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Process for the preparation of 8-fluoro-2-(4-((methylamino)methyl)phenyl)-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6(3H)-one

IP.com Disclosure Number: IPCOM000249836D
Publication Date: 2017-Apr-13
Document File: 1 page(s) / 211K

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Process for the preparation of 8-fluoro-2-(4-((methylamino)methyl)phenyl)-4,5-dihydro-

1H-azepino[5,4,3-cd]indol-6(3H)-one

8-Fluoro-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6(3H)-one (referred herein as compound 1)

is an intermediate in the preparation of 8-fluoro-2-(4-((methylamino)methyl)phenyl)-4,5-

dihydro-1H-azepino[5,4,3-cd]indol-6(3H)-one (referred to herein as compound A).

Compound 1 is prepared in three steps starting from methyl 6-fluoro-1H-indole-4-

carboxylate. In the first step, 6-fluoro-1H-indole-4-carboxylate reacts with formaldehyde and

dimethylamine, in aqueous acetic acid as a solvent, to form methyl 3-

((dimethylamino)methyl)-6-fluoro-1H-indole-4-carboxylate. In the second step , methyl 3-

((dimethylamino)methyl)-6-fluoro-1H-indole-4-carboxylate reacts with potassium cyanide in

the presence of methyl iodide to give methyl 3-(cyanomethyl)-6-fluoro-1H-indole-4-

carboxylate. Methyl 3-(cyanomethyl)-6-fluoro-1H-indole-4-carboxylate is hydrogenated in

the third step in alcoholic ammonia solution (for example ethanol or methanol) over metal

catalyst such as Raney Nickel, Pd/C or Pt/C, to form compound 1.

Compound 1 can be converted to 2-bromo-8-fluoro-4,5-dihydro-1H-azepino[5,4,3-cd]indol-

6(3H)-one by employing the process described in the Org. Process Res. Dev. 2012, 16,

1897−1904 or conventional methods of organic synthesis practiced by those skilled in the art

(for example bromination with bromine, N-bromosuccinimide or 1,3-dibromo-5,5-

dimethylhydantoin).

2-Bro...