Expanding Access to Remdesivir via an Improved Pyrrolotriazine Synthesis: Supply Centered Synthesis

Article abstract of DOI:10.1021/acs.orglett.0c02848

Pyrrolotriazine 1 is an important precursor to remdesivir. Initial results toward an efficient synthesis are disclosed consisting of sequential cyanation, amination, and triazine formation beginning from pyrrole. This route makes use of highly abundant, commoditized raw material inputs. The yield of triazine was doubled from 31% to 59%, and the synthetic step count was reduced from 4 to 2. These efforts help to secure the remdesivir supply chain.

Full text of DOI:10.1021/acs.orglett.0c02848

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Letter
Expanding Access to Remdesivir via an Improved Pyrrolotriazine
Synthesis: Supply Centered Synthesis
Dinesh J. Paymode,§ Flavio S. P. Cardoso,§ Toolika Agrawal, John W. Tomlin, Daniel W. Cook,
Justina M. Burns, Rodger W. Stringham, Joshua D. Sieber, B. Frank Gupton, and David R. Snead*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02848
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ABSTRACT: Pyrrolotriazine 1 is an important precursor to
remdesivir. Initial results toward an efficient synthesis are disclosed
consisting of sequential cyanation, amination, and triazine
formation beginning from pyrrole. This route makes use of highly
abundant, commoditized raw material inputs. The yield of triazine
was doubled from 31% to 59%, and the synthetic step count was
reduced from 4 to 2. These efforts help to secure the remdesivir
supply chain.
ntroduction: The Need for Supply Chain Improvements.
ICOVID-19’s emergence has greatly elevated awareness of
the pharmaceutical supply chain’s importance,1 and the desire
to make remdesivir broadly available presents a case in point.2
Initial supply is constrained after it emerged as a viable
COVID-19 treatment, and Gilead subsequently donated the
existing active pharmaceutical ingredient (API) stock.
Production of final drug substance is a challenge and can
take up to one year as a result of scarce, long lead-time raw
materials and several low yielding steps.3 Due to issues of
pricing and licensing, countries are left questioning who will or
will not have access to the drug.2c A more robust supply chain
can be developed by inventing from inherently available
building blocks (commodities) and increasing the route’s
yields and throughput. We call this “Supply Centered
Synthesis” (SCS).4
The topic of supply chain security was examined within the
construct of remdesivir’s pyrrolotriazine synthesis (Figure 1).
The triazine passes through several low yielding steps, and as
an early raw material, large quantities are required. Possibly a
preferred route could help overcome recent challenges related
to supply and price. The only full route to the base triazine 1
was published by Bayer Healthcare5,6 despite the biological
importance of the pyrrolo[2,1-f ][1,2,4]triazine framework.7
The sequence above nicely supplied preparative quantities of
triazine (50 g scale); however, some aspects of the route
warrant improvement.
Figure 1. An atom economic route to triazine from abundant
chemicals.
Received: August 25, 2020
1. The yield is 31% over four steps. Increasing yield would
decrease consumption of raw materials.
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2. Hydrazine is protected as a carbazate, and then
carbamate 2 must be deprotected to reveal amine 3.
This creates mass inefficiency, adds to the step-count,
and decreases overall yield.
3. 2,5-Dimethoxytetrahydrofuran and tert-butyl carbazate
are not commodity materials. 2,5-Dimethoxytetrahydro-
furan is made in two steps from furan.8 tert-Butyl
carbazate is made in four chemical steps from tert-
butanol and ammonia.9 Derivatizing commodities
requires additional chemical processing and creates
waste.
