Process development of ONO-2506: A therapeutic agent for stroke and Alzheimer's disease

Article abstract of DOI:10.1021/op034008f

A process for the synthesis of ONO-2506, an agent that suppresses astrocyte activation, has been developed. Significant improvement of the level of impurities in the final product has been achieved compared with the laboratory-scale procedure. Kilogram quantities of the compound have been supplied for preclinical studies by this improved process, with both a high quality (99.8%) and a high optical purity (99.6% ee). This was achieved by formation of a crystalline salt of an intermediate which could be recrystallized to give high purity. Toward the future launch of this product, residual problems such as byproduct formation during stereoselective allylation and removal of chiral auxiliary steps were also solved by further investigation.

Full text of DOI:10.1021/op034008f

Organic Process Research & Development 2003, 7, 168−171
Process Development of ONO-2506: A Therapeutic Agent for Stroke and
Alzheimer’s Disease
Tomoyuki Hasegawa,* Yasufumi Kawanaka, Eiji Kasamatsu, Yoichi Iguchi, Yoshihira Yonekawa, Masaki Okamoto,
Chiaki Ohta, Shinsuke Hashimoto, and Shuichi Ohuchida
Chemical Process Research Laboratories, Fukui Research Institute, Ono Pharmaceutical Co., Ltd., Technoport,
Yamagishi, Mikuni, Sakai, Fukui 913-8538, Japan
Abstract:
A process for the synthesis of ONO-2506, an agent that
suppresses astrocyte activation, has been developed. Significant
improvement of the level of impurities in the final product has
been achieved compared with the laboratory-scale procedure.
Kilogram quantities of the compound have been supplied for
preclinical studies by this improved process, with both a high
quality (99.8%) and a high optical purity (99.6% ee). This was
Figure 1.
achieved by formation of a crystalline salt of an intermediate
which could be recrystallized to give high purity. Toward the
future launch of this product, residual problems such as
byproduct formation during stereoselective allylation and
removal of chiral auxiliary steps were also solved by further
investigation.
Table 1. Impurity profiles of 1
GC analysis (area%)
entry
1
by-pro A
by-pro B
sultam
1a
2b
3c
4d
98.7
99.4
99.6
99.9
0.03
0.03
NDe
ND
0.24
0.14
0.21
0.02
0.73
0.24
ND
Introduction
ONO-2506 (1) delays the expansion of cerebral infarcts
by modulating the activation of astrocytes through inhibition
of S-100â synthesis, and it has been developed as a novel
therapeutic agent for stroke and Alzheimer’s disease.1
Laboratory-scale synthesis of this candidate was previously
reported, which was achieved with a high optical purity by
use of Oppolzer’s camphorsultam.2 The synthetic process
involved the acylation of camphorsultam, diastereoselective
allylation, removal of the chiral auxiliary by hydrogen
peroxide-mediated hydrolysis in the presence of n-tetrabu-
tylammonium hydroxide, and hydrogenation of the double
bond (Scheme 1). To support continued development,
kilogram quantities of 1 were required for various preclinical
studies. Here we describe further improvements to the
synthetic process before and after production on a pilot scale,
especially with regard to removal of impurities and suppres-
sion of byproduct formation.
ND
a Distillation. b Distillation twice. c Purification via amine salt and distillation.
d Use of pure n-octanoyl chloride and same as entry 3 e ND: not detected.
yield. However, the final product contained some impurities,
the structures and profiles of which are shown in Figure 1
and Table 1.
Byproduct A was formed during the hydrogenation step
through palladium-mediated double bond migration, while
byproduct B was derived from commercially available
n-octanoyl chloride that containes a small amount of n-
decanoyl chloride. Because the active pharmaceutical ingre-
dient will be used as an injectable drug, the most critical
problem for our project was contamination of 1 by highly
crystalline camphorsultam, which could generate insoluble
foreign matter. Analysis of 1 purified by distillation indicated
a residual camphorsultam content of 0.73% (entry 1).
