Synthesis and activities of new 4-hydroxy benzoxazolone derivatives

Article abstract of DOI:10.1016/j.cclet.2009.09.006

A series of new 4-substituted benzoxazolone derivatives were synthesized according to a convenient method, their anti-inflammatory and analgesic activities in vivo were evaluated. All of them were new compounds, the structures of all the synthesized compounds were confirmed by ¹H NMR, ¹³C NMR, ESI-MS and HR-MS. Most of the compounds exhibited anti-inflammatory activity.

Full text of DOI:10.1016/j.cclet.2009.09.006

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 63–66
www.elsevier.com/locate/cclet
Synthesis and activities of new 4-hydroxy benzoxazolone
derivatives
Li Tang a, Shu Rong Ban a, Xiu E. Feng a, Wen Han Lin b, Qing Shan Li a,
*
a School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, China
b State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100083, China
Received 16 June 2009
Abstract
A series of new 4-substituted benzoxazolone derivatives were synthesized according to a convenient method, their anti-
inflammatory and analgesic activities in vivo were evaluated. All of them were new compounds, the structures of all the synthesized
1
compounds were confirmed by H NMR, 13C NMR, ESI-MS and HR-MS. Most of the compounds exhibited anti-inflammatory
activity.
# 2009 Qing Shan Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Synthesis; 4-Hydroxy benzoxazolone derivatives; Anti-inflammatory activity
Benzoxazolones were widely distributed in many kinds of plants and had been shown to present the biological
activity of detoxification and antibacterial [1,2]. So far, great efforts have been done on the structural modification, and
primary active investigations showed that some derivatives exhibited the activities of analgesic, disinfection and
antivirus. It could been noticed that most of the known benzoxazolone derivatives were N-alkylarion, N-acylation, 5-
or 6-substituted compounds [3,4], and generally the substituted position could obviously affect the bioactivities of
these compounds. However, the 4-substituted benzoxazolone derivatives were scarcely prepared. Recently, a natural
product 4-O-b-D-glucopyranosyl benzoxazolin-2 (3H)-one which was a new 4-substituted benzoxazolone compound
was isolated from the plant Acanthus ilicifolius L. [5] which was used as anti-inflammatory and antihepatitis medicine
widely for its special activities. So, we tried to prepare a series of 4-substituted benzoxalone derivatives. Amino acid
was the basic unity of protein and a lot of thesis reported that the activities could been improved because of the
inletting of amino acid [6]. So we designed a convenient synthetic route which was described in Scheme 1 to prove that
if the activity could been increased by the inletting of the amino acids. All of the compounds had the same basic
compages of chlorzoxazone which was widely used as analgesic in clinic. Meanwhile, we established the anti-
inflammatory model in vivo by using chlorzoxazone as the positive control to appraise their activities, then analyzed
the structure–biological activity relationship which would provide valuable information for further studies.
Melting points were determined on X-4 instrument, and the thermometer was uncorrected. The 1H NMR and 13
C
NMR spectra in CDCl3 with Bruker ARX-300 MHz nuclear magnetic resonance spectrometer were tested using
* Corresponding author.
E-mail address: qingshanl@yahoo.com (Q.S. Li).
1001-8417/$ – see front matter # 2009 Qing Shan Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.09.006