surprising simplicity by adding water or ethanol prior to adding
the hydroxylamine salt to give the product in >80% assay yield
(AY) (entries 1−2). A recent paper nicely demonstrated use of
DMPU·HCl as a key additive, but in our case, DMF as solvent
worked sufficiently well.16c The yield was further improved to
>90% AY by activating the oxime formed in situ with acetic
anhydride and base (entries 3−6). Distillation provided pure
material for downstream investigations (entries 8−9). There
are very few examples of one-pot nitrile formation via strategies
that make use of an oxidative Vilsmeier cascade, and this
avoids the use of costly and high molecular weight iodine.18
II. Assessing Amination Feasibility. The conditions of
Hynes Jr. were used as a starting point to explore the critical
amination (Figure 3). Chloramine was made from bleach and
The ideal synthesis would increase overall yield, proceed
from commodity materials, and reduce step count, thus
strengthening the remdesivir supply chain. This work describes
investigation of the bond-forming steps to do so from pyrrole
which is abundant and made commercially in one step from
furan.11 Formyl groups are easily installed in the 2-position of
pyrroles,12 and aldehydes can be oxidized to nitriles via
aldoxime intermediates.13 Moreover N-amination of pyrroles
and indoles, though challenging, are known.14 The hypo-
thetical synthesis would intercept the penultimate intermediate
3 at this point, and the demonstrated literature condensation
with formamidine acetate would render triazine 1. One could
foresee how these transformations could be executed with
reagents having high atom economy and market availability.15
Perhaps efficiency could be further increased by reducing the
step count and thus eliminating associated workups.
Figure 3. Clean amination of pyrrole from bleach and ammonia under
highly dilute conditions.
Results and Discussion. I. A One-Pot Oxidative Vilsmeier
Cascade. This effort began with functionalization of pyrrole
(Figure 2). Perhaps isolation of the aldehyde or aldoxime
ammonia and then extracted into MTBE. Pyrrole 4 converted
cleanly to the N-amino product (95% AY) resolving the
discrepancy between moderate isolated yield and high
conversion.14b,19 This serves as a drop-in replacement for 3
and improves yield to 88% as compared to 41% by the
literature route. Unfortunately the reaction conditions are
highly dilute (1 wt %) as a function of extracting monochlor-
amine from water into MTBE, thus limiting overall throughput
and jeopardizing supply. For this reason, strategies which
would increase throughput of N-amino-2-cyanopyrrole were
needed. This was also the likely conclusion of Bristol Myers
Squibb, whose subsequent disclosures focused on improved
efficiencies via in situ chloramine production in a biphasic
mixture20 and production of gaseous chloramine to negate the
need for dilute organic solution.21
Amination attempts with the biphasic conditions were
unsuccessful, and we did not have access to the degree of
engineering required for gaseous chloramine generation;
however use of solid aminating reagents such as O-(4-
Nitrobenzoyl)hydroxylamine provided a means to run
reactions at 15−20 volumes, thus greatly increasing product
throughput.22 This reagent has been used at scale;14d however,
neither aminating reagent is available at commodity levels, they
are not atom economic, and there are safety concerns with use
of these reagents at increasing temperatures and concen-
trations.23 Complements to these existing strategies were thus
the focal point of remaining efforts.
It is worth mentioning the safety hazards of monochlor-
amine production. Monochloramine is a common water
treatment chemical produced onsite at hospitals, food and
beverage facilities, and hotels;24 however, if reaction conditions
are not carefully controlled, NCl3 (explosive) can be
coproduced.25 Important factors to consider include pH,
Figure 2. A simple one-pot cyanation.
intermediates is unnecessary. 2-Formyl pyrrole is a low melting
solid not easily distilled or recrystallized in good yield.
Moreover, waste will be generated in the process of purifying
the aldehyde, aldoxime, or other intermediates. The iminium
chloride salt could possibly be used to form nitrile 4 directly in
a one-pot process. Residual POCl3 and related species would
need to be quenched due to chemical incompatibility with
hydroxylamine; however, the HCl generated in the course of
the quench could be used as a catalyst for the dehydration of
aldoxime.16 The POCl3 quench should be monitored to ensure
completion.17 This concept was validated experimentally with
B
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temperature, concentration of reactants, and source of NH3. It
is desirable to keep the pH above 8, use NH4Cl in place of
NH4SO4, and cool the reaction during synthesis. Here, the pH
is kept ≥12 at all stages of reaction. Facilities should carefully
assess production prior to scaling.
III. Increasing Amination Space−Time Yield. The
remainder of the investigation centered on use of monochlor-
amine. It is an optimal reagent to install the nitrogen atom
because atom economy is high, and it is made from simple
ingredients which can be accessed anywhere in the world,
bleach and ammonia. To render monochloramine accessible,
the volumes of extraction solvent (MTBE) must be mitigated.
