Convenient synthesis of antisepsis agent TAK-242 by novel optical resolution through diastereomeric N-acylated sulfonamide derivative

Article abstract of DOI:10.1016/j.tet.2007.02.127

A convenient synthesis method of antisepsis agent TAK-242 ((R)-1) through diastereomeric resolution was developed. By condensation of racemate rac-1 with chiral acid (S)-O-acetylmanderic acid (6a), the desired diastereomer 5a was isolated with 98% de in 39% yield by simple crystallization. Deacylation of 5a with aq NaOH followed by recrystallization provided (R)-1 with 99% ee in 20% yield from rac-1.

Full text of DOI:10.1016/j.tet.2007.02.127

Tetrahedron 63 (2007) 4048–4051
Convenient synthesis of antisepsis agent TAK-242 by novel optical
resolution through diastereomeric N-acylated sulfonamide
derivative
*
Atsuko Nishiguchi, Tomomi Ikemoto and Kiminori Tomimatsu
Chemical Development Laboratories, Takeda Pharmaceutical Company Limited, 2-17-85 Jusohonmachi,
Yodogawa-ku, Osaka 532-8686, Japan
Received 23 January 2007; revised 28 February 2007; accepted 28 February 2007
Available online 3 March 2007
Abstract—A convenient synthesis method of antisepsis agent TAK-242 ((R)-1) through diastereomeric resolution was developed. By con-
densation of racemate rac-1 with chiral acid (S)-O-acetylmanderic acid (6a), the desired diastereomer 5a was isolated with 98% de in 39%
yield by simple crystallization. Deacylation of 5a with aq NaOH followed by recrystallization provided (R)-1 with 99% ee in 20% yield from
rac-1.
Ó 2007 Elsevier Ltd. All rights reserved.
CO2Et
CO2H
1. Introduction
Cl
Cl
hydrolysis
H
H
N
N
S
S
TAK-242 ((R)-1), a potent NO and cytokine production
inhibitor, was discovered by Yamada et al. in the course of
research into new antisepsis agents.1,2 This optically active
cyclohexene derivative (R)-1 was first obtained from chiral
phase HPLC resolution of racemate rac-1 (Fig. 1).
O2
O2
F
F
rac-1
rac-2
enzymatic resolution
method
diastereomeric resolution
method
Recently, two other synthetic methods by diastereomeric
resolution1b and enzymatic resolution1b were also reported
by the same group; however, these three methods were not
satisfactory for large-scale preparation. The HPLC method
requires rather special apparatus, and the resolution effi-
ciency largely depends on the size of the apparatus. Dia-
stereomeric resolution and enzymatic resolution are shown
in Scheme 1.
S
O
Ar
CO2CH2OAc
Cl
H
O
Cl
N
S
H
N
R
O2
S
O2
F
(R)-4
F
diastereomer-3
CO2Et
In these two methods, rac-1 was converted to carboxylic
acid rac-2 followed by diastereomeric ester 3 or enzymatic
substrate (R)-4. Hydrolysis of rac-1 was accompanied by
Cl
H
N
S
O2
F
(R)-1
CO2Et
Cl
H
Scheme 1. Previous synthesis method of (R)-1.
N
S
O2
F
(R)-1
a certain amount of decomposition, and the yield of rac-2
was relatively low (74% yield). Moreover, 3 was synthesized
through Mitsunobu reaction utilizing an azo compound,
DEAD, which is not favorable for large-scale production.
Since the ester moiety of rac-1 was converted to different es-
ters, these methods consisting of resolution and ester recon-
struction were unfavorable for short-step preparation and to
Figure 1. Structure of (R)-1.
Keywords: Antisepsis agent; Diastereomeric resolution; Sulfonamide;
Chiral acid; Deacylation.
* Corresponding author. Tel.: +81 6 6300 6378; fax: +81 6 6300 6251;
e-mail: nishiguchi_atsuko@takeda.co.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.127

A. Nishiguchi et al. / Tetrahedron 63 (2007) 4048–4051
4049
Table 1. Results of N-acylation and diastereomeric resolution
R*-CO2H
6
ensure a high total yield. The diastereomeric resolution
method gave 14% yield in four steps, and the enzymatic
resolution method gave 17% yield in three steps.
