title: Synthesis of 4-methoxy-2,3,5-trimethylpyridine: a specific building block for compounds with gastric-acid inhibiting activity.
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%.
authors.affiliation: Institute for Organic Chemistry, Karl-Franzens University, Graz, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Mittelbach
authors.forename: H W
authors.initials: HW
authors.lastname: Schmidt
authors.forename: G
authors.initials: G
authors.lastname: Uray
authors.forename: H
authors.initials: H
authors.lastname: Junek
authors.forename: B
authors.initials: B
authors.lastname: Lamm
authors.forename: K
authors.initials: K
authors.lastname: Ankner
authors.forename: A
authors.initials: A
authors.lastname: Brändström
authors.forename: R
authors.initials: R
authors.lastname: Simonsson
mesh_terms: D000897:Anti-Ulcer Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D011725:Pyridines / Q000138:chemical synthesis*
chemical_list: D000897:Anti-Ulcer Agents; D011725:Pyridines; C058627:4-methoxy-2,3,5-trimethylpyridine