Studies on Synthesis of Pyrimidine Derivatives and their Pharmacological Evaluation

http://www.e-journals.net ISSN: 0973-4945; CODEN ECJHAO E-Journal of Chemistry Vol. 4, No.1, pp 60-66, January 2007 Studies on Synthesis of Pyrimidine Derivatives and their Pharmacological Evaluation T. A. NAIK and K. H. CHIKHALIA* Department of chemistry, Veer Narmad South Gujarat University, Surat-395 007, Gujarat, India E-mail: Received 14 August 2006; Accepted 3 October 2006 Abstract: 1,3,4-oxadiazoles were associated with broad spectrum of biological activities including antituberculosis, anticonvulsant, antiinflammatory, insecticidal, antifungal, analgesic and antitumor properties. Morpholine derivatives find their wide spectrum of antimicrobial activity and exhibit anthelmintic, bactericidal and insecticidal activity. Pyrimidine derivatives are also reported to possess antibacterial, antimicrobial, antifungal, anticancer and anticonvulsant activities. Encouraged by this observations we decided to synthesised novel pyrimidine derivatives. Keywords: Oxadiazoles, Pyrimidine Derivatives, Synthesis Introduction The biological significance of the pyrimidine derivatives has led us to the synthesis of substituted pyrimidine. As pyrimidine is a basic nucleus in DNA & RNA, it has been found to be associated with diverse biological activities.1 The synthesis of substituted pyrimidine and many detailed reviews have been appeared.2,3. The nitrogen containing fragment may be an amidine, urea, thiourea or guanidine and acetyl acetone serves as an excellent illustrative example in that it readily undergoes reaction with formamidine,4 guanidin,5 urea,6 or thiourea7 to produce the corresponding 4,6-dimethyl pyrimidine. Pyrimidines and their derivatives are considered to be important for drugs and agricultural chemicals. Pyrimidine derivatives possess several interesting biological 61 K. H. CHIKHALIA et al. activities such as antimicrobial8, antitumour9 and antifungal activities10. Many Pyrimidine derivatives are used for thyroid drugs and leukemia. Step – 1 O N NH N NH2 CS2 / KOH N N N O 2-Morpholino-3-pyridinylic acid hydrazide Cl Cl C + CH3 R O F 20% NaOH/ MeOH Cl At room temp. F Aromatic aldehyde Step – 3 NH + 2-{2-(Morpholino)-3-pyridinyl}-5mercapto-1,3,4-oxadiazole : (A) Cl R O 2,4-Dichloro-5-fluoroacetophenone (B) OHC SH O O Step – 2 N H2N 1-(2,4-Dichloro-5-fluoro phenyl)-3(aryl)-2-propene-1-one : (B) 25% MeONa/ MeOH NH2 . HNO 3 Reflux temp Cl Cl R F N Guanidine nitrate N NH2 2-Amino-4-(2,4-dichloro-5-fluoro phenyl)-6-(aryl)-pyrimidine : (C) Step – 4 (C) + Cl Cl O Chloroacetyl chloride Benzene/ Tryethyl amine Cl Reflux temp F Cl R N N HN Cl O N-Chloro acetyl-2-amino-4-(2,4-dichloro5-fluoro phenyl)-6-(aryl)-Pyrimidine : (D) Studies on Synthesis of Pyrimidine Derivatives Step – 5 (A) Cl + K2CO3 (D) Cl R F - HCl 62 N N HN N S N O O N N O 2-[{2-(Morpholino)-3-pyridinyl-5-thio} -2-oxoethyl oxadiazolyl]-amino-4(2,4-dichloro-5-fluoro phenyl)-6-(aryl)-pyrimidines (TN-1 to TN-10) 4- CH3·C6H4 4-N(CH3)2·C6H4 2-OH·C6H4 4-OH·C6H4 4-Cl·C6H4 2,4-(Cl)2·C6H3 4-F·C6H4 2-OCH3·C6H4 4-OCH3·C6H4 3,4,5-(OCH3)3·C6H2 Where R = Experimental Step–1: Preparation oxadiazole ( A ) of - TN-1 - TN-2 - TN -3 - TN -4 - TN -5 - TN -6 - TN -7 - TN -8 - TN -9 - TN -10 2-{2-(Morpholino)-3-pyridinyl}-5-mercapto-1,3,4- To a solution of 2-Morpholino-3-pyridinylic acid-hydrazide (0.1 mole, 22.2 g.), CS2 (0.1 mole, 7.6 ml) and 20% KOH solution (10 ml) in methanol (82 