合成路线1

The intermediate 4-fluoro-5-hydroxy-2-methylindole (X) can be prepared by three alternative methods. The condensation of 2-fluoro-4-nitroanisole (XI) with 4-chlorophenoxyacetonitrile (XII) by means of potassium tert-butoxide produces a regioisomeric mixture of ortho-nitroarylacetonitriles (XIIIa) and (XIIIb) which, without separation, are reductively cyclized to indoles (XIVa) and (XIVb) by catalytic hydrogenation over Pd/C. After protection of indoles (XIV) as the respective N-Boc derivatives (XVa) and (XVb), metalation with tert-butyllithium followed by treatment with iodomethane yields the corresponding 1-Boc-2-methylindoles, which are further deprotected to (XVIa) and (XVIb) utilizing TFA. Demethylation of the mixture of methoxyindoles (XVI) with BBr3 in cold CH2Cl2 leads to the analogous hydroxyindoles, which are separated by column chromatography to provide the target 4-fluoro-5-hydroxy-2-methylindole (X) (2). In a different method, 2,3,4-trifluoronitrobenzene (XVII) is condensed with ethyl acetoacetate (XVIII) by means of NaH in THF followed by chromatographic separation of the resulting regioisomeric mixture to provide the 2-aryl acetoacetate (XIX). After acidic decarboxylation of (XIX), the obtained arylacetone derivative (XX) is protected as the dimethyl ketal (XXI) with trimethyl orthoformate and montmorillonite K10. Selective displacement of one fluoride group in (XXI) with sodium methoxide in methanol affords 1-(2-fluoro-3-methoxy-6-nitrophenyl)acetone dimethyl ketal (XXII), which is hydrolyzed to ketone (XXIII) under acidic conditions. The reductive cyclization of (XXIII) by means of TiCl3 and ammonium acetate provides 4-fluoro-5-methoxy-2-methylindole (XVIa), which is demethylated to (X) by using BBr3 as above (1, 2). Alternatively, the difluorophenyl ketal (XXI) is displaced with benzyl alcohol in the presence of NaH to give the benzyl ether (XXIV), which undergoes further ketal hydrolysis to the ketone (XXV) under acidic conditions. Finally, simultaneous cyclization and deprotection of (XXV) with H2 and Pd/C furnishes the desired 4-fluoro-5-hydroxy-2-methylindole (X) (2). Scheme 2.