Abstract
Cross-coupling reactions have changed the way complex molecules are synthesized. In particular, Suzuki–Miyaura and Buchwald–Hartwig amination reactions have given opportunities to elegantly make pharmaceutical ingredients. Indeed, these reactions are at the forefront of both the stages of drug development, medicinal chemistry, and process chemistry. On the one hand, these reactions have given medicinal chemists a resource to derivatize the core compound to arrive at scaffold rapidly. On the other hand, these cross couplings have offered the process chemists a smart tool to synthesize the development candidates safely, quickly, and efficiently. Generally, the application of cross-coupling reactions is broad. This review will specifically focus on their real (pharma) world applications in large-scale synthesis appearing in the last three years.
Highlights
Buchwald–Hartwig Couplings inMetal catalyzed cross couplings have played a crucial role in different stages of drug development
Acidification withto the addition of ester 2, with G2 selected after further optimization; 90 mol% of 3, which was synthesized on a kilogram scale through four steps, and 200 mol% of 1 M LiOH were added directly to the reaction vessel following borylation to carry out the Suzuki–Miyaura coupling
Baenziger and coworkers [16] from Novartis reported the development of a synthesis of dactolisib 27 [17], a dual kinase inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin currently investigated as the treatment of solid scale
Summary
Metal catalyzed cross couplings have played a crucial role in different stages of drug development. The ability of cross-coupling reactions to quickly derivatize the core compound results in the multiple compounds available for biological studies The aim at this stage remains to get the compound in milligrams scale. According to Food Drug Administration (FDA), ≤10 ppm Pd is allowed per dose [1,2] This suggests that the old practice of cross-coupling reactions done using 5–10 mol% (50,000–100,000 ppm) Pd catalyst would most probably lead to very high residual Pd. a tedious and costly downstream Pd cleaning process would be required. Pd scavenging processes [5] have mostly solved this issue How these two pathbreaking coupling reactions, Suzuki–Miyaura and Buchwald–Hartwig, are becoming the essence of drug development is discussed in this review.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
