Utilizing Native Directing Groups: Synthesis of a Selective IKur Inhibitor, BMS-919373, via a Regioselective C-H Arylation

Article abstract of DOI:10.1021/acs.joc.8b02254

BMS-919373 is a highly functionalized quinazoline under investigation as a selective, potent I_Kur current blocker. By utilizing the aminomethylpyridine side chain at C-4, a selective C-H functionalization at C-5 was invented, enabling the effic

Full text of DOI:10.1021/acs.joc.8b02254

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Article
Utilizing Native Directing Groups: Synthesis of a Selective
IKur Inhibitor, BMS-919373, via a Regioselective C-H Arylation
Steven R. Wisniewski, Jason M Stevens, Miao Yu, Kenneth
J. Fraunhoffer, Evan O. Romero, and Scott A. Savage
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02254 • Publication Date (Web): 05 Nov 2018
Downloaded from http://pubs.acs.org on November 5, 2018
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The Journal of Organic Chemistry
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Utilizing Native Directing Groups: Synthesis of a Selective IKur
Inhibitor, BMS-919373, via a Regioselective C-H Arylation
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Steven R. Wisniewski, Jason M. Stevens, Miao Yu, Kenneth J. Fraunhoffer, Evan O. Romero, and Scott
A. Savage*
Chemical and Synthetics Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey,
08903, United States
KEYWORDS (Word Style “BG_Keywords”). If you are submitting your paper to a journal that requires keywords, provide
significant keywords to aid the reader in literature retrieval.
native directing group
C-H Activation
N
O
HN
O
N
O
O
S
N
H
O
N
NH2
N
BMT-919373
ABSTRACT: BMS-919373 is a highly functionalized quinazoline under investigation as a selective, potent IKur current blocker. By
utilizing the aminomethylpyridine side-chain at C-4, a selective C-H functionalization at C-5 was invented, enabling the efficient
synthesis of this molecule. The strategy of leveraging this inherent directing group allowed the synthesis of this complex heterocycle
in only six steps from commodity chemicals. The scope of the C-H activation was further investigated, and the generality of the
transformation across a series of bicyclic aromatic heterocycles was explored.
INTRODUCTION
To allow effective production of numerous
phenylquinazoline analogs, the initial synthesis of BMS-
919373 centered around derivatization of 2,4-dichloro-5-
phenylquinazoline, which was prepared from 4-bromoisatin in
5 steps. This enabled the use of SnAr chemistry to install
various aryl substituted amines at the 4-position and Suzuki
couplings to install small heterocycles at the 2-position.
However, while the dichloroquinazoline was a versatile
intermediate to explore SAR at the C2 and C4 positions, once
BMS-919373 was selected as the lead candidate a more targeted
synthetic approach was required.
Atrial fibrillation (AF or AFib) is the most common type
of heart arrhythmia and is often represented by a rapid, irregular
heartbeat. An estimated 2.7 – 6.1 million people have AF in the
United States.1 More than 750,000 hospitalizations occur each
year in the United States2 at a cost of an estimated $26.0
,
billion.3 4
Current antiarrhythmic drugs for the treatment of AF affect
both the atria and ventricles and are made up of sodium channel
blockers, potassium channel blockers, and mixed ion channel
blockers. More recent studies have focused on agents that
selectively target the atria to provide potentially safer
medications.5 An example of this approach is the inhibition of
the atrial-specific ultrarapid delayed rectifier potassium current
(IKur) enzyme. One such compound, the active pharmaceutical
ingredient (API), BMS-919373 (Figure 1, 1),6 was recently
identified as a potent and selective IKur inhibitor that showed
robust effects in rabbit and canine pharmacodynamic models
and was advanced as a clinical candidate.
RESULTS AND DISCUSSION
Route Scouting Efforts toward the Synthesis of API
Retrosynthetic analysis yielded a number of potential
approaches to assemble the quinazoline core (Figure 2). The
key decision on the route, however, was the method for
installing the phenyl group at C5. One targeted disconnection
would be to install the group early in the route through a cross-
coupling, to afford a 1,2,3-trisubstituted arene, which would
then be further elaborated through cyclization or substitution
reactions to form the quinazoline core.
The second strategy was to install the phenyl ring via C-H
activation. The picolyl amine was conceived to be a built-in
directing group that would enable an efficient synthesis of the
phenyl substituted quinazoline. There are, however, limited
reports on direct arylations of these systems, and to the best of
N
HN
N
O
O
S
N
NH2
1
N
Figure 1. Structure of IKur Inhibitior, BMS-919373 (1)
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our knowledge, picolyl amine has not been reported as a activation would allow us to start from a simpler and more
1
2
3
4
5
6
7
8
directing group in this type of C-H activation.
readily available 1,2-disubstituted arene. The direct arylation
would create the required 1,2,3-trisubstituted core in one step.
Utilizing the direct arylation should afford the shortest overall
route to API via a back-to-back palladium catalyzed Suzuki and
C-H activation from the commercially available 2,4-
dichloroquinazoline (Figure 2, Path D).
There are multiple benefits to utilizing the C-H activation
in lieu of the early-stage cross-coupling. Most importantly, the
cross-coupling route would require the use of a halogenated
1,2,3-trisubstituted arene intermediate, prepared from 4-
bromoisatin through a series of transformations. Although
commercially available, 4-bromoisatin itself is derived from 3-
bromoaniline in 2 steps,7 whereas implementation of the C-H
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NH2
Path A
N
N
O
S
O
X
+
N
NH2
N
Br
O
O
Path B
N
N
H2N
NH
O
O
S
O
+
HN
N
N
NH2
H
N
O
S
O
N
N
NH2
N
O O
1
N
Cl
N
Path C
Path D
M
S
H2N
NH2
+
+
N
N
N
+
Cl
Cl
N
N
O
O
HN
X/M
N
M
S
NH2
+
Cl
N
N
Cl
Figure 2. Retrosynthetic Analysis of BMS-919373
(PCy3)2PdCl2 (0.75 mol %)
B2pin2 (1.0 equiv)
From this analysis, we made the strategic decision to focus
our efforts on the C-H functionalization and on the use of 2,4-
dichloroquinaozline as our starting point to access the des-
phenyl API (Figure 2, Path D). A benefit of this approach was
the methodology developed should transfer to route/path C, if
needed, as we believed that the aryl group on the quinazoline
ring would not have a significant impact on the chemistry
developed.
Starting from 2,4-dichloroquinazoline, installation of the
picolyl amine fragment proceeds in 93% yield (eq 1). The
Suzuki coupling partner was prepared via a palladium-
catalyzed Miyuara borylation of the substituted 3-
bromopyridine 4, which affords the pinacol boronate ester 5 in
83% yield with less than 1 mol % Pd (eq 2). The use of the tert-
butyl sulfonamide improves solubility and thus reactivity of
substrates. The Suzuki coupling was performed utilizing 2 mol
% of (Cy3P)PdCl2, 3.0 equiv of K2CO3 in 1:1 MeTHF/H2O, and
the product crystallized out of solution during the reaction
allowing isolation with no work-up in 82% yield. (eq 3).
O
O
O
O
O
KOAc (3.0 equiv)
Br
S
B
S
N
(2)
O
N
H
H
Dioxane
100 °C, 18 h
83%
N
N
5
4
N
HN
(Cy3P)PdCl2 (2 mol %)
K2CO3 (3.0 equiv)
N
O
O
5
3
(3)
+
S
1:1 MeTHF/H2O (9 vol)
75 °C, 20 h
N
N
H
82%
N
6
Based on the results of the cross-couplings above, we were
confident that we could achieve proof of concept on path C by
utilizing 2,4-dichloro-5-phenylquinazoline as the starting
material and proceeding through the same series of
transformations. From here, we turned our attention to the key
transformation, installation of the arene through a metal-
catalyzed C-H activation. Utilization of picolinamide as a direct
group led to installation of anisole through a C-H activation on
a similar naphthalene system with a catalytic amount of
palladium and an acetate base at elevated temperatures,
providing us insight to potential reaction conditions (Scheme
1).8
N
Cl
i-Pr2NEt (1.1 equiv)
2-picolylamine (1.1 equiv)
HN
N
N
N
(1)
IPA, 23 °C
93%
N
Cl
Cl
Pd(OAc)2 (5 mol %)
2
3
OMe
OMe
Pd(OAc)2 (15 mol %)
4-iodoanisole (4.0 equiv)
KOAc (2.0 equiv)
4-iodoanisole (4.0 equiv)
CuBr2 (10 mol %)
N
N
N
MOAc (4.0 equiv)
HN
O
HN
O
HN
O
xylene, 130 °C
73%
t-amylOH, 140 °C
M = Cs, 73%
M = Ag, 98%
Scheme 1. Direct Arylation on a Similar Naphthalene
System
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In addition to compound 6, we envisioned preparing three
additional substrates (all prepared from 2,4-
addition products, that were challenging to separate, were
observed under an array of reaction conditions (Path A).10
However, a condensation based approach would afford a
quinazolinone as the penultimate compound. The installation of
the picolylamine fragment through an SnAr reaction would then
yield the API (Path B). Proof of concept for this route was
achieved by the condensation of 6-phenyl isatoic anhydride and
the amidine of 9 to afford the quinazolinone is 46% yield (eq
5). As in other strategies, the tert-butyl group on the sulfamide
was installed to improve solubility of the intermediates.
