Lewis acid free high speed synthesis of nimesulide-based novel N-substituted cyclic imides

Article abstract of DOI:10.1590/S0103-50532010000600015

The frst synthesis of nimesulide-based novel cyclic imides has been accomplished via the reaction of an amine prepared from nimesulide with appropriate anhydrides in the presence of sodium acetate. Using this process a variety of N-substituted cyclic imides was prepared in good yields in glacial acetic acid. Some of the compounds synthesized showed anti-infammatory activities when tested in vivo.

Full text of DOI:10.1590/S0103-50532010000600015

J. Braz. Chem. Soc., Vol. 21, No. 6, 1060-1064, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Lewis Acid Free High Speed Synthesis of Nimesulide-Based Novel
N-Substituted Cyclic Imides
Kavitha Kankanala,a,b Vangala Ranga Reddy,c Khagga Mukkantia and Sarbani Pal*,b
aJNT University Hyderabad, Kukatpally, Hyderabad-500085, India
bDepartment of Chemistry, MNR Degree and PG College, Kukatpally, Hyderabad-500072, India
cDr. Reddy’s Laboratories Ltd. Integrated Product Development, Bachupally,
Hyderabad-500090, India
A primeira síntese de novas imidas cíclicas derivadas de nimessulida foi realizada via reação
de uma imina preparada a partir de nimessulida com anidridos apropriados na presença de acetato
de sódio. Usando este processo, uma variedade de imidas cíclicas N-substituídas foi preparada
em bons rendimentos em ácido acético glacial. Alguns dos compostos sintetizados mostraram
atividades anti-inflamatórias quando testados in vivo.
The first synthesis of nimesulide-based novel cyclic imides has been accomplished via the
reaction of an amine prepared from nimesulide with appropriate anhydrides in the presence of
sodium acetate. Using this process a variety of N-substituted cyclic imides was prepared in good
yields in glacial acetic acid. Some of the compounds synthesized showed anti-inflammatory
activities when tested in vivo.
Keywords: nimesulide, anhydride, cyclic imide, anti-inflammatory activities
NHSO2CH3
Introduction
O
NHSO2CH3
O
R1
O
N-Substituted cyclic imides A (Figure 1) represent an
important class of bioactive molecules that show a wide
range of pharmacological activities such as androgen
receptor antagonistic, anti-inflammatory, anxiolytic,
antiviral, antibacterial, and antitumor properties.1-11
On the other hand N-(4-nitro-2-phenoxy phenyl)
methanesulfonamide or nimesulide B (see Figure 1), a
preferential cyclooxygenase-2 (COX-2) inhibitor is one
of the well known non-steroidal anti-inflammatory drugs
(NSAIDs) that has been utilized to treat pain and other
inflammatory diseases. Because of their common anti-
inflammatory properties and our interest in nimesulide
derivatives12 as potential anti-inflammatory agents we
decided to prepare compound C having structural features
of both A and B.
N R
O
O
O
N
NO2
R2
R1
R2
A
B
C
R1, R2 = diverse substituents
Figure 1. Design of novel cyclic imide derived from nimesulide.
temperature,15 (ii) the cyclization of the amic acid in the
presence of acidic reagents,16 (iii) N-alkylation of maleimide
with alcohols under Mitsunobu reaction conditions,13
(iv) Lewis acids or hexamethyldisilazane catalyzed synthesis
of N-alkyl and N-arylimide derivatives17 and dehydrative
cyclization of acid anhydrides, imides and dicarboxylic
acids with substituted amines in the presence of DPPOx
and Et3N.18 However, many of these methodologies suffer
from several drawbacks such as (i) the use of expensive
catalysts or Lewis acids and carcinogenic solvent media
and (ii) formation of numerous by-products leading to the
poor yields of products. Moreover, only a narrow range of
imide derivatives can be synthesized by using these methods.
In spite of their extensive pharmaceutical and industrial
use only a limited number of procedures are available for
the synthesis of A.13,14 These include (i) the dehydrative
condensation of an anhydride and an amine at high
*e-mail: sarbani277@yahoo.com