0.5−0.9 M NH2Cl/MTBE solutions were produced which
were five to ten times stronger than the reported value. This
suggested that the literature procedure added NH2Cl in 4-fold
excess. Decreasing chloramine equivalents would greatly
increase concentration by reducing MTBE consumption.
Probing the relationship between base and chloramine
equivalents showed an interdependent nature, where as much
chloramine as base is required (Figure 4). Perhaps this is due
to the acidic nature of chloramine which has an estimated pKa
of 14. With 1.25 equiv of base and 0.5 M NH2Cl, 25 volumes
of MTBE are needed. In theory this can be decreased to a
minimum of 17 volumes with a 0.9 M NH2Cl and 1.1 equiv of
NaH, which is an 80% reduction in solvent usage. Still, dilution
remains at levels higher than desired.
Perhaps, an effectively high concentration “gaseous” form of
chloramine can be accessed by recycling MTBE solvent
(Figure 4). The reagent can be considered gaseous because at
the extreme, infinite recycle of MTBE, only chloramine, a gas,
is consumed. Addition of chloramine in fractional charges with
subsequent evaporation and recycle of MTBE would seem to
present one such option for achieving that aim. With this
strategy in mind, the chloramine was added to 4 in four
portions of 10 volumes with the MTBE removed and reused at
the end of each addition. The effective chloramine
concentration becomes 2.0 M rather than 0.5 M. Assay yields
of 3 matched those of the original procedure, and the total
reaction volume was limited to 15 volumes (10 MTBE, 5
DMF) with an end point of 5 volumes and 20 wt % pyrrole in
DMF.
Figure 4. (a) Lower equivalents of chloramine can be used at lower
loadings of NaH. (b) Addition of NH2Cl in multiple charges with
subsequent solvent recycle increases throughput and decreases solvent
consumption.
Effective cycle time for this operation can be achieved
because MTBE is easily removed from reaction solution due to
its low boiling point (55 °C), and because the amination of
pyrrole is very rapid, occurring in less than 5 min. This
presents a reasonable path toward manufacturing, and 90% of
solvent was recycled. Aminated pyrrole was made in 90% assay
yield, and this result was scaled 100× to 10 g without change in
performance. The amination investigation was concluded with
preliminary exploration of strategies which might address the
hazards of NaH and DMF mixtures.22,26 Preliminary
calorimetric data to be released in a follow-up publication
indicated low thermal risk; however, the hazard can be
eliminated by replacing DMF with diglyme (97% AY).
IV. On-Demand Chloramine. Despite the advantages of
monochloramine, use of NH2Cl at scale poses practical
challenges. This includes hazards associated with monochlor-
amine accumulation, storage of large reagent quantities (up to
40 Vol), and instability of reagent (half-life of 50−100 h).24
Perhaps for these reasons, monochloramine is typically made
on site.
would prevent NH2Cl accumulation (amination complete
within 5 min) and eliminate requirement for large volume
reagent storage. Further, the concept of on-demand chlor-
amine fits perfectly within a scheme designed to capture and
recycle solvent, thus limiting waste and improving throughput.
High concentration aqueous chlora mine solutions have been
produced for on-site water treatment and manufacturing via a
continuous stirred-tank reactor (CSTR) at concentrations up
to 2 M.28 The conditions of Hynes were modified for
continuous synthesis and separation to demonstrate proof of
concept. Chloramine was simultaneously made and extracted
into MTBE in a CSTR with a 10 min residence time. This
biphasic mixture flowed into a gravity separator. Steady state
was reached within 30 min, and titration of the MTBE layer
showed that ∼0.45 M chloramine was produced as compared
to a 0.52 M solution made in batch.
The on-demand NH2Cl solution flowed into a pot
containing a solution of deprotonated pyrrole 4 in DMF.
The system was placed under occasional vacuum to keep the
Application of a chloramine generator27 presents a solution
(Figure 5). Continuous synthesis and use of monochloramine
C
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Figure 6. One-pot triazine synthesis from cyanopyrrole 4.
of reaction mixture followed by addition of water afforded the
desired triazine in >60% IY over two steps.
