Method for preparing piperazine pyridine compound through continuous reaction

Abstract

The invention relates to a method for preparing a piperazine pyridine compound through a continuous reaction. The method comprises the steps of continuous condensation and hydrogenation. The continuous condensation reaction comprises the following steps: mixing a piperazine alkali solution and a pyridine solution which are used as raw materials, and reacting in a pipeline reactor. The reaction temperature of the pipeline reactor can be set in a temperature range of 10-80 DEG C, preferably 20-60 DEG C. The reaction time can also be set, for example, the reaction time ranges from 30 S to 300 S, and preferably, the reaction time is about 80 S. Then, a continuous hydrogenation reaction step is carried out, the temperature of the continuous hydrogenation reaction is controlled to be 10-100 DEG C, preferably about 40-80 DEG C, and the reaction time is controlled to be 20-200 S, preferably about 100 S. The continuous hydrogenation reduction reaction can be carried out in a catalyst fixed bed, and can also be carried out in a continuous microreactor.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a preparation method of a piperazine pyridine compound. Background technique [0002] Palbociclib combined with letrozole as endocrine-based first-line therapy for patients with advanced breast cancer. [0003] The main synthetic method of palbociclib is 4-(6-aminopyridin-3-yl)piperazine-tert-butyl carboxylate and 6-bromo-2-chloro-8-cyclopentyl-5-methyl-pyridine Condensation of [2,3-D]pyrimidin-7(8H)-one, followed by heck reaction, and then deprotection to form a salt. Among them, the synthesis of 4-(6-aminopyridin-3-yl)piperazine-tert-butyl carboxylate, according to literature reports, mainly contains the following two synthetic routes: According to the WO2010020675 process description, using 5-chloro-2-nitro Pyridine and piperazine are condensed in tert-butanol, and then in tetrahydrofuran, potassium carbonate is used as a base, free amino groups are protected with Boc...

AI Technical Summary

Problems solved by technology

Low heat transfer efficiency will lead to high local temperature, and uneven mass transfer will lead to high local concentration of the material, which will easily lead to rapid temperature rise and lead to out-of-control reaction, eventually causing dangers such as overflow and explosion.

And as the reaction proceeds, the concentration of the reaction substrate will gradually decrease, and the reaction will gradually slow down or even stop. Even if the reaction time is increased, it is difficult to ensure the complete conversion of the reactant

On the one hand, it causes a large amount of unreacted Grignard reagent to be wasted; on the other hand, due to the high activity of Grignard reagent, post-processing such as quenching has a high risk

Therefore, it is difficult to meet the requirements of safety, stability and high efficiency of the reaction at the same time based on the batch tank process developed by the existing technology.

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