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Synthesis and Anti-Microbial Activity of Some Pyrimidine Derivatives

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Synthesis and Anti-Microbial Activity of Some Pyrimidine Derivatives Indi an Journal of Chemistry Vol. 428, April 2003, pp. 910-9 15 Synthesis and anti-microbial activity of some pyrimidine derivatives A K Padhy National In stitute of Science & Technology, Palur Hills, Berhampur-761 008, Orissa, India and M Bardhan & C S Panda* Synthetic Organic Laboratory, Deptt of Chemistry, Berhampur Uni versity, Berhampur-760 007, Orissa. India Receil•ed 25 July 200 I; accepted (revised) II March 2002 4-Aryl-5-carboethoxy-6-mcthyl- 1, 2,3,4-tetrahydropyrimidin-2-ones have been synthesized from easil y avai lable start­ ing materials. The carboethoxy group at the C5-position of the pyrimidine ring is converted to corresponding hydrazide which in turn is condensed with cycli sin g agents such as aromatic aldehydes, CS2 etc. to give fu sed heterocycles. The fu sed heterocycles are then subjected to phenacyl ation to give Nr phenacylpyrimido-heterocycles in excellent yield. In a slightly modified way, uracil derivatives are condensed with ethyl bromoacetate to give Nrl)-cthoxycarbonyl derivati ves. The hy­ drazide derivatives of these Nr l)-ethoxycarbonyl derivatives subsequently react with 1,2-diketones to give corresponding pyrimido pyridazine derivatives. Pyrimidines are of great importance in fundamental N-C-N reagents and I ,3-diketones, diesters and dini­ metabolism, for uracil, thiamine and cytosine are triles are typical C-C-C reagents. 1 three of the six bases found in the nucleotide • Many Thus, employing a slightly modified method ethyl derivatives of pyrimidine have been used as therapeu­ acetoacetate and cyanoethyl acetate (C-C-C unit) can 2 tic agents .3 . Several triazolo and pyrazolopyrimidines condense with urea or thiourea (N-C-N unit) in pres­ are found to possess antifungal and antileishmanial ence of diverse aromatic aldehydes to give pyrimidine activit/. Pyrimjdine derivatives are known to possess derivatives 1 and 2 in appreciable yields. The struc­ analgesic and anti-inflammatory activit/. Also some tural analysis of the product formed retains the car­ oxadiazolopyrimidines were reported6 to possess fun­ boethoxy group of ethyl acetoacetate and the cyano gicidal activity. In recent years, pyrimidine deriva­ group of the cyanoethyl acetate. This suggests th at th e tives have received significant attention owing to their requisite C-C-C funct ionality for the construction of diverse range of biological properties particularly be­ the pyrimidine ring uses onl y two carbon centers of 7 ing calcium channel blockers • 4-Amino-5- these esters and the third carbon being provided by oxopyrido[2,3-d]pyrimidine riboside was found to be the aldehydic function of the aldehydes employed. 8 very potent inhibitor of cancer cell profilation . The availability of the carboethoxy group at C-5 of The C5 position of pyrimidine nucleus is an attrac­ the pyrimidine rings helped us to think of exploring tive site for modification as it is located at the major the possible modi fications that can be made at thi s groove surface in the duplex form and will not di ­ position thereby forming modified bases of significant rectly inhibit the hydrogen bond in an A : T base structural importance. Incidentally, the carboethoxy 9 10 pair · . group of 1 was converted to its hydrazide deri vative The most general and widely employed route to 3, which furnishes better reaction site for the con­ pyrimidines involves the combination of a reagent struction of modified structural units. Thus, the hy­ containing the N-C-N skeleton with C-C-C unit. drazides of 1 were condensed with diverse cyclising These syntheses are typical examples of the bi s­ agents such as aromatic aldehydes, CS 2 to give nucleophile plus bis-electrophile method of construct­ pyrimidotriazoles 4 and pyrimidothiadiazoles 5 re­ ing heterocycles. Both the nitrogen atoms of the N-C­ spectively (Scheme 1). N reagent act as nucleophiles and both the terminal The structure-activity relationship study of carbon atoms of C-C-C reagents are electrophiles. pyrimidines reveals that N-alkyl derivati ves are more Urea, thiourea and guanidine are commonly used as potent towards the microorgani sms th an that of the PADHY et al.: SYNTHESIS OF PYRIMIDINE DERIVATIVES 911 CH3COCH2COEt + ArCHO+ CJl X=O, S 2 Ar = Ar'= C6H5, m-N02C6H4, p-CIC6H4, p-N(CH3)2CsH4 A= C6H5, m-N02CsH4 Scheme I unsubstituted ones as they increase the toxicity of the