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L. Tang et al. / Chinese Chemical Letters 21 (2010) 63–66
Scheme 1. Synthetic route of 4-substitued compounds 4a–4i. Reagent and conditions: (a) THF, N2, reflux, 4 h; (b) THF, DCC, DMAP, r.t.
tetramethylsilane as an internal standard. Mass spectra were determined with Alliance2695–ZQ4000 liquid
chromatograph–mass spectrometer. High resolution mass spectrum was determined with high resolution ESI-FTICR
mass spectrometry (Varian 7.0T). All the reagents used were AR grade. Column chromatography employed silica gel
of 200–300 mesh.
The synthetic pathway for compound 4 and the key intermediate 3 was summarized in Scheme 1. 2-Amino-
resorcinol 1 and bis(trichloromethyl)-carbonate 2 were chosen as the starting materials to prepare the key
intermediate-4-hydroxybenzoxazolone 3. The mixture was refluxing at N2 atmosphere. A high yield (78.8%) was
procured by processing the column chromatography. To a solution of 3 (0.66 mmol) in THF, DCC (0.66 mmol),
DMAP (0.13 mmol) and R-carboxylic acid (0.79 mmol) were added (compound 4b–4h were L configuration). The
mixture was stirred at room temperature until the 4-hydroxybenzoxazolone was consumed nearly (monitored by
TLC). The filtrate was concentrated and purified by column chromatography. The structures of R-COOH were
summarized in Table 1.
In total, 10 new compounds 4a–4i were prepared, their structures were confirmed by 1H NMR, 13C NMR, ESI-MS
and HR-MS [7].
Most of the prepared compounds were subjected to anti-inflammatory activity in vivo using the model of xylene-
induced ear edema in mice. The compounds were given to mice by oral administration of 150 mg/kg. We chosen
xylene as a phlogogenic drug, suppression ratio as anti-inflammatory activity indicator. Chlorzoxazone were used as
the positive control. The investigation results are listed in Table 2.
The results showed that most of the compounds existed moderate anti-inflammatory activities which
were identical to that of chlorzoxazone. The activities of compounds 4e and 4g were better than that of
chlorzoxazone. From the data of anti-inflammatory activity and the structures of the compounds, it could been
concluded that the activity was increased due to the inletting of the aromatic ring, and was decreased due to the
Table 1
The structures of R-COOH.
Compd.
R-COOH
Compd.
R-COOH
Compd.
R-COOH
4a
4b
4c
4d
4g
4e
4f
4i
4h

