Diaryl ether and diaryl thioether syntheses on solid supports via copper (I)-mediated coupling.
An efficient method to synthesize diaryl ethers and thioethers on solid supports is described. Starting from immobilized phenols or arylhalides, coupling with an access of aryliodides/arylbromides or phenolic/thiophenolic substrates in solution was successful in the presence of CuCl and Cs(2)CO(3) as base. Coupling conditions known from solution-phase syntheses of diaryl ethers have been effectively modified and adapted to solid-phase synthesis. Optimized conditions enabled the coupling of sterically hindered and/or electronically deactivated aryl moieties. After coupling, a newly developed diversity-generating linker based on cinnamic acid allowed the diaryl ethers to be cleaved from the resin either via saponification/transesterification or via ozonolysis. Latter offers the possibility of generating several additional compounds by simple variation of the cleavage conditions. The target substances were generally isolated in good to excellent yields and high purities.
Translation of microwave methodology to continuous flow for the efficient synthesis of diaryl ethers via a base-mediated SNAr reaction
Whilst microwave heating has been widely demonstrated as a synthetically useful tool for rapid reaction screening, a microwave-absorbing solvent is often required in order to achieve efficient reactant heating. In comparison, microreactors can be readily heated and pressurised in order to “super-heat” the reaction mixture, meaning that microwave-transparent solvents can also be employed. To demonstrate the advantages associated with microreaction technology a series of SNAr reactions were performed under continuous flow by following previously developed microwave protocols as a starting point for the investigation. By this approach, an automated microreaction platform (Labtrix® S1) was employed for the continuous flow synthesis of diaryl ethers at 195 °C and 25 bar, affording a reduction in reaction time from tens of minutes to 60 s when compared with a stopped-flow microwave reactor.
Pharmacokinetics of amikacin and chloramphenicol in the aqueous humor of rabbits
Composite data describing ocular pharmacokinetics are unreliable because of intersubject variation. To address this problem, an animal model was developed in which multiple aqueous samples from single subjects were obtained. Following direct anterior chamber or intravenous administration of amikacin or chloramphenicol, pharmacokinetic analysis of drug concentrations in the serum and anterior chamber was performed by using a nonlinear least-squares regression program. The number of anterior chamber paracenteses performed did not alter the beta elimination rates or percent penetration into the anterior chamber. The aqueous humor and peripheral-compartment terminal slopes were identical. These data indicate that complete ocular concentration-time curves can be obtained without altering antibiotic pharmacokinetics. Following direct injection into the anterior chamber, the elimination rates for both antibiotics followed a one-compartment model, whereas those following intravenous administration best fit an open, first-order, two-compartment model. Following intravenous administration, the anterior chamber elimination rate constants for both drugs were equal to that of the serum and significantly longer than that following direct injection. The elimination rates of both drugs following direct injection were similar. Systemic administration resulted in drug levels in aqueous humor that persisted longer than those following direct injection. Chloramphenicol, a lipophilic compound, gave higher mean concentrations in aqueous humor than did amikacin. Our model provides a new approach which rigorously examines ocular pharmacokinetics and provides data which suggest that for selected compounds the parenteral route of administration is preferable.