3-Amino-2-chloro-4-methylpyridine: Overview and Applications as Drug Intermediates

3-Amino-2-chloro-4-methylpyridine is a Light brown Solid Crystalline with Unpleasant odor, it is stable under normal conditions.

Application

3-Amino-2-chloro-4-methylpyridine is a key intermediate in the production of nevirapine, a non-nucleosidic reverse transcriptase inhibitor that has been established to be clinically useful for the treatment of infection by HIV-1.

Synthesis

A method for making 3-amino-2-chloro-4-methylpyridine comprising the following steps:

(a) reacting malononitrile with acetone to yield isopropylidenemalononitrile;

(b) condensing the isopropylidenemalononitrile so produced with triethyl ortho formate in acetic acid anhydride yield a mixture of 2-(3-ethoxy-l-methyl-(E)-2- propenylidene)malononitrile and 2-(3 ,3 -diethoxy- 1 -methylpropylidene)malononitrile;

(c) treating the mixture of 2-(3 -ethoxy- 1 -methyl-(E)-2- propenylidene)malononitrile and 2-(3,3-diethoxy-l-methylpropylidene)malononitrile so produced with anhydrous ammonia in ethanol, to effect ring closure, thus producing 2-amino- 4-methyl-pyridine-carbonitrile;

(d) reacting the 2-amino-4-methyl-pyridine-carbonitrile so produced with sodium nitrite, to yield the diazonium salt thereof, and thereafter treating the diazonium salt in situ with water to yield 2-hydroxy-4-methyl-3-cyanopyridine;

(e) reacting the 2-hydroxy-4-methyl-3-cyanopyridine so produced with phosphorus oxychloride to yield 2-chloro-4-methyl-3-pyridinecarbonitrile;

(f) treating the 2-chloro-4-methyl-3-pyridinecarbonitrile so produced with concentrated sulfuric acid, to effect hydrolysis, to yield 2-chloro-4-methyl-3-carboxamide; and,

(g) converting the 2-chloro-4-methyl-3-carboxamide so produced, via the Hofmann reaction (treatment with solution of chlorine or bromine in excess sodium hydroxide), to 3-amino-2-chloro-4-methylpyridine.1

Reference

1.WO2000043365A1

You may like