1,3-Propanediamine → 1-(3'-Aminopropyl)-3-hydroxy-2-methyl-4-pyridinone

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The chelator 2-methyl-N-(3′-aminopropyl)-3-hydroxyl-4-pyridinone (MAHP) was synthesized using a modification of a procedure known in the art. In brief, 3-hydroxyl-2-methyl-4-pyranone (44.4 g, 0.352 mol) and benzyl chloride (51 g, 0.403 mol) were mixed in a solution of water (50 ml) and methanol (400 ml) in the presence of NaOH (15 g). The mixture was refluxed for 6 h with magnetic stirring. After removing methanol under vacuum, 70 ml of water were added and 3-benzyloxy-2-methyl-4-pyranone was extracted 3 times with 60 ml portions of methylene chloride. The combined methylene chloride was washed with 5% NaOH aqueous solution (50 ml), followed by water (50 ml) and dried over MgSO4. The product was obtained after evaporation of the solvent under vacuum (94% yield). The product (4.41 g, 0.019 mol) was then reacted with 1,3-diaminopropane (1.15 g, 0.019 mol) in aqueous ethanol solution (30 ml water and 20 ml ethanol) at room temperature. After one week, solvents and residual diamine were evaporated under vacuum and the residue was dissolved in chloroform, washed 3 times with water and dried using Na2SO4. After removing the chloroform, methanol was added and the pH adjusted to 1 with HCl. The 1-(3′-aminopropyl)-3-benzyloxy-2-methyl-4-pyridinone was precipitated as dihydrochloride salt and collected by filtration. The pure product was obtained by crystallization from methanol and ether (yield: 80%) and the product (2 g, 0.0058 mol) further reacted with BBr3 (30 ml, 1.0 M solution of CH2Cl2) in 120 ml of CH2Cl2. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. Then, 160 ml of water was added and stirring was continued for an additional 4 h. The aqueous phase containing the MAHP was separated and evaporated under vacuum. The crude MAHP was purified through crystallization twice using ethanol and ether (96% yield). Pure MAHP was identified by 1H-NMR and elemental analysis. 1H-NMR (DMSO-d6): 8.214 (1H, d, H-6), 7.104 (1H, d, H-5), 4.407 (2H, t, 1′-position propylenic CH2), 2.866 (2H, m, 3′-position propylenic CH2), 2.516 (3H, s, 2-position CH3), 2.021 (2H, m, 2′-position propylenic CH3).

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