Repeated distillation was effective in reducing the content
(entry 2). Various attempts to prepare an amine salt of 1 all
failed, but we found that crude 4 formed a good crystalline
salt with cyclohexylamine (Scheme 2). The yield of 4 after
hydrogen peroxide-mediated hydrolysis was estimated as
88% yield by HPLC analysis using 4-nonyloxybenzoic acid
as the internal standard.2b Hence, 0.9 equiv of cyclohexyl-
amine was employed with crude 4 to produce 5. The amine
salt was readily recrystallized from AcOEt to give 5 as color-
less needles in 76% yield and was freed under usual acidic
conditions to obtain pure 4 in small-scale synthesis. Subse-
quent hydrogenation and distillation in the same manner of
entry 1 completely removed the troublesome impurity (entry
3). Although direct hydrogenation of 5 followed by acidic
Results and Discussion
Improvements To Eliminate Impurities in the Final
Product. The laboratory-scale procedure furnished 1 with a
satisfactory result of enantiomeric purity and a high overall
* Corresponding author. Telephone: +81-776-82-6161. Fax: +81-776-82-
8420. E-mail: t.hasegawa@ono.co.jp.
(1) Tateishi, N.; Ohno, H.; Kishimoto. K.; Ohuchida, S. JP 7-316092, 1995.
Matsui, T.; Mori, T.; Tateishi, N.; Kagamiishi, Y.; Satoh, S.; Katsube, N.;
Morikawa, E.; Morimoto, T.; Ikuta, F.; Asano, T. J. Cereb. Blood Flow
Metab. 2002, 22, 711; Tateishi, N.; Mori, T.; Kagamiishi, Y.; Satoh, S.;
Katsube, N.; Morikawa, E.; Morimoto, T.; Matsui, T.; Asano, T. J. Cereb.
Blood Flow Metab. 2002, 22, 723.
(2) (a) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989, 30, 5603.
Oppolzer, W.; Rosset, S.; De Brabander, J. Tetrahedron Lett. 1997, 38,
1539. (b) Hasegawa, T.; Yamamoto, H. Synlett 1998, 882; Hasegawa, T.;
Yamamoto, H. Bull. Chem. Soc. Jpn. 2000, 73, 423.
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Vol. 7, No. 2, 2003 / Organic Process Research & Development
10.1021/op034008f CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/11/2003

Scheme 1
Scheme 2
Table 2. Effect of bases to reduce byproduct for
diastereoselective allylation
HPLC (area %)
temp
(°C)
reaction
3
3 yield
entry base
2
3
6
(de %) (de %)a (%)a
1
2
3
4
5
6
LDA
LDA
-78
-40
2.9 85.8 1.9
2.9 71.4 5.4
10.0 77.5 4.0
93.2
91.7
92.7
93.2
91.8
86.3
99.4
97.2
-
98.6
99.4
98.7
66
53
-
68
69
36
workup to achieve transformation into 1 seemed to be a more
efficient alternative route, the process yielded crude 1 with
a 5.5% content of byproduct C, which was difficult to remove
by distillation. No change of byproduct C resulted from a
longer hydrogenation time, so that the relatively basic
substrate presumably induced deactivation of the catalyst.
Finally, use of distilled pure n-octanoyl chloride provided
the highest quality (entry 4). Pilot-scale synthesis was
performed by the improved procedure described above with
the optimized amounts of reagents.
n-BuLi -78
LTMPb -35 to -20 6.1 89.2 0.3
LIPCc -35 to -20 3.5 89.0 0.5
LIPC
-5 to 5
8.3 75.1 3.2
a After purified by recrystallization twice. b LTMP: lithium 2,2,6,6-tetra-
methylpiperidide. c LIPC: lithium n-isopropylcyclohexylamide.
Scheme 3
To Suppress Byproduct Formation for Future Process
Optimization. In the previous pilot-scale procedure, a
cryogenic temperature was required during the allylation step
due to an increase of byproduct 6 at higher temperatures
through formation of dienolate 2 (Table 2, entries 1 and 2).
