pubs.acs.

org/OPRD Article

Toward the Development of a Manufacturing Process for Milvexian:

Scale-Up Synthesis of the Side Chain
Simon Wagschal,* Diego Broggini,* Trung D.C. Cao, Pascal Schleiss, Kristian Paun, Jessica Steiner,
Anna-Lena Merk, Joachim Harsdorf, Winfried Fiedler, Stefan Schirling, Sven Hock, Tobias Strittmatter,
Jan Dijkmans, Ivan Vervest, Tim Van Hoegaerden, Brecht Egle, Matthew P. Mower, Zhi Liu,
Zhiyong Cao, Xiaoning He, Lei Chen, Lei Qin, Hongyu Tan, Jun Yan, Nicolas Lucien Cunier̀ e,
Carolyn S. Wei, Venkata Vuyyuru, Rajaram Ayothiraman, Sundaramurthy Rangaswamy, Mohamed Jaleel,
Rajappa Vaidyanathan, Martin D. Eastgate, Richard Klep, Cyril Benhaïm, Ilse Vogels, Koen Peeters,
and Sébastien Lemaire
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sı Supporting Information

ABSTRACT: Anticoagulants play a critical role in the prevention and treatment of thrombotic-driven cardiovascular diseases.
Factor XIa (FXIa) inhibitors have the potential to improve the benefit/risk profile of existing anticoagulants through a safer bleeding
profile in a variety of conditions where patients are predisposed to a high risk of thrombotic or bleeding events. To support the
clinical development program of milvexian (BMS-986177/JNJ-70033093), a FXIa inhibitor that recently completed phase II clinical
trials, we improved the discovery route to deliver the suitable quantity of key intermediate 1 for clinical supply. This paper describes
our optimization of the Suzuki cross-coupling and how we simplified and improved the isolation of 4-trimethylsilyl-1,2,3-triazole 6
after the azidation−click sequence. On top of streamlining the processes for the chlorination and demethylation steps, we
demonstrated that the recrystallization of the penultimate intermediate 7 was key to control the purity and the color of the desired 4-
chloro-1,2,3-triazole 1, which could be obtained in a 70% yield over five steps.
KEYWORDS: milvexian, Suzuki, click, azide, chlorination, factor XIa inhibitor

■ INTRODUCTION
Cardiovascular diseases (CVDs) are among the leading causes
of death worldwide.1 Despite significant advances in the
prevention and management of thrombosis, the residual risk of
ischemic events remains high. Genetic, pre-clinical, and clinical
evidence suggest that FXIa inhibition has the potential to
reduce the burden of vascular and thromboembolic diseases
while preserving hemostasis.2 Milvexian (BMS-986177/JNJ-
70033093) is a potentially first-in-class oral small-molecule
FXIa inhibitor, which recently completed phase II studies to
prevent thrombotic events in multiple patient populations.3
Milvexian is a complex molecule that can be accessed from
4-chloro-1,2,3-triazole 1, a key intermediate first described in
the discovery route used to prepare milvexian (Scheme 1).
Boronic ester 2 reacted with 4-chloro-6-methoxypyrimidine 3
via a Suzuki−Miyaura coupling4 to deliver aniline 4. This
intermediate was further functionalized to the 4-TMS-
substituted triazole 6, employing a sequence of diazotization/
azidation5 and regioselective click chemistry.6 A chlorination
reaction on compound 6 to exchange the trimethyl silyl group
with a chlorine atom followed by an O-demethylation provided
the desired compound 1. This enabling process showed
acceptable yields, quality, and good reproducibility at a lab
scale. However, the current route proved to be insufficient at
the plant scale to deliver the quantity suitable for clinical
supply, prompting the team to further optimize the synthesis of
target 1 with cost and sustainability in mind.
Several aspects of the discovery route shown in Scheme 1
needed reinvestigation for the synthesis of compound 1 at the
plant scale. The Pd-catalyzed Suzuki−Miyaura coupling of step
1 required a 10 mol % Pd catalyst and afforded aniline 4 in a
moderate 56% yield. The click reaction required 3 equiv of
expensive trimethylsilylacetylene (TMSA). The chlorination of
compound 6 was performed with silica gel, and 10 equiv of
corrosive HBr in acetic acid were required in the final
demethylation step. Overall, all intermediates including
compound 1 were isolated using chromatography, making
this process not sustainable to deliver the suitable quantity for
clinical supply. Herein, we report our research in addressing
these shortfalls to enable successful deliveries and support
clinical studies.
Received: December 23, 2022
Published: April 3, 2023

© 2023 American Chemical Society https://doi.org/10.1021/acs.oprd.2c00399

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Scheme 1. Discovery Chemistry Route for 1

Table 1. Base Screening for the Suzuki-Miyaura Cross-Coupling between 2 and 3

entry base compound 4 (area %)a compound 11 (area %)a

1 K3PO4 52.5 18.2
2 AcOK 46.9 14.4
3 NaHCO3 50.9 6.9
4 DIPEA 53.7 3.9
5 Et3N 65.7 1.7
6 TMG 85.9 NDb
a
Area % on the crude reaction mixture after 5 h reaction time. bNot detected.

