ISSN: 2456–5474 RNI No.  UPBIL/2016/68367 VOL.- VIII , ISSUE- VII August  - 2023
Innovation The Research Concept

An Efficient Approach to The Synthesis of Biologically Important Thiazolyl Substituted Pyrimidine Condensed Pyrimidine-diones
Paper Id :  18039   Submission Date :  13/08/2023   Acceptance Date :  22/08/2023   Publication Date :  25/08/2023
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Pragati Sharma
Assistant Professor
Department Of Chemistry
B.R.S.B.S.M.PG College,
Babrala,UP, India
Abstract

Thiazolyl substituted pyrimidine condensed pyrimidine-diones 3 to 5 and from 6 to 8 have been synthesized by the cyclocondensation of corresponding N-(4-(2-(5-(bis(methylthio)methylene)-2,4,6-trioxo-3-phenyltetrahydropyrimidin-1(2H)-yl)thiazol-4-yl)phenyl)methanesulfonamide 1 and (Z)-N-(4-(2-(5-benzylidene-2,4,6-trioxo-3-phenyltetrahydropyrimidine-1(2H)-yl)thiazol--yl)phenyl)methanesulfonamide 2 of thiazolyl-substituted pyrimidine-diones with urea, thiourea and guanidine respectively following the strategy shown in Scheme-1. The structures of all the compounds have been established on the basis of their elemental analysis and spectral (IR, 1NMR, and MS) data.
Keywords Pyrimidine derivatives, Urea, Thiourea, Guanidine.
Introduction

Pyrimidines play a vital role in many biological processes since their ring system is present in several vitamins, coenzymes, nucleic acids etc. synthetic members of this group are also important as chemotherapeutic agents.Hydroxyl, mercapto, amino pyrimidines are relatively lass studied heterocyclic systems, but these are of interest on the context of drug design and developed in the field of medicinal chemistry. pyrimidines, bearing these substituents, are signicantly important in a number of compounds which have been used in synthetic, analytical and medicinal chemistry. The biological significance of the pyrimidine derivatives has led us to the synthesis of newer pyrimidines and their derivatives. As pyrimidines are a basic nucleus in DNA & RNA, it has been found to associate with diverse biological activities. Fused pyrimidines (e.g. purines, pyrrolopyrimidine, pyrimidopyrimidines, pteridines, etc.) are found in a variety of natural products, agrochemical, veterinary products[1-4] and attract to researchers due to their wide variety of interesting pharmacological activities[5-6]. Pyrimidine and their fused derivatives are found in the drugs used for cancer and viral treatment[7-8]. The discovery of the anti-HIV activity as AZT[9-10], the pyrimidine nucleus has stimulated a renewed interest in these molecules and has prompted us to focus the research on the synthesis and study of biological properties of newer series of pyrimidine derivatives. The pyrimidine nucleus also occurs in natural products of vital importance to living organisms[11-13]. As a structural component of key bio-molecules, the pyrimidine moiety is widely incorporated in the molecules of privileged structures.
Aim of study

The present project is undertaken for synthesis of thiazolyl substituted pyrimidine condensed pyrimidine-diones by the cyclocondensation of the N-(4-(2-(5-(bis(methylthio)methylene)-2,4,6-trioxo-3-phenyltetrahydropyrimidin-1(2H)-yl)thiazol-4-yl)phenyl)methanesulfonamide and (Z)-N-(4-(2-(5-benzylidene-2,4,6-trioxo-3-phenyltetrahydropyrimidine-1(2H)-yl)thiazol--yl)phenyl)methanesulfonamide with urea, thiourea, and guanidine respectively.
Review of Literature

Pyrimidine has a long and distinguished history extending from the days of their discovery as important constituents of nucleic acids to their current use in the chemotherapy of cancer and viral treatment. The pyrimidine derivatives have been reported to possess a variety of biological activity, notable among which are the analgesics14, anti-hypertensive15, anti-pyretic16, anti-viral17, and anti-inflammatory activity18. These are also associated with antibiotic, anti-malarial, and anti-cancer drugs19. Many of the pyrimidine derivatives are reported to possess potential CNS depressant properties20.
Result and Discussion

