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Process for the synthesis of 6-amino-4-(3-chloro-4-fluorophenylamino)-7-ethoxyquinoline-3-carbonitrile

Process for the synthesis of 6-amino-4-(3-chloro-4-fluorophenylamino)-7-ethoxyquinoline-3-carbonitrile description/claims

This application claims priority from copending provisional application Ser. No. 60/503,106, filed Sep. 15, 2003, the entire disclosure of which is hereby incorporated by reference.

The two most frequently used synthetic methods for the preparation of 3-cyano-4-quinolones or 3-carboalkyloxyquinolones are intramolecular Friedel-Crafts reactions and electrocyclic ring closures of N-(2-carboxyvinyl)-aniline derivatives. Friedel-Crafts conditions work well for electron rich anilines, moderately for unsubstituted anilines, and poorly or not at all for electron-deficient anilines and are not useful for large scale preparation of 3-cyano-4-quinolones especially utilizing electron deficient anilines. The electron withdrawing groups of the aniline reduce the nucleophilicity of the aromatic ring to the point that side reactions compete with, if not dominate, the desired intramolecular condensation.

Thermal conditions for electrocyclic ring closures of N-(2-carboxyvinyl)-aniline derivatives typically require temperatures in excess of 240° C. In U.S. Pat. No. 6,002,008 the construction of 3-cyano-4-quinolones has been achieved by electrocyclic ring closure reactions of N-(2-carboxyvinyl) aniline derivatives by heating to 260° C. in diphenyl ether. Thermal decomposition of either the final product and/or the starting material may compromise the purity of the final product as a result of the high temperature reaction conditions. As a result, reactions are often run at high dilution resulting in an inefficient large-scale process due to low throughput.

The production of 3-cyano-4-quinolones by electrocyclic ring closure suffers from all of the problems mentioned above. For example, it is known that 7-ethoxy-4-hydroxy-6-nitroquinoline-3-carbonitrile decomposes at 240° C. while the minimum temperature required for cyclization is 256° C.

There is a need for a process which overcomes the problem of thermal decomposition of intermediate compounds, including 6-amino-4-(3-chloro-4-fluoro-1-phenylamino)-7-ethoxy-quinoline-3-carbonitrile used to epidermal growth factor receptor (EGFR) inhibitors useful in the treatment of cancer.

The following experimental details are set forth to aid in an understanding of the invention, and are not intended, and should not be construed to limit in any way the invention set forth in the claims that follow thereafter.

This invention relates to producing 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitrile which comprises: (a) acylating 2-Amino-5-nitrophenol with an acylating agent to obtain 2-Acetamido-5-nitrophenol; (b) alkylating 2-Acetamido-5-nitrophenol of step (a) with an alkylating agent in the presence of a base to obtain 4-Acetamide-3-ethoxynitrobenzene; (c) reacting 4-Acetamide-3-ethoxynitrobenzene of step (b) to obtain 4-Acetamido-3-ethoxy-aniline; (d) condensing 4-Acetamido-3-ethoxy-aniline of step (c) with (ethoxymethylene)cyanoacetate to yield 3-(4-acetamido-3-ethoxyaniline)-2-cyano-propenoic acid ethyl ester; (e) cyclizing 3-(4-Acetamido-3-ethoxyaniline)-2-cyano-propenoic acid ethyl ester of step (d) to yield 3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline; (f) reacting 3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline of step (e) with a chlorine-substituting reagent to obtain 4-Chloro-3-cyano-7-ethoxy-6-N-acetylquinoline; (g) hydrolyzing 4-Chloro-3-cyano-7-ethoxy-6-N-acetylquinoline of step (f) with acid to yield 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitrile; (h) optionally converting 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitrile to a pharmaceutically acceptable salt form thereof.

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