Synthesis of some novel benzoxazolinonylcarboxamides as potential anti-inflammatory agents

Article abstract of DOI:10.3184/174751914X13981878697248

The synthesis of new 2(3H )-benzoxazolinonylcarboxamides starting from 2-amino-4,6-dimethylpyridine and 2(3H )-benzoxazolone which were designed as anti-inflammatory agents is described. These derivatives were synthesised from 2(3H )-(benzoxazolinon-6-yl)carboxylic acids, which were obtained by Friedel-Crafts acylation of 2(3H )-benzoxazolone derivatives with oxalyl chloride and acetylchloride in the presence of the AlCl₃-DMF complex. The constitution of the products was supported by elemental analysis IR and 1H NMR spectral data.

Full text of DOI:10.3184/174751914X13981878697248

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 JUNE, 331–333
RESEARCH PAPER 331
Synthesis of some novel benzoxazolinonylcarboxamides as potential
anti-inflammatory agents
Liacha Messaoud*, Yahia Wassila, Seddiki Khemissi, Adjeroud Yasmina and Chabane Hanane
Laboratoire de Synthèse et Biocatalyse Organique, Faculté des Sciences, Université Badji-Mokhtar-Annaba, PB 12, 23000 Annaba, Algeria
The synthesis of new 2(3H)-benzoxazolinonylcarboxamides starting from 2-amino-4,6-dimethylpyridine and
2
(3H)-benzoxazolone which were designed as anti-inflammatory agents is described. These derivatives were synthesised
from 2(3H)-(benzoxazolinon-6-yl)carboxylic acids, which were obtained by Friedel–Crafts acylation of 2(3H)-benzoxazolone
derivatives with oxalyl chloride and acetylchloride in the presence of the AlCl –DMF complex. The constitution of the products
was supported by elemental analysis IR and H NMR spectral data.
3
1
Keywords: carboxamides, 2(3H)-benzoxazolone, Friedel–Crafts, acylation, anti-inflammatory drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) represent
one of the most extensively utilised classes of pharmaceutical
agents worldwide, and have been used in the treatment of
pain, nociception, fever and inflammatory diseases, especially
of the molecule. In an effort to pursue the study of the structure–
activity relationships of 2(3H)-benzoxazolone analogues, we
first considered the importance of the length of alkyl side chain
of the benzamides between the aromatic and the amidic portion,
and consequently we synthesised carboxamide (n=0) instead
1,2
arthritis. Since the discovery of an inducible isoform of the
enzyme COX later identified as COX-2, in the early 1990s by
14
of acetamide (n=1) compounds. In this study, we report the
3
–5
Needleman, Simmons and Herschman’s group, numerous
COX-2 selective inhibitors have been proposed. Several studies
show that the inhibition of cyclooxygenases-2 can delay or
prevent certain forms of cancer. In addition to intensive drug
discovery programs targeting COX-2 inhibitors, another
and perhaps more original approach has been concerned
with the exploration of the pharmacological potentials of
synthesis and characterisation of some novel benzoxazolinonic
carboxamide derivatives.
Results and discussion
We now report the preparations of the benzoxazolinonyl-
carboxamide derivatives (4a, 4b). The synthesis of the
benzoxazolinonylcarboxamides derived from 2-amino-4,6-
dimethylpyridine was achieved from 2(3H)-benzoxazolone or
2
-amino-4,6-dimethylpyridine amide derivatives as mixed
inhibitors of both eicosanoid biosynthesis and IL-1/TNF-
3
-methyl-2(3H)-benzoxazolone as shown in Scheme 1. It was
6
alpha production. The major compounds in this family are
necessary, however, to develop a good synthesis of the benzoic
benzamide or phenylacetamide derivatives of 2-amino-4,6-
17
7
–13
acidunit. Previousworks haveshownthatthismaterialcouldbe
obtained by haloform reaction of the readily available 6-acetyl-
dimethylpyridine.
In this connection, we recently reported the synthesis of
potentially anti-inflammatory compounds in which the aryl
2
(3H)-benzoxazolone (Method A). However, the scaling up of
14
this reaction was troublesome. 6-Acetyl-2(3H)-benzoxazolone
derivatives were obtained as previously reported by taking
moietycompriseda2(3H)-benzoxazoloneringandnequalto1.
That work was an extension of previous work which our group
advantage of the AlCl –DMF complex used as a Friedel–
devoted to anti-inflammatory 6-benzoyl-2(3H)-benzoxazolone
3
18–20
15,16
Crafts catalyst.
