The novel rhodium complex [Rh(S)-PhanephosA C H T U N G T R E N N U N G (cod)]-catalyzed hydrogenation of disubstituted (E)-enol acetate carboxylic acids is reported. The catalytic cycle works under 30 bar of hydrogen under conventional heating giving different 3acetoxy-2,3-disubstituted carboxylic acids with ee ! 90%. Hydrogenation occurred also under microwave dielectric heating without eroding the enantioselectivity but improving the overall efficiency of the process. With microwaves, hydrogen pressure and reaction time required for complete hydrogenation dropped to 5 bar and 30 min, respectively. The best performance of this catalyst under microwave irradiation was TON 100, TOF 196 h À1 with ee 99% on a 6-g scale.
A novel synthesis
of the renin inhibitor aliskiren based on an
unprecedented disconnection between C5 and C6 was developed, in which
the C5 carbon acts as a nucleophile and the amino group is introduced
by a Curtius rearrangement, which follows a simultaneous stereocontrolled
generation of the C4 and C5 stereogenic centers by an asymmetric hydrogenation.
Operational simplicity, step economy, and a good overall yield makes
this synthesis amenable to manufacture on scale.
Lesinurad,
a uric acid reabsorption inhibitor that received Food and Drug Administration
approval in 2015, is known to crystallize in three unsolvated crystal
forms and in a few solvated phases. The structures of the former have
been determined by state-of-the-art powder diffraction methods, highlighting
significant conformational as well as supramolecular differences,
resulting in hydrogen bonded centrosymmetric dimers (Form 1) or helical
chains (Form 2). In the complex crystal packing in Form 3, additional
one-dimensional (1D) ribbons held together by unexpected CO···Br
interactions of the halogen-bond type are found. Thermal analyses
and variable-temperature powder diffraction measurements (including
high-temperature synchrotron X-ray diffraction experiments) provided
evidence for the reversible formation of a new phase, Form 2hT, obtained
upon heating above 100 °C powders of Form 2. Structure solution
and refinement of the high-temperature phase made it possible to attribute
the structural change to a 60° rotation of the cyclopropyl residue,
leaving unaffected the conformation of the (longer) polar branch and
the supramolecular 1D helical chain arrangement found in the RT phase.
The preparation of Sofosbuvir, the potent key component of recent Hepatitis C (HCV) infection therapies, is reported. The process is based on the dynamic kinetic resolution of the stereochemically unstable isopropyl‐2‐{[chloro(phenoxy)phosphoryl]‐amino}propanoate (8). A high stereoselectivity was obtained when the right protective group for 3′‐OH was chosen. Ester and carbonate‐based protective groups gave lower stereoselectivities, but benzyl protection allowed the phosphorylation to occur with a 92:8 ratio in favour of the product with the right configuration at the P‐stereogenic centre. Starting from the γ‐lactone of 2‐deoxy‐2‐fluoro‐2‐methylpentonic acid, the synthesis was accomplished in eight steps in 40 % overall yield using commercially available reagents, and without any enzymatic or chemical resolution technique.
Eltrombopag, of C25H22N4O4 chemical formula, is a drug used against thrombocytopenia, marketed worldwide under different tradenames in the form of its bis-olamine salt. The free acid (CAS no. 496775-61-2) is an intermediate species used for the final drug isolation and is reported to crystallize in more than 20 distinct crystal forms, including a large number of hydrates and solvates. Their identification, and, ultimately, their quantification in industrial lots require the usage of accurately measured X-ray powder diffraction pattern, as well as the assessment of the metrical features (crystal symmetry and lattice parameters), nowadays accessible by powerful crystallographic software. Here, the complete indexing of 13 monophasic samples, prepared using literature or newly tailored crystallization methods, jointly to simultaneous thermogravimetric and calorimetric analyses and to variable temperature X-ray diffraction studies, provide a clear picture of the stability fields of the different crystal phases and their mutual interconversion processes, leading, in a few cases, to new and unexpected crystalline polymorphs or solvates of the pristine unsolvated Form I.
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