A Schiff base has been prepared by the reaction of 4-acetyl-5-methyl-2-(4-methylphenyl)-2,4-dihydro-3H-pyrazole-3-one with different substituted amines. Treatment of this Schiff base with chlorobactyl chloride affords the corresponding azetidinone in good yield. All the new compounds have been characterized by IR, 1H NMR, GC-MS and elemental analysis. The antibacterial activity of these compounds has been determined with the reference of standard drug

BHABHOR, FALGUNI 

Bhabhor, Falguni 

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Indian Journal of Chemistry Vol. 60B, October 2021, pp. 1396-1399 Synthesis and biological evaluation of azetidinone derivatives with pyrazolone moiety Falguni Bhabhor & Harish Dabhi* Department of Chemistry, Navjivan Science College, Dahod 389 151, India E-mail: ammy44433@gmail.comReceived 19 February 2020; accepted (revised) 26 August 2021 A Schiff base has been prepared by the reaction of 4-acetyl-5-methyl-2-(4-methylphenyl)-2,4-dihydro-3H-pyrazole-3-one with different substituted amines. Treatment of this Schiff base with chlorobactyl chloride affords the corresponding azetidinone in good yield. All the new compounds have been characterized by IR, 1H NMR, GC-MS and elemental analysis. The antibacterial activity of these compounds has been determined with the reference of standard drug. Keywords: 2-Azetidinone, pyrazolone, Schiff base, antimicrobial activity The synthesis of heterocyclic compound has always drawn the attention of chemist over the years mainly. Because of their important biological activities1. Pyrazolones is a five-member heterocyclic compound containing one ketonic group and two nitrogen atoms adjacent to each other. Pyrazolone derivatives play an important role in heterocyclic compound history and possess considerable biological activities, thus making it an important pharmacophore for carrying out further drug research2. One such heterocyclic, 2-azetidinone, a very well-known compound for the medicinal chemistry, since it forms a part of antibiotic molecules3. They are carbonyl derivatives of azetidinone containing carbonyl group at position- 2. These are known as 2- azetidinone4. The 2- azetidinone ring system, a common structural features of a number of wide spectrum β-lactam antibiotics, including penicinils, cephalosporin, carbapenems, nocardiacins and monobactams, which have been widely use as chemotherapic agent to treat bacterial infections and microbial diseases5. The utility of azetidinone as synthon for various biological active compounds as well their recognitions as antibacterial6, anticonvulsant7, antimicrobial8, antitubercular9, anti-inflammatory10, anthelmintic11, anesthetic12, antioxidant13. They also function as enzyme inhibitors14 and are effective on the CNS15. Cycloaddition of monochloroacetylchloride with imines (Schiff base) result in formation of 2- azetidinone(β-lactam). The reaction involves direct acylation of Schiff base with monochloroacetylchloride. The reaction is carried out with base as triethylamine gives β- lactam. Result and Discussion ChemistryAzetidinone derivatives III1-5 were prepared using the method summarized in Scheme I. First, 3-methyl-1-(4-methylphenyl)-2-pyrazolineon acylation gives 4-acetyl-5-methyl-2-(4-methyl- phenyl)-2,4-dihydro-3H-pyrazole-3-one derivatives I(1-5). Compounds I(1-5) on reaction with substituted amines afforded Schiff base derivatives II(1-5). Finally the Schiff bases upon