Integrated cross-coupling strategy for an -carboline-based aurora b kinase inhibitor

Article abstract of DOI:10.1021/jo502489x

An efficient and practical synthetic process for an α-carboline-based Aurora B kinase inhibitor was achieved using an integrated Pd-catalyzed cross-coupling strategy. The process features a mild and efficient method for construction of the α-carboline cor

Full text of DOI:10.1021/jo502489x

Article
pubs.acs.org/joc
Integrated Cross-Coupling Strategy for an α‑Carboline-Based Aurora
B Kinase Inhibitor
Masahiro Mineno,*,† Misayo Sera,† Tsuyoshi Ueda,† Hideya Mizufune,*,† Atsuhiko Zanka,†
Colin O’Bryan,‡ Jason Brown,§ and Nick Scorah§
†Chemical Development Laboratories, CMC Center, Takeda Pharmaceutical Company Limited, 17-85, Juso-honmachi 2-chome,
Yodogawa-ku, Osaka 532-8686, Japan
§
‡Chemical Development Laboratories, CMC Center, and Department of Medicinal Chemistry, Takeda California, Inc., 10410
Science Center Drive, San Diego, California 92121, United States
S
* Supporting Information
ABSTRACT: An efficient and practical synthetic process for an α-carboline-based
Aurora B kinase inhibitor was achieved using an integrated Pd-catalyzed cross-
coupling strategy. The process features a mild and efficient method for construction
of the α-carboline core by employing a Pd-catalyzed sequence of Buchwald−Hartwig
amination and intramolecular direct C−H arylation at the ortho position of an
unsubstituted aniline moiety, which is a key functionality for further derivatization
with a Suzuki coupling via Sandmeyer iodination. The process has eliminated
expensive starting materials and column chromatography purifications and enabled
considerable enhancement of the total yield from 11% to 48%.
a
Scheme 1. Initial Synthetic Strategy for 1
INTRODUCTION
■
Species in the Aurora kinase family (A−C) are homologous
serine-threonine protein kinases, which play important roles in
the formation and distribution of chromosomes and
cytokinesis.1 Aurora B kinase is the catalytic component of
the chromosomal passenger complex and is thought to have a
critical role in cell division during the metaphase to anaphase
stages. Hence, inhibition of Aurora B kinase activity has been
considered as an attractive target for pharmacological
intervention in the oncology drug field.2
During the course of our medicinal chemistry team’s
investigations into small-molecule Aurora B kinase inhibitors
for antineoplastic activity, 1 was selected as a potent drug
candidate in this area with a suitable profile for further clinical
studies (Scheme 1).3 The synthetic challenges associated with
the chemical structure were identified as efficient synthesis of
the α-carboline (pyrido[2,3-b]indole) core and regioselective
installation of several substituents. While an early medicinal
chemistry synthesis of 1 on the laboratory scale enabled
successful preparation of the material for early toxicological and
preclinical studies, the synthesis of 1 for further clinical
evaluation was hampered by the limited scalability. In this
context, a practical and scalable synthesis of 1 was required.
Herein, we describe an efficient synthesis of 1 employing
integrated cross-coupling reactions.
a
Reagents and conditions: (a) Cu, NMP, 190 °C, 43%; (b) Pd2(dba)3,
PCy3, Cs2CO3, dioxane, reflux, 61%; (c) Fe, AcOH, 80 °C. 96%; (d)
AcOH, reflux, 87%; (e) H2SO4, 120 °C, 96%; (f) HATU, TEA, DMF,
25 °C, 58%.
group and the final intramolecular cyclization with a SNAr
reaction between the fluorine and aromatic amine. However,
the approach had several drawbacks from the viewpoint of
RESULTS AND DISCUSSION
■
The initial synthesis for preparing small quantities of 1 is
outlined in Scheme 1.4 The assembly of the α-carboline core
was achieved by a sequence of Ullmann coupling of 2-fluoro-3-
iodo-5-methylpyridine (2) with 2,3-dichloro-5-trifluoromethyl-
6-methylnitrobenzene (3), followed by reduction of the nitro
Received: October 29, 2014
© XXXX American Chemical Society
A
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large-scale preparation to support further evaluation (e.g.,
clinical study), particularly in the Ullmann coupling step. For
example, expensive and less commercially available 2 and 3
were used. Potentially explosive high-temperature cyclization
(190 °C) of the nitro compound 3 was needed. In addition, this
process was poorly reproducible in yield and quality; as the
scale of the Ullmann reaction increased, the isolated yield of 4
and the amount of byproducts arising from poor regioselectivity
and homocoupling were highly variable.
