Pharmaceuticals
This chapter describes the design and development of biologically active compounds using cross-coupling reactions as key steps. These biologically active compounds are of both academic and industrial importance. Drug candidates can be prepared from easily
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Pharmaceuticals Jiao Jiao and Yasushi Nishihara
Abstract This chapter describes the design and development of biologically active compounds using cross-coupling reactions as key steps. These biologically active compounds are of both academic and industrial importance. Drug candidates can be prepared from easily available substrates in a few steps through crosscoupling—underscoring the versatility, effectiveness, functional group tolerance, and mild reaction conditions of the cross-coupling methods. Due to these advantages, palladium-catalyzed cross-coupling reactions are being utilized in the industrial production of pharmaceuticals. Keywords Pharmaceutical
Large-scale synthesis Functional group tolerance
4.1 Introduction Owing to many pioneering chemists’ unremitting efforts, recent innovations have replaced earlier protocols to achieve milder, broader, and more efficient catalytic methods for carbon–carbon bond formations [1–11]. The cross-coupling protocols are appropriately considered to be the cornerstones for the synthesis of pharmaceuticals. These reactions provide new entries into pharmaceutical ingredients of continuously increasing complexity. Transition-metal catalysts such as Ni, Cu, Rh, and Ru have been substantially developed in the synthesis of drugs or their precursors [12–16]; however, Pd catalysis, with its high activity and mild reaction conditions, has considerable potential in large-scale applications for pharmaceuticals.
J. Jiao Y. Nishihara (&) Division of Earth, Life, and Molecular Sciences, Graduate School of Natural Science and Technology Okayama University, 3-1-1 Tsushimanaka.Kita-ku, Okayama 700-8530, Japan e-mail: [email protected]
Y. Nishihara (ed.), Applied Cross-Coupling Reactions, Lecture Notes in Chemistry 80, DOI: 10.1007/978-3-642-32368-3_4, Ó Springer-Verlag Berlin Heidelberg 2013
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J. Jiao and Y. Nishihara
4.2 Suzuki–Miyaura Coupling The most representative coupling for the synthesis of pharmaceuticals is the Suzuki–Miyaura coupling, which has been widely studied in the past decade. One of the earliest examples of industrial-scale Suzuki–Miyaura coupling in pharmaceuticals was reported in 1999 [17], which described the synthetic pathway of SB245570, a candidate for the treatment of depression (Scheme 4.1). This synthesis was efficient and inexpensive. The Pd/C-catalyzed Suzuki–Miyaura coupling provided access to the desired product, and reaction in MeOH/H2O gave an improved product yield with a residual Pd level of \6 ppm. Me N
Br Pd/C (1.2 mol%) Na2CO3
O
Me N
+ (HO)2B
CO2H
MeOH/H2O (1:1) reflux, 5 h 91%
CO2H
O Me N
Me O N N O
O SB-245570
Scheme 4.1 A synthetic route to SB-245570
Cameron et al. published the preparation of a GABAA R2/3 agonist for the treatment of generalized anxiety disorder (Scheme 4.2) [18]. The biaryl system was assembled from the palladium-catalyzed Suzuki–Miyaura coupling of an aryl bromide with an arylboronic acid. The arylboronic acid was prepared via ortholithiation of 4-chlorofluorobenzene with lithium 2,2,6,6-te
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