The application of flow microreactors to the preparation of a family of casein kinase I inhibitors

Abstract

In this article we demonstrate how a combination of enabling technologies such as flow synthesis, solid-supported reagents and scavenging resins utilised under fully automated software control can assist in typical medicinal chemistry programmes. In particular automated continuous flow methods have greatly assisted in the optimisation of reaction conditions and facilitated scale up operations involving hazardous chemical materials. Overall a collection of twenty diverse analogues of a casein kinase I inhibitor has been synthesised by changing three principle binding vectors.

Chemical approaches towards unravelling kinase-mediated signalling pathways

“…28 Recently, a mixture of organolithium, carbonyl and nucleophilic aromatic substitution methods has allowed automated, multistep synthesis of a small library of potential kinase inhibitors, 40 based on imidazo[1,2-b]pyridazines, using a microflow reactor ( Figure 3B). 29 However, the preparation of nucleotide triphosphates and their analogues is often a much more laborious task, even though clear, prescriptive procedures are available. 31 70 Usually, the assembly of ATP analogues can be broken down into two major disconnective steps; (i) preparation of the modified nucleoside, and (ii) elaboration to the triphosphate or its analogue (Scheme 5).…”

Flow chemistry approaches directed at improving chemical synthesis

“…It was discovered that when the dimethyll -tartrate and trimethyl orthoformate were premixed, rapid formation of an intermediate diacetal occurred, which was observed using the ReactIR flow cell ( Scheme 17 ). This proved to be an important observation and optimization of Guanadine library [80] Thiazole library [79] Oxazole library [83] Grossamide [81] Zolpidem [72] Meclinertant SR 48692 [74] Casein Kinase Inhibitors library [77] Aminopyrrolidines [78] Polypeptides [82] Scheme 15 A range of other targeted structures achieved using multi-step flow synthesis.…”

Managing Hazardous Reactions and Compounds in Process Chemistry

“…The major product is the ketoester (183). Reaction of an organolithium with an ester can provide the ketone without the frequent problem of further reaction to the tertiary alcohol (184).…”