A kind of industrial preparation method of Ribociclib

Abstract

The invention relates to an industrial preparation method for ribociclib. The method comprises the following steps: carrying out a condensation reaction on N,N-dimethyl-2,2-dihalo-4-cyano-n-butanamide(II) and a methylenenation reagent (III) to prepare a compound of formula IV; condensing the compound of formula IV and a compound of formula V to obtain a compound of formula VI; carrying out an N-substitution reaction on the compound VI and cyclopentane halide to obtain N,N-dimethyl-7-cyclopentyl-2-{5-[(4-PG-substituted)piperazin-1-yl)pyridin-2-yl]}amino-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (VIII), and removing the PG substituent from the compound VIII to obtain the ribociclib. The method of the invention has the advantages of cheap and easily available raw materials, simple process flow, safety in operation, and low cost.

Description

technical field

[0001] The invention relates to an industrial preparation method of ribociclib, which belongs to the technical field of medicinal chemistry. Background technique

[0002] Ribociclib, whose trade name is Kisqali, is a dual inhibitor of highly specific cell cycle-dependent kinases (CDK4 and CDK6) being developed by Novartis. Studies on 17 neuroblastomas have shown that Ribociclib Sidney (I) can significantly inhibit the growth of 12 types of neurocytoma, and was approved by the US FDA and European EMA in March and August 2017, respectively, for premenopausal hormone receptor-positive and human epidermal growth factor-responsive Treatment of body 2 negative advanced breast cancer. The results of the second clinical phase III of Ribociclib for the treatment of advanced or metastatic breast cancer announced by Novartis showed that the treatment effect is significant. In addition, Ribociclib has high protein binding rate, long physiological half-life, effective o...

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