L. Tang et al. / Chinese Chemical Letters 21 (2010) 63–66
65
Table 2
Anti-inflammatory activity of the synthesized compounds.
Compd.
Dose (mg/kg)
n
Swollen extent, x Æ s (mg)
Inhibition (%)
Control
–
150
150
150
150
150
150
150
150
150
150
150
10
10
10
10
10
10
10
10
10
10
10
10
11.19 Æ 2.91
7.47 Æ 3.86
8.39 Æ 4.01
5.09 Æ 4.20
6.64 Æ 4.44
6.54 Æ 3.18
5.99 Æ 1.72
4.03 Æ 3.33
8.42 Æ 4.02
4.37 Æ 2.47
5.43 Æ 4.00
5.20 Æ 2.92
–
Chlorzoxazone
33.24
25.02
54.51
40.66
41.55
46.47
63.99
24.75
60.95
51.47
53.53
3
4a
4b
4c
4d
4e
4f
4g
4h
4i
inletting of sulfur atom inversely. It could also been inferred that the activity was not influenced by the introduced
number of the alkyl group.
Considering the strong anti-inflammatory activity of compound 4e, we chosen the model of acetic acid-induced
mice’s writhing to evaluate the analgesic biological activity of compound 4e. The inhibition of positive control
chlorzoxazone and the compound 4e were 54.32% and 38.72% respectively.
Hence, the structure and the data of activity could provide some important information for future studies and the
compounds appeared to offer a great potential as an antiphlogiston.
Acknowledgments
Financial supports form the National ‘‘863’’ program of China (No. 2006AA09Z446), from the overseas scholar
supporting program (No. 2008-51), from Shanxi Province Science Foundation for Youths (No. 2009021041-1) and
from the innovative program of Shanxi Medical University (No. 38) is gratefully acknowledged.
References
[1] M. Zikmundova, K. Drandarov, L. Bigler, Appl. Environ. Microb. 68 (2002) 4863.
[2] A. Friebe, V. Vilich, L. Hennig, Appl. Environ. Microb. 64 (1998) 2386.
[3] Z.K. Hou, Y.G. Ren, M.X. Lei, Trans. Tianjin Univ. 11 (2005) 026.
[4] J.D. Lambert, J.E. Rice, J. Hong, Bioorg. Med. Chem. Lett. 15 (2005) 873.
[5] C.H. Huo, D.G. An, B. Wang, Magn. Reson. Chem. 43 (2005) 343.
[6] X.Z. Fu, S.H. Jiang, Y.S. Yang, Acta Pharm. Sin. 43 (2008) 495.
[7] 4a 4-2-(tert-Butoxycarbonylamino)acetyloxy-2(3H)-benzoxazolone: yield 47%. Mp 134–136 8C. 1H NMR (CDCl3, 300 MHz): d 1.47 (s, 9H,
CH3), 4.01 (d, 2H, CH2), 5.29 (s, 1H, NH), 6.90 (m, 1H, ArH), 7.08 (m, 2H, ArH), 9.99 (s, 1H, NH). 13C NMR (CDCl3, 75 MHz): d 34.07, 48.83,
87.40, 113.70, 122.36, 128.01, 139.40, 150.72, 159.88, 162.74, 173.94. ESI-MS (m/z) 309.3 ([M+H]+). HR-MS (M+Na+) 331.0901. Found:
331.0908.;
4b 4-2-(tert-Butoxycarbonylamino)propionyloxy-2(3H)-benzoxazolone: yield 38%. Mp 169–171 8C. 1H NMR (CDCl3, 300 MHz): d 1.49 (s,
9H, CH3), 1.55 (d, 3H, CH3), 4.27 (m, 1H, CH2), 5.13 (m, 1H, NH), 6.87 (m, 1H, ArH), 7.07 (m, 2H, ArH), 9.31 (s, 1H, NH). 13C NMR (CDCl3,
75 MHz): d 15.80, 27.82, 49.58, 81.42, 107.29, 115.75, 121,50, 122.23, 133.15, 144.42, 153.16, 156.11, 170.50. ESI-MS (m/z) 321.5([MÀH]À).
HR-MS (M+Na+) 345.1057. Found: 345.1062.;
4c 4-[2-(tert-Butoxycarbonylamino)3-isopropyl]propionyloxy-2(3H)-benzoxazolone: yield 30%. Mp 57–59 8C. 1H NMR (CDCl3, 300 MHz): d
1.04 (m, 6H, CH3), 1.49 (s, 9H, CH3), 1.78 (m, 3H, CH, CH2), 4.26 (m, 1H, CH), 5.07 (s, 1H, NH), 6.86 (m, 1H, ArH), 7.07 (m, 2H, ArH), 9.32 (s,
1H, NH). 13C NMR (CDCl3, 75 MHz): d 21.67, 23.97, 27.41, 38.60, 52.16, 81.14, 106.88, 115.25, 121.03, 121.87, 132.70, 144.00, 152.63,
155.97, 170.17. ESI-MS (m/z) 363.5([MÀH]À). HR-MS (M+Na+) 387.1527. Found: 387.1527.;
4d 4-[2-(tert-Butoxycarbonylamino)3-methyl]butyryloxy-2(3H)-benzoxazolone: yield 85%. Mp 130–131 8C. 1H NMR (CDCl3, 300 MHz): d
1.18 (m, 6H, CH3), 1.54 (s, 9H, CH3), 1.28 (m, 1H, CH), 4.05 (m, 1H, CH), 5.10 (s, 1H, NH), 6.87 (m, 1H, ArH), 7.10 (m, 2H, ArH), 9.33 (s, 1H,
NH). 13C NMR (CDCl3, 75 MHz): d 22.36, 31.73, 32.99, 63.75, 85.36, 111.18, 119.67, 125.37, 137.02, 148,33, 157.01, 160.46, 173.60. ESI-MS
(m/z) 373.4 ([M+Na]+). HR-MS (M+Na+) 373.1370. Found: 373.1377.;
4e 4-[2-(tert-Butoxycarbonylamino)3-phenyl]propionyloxy-2(3H)-benzoxazolone: yield 38%. Mp 149–151 8C. 1H NMR (CDCl3, 300 MHz): d
1.48 (s, 9H, CH3), 3.20 (m, 2H, CH2), 4.44 (m, 1H, CH), 5.10 (s, 1H, NH), 6.68 (m, 1H, ArH), 7.05 (m, 2H, ArH), 7.27 (m, 2H, ArH), 7.38 (m,