Scheme 3. Preparation of Aryl Iodide 16
After considering these drawbacks of the previous synthesis,
we sought to explore an alternative synthetic strategy for the α-
carboline pharmacophore by employing a versatile Pd-catalyzed
sequence of Buchwald−Hartwig amination5 and direct C−H
arylation,6 which we investigated on the basis of Sakamoto and
co-workers’ precedent.7 After our initial study on using this
strategy, we reported the optimal catalyst systems: Pd(OAc)2/
XANTPHOS (4,5-bis(diphenylphosphino)-9,9′-dimethylxan-
thene)/Cs2CO3 for the amination and Pd(OAc)2/DCHPB
(2-dicyclohexylphosphino-2′-biphenyl)/DBU for the direct C−
H arylation, respectively.8 The outstanding feature of the
synthetic sequence is that a combination of DCHPB and DBU
plays a critical role in not only enhancing the reactivity but also
suppressing the hydrodehalogenation for the direct C−H
arylation,9 and consequently the protocol enables a rapid and
divergent synthesis of α-carbolines with various substituents,
including base-sensitive ones such as ester groups. Using this
protocol, an improved synthetic strategy has been proposed, as
outlined retrosynthetically in Scheme 2. The key points of our
As the downstream Pd-catalyzed cross-coupling reactions were
inhibited by the carboxylic acid moiety and our preliminary
study showed that ester groups are tolerated under the
sequence of Pd-catalyzed reaction conditions,8 methyl ester-
ification of 15 was carried out using Fisher esterification
conditions to provide 16 in 94% yield (Scheme 3).13
α-Carboline Construction. With the desired aryl iodide 16
in hand, our subsequent efforts were turned to the construction
of the α-carboline core. First, Pd-catalyzed Buchwald−Hartwig
amination with our previously established catalyst system
(Pd(OAc)2/XANTPHOS/Cs2CO3) was conducted. The cata-
lyst system was successfully applied to the coupling of 16 with
2-amino-3-bromo-5-methylpyridine (13). The reaction was
completed within 5 h, and the coupling product 17 was
obtained in 99% yield (Scheme 4).
Subsequently, Pd-catalyzed direct C−H arylation of 17 was
addressed. However, the initial attempt to use the optimized
catalyst system (Pd(OAc)2/DCHPB/DBU) provided the
undesired product 18, arising from ester hydrolysis of 17, as
the main product rather than the desired α-carboline 19. On
considering the unexpected result that is inconsistent with our
preliminary data that the ester group is tolerated under the
reaction conditions,8 we assumed that the hydrolysis could be
attributed to the strong electron-withdrawing property of the
nitro group on the aromatic ring. Therefore, we expected that
increasing the electron density on the aromatic ring by
reduction of the nitro group to an amino group prior to direct
C−H arylation would suppress the ester hydrolysis of 17. In
addition, we considered that the increased electron density at
the ortho position of the amino aromatic would promote
electrophilic C−H insertion of Pd(II), similar to the promotion
of an intramolecular direct arylation at the ortho position of a
phenol.14 Thus, we refocused our attention on the alternative
route, by way of reducing the nitro group of 17 (Scheme 4).
Among the various precedent reduction methods for an
aromatic nitro group, selective reduction of an aromatic nitro
function over an aromatic bromide was required for the
synthesis. Some reduction systems with metals in aqueous
acidic solution were initially investigated. Although early studies
using Fe- or Zn-based reduction systems suffered from side
reactions such as hydrodehalogenation and incomplete
conversion, the Sn-based reduction system (SnCl2/HCl) gave
satisfactory results, with 20 being exclusively obtained in 85%
yield (Scheme 4).
