A practical procedure for the synthesis of Esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid, an antirheumatic agent. II

Article abstract of DOI:10.1081/SCC-120021986

An efficient large-scale synthesis of Esonarimod, (R,S)-2-acetylthio-methyl-4-(4-methylphenyl)-4-oxobutanoic acid (1), a new antirheumatic drug, was established. A small amount of water increased the yield of the Michael addition of thioacetic acid (4) to

Full text of DOI:10.1081/SCC-120021986

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A Practical Procedure for the Synthesis of Esonarimod,
(R,S)-2-Acetylthiomethyl-4- (4-methylphenyl)-4-
oxobutanoic Acid, an Antirheumatic Agent. II
a
a
b
b
a
Toshiya Noguchi , Akira Onodera , Masato Ito , Mamoru Yoshida & Sadakazu Yokomori
a
Medicinal Research Laboratories , Taisho Pharmaceutical Co., Ltd. , Saitama, Saitama,
Japan
b
Omiya Factory , Taisho Pharmaceutical Co., Ltd. , Saitama, Saitama, Japan
Published online: 17 Aug 2006.
To cite this article: Toshiya Noguchi , Akira Onodera , Masato Ito , Mamoru Yoshida & Sadakazu Yokomori (2003) A
Practical Procedure for the Synthesis of Esonarimod, (R,S)-2-Acetylthiomethyl-4- (4-methylphenyl)-4-oxobutanoic Acid, an
Antirheumatic Agent. II, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:15, 2657-2670, DOI: 10.1081/SCC-120021986
To link to this article: http://dx.doi.org/10.1081/SCC-120021986
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 15, pp. 2657–2670, 2003
A Practical Procedure for the Synthesis
of Esonarimod, (R,S)-2-Acetylthiomethyl-4-
(
4-methylphenyl)-4-oxobutanoic Acid,
an Antirheumatic Agent. II
#
1
,
1
2
Toshiya Noguchi, * Akira Onodera, Masato Ito,
2
Mamoru Yoshida, and Sadakazu Yokomori
1
1
Medicinal Research Laboratories, and
2
Omiya Factory, Taisho Pharmaceutical Co., Ltd.,
Saitama, Saitama, Japan
ABSTRACT
An efficient large-scale synthesis of Esonarimod, (R,S )-2-acetylthio-
methyl-4-(4-methylphenyl)-4-oxobutanoic acid (1), a new antirheu-
matic drug, was established. A small amount of water increased the
yield of the Michael additionof thioacetic acid ( 4) to 2-methylene-4-
(4-methylphenyl)-4-oxobutanoic acid (2) to give 1. Multikilogram
amounts of 1 (over 25 kg) were successfully obtained using this
#
See Ref. [1]
Correspondence: Toshiya Noguchi, Medicinal Research Laboratories, Taisho
*
Pharmaceutical Co., Ltd., 1-403, Yoshinocho, Saitama, Saitama, 330-8530,
Japan.
2
657
DOI: 10.1081/SCC-120021986
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2
658
Noguchi et al.
procedure. In addition, this procedure was repeated nine times, and
reproducible results were obtained.
Key Words: Esonarimod; Antirheumatic drug; Friedel–Crafts
acylation; Michael addition; Process chemistry.
INTRODUCTION
We have previously developed Esonarimod, (R,S )-2-acetylthio-
methyl-4-(4-methyl phenyl)-4-oxobutanoic acid (1), as a new antirheu-
[
2–4]
matic drug.
clinical trials, a large-scale synthesis of 1 was required. Inour previous
To support further pharmacological evaluationadn
[1]
article, an efficient process with regard to the large-scale synthesis of 1
was established at a 60-grams scale. However, this procedure was not
completely satisfactory and required further improvement for larger-scale
production. In this article, we report the results of extensive laboratory
studies and a pilot plant study (over 25-kilogram scale).
RESULTS AND DISCUSSION
Synthesis of 2 (Step 1) in the Laboratory
[
1]
Inour previous article, the synthesis of 1 was reported as follows.
The synthetic procedure of 1 is outlined in Sch. 1. 2-Methylene-4-(4-
methylphenyl)-4-oxobutanoic acid (2) was obtained by Friedel–Crafts
acylationof tolue ne with commercially available itaco ni c a nh ydride (
3)
inthe presence of aluminum trichloride (AlCl 3) and nitrobenzene in 63%
yield. Compound 1 was obtained in 74% yield by the Michael addition of
thioacetic acid (4) to 2 in the presence of triethylamine and toluene.
Additionally, 1 was recrystallized from isopropylether (IPE) for purifica-
tion. The overall yield of 1 was 47% from 3. However, the reaction
conditions of each step were not enough studied. Then the amount of
reagents and the reaction temperature were investigated in laboratory
studies.
The reaction conditions for the first step were investigated about
the amount of AlCl and toluene, and reaction temperature in the pre-
3
sent study, and the results are shown in Table 1. These results are
consistent with the fact that the amount of AlCl should be 2.0 equiva-
3
lents (Entries 1–4), and toluene gave good results at 1.7 equivalents
(
Entries 3, 5–8). When the amount of toluene increased, by-product 5

