Research Article Synthesis, Anti-Inflammatory, and Analgesic...

Research ArticleSynthesis Anti-Inflammatory and Analgesic Activities ofDerivatives of 4-Hydroxy-2-benzoxazolone

Guangjin Zheng Tieyu Chen Xing Peng and Shengjing Long

Guangxi Medical University Guangxi 530021 China

Correspondence should be addressed to Xing Peng xingpenggxmueducn and Shengjing Long shjlong126com

Received 6 March 2015 Revised 14 June 2015 Accepted 16 June 2015

Academic Editor Patricia Valentao

Copyright copy 2015 Guangjin Zheng et alThis is an open access article distributed under theCreativeCommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Benzoxazolones are widely distributed in plants and are of increasing interest for a variety of pharmacological properties suchas detoxification antibacterial anti-inflammatory and analgesic activities and tranquilizers (Michaelidou and Hadjipavlou-Litina2005 Dogruer et al 1998) 4-Hydroxy-2-benzoxazolone (HBOA) is one of the major bioactive compounds in traditional Chineseherb drug Acanthus ilicifolius (Peng and Long 2006) which has obvious anti-inflammatory and analgesic activities (Huo et al2004 Mani Senthil Kumar et al 2008 Babu et al 2001) In this research we used 2-nitroresorcinol as starting material to prepareHBOA with a novel ldquoone-pot-wayrdquo Derivatives of HBOA TC-2simTC-4 were obtained via electrophilic reagents and reacted withcorresponding primary amines to afford Schiff Base derivatives TC-5simTC-10 for further study Anti-inflammatory and analgesicactivities of those derivatives were determined by using carrageenan-induced rat paw edema test The analgesic activities of thederivatives were determined by the hot-plate test

1 Introduction

In recent years reports showed Acanthus ilicifolius has obvi-ous anti-inflammatory analgesic activities and 4-hydroxy-2-benzoxazolone (HBOA) is one of the major bioactive ben-zoxazolones compounds [1] According tomodernmedicinaltheory HBOA is a bioisosterism of Chlorzoxazone and hasthe possibility to be a kind of nonsteroidal anti-inflammatorydrugs (NSAIDs) Since benzoxazolones are of bioactivitiesmany molecular modification and preliminary bioactivityevaluation studies have been performed [1ndash3] Several usefulcompounds have been developed and evaluated for theiranalgesic properties anti-inflammatory properties and anti-fungal properties [4ndash7] Neverthelessmost efforts focused onN- 4- 5- or 6-substituted HBOA Currently 7-substitutedbenzoxazolone derivatives as well as their anti-inflammatoryor analgesic properties have been scarcely reported There-fore we report the new method for synthesis of HBOA(Scheme 1) some new C-7 HBOA derivatives and their anti-inflammatory as well as analgesic activities

2 Experimental

Reagents and solvents used below were obtained fromcommercial sources Melting points were measured by X4micromelting point appearance IR spectra were obtainedwith Perkin-Elmer Spectrum 100 The 1H-NMR and 13C-NMR spectra were run on a Bruker AVTCCE AV 600MHzThe mass spectrum was obtained on a Waters AutoSpecPremier P776 Progress of the reactionwasmonitored byTLCusing sheets precoated with UV fluorescent silica gel Merck60F 254

21 Preparation of HBOA To a suspension of 40 g FeCl3sdot

6H2O in 200mL methanol 90 g activated carbon was added

and refluxed for 30minutes 310 g 2-nitroresorcinol (02mol)was added and then 36mL 80 hydrazine hydrate by dropswas added in 2 hours Keep stirring and refluxing for another4 hours We filtered all solution to another flask and driedall solvent under vacuum to yield dark syrup 300mL butylacetate and 600 g (1mol) urea were added to the syrup

Hindawi Publishing CorporationJournal of ChemistryVolume 2015 Article ID 534156 5 pageshttpdxdoiorg1011552015534156

2 Journal of Chemistry

Butyl acetate

O

NHO

OHOH

OH

FeCl3middot

middot

6H2O NH2CONH2

80 NH NH22 6H2O

NO2

Scheme 1 Methodology for synthesis of HBOA

O

NH

O

OH

O

NH

O

OH

Cl

+ H2O2 + HCl

Scheme 2 Methodology for synthesis of TC-2

stirred at 90∘C for 5 hours and then cooled to roomtemperatureThe crude HBOAwas obtained by filtration andpurified by recrystallization in 80 ethanol (yield 695)