Scheme 2. Retrosynthetic Analysis of 1
synthetic strategy include achieving the Pd-catalyzed cyclization
for α-carboline 11 with an ester group to be amidated with
amine 10 and a substituent to be converted to a leaving group
for the Suzuki coupling reaction with 3-ethylsulfonylphenylbor-
onic acid (5).
Aryl Iodide Preparation. Our initial efforts centered on
the preparation of the adequate aryl iodide for the Pd-catalyzed
amination.10 Among a number of aromatic precursor
candidates, readily available 2-methyl-5-nitrobenzoic acid
derivatives were selected for the iodination, as we envisaged
that the nitro group would contribute to the regioselective
iodination and would be converted to a halogen through a
reduction of the nitro group followed by a Sandmeyer reaction.
After an intensive screening of aromatic precursors and
iodination methods, 2-methyl-5-nitrobenzoic acid (14) was
successfully iodinated by an effective iodination system (I2/
NaIO3/concentrated H2SO4)11 to afford the corresponding aryl
iodide 15 in 93% yield with high regioselectivity (Scheme 3).12
With 20 in hand, the optimal catalyst system (Pd(OAc)2/
DCHPB/DBU) was again applied to intramolecular cyclization
of 20, and a full conversion was gratifyingly achieved with less
than 3% of hydrolyzed product 22. Undesired 22 was effectively
removed through the crystallization workup, and crystalline 21
was finally isolated in 91% yield (Scheme 4). Importantly, the
reaction was selective for intramolecular direct C−H arylation,
and no coupling by-product arising from the intra- and
intermolecular C−N coupling of aryl bromide with the N-
unsubstituted aniline group was observed.
B
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Scheme 4. Synthesis of α-Carboline 21
Functional Group Introduction on the α-Carboline.
With the preparation of α-carboline 21 established, our
subsequent efforts were focused on functionalization of the α-
carboline. To accomplish the synthesis of 1, halogenation and
arylation at the 5-position and amide formation at the 7-
position are required. First, a Sandmeyer reaction to halogenate
the amino group was examined. Although the initial
examination for bromination suffered from some side reactions,
including dediazonation, the diazonation of 21 using NaNO2/
concentrated HCl/acetonitrile followed by addition of aqueous
KI solution afforded 23 in 93% yield (Scheme 5). Subsequently,
CONCLUSION
■
An efficient and practical synthesis for Aurora B kinase inhibitor
1 has been established using an integrated Pd-catalyzed cross-
coupling strategy. The synthesis features an efficient α-
carboline assembly, employing a Pd-catalyzed sequence of a
Buchwald−Hartwig amination and an intramolecular direct C−
H arylation at the ortho position of an unsubstituted aniline
moiety, which is then further derivatized by Sandmeyer
iodination and Suzuki coupling. The present strategy is more
practical than the former synthesis from the viewpoint of
process robustness, the availability of starting compounds, and
the versatility of the synthetic approach. While the former
process relied on the Ullmann coupling reaction that is poorly
reproducible on scaleup and is largely restricted to less
commercially available and highly functionalized starting
compounds, the current process consists of an effective Pd-
catalyzed sequence from readily available starting compounds
(2-amino-3-bromopyridine and nitrobenzene derivatives), and
the strategy should be applicable to other derivatives.
Furthermore, the process eliminates complicated column
chromatography purifications, and all intermediates could be
isolated as crystals following simple workup. Overall, the new
process contributed to a considerable enhancement of the total
yield, from 11% to 48%.
Scheme 5. Synthesis of 1
EXPERIMENTAL SECTION
■
General Considerations. All chemicals were obtained from
commercial suppliers and were used without further purification.
Degassing of solvents was conducted by repeating an evacuation/
nitrogen refilling cycle. 1H NMR and 13C NMR spectra were recorded
on 500 MHz spectrometers with tetramethylsilane as an internal
standard. Chemical shifts are shown in ppm.
