ABSTRACT
The application of in situ Raman spectroscopy at small scale (maximum 80 mL) during the development of a manufacturing process is disclosed. The reaction was run in aqueous solution between ambient and 100 °C. Raman spectroscopy has proven to be a viable method to track the reaction. Three distinct phases could be followed: dissolution of the starting material, production of a reactive intermediate, and then subsequent conversion of that intermediate to form product. The objective of the work was to confirm the presence of a reactive intermediate and this could only be carried out via in situ spectroscopy as the intermediate was known to be unstable. Toward the end, the reaction passes though several neutralization points and these are consistent with changes in the spectra. Comparison of data obtained at an illumination wavelength of 998 nm with that obtained at 785 nm is also disclosed. The data obtained at shorter wavelength was contaminated by reasonably strong fluorescence, whereas the data obtained at 998 nm was free of fluorescence. An unexpected observation from this work was that the reaction time was much shorter than expected and this work was key in showing that a reduction in batch cycle time was possible during commercial manufacture.
Subject(s)
Spectrum Analysis, Raman/methods , Technology, Pharmaceutical/methods , Chemical Phenomena , Fluorescence , Hydrogen-Ion Concentration , Temperature , WaterABSTRACT
3-Azabicyclo[3.1.0]hexane compounds were designed as novel achiral µ opioid receptor ligands for the treatment of pruritus in dogs. In this paper, we describe the SAR of this class of opioid ligand, highlighting changes to the lead structure which led to compounds having picomolar binding affinity, selective for the µ receptor over δ and κ subtypes. Some subtleties of functional activity will also be described.
Subject(s)
Antipruritics/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Hexanes/chemical synthesis , Pruritus/drug therapy , Receptors, Opioid, mu/antagonists & inhibitors , Animals , Antipruritics/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Dogs , Guinea Pigs , Hexanes/pharmacology , Humans , In Vitro Techniques , Kinetics , Ligands , Pruritus/metabolism , Receptors, Opioid, delta/antagonists & inhibitors , Receptors, Opioid, delta/metabolism , Receptors, Opioid, kappa/antagonists & inhibitors , Receptors, Opioid, kappa/metabolism , Receptors, Opioid, mu/metabolism , Structure-Activity RelationshipABSTRACT
A short, efficient route has been developed to analogues of myxovirescin using ring-closing metathesis whereby the antibacterial activity has been retained.