22 Preparation of TC-2 Compound TC-2 was prepared viachlorination reaction and TC-3 to TC-4 were prepared viaFriedel-Crafts acylation on HBOA To a solution of 151 g(001mol) HBOA in 15mL glacial acetic acid and 2mL(0024mol) 37 HCl 180 g (0015mol) H

2O2was added

in 30 minutes by drops at 45∘C and then temperature wasraised to 80∘C and stirred for another 2 hours cooled toroom temperature filtered and washed with distilled waterto obtain compound TC-2 (Scheme 2)

7-Chloro-4-hydroxy-2-benzoxazolone (TC-2) White solid(yield 61) mp 226sim228∘C FT-IR (KBr) 120592 3384 (OH)3175 (NH) 1748 (C=O) 1625 1562 1492 1467 cmminus1 1H-NMR(DMSO-d6) 120575 1190 (1H sN-H) 1038 (1H sO-H) 707 (1Hd 119869 = 852Hz 6-ArH) 685 (1H d 119869 = 852Hz 5-ArH)13C-NMR (DMSO-d6) 1205751541 (2-C) 1434 (4-C) 1380 (7a-C)1224 (6-C) 1168 (7-C) 1122 (3a-C) 1031 (5-C) EI mz 185(M+ 100)

23 Preparation of TC-3 to TC-4 To slurry of 151 g (001mol)HBOA 80 g (006mol) AlCl

3in 20mL 12-dichloroethane

and 2mL nitrobenzene 004mol acyl chloride was addedby drops and stirred at rt for 1 hour Then temperature wasraised to 80∘C and stirred for another 4 hours The reactionwas quenched by cooling to rt and pouring the slurry into300mL ice-cold water Filtered and recrystallized with 90ethanol to yield pure compounds TC-3 and TC-4 (Schemes 3and 4)

7-Acetyl-4-hydroxy-2-benzoxazolone (TC-3) White solid(68) mp 226sim228∘C FT-IR (KBr) 120592 3358 (OH) 29832844 1769 (C=O) 1702 (C=O) 1659 1625 1512 1473 14271356 cmminus1 1H-NMR (DMSO-d6) 120575 1188 (1H s N-H)1108 (1H s O-H) 746 (1H d 119869 = 882Hz 6-ArH) 674 (1Hd 119869 = 882Hz 5-ArH) 265 (3H s COCH3

) 13C-NMR

(DMSO-d6) 120575 1933 (COCH3) 1545 (2-C) 1469 (4-C)

1449 (7a-C) 1237 (6-C) 1187 (7-C) 1136 (3a-C) 1112 (5-C)302 (COCH

3) EImz 193 (M+ 78)

7-Butyryl-4-hydroxy-2-benzoxazolone (TC-4) White solid(72) mp 168sim170 FT-IR (KBr) 120592 3138 (OH) 2964 29332901 2875 1777 (C=O) 1748 (C=O) 1659 1632 1494 14721376 1237 1156 1H-NMR (DMSO-d6) 120575 1187 (1H s N-H) 1005 (1H s O-H) 748 (1H d 119869 = 882Hz 6-ArH)675 (1H d 119869 = 882Hz 5-ArH) 293 (2H t 119869 = 714HzCOCH2

CH2CH3) 164 (2H m COCH2CH2CH3) 093

(3H t 119869 = 738Hz COCH2CH2CH3) 13C-NMR (DMSO-

d6) 120575 1957 (COCH2CH2CH3) 1545 (2-C) 1467 (4-C)

1447 (7a-C) 1260 (6-C) 1236 (7-C) 1134 (3a-C) 1113 (5-C) 436 (COCH

2CH2CH3) 174 (COCH2

CH2CH3) 142(COCH2CH2

CH3) EImz 221 (M+ 45)

24 Preparation of TC-5 to TC-10 Compounds TC-5 to TC-10 were prepared by reaction with corresponding primaryamines to afford Schiff Base derivatives To a solution of001mol starting material in 300mL ethanol 15 eq primaryamine derivatives were added refluxed for 3 hours and thencooled to rt and filtered and washed with distilled water toyield compounds TC-5simTC-10

