Rapid and efficient synthesis of a novel cholinergic muscarinic M1 receptor positive allosteric modulator using flash chemistry
| Autor: | Makoto Kanematsu, Koichiro Fukuda, Tetsuji Kawamoto, David G. Cork, Shinichi Masada, Hirotsugu Usutani, Shotaro Miura |
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| Rok vydání: | 2019 |
| Předmět: |
Allosteric modulator
010405 organic chemistry Organic Chemistry Muscarinic acetylcholine receptor M1 010402 general chemistry 01 natural sciences Biochemistry Aryne Reductive amination Combinatorial chemistry 0104 chemical sciences Formylation chemistry.chemical_compound chemistry Physical and Theoretical Chemistry Pharmacophore Carbonylation Derivative (chemistry) |
| Zdroj: | Organic & Biomolecular Chemistry. 17:8166-8174 |
| ISSN: | 1477-0539 1477-0520 |
| Popis: | Continuous flow-flash synthesis of a 2-bromobenzaldehyde derivative 18 as a key intermediate of a novel cholinergic muscarinic M1 positive allosteric modulator 1 bearing an isoindolin-1-one ring system as a pharmacophore has been achieved using flow microreactors through selective I/Li exchange of 1-bromo-2-iodobenzene derivative 17 with BuLi and subsequent formylation at −40 °C of the highly reactive 2-bromophenyllithium intermediate using DMF, which is difficult to achieve by a conventional batch process due to the conversion of the highly reactive 2-bromophenyllithium intermediate into benzyne even at −78 °C. Late-stage cyclization to give the isoindolin-1-one ring system, through reductive amination of 18 followed by palladium-catalyzed carbonylation with carbon monoxide and intramolecular cyclization, efficiently afforded 1 for its further research and development. |
| Databáze: | OpenAIRE |
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