3-Iodo-2-methyl-5-nitrobenzoic Acid (15). To a mixture of 2-
methyl-5-nitrobenzoic acid (14; 10.0 g, 55.2 mmol), iodine (5.6 g, 22.1
mmol, 0.4 equiv), and concentrated sulfuric acid (40 mL) was added
sodium iodate (4.4 g, 22.1 mmol, 0.4 equiv) at 10−30 °C. The
reaction mixture was stirred at 25−30 °C for 3 h. To a mixture of
sodium sulfite (17.4 g, 138.0 mmol, 2.5 equiv), water (100 mL), and
methanol (40 mL) was added the reaction mixture at 5−30 °C. After
the mixture was stirred at 20−30 °C for 2 h, the resulting precipitates
were filtered and washed with methanol/water (1/2, 20 mL × 2), and
dried at 50 °C in vacuo to give 15.8 g (93% yield) of the title
Pd-catalyzed Suzuki coupling was studied, and the coupling of
23 with boronic acid 5 was achieved using Pd(PPh3)4 and
K2CO3 to give 24 in 79% isolated yield, along with 8% of 9
arising from hydrolysis of 24. To further simplify the sequential
process, we attempted to combine the Suzuki coupling with the
ester hydrolysis in one pot. In fact, after completion of the
Suzuki coupling, hydrolysis with 10% KOH successfully
provided 9 in 88% yield from 23. Finally, amide formation of
carboxylic acid 9 with 1-methylpiperidin-4-amine (10) was
carried out in the presence of HBTU in NMP to afford 1 in
88% yield.
1
compound as off-white crystals. Mp: 178.3 °C. H NMR (500 MHz,
DMSO-d6): δ 2.67 (s, 3H), 8.41 (d, J = 2.5 Hz, 1H), 8.68 (d, J = 2.2
Hz, 1H). 13C NMR (125 MHz, DMSO-d6): δ 26.7, 104.6, 124.0,
135.1, 135.3, 145.8, 148.2, 167.6. HRMS (EI): m/z calcd for [M]+
C8H6INO4, 306.9342; found, 306.9333.
C
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Methyl 3-Iodo-2-methyl-5-nitrobenzoate (16). To a mixture of
3-iodo-2-methyl-5-nitrobenzoic acid (15; 15.0 g, 48.9 mmol) and
methanol (75 mL) was added dropwise concentrated sulfuric acid
(10.4 mL, 195.4 mmol, 4.0 equiv) below 50 °C. The mixture was
stirred at 60 °C for 6 h. After the mixture was stirred at 50 °C for 30
min, a solution of sodium sulfite (1.2 g, 9.8 mmol, 0.2 equiv) and water
(30 mL) was added. The pH of the mixture was adjusted to 8−9 with
5% aqueous NH3 at 50 °C. After the mixture was cooled to room
temperature, water (30 mL) was added. The mixture was stirred at 50
°C for 30 min and 5 °C for 1 h. The resulting precipitates were
filtered, and washed with methanol/H2O (1/2, 30 mL × 2), and dried
at 50 °C in vacuo to give 14.8 g (94% yield) of the title compound as
pale yellow crystals. Mp: 64.9 °C. 1H NMR (500 MHz, DMSO-d6): δ
2.65 (s, 3H), 3.91 (s, 3H), 8.46 (d, J = 2.5 Hz, 1H), 8.72 (d, J = 2.5
Hz, 1H). 13C NMR (125 MHz, DMSO-d6): δ 26.7, 53.5, 104.8, 124.4,
132.4, 136.2, 145.8, 148.6, 166.1. HRMS (EI): m/z calcd for
[M]+C9H8INO4, 320.9498; found, 320.9492.