molecules. Thus, the synthetic pyrimidines 4 were subjected to phenacylation with the implication that it will increase the potential of the molecules. There are two sites available for the phenacylation 7 2 N 1- and N3- in those molecules. However, the Nrsite is preferred over the N 1-site as the N 3-proton is com­ 1 paratively more acidic than N 1, being flanked by a carbonyl group and aromatic nucleus. The question of formation of the mixed product was overruled on the basis that compound 6 is not only having the sharp melting points but also the CH3 peak in the 'H NMR is free from any NOE (Nuclear Overhauser 8 Effect). a. C 6 H5, X = 0, b . Ar = C 6 Hs. X = S Compound 2, which has an analogous nucleus as c. Ar= m-N02C 6H4, X=S, d . Ar = p -C IC 6H 4, X=O e. Ar= p-CIC 6 H 4, X=S, f. Ar= p-N(CH 3 ) 2 C 6 H4 , X=O uracil can therefore be named as uracil derivative, g . Ar= p-N(CH 3 bCsH•, X= S having active site N3-. The proton is being more acidic and therefore can undergo facile alkylation Scheme II with ethyl bromoacetate to give corresponding N 3 -~­ ethoxycarbonyl derivatives 7. The hydrazides of 7 A disquitening trend after 1950's has been the possess a dinucleophilic locus and thus in turn con­ emergence of more sinister type of fungal infections, dense with 1,2-diketones to give corresponding fused which are, to a large extent, inatrogenic. These are pyrimidinopyridazine derivatives 8 (Scheme II). associated with the use of broad-spectrum antibiotics, 912 INDIAN J. CHEM .. SEC B, APRIL 2003 corticosteroids, cytotoxic drugs indwelling characters 255°C; Found: C, 57.61; H, 3.01; N, 18 .3. Calcd for and implants and emergence of AIDS. Looking to the C11H7N30S: C, 57.64; H, 3.05; N, 18.34%. 2c: m.p. broad spectrum of biological activity, we screened 179°C; Found: C, 48. 15 ; H, 2. 16; N, 20.41. Calcd for some of these synthetic compounds against Staphyllo C1IH6N30 3S: C, 48.17; H, 2.1 8; N, 20.43%. 2d: m.p. coccous, E. coli and Candida albicmzs. It has been 278°C; Found: C, 53.3 L; H, 2.4; N, 16.93. Calcd for observed that compounds 6b, 6h and 6v are active C11 H6N 30 2CI: C, 53.33; H, 2.42; N. 16.96%; 2e: m.p. against Candida albicans, whereas only 6h is possess­ 252°C; Found: C, 50.07; H, 2.25; N, 15 .91. Calcd for ing significant activity. All these activities were com­ C IIH6N30SCI: C. 50.09; H, 2.27; N, 15.93%; 2f. m.p. pared with the standard drugs chloramphenicol and 238°C; Found: C, 60.9 1; H, 4.65; N, 21.86. Calcd for clotrimazole by measuring the zone of inhibition. C13H12N402: C, 60.93; H, 4.68; N, 2 1.87%; 2g: m.p. 2 15 °C; Found: C, 57.33; H, 4.39; N, 20.54. Calcd for Experimental Sections C1 3H1 2N40S: C, 57.35; H, 4.41; N, 20.58%. All the m.ps were measured and uncotTected. IR spectra were taken in Perkin-Elmer FT-IR spectropho­ Reaction of 1 with hydrazine hydrate: Synthesis tometer. 1H NMR was taken in 90MHz Perkin-Elmer of 3. To 1 (0. 1mol e) in ethanol (20mL) was added spectrophotometer. The microbial screening was done hydrazine hydrate (0. 1mol e) followed by the addition 11 employing cup-plate agar method . of a catalytic amount of cone. H 2 SO~ (5clrops). The Synthesis of 4-aryl-5-cal"lJOethoxy-6-methyl·2- mixture was refluxed for 2hr. Excess solvent was re­ pyrimidinone 1: General procedure. Urea (0.5 mole), moved and on cooling a solid was formed. The solid was crystall ised from ethanol to give 3. 3a: IR: ethyl acetoacetate (0.75mole) and aromatic aldehyde 1 1 (0.5 mole) were mixed in ethanol (25 mL). Catalytic 1570(C-N), 1650 (amide), 3350(NH) cm. ; H NMR amount of cone. HCI was added to the mixture, which (90mHz) : 82.5 (d,2H, NH 1-/2), 3.4 (s, C- H-CO), was then refluxed fo r 3hr. T he contents were kept in 5. 1 (s, CO-NH-CO), 4. 1 (t, CONHN), 7-8 (m. 5H, refrigerator overnight. The sol id separated out was ArH), m.p. 196°C, 3b: m.p. 195°C, 3c: m.p. 175°C, filtered off. The filtrate was further refluxed on a wa­ 3d: m.p. 190°C. ter bath for 1.5hr. On cooling a solid separated out Synthesis of triazolo-pyrimidinone derivative 4. was filtered and recrystalli zed from ethanol to give 1. To a solution of 3 (0. 1mo le) in acetic acid (20mL) a la: IR (v): I 570(C-N), 1650 (amide), 1730 (ester), pinch of ammonium acetate was added followed by 1 1 3350(NH) cm· ; H NMR (90MHz): 8 1.5 (s, CH3), the addition of aromatic aldehyde (0.1mole ). The mix­ 1.8 (t, COOCH2CH3), 2.5 (q, COOCH2CH3), 3.4 (s, ture was stirred for 2.4 hr at room temperature. The C-NH-CO), 5.4 (s, Ar-Nl-1-CO), 6.4 (s, Ar-CH), 7-8 mother liquor on neutralization wi Lh ammonia solu­ (m, 5H.
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