Conclusions. This work describes an efficient means to
produce the aminotriazine required for manufacturing
remdesivir. Importantly, the synthesis makes use of highly
abundant materials to bolster supply chain security. It is
expected that these common materials will decrease costs
associated with chemical inputs, an important objective given
concerns around remdesivir supply and price. The synthesis
has high atom economy and avoids derivatization and
protecting groups. Yield is approximately doubled over the
prior procedure described for the triazine while step count is
cut in half. This should facilitate improved throughput of this
important API intermediate. Moreover, development of a
continuous platform afforded access to a noncommercial
aminating reagent, monochloramine, while simultaneously
preventing buildup of reagent to mitigate potential safety
concerns.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02848.
Experimentals and compound characterization (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Figure 5. Steady state operation of chloramine CSTR and schematic
for chloramine generator.
David R. Snead − Chemical Development, Medicines for All
Institute, Richmond, Virginia 23298-0100, United States;
orcid.org/0000-0003-1239-533X; Email: drsnead@
vcu.edu
reaction volume at a minimal level by splitting the charge of
chloramine into four portions. The MTBE was collected by
condensation in a separate pot and then recycled to extract
more chloramine. The total recycle rate of MTBE was 80−
89%, and pyrrole 4 was aminated in 94% AY (1 g, 10 g scales).
Optionally, the amination can also be conducted in flow. This
demonstrates proof of concept for a chloramine generator
which helps overcome throughput issues related to dilute
aminations.
VI. Amination and Triazine Formation in One Pot. For
efficiency’s sake the synthesis was telescoped through to the
triazine rather than isolate at this stage (Figure 6). Prior
experience with hydroxypropyl adenine (HPA) suggested that
DMF might be a good solvent for the condensation reaction of
the aminonitrile with formamidinium acetate.29 Formamidine
acetate was added to the amination reaction mixture and
heated to form the triazine. This provided 1 in 75% AY over
two steps. A quick solubility study suggested that water or
MTBE would be appropriate antisolvents. In situ concentration
Authors
Dinesh J. Paymode − Chemical Development, Medicines for All
Institute, Richmond, Virginia 23298-0100, United States
Flavio S. P. Cardoso − Chemical Development, Medicines for
All Institute, Richmond, Virginia 23298-0100, United States;
orcid.org/0000-0002-8608-5054
Toolika Agrawal − Chemical Development, Medicines for All
Institute, Richmond, Virginia 23298-0100, United States
John W. Tomlin − Chemical Development, Medicines for All
Institute, Richmond, Virginia 23298-0100, United States
Daniel W. Cook − Analytical Development, Medicines for All
Institute, Richmond, Virginia 23298-0100, United States;
orcid.org/0000-0003-0621-3624
Justina M. Burns − Analytical Development, Medicines for All
Institute, Richmond, Virginia 23298-0100, United States
Rodger W. Stringham − Analytical Development, Medicines for
All Institute, Richmond, Virginia 23298-0100, United States
D
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Wang, G.; Ma, X.; Ying, S.; McClure, A.; Achebe, F.; Lobell, M.;
Ehrgott, F.; Iwuagwu, C.; Parcella, K. US 8431695, 2006.
(6) Private correspondence with generic manufacturers confirmed
that this route is used to supply material for remdesivir.
(7) (a) Song, Y.; Zhan, P.; Zhang, Q.; Liu, X. Curr. Pharm. Des.
2013, 19, 1528−1548. (b) Cascioferro, S.; Parrino, B.; Spano, V.;
Carbone, A.; Montalbano, A.; Barraja, P.; Diana, P.; Cirrincione, G.
Eur. J. Med. Chem. 2017, 142, 328−375.
Joshua D. Sieber − Chemical Development, Medicines for All
Institute, Richmond, Virginia 23298-0100, United States;
orcid.org/0000-0001-6607-5097
B. Frank Gupton − Chemical Development, Medicines for All
Institute, Richmond, Virginia 23298-0100, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02848
(8) Hoydonckx, H. E.; Van Rhijn, W. M.; Van Rhijn, W.; DeVos, D.
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Author Contributions
§D.J.P. and F.S.P.C. contributed equally.
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the Bill and Melinda Gates Foundation for their
longstanding support of our research. We express gratitude to
Trevor Laird (Trevor Laird Associates) and John Dillon (JLD
Pharma Consulting) for their thoughtful commentary and
discussion throughout this work, and we also thank Silpa
Sundaram (BMGF) and Dr. Susan Hershenson (BMGF) for
fostering an ecosystem where rapid decisions on project
direction can be made.
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