Ultrasound assisted synthesis of 4-( benzyloxy )-N-( 3-chloro-2-( substituted phenyl )-4-oxoazetidin-1-yl ) benzamide

Maulana Azad Post Graduate and Research Centre, Dr. Rafiq Zakaria Campus, Rauza Baug, Aurangabad 431001, India; urjasatish@gmail.com Departamento de QuímicaOrgánica, Facultad de Ciencias, Universidad of Santiago de Compostela,Alfonso X el Sabio, Lugo 27002, Spain; julioa.seijas@usc.es; pilar.vazquez.tato@usc.es Y. B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Rauza Baug, Aurangabad 431001, India*

The four-membered cyclic amides commonly known as 2-azetidinones or β-lactam occupy a eminent place in organic and medicinal chemistry since the structure of penicillin showed the presence of β-lactam ring in it and various potent activities of penicillin are due to the presence of β-lactam ring. The discovery of several β-lactam antibiotics such as, carbapenams, cephalosporin 's, monobactams, trinems, etc [12-14] plays very important role for the treatment of microbial infections in human kind. The research has directed towards the development of several novel methodologies for designing of drugs containing β-lactam ring. Azetidinone are known to exhibits various biological activities particularly anti-tubercular [15][16][17][18][19][20] antibacterial and antifungal activities [21][22]. 5 Sono-chemistry is the application of ultrasound technique has undergone very intensive research and development in the last 15-20 years to carry out chemical transformation. Ultrasound offers potential for cleaner reactions called green protocol keeping in mind to protect environment clean and green through improved product yields and selectivity towards desired product, reduce the time of completion of reaction [23][24][25] and enhanced ease of product recovery. When liquids are irradiated with ultrasound, the alternating expansive and compressive acoustic waves creates bubbles i.e., cavities. The effects of ultrasound on organic reactions are attributed to cavitation effect, a physical process that generates, increases, and collapses gaseous and vaporous cavities in an irradiated liquid [26]. The cavitation induces very high local temperatures and pressures inside the cavities, leading to a turbulent flow in the liquid and enhanced mass transfer [27]. Ultrasound-promoted synthesis has various advantages over conventional synthesis techniques such as reactions were carried at room temperature and require much less time for completion hence saves time and electricity, highly accelerated reaction rate, requires use of very less amount of solvents, shortened work-up procedure. practically good yield of product, simple instrument with control on reaction parameters, and most important is eco-friendly neat and clean synthetic protocol.
In this research work we are reporting the synthesis of 4-(benzyloxy)-N-(3-chloro-2-(substituted phenyl)-4oxoazetidin-1-yl) benzamide 6a-j derivatives in excellent yield using eco-friendly, prompt and suitable ultrasound-assisted green chemistry protocol. 6 The shortcomings associated with conventional method of synthesis of 4-(benzyloxy)-N-(3-chloro-2-(substituted phenyl)-4-oxoazetidin-1-yl) benzamide 6a-j. like stirring at room temperature required 20-28 hr and by refluxing nearly takes 8-10 hours for completion of reaction which consumes more time and electricity. Green chemistry is a new branch of chemistry which become a major motivation for organic chemists and druggist to develop environmentally gentle path for synthesis of organic compounds of biological importance. Ultrasound offers potential tool for cleaner reactions called green protocol keeping in mind to protect environment clean and green through improved product yields and selectivity towards desired product, reduce the time of completion of reaction [23][24][25] and enhanced ease of product recovery.
2-azetidinones or β-lactam occupy an eminent place in organic and medicinal chemistry since the structure of penicillin showed the presence of β-lactam ring in it and various potent activities of penicillin are due to the presence of β-lactam ring. Hence, there is a need to synthesised the derivatives containing 2-azetidinones scaffold.
 To conduct physicochemical characterization of intermediates and synthesized compounds. All the synthesized compounds were characterized by 1 H NMR, 13 C NMR, mass spectroscopy and IR.
Physical characterization data of Schiff bases 5 a-j were shown in Table1 The synthesis of all derivatives of 4-(benzyloxy)-N-(3-chloro-2-(substituted phenyl)-4-oxoazetidin-1-yl) benzamide 6a-j was carried out by refluxing and ultrasonic irradiation methods for comparison of conventional and modern green chemistry tool using ultra-sonication. The time required for completion of reaction with yield in percent is mentioned in

EXPERIMENTAL WORK & PHYSICAL CONSTANTS DATA  Step I: General procedure for the synthesis of 4-(benzyloxy)benzoate (3):
Synthesis of methyl-4-(benzyloxy) benzoate was carried out in ultrasonic processor by taking equivalent ratio of benzyl chloride and methyl-4-hydroxybenzoate (0.01mol) using DMF as solvent in beaker with catalytic amount of K 2 CO 3. Reaction was completed in four hr. The completion of reaction was monitored by TLC. The reaction mixture was poured into ice-water. The product obtained was filtered, dried and recrystallized from Step II: General procedure for the synthesis of 4-(benzyloxy) benzohydrazide ( Step III: General procedure for the synthesis of Schiff bases 5 Schiff's bases 5a-j were obtained by condensation of equimolar quantities of 4-(benzyloxy)benzohydrazide (0.01 mol) and different substituted aldehydes (0.01 mol) in the presence of glacial acetic acid (0.02 mol) as a catalyst in absolute ethanol (25 ml) refluxed for for 2 to 3 hours. The completion of reaction was monitored by TLC. The reaction mixture was concentrated and cooled. The obtained solid was filtered and dried. The product was recrystallized from ethanol. The melting point and yield were recorded and are given in Table1.
Step IV: General procedure for synthesis of 4
The structure analogy of the reported azetidinone derivatives with β-lactam ring, enhance the potential of 4-(benzyloxy)-N-(3-chloro-2-(substituted phenyl)-4oxoazetidin-1-yl) benzamide to be developed as antimicrobial agents and can act as an excellent scaffold for lead optimization and drug discovery.