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]naphthalen e-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 t he construction of the 1-(2-methoxyethyl)-2-pyridone moiety, We examined an N-selective alkylation of pyridone derivative (2) in basic media, 2-Methox yethylation of 2 with 2-methoxyethyl iodide utilizing LiH as the base gave predominantly an N-alkyl pyridone derivative (3a) in 82% yield (N/O-alkylat ion=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.