Methyl 3-[(3-Bromo-5-methylpyridin-2-yl)amino]-2-methyl-
5-nitrobenzoate (17). To a mixture of palladium acetate (349.1 mg,
1.6 mmol, 0.05 equiv) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-
xanthene (XANTPHOS; 1.4 g, 2.3 mmol, 0.075 equiv) in degassed
anisole (130 mL) were added methyl 3-iodo-2-methyl-5-nitrobenzoate
(16; 10.0 g, 31.1 mmol, 1 equiv), 3-bromo-5-methylpyridin-2-ylamine
(13; 6.1 g, 32.7 mmol, 1.05 equiv), and cesium carbonate (14.2 g, 43.5
mmol, 1.4 equiv) under a nitrogen atmosphere. The resulting mixture
was stirred at room temperature for 1 h and then stirred at 125 °C for
5 h. After the reaction mixture was cooled to room temperature, water
(65 mL) was added. The mixture was concentrated in vacuo. The
resulting residue was suspended in methanol (100 mL) and acetone
(20 mL). The pH of the mixture was adjusted to 6.5−7.5 with 6 mol/
L aqueous HCl (ca. 10 mL). The mixture was refluxed for 1 h and
stirred at room temperature for 1.5 h. The resulting precipitates were
filtered and washed with methanol/acetone/water (10/2/1, 10 mL ×
2) and dried at 60 °C in vacuo to give 11.7 g (99%) of the title
compound as dark brown crystals. Mp: 187.3 °C. 1H NMR (500 MHz,
DMSO-d6): δ 2.20 (s, 3H), 2.37 (s, 3H), 3.91 (s, 3H), 7.89 (d, J = 1.6
Hz, 1H), 7.95 (d, J = 1.3 Hz, 1H), 8.16 (s, 1H), 8.29 (d, J = 2.5 Hz,
1H), 8.56 (d, J = 2.5 Hz, 1H). 13C NMR (125 MHz, DMSO-d6): δ
16.3, 17.0, 53.2, 106.8, 119.6, 121.1, 126.9, 132.7, 140.8, 142.2, 142.5,
145.6, 146.5, 150.8, 166.8. HRMS (EI): m/z calcd for [M]+
C15H14BrN3O4, 379.0168; found, 379.0159.
Methyl 5-Amino-3-[(3-bromo-5-methylpyridin-2-yl)amino]-
2-methylbenzoate (20). To a solution of methyl 3-[(3-bromo-5-
methylpyridin-2-yl)amino]-2-methyl-5-nitrobenzoate (17; 15.2 g, 40.0
mmol, 1 equiv) and tin(II) chloride dihydrate (28.0 g, 120.0 mmol, 3
equiv) in methanol (152 mL) was added concentrated HCl (36%)
(15.2 mL). The mixture was stirred at 50 °C for 4 h. The mixture was
diluted with tetrahydrofuran (228 mL). The pH of the mixture was
adjusted to 7−9 with 25% ammonia solution (30.4 mL) with cooling
in an ice bath, before 20% aqueous potassium sodium (+)-tartrate
tetrahydrate solution (460 mL) was added to the mixture. After the
mixture was stirred at room temperature for 1 h, ethyl acetate (228
mL) and NaCl (60.8 g) were added, and the mixture was stirred at
room temperature for 1 h. The organic layer was separated,
successively washed with 5% aqueous NaHCO3 (228 mL) and 20%
aqueous NaCl (228 mL), and concentrated in vacuo. The resulting
residue was suspended in ethanol (80 mL) at room temperature for
0.5 h. The resulting precipitates were filtered and washed with ethanol
(20 mL) and further dried at 50 °C in vacuo to give 11.9 g (85% yield)
of the title compound as brown crystals. Mp: 122.9 °C. 1H NMR (500
MHz, DMSO-d6): δ 2.11 (s, 3H), 2.16 (s, 3H), 3.79 (s, 3H), 5.12 (s,
2H), 6.83 (d, J = 2.5 Hz, 1H), 6.89 (d, J = 2.2 Hz, 1H), 7.51 (s, 1H),
7.76 (d, J = 1.0 Hz, 1H), 7.84 (d, J = 1.7 Hz, 1H). 13C NMR (125
MHz, DMSO-d6): δ 14.6, 16.9, 52.2, 105.7, 112.0, 115.2, 120.6, 124.7,
131.8, 141.0, 141.6, 146.5, 146.8, 151.9, 168.9. HRMS (EI): m/z calcd
for [M]+ C15H16BrN3O2, 349.0426; found, 349.0424.