■ RESULTS AND DISCUSSION

Initial reaction optimization focused on the reaction selectivity
Table 2. Solvent Screening for the Suzuki−Miyaura Cross-
Coupling between 2 and 3
between the formation of the desired aniline 4 and undesired
Buchwald−Hartwig impurity 11, resulting from a C−N
coupling of 3 with 4 (Table 1). The purging for this impurity
required up to three HBr salt formation/free basing/re-slurry
cycles to reach the required >99.5 area % purity for compound
4. Screening the reaction conditions with different bases in 2-
MeTHF/water (3.6/1 v/v ratio) quickly identified 1,1,3,3-
tetramethylguanidine (TMG) for minimizing impurity 11.7
While NaHCO3 performed better than K3PO4 and AcOK as an entry solvent reaction purity (area %) in situ yield (%)
a
inorganic base (entries 1−3), the best outcome was obtained 1 2-MeTHF 93.3 98.1
when using organic bases such as DIPEA, Et3N, or TMG 2 MeCN 94.9 100
(entries 4−6).8 3 THFa 93.5 97.4
After further optimization, aniline 4 could be obtained in a 4 2-propanol 92.5 98.1
a
>98% in situ yield using 1 mol % Pd(dppf)Cl2·DCM in the Biphasic reaction mixture.
presence of 2 equiv TMG and 10 equiv water in 2-MeTHF
within 4 h at 65 °C (Table 2). However, the conversion
profiles obtained with this biphasic system were not performed similarly under the same reaction conditions,
reproducible, which led us to investigate water-miscible affording the desired product in a more than 97% in situ
solvents to avoid mixing effects on a larger scale and allow yield in all cases. MeCN was finally selected for further
direct anti-solvent crystallization after the addition of water. development due to the slightly higher purity and yield
Acetonitrile (MeCN), 2-propanol, and tetrahydrofuran (THF) obtained.
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Figure 1. Same excess experiment showing the overlay between standard and same excess reactions, indicating no catalyst deactivation under these
conditions. Left: raw reaction curves before the time shift. Right: Same excess curve time-shifted to place the initial point on the curve of the
standard reaction.
We then performed a kinetic analysis of the reaction to
assess the robustness of the optimized catalytic conditions. The
reaction progress was monitored with both ReactIR and UPLC
sampling (Figure 1). Kinetic interpretation of the data was
accomplished using the technique of variable time normal-
ization analysis (VTNA).9 Catalyst robustness was first
investigated using a series of “same excess” experiments.10
The standard and same-excess curves displayed a good overlay,
indicating that no catalyst deactivation occurred during the
first 50% of the turnovers performed by the standard reaction.
A series of “different excess” experiments revealed a first order
in 3 and zeroth order in 4 (see the Supporting Information).
The main impurities observed under those conditions were
the boronic ester protodeboronation 8 and homocoupling
side-product 9 along with the phosphine oxide 10 and
previously mentioned Buchwald−Hartwig impurity 11 (Figure
2). Apart from 11, usually observed at 1−2 area %, all
impurities were formed below 1 area % and could be depleted
below 0.1 area % after crystallizing 4 in MeCN/water.
Figure 2. Main impurities identified in the Suzuki−Miyaura cross-
coupling.
With the next step involving azide chemistry, we needed to
control the residual palladium to very low levels to avoid the
formation of highly shock-sensitive palladium azide11 in the
next step. We found that palladium azide is rapidly formed
Scheme 2. Outcome of Azidation when Dosing tert-Butyl Nitrite Followed by TMS Azide
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when a Pd(II) salt is mixed with TMS-azide in MeCN/2-
MeTHF. It precipitates as a brown solid that explodes on
touch if allowed to dry. We first screened several metal
scavengers (e.g., N-acetyl cysteine, EDTA, citric acid, and
tributylphosphine) and found that 1,3,5-triazine-2,4,6-trithiol
trisodium salt (TriNaTMT) was the best performer.12 After
reaction completion, an aqueous solution of TriNaTMT (10
equiv relative to the Pd catalyst) was dosed at the reaction
temperature to trigger crystallization followed by a cooling
ramp from 65 to 10 °C to maximize the yield. The addition of
TriNaTMT at the end of the reaction minimized the formation
of the Buchwald−Hartwig amination impurity 11 from 4 by
quenching the active catalyst. We also observed a beneficial
effect of TriNaTMT on the product desaturation kinetics
during the crystallization (2 h instead of 20 h without
TriNaTMT). On a 100 g scale, these conditions afforded
compound 4 in a 90−95% isolated yield and >98 area % purity
with 50−100 ppm residual palladium.
During our first scale-up, the conversion and crystallization
of the desired product matched the 100 g scale reaction, but
the Pd levels in the isolated product were approximately 1000
ppm. The isolation from MeCN/water also resulted in a low
weight assay (90−95% w/w) and long drying times due to the
high water content at the end of filtration.13 These issues were
resolved by dissolving wet solid 4 in 2-MeTHF (the next step’s
solvent) and performing two washes with an aqueous solution
of N-acetyl cysteine followed by a sodium bicarbonate and a
brine wash. This procedure reliably decreased the residual
palladium levels to ≤100 ppm. The water content could be
reduced below 0.1% after an azeotropic distillation, thus
reducing the cycle time by avoiding the need to dry compound
4. On multi-kilogram scale, the yield for this telescoped process
was 93% with 97.7 area % purity, containing 0.1% w/w water
and 55 ppm residual palladium. The resulting intermediate 4
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Figure 3. DSC thermogram of the isolated azide 5.
Figure 4. Influence of the copper source and base on the reduction of 5 to 4.
solution in 2-MeTHF was directly used in the subsequent
azide formation step.
Due to the poor aqueous solubility of aniline 4, the aqueous
azidation conditions using sodium nitrite and sodium azide did
not work. 2-MeTHF and THF exhibited the highest solubility
for compounds 4 and 5, and 2-MeTHF was selected to allow
better phase separation after the aqueous NaOH washes.
MeCN as a co-solvent increased the azidation kinetics and
improved the phase separation after the basic washes. A sharp
contrast in the reaction outcome was observed when
comparing two possible addition orders for the azidation
step. Upon the addition of tert-butyl nitrite to a mixture of
compound 4 in MeCN/2-MeTHF, intermediate 12 formed
rapidly, and a thick slurry was obtained. A subsequent slow
addition of TMS azide produced azide 5 in low conversion
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with significant formation of an unknown solid later identified
as triazene 13 (Scheme 2).
We hypothesized that the diazene intermediate 12 would
react more selectively to form desired product 5 if the TMS
azide were present in excess. When adding slowly tert-butyl
nitrite to a solution containing 4 and 1.2 equiv TMS azide, the
reaction proceeded smoothly with full conversion and no
formation of 13 was observed. Since TMS azide reacts directly
with tert-butyl nitrite, as evidenced by a gas release upon
mixing the two reagents, a slight excess of both reagents was
used in the process.
