Development of Two Synthetic Approaches to an APJ Receptor Agonist Containing a Tetra- ortho-Substituted Biaryl Pyridone

Article abstract of DOI:10.1021/acs.oprd.1c00088

The development and implementation of two process syntheses to provide BMS-986224, an agonist of the APJ receptor, are reported. The first-generation synthesis of BMS-986224 relied on a key enamine cyclization to construct the pyridone core; however, the overall efficiency of this route was limited by the linear synthesis of the hindered biaryl pyridone. This lack of convergence is solved in a second-generation route that minimizes low-temperature lithiation chemistry, replaces costly Pd coupling with scalable nucleophilic arylation, and reduces step count. The improved synthesis was enabled by a new Negishi coupling method that addresses limitations of the Suzuki-Miyaura literature for tetra-ortho-substituted biaryl pyridones.

Full text of DOI:10.1021/acs.oprd.1c00088

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Article
Development of Two Synthetic Approaches to an APJ Receptor
Agonist Containing a Tetra-ortho-Substituted Biaryl Pyridone
Matthew J. Goldfogel,* Christopher R. Jamison, Scott A. Savage, Matthew W. Haley, Subha Mukherjee,
Chris Sfouggatakis, Manjunath Gujjar, Jayaraj Mohan, Souvik Rakshit, and Rajappa Vaidyanathan
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ABSTRACT: The development and implementation of two process syntheses to provide BMS-986224, an agonist of the APJ
receptor, are reported. The first-generation synthesis of BMS-986224 relied on a key enamine cyclization to construct the pyridone
core; however, the overall efficiency of this route was limited by the linear synthesis of the hindered biaryl pyridone. This lack of
convergence is solved in a second-generation route that minimizes low-temperature lithiation chemistry, replaces costly Pd coupling
with scalable nucleophilic arylation, and reduces step count. The improved synthesis was enabled by a new Negishi coupling method
that addresses limitations of the Suzuki−Miyaura literature for tetra-ortho-substituted biaryl pyridones.
KEYWORDS: process synthesis, heart failure, APJ receptor agonist, Negishi coupling, tetra-ortho-substituted heteroarene
Scheme 1. Prior Work in Developing and Synthesizing
BMS-986224 and Comparison to Process Retrosynthetic
Disconnections
eart failure is a chronic disease diagnosed in more than
H24 million people worldwide each year and currently
affects over 5 million patients within the United States.1,2
Some severe cases present as systolic heart failure (or HFrEF),
where there is a reduction in the left ventricular ejection
fraction by over 50%. Despite extensive pharmaceutical
research and state-of-the-art medical care, only half of patients
with this type of heart failure survive beyond 5 years.3,4 This
highlights the significant need for new therapeutics and
treatments to assist patients living with this condition.
The APJ system plays a key role in cardiovascular
regulation,5−9 and significant effort has been devoted to the
study of its endogenous peptide ligand apelin as a potential
therapeutic option for treating heart failure and HFrEF.10,11
Intraveneous administration of apelin-13 was shown to
improve cardiac output with minimal increase in blood
pressure or heart rate.12−15 Unfortunately, apelin-13 rapidly
degrades in the human body and is not suitable as a
therapeutic for chronic treatment.16 This promising medical
proof-of-concept inspired the design and synthesis of many
apelin peptide mimics and small molecule APJ agonists as
potential therapeutics.17−23 Medicinal chemistry research at
Bristol Myers Squibb contributed to this field and identified a
series of pyrimidinone agonists of the APJ receptor (Scheme
1A).24 Ongoing drug development improved upon these initial
hits with structure−activity relationship (SAR) studies and
introduced an ortho-disubstituted biaryl pyridone structure to
increase chemical stability.25 This culminated in the design of
BMS-986224, which was advanced as a clinical drug
candidate.26
accomplished through a late-stage introduction of the
oxadiazole to the key biaryl pyridone core (Scheme 1B).
Special Issue: Excellence in Industrial Organic Syn-
thesis 2021
BMS-986224 is comprised of three linked arenes including a
central, fully substituted pyridone. This pyridone is function-
alized in the 3-position by an unusual oxadiazole with a
pendant pyridylmethylene, and in the 5-position by a hindered
2,6-dimethoxyphenyl. Analog synthesis for SAR studies was
Received: March 9, 2021
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A

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This heterobiarene was linearly constructed through lithiations
of 1,3-dimethoxybenzene and subsequent pyridone formation
via a Guareschi−Thorpe type cyclization.27−29 While imple-
menting this synthetic strategy on multikilogram scale to
provide material for clinical studies (vide infra), opportunities
for improvement prior to selecting a commercial process were
identified: (1) route efficiency and project timelines were
impacted by the linear approach to building the biaryl
pyridone; (2) undesirable cryogenic lithiations were required
to functionalize the 2,6-dimethoxyarene and alkylate the
pyridine side-chain; and (3) formation of several process
impurities complicated the isolation and purification of
synthetic intermediates. Based on these key drivers, a
second-generation route was designed to support further
clinical supply of BMS-986224 (Scheme 1C).
Figure 1. First-generation synthesis of biaryl pyridone core to BMS-
986224.
This second-generation approach required overcoming state-
of-the-art cross-coupling limitations to forming the key tetra-
ortho-substituted biaryl bond. Literature methods that employ
5-arylpyridones in cross-coupling are quite rare,30−32 and
reduced yields are routinely obtained when compared to
simple arenes.33−38 Forming the biaryl linkage in BMS-986224
is further complicated by the sterics of the tetra-ortho-
substitution pattern. Cross-coupling of hindered arenes
remains a synthetic challenge despite the maturity of the
field and is an active area of research.39−51 To the best of our
knowledge, the reported second-generation synthesis of BMS-
986224 marks the first example of forming a tetra-ortho-
substituted biaryl pyridone via cross-coupling.
Herein are reported learnings from pilot plant-scale
utilization of the first-generation synthesis (Scheme 1B) and
the subsequent development of a convergent second-
generation synthesis of BMS-986224 (Scheme 1C). Additional
development work focused on synthesizing the benzylic
hydrazide through nucleophilic aromatic substitution of 5-
chloro-2-fluoropyridine to avoid cryogenic lithiation and
palladium catalysis. This second-generation route culminated
with a late-stage hydrazide coupling that was performed
without amide coupling agents, many of which are a safety risk
due to their sensitizing properties.52
impurities, the subsequent cyclization was tolerant of them and
adequate purging was observed in the downstream synthesis.
Crude enamine 4 was subjected to N-acylation conditions
with ethylmalonyl chloride to generate 6. The efficiency of this
reaction was pH dependent, as bis-amidation to form 12 was
observed under basic conditions. This was addressed by
charging ethylmalonyl chloride 5 and pyridine simultaneously
to maintain a pH of 4−6, which reduced the formation of 12 to
tolerable levels. (In keeping with standard industrial practice
for rapid reaction analysis, in-process yields are assessed using
“area percentage” (AP) yields and are uncorrected for the
difference in LC response factor between the reaction
components. While approximate, AP values provide insight
into general trends and aid in determining improvements in
reaction conversion and selectivity.) Cyclization to biaryl
pyridone 6 was promoted by the addition of sodium ethoxide
and crystallization of this solid from DCM and MTBE enabled
the purge of impurities retained from the telescope (vide
supra); pyridone 6 was isolated over three batches in 43−52%
yield with 98.6% purity. Subsequent reaction with hydrazine
hydrate provided 96.9 kg of hydrazide 7 in 75−76% yield over
two batches. The hydrazide also provided excellent impurity
purge and served as a quality gatekeeper of BMS-986224.