7-(1-(2-Hydroxyethylimino)ethyl)-4-hydroxy-2-benzoxazolo-ne (TC-5) Yellow solid (91) mp 270sim271∘C FT-IR (KBr)120592 3429 (O-H) 2963 2873 1757 (C=O) 1635 1576 15361444 1380 1300 1286 1H-NMR (DMSO-d6) 120575 1680 (1H sN-H) 1620 (1H s C

4-OH) 737 (1H d 119869 = 90Hz 6-ArH)

646 (1H d 119869 = 90Hz 5-ArH) 369 (7H m) 343 (1H s)13C-NMR (DMSO-d6) 120575 1756 (C=N) 1612 (2-C) 1550(4-C) 1472 (7a-C) 1250 (6-C) 1212 (7-C) 1130 (3a-C) 973(5-C) 600 (CNCH

2CH2OH) 482 (CNCH2

CH2OH) 152(CH3) EImz 236 (M+ 100)

7-(1-(2-Hydroxyethylimino)butyl)-4-hydroxy-2-benzoxazolo-ne (TC-6) Light yellow solid (45) mp 255sim257∘C FT-IR(KBr) 120592 3431 (O-H) 3323 (N-H) 3027 (=C-H) 2957

Journal of Chemistry 3

AlCl3+

O

NHO

O

R Cl

OH

O

NHO

OH

O RTC-3 R = -CH3

TC-4 R = -CH2CH2CH3

Scheme 3 Methodology for synthesis of TC-3 and TC-4

+O

NH N

N

H

O O

OH

O

OH

O R1

H2N R2

R1 R2

TC-5 R1 = -CH3 R2 = -CH2OH

TC-6 R1 = -CH2CH2CH3 R2 = -CH2OH

TC-7 R1 = -CH2CH2CH3 R2 = -CH2COOH

TC-8 R1 = -CH2CH2CH3 R2 = -CH(CH3)COOHTC-9 R1 = -CH2CH2CH3 R2 = -CH2(CH2)4COOHTC-10 R1 = -CH2CH2CH3 R2 = O


2863 1751 (C=O) 1634 1617 1571 1441 1383 1286 10721H-NMR (DMSO-d6) 120575 1684 (1H s N-H) 1630 (1H sC4-OH) 736 (1H d 119869 = 90Hz 6-ArH) 647 (1H d 119869 =

90Hz 5-ArH) 370 (4H m) 351 (1H s) 288 (2H t 119869 =228Hz) 161 (2H m) 104 (3H d 119869 = 228Hz) 13C-NMR(600MHz DMSO) 120575 1782 (C=N) 1616 (2-C) 1550(4-C) 1471 (7a-C) 1248 (6-C) 1214 (7-C) 1118 (3a-C) 975(5-C) 601 (CNCH

2CH2OH) 479 (CNCH2

CH2OH) 294(CH2CH2CH3) 220 (CH2

CH2CH3) 144 (CH2CH2CH3)

EImz 264 (M+ 100)

2-(1-(4-Hydroxy-2-benzoxazolone-7-yl)butylide-neamino)ace-tic Acid (TC-7) White solid (56) mp 80sim182∘C FT-IR(KBr) 120592 3333 (O-H) 3138 (N-H) 2969 2880 1740 (C=O)1721 (C=O) 1625 1593 1509 1425 1370 1228 1057 1H-NMR(DMSO-d6) 120575 1345 (1H s COO-H) 1168 (1H s N-H) 824(1H s O-H) 764 (1H d 119869 = 90Hz 6-ArH) 645 (1H d 119869 =90Hz 5-ArH) 385 (2H s CNCH2

COOH) 295 (2H t 119869= 738Hz CH2

CH2CH3) 166 (2H m CH2CH2CH3) 095

(3H t 119869 = 738Hz CH2CH2CH3) 13C-NMR (DMSO-d6)120575

1776 (COOH) 1721 (C=N) 1580 (2-C) 1566 (4-C)1471 (7a-C) 1280 (6-C) 1151 (7-C) 1127 (3a-C) 1101(5-C) 601 (CNCH

2COOH) 422 (CH

2CH2CH3) 183

(CH2CH2CH3) 141 (CH2CH2

CH3) EI mz 278 (M+12)

