Improved Process for a Copper-Catalyzed C-N Coupling in the Synthesis of Verubecestat

Article abstract of DOI:10.1021/acs.oprd.9b00192

Verubecestat is a β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor which was previously evaluated for the treatment of Alzheimer's disease. The synthesis of verubecestat relies on a Cu-catalyzed carbon-nitrogen coupling. During process development, observations of impurity formation led to a more robust understanding of the catalyst. The transformation was discovered to be highly dependent on the ratio of ligand to substrate concentration during the course of the reaction. In-depth studies aimed at attaining mechanistic understanding provided an explanation of experimental findings and ultimately led to the identification of conditions that resulted in a more robust process.

Full text of DOI:10.1021/acs.oprd.9b00192

Communication
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Improved Process for a Copper-Catalyzed C−N Coupling in the
Synthesis of Verubecestat
Eric M. Phillips,* Mikhail Reibarkh, John Limanto, Minh Kieu, Azzeddine Lekhal, and Daniel Zewge
Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States
S
* Supporting Information
product from the reaction between the ligand and product 7
ABSTRACT: Verubecestat is a β-site amyloid precursor
protein cleaving enzyme 1 (BACE1) inhibitor which was
previously evaluated for the treatment of Alzheimer’s
disease. The synthesis of verubecestat relies on a Cu-
catalyzed carbon−nitrogen coupling. During process
development, observations of impurity formation led to
a more robust understanding of the catalyst. The
transformation was discovered to be highly dependent
on the ratio of ligand to substrate concentration during
the course of the reaction. In-depth studies aimed at
attaining mechanistic understanding provided an explan-
ation of experimental findings and ultimately led to the
identification of conditions that resulted in a more robust
process.
(Figure 1). The high temperature also necessitates the use of
excess amide 6. Hydrolysis of 6 to carboxylic acid 11 is a
prominent side reaction but has not been problematic as the
acid is easily washed away in the aqueous phase and residual 6
can be removed downstream via crystallization if it is present in
<5 area%5 following isolation of product 7. However, during
our extensive Design of Experiments (DoE) studies,6 variable
amounts of residual 6 were present at the end of reaction with
upward of 8 area% remaining. While we could reduce the
residual amide at the end of the reaction by extending the
reaction time or running at higher temperature to promote
hydrolysis, these changes would result in an increase of
impurity 107 whose presence is greatly increased at temper-
atures above 100 °C and has limited rejection downstream.
These robustness issues compelled us to gain a better
understanding of this transformation.
KEYWORDS: C−N coupling, BACE1 inhibitor,
NMR spectroscopy, copper catalysis
We began by evaluating the root cause of the hydrolysis of
amide 6 and whether the catalytic system may be involved in
the hydrolysis mechanism (Table 1). We subjected 6 to
toluene and water in the presence of K2CO3 and heated the
mixture at 104 °C. After 5 h, approximately 8% conversion to
the carboxylic acid (11) was observed. Heating for a total of 10
h produced only 14% of 11. When the reaction is repeated
with 20 mol % of CuI, a significant rate enhancement of
hydrolysis ensues, where 19 and 31% of 11 is produced after 5
and 10 h aging, respectively. Notably, introduction of ligand L1
to mimic the copper coupling reaction retards the rate of the
hydrolysis but still significantly outpaces the rate of reaction
without copper present. These results indicate that copper
plays a significant role in the hydrolysis of 6 and a competition
for copper binding between the ligand and amide substrate
exists.
erubecestat (1)1 is a β-secretase 1 (BACE1) inhibitor
Vthat was previously under clinical investigation for the
treatment of Alzheimer’s disease.2 We recently disclosed a
commercial manufacturing route of the active pharmaceutical
ingredient which begins with a Mannich-type addition of
sulfonamide 3 to tert-butyl sulfinimine 2. Successive copper-
catalyzed coupling with 5-fluoropicolinamide 6 and p-
methoxybenzyl deprotection provide the central amide present
in the active pharmaceutical ingredient (API). Lastly,
guanidinylation with cyanogen bromide furnishes verubecestat
in 61% overall yield (Scheme 1).3
During development, the C−N coupling between 5 and 6
drew interest due to the varying impurity profile generated
during experiments exploring process robustness (Scheme 2).