Vol. 21, No. 6, 2010
Kavitha et al.
1061
Table 1. Synthesis of novel N-substituted cyclic imides
While microwave assisted addition of amines to phthalic
anhydride has been studied,19 no significant difference was
observed when the reaction was carried out by microwave
or conventional heating in DMF.20 Moreover, microwave-
assisted solvent free synthesis of cyclic imides required the
use of TaCl5-silica gel as catalyst.21 To overcome all these
issues, we herein report the Lewis acid free rapid synthesis22
of novel N-substituted cyclic imides derived from nimesulide
under conventional heating.
Cyclic
Entry anhydrides
Reaction
conditionsa Yieldb
%
Products (3)
(2)
1.
3a 110-120 ºC 62c
1.5 h
2a
2.
3.
2a
3a 110-120 ºC 73d
Results and Discussion
10 min
3b 110-120 ºC 65d
The starting compound 1 required for our study was
prepared12 in quantitative yield from nimesulide B via
reducing its nitro group as shown in Scheme 1.
15 min
2b
The aromatic amine was then treated with a variety
of cyclic anhydrides 2 (Scheme 1) and the results are
summarized in Table 1. In the beginning of our study,
the reaction of aromatic amine 1 with phthalic anhydride
2a was examined under a conventional condition. After
refluxing the reaction mixture in glacial acetic acid for 1.5 h
the desired imide 3a was isolated in 62% yield (Entry 1,
Table 1). In order to improve the product yield the above
reaction was carried out in the presence of NaOAc in the
same solvent.
The reaction was completed within 10 min affording
3a in 73% yield (Entry 2, Table 1). A further accelerating
effect was observed when the reaction was carried out
in the presence of NaOAc providing 3a in 62 and 73%
yield respectively (Entry 1 and 2, Table 1). Encouraged by
these observations, especially in the presence of NaOAc
(Entry 2, Table 1) when the reaction was completed within
10.0 min, we decided to asses the generality of this process
for the synthesis of other related derivatives. As indicated
in Table 1 that nitro substituted phthalic anhydrides (2b
and 2c) reacted with 1 even slower than 2a (Entries 3 and
4 vs 2, Table 1) in the presence of sodium acetate. Among
the aliphatic anhydrides, the six-membered anhydride
2f (Entry 7, Table 1) produced the best result. All these
reactions were also performed under conventional heating
condition without sodium acetate (c.f. Entry 1, Table 1)
and the results were compared with that of sodium acetate
4.
3c 110-120 ºC 65d
15 min
2c
5.
6.
3d 110-120 ºC 65d
15 min
2d
2e
3e 110-120 ºC 65d
20 min
7.
3f 110-120 ºC 75d
20 min
2f
aAll the reactions were carried out using compound 1 (1.0 mmol), cyclic
anhydride 2 (1.0 mmol) and anhydrous NaOAc (100 mg, 1.2 mmol).
bIsolated yield. cThe reaction was carried out in the absence of NaOAc.
dGlacial acetic acid was used as a solvent.
O
O
O
NHSO2CH3
O
NHSO2CH3
O
NHSO2CH3
O
Sn/HCl
2
O
O
N
90 oC, 3h
NO2
NH2
B
1
3
Scheme 1. Preparation of N-substituted cyclic imides from nimesulide.

