An efficient synthesis of the anti-asthmatic agent T-440: a selective N-alkylation of 2-pyridone.
6,7-Diethoxy-1-[1-(2-methoxyethyl)-2-oxo-1,2-dihydropyridin- 4-yl]naphthalene-2,3-dimethanol [T-440, (1)] is a potential anti-asthmatic agent based on selective phosphodiesterase 4 inhibition. It was necessary for the further evaluation of 1 to develop an efficient synthetic route for 1, especially the construction of the 1-(2-methoxyethyl)-2-pyridone moiety. We examined an N-selective alkylation of pyridone derivative (2) in basic media. 2-Methoxyethylation of 2 with 2-methoxyethyl iodide utilizing LiH as the base gave predominantly an N-alkyl pyridone derivative (3a) in 82% yield (N/O-alkylation=92/8), which is compatible with an ab initio calculation of transition-state structures for the methylation of 2-pyridone. Single crystallization of a crude mixture of 3a and 4a furnished pure 3a, which is a key synthetic intermediate of 1.
Sugahara
M
M
Product & Technology Development Laboratory, Tanabe Seiyaku Co., Ltd., Yodogawa, Osaka, Japan.
Moritani
Y
Y
Kuroda
T
T
Kondo
K
K
Shimadzu
H
H
Ukita
T
T
D000478:Alkylation; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis*; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis*; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry*
D018927:Anti-Asthmatic Agents; D009281:Naphthalenes; D011728:Pyridones; C101791:T 440; C017679:2-hydroxypyridine