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