The First Asymmetric Pilot-Scale Synthesis of TV-45070
| Autor: | Joseph A. Sclafani, Jian Chen, Mina Gadelrab Dimitri, Mark A. Olsen, Christopher J. Neville, Christie Michael, Roger P. Bakale, Daniel V. Levy, Harlan F. Reese, Partha S. Mudipalli |
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| Rok vydání: | 2017 |
| Předmět: |
Diphenylphosphine
010405 organic chemistry Stereochemistry Precipitation (chemistry) Organic Chemistry Pilot scale Leaving group 010402 general chemistry 01 natural sciences Combinatorial chemistry 0104 chemical sciences chemistry.chemical_compound Enantiopure drug Aldol reaction chemistry Lactam Racemic mixture Physical and Theoretical Chemistry |
| Zdroj: | Organic Process Research & Development. 21:1616-1624 |
| ISSN: | 1520-586X 1083-6160 |
| DOI: | 10.1021/acs.oprd.7b00237 |
| Popis: | TV-45070 is a small-molecule lactam containing a chiral spiro-ether that has been reported as a potential topical therapy for pain associated with the Nav1.7 sodium ion channel encoded by the gene SCN9A. A pilot-scale synthesis is presented that is highlighted by an asymmetric aldol coupling at ambient temperature, used to create a quaternary chiral center. Although only a moderate ee is obtained, the removal of the undesired isomer is achieved through preferential precipitation of a near racemic mixture from the reaction, leaving the enantiopure isomer in solution. Cyclization to form the final API uses an uncommon diphenylphosphine-based leaving group which proved successful on the neopentyl system when other traditional leaving groups failed. |
| Databáze: | OpenAIRE |
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