From a safety perspective, all lab and plant scale reactions
were run under a constant nitrogen flow to avoid accumulation
of the highly explosive and toxic hydrazoic acid (HN3) if it
were to form in the reactor head space.14 Furthermore, the
nitrogen flow was passed through a double aq. NaOH trap.
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Table 3. Optimization of the Click Reaction of Azide 5 with TMS Acetylene
entry Cu source reductant
1 CuSO4−5H2O Na ascorbate
2 CuSO4−5H2O Na ascorbate
3 CuSO4−5H2O Na ascorbate
4 CuI
5 CuI
6 CuI
Scheme 3. Optimized Process for the Azidation−Click Sequence to 4-TMS-1,2,3-triazole 6
Hydrazoic acid was indirectly measured as sodium azide in the
NaOH trap. Hydrazoic acid content in solution was controlled
prior to the click step by four consecutive aqueous NaOH
washes and one brine wash to avoid the formation of the
explosive copper azide Cu(N3)2. Each organic and aqueous
layer was tested for azide content using ion chromatography,
and the results were typically below 3 ppm after two washes.
The solubility of compound 5 turned out to be quite low in
most organic solvents (toluene, EtOAc, IPAc, MEK, MIBK,
and MeCN), and the isolation of azide 5 was considered to
reduce the solvent consumption. Thermal stability testing
using differential scanning calorimetry (DSC) showed that
compound 5 has a very high decomposition energy (1001 J/g)
with autocatalytic behavior (Figure 3). The maximum
allowable temperature was set at 50 °C based on isothermal
DSC experiments. While this intermediate was not shock-
sensitive according to the BAM fallhammer test, degradation
under impact was observed (color change and partial triggering
of the decomposition exotherm). The potential of this
compound to degrade by impact or friction combined with
its unfavorable thermal stability profile prompted us to discard
the option of isolating 5 on the scale. The resulting 2-MeTHF
solution containing 5 was then used as such in the next step.
For the click chemistry development, we first evaluated the
CuSO4/sodium ascorbate system to perform the coupling of
azide 5 with trimethylsilylacetylene and found that the initial
reaction conditions were satisfactory to support a rapid scale-
up.15 However, the formation of aniline 4 from azide 5 was
observed between 3 and 20 area % during the plant-scale
synthesis, indicating a lack of reaction robustness. This
prompted us to investigate the role of copper on the reduction
of azide 5 to aniline 4 (Figure 4). In the absence of CuSO4,
only a trace amount of 4 was observed in a mixture of 5 and
sodium ascorbate. In contrast, 66 area % 4 was formed after 3
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base solvent 6 (area %) 4 (area %)
none THF/H2O 82 17
K2CO3 THF/H2O 93 3.6
Et3N THF/H2O 95 2.1
K2CO3 THF/H2O 98 0.7
Et3N THF/H2O 99 0.4
Et3N THF 99 0.4
h in the presence of CuSO4 and sodium ascorbate. These
control studies indicated that the reduction of 5 by sodium
ascorbate is catalyzed by CuSO4, which is consistent with
literature reports of ortho-directed azide reduction occurring in
the presence of copper.16 Since the role of sodium ascorbate is
to reduce the Cu(II) source to the catalytically reactive Cu(I)
species, we reasoned that the replacement of CuSO4/sodium
ascorbate with CuI could obviate the need for a reductant.
Indeed, the reduction of 5 to 4 was reduced to ≤5 area % when
CuI was the copper source (Figure 4). The role of base in the
click reaction was also examined, and it was found that,
although the CuSO4/sodium ascorbate conditions proceeded
to full conversion in the absence of K2CO3, the amount of 4
was nearly 17 area % after 3 h (Table 3, entry 1). In the
presence of K2CO3, the click reaction gave only ≤4 area % 4,
suggesting that the presence of a base inhibits azide reduction
(entry 2). Since K2CO3 has poor solubility in the reaction
solvent THF, we switched to organic base Et3N and found a
further decrease in the amount of 4 (entry 3). Using a
combination of CuI and Et3N, we were able to lower the
aniline impurity to ≤0.4 area % (entries 4 and 6). The final
conditions using CuI/Et3N in THF delivered up to 12 kg of
triazole 7 with good control of the aniline impurity 4.
While the impurity profile and scalability were acceptable at
the time, this sequence required further development as the
clinical demand increased. We optimized the click step using
the 2-MeTHF azide solution previously described, and the
amount of TMS acetylene could be reduced from 4 to 1.2
equiv in the presence of 10 mol % CuI and 2.2 equiv Et3N
without an impact on the reaction purity. After full conversion
to the click product 7, the reaction mixture was quenched with
aqueous ammonia. After a celite bed filtration, the Pd and Cu
levels (100 and 2000 ppm, respectively) remained the same,
even after treatment with silica thiol. Additional ammonia
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Figure 5. Major impurities observed during the formation of 6.
washes did not further decrease the metal content. We later
demonstrated that adding solid TriNaTMT at the end of the
reaction followed by a celite bed filtration, an aqueous
ammonia wash, and an aqueous sodium sulfate wash could
reliably reduce the copper level below 100 ppm. Finally, put-
and-take solvent switch from 2-MeTHF to heptane17 afforded
compound 6 in an acceptable purity and yield with a low
mother liquor loss (Scheme 3).
