A Mild Synthesis of Aryl Triflates Enabling the Late-Stage Modification of Drug Analogs and Complex Peptides.

We report the discovery of a straightforward protocol to convert phenols into the corresponding aryl triflates using 1-methyl-3-((trifluoromethyl)sulfonyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one in the presence of a fluoride source. This novel reagent can be handled without any precautions to exclude air or moisture making this method highly convenient. The reactions generally show very clean conversions within only a few minutes at room temperature. The mild conditions allow the so far unprecedented O-triflation of tyrosine in peptides bearing challenging side chains present for example in arginine and histidine including the late-stage triflation of complex bioactive peptides. We show how aryl triflates - an interesting but so far underutilized group - can be used to optimize physicochemical and in vitro properties of compound series in medicinal chemistry. We believe that this method is highly attractive for applications in peptide functionalization as well as automated and medicinal chemistry.

Solubility Improvement of Benexate through Salt Formation Using Artificial Sweetener.

Benexate, a drug used clinically as a defensive type anti-ulcer agent, has poor solubility and a bitter taste. To improve its solubility, a crystal engineering approach was proposed with the formation of novel salts using an artificial sweetener as a salt co-former. This was also expected to address the bitter taste of the drug. In this work, we report on the preparation and evaluation of the physicochemical properties of the novel salts benexate saccharinate monohydrate and benexate cyclamate whose crystal structures were determined by single-crystal X-ray structure analysis. These novel salts showed higher solubility and faster dissolution profiles that were associated with the occurrence of local layered-like structures. They also showed better moisture uptake profiles and were classified as non-hygroscopic materials. Therefore, benexate saccharinate monohydrate and benexate cyclamate expedited the development of sweet pharmaceutical salts of benexate with improved performances.

Crystal structure of olivetolic acid: a natural product from Cetrelia sanguinea (Schaer.).

The title compound, C12H16O4 (systematic name: 2,4-dihy-droxy-6-pentyl-benzoic acid) is a natural product isolated from C. sanguinea (Schaer.) and is reported to have various pharmacological activities. The mol-ecule is approximately planar (r.m.s. deviation for the non-H atoms = 0.096 Å) and features an intra-molecular O-H⋯O hydrogen bond. In the crystal, each olivetolic acid mol-ecule is connected to three neighbours via O-H⋯O hydrogen bonds, generating (10-1) sheets. This crystal is essentially isostructural with a related resorcinolic acid with a longer alkyl chain.