Synthesis of the pyridine side-chain 15 was accomplished via
a two-step telescope from 2-bromo-5-chloropyridine 13 and
tert-butyl acetate (Figure 2). Deprotonation of tert-butyl
RESULTS AND DISCUSSION
■
First-Generation Synthesis. In order to rapidly supply
API for toxicology and early clinical studies, the first-
generation route was implemented on kilogram scale. This
synthesis employed the retrosynthetic strategy highlighted in
Scheme 1B which affords the biaryl pyridone core in 5 steps.
Synthesis of BMS-986224 began with alkylation of an
organocuprate, derived from 300 kg of 1,3-dimethoxybenzene
1, using ethylbromoacetate at −60 °C (Figure 1). The reaction
provided 2 in 50−72% yield. Careful temperature control from
−50 to 25 °C proved necessary to avoid sudden exotherms and
side products from bis-alkylation.
Figure 2. First-generation synthesis of pyridine side chain.
Compound 2 was then lithiated and the resulting enolate
reacted with 2-ethoxyacetyl chloride to provide β-ketoester 3
in 74% assay yield. This low conversion was traced to
impurities 8, 9, and 10 which are derived from nonselective
acylation of the enolate. Additionally, oxygen exclusion to
<1000 ppm was necessary to avoid generation of oxidation
impurity 11. As intermediate 3 was not crystalline, it was
telescoped to enamine 4 through treatment with ammonium
acetate and 4 was isolated in 69−70% in-process yield.
Although the lack of crystalline intermediates between β-
ketoester 3 and enamine 4 led to the retention of several
acetate with LiHMDS under cryogenic conditions and
subsequent palladium-catalyzed cross-coupling with 2-bromo-
pyridine 13 generated 14. On scale, an unexpected bromine
impurity 16 was formed due to trace quantities of 2,5-
dibromopyridine present in starting material 13. This impurity
proved inseparable from the desired product, but was
controlled through sourcing of 13 with <0.15 wt % of the
2,5-dibromopyridine. This analytical control of input quality
was critical as the bromo analogue 16 reacted downstream to
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form brominated API. Alkylation was followed by ester
hydrolysis with concentrated hydrochloric acid to provide
56.7 kg of the desired pyridine benzylic acid salt 15 in three
batches with 74%, 32%, and 76% yield, respectively. (The
unexpectedly low yield of the second batch was caused by
reaction stalling and incomplete conversion of 14 despite
kicker charges of LiHMDS and tert-butyl acetate. This poor
reactivity was traced to catalyst death due to salt impurities
and/or water contamination left in the reactor following the
first batch and was solved prior to the third batch by
implementing a thorough reactor cleaning protocol.) An
additional challenge occurred during vacuum drying, as
impurity 17 was generated during prolonged drying at 50
°C. This impurity arose from decarboxylation of 15 and was
avoided by drying at reduced temperature and instituting long-
term storage at <10 °C.
Second-Generation Synthesis. The high linearity and
PMI of the first-generation synthesis, the need for cryogenic
enolate conditions, and the formation of unexpected process
impurities drove the development of a second-generation route
to BMS-986224. The first-generation approach prepared
intermediate biaryl pyridone 6 in a 5-step linear sequence in
14.8% overall yield. A more convergent second-generation
approach would break BMS-986224 into three components
with key disconnections of cross-coupling and amidation
(Figure 4). The pyridone core would be generated from
With both biaryl pyridone 7 and acid 15 in hand, the end-
game synthesis of BMS-986224 was undertaken (Figure 3). N-
Figure 4. Synthetic strategy and commercial starting materials for
second-generation synthesis.
commercially available ethyl 4-ethoxy-3-oxobutanoate via a
modified Guareschi−Thorpe cyclization with diethyl malonate,
while the 5-chloropyridine side chain would be prepared via an
SNAr reaction between a stabilized enolate and 2-fluoro-5-
chloropyridine. This eliminated the need for cryogenic
conditions and removed palladium catalysis from the side
chain synthesis. Reduction in the step count would be
accomplished by reversing the hydrazide coupling partners to
shift hydrazide formation out of the longest linear sequence.
Implementation of this route faced the significant challenge
of cross-coupling a tetra-ortho-substituted heterocyclic biarene
containing acidic O−H and N−H bonds. In fact, earlier
internal efforts to form this biaryl linkage via Suzuki-Miyaura
coupling failed and were abandoned in favor of the cuprate
alkylation employed in the first-generation route. As such, the
development of a method for cross-coupling 5-halo-pyridones
would enable our second-generation route to BMS-986224
and fill a gap in current methodology.
Figure 3. Amidation and cyclization endgame for first-generation
synthesis of BMS-986224.
Acyl hydrazide formation with acid 15 was accomplished using
the peptide coupling reagent N,N,N′,N′-tetramethylchloro-
formamidinium hexafluorophosphate (TCFH) with N-meth-
ylimidazole (NMI) as a base.53 This process provided 18 in
73−87% yield, but full conversion was not reached despite
additional kicker charges of TCFH or acid 15. The incomplete
conversion was caused by entrapment of the starting material
during spontaneous crystallization of the product. This
insoluble material was then unable to react with the TCFH
present in the solution phase. The reaction was further
complicated by dimerization of 15 to form impurity 19, and
unproductive TCFH activation of 7 to form impurity 20.
Fortunately, recrystallization from DCM and MeOH effec-
tively purged these impurities and residual acid 7. Post-
campaign optimization found that starting material encapsu-
lation could be avoided by using DMF as a cosolvent to enable
a homogeneous reaction stream following TCFH addition. Use
of water as an antisolvent eliminated the need for a
recrystallization from DCM/MeOH and enabled a direct
isolation of 18. The improved amidation reliably afforded 18 in
>95% yield and reduced the PMI from 102 to 14.
The API step proceeded uneventfully with little deviation
from the discovery procedure. Cyclization of N-acyl hydrazide
18 to form the oxadiazole was accomplished by cyclo-
dehydration with T3P and provided 71.5 kg of BMS-986224
in 80% yield. Overall, the first-generation route generated API
in 10% yield over 9 transformations with a longest linear
sequence of 7 steps. The cumulative process mass intensity
(PMI) of the synthesis was 1,160, with the biaryl pyridone core
accounting for 5 out of 9 steps with 71% of the total PMI.54−56
Testing this key cross-coupling disconnection required
isolation of the proposed 5-bromopyridone coupling partner
24 (Figure 5). Synthesis of 24 began with treatment of 4-
Figure 5. Second-generation synthesis of pyridone core.
ethoxy-3-oxobutanoate with 7 N ammonia in MeOH under
anhydrous conditions to form intermediate 22. Telescoped
cyclization of 22 with diethyl malonate in the presence of
sodium ethoxide then provided pyridone 23 in 39% yield over
two steps on 170 g scale.57−60 This improved upon the
Guareschi−Thorpe strategy used in the first-generation
synthesis by removing the stepwise amidation of the enamine
with an acyl chloride and reducing the PMI from 230 to 55.
