An improved process to the novel 4-aminoquinoline antimalarial GSK369796 is described. Although the initial synthetic route consisted of only two steps from readily available starting materials, the product isolated via the key Mannich reaction was hampered by both low yields and low purity. In addition to instability under the reaction conditions used for the Mannich reaction, the drug substance was found to decompose during attempts to purify by recrystallisation. Reaction conditions were developed that resolved these issues, culminating in the successful production of multi-kg quantities of GSK369796 in >98% a/a purity and in 57% overall yield.
Control of trace inorganics and an understanding of reaction kinetics and impurity generation proved critical in allowing safe and reliable scale-up of a high-temperature Claisen reaction in support of multikilogram manufacture of a key chromene intermediate 4. Implementation of a Medicinal Chemistry route allowed for rapid early phase delivery of 1 to support early clinical studies.
Methodologies to access water soluble large ringed calixarenes in good yield using efficient synthetic procedures have been investigated. Symmetrical partial functionalisations at the lower rim are described using activated [n]ethylene glycol chains and the addition behaviour contrasted with that of bromoalkanenitriles which proceeds with no observed regioselectivity. Full functionalisations of the calixarenes bearing hydrophilic groups are then investigated and a two-step procedure established which appears to be generally applicable for the addition of different [n]ethylene glycol chains. Furthermore, difunctionalisation under different reaction conditions are described. Throughout, strategies for the characterisation of these high mass compounds are outlined.
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