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Microwave Assisted Synthesis of Novel Ethyl 2-(3,4-Dihydro-6-Methyl-2- oxo-4-Phenyl-5-Propionylpyrimidin-1(2H)-yl) Acetohydrazide Derivatives

Research Article Open Access
Vishal D. Khamgaonkar*, Pradeep V. Kore, Mahesh M. Game-Patil and Sandip S. Kshirsagar
Department of Pharmaceutical Chemistry, JSPM’S Charak College of Pharmacy and Research, Pune-Nagar Road, Wagholi, Pune, India
*Corresponding author: Vishal D. Khamgaonkar
Department of Pharmaceutical Chemistry
JSPM’S Charak College of Pharmacy and Research
Pune-Nagar Road, Wagholi
Pune-412207, India
E-mail: sanpals24@rediffmail.com
 
Received August 31, 2012; Published September 22, 2012
 
Citation: Khamgaonkar VD, Kore PV, Game-Patil MM, Kshirsagar SS (2012) Microwave Assisted Synthesis of Novel Ethyl 2-(3,4-Dihydro-6-Methyl-2-oxo-4-Phenyl-5-Propionylpyrimidin-1(2H)-yl) Acetohydrazide Derivatives. 1:326. doi:10.4172/scientificreports.326
 
Copyright: © 2012 Khamgaonkar VD, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
 
Abstract
 
A new series of 2-(3,4-dihydro-6-methyl-2-oxo-4-substituted-5-propionylpyrimidin-1(2H)-yl) acetohydrazide have been synthesized by one pot three component cyclo condensation reaction using zinc metal and lead as a catalyst. The success of the reaction was observed by TLC and melting. The structures of these compounds were established on the basis of spectral data and elemental analysis. All compounds were evaluated for antibacterial activity by the broth microdilution assay method and found moderately active.
 
Keywords
 
DMHP; Microwave; Dihydropyrimidone; Biginelli reaction
 
Introduction
 
In 1893, the synthesis of functionalize 3,4-dihydropyrmidine 2-(one H) ones (DHPMs) by a three compound condensation reaction of an aromatic aldehyde, urea and ethyl aceto acetate, was reported for first time by P. Biginelli. In post decade, such Biginelli type dihydropyrimidines have received a considerable amount of attention, due to interesting pharmacological property associated with calcium channel blocker activity, antihypertensive activity, antibacterial and antimicrobial activity. The use of microwave irradiation in organic synthesis has become increasingly popular within the pharmaceutical and academic arenas, because it is a new enabling technology for drug discovery and development [1]. By taking advantage of this efficient source of energy, compound libraries for lead generation and optimization can be assembled in a fraction of time required by classical thermal methods. In the past decade, dihydropyrimidine derivatives have exhibited important pharmacological properties, as the integral backbone of several calcium channel blocker, antihypertensive agents, alpha-la-antagonists and neuropeptide Y (NPY) antagonist [2-7]. One of the most potent drug synthesized was [4 substituted phenyl-5-ethoxycarbonyl-6-methyl]3,4-dihydroxypyrimidine 2(1 H) one, which has been found to be potent anti-hypertensive, calcium channel antagonism that is comparable with standard drug Nifedipine. A classical root to obtain [4 substituted phenyl-5-ethoxycarbonyl- 6-methyl]3,4-dihydroxypyrimidine 2(1 H) one is by reaction of aldehyde, ethyl acetoacetate and urea along with refluxing with ethanol, hydrazine hydrate (for 24 hours) following Biginelli reaction was carried out [8-10]. However, in generality of the methods is limited and mostly required long time and hence, considering the importance of dihydropyrimidine moiety as pharmacophoric scaffold, we applied the application of microwave irradiation to the reaction using zinc metal and lead as a catalyst. Thus, it has accelerated the rate and yield of product [11-13].
 
Materials and Methods
 
The microwave assisted synthesis were carried out using a Synthos 300 monomode oven monitored manually and temperature maintained at a constant value 140°C within the power modulation of 200 W. Stirring was provided manually in intervals, while reactions were performed in open glass vessels within a ramp time of 10 sec to 2 min. All reagents were obtained from Merk Chemicals Limited. Solvents used were of analytical grade and when necessary, were purified and dried by standard methods.
 