Cross-coupling substrate 24 was prepared by bromination of
the 5-position of 23 with N-bromosuccinimide in the presence
of catalytic NH4NO2.24,61 This provided 5-halopyridine 24 in
72% yield with a PMI of 29.
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With the prospective aryl bromide 24 in hand, a broad
survey of cross-coupling conditions was undertaken using
organometallic coupling partners 2,6-dimethoxyphenylboronic
acid (Suzuki−Miyaura), 2,6-dimethoxyphenylmagnesium
chloride (Kumada), and 2,6-dimethoxyphenzylzinc chloride
(Negishi). High throughput experimentation (HTE) was used
to survey the reaction space for each nucleophile by varying
ligand, solvent, temperature, and base.62,63 As observed by our
discovery group, all attempts at Suzuki−Miyaura or Kumada
coupling failed to provide 6 under any conditions. (The
difficulty of this Suzuki−Miyaura coupling was further
confirmed by testing phenylboronic acid as an unhindered
analog of 2,6-dimethoxyphenylboronic aciddespite the
removal of the tetra-ortho-biaryl substitution pattern, cross-
coupling still occurred in <20 AP.) However, Negishi coupling
with 1,3-dimethoxyphenylzinc chloride provided 6 in moderate
conversion (Figure 6A). Further screening showed that
HBF4 as a more cost-effective ligand and increase the reaction
concentration.
These optimizations culminated in the process shown in
Figure 6B, where 6 was generated by reacting 5-bromo-
pyridone 24 with 2,6-dimethoxyphenylzinc chloride. The
presence of excess 1,3-dimethoxybenzene (generated from
quenching the arylzinc reagent) complicated crystallization,
but acidifying the reaction stream allowed for the removal of
this impurity by heptane wash. Subsequent extraction with
EtOAc, solvent swap to iPrOH, and crystallization with water
provided 6 in 41% yield with a PMI of 150. To our knowledge,
this is the first example of forming a tetra-ortho-substituted
biarylpyridine through cross-coupling and demonstrates how
access to this new disconnection can significantly improve
process efficiency.
After completion of the biaryl pyridone core, focus turned to
the synthesis of the side-chain hydrazide 32. In particular, a
route that could access 32 without the use of palladium
catalysis to generate the carbon−carbon bond between the
acetate and the heteroaryl moieties was desired as a cost
reducing measure. The feasibility of an uncatalyzed carbon−
carbon bond formation via nucleophilic aromatic substitution
was evaluated on 2-fluoro-5-chloropyridine 25 with a panel of
nucleophiles including acetonitrile, tert-butyl acetate, diethyl
malonate, Meldrum’s acid, and tert-butyl cyanoacetate (26).
From this study, tert-butyl cyanoacetate was selected as
optimal due to its high nucelophilicity, clean reaction profile,
and the crystallinity of the resultant adduct 27. Scale up
demonstrated that 25 reacted with 26 and potassium
carbonate at 120 °C in DMF to form pyridine 27 in 57%
isolated yield after crystallization from DMF and water (Figure
7A).
Figure 6. Discovery and development of a Negishi coupling method
for synthesizing biaryl pyridone 6.
homogeneous reactions were obtained with amide solvents
and that the optimal reaction temperature was 60 °C; higher
temperatures resulted in protodebromination to 23, while
lower temperatures reduced conversion. Ligand identity had
the greatest effect on product and side-product formation, and
Ph-SPhos and P(tBu)3-HBF4 were selected for further study
on the basis that they provided >60 AP 6 with minimal
protodebromination.
Figure 7. Palladium-free synthesis of the hydrazide side chain 32.
Further development was undertaken to translate the HTE
screening conditions to a gram-scale process. Scalable
preparation of the organometallic coupling reagent 2,6-
dimethoxyphenylzinc chloride was accomplished via lithiation
followed by transmetalation to ZnCl2 at 0 °C. Initial reaction
conditions employed THF as a solvent but resulted in
inconsistent yields due to super saturation of the LiCl
byproduct and uncontrolled precipitation during reagent
storage. This was solved by switching the reaction solvent to
2-MeTHF to reduce the solubility of LiCl and enable removal
by filtration. Additionally, the cross-coupling was improved by
replacing the solvent N-methyl-2-pyrrolidone (NMP) with
N,N-dimethylacetamide (DMAc) to allow the use of P(tBu)3-
Despite the attractive features of the synthesis, initial
attempts to convert 27 to hydrazide 32 proved troublesome,
as has been previously reported in the literature for hydrolysis
of such tert-butyl cyanoacetate adducts.64 Hydrolysis of 27
with aqueous acid resulted in the formation of side products 17
and 30 (Figure 7B). Methylpyridine 17 resulted from
overdecarboxylation of the unstable acid intermediate 29
under highly acidic conditions, whereas tert-butyl amide 30
was generated via a Ritter reaction between intermediate nitrile
28 and the isobutylene liberated from the acid-mediated
decarboxylation of tert-butyl ester 27. Despite initial setbacks,
it was found that the desired transformation of 27 to 32 could
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be accomplished with anhydrous methanesulfonic acid and
LiCl in n-butanol (Figure 7C). Anhydrous conditions were
necessary to suppress overdecarboxylation to methylpyridine
17 by protecting the unstable acid moiety as n-butyl ester 31.
The LiCl additive was included to minimize formation of the
Ritter byproduct 30 by trapping the tert-butyl carbocation
generated during decarboxylation. Clean formation of the
intermediate n-butyl ester 31 was followed by a telescoped
hydrazide formation to form 32, which was isolated via
crystallization from n-butanol in 61% yield with a PMI of 33
for the telescope. Overall, the second-generation synthesis of
side-chain 32 was accomplished in 35% yield from 2-fluoro-5-
chloropyridine without the need for cryogenic conditions,
palladium catalysis, or peptide coupling reagents.
substituted biaryl pyridone through a newly enabled Negishi
coupling. This disconnection was not possible using traditional
Suzuki−Miyaura conditions, and this report details the first use
of cross-coupling to form a tetra-ortho-substituted biaryl
pyridone. The second-generation synthesis improved the
synthesis of the pyridyl side chain by forming it through
aromatic substitution in place of expensive palladium catalysis.
Overall, the improved route was demonstrated on gram scale
to reduce the PMI to 413 and will be used to enable any future
kilogram-scale campaigns.