With this optimized process, we next turned our attention to
the other impurities present in 7 (Figure 5). On the lab scale,
the des-amino impurity 14 formed during the azidation step
was observed in low amounts (0.1−0.2 area %). However, in
the first 1 kg scale up, the azidation produced up to 3.5 area %
14. After investigation, we found that the nitrogen flow
through the reactor headspace removed part of the TMS azide
that was dosed on top of the reaction mixture. This
phenomenon was confirmed in the lab by undercharging
TMS azide. In the following batch, impurity 14 was controlled
by performing sub-surface addition of TMS azide. We also
found that it was critical to control the pH of the solution
containing azide 5 to below 9 to minimize the cleavage of the
carbon-silicon bond of 6 leading to impurity 15. Additional
washes with aqueous saturated Na2SO4 solutions following the
aqueous NaOH wash effectively controlled the pH of the
telescoped stream of 5. The oxidative dimer 16 was first
observed at 1.6 area % after an oxygen ingression in one of the
manufacturing batch. This impurity could not be purged
during the isolation of compound 6 and was reacted in the next
step to give the corresponding chlorinated impurity in
compound 7 (vide infra). Impurity 11 carried over from the
Suzuki coupling step was unreactive under the azidation and
click reaction conditions and had poor purge efficiency during
the isolation of 6. On the scale, compound 6 was isolated as a
brown solid in a 90% yield, 99.4 area % purity, and 98.6% assay
and contained 46 ppm Pd and 94 ppm Cu.
Optimization of the N-chlorosuccinimide (NCS) chlorina-
tion of TMS-triazole 6 to compound 7 indicated that DMF
was by far the best solvent when compared to DMAc, EtOAc,
AcOH, DCM, MeCN, 2-MeTHF, and MTBE (Figure S4). N-
Butyl pyrrolidinone (NBP) provided slower conversion, a
lower purity, and higher levels of des-TMS impurity 15 (up to
90 area % in 2-MeTHF/DMF). In order to use a more
environmentally benign solvent, the reaction in MeCN was
optimized and found to proceed in the presence of water (0.5
equiv) and sulfuric acid (0.1 equiv), but the purity was lower
(89−91%) than in DMF (>98%).
Other chlorinating agents were also evaluated to avoid the
use of DMF (Figure 6). Palau’chlor18 did not provide any
promising results, and trichloro isocyanuric acid (TCCA) in
methanol, although initially promising, was abandoned after
compatibility experiments showed that the combination of
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Figure 6. Alternative chlorinating agents.
methanol and TCCA results in a mixture that is thermally
unstable in the presence of metals.
1,3-Dichloro-5,5-dimethylhydantoin (DCDMH) provided
full conversion to compound 7 in 2 h in DMF with 0.3−0.5
area % des-TMS impurity 15. In other solvents such as NBP,
MeCN, 2-MeTHF, and DCM, the reaction gave poor yields
and selectivity. When looking more closely at the reaction
conditions, we found that 0.5 equiv water and 0.6 equiv
chlorinating agent were necessary to reach full conversion and
a catalytic amount of sulfuric acid was not required. The
reaction temperature turned out to be key to control the
amount of protodesilylation: 5 °C was found to be optimal,
leading to 0.2 area % des-TMS impurity after 23 h (1 and 5
area % were obtained at 15 and 25 °C, respectively). When
varying the amount of water between 0.4 and 2.0 equiv, we
found that 0.5 equiv water was required for the reaction to
proceed and additional water had minimal impact on the
reaction. In order to ensure reaction robustness, the final
conditions used 1.0 equiv water (Table 4, entries 4−7). We
also examined higher amounts of DCDMH and found no
significant impact on the purity (entries 4 and 5).
From a safety perspective, the use of DCDMH is safer than
NCS (decomposition energy of 30 vs 104 J/g in 5 V of DMF).
The thermal stability of the reaction mixtures was assessed
using DSC since it has been reported that N-haloimides may
be incompatible with DMF.19 Using DCDMH as the
halogenating agent instead of NCS resulted in a thermally
more stable reaction mixture. An RC1 experiment with single-
portion addition of DCDMH was performed on a 30 g scale to
obtain calorimetric data: The reaction is classified as a Stoessel
class 1 process, meaning that it has a very low thermal risk.20
The addition of DCDMH in one portion was however
discounted from a quality perspective since the potential
adiabatic temperature rise (24 °C) could result in a reaction
temperature that may generate significant amounts of the des-
TMS impurity in case of inadequate cooling. The option of
slow-dosing DCDMH in solution was evaluated in DMF, but
the concentration tested (2 L of DMF per kg of DCDMH) was
not stable as gas evolution was observed at elevated
temperatures. Portion-wise addition of a neat chlorinating
agent to the reaction mixture was then tested from −5 to 5 °C
and gave satisfactory results with the addition of three portions
of 0.3 equiv DCDMH each (Table 4, entries 6 and 7). The
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Table 4. Impact of DCDMH and Water on the Chlorination of 6

entry scale (g) DCDMH (equiv) water (equiv) 6 (area %) 7 (area %) 15 (area %) isolated yield (%) purity (area %)
1 10 0.6 0.4 20.6 77.0 1.3 88.5 97.4
2 10 0.6 0.5 0 97.5 0.4 89.5 99.0
3 20 0.6 2.0 0 97.4 0.1 87.5 98.9
4 20 0.8 1.0 0 97.8 0.2 89.8 99.4
5 20 1.0 1.0 0 97.6 0.2 91.8 98.8
6 30 3 × 0.2 1.0 0 98.1 0.2 91.3 99.3
7 30 3 × 0.3 1.0 0 97.6 0.3 93.2 98.8

current conditions feature first the addition of water followed
by the addition of three portions of DCDMH (0.25 equiv
each) at −5 °C to ensure reaction robustness. The reaction is
then warmed to 5 °C to reach full conversion within 2−3 h.
We improved the crystallization of compound 7 by seeding
after adding a first portion of water (0.5 L/kg). One hour after
seeding, the desaturation reached a plateau; adding the second
water portion (4.5 L/kg) over 4 h allowed the crystallization of
99% of compound 7. On the scale, this step performed well
and the impurity 15 was not observed during the reaction
conversion. As mentioned earlier, the oxidative dimer impurity
16 formed in the click step was chlorinated and the resulting
impurity was not purged in the isolation of 7 from DMF/
water. This prompted us to evaluate a recrystallization of
compound 7 in non-polar systems such as DCM/heptane.21
Dosing heptane slowly to a DCM solution of 7 at low
temperature efficiently removed all non-polar impurities such
as oxidative dimer derivatives and delivered 7 in a 99.9 area %
purity, starting from crude 7 with a 96.0 area % purity. In the
long term, we implemented a charcoal treatment of the DCM
solution of 7 to remove the color coming from 6 and obtained
7 as a white solid. On the scale, crude 7 was isolated in a 92%
yield with a 99.3 area % purity, which was improved to 99.9
area % and a 100% assay after the DCM/heptane
recrystallization (94% recovery).
