An efficient synthesis of ABT-263, a novel inhibitor of antiapoptotic Bcl-2 proteins

Article abstract of DOI:10.1055/s-2008-1067129

ABT-263, a newly developed Bcl-2 inhibitor, was efficiently synthesized. The key intermediates 4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl] methyl}piperazin-1-yl)benzoic acid and 4-fluoro-3-[(trifluoromethyl)sulfonyl] benzenesulfonamide were eff

Full text of DOI:10.1055/s-2008-1067129

2398
PAPER
An Efficient Synthesis of ABT-263, a Novel Inhibitor of Antiapoptotic Bcl-2
Proteins
An
E
fficient Synth
u
esis of
A
BT
a
a
Key Laboratory of Cellulose and Lignocellulosics Chemistry, Guangzhou Institute of Chemistry, Chinese Academy of Sciences,
Guangzhou 510650, Guangdong, P. R. of China
b
Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, International
Business Incubator A-3, Guangzhou Science Park, Guangzhou 510663, Guangdong, P. R. of China
Fax +86(20)32290485; E-mail: ding_ke@gibh.ac.cn
c
Graduate School of the Chinese Academy of Sciences, Beijing 100039, Beijing, P. R. of China
Received 27 February 2008; revised 14 April 2008
antiapoptotic members such as Bcl-2, Bcl-xL, Bcl-w, and
so forth.1–3 Antiapoptotic Bcl-2 proteins are overex-
pressed in a variety of human cancers, and such overex-
pression contributes greatly to cancer-cell resistance to
Abstract: ABT-263, a newly developed Bcl-2 inhibitor, was effi-
ciently synthesized. The key intermediates 4-(4-{[2-(4-chlorophe-
nyl)-5,5-dimethylcyclohex-1-enyl]methyl}piperazin-1-yl)benzoic
acid and 4-fluoro-3-[(trifluoromethyl)sulfonyl]benzenesulfon-
amide were efficiently prepared by a three-component Mannich current therapeutic agents.4–12 Consequently, these pro-
reaction and by nucleophilic fluorination of 1-nitro-2-[(trifluoro-
teins are considered to be promising molecular targets for
methyl)sulfonyl]benzene as the key steps, respectively. Our work
new anticancer drug development. Much effort has been
may lay a foundation for a new process development of this prom-
devoted to designing and synthesizing small-molecule in-
ising anticancer drug candidate.
hibitors of Bcl-2, Bcl-xL, Bcl-w, and other antiapoptotic
Bcl-2 family proteins.13–27
Key words: Bcl-2 family protein inhibitor, anticancer drugs,
ABT-263, synthesis, sulfonamides
ABT-263 (1, Scheme 1), developed by Abbott Laborato-
ries, is one of the most promising orally bioavailable
small-molecule inhibitors of Bcl-2 family proteins.26,27 It
has a Ki £ 1 nM against Bcl-2, Bcl-xL, and Bcl-w, and ex-
hibits submicromolar activity against a variety of human
totic proteins such as Bak, Bax, Bim, and Bad, and
The Bcl-2 (B-cell lymphoma 2) family proteins are funda-
mental regulators of apoptosis. They comprise proapop-
O
F3C
F
S
O
H
SO2CF3
N
O
OH
S
H
O
N
S
O
SO2NH2
O
N
O
3
N
N
N
N
H2N
S
N
O
Cl
Cl
ABT-263 (1)
2
4
MgBr
O
N
O
Cl
N
OR
5
6
Scheme 1 Retrosynthetic analysis of ABT-263.
SYNTHESIS 2008, No. 15, pp 2398–2404
x
x.
x
x
.
2
0
0
8
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1067129; Art ID: F04408SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
An Efficient Synthesis of ABT-263
2399
O
CO2H
H
N
N
N
N
N
a
N
b
CO2t-Bu
CO2t-Bu
Cl
7
5
2
Scheme 2 Synthesis of building block 2. Reagents and conditions: (a) 4,4-dimethylcyclohexanone, HCHO, HCl, t-BuOH, reflux (53%);
(b) 1. 4-ClC6H4MgBr (6), THF, –40 to 20 °C; 2. 6 M aq HCl, reflux (74%).
