The condensation of 2-bromo-4,5-diethoxybenzaldehyde dimethyl ketal (I) with pyridine-4-carbaldehyde (II) by means of NaH in THF gives the expected addition product (III), which by treatment with acetic acid in refluxing toluene yields the isobenzofuran (IV) (unstable, not isolated compound) that is submitted immediately to a Diels-Alder cyclization with dimethyl maleate (V) to afford the epoxy-tetrahydronaphthalene (VI). The aromatization of (VI) with trifluoroacetic acid (TFA) in chloroform, or with BF3/ethyl ether in acetonitrile gives 6,7-diethoxy-1-(4-pyridyl)naphthalene-2,3-dicarboxylic acid dimethyl ester (VII). The oxidation of (VII) with m-chloroperbenzoic acid (MCPBA) in dichloromethane gives the corresponding N-oxide (VIII), which is isomerized to the pyridone (IX) by refluxing in acetic anhydride. The condensation of (IX) with 2-chloroethyl methyl ether (X) by means of NaH or Li in DMF affords the N-substituted pyridone (XI), which is finally reduced with NaBH4 in THF.

The condensation of 2-bromo-4,5-diethoxybenzaldehyde dimethyl ketal (I) with pyridine-4-carbaldehyde (II) by means of NaH in THF gives the expected addition product (III), which by treatment with acetic acid in refluxing toluene yields the isobenzofuran (IV) (unstable, not isolated compound) that is submitted immediately to a Diels-Alder cyclization with dimethyl maleate (V) to afford the epoxy-tetrahydronaphthalene (VI). The aromatization of (VI) with trifluoroacetic acid (TFA) in chloroform, or with BF3/ethyl ether in acetonitrile gives 6,7-diethoxy-1-(4-pyridyl)naphthalene-2,3-dicarboxylic acid dimethyl ester (VII). The oxidation of (VII) with m-chloroperbenzoic acid (MCPBA) in dichloromethane gives the corresponding N-oxide (VIII), which is isomerized to the pyridone (IX) by refluxing in acetic anhydride. The condensation of (IX) with 2-chloroethyl methyl ether (X) by means of NaH or Li in DMF affords the N-substituted pyridone (XI), which is finally reduced with NaBH4 in THF.

The condensation of 2-bromo-4,5-diethoxybenzaldehyde dimethyl ketal (I) with pyridine-4-carbaldehyde (II) by means of NaH in THF gives the expected addition product (III), which by treatment with acetic acid in refluxing toluene yields the isobenzofuran (IV) (unstable, not isolated compound) that is submitted immediately to a Diels-Alder cyclization with dimethyl maleate (V) to afford the epoxy-tetrahydronaphthalene (VI). The aromatization of (VI) with trifluoroacetic acid (TFA) in chloroform, or with BF3/ethyl ether in acetonitrile gives 6,7-diethoxy-1-(4-pyridyl)naphthalene-2,3-dicarboxylic acid dimethyl ester (VII). The oxidation of (VII) with m-chloroperbenzoic acid (MCPBA) in dichloromethane gives the corresponding N-oxide (VIII), which is isomerized to the pyridone (IX) by refluxing in acetic anhydride. The condensation of (IX) with 2-chloroethyl methyl ether (X) by means of NaH or Li in DMF affords the N-substituted pyridone (XI), which is finally reduced with NaBH4 in THF.

The condensation of 2-bromo-4,5-diethoxybenzaldehyde dimethyl ketal (I) with pyridine-4-carbaldehyde (II) by means of NaH in THF gives the expected addition product (III), which by treatment with acetic acid in refluxing toluene yields the isobenzofuran (IV) (unstable, not isolated compound) that is submitted immediately to a Diels-Alder cyclization with dimethyl maleate (V) to afford the epoxy-tetrahydronaphthalene (VI). The aromatization of (VI) with trifluoroacetic acid (TFA) in chloroform, or with BF3/ethyl ether in acetonitrile gives 6,7-diethoxy-1-(4-pyridyl)naphthalene-2,3-dicarboxylic acid dimethyl ester (VII). The oxidation of (VII) with m-chloroperbenzoic acid (MCPBA) in dichloromethane gives the corresponding N-oxide (VIII), which is isomerized to the pyridone (IX) by refluxing in acetic anhydride. The condensation of (IX) with 2-chloroethyl methyl ether (X) by means of NaH or Li in DMF affords the N-substituted pyridone (XI), which is finally reduced with NaBH4 in THF.

An efficient N-alkylation process suitable for the large-scale synthesis of T-440 has been reported: Alkylation of the previously reported pyridone (I) with 2-methoxyethyl iodide (II) by means of LiH in hot DMF gives the N-alkylated pyridone (II) purified by crystallization. Finally, this compound is reduced with NaBH4 and MeOH in refluxing THF.