2-(1-(4-Hydroxy-2-benzoxazolone-7-yl)butylide-neamino)pro-panoic Acid (TC-8) White solid (56) mp 144sim146∘CFT-IR (KBr) 120592 3352 (O-H) 2966 2937 2876 1721 (C=O)1702 (C=O) 1642 1605 1512 1456 1383 1232 1067 8021H-NMR (DMSO-d6) 120575 1349 (1H s COO-H) 1316(1H s N-H) 814 (1H s O-H) 763 (1H d 119869 = 90Hz6-ArH) 645 (1H d 119869 = 90Hz 5-ArH) 419 (1H q 119869 =72Hz CNCH(CH

3)COOH) 296 (2H t 119869 = 366Hz

CH2CH2CH3) 165 (2H m CH2CH2

CH3) 133 (3Hd 119869 = 288Hz CNCH(CH3

)COOH) 095 (3H t 119869 =360Hz CH2CH2CH3

) 13C-NMR (600MHz DMSO)120575 1956 (COOH) 1767 (C=N) 1545 (2-C) 1467 (4-C)1447 (7a-C) 1260 (6-C) 1235 (7-C) 1134 (3a-C) 1055(5-C) 606 (CNCH(CH

3)COOH) 435 (CH

2CH2CH3)

300 (CH2CH2CH3) 175 (CNCH(CH3)COOH) 142

(CH2CH2CH3)mz 292 (M+ 40)

6-(1-(4-Hydroxy-2-benzoxazolone-7-yl)butylide-neamino)hexanoic Acid (TC-9) Light yellow solid (44) mp1385sim140∘C FT-IR (KBr) 120592 3368 (O-H) 2962 2943 28741732 (C=O) 1707 (C=O) 1637 1606 1517 1465 1375 1088798 1H-NMR (DMSO-d6) 120575 1351 (1H s COO-H) 1206(1H s N-H) 796 (1H s O-H) 761 (1H d 119869 = 90Hz6-ArH) 643 (1H d 119869 = 90Hz 5-ArH) 311 (2H t 119869 =684Hz CNCH2

CH2CH2CH2CH2COOH) 296 (2H m


CNCH2CH2CH2CH2CH2COOH) 221 (2H t 119869 = 738Hz

CH2CH2CH3) 164(2HmCNCH2CH2

CH2CH2CH2COOH)152 (2H m CNCH2CH2CH2CH2

CH2COOH) 145(2H m CNCH2CH2CH2

CH2CH2COOH) 131 (2H mCH2CH2

CH3) 093 (3H t 119869 = 738Hz CH2CH2CH3) 13C-

NMR (DMSO-d6) 120575 1749 (COOH) 1723 (C=N) 1581(2-C) 1560 (4-C) 1557 (7a-C) 1275 (6-C) 1155 (7-C) 1125(3a-C) 1104 (5-C) 594 (CNCH

2CH2CH2CH2CH2COOH)

477 (CNCH2CH2CH2CH2CH2COOH) 341

(CH2CH2CH3) 296 (CNCH2

CH2CH2CH2CH2COOH)264 (CNCH2CH2CH2

CH2CH2COOH) 247(CNCH2CH2

CH2CH2CH2COOH) 183 (CH2CH2CH3)

141 (CH2CH2CH3)mz 334 (M+ 32)

7-(1-(4-Methoxyphenylimino)butyl)-4-hydroxy-2-benzoxa-zolone (TC-10) Light yellow solid (52) mp 206sim207∘CFT-IR (KBr) 120592 3438 (O-H) 2972 2876 2836 1778 (C=O)1631 1608 1570 1510 1442 1376 1071 1034 (]s(C7a-O-C2)850 1H-NMR (DMSO-d6) 120575 1209 (1H s N-H) 1185 (1Hs O-H) 754 (1H d 119869 = 876Hz 6-ArH) 708 (2H d 119869 =894Hz 3101584051015840-ArH) 682 (1H d 119869 = 876Hz 5-ArH) 651(2H d 119869= 894Hz 2101584061015840-ArH) 379 (3H s OCH3

) 274 (2Ht 119869 = 576Hz CH2

CH2CH3) 158 (2H m CH2CH2CH3)