Subsequent reaction with 2-picolylamine affords the tert-butyl
protected API.
1
2
3
4
5
6
7
8
dichloroquinazoline) to investigate the C-H activation (Figure
3). The Schiff base (7A) proved difficult to synthesize under an
array of reaction conditions. The picolinamide model system
(without the sulfonamide) was prepared, but provided modest
levels of conversation in the C-H arylation, likely due to poor
solubility (7B). This substrate was a less preferred option as it
would require an additional reduction step to yield the desired
picolyl amine. The unprotected sulfonamide (7C) suffered from
even lower solubility, leading to no reactivity in the attempted
coupling. Therefore, the tert-butyl protected sulfonamide (6)
was our lead candidate for the exploration of the key C-H
9
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O
S
O
activation event.
O
(1) 10% NaOMe, then NH4Cl
NC
O
N
NH
O
S
O
(5)
H
N
N
Ph
O
(2)
N
N
HN
N
N
9
N
10
N
H
O
N
N
O
S
O
N
N
H
O
N
H
THF, 65 °C
N
N
Based on the success of this transformation, we quickly
realized the full synthesis. Isatoic anhydride (11) can be utilized
in place of the 6-phenyl derivative in the condensation reaction
to generate the quinazoline core, which can then be converted
to the starting material for the C-H activation (Scheme 2). The
switch from 4-bromoisatin to isatoic anhydride, provides both
cost reduction and improved sustainability of the starting
material.
7A
7B
N
N
HN
N
HN
N
N
N
O
O
S
O
O
S
HN
NH2
N
N
7C
6
N
Figure 3. Substrates for the C-H Activation
HN
N
O
HN
N
O
O
O
N
O
S
S
O
N
N
Proof of concept on the C-H arylation was quickly
achieved. Excellent conversion (93 area percent by HPLC)9 of
the desired product was observed with a catalytic amount of
Pd(OAc)2 in iodobenzene with potassium acetate as the base (eq
4).
N
H
O
H
N
NH2
N
6
N
11
1
Scheme 2. Condensation/C-H Activation Route to API
N
Condensation/C-H Activation Route Development
HN
N
Pd(OAc)2 (5 mol %)
KOAc (3.0 equiv)
HN
N
O
S
O
(4)
N
The six-step route to BMS-919373 is shown in Scheme 3.
A robust process was developed for each step with a focus on
the greenness of the overall route. The efficiency of each step
developed can be measured by calculating the process mass
intensity (PMI), which is the amount of material input (kg) /
amount of product isolated (kg), where a lower PMI
corresponds to a greener, more efficient process.
The first step in the sequence installs the tert-butyl
sulfonamide by formation of the heteroarylgrignard with i-
PrMgCl-LiCl. Addition of sulfuryl chloride forms the sulfonyl
chloride in-situ, which is then reacted with tert-butyl amine to
afford the desired sulfonamide 7 in 70% isolated yield. Several
in-process by-products were observed from impurities in the
input reagents (Figure 4). A pH controlled wash of the reaction
mixture with 1.5 M HCl selectively removes the dehalogenated
3-bromopyridine. After a basic wash with 1.0 M NaHCO3, a
solvent swap to MeOH resulted in crystallization of the sulfone
dimer impurity, which can be removed by a simple polish
filtration. After crystallization of the desired sulfonamide 7, the
dihalogenated impurities, 3-bromo-5-chloropyridine and 3,5-
dibromopyridine could be removed with a heptane wash of the
isolated solid, resulting in ~98 AP material.
O
S
HN
Iodobenzene, 0.1 M
(~90 equiv)
O
N
HN
N
118 °C
N
93 AP in-process
N
6
8
This initial hit for the C-H activation validated our
hypothesis of leveraging the built-in directing group to install
the arene through a late stage palladium-catalyzed reaction.
With the use of 2,4-dichloroquinazoline, this route affords API
in a five step longest linear route after deprotection of the
sulfonamide.
Because of its inherent insolubility, the purification of 6
after the Suzuki coupling was a challenge, specifically the
removal of residual palladium and ligands that could interfere
with the direct arylation. Although we believed we could
address this concern, the second, and perhaps more significant
issue, was the long term viability of 2,4-dichloroquinazoline as
our starting material, which was being accessed through the
global chlorination of the quinazolinedione. In order to employ
the C-H activation, we focused our attention on determining an
efficient and sustainable route to quinazoline 6.
Concurrent to the investigations into the Suzuki/C-H
Activation route, we evaluated alternative methods for
accessing the quinazoline core (Paths A and B). The alkylation
of the aminoquinazoline in Path A with 2-chloromethylpyridine
suffered from poor selectivity as a mixture of mono- and bis-
O
O
O
O
Cl
S
Br
S
Br
Br Cl
Br
N
H
N
N
N
N
N
Figure 4. Impurities Generated in the Sulfonylation
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dimethylacetamide (DMAc) was the minimum volume to
1
2
3
4
5
6
7
8
The next step in the route is a palladium-catalyzed
cyanation of 7. Zn(CN)2 proved to be the most effective cyanide
source along with Pd2dba3 as the palladium source and
XantPhos as the ligand. The reaction rate was dependent on the
achieve acceptable kinetics. The reaction resulted in complete
conversion with minimal impurities and an in-process yield of
98%.
solubility of Zn(CN)2, and
5
vol (mL/g, L/kg) of
1) i-PrMgCl-LiCl (1.5 equiv)
THF, –20 °C
Pd2dba3 (0.5 mol %)
XantPhos (1 mol %)
Zn(CN)2 (0.65 equiv)
2) SO2Cl (1.5 equiv)
DCM, –20 °C
3) t-BuNH2 (4.0 equiv)
NH
O
S
O O
O
S
HN
O
Br
Br
O
Br
NC
S
NaOMe (0.1 equiv)
MeOH (7 vol), 0 °C
N
MeO
HN
H
N
DMAc (5 vol), 85 °C
70% yield
9
N
N
N
82% yield
12
4
9
13
10
11
12
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N
O
2-Picolylamine (2.0 equiv)
PyBrop (1.1 equiv)
HN
NH
O
S
HN
11
(1.0 equiv)
NH4Cl (1.25 equiv)
MeOH, 50 °C
O
NH
O
S
O
N
DBU (1.15 equiv)
O
O
H2N
THF (5 vol), 65 °C
90% yield
S
N
N
N
N
MeCN (20 vol), rt
82% yield
H
N
14
H
N
N
6
10
Pd(OAc)2 (5 mol %)
PhI (12 equiv)
Cs2CO3 (0.51 equiv)
PivOH (1.05 equiv)
N
N
N
HN
N
HN
N
conc HCl (18 equiv),
N
N
O
S
HN
H2O (1 vol), 80 °C
83% yield
O
O
O
S
Anisole (5 vol), 120 °C
76% yield
NH2
N
1
(BMT-919373)
8
Scheme 3. Optimized Condensation/C-H Activation Route to BMS-919373
A work-up to remove both the palladium and zinc was
required.11 A scavenger screen (Table 1) showed that the only
effective scavenger at removing both Pd and Zn was ethylene
diamine (EDA). The addition of ethylene diamine at the end of
the reaction was exothermic and had to be added slowly while
maintaining the batch temperature below 15 °C to prevent Zn
aggregation. The product was then isolated through a
crystallization with IPA/H2O to afford the desired product in an
average of 82% yield on 30-45 kg scale. The average residual
Pd and Zn was ~20 ppm Pd and 30 ppm Zn, and the product
was isolated in 96 AP. Interestingly, 2.5 AP were attributed to
the XantPhos and dba ligands, and the remaining 1.5 AP was
residual impurities from the input. However, all of these
impurities can be purged in the subsequent step.
sought to develop an improved condensation manifold to build
the desired quinazolinone moiety directly from aryl nitriles
such as 9 and a suitable coupling partner under mild reaction
conditions. A variant of Niementowski reaction13 that had been
shown to effect the condensation of amidines with isatoic
anhydrides was particularly intriguing,14 although, utilizing
amidines without substitution at the amidine nitrogens, a
necessity for accessing quinazolin-4(3H)-ones, had not been
demonstrated. Therefore, we sought to exploit the ability to
access the amidine (14) of aryl nitrile 9 in situ to facilitate a
telescoped Niemetowski condensation of aryl nitriles with
isatoic anhydrides under mild reaction conditions.
