Process research and scale-up of the κ-opioid receptor agonist CJ-15,161 drug candidate

被引:5
作者
Andresen, Brian M. [1 ]
Caron, Stephane [1 ]
Couturier, Michel [1 ]
DeVries, Keith M. [1 ]
Do, Nga M. [1 ]
Dupont-Gaudet, Kristina [1 ]
Ghosh, Arun [1 ]
Girardin, Melina [1 ]
Hawkins, Joel M. [1 ]
Makowski, Teresa M. [1 ]
Riou, Maxime [1 ]
Sieser, Janice E. [1 ]
Tucker, John L. [1 ]
Vanderplas, Brian C. [1 ]
Watson, Timothy J. N. [1 ]
机构
[1] Pfizer Inc, Chem Res & Dev, Groton, CT 06340 USA
关键词
N-arylation; aziridinium; copper; oxazolidinone; palladium; process chemistry;
D O I
10.2533/chimia.2006.554
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
This account depicts strategies adopted during the development of the K-opioid receptor agonist CJ-15,161. While the original discovery synthesis was enabled for scale-up, concomitant process research aimed at identifying a novel and more efficient route was undertaken. In the former case, an efficient four-step sequence has been developed, where the process features four consecutive regioselective and stereospecific inversions at a single aziridinium stereogenic center, which leads to overall retention of stereochemistry in a single operation. The search for novel routes has also resulted in two converging methods involving efficient intermolecular N-arylation strategies. The first approach involves Pd-catalyzed intermolecular N-arylation of an appropriately functionalized diamine, obtained from the precursor alpha-amino acids or, more conveniently, from the corresponding 1,2-amino alcohols. The second approach exploits efficient intermolecular N-arylation of oxazolidinones using catalytic copper in the presence of a bidentate ligand leading to a straightforward and practical synthesis of CJ-15,161.
引用
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页码:554 / 560
页数:7
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