A practical procedure for the synthesis of esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid, an antirheumatic agent (part 1).

Article abstract of DOI:10.1248/cpb.50.1407

An efficient and practical procedure for the synthesis of esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (1), a new antirheumatic drug, has been developed. The intermediate, 2-methylene-4-(4-methylphenyl)-4-oxobutanoic acid (2), was prepared by Friedel-Crafts acylation of toluene with itaconic anhydride (3) in the presence of aluminum trichloride and nitrobenzene in 63% yield without silica gel column purification. Compound 1 was prepared by Michael addition of 2 with thioacetic acid (4) in 74% yield. Overall, 1 was obtained in 47% yield from 3. The structures and synthetic mechanisms of by-products (five compounds) of 2 were also clarified.

Full text of DOI:10.1248/cpb.50.1407

October 2002
Notes
Chem. Pharm. Bull. 50(10) 1407—1412 (2002)
1407
A Practical Procedure for the Synthesis of Esonarimod, (R,S)-2-
Acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic Acid,
an Antirheumatic Agent (Part 1)
Toshiya NOGUCHI,* Akira ONODERA, Kazuyuki TOMISAWA, and Sadakazu YOKOMORI
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd.; 1–403 Yoshino-cho, Saitama, Saitama 330–8530,
Japan. Received June 4, 2002; accepted August 5, 2002
An efficient and practical procedure for the synthesis of esonarimod, (R,S)-2-acetylthiomethyl-4-(4-
methylphenyl)-4-oxobutanoic acid (1), a new antirheumatic drug, has been developed. The intermediate, 2-meth-
ylene-4-(4-methylphenyl)-4-oxobutanoic acid (2), was prepared by Friedel–Crafts acylation of toluene with ita-
conic anhydride (3) in the presence of aluminum trichloride and nitrobenzene in 63% yield without silica gel col-
umn purification. Compound 1 was prepared by Michael addition of 2 with thioacetic acid (4) in 74% yield.
Overall, 1 was obtained in 47% yield from 3. The structures and synthetic mechanisms of by-products (five com-
pounds) of 2 were also clarified.
Key words esonarimod; antirheumatic drug; Friedel–Crafts acylation; Michael addition; process chemistry
We originally developed esonarimod, (R,S)-2-acetylthio-
When dichloromethane was used, 2 was obtained in 57%
methyl-4-(4-methylphenyl)-4-oxobutanoic acid (1), as a new yield, along with small amounts of 3-methylene-4-(4-
antirheumatic drug.1,2) Compound 1 has a variety of effects methylphenyl)-4-oxobutanoic acid (5), 6-methyl-4-oxo-
on cellular and mediator events in inflammatory processes, 1,2,3,4-tetrahydro-2-naphthoic acid (6), 6-methyl-1-oxo-2,3-
inhibits the production of inflammatory cytokines including dihydro-1H-inden-2-ylacetic acid (7), 4-(4-methylphenyl)-2-
interleukin-1, interleukin-6, and tumor necrosis factor-a [(4-methylphenyl)methyl]-4-oxobutanoic acid (8) and 2-
from human peripheral blood mononuclear cells,3) and sup- methyl-4-(4-methylphenyl)-4-oxo-2-butenoic acid (9) (Entry
presses the development of arthritis in various animal mod- 1). These compounds were separated by silica gel column
els.1,2,4)
Our initial method for synthesizing 1 is outlined in Chart separate and obtained as a mixture. Consequently, the yields
chromatography, except for 6 and 7, which were difficult to
1
1.5,6)
of 6 and 7 were determined by H-NMR spectroscopy (d
In Step 1, 2-methylene-4-(4-methylphenyl)-4-oxobutanoic 7.85, 7.58). The yield of 2 was slightly higher than reported
acid (2) is obtained by Friedel–Crafts acylation of toluene previously.5) Among the solvents tested, nitroethane gave the
with commercially available itaconic anhydride (3) in the best yield (82%) with only small amounts of by-products, 5
presence of aluminum trichloride. When dichloromethane or and 9 (Entry 2). However, nitroethane is explosive.10) There-
1,2-dichloroethane was used as the solvent, 2 was obtained fore, we next examined nitrobenzene, although nitrobenzene
in 53% and 52% yield, respectively.5,6) However, 1,2-
dichloroethane is a Class 1 residual solvent, which should be
avoided if possible in the manufacture of drug substances be-
cause of their unacceptable toxicity or their deleterious envi-
ronmental effects.7,8) Dichloromethane is also not an environ-
mentally friendly solvent.9) Finally the yield was not satisfac-
tory.
In Step 2, 1 was obtained in 73% yield by Michael addi-
tion of 2 with thioacetic acid (4). In the previous paper,
potassium carbonate was used as the base for this reaction,
and N,N-dimethylformamide and water were used as the sol-
vent. Therefore, a large amount of solvent such as ethyl ac-
etate was required for the extraction of 1.
