Method for synthesizing 2-position arylpyrido[2, 3-d] pyrimidine derivative

Abstract

A method for synthesizing a 2-position arylpyrido[2, 3-d] pyrimidine derivative comprises the following steps: firstly, dissolving 3-aminomethylpyridin-2-amine and aryl aldehyde in acetonitrile, and then adding cuprous chloride, 2, 2, 6, 6-tetramethylpiperidin-1-oxide free radical and triethylene diamine into a reaction solution in an oxygen atmosphere, refluxing till the completion of a reaction,removing a solvent, and performing thin-layer chromatographic separation on a residue to obtain a 2-substituted pyrido[2, 3-d] pyrimidine. The method has the advantages as follows: 1), the preparation of a catalyst is simple and high in efficiency; 2), the catalyst does not contain precious metals, is low in price, and has very high chemical stability; 3), the catalytic process is good in selectivity, free of other side reactions, high in efficiency and environment-friendly; the operation is convenient, the cost is low, the yield is high, mass synthesis can be performed, and the method is applicable to industrial production.

Description

technical field

[0001] The invention relates to the field of chemical industry, in particular to a new synthesis method of 2-arylpyrido[2,3-d]pyrimidine derivatives. Background technique

[0002] Pyridopyrimidine compounds are a class of heterocyclic compounds with high activity, which have the functions of sterilization, antifungal, antitumor, antigout and anticardiovascular diseases, and have herbicide and insecticide effects in the field of pesticides. Therefore, it has become one of the research hotspots in the field of chemistry today. Among them, pyrido[2,3-d]pyrimidine compounds are a class of pyridopyrimidine heterocyclic compounds that have been studied more, and the demand for such compounds is also increasing.

[0003] At present, there are many synthetic techniques for pyridopyrimidine compounds, but most of them use more expensive raw materials, or the reaction conditions are relatively harsh, or the yield is low, and at the same time, they are not friendly to ...

Examples

Embodiment 1

[0015] Synthesis of 2-Phenylpyrido[2,3-d]pyrimidine

[0016] Add 3.0g (24.4mmol) 3-aminomethylpyridin-2-amine and 2.5g (24.4mmol) benzaldehyde in a dry round bottom flask, 30mL acetonitrile as solvent, stir at 80ºC for 2h, and then under oxygen atmosphere, Add 123mg of cuprous chloride, 384mg of 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO), and 280mg of triethylenediamine (DABCO) into the reaction solution, heat to reflux, and stop the reaction , neutralized with sodium sulfite, suction filtered to obtain a solid, and the crude product was separated by thin-layer chromatography (dichloromethane:methanol=5:1) to obtain a white solid 2-phenylpyrido[2,3-d]pyrimidine, m.p. : 197-197.2ºC. Yield: 4.9 g (97.2%). Characterization data: 1 H NMR (400 MHz, DMSO) δ: 9.52 (s, 1H), 9.26 (s,1H), 8.73 (m,1H), 8.29 (1H), 7.54 (m,2H), 7.28 (s,3H) ppm . EI-MS (m / z): 207.

Embodiment 2

[0018] Synthesis of 2-(4-methoxy)phenylpyrido[2,3-d]pyrimidine

[0019] Add 3.0g (24.4mmol) 3-aminomethylpyridin-2-amine and 2.5g (24.4mmol) p-methoxybenzaldehyde in a dry round-bottomed flask, 30mL acetonitrile as solvent, stir at 80ºC for 2h, then Under an oxygen atmosphere, add 123mg of cuprous chloride, 384mg of 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO), and 280mg of DABCO into the reaction liquid, and heat to reflux. After the reaction stops, use sodium sulfite Neutralize and filter with suction to obtain a solid, and the crude product is separated by thin-layer chromatography (dichloromethane:methanol=10:1) to obtain an off-white solid 2-(4-methoxy)phenylpyrido[2,3- d] Pyrimidine, melting point: 157.6-157.9ºC. Yield: 5.61 g (96.9%). Characterization data: 1 H NMR (400 MHz, DMSO) δ: 9.48(s, 1H), 9.24(s, 1H), 8.29(s, 1H), 8.27(s, 1H), 7.52(m, 2H), 7.27 (s, 2H ), 3.92(s, 3H) EI-MS (m / z): 237.

