Synthesis of a Versatile Building Block Combining Cyclen-derivative DO3A with a Polyamine via a Rigid Spacer

Abstract

Abstract:The five-step synthesis of a polydentate building block combining a cyclen-based macrocycle (DO3A) with N-(2-aminoethyl)propane-1,3-diamine, which are linked through the xylylen moiety as a rigid C-spacer is described. These two molecular parts were coupled by subsequent bromine atom substitution in 1,4-bis(bromomethyl)benzene. First, N-(2-aminoethyl)propane-1,3-diamine was protected by phthaloyl moieties and then it was reacted with 1,4-bis(bromomethyl)benzene to form (2-phthalimidoethyl)(3-phthalimidoprop-1-yl)(4-bromomethylbenzyl)amine (2). This compound underwent a substitution reaction with DO3A in the form of its tert-butyl esters leading to the intermediate 1-{4-[(2-phthalimidoethyl)(3-phthalimidoprop-1-yl)aminomethyl]phenylmethyl}-4,7,10-tris(t-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (3). The phthaloyl as well as the t-butyl protecting groups were removed in the next two reaction steps to form the final product 1-{4-[(2-aminoethyl)(3-aminoprop-1-yl)aminomethyl]phenylmethyl}-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (5). The intermediates 1-4 as well as the final product 5 were characterized by elemental analysis, mass spectrometry, and multinuclear ( 1 H and 13 C) and two-dimensional NMR spectroscopy. The final product 5 could serve as a potential building block in subsequent syntheses of binuclear complexes of lanthanides and/or transition metals.

Design, synthesis and relaxation studies of triazole linked gadolinium(iii)–DO3A-BT-bistriazaspirodecanone as a potential MRI contrast agent

“…The DO3A-bis(triazole-triazaspirodecanone) compound (9) was synthesized using click conjugation of the chloroacetylated bisazide (2) of trisubstituted cyclen (6) and alkynylated 1 phenyl-1,3,8-triazaspiro [4,5]decan-4-one (4). The chloroacetylated bisazide (2) synthesis involved bisazidation followed by secondary amine functionalization by the chloroacetyl group.…”

“…The chloroacetylated bisazide (2) synthesis involved bisazidation followed by secondary amine functionalization by the chloroacetyl group. Click conjugation of alkyne and N-functionalized bisazide so formed gives rise to a free chloro atom (5). In order to synthesize the desired compound, this free chloroatom is to be conjugated with trisubstituted cyclen (6) in the final step.…”

“…The reaction mixture was extracted with chloroform/water and the organic extracts were combined and dried over anhydrous sodium sulphate, evaporated under reduced pressure to obtain the transparent light yellow coloured oily product and purified by silica gel chromatography (1.5% methanol in chloroform with a yield of 2.15 g, 84.6%). 1 Synthesis of 1-phenyl-8-(prop-2-yn-1-yl)-1,3,8-triazaspiro [4,5]decan-4-one (4). 1-Phenyl-1,3,8-triazaspiro [4,5]decan-4-one 4 (1.0 eq., 1.00 g, 4.32 mmol) was stirred at 70 1C in 3 mL dimethyl formamide with potassium carbonate (0.8 eq., 0.48 g, 3.46 mmol) in an inert atmosphere.…”

“…1 Synthesis of 1-phenyl-8-(prop-2-yn-1-yl)-1,3,8-triazaspiro [4,5]decan-4-one (4). 1-Phenyl-1,3,8-triazaspiro [4,5]decan-4-one 4 (1.0 eq., 1.00 g, 4.32 mmol) was stirred at 70 1C in 3 mL dimethyl formamide with potassium carbonate (0.8 eq., 0.48 g, 3.46 mmol) in an inert atmosphere. After the desired temperature was attained, a solution of propargyl bromide (1.0 eq., 0.33 mL, 4.32 mmol) in 10 mL dimethyl formamide was added dropwise.…”

“…Tetraazamacrocycles are the most common frameworks and some well-known structures are cyclen (1,4,7,10-tetraazacyclododecane) and cyclam (1,5,8,11tetraazacyclotetradecane), and they have many applications, including as contrast agents for MRI and in optical imaging, Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT). 5 Diagnostic and therapeutic agents are synthesized by the derivatization of ring nitrogen atoms and subsequent complexation with Ln 3+ ions. The nitrogen atoms of cyclen ring based macrocyclic chelates carry a pendant and a phosphonic or a carboxylic acid metal coordinating group.…”