reaction with chloroacetyl chloride in the presence of triethylamine afforded azetidinone derivatives III(1-5). The structure of compounds was assigned on the basis of spectral data. In the IR spectra of azetidinone derivatives the carbonyl group of the β-lactam ring appeared as a characteristic absorption band in the IR range 1660-1675 cm–1.The IR absorption bands and 1H NMR signal characteristic of azomethine group disappeared from the spectra of azetidinone derivatives which conforms that the cyclization reaction with chloroacetyl chloride took place. The 1H NMR spectra of III(1-5) showed signals, which are characteristic for CH-Cl that appears in the range of 5.2-5.9. Synthetic route is given as below. Experimental Section Melting points were recorded in open capillary tube and are uncorrected. The IR spectra were recorded on a Perkin–Elmer 37 spectrophotometer and 1H NMR spectra were recorded in DMSO-d6 withTMS as internal standard on Bruker AM 400 BHABHOR & DABHI: AZETIDINONE DERIVATIVES WITH PYRAZOLONE   1397 instrument (at 400 MHz). Mass spectra were recorded on MS route JMS 600-H. All the synthesized compounds were purified by recrystalization. All the chemicals and solvents were AR grade and were used without further purification.  General procedure  Step-1: Synthesis of 4-acetyl-5-methyl-2-(4-methylphenyl)-2, 4-dihydro-3H-pyrazole-3-one 3-Methyl-1-(4-methylphenyl)-2-pyrazoline-one in solution of dioxane and acetyl chloride was refluxed for 2h in oil bath with calcium hydroxide and cooled to RT. The resulting reaction mass is added to dil. HCL, the crude product (I1-5) was collected by filtration and washed several time with water and then dried in air.  Step- 2: Synthesis of Schiff base 4-Acetyl-5-methyl-2-(4-methylphenyl)-2, 4-dihydro-3H-pyrazole-3-one (0.01mol) is treated with substituted amine in ethanol reflux for 3-5 h. Then mixture is cooled. Solid yellow product (II1-5) filtered and washed with methanol or ethanol.  Step-3: Synthesis of 2-azetidinone derivatives Schiff bases obtained in step-2 (0.01mol) in DMF on further treatment with base triethylamine (0.01 mol) and acylated with chloroacetyl chloride (0.01mol) as cyclic agent. The reaction mixture was stirred for 5-7 hrs. The product (III1-5) was isolated and purified by recrystallization from ethanol.  III1.4-(3-Chloro-2-methyl-4-oxo-1-phenyl-azetidin-2-yl)-5-methyl-2-p-tolyl-2,4-dihydro-pyrazol-3-one m.p.141-143°C (uncorrected). Yield: 65%. IR: 2893 Aromatic C-H stretching, 1669 C=O, 1605, C=N, 1537, C=C Ar., 759 cm–1 C-Cl; 1H NMR: δ 6.98-7.63 (8H, m, Ar-H), 3.1 (1H, s, Pyrazolone), 5.04 (1H, s, CH), 1.96 (3H, s, CH3), 2.34 (3H, s, CH3), 1.56 (3H, s, CH3). Anal. Calcd for C20H20ClN3O2: C, 66.05; H, 5.28; N, 11.0. Found: C, 66.03; H, 5.30; N, 11.04%.   Scheme I  INDIAN J. CHEM., SEC B, OCTOBER 2021   1398 III2. 4-[3-Chloro-1-(4-chloro-phenyl)-2-methyl-4-oxo-azetidin-2-yl]-5-methyl-2-p-tolyl-2,4-dihydro-pyrazol-3-one m.p.156-157°C (uncorrected). Yield: 68%. IR: 2896 Aromatic C-H stretching, 1665 C=O, 1602, C=N, 1542, C=C Ar., 762 cm–1 C-Cl; 1H NMR: δ 7.0-8.09 (8H, m, Ar-H), 3.0 (1H, s, Pyrazolone), 5.04 (1H, s, CH), 1.93 (3H, s, CH3), 2.33 (3H, s, CH3), 1.53 (3H, s, CH3). Anal. Calcd for C20H19Cl2N3O2: C, 60.57; H, 4.65; N, 10.1. Found: C, 60.59; H, 4.60; N, 10.09%.  III3. 