The product of the haloform reaction was
and 6-benzoyl-2(3H)-benzothiazolone derivatives.
Another
merit of this design relies on the creation of a radicalar sensitive
centre stabilised by the dipolar arrangement of electron-rich
hydrolysed in basic medium to give the corresponding acid
(3a). Treatment of these acids with thionyl chloride gave the
intermediate acid chloride which was coupled with 2-amino-
4,6-dimethylpyridine to provide the target amide (4a).
(2(3H)-benzoxazolone) and electron-deficient (pyridine)
heterocycles placed on either side of the central amide function
R
R
R
N
AlCl -DMF
N
N
3
NaOH
O
O
O
CH COCl
CH3 NaOCl
OH
3
O
O
O
1
a-b
2a-b
3a-b
O
O
1
) SOCl2 2)
N
R
NH2
N
H
N
O
N
O
O
4
a-b
R=H, CH3
Scheme 1 Preparation of benzoxazolinonylcarboxamides from (benzoxazolinon-6-yl)carboxylic acids.
*
Correspondent. E-mail: m_liacha@yahoo.fr; messaoud.liacha@univ-annaba.dz
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332 JOURNAL OF CHEMICAL RESEARCH 2014
To access to the N-methyl derivative acid (R=CH , 4b), we
homogenous in two standard solvents, i.e. ethylacetate/cyclohexane
(6:4, v/v) and methanol/chloroform equilibrated with ammonia
3
initially planned to use on 3-methyl-2(3H)-benzoxazolone in
the same procedure described above for the N-unsubstituted
derivative (4a). However, alkaline hydrolysis of the resulting
(1:9, v/v).
FC acylation of 2(3H)-benzoxazolone and 3-methyl-2(3H)-
benzoxazolone; general procedure
3
-methyl-6-acetyl-2(3H)-benzoxazolone (2b) resulted in
degradation (ring opening) of the heterocycle rather than
oxidation of acetyl group. Consequently, we developed a new
route based on Friedel–Crafts reaction of 2(3H)-benzoxazolone
6
-Acetylbenzoxazolinones (2a, 2b) and acid (3a, Method A) were
prepared according to the reported method and the physical properties
1
17,20
(
m.p., IR, H NMR) are in accordance with published data.
with oxalyl chloride using the AlCl –DMF complex as catalyst
3
Synthesis of the 2(3H)-(benzoxazolinon-6-yl) carboxylic acid
derivatives (3a, 3b); general procedure
(Method B). Indeed, in recent years, our group has developed
expertise in the Friedel–Crafts acylation of highly activated
Method B: Anhydrous AlCl (13.334 g, 0.10 mol), and under stirring,
3
substrates using the AlCl –DMF reagent (Thyes’ reagent). We
3
over 15 min dropwise anhydrous DMF (1.5 mL, 0.02 mol) were added
to a 250 mL three-necked flask. When HCl evolution had subsided
therefore looked for a suitable route for converting an aromatic
21
substrate directly to an aromatic carboxylic acid.
2
(3H)-benzoxazolone (1.351 g, 0.01 mol) was added in one portion.
Initial attempts to run the reaction with 2(3H)-benzoxazolone
Over a 1 h period oxalyl chloride (1.90 g, 0.015 mol) was added. The
temperature of the oil bath was then raised to 80 °C for 5 h, after which
time the reaction was poured onto 0.1 kg of ice containing concentrated
HCl (3.0 mL). The mixture was allowed to melt under stirring and after
as an electron-rich substrate and AlCl –DMF as catalyst indeed
3
gave the target compound albeit in relatively low yield (33%).
Additional trials using 3-methyl-2(3H)-benzoxazolone resulted
in recoveries of the same order (37%).
1
(
h; the precipitate was collected and rinsed with cold distilled water
30.0 mL). The powder so obtained was filtered and recrystallised from
suitable solvents to give the desired acids (3a) (33%) and (3b) (37%).