In the present work, the thiazolyl substituted pyrimidine condensed pyrimidine-diones were synthesized by the cyclocondensation of corresponding oxoketenedithioacetals and chalcones with urea, thiourea and guanidine respectively. Oxoketene dithioacetals 1 and chacones 2 with urea, thiourea and guanidine furnished corresponding pyrimidine derivatives from 3 to 8 (Scheme-1)

Scheme-1

Experimental Part:

Preparation of

N-(4-(2-(7-hydroxy-5-(methylthio)-2,4-dioxo-1-phenyl-1,2-dihydro-pyrimido[4,5-d]pyrimidine-3(4H)-yl)thiazol-4-yl)phenyl)methanesulfonamide 3:

To a mixture of urea (1.2g, 0.02mol) and sodium ethoxide (1.36g, 0.02mol) in ethanol, appropriate oxoketene dithioacetals 1 (0.05g, 0.001mol) was added. The reaction mixture was refluxed for 10-14hrs. the solvent was removed by distillation and the residue was treated with glacial acetic acid (8-10ml) just enough to dissolve sodium salt of pyrimidine and refluxed for 15min. The reaction mixture was poured on crushed ice and the precipitate obtained was purified by recrystallization from ethanol to give 3. Yield 0.46 (83.6%) and m.p.230-2320C.


Preparation of

N-(4-(2-(7-mercapto-5-(methylthio)-2,4-dioxo-1-phenyl-1,2-dihydro-pyrimido[4,5-d]pyrimidin-3(4H)-yl)thiazol-4-yl)phenyl)methanesulfonamide 4

To a mixture of thiourea (1.5g, 0.02mol) and sodium ethoxide (1.36g, 0.02mol) in ethanol, appropriate oxoketene dithioacetals 1 (0.56g, 0.001mol) was added. The reaction mixture was refluxed for 10-14hr. The solvent was removed by distillation and the residue was treated with glacial acetic acid (8-10ml) just enough to dissolve sodium salt of pyrimidine and refluxed for 15min. The reaction mixture was poured on crushed ice and the precipitate obtained was purified by recrystallization from ethanol to give 4. Yield 0.42g (73.68%) and m.p. 260-2620C. The compounds 5 were prepared from reaction of 2 with guanidine.

Preparation of N-(4-(2-(7-hydroxy-2,4-dioxo-1,5-diphenyl-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)thiazol-4-yl)phenyl)methanesulfonamide 6

To a solution of 2 (0.54g, 0.001mol), urea (1.2g, 0.02mol) in 20ml ethanol and 0.2g NaOH in 25ml of 80% ethanol was refluxed for 15h. Concentrated to half its volume and cooled, filtered off and recrystallized from ethanol to give 6. Yield 0.48g (84.2%) and m.p. 255-2580C.

Preparation of N-(4-(2-(7-mercepto-2,4-dioxo-1,5-diphenyl-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)thiazol-4-yl)phenyl)methanesulfonamide 7

To a solution of 2 (0.54g, 0.001mol), thiourea (1.5g, 0.02mol) in 20ml ethanol and 0.2g NaOH in 25ml of 80% ethanol was refluxed for 15h. Concentrated to half its volume and cooled, filtered off and recrystallized from ethanol to give 7. Yield 0.50g (84.7%) and m.p. 252-2540C. the compounds 8 were prepared from reaction of 2 with guanidine.
Conclusion

The present investigation was undertaken with a view of streamline of the synthetic strategies which have been devised in the literature for the preparation of pyrimidine derivatives using oxoketene dithioacetals and chalcones as starting materials or reactive intermediates. Although the literature is replete with great variety of synthetic methods that have been employed for the synthesis of medicinally potent pyrimidines but some methods have very serious limitation on the use of these procedures and call attention to develop much simpler routes in which easily accessible starting materials have been or are to be used. Clearly, a refinement of the existing methodology and development of newer strategies for their synthesis was required. Therefore, consideration of reactivity, compound availability, synthetic economy and simplicity in operation has led us to favour the use of oxoketene dithioacetals and chalcones as starting materials for the synthesis of pyrimidine derivatives.
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