Br
O
Br
N
CHO
a
b
N
10
CO2Et
8
9
CO2H
N
N
c
2
Cl
Scheme 3 Abbott’s reported method for the synthesis of building block 2.28 Reagents and conditions: (a) CHCl3, DMF, Br3P; (b) ethyl
4-(piperazin-1-yl)benzoate, NaBH3CN; (c) 1. 4-ClC6H4B(OH)2, [PdCl2(PPh3)2]; 2. LiOH.
cancer cells in vitro.26 ABT-263 (1) is currently in phase From the chemical structure, it is clear that compound 2
I/IIa clinical trials for treatment of small cell lung cancer, might be synthesized by a direct condensation of Grignard
nonhematological malignancies, and so forth.26,27 Due to reagent 6 with intermediate 5 (Scheme 1). And it should
its superpotency and selectivity, ABT-263 (1) provides an be possible to prepare intermediate 5 by a three-compo-
important small-molecular tool for the further investiga- nent Mannich addition of a 4-(piperazin-1-yl)benzoic acid
tion of biological functions of antiapoptotic Bcl-2 family ester with 4, 4-dimethylcyclohexanone and formaldehyde
proteins in different cell types. The chemical structure of (Scheme 2).
ABT-263 (1) has been released. Most recently, a general
Firstly, compound 7 was prepared in 95% yield by the nu-
synthetic method for ABT-263 (1) and its related deriva-
cleophilic substitution of tert-butyl 4-fluorobenzoate with
tives has been provided in a disclosed patent application,
piperazine at 120 °C.30 A three-component Mannich reac-
but no experimental details were given.28 As a part of our
tion of compound 7 with formaldehyde and 4,4-dimethyl-
cyclohexanone was then successfully carried out to
chemical biology program, we aimed to synthesize ABT-
263 (1) as a chemical tool to study the potential regulating
produce compound 5 in 53% yield (Scheme 2). Com-
function of Bcl-2 family proteins in the differentiation,
pound 5 reacted with Grignard reagent 6 to give a conden-
sation product, which was treated in a one-pot
self-renewal, and/or cell cycle of embryonic stem cells.
Herein, we report a new efficient synthesis of this mole-
dehydration and deprotection procedure in a six-molar hy-
cule.
drochloric acid solution to give building block 2 in 74%
A retrosynthetic analysis of ABT-263 (1) revealed that the yield (over two steps) (Scheme 2).
molecule could be synthesized through three key building
In the disclosed patent application,28 a different strategy
blocks 2, 3, and 4 (Scheme 1). Intermediate 4 is readily
for the synthesis of intermediate 2 was described, namely
prepared by a previously reported procedure.23,29 Our ef-
a one-pot bromination–carbonylation and a Suzuki cou-
fort mainly focused on the preparation of building blocks
pling reaction as the key steps (Scheme 3). However,
2 and 3.
there were no experimental details and isolated yields pro-
vided.
Synthesis 2008, No. 15, 2398–2404 © Thieme Stuttgart · New York

2400
G. Wang et al.
PAPER
F
F
F
F
SO2Cl
SO2CF3
SO2Cl
a
b
F
F
SO2NH2
12
SO2NH2
SO2NH2
11
14
SO2CF3
SO2CF3
c
3
F
B(OH)2
SO2NH2
13
3
c
15
Scheme 4 Attempts at introducing a (trifluoromethyl)sulfonyl
group onto a phenyl ring. Reagents and conditions: (a) ClSO3H, ref-
lux; (b) CF3CO2Na, CuI, DMF, 170 °C; (c) (CF3SO2)2O or CF3SO2Cl.
Scheme
5
Alternative attempts to synthesize compound 3.
