Knutson, Daniel E. published the artcileImproved scale-up synthesis and purification of clinical asthma candidate MIDD0301, Formula: C19H21N, the publication is Organic Process Research & Development (2020), 24(8), 1467-1476, database is CAplus and MEDLINE.
An improved and scalable synthesis of MIDD0301, a pos. GABAA receptor modulator that is under development as oral and inhaled treatments for asthma was reported. 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 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-member 1,4-diazepine ring resulted in racemization of the chiral center. It was found that neutral conditions comparable to the pKa of the primary amine where sufficient to support the formation of the intramol. imine but did not enable the simultaneous removal of the protecting group. Both difficulties were overcome with the application of the N-carboxyanhydride of D-alanine. Activated in the presence of acid, this compound reacted with non-basic 2-amino-5-bromo-2′-fluorobenzophenone and formed the 1,4-diazepine upon neutralization with triethylamine. Carefully designed workup procedures and divergent solubility of the synthesis intermediates in solvents and solvent combinations were utilized to eliminate the need for column chromatog. To improve compatibility with large scale reactors, temperature-controlled slow addition of reagents generated the imidazodiazepine at -20°C. All intermediates were isolated with a purity of >97% and impurities were identified and quantified. After the final hydrolysis step, MIDD0301 was isolated with a 44% overall yield and purity of 98.9% after recrystallization The enantiomeric excess was higher than 99.0%.
Organic Process Research & Development published new progress about 35661-58-6. 35661-58-6 belongs to piperidines, auxiliary class Piperidine,Benzene, name is 1-((9H-Fluoren-9-yl)methyl)piperidine, and the molecular formula is C19H21N, Formula: C19H21N.
Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem