Preparation method of regorafenib hydrate

Abstract

The invention belongs to the field of drug synthesis and particularly relates to a preparation method of regorafenib hydrate. 4-methyl-2-pentanone, 4-amino-3-fluorophenol and N-methyl-4-chloro-2-pyridine carboxamide are condensed to obtain a regorafenib intermediate 1, 4-chloro-3-(trifluoromethyl)isocyanate is added for condensation and salt-forming reactions to produce a regorafenib intermediate2, and finally, free hydration is performed in an alkaline acetone aqueous solution to obtain the regorafenib hydrate. The preparation method of the regorafenib hydrate is simple to operate and easy to monitor, has yield up to 90% or above and high efficiency and is applicable to mass industrial production. The prepared regorafenib hydrate has low impurity content, has no solvent residues basically, significantly shortens purification time, has stable properties, keeps stable in accelerated stability tests and has high safety.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of regorafenib hydrate. Background technique [0002] Regorafenib (regorafenib), the chemical name is 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N -Methylpyridine-2-carboxamide, developed by Bayer Healthcare Pharma in Germany and approved by the FDA in the United States, the trade name is Stivarga, which is a new type of diphenylurea tyrosine with oral activity, multi-target and broad spectrum Acid kinase inhibitors can inhibit kinases including VEGFRI-2, PDGFR-β, FGFR1, KIT, etc., thereby exerting anti-tumor effects, and are clinically used for the treatment of metastatic colorectal cancer. [0003] At present, the synthesis of regorafenib mainly includes the following schemes: [0004] Technical scheme 1: Liu Yafang etc. (fine chemical intermediates, 2012,42 (6), 31-34 pages) disclose a kind of method for prepari...

AI Technical Summary

Problems solved by technology

However, the overall yield of this method is low, and N, N-dimethylformamide, which is difficult to recycle, is used in the ether-forming reaction, the synthesis cost is high, the pollution is large, and the synthesis yield of phenyl chloroformate is low. At the same time, the purification of the product also needs column chromatography separation method, which is too economical; although the synthesis process avoids the use of triphosgene, the raw materials -2-nitrophenyl chloroformate and phenyl chloroformate are unstable and corrosive. It has certain damage to the equipment, the industrial production is dangerous, and it is not friendly to the environment

In addition, the resulting product regorafenib monohydrate has poor stability, and it is easy to lose crystal water in organic solvents to become regorafenib free base with poorer solubility, plus regorafenib monohydrate High hygroscopicity and poor stability

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