4-[3-Chloro-1-(3-chloro-phenyl)-2-methyl-4-oxo-azetidin-2-yl]-5-methyl-2-p-tolyl-2,4-dihydro-pyrazol-3-one m.p.147-148°C (uncorrected). Yield: 67%. IR: 2899 Aromatic C-H stretching, 1668 C=O, 1609, C=N, 1540, C=C Ar., 763 cm–1 C-Cl; 1H NMR: δ 7.0-8.09 (8H, m, Ar-H), 3.1 (1H, s, Pyrazolone), 5.06 (1H, s, CH), 1.93 (3H, s, CH3), 2.34 (3H, s, CH3), 1.52 (3H, s, CH3). Anal. Calcd for C20H19Cl2N3O2: C, 60.59; H, 4.60; N, 10.9. Found: C, 60.6; H, 4.61; N, 10.07%.  III4. 4-(3-Chloro-2-methyl-4-oxo-1-p-tolyl-azetidin-2-yl)-5-methyl-2-p-tolyl-2,4-dihydro-pyrazol-3-one m.p.154-155°C (uncorrected). Yield: 70%; IR: 2896 Aromatic C-H stretching, 1662 C=O, 1610, C=N, 1535, C=C Ar., 757 cm–1 C-Cl; 1H NMR: δ 6.99-7.86 (8H, m, Ar-H), 3.04 (1H, s, Pyrazolone), 5.02 (1H, s, CH), 1.96 (3H, s, CH3), 2.33 (3H, s, CH3), 1.52 (3H, s, CH3). Anal. Calcd for C22H22ClN3O2: C, 66.75; H, 5.60; N, 10.61. Found: C, 66.8; H, 5.59; N, 10.62%.  III5. 4-[3-Chloro-2-methyl-1-(4-nitro-phenyl)-4-oxo-azetidin-2-yl]-5-methyl-2-p-tolyl-2,4-dihydro-pyrazol-3-one m.p.154-155°C (uncorrected). Yield: 70%. IR: 2902 Aromatic C-H stretching, 1670 C=O, 1608, C=N, 1534, C=C Ar., 756 cm–1 C-Cl; 1H NMR: δ 7.0-8.86 (8H, m, Ar-H), 3.2 (1H, s, Pyrazolone), 5.09 (1H, s, CH), 1.96 (3H, s, CH3), 2.35 (3H, s, CH3), 1.55 (3H, s, CH3). Anal. Calcd for C21H19ClN4O4: C, 59.09; H, 4.49; N, 1.13. Found: C, 59.11; H, 4.48; N, 13.1%.  Biological Study  Antibacterial activity We have used the Agar cup Method to evaluate the antibacterial activity. It is one of the non automated in vitro bacterial susceptibility tests. This classic method yields a zone of inhibition in mm result for the amount of antimicrobial agents that is needed to inhibit growth of specific microorganisms (Figure 1). It is carried out in Petri plates. Antibacterial activity of compounds is shown in Table I.  Antifungal activity Antifungal activity of compounds (III 1-5) is shown in Table II and Figure 2.   Figure 1 — Graphical representation of antibacterial activity    Figure 2 — Graphical representation of antifungal activity  Table I — Antibactarial activity of compounds III1-5 Compd Zone of Inhibition Gram Positive Gram Negative III1 17 16 19 15 III2 09 07 08 10 III3 17 17 15 16 III4 10 07 09 06 III5 08 10 09 11 Chloroamphinocol 20 20 23 19  Table II — Antifungal activity of compounds III1-5 Compd Zone of Inhibition (in mm) C. albicans A. niger III1 08 07 III2 17 21 III3 17 20 III4 19 19 III5 19 20 Greseofulvin 27 29 BHABHOR & DABHI: AZETIDINONE DERIVATIVES WITH PYRAZOLONE   1399 Compounds III 1-5 showed moderate to good antimicrobial activity against standard drugs.  Conclusion In this study new 2-azetidionone derivatives have been synthesize from Schiff Bases. The structures of all new compounds were proved using spectral methods. The compounds were evaluated for their antimicrobial. Antimicrobial potential of all compounds was reduced.  Acknowledgement The authors express their grateful thanks to Dahod Anaj Mahajan Sarvajanic Education Society and to the Head, Department of Chemistry for providing facilities for research work. The authors are also thankful to RGNF for financial support and to the Sophisticated Instrumentation Center for Applied Research and Testing (SICART), Vidhyanagar, India for analytical work.  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Synthesis and biological evaluation of azetidinone derivatives with pyrazolone moiety 

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Synthesis and biological evaluation of azetidinone derivatives with pyrazolone moiety

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