{"id":2806,"date":"2015-04-28T06:15:15","date_gmt":"2015-04-28T06:15:15","guid":{"rendered":"http:\/\/biomedpharmajournal.org\/?p=2806"},"modified":"2016-10-19T08:09:37","modified_gmt":"2016-10-19T08:09:37","slug":"synthesis-and-biological-activity-of-new-derivatives-of-6-chloro-5-4-chlorophenyldiazenylpyrimidine-24-diamine-and-4-chloro-6-methoxy-nn-dimethylpyrimidin-2-amine","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol6no2\/synthesis-and-biological-activity-of-new-derivatives-of-6-chloro-5-4-chlorophenyldiazenylpyrimidine-24-diamine-and-4-chloro-6-methoxy-nn-dimethylpyrimidin-2-amine\/","title":{"rendered":"Synthesis and Biological Activity of New Derivatives of 6-chloro-5-((4-chlorophenyl)diazenyl)pyrimidine-2,4-diamine and 4-chloro-6-methoxy-N,N-dimethylpyrimidin-2-amine"},"content":{"rendered":"

Introduction<\/strong><\/p>\n

Pyrimidine is a prominent member of the diazine family of heterocyclics. It is found throughout nature as a component of nucleic acids, nucleotides and corresponding nucleosides. Pyrimidine was first isolated by Gabriel and Colman in 1899 [1]. Pyrimidine represents one of the most active class of compounds possessing wide\u00a0 spectrum of biological activity viz. significant in vitroactivity against unrelated DNA and RNA, viruses including polio herpes viruses, diuretic, antitumor, anti HIV, cardiovascular [2]. Methoprim, 5-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diamine (1) [3], is a potent and interesting pyrimidine analogue was used, since 1980, in combination with sulfamethoxazole as a bacteriostaticantibiotic (Co-trimoxazole) and mainly prescribed in the treatment of urinary tract infections and Pneumocystis jirovecii pneumonia, the most prevalent opportunistic microorganisms afflicting individuals with HIV positive patients.<\/p>\n

Here cited compounds\u00a0<\/strong><\/p>\n

The biodynamic property of the pyrimidine ring system prompted us to account for their pharmacological properties as antimicrobials acting against microorganisms [4]. In addition to this, pyrimidines ring is also found in vitamin B1, barbituric acid (2,4,6-trihydroxy pyrimidine) and its several derivatives e.g. Veranal2, which are used as hypnotics [5]. In 1957, Heidelberger and Duschinsky [6] had discovered 5-fluorouracil (5FU) 3 as a potential drug for tumor inhibition in mice and till update; this drug is used for treatment of cancer, in general.<\/p>\n

Result and Discussion<\/strong><\/p>\n

Chemistry<\/p>\n

Synthesis of 5-azoaryl-4-thioalkyl- and 4-benzylhydrazinyl-pyrimidines.<\/p>\n

Synthesis<\/p>\n

The azo-pyrimidine derivative 2 have been prepared previously by Al-Masoudiet al. [7] from the commercially available 2,6-diamino-4-chloropyrimidine 1, and selected in our synthetic targets as a starting material for the synthesis of various pyrimidine analogs. Thus, treatment of 1 with p-chlorophenyldiazonium salt, prepared from reaction of p-chloroaniline with NaNO2<\/sub> and HCl at 0-5o<\/sup>C, afforded 2,6-diamino-4-(p-chlorophenyl-azo)-4-chloropyrimidine 2. Nucleophilic substitution with primary and secondary aliphatic amines, as well as O- and S-nucleophiles (phenoxide and thiophenoxide ions), which are formed in situ in the reactions of phenols and thiophenols with bases, has been reported to be successful to some extent and well known [1-5]. Therefore, the presence of azo group at position 5 of compound 2 would facilitate the nucleophilic replacement of chloro group at position 4 by S-nucleophiles and amines. Treatment of 2 with NaSPh or NaSEt in DMF afforded, vianucleophilic displacements of the chlorine group, 3 and 4 in 89 and 90% yield, respectively. Similary, reaction of 2 with benzylhydrazine afforded compound 5 in 88% yields as shown in Scheme 1.<\/p>\n