Scheme of Reaction
 
 
Experimental Part
 
Synthesis of ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4- phenylpyrimidine-5-carboxylate (1a)
 
To a mixture of urea (0.1 mole), benzaldehyde (0.1 mole) and ethylacetoacetate (0.1 mole) in ethanol, 4 drops of concentrated hydrochloric acid was added and was refluxed under microwave for 3 min at 200 W. The reaction mixture was poured into ice water (100 ml) with stirring and left overnight at room temperature. Filtered and residue was dried at room temperature, recrystallised from ethanol. IR: 1648 cm-1 (amide C=O); 1703 cm-1 (C=O ester); 3244 cm-1 (NH) 1H NMR Spectral Data of compound: δ ppm, CDCl3,1.15(t, 3H, CH3 ester); 2.25 (s, 3H, dihydropyridyl CH3); 4.05 (q, 2H, CH2 ester); 6.8(s, 1H, dihydropyridyl-CH); 7.2-7.3 (m, 4H, Ar H) 7.4 (s, 1H, 3 NH); 8.9 (s, 1H, 1 NH). Mass (FAB):237(M+, 12%), 189(Base peak 100%).
 
Synthesis of Ethyl 1-[(ethoxycarbonyl)methyl]-1,2,3,4- tetrahydro-6-methyl-2-oxo-4-phenylpyrimidine-5- carboxylate (2a)
 
The compound 1 (0.1 mol) was dissolved in a solution prepared by reacting Na (0.1 mol) with 200 ml of absolute ethanol. The solution was kept in microwave for 10 min at 200 W. Ethyl chloroacetate (0.1 mol) was added in three portions over a period of 2 min. The reaction mixture was filtered while hot to remove precipitated sodium chloride; the solvent was removed on a rotary vacuum evaporator. The crude product was collected and recrystallised from ethanol. Compounds 2b- 2g has been synthesized in above manner. Spectral data of 2a- IR (KBr) 1648 cm-1 (CONH), 1701 cm-1 (C=O of ring carbonyl), 1725 cm-1 (C=O ester), 2978 cm-1 (aromatic proton stretching), 3116 cm-1 (CONH), 3245 cm-1 (NH stretching), 1H NMR δ ppm CDCl3, 1.1 (t,6H,CH3), 2.45 (s,3H,CH3), 4.13 (s,3H,CH3) 4.2 (q,4H,CH2), 4.45 (d,2H,CH2), 5.2 (s,1H,dihydropyridyl-CH), 7.3-7.4 (m,10 H Ar), 7.9 (S,1H,NH). Mass (FAB): 265 (M+, 12%), 178 (Base peak 100%).
 
Synthesis of 2-(3,4-dihydro-6-methyl-2-oxo-4-phenyl-5- propionylpyrimidin-1(2H)-yl)acetohydrazide (3a)
 
A mixture of the appropriate compound 2 (0.1 mol), hydrazine hydrate (8 drops), and 10 ml of 95% ethanol was refluxed under microwave for 3 min at 200 W. The solvent was removed by evaporating the compound at the room temperature and the residue was poured into cold water. The solid that formed was collected, washed with ice-cold water, and recrystallized from ethanol. All derivatives have been synthesized in this manner. Spectral data of 3a- IR (KBr) 1608 cm-1 (amide C=O), 1647 cm-1 (ester C=O), 1706 cm-1 (carbohydrazide C=O), 3238 cm-1(-NH) 1H NMR δ ppm, CDCl3, 1.14 (t, 3H, CH3 of C2H5), 1.5 (s,3H, dihydropyridyl CH3), 4.04 (q,2H,CH2 of C2H5) 5.4 (s, NH2); 5.6 (d, 1H, NH); 7.22-7.3 (m, 4H, Ar H), 7.8 (s, 1H, 1 NH) Mass (FAB):251(M+, 9%), 186(Base peak 100%) Elemental analysis: C, 59.60; H, 6.20; N, 17.53; O, 14.84 (Table 1).
 
Table 1: Physiochemical Parameters of Synthesised Compounds (3a-3g).
 
Results
 
Antibacterial activity
 
All the newly synthesized compounds were evaluated for antibacterial activity by broth microdilution assay against Grampositive bacteria Staphylococcus aureus (ATCC 11632), and Gram negative bacteria Escherichia coli (ATCC 10536). Serial dilutions of the test compounds and reference drugs were prepared in Mueller- Hinton agar. The tubes were inoculated with 105 cfu.ml-1 (colony forming unit/ml) and incubated at 37°C for 18 h. Procaine penicillin and streptomycin were used as standard drugs. The data of activity is summarized in table-2: Zone of inhibition.
 
Table 2: Zone of Inhibition.
 
Conclusion
 
Derivatives presented herein showed antibacterial activities. Compounds (3c, 3d, 3f) were highly active against Gram positive bacteria. Compounds (3a-3b) exhibited activity against pathogenic Gram-negative bacteria at higher concentration, while compounds (3e-3g) specifically exhibited excellent antibacterial activity even at lower concentration. Suitable molecular modification of these compounds may generate potent antimicrobial agents in future.
 
 
References