Regioisomerism in the synthesis of a chiral aminotetralin drug compound: unraveling mechanistic details and diastereomer-specific in-depth NMR investigations

During chemical process development of a novel 2-aminotetralin derivative intended for use as an antidepressant, scrutiny of the byproduct present in the drug molecule revealed a set of regioisomers. Detailed studies showed that this impurity issue originated from an early synthetic step in which a brominated tetralone motif was generated in a ring-closing protocol. It was found that this reaction was accompanied by a migration of the aromatic bromo substituent via different bromonium species along two discrete pathways. This example of the halogen dance reaction resulted in the formation of a series of tetralone impurities with a bromine distributed across all available aromatic positions of the tetralin nucleus. Subsequently, when subjected to reductive amination conditions, each of these tetralones gave rise to pairs of aminotetralins in a diastereomeric relationship. NMR investigations revealed that the alicyclic portion of the compounds thus formed displayed very complex signal patterns, which required further in-depth studies using a variety of sophisticated techniques. As a result, a deep insight into the structural features of the current 2-aminotetralin family was obtained, which is emphasized by the definition of a novel "0.2 ppm rule" allowing the absolute configuration at tetralin C-2 to be determined.     

Synthesis of <Emphasis Type="Italic">O</Emphasis>-[2-[<Superscript>18</Superscript>F]fluoro-3-(2-nitro-1<Emphasis Type="Italic">H</Emphasis>-imidazole-1-yl)propyl]tyrosine ([<Superscript>18</Superscript>F]FNT]) as a new class of tracer for imaging hypoxia

For detection of hypoxic tumor tissue, all radiotracers synthesized until now, are based on the concept that cellular uptake is being controlled by diffusion. As a new approach, we chose the concept to have the tracer hypothetically transported into the cells by well known carrier systems like the amino acid transporters. For this purpose, radiosynthesis of O-[2-[¹⁸F]fluoro-3-(2-nitro-1H-imidazole-1yl)propyl]tyrosine ([¹⁸F]FNT]) was carried out from methyl 2-(benzyloxycarbonyl)-3-(4-3-(2-nitro-1H-imidazol-1-yl)-2-(tosyloxy)propoxy) phenyl)propanoate via no-carrier-added nucleophilic aliphatic substitution. After labelling, 81 ± 0.9% of labelled intermediate i.e. methyl 2-(benzyloxycarbonyl)-3-(4-(2-[¹⁸F]fluoro-3-(2-nitro-1H-imidazole-1-yl)propoxy) phenyl)propanoate was obtained at 140 °C. At the end of radiosynthesis, [¹⁸F]FNT was obtained in an overall radiochemical yield of 40 ± 0.9% (not decay corrected) within 90 min in a radiochemical purity of >98% in a formulation ready for application in the clinical studies for PET imaging of hypoxia.     

Modeling Unsaturated Flow in Absorbent Swelling Porous Media: Part 1. Theory

The flow and deformation processes in swelling porous media are modeled for absorbent hygiene products (e.g., diapers, wipes, papers etc.). The first part of the article derives the fundamental equations for the hysteretic unsaturated flow, liquid absorption, and large deformation. The final set of model equations consists of balance equations of mobile and absorbed (immobile) liquid combined with a series of constitutive relationships. The resulting equation system is strongly nonlinear and requires advanced numerical strategies for solving. The second part of the article focuses on numerical solution and presents simulation results for 2D and 3D applications.     

Einstein and Cosmic Physics

The article gives an overview on Albert Einstein's activity in relation to geophysics. Various aspects of his fundamental investigations and their significance for geophysical research are discussed.     

The energy-momentum spectrum in local field theories with broken Lorentz-symmetry

Assuming locality of the observables and positivity of the energy it is shown that the joint spectrum of the energy-momentum operators has a Lorentz-invariant lower boundary in all superselection sectors. This result is of interest if the Lorentz-symmetry is (spontaneously) broken, such as in the charged sectors of quantum electrodynamics.     

Solution formulas for linear difference equations with applications to continued fractions

For any system of linear difference equations of arbitrary order, a family of solution formulas is constructed explicitly by way of relating the given system to simpler neighboring systems. These formulas are then used to investigate the asymptotic behavior of the solutions. When applying this difference equation method to second-order equations that belong to neighboring continued fractions, new results concerning convergence of continued fractions as well as meromorphic extension of analytic continued fractions beyond their convergence region are provided. This is demonstrated for analytic continued fractions whose elements tend to infinity. Finally, a recent result on the existence of limits of solutions to real difference equations having infinite order is extended to complex equations.     

Already unified field theory with non-covariant geometrization

In general relativity the non-covariant ansatzA ⁱ = ₄ ⁱ for the vectorpotentialA _k gives the general solution of the Maxwell equations as four coordinate conditions which are the conditions of integrability of the Einstein equations. In the some sense the ansatz=X ⁴ is a general solution of the scalar wave-equation in a reference system given by one coordinate-condition. We discuss the meaning of the canonical quantization of the fields in such reference systems.     

Statistics of complex levels of random matrices for decaying systems

We present analytical and numerical results for the level density of a certain class of random non-Hermitian matrices =H+i. The conservative partH belongs to the Gaussian orthogonal ensemble while the damping piece is quadratic in Gaussian random numbers and may describe the decay of resonances through various channels. In the limit of a large matrix dimension the level density assumes a surprisingly simple dependence on the relative strength of the damping and the number of channels. Moreover, we identify situations with cubic repulsion between the complex eigenvalues of , to within a logarithmic correction.     

On local approximation methods for multivariate polynomial spline surfaces

We present a construction method for quasiinterpolants using the multivariate splines of Dahmen, Micchelli, and Seidel [7]. The key instrument is the concept of polar forms. The quasiinterpolants apply to continuous functions and are shown to have optimal rates of convergence.     

The Weyl-Cartan Space Problem in Purely Affine Theory

According to Poincaré, only the epistemological sum of geometry and physics is measurable. Of course, there are requirements of measurement to be imposed on geometry because otherwise the theory resting on this geometry cannot be physically interpreted. In particular, the Weyl-Cartan space problem must be solved, i.e., it must be guaranteed that the comparison of distances is compatible with the Levi-Civita transport. In the present paper, we discuss these requirements of measurement and show that in the (purely affine) Einstein-Schrödinger unified field theory the solution of the Weyl-Cartan space problem simultaneously determines the matter via Einstein's equations. Here the affine field ⁱ _kl represents Poincaré's sum, and the solution of the space problem means its splitting in a metrical space and in matter fields, where the latter are given by the torsion tensor ⁱ _[kl].