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Esonarimod Acid. II
2659
ꢀ
ꢀ
Scheme 1. (a) AlCl
4
3
, nitrobenzene, 50 C, 40 min, 63%; (b) Et
3
N, toluene, 60 C,
h, 74%.
Table 1. Conditions for the synthesis of 2.
Conditions
2
AlCl
Entry (equiv.)
3
Toluene Temperature Yield
ꢀ
Purity
(area%)
By-product 5
(area%)
(equiv.)
( C)
(%)
1
2
3
4
5
6
7
8
9
0
1.0
1.5
2.0
3.0
2.0
2.0
2.0
2.0
2.0
2.0
1.7
1.7
1.7
1.7
1.1
2.3
2.9
5.7
1.7
1.7
50
50
50
50
50
50
50
50
40
70
29.5
60.0
68.4
67.8
64.7
68.2
69.6
70.8
69.1
62.0
99.36
99.34
99.36
99.45
99.49
99.39
97.77
95.74
99.18
99.12
—
—
—
—
—
—
1.69%
3.67%
—
1
—
All reactions were conducted on a 28 g (3) scale.
All reactiontimes were fixed at 2 h.
ꢀ
AlCl
The purity of 2 and 5 were determined by HPLC.
3
, 3, and toluene were added under 20 C.
[
1,5]
was formed (Entries 7, 8).
The structure of 5 is showninFig. 1. In
[1]
the previous article, five by-products, 6–9 were reported inthis reac-
tion(Fig. 1). However, these compou nd s except 5 were not detected.
Whenthe reactiontemperature was 50 C, the yield and purity of 2 were
ꢀ

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2
660
Noguchi et al.
Figure 1. Structure of by-products.
Table 2. Reaction temperature during the addition of reagents for step 1.
ꢀ
The additiontemperature ( C)
2
Entry
AlCl
3
3
Toluene
HCl
Yield (%) Purity (area%)
1
2
3
4
5
20
30
36
47
47
24
24
40
49
48
32
32
40
48
55
18
18
18
18
85
69.1
71.8
70.4
68.0
66.9
99.11
99.20
99.33
99.05
99.69
All reactions were conducted on a 20 g (3) scale.
AlCl : 2.0 equivalents, toluene : 1.7 equivalents,
3
2
HCl: conc. HCl (50 mL) and H O (200 mL).
The addition temperature indicates the reaction temperature during the addition
of reagents to the reaction mixture.
The purity of 2 was determined by HPLC.
ꢀ
similar to those at 40 C (Entry 9). When the temperature was raised to
ꢀ
70 C, the yield of 2 decreased. However, the purity of 2 did not come
down(E nt ry 10).
The additionof the reage nt s, such as AlCl 3, 3, and toluene, to the
reactionmixture was exothermic. Therefore, the reage tn s should be
added to the reaction mixture slowly in portions with cooling. The reac-
tion temperature should be kept above the freezing point of nitrobenzene
ꢀ
(8 C). Therefore, we investigated the acceptable temperature level during
the additionof these reage nt s. The results are showninTable 2. Three