CO2Et
CO2Et
Cl
(COCl)2
SO2 Cl
N
H
R
N
Meanwhile, it is known that Oppolzer’s sultams,3 used as
a chiral auxiliary, are readily N-acylated with acyl chlorides,
and N-acylated sultams are readily cleaved4 under mild con-
ditions without loss of optical purity.
S
O
crystallization
O2
R*
F
F
rac-1
diastereomer-5
Reagents: (1) 6, (COCl)2, in toluene at 5 °C (2) pyridine in toluene at -15 °C
We focused on the sulfonamide moiety of rac-1 for derivati-
zation to diastereomeric mixtures to be resolved. Scheme 2
depicts our methodology;5 N-acylation of racemic sulfon-
amide A with chiral acid B followed by resolution of resul-
tant diastereomeric mixtures C provides pure isomer C.
Isomer C is then deacylated to obtain optically active A.
To the best of our knowledge, there are no reports on N-
acylated sulfonamide diastereomers being applied for opti-
cal resolution. Furthermore, it is suitable for short-step
preparation because of the add-on-type conversion on the
sulfonamide nitrogen.
Entry
1
R
Yielda (%)
deb (%)
98
Ph
OAc
5ac: 39
6a
CO2Me
2
3
5bc: 41
97
Me
6b
Ph
Not crystallized
OMe
6c
R3-COCl
chiral acid B
O
R3
R2
4
5
Not crystallized
Not crystallized
O
H
N
R1
R1
N
S
R2
S
6d
O2
O2
OMe
diastereomeric
racemate A
mixtures C
resolution
Me
6e
Me
single isomer C
deacylation
O
H
N
R1
6
Not crystallized
R2
Me
6fd
Me
S
O2
optically active A
a
Isolated yield.
Determined by HPLC analysis.
b
c
d
Scheme 2. Strategy of optical resolution.
More crystallizable isomer.6
Instead of 6f, commercially available (ꢁ)-menthyl chloroformate was
used.
2. Results and discussion
Table 2. Isolation of 5a by crystallization
First, N-acylation of rac-1 was investigated (Table 1). Com-
mercially available chiral carboxylic acids 6a–f were used
for N-acylation as corresponding acid chlorides. Although
pyridine, triethylamine, and collidine could be used as bases,
pyridine was most suitable. N-acylation of rac-1 with (S)-
O-acetylmanderic acid 6a6 and (R)-3-methylsuccimate 6b6
afforded the single diastereomers 5a and 5b, respectively,
as crystalline solids by filtration (entries 1 and 2). Other
diastereomeric mixtures derived from 6c–f did not give
crystalline isomers (entries 3–6).7
Entry
Solvent
Temp (ꢀC)
Yielda of 5a (%)
deb (%)
1
2
3
Methanol
1-Propanol
2-Propanol
rt
35
22
39
98
98
98
rt
40c
a
Isolated yield.
Determined by HPLC analysis.
Temperature was raised because gummy oil was separated out at rt.
b
c
For optimization of deacylation of 5a, various bases and
acids were investigated (Table 3). When using H2SO4,
AlCl3, NH4Cl, and AcONa, the sulfonamide bond was
cleaved chiefly to give 7.9 With NaHCO3 and Na2CO3,
deacylation proceeded very slowly at rt. Even at 80 ꢀC, it
proceeded slowly (entries 1 and 2), and impurity 7 and its
hydrolyzate 89 were produced conspicuously. The use of
strong bases afforded different results. Deacylation with
Ba(OH)2 at rt proceeded faster than with the above bases,
and the amounts of 7 and 8 relatively decreased (entry 3).
On the other hand, deacylation with NaOH or NH3 pro-
ceeded quickly even at 0 ꢀC (entries 4 and 5). Impurities 7
The subsequent N-deacylation of 5b showed a remarkable
decrease in the enantiomeric excess of the resulting (R)-1
(from 98% de of 5b to 80% ee of (R)-1).8 The plausible rea-
son why the ee value decreased was that deacylation of 5b
proceeded slowly; therefore, we chose 6a as the resolving
agent.
The single isomer 5a could be isolated by crystallization
from alcohols such as methanol and propanol; in particular,
2-propanol was preferable to obtain 5a in good yield with
high diastereomeric excess (Table 2).