The condensation reaction between 7 and 12 required
generation of the amidine of 7 via the intermediacy of an
imidate (13) prepared via the action of catalytic sodium
methoxide (10 mol %). Interestingly, studying the conversion
of the nitrile to the imidate as a function of time and temperature
showed that the formation of the imidate was an equilibrium
process where higher conversion is observed at lower
temperature (Figure 5). For example, keeping the temperature
at 60 °C results in ~80% conversion, then cooling to 30 °C
increases the conversion to ~90%. Decreasing the temperature
further to 0 °C results in ~98% conversion (light blue line). The
equilibrium process for the conversion of nitriles to imidates
under basic conditions is surprisingly underexplored despite the
prevalence of imidates as intermediates in heterocycle
synthesis.15 Therefore, the formation of the imidate was
performed initially at 25 °C to rapidly bring the reaction to
~90% conversion then cooled to 0 °C to drive the reaction to
near complete conversion.
Table 1. Palladium and Zinc Remediation from the
Palladium-Catalzyed Cyanation (NAC = N-Acetyl Cysteine,
DTC = ammonium pyrrolidinedithiocarbamate)
Scavenger
Pd (ppm)
Zn (ppm)
DARCO G-60
NH4OH
NAC
620
140
280
31
<25
910
850
1550
1240
47
DTC
EDTA
230
46
EDA
At the outset of this work it was found that the use of
condensation reactions for the direct synthesis of 2-substituted
quinazolin-4(3H)-ones such as 10 typically employed harsh
reaction conditions or utilized starting materials such as
aldehydes that produce the 2,3-dihydroquinazolin-4(1H)-ones,
which then require subsequent oxidation of the aminal to
deliver the desired quinazolin-4(3H)-one.12 Therefore, we
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1
2
3
4
5
6
7
8
9
N
O-DBUH
N
O
N
P
DBU
N
N
O
S
O
PyBrop
ACN, 23 °C
Br
10
N
N
O
S
O
ACN, 23 °C
H
N
N
N
H
N
N
OH
H2N
N
N
N
N
6
N
+
+
O
O
N
O
S
O
S
N
N
N
H
H
N
10
11
12
13
14
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60
N
Figure 5. Impact of Temperature on Imidate (13) Formation
15
16
Figure 6. SnAr Reaction Pathway and Impurities
As expected, the conversion of the imidate (13) to the
amidine (14) is dependent on the concentration of ammonium
chloride.16 Furthermore, increasing ammonium chloride
concentration resulted in quicker reaction times which also
suppressed the formation of a dimer resulting from reaction of
the amidine product with the starting imidate. Based on this
data, the concentration of the amidine formation sequence was
reduced to from 15 to 7 vol, which resulted in high conversion
with only 1.25 equivalents of ammonium chloride. With these
optimized conditions for the formation of the amidine (14), the
target condensation reaction was explored.
During our development of the condensation between the
amidine (14) and isatoic anhydride (11) it was found that the
reaction occurred spontaneously and was typically complete
within minutes of heating to 60 °C as evidenced by the
liberation of CO2. This condensation tolerated numerous
solvents such as acetonitrile and t-AmOH although the reaction
gave the best performance in THF, likely due to the lower
solubility of ammonium chloride in this solvent, which
prevented the liberated ammonium chloride from intercepting
the incoming isatoic anhydride to give anthranilamide.
Therefore, the process was performed by swapping the solvent
of the incoming amidine methanol solution to THF, adding the
isotoic anhydride, then heating to 65 °C to obtain a homogenous
solution. At this stage THF was also beneficial as a direct drop
crystallization could be performed by simply adding water. The
development of this telescoped Niementowski-type
condensation reaction afforded the desired quinazolinone 10 in
90% yield with 99.2 AP purity on 30 kg scale under mild
reaction conditions directly from aryl nitrile 9 using only 10
mol % sodium methoxide and 1.25 equivalents of ammonium
chloride as reagents.
The DBU impurity (16), however, could be observed at
levels upwards of 10 AP after holding the activated
intermediate for 3 hours with 1.5 equiv of DBU (Figure 7). This
was a critical issue as the length of this hold time could vary
during processing. To solve this issue a DoE (design of
experiments) study was conducted that examined DBU
equivalents, reaction concentration and temperature as a
function of time. The study showed that by lowering the charge
of DBU to 1.15 equiv, decreasing the reaction concentration
from 10 vol to 20 vol, and reducing the reaction temperature
from 23 °C to 10 °C, the desired SnAr was favored while the
DBU impurity was decreased to observed levels of < 2 AP,
even after holding the activated intermediate stream for 24 h.18
Under these optimized conditions, the crystallization was
performed by simply adding water to afford the isolated product
×
in 99.5 AP in 88% average yield on 2
17 kg scale.
Figure 7. Impact on DBU Charge on the Formation of the DBU
Impurity
The next step in the route is the installation of the picolyl
amine through an SnAr reaction to yield 6. It was found that
bromotripyrrolidinophosphonium
hexafluorophosphate
Extensive high throughput screening was completed on the
C-H activation of 6, with several interesting trends being
observed.19 Ligands (phosphines, pyridines, phosphites) as well
as coordinating solvents (DMF, DMAc, NMP) completely shut
down the reaction. Iodobenzene was the only effective arene
source as both bromobenzene and phenyl triflate were
unreactive under an array of conditions.
The optimized conditions reduced the amount of
iodobenzene to 12 equivalents (~3 vol) and utilized anisole (5
vol) as a co-solvent. Anisole is an effect co-solvent as it allows
for the needed solubility at the reaction temperature of 120 °C.
CsOPiv is formed in-situ via the reaction of Cs2CO3 and pivalic
acid.
(PyBrop) and DBU were effective reagents at activating the
quinazolinone for nucleophilic substitution.17 The DBU was
required to solubilize the remarkably insoluble quinazolinone
10 and was also found to produce consistent kinetics and
reliable reactivity. However, the challenges to this system were
the impurities associated with the addition of the DBU base (16)
and the residual pyrrolidine derived from the PyBrop reagent
(15), presumably from the reaction of these two amines with the
activated quinazoline intermediate (Figure 6). The pyrrolidine
impurity could be controlled through the procurement of high
quality PyBrop (> 99%), which resulted in the observation of <
5 AP of this impurity during the process.
The C-H Activation is not sensitive to oxygen as it is
believed to proceed through a Pd(II)/Pd(IV) cycle.20 However,
inertion is important to minimize the formation of one key
impurity, the dimer of the product (Figure 8). Formation of a
radical at the benzylic position will result in dimerization,
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which is observed as a pair of diastereomers. The formation is been reported as a directing groups in C-H activations catalyzed
by palladium, copper, and ruthenium.23 However, a recent
report on the C(sp3)-H activation of tertiary aldehydes with
transient imine directing groups showed the use of 2-
picolylamine as ineffective because of direct complexation with
Pd.24 Therefore, we sought to investigate the generality of the
C-H activation developed in the route to BMS-919373.
The standard reaction conditions were subjected to an
array of iodoarenes. Eight substrates performed well, with >90
AP product at the end of the reaction (Table 2). However,
challenging isolations of the products resulted in lowered
yields. Halo-containing iodoarenes were good substrates for the
reaction as 3,5-dichloro-, 3-bromo-, and 4-fluoro- substituted
arenes afforded the desired product in moderate to good yield
(entries 1-3). No conversion of the aryl bromide or chloride was
observed in the reaction conditions. Tolyl- and methoxy-
substituents on the arene did not impact the reaction as complete
conversion was observed with yields around 70% (entries 4-6).
Larger (hetero)arenes such as indole and naphthalene are also
effective in the transformation as the products were obtained in
high yield (entries 7-8).
1
2
3
4
5
6
7
8
believed to occur via a single electron mechanism as the
addition of BHT results in BHT incorporation into the product.
The formation of these diastereomers can be decreased from
~3AP to <1 AP by properly degassing the solvents and
headspace.
N
NH
N
S
O
O
N
N
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NH
N
N
HN
O
S
O
N
HN
N
17
Figure 8. Impurities in the C-H Activation
Because the product of the C-H activation has limited
solubility (<10 mg/ml in MeOH, acetone, DMSO, EtOAc,
MeTHF, DCM), a phase split is not possible as the molecule
only has appreciable solubility in one solvent (70 mg/ml in
NMP). The addition of an anti-solvent to the
anisole/iodobenzene mixture does not increase the amount of
desaturation, and therefore, we took advantage of the
insolubility by cooling the reaction mixture to 0 °C and filtering
off the product. The cake was washed with IPA/H2O to remove
CsI, and recrystallized from DMAc/H2O to afford the product
in ~76% average yield and >99 AP. Pd complexation to the
product was removed by addition of ethylene diamine21 during
the recrystallization. The amount of Pd observed in the isolated
product was <20 ppm.