Since this initial synthetic method had several drawbacks
from the standpoint of commercial production, as described
Chart 1
above, a more efficient and practical procedure for the syn-
thesis of 1 was required. We report here a process for the Table 1. Solvent Effect for the Acylation of Toluene with Itaconic Anhy-
dride (3)
synthesis of 1. We also discuss the structures of the by-prod-
ucts of the Friedel–Crafts reaction and the mechanism of
their formation.
Entry
Solvent
2
5
6
7
8
9
1
2
3
4
Dichlromethane 57% 5%
3%
—
0.4%
12%
2% 8% 0.2%
Nitroethane
Nitrobenzene
Toluene
82% 2%
70% 3%
—
—
—
—
1%
1%
—
Results and Discussion
Synthesis of 2 (Step 1) A more appropriate solvent for
the Friedel–Crafts reaction of toluene with 3 was investigated
(Table 1).
29%
—
8% 8%
* To whom correspondence should be addressed. e-mail: t.noguchi@po.rd.taisho.co.jp
© 2002 Pharmaceutical Society of Japan

1408
Vol. 50, No. 10
Chart 2
Chart 3
Chart 4
is highly toxic.11,12) The reaction in nitrobenzene gave 2 in
70% yield (Entry 3). The use of toluene as the solvent re-
duced the yield of 2 and increased the formation of the unde-
sired products 6—8 (Entry 4).
When the reaction of toluene with 3 was carried out in ni-
trobenzene using AlCl3 followed by treatment with 3 mol/l
hydrochloric acid and hexane, 2 was obtained in 63% yield
as precipitates.
The Friedel–Crafts reaction of toluene with 3 produced
byproducts such as 5—9. Their structures are as shown in
Table 1. The formation of these minor compounds 5, 8, and
9, can be explained as follows (Chart 2).
Friedel–Crafts acylation of toluene with 3 (route A) pro-
duced 2. The Michael addition of toluene to 2 formed 8. On
the other hand, 2 isomerized and gave 9.13,14)
was recovered unchanged (Chart 3).
To confirm the structure of 6, we prepared 6 and the iso-
meric compound 10 by the unambiguous method15) starting
with 4-methylbenzylchloride (11) and 3-methylbenzylchlo-
ride (12), respectively (Chart 4). The reaction of diethyl 2-
acetylsuccinate with 13 gave 14, which was hydrolyzed to
the acid (15) and then treated with acetic anhydride to give
the anhydride (16). The intramolecular Friedel–Crafts acyla-
tion of 16 gave the desired 6. In the same way, 10 was ob-
tained from 12 via 17—20.
1
The H-NMR spectrum of 6 obtained from the reaction
mixture was completely identical to that of authentic sample
(Table 2).16)
Likewise, the structure of 7 was initially assumed to be
5-methyl-1-oxo-2,3-dihydro-1H-inden-2-ylacetic acid (21),
which could be produced by the intramolecular acylation of
5. Indeed, when 5 was treated under these reaction condi-
tions, 21 was produced in 38% yield (Chart 5).
The structure of 6 was initially assumed to be 7-methyl-4-
oxo-1,2,3,4-tetrahydro-2-naphthoic acid (10) formed by the
intramolecular cyclization of 2. However, treatment of 2
under these reaction conditions gave neither 6 nor 10, and 2
To confirm the structure of 7, the authentic sample was

October 2002
1409
Table 2. 1H-NMR Data of 6 Obtained from the Reaction Mixture, Authentic 6, and Authentic 10 in CDCl3
6 obtained from the reaction mixture
Authentic 6
2.37 (3H, s)
Authentic 10
2.39 (3H, s)
2.37 (3H, s)
2.75—3.02 (2H, m)
3.22 (3H, m)
7.18 (1H, d, Jϭ8.0 Hz)
7.33 (1H, dd, Jϭ2.0, 8.0 Hz)
7.85 (1H, d, Jϭ2.0 Hz)
2.74—3.04 (2H, m)
3.12—3.32 (3H, m)
7.19 (1H, d, Jϭ7.7 Hz)
7.34 (1H, dd, Jϭ1.5, 7.7 Hz)
7.84 (1H, br s)
2.73—3.03 (2H, m)
3.12—3.32 (3H, m)
7.10 (1H, s)
7.16 (1H, d, Jϭ8.1 Hz)
7.94 (1H, d, Jϭ8.1 Hz)
Chart 5
Chart 6
Table 3. 1H-NMR Data of 7 Obtained from the Reaction Mixture, Authentic 7, and Authentic 21 in CDCl3
7 obtained from the reaction mixture
Authentic 7
2.41 (3H, s)
Authentic 21
2.41 (3H, s)
2.45 (3H, s)
2.64 (1H, dd, Jϭ10.0, 17.0 Hz)
2.85 (1H, dd, Jϭ4.0, 17.0 Hz)
2.95—3.12 (2H, m)
2.63 (1H, dd, Jϭ9.6, 17.5 Hz)