The current reaction conditions require combining sulfona-
mide 5 and 1.15 equiv of picolinamide 6 in a toluene:water
(∼2.5:1) mixture in the presence of 20 mol % CuI and 25 mol
% ligand L1.4 The resulting biphasic mixture is heated at 104
°C under a closed, inert system for 20 h with 7 equiv of
K2CO3. Upon cooling, the reaction is diluted with EtOAc and
washed with ethane-1,2-diamine. Distillation to remove
residual water and EtOAc and direct crystallization upon
addition of heptane furnishes desired amide 7 in 89−92%
isolated yield.
NMR Studies of Copper Interactions. Given our data
showing the impact of copper on hydrolysis coupled to the
observation that the ligand inhibits conversion to the
carboxylic acid, we hypothesized that the ligand and amide
compete for the metal center. We utilized NMR spectroscopy
to investigate this hypothesis, where initial experiments
1
included recording H and 13C NMR spectra of ligand L1 in
toluene-d8 in the presence of 0, 0.5, 1, 2, and 5 equiv of CuI
1
(Figure 2). Observable shifts in H and 13C resonances of L1
While the reaction typically generates 7 in reproducibly
>89% yield and has been demonstrated on >50 kg scale, it
suffers from a few notable issues. Specifically, reaction
temperatures of >100 °C are required to obtain satisfactory
conversion, which results in generation of impurity 10, a side
Special Issue: Honoring 25 Years of the Buchwald-Hartwig
Amination
Received: April 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.9b00192
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Organic Process Research & Development
Communication
Scheme 1. Synthesis of Verubecestat
was increased to 1 equiv, consistent with the hypothesis of a
competition for copper between the ligand and the reactant
(Figure 2, spectra D−F). Notably, product 7 did not show
competitive binding observed for amide 6 as supported by a
similar experiment where increasing loading of 7 did not
change chemical shifts of 1:1 Cu−ligand complex (see the
Supporting Information). The final NMR experiment run was
to simulate reaction conditions in which 1.15 equiv of 6 was
charged to 0.2 equiv of CuI and 0.25 equiv of L1. 1H chemical
shifts of L1 resonances are very similar to those in an earlier
experiment with copper−ligand ratio of 0.5 (Figure 2, spectra
B and G). These results indicate that under the reaction
concentrations, approximately half of all copper was bound to
the ligand L1 with the other half being sequestered by binding
the reactant 6. Our NMR data demonstrate that 6 binds
copper efficiently and competitively with L1 with large
excesses of 6 inhibiting the binding of L1 to the metal. This
observation is underscored by a recent disclosure by McGowan
and coworkers where they found picolinamides can be effective
Cu−ligands for C−O coupling reactions.9 On the basis of
these experiments, we hypothesized that minimizing the
concentration of amide 6 during the course of the reaction
may allow us to obtain better catalyst performance and
minimize side reactions such as hydrolysis and SNAr chemistry
between the ligand and product that lead to the formation of
10 and 11.
Proposed Reaction Pathway. On the basis of our
observations from the NMR studies combined with previous
work out of the Buchwald laboratory, we proposed a possible
reaction pathway for the formation of 7 (Figure 3).10
Coordination and subsequent deprotonation of the amide to
the Cu−ligand (Cu−L1) complex forms catalyst complex B.
Reaction with aryl bromide 5 allows the process to proceed
toward a productive pathway. However, when the amide is
present in high concentration, a second equivalent of amide
can displace L1, resulting in the generation of C, which could
also exist in equilibrium with complex D, leading to hydrolysis
of the amide starting material and is a nonproductive pathway.
As first proposed by Bacon and Karim11 and later supported by
the group of Hartwig,12 the optimal nucleophile to Cu ratio is
<1, which should prevent or minimize the concentration of C
in the reaction. This problem is potentially exacerbated by
having an additional Lewis basic site present on the amide.