The final step in the route is an acid mediated deprotection
to yield the free sulfonamide. The API was isolated in 92%
yield and >99 AP as a white crystalline solid. The only key
impurity from the API step was tert-butyl incorporation onto
the pyridine ring, which was controlled through the
crystallization to <0.02 AP (Figure 9). An optional
recrystallization of the product further improved the purity to
~99.9 AP.
Table 2. Scope of the C-H Activation with (Hetero)Aryl
Iodides
N
N
HN
Ar HN
Pd(OAc)2 (5 mol %)
CsOPiv (1.0 equiv)
(Hetero)ArI (12 equiv)
O
O
O
O
S
S
N
N
N
N
H
H
Anisole (5 vol)
120 °C
N
N
6
19a-19h
entry
product
Cl
entry
product
Cl
Br
N
N
N
HN
N
HN
N
1
2
N
O
S
O
NH
NH
S
N
O
O
N
19a, 46% (90 AP)
19b, 71% (90 AP)a
F
OMe
N
N
N
HN
HN
N
3
4
N
N
O
S
O
S
NH
NH
N
N
O
O
N
HN
N
19c, 81% (90 AP)
19d, 73% (94 AP)
O
O
Me
Me
S
N
NH2
N
HN
N
N
HN
Cl
5
6
N
18
O
S
NH
N
O
S
NH
N
O
N
O
Figure 9. Tert-Butyl Incorporated Impurity from API Step
N
N
19e, 70% (98 AP)
NH
19f, 66% (95 AP)
The six-step overall route to BMS-919373 proceeded in
27% yield and an overall PMI22 of 407.3. No route related
impurities were present in the API above detectable limits.
N
N
HN
N
HN
7
8
N
GENERALITY OF THE C-H ACTIVATION
O
S
N
O
S
NH
NH
N
O
O
The direct arylation optimized in this route takes advantage
of the unique nature of the molecule, allowing us to install the
arene late in the synthesis and to start from commodity
chemicals. To the best of our knowledge, picolinamides have
N
N
19g, 77% (99 AP)a
a10 mol % Pd(OAc)2
19h, 86% (95 AP)b
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The Journal of Organic Chemistry
Sterically hindered iodides such as 2-iodotoluene and 1-
shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, m
= multiplet, br = broad), coupling constant J (Hz), and
integration. Analytical thin-layer chromatography (TLC) was
performed on TLC silica gel plates (0.25 mm) precoated with a
fluorescent indicator. Visualization of the TLC plates was
effected with ultraviolet light. Standard flash chromatography
procedures were followed using 100-200 mesh silica gel.
HRMS samples were run on the Thermo LTQ-Orbitrap with
Acquity Classic inlet. Note: A representative lab procedure for
each step in the route to BMS-919373 is shown below. The
yields may vary slightly from those observed from the on-scale
batch execution.
1
2
3
iodonapthalene were unsuccessful substrates as only starting
material was observed. 4-iodopyridine was not stable at the
reaction temperature.
To demonstrate that the 2-picolylamine directing group
was not specific to the case of BMS-919373, an array of
bicyclic aromatic compounds were prepared and subjected to
the general C-H activation conditions (Table 3). Other
quinazoline cores, such as those substituted by phenyl and
methyl, are good substrates for the C-H activation, affording the
products in yields of 76 and 52% (entries 1-2). Naphthalene is
a suitable substrate for the catalysis as the arylated product was
obtained in good yield (entry 3). Interestingly, a major by-
product in the reaction with the naphthalene substrate was the
removal of the picolyl group after direct arylation to yield the
free amine. 4-Aminoquinoline was unreactive under the
standard reaction conditions; however, a trifluoromethyl
substituted quinoline afforded the arylated product in good
yield (entry 4).
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Preparation
of
5-bromo-N-tert-butylpyridine-3-
sulfonamide (4). A clean 500 mL reactor was purged with
nitrogen for 1 h and charged with i-PrMgCl-LiCl complex (1.3
M in THF, 195 mL, 253 mmol, 1.5 eq). The solution was cooled
to –13 °C. 3,5-dibromopyridine (40g, 168.8 mmol) was
dissolved in THF (320 mL, 8 vol). The substrate solution was
added dropwise to the Grignard solution, maintaining the
temperature was below –8 °C. After the addition, the mixture
was allowed to stir for 10 mins, at which point HPLC analysis
indicated complete consumption of the starting material. A
separate, clean 1 L reactor was purged with nitrogen for 1 hour
and charged with DCM (100 mL, 2.5 vol) and sulfuryl chloride
(20.5 mL, 1.5 eq). The DCM solution was cooled to –16 °C.
The pre-generated arylmagnesium chloride was transferred to
sulfuryl chloride solution by cannula; maintaining the
temperature below –9 °C. After the addition, the mixture was
allowed to stir for 20 min. tert-Butylamine (71 mL, 4 eq) was
added dropwise; maintaining the temperature below –5 °C.
After the addition, the mixture was allowed to stir for 12 h. The
reaction was quenched by the addition of 2M HCl (5 vol, 200
mL) at –10 °C followed by the addition of DCM (5 vol, 200
mL). The layers were partitioned and organic layer was
collected. The aqueous layer was back-extracted with DCM (5
vol, 200 mL) and partitioned. The combined organic layer was
transferred to the 1 L reactor, and the solvent was distilled at 50
°C (jacket temperature) under house vac, from ~1100 mL (28
vol) to 100 mL (2.5 vol). MeOH (5 vol, 200 mL) was added to
rinse off the solid on the side of the reactor and solvent was
distilled again under same condition to 100 mL (2.5 vol).
MeOH (5 vol, 200 mL) was again added to rinse off the solid
on the side of the reactor and solvent was distilled again under
same condition to 100 mL (2.5 vol). MeOH was added to reach
250 mL and the mixture was heated at 50 °C until it became
homogenous. Water (320 mL, 8 vol) was added while stirring.
The mixture was allowed to cool to rt and stir overnight. The
product was collected by filteration under vacuum. The cake
was washed with 80 mL hexane (2 vol). The solid was allowed
to dry on the filter for 5 hours. The solid was collected and was
dried at 50 °C for 2 hours to yield the product (37.12 g, 70%).
mp 103-105 °C. 1H NMR (500 MHz, d6-DMSO): δ 8.94 (dd, J
= 7.5 Hz, 2.0 Hz, 2H), 8.40-8.38 (m, 1H), 7.88 (s, 1H), 1.12 (s,
9H); 13C{1H} NMR (125.8 MHz, d6-DMSO): δ 153.3, 145.2,
141.8, 136.2, 120.2, 54.0, 29.7; IR (neat) 3280, 3067, 3060,
1564, 1318, 1147, 689 cm-1; HRMS (ESI-TOF) m/z: 292.9954
calcd for C9H14BrN2O2S [M+H]+, found 292.9949.
Table 3. Scope of the Heterocycles in the Direct Arylation
N
N
HN
Ph HN
Pd(OAc)2 (5 mol %)
CsOPiv (1.0 equiv)
PhI (12 equiv)
X
X
X
X
R
X
X
R
Anisole (5 vol)
120 °C
X = N, C
R = H, Me, Ph
20a-20e
entry
product
entry
product
N
HN
N
N
HN
N
1
2
N
N
Me
20b, 42% (84 AP)a
20a, 76% (82 AP)
N
N
HN
HN
3
4
N
CF3
20c, 44% (55 AP)b
20d, 49% (62 AP)
bPhI (24 equiv) b10 mol % Pd(OAc)2, 1.5 equiv CsOAc, PhI (24 equiv)
CONCLUSION
In summary, we have demonstrated an innovative, eco-
nomical, and efficient synthesis of BMS-919373 enabled by the
identification and implementation of a late stage palladium-
catalyzed C-H arylation directed by picolyl amine. The novel,
six-step route from isatoic anhydride led to significant
improvements in overall sustainability and a 50 fold decrease
in starting material cost over previous routes. The scope and
generality of the pivotal C-H transformation was investigated
using an array of iodoarenes, as well as a variety of heterocyclic
partners.
Preparation
of
N-(tert-butyl)-5-cyanopyridine-3-
EXPERIMENTAL
sulfonamide (9). N,N-Dimethylacetamide (100 mL, 5 L/kg)
was charged to a reactor, where it was sparged with N2 for at
least 15 minutes. 4 (20.0 g, 68.25 mmoles, LR), Zinc cyanide
General Considerations. All reagents were purchased
from commercial sources. Standard benchtop techniques were
employed for handling air-sensitive reagents. Melting points
(°C) are uncorrected. NMR spectra were recorded on a 400 or
500 MHz spectrometer. Data are presented as follows: chemical
(5.31
g,
44.36
mmol,
0.65
equiv),
Tris(dibenzylideneacetone)dipalladium (0.329 g, 0.35 mmol,
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0.005 equiv), XantPhos (0.407 g, 0.69 mmol, 0.01 equiv) were DMSO): δ 12.94 (s, 1H), 9.45 (s, 1H), 9.15 (s, 1H), 8.90 (s, 1H),
1
2
3
4
5
6
7
8
successively charged to the reactor with agitation under a
nitrogen atmosphere. The reaction mixture was heated to 85 °C.