ml) was added and refluxed for eight hours. After the completion of reaction, the resultant mixture was poured in crushed ice. Product was filtered, washed with water and crystallized from ethanol to give white needles of the title compound. Step–2: preparation of 1-(2,4-dichloro-5-fluoro phenyl)-3(aryl)-2-propene-1-one ( e ) To a thoroughly stirred solution of 2,4-dichloro-5-fluoro acetophenone (0.05 mole, 9.7 g.) & aromatic aldehyde (0.05 mole, 5.3 g.) in methanol (98 ml.), was added 20% NaOH solution (10 ml.). The reaction mixture was stirred for thirty minutes at room temperature and left over night. After the completion of reaction, it was poured into ice water, acidified to neutral, filtered and crystallized from ethanol. Step–3: preparation of 2-amino-4-(2,4-dichloro-5-fluoro phenyl)-6-(aryl)pyrimidine: ( f ) A mixture of (E) (0.05 mole, 15.3 g.), guanidine nitrate (0.15 mole, 18.3 g.) and sodium methoxide (25%) in methanol (100 ml.) was refluxed for six hours. After the completion of reaction, the resultant mixture was cooled to room temperature. Separated product was filtered, washed with water, dried and crystallized from methanol. 63 K. H. CHIKHALIA et al. Step–4: preparation of n-chloro acetyl- 2-amino-4-(2,4-dichloro-5-fluoro phenyl)6-(aryl)-pyrimidine ( g ) In benzene (30 ml), chloro acetyl chloride (0.05 mole, 5.6 ml) and 2-3 drops of TEA were added and the mixture was stirred in water bath for 10 mins. The solution of (F) (0.05 mole) in benzene (80 ml) was added drop wise and refluxed for two hours. Then cooled the reaction mixture. The resulting white precipitates were filtered and washed with benzene, purified by recrystallization from alcohol. Step-5: preparation of 2-[{2-(morpholino)-3-pyridinyl-5-thio}-2-oxoethyl oxadiazoly]]-amino-4-(2,4-dichloro-5-fluoro phenyl)-6-(aryl)-pyrimidine: To a solution of (D) (0.005 mole) in acetone, (G) (0.005 mole) and KOH solution (10 ml) in acetone (80 ml) was added and refluxed for two hours. After the completion of reaction, the resultant mixture was poured in to crushed ice. Product was filtered, washed with water and crystallized from ethanol. Similarly other compounds (TN-2) to (TN-10) were prepared by the above method from intermediate (D) and the corresponding N-chloro acetyl-2-amino-4-(2,4-dichloro-5-fluoro)6-(aryl)-pyrimidines (G) and were purified by crystallization from absolute alcohol. Table . 1 2-[{2-(morpholino)-3-pyridinyl-5-thio}-2-oxoethyl oxadiazolyl]-amino-4-(2,4dichloro-5-fluoro phenyl)-6-(aryl)-pyrimidines (TN-1 to TN-10) R Mol. Formula M.P. ° C TN-1 4-CH3 C6H4 C30H24N7O3SFCl2 182 75 TN-2 4-N(CH3)2 C6H4 C31H27N8O3SFCl2 162 60 TN-3 2-OH C6H4 C29H22N7O4SFCl2 155-157 60 TN-4 4-OH C6H4 C29H22N7O4SFCl2 175 68 TN-5 4-Cl C6H4 C29H21N7O3SFCl3 195 70 TN-6 2,4-(Cl)2 C6H3 C29H20N7O3SFCl4 205-206 73 TN-7 4-F C6H4 C29H21N7O3SF2Cl 178 70 2 Elemental Analyses % Yield % S.No TN-8 2-OCH3 C6H4 C30H24N7O4SFCl2 152 62 TN-9 4- OCH3 C6H4 C30H24N7O4SFCl2 178 65 TN-10 3,4,5-(OCH3)3 C6H2 C32H28N7O6SFCl2 215 78 R F R F R F R F R F R F R F R F R F R F C H N 55.22 55.18 54.63 54.59 53.22 53.17 53.22 53.16 51.76 51.71 49.26 49.20 53.09 53.02 53.90 53.85 53.90 53.82 52.75 52.69 3.71 3.62 3.99 3.84 3.39 3.32 3.39 3.31 3.15 3.09 2.85 2.78 3.23 3.15 3.62 3.52 3.62 3.51 3.87 3.81 15.07 14.99 16.44 16.18 14.98 14.93 14.98 14.89 14.57 14.51 13.86 13.81 14.94 14.86 14.67 14.61 14.67 14.61 13.46 13.39 Studies on Synthesis of Pyrimidine Derivatives Cl Cl (...truncated)