EXPERIMENTAL SECTION
■
General Considerations. All starting materials, reagents,
and solvents were purchased from commercial suppliers and
used as received unless indicated. All reactions were performed
under a nitrogen atmosphere with <0.1% oxygen unless
Completion of BMS-986224 via our second-generation
synthesis relied on the condensation of hydrazide 32 and biaryl
ester 6 (Figure 8). Formation of the N-acyl hydrazide 18
1
otherwise specified. H NMR (400 MHz) and 13C NMR
spectra were measured on a Bruker AVANCE 400 at 400 MHz
for proton and 100 MHz for carbon, and chemical shifts are
reported in parts per million using the residual solvent peak as
a reference. LC-MS analysis was performed on a Shimadzu
LCMS-2020 mass spectrometer primarily using an Agilent
Poroshell 120 EC-C18 column (2.1 mm × 50 mm, 1.9 μm)
and HRMS samples were run on an Agilent 6230B LC-ToF
(see the Supporting Information for more details on the
respective spectra).
Figure 8. Hydrazide formation and oxadiazole cyclization in second-
generation synthesis.
Preparation of Ethyl 2-(2,6-Dimethoxyphenyl)acetate
(2). A dried titanium reactor under positive nitrogen pressure
was charged with THF (873 kg) and 1,3-dimethoxybenzene
(100.2 kg, 1.0 equiv) before being cooled to 10−20 °C. A
solution of 2.5 M n-BuLi in hexanes (221.5 kg, 1.1 equiv) was
charged slowly while maintaining a temperature of <20 °C, and
the reaction was agitated for 1 h. CuI (76.9 kg, 0.55 equiv) was
added, and the mixture was agitated at 20 °C for 1 h. The
reaction was cooled to −80 °C, and ethyl bromoacetate (132.2
kg, 1.1 equiv) was charged slowly while maintaining a
temperature below −60 °C. The reaction was warmed to
−45 °C and agitated for 12.5 h before being warmed to 20 °C.
Water (799 kg) was slowly added to quench the reaction
stream at 10−20 °C. The reaction mixture was filtered through
Celite (50.5 kg), and the Celite was rinsed with MTBE (267.8
kg). The mother liquor was extracted with MTBE (2 × 370.5
kg), and the collected organic layer was washed with a 5%
solution of ammonium hydroxide (4× 375 kg) and water (3×
503.3 kg). The organic layer was collected, and the solvent was
swapped to heptane (2× 478 kg) via put-and-take distillation
under reduced pressure at <50 °C with a final volume of ∼2 V
(∼200 L). The product was crystallized from the heptane
solution by cooling to −5 °C and agitating for >5 h. The
product was isolated by filtration, and the solid was rinsed with
heptane (136 kg) at −5 °C. The resulting solid was dried
under reduced pressure at <30 °C to provide 2 (80.1−115.3
kg) as an off-white solid in 50−72% yield over three batches.
1H NMR (400 MHz, DMSO-d6) δ 7.23 (t, J = 8.3 Hz, 1H),
6.65 (d, J = 8.4 Hz, 2H), 4.05 (q, J = 7.1 Hz, 2H), 3.75 (s, 6H),
3.56 (s, 2H), 1.17 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz,
DMSO-d6) δ 171.5, 158.4, 128.8, 111.3, 104.3, 60.3, 56.2, 28.9,
14.5. Spectra match literature characterization data.25
occurred readily at 110 °C in DMF without the need for a
peptide coupling reagent. This unusual and efficient amidation
is possible due to the nucleophilicity of the hydrazide and
corresponding electrophilic activation of the ester by the
electron poor pyridone ring. Reaction of 6 and 32 provided the
product 18 in 70% yield with a PMI of 18. BMS-986224 was
accessed from 18 via the unaltered first-generation protocol
without any changes to the purity profile or yield (80%).
Overall, the second-generation route enabled the synthesis
of BMS-986224 in 8 steps with a longest linear sequence of 6
steps (Table 1). This required only 7 isolations and removed
Table 1. Comparison of First and Second Generation
Synthetic Routes
First Generation
Second Generation
Step Count
Longest Sequence
Cryogenic Steps
PMI
9
7
3
8
6
0
413
6.4%
1,160
10%
Overall Yield
all cryogenic steps. The route provided a yield of 6.4% and a
cumulative PMI of 413, which is nearly a 3-fold improvement
over the first-generation route.
CONCLUSION
■
Two synthetic routes to BMS-986224 are reported. The first
route was used to rapidly deliver 71.5 kg of API with a PMI of
1,160. Focusing on speed to patient, initial deliveries fulfilled
early clinical needs via a near-linear route. In preparation for
Phase II trials, an improved second-generation route was
developed to (1) remove multiple cryogenic lithiations, (2)
reduce the formation of process impurities, and (3) reduce the
longest linear sequence. This convergent second-generation
route was made possible by disconnecting the tetra-ortho-
Preparation of Ethyl (Z)-3-Amino-2-(2,6-dimethoxy-
phenyl)-4-ethoxybut-2-enoate (4). A dried glass-lined
reactor under positive nitrogen pressure was charged with
THF (1073 kg) and 2 (100.0 kg, 1.0 equiv). The solution was
sparged with nitrogen to obtain <0.1% oxygen and then cooled
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to 10 °C. A 1.0 M solution of lithium bis(trimetlysilyl)amide in
THF (410.1 kg, 1.1 equiv) was charged slowly while
maintaining a temperature below 20 °C, and the solution
was agitated for 1 h. Ethoxyacetyl chloride (38.4 kg, 0.7 equiv)
was charged slowly while maintaining a temperature below 20
°C, and the solution was allowed to stir for 1 h. The base and
acyl chloride addition was then repeated by charging a 1.0 M
solution of lithium bis(trimetlysilyl)amide in THF (410.2 kg,
1.1 equiv), agitating for 1 h, and then charging ethoxyacetyl
chloride (38.0 kg, 0.7 equiv). The reaction mixture was
agitated at 10−20 °C for 6 h before being quenched with
aqueous ammonium chloride (15 wt %, 1000.3 kg). The
solution was extracted with MTBE (3× 370 kg), and the
organic layers were combined and washed with aqueous
sodium chloride (5 wt %, 2999.8 kg). The organic layer was
collected, and the solvent was swapped to ethanol (2× 790 kg)
via put-and-take distillation under reduced pressure at <45 °C
with a final volume of ∼2 V (∼200 L).
