated by rotary evaporation to obtain the crude quinazoline product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to obtain the pure product.
[0052] The compound (2-(p-methoxyphenyl)quinazolin) synthesized in this embodiment 1 H-NMR spectrum as follows Figure 5 As shown.
[0053] The compound (2-(p-methoxyphenyl)quinazolin) synthesized in this embodiment 13 C-NMR spectra as follows Figure 6 As shown.
[0054] Example 4: The complete scheme for synthesizing compound (2-(p-chlorophenyl)quinazoline) is as follows:
[0055]
[0056] The specific synthetic steps for 2-(p-chlorophenyl)quinazoline are as follows:
[0057] 1 mmol (119 mg) of aminoanisidine, 1.4 mmol (197 mg) of p-chlorobenzylamine, 0.2 mmol (36 mg) of copper acetate, and 1 mmol (326 mg) of cesium carbonate were weighed sequentially and mixed in a 35 mL pressure-resistant tube. 5 mL of dimethyl sulfoxide was added as a solvent, and the mixture was reacted at 120 °C for 3 h, monitored in real time, until complete conversion. Then, 20 mL of saturated brine was added, and the mixture was extracted twice with 20 mL of ethyl acetate. The supernatant was collected, and the organic phase was dried over anhydrous Na₂SO₄. The solution was then concentrated by rotary evaporation to obtain the crude quinazoline product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to obtain the pure product.
[0058] The compound (2-(p-chlorophenyl)quinazoline) synthesized in this embodiment 1 H-NMR spectrum as follows Figure 7 As shown.
[0059] The compound (2-(p-chlorophenyl)quinazoline) synthesized in this embodiment 13 C-NMR spectra as follows Figure 8 As shown.
[0060] Example 5: The complete scheme for synthesizing compound (2-(p-nitrophenyl)quinazoline) is as follows:
[0061]
[0062] The specific synthetic steps for 2-(p-nitrophenyl)quinazoline are as follows:
[0063] 1 mmol (119 mg) of aminoanisidine, 1.4 mmol (213 mg) of p-nitrobenzylamine, 0.2 mmol (36 mg) of copper acetate, and 1 mmol (326 mg) of cesium carbonate were weighed sequentially and mixed in a 35 mL pressure-resistant tube. 5 mL of dimethyl sulfoxide was added as a solvent, and the mixture was reacted at 120 °C for 3 h, monitored in real time, until complete conversion. Then, 20 mL of saturated brine was added, and the mixture was extracted twice with 20 mL of ethyl acetate. The supernatant was collected, and the organic phase was dried over anhydrous Na₂SO₄. The crude quinazoline product was then concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to obtain the pure product.
[0064] The compound (2-(p-nitrophenyl)quinazoline) synthesized in this embodiment 1 H-NMR spectrum as follows Figure 9 As shown.
[0065] The compound (2-(p-nitrophenyl)quinazoline) synthesized in this embodiment 13 C-NMR spectra as follows Figure 10 As shown.
[0066] Example 6: The complete scheme for synthesizing compound (2-(p-ethoxyphenyl)quinazoline) is as follows:
[0067]
[0068] The specific synthetic steps for 2-(p-ethoxyphenyl)quinazoline are as follows:
[0069] 1 mmol (119 mg) of aminoanisidine, 1.4 mmol (211 mg) of p-ethoxybenzylamine, 0.2 mmol (36 mg) of copper acetate, and 1 mmol (326 mg) of cesium carbonate were weighed sequentially and mixed in a 35 mL pressure-resistant tube. 5 mL of dimethyl sulfoxide was added as a solvent, and the mixture was reacted at 120 °C for 3 h, monitored in real time, until complete conversion. Then, 20 mL of saturated brine was added, and the mixture was extracted twice with 20 mL of ethyl acetate. The supernatant was collected, and the organic phase was dried over anhydrous Na₂SO₄. The crude quinazoline product was then concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to obtain the pure product.
[0070] The compound (2-(p-ethoxyphenyl)quinazoline) synthesized in this embodiment 1 H-NMR spectrum as follows Figure 11 As shown.
[0071] The compound (2-(p-ethoxyphenyl)quinazoline) synthesized in this embodiment 13 C-NMR spectra as follows Figure 12 As shown.
