Phosphorus oxychloride → 2-Chloro-4-methyl-nicotinonitrile

In accordance with the invention, and as shown in the reaction scheme shown above, the Knoevenagel reaction of acetone (2) with malononitrile (3) gives isopropylidenemalononitrile (4). This is condensed with triethyl orthoformate in acetic acid anhydride to give a mixture of the beta-gamma-unsaturated aldehyde equivalent (5) and the enol ether (6). The mixture of (5) and (6) is ring closed with anhydrous ammonia in ethanol, to give 2-amino-4-methyl-pyridine-carbonitrile (7). The intermediate (7) is converted with sodium nitrite to the diazonium salt which is then treated in situ with water to yield the 2-hydroxy-4-methyl-3-cyanopyridine (8). The 2-hydroxy-pyridine derivative (8) is chlorinated with phosphorus oxychloride to yield 2-chloro-4-methyl-3-pyridinecarbonitrile (9). The nitrile (9) is hydrolyzed in concentrated sulfuric acid to yield 2-chloro-4-methyl-3-carboxamide (10). Finally, the amide (10) is converted via the Hofmann amide degradation reaction (treatment with solution of chlorine or bromine in excess sodium hydroxide by means of hypohalides), in a known per se manner, to the desired end product, 3-amino-2-chloro-4-methylpyridine (1).