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 CO···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.

Dedicated to Professor Cesare Gennari on the occasion of his 70th birthdayEthyl diazoacetate (EDA), which is easily prepared from ethyl glycinate and NaNO 2 , reacts in situ with alkynes in a water micelle environment without organic solvent to form pyrazoles. The reaction is pH dependent, as in the presence of protic catalysis (H 2 SO 4 4 %, pH 3.5) a mixture of 3,5-and 4,5disubstituted pyrazoles was obtained, while, at pH 5.5, only the 3,5-disubstituted isomer was obtained. The presence of the surfactant TPGS-750-M was crucial to secure clean crude reaction mixtures and high yields of the products. The same protocol was successfully applied to the synthesis of substituted pyrazolines.

This paper is dedicated to Professor Franco Cozzi on his 70th Birthday. We report here a short enantioselective synthesis of Ozanimod, a potent modulator of the enzyme Sphingosine-1-phosphate receptor (S1P R), recently approved by FDA and EMA for the treatment of relapsing-remitting multiple sclerosis. Amongst different synthetic approaches explored, we achieved the best result introducing the stereogenic centre in the last step through imine asymmetric transfer hydrogenation (ATH) using Wills' catalysts. Besides the reduced numbers of enantiomeric purity controls required, this process culminates in an exceptionally high enantioselective reductive amination obtained with commercially available tethered Ru catalysts. Starting from commercially available 4-cyano-indanone, enantiomerically pure Ozanimod was obtained in 5 steps in 62 % overall yield and 99 % ee.

Tafamidis, chemical formula C14H7Cl2NO3, is a drug used to delay disease progression in adults suffering from transthyretin amyloidosis, and is marketed worldwide under different tradenames as a free acid or in the form of its meglumine salt. The free acid (CAS no. 594839-88-0) is reported to crystallize as distinct (polymorphic) crystal forms, the thermal stability and structural features of which remained thus far undisclosed. In this paper, we present—by selectively isolating highly pure batches of Tafamidis Form 1 and Tafamidis Form 4—the full characterization of these solids, in terms of crystal structures (determined using state-of-the-art structural powder diffraction methods) and spectroscopic and thermal properties. Beyond conventional thermogravimetric and calorimetric analyses, variable-temperature X-ray diffraction was employed to measure the highly anisotropic response of these (poly)crystalline materials to thermal stimuli and enabled the determination of the linear and volumetric thermal expansion coefficients and of the related indicatrix. Both crystal phases are monoclinic and contain substantially flat and π-π stacked Tafamidis molecules, arranged as centrosymmetric dimers by strong O-H···O bonds; weaker C-H···N contacts give rise, in both polymorphs, to infinite ribbons, which guarantee the substantial stiffness of the crystals in the direction of their elongation. Complete knowledge of the structural models will foster the usage of full-pattern quantitative phase analyses of Tafamidis in drug and polymorphic mixtures, an important aspect in both the forensic and the industrial sectors.