Here cited scheme<\/strong><\/p>\n

Scheme 1: Synthesis of compounds 3-5.<\/p>\n

1<\/sup>H and 13<\/sup>C NMR study<\/strong><\/p>\n

Structures of compounds 3-5 were assigned by the 1<\/sup>H and 13<\/sup>C NMR spectra. The 1<\/sup>H NMR spectra showed rather similar patterns for the phenyl and ethyl protons, while the singlets at d= 4.31-3.84 ppm was attributed to methylene of the benzylhydrazine group. The methylene protons (SCH2<\/sub>) of compound 4 appeared at d 3.26 (J = 7.1 Hz) as a quartet, while methyl protons (SCH3<\/sub>) appeared as a triplet at d = 1.29 ppm (J = 7.1 Hz). The aromatic protons H-3 and H-5 of 3 resonated at d = 7.78 ppm as a doublet (J = 7.0 Hz), while H-2 and H-6 appeared as a doublet at \u03b4 = 7.54 ppm (J = 7.0 Hz). C6<\/sub>-NH2<\/sub> and C2<\/sub>-NH2<\/sub> protons resonated at d = 9.25 and 8.10 ppm as two doublets (J = 5.0 and 5.1 Hz), respectively. The aromatic protons of 4 resonated in the range d = 7.90-7.80 ppm as a multiplet, while C6<\/sub>-NH2<\/sub> and C2<\/sub>-NH2<\/sub> protons appeared at \u03b4 = 9.25 and 6.88 ppm as two broad singlets, respectively. In13<\/sup>C NMR spectra of 3 and 4, C-4 of the pyrimidine ring resonated at d= 182.1 and d = 164.7 ppm, respectively, while C-2, C-5 and C-6 resonated at the regions (\u03b4 164.6, 160.5 ppm), (\u03b4 = 118.5, 118.7 ppm) and (\u03b4 = 155.4, 155.9 ppm), respectively. The resonances at the regions \u03b4= 166.9-161.0 ppm were attributed to C-4 and C-2 of 5, while, the resonances at \u03b4 = 104.7 and 105.5 ppm were assigned to C-5. The S-ethyl group of compound 4 were resonated at d = 14.5 ppm (CH2<\/sub> carbon atom) and d \u00a0= 23.0 ppm (CH3<\/sub> carbon atom).<\/p>\n

ests. Structural modification of these compounds might optimize their biological activity by introducing diverse and potent functional group at pyrimidine back bone.<\/p>\n

Experimental Section<\/strong><\/p>\n

Chemistry<\/strong><\/p>\n

General remarks<\/strong><\/p>\n

Melting points are uncorrected and were measured on a Stuart melting point apparatus (SMP30, England). The nuclear magnetic resonance data were obtained 400 and 600 MHz (1<\/sup>H) and 150.91 MHz (13<\/sup>C) spectrometers (Avance III, Bruker, Germany), Tetramethylsilane TMS used as internal reference. The spectral data were reported in delta (\u03b4) scale in ppm units relative to TMS reference line. Multiplicities (s = singlet, d = doublet, t = triplet, q = quartet and m = multiples).Heteronuclear assignments were verified by 1<\/sup>H-13<\/sup>C HSQC experiments. Microanalytical data were obtained with a Vario, Elemental apparatus (Shimadzu, Japan). Thin layer chromatography (TLC) was carried out using TLC-silica plates GOF254 (0.2 mm) of the Merck Company. The detection was followed by UV-Lamp at 254 nm or through coloring with iodine. The chromatographic separations were carried out using silica gel (60-230 mesh). The ratio of the solvent and mixed mobile phases was given in volume ratio.<\/p>\n

Solvents<\/strong><\/p>\n

Solvents were dried and purified by conventional methods prior to use. Acetone was dried and distilled prior to use from phosphorus pentaoxide (P2<\/sub>O5<\/sub>). Chloroform and dichloromethane were dried and distilled over dry Calcium chloride, collected over magnesium sulphate then filtered over magnesium sulphate. All of these solvent obtained from Scharalau. But Hexane, Ethanol, Methanol, Propanol, DMF obtained from Thomas Baker (chemicals) limited. Whereas THF and ethyl acetate were obtained from a BDH Chemical Ltd (pode England).<\/p>\n

Chemicals<\/strong><\/p>\n

6-chloro-5-((4-chlorophenyl)diazenyl)pyrimidine-2,4-diamine were given from Prof. Najim Al-Masoudi prepared by same procedure puplished in .J.Med.Chem [7].<\/p>\n

6-chloro-1,3-dimethyl-5-nitropyrimidine-2,4(1H,3H)-dione,2,6-Diamino-4-chloro-pyrimidine and all arylboronic acids listed below were purchased from Sigma-Aldrich.<\/p>\n

synthesis<\/strong><\/p>\n

Preparation of 2,6-diamono-4-chloro-5-p-chlorophenylazopyrimidine<\/strong><\/p>\n