1062
Lewis Acid Free High Speed Synthesis of Nimesulide-Based Novel
J. Braz. Chem. Soc.
catalysed method. Nevertheless, all the compounds
prepared are novel and well characterized by spectral
and analytical data.
Preparation of cyclic amides (3)
Typical procedure for the preparation of 3a
Having synthesized a range of nimesulide-based novel
cyclic imides we decided to examine anti-inflammatory
activities of selected compounds e.g. 3a, 3b, 3c, 3e and
3f. The anti-inflammatory activity of these compounds
was evaluated in a carrageenan-induced rat model
of inflammation23 using indomethacin as a reference
compound. At a dose of 100 mg kg-1 (i.p.) compound 3f
showed 20, 25, 45 and 40% inhibition of edema after 1, 2,
3 and 4h when indomethacin showed 24, 43, 66 and 93%
inhibition at 10 mg kg-1 at the same time points. Though
the other compounds were also found to be active (15-25%
inhibition of edema at various time points) when dosed
at 100 mg kg-1 the compound 3f was found to be the best
among them.
To a mixture of compound 1 (278 mg, 1.0 mmol) and
phthalic anhydride 2a (148 mg, 1.0 mmol) in glacial acetic
acid (3 mL) was added anhydrous sodium acetate (100 mg,
1.2 mmol) and the mixture was allowed to reflux for 10 min.
After completion of the reaction (as indicated by TLC) the
mixture was added to crushed ice (50 g) and stirred. The
solid separated was filtered and dried. The crude product
was purified by column chromatography followed by re-
crystallization from methanol.
N-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-phenoxy-
phenyl]methanesulfonamide (3a)
White solid; mp 230-232 ºC; Rf 0.95 (CHCl3:
Ethylacetate = 9:1), IR (KBr) νmax/cm-1: 1714, 1HNMR
(400 MHz, CDCl3) d 3.0 (s, 3H), 6.8 (m, 2H), 7.1 (m, 2H),
7.2 (m, 2H),7.4 (m, 2H), 7.7 (m, 3H), 7.9 (m, 2H); 13CNMR
(75 MHz, CDCl3) d 40.0 (CH3), 116.1 (CH), 118.9 (CH),
121.1 (CH), 122.1 (CH), 123.8 (CH), 124.8 (CH), 127.6
(C), 128.6 (C), 130.2 (CH), 131.5 (C), 134.5 (CH), 147.2
(C), 155.2 (C), 166.8 (C); MS 408 (M+, 100%); Elemental
analysis found: C, 61.70, H 3.94, N 6.89; C21H16N2O5S
requires C, 61.75; H, 3.95; N, 6.86%.
Conclusions
We have described a simple and rapid synthesis of novel
cyclic substituted imides24 that were designed from a well
known drug nimesulide. The aromatic amine prepared from
nimesulide was reacted with a variety of cyclic anhydrides
in the presence of sodium acetate to afford the desired
products within few minutes. Overall, due to the shorter
reaction time and simple operational procedure that does
not require the use of expensive catalysts / solvents, would
find wide application in the synthesis of various nimesulide-
based cyclic imides of potential pharmacological interest.
Some of the compounds synthesized showed anti-
inflammatory activity when tested in rats.
N-[4-(4-nitro-1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-phenoxy-
phenyl]methanesulfonamide (3b)
Light green solid; mp 214-216 ºC; Rf 0.68 (CHCl3:
1
Ethylacetate = 9:1); IR (KBr) νmax/cm-1: 1732; HNMR
(400 MHz, DMSO-d6) d 3.0 (s, 3H), 7.0 (s, 1H), 7.1 (d,
J 7.8 Hz, 2H), 7.2 (m, 2H), 7.4 (t, J 7.8 Hz, 2H), 7.6 (d,
J 8.3 Hz, 1H), 8.0 (t, J 7.8 Hz, 1H), 8.2 (d, J 6.7 Hz, 1H),
8.3 (d, J 7.4 Hz, 1H), 9.5 (bs, 1H, NH); 13CNMR (75 MHz,
CDCl3) d 39.9 (CH3), 116.0 (CH), 119.0 (CH), 120.8 (CH),
122.2 (CH), 125.0 (CH), 127.4 (CH), 127.6 (C), 128.3 (CH),
128.9 (C), 130.3 (CH), 135.8 (CH), 147.2 (C), 155.1 (C); MS
453 (M+, 100%); Elemental analysis found: C, 55.69, H 3.35,
N 9.19; C21H15N3O7S requires C, 55.63; H, 3.33; N, 9.27%.
Experimental
Melting points were determined by open glass capillary
method on a Cintex melting point apparatus and are
uncorrected. IR spectra were recorded on a Perkin-Elmer
1
spectrometer using KBr pellets. HNMR spectra were
recorded on a Bruker ACF-300 machine and a Varian 300
and 400 MHz spectrometer using CDCl3 or DMSO-d6,
with reference to tetramethylsilane as an internal reference.
13CNMR spectra were recorded on a 75 MHz spectrometer.
Elemental analyses were performed byVarian 3LV analyzer
series CHN analyzer. Mass spectra were recorded on a Jeol
JMC D-300 instrument by using Electron ionization at
70 ev. All reactions were monitored by TLC on pre-coated
silica gel plates. Column chromatography was performed
on 100-200 mesh silica gel (SRL, India) using 10-20 times
(by weight) of the crude product. All the anhydrides used
are commercially available.
N-[4-(5-nitro-1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-
phenoxyphenyl]methanesulfonamide (3c)
Light yellow solid; mp 192-194 ºC; Rf 0.86 (CHCl3:
1
Ethylacetate = 9:1); IR (KBr) νmax/cm-1: 1719; HNMR
(400 MHz, DMSO-d6) d 3.0 (s, 3H), 7.0-7.3 (m, 5H), 7.4
(t, J 6.4 Hz, 2H,), 7.6 (d, J 8.3 Hz, 1H,), 8.2 (d, J 8.3 Hz,
1H,), 8.5 (d, J 1.5 Hz, 1H,), 8.6 (dd, J 7.7 and 1.9 Hz, 1H),
9.6 (bs, 1H, NH); 13CNMR (75 MHz, CDCl3) d 39.9 (CH3),
115.7 (CH), 119.1 (CH), 120.9 (CH), 121.9 (CH), 125.0
(CH), 127.7 (C), 128.2 (C), 129.7 (CH), 130.3 (CH), 132.9
(C), 135.8 (C), 147.3 (C), 152.0 (C), 155.0 (C), 164.5 (C);