The worst case was a 4.0% content of 6 when n-butyllithium
was used as the base, even at -78 °C (entry 3). Because
easy control of the reaction temperature is a crucial factor
for development of a robust process, we examined the use
of sterically hindered bases to prevent enolate formation at
the R-position of sulfone by steric repulsion. Successful
results were obtained by using LTMP or LIPC, which
reduced the content of 6 to 0.5%, even at -20 °C, without
any loss of diastereoselectivity (entries 4 and 5).3 Raising
the temperature to -5 to 5 °C led to an increase of 6 (entry
6). These results were useful for the next stage of process
development.
with aqueous Na2SO3 solution, extension of the time for
addition of aqueous HCl to the mixture was found to
significantly decrease the yield of the desired product 4.
Several harsh tests of 4 reacted with aqueous Na2SO3 solution
which indicated that hydrosulfonylation of the terminal olefin
of 4 occurred at a neutral pH and produced compound 7
(Scheme 3).4 Hence, inverse addition of aqueous HCl to
maintain a low pH range of the reaction mixture seemed to
be a critical point for further scaling up of production.
Conclusions
In summary, the laboratory synthesis procedure for ONO-
2506 was improved to remove highly crystalline camphor-
sultam from the final product by addition of a purification
step through amine salt 5. This method provided high
quality 1 and allowed easy access to development of the
drug. Working toward full-scale production, we clarified the
Another problem was encountered during workup for
removal of the chiral auxiliary. After quenching the reaction
(3) Rathke, M. W.; Lindert, A. J. Am. Chem. Soc. 1971, 93, 2318; Nudelman,
N. S.; Pe´rez, D. J. Org. Chem. 1983, 48, 133; Nudelman, N. S.; Lewkowicz,
E. S.; Pe´rez, D. G. Synthesis 1990, 917; Nudelman, N. S.; Lewkowicz, E.;
Furlong, J. J. P. J. Org. Chem. 1993, 58, 1847.
(4) Sonnek, G.; Rabe, C.; Schmaucks, G. J. Organomet. Chem. 1991, 405, 179.
Vol. 7, No. 2, 2003 / Organic Process Research & Development
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169

mechanism of byproduct formation and solved the problem
by changing the reagent system and the workup procedure.
and brine (3.0 kg of NaCl in 15 L of water). Subsequently,
the organic layer was transferred to a 300-L glass-lined
reactor (rinsed with 68.5 L of isopropyl alcohol), and 68.5
L of water was added. The mixture was heated to 70 °C,
and the resulting solution was cooled to room temperature
over 18 h. Then the slurry was cooled to 0 °C and stirred
for 1 h, after which the mixture was filtered by a centrifuge
to give the crude product (wet 7.75 kg). A 300-L glass-lined
reactor was charged with the above crude cake, isopropyl
alcohol (65.5 L), and water (23.8 L), and the recrystallization
process was repeated. The resulting cake was washed with
a mixture of water (8.1 L) and isopropyl alcohol (5.4 L),
and dried at 60 °C under reduced pressure to afford 3 (6.31
kg, 59.3% in two steps) as colorless crystals. HPLC 99.8
area %, 99.7% de; Chiralcel OJ-R; CH3CN/H2O ) 55/45;
flow rate, 1 mL/min; detection, 210 nm; retention time, 10.7
min (R) and 12.4 min (S).
5.80 (ddt, 1 H, J ) 15.6, 9.8, 7.2 Hz), 5.05 (dd, 1 H, J )
15.6, 2.2 Hz), 4.98 (dd, 1 H, J ) 9.8, 2.2 Hz), 3.90 (t, 2 H,
J ) 6.3 Hz), 3.51 (d, 1 H, J ) 13.9 Hz), 3.42 (d, 1 H, J )
13.9 Hz), 3.12 (m, 1 H), 2.36 (t, 2 H, J ) 7.0 Hz), 2.03 (d,
2 H, J ) 6.4 Hz), 1.88 (m, 2 H), 1.74 (m, 1 H), 1.26 (m, 10
H), 1.16 (s, 3 H), 0.96 (s, 3 H), 0.86 (t, 3 H, J ) 6.4 Hz); IR
(KBr) 2950, 1684, 1326 cm-1, mp ) 94-95 °C.
