Synthesis of chiral iminoalkyl functionalised N-Heterocyclic carbenes and their use in asymmetric catalysis

The steric and electronic properties of N-Heterocyclic carbenes and their use as ligands in asymmetric catalysis are reviewed. Key features of enantioselective palladium-catalysed allylie substitution and copper-catalysed conjugate addition reaction are discussed. A modular design approach was applied to the synthesis of iminoalkyl imidazol-2-ylidenes to enable simple structural modifications and fine-tuning catalytic performance for selected reactions. A range of novel chiral imino alkyl alkylimidazolium salts and imino alkyl arylimidazolium salts have been prepared via the N-alkylation of substituted imidazoles with iminoalkyl bromides in moderate to good yields. The chiral iminoalkyl bromides were synthesised from amino acids using a five-step procedure, involving reduction, N-BOC protection, bromination, N-BOC deprotection and imination. The synthesis of chiral iminoalkyl alkylimidazolium salts derived from glycine, alanine, leucine, valine and phenylalanine and N-methyl-, N-benzyl-, N-phenyl and N-mesitylimidazoles is reported. The preparation of both benzylideneamine- and benzylhydrylideneamine derivatives was achieved. One example of an imidazolin-2-ylidene ligand precursor, derived from a dihydroimidazole is also reported. Silver iminoalkyl imidazol-Z-ylidene complexes were prepared by deprotonation of the corresponding imidazolium salts with silver(I) oxide. An X-ray crystal structure of example is reported; it shows the monodentate co-ordination of the iminoalkyl complexes failed. Nonetheless, the silver complexes were successfully employed as earbene transfer reagents for the generation of imino alkyl imidazol-2-ylidene palladium catalysts for use in asymmetrie allylie substitution. The application and performance of the small library of imino alkyl imidäzol-z-ylidene ligands in asymmetric palladium-catalysed allylie substitution is reported and discussed. Catalytic testing demonstrated that variation of the imidazole substituent had a greater effect on enantioselectivity than changing the alkyl substituent at the stereogenic centre on the ligand backbone. The highest enantiomeric excess obtained for the substitution of 1,3-diphenylprop-3-enyl acetate with dimethyl malonate was 53%. The ligands were also screened for enantioselectivity towards copper catalysed conjugate addition of diethyl zinc to cyclohexenone. Performance for this reaction was poor with a highest enantiomeric excess of 18% being obtained

Stability of amoxicillin and clavulanic acid in separate containers for administration via a Y-site

With the discovery of new antibiotics diminishing, optimising the administration of existing antibiotics such as amoxicillin-clavulanic acid has become a necessity. At present, the optimal approach for enhancing the effectiveness of time-dependent antibiotics involves extending the time at which antibiotic concentrations are maintained above the minimal inhibitory concentration by prolonging the infusion time. This pharmacodynamic rationale cannot be applied to co-amoxiclav because of poor stability at room temperature. The aim of this study was to establish the shelf-life of amoxicillin and clavulanic acid prepared in separate containers to determine the feasibility of 24-hr continuous infusion therapy. A previously developed and validated stability-indicating HPLC method was used to establish the shelf-life of reconstituted amoxicillin and clavulanic acid when prepared in separate containers. Stability at clinical concentration was evaluated at three temperatures. To establish whether there were significant differences at the level of both active ingredients and temperature, results were analysed using analysis of covariance (ANCOVA) to assess differences between the attained slopes of regression. Data obtained indicated amoxicillin and clavulanic acid stability superior to that previously proposed making it suitable for continuous infusion therapy. Analysis of regression slopes via ANCOVA showed that temperature significantly affected amoxicillin and clavulanic acid stability. Amoxicillin retained 90% of its initial concentration for 80.3 hrs when stored at 4°C, 24.8 hrs at 25°C and 9 hrs when incubated at 37°C. Clavulanic acid retained 90% of its initial concentration for 152 hrs when stored at 4°C, 26 hrs at 25°C and 6.4 hrs when incubated at 37°C. Amoxicillin and clavulanic acid are suitable for administration via continuous infusion when prepared, stored, and administered in separate containers. Results obtained from this study aid in ameliorating current dosing regimens to optimise antibiotic efficacy; however, more in-depth amoxicillin and clavulanic acid y-site compatibility studies are warranted. [Abstract copyright: © 2021 Fawaz et al.

1-(2,5-Dimethoxy-4-nitrophenyl)piperidine

Treatment of the non-purified mixture of dinitro isomers obtained from the nitration of 1,4-dimethoxybenzene with piperidine led to the isolation of novel but minor adduct, 1-(2,5-dimethoxy-4-nitrophenyl)piperidine (2b) in 15% yield. Yields of nucleophilic aromatic substitution adducts are high when using purified 1,4-dimethoxy-2,5-dinitrobenzene (1b) with piperidine and pyrrolidine to give (2b) and 1-(2,5-dimethoxy-4-nitrophenyl)pyrrolidine (3b) in 76% and 82% yield, respectively