Asymmetric Synthesis of Telcagepant, a CGRP Receptor Antagonist for the Treatment of Migraine

Abstract

A highly efficient, asymmetric synthesis of telcagepant (1), a CGRP receptor antagonist for the treatment of migraine, is described. This synthesis features the first application of iminium organocatalysis on an industrial scale. The key to the success of this organocatalytic transformation was the identification of a dual acid cocatalyst system, which allowed striking a balance of the reaction efficiency and product stability effectively. As such, via an iminium species, the necessnary C-6 stereogenicity was practically established in one operation in >95% ee. Furthermore, we enlisted an unprecedented Doebner-Knoevenagel coupling, which was also via an iminium species, to efficiently construct the C3-C4 bond with desired functionality. In order to prepare telcagepant (1) in high quality, a practical new protocol was discovered to suppress the formation of desfluoro impurities formed under hydrogenation conditions to <0.2%. An efficient lactamization facilitated by t-BuCOCl followed by a dynamic epimerization-crystallization resulted in the isolation of caprolactam acetamide with the desired C3 (R) and C6 (S) configuration cleanly. Isolating only three intermediates, the overall yield of this cost-effective synthesis was up to 27%. This environmentally responsible synthesis contains all of the elements required for a manufacturing process and prepares telcagepant (1) with the high quality required for pharmaceutical use.

A practical and catalyst-free trifluoroethylation reaction of amines using trifluoroacetic acid

“…For example, β -fluoroalkylamines are less basic than their hydrocarbon counterparts (p K a H 10.7 versus 5.7 for ethylamine and trifluoroethylamine respectively)27 and often exhibit decreased acute toxicity and increased metabolic stability rendering them very attractive in pharmaceutical contexts (for examples, see Fig. 1b)2829303132. Unfortunately, while many C–H trifluoroethylation methods have been reported333435363738, there are fewer reagents for the trifluoroethylation of amines (Fig.…”

Total Synthesis of Estradiol Methyl Ether and Its Five‐Pot Synthesis with an Organocatalyst

“…As previous studies indicated that alcohols or THF/H 2 O are suitable solvents for the asymmetric Michael reaction of nitroalkane, we investigated solvents such as MeOH, i PrOH and THF/H 2 O (Table , entries 1, 2, 3) and found that i PrOH was suitable. The ratio of nitroalkane 3 and cinnamaldehyde 4b was then examined, which revealed that an excess of nitroalkane gave better yield (entries 3, 4, 5, 6).…”

Asymmetric Organocatalysis at the Service of Medicinal Chemistry

“…To this end, an organocatalytic approach, namely, an iminium ion catalysed conjugate addition of nitromethane to a proper cinnamaldehyde [113], was judged as more promising than other asymmetric preparations based on transition metal catalysed reactions, such as ruthenium-catalysed hydrogenation [114] and rhodium based Hayashi-Miyaura addition [115]. Although previously reported with related substrates [116, 117] the organocatalytic step required a careful optimisation for its large scale implementation, as the formation of several by-products was observed under the reported conditions.…”