2.85 (1H, dd, Jϭ4.5, 17.0 Hz)
2.99—3.08 (1H, m)
2.61 (1H, dd, Jϭ9.6, 18.0 Hz)
2.85 (1H, dd, Jϭ4.3, 17.0 Hz)
2.98—3.07 (1H, m)
3.04 (1H, dd, Jϭ4.2, 17.5 Hz)
3.44 (1H, dd, Jϭ7.8, 17.0 Hz)
7.36 (1H, d, Jϭ7.8 Hz)
7.44 (1H, dd, Jϭ1.2, 7.8 Hz)
7.58 (1H, d, Jϭ1.2 Hz)
3.04 (1H, dd, Jϭ4.5, 18.0 Hz)
3.43 (1H, dd, Jϭ7.7, 17.0 Hz)
7.20 (1H, dd, Jϭ0.5, 8.0 Hz)
7.26 (1H, d, Jϭ0.5 Hz)
3.43 (1H, dd, Jϭ8.0, 17.0 Hz)
7.34 (1H, d, Jϭ8.0 Hz)
7.44 (1H, d, Jϭ8.0 Hz)
7.58 (1H, s)
7.67 (1H, d, Jϭ8.0 Hz)
prepared by the unambiguous route shown in Chart 6. The yield (76%), but did not obtain 7. On the other hand, the
reaction of 3-methylbenzaldehyde (22) with vinylmagnesium treatment of 16 with AlCl3 in toluene at room temperature
bromide gave 23, which was converted to 24 via 25 in 3 for 30 min gave 5- and 6-membered cyclization products 6
steps. Treatment of 24 with AlCl3 in nitrobenzene afforded 7. and 7 (the ratio was about 3 : 2) by the intramolecular acyla-
The 1H-NMR spectrum of 7 obtained from the reaction mix- tion of both of the carbonyl group of 16. This result sup-
ture was completely identical to that of the authentic sample ported the notion that 16 was a common intermediate to 6
(Table 3).16)
and 7.
Synthesis of Esonarimod (1) (Step 2) For the Michael
These results indicated that 2 and 5 were not the interme-
diates to 6 and 7, respectively. A plausible mechanism for the addition of 2 with 4, toluene was selected as the solvent and
formation of 6 and 7 is shown in Chart 7. Compound 16 triethylamine as the base due to cost considerations. To pre-
would be a key intermediate to 6 and 7, but has not yet been vent the isomerization of 2 to 9 by an excess of amine, the
isolated. Fortunately, 16 was used as the intermediate for the minimum amount of base required was examined. When 0.2
authentic sample of 6, as shown in Chart 4. Therefore, we equivalents of triethylamine and 1.2 equivalents of 4 were
treated 16 with AlCl3 in nitrobenzene and obtained 6 in high used at 60 °C, the reaction was completed within 2 h.

1410
Vol. 50, No. 10
Chart 7
Table 4. Solvents for the Recrystallization of Esonarimod (1)
determined using a JEOL JMS-SIX102 spectrometer. Elemental analyses
were performed on a Perkin-Elmer 2400. TLC was performed on silica gel
pre-coated plates (Merck, Kieselgel 60F254). Column chromatography was
performed over silica gel (Wako, Wako gel C-200). Spots and bands were
detected by UV irradiation (254 nm). HPLC was performed on an ODS-80
TM column (Tosoh, 4.6ϫ150 mm) with 250 nm. Gas chromatography was
performed on a CBP20-S25-50 column (Shimadzu, 0.33 mmϫ25 mϫ0.50
mm) with flame ionization detector. AlCl3, powder type, was purchased from
Toyama Chemical.17) Thioacetic acid (4) was purchased from Toyo Kasei
Kogyo.18)
Entry
Solvent
Prurified 1
1
2
3
4
5
6
7
8
9
1,4-Dioxane (5 ml)
Acetone (5 ml)
Ethyl acetate (5 ml)
Methanol (5 ml)
Ethanol (5 ml)
IPA (5 ml)
Toluene (5 ml)
Toluene (20 ml)
IPE (50 ml)
27%
47%
68%
54%
74%
71%
91%
84%
88%
3-Methylene-4-(4-methylphenyl)-4-oxobutanoic Acid (5), 6-Methyl-4-
oxo-1,2,3,4-tetrahydro-2-naphthoic Acid (6), 6-Methyl-1-oxo-2,3-dihy-
dro-1H-inden-2-ylacetic Acid (7), 4-(4-Methylphenyl)-2-[(4-methylphenyl)-
methyl]-4-oxobutanoic Acid (8) and 2-methyl-4-(4-methylphenyl)-4-oxo-
2-butenoic Acid (9) A mixture of 3 (112 g, 999 mmol) and toluene
(200 ml, 1.88 mol) was added dropwise to AlCl3 (250 g, 1.87 mol)–
dichloromethane (250 ml). The reaction mixture was stirred under ice cool-
ing for 1 h, and then at room temperature for 6 h. The reaction mixture was
poured into 3 mol/l hydrochloric acid, and the precipitate was collected by
filtration. The crude product was recrystallized from ethyl acetate–hexane to
give 106 g (52%) of 2. This 2 included byproducts 5—9, which were iso-
lated by silica gel column chromatography.
