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Synthesis of some novel schiff's bases of N-aryl anthranilic acid derivatives.

Introduction

N-aryl anthranilic acid and its derivatives show a wide spectrum of pharmacological activities such as skeletal muscle relaxant [1], anti-inflammatory activity [2,3,4], anti diabetic activity, antipyretic activity [5,6], antiangiogenic and anti tumor activity [7], antiproliferative activity, analgesic activity, trichomonoas vaginalis, antibacterial and antifungal activities.

N-aryl anthranilic acid nucleus is an effective NSAID, used for skeletal muscle relax tent also pain relief agents. Mefenamic acid, Flufenamic Acid and Glafenine is a non-steroidal anti-inflammatory agent with analgesic, anti-inflammatory, and antipyretic properties. [9] Anthranilic acid is the biochemical precursor to the amino acid tryptophan. Anthranilic acid is vitamin-L is thought to be necessary for lactation in human females that is reason for the "L" [sup.10]Ullmann--type aryl amination has been the reaction of choice for the preparation of N-aryl anthranilic acid derivatives since the discovery in 1903 [11,12].

Materials and methods

Experimental

All the melting points were taken in Veego-Vmp 1 melting point apparatus are uncorrected. IR spectra were recorded on Perkin Elmer FT-IR spectrometer. NMR spectra were recorded on Bruker spectrospeir 200MHZ, the chemical shifts referenced to TMS. The molecular formula, solubility, physical character and TLC were determined. (Table 1,2,3,4)

Synthesis of VV-aryl anthranilic acid derivatives

p-substituted N-aryl anthranilic acid derivatives were synthesized by refluxing a mixture of O-Chlorobenzoic acid 3.12gm (0.02mol), various P-substituted anilines X gm (0.022mol) cupric oxide (20-25 mg) and anhydrous Potassium carbonate (80-100 mg) was heated under reflux for 7-8 hrs. Add water the un dissloved materials were removed by filtration. Finally the compounds were precipitated with the help of dilute hydrochloric acid, filtered, dried and recrystallized from ethanol (95%) .

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Phytochemical investigation [13,14,15] Compound (IIb)

Name: 2-[(4-chlorophenyl) amino] benzoic acid

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IR spectra 3300 [cm.sup.-1] O-H stretching, 1687 [cm.sup.-1], C = O stretching, 1477 [cm.sup.-1] C=C stretching, 3083-2821 [cm.sup.-1] C-H stretching,3500-3300 [cm.sup.-1] N-H stretching, 1313-1265 [cm.sup.-1] C-N stretching 1045 [cm.sup.-1] Ar-Cl, 813-790 [cm.sup.-1] C-Cl.

Compound (IIc)

Name: 2-[(4-hydroxyphenyl) amino] benzoic acid (ic)

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IR spectra 3300 [cm.sup.-1] O-H stretching, 1687 [cm.sup.-1], C = O stretching, 1475 [cm.sup.-1] C=C stretching, 3083-2821 [cm.sup.-1] C-H stretching, 3550-3300 [cm.sup.-1] N-H stretching, 1315-1265 [cm.sup.-1] C-N stretching.

Compound (IIe)

Name: 2-[(4-carboxyphenyl) amino] benzoic acid (Ie)

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IR spectra 3300 [cm.sup.-1] O-H stretching, 1687 [cm.sup.-1], C=O stretching, 1475 [cm.sup.-1] C=C stretching, 3091-2925 [cm.sup.-1] C-H stretching, 3600-3300 [cm.sup.-1] N-H stretching, 1313-1271 [cm.sup.-1] C-N stretching.

Compound (IIg)

Name: 2-{[4-(acetylamino) phenyl] amino} benzoic acid (Ig)

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IR(KBr pellet) spectra 3300 [cm.sup.-1] O-H stretching, 1687 [cm.sup.-1], C=O stretching, 1477 [cm.sup.-1] C=C stretching, 3091-2925 [cm.sup.-1] C-H stretching, 3600-3300 [cm.sup.-1] N-H stretching, 1315-1265 [cm.sup.-1] C-N stretching. [sup.1]HNMR (CD[Cl.sub.3]) 7.3 oppm aromatic C[H.sub.2] protons, 8.5 [delta] ppm -NH protons, 7.5 [delta] ppm-OH proton

Compound (IIh)

Name: 2-[(4-nitrophenyl) amino] benzoic acid (Ih)

