Abstract
Vandetanib is an orally available tyrosine kinase inhibitor used in the treatment of cancer. The current synthesis proceeds via an unstable 4-chloroquinazoline, using harsh reagents, in addition to requiring sequential protection and deprotection steps. In the present work, use of the Dimroth rearrangement in the key quinazoline forming step enabled the synthesis of Vandetanib in nine steps (compared to the previously reported 12–14).
Highlights
Vandetanib (CaprelsaTM), discovered by AstraZeneca, is an orally available tyrosine kinase inhibitor with activity against VEGFR2/ EGFR/RET which is currently used in the treatment of medullary thyroid cancer (Fig. 1).[1]
As part of a programme of work investigating the use of tyrosine kinase inhibitors (TKI’s) for application to Positron Emission Tomography (PET) imaging of receptor expression, the improved synthesis of Vandetanib and related compounds was investigated
The synthesis commenced from the inexpensive building block 4-hydroxy-3-methoxybenzonitrile 4 (Scheme 2), which was alkylated with benzyl bromide in quantitative yield without the need for extensive purification.[11]
Summary
Vandetanib (CaprelsaTM), discovered by AstraZeneca, is an orally available tyrosine kinase inhibitor with activity against VEGFR2/ EGFR/RET which is currently used in the treatment of medullary thyroid cancer (Fig. 1).[1]. The current literature precedence for the synthesis of Vandetanib via the quinazolinone intermediate 3 is summarised in Scheme 1 (shown in more detail in ESI, Scheme S1). This is a time-consuming synthetic strategy involving twelve steps overall and harsh reagents/reaction conditions. (Scheme 1).[4,5,6] More recent patents have avoided the use of Gold’s reagent and proceeded via benzoic acid 2; this still involves progression through multiple protection and deprotection steps.[4] The current work reports a new and improved synthesis of Vandetanib, avoiding quinazolinone 3 and utilising the Dimroth rearrangement for a streamlined synthetic procedure.[7,8,9,10]
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