083 (3H t 119869 = 738Hz CH2CH2CH3) 13C-NMR (DMSO-

d6) 120575 1774 (C=N) 1576 (11015840-CAr) 1549 (2-C) 1512 (4-C)1469 (7a-C) 1372 (41015840-CAr) 1245 (6-C) 1236 (3101584051015840-CAr)1196 (7-C) 1150 (2101584061015840-CAr) 1134 (3a-C) 1005 (5-C) 558(OCH

3) 311 (CH

2CH2CH3) 226 (CH2

CH2CH3) 144(CH2CH2

CH3)mz 326 (M+ 38)

3 Result and Discussion

31 Biological Testing

311 Analgesic Activity Analgesic activity was examined byusing the hot-plate test protocol [8 9] 120 Webster miceof both sexes weighing 18ndash22 g were used for study Allanimals were fed diet in pellets following standard goodlaboratory practices Mice were divided into 12 groups Allof the compounds and the reference drug were suspendedin 05 carboxymethyl cellulose (CMC) solution The firstgroup as negative control received 5 CMC solution andthe second group received aspirin (g) as a reference drugwhile the other groups received the 10 test compounds Micewere dropped gently in a dry glass beaker of 1 dm3 capacitymaintained at 505ndash55∘C Normal reaction time in secondsfor all mice was determined at time intervals of 30 60 and90 minutes this is the interval extending from the instantthe mouse reaches the hot beaker till the animal licks itsfeet or jumps out of the beaker (dose 10mgkg) The relativepotencies to aspirin (g) were then determined (Table 1) Micewere maintained under 12 h lightdark cycles with controlledtemperature (28∘C)

HBOA and TC-3 TC-5 TC-7 TC-8 and TC-9 exhibitedmore petent analgesic than aspirin Compounds TC-3 TC-8and TC-9 showed around twice the activity of aspirin after 90minutes

Table 1 Analgesic activities of test compounds

Comp numberComparative analgesic potency to aspirin after

time in minutes30min 60min 90min

HBOA 116 plusmn 003 188 plusmn 009 110 plusmn 016TC-2 070 plusmn 009 155 plusmn 012 055 plusmn 008TC-3 037 plusmn 007 188 plusmn 013 214 plusmn 014TC-4 035 plusmn 003 080 plusmn 007 087 plusmn 013TC-5 091 plusmn 005 112 plusmn 008 145 plusmn 015TC-6 015 plusmn 004 045 plusmn 009 056 plusmn 009TC-7 101 plusmn 006 120 plusmn 012 135 plusmn 013TC-8 068 plusmn 007 088 plusmn 011 198 plusmn 014TC-9 060 plusmn 005 091 plusmn 010 181 plusmn 021TC-10 098 plusmn 008 040 plusmn 07 031 plusmn 008Aspirin 100 100 100All results were significantly different from the standard and normal controlValue at 119875 = 005

Table 2 Anti-inflammatory of test compounds

Comp numberIncrease in

edema (mL) plusmnSEM

protection Activity relativeto aspirin

Control 106 plusmn 004 00 00HBOA 082 plusmn 003 225 54TC-2 064 plusmn 003 396 95TC-3 048 plusmn 003 547 131TC-4 073 plusmn 003 311 75TC-5 057 plusmn 003 462 111TC-6 085 plusmn 003 198 48TC-7 073 plusmn 003 311 75TC-8 046 plusmn 003 566 136TC-9 078 plusmn 003 264 64TC-10 095 plusmn 003 104 25Aspirin 062 plusmn 003 415 100All results were significantly different from the standard and normal controlValue at 119875 = 005

312 Anti-Inflammatory Activity Anti-inflammatory activ-ity was examined by using carrageenan-induced rat pawedema test [10] Seventy-two adult Sprague-Dawley ratsweighing 150ndash180 g were used All animals were fed dietin pellets following standard good laboratory practices Theanimals were randomly divided into 12 groups of six animalseach All of the compounds and the reference drug weresuspended in 05 carboxymethyl cellulose (CMC) solutionThe standard drug aspirin and the test compoundswere givenat a dose of 20mgkg After one hour of the administration ofthe compounds and standard drug 01mL of 1 carrageenansolution in saline was injected into the subplantar region ofthe right hind paw of each rat The right hind paw volumewas measured after 3 h of carrageenan treatment by means ofplethysmometer

The test compounds showed anti-inflammatory activityranging from 104 to 566 whereas the standard drugaspirin showed 415 inhibition of edema after three hoursCompounds TC-3 TC-5 andTC-8 showedmore potent anti-inflammatory activity than aspirin (Table 2)