The intermediate solution of 3 was cooled to 10−20 °C
prior to charging 4 Å molecular sieves (25.1 kg, 0.25 kg/kg wrt
2) and ammonium acetate (149.6 kg, 4.0 equiv). The solution
was allowed to stir at 20 °C for 20 h and then filtered, and the
cake was rinsed with DCM (657.9 kg). The mother liquor and
filtrate were collected, and the solvent was swapped to DCM
(1330.9 kg) via distillation under reduced pressure at <45 °C
with a final volume of ∼3 V (∼300 L). The resulting solution
was diluted with DCM (1330.9 kg) before being washed with
aqueous sodium bicarbonate (10 wt %, 2× 1003 kg) and water
(500 kg). The organic layers were collected, and the solvent
swap to DCM (3× 655 kg), via put-and-take distillation under
reduced pressure at <45 °C to ∼2 V (∼200 L), was repeated to
minimize residual ethanol. This provided 4 (850.0 kg, 11.3 wt
%) as a brown solution in 69.0−70.2% in-process yield over
three batches. 1H NMR (400 MHz, D2O-d2) δ 7.16 (t, J = 8.4
Hz, 1H), 6.57 (d, J = 8.4 Hz, 2H), 3.87 (q, J = 7.1 Hz, 2H),
3.64−3.57 (m, 7H), 3.26 (q, J = 6.9 Hz, 2H), 1.03 (t, J = 7.0
Hz, 3H), 0.96 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz,
DMSO-d6) δ 169.1, 159.0, 158.3, 128.7, 113.9, 104.3, 85.4,
67.8, 66.1, 58.1, 55.9, 15.2, 15.0. Spectra match literature
characterization data.25
hydrochloric acid (2 wt %, 2× 413 kg) and water (955.0 kg)
before being solvent swapped to MTBE (980.4 kg) via
distillation under reduced pressure at <45 °C and concentrated
to ∼2.5 V (∼250 L). The product was crystallized by cooling
the reaction mixture to 0 °C for 8 h. The solids were isolated
by filtration and rinsed with MTBE (299.9 kg) prior to being
dried under reduced pressure at <45 °C to provide 6 (50.6−
61.2 kg) as a brown solid in 42.6−51.5% yield over three
batches. 1H NMR (400 MHz, MeOD-d4) δ 7.37 (s, 1H), 6.71
(d, J = 8.3 Hz, 2H), 4.84 (m, 2H), 4.49−4.37 (m, 2H), 4.08 (s,
2H), 3.75 (s, 6H), 3.50−3.36 (m, 2H), 1.45−1.33 (m, 3H),
1.21−1.06 (m, 3H) 13C NMR (101 MHz, MeOD-d4) δ 174.6,
171.9, 161.6, 158.5, 149.0, 130.4, 107.7, 104.7, 103.6, 97.0,
66.3, 65.6, 61.4, 54.9, 13.8, 13.1. HRMS [M + H]+ calcd for
C19H23NO7 378.1547, found 378.1538.
Preparation of 5-(2,6-Dimethoxyphenyl)-6-(ethoxy-
methyl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carbo-
hydrazide (7). A dried glass-lined reactor under positive
nitrogen pressure was charged with methanol (298.3 kg) and 6
(75.0 kg, 1.0 equiv). The reaction was cooled to 10−15 °C,
and hydrazine hydrate (98.0 kg, 8.0 equiv) was charged slowly
while maintaining a temperature of <15 °C. The reaction was
warmed to 20−30 °C and allowed to stir for 5 h. The product
was crystallized by cooling the solution to 0 °C for 2 h and
isolated by filtration followed by cake washes with methanol
(111.1 kg) and water (370.2 kg). The isolated solid was then
recrystallized by dissolving in DCM (432.9 kg) and methanol
(122.3 kg) at 35−40 °C before charging MTBE (579.2 kg) as
an antisolvent. The resulting slurry was cooled to 20 °C and
agitated for 2 h before being filtered to isolate the solid. The
solid cake was rinsed with MTBE (140.7 kg) and dried under
reduced pressure at <45 °C to provide 7 (54.2−55.1 kg as a
white solid in 74.9−76.1% yield. 1H NMR (500 MHz, DMSO-
d6) δ 15.72 (s, 1H), 11.55 (br s, 1H), 10.94 (s, 1H), 7.35 (t, J
= 8.3 Hz, 1H), 6.72 (d, J = 8.4 Hz, 2H), 4.77 (br s, 2H), 3.96
(s, 2H), 3.69 (s, 6H), 3.27 (q, J = 7.0 Hz, 2H), 0.99 (t, J = 7.0
Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 173.4, 168.9,
162.7, 158.6, 146.6, 130.6, 108.9, 106.3, 104.5, 96.8, 66.1, 65.9,
56.1, 15.2. HRMS [M + H]+ calcd for C17H21N3O6 364.1503,
found 364.1521.
Preparation of Ethyl 5-(2,6-Dimethoxyphenyl)-6-
(ethoxymethyl)-4-hydroxy-2-oxo-1,2-dihydropyridine-
3-carboxylate (6). A dried glass-lined reactor under positive
nitrogen pressure was charged with DCM (903.4 kg) and a
solution of 4 in DCM (∼11.3 wt %, 849.0 kg, 1.0 equiv). The
reaction was cooled to −5 °C, and a solution of pyridine in
DCM (22 wt %, 178.0 kg, 1.4 equiv) and ethyl malonyl
chloride in DCM (50 wt %, 183.7 kg, 1.6 equiv) were charged
simultaneously to maintain a pH of 4−7 during the addition.
The reaction was agitated at −5 °C for 5 h before being
quenched with an aqueous solution of sodium bicarbonate (9
wt %, 909.1 kg) while maintaining a reaction temperature <20
°C. The organic layer was collected and washed with aqueous
sodium bicarbonate (9 wt %, 899.6 kg) and water (958.0 kg).
The organic phase was collected, and the solvent was swapped
to ethanol (636.0 kg) via distillation under reduced pressure at
<45 °C with a final volume of ∼2.5 V (∼250 L). The resulting
solution was cooled to 20 °C and charged with ethanol (430.3
kg) and sodium ethoxide in ethanol (>18 wt %, 201.9 kg, 2.0
equiv) before being allowed to stir at 30 °C for 8 h. The
reaction mixture was concentrated under reduced pressure at
<45 °C to ∼2.5 V (∼250 L) before being diluted with DCM
(1808 kg). The resulting solution was washed with aqueous
Preparation of 2-(5-Chloropyridin-2-yl)acetic Acid
Hydrochloride (15). A dried titanium reactor under positive
nitrogen pressure was charged with toluene (85.3 kg) and a
solution of lithium bis(trimethylsilyl)amide in toluene (1.0 M,
403.7 kg, 2.5 equiv). The reaction mixture was cooled to −60
°C, and tert-butylacetate (50.9 kg, 2.3 equiv) was charged
slowly while maintaining a temperature of −60 °C. The
resulting solution was allowed to stir for 1 h at −60 °C and
held at this temperature for further use.
A second dried glass-lined reactor under positive nitrogen
pressure was charged with toluene (158.0 kg) and sparged with
nitrogen to obtain <0.1% oxygen. Palladium acetate (1.28 kg, 3
mol %) and dimethylbisdiphenylphosphinoxanthene [xant-
phos] (3.3 kg, 3 mol %) were charged, and the mixture was
allowed to stir at 25−30 °C for 1 h. 2-Bromo-5-chloropyridine
(36.5 kg, 1.0 equiv) was charged to this solution followed by
the prepared solution of lithium bis(trimethylsilyl)amide and
tert-butylacetate. The reaction was allowed to stir at 25−30 °C
for 5 h before being cooled to 10−20 °C. The crude reaction
stream was washed with a solution of aqueous citric acid (17
wt %, 2× 219 kg) and water (2× 183 kg), and the organic layer
was collected. The organic solution was treated with active
carbon (11.0 kg) and an aqueous solution of N-acetyl-cysteine
F
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(3 wt %, 70.3 kg) and agitated for 4 h at 20−30 °C. The
resulting solution was filtered, and the cake and reactor were
rinsed with toluene (221.3 kg). The mother liquor was
collected, and a solution of intermediate 14 was isolated in
acetonitrile by solvent swapping to acetonitrile (3× 173 kg) via
put-and-take distillation under reduced pressure at <55 °C
with a final volume of ∼125 L.