Embodiment 3

[0021] Synthesis of 2-(4-fluoro)phenylpyrido[2,3-d]pyrimidine

[0022] Add 3.0g (24.4mmol) 3-aminomethylpyridin-2-amine and 3.0g (24.4mmol) p-fluorobenzaldehyde in a dry round bottom flask, 30mL acetonitrile as a solvent, stir at 80ºC for 2h, and then oxygen atmosphere 123mg of cuprous chloride, 384mg of 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO), and 280mg of DABCO were added to the reaction solution, heated to reflux, and neutralized with sodium sulfite after the reaction stopped. , suction filtered to obtain a solid, and the crude product was separated by thin-layer chromatography (dichloromethane:methanol=10:1) to obtain an off-white solid 2-(4-fluoro)phenylpyrido[2,3-d]pyrimidine, Melting point: 210.6-211.8ºC. Yield: 5.37 g (98.0%). Characterization data: 1 H NMR (400 MHz, DMSO)δ: 9.53(s,1H),9.29(s,1H),8.75(s,1H),8.32(s,1H),7.70(m,2H), 7.27(s,2H ), EI-MS (m / z): 224.

technical field

[0001] The invention relates to the field of chemical industry, in particular to a new synthesis method of 2-arylpyrido[2,3-d]pyrimidine derivatives. Background technique

[0002] Pyridopyrimidine compounds are a class of heterocyclic compounds with high activity, which have the functions of sterilization, antifungal, antitumor, antigout and anticardiovascular diseases, and have herbicide and insecticide effects in the field of pesticides. Therefore, it has become one of the research hotspots in the field of chemistry today. Among them, pyrido[2,3-d]pyrimidine compounds are a class of pyridopyrimidine heterocyclic compounds that have been studied more, and the demand for such compounds is also increasing.

[0003] At present, there are many synthetic techniques for pyridopyrimidine compounds, but most of them use more expensive raw materials, or the reaction conditions are relatively harsh, or the yield is low, and at the same time, they are not friendly to ...

Examples

Embodiment 1

[0015] Synthesis of 2-Phenylpyrido[2,3-d]pyrimidine

[0016] Add 3.0g (24.4mmol) 3-aminomethylpyridin-2-amine and 2.5g (24.4mmol) benzaldehyde in a dry round bottom flask, 30mL acetonitrile as solvent, stir at 80ºC for 2h, and then under oxygen atmosphere, Add 123mg of cuprous chloride, 384mg of 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO), and 280mg of triethylenediamine (DABCO) into the reaction solution, heat to reflux, and stop the reaction , neutralized with sodium sulfite, suction filtered to obtain a solid, and the crude product was separated by thin-layer chromatography (dichloromethane:methanol=5:1) to obtain a white solid 2-phenylpyrido[2,3-d]pyrimidine, m.p. : 197-197.2ºC. Yield: 4.9 g (97.2%). Characterization data: 1 H NMR (400 MHz, DMSO) δ: 9.52 (s, 1H), 9.26 (s,1H), 8.73 (m,1H), 8.29 (1H), 7.54 (m,2H), 7.28 (s,3H) ppm . EI-MS (m / z): 207.

Embodiment 2

[0018] Synthesis of 2-(4-methoxy)phenylpyrido[2,3-d]pyrimidine

[0019] Add 3.0g (24.4mmol) 3-aminomethylpyridin-2-amine and 2.5g (24.4mmol) p-methoxybenzaldehyde in a dry round-bottomed flask, 30mL acetonitrile as solvent, stir at 80ºC for 2h, then Under an oxygen atmosphere, add 123mg of cuprous chloride, 384mg of 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO), and 280mg of DABCO into the reaction liquid, and heat to reflux. After the reaction stops, use sodium sulfite Neutralize and filter with suction to obtain a solid, and the crude product is separated by thin-layer chromatography (dichloromethane:methanol=10:1) to obtain an off-white solid 2-(4-methoxy)phenylpyrido[2,3- d] Pyrimidine, melting point: 157.6-157.9ºC. Yield: 5.61 g (96.9%). Characterization data: 1 H NMR (400 MHz, DMSO) δ: 9.48(s, 1H), 9.24(s, 1H), 8.29(s, 1H), 8.27(s, 1H), 7.52(m, 2H), 7.27 (s, 2H ), 3.92(s, 3H) EI-MS (m / z): 237.

Embodiment 3

[0021] Synthesis of 2-(4-fluoro)phenylpyrido[2,3-d]pyrimidine

[0022] Add 3.0g (24.4mmol) 3-aminomethylpyridin-2-amine and 3.0g (24.4mmol) p-fluorobenzaldehyde in a dry round bottom flask, 30mL acetonitrile as a solvent, stir at 80ºC for 2h, and then oxygen atmosphere 123mg of cuprous chloride, 384mg of 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO), and 280mg of DABCO were added to the reaction solution, heated to reflux, and neutralized with sodium sulfite after the reaction stopped. , suction filtered to obtain a solid, and the crude product was separated by thin-layer chromatography (dichloromethane:methanol=10:1) to obtain an off-white solid 2-(4-fluoro)phenylpyrido[2,3-d]pyrimidine, Melting point: 210.6-211.8ºC. Yield: 5.37 g (98.0%). Characterization data: 1 H NMR (400 MHz, DMSO)δ: 9.53(s,1H),9.29(s,1H),8.75(s,1H),8.32(s,1H),7.70(m,2H), 7.27(s,2H ), EI-MS (m / z): 224.

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