4050
A. Nishiguchi et al. / Tetrahedron 63 (2007) 4048–4051
Table 3. Deacylation of 5a
Laboratories Limited. Optical rotations were determined by
CO2Et
Takeda Analytical Research Laboratories Limited. The de
and ee of compounds were determined by HPLC. The con-
ditions were as follows: column: CHIRALPAKÒ AD,
4.6 mm i.d.ꢂ250 mm; mobile phase: n-hexane/EtOH¼9/1;
flow rate: 1 mL minꢁ1; detector: UV 254 nm. The yields in
Table 3 were determined by HPLC. The conditions were
as follows: column: YMS-Pack ODS-A A-302, 4.6 mm
i.d.ꢂ250 mm; mobile phase: 0.05 M KH2PO4/MeCN¼3/7;
flow rate: 1 mL minꢁ1; detector: UV 254 nm.
CO2Et
Cl
deacylation
H
SO2 Cl
N
R
N
O
S
R
O2
F
Ph
OAc
F
S
(R)-1
5a
Entry Reagent (equiv)
Solvent
Tempa Time Yieldb eeb
(ꢀC)
(h)
(%)
(%)
1
2
3
4
5
NaHCO3 (2)
Na2CO3 (1)
Ba(OH)2 (1)
2 M NaOH aq (10) THF
25% NH3 aq (72) THF
MeCN–H2O rt–80 12
MeCN–H2O rt–80 12
18
31
72
95
81
91
88
95
94
98
4.1.1. Ethyl (6R)-6-{[[(2S)-2-(acetyloxy)-2-phenylace-
tyl](2-chloro-4-fluorophenyl)amino]sulfonyl}cyclohex-1-
ene-1-carboxylate (5a). Oxalyl chloride (1.7 mL, 20 mmol)
was added dropwise to an ice-cooled solution of (2S)-2-(ace-
tyloxy)-2-phenylethanoic acid (6a, 1.9 g, 10 mmol) in DMF
(0.1 mL) and toluene (30 mL), and then stirred for 1 h at rt.
After the mixture was cooled to ꢁ15 ꢀC, rac-1 (1.8 g,
5 mmol) and pyridine (3.5 mL, 44 mmol) were added to
the mixture at ꢁ15 ꢀC. The mixture was stirred for 2 h,
and then water (15 mL) was added. The organic layer was
washed with 2 M HCl aq (15 mL) and water (15 mL, three
times), and concentrated in vacuo. The residue was dissolved
in 2-PrOH (6 mL) under reflux. The mixture was stirred for
1 h at 40 ꢀC, and then stirred for 2 h at rt. The precipitate was
washed with cold 2-PrOH (1 mL) to give 5a (1.1 g, 39%,
98% de, tR of 5a, 7.4 min; tR of (6S)-isomer, 10.0 min) as
a white solid. Mp 133–134 ꢀC. [a]D20 +157.0 (c 1.0,
DMSO). Anal. Calcd for C25H25NO7SClF: C, 55.81; H,
4.68; N, 2.60; S, 5.96; Cl, 6.59; F, 3.53. Found: C, 55.85;
H, 4.38; N, 2.62; S, 5.92; Cl, 6.71; F, 3.23. 1H NMR
(CDCl3): d 1.24 (3H, t, J¼7.1 Hz), 1.70–1.95 (3H, m),
2.05–2.30 (4H, m), 2.35–2.45 (1H, m), 3.06 (1H, br d,
J¼14.2 Hz), 4.19 (2H, q, J¼7.1 Hz), 5.20 (1H, br d,
J¼3.9 Hz), 5.66 (1H, s), 6.95–7.00 (2H, m), 7.05–7.15
(1H, m), 7.20–7.35 (5H, m), 8.02 (1H, dd, J¼8.9, 5.7 Hz).
MeCN–H2O rt
6
2
2
0
0
a
Temperature was raised according to the reaction rates.
Determined by HPLC analysis.
b
Cl
Cl
H
N
H
N
O
O
Ph
OH
F
Ph
OAc
F
7
8
Figure 2. Structure of 7 and 8.
and 8 were produced similarly to Ba(OH)2 when NH3 was
used, and it was difficult to isolate (R)-1 by crystallization
from crude oil. Although deacylation with NaOH provided
(R)-1 accompanied by 7, crude (R)-1 was crystallized easily
to obtain 74% isolated yield with 93% ee (Fig. 2).
To achieve high enantiomeric purity of (R)-1, a higher crys-
tallization property of rac-1 than that of (R)-1 was utilized.
Namely, crude (R)-1 was dissolved in 2-propanol and rac-
1 was crystallized out. Crystallization from enriched mother
liquor afforded (R)-1 in 68% yield with 99% ee.