(ethoxymethyl)-4-hydroxypyridin-2(1H)-one (BMS-
986224). A dried reactor under positive nitrogen pressure
was charged with acetonitrile (274.9 kg) and 18 (43.5 kg, 1.0
equiv) before being warmed to 20−35 °C. 1-Methylimidazole
(15.2 kg, 2.2 equiv) and a solution of propylphosphonic
anhydride [T3P] (50 wt % in EtOAc, 139.2 kg, 2.6 equiv) was
charged, and the reaction was warmed to 75 °C and agitated
for 24 h. The resulting slurry was cooled to 20−30 °C, and
water (435.0 kg) was charged as an antisolvent. The reaction
was cooled to 0−5 °C and agitated for 1 h before the solids
were isolated by filtration, and the cake was rinsed with a
solution of acetonitrile and water (50/50 v/v, 2× 77.9 kg) and
water (3× 261.0 kg). The resulting solids were dried under
reduced pressure at <50 °C to provide 1 (33.8 kg) as a white,
The isolated solution of 14 in acetonitrile was telescoped
into decarboxylation by charging concentrated hydrochloric
acid (37 wt %, 87.1 kg) at 25 °C, and the mixture was agitated
for 14 h at 25−30 °C. The product was crystallized by charging
MTBE (346.3 kg), cooling the reaction mixture to −5 °C, and
agitating for 6 h. The solids were isolated by filtration, and the
reactor and cake were rinsed with MTBE (86.6 kg). The
resulting solids were dried under reduced pressure at <30 °C
to provide 15 (12.5−29.9 kg) as a light yellow powder in
73.9%, 31.6%, and 75.7% yield over three batches. The
unexpectedly low yield in the second batch was the result of
reaction stalling caused by water and/or salt impurities carried
over in the reactor from the first batch. This was solved prior
to the third batch by implementing a thorough reactor cleaning
1
free-flowing powder in 80.4% yield. H NMR (500 MHz,
DMSO-d6) δ 12.14−11.70 (m, 1H), 11.44 (br s, 1H), 8.56 (d,
J = 2.4 Hz, 1H), 7.97 (dd, J = 8.4, 2.6 Hz, 1H), 7.55 (d, J = 8.4
Hz, 1H), 7.36 (t, J = 8.3 Hz, 1H), 6.73 (d, J = 8.4 Hz, 2H),
4.58 (s, 2H), 3.95 (s, 2H), 3.69 (s, 6H), 3.26 (q, J = 6.9 Hz,
2H), 0.98 (t, J = 6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-
d6) δ 168.1, 164.1, 163.4, 159.5, 158.7, 153.8, 148.3, 147.4,
137.4, 130.7, 130.4, 125.4, 109.0, 104.6, 104.5, 94.5, 66.2, 65.8,
56.2, 33.3, 15.2. HRMS [M + H]+ calcd for C24H23ClN4O6
499.1379, found 499.1385.
1
protocol. H NMR (500 MHz, MeOD-d4) δ 9.05 (d, J = 2.3
Hz, 1H), 8.63 (dd, J = 8.7, 2.3 Hz, 1H), 8.06 (d, J = 8.5 Hz,
1H), 5.01 (br s, 4H). 13C NMR (101 MHz, MeOD-d4) δ
168.3, 148.8, 145.5, 141.8, 133.3, 129.2. HRMS [M + H]+
calcd for C7H6ClNO2172.0160, found 172.0161.
Preparation of Ethyl 6-(Ethoxymethyl)-4-hydroxy-2-
oxo-1,2-dihydropyridine-3-carboxylate (23). A dried
reactor under positive nitrogen pressure was charged with
ethyl 4-ethoxy-3-oxobutanoate [21] (174.7 g, 1.0 equiv) and a
solution of ammonia in methanol (7.0 M, 730 mL, 5.1 equiv)
at 20−30 °C. The reaction mixture was agitated for 18 h, and
the solvent was removed by azeotropic distillation with toluene
(2× 400 mL) to ∼1 V. The resulting light yellow oil was
filtered to remove any solids, analyzed by NMR to determine
potency. Intermediate 22 (169.3 g) was isolated in 97.5% yield
and telescoped into the next step without further purification.
A dried reactor under positive nitrogen pressure was charged
with ethanol (1100 g), 22 (169.3 g, 1.0 equiv), and diethyl
malonate (433.2 g, 3.0 equiv) at 20−30 °C. The reaction
mixture was agitated, and sodium ethoxide (183.6 g, 3.0 equiv)
was charged portionwise while maintaining a temperature of
<35 °C. The mixture was heated to 85 °C and agitated for 22 h
before being cooled to 20−30 °C. The resulting heterogeneous
tan slurry was solubilized by charging water (680 mL), and the
product was then crystallized via the slow addition of
hydrochloric acid (1.4 M, 2080 mL) over 1 h. The resulting
slurry was agitated for 1 h before the solid was isolated by
filtration, and the cake was washed with water (525 mL) and
MTBE (263 mL). The isolated solid was dried under reduced
pressure at <55 °C to provide 23 (83.2 g) as a tan powder in
Preparation of N′-(2-(5-Chloropyridin-2-yl)acetyl)-5-
(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-4-hydroxy-2-
oxo-1,2-dihydropyridine-3-carbohydrazide (18). A dried
reactor under positive nitrogen pressure was charged with
acetonitrile (304.2 kg), 15 (24.1 kg, 1.2 equiv), and 1-
methylimidzole (29.3 kg, 3.7 equiv) at 20−30 °C. To the
agitated reaction mixture was charged 7 (35.0 kg, 1.0 equiv)
followed by an acetonitrile (27.7 kg) rinse, and the reactor was
cooled to 0−5 °C. A second dried reactor under positive
nitrogen pressure was charged with acetonitrile (110.6 kg) and
N,N,N′,N′-tetramethylchloroformamidinium hexafluoro-
phosphate [TCFH] (31.1 kg, 1.15 equiv) before being agitated
at 20−35 °C for 30 min to obtain a homogeneous solution.