Reagents and conditions: (a) CF3CO2Na, CuI; (b) CF3SO2Cl, PdCl2;
(c) 1. ClSO3H; 2. NH4OH.
Building block 3 seemed structurally very simple. Yet the
preparation of this compound cost us much effort, due to
the difficulty of introducing a (trifluoromethyl)sulfonyl
group onto the phenyl ring (Scheme 4). Initially, we
planned to prepare intermediate 3 through a direct
Friedel–Crafts reaction of 4-fluorobenzenesulfonamide
(11) with trifluoromethanesulfonyl chloride or trifluo-
romethanesulfonic anhydride (Scheme 4). Unfortunately,
no desired product was obtained, although a variety of
Lewis acids were tested under different conditions.
an efficient synthetic method for compound 18, access to
compound 3 should be easy. On the basis of this consider-
ation, an alternative approach was designed for the syn-
thesis of intermediate 3 (Scheme 6). First, commercially
available compound 16 was heated with potassium tri-
fluoroacetate at 180–230 °C; this gave pure 17 directly af-
ter distillation in a yield of 70% (Scheme 6).34 However,
the oxidation of 17 gave 18 in only 17% yield when chro-
mium(VI) oxide was utilized as the oxidant at 100 °C.33
Although other strong oxidants such as potassium dichro-
mate, potassium permanganate, and sodium periodate
were also tested, the oxidation yield could be improved
with none of these agents. Fortunately, when periodic acid
was combined with a catalytic amount of chromium(VI)
oxide, the oxidization yield improved to 80%, even when
the reaction was carried out at room temperature
(Scheme 6). With compound 18 in hand, compound 13
was readily prepared by Beaumont and Clark’s procedure
(Scheme 6).33 Compound 13 was then chlorosulfonated
with chlorosulfuric acid at 85 °C for 24 hours, and the re-
sulting product was treated with ammonia at 0 °C for a
few minutes to yield the important building block 3 in a
combined yield of 65% over two steps (Scheme 6). {It is
important that during the last step, the mixture must be
neutralized with acid before any workup, because
otherwise 4-amino-3-[(trifluoromethyl)sulfonyl]benzene-
sulfonamide will be obtained.}
Recently, a highly efficient method was reported for the
preparation of a [(trifluoromethyl)sulfonyl]aryl group
from an aromatic sulfonyl chloride by treatment with so-
dium trifluoroacetate in the presence of copper(I) iodide
as the catalyst.31 We therefore tried to apply this method
to the synthesis of key intermediate 3 (Scheme 4). Al-
though 3-(aminosulfonyl)-6-fluorobenzenesulfonyl chlo-
ride (12) was obtained in up to 85% yield by treatment of
4-fluorobenzenesulfonamide (11) with sulfurochloridic
acid, it could not be converted into intermediate 3 under
the reported conditions (Scheme 4).
Because of the high challenge of directly introducing a
(trifluoromethyl)sulfonyl group, we explored other strate-
gies to synthesize key building block 3. If we could obtain
1-fluoro-2-[(trifluoromethyl)sulfonyl]benzene (13) as an
alternative, we would be able to prepare intermediate 3
from 13 by chlorosulfonylation followed by sulfonamida-
tion with ammonium hydroxide (Scheme 5). We therefore
first treated 2-fluorobenzenesulfonyl chloride (14) with
sodium trifluoroacetate in N,N-dimethylformamide at
180 °C in the presence of copper(I) iodide (Scheme 5).
However, instead of compound 13, an unidentified prod-
uct was obtained; this might be due to the high reactivity
of the fluoride moiety. Other methods such as palladium-
catalyzed coupling of 2-fluorophenylboronic acid (15)
with potassium trifluoromethanesulfinate or trifluo-
romethanesulfonyl chloride were also explored,32 but
none of these attempts yielded the desired product 13
(Scheme 5).
Scientists at Abbott Laboratories revealed a different pro-
cedure in the disclosed patent application29 for the synthe-
sis of building block 3; for this, direct trifluoro-
methylation of 2-fluorobenzenethiol (19) was used as the
key step (Scheme 7). But no experimental details or iso-
lated yields were provided.