After 4 hr of reaction at 85 °C, a sample was pulled from the
reaction mixture and analyzed for reaction completion. The
reaction mixture was cooled to 0 °C. Ethylenediamine (3.98 g,
66.22 mmol, 0.97 equiv) was added slowly, maintaining a batch
temperature below 15 °C. The reaction mixture stirred for 10
minutes. Ethyl acetate (200 mL, 10 L/kg) was added, stirred for
10 minutes, and the reaction was allowed to warm to 20-25 °C.
15 wt% NaCl in water (200 mL, 10 L/kg) was charged to the
agitated reaction mixture and stirred for 5 min (avoiding high
agitation rates to prevent an emulsion). The agitation was
stopped, the layers separated and split. Water (200 mL, 10 L/kg)
was charged to the agitated reaction mixture and stirred for 5
min. The agitation was stopped, the layers separated and split.
The organic stream was filtered through a 5 µm filter and
recharged to the reactor. The organic stream was concentrated
to 100 mL (5 L/kg) at Tj = 80 °C under 200 torr vacuum (Tr =
42 °C). Note: the maximum jacket temperature should be
limited to 80 °C and the maximum batch temperature to 60 °C.
Isopropanol (200 mL (10 L/kg) was then introduced through a
constant volume distillation with a Tj = 80 °C and a vacuum of
200 torr. The Tr increased to ~50 °C as the solvent swap
proceeded. The product began crystallizing during the solvent
swap. The organic stream was concentrated to 80 mL (4 L/kg)
at Tj = 80 °C under 200 torr vacuum (Tr ~ 50°C). With a Tr =
50 °C, water (180 mL, 9 L/kg) was added dropwise over ~ 2
hours, resulting in further crystallization of the product. After
the addition of water was complete, the mixture was slowly
cooled to 20-25 °C over the course of several hours, where it
was aged for 6 hours. The resultant solid was filtered and
washed with 1:3 IPA/water (60 mL, 3 L/kg). The cake was
washed a second time with 1:3 IPA/water (60 mL, 3 vol). The
solid was dried in a vacuum oven at 60 °C for 16 h to yield the
product as a white solid (14.35g, 91% yield). mp 122-124 °C.
1H NMR (500 MHz, d6-DMSO): δ 9.22 (dd, J = 9.8 Hz, 1.7 H,
2H), 8.69 (t, J = 2.0 Hz, 1H), 7.96 (s, 1H), 1.13 (s, 9H); 13C{1H}
NMR (125.8 MHz, d6-DMSO): δ 115.0, 150.1, 140.6, 131.7,
115.8, 109.7, 54.2, 29.7; IR (neat) 3291, 3072, 2238, 1984,
1556, 1316, 1147, 694 cm-1; HRMS (ESI-TOF) m/z: 240.0801
calcd for C10H14N3O2S [M+H]+, found 240.0791.
8.18 (d, J = 7.6 Hz, 1H), 7.95 (s, 1H), 7.87 (t, J = 7.3 Hz, 1H),
7.82-7.77 (m, 1H), 7.57 (t, J = 7.3 Hz, 1H), 1.16 (s, 9H);
13C{1H} NMR (125.8 MHz, d6-DMSO): δ 162.5, 151.7, 150.2,
149.4, 148.8, 141.0, 135.2, 133.9, 129.6, 128.1, 127.7, 126.4,
121.8, 54.5, 30.3; IR 3189, 3144, 3070, 2967, 1679, 1600, 1143,
778 (neat) cm-1; HRMS (ESI-TOF) m/z: 359.1172 calcd for
C17H19N4O3S [M+H]+, found 359.1166.
Preparation
of
N-(tert-butyl)-5-(4-((pyridin-2-
ylmethyl)amino)quinolin-2-yl)pyridine-3-sulfonamide (6). To
a 1 L reactor was charged with a slurry of 10 (20.0 g, 55.8
mmol) in acetonitrile (20.0 mL/g, 7630 mmol) at 30 °C. The
white slurry was treated with 1,8-diazabicyclo[5.4.0]undec-7-
ene (1.15 equiv, 64.2 mmol) and stirred for 10 min as the slurry
went into solution. The yellow solution was cooled to 12 °C.
Pybrop (1.1 equiv, 61.4 mmol) was added to the reactor
followed by 2-(aminomethyl)pyridine (12.45 g, 114.0 mmol).
The reactor stirred overnight at 10 °C, at which time HPLC
indicated complete conversion. The stream was heated to 70 °C
and water (400 mL, 20 vol) was then added dropwise over 40
min, resulting in crystallization of the product. The slurry was
held at 60 °C for 3 h and then ramped to 20 °C over 3 h. The
slurry was isolated by filtration, and the cake was washed with
1:1 ACN/water (80 mL, 4 vol) and ACN (80 mL, 4 vol). The
wet cake was dried overnight in a vacuum oven at 50 °C. The
crude product was recrystallized from 5:1:3 THF/MeOH/Water
vol/vol/vol at 60 °C to provide the product as an off-white solid
(23.04g, 88% yield). mp 191-193 °C. 1H NMR (500 MHz, d6-
DMSO): δ 9.61 (d, J = 1.5 Hz, 1H), 9.26-9.20 (m, 1H), 9.09-
9.06 (m, 2H), 8.54 (d, J = 4.9 Hz, 1H), 8.40 (d, J = 8.2 Hz, 1H),
7.93 (s, 1H), 7.85-7.79 (m, 2H), 7.73-7.68 (m, 1H), 7.60-7.55
(m, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.25-7.21 (m, 1H), 5.01 (d, J
= 5.5 Hz, 2H), 1.12 (s, 9H); 13C{1H} NMR (125.8 MHz, d6-
DMSO): δ 160.3, 159.1, 156.8, 152.1, 150.0, 149.4, 148.4,
140.9, 137.1, 134.5, 133.7, 133.2, 128.4, 126.8, 123.4, 122.6,
121.8, 114.7, 54.3, 46.6, 30.3; IR (neat) 3258, 3064, 2975,
1582, 1368, 1152, 760 cm-1; HRMS (ESI-TOF) m/z: 449.1754
calcd for C23H25N6O2S [M+H]+, found 449.1763.
Preparation of N-(tert-butyl)-5-(5-phenyl-4-((pyridin-2-
ylmethyl)amino)quinazolin-2-yl)pyridine-3-sulfonamide (8).
To a 250 mL reactor was added iodobenzene (220.2 g, 1058
mmol), and anisole (202.5 g, 1870 mmol) which was degassed
by bubbling N2 for 30 minutes. Then 6 (40.17 g, 85.98 mmol),
Cesium Carbonate (14.24 g, 43.70 mmol), Pivalic Acid (9.3 g,
90 mmol,), and Palladium(II) Acetate (963.5 mg, 4.29 mmol)
were added, and the reaction was heated to 120 °C under N2 for
6 h, at which time complete conversion was observed by HPLC.
After cooling to 0 °C, the solids were collected by vacuum
filtration. The reactor was rinsed with anisole (120 mL), which
was then used to watch the cake. The reactor was then rinsed
with 1:1 IPA/H2O (120 mL), which was then used to wash cake,
twice. The solids were dried by vacuum filtration for 30 min.
