Development of a Continuous Flow Process for a Matteson Reaction: From Lab Scale to Full-Scale Production of a Pharmaceutical Intermediate

Abstract

Within this paper, we present the design, development, and scale-up of a process for a continuous Matteson reaction to produce a key intermediate toward the β-lactamase inhibitor vaborbactam. This includes the successful implementation of the continuous concept at a multiton production scale for the API at Patheon, part of Thermo Fisher Scientific. The first-generation continuous flow production with its discontinuous downstream processing was further developed to a fully continuous production through installation of a continuous loop reactor. This enabled increased productivity and energy efficiency, eliminated volume and time bottlenecks, and reduced waste.

Organolithium Bases in Flow Chemistry: A Review

“…Similarly, Schuster and co-workers reported the optimization of a continuous flow reaction setup for the synthesis of 11 , a key intermediate of the API vaborbactam . A review by Hughes also outlined a 2016 patent by Rempex for this synthesis .…”

Flow Technology for the Genesis and Use of (Highly) Reactive Organometallic Reagents

“…Chem. Eur.J.2020, 26,[19][20][21][22][23][24][25][26][27][28][29][30][31][32] www.chemeurj.org Concept stable hetero-substituted organolithiums generated in flow by deprotonation has been reported by Barker andc o-workers. [23] Ad ifferent approach, for the introduction of ad ihalomethylenic unit, was recently reported by Knochel, who developed a continuousf low tactic for homologation of esters using di-chloroacetic acid 13.T he reported strategy, was an unprecedented mild and scalable Claisen reactiont hat used an unstable chloroacetated ianion tamed using flow technology (Scheme 6).…”

“…It is worth noting that the generation and use of the lithiated reagents requires −78 °C in batch conditions. Schuster and co‐workers recently applied this methodology for a flow synthesis and scale‐up of a Matteson reaction involving (dichloromethyl)lithium, and leading to a precursor of vaborbactam, a β‐lactamase inhibitor (Scheme ) …”

“…Chem. Eur.J.2020, 26,[19][20][21][22][23][24][25][26][27][28][29][30][31][32] www.chemeurj.org tion of an aldol reactioni nvolving an ester lithium enolate and an aldehydee nding up with adduct 29 (Scheme 14). [41] To comply with recommendations by pharmaceutical regulatory authorities, the process was designedt aking advantages from processa nalytical technology( PAT) that allow for an accurate processd evelopment.…”

“…Schustera nd co-workersr ecently appliedt his methodology for af low synthesis and scale-up of aM attesonr eaction involving (dichloromethyl)lithium, and leading to ap recursor of vaborbactam, a b-lactamase inhibitor (Scheme 4). [21] In the context of haloalkyllithiums, Ley reported an ew reactivity pattern by generating highly unstable (dibromomethyl)lithium (LiCHBr 2 )i namicroflow system at À90 8C. Besides the requirement of av ery low temperature, the use of flow technologya llowedt ot ackle with electrophilic partners that failed when used under batch conditions.…”