All reactions were conducted on a 5.0 g scale. The purity of 1 was detected by
HPLC. IPA: isopropyl alcohol, IPE: isopropyl ether.
We finally studied the purification of crude 1. We exam-
ined the solvents for recrystallization, and the results are
shown in Table 4.
Toluene was found to be a suitable solvent for the recrys-
tallization of 1. However, toluene then had to be removed.
5: mp 57—58 °C. 1H-NMR (300 MHz, CDCl3) d: 2.42 (3H, s), 3.56 (2H,
s), 5.81 (1H, s), 6.02 (1H, s), 7.25 (2H, d, Jϭ8.0 Hz), 7.47 (2H, d,
The residual toluene in 1 was over 1000 ppm. Toluene is a Jϭ8.0 Hz). IR (KBr) cmϪ1: 3146, 1724, 1642, 1606, 1344. MS m/z: 205
(MH)ϩ. Anal. Calcd for C12H12O3: C, 70.57; H, 5.92. Found: C, 70.43; H;
Class 2 residual solvent.7,8) Therefore, we next selected iso-
5.89.
propyl ether as the recrystallization solvent. The residual iso-
6: mp 208—209 °C. 1H-NMR was written in Table 2, IR (KBr) cmϪ1
:
propyl ether was under 500 ppm, although the yield from 2
was 74%. Thus, 1 was obtained in the overall yield of 47% in
2 steps from 3.
2950, 1702, 1684, 1612. Anal. Calcd for C12H12O3: C, 70.57; H, 5.92.
Found: C, 70.32; H; 5.88.
7: mp 145—148 °C. 1H-NMR was written in Table 3, IR (KBr) cmϪ1
:
2925, 1740, 1670, 1605. Anal. Calcd for C12H12O3: C, 70.57; H, 5.92.
Found: C, 70.63; H, 5.89.
8: mp 156—157 °C. H-NMR (200 MHz, CDCl3) d: 2.29 (3H, s), 2.41
Conclusion
1
An efficient process for the large-scale synthesis of es-
onarimod (1) was established. Compound 1 was obtained in a
higher overall yield than in the initial synthesis (47% from
commercially available itaconic anhydride (3) vs. 39%).
In Step 1, some by-products, 5—9, were found to be pro-
duced. The structures and the mechanism of the formation of
these compounds were also clarified.
(3H, s), 2.43 (1H, dd, Jϭ4.6, 17.4 Hz), 2.56 (1H, dd, Jϭ9.5, 14.0 Hz), 2.91
(1H, dd, Jϭ9.5, 17.4 Hz), 3.04 (1H, dd, Jϭ4.6, 14.0 Hz), 3.98—4.15 (1H,
m), 7.02 (2H, d, Jϭ8.1 Hz), 7.07 (2H, d, Jϭ7.9 Hz), 7.26 (2H, d, Jϭ7.9 Hz),
7.88 (2H, d, Jϭ8.1 Hz). IR (KBr) cmϪ1: 3020, 2926, 1706, 1664, 1604,
1436, 1342, 1012. MS m/z: 297 (MH)ϩ. Anal. Calcd for C19H20O3: C, 77.00;
H, 6.80. Found: C, 76.93; H, 6.61.
9: mp 140—141 °C. 1H-NMR (200 MHz, CDCl3) d: 2.18 (3H, d,
Jϭ1.5 Hz), 2.44 (3H, s), 7.31 (2H, d, Jϭ8.1 Hz), 7.83 (1H, q, Jϭ1.5 Hz),
7.89 (2H, d, Jϭ8.1 Hz). IR (KBr) cmϪ1: 2990, 2622, 1702, 1658, 1604,
1572, 1364. MS m/z: 205 (MH)ϩ. Anal. Calcd for C12H12O3: C, 70.57; H,
5.92. Found: C, 70.57; H, 5.87.
Synthesis of 6-Methyl-4-oxo-1,2,3,4-tetrahydro-2-naphthoic Acid (6).