To a clean 250 mL reactor, N,N-Dimethylacetamide (280 mL)
was added followed by the crude solid. Ethylenediamine (1.44
mL, 0.25 equiv) was then added, and the batch heated to 80 °C
with stirring. After 30 min, water (10 mL) was added. The
reactor was then cooled 60 °C and aged for 1 h. Water (30 mL)
was then added dropwise. The batch slowly cooled to rt and
aged overnight. The solids were collected by vacuum filtration,
where they were subsequently washed with 7:1 DMAc/H2O
(120 mL) and water (120 mL). The product was dried by
vacuum filtration at 65 °C to yield a white solid (34.7g, 78%
yield). mp 226-228 °C. 1H NMR (500 MHz, d7-DMF): δ 9.87
(d, J = 1.8 Hz, 1H), 9.33 (t, J = 2.1 Hz, 1H), 9.18 (d, J = 2.4 Hz,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Preparation
of
N-(tert-butyl)-5-(4-oxo-3,4-
dihydroquinazolin-2-yl)pyridine-3-sulfonamide (10). To a 1 L
reactor was charged methanol (297 g, 375 mL, 15 vol) followed
by 9 (25.0 g, 104.5 mmol), which was stirred at 25 °C for no
less than 1 h. The stream was then distilled 6 vol under vacuum
(200 torr with Tj = 60 °C). MeOH (1 vol) was then charged to
the reactor. 25 wt% Sodium methoxide in methanol solution
(2.2 g, 10.5 mmol) was added, and the reaction stirred at 25 °C
for 8 h. The reactor was then cooled to 0 °C for no less than 12
h. Ammonium chloride (6.8 g, 130.6 mmol) was then added at
0 °C and stirred for 1 h before heating to 45 °C for 8 h. The
solvent was swapped to THF by constant volume vacuum
distillation (250 torr with 50 °C jacket, requiring 30 vol of
THF). Isatoic anhydride (17.3 g, 104.5 mmol) was then added
at 25 °C, and the reactor heated to 65 °C for 6 h. Water (82.5
mL, 3.3 vol) was then added at 60 °C over 30 min. After aging
the slurry for 4 h at 60 °C, it was slowly cooled to 23 °C over 4
h and aged no less than 12 h. The product was isolated by
vacuum filtrated, washed with 75% THF/water (5 vol) and THF
(5 vol). The cake was dried under full vacuum at 60 °C for no
less than 12 h to yield the product as a light yellow solid
1
(32.58g, 87% yield). mp >250 °C. H NMR (500 MHz, d6-
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1H), 8.32 (d, J = 4.6 Hz, 1H), 7.97-7.95 (m, 1H), 7.92-7.86 (m, (3) For 19f and 19g, water (10 mL) was added, which
1
2
3
4
5
6
7
8
2H), 7.79-7.75 (m, 1H), 7.64-7.59 (m, 5H), 7.41-7.36 (m, 2H),
7.28-7.25 (m, 1H), 7.06-7.04 (m, 1H), 4.85 (d, J = 4.3 Hz, 2H),
1.28 (s, 9H); 13C{1H} NMR (125.8 MHz, d7-DMF): δ 159.8,
156.8, 156.2, 152.3, 151.7, 148.8, 148.6, 141.4, 140.6, 139.7,
137.0, 134.6, 133.5, 132.4, 129.9, 129.7, 129.5, 129.8, 128.5,
122.4, 121.9, 112.4, 54.4, 46.7; IR (neat) 3368, 3297, 2975,
1517, 1322, 1137, 752, 667 cm-1; HRMS (ESI) m/z: 525.2067
calcd for C29H29N6O2S [M+H]+, found 525.2080.
resulted in a phase split. The aqueous was discarded.
The organic layer was concentrated en vacuo to ~2-3
vol and passed through a SiO2 plug eluting with
EtOAc and then MeOH to separate the aryl iodide and
the product. The MeOH solution was concentrated to
a solid and recrystallized from 7:1 DMAc/H2O.
Preparation of N-(tert-butyl)-5-(5-(3,5-dichlorophenyl)-4-
((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridine-3-
sulfonamide (19a). The title compound was obtained as an off-
Preparation
of
5-(5-phenyl-4-((pyridin-2-
9
1
ylmethyl)amino)quinolin-2-yl)pyridine-3-sulfonamide (1). To
a 250 mL reactor was added concentrated HCl (30 mL, 1.5 vol)
followed by 8 (20g) in five portions. Concentrated HCl (20 mL,
1 vol) and water (10 mL, 0.5 vol) were then added. The mixture
was allowed to age for 1 h to ensure dissolution, which was then
polish filtered. The reactor was then heated to 80 °C for 3 h, at
which time HPLC showed complete conversion. After cooling
to 45 °C, The batch was diluted with water (60 mL, 3 vol)
followed by 5M KOH (100 mL, 5 vol), maintaining the
temperature below 60 °C. Ethanol (280 mL, 14 vol) was then
added. 5 M KOH (30 mL, 1.5 vol) is then added at 45 °C,
resulting in crystallization of the product. 2.5 M K2CO3 (10 mL,
0.5 equiv) is then added to reach a pH of 7. The batch is then
cooled to 20 °C over 2 h and aged 1 h. The solids are collected
by vacuum filtration and washed with 60/40 ethanol/water (3
vol) followed by water (3x2.25 vol) and ethanol (3 vol). The
product is dried under vacuum at 45 °C to afford the product as
white solid in 46% yield (1.22 g). mp 221-223 °C. H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(500 MHz, d7-DMF): δ 9.89 (s, 1H), 9.34 (s, 1H), 9.19 (s, 1H),
8.40 (d, J = 4.6 Hz, 1H), 8.00-7.97 (m, 1H), 7.93-7.81 (m, 4H),
7.73 (s, 2H), 7.50 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 7.0 Hz, 1H),
7.36-7.32 (m, 1H), 7.20 (s, 1H), 4.92 (d, J = 3.7 Hz, 2H), 1.28
(s, 9H); 13C{1H} NMR (125.8 MHz, d7-DMF): δ 159.1, 156.8,
155.7, 152.2, 151.4, 148.5, 148.4, 143.7, 141.1, 137.0, 136.3,
135.3, 134.3, 133.3, 132.2, 129.7, 129.1, 128.4, 128.4, 122.4,
122.0, 112.0, 54.2, 46.3; IR (neat) 3356, 3062, 2979, 1575,
1519, 1331, 1143, 998, 801 cm-1; HRMS (ESI) m/z: 593.1288
calcd for C29H27Cl2N6O2S [M+H]+, found 593.1268.
Preparation
of
5-(5-(3-bromophenyl)-4-((pyridin-2-
ylmethyl)amino)quinazolin-2-yl)-N-(tert-butyl)pyridine-3-
sulfonamide (19b). The title compound was obtained as an off-
1
white solid in 71% yield (1.91 g). mp 186-188 °C. H NMR
(500 MHz, d7-DMF): δ 9.89 (s, 1H), 9.34 (s, 1H), 9.20 (s, 1H),
8.36 (d, J = 4.3 Hz, 1H), 7.98-7.95 (m, 1H), 7.91-7.77 (m, 4H),
7.61-7.55 (m, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 7.0 Hz,
1H), 7.32-7.28 (m, 1H), 7.17-7.14 (m, 1H), 4.93-4.81 (m, 2H),
1.29 (s, 9H); 13C{1H} NMR (125.8 MHz, d7-DMF): δ 159.2,
156.7, 155.7, 152.1, 151.4, 148.5, 148.4, 142.6, 141.1, 137.7,
136.9, 134.3, 133.3, 132.2, 132.2, 131.6, 131.2, 129.7, 128.7,
128.7, 122.8, 122.3, 121.8, 112.1, 54.2, 46.4; IR (neat) 3323,
3297, 3260, 2979, 1581, 1545, 1528, 1324, 1141, 743 cm-1;
HRMS (ESI) m/z: 603.1172 calcd for C29H28BrN6O2S [M+H]+,
found 603.1151.
1
a white solid (14.58g, 82% yield). mp 203-205 °C. H NMR
(500 MHz, d6-DMSO): δ 9.79 (d, J = 1.8 Hz, 1H), 9.17 (t, J =
2.1 Hz, 1H), 9.10 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 4.6 Hz, 1H),
7.91-7.88 (m, 1H), 7.85-7.75 (m, 3H), 7.72-7.69 (m, 1H), 7.57-
7.48 (m, 5H), 7.30 (t, J = 8.1 Hz, 2H), 7.22 (dd, J = 7.2 Hz, 5.3
Hz, 1H), 6.93 (s, 1H), 4.73 (d, J = 4.0 Hz, 2H); 13C{1H} NMR
(125.8 MHz, d6-DMSO): δ 158.9, 156.0, 155.2, 151.8, 150.7,
148.1, 147.5, 140.1, 139.7, 138.9, 136.6, 133.7, 132.3, 132.1,
129.3, 129.0, 129.0, 128.3, 127.8, 122.1, 121.5, 111.6, 46.0; IR
(neat) 3362, 3342, 3049, 1525, 1355, 1162, 739 cm-1; HRMS
(ESI) m/z: 469.1441 calcd for C25H21N6O2S [M+H]+, found
469.1431.
