An environmentally responsible route to tezacaftor, a drug for treatment of cystic fibrosis prepared in water via ppm Au catalysis as entry to 2-substituted indoles

Abstract

An environmentally responsible synthesis of tezacaftor, a drug approved in 2018 currently in use for treatment of cystic fibrosis, is described utilizing chemistry in water enabled by the nonionic surfactant...

Gate to a parallel universe: utilization of biosurfactants in micellar catalysis

“…4 Several successful micellar methods for transition metal catalysed transformations have been reported using traditional and precisely designed surfactants. 5–10 Considering that the currently applied synthetic surfactants are mostly derived from the petrochemical sector, and the growing demand for the utilization of sustainable and renewable chemicals, in our work we demonstrated the applicability of biosurfactants in micellar catalytic organic transformations as an environmentally friendly, biodegradable alternative to synthetic surfactants (Scheme 1). Biosurfactants represent a sustainable and green alternative to their synthetic counterparts.…”

API Syntheses in Aqueous Media: Assessing the Environmental Footprint en route from Academic Discovery to Industrial Applications as “Green Opportunity” for Process Chemistry

“…As part of the synthesis of tezacaftor, a recently approved API for the treatment of cystic fibrosis, the respective indole portion was obtained by a metal-catalyzed cyclization of a 2alkynylaniline (Figure 5). While the patented process 44 utilizes 10 mol % of Pd(CH 3 CN) 2 Cl 2 /CuI for this step, Lipshutz et al 45 conducted this transformation with a catalyst loading as little as 0.5 mol % of a gold(I)-NHC complex in aqueous surfactant. An intriguing aspect of this example is that a Pdprecatalyst with low molecular complexity was substituted by a more complex Au-catalyst, allowing the effective metal loading to decrease by a factor of 20.…”

“…Cyclization of a 2-alkynylaniline en route to the API tezacaftor with the patented route by Vertex Pharmaceuticals in red and a recently developed route in aqueous surfactant in green.…”

Surfactant-Dependent Partitioning of Organics in Aqueous–Organic Reaction Systems

“…Water-surfactant emulsions provide a promising and sustainable medium for performing organic chemistry, while avoiding the toxicity associated with organic solvents [1][2][3] and have been applied in highly impactful applications from academic to agrochemical to pharmaceutical synthesis. [4][5][6][7][8][9][10][11][12][13][14][15] Unpredictable or irreproducible behavior, however, is currently limiting progress. 16,17 The complexity of these systems has so far restricted understanding of partitioning and thus of valuable mechanistic insight that may arise to overcome irreproducibility challenges and aid in the development of broader applications (Figure 1a).…”