4-Methylbenzyliodide (13) To a solution of 4-methylbenzylchloride (11)
(11.5 g, 81.8 mmol) in acetone (115 ml) was added sodium iodide (13.5 g,
Experimental
General Melting points were determined by a Buchi 535 melting point
apparatus and were uncorrected. IR spectra were obtained on a Perkin-Elmer
1760 spectrometer. 1H-NMR spectra were recorded on a Varian VXL-200 or
VXR-300 spectrometer. Chemical shifts are reported in ppm (d) values, as

October 2002
1411
90.1 mmol). The mixture was stirred at room temperature for 3 h. Sodium was dissolved in ethyl acetate, dried over MgSO4, and evaporated in vacuo
iodide (1.00 g, 6.67 mmol) was added, the mixture was stirred for an addi-
to afford a pale yellow powder, which was washed with hexane and recrys-
tional 40 min. The reaction mixture was then diluted with water and ex- tallized from ethyl acetate to give 1.10 g (54%) of 10. mp 196—197 °C, 1H-
tracted with hexane. The extract was washed with water, dried over MgSO4, NMR was written in Table 2, IR (KBr) cmϪ1: 2974, 1700, 1678, 1608, 1438,
and evaporated in vacuo to give 18.4 g (97%) of 13 as a yellow oil.
Diethyl 2-Acetyl-2-(4-methylphenyl)succinate (14) To a solution of
diethyl acetylsuccinate (11.9 g, 55.0 mmol) in toluene (100 ml) was added
1262. MS m/z: 204 (Mϩ). Anal. Calcd for C12H12O3: C, 70.57; H, 5.92.
Found: C, 70.57; H; 5.83.
Synthesis of 6-Methyl-1-oxo-2,3-dihidro-1H-inden-2-ylacetic Acid (7).
1.30 g (54.2 mmol) of sodium hydride oil suspension. Compound 13 (14.2 g, 1-(3-Methylphenyl)-3-buten-1-ol (23) To a solution of 3-methylbenzalde-
61.2 mmol) was then added, an insoluble compound was produced immedi- hyde (22) (4.00 g, 33.3 mmol) in tetrahydrofuran (50 ml) was added 50 ml of
ately (probably sodium iodide). The reaction mixture was stirred at room vinylmagnesium bromide (1 mol/l hexane solution) under ice cooling. The
temperature overnight, then acidified by aqueous hydrochloric acid and ex- reaction mixture was stirred at room temperature for 1 h and then 1 mol/l hy-
tracted with toluene. The extract was washed with water, dried over MgSO4, drochloric acid (20 ml) was added. The mixture was then extracted with
and evaporated in vacuo to give 23.3 g of 14 as a yellow oil.
ethyl acetate, washed with brine and water, dried over MgSO4, and evapo-
2-(4-Methylphenyl)succinic Acid (15) To 14 (23.3 g, 72.7 mmol) was rated in vacuo. The residue was purified by column chromatography using
added a solution of sodium hydroxide (8.70 g, 218 mmol) in water (100 ml),
and the mixture was refluxed for 17 h. Sodium hydroxide (1.50 g, oil.
37.5 mmol) and water (10 ml) were added, and the mixture was refluxed for
ethyl acetate : hexaneϭ1 : 3—1 : 1 to give 4.80 g (89%) of 23 as a colorless
4-(3-Methylphenyl)-4-oxobutanoic Acid (25) To a solution of 23
an additional 4 h. The reaction mixture was cooled, acidified with aqueous (7.44 g, 45.9 mmol) in tetrahydrofuran (30 ml) was added 7.44 g of
hydrochloric acid and extracted with ether. The extract was washed with borane–tetrahydrofuran complex (1 mol/l). The reaction mixture was stirred
water, dried over MgSO4, and evaporated in vacuo to afford a yellow oil. The at room temperature for 1 h and diluted with water (11.2 ml) and 3 mol/l
residue was recrystallized from ethyl acetate–hexane to give 5.10 g (38% sodium hydroxide (15 ml). Next, 30% hydrogen peroxide (15 ml) was added
from 13) of 15 as a white powder.
slowly, and the mixture was stirred at room temperature for 1 h. It was then
2-(4-Methylphenyl)succinic Anhydride (16) A mixture of 15 (2.22 g, diluted further with 150 ml of water and extracted with ethyl acetate. The ex-
9.99 mmol) and acetic anhydride (10.2 g, 99.9 mmol) was heated to 110 °C. tract was washed with brine, water, dried over MgSO4 and evaporated in
After stirring for 30 min, acetic anhydride was azeotroped with toluene to af- vacuo. The residue was purified by column chromatography using ethyl ac-
ford a pale yellow oil, which was recrystallized from hexane to give 1.86 g
(91%) of 16.
etate : hexaneϭ2 : 3—1 : 0 to give 6.32 g (76%) of 1-(3-methylphenyl)-1,4-
butanediol as a white crystal.