(DMAc) (20 mL) were added DBU (0.9 g, 60.0 mmol, 2.0 equiv) and
methyl 5-amino-3-[(3-bromo-5-methylpyridin-2-yl)amino]-2-methyl-
benzoate (20; 10.5 g, 30.0 mmol, 1 equiv) under a nitrogen
atmosphere. The resulting mixture was stirred at room temperature
for 0.5 h and then stirred at 130 °C for 1 h. The reaction mixture was
cooled to room temperature, and water (40 mL) was added to the
mixture. The resulting slurry was stirred at room temperature for 0.5 h
and in an ice bath for 0.5 h. The resulting precipitates were filtered,
washed with water (10 mL × 2), and dried at 60 °C in vacuo to give
7.4 g (91% yield) of the title compound as light yellow crystals. Mp:
1
295.1 °C. H NMR (500 MHz, DMSO-d6): δ 2.46 (s, 3H), 2.60 (s,
3H), 3.84 (s, 3H), 5.67 (s, 2H), 6.99 (s, 1H), 8.24 (d, J = 1.3 Hz, 1H),
8.49 (d, J = 1.0 Hz, 1H), 11.62 (s, 1H). 13C NMR (125 MHz, DMSO-
d6): δ 14.5, 18.6, 52.1, 106.6, 109.9, 110.3, 115.3, 123.9, 127.9, 130.3,
140.4, 142.3, 145.9, 151.2, 168.9. HRMS (EI): m/z calcd for [M]+
C15H15N3O2, 269.1164; found, 269.1151.
Methyl 5-Iodo-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-car-
boxylate (23). To a mixture of methyl 5-amino-3,8-dimethyl-9H-
pyrido[2,3-b]indole-7-carboxylate (21); 2.7 g, 10.0 mmol) and 6 mol/
L aqueous HCl (54 mL) was added dropwise sodium nitrite (724.5
mg, 10.5 mmol, 1.05 equiv) in water (54 mL) below 10 °C. The
mixture was stirred at 0−10 °C for 30 min. Potassium iodide (5.0 g,
30.0 mmol, 3.0 equiv) in water (54 mL) was added dropwise to the
mixture below 10 °C. The mixture was stirred at room temperature for
2 h. Methanol (16 mL) and aqueous 10% sodium sulfite solution (54
mL) were added to the reaction mixture. The pH of the reaction
mixture was adjusted to 7−9 with 5 mol/L aqueous NaOH (55 mL)
below 30 °C. The mixture was stirred at 5−10 °C. The resulting
precipitates were filtered, washed with cold water (20 mL × 2), and
dried at 60 °C in vacuo to give 3.5 g (93% yield) of the title compound
1
as brown crystals. Mp: 270.5 °C. H NMR (500 MHz, DMSO-d6): δ
2.51 (s, 3H), 2.74 (s, 3H), 3.88 (s, 3H), 8.06 (s, 1H), 8.47 (d, J = 1.0
Hz, 1H), 8.89 (s, 1H), 12.23 (s, 1H). 13C NMR (125 MHz, DMSO-
d6): δ 15.2, 18.7, 52.6, 84.4, 115.7, 123.7, 124.0, 124.2, 128.1, 129.5,
131.1, 140.0, 149.3, 151.7, 167.0. HRMS (EI): m/z calcd for [M+]
C15H13IN2O2, 380.0022; found, 380.0027.
5-[3-(Ethylsulfonyl)phenyl]-3,8-dimethyl-9H-pyrido[2,3-b]-
indole-7-carboxylic Acid (9). To a solution of tetrakis-
(triphenylphosphine)palladium (Pd(PPh3)4; 174.0 mg, 0.15 mmol,
0.05 equiv), methyl 5-iodo-3,8-dimethyl-9H-pyrido[2,3-b]-indole-7-
carboxylate (23; 1.1 g, 3.0 mmol), and 3-(ethylsulfonyl)phenylboronic
acid (5; 1.3 g, 6.0 mmol, 2 equiv) in degassed N,N-dimethylacetamide
(DMAc; 25 mL) was added potassium carbonate (829.2 mg, 6.0
mmol, 2.0 equiv) in water (10 mL). The resulting mixture was stirred
at room temperature for 0.5 h and heated at 90 °C for 1 h. A 2 mol/L
aqueous NaOH solution (30 mL) was added to the reaction mixture
below 95 °C, and this mixture was stirred at 90 °C for 1 h. After the
mixture was cooled to room temperature, the pH was adjusted to 5−7
with 6 mol/L aqueous HCl (10 mL) below 30 °C. The mixture was
stirred in an ice bath for 0.5 h, and the resulting precipitates were
filtered, washed with cold water (10 mL × 2), and dried at 60 °C in
vacuo to give 1.1 g (88% yield) of the title compound as gray crystals.