For the last step, HCl was investigated as an alternative to
HBr for the O-demethylation of compound 7 to target 1 as it is
cheaper and less corrosive. When testing different temper-
atures with 10 equiv HCl, we found that full conversion could
be achieved at 35−55 °C overnight, giving 1 in excellent purity
in all cases (Table 5, entries 1−3). A reaction temperature of
45 °C was selected for further examination, and various
amounts of HCl were tested. Full conversion to 1 can be
reached overnight with 5 or 15 equiv of concentrated aqueous
HCl (entries 4 and 5). However, the reaction volume was not
sufficient for proper stirring with 5 equiv HCl (1.5 L/kg) and
45 °C with 10 equiv HCl was chosen for process develop-
ment.22
Those concentrated conditions (3 L/kg) offered the
advantage of generating highly pure compound 1 in acidic
aqueous media (pH = −1.5 at the end of the reaction).23
Target compound 1 was insoluble in water below pH 7 and
crystallized at room temperature upon the addition of water or
an aqueous sodium chloride solution (Table 6, entries 1 and
2). The lower yield observed when quenching with water was
686
Table 5. Influence of the HCl Amount and Temperature on
the Conversion and Purity of the Demethylation of 7
entry HCl (equiv) temp (°C) time (h) conversion (%) 1 (area %)
1 10 35 21 99.9 99.5
2 10 45 4 99.6 98.2
3 10 55 4 99.0 98.3
4 5 45 22 99.8 99.0
5 15 45 5.5 100 99.5
due to the material sticking to the reactor wall. Addition of
water at 45 °C at the end of reaction followed by slow cooling
to 5 °C turned out to be optimal with respect to the particle
size, filterability, yield, and total volume (entry 3). Despite a
highly acidic pH, a low chlorine content measurement on the
isolated product suggested no retention of HCl. While direct
filtration of 1 in acidic aqueous media would be very attractive
from a productivity perspective, it would require specific plant
equipment to avoid corrosion. Neutralizing the reaction
mixture prior to isolation would avoid these technical
limitations but would also require a good pH control. Indeed,
the phenol function of 1 is quite acidic (pKa of ∼7) and 1 is
fully dissolved in water at pH 10. Attempts to crystallize the
product by acidification from basic pH were not satisfactory.
We tested several aqueous bases and found that potassium
phosphate or ammonia offered a better pH control over NaOH
(entries 4−6). In both cases, excellent yields were obtained,
and ammonia was selected due the lower peak volume.
On a 750 g scale starting from 98.5 area % pure 7, full
conversion and 98.8 area % purity were achieved within 16 h
followed by isolation of compound 1 in a 96% assay-corrected
yield and 99.5 area % purity. This straight-forward process was
however not purging some of the impurities present in 7. As a
control strategy, we developed an acetone/heptane recrystal-
lization of 1 to increase the purity of 1 up to >99.9 area % with
a 91% recovery on the 500 g scale. During a second run on the
450 g scale, the use of recrystallized 7 (99.9 area % purity) was
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Table 6. Different Quenching Methods Tested for the Isolation of 1
entry quenching method temperature (°C) filtration temperature (°C)
1 water (10 V) 25 20
2 aq. 10% NaCl (10 V) 25 20
3 water (10 V) 45 5 0.5−1
4 aq. 2 M NaOH (12 V) 45 20
5 aq. 32% K3PO4 (12 V) 45 20
6 aq. 10% NH3 (5 V) 45 5 6−7
Scheme 4. Optimized Medicinal Chemistry Route Demonstrated on the Scale for Compound 1
able to suppress the unknown impurity formation and deliver 1
in a 93% yield and 100% area % purity with no need for
acetone/heptane recrystallization. On the scale, compound 1
was isolated in a 96.4% assay-corrected yield with no impurities
and within specifications for residual metals and solvents. It
should be noted that compound 1 has a high decomposition
energy (610 J/g) that is accompanied by strong gas evolution,
owing to the triazole ring. The maximum allowable temper-
ature is set at 130 °C based on isothermal DSC experiments.
■ CONCLUSIONS
The synthesis of pyrimidinol 1, a key intermediate for the
synthesis of milvexian, was further optimized, bearing the
scalability, robustness, and control strategy in mind. The Pd
loading for the Suzuki cross-coupling was reduced from 10 to 1
mol %, and the resulting aniline 4 was isolated with a direct
anti-solvent crystallization, increasing the isolated yield from
56 to >90%. The azidation−click sequence could be performed
on the scale after a thorough safety analysis, and 4-TMS
triazole 6 was isolated by crystallization of 2-MeTHF/heptane
in a >90% yield over the two steps. Performing the
chlorination in DMF in the presence of DCDMH alleviated
the need for silica gel, and 4-chloro-1,2,3-triazole 7 was isolated
by the addition of water to the reaction mixture. A
recrystallization of penultimate intermediate 7 in DCM/
heptane together with a charcoal treatment was implemented
to control color and impurity profiles. Corrosive HBr was
replaced by HCl in the last demethylation step, and final target
1 crystallized upon the addition of aqueous ammonia in a
>90% yield. Overall, compound 1 was obtained in a 70%
overall yield starting from boronic ester 3 (Scheme 4).