32 Chemistry In this research we synthesized compoundsTC-2 to TC-10 and their bioactivities were tested bycarrageenan-induced rat paw edema and hot-plate test meth-ods The results show that compounds HBOA and TC-3 TC-5 TC-7 TC-8 and TC-9 are active as analgesicand compounds TC-3 TC-5 and TC-8 are active as anti-inflammatory agent while the other compounds are poorlyactive towards the tested organisms

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Tieyu Chen and Guangjin Zheng have equally contributed tothis work

Acknowledgment

The authors gratefully thank their universities for theirequipment and financial support

References

[1] B-L Deng M D Cullen Z Zhou et al ldquoSynthesis andanti-HIV activity of new alkenyldiarylmethane (ADAM) non-nucleoside reverse transcriptase inhibitors (NNRTIs) incorpo-rating benzoxazolone and benzisoxazole ringsrdquo Bioorganic andMedicinal Chemistry vol 14 no 7 pp 2366ndash2374 2006

[2] Y Ivanova G Momekov O Petrov M Karaivanova and VKalcheva ldquoCytotoxicMannich bases of 6-(3-aryl-2-propenoyl)-2(3H)-benzoxazolonesrdquo European Journal of Medicinal Chem-istry vol 42 no 11-12 pp 1382ndash1387 2007

[3] P Carato S Yous D Sellier J H Poupaert N Lebegue and PBerthelot ldquoEfficient and selective deprotection method for N-protected 2(3H)-benzoxazolones and 2(3H)-benzothiazolonesrdquoTetrahedron vol 60 no 45 pp 10321ndash10324 2004

[4] K Shankaran K L Donnelly S K Shah et al ldquoInhibitionof nitric oxide synthase by benzoxazolonesrdquo Bioorganic andMedicinal Chemistry Letters vol 7 no 22 pp 2887ndash2892 1997

[5] D D ErolM D Aytemir andN Yulug ldquoSynthesis and antibac-terial and antifungal properties of thiazolinoethyl-2(3H)-benzoxazolone derivatives IIrdquo European Journal of MedicinalChemistry vol 31 no 9 pp 731ndash734 1996

[6] L Tang W-H Ma Y-L Ma S-R Ban X-E Feng andQ-S Li ldquoSynthesis and biological activity of 4-substitutedbenzoxazolone derivatives as a new class of sEH inhibitors withhigh anti-inflammatory activity in vivordquoBioorganicampMedicinalChemistry Letters vol 23 no 8 pp 2380ndash2383 2013

[7] L Tang S R Ban X E FengW H Lin and Q S Li ldquoSynthesisand activities of new 4-hydroxy benzoxazolone derivativesrdquoChinese Chemical Letters vol 21 no 1 pp 63ndash66 2010

[8] H-L Xin X-F Zhai X Zheng L Zhang Y-L Wang andZ Wang ldquoAnti-inflammatory and analgesic activity of totalflavone of Cunninghamia lanceolatardquo Molecules vol 17 no 8pp 8842ndash8850 2012

[9] E M Franzotti C V F Santos H M S L Rodrigues RH V Mourao M R Andrade and A R Antoniolli ldquoAnti-inflammatory analgesic activity and acute toxicity of Sidacordifolia L (Malva-branca)rdquo Journal of Ethnopharmacologyvol 72 no 1-2 pp 273ndash277 2000

[10] C A Winter E A Risley and G W Nuss ldquoCarrageenin-induced edema in hind paw of the rat as an assay for anti-iflammatory drugsrdquo Proceedings of the Society for ExperimentalBiology and Medicine vol 111 pp 544ndash547 1962

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CatalystsJournal of


Butyl acetate

O

NHO

OHOH

OH

FeCl3middot

middot

6H2O NH2CONH2

80 NH NH22 6H2O

NO2

Scheme 1 Methodology for synthesis of HBOA

O

NH

O

OH

O

NH

O

OH

Cl

+ H2O2 + HCl

Scheme 2 Methodology for synthesis of TC-2

stirred at 90∘C for 5 hours and then cooled to roomtemperatureThe crude HBOAwas obtained by filtration andpurified by recrystallization in 80 ethanol (yield 695)

