An efficient synthesis of the piperidinyl dihydroquinazolinone (PDQ) fragment of olcegepant

Article abstract of DOI:10.1016/j.tetlet.2018.08.002

Olcegepant is one of the most potent and selective small molecule CGRP antagonists for the treatment of migraine headaches. Herein, we describe a new and efficient synthesis of the key piperidinyl dihydroquinazolinone (PDQ) fragment of olcegepant. PDQ plays a key role in the activity of CGRP antagonists. Primary improvements over existing methods include a high-yielding reductive amination step, greater overall yield, and operational simplicity. Coupling of PDQ to a D-tyrosine derivative effectively produced over one half of the total molecular structure of olcegepant. A unique tandem deprotection-nucleophilic addition sequence was also applied to the coupling of Fmoc-PDQ with phenyl isocyanate.

Full text of DOI:10.1016/j.tetlet.2018.08.002

Accepted Manuscript
An Efficient Synthesis of the Piperidinyl Dihydroquinazolinone (PDQ) Frag-
ment of Olcegepant
Stephen A. Habay, Julia M. Miller, Matthew M. Bowler, Randi Manchak, John
Z. Thomas
PII:
S0040-4039(18)30971-7
https://doi.org/10.1016/j.tetlet.2018.08.002
TETL 50177
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 June 2018
24 July 2018
1 August 2018
Please cite this article as: Habay, S.A., Miller, J.M., Bowler, M.M., Manchak, R., Thomas, J.Z., An Efficient
Synthesis of the Piperidinyl Dihydroquinazolinone (PDQ) Fragment of Olcegepant, Tetrahedron Letters (2018),
doi: https://doi.org/10.1016/j.tetlet.2018.08.002
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Graphical Abstract
An Efficient Synthesis of the Piperidinyl
Dihydroquinazolinone (PDQ) Fragment of
Olcegepant
Leave this area blank for abstract info.
Stephen A. Habay, Julia M. Miller, Matthew M. Bowler, Randi Manchak, and John Z. Thomas

