Optimization of a Novel Synthetic Route to Generate New MIDD0301 Analogs
Mentor 1
Alexander Arnold
Start Date
29-4-2022 9:00 AM
Description
MIDD0301 is a novel anti-inflammatory asthma drug candidate that targets gamma amino butyric acid type A receptors (GABAAR) without causing systematic immune suppression. In developing a comprehensive structure activity relationship, the use of a novel synthetic strategy involving various amino acid N-carboxyanhydrides (NCAs) has proven to enable a route towards the synthesis of disubstituted imidazodiazepines that was not accessible using the reported methods involving peptide coupling reagents. Numerous NCAs were synthesized and used to cyclize substituted anilines to form benzodiazepines in good yield. This reaction has been extensively optimized for the equivalents of trifluoroacetic acid (TFA) and triethyl amine that are needed to progress this reaction towards completion. However, it has become increasingly clear that the concentration of TFA in toluene plays an important role for reaction progress. Numerous trials were carried out in an effort to determine the optimum ratio between TFA and the solvent. Following this reaction is a two-step process using diethyl chlorophosphate and ethyl isocyanoacetate as well as potassium t-butoxide as a base, which enabled the formation of imidazodiazepines. Hydrolysis under strong basic conditions yields the desired analogs which are currently being evaluated in comparison to MIDD0301 for their ability to interact with GABAARs and relax airway smooth muscle.
Optimization of a Novel Synthetic Route to Generate New MIDD0301 Analogs
MIDD0301 is a novel anti-inflammatory asthma drug candidate that targets gamma amino butyric acid type A receptors (GABAAR) without causing systematic immune suppression. In developing a comprehensive structure activity relationship, the use of a novel synthetic strategy involving various amino acid N-carboxyanhydrides (NCAs) has proven to enable a route towards the synthesis of disubstituted imidazodiazepines that was not accessible using the reported methods involving peptide coupling reagents. Numerous NCAs were synthesized and used to cyclize substituted anilines to form benzodiazepines in good yield. This reaction has been extensively optimized for the equivalents of trifluoroacetic acid (TFA) and triethyl amine that are needed to progress this reaction towards completion. However, it has become increasingly clear that the concentration of TFA in toluene plays an important role for reaction progress. Numerous trials were carried out in an effort to determine the optimum ratio between TFA and the solvent. Following this reaction is a two-step process using diethyl chlorophosphate and ethyl isocyanoacetate as well as potassium t-butoxide as a base, which enabled the formation of imidazodiazepines. Hydrolysis under strong basic conditions yields the desired analogs which are currently being evaluated in comparison to MIDD0301 for their ability to interact with GABAARs and relax airway smooth muscle.
