Aryl pyridone compound preparation method

Abstract

The invention provides an aryl pyridone compound preparation method which includes the step: reacting N-methyl-2-pyrolidone and aromatic heterocyclic boronic acid in organic solvents under rhodium catalysts and ligands to obtain aryl-substituted pyridone compound. According to the method, high-yield synthesis of the aryl pyridone compound is achieved, and the aryl pyridone compound has good application prospect and industrial production potential.

Description

technical field

[0001] The invention relates to a preparation method of a biologically active intermediate compound, more particularly to a preparation method of a pharmaceutical intermediate aryl pyridone compound, which belongs to the technical field of medicine and organic chemical synthesis. Background technique

[0002] The structure of arylpyridone widely exists in natural active compounds and medicines, and this kind of compounds have very important applications in the pharmaceutical industry as synthetic intermediates. The preparation method of aryl pyridone compounds has been paid more and more attention by scientists, and a lot of researches have been done on it. So far, the preparation methods of arylpyridones have been reported in the prior art, such as "Iron catalyzedregio-selective directarylation at C-3position of N-alkyl-2-pyridone" reported by Atanu Modak et al. However, these existing methods still have some defects, such as low product yield, complicated ...

Examples

Embodiment 1

[0025]

[0026] At 0°C, add 1 mmol N-methyl-2-pyridone, 1.2 mmol formula (II-1) compound, 0.1 mmol bis(1,5-cyclooctadiene) rhodium tetrafluoroborate to the reactor , 0.1 mmol of Ligand L, 8 ml of N,N-dimethylformamide and 2 ml of toluene, stirred at 60°C for 6 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate, the organic phase was combined to remove the solvent, and the resulting residue was separated by silica gel column chromatography to obtain the compound of formula (III-1) with a yield of 89.5%. 1 HNMR (CDCl 3 ,400MHz): δ3.61(s,3H),6.27(dd,J=6.9,6.9Hz,1H),7.35(dd,J=2.0,6.9Hz,1H),7.53(dd,J=2.0,6.9 Hz, 1H), 7.62 (d, J=8.2Hz, 2H), 7.81 (d, J=8.2Hz, 2H).

Embodiment 2

[0028]

[0029] At 0°C, add 1 mmol N-methyl-2-pyridone, 1.5 mmol formula (II-2) compound, 0.1 mmol bis(1,5-cyclooctadiene) rhodium tetrafluoroborate to the reactor , 0.1 mmol of Ligand L, 6 ml of N,N-dimethylformamide and 4 ml of toluene, stirred at 60°C for 6 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate, the organic phase was combined to remove the solvent, and the resulting residue was separated by silica gel column chromatography to obtain the compound of formula (III-2) with a yield of 85.2%. 1 HNMR (CDCl 3 ,400MHz): δ2.37(s,3H),3.60(s,3H),6.22(dd,J=6.9,6.9Hz,1H),7.20(d,J=7.9Hz,2H),7.28(dd, J=2.0, 6.9Hz, 1H), 7.46(dd, J=2.0, 6.9Hz, 1H), 7.59(d, J=7.9Hz, 2H).

Embodiment 3

[0031] At a temperature of 0°C, 1 mmol of N-methyl-2-pyridone, 1.2 mmol of the compound of formula (II-1), 0.1 mmol of bis(1,5-cyclooctadiene) rhodium chloride, 0.1 mmol of Ligand L, 8 ml of N,N-dimethylformamide and 2 ml of toluene were stirred at 60°C for 6 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate, the organic phase was combined to remove the solvent, and the resulting residue was separated by silica gel column chromatography to obtain the compound of formula (III-1) with a yield of 86.7%.

technical field

[0001] The invention relates to a preparation method of a biologically active intermediate compound, more particularly to a preparation method of a pharmaceutical intermediate aryl pyridone compound, which belongs to the technical field of medicine and organic chemical synthesis. Background technique

[0002] The structure of arylpyridone widely exists in natural active compounds and medicines, and this kind of compounds have very important applications in the pharmaceutical industry as synthetic intermediates. The preparation method of aryl pyridone compounds has been paid more and more attention by scientists, and a lot of researches have been done on it. So far, the preparation methods of arylpyridones have been reported in the prior art, such as "Iron catalyzedregio-selective directarylation at C-3position of N-alkyl-2-pyridone" reported by Atanu Modak et al. However, these existing methods still have some defects, such as low product yield, complicated ...

Examples

Embodiment 1

[0025]

[0026] At 0°C, add 1 mmol N-methyl-2-pyridone, 1.2 mmol formula (II-1) compound, 0.1 mmol bis(1,5-cyclooctadiene) rhodium tetrafluoroborate to the reactor , 0.1 mmol of Ligand L, 8 ml of N,N-dimethylformamide and 2 ml of toluene, stirred at 60°C for 6 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate, the organic phase was combined to remove the solvent, and the resulting residue was separated by silica gel column chromatography to obtain the compound of formula (III-1) with a yield of 89.5%. 1 HNMR (CDCl 3 ,400MHz): δ3.61(s,3H),6.27(dd,J=6.9,6.9Hz,1H),7.35(dd,J=2.0,6.9Hz,1H),7.53(dd,J=2.0,6.9 Hz, 1H), 7.62 (d, J=8.2Hz, 2H), 7.81 (d, J=8.2Hz, 2H).

Embodiment 2

[0028]

[0029] At 0°C, add 1 mmol N-methyl-2-pyridone, 1.5 mmol formula (II-2) compound, 0.1 mmol bis(1,5-cyclooctadiene) rhodium tetrafluoroborate to the reactor , 0.1 mmol of Ligand L, 6 ml of N,N-dimethylformamide and 4 ml of toluene, stirred at 60°C for 6 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate, the organic phase was combined to remove the solvent, and the resulting residue was separated by silica gel column chromatography to obtain the compound of formula (III-2) with a yield of 85.2%. 1 HNMR (CDCl 3 ,400MHz): δ2.37(s,3H),3.60(s,3H),6.22(dd,J=6.9,6.9Hz,1H),7.20(d,J=7.9Hz,2H),7.28(dd, J=2.0, 6.9Hz, 1H), 7.46(dd, J=2.0, 6.9Hz, 1H), 7.59(d, J=7.9Hz, 2H).

Embodiment 3

[0031] At a temperature of 0°C, 1 mmol of N-methyl-2-pyridone, 1.2 mmol of the compound of formula (II-1), 0.1 mmol of bis(1,5-cyclooctadiene) rhodium chloride, 0.1 mmol of Ligand L, 8 ml of N,N-dimethylformamide and 2 ml of toluene were stirred at 60°C for 6 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate, the organic phase was combined to remove the solvent, and the resulting residue was separated by silica gel column chromatography to obtain the compound of formula (III-1) with a yield of 86.7%.

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