An alternative synthesis of Vandetanib (Caprelsa) via a microwave accelerated Dimroth rearrangement

Article abstract of DOI:10.1016/j.tetlet.2017.02.082

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).

Full text of DOI:10.1016/j.tetlet.2017.02.082

Accepted Manuscript
An alternative synthesis of Vandetanib (Caprelsa™) via a microwave acceler-
ated Dimroth rearrangement
Kayleigh L. Brocklesby, Jennifer S. Waby, Chris Cawthorne, Graham Smith
PII:
S0040-4039(17)30270-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.082
TETL 48693
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 January 2017
24 February 2017
27 February 2017
Please cite this article as: Brocklesby, K.L., Waby, J.S., Cawthorne, C., Smith, G., An alternative synthesis of
Vandetanib (Caprelsa™) via a microwave accelerated Dimroth rearrangement, Tetrahedron Letters (2017), doi:
http://dx.doi.org/10.1016/j.tetlet.2017.02.082
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An alternative synthesis of Vandetanib (Caprelsa™) via a
microwave accelerated Dimroth rearrangement
Kayleigh L. Brocklesby1,2, Jennifer S. Waby3§, Chris Cawthorne4 and Graham Smith2*
1Hull-York Medical School, University of York, Heslington, York YO10 5DD; 2Division
of Radiotherapy and Imaging, Institute of Cancer Research, London, SW7 3RP, UK;
3School of Biological, Biomedical and Environmental Sciences, University of Hull,
4
Cottingham Road, Hull, HU6 7RX, UK; PET Research Centre, University of Hull,
Cottingham Road, Hull, HU6 7RX, UK.
* Email: graham.smith@icr.ac.uk; Tel +44 (0)2087224482
§Present address: Faculty of Life Sciences, Richmond Building Room H15,
University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK.
Graphical Abstract
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).
Keywords
Vandetanib, quinazoline, Dimroth rearrangement, tyrosine kinase inhibitor

Introduction
Vandetanib (Caprelsa™), 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 Vandetanib is representative of a
wide class of 4-anilinoquinazoline drug molecules that function as adenosine
mimetics and bind at the tyrosine kinase intracellular receptor site; other examples of
2
this compound class include Erlotinib and Gefitinib (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.
Figure 1: Structures of Vandetanib (Caprelsa™), Gefitinib (Iressa™) and Erlotinib (Tarceva™)
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. The original synthesis utilised amide
1,3 which requires pre-preparation due to a lack of commercial availability and Gold`s
reagent ([3-(dimethylamino)-2-azaprop-2-en-1-ylidene]dimethylammonium chloride)
to directly construct 3 (Scheme 1).4-6 More recent patents have avoided the use of
Gold`s reagent and proceeded via benzoic acid 2; however, 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.7-10

Scheme 1: Current synthetic procedure to Vandetanib via the key quinazolinone intermediate 3
Results and Discussion
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 Nitration of 5 under
mild conditions afforded 6 in 93% yield as a yellow precipitate which required no
further purification.
Scheme 2: Reagents and conditions: i) Benzyl bromide, K2CO3, DMF, rt, 18 h; ii) Nitric acid, Ac2O, 0
°C to rt, 18 h; iii) NaHCO3, tetra-butyl ammonium chloride, Sodium dithionite, DCM, water, rt, 2 h; iv)
DMF-DMA, microwave, 90 °C, 15 min.
Literature precedence for the reduction of 6 using iron and ammonium formate,
revealed a difficult work-up, associated with poor yields;12 alternative literature
procedures suggested the use of sodium dithionite.13 Pleasingly, reduction using
sodium dithionite gave 7 in 74% yield, with no purification required (Scheme 2). The
synthesis of 8 (Scheme 2 and Table 1) was troublesome due to the poor solubility of
aniline 7 in organic solvents. Ultimately the reaction was performed neat with a large
excess of DMF-DMA to aid solubility and formation of the formamidine; toluene was
also tested as a co-solvent with no observable effect on the reaction progress.
Microwave irradiation for 15 minutes at 90 °C (Entry 1) afforded only minimal
conversion to formamidine 8; however, extension of the reaction time by a further 15