With all three building blocks 2, 3, and 4 available, target
molecule ABT-263 (1) was readily prepared by the proce-
dure outlined in Scheme 8. Briefly, compound 21 was ob-
tained by a simple nucleophilic substitution reaction
between compounds 3 and 4. Coupling of 21 with inter-
mediate 2 produced the target molecule ABT-263 (1) in
84% yield (Scheme 8).
Beaumont and Clark reported on the synthesis of 1-fluoro-
2-[(trifluoromethyl)sulfonyl]benzene (13) in high yield
by the fluorination of 1-nitro-2-[(trifluoromethyl)sulfo-
nyl]benzene (18) (Scheme 6).33 Thus, if we could develop
In summary, an alternative efficient synthesis of Bcl-2
family protein inhibitor ABT-263 (1) is described. Key in-
Synthesis 2008, No. 15, 2398–2404 © Thieme Stuttgart · New York

PAPER
An Efficient Synthesis of ABT-263
2401
NO2
NO2
NO2
O
O
SCF3
S
S
a
b
CF3
S
NO2
17
18
16
F
F
SO2CF3
SO2CF3
c
d
SO2NH2
13
3
Scheme 6 Synthesis of compound 3. Reagents and conditions: (a) CF3CO2K, sulfolane, 180–230 °C (70%); (b) H5IO6, CrO3, MeCN, r.t.
(80%; 55% from 16); (c) KF, Ph4PBr, DMSO, 130 °C (85%); (d) 1. ClSO3H, 85 °C; 2. NH4OH, 0 °C (65%).
F
F
F
F
O
O
O
O
S
S
S
SH
c
a
CF3
b
CF3
CF3
SO2NH2
19
20
13
3
Scheme 7 Synthetic method for the synthesis of 3 in the disclosed patent application.29 Reagents and conditions: (a) CF3I; (b) RuCl3, NaIO4;
(c) 1. ClSO3H; 2. NH4OH.
H2N
S
F3C
SO2
F
H
N
SO2CF3
a
S
N
O
+
H2NO2S
N
O
SO2NH2
4
3
21
ABT-263
b
1
Scheme 8 A final synthesis of ABT-263. Reagents and conditions: (a) DIPEA, DMSO, r.t. (87%); (b) benzoic acid 2, EDCI, DMAP, CH2Cl2
(84%).
meter; CDCl3 or DMSO-d6 were used as solvents and TMS as an in-
ternal standard. Mass spectra were recorded on an Agilent 1200 LC-
MS or HP5989A spectrometer. HRMS was carried out on a Finni-
gan MAT-95 spectrometer from the Shanghai Institute of Materia
Medica (CAS).
termediates 4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcy-
clohex-1-enyl]methyl}piperazin-1-yl)benzoic acid (2)
and
4-fluoro-3-[(trifluoromethyl)sulfonyl]benzenesul-
fonamide (3) were efficiently synthesized by use of a
three-component Mannich reaction and nucleophilic fluo-
rination of 1-nitro-2-[(trifluoromethyl)sulfonyl]benzene
(18) as the key steps, respectively. Our work may lay a
foundation for a new process development of this promis-
ing anticancer drug candidate. Furthermore, this work
provided us with an important chemical tool for studying
the potential regulating function of Bcl-2 family proteins
in the differentiation, self-renewal, and/or cell cycle of
stem cells.
tert-Butyl 4-Piperazin-1-ylbenzoate (7)
tert-Butyl 4-fluorobenzoate (4.9 g, 25 mmol) was added to a soln of
piperazine (6.4 g, 75 mmol) in DMSO (20 mL) at r.t. The mixture
was stirred at 120 °C for 20 h, and was then poured into a brine soln
(100 mL). The resulting mixture was extracted with EtOAc (3 × 50
mL) and the organic phase was dried (Na2SO4). The solvent was re-
moved under reduced pressure and the residue was purified by col-
umn chromatography (silica gel, CH2Cl2–MeOH, 5:1); this gave 7.