Preparation of N-(tert-butyl)-5-(5-(4-fluorophenyl)-4-
((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridine-3-
sulfonamide (19c). The title compound was obtained as a white
1
General Procedure for the C-H Activation with
(Hetero)Aryl Iodides: To a 40 mL scintillation vial with stir bar
solid in 81% yield (1.96 g). mp 190-192 °C. H NMR (500
MHz, d7-DMF): δ 9.89 (s, 1H), 9.34 (s, 1H), 9.19 (s, 1H), 8.32
(d, J = 4.6 Hz, 1H), 7.96-7.92 (m, 1H), 7.90-7.85 (m, 2H), 7.81-
7.77 (m, 1H), 7.67-7.63 (m, 2H), 7.45-7.40 (m, 3H), 7.37-7.34
(m, 1H), 7.33-7.28 (m, 1H), 7.12 (s, 1H), 4.85 (d, J = 3.4 Hz,
2H), 1.29 (s, 9H); 13C{1H} NMR (125.8 MHz, d7-DMF): δ
163.3 (d, J = 245 Hz), 159.5, 156.8, 155.9, 152.3, 151.6, 148.5
(d, J = 20 Hz), 141.3, 138.5, 137.0, 136.8 (d, J = 4 Hz), 134.5,
133.4, 132.3, 131.9, 131.8, 130.0, 128.5, 122.5, 122.1, 116.2 (d,
J = 21 Hz), 112.4, 54.4, 46.5; IR (neat) 3366, 3297, 2975, 1515,
1137, 752, 665 cm-1; HRMS (ESI) m/z: 543.1973 calcd for
C29H28FN6O2S [M+H]+, found 543.1955.
was
added
N-(tert-butyl)-5-(4-((pyridin-2-
ylmethyl)amino)quinazolin-2-yl)pyridine-3-sulfonamide (9)
(2.0g, 4.47 mmol), Pd(OAc)2 (0.05 equiv), cesium pivalate (1
equiv to 1.5 equiv), (hetero)aryliodide (12 equiv), and anisole
(10 mL). The vial was capped with a pressure relief septa. The
reaction mixture was heated to 120 °C until complete
conversion was observed, as judged by UPLC-MS (~16 h).
Products were isolated by one of the following procedures.
Note that some 1H NMR show residual DMAc from the
recrystallization, which was presumably trapped during the
crystallization and not removed by the water wash. The yields
have been accounted for this residual solvent.
Preparation of N-(tert-butyl)-5-(5-(4-methoxyphenyl)-4-
((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridine-3-
sulfonamide (19d). The title compound was obtained as a white
(1) For 19a, 19b, 19c, water (10 mL) was added, which
resulted in crystallization of the product. The crude
product was filtered, washed with 1:1 IPA/H2O (10
mL), and recrystallized from 7:1 DMAc/H2O.
(2) For 19d, 19e, and 19h, water (10 mL) was added,
which resulted in a phase split. The aqueous was
discarded. The organic layer was concentrated en
vacuo to ~2-3 vol. Hexane (10 mL) was added to
crystalline the product. The crude product was
filtered, washed with 1:1 IPA/H2O (10 mL), and
recrystallized from 7:1 DMAc/H2O.
1
solid in 73% yield (1.81 g). mp 162-164 °C. H NMR (500
MHz, d7-DMF): δ 9.87 (s, 1H), 9.33 (s, 1H), 9.19 (s, 1H), 8.31
(d, J = 4.3 Hz, 1H), 7.93-7.89 (m, 1H), 7.88-7.83 (m, 2H), 7.81-
7.75 (m, 1H), 7.49 (d, J = 7.9 Hz, 2H), 7.41 (d, J = 7.6 Hz, 1H),
7.34 (d, J = 7.0 Hz, 1H), 7.31-7.26 (m, 1H), 7.18-7.10 (m, 3H),
4.84 (d, J = 3.7 Hz, 1H), 3.92 (s, 3H), 1.29 (s, 9H); 13C{1H}
NMR (125.8 MHz, d7-DMF): δ 160.3, 159.8, 156.7, 156.2,
152.3, 151.6, 148.6, 148.5, 141.3, 139.5, 136.9, 145.6, 133.4,
132.5, 132.3, 130.9, 129.9, 128.1, 122.5, 122.0, 114.8, 112.5.
55.3, 54.4, 46.7; IR (neat) 3347, 3271, 2977, 2837, 1578, 1526,
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Page 10 of 12
1149, 987, 742, 663 cm-1; HRMS (ESI) m/z: 555.2173 calcd for
C30H31N6O3S [M+H]+, found 555.2157.
Preparation of N-(tert-butyl)-5-(4-((pyridin-2-
stir bar was added the corresponding heterocycle (1 mmol),
1
2
3
4
5
6
7
8
Pd(OAc)2 (0.05 equiv), cesium pivalate (1 equiv to 1.5 equiv),
(hetero)aryliodide (12 equiv), and anisole (10 mL). The vial
was capped with a pressure relief septa. The reaction mixture
was heated to 120 °C until complete conversion was observed,
as judged by UPLC-MS (~16 h). An aqueous wash, water (4
mL) was performed. The reactions were concentrated en vacuo
and purified by column chromatography using DCM/MeOH.
ylmethyl)amino)-5-(m-tolyl)quinazolin-2-yl)pyridine-3-
sulfonamide (19e). The title compound was obtained as a white
1
solid in 70% yield (1.68 g). mp 150-152 °C. H NMR (500
MHz, d7-DMF): δ 9.88 (s, 1H), 9.34 (s, 1H), 9.19 (s, 1H), 8.34
(d, 4.3 Hz, 1H), 7.96-7.92 (m, 1H), 7.89-7.86 (m, 2H), 7.80-
7.75 (m, 1H), 7.46-7.34 (m, 6H), 7.30-7.26 (m, 1H), 7.02 (s,
1H), 4.90-4.80 (m, 2H), 2.40 (s, 3H), 1.29 (s, 9H); 13C{1H}
NMR (125.8 MHz, d7-DMF): δ 159.7, 156.7, 156.3, 152.3,
151.6, 148.8, 148.6, 141.3, 140.5, 139.8, 139.1, 136.9, 134.6,
133.4, 132.3, 130.2, 129.7, 129.4, 128.3, 126.6, 122.4, 121.9,
112.3, 54.5, 46.7, 20.1; IR (neat) 3306, 3283, 2977, 2863, 1578,
1324, 1139, 740, 665 cm-1; HRMS (ESI) m/z: 539.2224 calcd
for C30H31N6O2S [M+H]+, found 539.2209.
Preparation
of
2,5-diphenyl-N-(pyridin-2-
ylmethyl)quinazolin-4-amine (20a). The title compound was
obtained as a white solid in 76% yield (295 mg). mp 133-135
°C. 1H NMR (400 MHz, CDCl3): δ 8.61 (d, J=7.3 Hz, 2H), 8.30
(d, J=5.0 Hz, 1H), 7.98 (dd, J=8.5, 1.1 Hz, 1H), 7.71 (dd, J=8.3,
7.3 Hz, 1H), 7.60 - 7.47 (m, 9H), 7.24 - 7.11 (m, 3H), 6.55 (br
s, 1H), 4.83 (d, J=4.5 Hz, 2H); 13C{1H} NMR (125.8 MHz,
CDCl3): δ 160.1, 159.4, 156.6, 152.0, 148.6, 140.9, 138.9,
138.7, 136.3, 131.2, 130.0, 129.4, 128.9, 128.4, 128.4, 128.3,
128.2, 128.1, 121.9, 121.4, 112.0, 46.7; IR (neat) 3355, 3336,
3056, 2854, 1519, 830, 767, 748, 711, 687 cm-1; HRMS (ESI-
TOF) m/z: 389.1761 calcd for C26H21N4 [M+H]+, found
389.1767.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Preparation
of
N-(tert-butyl)-5-(4-((pyridin-2-
ylmethyl)amino)-5-(p-tolyl)quinazolin-2-yl)pyridine-3-
sulfonamide (19f). The title compound was obtained as a white
1
solid in 66% yield (1.58 g). mp 171-173 °C. H NMR (500
MHz, d7-DMF): δ 9.89 (s, 1H), 9.34 (s, 1H), 9.20 (s, 1H), 8.35
(d, J = 4.6 Hz, 1H), 7.94-7.91 (m, 1H), 7.89-7.85 (m, 2H), 7.79-
7.75 (m, 1H), 7.45-7.42 (m, 2H), 7.40-7.35 (m, 3H), 7.35-7.32
(m, 1H), 7.30-7.27 (m, 1H), 7.03 (s, 1H), 4.86 (d, J = 3.7 Hz,
2H), 2.46 (s, 3H), 1.30 (s, 9H); 13C{1H} NMR (125.8 MHz, d7-
DMF): δ 159.7, 156.2, 152.3, 151.6, 148.7, 148.5, 141.3, 139.6,
138.4, 137.6, 136.9, 134.6, 133.4, 132.3, 130.0, 129.8, 129.5,
128.2, 122.4, 122.0, 112.4, 54.4, 46.8, 20.9; IR (neat) 3345,
3323, 3303, 2975, 1579, 1530, 1327, 1154, 994, 743, 667 cm-1;
HRMS (ESI) m/z: 539.2224 calcd for C30H31N6O2S [M+H]+,
found 539.2204.