Mp: 332.5−338.5 °C dec. 1H NMR (500 MHz, DMSO-d6): δ 1.18 (t,
J = 7.3 Hz, 3H), 2.27 (s, 3H), 2.85 (s, 3H), 3.43 (q, J = 7.5 Hz, 2H),
7.52 (s, 1H), 7.58 (s, 1H), 7.87−7.90 (m, 1H), 8.02 (d, J = 7.6 Hz,
1H), 8.05 (d, J = 7.8 Hz, 1H), 8.12 (s, 1H), 8.35 (s, 1H), 12.13 (s,
1H). 13C NMR (125 MHz, DMSO-d6): δ 7.7, 15.3, 18.4, 49.5, 114.3,
119.1, 122.8, 123.0, 124.1, 127.6, 128.2, 129.5, 130.0, 130.7, 132.6,
134.5, 139.5, 140.0, 141.3, 148.3, 151.9, 169.7. HRMS (FAB-double-
focusing magnetic sector): m/z calcd for [M − H]− C22H20N2O4S,
407.1055; found, 407.1066.
5-[3-(Ethylsulfonyl)phenyl]-3,8-dimethyl-N-(1-methylpiperi-
din-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide (1). To N-
methyl-2-pyrrolidinone (NMP; 94.7 mL) was added 5-[3-
(ethylsulfonyl)phenyl]-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carbox-
ylic acid (9; 33.9 g, 82.9 mmol). The mixture was stirred at 65−75 °C
until the dissolution of 9. After the mixture was cooled to 25−35 °C,
N-methyl-4-aminopiperidine (10; 18.9 g, 165.8 mmol, 2.0 equiv) and
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophos-
phate (HBTU; 34.6 g, 91.2 mmol, 1.1 equiv) were added to the
Methyl 5-Amino-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-car-
boxylate (21). To a mixture of palladium acetate (202.1 mg, 0.9
mmol, 0.03 equiv) and 2-(dicyclohexylphosphino)biphenyl (DCHPB;
630.9 mg, 1.8 mmol, 0.06 equiv) in degassed N,N-dimethylacetamide
D
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mixture. The mixture was stirred at 20−30 °C for 2 h, and water (24
mL) was added to the reaction mixture. A solution of KOH (8.4 g,
149.2 mmol, 1.8 equiv) dissolved in water (26 mL) was added
dropwise to the mixture. Additional water (52 mL) was then added to
the mixture. The mixture was stirred at room temperature. The
resulting precipitates were filtered and washed with 25% aqueous
NMP (28 mL × 2) and dried at 60 °C in vacuo to give 36.8 g (88%
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Zhang, L.; Elliott, S.; Fabrey, R.; Lee, B.; Halkowycz, P.; Sang, B.;
Ishino, S.; Nomura, T.; Teratani, M.; Ohta, Y.; Grimshaw, C.; Paraselli,
B.; Satou, T.; de Jong, R. Mol. Cancer Ther. 2013, 12, 460.
(4) Brown, J. W.; Dong, Q.; Gong, X.; Kaldor, S. W.; Liu, Y.;
Paraselli, B. R.; Scorah, N.; Stafford, J. A.; Wallace, M. B. WO
2007044779, 2007; Chem. Abstr. 2007, 146, 441771.
(5) For reviews, see: (a) Surry, D. S.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2008, 47, 6338. (b) Buchwald, S. L.; Mauger, C.; Mignani, G.;
Scholz, U. Adv. Synth. Catal. 2006, 348, 23. (c) Schlummer, B.; Scholz,
S. B. Adv. Synth. Catal. 2004, 346, 1599.
(6) For reviews, see: (a) Ackermann, L.; Vicente, R.; Kapdi, A. R.
Angew. Chem., Int. Ed. 2009, 48, 9792. (b) Chen, X.; Engle, K. M.;
Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094.