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resulting pH at rt yield 1 (%) purity 1 (area %) ML loss (%)
0.5−1 85 99.6 3
0.5−1 94 98.4 5
95 99.2 3
7−8 92 99.8 0.3
6−7 96 98.2 0.5
96 98.3 1.7
■ EXPERIMENTAL SECTION
All reactions were performed under a protective nitrogen
atmosphere using standard laboratory techniques. All reagents
and solvents were purchased from local suppliers and were
used as received. NMR spectra were recorded on a Bruker
spectrometer operating at 300 MHz for 1H, 75 MHz for
13
C{1H}. Chemical shifts are expressed in parts per million (δ,
ppm) and referenced to residual solvent peaks. All coupling
constants (J) are absolute values (Hz), and descriptions of
signals are s (singlet), d (doublet), t (triplet), and m
(multiplet). HPLC analyses were performed on a Waters
ACQUITY H-Class UPLC system equipped with a quaternary
pump, refrigerated sample chamber, flow-through needle
autosampler/injector operating in the partial loop needle
overfill mode, column heater, and photodiode array detector.
The amounts of the isolated product are corrected by assay
(weight percent purity). Assays were determined by HPLC
against a purified external reference standard. Mettler Toledo
ReactIR 15 was used for inline FTIR monitoring. Wavelengths
of interest were selected manually and verified against HPLC
samples. The latter were also used to calibrate the IR trends for
use in the VTNA analysis. The BAM fallhammer test was
performed as described in the “UN Recommendation on the
Transport of Dangerous Goods, Manual of Tests and Criteria:
Test 3-a-ii” using a 5 kg weight at a height of 80 cm. DSC
experiments were performed on a Mettler-Toledo DSC 822C
using M20 gold-plated, pressure-resistant crucibles (TÜ V
SÜ D). All analytical data for isolated compounds 4, 5, 6, 7,
and 1 were aligned with reported literature.3
4-Chloro-2-(6-methoxypyrimidin-4-yl)aniline (4). A 2
L reactor was charged with acetonitrile (500 mL, 5 L/kg),
compound 3 (100 g, 1.0 equiv), compound 4 (60 g, 1.05
equiv), TMG (93.2 g, 2.05 equiv), and water (70.8 g, 10
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Org. Process Res. Dev. 2023, 27, 680−691
Organic Process Research & Development
equiv). The reactor headspace was purged using a nitrogen
flow. Pd(dppf)Cl2·DCM (3.2 g, 1 mol %) was added to the
reaction mixture, and the reaction mixture was heated to 65 °C
in 1 h and stirred at that temperature for 16 h. After reaction
completion, 1,3,5-triazine-2,4,6(1H,3H,5H)-trithione sodium
salt (TriNaTMT) (10 g, 10% w/w) was dissolved in water (50
mL, 0.5 L/kg) and added to the reaction mixture. Warm water
(280 mL, 2.8 L/kg) was then slowly dosed over 4 h to the
reaction mixture while keeping the internal temperature at 60−
65 °C. After aging for 4 h, warm water (350 mL, 3.5 L/kg) was
then slowly dosed over 6 h to the reaction mixture while
keeping the internal temperature at 60−65 °C. The reaction
mixture was then cooled down to 10−15 °C over 4 h and
further aged at 10−15 °C for 3 h. The slurry was then filtered,
and the cake was washed with a cooled MeCN/water solution
(2:1 v/v ratio, 5 L/kg). Wet compound 5 was obtained in a
90−95% assay yield and 98 area % purity and was used as such
in the next step. A 5 L reactor was charged with wet compound
4 (100 g, 1.0 equiv), 2-MeTHF (1.5 L, 15 L/kg), and an
aqueous N-acetyl L-cysteine solution (32 g in 1.5 L of water).
The resulting mixture was stirred for 2 h at 25 °C and filtered
through Celite (30 g, 0.3 kg/kg). After phase separation, the
organic layer was then successively washed with aqueous N-
acetyl L-cysteine solution (32 g in 1.5 L of water), aqueous
sodium bicarbonate (70 g in 1 L water), and aqueous sodium
sulfate (100 g in 1 L of water). The upper layer was kept in the
reactor and diluted with 2-MeTHF (1 L, 10 L/kg), and the
resulting solution was concentrated under vacuum to 500−600
mL (5−6 L/kg). The solution was then diluted with 2-MeTHF
(1 L, 10 L/kg), and the resulting solution was concentrated
under vacuum to 500−600 mL (5−6 L/kg). The solution
containing compound 4 was then diluted with 2-MeTHF (1 L,
10 L/kg), and the water content was measured (KF below
0.1%).
4-(5-Chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)-
phenyl)-6-methoxypyrimidine (6). A reactor was charged
with the 2-MeTHF solution containing compound 4 (100 g in
1.5 L of 2-MeTHF), 2-MeTHF (1.5 L, 15 L/kg), and MeCN
(1 L, 10 L/kg), and the resulting mixture was cooled to 5−10
°C. TMS azide (59.0 g, 1.2 equiv) was dosed slowly to the
reactor. tBuONO (53.0 g, 1.2 equiv) was dosed slowly to the
reactor at 5−10 °C, and the mixture was stirred at 10 °C for 4
h. An aqueous NaOH solution (100 g in 1 L of water) was
slowly added to the mixture, which was then warmed up to 25
°C, stirred for 30 min, and left standing for 30 min at 25 °C.
After phase separation, the upper layer was left in the reactor
and was washed two more times with an aqueous NaOH
solution (100 g in 1 L of water). After the third wash, the
upper layer was left in the reactor and the residual azide was
measured (residual N3 < 3 ppm). An aqueous sodium sulfate
solution (100 g in 1 L of water) was then added to the mixture,
which was then stirred for 30 min and left standing for 30 min
at 25 °C. After phase separation, the upper layer was left in the
reactor and was washed two more times with an aqueous
sodium sulfate solution (100 g in 1 L of water). After phase
separation, the pH was measured (pH < 9) and the solution
containing azide 5 was cooled to 10 °C. After bubbling
nitrogen for 30 min, triethylamine (95.0 g, 2.2 equiv) was
charged slowly to the reaction mixture while keeping the
temperature at 5−15 °C. Trimethylsilylacetylene (50.0 g, 1.2
equiv) was charged slowly to the reaction mixture, while
keeping the temperature at 5−15 °C, and the reactor was
purged with nitrogen until the oxygen level was below 0.1%.