(3H)-(Benzoxazolinon-6-yl)carboxylic acid [3a, Method A (90%)
In order to achieve the condensation between 2(3H)-
(
benzoxazolinon-6-yl)carboxylic acid or its N-methyl
derivative with the 2-amino-4,6-dimethylpyridine to obtain the
corresponding amides, these two carboxylic acid derivatives
2
–1
–1
and Method B (33%)], m.p. 330 °C. IR (KBr, cm ): νNH 3140 cm ,
νCO 1775 and 1680 cm ; H NMR (DMSO-d ) δ 7.17 (d, J=9 Hz, 1H,
–1 1
(2(3H)-(benzoxazolinon-6-yl)carboxylic acids (4a–b) were
6
subjected to three different condensation conditions and
tested using different catalysts (Methods C–E). The results are
reported in Table 1. The proposed structures of the described
H4); 7.75 (d, J=1.80 Hz, 1H, H7); 7.83 (m, J=9.0, 1.80 Hz, 1H, H5);
11.97 (br s, 1H, exchanged with D O); 12.98 (br s, 1H, exchanged with
2
D O). Anal. calcd for C H NO : C, 53.64; H, 2.81; N, 7.82; found: C,
2
8
5
4
1
compounds accord with their IR and H NMR spectra.
53.42; H, 2.96; N, 7.91%.
3
-Methyl-2(3H)-(benzoxazolinon-6-yl) carboxylic acid [3b, Method
B (37%)], in the same way as above for 2(3H)-(benzoxazolinon-
-yl)carboxylic acid, this material was obtained from methanol,
Table 1 Synthesis of benzoxazolinonic acids (3a, 3b) and carboxamides
6
(4a, 4b)
–1
–1
m.p.>250 °C dec. IR: νOH 2400–3100 cm , νCH 2950 cm , νCO
3
Compounds
R
M.p./°C
Yield/%a
Formulad
1780 and 1680 cm , νC=C 1620 cm . H NMR (DMSO-d ): δ 3.37
–1
–1
1
a
r
6
b
c
(s, 3H, N–CH ), 7.35 (d, J=7.89 Hz, 1H, H4), 7.78 (s, 1H, H7), 7.88 (d,
3
3
4
4
a (Method A,B)
b (Method B)
a (Method D,E)
b (Method D,E)
H
CH3
H
CH3
b
330
>250 dec
>260
90 , 33
C H NO
3
8
5
4
c
J=7.89 Hz, 1H, H5), 13.00 (br s, 1H, exchanged with D2O). Anal. calcd
–, 37
C H NO
9 7
4
e
f
for C H NO : C, 55.99; H, 3.65; N, 7.25; found: C, 56.03; H, 3.76; N,
25 , 63
C H N O
3
9
7
4
15
13
3
176–178
47 , 65f
e
C H N O
3
7.34%.
16
15
3
a
c
Pure isolated products; 20% NaOH, NaOCl, 1 h; oxalyl chloride AlCl –
DMF, 80 °C, 5 h, see Experimental; dicyclohexylcarbodiimide, anhydrous
DMF, room temperature, 24 h; HOBt, EDC, anhydrous DMF and TEA, room
temperature, 18 h, see Experimental; Thionyl chloride, CHCl , reflux, 5 h,
Syntheses of the N-(4,6-dimethylpyridin-2-yl)-2(3H)-(benzoxazolinon-
6-yl)carboxamides (4a, 4b)
Method D: A solution of 3-methyl-2(3H)-(benzoxazolinon-6-yl)
carboxylic acid 3b (0.59 g, 3 mmol), 2-amino-4,6-dimethylpyridine
3
d
e
f
3
see Experimental.
(0.43 g, 3.6 mmol), HOBt (0.51 g, 3.8 mmol), EDC (0.72 g, 3.8 mmol)
in anhydrous DMF (10 mL) and TEA (0.95 mL, 6.8 mmol) was
stirred initially at 0 °C for 1 h; it was then allowed to come to room
temperature and stirred for additional 18 h after which time the
reaction mixture was poured into water (50 mL). The resulting
precipitate was recrystallised from 95% ethanol.
Method E: A solution of the appropriate acid 3a (0.91 g, 5.1 mmol) in
chloroform (20 mL) was cooled to 0 °C with stirring. Thionyl chloride
(1.75 mL, 24 mmol) was added dropwise, and the reaction mixture
was heated at reflux for 5 h. After evaporation, the resulting crude
acid chloride was dissolved in dichloromethane (50 mL),to 4 °C, and
added dropwise to a cooled mixture of 2-amino-4,6-dimethylpyridine
Conclusions
This paper describes the successful synthesis of two
derivatives, 2(3H)-(benzoxazolinon-6-yl)carboxylic acids,
and N-(4,6-dimethylpyridin-2-yl)-2(3H)-(benzoxazolinon-6-
yl)carboxamide derivatives. Optimisations of the synthesis
under three different condensation conditions, using different
catalysts were achieved. In conclusion, these results provide
useful additions to the design of drugs for the treatment of
inflammatory disease.
