Design, synthesis and pharmacological tests of leukotrienes A4 Dissertation

Design, synthesis and pharmacological tests of leukotrienes A4 hydrolase inhibitors as a potential targets of interest in cancer - Dissertation Example Chemical shifts (?) are reported in parts per million (ppm) relative to TMS and the coupling constants (J) are described in hertz. IR spectrums were obtained using Perkin Elmer Spectrum 100 FT-IR spectrometer, wavenumbers (?) in cm-1 Methods 1. Preparation of (Z)-(((5-(2-bromo-2-nitrovinyl)-1,3-phenylene)bis(oxy))bis (methylene))dibenzene (43) Scheme 26 Synthesis of (E)-(((5-(2-nitrovinyl)-1,3-phenylene)bis(oxy))bis(methylene))dibenzene (43). In a 25 ml round bottom flask a solution of 3,5-dibenzyloxy-benzaldexyde (318.4 mg, 1.0 mmol) in xylene (mixture of isomers, 10 ml) were added bromonitromethane (279.9 mg, 2 mmol), dimethylamine bromide (1.134 g, 9 mmol) and potassium fluoride (8.7 mg, 0.15 mmol). The flask was equipped with a Dean-Stark system and the mixture was heated at reflux temperature until the disappearance of the aryl-aldehyde by TLC (usually noted after a reaction time of 4-5 hours). Toluene (10 ml) was added and the reaction was left refluxing for 18 hours. After bei ng cooled at room temperature, the reaction mixture was evaporated under vacuum to remove xylene, then diluted with water and extracted with CH2Cl2 (3?20 mL). In some cases a filtration over Celite ® surface was required in order to remove excess of reagent residues prior to extraction. The organic phase was then washed with water, dried over anhydrous MgSO4, filtered and concentrated under vacuum. Crude product was purified by chromatography on silica gel (40 g) using mixtures of Hexane and AcOEt of increased polarity. The target compound was afforded as a brown oil (45 mg, 10% yield) 2. Preparation of (E)-1-(benzyloxy)-4-(2-nitrovinyl)benzene (50) Scheme 27 Synthesis of (E)-1-(benzyloxy)-4-(2-nitrovinyl)benzene (50). In a round 250 ml bottom flask, a solution of 4-bezyloxybenzaldehyde (6.36 g, 0.03 mol) in toluene (75 ml) was prepared. To this solution, nitromethane (17.7 ml, 0.33 mol), dimethylamine hydrobromide (15.108 g, 0.12 mol) and potassium fluoride (341.5 mg, 4.5 mmol) w ere added. The flask was equipped with a Dean-Stark system and the mixture was heated at reflux temperature until the disappearance of the aryl-aldehyde by TLC. After 3 hours and 45 minutes, the reaction flask was cooled at room temperature and the reaction mixture was evaporated under vacuum to remove toluene, then filtered under Celite surface and the filtrate was diluted with brine, dried over anhydrous MgSO4, filtered and concentrated under vacuum. After, the crude product was purified by chromatography on silica gel (90 ml of pure CH2Cl2) to provide the corresponding (E)-1-(benzyloxy)-4-(2-nitrovinyl) benzene (50) as a solid mass (0.55 g, 7.25% yield), which was later purified by flash column chromatography. IR ?max (KBr): 3109.9, 1687.9, 1625.9, 1596.8, 1509.3, 1490.6, 1463.2, 1455.4, 1425.0, 1384.9, 1336.9, 1307.3, 1245.7, 1167.2, 1122.4, 1080.9, 1031.2, 987.0, 921.2, 869.5, 849.4, 818.6, 751.1, 726.9, 697.1, 654.9, 616.2, 551.6, 528.5, 520.0, 505.3, 463.0, 416.9, 406.0 cm-1. 3. Preparation of 1-(benzyloxy)-4-(2-nitroethyl)benzene (51) Scheme 28 Synthesis of 1-(benzyloxy)-4-(2-nitroethyl)benzene. 200mg of (E)-1-(benzyloxy)-4-(2-nitrovinyl)benzene were added to a flask containing 1.55g of silica gel. Then 2.3 ml of 2-propanol and 12.5 ml of chloroform were added. Then 117mg, 3.1 mmol of NaBH4 was added. The solution was stirred at room tempera