Preparation of N-(2S)-(2-Hexyl-4-pentenoyl)-(1S)-(-)-
10,2-camphorsultam 3 Using LIPC. A solution of n-
isopropylcyclohexylamine (2 mL, 12 mmol) in THF (5 mL)
was cooled to -10 to -5 °C, and n-BuLi (1.6 M in hexane,
6.9 mL, 11 mmol) was added below 15 °C and stirred for
0.5 h. A solution of crude 2 (3.4 g, 10 mmol) in THF (7
mL) was cooled to -35 °C, and the prepared LIPC solution
was added below -25 °C and stirred for 0.5 h. To this
mixture was added allylbromide (1.3 mL, 15 mmol) and DMI
(2 mL). The reaction mixture was stirred at about -20 °C
for 2.5 h and then warmed to room temperature. To the
mixture was added aqueous HCl (2 M, 15 mL) and the
organic layer was separated. This layer was washed with
water and brine, and concentrated in vacuo. Then the residue
was crystallized from IPA (35 mL) and water (35 mL) to
give the first crop (4.3 g, 97.0% de.), which was further
recrystallized from IPA (4 mL) and water (6 mL) to afford
3 (2.6 g, 69%, 99.4% de) as colorless crystals.
Preparation of (2S)-2-Hexyl-4-pentenoic Acid Cyclo-
hexylamine Salt 5. A 100-L glass-lined reactor was charged
with 3 (3.50 kg, 9.17 mol), 2-methyl-2-butene (1.93 kg, 27.5
mol), aqueous hydrogen peroxide (30 wt %, 2.07 kg, 18.3
mol), and DME (37 L). A solution of aqueous n-Bu4NOH
(40 wt %, 11.8 kg, 18.2 mol) in DME (8.7 L) was added to
the mixture at -10 to 0 °C and the oxygen level maintained
at less than 5% by use of nitrogen gas purge. Then the
reaction mixture was warmed to 0-5 °C and stirred for 3 h.
The reaction was quenched with aqueous Na2SO3 (2.32 kg,
18.4 mol in 12 L of water) after which the mixture was
warmed to 20-25 °C and stirred for 0.5 h. Next the mixture
was transferred to a 300-L glass-lined reactor and cooled to
0 °C. To the mixture was added aqueous HCl (concentrated
HCl, 17.5 L in 12.3 L of water), and the product was
extracted with tert-butylmethyl ether (35 L). The organic
layer was transferred to a 100-L glass-lined reactor and
washed with aqueous oxalic acid dihydrate (1.76 kg, 14.9
Experimental Section
General. Infrared (IR) spectra were recorded on a Jasco
VALOR:III spectrometer. Mass spectra (MS) were obtained
1
on a JEOL JMS-DX303HF mass spectrometer. H NMR
spectra were measured with a Varian Gemini-300 (300 MHz)
or a Varian Gemini-200 (200 MHz) spectrometer. The
1
chemical shifts on H NMR spectra were reported relative
to that of tetramethylsilane (δ 0). Microanalysis and mass
spectra (HRMS) were done at the Minase Research Institute,
Ono Pharmaceutical Co., Ltd.
Preparation of N-Octanoyl-(1S)-(-)-10,2-camphorsul-
tam 2. A 100-L stainless steel reactor was successively
charged with (1S)-(-)-10,2-camphorsultam (6.00 kg, 27.9
mol), Et3N (4.23 kg, 41.8 mol), 4-N,N-(dimethylamino)-
pyridine (341 g, 2.79 mol), and THF (39 L). The resulting
solution was cooled to -5 °C, and a solution of octanoyl
chloride (4.99 kg, 30.7 mol) in THF (9.0 L) was added slowly
at -5 to 0 °C. After stirring for 0.5 h, the reaction was
quenched with water (5.6 L), and aqueous HCl (3.3 L, 38
mol of concentrated HCl in 5.6 L of water) was added. The
batch was transferred to a 300-L stainless steel reactor and
rinsed with AcOEt (80 L). Then the organic layer was
separated and washed with brine (2.8 kg of NaCl in 16 L of
water). Next, the organic layer was washed twice with
aqueous NaOH (320 g, 8.0 mol of NaOH in 8 L of water)
to remove excess octanoyl chloride and brine (1.6 kg of NaCl
in 16 L of water and then 4.1 kg of NaCl in 12 L of water).