Yield: 6.3 g (95%); white solid.
1H NMR (400 MHz, CDCl3): d = 7.86 (d, J = 8.8 Hz, 2 H), 6.84 (d,
J = 8.8 Hz, 2 H), 3.27 (t, J = 4.8 Hz, 4 H), 3.03 (t, J = 4.8 Hz, 4 H),
1.56 (s, 9 H).
All the starting materials and chemical reagents were obtained from
commercial suppliers and were used without further purification.
1H and 13C NMR spectra were recorded on a Bruker 400M spectro-
Synthesis 2008, No. 15, 2398–2404 © Thieme Stuttgart · New York

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G. Wang et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 165.9, 154.3, 130.9, 121.9, 131.8,
1H NMR (400 MHz, CDCl3): d = 7.85 (d, J = 8.8 Hz, 2 H), 7.18 (d,
J = 8.4 Hz, 2 H), 6.90 (d, J = 8.4 Hz, 2 H), 6.72 (d, J = 8.8 Hz, 2 H),
3.21 (d, J = 4.8 Hz, 4 H), 2.78 (s, 2 H), 2.32 (s, 4 H), 2.17 (s, 2 H),
1.95 (s, 2 H), 1.37 (t, J = 6.4 Hz, 2 H), 0.89 (s, 6 H).
80.1, 48.7, 45.8, 28.3.
ESI-MS: m/z = 263.3 [M + H]+.
tert-Butyl 4-{4-[(5,5-Dimethyl-2-oxocyclohexyl)methyl]piper-
azin-1-yl}benzoate (5)
13C NMR (100 MHz, CDCl3): d = 171.7, 154.5, 141.8, 135.3, 132.1,
131.8, 129.7, 129.0, 128.4, 119.1, 113.4, 60.5, 52.3, 47.1, 41.5,
35.6, 30.9, 28.9, 28.1.
ESI-MS: m/z = 439.0 [M + H]+.
HRMS–FAB: m/z [M + H]+ calcd for C26H32ClN2O2: 439.2147;
Concd HCl (0.5 mL) was added to a suspension of paraformalde-
hyde (60 mg, 20 mmol), 4,4-dimethylcyclohexanone (1.89 g, 15
mmol), and 7 (2.62 g, 10 mmol) in t-BuOH (20 mL). The resulting
mixture was refluxed for 3 h with vigorous stirring. The mixture
was then concentrated to 10 mL under reduced pressure, and poured
into sat. NaHCO3 (20 mL). The mixture was extracted with EtOAc
(3 × 20 mL). The organic phases were combined and dried
(Na2SO4). The solvent was removed under reduced pressure and the
residue was purified by column chromatography (silica gel, PE–
EtOAc, 5:1); this gave 5.
found: 439.2138.
1-Nitro-2-[(trifluoromethyl)sulfonyl]benzene (18)
Disulfide 16 (6.16 g, 20 mmol) and CF3CO2K (6.08 g, 40 mmol)
were dissolved in sulfolane (4 mL), and the resulting mixture was
heated to 180 °C. After the release of CO2 at 180 °C, the reaction
temperature was increased to 230 °C, and the distilled yellow oil
was collected; this gave 17 as a crude product, which was used for
the next step without further purification.
Yield: 2.12 g (53%); white solid.
1H NMR (400 MHz, CDCl3): d = 7.84 (d, J = 8.4 Hz, 2 H), 6.82 (d,
J = 8.8 Hz, 2 H), 3.29 (m, 4 H), 2.82–2.86 (m, 1 H), 2.59–2.69 (m,
1 H), 2.60 (m, 2 H), 2.52 (m, 3 H), 2.22–2.25 (m, 2 H), 1.93–1.98
(m, 1 H), 1.73 (m, 1 H), 1.66 (m, 1 H), 1.55 (s, 9 H), 1.35 (m, 2 H),
1.28 (s, 3 H), 1.06 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 212.7, 165.9, 153.9, 130.9, 121.8,
113.7, 80.0, 57.2, 53.2, 47.6, 45.7, 43.8, 40.2, 38.6, 31.4, 30.8, 28.3,
24.5.