Buchwald postulates that under these conditions, the reaction
is first order in L1 and inversely related to the concentration of
amide 6.7 Thus, the desired copper coupling reaction rate
should be suppressed by having a high concentration of amide
in solution. A possible solution to improving the impurity
profile would be to maintain a low concentration of 6
throughout the course of the reaction. The change in protocol
Scheme 2. Cu-Catalyzed C−N Coupling
Figure 1. Impurities generated during C−N coupling reaction.
Table 1. Hydrolysis Study
conversion
(5 h, %)
conversion
(10 h, %)
entry
conditions
1
2
3
K2CO3
K2CO3/CuI (20 mol %)
K2CO3/CuI, L1 (20
mol %)
8
19
11
14
31
25
were observed when going from 0 to 0.5 to 1 equiv of CuI, but
adding more than 1 equiv provided no changes (Figure 2,
spectra A−C). These results suggest a formation of L1−Cu
complex with 1:1 stoichiometry. Another important observa-
tion is that the interaction occurs in a fast exchange regime on
the NMR time scale, where apparent chemical shifts are a
weighted average between the free and bound states, resulting
in apparent shifts of L1 resonances. The upfield shift upon
binding Cu(I) and downfield shift upon decomplexation is
consistent with that previously reported in the literature.8
Having investigated the copper−ligand complex by NMR
spectroscopy, we explored how another major reaction
component, amide 6, would affect its equilibrium. If 6 disrupts
the interaction between L1 and copper, the resonances of L1
were expected to shift back toward the free state. We designed
a competition experiment by charging increasing amounts of 6
to the 1:1 mixture of L1 and CuI. While addition of 10 mol %
of 6 yielded minimal changes, increasing the amount to as high
1
as 50 mol % resulted in expected shifts in L1 H resonances,
indicating that the fraction of the ligand is becoming unbound.
The shifts were even more pronounced when the amount of 6
B
DOI: 10.1021/acs.oprd.9b00192
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Communication
Figure 2. 1H NMR study of competitive Cu binding between the ligand L1 and reactant 6. A: 1 equiv of L1, no copper or 6; B: 1 equiv of L1 and
0.5 equiv of CuI; C: 1 equiv of L1 and CuI each; D: 1 equiv of L1 and CuI each and 0.1 equiv of 6; E: 1 equiv of L1 and CuI each and 0.5 equiv of
6; F: 1 equiv of L1, CuI and 6 each; G: 1.15 equiv of 6, 20 mol % of CuI, and 25 mol % of L1. All experiments were performed in toluene-d8, D2O,
and K2CO3.
Figure 3. Proposed reaction pathway.
could possibly allow us to perform the reaction at lower
temperatures and lower the charging of amide 6 due to
decreased rates of hydrolysis.
0.25 equiv, which matched the charging of ligand L1. The
internal temperature of the reaction was brought to 80 °C, and
the remaining amount of amide was charged in 5 aliquots over
the extended time. After mixing for 20 h, only 91% conversion
and 89% assay yield had been achieved (Table 2, entry 1). We
attributed this incomplete conversion to the lower temperature
at which the reaction was performed. Increasing the temper-
ature to a range of 94−100 °C allowed for 99% conversion of
the starting material and 97% assay yield (entry 2). Increasing
the scale to 5 g allowed for a better control of the temperature
while affording a similar high conversion and assay yield.
Lastly, we increased the scale to 75 g (entry 4). This size of
reaction allows us to mimic pilot scale conditions with the use
of overhead mixing assauging our concerns about the
scalability of our process. Maintaining an inert atmosphere
Modified Procedure. To keep the concentration of amide
low during the course of the reaction, we decided to charge 6
in aliquots over the course of 8−10 h to the reaction solution.