The compound was prepared by method described in reference [7] from the commercially available 2,6-diamino-4-chloropyrimidine 2 (2.55 g, 20 mmol) in 6N HCl (10 mL) and p-chlorophenyldiazonium salt [from NaNO2<\/sub> (1.38 g, 20 mmol) in water (6 mL) at 0 o<\/sup>C]. Yield: 78%, m.p. 267 o<\/sup>C, Lit. 268 o<\/sup>C.<\/p>\n

Diamino-6-phenylthio-5-p-chlorophenylazopyrimidine<\/strong><\/p>\n

A solution of 2 (250 mg, 0.89 mmol) in benzene (20 mL) containing NaSPh (110 mg, 0.89 mmol) was heated under reflux. After for 8 h, the color of solution was changed into an yellow color, where the completion of reaction was monitored by TLC. After cooling, the solution was concentrated and left overnight at low temperature. The yellow crystals werecollected and recrystallized from EOH to give 3 (281 mg, 89%), m.p. 237-238 o<\/sup>C.1<\/sup>H NMR (DMSO-d6<\/sub>): \u03b4 = 9.25 (br s., 2H, C6<\/sub>-NH2<\/sub>); 7.90-7.30 (m, 9H, Harom<\/sub>), 6.88 (br s., 2H, C2<\/sub>-NH2<\/sub>). 13<\/sup>C NMR (DMSO-d6<\/sub>): \u03b4 = 182.1 (C-4); 164.6 (C-2); 155.4 (C-6); 139.8 (Carom<\/sub>-Cl); 133.4 (C1”<\/sup>arom<\/sub>-S); 129.4, 129.3, 128.7, 128.3, 127.5, 125.4, 124.1, 122.9 (Carom<\/sub>); 118.5 (C-5). Anal. calcd. For C16<\/sub>H13<\/sub>ClN6<\/sub>S (356.83): C, 53.85; H, 3.67; N, 23.55. Found; C, 53.53; H, 3.54; N, 23.72.<\/p>\n

Diamino-4-ethylthio-5-p-chlorophenylazapyrimidine<\/strong><\/p>\n

Method was analogues to the proceeding procedure, using instead 2 (250 mg, 0.87 mmol) and NaSEt (74 mg, 0.887 mmol). Yield: 235 mg (90%), m.p. 267-268 o<\/sup>C.1<\/sup>H NMR (DMSO-d6<\/sub>): \u03b4 = 9.25 (d, 2H, J = 5.0 Hz, C6<\/sub>-NH2<\/sub>); 8.10 (d, 2H, J = 5.1 Hz, C2<\/sub>-NH2<\/sub>); 7.78 (d, 2H, J = 7.0 Hz, Harom<\/sub>-3 + Harom<\/sub>-5); 7.54 (d, 2H, J = 7.0 Hz, Harom<\/sub>-2 + Harom<\/sub>-6). 13<\/sup>C NMR (DMSO-d6<\/sub>): \u03b4 =164.7 (C-4); 161.2 (C-2); 155.9 (C-6); 133.5 (Carom<\/sub>-Cl); 129.3, 123.3 (Carom<\/sub>); 118.7 (C-5). Anal. calcd. For C12<\/sub>H13<\/sub>ClN6<\/sub>S (308.79): C, 46.68; H, 4.24; N, 27.22. Found; C, 46.38; H, 4.18; N, 27.39.<\/p>\n

Diamino-4-(2-benzylhydrazinyl)-5-p-chlorophenylazopyrimidine<\/strong><\/p>\n

To a solution of 2 (1.0 g, 3.54 mmol) in EtOH (30 mL) was added benzylhydrazine hydrochloride (0.45 g, 2.84 mmol) and the mixture was heated under reflux for 2 h. After cooling, the orange solution was concentrated and left overnight at 0 o<\/sup>C. The orange crystals werre filtered, and recrystallized from EtOH to give 8 (1.14 g, 88%), m.p. 211-215 o<\/sup>C.1<\/sup>H NMR (DMSO-d6<\/sub><\/em>): \u03b4 = 9.31 (br s., 2H, C6<\/sub>-NH2<\/sub>), 9.00-8.96 (m, 2H, 2xNH); 8.26 (brs., 2H, C4<\/sub>-NH2<\/sub>); 7.99-7.35 (m, 9H, Harom<\/sub>); 4.06 (s, 2H, CH2<\/sub>). 13<\/sup>C NMR (DMSO-d6<\/sub>): \u03b4 = 164.7 (C-4); 160.5 (C-2); 155.4 (C-6); 139.8 (C1<\/sup>phenylhydraz.<\/sub>); 133.4 (Carom<\/sub>-Cl); 129.3, 129.2, 128.4, 128.1 (Carom<\/sub>); 103.8 (C-5); 53.6 (CH2<\/sub>). Anal. calcd. For C17<\/sub>H17<\/sub>ClN8<\/sub>. (368.82): C, 55.36; H, 4.65; N, 30.38. Found C, 55.36; H, 4.50; N, 30.21.<\/p>\n