(
0.51 g, 4.8 mmol) and triethylamine (0.95 mL, 6.8 mmol) in
Experimental
dichloromethane (50 mL). The reaction mixture was then stirred at
room temperature for 18 h. After evaporation of dichloromethane
under vacuum, the residue was treated with water and the resulting
precipitate filtered, washed with water, dried and recrystallised from
95% ethanol. Compound (4b) was synthesised in an identical fashion
to (4a).
N-(4,6-Dimethylpyridin-2-yl)-2(3H)-(benzoxazolinon-6-yl)
carboxamide [4a, Method D (25%) and Method E (63%)], m.p.>260 °C.
IR: νNH 3400 and 3392 cm , νCO 1772 and 1662 cm . H NMR
Melting points were determined in open capillary tubes using a Büchi
530 melting point apparatus and are uncorrected. The IR spectra were
recorded using potassium bromide disks with a PerkinElmer 297
–1
1
spectrometer, and wavenumbers are expressed in cm . The H NMR
spectra were recorded using a Brücker AC 300 spectrometer. Chemical
shifts (δ) are reported in ppm with tetramethylsilane as internal
standard. Elemental analysis was performed by the “Service central
d’analyse”, CNRS at Solaize Vernaison, France and is within +0.4%
of the calculated values. TLC analyses were performed on Merck
TLC plates (silica gel, 60 F 254, E. Merck, Darmstadt, ref. 5735).
All the compounds reported here were found chromatographically
–1
–1
1
(CDCl3) δ 2.30 (s, 3H, –CH ), 2.40 (s, 3H, –CH ), 6.87 (s, 1H, H5′), 7.18
(d, J=8.07 Hz, 1H, H4), 7.86 (s, J=0.75 Hz, 1H, H7), 7.90 (dd, J=8.07;
J=0.75 Hz, 1H, H5), 7.99 (s, 1H, H3′), 10.60 (br s, 1H, exchanged with
3
3
JCR1402476_FINAL.indd 332
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JOURNAL OF CHEMICAL RESEARCH 2014 333
D O), 11.00 (br s, 1H, exchanged with D O). Anal. calcd for C H N O :
4
W.L. Xie, J.G. Chipman, D.L. Robertson, R.L. Erikson and D.L. Simmons,
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2
2
15 13
3
3
C, 63.60; H, 4.59; N, 14.84; found: C, 63.80; H, 4.30; N, 14.54%.
-Methyl-N-(4,6-dimethylpyridin-2-yl)-2(3H)-(benzoxazolinon-
-yl)carboxamide [4b, Method D (46%) and Method E (65%)], m.p.
5
6
3
6
–1 1
176–178 °C. IR: νNH 3363, νCO 1778 and 1660 cm . H NMR (CDCl3)
7
δ 2.31 (s, 3H, –CH ), 2.41 (s, 3H, –CH ), 3.38 (s, 3H, N–CH ), 6.89 (s,
3
3
3
1H, H3′), 7.36 (d, J=7.85 Hz, 1H, H4), 7.64 (m, 2H, H7; H5′), 7.99 (d,
8
9
J=7.85 Hz, 1H, H5), 10.60 (br s, 1H, exchanged with D2O). Anal. calcd
for C H N O : C, 64.61; H, 5.08; N, 14.12; found: C, 64.67; H, 5.05; N,
16
15
3
3
14.20%.
10
This work was financially supported by the Algerian Ministry
of Higher Education and Scientific Research (MESRS). We
thank Prof. D. Lesieur, Institut de Chimie Pharmaceutique,
Lille, France, and Prof. Jacques H. Poupaert, Ecole de
Pharmacie, Faculté de Médecine, Université Catholique de
Louvain, Brussels, Belgium for helpful discussions during the
preparation of this manuscript.
11
915.
12 J.M.H. Robert, O. Rideau, S. Robert-Piessard, M. Duflos, G. Le Baut, N.
Grimaud, M. Juge and J.Y. Petit, Drug. Res., 1997, 47, 635.
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Robert-Piessard and G. Le Baut, J. Enzym. Inhib., 1997, 12, 13.
13
14
M. Liacha, S. Yous, P. Depreux, J.H. Poupaert and D. Lesieur, Heterocycles,
1999, 51, 1929.
Received 19 February 2014; accepted 27 March 2014
Paper 1402476 doi: 10.3184/174751914X13981878697248
Published: 10 June 2014
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