Process Development and Scale-Up of a PPARγ Agonist: Selection of the Manufacture Route

• Published in: Organic process research & development 2009-03, Vol.13 (2), p.303-309
• Main Authors: Bullock, Kae M, Burton, Delphilia, Corona, John, Diederich, Ann, Glover, Bobby, Harvey, Kim, Mitchell, Mark B, Trone, Mark D, Yule, Robert, Zhang, Yong, Toczko, Jennifer F
• Format: Article
• Language: English
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/op800211c

Two short, high-yielding routes to the selective PPARγ agonist GSK376501A were developed and carried out on scale. The key bond -forming reaction in each synthesis was the substitution of a 3,5-difluoro or 3,5-dibromo aryl intermediate with 2-methoxyethanol. A nucleophilic aromatic (SNAr) substitution reaction under basic conditions was developed for the aryl fluoride substrate. The 3,5-dibromo aryl halide intermediate required copper-catalyzed conditions to achieve substitution of the second bromide. In addition, a 2-methoxyethanol decomposition pathway to generate methanol and ethylene oxide under basic reaction conditions as well as its effect on impurity formation, was elucidated. Both the difluoro and dibromo intermediates were considered as the basis for the final route of manufacture. The difluoro substrates were chosen due to straightforward chemistry, controllable impurity profile, and ease of fluoride removal.