General procedure of Suzuki reaction for preparation of 7 and 12- 15<\/strong><\/p>\n

Diamino-4-(2-benzylhydrazinyl)-5-(4′-fluoro-[1,1′-biphenyl]-4-yl)pyrimidine\u00a0<\/strong><\/p>\n

A mixture of halopyrimidine and arylboronic acid in n-propanol (15 mL) was stirred for 15 min. To this mixture was added Pd(OAc)4<\/sub> (650 mg, 0.19 mmol), triphenylphosphene (498 mg, 0.19 mmol) and 2M aq. solution of Na2<\/sub>CO3<\/sub> (3.5 mL). The reaction mixture was refluxed under nitrogen for 4-6 h and completion ofreaction was monitored by TLC. After cooling, water was added (7 mL), followed by stirring for 5 min. The mixture was partitioned with ethyl acetate (3\u00d710 mL) and the combined organic layers were washed subsequently with 5% Na2<\/sub>CO3<\/sub> solution (2\u00d710 mL), brine solution (2\u00d710 mL) and finally with water (10 mL). The organic phase was decolorized with charcoal, filtered and the filtrate was dried (Na2<\/sub>SO4<\/sub>), filtered through celite and evaporated to dryness to give, after purification, the desired product.<\/p>\n

From 5 (70 mg, 0.19 mmol) and p-fluorophenylboronic acid 6 (27 mg, 0.19 mmol). Yield: 63 mg (78%), as a brown crystals, m.p. 180-182 o<\/sup>C (dec), Rf<\/sub> = 0.67 (eluent: etheyl acetate\/ hexane 3:2). 1<\/sup>H NMR (DMSO-d6<\/sub>): \u03b4 = 8.03 (br s., 2H, C6<\/sub>-NH2<\/sub>). 7.82-7.67 (m, 4H, C2<\/sub>-NH2<\/sub>+2xNH); 7.64-7.31 (m, 13H, Harom<\/sub>); 4.31 (d, 2H, J = 5.5 Hz, CH2<\/sub>). 13<\/sup>C NMR (DMSO-d6<\/sub>): \u03b4 = 166.9 (C-4); 162.1 (C-2); 161.1 (d, JC4”,F<\/sub> = 250 Hz, C4”<\/sub>-F); 152.2 (C-6); 139.5 (C-4′ + C1<\/sup>phenylhydraz.<\/sub>); 139.2 (d, JC-1”,F<\/sub> = 2.4 Hz, C-1”); 133.9, 133.1, 131.9, 131.4, 129.2, 128.7, 128.6, 127.2, 119.2 (Carom<\/sub>); 104.7 (C-5); 55.4 (CH2<\/sub>). Anal. calcd. For C23<\/sub>H21<\/sub>FN8<\/sub> (428.46): C, 64.47; H, 4.94; N, 26.15. Found: C, 64.24; H, 4.90; N, 25.94.<\/p>\n

Diamino-4-(3,4-dimethoxyphenyl)-5-(3,4-dimethoxy[1,1′-biphenyl]-4-yl) pyrimidine\u00a0<\/strong><\/p>\n

From 5 (122 mg, 0.40 mmol) and 3,4-dimethoxyphenylboronic acid9 (155 mg, 0.85 mmol). Yield: 193 mg (92%), as a red crystals, m.p. 165-166 o<\/sup>C, Rf<\/sub>= 0.54 (eluent: etheyl acetate\/ hexane 3:2). 1<\/sup>H NMR (DMSO-d6<\/sub>): \u03b4 = 9.00 (br s, 2H, C6<\/sub>-NH2<\/sub>); 7.73-7.65 (m, 10H, Harom<\/sub>); 6.71 (br s, 2H, C2<\/sub>-NH2<\/sub>); 3.83, 3.76, 3.74 (m, 12H, 4\u00d7OMe). 13<\/sup>C NMR (DMSO-d6<\/sub>): \u03b4 = 163.7 (C-2); 161.7 (C-4), 160.9 (C-6), 151.8, 147.0 (4\u00d7C-OMe); 141.0 (C-1′); 131.9, 131.4, 131.3, 129.2, 128.7, 128.5 (Carom<\/sub>); 122.9 (C-5); 113.5, 112.1, 110.3 (Carom<\/sub>); 55.1 (4\u00d7OMe). Anal. calcd. for C26<\/sub>H26<\/sub>N6<\/sub>O4<\/sub> (486.52): C, 64.19; H, 5.39; N, 17.27. Found: C, 64.56; H, 5.31; N, 17.20.<\/p>\n