IR (KBr): 1749, 1700, 1488, 1340, 1213, 1164 cmꢁ1
.
4.1.2. Ethyl (6R)-6-({(2-chloro-4-fluorophenyl)[(2R)-
4-methoxy-2-methyl-4-oxobutanoyl]amino}sulfonyl)-
cyclohex-1-ene-1-carboxylate (5b). Compound (5b) was
prepared in 41% yield with 97% de (tR of 5b, 8.4 min; tR
of (6S)-isomer, 11.2 min) as a white solid from rac-1 accord-
ing to a procedure similar to that described above (the prep-
aration of 5a). Mp 141–142 ꢀC. [a]D20 +110.3 (c 1.0, DMSO).
Anal. Calcd for C21H25NO7SClF: C, 51.48; H, 5.14; N, 2.86;
S, 6.54; Cl, 7.24; F, 3.88. Found: C, 51.40; H, 5.27; N, 2.83;
3. Conclusion
In conclusion, we developed a novel synthesis method of
TAK-242 by diastereomeric resolution. The introduction
of (S)-O-acetylmanderic acid 6a to a sulfonamide moiety
of rac-1 provided diastereomeric mixtures from which the
single isomer 5a was isolated easily by crystallization in
39% yield with 98% de. Deacylation of 5a afforded crude
(R)-1 in 74% with 93% ee, and subsequent recrystallization
including racemate removal treatment provided (R)-1 in
68% yield with 99% ee. The total yield from rac-1 was
20% in three steps.
1
S, 6.38; Cl, 7.29; F, 3.67. H NMR (CDCl3): d 1.12 (3H, t,
J¼2.3 Hz), 1.26 (3H, t, J¼7.1 Hz), 1.76–1.85 (2H, m),
1.90–2.05 (1H, m), 2.15–2.50 (3H, m), 2.60–2.70 (1H, m),
2.80–2.99 (1H, m), 3.03 (1H, br d, J¼12.9 Hz), 3.68 (3H,
s), 4.19 (2H, q, J¼7.1 Hz), 5.20 (1H, br s), 7.04–7.10 (1H,
m), 7.24–7.10 (2H, m), 7.80 (1H, dd, J¼8.9, 5.7 Hz). IR
4. Experimental
(KBr): 1733, 1693, 1492, 1342, 1203, 1141 cmꢁ1
.
4.1. General methods
4.1.3. Ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulf-
amoyl]cyclohex-1-ene-1-carboxylate ((R)-1). The dia-
stereomer (5a) (30.0 g, 55.8 mmol) was added to a
suspension of 2 M NaOH (280 mL, 557.6 mmol) in THF
(280 mL) at 0 ꢀC, and stirred for 2 h. The mixture was
adjusted with 1 M HCl to pH 4 at 0 ꢀC, and extracted with
AcOEt (140 mL). The aqueous layer was extracted with
¨
Melting points were recorded on a BUCHI melting point
B-540 and were uncorrected. IR spectra were recorded on
1
a FT-IR Thermo Electron Nicolet 4700. H NMR spectra
€
were recorded on a Bruker DPX-300 (300 MHz) spectrom-
eter using tetramethylsilane as an internal standard. Elemen-
tal analyses were carried out by Takeda Analytical Research

A. Nishiguchi et al. / Tetrahedron 63 (2007) 4048–4051
4051
Yamada, M.; Ichikawa, T.; Yamano, T.; Kikumoto, F.;
Nishikimi, Y.; Tamura, N.; Kitazaki, T. Chem. Pharm. Bull.
2006, 54, 58; (c) Ii, M.; Matsunaga, N.; Hazeki, K.;
Nakamura, K.; Takashima, K.; Seya, T.; Hazeki, O.; Kitazaki,
T.; Iizawa, Y. Mol. Pharmacol. 2006, 69, 1288.
