A Spectroscopic and Diffractometric Study of Polymorphism in Ethyl 3‑{3-[((2<i>R</i>)‑3-{[2-(2,3-dihydro‑1<i>H</i>‑inden-2-yl)-1,1-dimethylethyl]amino}-2-hydroxypropyl)oxy]-4,5-difluorophenyl}propanoate Hydrochloride

Two polymorphic forms of ethyl 3-{3-[((2<i>R</i>)-3-{[2-(2,3-dihydro-1<i>H</i>-inden-2-yl)-1,1-dimethylethyl]­amino}-2-hydroxypropyl)­oxy]-4,5-difluorophenyl} propanoate hydrochloride, an investigational pharmaceutical compound, are characterized using spectroscopic and diffractometric techniques. These polymorphic forms exhibit very similar spectra and diffraction patterns and present challenges for analytical and physical characterization techniques. Capillary powder X-ray diffraction (PXRD) patterns for the two forms show minor but distinct differences. A single crystal X-ray diffraction structure for one of the forms was obtained. The unit cell of the other form was obtained by PXRD indexing. Detailed solid-state nuclear magnetic resonance (SSNMR) studies observing the ¹H, ¹³C, ¹⁵N, ¹⁹F, and ³⁵Cl nuclei are performed to characterize the subtle structural differences between the two forms. Molecular spectroscopic methods including infrared, Raman, UV–visible, and fluorescence spectroscopy are also applied. The combined results, particularly the results obtained from X-ray diffraction analysis, ¹³C, ¹⁵N, and ³⁵Cl SSNMR, and fluorescence spectroscopy, are consistent with the more thermodynamically stable form having a structure that is an extended, perturbed superstructure of the less stable form

A Spectroscopic and Diffractometric Study of Polymorphism in Ethyl 3‑{3-[((2<i>R</i>)‑3-{[2-(2,3-dihydro‑1<i>H</i>‑inden-2-yl)-1,1-dimethylethyl]amino}-2-hydroxypropyl)oxy]-4,5-difluorophenyl}propanoate Hydrochloride

Two polymorphic forms of ethyl 3-{3-[((2<i>R</i>)-3-{[2-(2,3-dihydro-1<i>H</i>-inden-2-yl)-1,1-dimethylethyl]­amino}-2-hydroxypropyl)­oxy]-4,5-difluorophenyl} propanoate hydrochloride, an investigational pharmaceutical compound, are characterized using spectroscopic and diffractometric techniques. These polymorphic forms exhibit very similar spectra and diffraction patterns and present challenges for analytical and physical characterization techniques. Capillary powder X-ray diffraction (PXRD) patterns for the two forms show minor but distinct differences. A single crystal X-ray diffraction structure for one of the forms was obtained. The unit cell of the other form was obtained by PXRD indexing. Detailed solid-state nuclear magnetic resonance (SSNMR) studies observing the ¹H, ¹³C, ¹⁵N, ¹⁹F, and ³⁵Cl nuclei are performed to characterize the subtle structural differences between the two forms. Molecular spectroscopic methods including infrared, Raman, UV–visible, and fluorescence spectroscopy are also applied. The combined results, particularly the results obtained from X-ray diffraction analysis, ¹³C, ¹⁵N, and ³⁵Cl SSNMR, and fluorescence spectroscopy, are consistent with the more thermodynamically stable form having a structure that is an extended, perturbed superstructure of the less stable form

A Spectroscopic and Diffractometric Study of Polymorphism in Ethyl 3‑{3-[((2<i>R</i>)‑3-{[2-(2,3-dihydro‑1<i>H</i>‑inden-2-yl)-1,1-dimethylethyl]amino}-2-hydroxypropyl)oxy]-4,5-difluorophenyl}propanoate Hydrochloride

Two polymorphic forms of ethyl 3-{3-[((2<i>R</i>)-3-{[2-(2,3-dihydro-1<i>H</i>-inden-2-yl)-1,1-dimethylethyl]­amino}-2-hydroxypropyl)­oxy]-4,5-difluorophenyl} propanoate hydrochloride, an investigational pharmaceutical compound, are characterized using spectroscopic and diffractometric techniques. These polymorphic forms exhibit very similar spectra and diffraction patterns and present challenges for analytical and physical characterization techniques. Capillary powder X-ray diffraction (PXRD) patterns for the two forms show minor but distinct differences. A single crystal X-ray diffraction structure for one of the forms was obtained. The unit cell of the other form was obtained by PXRD indexing. Detailed solid-state nuclear magnetic resonance (SSNMR) studies observing the ¹H, ¹³C, ¹⁵N, ¹⁹F, and ³⁵Cl nuclei are performed to characterize the subtle structural differences between the two forms. Molecular spectroscopic methods including infrared, Raman, UV–visible, and fluorescence spectroscopy are also applied. The combined results, particularly the results obtained from X-ray diffraction analysis, ¹³C, ¹⁵N, and ³⁵Cl SSNMR, and fluorescence spectroscopy, are consistent with the more thermodynamically stable form having a structure that is an extended, perturbed superstructure of the less stable form

Solid-State NMR Analysis of a Complex Crystalline Phase of Ronacaleret Hydrochloride

A crystalline phase of the pharmaceutical compound ronacaleret hydrochloride is studied by solid-state nuclear magnetic resonance (SSNMR) spectroscopy and single-crystal X-ray diffraction. The crystal structure is determined to contain two independent cationic molecules and chloride anions in the asymmetric unit, which combine with the covalent structure of the molecule to yield complex SSNMR spectra. Experimental approaches based on dipolar correlation, chemical shift tensor analysis, and quadrupolar interaction analysis are employed to obtain detailed information about this phase. Density functional theory (DFT) calculations are used to predict chemical shielding and electric field gradient (EFG) parameters for comparison with experiment. ¹H SSNMR experiments performed at 16.4 T using magic-angle spinning (MAS) and homonuclear dipolar decoupling provide information about hydrogen bonding and molecular connectivity that can be related to the crystal structure. ¹⁹F and ¹³C assignments for the <i>Z</i>′ = 2 structure are obtained using DFT calculations, ¹⁹F homonuclear dipolar correlation, and ¹³C–¹⁹F heteronuclear dipolar correlation experiments. ³⁵Cl MAS experiments at 16.4 T observe two chlorine sites that are assigned using calculated chemical shielding and EFG parameters. SSNMR dipolar correlation experiments are used to extract ¹H–¹³C, ¹H–¹⁵N, ¹H–¹⁹F, ¹³C–¹⁹F, and ¹H–³⁵Cl through-space connectivity information for many positions of interest. The results allow for the evaluation of the performance of a suite of SSNMR experiments and computational approaches as applied to a complex but typical pharmaceutical solid phase

Carbamoyl Pyridone HIV‑1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744)

We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (<b>3</b>) and S/GSK1265744 (<b>4</b>). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure–activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of <b>3</b> and <b>4</b>, which are currently in clinical development