Diamino-4-(4-fluorophenyl)-5-(4-fluoro[1,1′-biphenyl]-4-yl) pyrimidine\u00a0<\/strong><\/p>\n

From 2 (86 mg, 0.30 mmol) and 4-Flurophenylboronic acid 6 (85 mg, 0.60 mmol) Yield: 93 mg (76%), as a red crystals, m.p. 179-180 o<\/sup>C, Rf<\/sub> = 0.70 (eluent: etheyl acetate\/ hexane 2:1). 1<\/sup>H NMR (DMSO-d6<\/sub>): \u03b4 = 9.43 (br s, 2H, C6<\/sub>-NH2<\/sub>) 8.05-7.31 (m, 12H, Harom<\/sub>); 7.06 (br s, 2H, C2<\/sub>-NH2<\/sub>). 13<\/sup>C NMR (DMSO-d6<\/sub>): \u03b4 = 165.4 (C-2); 161.0 (m, C-4 + 2xC4”<\/sub>-F); 155.9 (C-6); 139.7 (C-1′); 133.9, 133.1, 132.1, 131.45, 131.36, 130.67, 129.9, 127.2 (Carom<\/sub>); 122.3 (C-5); 120.8, 116.2, 115.3 (Carom<\/sub>-c+ Carom<\/sub>-e+C-3”+C5”). Anal. calcd. For C22<\/sub>H16<\/sub>F2<\/sub>N6<\/sub> (402.40): C, 65.66; H, 4.01; N, 20.88. Found: C, 65.42: H, 3.96; N, 20.65.<\/p>\n

Diamino-4-(3,4-dimethoxyphenyl)-5-(3,4-dimethoxy[1,1′-biphenyl]-4-yl) pyrimidi<\/strong><\/p>\n

From 2 (122 mg, 0.40 mmol) and 3,4-dimethoxyphenylboronic acid 9 (155 mg, 0.85 mmol). Yield: 193 mg (92%), as a red crystals, m.p. 165-166 o<\/sup>C, Rf<\/sub>= 0.54 (eluent: etheyl acetate\/ hexane 3:2). 1<\/sup>H NMR (DMSO-d6<\/sub>): \u03b4 = 9.00 (br s, 2H, C6<\/sub>-NH2<\/sub>); 7.73-7.65 (m, 10H, Harom<\/sub>); 6.71 (br s, 2H, C2<\/sub>-NH2<\/sub>); 3.83, 3.76, 3.74 (m, 12H, 4\u00d7OMe). 13<\/sup>C NMR (DMSO-d6<\/sub>): \u03b4 = 163.7 (C-2); 161.7 (C-4), 160.9 (C-6), 151.8, 147.0 (4\u00d7C-OMe); 141.0 (C-1′); 131.9, 131.4, 131.3, 129.2, 128.7, 128.5 (Carom<\/sub>); 122.9 (C-5); 113.5, 112.1, 110.3 (Carom<\/sub>); 55.1 (4\u00d7OMe). Anal. calcd. For C26<\/sub>H26<\/sub>N6<\/sub>O4<\/sub> (486.52): C, 64.19; H, 5.39; N, 17.27. Found: C, 64.56; H, 5.31; N, 17.20.<\/p>\n

Diamino-4-(2-benzylhydrazinyl)-5-(2′-fluoro-[1,1′-biphenyl]-4-yl)pyrimidine<\/strong><\/p>\n

From 5(70 mg, 0.19 mmol) and o-fluorophenylboronic acid (27 mg, 0.19 mmol). Yield: 63 mg (78%), as a brown crystals, m.p. 180-182 o<\/sup>C (dec), Rf<\/sub> = 0.67 (eluent: etheyl acetate\/ hexane 3:2). 1<\/sup>H NMR (DMSO-d6<\/sub>): \u03b4 = 8.03 (br s., 2H, C6<\/sub>-NH2<\/sub>). 7.82-7.67 (m, 4H, C2<\/sub>-NH2<\/sub>+2xNH); 7.64-7.31 (m, 13H, Harom<\/sub>); 4.31 (d, 2H, J = 5.5 Hz, CH2<\/sub>). 13<\/sup>C NMR (DMSO-d6<\/sub>): \u03b4 = 166.9 (C-4); 162.1 (C-2); 161.1 (d, JC4”,F<\/sub> = 250 Hz, C4”<\/sub>-F); 152.2 (C-6); 139.5 (C-4′ + C1<\/sup>phenylhydraz.<\/sub>); 139.2 (d, JC-1”,F<\/sub> = 2.4 Hz, C-1”); 133.9, 133.1, 131.9, 131.4, 129.2, 128.7, 128.6, 127.2, 119.2 (Carom<\/sub>); 104.7 (C-5); 55.4 (CH2<\/sub>). Anal. calcd. for C23<\/sub>H21<\/sub>FN8<\/sub> (428.46): C, 64.47; H, 4.94; N, 26.15. Found: C, 64.24; H, 4.90; N, 25.94.<\/p>\n