22 Preparation of TC-2 Compound TC-2 was prepared viachlorination reaction and TC-3 to TC-4 were prepared viaFriedel-Crafts acylation on HBOA To a solution of 151 g(001mol) HBOA in 15mL glacial acetic acid and 2mL(0024mol) 37 HCl 180 g (0015mol) H

2O2was added

in 30 minutes by drops at 45∘C and then temperature wasraised to 80∘C and stirred for another 2 hours cooled toroom temperature filtered and washed with distilled waterto obtain compound TC-2 (Scheme 2)

7-Chloro-4-hydroxy-2-benzoxazolone (TC-2) White solid(yield 61) mp 226sim228∘C FT-IR (KBr) 120592 3384 (OH)3175 (NH) 1748 (C=O) 1625 1562 1492 1467 cmminus1 1H-NMR(DMSO-d6) 120575 1190 (1H sN-H) 1038 (1H sO-H) 707 (1Hd 119869 = 852Hz 6-ArH) 685 (1H d 119869 = 852Hz 5-ArH)13C-NMR (DMSO-d6) 1205751541 (2-C) 1434 (4-C) 1380 (7a-C)1224 (6-C) 1168 (7-C) 1122 (3a-C) 1031 (5-C) EI mz 185(M+ 100)

23 Preparation of TC-3 to TC-4 To slurry of 151 g (001mol)HBOA 80 g (006mol) AlCl

3in 20mL 12-dichloroethane

and 2mL nitrobenzene 004mol acyl chloride was addedby drops and stirred at rt for 1 hour Then temperature wasraised to 80∘C and stirred for another 4 hours The reactionwas quenched by cooling to rt and pouring the slurry into300mL ice-cold water Filtered and recrystallized with 90ethanol to yield pure compounds TC-3 and TC-4 (Schemes 3and 4)

7-Acetyl-4-hydroxy-2-benzoxazolone (TC-3) White solid(68) mp 226sim228∘C FT-IR (KBr) 120592 3358 (OH) 29832844 1769 (C=O) 1702 (C=O) 1659 1625 1512 1473 14271356 cmminus1 1H-NMR (DMSO-d6) 120575 1188 (1H s N-H)1108 (1H s O-H) 746 (1H d 119869 = 882Hz 6-ArH) 674 (1Hd 119869 = 882Hz 5-ArH) 265 (3H s COCH3

) 13C-NMR

(DMSO-d6) 120575 1933 (COCH3) 1545 (2-C) 1469 (4-C)

1449 (7a-C) 1237 (6-C) 1187 (7-C) 1136 (3a-C) 1112 (5-C)302 (COCH

3) EImz 193 (M+ 78)

7-Butyryl-4-hydroxy-2-benzoxazolone (TC-4) White solid(72) mp 168sim170 FT-IR (KBr) 120592 3138 (OH) 2964 29332901 2875 1777 (C=O) 1748 (C=O) 1659 1632 1494 14721376 1237 1156 1H-NMR (DMSO-d6) 120575 1187 (1H s N-H) 1005 (1H s O-H) 748 (1H d 119869 = 882Hz 6-ArH)675 (1H d 119869 = 882Hz 5-ArH) 293 (2H t 119869 = 714HzCOCH2

CH2CH3) 164 (2H m COCH2CH2CH3) 093

(3H t 119869 = 738Hz COCH2CH2CH3) 13C-NMR (DMSO-

d6) 120575 1957 (COCH2CH2CH3) 1545 (2-C) 1467 (4-C)

1447 (7a-C) 1260 (6-C) 1236 (7-C) 1134 (3a-C) 1113 (5-C) 436 (COCH

2CH2CH3) 174 (COCH2

CH2CH3) 142(COCH2CH2

CH3) EImz 221 (M+ 45)

24 Preparation of TC-5 to TC-10 Compounds TC-5 to TC-10 were prepared by reaction with corresponding primaryamines to afford Schiff Base derivatives To a solution of001mol starting material in 300mL ethanol 15 eq primaryamine derivatives were added refluxed for 3 hours and thencooled to rt and filtered and washed with distilled water toyield compounds TC-5simTC-10

