Preparation method for high-purity regorafenib

Abstract

The invention discloses an improved preparation method for high-purity regorafenib (a compound I), particularly a preparation method for a compound 3 (a regorafenib intermediate) with the structure shown in the description, wherein the compound 3 is further used for industrial preparation of regorafenib with extremely excellent purity. By adopting a phase transfer catalyst, the method is simple and convenient to operate and environmental-friendly, can effectively inhibit generation of impurities, is low in requirement on equipment and is suitable for industrial production of high-purity regorafenib on a large scale.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry. Specifically relates to the drug commonly known as Regorafenib, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-2-fluoro-(4-(2-(N- A method for preparing a high-purity product of methylcarbamoyl)-4-pyridyloxy)phenyl)urea. Background technique [0002] The Chinese name of Regorafenib is: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-2-fluoro-(4-(2-(N-methylammonia) Formyl)-4-pyridyloxy)phenyl)urea, English name: [0003] 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea. Trade name: Stivarga. The structural formula is as follows: [0004] [0005] Regorafenib is a new type of multikinase inhibitor, which can block various enzymes that promote tumor growth, and was discovered and developed by Bayer (Bayer). In September 2012, the US FDA approved it for the treatment of metastatic colorectal cancer. In February 2013, its new indication (...

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Problems solved by technology

[0010] This route has the following disadvantages: (1) the first step reaction requires a high temperature of 100 ° C for more than 16 hours, and the reaction cycle is long; (2) the second step reaction requires room temperature for more than 72 hours, and the reaction cycle is long; (3) the first step reaction There are unavoidable impurity A, impurity B-1, impurity C-1, impurity 3-1 and impurity D-1 (both 5-20%) to generate in the final product, and then lead to impurities in the final product (impurity A, impurity B , impurity C and impurity D) are difficult to remove, and high-purity regorafenib finished products cannot be obtained

[0012] Although the preparation method of regorafenib is disclosed in the patent WO2008043446, the method has the following disadvantages: (1) the impurity removal effect is poor, and the resulting product has low purity (Example 1.1); (2) the crystallization conditions are harsh (-20 ℃ evaporation solvent, crystallization), is unfavorable for industrialization (embodiment 1.2); (3) crystallization period is long (1~2 weeks, embodiment 1.3, embodiment 1.4), and then limits the industrialized production of regorafenib

[0015] The working example in the patent WO2011128261 discloses an optimized method for synthesizing regorafenib (synthetic method 3), which has the following disadvantages: (1) protection and deprotection, many steps, cumbersome operation; (2) the reaction of stage 1 The color of the liquid is very dark, dark black, and the post-treatment extraction and layering operations are very difficult; (3) in the reaction of stage 1, impurity A, impurity B-1, and impurity C-1 are also inevitably generated (more than 5% ); (4) In stage 3, the crude product of regorafenib needs to be salted first and then freed to obtain the finished product of regorafenib; (5) The crystallization process requires crystal seed induction

This method has the following disadvantages: (1) the reaction solution in step 1 has low purity (less than 50%) and many impurities, resulting in excessive impurities in the finished product of regorafenib including impurity A, impurity B, impurity C and impurity D; (2) ) Intermediate 3 requires column chromatography purification to remove impurities, which is not conducive to industrial production

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