D iCE: Diastereomeric in Silico Chiral Elucidation, Expanded DP4 Probability Theory Method for Diastereomer and Structural Assignment.

NMR chemical shift prediction at the B3LYP/cc-pVDZ level of theory was used to develop a highly accurate probability theory algorithm for the determination of the stereochemistry of diastereomers as well as the regiochemistry. DFT-GIAO calculations were performed for each conformer using geometry optimization and a CPCM solvent model. Boltzmann averaged shielding constants were converted to chemical shifts for 1H and 13C, using the generalized linear scaling terms determined in four different solvents for 1H and 13C and extended to 15N in DMSO. The probability theory algorithm, D iCE, was based on the DP4 method and developed for 1H, 13C, and 15N NMR using individual and combined probability data. The chemical shift calculation errors were fitted to a Student's t-distribution for 1H and 13C and a normal distribution for 15N. The application yielded a high accuracy for structural assignment with a low computational cost.

Development of a 13C NMR Chemical Shift Prediction Procedure Using B3LYP/cc-pVDZ and Empirically Derived Systematic Error Correction Terms: A Computational Small Molecule Structure Elucidation Method.

An accurate and efficient procedure was developed for performing 13C NMR chemical shift calculations employing density functional theory with the gauge invariant atomic orbitals (DFT-GIAO). Benchmarking analysis was carried out, incorporating several density functionals and basis sets commonly used for prediction of 13C NMR chemical shifts, from which the B3LYP/cc-pVDZ level of theory was found to provide accurate results at low computational cost. Statistical analyses from a large data set of 13C NMR chemical shifts in DMSO are presented with TMS as the calculated reference and with empirical scaling parameters obtained from a linear regression analysis. Systematic errors were observed locally for key functional groups and carbon types, and correction factors were determined. The application of this process and associated correction factors enabled assignment of the correct structures of therapeutically relevant compounds in cases where experimental data yielded inconclusive or ambiguous results. Overall, the use of B3LYP/cc-pVDZ with linear scaling and correction terms affords a powerful and efficient tool for structure elucidation.

Systematic investigation of DFT-GIAO 15N NMR chemical shift prediction using B3LYP/cc-pVDZ: application to studies of regioisomers, tautomers, protonation states and N-oxides.

The calculation of 15N NMR chemical shifts has been systematically investigated using density functional theory-gauge including/invariant atomic orbitals (DFT-GIAO) approximation at the B3LYP/cc-pVDZ level of theory. General linear regression terms for 15N chemical shift predictions were calculated for nitromethane and liquid ammonia references in DMSO. Both aliphatic and aromatic nitrogens were studied using a diverse set of molecular scaffolds. Statistical error analysis between experiment and prediction revealed that, with the exception of primary amines, 95% of linear scaled N-15 chemical shifts are within a ±9.56 ppm range. Comparison of the 15N calculated isotropic chemical shifts with the experimentally determined chemical shifts provided accurate assignment of the correct structure in cases where experimental data was ambiguous or inconclusive. Application of 15N prediction proved to be highly effective in identifying the correct regio-isomer, oxidation state, protonation state and preferred tautomer in solution.

Structure Elucidation of Poly-Faldaprevir: Polymer Backbone Solved Using Solid-State and Solution Nuclear Magnetic Resonance Spectroscopy.

A large-scale synthesis of the hepatitis C virus drug Faldaprevir revealed precipitation of an unknown insoluble solid from methanol solutions of the drug substance. The unknown impurity was determined to be a polymer of Faldaprevir based on analytical methods that included size exclusion chromatography in combination with electrospray ionization mass spectrometry, solution nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization-time of flight, ultracentrifugation, elemental analysis, and sodium quantitation by atom absorption spectroscopy. Structure elucidation of the polymeric backbone was achieved using solid-state NMR cross-polarization/magic angle spinning (CP/MAS), cross polarization-polarization inversion, and heteronuclear correlation (HETCOR) experiments. The polymerization was found to occur at the vinyl cyclopropane via a likely free radical initiation mechanism. Full proton and carbon chemical shift assignments of the polymer were obtained using solution NMR spectroscopy. The polymer structure was corroborated with chemical synthesis of the polymer and solution NMR analysis.

Probing the cation binding modes of macrocyclic HCV protease inhibitor BILN 2061 by multinuclear NMR.

The ability of the macrocyclic HCV protease inhibitor BILN 2061 to bind different classes of cations has been studied by (15)N, (13)C, and (1)H NMR. (15)N NMR experiments were performed at natural abundance or with isotopically labeled materials. Three classes of cations: alkali metals, alkaline earth metals, and transition metals, were examined, using two members of each class. The behavior of each cation class was found to be different, and provided insight into how metal ions interact with the molecular scaffold. These specific interactions were uncovered by examining coordination shifts, NOE correlations, and line broadening across all three nuclei.

Drug-excipient complexation in lipid based delivery systems: an investigation of the Tipranavir-1,3-dioctanolyglycerol complex.

This report describes the solubility properties of a poorly soluble drug-excipient complex in a lipid based formulation. Tipranavir (TPV) was used as the model drug and 1,3-dioctanoylglycerol (DOG) as the excipient. The TPV-DOG complex was prepared by dissolving TPV and DOG in ethanol at 60 degrees C followed by evaporation of ethanol. The formation of the complex with a 4:1 TPV-to-DOG molar ratio was confirmed by XRPD, DSC, and NMR. At 25 degrees C, total solubility of TPV decreased with increasing DOG concentration. The solubility properties of the TPV-DOG complex can be described by two simultaneous equilibria: a liquid-solid phase equilibrium of the complex and a species equilibrium among the various species in the liquid phase. A model equation was derived accordingly with two parameters, the intrinsic solubility of the complex (S(o)), and the solution complex constant (K(41)). The model was in good agreement with experimental results. The values of S(o) and K(41) are 0.0186 +/- 0.0025 (M) and 21.97 +/- 7.19 (1/M(4)), respectively. The equation can successfully predict the concentrations of total and free TPV as a function of DOG in the formulation. The approach developed provides a useful tool for rationale selection of excipients and their levels to avoid drug precipitation in lipid based formulations.

Structure elucidation and total synthesis of a unique group of trace impurities in Tipranavir drug product.

Four unknown trace impurities (7-10) were observed in the capsule formulation of the HIV drug Tipranavir after prolonged storage at 30 degrees C/70% RH. Extensive NMR and LC/MS analyses revealed the compounds to be covalent adducts between TRIS, an excipient of the formulation, and diastereomeric Tipranavir alcohols formed via slow air oxidation of the drug substance. The structures were ultimately confirmed by total synthesis with final purification by chiral, preparative supercritical fluid chromatography. A novel Favorskii rearrangement to furnish butyrolactones was also uncovered during the synthesis.

Electronic control of chiral quaternary center creation in the intramolecular asymmetric heck reaction.

The Boehringer-Ingelheim phosphinoimidazoline (BIPI) ligands were applied to the formation of chiral quaternary centers in the asymmetric Heck reaction. Several different substrates were examined in detail, using more than 70 members of this new ligand class. Hammett relationships were determined through systematic variation of the ligand electronics. All substrates showed essentially the same Hammett behavior, where enantioselectivity increased as the ligands were made more electron-deficient. Ligand optimization has led to catalysts which give the highest enantioselectivities reported to date for these difficult systems.