AcOEt (250 mL), and the combined organic layers were
washed with satd NaHCO3 (250 mL) and 10% aq NaCl
(250 mL), and concentrated in vacuo. The residue was dis-
solved in a solution of i-Pr2O (15 mL) and cyclohexane
(60 mL) at 60 ꢀC, and stirred for 1 h at rt. The mixture was
stirred below 10 ꢀC for 1.5 h. The precipitate was washed
with cold cyclohexane (25 mL) to give crude (R)-1
(15.0 g, 74%, 93% ee) as a white solid. Crude (R)-1 (3.0 g)
was dissolved in 2-PrOH (15 mL) at 60 ꢀC, and stirred for
15 h at rt. The resulting precipitate was filtered off, and
washed with 2-PrOH (3 mL). To the mother liquor and the
washings was added n-heptane (18 mL) at 60 ꢀC, which
was stirred for 0.5 h at rt. The mixture was stirred for 2 h
below 10 ꢀC, and the precipitate was washed with cold
n-heptane (9 mL) to give (R)-1 (2.1 g, 68%, 99% ee, tR of
(R)-1, 11.7 min; tR of (S)-isomer, 10.0 min) as a white solid.
Mp 69–70 ꢀC (lit.1b 68–69 ꢀC). [a]2D0 +110.2 (c 1.0, methanol)
{lit.1b +110.0 (c 1.0, methanol)}. Anal. Calcd for
C15H17NO4SClF: C, 49.79; H, 4.74; N, 3.87; S, 8.86; Cl,
9.80; F, 5.25. Found: C, 49.71; H, 4.67; N, 3.90; S, 8.80;
Cl, 9.87; F, 5.22. 1H NMR (CDCl3): d 1.24 (3H, t,
J¼7.1 Hz), 1.69–1.78 (2H, m), 2.16–2.30 (2H, m), 2.41–
2.55 (2H, m), 4.15 (2H, q, J¼7.1 Hz), 4.71 (1H, br d,
J¼4.7 Hz), 6.96–7.00 (2H, m), 7.12–7.16 (1H, m), 7.28–
7.31 (1H, m), 7.69 (1H, dd, J¼9.1, 5.3 Hz). IR (KBr):
2. Sepsis is caused by some bacterial components that stimulate the
production of various kinds of mediators. (a) Van Amersfoort,
E. S.; Van Berkel, T. J. C.; Kuiper, J. Clin. Microbiol. Rev.
2003, 16, 379; (b) Hack, C. E.; Aarden, L. A.; Thijs, L. G.
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N. C.; Guo, R. F.; Ward, P. A. Nature Med. 2003, 9, 517.
3. Oppolzer, W. Tetrahedron 1987, 43, 1969.
4. N-Acylated sulfonamides are readily cleaved. (a) Kondo, K.;
Sekimoto, E.; Miki, K.; Murakami, Y. J. Chem. Soc., Perkin
Trans. 1 1998, 2973; (b) Beers, S. A.; Malloy, E. A.; Wu, W.;
Wachter, M.; Ansell, J.; Singer, M.; Steber, M.; Barbone, A.;
Kirchner, T.; Ritchie, D.; Argentieri, D. Bioorg. Med. Chem.
1997, 5, 779; (c) Taylor, E. D.; Petrov, V. A.; Schaeffer, M.;
Drauz, K.; Vogt, A.; Weckbecker, C.; Swearingen, S. H.;
Kamireddy, B. U.S. Patent 6,384,234, 2002; Chem. Abstr. 1998,
129, 202944.
5. Ikemoto, T.; Nishiguchi, A.; Tomimatsu, K. U.S. Patent
6,982,344, 2006.
6. Stereochemistry was determined by correlating with the desired
(R)-1. The chiral acid isomers, (R)-O-acetylmanderic acid and
(S)-3-methylsuccimate, were also used to prepare diastereomers
followed by deacylation. Compared with both results, stereo-
chemistry was confirmed unambiguously.
3253, 1709, 1649, 1492, 1333, 1234, 1149 cmꢁ1
.
Acknowledgements
7. Since each mixture of diastereomers derived from 6c–f was sep-
arated on analytical TLC or HPLC, they could also be separated
chromatographically on a preparative scale. We considered,
however, that it was favorable to isolate by crystallization for
large-scale preparation.
We would like to thank Mr. Kokichi Yoshida, Mr. Yuzuru
Saito, and Dr. Shokyo Miki for their encouragement
throughout this work.
8. Deacylation of 5b was conducted under the conditions of Table
3, entry 4.
References and notes
9. The structures of 7 and 8 were estimated by LCMS (7;
LCMS (ESI) m/z 320 (MꢁH)ꢁ. 8; LCMS (ESI) m/z 278
(MꢁH)ꢁ).
1. (a) Yamada, M.; Ichikawa, T.; Ii, M.; Sunamoto, M.; Itoh, K.;
Tamura, N.; Kitazaki, T. J. Med. Chem. 2005, 48, 7457; (b)