This change should allow for roughly equal concentrations of 6
and L1 throughout the reaction timeline. Our previous studies
indicated that we could remove up to 5 area% of 6
downstream, so we limited the total charging of the amide
(6) to 1.05 equiv. Due to the limited solubility of 6 in toluene
at room temperature, we decided to charge amide to the
reaction as a solid, and because of this constraint, we
performed the reactions inside an oxygen-free glovebox.13
We started by adjusting the initial loading of amide 6 to only
C
DOI: 10.1021/acs.oprd.9b00192
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Communication
a
Table 2. Controlled Addition Study
b
c
c
c
c
entry
scale (g)
temperature (°C)
equiv of 6
charges of 6
conversion (%)
assay yield (%)
area % 10
area % 6
1
2
3
4
5
5
1
5
75
45
45
80
94−100
96
94
104
92−96
1.05
1.05
1.05
1.05
1.00
1.15
5
4
5
8
91
99
98
98
95
95
89
97
95
94
90
88
n/d
3.4
1.7
3.3
1.2
0.08
8.0
d
0.19
0.17
0.16
0.32
0.08
e
f
f
6
a
Reactions performed by initially charging 0.25 equiv of 6 and bringing the mixture to the desired reaction temperature. The remaining 0.8 equiv of
b
c
6 charged over 8 h with total reaction time being 20 h. Amount of parent amine following salt break. Determined by reverse phase HPLC.
d
e
f
Reaction was aged on a hot plate, rendering temperature control difficult. Amide 6 was charged as a slurry. The entire charge of 6 was performed
at the beginning of the reaction.
while charging 6 was challenging and impractical on scale. To
render the procedure amenable to pilot plant scale, we opted
to charge the amide as a suspended slurry mixture and run the
reaction open with a reflux condenser as opposed to the closed,
pressurized system on small scale. This modification forced us
to begin the Cu-catalyzed reaction at a slightly higher
concentration as the volume would increase over time. We
began by running the reaction in ∼4 mL of toluene per gram of
aryl bromide 5. Amide 6 was slurried in 1 mL/g of toluene
with respect to 5. Nonetheless, the increase in scale and
modified reaction procedure provided nearly identical results
to the smaller scale runs, where high conversion and assay
yields were obtained. Importantly, in all four of these runs, the
impurity 10 was maintained below 0.2 area% in the reaction
stream, and amide 6 was consistently below 5 area%. The
portion-wise addition of amide 6 resulted in improved reaction
performance compared to the initial procedure. Using only 1.0
equiv of amide 6 charged upfront and maintaining the reaction
at 104 °C afforded only 95% conversion, lower assay yield, and
increased amide hydrolysis (entry 5). We also performed the
conventional batch mixing procedure between 92 and 96 °C
while keeping the amide loading at 1.15 equiv. Again, the
reaction failed to exceed 95% conversion.
In summary, we demonstrated that there is a competition
between the ligand (L1) and the amide substrate (6) with the
copper catalyst used in the formation of 7. This critical
attribute of the reaction requires the process to be run at high
temperatures, increasing the risk of impurity generation and
inconsistent reaction profiles. We used NMR spectroscopy to
interrogate the catalyst system and used that data to develop a
revised procedure where the concentration of the amide
substrate is kept roughly equal to the concentration of the
ligand during the course of the reaction. This change improves
catalyst performance and allows the process to be run at lower
temperatures. This process improvement alleviates the risk that
critical impurity levels could increase and allows us to decrease
stoichiometry of the expensive reagent (i.e., amide 6). We
anticipate that these findings could be impactful to other Cu-
mediated C−N bond-forming transformations which are
ubiquitous in academic and industrial applications.
methylsulfamoyl)propan-2-aminium (S)-2-hydroxy-2-phenyla-
cetate (5, 100 g, 167 mmol). Toluene (500 mL) and H2O
(420 mL) were added, and the internal temperature was
adjusted to 50 °C. After mixing for 2 h, the mixture was cooled
to 35 °C, and the phases were settled and separated.
Stage 2. The organic layer was charged to a 1-L cylindrical
reactor equipped overhead stirrer, reflux condenser, N2 inlet,
and thermocouple containing 5-fluoropicolinamide (4.25 g, 30
mmol), CuI (5.91 g, 30 mmol), and K2CO3 (147 g, 1.06 mol).
H2O (182 mL) and L1 (5.48 g, 38 mmol) were charged. The
reactor was closed and sparged with N2 for approximately 1 h.
