Novel synthetic method of CDK-4/6 inhibitor

Abstract

The invention discloses a novel synthetic method of a CDK-4 / 6 inhibitor. The method comprises the steps of mixing 1:2,4-dichloro, 5-acetyl pyrimidine and alkali in a solvent, reacting and carrying out crystallization and suction filtration to obtain a compound 2-chloro-4-cyclopentylamine-5-acetyl pyrimidine; dissolving fructone into anhydrous tetrahydrofuran, and performing recrystallization with ethyl acetate to obtain a compound 4,6-acetyl-2-chloro-8-cyclopentyl-5-methylpyridine (2,3-d) pyrimidino-7(8H)-ketone; mixing the 4,6-acetyl-2-chloro-8-cyclopentyl-5-methylpyridine (2,3-d) pyrimidino-7(8H)-ketone with alkali and a compound 5 tert-butyl4-(6-aminopyridine-3-yl) piperazine-1-carboxyl tert-butyl ester in DMF, methylbenzene and dimethylsulfoxide, heating and reacting to obtain a compound 6 4-(6-(8-cyclopentyl-5-methyl-6-(2-methyl-1,3-dioxolame-2-yl)-7-oxo-7,8-dihydropyridino-(2,3-d) pyrimidine-2-yl) amino) pyridine-3-yl) piperazine-1-carboxyl tert-butyl ester; and finally, adding the compound 6 4-(6-(8-cyclopentyl-5-methyl-6-(2-methyl-1,3-dioxolame-2-yl)-7-oxo-7,8-dihydropyridino-(2,3-d) pyrimidine-2-yl) amino) pyridine-3-yl) piperazine-1-carboxyl tert-butyl ester into acid liquid, and reacting to obtain the corresponding salt of 6-acetyl-8-cyclopentyl-5-methyl-2-((5(piperazine-1-yl) pyridine-2-yl) amino) pyridino-(2,3-d) pyrimidine-7(8H)-ketone. The synthetic process is low in cost, is simple and environment-friendly and is suitable for industrial volume production.

Description

technical field [0001] The invention relates to the medical industry, in particular to a method for synthesizing protein-dependent kinase 4 and 6 inhibitors. Background technique [0002] Palbociclib is an experimental, oral, targeted agent that selectively inhibits cyclin-dependent kinase 4 and 6 (CDK4 / 6), restores cell cycle control, and blocks tumor cell proliferation. Previously, the FDA granted palbociclib the breakthrough therapy designation for the treatment of advanced or metastatic ER+ / HER2- breast cancer in April 2013. The loss of cell cycle control is a hallmark feature of cancer, and CDK4 / 6 is overactive in many cancers, leading to Cell proliferation is out of control. CDK4 / 6 is a key regulator of the cell cycle, which can trigger the transition of the cell cycle from the growth phase (G1 phase) to the DNA replication phase (S1 phase). In estrogen receptor-positive (ER+) breast cancer (BC), hyperactivity of CDK4 / 6 is very frequent, and CDK4 / 6 is a key downstrea...

AI Technical Summary

Problems solved by technology

[0003] The disadvantage of this process is that the reaction conditions are relatively harsh, and the yield is low and the number of reaction steps is large. The synthesis process needs to use flammable and explosive materials such as lithium aluminum tetrahydrogen and sodium hydride; this route is only suitable for laboratory-scale production. In commercial scale production, that is, in kilogram-level production, the purity and yield cannot meet the requirements, so people are still exploring new synthetic routes

[0004] Wherein the above-mentioned second and fifth steps use a very expensive homogeneous catalyst for two times, and the requirements for the reaction device are very strict; it is an anhydrous and oxygen-free reaction, and the cost is high, which is not suitable for industrial production; and the final product The first two steps use heavy metal catalysts, as a pharmaceutical intermediate, it is necessary to remove the precious metal palladium, which greatly increases the difficulty and complexity of the process