With
the first generation medicinal chemistry synthesis as a starting
point, we describe herein process development of AZD4573, an oncology drug candidate. In addition to improved yields and
removal of chromatographic steps, we have addressed other factors
such as availability of starting materials as well as safety of the
chemistry involved. With several steps involving volatile, reactive,
and non-UV active materials, reaction optimization was facilitated
by implementing off-line 1H NMR analysis of crude mixtures.
Key transformations targeted for process development included a Wolff–Kishner
reduction, an iridium-catalyzed borylation, and enzymatic resolution
of a racemic amino-ester.
A large-scale asymmetric synthesis has been developed for the kilo-lab manufacture of AZD8186. The process initially employs a regioselective Heck coupling in water to provide the starting aromatic ketone. This ketone is reduced asymmetrically under ruthenium-catalyzed transfer hydrogenation conditions to provide a chiral alcohol in high enantiomeric purity. The key synthetic step then requires the reaction of this chiral alcohol with the activated derivative of 3,5-difluoroaniline under the Mitsunobu reaction conditions. The common issues associated with the use of the Mitsunobu reaction, such as removal of triphenylphosphine oxide and reduced diisopropyl azodicarboxylate (DIAD) by-products, have been eliminated through crystallization of the relevant intermediates.
During the development of a new route to AZD2563 DSP (DSP ) disodium phosphate), a selective enzyme-catalysed hydrolysis of a 1,2-diester moiety to produce the secondary monoester was developed. Apart from two esters, the target molecule also contained three further functional groups prone to hydrolysis. A major challenge to the chosen approach was the very facile rearrangement of the desired secondary monoester product to the undesired primary monoester. This rearrangement was found to be catalysed by a wide range of chemicals and inorganic materials usually considered as inert. The unique selectivity and mild operating conditions of biocatalysis allowed the desired reaction to be developed and successfully scaled up.
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