An Efficient Synthesis of the Anti-asthmatic Agent T-440

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.