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L. Tang et al. / Chinese Chemical Letters 21 (2010) 63–66
3H, ArH), 9.10 (s, 1H, NH). 13C NMR (CDCl3, 75 MHz): d 28.58, 37.08, 56.01, 82.38, 108.11, 116.46, 122.26, 122.97, 127.93, 129.33, 133.66,
135.28, 145.14, 153.79, 156.77, 179.21. ESI-MS (m/z) 397.3 ([MÀH]À). HR-MS (M+Na+) 421.1370. Found: 421.1362.;
4f 4-[2-(tert-Butoxycarbonylamino)4-meththio]butyryloxy-2(3H)-benzoxazolone: yield 57%. Mp 145–146 8C. 1H NMR (CDCl3, 300 MHz): d
1.49 (s, 9H, CH3), 2.15 (m, 5H, CH2, CH3), 2.69 (m, 2H, CH2), 4.39 (m, 1H, CH), 5.45 (s, 1H, NH), 6.82 (m, 1H, ArH), 7.08 (m, 2H, ArH), 9.31
(s, 1H, NH). 13C NMR (CDCl3, 75 MHz): d 16.18, 29.08, 30.34, 30.89, 54.32, 82.80, 108.64, 117.08, 122.80, 123.48, 134.33, 145.73, 154.42,
157.42, 170.76. ESI-MS (m/z) 381.3 ([MÀH]À). HR-MS (M+Na+) 405.1091. Found: 405.1099.;
4g 4-[2-(tert-Butoxycarbonylamino)3-(1H)indole-3-yl]propionyloxy-2(3H)-benzoxazolone: yield 78%. Mp 91–94 8C. 1H NMR (CDCl3,
300 MHz): d 1.46 (s, 9H, CH3), 3.331, 3.42 (m, 2H, CH2), 4.56(m, 1H, CH), 5.16 (s, 1H, NH), 6.63 (d, 1H, ArH), 7.02 (dd, 2H, ArH),
7.17 (d, 2H, ArH), 7.29 (d, 1H, ArH), 7.45 (d, 1H, ArH), 7.64 (d, 1H, Arh), 8.21 (s, 1H, NH), 9.06 (s, 1H, NH). 13C NMR (CDCl3, 75 MHz): d
27.92, 29.28, 55.81, 82.83, 108.72, 110.28, 112.48, 117.30, 119.41, 121.04, 122.92, 123.70, 124.09, 127.88, 134.52, 137.30, 145.83, 154.56,
157.53, 171.33. ESI-MS (m/z) 460.4 ([M+Na]+). HR-MS (M+Na+) 460.1479. Found: 460.1483.;
4h 4-[N-tert-Butoxycarbonylpyrrolidine-2-formyloxy]-2(3H)-benzoxazolone: yield 69%. Mp 163–164 8C. 1H NMR (CDCl3, 300 MHz): d 1.52
(s, 9H, CH3), 2.00 (m, 1H, pyrrolidine-H), 2.15 (m, 2H, pyrrolidine-H), 2.40 (m, 1H, pyrrolidine-H), 3.56 (m, 2H, pyrrolidine-H), 4.41 (t, 1H,
CHCO), 6.86 (t, 1H, ArH), 7.06 (d, 2H, ArH), 9.70 (s, 1H, NH). 13C NMR (CDCl3, 75 MHz): d 24.98, 28.54, 29.79, 46.98, 59.12, 81.95, 107.75,
116.22, 121.89, 123.13, 133.78, 145.02, 153.73, 155.63, 170.89. ESI-MS (m/z) 347.5 ([MÀH]À). HR-MS (M+Na+) 371.1214. Found:
371.1216.;
4i 4-Pyridine-3-yl-formyloxybenzoxazolone: yield 76%. Mp 221–226 8C. 1H NMR (CDCl3, 300 MHz): d 7.04 (m, 1H, ArH), 7.18 (m, 2H,
ArH), 7.45 (m, 1H, ArH), 8.33 (d, 1H, ArH), 8.83 (m, 1H, ArH), 9.34 (s, 1H, ArH), 10.22 (s, 1H, NH). 13C NMR (CDCl3, 75 MHz): d 102.64,
109.16, 123.69, 124.33, 124.81, 133.96, 135.48, 148.88, 152.37, 152.57, 154.83, 158.08, 169.56. ESI-MS (m/z) 257.2 ([M+H]+). HR-MS
(M+Na+) 279.0376. Found: 279.0380.