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Esonarimod Acid. II
Table 3. Amount of toluene and cooling temperature for isolation of 2.
Cooling
2661
2
Toluene for
for dilution (mL)
Temperature
ꢀ
Time
(min)
Yield
(%)
Purity
(area%)
Entry
( C)
1
2
3
4
5
6
360
360
0
À8
20
20
20
60
20
20
60.6
63.5
64.7
67.0
69.3
69.6
99.45
99.50
99.49
99.36
99.20
99.27
360
360
À15
À15
À15
À15
720
2160
All reactions were conducted on a 56 g (3) scale.
AlCl : 2.0 equivalents, toluene: 1.7 equivalents.
HCl: conc. HCl (100 mL) and H O (400 mL).
The purity of 2 was determined by HPLC.
3
2
mol/L hydrochloric acid was added to the reactionmixture for work-up,
and this was also an exothermic process. The effects of the temperature
were also examined.
Withinthe limits of Table 2, all of yield a nd purity of 3 were almost
the same. The reactiontemperature duri ng the additionof AlCl 3, 3, an d
ꢀ
toluene to the reaction mixture should be kept below 50 C. The tempera-
ture for the additionof aqueous hydrochloric acid at work-up should be
ꢀ
below 85 C. The reaction temperature was well controlled with stirring.
Inthe study of Table 2, by-product 5 was not detected. Then the produc-
tionof 5 seemed to independent of temperature.
The isolationof 2 from the reactionmixture was thenexamined. The
cooling temperature and amount of toluene for dilution were investi-
gated. The results are showninTable 3.
The purity of 2 was almost the same for all of the conditions examined
ꢀ
inTable 3. Whenthe reactionmixture was cooled to À15 C, 2 was obtained
ꢀ
inhigher yield thanat 0 C (Entry 3). There was no difference in the yield
and purity of 2 with a change in the cooling duration (Entries 3, 4). The
addition of a large amount of toluene for dilution also had little effect.
Synthesis of 1 (Step 2) in the Laboratory
The reaction conditions for the Michael addition of 4 to 2 were
investigated for larger-scale preparation of 1, and the results are shown
inTable 4.

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2
662
Noguchi et al.
Table 4. Conditions for the synthesis of crude esonarimod (1).
Conditions Crude 1
4
(equiv.)
Et
(equiv.)
3
N
H
2
O
Temperature
ꢀ
Yield
(%)
Purity
(area%)
Entry
(equiv.)
( C)
1
2
3
4
5
6
7
8
9
1.2
1.2
1.2
1.2
1.0
1.5
2.0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
—
—
2.5
5
60
60
60
60
60
60
60
60
60
60
60
40
50
70
80
81.9
88.8
89.0
89.0
86.3
86.8
82.2
76.9
89.1
88.0
88.7
86.7
90.1
86.6
80.0
98.53
98.86
98.81
99.05
98.07
98.99
99.06
82.58
98.93
98.85
98.83
98.99
98.82
98.46
98.80
10
5
5
5
5
0.1
0.3
0.4
0.2
0.2
0.2
0.2
5
1
1
1
1
1
1
0
1
2
3
4
5
5
5
5
5
5
5
All reactions were conducted on a 20 g (2) scale.
Toluene (solvent): 121 mL.
All of the reactiontimes were fixed at 4 h.
The purity of 1 was determined by HPLC.
Whenthe reactionof 2 and 4 was carried out inthe prese nc e of 0.2
ꢀ
equivalents of triethylamine (Et N) at 60 C for 4 h, 1 was obtained in
3
8
1.9% yield with 98.53% purity, whereas the additionof 2.5 equivale nt s
of water to the reactionmixture i nc reased the yield of 1 up to 88.8%
Entries 1, 2). A similar effect was observed with the addition of 5–10
(
equivalents of water (Entries 3, 4). This suggested that the addition of
some water might improve the yield of the Michael addition, although
the mechanism is not yet clear. Thus, it is possible that wet 2 could be
used for this reaction. This would save the time and labor needed for
drying, and would be preferable during manufacture at a pilot plant.
The additionof 1.2 equivale nt s of 4 to 2 gave a slightly better yield than
1.0 or 1.5 equivalents (Entries 3, 5, and 6). Compound 1 could be obtained
without Et N, but the yield and purity of 1 were both decreased (Entry 8).
3
The additionof 0.1 to 0.4 equivale nt s of Et 3N did not significantly affect
ꢀ
ꢀ
the yield (Entries 3, 9–11). Reaction temperature of 50 C an d 60C gave