minutes (to a total of 30 minutes) resulted in an improved yield of 95% (Entry 5) due
to the increased time for solubilisation in DMF-DMA to occur. Conventional heating
(Entry 2) at the same temperature provided 8 in a reduced yield of 58% despite
extending the reaction time to 120 minutes. Of note, on smaller scales
chromatographic removal of DMF-DMA was required, but on larger scales (e.g. 8
mmol) formamidine 8 was observed to precipitate from DMF-DMA.
Table 1: Optimisation for the synthesis of 8.
Entry
1
Solvent
Time (min) Heating (temp(ºC))
Work-up
A
Yield
2%
DMF-DMA
DMF-DMA-
toluene
DMF-DMA-
toluene
15
Microwave (90 °C)
Conventional (185
°C)*
2
3
120
none
A
58%
95%
30
Microwave (90 °C)
DMF-DMA-
toluene
DMF-DMA
4
5
30
30
Microwave (90 °C)
Microwave (90 °C)
B
94%
A or B
94-95%
A) Allowed to precipitate overnight; B) Removal of DMF-DMA using silica chromatography; *
Distillation facilitated removal of DMF-DMA from the product. Reagents and conditions: 7 (500 mg,
1.97 mmol), either DMF-DMA (3 mL) or DMF-DMA in toluene (1:1); C) Microwave reactions were
conducted in a Biotage Initiator with a maximum power output of 400W.
TFA mediated debenzylation of 8 was selected owing to the potential vulnerability to
hydrogenation induced reduction of the formamidine, and afforded 9 in an almost
quantitative yield. Alkylation of 9 afforded 10 in 58% yield using tert-butyl-4-
(tosyloxy)methyl)piperidine-1-carboxylate (A in Scheme 3), which was synthesised
according to a literature method.14
Scheme 3: Reagents and conditions: i) TFA, microwave (max. power 400 W), 70 ºC, 45 min; ii) A,
Cs2CO3, MeCN, reflux, 3 hr; iii) 4-bromo-2-fluoroaniline, 130 °C, 1 h.
The key Dimroth rearrangement step was then investigated commencing from 10 in
the presence of 4-bromo-3-fluoroaniline (1 equiv.) and acetic acid with microwave
heating at 130 °C for 45 minutes. No product was observed by either TLC or LCMS
when irradiated for 15 minutes at 118 °C; this contrasted with previous reports on the

synthesis of related 4-anilinoquinazolines such as Gefitinib.15, 16 Duration of the
microwave irradiation was irrelevant for the synthesis of 11, which was temperature
dependent and required 130 °C for complete conversion, highlighting the possible
inactivated nature of the reagents. Quinazoline 11 was isolated in 62% yield after
chromatographic purification. The proposed mechanism for this rearrangement is
illustrated in Scheme 4.
Scheme 4: Proposed mechanism for the Dimroth rearrangement; derived from Chandregowdra and
co-workers in their synthesis of Erlotinib and Gefitinib16
The penultimate step in the synthesis of Vandetanib was the BOC deprotection of
piperidine 11. Deprotection according to literature procedures resulted in low yields
during aqueous work-up (Scheme 5).3 However, through following the literature
deprotection procedure4 and avoiding aqueous work-up, direct silica chromatography
purification afforded 12 in 83% yield. Reductive amination with formaldehyde
according to the literature procedure4 yielded Vandetanib (Caprelsa™) in 84% yield,
an overall 7% yield over nine steps.
Scheme 5: i) TFA, DCM, rt, 2 h; ii) HCHO, AcOH, NaBH(OAc)3, MeOH, DCM, rt, 2 h.

Conclusion
In this report we have presented an alternative route to the synthesis of Vandetanib
via the Dimroth rearrangement. Ultimately this new synthetic procedure is a
reduction of three steps compared to the most concise published method and avoids
the series of protection and deprotection steps currently established by several
literature procedures. Chromatography is only required for four steps in this
synthesis compared to multiple steps in the previous reports. Overall Vandetanib
was synthesised in 7% yield over 9 steps compared to 4-20% yield over 12-14 steps
in the previously reported methods.
Experimental
Experimental data can be found in the supplementary data file associated with this
report. In addition to experimental information and characterisation data this file also
contains NMR spectra for selected compounds.
Acknowledgements
The Hull-York Medical School and the University of Hull are thanked for studentship
funding (to KLB). This work was supported by the Cancer Research UK-Cancer
Imaging Centre (grant: C1060/A16464), the Institute of Cancer Research and the
University of Hull. We thank Dr. Amin Mirza, Dr. Maggie Liu, and Meirion Richards
for assistance in analytical chemistry and spectroscopy.
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Highlights



Synthesis of Vandetanib achieved in fewer steps (9 versus the previous best of 12)
New synthetic route has fewer steps that require chromatographic purification
Key step is a microwave assisted Dimroth rearrangement to provide the core quinazoline