[0072] Example 7: The complete scheme for synthesizing compound (2-(m-cyanophenyl)quinazoline) is as follows:
[0073]
[0074] The specific synthetic steps for 2-(m-cyanophenyl)quinazoline are as follows:
[0075] 1 mmol (119 mg) of aminoanisidine, 1.4 mmol (185 mg) of m-cyanobenzylamine, 0.2 mmol (36 mg) of copper acetate, and 1 mmol (326 mg) of cesium carbonate were weighed sequentially and mixed in a 35 mL pressure-resistant tube. 5 mL of dimethyl sulfoxide was added as a solvent, and the mixture was reacted at 120 °C for 3 h, monitored in real time, until complete conversion. Then, 20 mL of saturated brine was added, and the mixture was extracted twice with 20 mL of ethyl acetate. The supernatant was collected, and the organic phase was dried over anhydrous Na₂SO₄. The crude quinazoline product was then concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to obtain the pure product.
[0076] The compound (2-(m-cyanophenyl)quinazoline) synthesized in this embodiment 1 H-NMR spectrum as follows Figure 13 As shown.
[0077] The compound (2-(m-cyanophenyl)quinazoline) synthesized in this embodiment 13 C-NMR spectra as follows Figure 14 As shown.
[0078] Example 8: The complete scheme for synthesizing the compound (6-methoxy-2-phenylquinazoline) is as follows:
[0079]
[0080] The specific synthetic steps for 6-methoxy-2-phenylquinazoline are as follows:
[0081] 1 mmol (149 mg) of 5-methoxybenzisoxazole, 1.4 mmol (150 mg) of benzylamine, 0.2 mmol (36 mg) of copper acetate, and 1 mmol (326 mg) of cesium carbonate were weighed sequentially and mixed in a 35 mL pressure-resistant tube. 5 mL of dimethyl sulfoxide was added as a solvent, and the mixture was reacted at 120 °C for 3 h, monitored in real time, until complete conversion. Then, 20 mL of saturated brine was added, and the mixture was extracted twice with 20 mL of ethyl acetate. The supernatant was collected, and the organic phase was dried over anhydrous Na₂SO₄. The solution was then concentrated by rotary evaporation to obtain the crude quinazoline product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to obtain the pure product.
[0082] The compound (6-methoxy-2-phenylquinazoline) synthesized in this embodiment 1 H-NMR spectrum as follows Figure 15 As shown.
[0083] The compound (6-methoxy-2-phenylquinazoline) synthesized in this embodiment 13 C-NMR spectra as follows Figure 16 As shown.
[0084] The above embodiments are merely preferred technical solutions of the present invention and should not be considered as limitations on the present invention. The embodiments and features described in these embodiments can be arbitrarily combined without conflict. The scope of protection of the present invention should be limited to the technical solutions described in the claims, including equivalent substitutions of the technical features described in the claims. That is, equivalent substitutions and improvements within this scope are also within the scope of protection of the present invention.
Claims
1. A method for synthesizing a 2-arylquinazoline compound, characterized in that, The chemical reaction formula for the synthesis method is as follows: , where R 1 Selected from hydrogen, halogen groups, alkyl, nitro, or alkoxy groups; R 2 It is selected from hydrogen, halogen groups, alkyl, trifluoromethyl, nitro or alkoxy.
2. The method for synthesizing a 2-arylquinazoline compound according to claim 1, characterized in that, Includes the following steps: Step 1: Add ammoniacal anhydride, benzylamine, copper acetate, and cesium carbonate to the reaction vessel, and add DMSO as the reaction solvent; Step 2: The reaction vessel is sealed, and the reaction is carried out at 120°C for 3 hours. Step 3: After the substrate disappears as detected by TLC, the reaction vessel is allowed to cool to room temperature. Then, it is extracted with saturated brine, retaining the organic phase. An equal volume of ethyl acetate is added to the aqueous phase for back-extraction to separate the organic and aqueous phases. Step 4: After drying the organic phase with anhydrous sodium sulfate, filter, evaporate to dryness, and separate by column chromatography to obtain the 2-arylquinazoline compound.
3. A method for synthesizing a 2-arylquinazoline compound according to claim 1 or 2, characterized in that, The molar ratio of the aminoanidine and benzylamine fed is 1:1.4.