Method for preparing pyrazol heteroaromatic compound
A heterocyclic compound and a pyrazolo technology are applied in the field of preparing pyrazolo aromatic heterocyclic compounds, and can solve the problems that the synthesis method of pyrazolo aromatic heterocyclic compounds needs to be improved, the preparation process is dangerous, and the reaction temperature is high, and the invention is suitable for The effect of large-scale industrial production, easy separation and purification, and simple process
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[0029] The method for preparing pyrazolo aromatic heterocyclic compounds according to the embodiments of the present invention has a simple process and can effectively overcome the adverse effects caused by the wolff, 1. Kishner, N.M reactions of hydrazine and aldehydes, and does not require the use of flammable and explosive The harsh reaction conditions such as anhydrous hydrazine and high temperature, the reaction can be carried out under mild conditions, the production cost is low, the environmental pollution is small, easy to separate and purify, the yield of the target product is significantly improved, and the content of the product can reach more than 95%. , suitable for large-scale industrial production.
[0030] In step (1), starting material 2 (i.e., 2-substituted or unsubstituted 5-fluoro-4-pyridinecarbaldehyde) and methoxyamine hydrochloride in a weakly basic organic solvent (e.g., tetrahydrofuran) A nucleophilic substitution reaction occurs to generate the imine ...
Embodiment 1
[0039] At room temperature, 2-methoxy-5-fluoro-4-formylpyridine (0.49mol, 73.0g), methoxyamine hydrochloride (0.51mol, 42.6g) and potassium carbonate (0.59mol, 81.5 g) were respectively added to the reaction kettle equipped with 1L tetrahydrofuran solution. After stirring overnight at room temperature, it was filtered and the filtrate was concentrated to give a residue. A 30% by weight aqueous solution of hydrazine hydrate (1 mol) was added dropwise to the residue and refluxed overnight. The progress of the reaction was monitored by LC-MS until the end of the reaction. After evaporating excess hydrazine, 1 L of water was added to the mixture, and after precipitation, the precipitate was filtered, washed with water, and dried to obtain a gray solid. After dissolving the gray solid in tetrahydrofuran, 5 mL of trifluoroacetic acid was added to reflux for 40 minutes, the reaction mixture was concentrated, washed three times with water and tert-butyl methyl ether to obtain a light...
Embodiment 2
[0041] At room temperature, 2-chloro-5-fluoro-4-formylpyridine (0.49mol, 75.0g), methoxylamine hydrochloride (0.51mol, 42.6g) and potassium carbonate (0.59mol, 81.5g) They were added to a reaction kettle containing 1L tetrahydrofuran solution. After stirring overnight at room temperature, it was filtered and the filtrate was concentrated to give a residue. An 85% by weight aqueous solution of hydrazine hydrate (1.47 mol) was added dropwise to the residue and then refluxed overnight, and the progress of the reaction was monitored by LC-MS until the end of the reaction. After evaporating off excess hydrazine, 1 L of water was added to the mixture, and after precipitation, the precipitate was filtered, washed with water, and dried to obtain a gray powder. After the gray powder was dissolved in THF, 10 mL of trifluoroacetic acid was added to reflux for 1 hour, the reaction mixture was concentrated, washed three times with water and tert-butyl methyl ether to obtain a light gray p...
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