1
Tetrahedron Letters
jo u r n a l h o m e p a g e : w w w . e ls e v ie r . c o m
An Efficient Synthesis of the Piperidinyl Dihydroquinazolinone (PDQ) Fragment of
Olcegepant
Stephen A. Habaya*, Julia M. Millera, Matthew M. Bowlera, Randi Manchaka, and John Z. Thomasa
aDepartment of Chemistry, Salisbury University, Salisbury, MD 21801, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Olcegepant is one of the most potent and selective small molecule CGRP antagonists for the
treatment of migraine headaches. Herein, we describe a new and efficient synthesis of the key
piperidinyl dihydroquinazolinone (PDQ) fragment of olcegepant. PDQ plays a key role in the
activity of CGRP antagonists. Primary improvements over existing methods include a high-
yielding reductive amination step, greater overall yield, and operational simplicity. Coupling of
PDQ to a D-tyrosine derivative effectively produced over one half of the total molecular
structure of olcegepant. A unique tandem deprotection-nucleophilic addition sequence was also
applied to the coupling of Fmoc-PDQ with phenyl isocyanate.
Available online
Keywords:
migraine
CGRP
reductive amination
isocyanate
2018 Elsevier Ltd. All rights reserved.
protecting groups
Olcegepant (BIBN4096BS) is a potent and highly selective
calcitonin gene-related peptide (CGRP) receptor antagonist that
was shown to be an effective treatment for migraines in clinical
trials.1 Additionally, olcegepant is used widely in the laboratory
as a chemical tool to block vasodilation.2 Within the chemical
pathways is the need to reduce a nitrobenzene moiety to an
aniline, which increases the number of steps.
structure of olcegepant lies
a key 3-(piperidin-4-yl)-3,4-
dihydroquinazolin-2[1H]-one (PDQ) fragment 1 (Scheme 1) that
is central to the activity of the drug.3 The PDQ substructure is
also present in a number of other CGRP antagonists such as
thiazolidinones,4 tyrosine surrogates,5 aspartates and succinates,6
caprolactams,7 benzodiazepines,8 carbamates,9 oxadiazoles,10 and
imidazoles.11 In addition, PDQ is an important heterocycle found
in constrained aminobenzazepinone peptidomimetics,12 inhibitors
of the Na+/Ca2+ exchanger,13 and muscarinic acetylcholine
receptor agonists.14
Given the importance of PDQ to the development of therapies
for migraine and other medical conditions, efficient methods of
synthesis are critical to advancing research in these areas.
Herein, we report a short, flexible, and scalable synthesis of PDQ
and its coupling to 3,5-dibromo-D-tyrosine methyl ester, to
effectively yield over one half of the olcegepant structure.
Additionally, we report a one-pot deprotection-coupling of N-
Fmoc-protected PDQ to phenyl isocyanate.
Scheme 1. Our approach to the synthesis of PDQ, highlighting
improved yields and protecting group diversity.
Our approach to the synthesis of PDQ (Scheme 1) proceeds
through a unique reductive amination between the more
nucleophilic benzyl amine of 2-aminobenzylamine 2 and an N-
protected 4-piperidone 3a-b in excellent yield. Subsequent cyclo-
condensation with 1,1’-carbonyldiimidazole (CDI) forms the 3,4-
dihydroquinazolin-2[1H]-one heterocycle 5a-b. At this point, the
Boc-protecting group can be removed from 5a by treatment with
trifluoroacetic acid to yield the final PDQ 1.18 This three-step
synthesis avoids the need to reduce a nitro group and represents
an efficient and operationally simple pathway to gram-scale
quantities of PDQ. The synthesis results in a 54% overall yield of
1 and requires only one chromatographic purification. The
synthetic route can also be accomplished with a N-benzyl
protecting group, which can be removed in the final step via
hydrogenolysis. We were also delighted to find that the benzyl
In our attempts to prepare PDQ through existing methods we
recognized that the process could be improved with respect to the
number of steps, overall yield, and operational simplicity by
pursuing an alternate pathway. PDQ was originally prepared by
Takai and co-workers in four steps (5% overall yield) through a
reductive amination strategy carried out between 2-
nitrobenzaldehyde and N-benzyl-4-aminopiperidine.15 More
recently, PDQ has been prepared through a four-step sequence
involving nucleophilic substitution by an aminopiperidine on 2-
nitrobenzyl bromide.16 A similar strategy was accomplished on
solid support.17 One common requirement of each of these