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IR(KBr pellet) spectra 3300 [cm.sup.-1] O-H stretching, 1689 [cm.sup.-1], C=O stretching, 1477 [cm.sup.-1] C=C stretching, 3083-2821 [cm.sup.-1] C-H stretching, 3550-3300 [cm.sup.-1] N-H stretching, 1315-1265 [cm.sup.-1] C-N stretching, 813-790 [cm.sup.-1] Ar-N[O.sub.2]

Result and Discussion

Ullmann-type aryl amination has been reaction of choice for the synthesis of anthranilic acid derivatives. However, low yield presumably due to high reaction temperature, suffered by cupper catalyst and less or more acidic made of filtrate. For best results, the reaction was carried out in different solvents (ethanol & water), used varying concentration of cupper catalyst, different temperature conditions (60[degrees]C and 100[degrees]C). in good yield was come from using distilled water as solvent, 20mg of cupper catalyst, anhydrous [K.sub.2]C[O.sub.3] with reactants were heated at 100oC for 8-10 hrs. The filtrate was carefully made acidic ([p.sub.H] = 5-3) with dilute HCl. The N-aryl anthranilic acid derivatives (compound- ii) was obtained starting from O-chlorobenzoic acid with different P-substituted aniline via Ullmann reaction.

The melting point of the isolated compounds were found out by open capillary tube method and the results were uncorrected. The purity of the compounds was checked by TLC using silica gel G as an adsorbent, ethyl acetate and chloroform (1:9) were used as mobile phase. The spot was visualized by iodine vapour or dinitrophenyl hydrazine solution. The structure of the isolated compounds was characterized by its IR, HNMR spectral analysis in which it complies with the normal values.

References

[1] The Merck index, an encyclopedia of chemicals & drugs, 9th edition

[2] Daniel ledninger, "The organic chemistry of drug synthesis", Vol-1, [110]

[3] Joshi, J.K, Patel, V.R, Rana, D. K.Shah, Ronak Patel and Rajesh Patel., 2007, Indian Journal of Pharmaceutical sciences., 69(5): 697-699.

[4] Ronald F.Borne, Richard L.Peden, W.Waters, Myra Weine, Robert Jordan and Eugene A.Coats., Journal of Pharmaceutical sciences, Vol-63, issue-4, pp.615-617.

[5] Keinanen S.,. Simila, S .,and. Kouvalainen. K, 1978, European Journal Of Clinical Pharmacology, Vol-13, No-5/sep, pp.331-334.

[6] Fadeyi O.O.,. Obafemi C.A, Adewunmi C.O. and walewa. E.O.i, 2004, African Journal of Biotechnology, Vol-3(8), pp.426-431.

[7] Paul W.Manley, Pascal Furet, Guido Bold, Josef Bruggen, Jurgen Mestan, Thmos Meyer, Christian R.Schnell and Jeanette Wood., 2002, Journal of Medicinal Chemistry., 45(26), pp. 5687-5693.

[8] Cenzo Congiu, Maria Teresa Cocco, Valentina Lilliu and Valentina Onnis., 2005, Journal of Medicinal Chemistry, 48(26), pp. 8245-8252.

[9] Florence Delmas, Carole Di Giorgio, Maxime Robin, Nadine Azas, Monique Gasquet, Claire Detang, Muriel Costa, Pierre Timon-David, and Jean-Pierre Galy., 2002, Antimicrobial Agents and Chemotherapy, Vol. 46, No. 8, pp. 2588-2594.

[10] Phosphorus, Sulfur, and Silicon and the Related Elements, 2008, Volume 183, issue 9, pp.2191-2203.

[11] Bull., 2005, Korean chem.soc. Vol.26, pp.10.

[12] Joshi, J. K., Patel, V. R. ., Rana, D.K., Shah., Ronak., Patel and Rajesh Patel.,2007, indian journal of pharmaceutical sciences., 69(5), 697-699.

[13] John R.Dyer., 1969, Applications of absorption spectroscopy of organic compounds, 1st edition, Prentice-Hall of india (P), New Delhi. pp. 33-38.

[14] Robert, M., Silverstein, Francis, X., Webster, 1988, Spectrometric identification of organic compounds, John Wiley and sons, inc.

[15] Mc Lafferty, F. W., 1974, interpretation of mass spectra, 2nd edition, W.A. Benjamin.inc. Publishers, New York.

P. Muthumani * (1), R. Meera (1), S. Venkatraman (1), Murugan (1), P. Devi (2), B. Kameswari (3) and B. Eswarapriya (4)

(1) Department of Pharmaceutical Chemistry

* Correspondence author E-mail: meeraharsa@yahoo.com.