Subsequently, the organic layer was transferred to a 100-L
stainless steel reactor (rinsed with 6 L of AcOEt), and the
solvent was removed under reduced pressure. The residue
was diluted with THF (9 L) and concentrated to give 2 as a
pale yellow oil. The crude product was used directly in the
next step. A 100% yield was obtained by removing the
solvent from the sample and calculating the weight of the
oil to be 10.0 kg. GC 99.2 area %; water content 0.04 wt %
by Karl Fischer titration. 1H NMR (200 MHz, CDCl3) δ 3.86
(t, 1 H, J ) 6.3 Hz), 3.49 (d, 1 H, J ) 13.2 Hz), 3.43 (d, 1
H, J ) 13.2 Hz), 2.72 (dt, 2 H, J ) 7.9, 2.6 Hz), 2.09 (m,
2 H), 1.88 (m, 3 H), 1.67 (m, 2 H), 1.31 (m, 10 H), 1.14 (s,
3 H), 0.96 (s, 3 H), 0.86 (t, 3 H, J ) 6.8 Hz); IR (neat)
2931, 1698, 1332 cm-1.
Preparation of N-(2S)-(2-Hexyl-4-pentenoyl)-(1S)-(-)-
10,2-camphorsultam 3. Crude 2 (10 kg) in a 100-L stainless
steel reactor was diluted with THF (15 L), transferred to a
150-L stainless steel reactor, and cooled to below -60 °C.
Then a solution of LDA (2 mol/L in n-heptane/THF/ethyl-
benzene, 12.5 kg, 30.7 mol) was added and stirred for 0.5 h.
Next a solution of allyl bromide (5.06 kg, 41.8 mol) in THF
(450 mL) was added below -65 °C, and LiI (750 g, 5.6
mol) in THF (3.5 L)-DMI 5(4.77 kg) was added successively.
The resulting mixture was warmed to -20 °C, after which
it was stirred at -20 to -15 °C for 3 h and at -5 to 5 °C
for 1 h. After the reaction was quenched with water (600
mL), aqueous HCl (3.3 L, 38 mol of concentrated HCl in
16.7 L of water) was added. The organic layer was separated,
and was washed three times successively with water (20 L)
1H NMR (200 MHz, CDCl3) δ
(5) 1,3-Dimethyl-2-imidazolidinone.
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mol in 17.5 L of water), water (17.5 L ×3), and brine (6.1
kg of NaCl in 17.5 L of water). Subsequently, the organic
layer was concentrated under reduced pressure, and n-heptane
(10.5 L) was added to the residue. The resulting slurry was
filtered, and the cake was washed with n-heptane (7 L). The
filtrate was concentrated under reduced pressure, and the
residue was transferred to a 20-L stainless steel reactor
(rinsed with 11.8 L of AcOEt). To the solution was added
cyclohexylamine (820 g, 8.26 mol), and it was heated to 45-
50 °C, after which the resulting solution was stirred at room
temperature. The slurry was cooled to 5-10 °C, stirred for
1 h, and filtered by a centrifuge. Then the resulting cake
was washed with AcOEt (6.9 L) and dried at 40 °C under
reduced pressure to afford 5 (1.94 kg, 74.7%) as colorless
needles. HPLC 97.1 area %, 1H NMR(200 MHz, CDCl3) δ
6.23 (4H, br), 5.81 (1H, m), 5.02 (1H, d, J ) 15.4 Hz), 4.95
(1H, dd, J ) 10.4, 2.0 Hz), 2.83 (1H, m), 2.20 (3H, m),
1.98 (2H, m), 1.75 (2H, m), 1.66-1.26 (16H, m), 0.87 (3H,
t, J ) 6.4 Hz); 13C NMR (50 MHz, CDCl3) δ 182.5, 137.5,
115.3, 50.1, 48.3, 37.3, 32.6, 31.9, 29.6, 27.9, 25.0, 24.6,
22.7, 14.1; MS (EI, Pos): m/z 184 (M+), 113, 100, 99, IR
(KBr) 2928, 1640, 1540, 1400 cm-1, mp ) 104 °C.