CrO3 (30 mg, 3 mmol) was added to a suspension of H5IO6 (13.68
g, 60 mmol) in MeCN (20 mL), and the resulting mixture was
stirred for 30 min. Then the crude product 17 obtained above was
added to the mixture, which was then stirred overnight. After the or-
ganic solvent was removed, sat. aq Na2SO3 was added at 0 °C until
the mixture became a clear blue soln. The resulting soln was extract-
ed with EtOAc (3 × 50 mL) and dried (Na2SO4). The solvent was
removed under reduced pressure and the residue was purified by
chromatography (silica gel, PE–EtOAc, 10:1); this gave 18.
ESI-MS: m/z = 424.1 [M + Na]+.
tert-Butyl 4-(4-{[2-(4-Chlorophenyl)-2-hydroxy-5,5-dimethyl-
cyclohexyl]methyl}piperazin-1-yl)benzoate
Yield: 2.81 g (55%, over 2 steps); yellow oil.
1H NMR (400 MHz,CDCl3): d = 8.22 (d, J = 7.6 Hz, 1 H), 8.01 (m,
1 H), 7.91 (m, 2 H).
A Grignard soln prepared from 1-bromo-4-chlorobenzene (1.15 g,
6 mmol) and Mg (0.22 g, 9 mmol) in THF (20 mL) was added drop-
wise to a soln of 5 (1.2 g, 3 mmol) in THF (20 mL), at –30 °C. The
temperature was allowed to rise to r.t. over 3 h, and the resulting
mixture was stirred overnight. Then sat. NH4Cl (20 mL) was added
to quench the reaction. The mixture was extracted with EtOAc (3 ×
20 mL). The organic phases were combined and dried (Na2SO4).
The solvent was removed under reduced pressure and the residue
was purified by chromatography (silica gel, PE–EtOAc, 10:1); this
gave tert-butyl 4-(4-{[2-(4-Chlorophenyl)-2-hydroxy-5,5-dimeth-
ylcyclohexyl]methyl}piperazin-1-yl)benzoate.
MS (EI): m/z = 255 [M]+.
1-Fluoro-2-[(trifluoromethyl)sulfonyl]benzene (13)
Freshly dried KF (0.58 g, 10 mmol), Ph4PBr (1.05 g, 2.5 mmol), and
18 (1.28 g, 5 mmol) were suspended in anhyd DMSO (10 mL), and
the resulting mixture was stirred at 130 °C for 15 min. After the
mixture had been cooled to r.t., H2O was added and the mixture was
extracted with EtOAc (3 × 100 mL) and dried (Na2SO4). The sol-
vent was removed under reduced pressure and the residue was puri-
fied by chromatography (silica gel, PE–EtOAc, 30:1); this gave 13.
Yield: 1.34 g (87%); white solid.
Yield: 969 mg (85%); yellow oil.
1H NMR (400 MHz, CDCl3): d = 7.85 (d, J = 8.8 Hz, 2 H), 7.45 (d,
J = 7.6 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 6.79 (d, J = 4.8 Hz, 2 H),
6.65 (s, 1 H), 3.25 (s, 4 H), 2.64 (s, 2 H), 2.43 (d, J = 13.6 Hz, 1 H),
2.25–2.28 (m, 2 H), 2.18 (d, J = 14.0 Hz, 1 H), 1.99–2.09 (m, 2 H),
1.73 (d, J = 5.6 Hz, 2 H), 1.64 (d, J = 9.6 Hz, 1 H), 1.56 (s, 9 H),
1.24 (d, J = 9.6 Hz, 2 H), 0.96 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 165.8, 153.6, 148.5, 131.9, 130.9,
128.0, 126.4, 122.3, 113.8, 80.2, 77.3, 60.1, 54.9, 48.0, 40.3, 40.1,
37.7, 34.6, 33.1, 30.9, 28.3, 23.8.