Diamino-4-(4-nitrophenyl)-5-(4-nitro[1,1′-biphenyl]-4-yl)pyrimidine<\/strong><\/p>\n

From 2 (213 mg, 0.75 mmol) and 4-nitrophenylboronic acid 11 (250 mg, 1.50 mmol). Yield: 323 mg, (94%), as a red crystals, m.p. 185-187 o<\/sup>C, Rf<\/sub> = 0.70 (eluent: etheyl acetate\/ hexane 2:1). 1<\/sup>H NMR (DMSO-d6<\/sub>): \u03b4 = 9.24 (s, 2H, C6<\/sub>-NH2<\/sub>); 8.16-6.96 (m, 12H, Harom<\/sub>); 6.94 (s, 2H, C2<\/sub>-NH2<\/sub>). 13<\/sup>C NMR (DMSO-d6<\/sub>): \u03b4 = 164.5 (C-2); 161.0 (C-4); 155.7 (C-6); 150.9 (C-1” + 2\u00d7C4”<\/sub>-NO2<\/sub>); 133.2, 131.8, 131.2, 129.1, 126.0, 122.6, 121.9 (Carom<\/sub>); 118.5 (C-5). Anal. calcd. For C22<\/sub>H16<\/sub>N8<\/sub>O4<\/sub> (456.41): C, 57.89; H, 3.53; N, 24.55. Found: C, 57.76; H, 3.48; N, 24.71.<\/p>\n

General procedure for preparation of 6-amino-4-methoxy-N,N-dimethyl-6-arylpyrimidines 20-23 via Suzuki reaction.<\/p>\n

A suspension of 2-amino-4-chloro-6-methoxy-N,N-dimethylpyrimidine 16 and arylboronic acid in n-propanol (15 mL), then it was stirring for 15 minute until the solid was dissolved. To this solution Pd(OAc)4<\/sub> (360 mg, 0.11 mmol), Ph3<\/sub>P (128 mg, 0.49 mmol) and 2M aq. solution of Na2<\/sub>CO3<\/sub> (4 mL)was added. The reaction mixture was refluxed under nitrogen for 4-8 h, and the reaction progress was monitored by TLC (eluent: etheyl acetate\/ hexane 1:1). After cooling, the reaction mixture was filtered, and concentrated under vaccum. The solid product was filtered and washed with cold ether to give the desired product.<\/p>\n

Amino-4-methoxy-N,N-dimethyl-6-(4-nitrophenyl)pyrimidine<\/strong><\/p>\n

From 16 (100 mg, 0.53 mmol) and p-nitrophenolboronic acid 11 (89 mg, 0.53 mmol). Yield: 100 mg (68%), as a green crystals, m.p. 137-139 o<\/sup>C, Rf<\/sub>= 0.40. 1<\/sup>H NMR (DMSO-d6<\/sub>): \u03b4 = 8.35-8.16 (m, 4H, Harom<\/sub>); 6.72 (s, 1H, H-5), 3.92 (s, 3H, OMe), 3.21 (s, 6H, NMe2<\/sub>). 13<\/sup>C NMR (DMSO-d6<\/sub>): \u03b4 =171.2 (C-4); 162.2 (C-2 + C-6); 148.8 (C4′<\/sub>-NO2<\/sub>); 143.8 (Carom<\/sub>-1′); 128.4 (Carom<\/sub>-2’+ Carom<\/sub>-6′); 124.1 (Carom<\/sub>-3’+ Carom<\/sub>-5′); 92.5 (C-5); 53.5 (OMe); 36.9 (NMe2<\/sub>). Anal. calcd. For C13<\/sub>H14<\/sub>N4<\/sub>O3<\/sub> (274.28): C, 56.93; H, 5.14; N, 20.43. Found: C, 56.71; H, 5.02; N, 20.21.<\/p>\n

