Paper
Synthesis of 4-methoxy-2,3,5-trimethylpyridine: a specific building block for compounds with gastric-acid inhibiting activity.
Published Sep 1, 1988 · M. Mittelbach, H. Schmidt, G. Uray
Acta chemica Scandinavica. Series B: Organic chemistry and biochemistry
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Abstract
A new synthesis of 4-methoxy-2,3,5-trimethylpyridine (2), an important building block for the preparation of gastric-acid inhibiting compounds, is described. Condensation of ethyl 3-amino-2-methyl-2-butenoate (3) and diethyl 2-methylmalonate (4) gives 4-hydroxy-3,5,6-trimethyl-2(1H)-pyridone 5. Reaction of 5 with phosphoryl chloride affords 2,4-dichloro-3,5,6-trimethylpyridine (9a), which, upon hydrogenolysis with palladium on charcoal, gives 2,3,5-trimethylpyridine (10). However, selective hydrogenolysis in acidic solution yields 4-chloro-2-3-5-trimethylpyridine (11). Substitution of the chlorine in 11 with methoxide ion gives 4-methoxy-2,3,5-trimethylpyridine (2), which can be oxidized to the corresponding N-oxide (13). This constitutes a new and efficient route to compound 2 in an overall yield of 43%.
This study presents a new and efficient route to 4-methoxy-2,3,5-trimethylpyridine, an important building block for gastric-acid inhibiting compounds, with an overall yield of 43%.
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