E-mail: Sabareesanmuthu@gmail.com

(2) Department of Pharmacognosy

(3) Department of Biochemistry, K.M. College of Pharmacy, Uthangudi, Madurai--625 107

(4) Department of Biotechnology, St.Michael college of Engineering, Sivagangai, TamilNadu, India
Table 1: Molecular formula and Practical yield of synthesized
compounds.

S.No   Compound code   R

1      IIa             H
2      lib             Cl
3      IIc             OH
4      IId             OC[H.sub.3]
5      lie             COOH
6      IIf             COC[H.sub.3]
7      IIg             NHCOC[H.sub.3]
8      Iih             N[O.sub.2]

S.No   Molecular formula                         Practical Yield

1      [C.sub.13][H.sub.11]N[O.sub.2]                 2..44
2      [C.sub.13][H.sub.10]CIN[O.sub.2]               3.26
3      [C.sub.13][H.sub.11]N[O.sub.3]                 2.04
4      [C.sub.14][H.sub.13]N[O.sub.3]                 2.34
5      [C.sub.14][H.sub.13]N[O.sub.4]                 3.08
6      [C.sub.15][H.sub.13]N[O.sub.3]                 2.58
7      [C.sub.15][H.sub.14][N.sub.2][O.sub.3]         2.34
8      [C.sub.13][H.sub.10][N.sub.2][O.sub.4]         3.66

Table 2: Physical characters of N-Aryl anthranilic acid
derivatives.

S.No   Compound        Molecular         Molecular
         code           formula           weight

1        IIa      [C.sub.13][H.sub.11]    213.23
                       N[O.sub.2]
2        IIb      [C.sub.13][H.sub.10]    247.67
                      CIN[O.sub.2]
3        IIc      [C.sub.13][H.sub.11]    229.23
                       N[O.sub.3]
4        IId      [C.sub.14][H.sub.13]    243.25
                       N[O.sub.3]
5        IIe      [C.sub.14][H.sub.13]    257.24
                       N[O.sub.4]
6        IIf      [C.sub.15][H.sub.13]    255.26
                       N[O.sub.3]
7        IIg      [C.sub.15][H.sub.14]    270.28
                   [N.sub.2][O.sub.3]
8        IIh      [C.sub.15][H.sub.10]    258.23
                   [N.sub.2][O.sub.4]

S.No   Colour and nature    Percentage      Melting
          of compounds        yield          point

1         Light yellow        57.28%     71[degrees]C
       crystalline powder
2            White            65.99%     96[degrees]C
       crystalline powder
3          Pale brown         44.51%     183[degrees]C
       crystalline powder
4        Bright yellow        48.15%     89[degrees]C
       crystalline powder
5         Pale yellow         59.92%     180[degrees]C
       crystalline powder
6       Yellowish white       50.58%     105[degrees]C
       crystalline powder
7         Grayish pink        43.33%     117[degrees]C
       crystalline powder
8            Yellow           70.93%     162[degrees]C
       crystalline powder

Table 3: Solubility characters of synthesized compounds.

S.No   Compounds   Soluble in              Insoluble in
       code

1      IIa         Hotwater, alcohol,      Cool water
                   DMSO DMF
2      IIb         Hotwater, alcohol,      Cool water
                   DMSO DMF,acetone
3      IIc         Hotwater, alcohol,      Cool water
                   DMSO DMF,acetone
4      IId         Hotwater, alcohol,      Cool water
                   DMSO DMF,ether
5      IIe         Hotwater, alcohol,      Cool water
                   DMSO DMF, acetic acid
6      IIf         Hotwater, alcohol,      Cool water
                   DMSO DMF, chloroform
7      IIg         Hotwater, alcohol,      Cool water
                   DMSO DMF, ether
8      IIh         Hotwater, alcohol,      Cool water
                   DMSO DMF, benzene

Table 4: TLC characters of synthesized compounds.

S.no   Compounds code   Colour of spot   Rf Values

1      IIa              Light yellow     0.68
2      IIb              Light yellow     0.68
3      IIc              Brown            0.70
4      IId              Light brown      0.71
5      IIe              Pale yellow      0.69
6      IIf              Pale yellow      0.70
7      IIg              Light yellow     0.72
8      IIh              yellow           0.69
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Author:Muthumani, P.; Meera, R.; Venkatraman, S.; Murugan; Devi, P.; Kameswari, B.; Eswarapriya, B.
Publication:International Journal of Applied Chemistry
Article Type:Report
Geographic Code:9INDI
Date:May 1, 2010
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