(N,N-Dimethylamino)-6-methoxypyrimidin-4-yl)benzoic acid\u00a0<\/strong><\/p>\n

From 16 (100 mg, 0.53 mmol), and 3-boronobenzoic acid 17 (88 mg, 0.53 mmol). Yield: 85 mg (59%), as a white powder, m.p. >300 o<\/sup>C (dec.), Rf<\/sub>= 0.60. 1<\/sup>H NMR (DMSO-d6<\/sub>): \u03b4 = 10.45 (s, 1H, CO2<\/sub>H); 8.29-8.02 (m, 4H, Harom<\/sub>); 6.62 (s, 1H, H-5); 3.90 (s, 3H, C4<\/sub>-OMe); 3.20 (s, 6H, NMe2<\/sub>). 13<\/sup>C NMR (DMSO-d6<\/sub>): \u03b4 =173.4 (CO2<\/sub>H); 170.5 (C-4); 162.7 (C-6); 161.7 (C-2); 132.2, 130.9, 129.6, 129.1, 128.7 (Carom<\/sub>); 91.4 (C-5); 52.8 (OMe); 36.3 (NMe2<\/sub>). Anal. calcd. For C14<\/sub>H15<\/sub>N3<\/sub>O3<\/sub> (273.29): C, 61.53; H, 5.53; N, 15.38. Found: C, 61.32; H, 5.41; N, 15.17.<\/p>\n

Amino-4-(2-fluorophenyl)-6-methoxy-N,N-dimethylpyrimidine \u00a0<\/strong><\/p>\n

From 16(100 mg, 0.53 mmol) and 2-(fluoro)phenylboronic acid 18 (75 mg, 0.53 mmol). Yield: 96 mg, (73%), as a yellowish powder, m.p. 249-253 o<\/sup>C, Rf<\/sub> = 0.48. 1<\/sup>H NMR (DMSO-d6<\/sub>): \u03b4 = 7.81-7.43 (m, 4H, Harom<\/sub>); 6.82 (s, 1H, H-5); 3.82 (s, 3H, C4<\/sub>-OMe); 3.13 (s, 6H, NMe2<\/sub>). 13<\/sup>C NMR (DMSO-d6<\/sub>): \u03b4 = 171.8 (C-4); 164.4 (C-6); 161.1 (C-2); 156.6 (d, JC2′,F<\/sub> = 251 Hz, C2′<\/sub>-F); 129.2, 129.1, 128.8, 127.5, 125.4, 122.9. 115.1 (m, JC,F<\/sub> couplings, Carom<\/sub>); 95.0 (C-5); 53.5 (OMe); 36.8 (NMe2<\/sub>). Anal. calcd. For C13<\/sub>H14<\/sub>FN3<\/sub>O (247.27): C, 63.15; H, 5.71; N, 16.99. Found: C, 62.90; H, 5.65; N, 15.82.<\/p>\n

(Dimethylamino)-6-methoxypyrimidin-4-yl)furan-2-carbaldehyde<\/strong><\/p>\n

From 16 (200 mg, 1.07 mmol) and (5-formyl-2-yl)boronic acid 19 (150 mg, 1.07 mmol). Yield: 177 mg (67%), as a pale brown powder, m.p. 248-250 o<\/sup>C (dec.), Rf<\/sub>= 0.61. 1<\/sup>H NMR (DMSO-d6<\/sub>): \u03b4 = 10.54 (s,1H, CHO); 8.58 (d, 1H, J = 5.2 Hz, Hfuran<\/sub>-4′); 7.96 (d, 1H, J = 5.2 Hz, Hfuran<\/sub>-3′); 6.83 (s, 1H, H-5); 4.25 (s, 3H, OMe); 2.94 (s, 6H, NMe2<\/sub>). 13<\/sup>C NMR (DMSO-d6<\/sub>): \u03b4 = 178.5 (CHO); 170.3 (C-4); 167.4 (C-6); 163.1 (C-2); 161.1 (Cfuran<\/sub>-1′); 152.3 (C-CHO); 124.6 (Cfuran<\/sub>-3′); 111.8 (Cfuran<\/sub>-2′); 102.3 (C-5); 53.8 (OMe); 38.1 (NMe2<\/sub>). Anal. calcd. For C12<\/sub>H13<\/sub>N3<\/sub>O3<\/sub> (274.25): C, 58.29; H, 5.30; N, 16.99. Found: C, 58.02; H, 5.22; N, 16.42.<\/p>\n

Biology<\/strong><\/p>\n

Tested Microbes<\/strong><\/p>\n

The antimicrobial effects of the fourteen synthetic organic compounds (under test) were experimented on the different local pathogenic isolates of gram positive bacteria (10 isolates of Staphylococcus aureus, 10 isolates of Staphylococcus saprophyticus \u00a0and 10 isolates of Streptococcus pyogenes), gram negative bacteria (10 isolates of Escherichia coli, 10 isolates of Klebsiella pneumonia and 10 isolates of Pseudomonas aeruginosa) and some of the clinically important yeast (10 isolates of Candida albicans and 10 isolates of Candida glabrata). All these isolates were gathered from the advanced microbiology lab, Biology departments in faculty of science- Babylon University, Iraq.<\/p>\n

