Acrylonitrile → 5-Hydroxy-6-methylpyridine-3-carbonitrile

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Reaction Steps

The 5-bromo-2-methyl-3-pyridinol, required for the syntheses of the brominated dihydrofuro- and dihydropyranopyridines, is produced by standard transformations of commercially available materials. Thus, 2-methylnicotinic acid (Aldrich Chemical Company) can be converted by sequential treatment with thionyl chloride, bromine, and ammonia, as described by Greco et al., J Het. Chem. 7: 761 (1970), into 5-bromo-2-methylnicotinamide. Hofmann rearrangement of 5-bromo-2-methylnicotinamide with hypochlorite will give 3-amino-5-bromo-2-methylpyridine, which can be converted to 5-bromo-2-methyl-3-pyridinol by diazotization with sodium nitrite in aqueous sulfuric acid. Alternatively, alanine ethyl ester (Aldrich Chemical Company) is converted (using ethyl formate) into its N-formyl derivative, which is then converted to 5-ethoxy-4-methyloxazole using phosphorous pentoxide (see Takeo et al., Japan Patent No. 45,012,732). A Diels-Alder reaction of 5-ethoxy-4-methyloxazole with acrylonitrile gives 5-hydroxy-6-methylnicotinonitrile, as described by Yoshikawa et al., Chem. Pharm. Bull. 13: 873 (1965), which is converted to 5-amino-2-methyl-3-pyridinol by hydration (nitrileamide) and Hoffman rearrangement (see Morisawa et al., Agr. Biol. Chem. 39: 1275 (1975)). The 5-amino-2-methyl-3-pyridinol can then be converted, by diazotization in the presence of copper (I) bromide, to the desired 5-bromo-2-methyl-3-pyridinol.

Provenance & Evidence