The reaction was then heated to refluxing temperature (94
°C). A separate round-bottom flask equipped with magnetic
stirring bar was charged with 5-fluoropicolinamide (20.3 g, 145
mmol) and toluene (75 mL). The flask was sealed with a
rubber septum and sparged with N2 for 30 min. The
picolinamide (6) solution was charged portion-wise every
hour for 8 h via cannula transfer. The reaction was aged for a
total of 20 h at 94 °C and then cooled to 30 °C. Ethane-1,2-
diamine (30.4 mL, 455 mmol) was added followed by EtOAc
(75 mL). Contents were aged for 30 min. Phases were settled
and separated. Organics were washed with water (2 × 300 mL)
and 10 wt % NaCl (300 mL). The organic layer was separated
and distilled to ∼200 mL. The batch was heated to an internal
temperature of ∼60 °C to dissolve any remaining solids. 2-
Propanol (15 mL) and n-heptane (80 mL) were added. The
batch was cooled to 50 °C and seeded with 7 (400 mg). The
mixture was aged for 2 h, and n-heptane (270 mL) was added
over 8 h. The mixture was cooled to 30 °C, and an additional
400 mL of n-heptane was added over 3 h. The mixture was
aged overnight and then filtered. The solids were washed with
a 2:3 mixture of toluene to n-heptane (200 mL) and once with
n-heptane to provide 7 as a white solid (69 g, 90% yield).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.9b00192.
■
S
General experimental methods for the hydrolysis study,
NMR spectroscopy study, modified C−N coupling
procedure, previous C−N coupling procedure, DoE
data, and characterization data for product 7 and
impurity 10 (PDF)
Procedure. Stage 1. To a 2-L cylindrical reactor equipped
with an overhead stirrer and thermocouple was charged (R)-2-
(5-bromo-2-fluorophenyl)-1-(N-(4-methoxybenzyl)-N-
D
DOI: 10.1021/acs.oprd.9b00192
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Communication
20, 17606. For recent examples, see: (b) Barnes, D. M.; Shekhar, S.;
Dunn, T. B.; Barkalow, J. H.; Chan, V. S.; Franczyk, T. S.; Haight, A.
R.; Hengeveld, J. E.; Kolaczkowski, L.; Kotecki, B. J.; Liang, G.;
Marek, J. C.; McLaughlin, M. A.; Montavon, D. K.; Napier, J. J.
Discovery and Development of Metal-Catalyzed Coupling Reactions
in the Synthesis of Dasabuvir, an HCV-Polymerase Inhibitor. J. Org.
Chem. 2019, 84, 4873. (c) Bernhardson, D. J.; Widlicka, D. W.;
Singer, R. A. Cu-Catalyzed Couplings of Heteroaryl Primary Amines
and (Hetero)aryl Bromides with 6-Hydroxypicolinamide Ligands.
Org. Process Res. Dev. 2019, DOI: 10.1021/acs.oprd.9b00195.
(10) Strieter, E. R.; Bhayana, B.; Buchwald, S. L. Mechanistic Studies
on the Copper-Catalyzed N-Arylation of Amides. J. Am. Chem. Soc.
2009, 131, 78.
AUTHOR INFORMATION
Corresponding Author
*E-mail: eric.phillips@merck.com.
ORCID
Eric M. Phillips: 0000-0003-3530-8876
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
The authors would like to thank Xiaodong Bu, Wenyong
Chen, William Morris, and Jake Song for helpful discussions.
■
(11) Bacon, R. G. R.; Karim, A. Metal ions and complexes in organic
reactions. Part XV. Copper-catalysed substitutions of aryl halides by
phthalimide ion. J. Chem. Soc., Perkin Trans. 1 1973, 1, 272.
(12) Tye, J. W.; Weng, Z.; Johns, A. M.; Incarvito, C. D.; Hartwig, J.
F. Copper Complexes of Anionic Nitrogen Ligands in the Amidation
and Imidation of Aryl Halides. J. Am. Chem. Soc. 2008, 130, 9971.
(13) Oxygen is detrimental to the reaction and has been shown to
limit conversion.
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