Well Diffusion Method<\/strong><\/p>\n

The synthetic organic compounds were used for studying their antibacterial activity. A loop full of the experimented isolates of bacteria or fungus was inoculated in 30 mL of Nutrient broth in a conical flask and incubated for 72 hrs to get active strain by using agar well diffusion method. Muller Hinton Agar (or Potato dextrose agar for fungus) was poured into Petri dishes. After solidification 0.25 ml of test, strains were inoculated in the media separately. Care was taken to ensure proper\u00a0homogenization. The experiment was performed under strict aseptic conditions. After the medium solidified, a well was made in the plates with sterile borer (5mm).The compound (50 \u03bcl) was introduced into the well and plates were incubated at 37\u00b0C for 72 hrs. All samples were tested in triplicates. Microbial growth was determined by measuring the diameter of zone of\u00a0inhibition [20]\n

Acknowledgements<\/strong><\/p>\n

We thank Mr. U. Haunz and Miss A. Friemel of chemistry department, University of Konstanz, Germany for NMR experiments.<\/p>\n

References<\/strong><\/p>\n

    \n
  1. S.; Colman. J, Ber. Dtsch. Chem. Ges.1899, 32, 1536.<\/li>\n
  2. C. O.Tetrahedron1993, 49, 6937-6963 (review).<\/li>\n
  3. P.; H. M. Hood, US Patent 62, 3,049,544, 1962.<\/li>\n
  4. M.; Saxena. S.; Rastogi. S.; Venkataramanan. R. Curr. Med.Chem.-Anti-Infect. Agents 2003,24,269-286.<\/li>\n
  5. M. K.;Sharnevsas. S. C.organic chemistry, III edition, 2008, 997-999.<\/li>\n
  6. C.; Chaudhuri. N. K.; Danneberg.P.; Mooren. D.; Griesbach. L.; R., Duschinsky. R.; Schnitzer. J.; Pleven. E.; Scheiner. J. Nature1957, 179, 663-666.<\/li>\n
  7. Fr\u00f6hlich. L. G.; Kotsonis. P.; Traub. ; Taghavi-Moghadam.S.; Al-Masoudi. N.; Strobel. H.;Matter.H.; Pfleiderer. H. W. J. Med. Chem. 1999, 42, 4108- 4121.<\/li>\n
  8. Stanforth. S. P. Tetrahedron1998, 54, 263-303.<\/li>\n
  9. Miyaura. N.; Yamada. K.; Suzuki. A. Tetrahedron Lett.1979, 20, 3437-3440.<\/li>\n
  10. Miyaura. N.; Suzuki. A. Chem. Comm.1979, 19, 866-867.<\/li>\n
  11. Miyaura. N.; Suzuki. A. Chem. Rev. 1995, 95, 2457-2483.<\/li>\n
  12. Gribble. J. J. Li, G. W. Palladium in Heterocyclic Chemistry; Tetrahedron Organic\u00a0Chemistry Series;Pergamon: Amsterdam, 2000; Vol. 20.Davis. A. L.; Keeler J.; Laue. E. D.; Moskau. D.J. Magn. Reson. 1992, 98, 207-216.<\/li>\n
  13. P.; Koymans. L.;Willemsens. S.; et al. Microbiology1999; 145(Pt10):2701\u201313.<\/li>\n
  14. X. Li, H.Drug. 2009,\u00a069\u00a0(12):1555\u2013623.<\/li>\n
  15. Z.A.; Perfect. J.R. Clinical Infectious Diseases. 2008, 46:120\u20138.<\/li>\n
  16. D.; Bille. J. Washington, DC: ASM Press, 2002:349\u201383.<\/li>\n
  17. E.; Garcia-Effron. G.; Alcazar-Fuoli. L.; Cuenca-Estrella. M.; Rodriguez- Tudela. J.L.;Antimicrob Agents Chemother. 2004, 48:2747\u201350.<\/li>\n
  18. E.; Garcia-Effron. G.; Alcazar-Fuoli. L.; Cuenca-Estrella. M.; Rodriguez- Tudela. J.L. Antimicrob Agents Chemother. 2007, 51:1897\u2013904.<\/li>\n
  19. Clinical and Laboratory Standards Institute (CLSI).Twentieth Informational Supplement. 2010, M100-S20; Vol. 30 No. 1 Replaces M100-S19 Vol. 29 No. 3: 1-157.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

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