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Copper iodide (8.0 g, 10 mol %) was charged to the reactor,
which was then purged again with nitrogen until the oxygen
level was below 0.1%. The reaction mixture was stirred at 5−15
°C for 16 h. After reaction completion, the reaction mixture
was warmed up to 25 °C and 1,3,5-triazine-2,4,6(1H,3H,5H)-
trithione sodium salt (TriNaTMT) (10 g, 10% w/w ) was
added. After 1 h of stirring at 25 °C, the mixture was filtered
through Celite (30 g, 0.3 kg/kg) and the cake was rinsed with
2-MeTHF (250 mL, 2.5 L/kg). The resulting solution
containing crude compound 6 was then washed with aqueous
ammonia solution (100 g in 1 L of water) then with aqueous
sodium sulfate solution (100 g in 1 L of water). After phase
separation, the upper layer was filtered through Celite (30 g,
0.3 kg/kg). After washing the Celite cake with 2-MeTHF (0.5
L, 5 L/kg), the mixture was concentrated at 45 °C under a
reduced pressure to 500−700 mL (5−7 L/kg). n-Heptane (1
L, 10 L/kg) was added dropwise to the reactor, and the
resulting mixture was concentrated at 45 °C under a reduced
pressure to 500−700 mL (5−7 L/kg). The reaction mixture
was then warmed up to 55−60 °C and kept stirring at that
temperature for 4 h. After cooling the reactor to 5−15 °C over
3 h, the slurry was aged at 10 °C and filtered. Compound 6 was
washed with n-heptane (1 L, 10 L/kg) and dried under a
reduced pressure at 40−45 °C for 12 h. Compound 6 was
isolated as a brown solid (137−147 g, >99.5 area % purity,
>99.0% w/w assay, and 90−96% corrected yield over the two
steps).
4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-
6-methoxypyrimidine (7). A reactor was charged with
compound 6 (100 g, 1.0 equiv), DMF (500 mL, 5 L/kg),
cooling to −10 °C, and then purified water (5 g, 1.0 equiv).
1,3-Dichloro-5,5-dimethylhydantoin (DCDMH, 13.7 g, 0.75
equiv) was charged in portions while keeping the internal
temperature below 5 °C. The internal temperature was then
adjusted to 0−10 °C, and the mixture was stirred at that
temperature for 12 h. After reaction completion, water (70 mL,
0.7 L/kg) was dosed to the reaction mixture over 1 h while
keeping the internal temperature below 15 °C. Compound 7
seeds (0.1 g, 0.001 kg/kg) were added to the reaction mixture,
which was then aged for 2 h at 0−10 °C. Water (530 mL, 5.3
L/kg) was dosed over 3 h at 0−10 °C, and the slurry was aged
for 4 h at 0−10 °C. The mixture was filtered, and the cake was
washed with cold water (0.5 L). Crude compound 7 was dried
under reduced pressure at 40−50 °C for 15 h. A reactor was
charged with crude compound 7 (100 g, 1.0 equiv) and DCM
(0.5 L, 5 L/kg), and the resulting solution was stirred for 0.5−
2 h at 20−30 °C. The resulting mixture was filtered through
charcoal and circulated for 6 h and then concentrated under a
reduced pressure to 300−360 mL (3.0−3.6 L/kg). The
mixture was then warmed up to 35−45 °C and refluxed for
30 min before being cooled down to 0−10 °C over 4 h then
further aged at 0−10 °C for 0.5−2 h. n-Heptane (1.6 L, 16 L/
kg) was then charged to the reactor at 0−10 °C over 3 h, and
the slurry was aged at 0−10 °C for 3 h. After filtration of the
slurry, purified compound 7 was washed with n-heptane (500
mL, 5 L/kg) and dried under reduced pressure at 40−50 °C
for 6−12 h. Compound 7 was isolated as an off-white solid
(78−82 g, >99.5 area % purity, >99.0% w/w assay, and 88−
92% corrected yield over the two steps).
6-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-
pyrimidin-4-ol (1). A reactor was charged with purified
compound 7 (100 g, 1.0 equiv) and aqueous HCl (35% w/w,
320 g, 10 equiv), and the reactor was warmed up to 40−50 °C
https://doi.org/10.1021/acs.oprd.2c00399
Org. Process Res. Dev. 2023, 27, 680−691
Organic Process Research & Development
in 3 h, and then the reaction mixture was stirred at that
temperature for 18 h. After reaction completion, an aqueous
ammonia solution (50 g in 500 mL) was added dropwise to
the reactor over 4 h at 40−50 °C to reach pH 5−7. The
reaction mixture was then cooled down to 0−10 °C in 3 h and
aged at that temperature for 3 h. After filtration of the slurry, a
crude compound 1 cake was washed with cold water (1 L at
0−10 °C, 10 L/kg) and dried under a reduced pressure at 40−
50 °C for 24 h. Crude compound 1 was isolated as an off-white
solid (89−93 g, >99.5 area % purity, >99.5% w/w assay, and
93−97% corrected yield). A reactor was charged with crude
compound 1 (100 g, 1.0 equiv) and acetone (1.4 L, 14 L/kg),
and the reactor was warmed up to 50−60 °C and stirred at that
temperature for 1−3 h. After seeding with compound 1 (0.5 g,
0.005 kg/kg), n-heptane (1.7 L, 17 L/kg) was dosed at 50−60
°C over 6 h, and the mixture was stirred at that temperature for
2 h before being cooled down to 5−15 °C over 4 h. After
filtration, pure compound 1 was washed with cold n-heptane
(0.5 L, 5 L/kg) and dried under reduced pressure at 80−90 °C
for 16 h. Compound 1 was isolated as an off-white solid (90−
95 g, >99.9 area % purity, >99.5% w/w assay, and 90−95%
corrected yield).
■
*
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.2c00399.
