A kind of synthetic method of anti-influenza drug

Abstract

The invention discloses a synthesis method of a novel anti-influenza drug baloxavir dipivoxil, which uses thiosalicylic acid compound 1 and 1-(halomethyl)-2,3-difluorobenzene compound 2 as starting materials Direct docking to obtain compound 3, and then use PPA ring closure to obtain 7,8-difluorodibenzo[b,e]thiapine-11(6H)-one compound 4, and then obtain the key compound 4 under the catalysis of chiral enzyme Chiral Thiazem Intermediate Compound 5. Then compound 5 is directly condensed with the key chiral fragment compound 6 by Mitsubobu reaction to obtain compound 7, and finally removes the alkyl protection and condenses with ((methoxycarbonyl) oxygen) 4-toluenesulfonic acid methyl ester to obtain the final product compound 9 bar loxavir dipivoxil. This synthetic route reduces the difficulty of enlarging the process operation of the route, reduces the generation of by-products, improves the product purity, and reduces the cost of the route. The specific route:

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a chemical synthesis method for the key intermediate and raw material of the novel anti-influenza drug baloxavir dipivoxil. Background technique [0002] In February 2018, the new anti-influenza drug Baloxavir marboxil (trade name: Xofluza), developed by Shionogi in Japan and jointly researched with Roche in Switzerland, received accelerated approval in Japan and was approved for marketing. Baloxavir dipivoxil is an innovative Cap-dependent endonuclease inhibitor and one of the few new drugs in the world that can inhibit the proliferation of influenza virus. In June 2018, the U.S. Food and Drug Administration (FDA) accepted the new drug application for baloxavir dipivoxil and granted it a priority review qualification. If approved, baloxavir dipivoxil will become the first oral single-dose antiviral drug, and also the first anti-influenza drug with an in...

AI Technical Summary

Problems solved by technology

This method has long steps, the preparation cost of the key thiazem fragment is high, and it needs to use the odorous and highly toxic reagent thiophenol, which makes industrial scale-up difficult; in addition, the key thiazem fragment is a racemate, and the subsequent docking reaction involves chiral Although the induction has a certain selectivity, not only part of the thiazem fragment material is wasted but also part of the optical isomer is generated, so the overall yield is low, the utilization rate of raw materials is not high, and the process cost is high

Images