Preparation
of
2-methyl-5-phenyl-N-(pyridin-2-
ylmethyl)quinazolin-4-amine (20b). The title compound was
obtained as a white solid in 42% yield (136 mg). mp 103-105
1
°C. H NMR (400 MHz, CDCl3): δ = 8.12 (d, J=4.8 Hz, 1H),
7.69 (dd, J=8.3, 1.3 Hz, 1H), 7.54 (t, J=7.4 Hz, 1H), 7.45 (t,
J=7.2 Hz, 1H), 7.38-7.29 (m, 6H), 7.21-7.21 (m, 1H), 7.20-7.19
(m, 1H), 7.19 (s, 1H), 7.09-6.97 (m, 3H), 6.48 (br s, 1H), 4.55
(d, J=4.3 Hz, 2H), 2.55 (s, 3H), 2.50 (s, 1H), 2.06 (s, 1H), 1.16
(s, 1H), 0.65-2.13 ppm (m, 1H); 13C{1H} NMR (125.8 MHz,
CDCl3): δ 163.9, 159.1, 156.1, 151.3, 148.5, 140.8, 138.6,
136.3, 131.1, 129.3, 128.8, 128.0, 128.0, 127.2, 121.8, 121.5,
111.2, 46.4, 26.3; IR (neat) 3345, 3059, 2919, 2854, 1521,
1359, 1154, 828, 761, 696 cm-1; HRMS (ESI-TOF) m/z:
327.1604 calcd for C21H19N4 [M+H]+, found 327.1607.
Preparation
of
5-(5-(1H-indol-5-yl)-4-((pyridin-2-
ylmethyl)amino)quinazolin-2-yl)-N-(tert-butyl)pyridine-3-
sulfonamide (19g). The title compound was obtained as a white
solid in 77% yield (1.94 g). mp >250 °C. 1H NMR (500 MHz,
d7-DMF): δ 11.39 (s, 1H), 9.87 (s, 1H), 9.34 (s, 1H), 9.19 (s,
1H), 7.95-7.92 (m, 1H), 7.89-7.84 (m, 2H), 7.78 (s, 1H), 7.68
(d, J = 4.6 Hz, 1H), 7.64-7.58 (m, 3H), 7.42 (d, J = 6.7 Hz, 1H),
7.26-7.21 (m, 3H), 7.11-7.07 (m, 1H), 6.62 (s, 1H), 4.80-4.75
(m, 2H), 1.29 (s, 9H); 13C{1H} NMR (125.8 MHz, d7-DMF): δ
160.0, 156.6, 156.1, 152.3, 151.5, 148.5, 141.4, 141.3, 136.8,
136.6, 134.7, 133.4, 132.1, 131.2, 130.2, 129.0, 127.8, 126.7,
122.7, 122.1, 121.5, 121.1, 112.8, 112.4, 102.2, 54.4, 46.7; IR
(neat) 3414, 3321, 3291, 2979, 1575, 1525, 1327, 1147, 1000,
741 cm-1; HRMS (ESI) m/z: 564.2176 calcd for C31H30N7O2S
[M+H]+, found 564.2153.
Preparation
of
8-phenyl-N-(pyridin-2-
ylmethyl)naphthalen-1-amine (20c). The title compound was
obtained as a light brown oil in 44% yield (136 mg). 1H NMR
(400 MHz, CDCl3): δ 8.72-8.69 (m, 1H), 8.08 (dd, J=8.2, 1.4
Hz, 1H), 7.75-7.80 (m, 3H), 7.56-7.71 (m, 6H), 7.46 (dd, J=7.1,
1.5 Hz, 1H), 7.35 (ddd, J=7.5, 4.9, 1.3 Hz, 1H), 7.26 (d, J=7.8
Hz, 1H), 6.78 (dd, J=7.3, 1.3 Hz, 1H), 5.15 (br s, 1H), 4.67-4.49
(m, 2H); 13C{1H} NMR (125.8 MHz, CDCl3): δ 158.4, 149.0,
144.6, 143.6, 138.1, 136.5, 136.0, 129.4, 128.9, 128.6, 128.2,
127.4, 127.0, 124.6, 121.9, 121.1, 120.9, 117.8, 105.6, 50.1; IR
(neat) 3345, 3055, 3012, 2993, 1519, 1359, 1154, 761, 696 cm-
1; HRMS (ESI-TOF) m/z: 311.1558 calcd for C22H19N2
[M+H]+, found 311.1543.
Preparation of N-(tert-butyl)-5-(5-(naphthalen-2-yl)-4-
((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridine-3-
sulfonamide (19h). The title compound was obtained as a white
Preparation
of
5-phenyl-N-(pyridin-2-ylmethyl)-2-
1
solid in 86% yield (2.21 g). mp 168-170 °C. H NMR (500
(trifluoromethyl)quinolin-4-amine (20d). The title compound
was obtained as an off-white solid in 49% yield (185 mg). mp
141-143 °C. 1H NMR (400 MHz, CDCl3): δ 8.26 (d, J=5.1 Hz,
1H), 8.11 (dd, J=8.5, 1.4 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.58
(t, J=7.4 Hz, 1H), 7.44 (s, 5H), 7.29-7.24 (m, 1H), 7.13 (dd,
J=6.8, 5.1 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 6.68 (s, 1H), 6.32
(br s, 1H), 4.32 ppm (d, J=4.0 Hz, 2H); 13C{1H} NMR (125.8
MHz, CDCl3): δ 154.8, 152.0, 149.0, 148.8, 148.4, 141.2,
138.3, 136.5, 130.3, 129.8, 129.4, 128.8, 128.7, 128.0, 122.3,
122.0 (q, J = 337 Hz),121.3, 116.7, 95.3 (q, J = 4 Hz), 48.3; IR
(neat) 3351, 3064, 3012, 2881, 1587, 1532, 1443, 1288, 1175,
1128, 953, 824, 765 cm-1; HRMS (ESI) m/z: 380.1369 calcd for
C22H17F3N3 [M+H]+, found 380.1380.
MHz, d7-DMF): δ 9.90 (s, 1H), 9.35 (s, 1H), 9.19 (s, 1H), 8.22
(s, 1H), 8.12-8.09 (m, 3H), 8.02-7.99 (m, 1H), 7.97-7.94 (m,
1H), 7.93 (s, 1H), 7.70-7.60 (m, 4H), 7.49 (d, J = 7.0 Hz, 1H),
7.32-7.27 (m, 2H), 7.11-7.08 (m, 1H), 7.01-6.97 (m, 1H), 4.82-
4.78 (d, J = 13.7 Hz, 2H), 1.29 (s, 9H); 13C{1H} NMR (125.8
MHz, d7-DMF): δ 159.5, 156.7, 155.4, 152.1, 151.5, 148.4,
147.8, 141.1, 139.5, 138.1, 136.5, 134.4, 133.9, 133.4, 133.3,
132.2, 129.8, 129.0, 128.5, 128.4, 128.3, 128.1, 127.4, 126.8,
126.7, 121.9, 121.5, 112.3, 54.2, 46.3; IR (neat) 3338, 2975,
1621, 1579, 1525, 1329, 1149, 1007, 745, 665 cm-1; HRMS
(ESI-TOF) m/z: 575.2224 calcd for C33H31N6O2S [M+H]+,
found 575.2199.
General Procedure for the C-H Activation of other
aromatic bicyclic compounds: To an 8 mL scintillation vial with
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The Journal of Organic Chemistry
ASSOCIATED CONTENT
1
M.; Xing, D.; Gupta, A. K.; Gupta, A.; Rampulla, R.;
2
3
4
5
6
7
Mathur, A.; Levesque, P.; Wexler, R. R.; Finlay, H. J.
Selective IKur Inhibitors for the Potential Treatment of
Atrial Fibrillation: Optimization of the Phenyl Quinazoline
Series Leading to Clinical Candidate 5-[5-Phenyl-4-
(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-
sulfonamide. J. Med. Chem. 2017, 60, 3795.
Supporting Information. Optimization data for the cross-
couplings and C-H Activation, characterization data for all
intermediates and API in the final route. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
(7) Reaction sequence: Sandmeyer reaction using 3-
bromoaniline, chloral, and hydroxylamine
8
9
Corresponding Authors
scott.savage@bms.com
(8) (a) Huang, L.; Li, Q.; Wang, C.; Qi, C. Palladium(II)-
Catalyzed Regioselective Arylation of Naphthylamides with
Aryl Iodides Utilizing a Quinolinamide Bidentate System. J.
Org. Chem. 2013, 78, 3030. (b) Nadres, E. T.; Santos, G. I.
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Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
ACKNOWLEDGMENT
Mike Peddicord (BMS) is acknowledged for helping obtain HRMS
data. Robert Wethman, John Wasylyk, and Ming Huang (BMS) are
acknowledged for helping obtain IR data. Neil Strotman and Martin
Eastgate (BMS) are acknowledged for insightful conversation. The
BMS Senior Leadership Team is acknowledged for support of this
manuscript.
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