Improved scale-up synthesis and purification of clinical asthma candidate MIDD0301.

ABSTRACT: We report an improved and scalable synthesis of MIDD0301, a positive GABA_A receptor modulator that is under development as oral and inhaled treatments for asthma. In contrast to other benzodiazepines in clinical use, MIDD0301 is a chiral compound that has limited brain absorption. The starting material to generate MIDD0301 is 2-amino-5-bromo-2'-fluorobenzophenone, which has a non-basic nitrogen due to electron withdrawing substituents in the ortho and para positions, reducing its reactivity towards activated carboxylic acids. Investigations of peptide coupling reagents on multigram scale resulted in moderate yields due to incomplete conversions. Secondly, basic conditions used for the formation of the seven-membered 1,4-diazepine ring resulted in racemization of th

SUBMITTER: Knutson DE 

PROVIDER: S-EPMC7497793 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature