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Current Organic Synthesis

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ISSN (Print): 1570-1794
ISSN (Online): 1875-6271

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Research Article

Synthesis of Phthaloylglycyl Hydrazide Derivatives: Selective Protection of Phthalimide Group from Hydrazinolysis

Author(s): Ankur Gera*, Chander Mohan and Sandeep Arora

Volume 15, Issue 6, 2018

Page: [839 - 845] Pages: 7

DOI: 10.2174/1570179415666180601083256

Price: $65

Abstract

Background: N-phthalimide amino acid hydrazide is a class of compounds that have the potential therapeutic use. In general, hydrazinolysis of N-substituted amino acid(s) ester removes the ester group and yields the corresponding hydrazide. However, in case if N-substitution group is phthalimide, phthalimide group is cleaved and not the ester group. The resulted compound, therefore, is amino acid ester rather than Nphthalimide amino acid hydrazide. The above class of compounds, because of susceptibility of phthalimide group to hydrazinolysis, has previously been synthesized by a lengthy three-step procedure.

Objective: N-phthaloylglycyl hydrazide was synthesized by using new efficient, simplified, one step process. Hydrazone derivatives from substituted benzaldehydes, and substituted furaldehyde were also synthesized.

Method: N-phthaloylglycyl hydrazide was synthesized from the corresponding carboxylic acid using 1-Ethyl- 3-(3-dimethylaminopropyl)carbodiimide (EDC) as a coupling agent and hydroxybenzotriazole (HOBt) as an activator. Hydrazone derivatives were synthesized by condensation of N-phthaloylglycyl hydrazide with substituted benzaldehyde/substituted furaldehydes. All the compounds were characterized by IR, 1H-NMR, 13CNMR, mass spectroscopy and elemental analysis.

Results: The presence of EDC/HOBt resulted in hydrazinolysis of the carboxylic acid group and not the phthalimide group. N-phthaloylglycyl hydrazide was synthesized in good yield.

Conclusion: We report the improved process of the synthesis of N-phthaloylglycyl hydrazide. This is the first report where stability of phthaloyl amino acid compound to hydrazine is demonstrated. The reaction may be explored for the reaction schemes where stability of phthalimide group to hydrazinolysis is required.

Keywords: Phthaloyl glycine, phthaloylglycyl hydrazide, hydrazinolysis, EDC, HOBt, phthaloyl aminoacid hydrazide.