6-Methyl-4-oxo-1,2,3,4-tetrahydro-2-naphthoic Acid (6) To a solution
of 16 (1.84 g, 9.01 mmol) in nitrobenzene (5 ml) was added 2.52 g (18.9
1-(3-Methylphenyl)-1,4-butanediol (6.00 g, 37.0 mmol) was dissolved in
acetone (50 ml), and 4 mol/l Jones reagent (29 ml) was added. The reaction
mmol) of AlCl3. The mixture was stirred at room temperature for 1 h, mixture was stirred at room temperature for 40 min and then diluted with
poured into aqueous hydrochloric acid and extracted with ethyl acetate. The water (100 ml) and extracted with ethyl acetate. The extract was washed with
extract was washed with water and evaporated in vacuo. Nitrobenzene was brine and dried over MgSO4. It was evaporated in vacuo, and recrystallized
azeotroped with water to give a white powder. The residue was dissolved in from ethyl acetate to give 3.02 g of 25. Its mother liquid was evaporated in
ethyl acetate, dried over MgSO4, and concentrated to recrystallize. The crys- vacuo and purified by column chromatography using ethyl acetate : hexaneϭ
1
tal was filtered to give 1.40 g (76%) of 6. mp 214—215 °C, H-NMR was 2 : 3—1 : 0 to give 2.47 g of 25. Overall, 5.49 g (86%) of 25 was obtained.
written in Table 2, IR (KBr) cmϪ1: 2950, 1702, 1684, 1612, 1572, 1410. MS
m/z: 205 (MH)ϩ. Anal. Calcd for C12H12O3: C, 70.57; H, 5.92. Found: C,
70.49; H; 5.88.
6-Methyl-1-oxo-2,3-dihydro-1H-inden-2-ylacetic Acid (7) To a mix-
ture of 25 (5.20 g, 27.1 mmol) and pyridine (22 ml) were added paraformalde-
hyde (2.70 g) and pyridine (0.45 ml) at room temperature. The mixture was
Synthesis of 7-Methyl-4-oxo-1,2,3,4-tetrahydro-2-naphthoic Acid (10). stirred at 70 °C for 5 h, and then at 75 °C for 2.5 h. The reaction mixture was
3-Methylbenzyliodide (17) To a solution of 3-methylbenzylchloride (12) diluted with 1 mol/l hydrochloric acid (30 ml) and extracted with 200 ml of
(11.1 g, 78.9 mmol) in acetone (111 ml) was added 23.7 g (158 mmol) of ethyl acetate. The extract was washed with brine, dried over MgSO4, and
sodium iodide, and the mixture was stirred at room temperature overnight evaporated in vacuo. The residue was purified by column chromatography
and then filtered. The solvent was evaporated in vacuo. The residue was di- using ethyl acetate : hexaneϭ2 : 3—1 : 0 to give 4.20 g of colorless crystals.
luted with water and extracted with ether. The extract was washed with Recrystallization from ether–hexane gave 2.74 g (50%) of 3-methylene-4-(3-
water and aqueous sodium thiosulfate, dried over MgSO4, and evaporated in methylphenyl)-4-oxobutanoic acid (24).
vacuo to give 17.1 g (93%) of 17 as yellow oil.
To a solution of 24 (1.95 g, 9.55 mmol) and nitrobenzene (15 ml) was
Diethyl 2-Acetyl-2-(3-methylphenyl)succinate (18) To a solution of
added 2.80 g (21.0 mmol) of AlCl3. The reaction mixture was stirred at
diethyl acetylsuccinate (15.4 g, 71.2 mmol) in toluene (100 ml) was added 60 °C for 2.5 h, diluted with 2 mol/l hydrochloric acid (400 ml) and extracted
1.70 g (70.8 mmol) of sodium hydride. Compound 17 (17.1 g, 73.7 mmol) with 200 ml of ethyl acetate. The extract was washed with brine, dried over
was added, and an insoluble compound was produced immediately (probably MgSO4, and evaporated in vacuo. The residue was purified by column chro-
sodium iodide). The reaction mixture was stirred overnight, acidified by matography using ethyl acetate : hexaneϭ1 : 2—2 : 1 to give 1.00 g of white
aqueous hydrochloric acid and extracted with toluene. The extract was crystals. Recrystallization from ethyl acetate–hexane gave 560 mg (29%) of
washed with water, dried over MgSO4, and evaporated in vacuo to give 7 as colorless needles. mp 151—153 °C, 1H-NMR was written in Table 3. IR
22.2 g (94%) of 18 as yellow oil.
2-(3-Methylphenyl)succinic Acid (19) To 18 (22.2 g, 69.3 mmol) was C, 70.57; H, 5.92. Found: C, 70.44; H, 5.82.
(KBr) cmϪ1: 2918, 1708, 1614, 1580, 1406, 1252. Anal. Calcd for C12H12O3:
added a solution of sodium hydroxide (8.30 g, 208 mmol) in water (100 ml).
