When Unsuspected Crystallinity Ruins Biological Testing in Early Discovery: A Case Study.

The impact of the crystalline or amorphous structure of a solid on the solubility and pharmacokinetic properties of a drug candidate is always considered by the pharmaceutical industry during the development of a new drug; however, it is not so frequently considered during the early drug discovery process by organic and medicinal chemists, particularly those working in academia. We want to share, as an example, the false negative obtained in the biological testing of a solid sample of a tyrosine kinase inhibitor due to its unexpected crystallinity and lower solubility with respect to a solid amorphous batch of the same compound and the experimentation carried out to establish the origin of such a discrepancy.

Direct, Stereodivergent, and Catalytic Michael Additions of Thioimides to α,ß-Unsaturated Aldehydes - Total Synthesis of Tapentadol.

Direct and stereodivergent Michael additions of N-acyl 1,3-thiazinane-2-thiones to α,ß-unsaturated aldehydes catalyzed by chiral nickel(II) complexes are reported. The reactions proceed with a remarkable regio-, diastereo-, and enantioselectivity, so access to any of the four potential Michael stereoisomers is granted through the appropriate choice of the chiral ligand of the nickel(II) complex. Simple removal of the heterocyclic scaffold furnishes a wide array of either syn or anti enantiomerically pure derivatives, which can be exploited for the asymmetric synthesis of biologically active compounds, as demonstrated in a new approach to tapentadol. In turn, a mechanism, based on theoretical calculations, is proposed to account for the stereochemical outcome of these transformations.

Powder X-ray diffraction as a powerful tool to exploit in organic electronics: shedding light on the first N,N',N''-trialkyldiindolocarbazole.

The first crystal structure of a fully N-alkylated diindolocarbazole derivative, namely, 5,8,14-tributyldiindolo[3,2-b;2',3'-h]carbazole (1, C36H39N3), has been determined from laboratory powder X-ray diffraction (PXRD) data. A complex trigonal structure with a high-volume unit cell of 12987 Å3 was found, with a very long a(=b) [52.8790 (14) Å] and a very short c [5.36308 (13) Å] unit-cell parameter (hexagonal setting). The detailed analysis of the intermolecular interactions observed in the crystal structure of 1 highlights its potential towards the implementation of this core as a semiconductor in organic thin-film transistor (OTFT) devices. Since the molecule has a flat configuration reflecting its π-conjugated system, neighbouring molecules are found to stack atop each other in a slipped parallel fashion via π-π stacking interactions between planes of ca 3.30 Å, with a centroid-centroid distance between the aromatic rings corresponding to the shortest axis of the unit cell (i.e. c). The alkylation of the three N atoms proves to be a decisive feature since it favours the presence of C-H...π interactions in all directions, which strengthens the crystal packing. As a whole, PXRD proves to be a valuable option for the resolution of otherwise inaccessible organic crystal structures of interest in different areas.

A captured room temperature stable Wheland intermediate as a key structure for the orthogonal decoration of 4-amino-pyrido[2,3-d]pyrimidin-7(8H)-ones.

Wheland intermediates are usually unstable compounds and only a few have been isolated at very low temperatures. During our work on tyrosine kinase inhibitors, we studied the bromination of 7 in order to obtain a dibromo substituted pyrido[2,3-d]pyrimidin-7(8H)-one which could be orthogonally decorated. Surprisingly, treatment of 7 with 3 equiv. of Br2 in acetic acid (AcOH) afforded 12, a captured room temperature stable Wheland bromination intermediate stabilized by the bromination of the imino tautomer of the amino group at C4 of the pyridopyrimidine skeleton. The structure was confirmed by crystal structure determination from powder X-ray diffraction data. Treatment of 12 with DMSO afforded the dibromo substituted compound 13 presenting a bromine atom at C6 and C5-C6 unsaturation. 13 was directly accessed by treating 7 with N-bromosuccinimide (NBS), a protocol extended to other compounds using NBS or N-iodosuccinimide (NIS) to afford 6-halo substituted systems. 26, bearing an iodine at C6 and a p-bromophenylamino at C2, allows the orthogonal decoration of pyridopyrimidines.

C4-C5 fused pyrazol-3-amines: when the degree of unsaturation and electronic characteristics of the fused ring controls regioselectivity in Ullmann and acylation reactions.

Pyrazol-3-amine is a scaffold present in a large number of compounds with a wide range of biological activities and, in many cases, the heterocycle is C4-C5 fused to a second ring. Among the different reactions used for the decoration of the pyrazole ring, Ullmann and acylation have been widely applied. However, there is some confusion in the literature regarding the regioselectivity of such reactions (substitution at N1 or N2 of the pyrazole ring) and no predictive rule has been so far established. As a part of our work on 3-amino-pyrazolo[3,4-b]pyridones 13, we have studied the regioselectivity of such reactions in different C4-C5 fused pyrazol-3-amines. As a rule of thumb, the Ullmann and acylation reactions take place, predominantly, at the NH and non-protonated nitrogen atom of the pyrazole ring respectively, of the most stable initial tautomer (1H- or 2H-pyrazole), which can be easily predicted by using DFT calculations.

Assembling the Puzzle of Apixaban Solid Forms.

An in-depth analysis of the solid forms of the anticoagulant drug Apixaban (APX) has been conducted to sort out the confusion in the scientific and patent literature regarding the solid forms landscape. The nomenclature employed and the accompanying characterization data are often unclear and incomplete, leading to a situation in which apparently the same form has been reported by different authors or claimed by different inventors. A comprehensive solid forms screen and a full and careful comparison with the literature data has been performed to draw a reliable picture of the solid forms landscape of APX.

Polymorphism of (S)-triphenylglycol: kinetic dependent transformation of a new multipolymorphic system.

The appearance of six new polymorphic forms of (S)-triphenylglycol and the kinetically dependent transformation observed by DSC by means of quenching from the melt are reported.

Modular bis(oxazoline) ligands for palladium catalyzed allylic alkylation: unprecedented conformational behaviour of a bis(oxazoline) palladium eta3-1,3-diphenylallyl complex.

New families of enantiopure bis(oxazolines) with 4,5-trans (5 a-g) or 4,5-cis (6 c) stereochemistry at the individual rings have been prepared in high yield. Their eta(3)-allyl palladium complexes (8 a-g, 9 c and 10) have been used as catalytic precursors in allylic alkylation reactions with excellent enantioselectivities (up to 96 %) for the trans oxazoline derivatives, while Pd/6 c system was inactive. NMR studies on palladium eta(3)-1,3-diphenylallyl intermediates (11 a, c and e) showed the presence of syn/syn- and syn/anti-allyl isomers in solution; this resembles the first example of eta(3)-eta(1)-eta(3) isomerism in Pd allylic complexes containing bis(oxazolines) derived from malonic acid.