7-(1-(2-Hydroxyethylimino)ethyl)-4-hydroxy-2-benzoxazolo-ne (TC-5) Yellow solid (91) mp 270sim271∘C FT-IR (KBr)120592 3429 (O-H) 2963 2873 1757 (C=O) 1635 1576 15361444 1380 1300 1286 1H-NMR (DMSO-d6) 120575 1680 (1H sN-H) 1620 (1H s C

4-OH) 737 (1H d 119869 = 90Hz 6-ArH)

646 (1H d 119869 = 90Hz 5-ArH) 369 (7H m) 343 (1H s)13C-NMR (DMSO-d6) 120575 1756 (C=N) 1612 (2-C) 1550(4-C) 1472 (7a-C) 1250 (6-C) 1212 (7-C) 1130 (3a-C) 973(5-C) 600 (CNCH

2CH2OH) 482 (CNCH2

CH2OH) 152(CH3) EImz 236 (M+ 100)

7-(1-(2-Hydroxyethylimino)butyl)-4-hydroxy-2-benzoxazolo-ne (TC-6) Light yellow solid (45) mp 255sim257∘C FT-IR(KBr) 120592 3431 (O-H) 3323 (N-H) 3027 (=C-H) 2957


AlCl3+

O

NHO

O

R Cl

OH

O

NHO

OH

O RTC-3 R = -CH3

TC-4 R = -CH2CH2CH3


+O

NH N

N

H

O O

OH

O

OH

O R1

H2N R2

R1 R2

TC-5 R1 = -CH3 R2 = -CH2OH







2CH2OH) 479 (CNCH2



EImz 264 (M+ 100)


COOH) 295 (2H t 119869= 738Hz CH2

CH2CH3) 166 (2H m CH2CH2CH3) 095



2COOH) 422 (CH

2CH2CH3) 183


CH3) EI mz 278 (M+12)


3)COOH) 296 (2H t 119869 = 366Hz


CH3) 133 (3Hd 119869 = 288Hz CNCH(CH3

)COOH) 095 (3H t 119869 =360Hz CH2CH2CH3


3)COOH) 435 (CH

2CH2CH3)


(CH2CH2CH3)mz 292 (M+ 40)









CH3) 093 (3H t 119869 = 738Hz CH2CH2CH3) 13C-


2CH2CH2CH2CH2COOH)






141 (CH2CH2CH3)mz 334 (M+ 32)


) 274 (2Ht 119869 = 576Hz CH2




3) 311 (CH

2CH2CH3) 226 (CH2

CH2CH3) 144(CH2CH2

CH3)mz 326 (M+ 38)






















Acknowledgment


References




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


AlCl3+

O

NHO

O

R Cl

OH

O

NHO

OH

O RTC-3 R = -CH3

TC-4 R = -CH2CH2CH3


+O

NH N

N

H

O O

OH

O

OH

O R1

H2N R2

R1 R2

TC-5 R1 = -CH3 R2 = -CH2OH







2CH2OH) 479 (CNCH2



EImz 264 (M+ 100)


COOH) 295 (2H t 119869= 738Hz CH2

CH2CH3) 166 (2H m CH2CH2CH3) 095



2COOH) 422 (CH

2CH2CH3) 183


CH3) EI mz 278 (M+12)


3)COOH) 296 (2H t 119869 = 366Hz


CH3) 133 (3Hd 119869 = 288Hz CNCH(CH3

)COOH) 095 (3H t 119869 =360Hz CH2CH2CH3


3)COOH) 435 (CH

2CH2CH3)


(CH2CH2CH3)mz 292 (M+ 40)









CH3) 093 (3H t 119869 = 738Hz CH2CH2CH3) 13C-


2CH2CH2CH2CH2COOH)






141 (CH2CH2CH3)mz 334 (M+ 32)


) 274 (2Ht 119869 = 576Hz CH2




3) 311 (CH

2CH2CH3) 226 (CH2

CH2CH3) 144(CH2CH2

CH3)mz 326 (M+ 38)






















Acknowledgment


References




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of







CH3) 093 (3H t 119869 = 738Hz CH2CH2CH3) 13C-


2CH2CH2CH2CH2COOH)






141 (CH2CH2CH3)mz 334 (M+ 32)


) 274 (2Ht 119869 = 576Hz CH2




3) 311 (CH

2CH2CH3) 226 (CH2

CH2CH3) 144(CH2CH2

CH3)mz 326 (M+ 38)






















Acknowledgment


References




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of







Acknowledgment


References




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

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