Synthesis of 5-Methyl-1-oxo-2,3-dihydro-1H-inden-2-ylacetic Acid
The reaction mixture was refluxed for 9 h and a solution of sodium hydrox- (21). 3-Methylene-4-(4-methylphenyl)-4-oxobutanoic Acid (5) To a mix-
ide (1.40 g, 35.0 mmol) in water (6 ml) was then added. The reaction mixture ture of succinic anhydride (15.0 g, 144 mmol) and toluene (91.5 ml, 859
was refluxed further overnight, cooled, acidified with aqueous hydrochloric mmol) was added 44.1 g (331 mmol) of AlCl3, and the mixture was stirred at
acid and extracted with ether. The extract was washed with water, dried over 50—60 °C for 2 h. It was then poured into 2.5 mol/l hydrochloric acid
MgSO4, and evaporated in vacuo to afford a brown oil. The residue was re- (250 ml), and the precipitate was collected by filtration. The precipitate was
crystallized from chloroform–hexane and then recrystallized again from ace- washed with 2.5 mol/l hydrochloric acid (100 ml), water (200 ml), and
tone–hexane to give 7.90 g (52%) of 19 as a colorless powder.
toluene (20 ml), recrystallized from ethyl acetate–hexane to give 24.0 g of 4-
2-(3-Methylphenyl)succinic Anhydride (20) A mixture of 19 (7.90 g, (4-methylphenyl)-4-oxobutanoic acid as colorless leaflets (1st crop). Its
35.5 mmol) and acetic anhydride (36.2 g, 355 mmol) was heated to 110 °C. mother liquid was evaporated in vacuo and recrystallized from ethyl ac-
After stirring for 30 min, acetic anhydride was azeotroped with toluene to af- etate–hexane to give 1.50 g of 2nd crop. Overall, 25.5 g (88%) of 4-(4-
ford a pale yellow oil, which was recrystallized from hexane to give 6.88 g
methylphenyl)-4-oxobutanoic acid was obtained.
(95%) of 20.
To a mixture of 4-(4-methylphenyl)-4-oxobutanoic acid (10.0 g, 52.0
7-Methyl-4-oxo-1,2,3,4-tetrahydro-2-naphthoic Acid (10) To a solu- mmol) and pyridine (20 ml) were added paraformaldehyde (2.36 g) and pyri-
tion of 20 (2.04 g, 9.99 mmol) in nitrobenzene (5 ml) was added 2.80 g dine (0.4 ml). The reaction mixture was stirred at 60 °C for 12 h, poured into
(21.0 mmol) of AlCl3. The reaction mixture was stirred at room temperature 1 mol/l hydrochloric acid (300 ml) and extracted with 400 ml of ethyl ac-
overnight, poured into aqueous hydrochloric acid and extracted with ethyl etate. The extract was washed with brine and water, dried over MgSO4, and
acetate. The extract was washed with water and evaporated in vacuo. Ni- evaporated in vacuo. The residue was purified by column chromatography
trobenzene was azeotroped with water to afford a white powder. The residue using ethyl acetate : hexaneϭ1 : 1—2 : 1 and recrystallized from ethyl ac-

1412
Vol. 50, No. 10
etate–hexane to give 5.68 g of 5 as colorless crystals.
References and Notes
5-Methyl-1-oxo-2,3-dihydro-1H-inden-2-ylacetic Acid (21) To a mix-
ture of 5 (5.20 g, 25.5 mmol) and nitrobenzene (39 ml) was added 7.48 g
(56.1 mmol) of AlCl3. The mixture was stirred at 70 °C for 3 h, poured into
1 mol/l hydrochloric acid (200 ml) and extracted with 300 ml of ethyl ac-
etate. The extract was washed with brine and water, dried over MgSO4, and
evaporated in vacuo. The residue was purified by column chromatography
using ethyl acetate : hexaneϭ1 : 1—1 : 0 and recrystallized from ethyl ac-
etate–hexane to give 1.60 g of 21 as colorless crystals. From the mother liq-
uid, 0.40 g of 21 was obtained. Overall, 2.00 g (38%) of 21 was obtained. mp
111—112 °C, 1H-NMR was written in Table 3, IR (KBr) cmϪ1: 3024, 2932,
1712, 1612, 1342, 1256. MS m/z: 204 (Mϩ). Anal. Calcd for C12H12O3: C,
70.57; H, 5.92. Found: C, 70.51; H, 5.87.
Synthesis of Esobnarimod (1). 2-Methylene-4-(4-methylphenyl)-4-
oxobutanoic Acid (2) One mole (134 g) of AlCl3 was added portionwise
to nitrobenzene (170 ml) at 25 °C and the mixture was stirred for 10 min.
Compound 3 (56.0 g, 500 mmol) was then added, and 60 ml (563 mmol) of
toluene was added dropwise over 10 min. The reaction mixture was stirred at
1) Takeshita K., Fukazawa I., Futaki N., Kameo K., Tomisawa K., Otomo
S., Aihara H., Arzneim.-Forsch./Drug Res., 38, 537—542 (1988).
2) Takahashi S., Inoue T., Higaki M., Mizushima Y., Drugs Exp. Clin.
Res., 24, 67—71 (1988).
3) Yasuda Y., Inoue T., Takeshita K., Drugs Exp. Clin. Res., 22, 1—8
(1996).