The prepared solution of TCFH in acetonitrile was charged to
the reactor containing 7 while maintaining a temperature of 0−
8 °C. The reaction mixture was agitated and allowed to stir for
4 h before the slurry was filtered, and the cake rinsed with
acetonitrile (2× 110.6 kg). The solid was collected and
transferred to a reactor for recrystallization using DCM (931.0
kg) and MeOH (55.4 kg) as solvents. The mixture was
warmed to 31−35 °C, and MTBE (259.0 kg) was charged as
an antisolvent. The reaction mixture was agitated for 1 h before
filtering and rinsing the solid with MTBE (2× 103.6 kg). The
resulting product was dried under reduced pressure at <55 °C
to provide 18 (39.5−43.5 kg) as an off-white powder in 73.1−
87.4% yield over two batches. 1H NMR (400 MHz, DMSO-d6)
δ 15.00−14.88 (m, 1H), 11.94 (br s, 1H), 11.78 (s, 1H), 10.89
(br s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 7.92−7.85 (m, 1H), 7.45
(d, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4
Hz, 2H), 3.97 (s, 2H), 3.79 (s, 2H), 3.68 (s, 6H), 3.26 (q, J =
7.0 Hz, 2H), 0.98 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz,
DMSO-d6) δ 171.7, 166.4, 164.9, 160.7, 156.5, 152.5, 145.8,
145.8, 134.7, 128.6, 127.8, 123.7, 106.4, 104.2, 102.4, 94.5,
64.0, 63.8, 54.0, 40.1, 13.1. HRMS [M + H]+ calcd for
C24H25ClN4O7 517.1485, found 517.1494.
1
38.6% yield over two steps. H NMR (400 MHz, CDCl3) δ
13.47 (s, 1H), 10.63−10.00 (m, 1H), 5.93 (s, 1H), 4.45 (q, J =
7.1 Hz, 2H), 4.38 (s, 2H), 3.61 (q, J = 7.1 Hz, 2H), 1.44 (t, J =
7.1 Hz, 3H), 1.28 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 176.2, 172.0, 161.6, 151.1, 97.7, 97.0, 67.5, 67.2,
61.8, 15.0, 14.2. HRMS [M
C11H15NO5242.1023, found 242.1037.
+
H]+ calcd for
Preparation of Ethyl 5-Bromo-6-(ethoxymethyl)-4-
hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate (24).
A dried reactor was charged with acetonitrile (54.1 g), ethyl 6-
(ethoxymethyl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3-car-
boxylate [23] (8.63 g, 1.0 equiv), N-bromosuccinimide (7.00
g, 1.1 equiv), and ammonium nitrate (0.315 g, 0.11 equiv) at
20−30 °C. The reaction mixture was agitated and warmed to
Preparation of 3-(5-((5-Chloropyridin-2-yl)methyl)-
1,3,4-oxadiazol-2-yl)-5-(2,6-dimethoxyphenyl)-6-
G
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85 °C for 2 h before being cooled to 20 °C. The product was
crystallized by charging water (173 g) slowly over 4 h. The
resulting slurry was filtered to isolate the solid, and the cake
was rinsed with water (18 mL) and MTBE (mL). The isolated
solid was dried under reduced pressure at <55 °C to provide
24 (11.5 g) as a yellow powder in 71.7% yield. 1H NMR (400
MHz, CDCl3) δ 14.58−14.18 (m, 1H), 9.57−8.77 (m, 1H),
4.54−4.42 (m, 4H), 3.72 (q, J = 7.0 Hz, 2H), 1.45 (t, J = 7.1
Hz, 3H), 1.33 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 172.3, 172.2, 158.8, 148.7, 97.9, 88.8, 67.7, 67.5,
62.5, 14.9, 14.2. HRMS [M + H]+ calcd for C11H14BrNO5
320.0128, found 320.0143.
crystallized by charging water (400 g) and hydrochloric acid
(1.0 M, 140 mL). The resulting slurry was filtered to isolate the
solid, and the cake was washed with a solution of DMF in
water (40/60 v/v, 50 mL) and water (200 mL). The solid was
dried under reduced pressure at <60 °C to provide 27 (27.5 g)
as a yellow powder in 57% yield. 1H NMR (400 MHz, CDCl3)
δ 14.37−13.94 (m, 1H, enol tautomer), 7.57 (dd, J = 6.1, 1.9
Hz, 1H), 7.45 (dd, J = 9.6, 2.3 Hz, 1H), 7.27 (s, 1H), 1.53 (s,
9H). 13C NMR (101 MHz, CDCl3) δ 170.4, 154.3, 139.8,
131.6, 121.5, 118.8 (d, J = 2.2 Hz, 1C), 81.6, 64.9, 28.5, 27.8.
HRMS [M + H]+ calcd for C12H13ClN2O2 253.0738, found
253.0738.
Preparation of 2-(5-Chloropyridin-2-yl)aceto-
hydrazide (32). A dried reactor under positive nitrogen
pressure was charged with n-butanol (80 mL), lithium chloride
(6.2 g, 3.7 equiv), and tert-butyl 2-(5-chloropyridin-2-yl)-2-
cyanoacetate hydrochloride [27] (10.0 g, 1.0 equiv), and the
mixture cooled to 20 °C. Methanesolufonic acid (19.0 g, 5.0
equiv) was slowly added to the reaction mixture while
maintaining a temperature of <40 °C. The reaction mixture
was then warmed to 80 °C and agitated for 5 h. The solution
was cooled to 10 °C and diluted with n-butanol (40 mL)
before being slowly quenched with a saturated aqueous
solution of sodium carbonate (40 mL) while maintaining a
temperature of <15 °C. The organic layer was collected and
washed with water (2× 30 mL) before being dried by
azeotropic distillation under reduced pressure at <50 °C to
∼10 V (∼100 mL) to provide a solution of intermediate butyl
2-(5-chloropyridin-2-yl)acetate [31]. Hydrazine monohydrate
(3.2 g, 1.6 equiv) was charged, and the reaction was warmed to
100 °C before agitating for 24 h. The reaction mixture was
slowly cooled to 10 °C to crystallize the product and agitated
for 1 h prior to filtration. The isolated solid was rinsed with n-
butanol (40 mL) and dried under reduced pressure at <55 °C
to provide 32 (4.5 g) as a tan crystalline solid in 61% yield. 1H
NMR (400 MHz, MeOD-d4) δ 8.47 (d, J = 2.3 Hz, 1H), 7.80
(dd, J = 8.4, 2.5 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 4.85 (s,
7H), 3.68 (s, 2H). 13C NMR (101 MHz, MeOD-d4) δ 169.9,
153.8, 147.4, 136.7, 130.5, 125.0, 41.7. HRMS [M + H]+ calcd
for C7H8ClN3O 186.0429, found 186.0431.