Preparation of (2S)-2-Hexyl-4-pentenoic Acid 4. A
100-L stainless steel reactor was charged with 5 (1.70 kg,
6.00 mol), AcOEt (6.8 L), n-hexane (27 L), and aqueous
HCl (concentrated HCl, 570 mL in 2.7 L of water). The
resulting solution was stirred for 0.5 h, and the organic layer
was separated. The organic layer was washed three times
with water (8.4 L), and the product was reverse-extracted
from the organic layer with aqueous NaOH (NaOH 950 g
in 9.1 L of water). Then the aqueous layer was washed twice
with a mixture of AcOEt (6.8 L) and n-hexane (27 L). To
the aqueous layer was added aqueous HCl (concentrated HCl,
2.3 L in 10 L of water) at 10 °C, and the product was
extracted with a mixture of AcOEt (6.8 L) and n-hexane (27
L). Subsequently, the organic layer was washed three times
with water (9.1 L) and brine (1.5 kg of NaCl in 4.4 L of
water), after which the solvent was removed under reduced
pressure to afford crude 4 (1.11 kg, 100%) as a colorless
oil. HPLC 97.5 area %, 1H NMR (200 MHz, CDCl3) δ 5.78
(ddt, 1 H, J ) 17.0, 10.1, 6.9 Hz), 5.10 (dd, 1 H, J ) 17.0,
1.9 Hz), 5.05 (dd, 1 H, J ) 10.1, 1.9 Hz), 2.44 (m, 2 H),
2.30 (m, 1 H), 1.64 (m, 1 H), 1.55 (m, 1 H), 1.30 (br s, 8
H), 0.90 (t, 3 H, J ) 6.8 Hz); 13C NMR (50 MHz, CDCl3)
δ 182.2, 135.2, 116.9, 45.2, 36.1, 31.6, 31.5, 29.2, 27.1, 22.6,
14.0; MS (EI) m/z 184 (M+), 143, 113; IR (neat) 2930, 1706,
1643, 917 cm-1.
was dissolved in a mixture of AcOEt (3.6 L) and n-hexane
(17.9 L), and the product was reverse-extracted from the
organic layer with aqueous NaOH (NaOH 481 g in 6 L of
purified water). After the aqueous layer was separated, a
mixture of AcOEt (3.6 L) and n-hexane (17.9 L) was added
to the organic layer, and the the resulting mixture was
acidified with concentrated HCl (1.1 L). The organic layer
was washed three times with 5.4 L of purified water and
brine (1.8 kg of NaCl in 5.4 L of water), dried over MgSO4
(900 g), and filtered (rinsed with a mixture of AcOEt (630
mL) and n-hexane (3.2 L)). The filtrate was concentrated
under reduced pressure, and the residue was purified by
distillation to yield 1 (1045 g, 93.6%) as a colorless oil. GC
99.8 area %, 99.6% ee (The ee value was determined by
HPLC [Chiralcel OJ-R; CH3CN/H2O ) 3/2; flow rate, 1 mL/
min; detection, 244 nm; retention time, 22.1 min (S) and
23.8 min (R).] After conversion into the corresponding
phenacyl ester (phenacyl chloride, Et3N/CH2Cl2).); [R]20
)
D
1
-6.1° (c ) 2.00, EtOH, 10 mL, 100 mm); H NMR (200
MHz, CDCl3) δ 2.38 (m, 1 H), 1.55 (m, 2 H), 1.53-1.20
(m, 12 H), 0.94 (t, 3 H, J ) 6.8 Hz), 0.90 (t, 3 H, J ) 6.8
Hz); 13C NMR (50 MHz, CDCl3) δ 182.9, 45.3, 34.4, 32.2,
31.7, 29.2, 27.3, 22.6, 20.6, 14.0 (2C); MS (EI) m/z 186
(M+), 169, 157, 144, 115, 102; IR (neat) 2959, 2931, 1706,
1467 cm-1; bp 120-121 °C at 133 Pa.