4) Hashimoto M., Kobayashi K., Yamagata N., Katsura T., Sugihara S.,
Iwabuchi H., Kasama T., Kasahara K., Takahashi T., Takeshita K.,
Otomo S., Agents Actions, 37, 99—106 (1992).
5) Kameo K., Ogawa K., Takeshita K., Nakaike S., Tomisawa K., Sota
K., Chem. Pharm. Bull., 36, 2050—2060 (1988).
6) Tomisawa K., Kameo K., Matsunaga T., Saito S., Sota K., Jpn. Patent
19383 (1988).
7) Erni F., Helboe P., Artiges A., Pharmeuropa, 8, 538—547 (1996).
8) Connelly J. C., Hasegawa R., McArdle J. V., Tucker M. L., Pharmeu-
ropa, 9, S1—S68 (1997).
9) Sidebottom H., Franklin J., Pure Appl. Chem., 68, 1757—1769 (1996).
50 °C for 40 min, and then poured into conc. hydrochloric acid (100 10) Lenda R. E., Votoupal K. L., “The Sigma-Aldrich Library of Regula-
ml)–water (400 ml) at 20 °C. Hexane (360 ml) was then added and the mix-
ture was stirred for 20 min and filtered. The filtrate was washed with 3 mol/l
tory and Safety Data,” by Sigma-Aldrich Corporation, 1993, pp.
443—444.
hydrochloric acid (100 ml), water (100 ml) (twice), and IPE (100 ml) (twice) 11) Dodd D. E., Fowler E. H., Snellings W. M., Pritts I. M., Tyl R. W.,
to give 64.3 g (63%) of 2. mp 147—148 °C, 1H-NMR (200 MHz, CDCl3) d:
2.42 (3H, s), 3.97 (2H, s), 5.80 (1H, d, Jϭ1.1 Hz), 6.52 (1H, d, Jϭ1.1 Hz),
Lyon J. P., O’Neal F. O., Kimmerle G., Fundam. and Appl. Toxicol., 8,
493—505 (1987).
7.26 (2H, d, Jϭ8.1 Hz), 8.35 (2H, d, Jϭ8.1 Hz). IR (KBr) cmϪ1: 1703, 1685, 12) Cattley R. C., Everitt J. I., Gross E. A., Moss O. R., Hamm T. E., Jr.,
1637, 1608, 1573, 1325, 1235, 809. MS m/z: 204 (Mϩ). Anal. Calcd for
C12H12O3: C, 70.57; H, 5.92. Found: C, 70.46; H, 5.87.
Esonarimod (1) To a mixture of 2 (64.3 g, 315 mmol) and 330 ml of
Popp J. A., Fundam. and Appl. Toxicol., 22, 328—340 (1994).
13) Fateen A. K., Sammour A. M., Ismail M. F., J. Chem. U.A.R., 10,
331—335 (1967).
toluene was added 4 (27.3 ml, 382 mmol), heated to 60 °C. A solution of tri- 14) Lutz R. E., Bailey P. S., Dien C., Rinker J. W., J. Am. Chem. Soc., 75,
ethylamine (9.1 ml, 65.3 mmol) in toluene (40 ml) was then added dropwise
over 30 min. The reaction mixture was stirred at 60 °C for 4 h, diluted in
100 ml of ethyl acetate, and washed with 1.5 mol/l sulfuric acid (35 ml),
water (35 ml) (twice), and brine (35 ml). The extract was dried over MgSO4
and evaporated in vacuo. The residue was recrystallized from 270 ml of iso-
5039—5044 (1953).
15) Haworth R. D., Jones B., Way Y. M., J. Chem. Soc., 1943, 10—13
(1943).
16) Noguchi T., Onodera A., Kamiyama H., Yokomori S., The 121th An-
nual Meeting of the Pharmaceutical Society of Japan, Abstracts, 2001,
No. 3, p. 12.
propylether to give 65.3 g (74%) of 1. The overall yield of 1 from 3 was
1
47%. mp 97 °C, H-NMR (300 MHz, CDCl3) d: 2.34 (3H, s), 2.41 (3H, s), 17) Toyama Chemical Co., Ltd., 3–2–5 Nishishinjuku, Shinjuku-ku,
3.15—3.40 (4H, m), 3.46 (1H, m), 7.26 (2H, d, Jϭ8.1 Hz), 7.85 (2H, d,
Jϭ8.1 Hz), 10.00 (1H, br s). IR (KBr) cmϪ1: 1714, 1697, 1673, 1607, 1211,
816. MS m/z: 281 (MHϩ). Anal. Calcd for C14H16O4S: C, 59.98; H, 5.75; S,
11.44. Found: C, 59.77; H, 5.72; S, 11.45.
Tokyo, Japan.
18) Toyo Kasei Kogyo Co., Ltd., Toyobo Building, 17–9 Nihonbashi,
Koami-cho, Chuo-ku, Tokyo, Japan.