Preparation of Ethyl 5-(2,6-Dimethoxyphenyl)-6-
(ethoxymethyl)-4-hydroxy-2-oxo-1,2-dihydropyridine-
3-carboxylate (6). A dried reactor under positive nitrogen
pressure was charged with 2-MeTHF (11.0 g), palladium(II)
acetate (67.7 mg, 6.0 mol %), and tri-tert-butylphosphonium
tetrafluoroborate (191.5 mg, 13 mol %). The resulting catalyst
solution was inerted by subsurface sparge with nitrogen and
agitated for 1 h at 20−25 °C. To this solution was charged
DMAc (14.8 g), and ethyl 5-bromo-6-(ethoxymethyl)-4-
hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate [24] (1.61
g, 1.0 equiv) and the resulting slurry were agitated at 20−25
°C for 30 min until fully homogeneous. A solution of 2,6-
dimethoxyphenylzinc chloride in 2-MeTHF (0.92 M, 16.1 mL,
3.0 equiv) was charged slowly to the reaction mixture while
controlling the mild exotherm to maintain a reaction
temperature <50 °C. The reaction mixture was then warmed
to 60 °C and agitated for 20 h. After reaction completion, the
solution was washed with heptane (13.5 g) in three portions
and acidified with 3 M hydrochloric acid (3.44 mL) before
being extracted with EtOAc (30.85 g) in three portions. The
organic extracts were combined and washed with saturated
brine (23.5 wt % NaCl, 7.53 g) in three portions and water
(1.66 g). The resulting solution was solvent swapped to iPrOH
(2.49 g) and warmed to 50 °C to obtain a homogeneous
solution. The product was crystallized from the solution by
charging water (6.40 g) as antisolvent over 2 h and cooling the
reaction mixture to 20 °C. The product was then isolated by
filtration and washed with water (3.2 mL). The resulting solid
was recrystallized by dissolving in iPrOH (2.49 g) at 60 °C and
cooling to 20 °C to form a suspension of white solid in a light
orange solution. The product was then isolated by filtration
and washed with iPrOH (1.64 g) and water (3.20 g) before
being dried in a vacuum oven for 18 h at 45 °C to provide 6
(768 mg) as an off-white powder in 41.3% yield and 97.8%
potency. 1H NMR (400 MHz, MeOD-d4) δ 7.37 (s, 1H), 6.71
(d, J = 8.3 Hz, 2H), 4.84 (m, 2H), 4.49−4.37 (m, 2H), 4.08 (s,
2H), 3.75 (s, 6H), 3.50−3.36 (m, 2H), 1.45−1.33 (m, 3H),
1.21−1.06 (m, 3H) 13C NMR (101 MHz, MeOD-d4) δ 174.6,
171.9, 161.6, 158.5, 149.0, 130.4, 107.7, 104.7, 103.6, 97.0,
66.3, 65.6, 61.4, 54.9, 13.8, 13.1. HRMS [M + H]+ calcd for
C19H23NO7 378.1547, found 378.1538.
Second-Generation Preparation of N′-(2-(5-Chloro-
pyridin-2-yl)acetyl)-5-(2,6-dimethoxyphenyl)-6-(ethox-
ymethyl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3-car-
bohydrazide (18). A dried reactor under positive nitrogen
pressure was charged with DMAc (15.2 mL) and 6 (1.90 g, 1.0
equiv) and agitated at 20−30 °C. To the reaction mixture was
charged 32 (1.16 g, 1.2 equiv). The reaction was sealed, and
the headspace was purged with nitrogen before warming to
110 °C and agitating for 24 h. The reaction was cooled to 20
°C, and water (7.60 mL) was charged to the reaction mixture
to selectively precipitate an impurity. The insoluble material
was removed by filtration, and additional water (3.8 mL) was
charged as antisolvent to crystallize the product. The
crystallization slurry was aged for 24 h, and the resulting
slurry was filtered to isolate the solid. The cake was washed
twice with water (2× 3.8 mL) before being dried under
reduced pressure at <50 °C to provide 18 (1.82 g) as a tan
Preparation of tert-Butyl 2-(5-Chloropyridin-2-yl)-2-
cyanoacetate Hydrochloride (27). A dried reactor under
positive nitrogen pressure was charged with DMF (142 g), 5-
chloro-2-fluoropyridine [25] (25.0 g, 1.0 equiv), tert-butyl 2-
cyanoacetate [26] (59.6 g, 2.2 equiv), and potassium carbonate
(68.3 g, 2.6 equiv) at 20−30 °C. The mixture was agitated and
warmed to 120 °C for 24 h before being cooled to 20 °C. The
reaction mixture was filtered to remove insoluble carbonate
salts, and the reactor and cake were rinsed with DMF (189 g).
The mother liquor was collected, and the product was
1
powder in 69.9% yield. H NMR (400 MHz, DMSO-d6) δ
15.00−14.88 (m, 1H), 11.94 (br s, 1H), 11.78 (s, 1H), 10.89
(br s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 7.92−7.85 (m, 1H), 7.45
(d, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4
Hz, 2H), 3.97 (s, 2H), 3.79 (s, 2H), 3.68 (s, 6H), 3.26 (q, J =
7.0 Hz, 2H), 0.98 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz,
H
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Article
DMSO-d6) δ 171.7, 166.4, 164.9, 160.7, 156.5, 152.5, 145.8,
145.8, 134.7, 128.6, 127.8, 123.7, 106.4, 104.2, 102.4, 94.5,
64.0, 63.8, 54.0, 40.1, 13.1. HRMS [M + H]+ calcd for
C24H25ClN4O7 517.1485, found 517.1494.
REFERENCES
■
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.1c00088.
Experimental details, characterization data, NMR
spectra, and HRMS spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Matthew J. Goldfogel − Chemical Process Development,
Bristol Myers Squibb, New Brunswick, New Jersey 08903,
United States; orcid.org/0000-0002-6911-3068;
Email: matthew.goldfogel@bms.com
Authors
Christopher R. Jamison − Chemical Process Development,
Bristol Myers Squibb, New Brunswick, New Jersey 08903,
United States
Scott A. Savage − Chemical Process Development, Bristol
Myers Squibb, New Brunswick, New Jersey 08903, United
States; orcid.org/0000-0002-7823-0696
Matthew W. Haley − Chemical Process Development, Bristol
Myers Squibb, New Brunswick, New Jersey 08903, United
States
Subha Mukherjee − Chemical Process Development, Bristol
Myers Squibb, New Brunswick, New Jersey 08903, United
States
Chris Sfouggatakis − Chemical Process Development, Bristol
Myers Squibb, New Brunswick, New Jersey 08903, United
States
Manjunath Gujjar − Chemical Development and API Supply,
Biocon Bristol Myers Squibb Research and Development
Center, Bangalore 560 099, India
Jayaraj Mohan − Chemical Development and API Supply,
Biocon Bristol Myers Squibb Research and Development
Center, Bangalore 560 099, India
Souvik Rakshit − Chemical Development and API Supply,
Biocon Bristol Myers Squibb Research and Development
Center, Bangalore 560 099, India
Rajappa Vaidyanathan − Chemical Development and API
Supply, Biocon Bristol Myers Squibb Research and
Development Center, Bangalore 560 099, India;
orcid.org/0000-0002-2236-5719
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.1c00088
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are thankful for the insight and assistance of Dr.
Heather Finlay in understanding the biochemistry of the APJ
receptor. The authors would like to thank the Isolation and
Structural Elucidation group at Bristol Myers Squibb (New
Brunswick, NJ) for their analytical support.
(15) Barnes, G. D.; Alam, S.; Carter, G.; Pedersen, C. M.; Lee, K.
M.; Hubbard, T. J.; Veitch, S.; Jeong, H.; White, A.; Cruden, N. L.;
Huson, L.; Japp, A. G.; Newby, D. E. Sustained Cardiovascular
Actions of APJ Agonism during Renin-Angiotensin System Activation
I
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