Preparation method of anti-tuberculosis candidate drug pa-824

Abstract

The invention relates to a synthetic method for an antituberculous candidate drug namely PA-824. The method realizes synthesis of the PA-824 through four steps of reactions which comprise a nucleophilic ring-opening reaction, an o-alkylation reaction, an ester deprotection reaction and a transition metal catalyzed carbon-hydrogen bond activated alkoxylation reaction. The preparation method provided by the invention has the advantages of cheap and easily available raw materials needed in the whole preparation process, avoids using an explosive raw material namely 2,4-dinitroimidazole, has simple and easily controllable operation, is convenient to purify, and facilitates to large-scale production.

Description

Technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to the synthesis of a nitroimidazole pyran compound PA-824, which is a candidate drug for anti-tuberculosis. Background technique [0002] PA-824 is a nitroimidazole pyran compound, which is effective against both sensitive and drug-resistant Mycobacterium tuberculosis. It can kill Mycobacterium tuberculosis in the incubation period and has no cross-resistance with first-line anti-tuberculosis drugs. In 2002, the Global Anti-TB Alliance (TB Alliance) and the National Institute of Allergy and Infectious Diseases reached an agreement to study PA-824 as a new anti-tuberculosis drug. The Phase II clinical trial has been completed (the results have not yet been announced), and it is also used as an active ingredient It forms a new compound preparation-PaMZ with moxifloxacin and pyrazinamide and is currently in phase II clinical trials. [0003] PA-824, light yellow crystalline pow...

AI Technical Summary

Problems solved by technology

In 1997, Pathogenesis invented the first synthetic route of PA-824. The synthetic route used silicon protecting groups and a large amount of reagents such as tetrabutylammonium fluoride, and the price was high.

In 2007, the Orita research group improved the first step reaction of the first route, using a solvent-free reaction, and the yield was significantly improved, but the use of silicon protecting groups led to higher synthesis costs and difficulty in the ring-forming reaction of deprotecting groups

In 2010, Sorensen's research group used 2-chloro-4-nitroimidazole as a five-step synthetic route as a raw material, and the overall yield of the route was not high

In 2010, Shanghai Yangfan Company reported a synthetic route using 2,4-dinitroimidazole (the compound needs to be prepared through a 3-step reaction) as a raw material, and a 2014 patent "Synthetic method of anti-tuberculosis drug candidate PA-824" ( Application No. 201410372448.6) disclosed synthetic method, although the yield of the synthetic route is significantly improved, it still needs to use explosive raw material 2,4-dinitroimidazole, which is not conducive to large-scale production

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