Analysis of the Reactions Used for the Preparation of Drug Candidate Molecules

Abstract

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Ruthenium-Catalyzed Amide-Bond Formation

“…In combination with the imidazolium salt 35b (see Table 1), sodium hydride and acetonitrile, this complex readily converted a variety of aliphatic and aromatic aldehydes into amides (Scheme 30). Further studies on the stoichiometric reactivity of [RuH 2 (PPh 3 ) 4 ] with NaH at 110ºC suggested the formation of ruthenium(0) species during the catalytic events. This proposal was also supported by fact that the ruthenium(0) complexes [Ru 3 (CO) 12 ] and [Ru(cod)(cot)], associated with 35b and NaH, proved to be also active in the process.…”

“…In this context, ruthenium complexes are among the most versatile nitrile hydration catalysts discovered with regard to activity, selectivity and tolerance to functional groups. 4 ] upon treatment with 1-2 equivalents of water in DME at 120 ºC, leading to the corresponding primary amides in high yields (TOF up to 2 h -1 ). A catalytic cycle involving the initial coordination of the nitrile to ruthenium, followed by intermolecular nucleophilic attack of water to generate an iminol that tautomerizes into the amide, was proposed (Scheme 2) [24].…”

“…Both processes were also catalyzed by [RuCl 2 (DMSO) 4 ], albeit a higher metal loading (5 mol%) was in this case needed [90]. Interestingly, using 5 mol% of the arene-ruthenium(II) complex [RuCl 2 ( 6 -C 6 Me 6 ){P(NMe 2 ) 3 }] (10 in Scheme 6), the rearrangement of aldoximes could be successfully performed in aqueous medium at 100 ºC [91].…”

“…They are also key structural motifs in multitude of natural products [1,2]. Studies carried out by leading pharmaceutical companies have pointed out that amide bond forming reactions are among the most executed chemical transformations in their laboratories [3,4]. Indeed, an in-depth analysis of medicinal chemistry databases revealed that the amide group is present in more than 25% of the drugs currently known [5].…”

Principles, Concepts and Strategies of Stereoselective Synthesis

“…and often is used for the production of chiral drugs 74 or drug intermediates as one of the preferred methods for the generation of chirality, 75 especially if the chirality should be introduced during one of the early stages of the drug synthesis sequence. 76 The reason for this choice is the high availability of screening methods and the increased understanding of crystallization during the scale-up process.…”