19F NMR (400 MHz, CDCl3): d = –78.39 (CF3), –103.81 (F).
MS (EI): m/z = 228 [M]+.
4-Fluoro-3-[(trifluoromethyl)sulfonyl]benzenesulfonamide (3)
Compound 13 (456 mg, 2.0 mmol) was suspended in ClSO3H (1
mL) at 0 °C, and the resulting mixture was heated under stirring at
90 °C for 24 h, and subsequently slowly cooled to r.t. H2O (10 mL)
was added carefully to quench the reaction, and the mixture was ex-
tracted with EtOAc (3 × 50 mL). The organic phases were combined
and dried (Na2SO4). The solvent was removed under reduced pres-
sure and the residue was purified by chromatography (silica gel,
PE–EtOAc, 30:1); this gave 4-fluoro-3-[(trifluoromethyl)sulfo-
nyl]benzenesulfonyl chloride.
ESI-MS: m/z = 513.3 [M + H]+.
4-(4-{[2-(4-Chlorophenyl)-5,5-dimethylcyclohex-1-enyl]meth-
yl}piperazin-1-yl)benzoic Acid (2)
The tert-butyl 4-(4-{[2-(4-chlorophenyl)-2-hydroxy-5,5-dimethyl-
cyclohexyl]methyl}piperazin-1-yl)benzoate obtained above (1.03
g, 2 mmol) was refluxed in 6 M HCl (10 mL) for 4 h. After the soln
was adjusted to pH 6 by the addition of sat. aq NaHCO3, the mixture
was extracted with EtOAc (3 × 20 mL) and dried (Na2SO4). The sol-
vent was removed under reduced pressure and the residue was puri-
fied by chromatography (silica gel, PE–EtOAc, 2:1); this gave 2.
NH4OH (2 mL) was added to the thus obtained 4-fluoro-3-[(trifluo-
romethyl)sulfonyl]benzenesulfonyl chloride at 0 °C, and the result-
ing soln was stirred for 5 min at 0 °C. Then the mixture was
neutralized with 2 M HCl at 0 °C, and extracted with EtOAc (3 ×
100 mL). The organic phases were combined and dried (Na2SO4).
The solvent was removed under reduced pressure and the residue
was purified by chromatography (silica gel, PE–EtOAc, 2:1); this
gave 3.
Yield: 0.75 g (85%); white solid.
Yield: 400 mg (65%, over 2 steps); white solid.
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PAPER
An Efficient Synthesis of ABT-263
2403
1H NMR (400 MHz, DMSO-d6): d = 8.46 (m, 1 H), 8.42 (m, 1 H),
7.97 (dd, J = 8.8 Hz, 1 H), 7.81 (s, 2 H).
MS (EI): m/z = 307 [M]+.
HRMS (EI): m/z [M]+ calcd for C7H5F4NO4S2: 306.9591; found:
306.9599.
Acknowledgment
We thank the Chinese Academy of Sciences (grant KSCX2-YW-R-
27), Natural Science Foundation of Guangdong province, and
Guangzhou Institute of Biomedicine and Health for their financial
support.
4-{[(R)-4-Morpholino-1-(phenylsulfanyl)butan-2-yl]amino}-3-
[(trifluoromethyl)sulfonyl]benzenesulfonamide (21)
References
Compounds 4 (266 mg, 1.0 mmol), 3 (307 mg, 1.0 mmol), and DI-
PEA (0.5 mL) were dissolved in DMSO (5 mL), and the resulting
mixture was stirred at r.t. for 16 h. EtOAc (100 mL) was added to
dilute the mixture, which was then washed sequentially with 3 M
HCl (30 mL), H2O (30 mL), and brine (2 × 30 mL). The organic
phase was dried (Na2SO4). The solvent was removed under reduced
pressure and the residue was purified by chromatography (silica gel,
CH2Cl2–MeOH, 20:1); this gave 21.
