Continuous Flow Techniques in Organic Synthesis

Abstract

As part of the dramatic changes associated with the need for preparing compound libraries in pharmaceutical and agrochemical research laboratories, the search for new technologies that allow automation of synthetic processes has become one of the main topics. Despite this strong trend for automation high-throughput chemistry is still carried out in batches, whereas flow-through processes are rather restricted to production processes. This is far from understandable because the main advantages of that approach are facile automation, reproducibility, safety, and process reliability, because constant reaction parameters can be assured. Indeed, methods and technologies are missing that allow rapid transfer from the research level to process development without time-consuming adaptation and optimization of methods from the laboratory scale to production plant scale. Continuous-flow processes are considered as a universal lever to overcome these restrictions and, only recently, joint efforts between synthetic and polymer chemists and chemical engineers have resulted in the first continuous-flow devices and microreactors; these allow rapid preparation of compounds with minimum workup. Many of these approaches use immobilized reagents and catalysts, which are embedded in a structured flow-through reactor. It is generally accepted, that for achieving best reaction and kinetic parameters for convective-flow processes monolithic materials are ideally suited as solid phases or polymer supports. In addition, immobilization techniques have to be developed that allow facile regeneration of the active species in the reactor.

Lipase-Catalyzed Kinetic Resolution of 1-(2-Hydroxycyclohexyl)Indoles in Batch and Continuous-Flow Systems

“…Even today, most of biosynthetic operations are performed as a fixed, batch based single step procedure. Although continuous processes offer several advantages -such as facile automation, reproducibility and safety -the benefits of the flow-through approach [40][41][42][43][44][45] have not been fully exploited so far.…”

Enantioselective Transamination in Continuous Flow Mode with Transaminase Immobilized in a Macrocellular Silica Monolith

“…Indeed, the flow mode generally allows lowering the E-factor of a production process, by maintaining the catalyst active over large duration, by minimizing unproductive sequences and by reducing the waste/products ratio [19]. To design a truly green and industrially practicable process, the conversion of a batch process to a continuous flow process is often an essential step [20]. In the context of biocatalytic transamination, Andrade et al demonstrated the flow production of chiral amines using immobilized mutants E. coli -designed as to overexpress the desired transaminase [21].…”

Synthesis of N,N′-dialkyl-6,6′-dibromoisoindigo Derivatives by Continuous Flow

“…Continuous-flow chemistry has been developed into a powerful complementary material production technique, partly satisfying the general trend toward faster, cheaper, and cleaner processes [19][20][21][22][23]. Many chemical companies, in particular the pharmaceutical ones and material providers, have been exploring the potential of flow methods and have implemented them in their research and production facilities, as a lot of processes can benefit from (micro/milli) flow reactor technology.…”