Novel preparation method of tofacitinib citrate

Abstract

The invention discloses a novel preparation method of tofacitinib citrate, and particularly provides a preparation method of tofacitinib citrate. The preparation method comprises the following steps:adding a tofacitinib intermediate crude product in a solvent, completely dissolving at a relatively high temperature, and adding medicinal activated carbon and activated aluminum oxide for stirring and adsorption; filtering to remove the medicinal activated carbon and the activated aluminum oxide, adding a pre-cooled alkaline aqueous solution in a filtrate, reducing the temperature to 0-5 DEG C for crystallization, washing and then drying to obtain a tofacitinib intermediate refined product; dissolving citric acid monohydrate in an ethanol aqueous solution, then adding the tofacitinib intermediate refined product and crystallizing to obtain the tofacitinib citrate. The novel preparation method disclosed by the invention has the benefits that hard-to-remove pigments and impurities in the tofacitinib intermediate crude product can be significantly reduced, and further, the high-purity tofacitinib intermediate refined product is obtained.

Description

technical field

[0001] The invention relates to the field of medicine, in particular to a novel preparation method of tofacitinib citrate. Background technique

[0002] Tofacitinib citrate is a Janus kinase inhibitor developed by Pfizer, and its chemical name is 3-{(3R,4R)-4-methyl-3-[formazan Base-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile citrate, the structural formula is as follows:

[0003]

[0004] The drug was approved by the U.S. Food and Drug Administration (FDA) in 2012 for the treatment of moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate therapy.

[0005] In the existing process, use N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-7-H-pyrrole[2,3-d]pyrimidin-4-amine as Raw materials, react with cyanoacetate compounds under alkaline conditions to prepare tofacitinib, such as the preparation method reported in the patent document WO2007012953A2, the yield is low (ab...

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