Synthesis of some 4-substituted -6-aryl-2-hydroxy-1,6- dihydropyrimidines and 4,5-disubstituted-6-alkyl-5- hydropyrimidin-2(1H)-ones

Abstract

3,4-dihydropyrimidin-2(1H)-ones and their derivatives have attracted increasing interest owing to their therapeutic and pharmaceutical properties, such as antiviral, antibacterial, anti-inflammatory and antitumor activities. Recently, functionalized dihydropyrimidinones have been successfully used as antihypertensive agents, calcium channel blockers, adrenergic and neuropeptide antagonists. Chapter one of this thesis covers the different chemical reactions that were utilized in the synthesis of dihydropyrimidines. A concise review of a wide range of biological activities associated with dihydropyrimidine ring system was covered and presented. In this work, eighteen compounds of dihydropyrimidine moiety were synthesized. The synthetic designing of these compounds was constructed with retrosynthetic analysis and disconnection approach. Therefore the prepared dihydropyrimidines in this work fall into three major categories depending upon the synthetic route. The first of these synthetic routes is a direct condensation reaction between a 1,3-dicarbonyl compound and urea in presence of ethanol and acetic acid under reflux for long period of time. This method suffered from some drawbacks concerning low yields, long reaction period and deficiency in designing substituents. The second synthetic route attempted in this work is the multi-component reaction involving a 1,3-dicarbonyl derivative, an aromatic aldehyde and urea, which is generally known as Biginelli reaction. The third synthetic route, which was mainly followed in this thesis is the synthesis of the target dihydropyrimidines through a Michaell type cyclization reaction between α,β-unsaturated carbonyl derivative (chalcone) and urea. This reaction is proved to be versatile and gave way to designed highly substituted dihydropyrimidines. Accordingly, the readily available or synthetic 1,3- dicarbonyl compounds and their corresponding diazotised derivatives were allowed to react with benzaldehyde or p-N,N-dimethylbenzaldehyde in ethanol and sodium hydroxide in cross aldol condensation, Claisen- Schemidt reaction to furnish the corresponding α,β−unsaturated carbonyl derivatives. The second step involves a cyclization reaction between the synthesized α,β−unsaturated carbonyl derivatives and urea to furnish the required dihydropyrimidine derivatives. The reaction progress was followed by TLC and the purity of the recrystallized compounds was checked by chromatographic means. The different mechanistic pathways leading to intermediate and final compounds were discussed and outlined. The structures of the different synthesized compounds were elucidated and confirmed by full spectral technique involving UV-Vis, IR, 1H and 13CNMR, MS and GC-MS. The spectral data were interpretated and assigned for each compound. The full range of the synthesized and intermediate compounds was screened for their antimicrobial activity. The compounds were tested for antibacterial activity against two gram-positive bacteria S. aureus and B., subtilis, two gram-negative bacteria E. coli and P. aeruginosa Compound XIX in a concentration of 100 μg/ml in PRG was found to be the most active derivative. This compound is characterized by the presence of a benzoyl group in position 5- of the dihydropyrimidine ring system. Compounds XIX and XXI showed the higher efficacy in terms of % reduction of parasitemia when tested against T. evansi in albino rats.