(c) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
(7) Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans I
1999, 1505.
1
yield) of the title compound as brown crystals. Mp: 240.2 °C. H
NMR (500 MHz, DMSO-d6): δ 1.19 (t, J = 7.4 Hz, 3H), 1.51−1.60
(m, 2H), 1.83 (d, J = 10.1 Hz, 2H), 1.91−2.04 (m, 2H), 2.17 (s, 3H),
2.28 (s, 3H), 2.61 (s, 3H), 2.76 (d, J = 12.0 Hz, 2H), 3.42 (q, J = 7.3
Hz, 2H), 3.72−3.80 (m, 1H), 7.09 (s, 1H), 7.52 (s, 1H), 7.88−7.92
(m, 1H), 8.01−8.06 (m, 2H), 8.12 (t, J = 1.6 Hz, 1H), 8.27 (d, J = 7.6
Hz, 1H), 8.31 (s, 1H), 12.02 (s, 1H). 13C NMR (125 MHz, DMSO-
d6): δ 7.7, 14.6, 18.4, 31.9, 46.5, 46.8, 49.5, 54.8, 114.5, 117.5, 119.0,
120.4, 124.0, 127.6, 128.2, 129.7, 130.7, 132.7, 134.5, 135.8, 139.4,
139.7, 141.4, 147.7, 151.7, 168.7. HRMS (ESI-orbitrap): m/z calcd for
[M + H]+ C28H33N4O3S, 505.2260; found, 505.2268.
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures giving 1H NMR and 13C NMR data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(8) (a) Mizuno, M.; Mizufune, H.; Sera, M.; Mineno, M.; Ueda, T.
WO 2008016184, 2008; Chem. Abstr. 2008, 148, 239178. (b) Mineno,
M.; Sera, M.; Ueda, T.; Mizuno, M.; Yamano, M.; Mizufune, H.;
Zanka, A. Tetrahedron 2014, 70, 5550.
(9) As a result of our extended screening of bases and ligands for the
direct C−H arylation, DBU was selected as the optimal base to
suppress the hydrodebromination, and DCHPB was selected as the
optimal ligand to enhance the reactivity.8b In addition, after our patent
publication,8a the following reports have indicated DBU is an effective
base for the direct C−H arylation: (a) Laha, J. K.; Petrou, P.; Cuny, G.
D. J. Org. Chem. 2009, 74, 3152. (b) Hostyn, S.; Baelen, G. V.;
AUTHOR INFORMATION
Corresponding Authors
*E-mail for M.M.: masahiro.mineno@takeda.com.
*E-mail for H.M.: hideya.mizufune@takeda.com.
Notes
■
The authors declare no competing financial interest.
́
Lemiere, G. L. F.; Maes, B. U. W. Adv. Synth. Catal. 2008, 350, 2653.
(10) To facilitate a Buchwald−Hartwig amination, aryl iodides were
favorable. No investigations for bromination and chlorination have
been performed.
ACKNOWLEDGMENTS
We thank Dr. Kenneth Goodwill, Dr. David Provencal, and Dr.
David Cork for helpful discussions.
■
(11) (a) Kraszkiewicz, L.; Sosnowski, M.; Skulsi, L. Synthesis 2006,
1195. (b) Kraszkiewicz, L.; Sosnowski, M.; Skulsi, L. Tetrahedron
2004, 60, 9113. (c) Katayama, S.; Ae, N.; Nagata, R. J. Org. Chem.
2001, 66, 3474.
(12) 2-Methyl-5-nitrobenzonitrile was unreactive toward iodination,
probably due to its strong electron deficiency.
(13) As both iodination and esterification were carried out under
similar reaction conditions, integration of these two processes in one
pot was attempted. However, some sticky materials were generated
during the esterification as the reaction proceeded, which prevented
good agitation.
(14) (a) Hennings, D. D.; Iwasa, S.; Rawal, V. H. J. Org. Chem. 1997,
62, 2. (b) Hennings, D. D.; Iwasa, S.; Rawal, V. H. Tetrahedron Lett.
1997, 38, 6379.
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DOI: 10.1021/jo502489x
J. Org. Chem. XXXX, XXX, XXX−XXX