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Esonarimod Acid. II
2663
ꢀ
similar results. However, at temperatures of 40, 70, and 80 C, the yield of 1
declined though the purity was unchanged (Entries 3, 12–15).
To purify the crude product 1, recrystallizationfrom IPE was
[1]
employed. As showninTable 4, the purity of crude 1 was so high
that the mainpurpose of purificationwas to remove residual tolue ne ,
which was the solvent used for this step. Crude 1 (20.0 g, purity: 99.53%)
(
Table 4, Entry 1) was recrystallized from 200 mL of IPE, and stirred at
ꢀ
À15 C for 30 minto give 18.6 g (93.1%) of 1. Its purity was 99.70%. The
overall yield of 1 was 59.5% from 3 inthe laboratory.
Synthesis of 1 in a Pilot Plant
Considering the above observations, we tried to synthesize 1 ona
pilot plant scale. A 20 kg sample of 3 was used as a starting material. The
procedure is illustrated inFig. 2.
Two equivalents of AlCl were used as the catalyst for the Friedel–
3
Crafts reaction according to the results obtained in Table 1. The synthe-
sis of 2 was carried out nine times by changing the amount of toluene
Figure 2. Synthetic diagram for 2.

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2
664
Noguchi et al.
Table 5. Synthesis of 2 (step 1) ina pilot pla nt .
2
Toluene Wet weight Dry weight Yield
(kg)
Purity
(area%)
By-product 5
(area%)
Entry (equiv.)
(kg)
(%)
1
2
3
4
5
6
7
8
9
1.7
1.7
1.4
1.4
1.4
1.4
1.4
1.4
1.4
31.0
32.3
34.6
33.2
30.4
30.7
32.3
32.9
30.3
23.8
25.4
27.1
26.5
24.2
25.3
25.6
26.2
25.1
65.5
69.5
74.2
72.5
66.6
69.8
70.0
71.7
69.2
96.22
97.47
99.68
99.75
99.50
99.64
98.32
99.68
99.78
3.30
2.30
—
—
0.20
0.10
1.20
—
—
All reactions were conducted on a 20-kg (3) scale.
AlCl : 2.0 equivalents.
The purity of 2 and 5 were determined by HPLC.
3
to identify reaction conditions that would avoid the formation of
by-product 5. The results are showninTable 5.
When 1.7 equivalents of toluene were used in the laboratory, 5 was
not obtained. However, at a 20 kg scale, 5 was produced (Entries 1, 2).
The reaction temperature was independent of 5 from Table 2. Although
the reason for this result was not clear, the amount of toluene seemed to
play a role inthe formationof 5. While by-product 5 was not always
produced when 1.4 equivalents of toluene were used (Entries 3–9), small
amount of 5 were formed under the conditions in Entries 5–7. These
problems will need to be solved before future larger-scale synthesis. In
all cases, the purity of 2 was quite good except for the productionof 5.
However the yield of 2 had some variation, which may also be a problem
for the stable supply of this substance.
The second step is the synthesis of 1. We used 2 without drying, since
the presence of water gave better results than non-water conditions in the
Michael reactionof 2 with 4 inthe laboratory. The procedure is illus-
trated inFig. 3.
The synthesis of crude 1 was carried out nine times, and the results
are showninTable 6.
Inthe large-scale sy nt hesis of 1, the ratio of the reactants (2:4:Et N)
3
ꢀ
was fixed at 1.0:1.2:0.2. Furthermore, the reactiontemperature was 60 C
based on the results of the laboratory examinations (Table 4). Although

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Esonarimod Acid. II
2665
Figure 3. Synthetic diagram for esonarimod (1).
the reaction time was shortened to 2 h based on Entry 5, this had no effect
onthe yield a nd purity of crude 1. The yield and purity were almost the
same as in the laboratory examination and each lot had a comparatively
stable yield and purity. By-product 5 (1.6–0.9%) produced inStep 1 was
not removed by this procedure (Entries 1, 2). However, a slight amount
of 5 could be removed (Entries 5–7).
The purificationof 1 is illustrated inFig. 4. This step was carried out
nine times and the results are shown in Table 7.

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2
666
Noguchi et al.
Table 6. Synthesis of crude esonarimod (1).
Crude 1
Purity
2
Wet
(kg)
Dry
(kg)
Reaction
time (h)
Yield
(%)
By-product 5
(area%)
Entry
(area%)
1
2
3
4
5
6
7
8
9
30.5
31.8
34.1
32.7
29.8
30.2
31.8
32.8
29.8
23.4
25.0
26.7
26.1
23.8
24.9
25.1
26.2
24.7
4
4
4
4
2
2
2
2
2
87.1
87.3
88.9
88.6
87.1
87.3
87.9
88.4
80.0
98.17
98.82
99.67
99.85
99.62
99.65
99.58
99.67
99.81
1.61
0.93
—
—
—
—
—
—
—
4: 1.2 equivalents, Et N: 0.2 equivalents.
The purity of 1 and 5 were determined by HPLC.
3
Figure 4. Purificationdiagram of eso na rimod ( 1).