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[1]
Braslau, R.; Anderson, M.O.; Rivera, F.; Jimenez, A.; Haddad, T.; Axon, J.R. Acyl hydrazines as precursors to acyl radicals. Tetrahedron, 2002, 58(27), 5513-5523.
[2]
Majumdar, P.; Pati, A.; Patra, M.; Behera, R.K.; Behera, A.K. Acid hydrazides, potent reagents for synthesis of oxygen-, nitrogen-, and/or sulfur-containing heterocyclic rings. Chem. Rev., 2014, 114(5), 2942-2977.
[3]
Rollas, S.; Küçükgüzel, G.S. Biological activities of hydrazone derivatives. Molecules, 2007, 12(8), 1910-1939.
[4]
Bibian, M.; El-Habnouni, S.; Martinez, J.; Fehrentz, J.A. Enantioselective synthesis of n-protected α-amino acid hydrazides. Synthesis, 2009, 2009(07), 1180-1184.
[5]
Beri, R.; Chandra, R. Synthesis and antitubercular activity of N-aryl glycyl hydrazides. Proc. Indian Nat. Sci. Acad Part A, 1991, 57(5), 645-654.
[6]
Balthasar, H.; Hugo, G.; Paul, Z. Amino acid hydrazides. U.S. Patent 3065265, 1962
[7]
Muanprasat, C.; Sonawane, N.D.; Salinas, D.; Taddei, A.; Galietta, L.J.V.; Verkman, A.S. Discovery of glycine hydrazide pore-occluding CFTR inhibitors. J. Gen. Physiol., 2004, 124(2), 125-137.
[8]
Lacerda, R.B.; da Silva, L.L.; de Lima, C.K.F.; Miguez, E.; Miranda, A.P.; Laufer, S.A.; Barreiro, E.J.; Fraga, C.A.M. Discovery of novel orally active anti-inflammatory N-phenylpyrazolyl-N-glycinyl-hydrazone derivatives that inhibit TNF-α production. PLoS One, 2012, 7(10), e46925.
[9]
Lacerda, R.B.; Sales, N.M.; da Silva, L.L.; Tesch, R.; Miranda, A.L.; Barreiro, E.J.; Fernandes, P.D.; Fraga, C.A. Novel potent imidazo[1,2-a]pyridine-N-glycinyl-hydrazone inhibitors of TNF-α production: In vitro and in vivo studies. PLoS One, 2014, 9(3), e91660.
[10]
Coêlho, L.; de Cardoso, M.; Moreira, D.; de Gomes, P.; Cavalcanti, S.; Oliveira, A.; de Filho, G.; de Siqueira, L.; de Barbosa, M.; de Borba, E.; da Silva, T.; Kaskow, B.; Karimi, M.; Abraham, L.J.; Leite, A. Novel phthalimide derivatives with TNF-α and IL-1β expression inhibitory and apoptotic inducing properties. Med. Chem. Commun, 2014, 5(6), 758-765.
[11]
Kajal, A.; Bala, S.; Kamboj, S.; Saini, V. Synthesis, characterization, and computational studies on phthalic anhydride-based benzylidene-hydrazide derivatives as novel, potential anti-inflammatory agents. Med. Chem. Res., 2014, 23(5), 2676-2689.
[12]
Hofmann, K.; Lindenmann, A.; Magee, M.Z.; Khan, N.H. Studies on polypeptides. III. Novel routes to α-amino acid and polypeptide hydrazides. J. Am. Chem. Soc., 1952, 74(2), 470-476.
[13]
Gross, E.; Meienhofer, J. Major Methods of Peptide Bond Formation; Academic Press: New York, 1979, Vol. 1, .
[14]
Radenhausen, R. Ueber hydrazide substituirter amidosäuren und das hydrazid der fumarsäure. J. Prakt. Chem., 1895, 52(1), 433-454.
[15]
Hofmann, K.; Katsoyannis, P.G. Synthesis and Function of Peptides of Biological Interest. In: The Proteins Composition, Structure, and Function; Neurath, H., Ed.; Academic Press: New York, 1963; pp. 53-188.
[16]
Anderson, G.W. New approaches to peptide synthesis. Ann. N. Y. Acad. Sci., 1960, 88(3), 676-688.
[17]
Surrey, A.R. Name reactions in organic chemistry, 2nd ed; Academic Press: New York, 1969.
[18]
Billman, J.H.; Harting, W.F. Amino acids. V. phthalyl derivatives. J. Am. Chem. Soc., 1948, 70(4), 1473-1474.
[19]
King, F.E.; Clark-Lewis, J.W.; Kidd, D.A.A.; Smith, G.R. Syntheses from phthalimido-acids. Part IV. p-glycylaminobenzoic acid and derivatives. J. Chem. Soc., 1954, 1039-1043.
[20]
King, F.E.; Clark-Lewis, J.W.; Smith, G.R. Syntheses from phthalimido-acids. Part VI. Further products from phthalyl-DL-aspartic anhydride, and the preparation of phthalylglycyl-DL-asparagine and -DL-serine. J. Chem. Soc., 1954, 1046-1049.
[21]
King, F.E.; Clark-Lewis, J.W.; Wade, R.; Swindin, W.A. Syntheses from phthalimido-acids. Part VII. Oxazolones and other intermediates in the synthesis of phthalylpeptides, and an investigation on maleic acid derivatives of amino-acids. J. Chem. Soc., 1957, 873-880.
[22]
King, F.E.; Kidd, D.A.A. A new synthesis of glutamine and of γ-dipeptides of glutamic acid from phthalylated intermediates. J. Chem. Soc., 1949, 3315-3319.
[23]
King, F.E.; Kidd, D.A.A. Synthesis from phthalimido-acids. Part III. The preparation of DL- and L-asparagine from phthalyl-DL- and -L-aspartic anhydride. J. Chem. Soc., 1951, 2976-2978.
[24]
Ing, H.R.; Manske, R.H.F. A modification of the Gabriel synthesis of amines. J. Chem. Soc., 1926, 129, 2348-2351.
[25]
Han, S.Y.; Kim, Y.A. Recent development of peptide coupling reagents in organic synthesis. Tetrahedron, 2004, 60(11), 2447-2467.
[26]
Quibell, M.; Turnell, W.G.; Johnson, T. Synthesis of azapeptides by the Fmoc/tert-butyl/polyamide technique. J. Chem. Soc., Perkin Trans. 1, 1993, 1993(22), 2843-2849.
[27]
Benassi, R.; Benedetti, A.; Taddei, F.; Cappelletti, R.; Nardi, D.; Tajana, A. Conformational analysis of hydrazones. 1H dynamic nuclear magnetic resonance and solvent effects in aryl- and 2-furylaldehyde ethylaminoacetylhydrazones. Org. Magnetic Reson., 1982, 20(1), 26-30.
[28]
Lopes, A.B.; Miguez, E.; Kummerle, A.E.; Rumjanek, V.M.; Fraga, C.A.; Barreiro, E.J. Characterization of amide bond conformers for a novel heterocyclic template of N-acylhydrazone derivatives. Molecules, 2013, 18(10), 11683-11704.
[29]
Ozdemir, A.; Turan-Zitouni, G.; Kaplancikli, Z.A.; Altintop, M.D. Synthesis of some new hydrazone derivatives containing benzothiazole moiety. J. Serb. Chem. Soc., 2012, 77(2), 141-146.
[30]
Palla, G.; Predieri, G.; Domiano, P.; Vignali, C.; Turner, W. Conformational behaviour and E/Z isomerization of N-acyl and N-aroylhydrazones. Tetrahedron, 1986, 42(13), 3649-3654.

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