Vol. 21, No. 6, 2010
Kavitha et al.
1063
MS 453 (M+, 100%); Elemental analysis found: C, 55.57,
H 3.30, N 9.31; C21H15N3O7S requires C, 55.63; H, 3.33;
N, 9.27%.
carrageenan (0.2%) suspension in gum acacia into the
right hind of the rats. Male adult albino Wister rats (100-
120 g) were divided into 12 groups of six animals each.
The rat paw thickness was measured with aVeriner caliper
before and 1 h after the carrageenan injection to detect the
carrageenan induced inflammation. Each test compound at a
dose of 100 mg kg-1 was injected i.p. to a separate group of
rats 1 h after carrageenan injection. Control group received
the vehicle (5% gum acacia), while the reference group
received indomethacin, 10 mg kg-1.
N-[4-(2,5-dioxo-2,5-dihydropyrrol-1-yl)-2-phenoxyphenyl]
methanesulfonamide (3d)
Pale yellow solid; mp 145-148 ºC; Rf 0.80 (CHCl3:
Ethylacetate = 9:1); IR (KBr) νmax/cm-1: 1725, 1708; 1HNMR
(400 MHz, CDCl3) d 3.0 (s, 3H), 6.80 (s, 2H), 6.88 (d, J 6.0
Hz, 1H), 6.96 (bs, 1H, NH), 7.05 (d, J 9.0 Hz, 2H), 7.12
(dd, J 12.0 Hz, J 6.0 Hz, 1H), 7.18 (t, J 9.0 Hz 1H), 7.40 (t,
J 12.0 Hz, 2H), 7.75 (d, J 12.0 Hz, 1H); 13CNMR (75 MHz,
CDCl3) d 39.7 (CH3), 115.6 (CH), 118.9 (CH), 121.2 (CH),
121.6 (CH), 124.7 (CH), 127.5 (C), 128.2 (C), 130.2 (CH),
134.1 (CH), 147.2 (C), 155.2 (C), 169.0 (CO); MS 359 (M+,
100%); Elemental analysis found: C, 56.90, H 3.96, N 7.97;
C17H14N2O5S requires C, 56.98; H, 3.94; N, 7.82%.
The difference between the thicknesses of the two paws
was taken as a measure of edema. The measurement was
carried out at zero, 1, 2, 3 and 4 h after injection of the test
compounds, reference drug, and the vehicle.
Acknowledgments
The authors (K. Kavitha and S. Pal) thank Mr. M. N.
Raju, the chairman of MNR Educational Trust for his
support and encouragement.
N-[4-(2,5-dioxo-pyrrolidin-1-yl)-2-phenoxyphenyl]methane-
sulfonamide (3e)
Off white solid; mp 225-228 ºC; Rf 0.33 (CHCl3:
Ethylacetate = 9:1); IR (KBr) νmax/cm-1: 1707; 1HNMR (300
MHz, CDCl3) d 2.7 (s, 4H), 3.1 (s, 3H), 6.8 (s, 1H), 7.1(
m, 3H,), 7.3 (m, 1H), 7.4 (m, 3H), 9.5 (s, NH,); 13CNMR
(75 MHz, CDCl3) d 28.3 (CH2), 39.8 (CH3), 115.9 (CH),
119.1 (CH), 120.8 (CH), 122.1 (CH), 124.8 (CH), 128.1(C),
128.6 (C), 130.2 (CH), 147.2 (C), 155.1 (C), 175.7 (CO);
MS 361 (M+, 100%); Elemental analysis found: C, 56.70,
H 4.50, N 7.74; C17H16N2O5S requires C, 56.66; H, 4.47;
N, 7.77%.
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Web Release Date: March 8, 2010