Methanol → 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one

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Reaction Steps

3-Hydroxy-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide has been prepared by the method, described in examples 45 to 48, 53, and 58 of WO98/154318. Allomaltol (1) is converted to 2-(1-hydroxymethyl)-6-methylpyromeconic acid (2) according to the procedure described in FR1516463. The 2-(1-hydroxymethyl)-6-methylpyromeconic acid (2) is reacted with benzyl bromide in sodium hydroxide in a 10:1 mixture of methanol and water to give the 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (3) which is then oxidized with diemthyl sulfoxide and sulfur trioxide.pyridine complex to give 2-formyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (4). Oxidation of the 2-formyl derivative with sulfamic acid and sodium hypochlorite in acetone and water affords 2-carboxyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (5). The 2-carboxyl derivative is reacted with dicyclohexyldiimide and 2-mercaptothiazoline and 4-dimethylaminopyridine to give the 3-(2-carbonyl-3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-1,3-thiazolidine-2-thione (6) which is reacted with methylamine in tetrahydrofuran to give 3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide (7). The 3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide (7) is converted to 1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-)N-methyl)-amide (8) with methylamine in alcohol. The 3-benzyloxy derivative was deprotected with hydrogenation using Pd/C in dimethylformamide as illustrated in Scheme 1 to give 1,6-dimethyl-3-hydroxy-4(1H)-pyridinone-2-carboxy-)N-methyl)-amide (9):

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