660392-15-4

Upstream product

• 50-00-0 formaldehyd 
• 103-49-1 dibenzylamine 

Downstream Products

• 660392-16-5 ethyl (N,N-dibenzylamino)methylphosphinate 

Relevant academic research and scientific papers

Selective and clean synthesis of aminoalkyl-H-phosphinic acids from hypophosphorous acid by phospha-Mannich reaction

Aminoalkyl-H-phosphinic acids, also called aminoalkylphosphonous acids, are investigated as biologically active analogues of carboxylic amino acids and/or as valuable intermediates for synthesis of other aminoalkylphosphorus acids. Their synthesis has been mostly accomplished by phospha-Mannich reaction of a P-H precursor, an aldehyde and an amine. The reaction is rarely clean and high-yielding. Here, reaction of H3PO2with secondary amines and formaldehyde in wet AcOH led to aminomethyl-H-phosphinic acids in nearly quantitative yields and with almost no by-products. Surprisingly, the reaction outcome depended on the basicity of the amines. Amines with pKa> 7-8 gave the desired products. For less basic amines, reductiveN-methylation coupled with oxidation of H3PO2to H3PO3became a relevant side reaction. Primary amines reacted less clearly and amino-bis(methyl-H-phosphinic acids) were obtained only for very basic amines. Reaction yields with higher aldehydes were lower. Unique carboxylic-phosphinic-phosphonic acids as well as poly(H-phosphinic acids) derived from polyamines were obtained. Synthetic usefulness of the aminoalkyl-H-phosphinic was illustrated in P-H bond oxidation and its addition to double bonds, and in selective amine deprotection. Compounds with an ethylene-diamine fragment,e.g.most common polyazamacrocycles, are not suitable substrates. The X-ray solid-state structures of seventeen aminoalkyl-phosphinic acids were determined. In the reaction mechanism,N-hydroxyalkyl species R2NCH2OH and [R2N(CH2OH)2]+, probably stabilized as acetate esters, are suggested as the reactive intermediates. This mechanism is an alternative one to the known phospha-Mannich reaction mechanisms. The conditions can be utilized in syntheses of various aminoalkylphosphorus compounds.

Lanthanide Complexes of DO3A-(Dibenzylamino)methylphosphinate: Effect of Protonation of the Dibenzylamino Group on the Water-Exchange Rate and the Binding of Human Serum Albumin

Protonation of a distant, noncoordinated group of metal-based magnetic resonance imaging contrast agents potentially changes their relaxivity. The effect of a positive charge of the drug on the human serum albumin (HSA)-drug interaction remains poorly understood as well. Accordingly, a (dibenzylamino)methylphosphinate derivative of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was efficiently synthesized using pyridine as the solvent for a Mannich-type reaction of tBu3DO3A, formaldehyde, and Bn2NCH2PO2H2 ethyl ester. The ligand protonation and metal ion (Gd3+, Cu2+, and Zn2+) stability constants were similar to those of the parent DOTA, whereas the basicity of the side-chain amino group of the complexes (logKA = 5.8) was 1 order of magnitude lower than that of the free ligand (log KA = 6.8). The presence of one bound water molecule in both deprotonated and protonated forms of the gadolinium(III) complex was deduced from the solid-state X-ray diffraction data [gadolinium(III) and dysprosium(III)], from the square antiprism/twisted square antiprism (SA/TSA) isomer ratio along the lanthanide series, from the fluorescence data of the europium(III) complex, and from the 17O NMR measurements of the dysprosium(III) and gadolinium(III) complexes. In the gadolinium(III) complex with the deprotonated amino group, water exchange is extremely fast (M = 6 ns at 25 °C), most likely thanks to the high abundance of the TSA isomer and to the presence of a proximate protonable group, which assists the water-exchange process. The interaction between lanthanide(III) complexes and HSA is pH-dependent, and the deprotonated form is bound much more efficaciously (13% and 70% bound complex at pH = 4 and 7, respectively). The relaxivities of the complex and its HSA adduct are also pH-dependent, and the latter is approximately 2-3 times increased at pH = 4-7. The relaxivity for the supramolecular HSA-complex adduct (r1b) is as high as 52 mM-1 s-1 at neutral pH (at 20 MHz and 25 °C). The findings of this study stand as a proof-of-concept, showing the ability to manipulate an albumin-drug interaction, and thus the blood pool residence time of the drug, by introducing a positive charge in a side-chain amino group.

Lanthanide(III) Complexes of Novel Mixed Carboxylic-Phosphorus Acid Derivatives of Diethylenetriamine: A Step towards More Efficient MRI Contrast Agents

Three novel phosphorus-containing analogues of H5DTPA (DTPA = diethylenetriaminepentaacetate) were synthesised (H6L1, H5L2, H5L3). These compounds have a -CH2-P(O)(OH)-R function (R = OH, Ph, CH2NBn2) attached to the central nitrogen atom of the diethylenetriamine backbone. An NMR study reveals that these ligands bind to lanthanide(III) ions in an octadentate fashion through the three nitrogen atoms, a P-O oxygen atom and four carboxylate oxygen atoms. The complexed ligand occurs in several enantiomeric forms due to the chirality of the central nitrogen atom and the phosphorus atom upon coordination. All lanthanide complexes studied have one coordinated water molecule. The residence times (τM 298) of the coordinated water molecules in the gadolinium(III) complexes of H6L1 and H5L2 are 88 and 92 ns, respectively, which are close to the optimum. This is particularly important upon covalent and noncovalent attachment of these Gd3+ chelates to polymers. The relaxivity of the complexes studied is further enhanced by the presence of at least two water molecules in the second coordination sphere of the Gd3+ ion, which are probably bound to the phosphonate/phosphinate moiety by hydrogen bonds. The complex [Gd(L 3)(H2O)]2- shows strong binding ability to HSA, and the adduct has a relaxivity comparable to MS-325 (40 s-1mM -1 at 40MHz, 37°C) even though it has a less favourable τM value (685 ns). Transmetallation experiments with Zn 2+ indicate that the complexes have a kinetic stability that is comparable to-or better than-those of [Gd(dtpa)(H2O)]2- and [Gd(dtpa-bma)(H2O)].