Novel Synthetic Routes for Generating Chiral and Achiral Disubstituted Imidazodiazepines to be Potentially Applied as an Oral and Inhaled Treatment for Asthma
Mentor 1
Alexander Arnold
Start Date
28-4-2023 12:00 AM
Description
Novel compounds related to the asthma drug candidate MIDD0301 were synthesized using three different synthetic routes each of which starts with various chiral and achiral amino acids that are converted to amino acid N-carboxyanhydrides (NCAs) in two of the described methods, Scheme 1 and Scheme 2. The diazepine ring is then formed by coupling the NCAs to the benzophenone under acidic and basic conditions to form the benzodiazepine. The imidazodiazepines are then formed through a two-step process using diethyl chlorophosphate and ethyl isocyanoacetate under basic conditions in the presence of potassium tert-butoxide. The resulting esters are then hydrolyzed under strong basic conditions and are then acidified to form the desired compounds. Scheme 2 involves a slightly different synthesis combining the last two steps of Scheme 1 into a one step using a one pot reaction. In Scheme 3, the benzodiazepine is formed using the coupling reagent N,N’- dicyclohexylcarbodimide (DCC) that couples the benzophenone to the Boc-protected amino acids, the rest of the synthesis is carried out using either Scheme 1 or Scheme 2. In this exploration, we compare the efficacy of each synthetic routes by comparing the overall yield, purity, purification methods, and the required workup.
Novel Synthetic Routes for Generating Chiral and Achiral Disubstituted Imidazodiazepines to be Potentially Applied as an Oral and Inhaled Treatment for Asthma
Novel compounds related to the asthma drug candidate MIDD0301 were synthesized using three different synthetic routes each of which starts with various chiral and achiral amino acids that are converted to amino acid N-carboxyanhydrides (NCAs) in two of the described methods, Scheme 1 and Scheme 2. The diazepine ring is then formed by coupling the NCAs to the benzophenone under acidic and basic conditions to form the benzodiazepine. The imidazodiazepines are then formed through a two-step process using diethyl chlorophosphate and ethyl isocyanoacetate under basic conditions in the presence of potassium tert-butoxide. The resulting esters are then hydrolyzed under strong basic conditions and are then acidified to form the desired compounds. Scheme 2 involves a slightly different synthesis combining the last two steps of Scheme 1 into a one step using a one pot reaction. In Scheme 3, the benzodiazepine is formed using the coupling reagent N,N’- dicyclohexylcarbodimide (DCC) that couples the benzophenone to the Boc-protected amino acids, the rest of the synthesis is carried out using either Scheme 1 or Scheme 2. In this exploration, we compare the efficacy of each synthetic routes by comparing the overall yield, purity, purification methods, and the required workup.