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Esonarimod Acid. II
2667
Table 7. Purificationof eso na rimod ( 1).
Purified 1
By-product 5
(area%)
Entry
Crude 1 (kg)
Yield (%)
Purity (area%)
1
2
3
4
5
6
7
8
9
27.8
29.8
32.5
31.6
28.4
29.6
30.1
31.8
30.5
90.0
90.9
89.8
92.4
88.4
91.9
91.6
90.7
90.3
98.62
99.91
99.90
99.92
99.83
99.84
99.85
99.80
99.87
1.29
0.01
—
—
—
—
—
—
—
The purity of 1 and 5 were determined by HPLC.
The pilot plant results were as good as those in the laboratory
and each lot of 1 had a comparatively stable yield and purity.
However, 5 produced in Step 1 was not removed in this step (Entry 1).
Uponthe seco dn recrystallizationof 1 (Entry 1), 22.8 kg of 1 was
obtained. The rate of recovery was 91.8%, the purity was 99.88%, and
the yield of 5 was 0.01%. The best overall yield of 1 was 59.2% from 3
(Tables 5–7, Entry 3), which was almost the same result as at a laboratory
scale (59.5%).
CONCLUSIONS
An effective and convergent process for the synthesis of Esonarimod
1) from toluene and itaconic anhydride (3) has beenexami ne d. This
(
method gives 2-methylene-4-(4-methylphenyl)-4-oxobutanoic acid (2)
and 1 in high yield and high purity. The presence of some water increased
the yield inthe Michael additionof thioacetic acid ( 4) to 2. At a labora-
tory scale, 1 was obtai ne d ina higher overall yield thaninthe i ni tial
synthesis (59.5% from commercially available itaconic anhydride (3)
vs. 47%).
Multikilogram amounts of 1 (over 25 kg) were successfully obtained
using this procedure. The overall yield of 1 from 3 was almost the same as

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2
668
Noguchi et al.
that inthe laboratory (59.2% vs. 59.5%). Furthermore, the procedure
was repeated nine times, and reproducible results were obtained.
EXPERIMENTAL
General
Melting points were determined by a Buchi 535 melting point
apparatus and were uncorrected. Infrared spectra were obtained on a
1
Perkin-Elmer 1760 spectrometer. H-NMR spectra were recorded ona
VarianVXL-200 or VXR-300 spectrometer. Chemical shifts are reported
inppm ( ꢀ) values, as determined using a JEOL JMS-SIX102 spectrometer.
TLC was performed onsilica gel pre-coated plates (Merck, Kieselgel
60F254). Spots and bands were detected by UV irradiation (254 nm).
HPLC was performed onanODS-80 TM column(Tosoh,
4
.6 Â 150 mm) with 250 nm. Itaconic anhydride, AlCl , and thioacetic
3
[
6–8]
acid were obtained commercially.
Synthesis of 1 in Laboratory
2-Methylene-4-(4-methylphenyl)-4-oxobutanoic acid (2). Aluminum
chloride (powder type) (66.7 g, 500 mmol) was added portionwise to
ꢀ
nitrobenzene (80 mL) at 20 C. After stirring for 20 min, itaconic anhy-
dride (3) (28.0 g, 250 mmol) was added and toluene (39.2 g, 425 mmol)
ꢀ
was added dropwise over 20 minat 20 C. The reactionmixture was
ꢀ
stirred at 50 C for 120 min, and then poured into conc. hydrochloric
ꢀ
acid (50 mL) –water (200 mL) at 20 C. Toluene (180 mL) was added,
ꢀ
the mixture was stirred at À15 C for 20 min, and the precipitate was
collected by filtration. The precipitate was washed with 3 mol/L hydro-
chloric acid (50 mL), water (50 mL, twice), and toluene (50 mL) (twice),
ꢀ
and then dried with an air drier at 50 C to give 39.4 g (68.4%) of 2-
ꢀ
methylene-4-(4-methylphenyl)-4-oxobutanoic acid (2). M.p.: 147–148 C
ꢀ
[1]
1
Lit. : m.p.: 147–148 C). Additionally, H-NMR spectra and IR spectra
(
were identical with the reported data.
[
1]
Crude esonarimod (1). To a mixture of 2 (20.0 g, 97.9 mmol) and
toluene (108 mL) –water (8.81 g, 489 mmol) was added thioacetic acid
ꢀ
(
of Et N (1.98 g, 19.6 mmol) intolue ne (13 mL) was thenadded dropwise
4) (8.94 g, 117 mmol), and the mixture was heated to 60 C. A solution
3
ꢀ
over 30 min. The reaction mixture was stirred at 60 C for 240 min, and

