5 research outputs found
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]Âamino}-2-hydroxypropyl)Âoxy]-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 <sup>1</sup>H, <sup>13</sup>C, <sup>15</sup>N, <sup>19</sup>F, and <sup>35</sup>Cl 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, <sup>13</sup>C, <sup>15</sup>N, and <sup>35</sup>Cl 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]Âamino}-2-hydroxypropyl)Âoxy]-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 <sup>1</sup>H, <sup>13</sup>C, <sup>15</sup>N, <sup>19</sup>F, and <sup>35</sup>Cl 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, <sup>13</sup>C, <sup>15</sup>N, and <sup>35</sup>Cl 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]Âamino}-2-hydroxypropyl)Âoxy]-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 <sup>1</sup>H, <sup>13</sup>C, <sup>15</sup>N, <sup>19</sup>F, and <sup>35</sup>Cl 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, <sup>13</sup>C, <sup>15</sup>N, and <sup>35</sup>Cl 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. <sup>1</sup>H 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. <sup>19</sup>F and <sup>13</sup>C assignments
for the <i>Z</i>′ = 2 structure are obtained using
DFT calculations, <sup>19</sup>F homonuclear dipolar correlation,
and <sup>13</sup>C–<sup>19</sup>F heteronuclear dipolar correlation
experiments. <sup>35</sup>Cl 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 <sup>1</sup>H–<sup>13</sup>C, <sup>1</sup>H–<sup>15</sup>N, <sup>1</sup>H–<sup>19</sup>F, <sup>13</sup>C–<sup>19</sup>F, and <sup>1</sup>H–<sup>35</sup>Cl 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