Kinetic study of the Suzuki cross-coupling using a
VTNA approach, solvent screen for chlorination step
using NCS, calorimetry data for azidation, click and
chlorination steps, and characterization and DSC data
for isolated compounds 4, 5, 6, 7, and 1 (PDF)
■ AUTHOR INFORMATION
Corresponding Authors
Simon Wagschal − Chemical Process Research and
Development, Janssen Pharmaceuticals, Schaffhausen 8200,
Switzerland; orcid.org/0000-0003-1979-5838;
Email: swagscha@its.jnj.com
Diego Broggini − Chemical Process Research and
Development, Janssen Pharmaceuticals, Schaffhausen 8200,
Switzerland; Email: dbroggin@its.jnj.com
Authors
Trung D.C. Cao − Chemical Process Research and
Development, Janssen Pharmaceuticals, Schaffhausen 8200,
Switzerland
Pascal Schleiss − Chemical Process Research and
Development, Janssen Pharmaceuticals, Schaffhausen 8200,
Switzerland
Kristian Paun − Chemical Process Research and Development,
Janssen Pharmaceuticals, Schaffhausen 8200, Switzerland
Jessica Steiner − Chemical Process Research and Development,
Janssen Pharmaceuticals, Schaffhausen 8200, Switzerland
Anna-Lena Merk − Chemical Process Research and
Development, Janssen Pharmaceuticals, Schaffhausen 8200,
Switzerland
Joachim Harsdorf − Chemical Process Research and
Development, Janssen Pharmaceuticals, Schaffhausen 8200,
Switzerland
689
pubs.acs.org/OPRD Article
Winfried Fiedler − Chemical Process Research and
Development, Janssen Pharmaceuticals, Schaffhausen 8200,
Switzerland
Stefan Schirling − Chemical Process Research and
Development, Janssen Pharmaceuticals, Schaffhausen 8200,
Switzerland
Sven Hock − Chemical Process Research and Development,
Janssen Pharmaceuticals, Schaffhausen 8200, Switzerland
Tobias Strittmatter − Chemical Process Research and
Development, Janssen Pharmaceuticals, Schaffhausen 8200,
Switzerland
Jan Dijkmans − Chemical Process Research and Development,
Janssen Pharmaceuticals, Beerse 2340, Belgium
Ivan Vervest − Chemical Process Research and Development,
Janssen Pharmaceuticals, Beerse 2340, Belgium
Tim Van Hoegaerden − Chemical Process Research and
Development, Janssen Pharmaceuticals, Beerse 2340, Belgium
Brecht Egle − Chemical Process Research and Development,
Janssen Pharmaceuticals, Beerse 2340, Belgium
Matthew P. Mower − Chemical Process Research and
Development, Janssen Pharmaceuticals, Beerse 2340, Belgium
Zhi Liu − Janssen (China) R&D Center, Shanghai 200030,
China
Zhiyong Cao − Janssen (China) R&D Center, Shanghai
200030, China
Xiaoning He − Janssen (China) R&D Center, Shanghai
200030, China
Lei Chen − Changzhou SynTheAll Pharmaceutical Co., Ltd.,
Changzhou, Jiangsu 213127, China
Lei Qin − Changzhou SynTheAll Pharmaceutical Co., Ltd.,
Changzhou, Jiangsu 213127, China
Hongyu Tan − Changzhou SynTheAll Pharmaceutical Co.,
Ltd., Changzhou, Jiangsu 213127, China
Jun Yan − Changzhou SynTheAll Pharmaceutical Co., Ltd.,
Changzhou, Jiangsu 213127, China
Nicolas Lucien Cunière − Chemical Process Development,
Bristol-Myers Squibb, New Brunswick, New Jersey 08903,
United States
Carolyn S. Wei − Chemical Process Development, Bristol-
Myers Squibb, New Brunswick, New Jersey 08903, United
States; Present Address: Process Development, Amgen
Inc., Thousand Oaks, California 91320, United States
Venkata Vuyyuru − Chemical Development and API Supply,
Biocon Bristol-Myers Squibb Research and Development
Center, Bengaluru 560099, India
Rajaram Ayothiraman − Chemical Development and API
Supply, Biocon Bristol-Myers Squibb Research and
Development Center, Bengaluru 560099, India
Sundaramurthy Rangaswamy − Chemical Development and
API Supply, Biocon Bristol-Myers Squibb Research and
Development Center, Bengaluru 560099, India
Mohamed Jaleel − Chemical Development and API Supply,
Biocon Bristol-Myers Squibb Research and Development
Center, Bengaluru 560099, India
Rajappa Vaidyanathan − Chemical Development and API
Supply, Biocon Bristol-Myers Squibb Research and
Development Center, Bengaluru 560099, India; Present
Address: SEAGEN INC, 22515 29th Dr. SE, Bothell,
Washington 98021, United States; orcid.org/0000-
0002-2236-5719
Martin D. Eastgate − Chemical Process Development, Bristol-
Myers Squibb, New Brunswick, New Jersey 08903, United
States; orcid.org/0000-0002-6487-3121
https://doi.org/10.1021/acs.oprd.2c00399
Org. Process Res. Dev. 2023, 27, 680−691
Organic Process Research & Development
Richard Klep − Chemical Process Research and Development,
Janssen Pharmaceuticals, Beerse 2340, Belgium
Cyril Benhaïm − Chemical Process Research and
Development, Janssen Pharmaceuticals, Beerse 2340, Belgium
Ilse Vogels − Chemical Process Research and Development,
Janssen Pharmaceuticals, Beerse 2340, Belgium
Koen Peeters − Chemical Process Research and Development,
Janssen Pharmaceuticals, Beerse 2340, Belgium
Sébastien Lemaire − Chemical Process Research and
Development, Janssen Pharmaceuticals, Beerse 2340,
Belgium; orcid.org/0000-0002-9343-0493
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.2c00399
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
This study was sponsored by Bristol-Myers Squibb and Janssen
Research & Development, LLC.
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691 https://doi.org/10.1021/acs.oprd.2c00399
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