2
Tetrahedron
protecting group could be easily exchanged by treatment with
Fmoc chloride in acetonitrile to yield 5c. We originally
developed this distinctive protecting group exchange to
circumvent decomposition during removal of a N-benzyl group
via hydrogenolysis on a different compound.19 Presumably, the
exchange proceeds through an intermediate quaternary
ammonium ion, followed by ejection of benzyl chloride via
nucleophilic substitution. The reaction is high yielding and
operationally simple due to precipitation of the product caused by
the relative insolubility of the Fmoc group in acetonitrile. The
diversity of protecting groups in our synthesis of PDQ adds
versatility, which is particularly important during the coupling of
PDQ to other chemical fragments in the development of CGRP
antagonists.
Scheme 3. Synthesis of over half of the olcegepant molecular
structure.
We were delighted to find that when 5c was suspended in
THF with phenyl isocyanate and treated with DBU, the desired
product 10 was produced in good yield (Scheme 4). The reaction
was judged complete at 15 minutes (by TLC). The product
precipitated upon addition of water to the reaction medium.
Presumably, DBU quickly deprotonates the Fmoc group, leading
to decomposition of the carbamate. The resultant soluble amine
then attacks phenyl isocyanate to produce urea 10.
During the reductive amination step, if the aryl amine of 2
were to react with the ketone, rather than the benzyl amine, a
constitutional isomer of 1 would result. Aniline is known to react
with N-Boc-4-piperidone in reductive amination reactions.20
However, no isomer was observed under our reaction conditions.
To verify that the more nucleophilic benzyl amine of 2 engaged
with the ketone of 3 preferentially during reductive amination,
we conducted the reaction with an aryl-N-Boc protected 621
(Scheme 2). Compound 7 was obtained in 59% yield. The yield
is lower than that observed in Scheme 1, presumably due to steric
hindrance on the nucleophilic benzyl amine from the adjacent N-
Boc group. After Boc removal and cyclo-condensation of 7, we
obtained the expected 5b. The NMR spectra matched that of 5b
prepared through the sequence described in Scheme 1.
Scheme 4. Rapid Fmoc deprotection and nucleophilic addition of
the resultant amine to phenyl isocyanate.
It should be noted that compounds containing the PDQ moiety
are prone to benzylic oxidation in solution over time.9 In fact,
olcegepant itself has been observed to undergo such oxidation,
and yet still retains good activity.24 We did not observe any
oxidation by-products during the course of our study. However,
any future development of PDQ-based libraries of CGRP
antagonists should be aware of the potential oxidation.
Scheme 2. Alternate synthesis of 5b used to verify that only the
benzyl amine participates in the reductive amination step.
With PDQ 1 in hand, we next wanted to demonstrate its
coupling to 3,5-dibromo-D-tyrosine methyl ester 8 (Scheme 3)
through a connecting urea spacer. The product 9, constitutes over
one half of the olcegepant total structure. Tyrosine derivative 8 is
prepared in two steps from D-tyrosine22 and may be used in the
coupling step directly as the hydrochloride salt. In our protocol
adapted from the olcegepant production patent,23 compound 8
was treated with CDI in the presence of 1,2,4-triazole, producing
intermediate 8a. PDQ 1 was added at room temperature and then
heated at 55 °C for 1.5 h to initiate nucleophilic acyl substitution
of the imidazolyl group of 8a with 1. The reaction was cooled to
room temperature and water added. Product 9 precipitated and
was then collected and purified by column chromatography. This
simplified procedure allows for an efficient and scalable
preparation of advanced intermediates in the synthesis of
olcegepant and its derivatives.
In summary, we report an efficient and operationally simple
three-step synthesis of PDQ 1 that is amenable to use of multiple
N-protecting groups. We demonstrated coupling of PDQ 1 to
tyrosine derivative 8, which is useful in the preparation of the
CGRP antagonist olcegepant. Finally, we successfully applied
our previously reported tandem deprotection-coupling strategy to
the reaction of Fmoc-PDQ 5c with phenyl isocyanate.
Acknowledgments
This work was supported by Salisbury University. The authors
also thank Dr. Papa Nii Asare-Okai and the University of
Delaware for assistance with HR-MS.
Conflicts of Interest
Previously, we developed
a
rapid, one-pot tandem
deprotection-coupling of an Fmoc-protected amine to
isocyanates.19 This strategy was used in the synthesis of SHA 68,
a potent and selective antagonist of the neuropeptide S receptor
(NPSR). The strategy proved useful in the development and
screening of a library of SHA 68-based NPSR antagonist
derivatives. We were curious if this tandem reaction would work
on Fmoc-protected PDQ 5c. If so, the procedure may prove
useful in the development of future PDQ-based libraries of
potential CGRP antagonists.
We declare no conflict of interest.
Supplementary Data
Supplementary Information is provided.

3
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4
Tetrahedron

5
Highlights
 Highly efficient synthesis of a piperidinyl
dihydroquinazolinone (PDQ) heterocycle
 High-yielding reductive amination step
improves the overall yield of PDQ
 Unique one-pot N-benzyl-to-Fmoc
protecting group exchange was
demonstrated
 Applied a tandem deprotection-isocyanate
coupling strategy to Fmoc-PDQ

6
Tetrahedron