3-Allyl-[N-(2S)-(2-hexyl-4-pentenoyl)]-(1S)-(-)-10,2-
camphorsultam 6. The regioisomer ratio was not deter-
1
mined. H NMR (300 MHz, CDCl3) δ 5.94 (m, 1H), 5.80
(m, 1 H), 5.40 (d, 1H, J ) 15.8 Hz), 5.24 (d, 1H, J ) 9.0
Hz), 5.08 (d, 1 H, J ) 15.8 Hz), 5.00 (d, 1 H, J ) 9.0 Hz),
4.08 (m, 1H), 3.75 (m, 1H), 3.42 (m, 1H), 3.24 (m, 1H),
2.78 (m, 1H), 2.38 (m, 2H), 2.03 (m, 2H), 1.88 (m, 2H),
1.20 (m, 1H), 1.26 (m, 10 H), 1.16 (s, 3 H), 0.96 (s, 3 H),
0.90 (t, 3 H, J ) 7.2 Hz); MS (EI, Pos): m/z 421 (M+),
350, 337, 174, 167; IR (KBr): 2959, 1700, 1327, 1217, 919
cm-1. Anal. Calcd for C24H39NO3S: C, 68.37; H, 9.32; N,
3.32; S, 7.60. Found: C, 68.39; H, 9.25; N, 3.33. S, 7.56.
Preparation of Disodium (2S)-2-(2-sulfonatoethyl)-
octanoate 7. To a solution of (200 mg, 1.07 mmol) in DME
(5.2 mL) was added aqueous Na2SO3 (1.5 mol/L, 1.4 mL,
2.1 mmol) and stirred for 22 h. The reaction mixture was
concentrated under reduced pressure, and the residue was
washed successively with DME and MeOH. The resulting
powder was dissolved in MeOH, and insoluble materials
were filtered, after which the filtrate was concentrated under
reduced pressure to give 7 (61 mg, 20%) as a white powder.
1H NMR (200 MHz, CD3OD) δ 2.80 (t, 1H, J ) 7.8 Hz),
2.19 (m, 1H), 1.80 (m, 2H), 1.53 (m, 2H), 1.28 (m, 10H),
0.88 (t, 3H, J ) 6.4 Hz); 13C NMR (50 MHz, CD3OD) δ
185.4, 52.6, 34.4, 33.3, 32.7, 30.4, 28.7, 24.2, 23.5, 14.4
(methyne carbon was not detected); MS (FAB, Pos): m/z
333 (M + Na), 311 (M + 1); IR (KBr): 3511, 2925, 1572,
1415, 1225, 1182, 1053 cm-1. HRMS (MALDI-TOF) m/z
Found: 311.0914. Calcd for C11H20Na2O5S: (M+H) 311.0905.
Preparation of (2R)-2-Propyloctanoic Acid 1. A 50-L
glass-lined autoclave was flashed with N2 gas. The reactor
was charged with 4 (1105 g, 6.00 mol) and isopropyl alcohol
(22 L), and then the mixture was stirred. The agitator was
stopped, and the resulting solution was purged three times
with N2 gas at 0.5 MPa. To the mixture was added a
suspension of 5% Pt/C (H2O content: 44 wt %, 126 g) in
isopropyl alcohol (5.4 L), after which the resulting suspension
was purged four times with H2 gas at 0.5 MPa and stirred at
30 °C for 3.5 h. The reaction mixture was filtered through
a 30-L filter press (rinsed with 8.9 L of isopropyl alcohol);
the filtrate was transferred to a 100-L stainless steel reactor
and concentrated under reduced pressure. Then the residue
Acknowledgment
WethankProfessorHisashiYamamoto(NagoyaUniversity,
presently at Chicago University) for his helpful suggestions.
Received for review January 10, 2003.
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