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1H NMR (400 MHz, CDCl3): d = 8.19 (s, 1 H), 7.95 (d, J = 8.4 Hz,
1 H), 7.39 (d, J = 7.6 Hz, 2 H), 7.28–7.32 (m, 2 H), 7.01 (d, J = 8.4
Hz, 1 H), 6.83 (d, J = 8.4 Hz, 1 H), 5.85 (s, 2 H), 4.07 (s, 1 H), 3.85
(br, 4 H), 3.09–3.18 (m, 2 H), 2.75–2.79 (br, 4 H), 2.20–2.23 (m, 1
H), 1.98–2.01 (m, 1 H), 1.42–1.54 (m, 1 H), 1.24–1.27 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 151.1, 136.2, 134.6, 132.9, 131.2,
130.3, 129.4, 127.5, 121.7, 118.4, 114.1, 108.9, 65.0, 54.3, 52.7,
50.7, 38.9, 28.4.
ESI-MS: m/z = 554.1 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C21H27F3N3O5S3: 554.1065;
found: 554.1060.
4-(4-{[2-(4-Chlorophenyl)-5,5-dimethylcyclohex-1-enyl]meth-
yl}piperazin-1-yl)-N-[(4-{[(R)-4-morpholino-1-(phenylsulfa-
nyl)butan-2-yl]amino}-3-
[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]benzamide (ABT-
263; 1)
Compound 21 (305 mg, 0.55 mmol) was added to a soln of 2 (219
mg, 0.5 mmol), EDCI (195 mg, 1.0 mmol), and DMAP (122 mg, 1.0
mmol) in CH2Cl2 (5 mL) at r.t. The resulting mixture was stirred for
36 h and then partitioned between H2O (50 mL) and CH2Cl2 (100
mL). The organic phase was washed with sat. aq NH4Cl (2 × 30 mL)
and dried (MgSO4). The solvent was removed under reduced pres-
sure and the residue was purified by chromatography (silica gel,
CH2Cl2–MeOH, 40:1); this gave ABT-263 (1).
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Yield: 408 mg (84%); pale yellow solid; [a]D20 –59 (c 0.28, CHCl3).
1H NMR (400 MHz, CDCl3): d = 8.34 (s, 1 H), 8.06 (d, J = 8.8 Hz,
1 H), 7.73 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 7.2 Hz, 2 H), 7.28 (d,
J = 7.2 Hz, 2 H), 7.23 (d, J = 5.6 Hz, 2 H), 7.15 (d, J = 8.4 Hz, 2 H),
6.99 (m, 1 H), 6.76 (d, J = 8.4 Hz, 2 H), 6.58 (d, J = 9.2 Hz, 1 H),
5.79 (s, 1 H), 3.89 (m, 1 H), 3.72 (s, 4 H), 3.36 (br, 3 H), 2.63–2.72
(m, 1 H), 2.40–2.63 (m, 8 H), 2.15–2.25 (m, 3 H), 1.85–2.04 (m, 4
H), 1.73 (m, 1 H), 1.32–1.53 (m, 3 H), 1.25 (s, 4 H), 0.89 (s, 3 H),
0.87 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 154.0, 151.7, 140.8, 137.9, 135.1,
134.6, 132.2, 131.1, 129.9, 129.3, 129.2, 128.4, 127.8, 127.4, 121.7,
118.5, 113.6, 112.9, 108.8, 66.3, 62.6, 54.5, 53.4, 52.9, 50.7, 46.7,
41.8, 39.8, 39.0, 32.6, 31.3, 29.8, 29.7, 29.3, 28.0, 25.4.
ESI-MS: m/z = 974.0 [M + H]+, 996.0 [M + Na]+.
ESI-HRMS: m/z [M + Na]+ calcd for C47H55ClF3N5NaO6S3:
996.2853; found: 996.2876.
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