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Esonarimod Acid. II
2669
thenwashed with 1.5 mol/L sulfuric acid (35 mL), water (35 mL, twice),
ꢀ
and brine (35 mL). The extract was stirred at 0 C, and the precipitate was
ꢀ
collected by the filtrationand dried with anair drier at 50 C to give 24.4 g
(
89.0%) of crude 1.
Esonarimod (1). A mixture of crude 1 (20.0 g, 71.3 mmol) and IPE
(
200 mL) was refluxed until it was dissolved. The mixture was cooled to
ꢀ
À15 C and stirred for 30 min, and the precipitate was collected by filtra-
ꢀ
tiona nd dried with anair drier at 50 C to give 18.6 g (93.1%) of 1. M.p.:
9
spectra were identical with the reported data.
[1]
ꢀ ꢀ
1
6–97 C (Lit. : m.p.: 97 C). Additionally, H-NMR spectra and IR
[
1]
Synthesis of 1 in a Pilot Plant
Aluminum chloride (50.0 kg, 375 mol) was added to nitrobenzene
ꢀ
(
131 kg) portionwise at 20 C over 10 min. Compound 3 (20.0 kg,
178 mol) was added, and 23.8 kg (258 mol) of toluene was then added
dropwise over 30 min. The reaction mixture was stirred at 50 C for
ꢀ
1
20 min and then poured into conc. hydrochloric acid (43 kg) –water
ꢀ
(
143 kg) at 20 C over 120 min. Toluene (112 kg) was added and the
ꢀ
mixture was stirred at À15 C for 60 min. The resulting precipitate was
collected by centrifugation and washed with water (35 kg) and
toluene (30 kg) to give 34.6 kg (wet) of 2. The amount of 2 (dry) was
2
2
7.1 kg (74.2%), which was determined by drying a small amount of
(wet).
A sample of 2 (wet) (34.1 kg), which was equivalent to 26.7 kg
131 mol) of 2 (dry), was suspended in toluene (144 kg). Compound 4
(
(
12.0 kg, 158 mol) was added and the reaction mixture was heated to
ꢀ
6
0 C. A solutionof Et N (2.65 kg, 26.2 mol) intolue ne (16.0 kg) was
3
ꢀ
ꢀ
thenadded dropwise at 60 C. The reactionmixture was stirred at 60 C
for 120 min, and washed with 1.5 mol/L of sulfuric acid (45 kg), water
(
45 kg), and brine (45 kg). Toluene (80.1 kg) was then added to the
ꢀ
organic layer, and the mixture was stirred at À15 C for 60 min. The
resulting precipitate was collected by centrifugation and dried with an
air drier at 50 C to give 32.6 kg (88.9%) of crude 1.
A sample of crude 1 (32.5 kg, 116 mol) was dissolved inIPE (325 kg)
ꢀ
with heating. The extraneous material was filtered with a pressure filter,
ꢀ
and the filtrate was stirred at À15 C for 60 min. The resulting preci-
pitate was collected by centrifugation and dried with an air drier at
ꢀ
ꢀ
[1]
ꢀ
50 C to give 29.2 kg (89.8%) of 1. M.p.: 96–97 C (Lit. : m.p.: 97 C).
Additionally, H-NMR spectra and IR spectra were identical with the
1
[1]
reported data.

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©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2
670
Noguchi et al.
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. Iwata Chemical Co., Ltd., 3069, Nakaizumi, Iwata, Shizuoka, Japan.
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Tokyo, Japan.
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Koami-Cho, Chuo-ku, Tokyo, Japan.
Received inJapanOctober 17, 2002