Improvements in the Synthesis of the Third-Generation EGFR Inhibitor Osimertinib

Osimertinib, a third generation potent and specific EGFR inhibitor is an important drug against many forms of cancer. It was synthesized by an improved and highly efficient protocol, revisiting the classical synthetic process and modifying parameters, such as solvents, temperature, reagents, and reaction time. A cost-effective, environmentally friendly methodology for the synthesis of osimertinib was established, which gave shorter reaction times, saved labor by eliminating purification steps through column chromatography, and enhanced yields. Four of the seven steps in total, were proceeded quantitatively or almost quantitatively (ca. 98 %). This synthetic protocol provides a very high overall yield, up to 68 %. In addition, the entire approach enables the preparation of osimertinib analogues and could be extended in the synthesis of other structurally similar bioactive compounds.     

New Calix[4]arene‐Cored Peripherally Functionalized Dendrimers: Synthesis and Conformational Characteristics

New calixarene‐based dendrimers, containing calix[4]arene as the core and different generations of Fréchet‐type poly(benzyl ether) dendrons as building blocks, which possess either Br‐atoms or COO^tBu groups at their surface were synthesized and presented herein for the first time. The new calix[4]arene‐cored dendritic macromolecules were fully characterized and found to prefer strictly the cone conformation.     

Silicon Analogues of Triarylmethanol Hosts. Inclusion Properties and Host–guest Structures: A Comparative Study

The simple triarylmethanol hosts, 2 and 4, and their silicon analogues, 1 and 3, have been studied for comparison of the formation of crystalline inclusion compounds. Clathrate formation experiments showed that replacement of the carbinol C atoms in 2 and 4 by Si atoms to give 1 and 3 resulted in a distinct increase of the capability to form inclusion compounds with organic guests, in particular with alcohols. Moreover, the naphthyl derivatives are much more efficient than the phenyl species, irrespective of the carbinol and silanol features. In order to investigate and compare the guest recognition modes and packing relations of hosts 1–4 in their crystalline inclusion compounds, 11 selected co-crystals, namely 1·DMSO (2:1), 3·EtOH (1:1), 3· i-PrOH (1:1), 3·acetone (1:1), 3·DMSO (1:1), 3·THF (1:1), 3·piperidine (1:1), 4·acetone (1:1), 4·DMSO (1:1), 4·1,4-dioxane (1:1) and 4·benzene (1:1), were studied by X-ray diffraction from single crystals. The survey contains additional 11 crystal structures from the literature and provides a detailed discussion of isostructurality relationships.Supplementary Data relevant to this publication have been deposited with the Cambridge Crystallographic Data Centre as supplementary publications nos. CCDC 274780–274790.     

Synthesis of β,γ-unsaturated primary amides from α,β-unsaturated acids and investigation of the mechanism

α,β-Unsaturated acids, through their acid chlorides, react with tritylamine in the presence of triethylamine under mild conditions, to afford in high yield and high regioselectivity the corresponding β,γ-unsaturated tritylamides. Detritylation with TFA generates quantitatively β,γ-unsaturated primary amides. An investigation of this deconjugative isomerization was performed.     

Synthesis of Chiral Starburst Dendrimers from PHB-Derived Triols as Central Cores

Chiral triols 1 – 3 (‘tris(hydroxymethyl)methane’ derivatives), prepared from (R)-3-hydroxybutanoic acid and aldehydes, are used as center pieces of dendrimers. The triols may be employed as such or after attachment of spacers containing alkyl or aryl moieties (see 5 and 7 ). The branches combined with the original or elongated triols are those first reported by Fréchet ( 9 – 12 , benzyl ethers of 3,5-dihydroxybenzyl alcohol and bromide). In this way, 1st-, 2nd-, and 3rd-generation chiral dendrimers without ( 13 – 15 ), or with aliphatic ( 16 – 18 ) or aromatic ( 19 – 21 ) spacers are prepared. The molecular weights range from 447 to 2716 Dalton. Two of the chiral triols, i.e., 2 and 3 , are used as center pieces for chiral dendrimers containing 6 NH₂, or 6 and 12 NO₂ groups on the periphery ( 22 – 27 ), with 3,5-dinitrobenzoyl chloride as the branching unit. All compounds thus synthesized are of course monodisperse and are fully characterized. In some cases, the optical activity of the dendrimers indicates that conformationally chiral substructures might be present. The NH₂- and NO₂-substituted compounds avidly clathrate smaller molecules; they are sorbents exchanging host molecules through the gas phase.     

Base-induced rearrangement of tritylamines to imines: discovery and investigation of the mechanism

An unexpected compound, the aniline derived benzophenone imine, was isolated when tritylamine was treated with n-BuLi and alkyl halides, during the formation of N-alkyl tritylamines, in the process of preparing primary amines. A nucleophilic attack of the nitrogen anion of tritylamide on the adjacent C-bonded phenyl, either substituted or not, involving a bridging anionic intermediate, is proposed for this base-induced tritylamine rearrangement to produce the corresponding imine. Electron-withdrawing groups in the aromatic ring, favoring the negative charge development, affect the relative migratory tendencies.     

Two terphenyl‐based diol hosts and corresponding solvent inclusions with dimethylformamide and acetonitrile

Having reference to an elongated structural modification of 2,2′‐bis(hydroxydiphenylmethyl)biphenyl, (I), the two 1,1′:4′,1′′‐terphenyl‐based diol hosts 2,2′′‐bis(hydroxydiphenylmethyl)‐1,1′:4′,1′′‐terphenyl, C₄₄H₃₄O₂, (II), and 2,2′′‐bis[hydroxybis(4‐methylphenyl)methyl]‐1,1′:4′,1′′‐terphenyl, C₄₈H₄₂O₂, (III), have been synthesized and studied with regard to their crystal structures involving different inclusions, i.e. (II) with dimethylformamide (DMF), C₄₄H₃₄O₂·C₂H₆NO, denoted (IIa), (III) with DMF, C₄₈H₄₂O₂·C₂H₆NO, denoted (IIIa), and (III) with acetonitrile, C₄₈H₄₂O₂·CH₃CN, denoted (IIIb). In the solvent‐free crystals of (II) and (III), the hydroxy H atoms are involved in intramolecular O—H...π hydrogen bonding, with the central arene ring of the terphenyl unit acting as an acceptor. The corresponding crystal structures are stabilized by intermolecular C—H...π contacts. Due to the distinctive acceptor character of the included DMF solvent species in the crystal structures of (IIa) and (IIIa), the guest molecule is coordinated to the host via O—H...O=C hydrogen bonding. In both crystal structures, infinite strands composed of alternating host and guest molecules represent the basic supramolecular aggregates. Within a given strand, the O atom of the solvent molecule acts as a bifurcated acceptor. Similar to the solvent‐free cases, the hydroxy H atoms in inclusion structure (IIIb) are involved in intramolecular hydrogen bonding, and there is thus a lack of host–guest interaction. As a result, the solvent molecules are accommodated as C—H...N hydrogen‐bonded inversion‐symmetric dimers in the channel‐like voids of the host lattice.