4,5-Dibromo-2-phenyl-3(2H)-pyridazinone

Mucobromic acid (10.0 g, 38.8 mmol) was dissolved in 250 ml of 6N HCl in a 500 ml round bottom flask at room temperature. Phenyl hydrazine (4.58 ml, 46.6 mmol) was dissolved in 100 ml of 6 N HCl and added to the reaction with vigorous stirring at 70 C. for 18 hours. An off-white precipitate formed immediately. After 18 hours, LC/MS showed reaction completion. The reaction was allowed to partially cool. 100 ml of ethyl acetate was then added in an attempt to extract the product. The precipitate went into solution, but the solution was homogenous and not two layers as expected. The reaction was allowed to stand in an attempt to allow the two layers to separate. As the reaction cooled, a large amount of precipitate formed. It was found that the HCl converted the ethyl acetate to ethanol and acetic acid, which caused the solution to become homogenous and caused product precipitation. The solid was filtered, washed with diethyl ether and dried under vacuum to afford 10.54 g of an off-white solid. 1H NMR (300 MHz, CDCl3) delta 7.96 (s, 1H), 7.60-7.42 (m, 5H); LC/MS, tr=2.35 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50 C.), (M+H), Calculated=329, Found=329; HR/MS (M+H), Calculated=328.8920, Found=328.8927 (Delta mmu=0.7).A mixture of 4, 5-dibromo-2-phenyl-3 (2H) -pyridazinone 33 g (0.1 mol), tributylamine 55 g (0.3 mol)Into a 100-ml three-necked flask, carbon dioxide and hydrogen fluoride gas produced by the decomposition of trifluoromethane (HFC-23) were directly fed at 80 C, stirred and reacted, and after the completion of the thin layer chromatography, the reaction mixture was cooled with methylene chloride 10 ml, and the residue was purified by column chromatography (silica gel GF254, eluent: ethyl acetate / petroleum ether V / V = 1: 1) to give 25 g of product as a white powder, yield 93%.General procedure: A mixture of 4, 5-dibromopyridazin-3(2H)-one (1) (0.20 g, 0.79 mmol), (2, 5-dimethylthiophen-3-yl) boronic acid (4) (0.37 g, 2.36 mmol), potassium carbonate (1.08 g, 7.84 mmol), tetrakis(triphenylphosphine) palladium(0) (0.11 g, 0.095 mmol), and a catalytic amount of tris(dibenzylideneacetone) dipalladium(0) in THF (10 ml) and H2O (2 ml) was stirred for 1 h at 40-50 C, and then this mixture was refluxed for 2 h. The progress of reaction was monitored by TLC. The reaction mixture was quenched by aqueous solutions of 10% NaHCO3 and extracted with ethyl acetate. The organic layer was washed with sat. aq. NaCl, dried with anhydrous Na2SO4, and the drying agent was filtered off. After removing the solvent in a rotary evaporator, the mixture was purified by column chromatography on silica gel using ethyl acetate/hexane as the eluent. Further purifications were required by preparative thin layer chromatography (PTLC) to obtain 1O as a white solid. Yield 0.075 g (30%) mp: 134-135 C.General procedure: A mixture of 4, 5-dibromopyridazin-3(2H)-one (1) (0.20 g, 0.79 mmol), (2, 5-dimethylthiophen-3-yl) boronic acid (4) (0.37 g, 2.36 mmol), potassium carbonate (1.08 g, 7.84 mmol), tetrakis(triphenylphosphine) palladium(0) (0.11 g, 0.095 mmol), and a catalytic amount of tris(dibenzylideneacetone) dipalladium(0) in THF (10 ml) and H2O (2 ml) was stirred for 1 h at 40-50 C, and then this mixture was refluxed for 2 h. The progress of reaction was monitored by TLC. The reaction mixture was quenched by aqueous solutions of 10% NaHCO3 and extracted with ethyl acetate. The organic layer was washed with sat. aq. NaCl, dried with anhydrous Na2SO4, and the drying agent was filtered off. After removing the solvent in a rotary evaporator, the mixture was purified by column chromatography on silica gel using ethyl acetate/hexane as the eluent. Further purifications were required by preparative thin layer chromatography (PTLC) to obtain 1O as a white solid. Yield 0.075 g (30%) mp: 134-135 C.Similar reaction of 30 (1.073g, 3.25mmol, 1.00 equiv) and tetrahydrofurfuryl amine (0.70mL, 6.78mmol, 2.09 equiv) were heated under reflux in EtOH (32mL) for 16h, then cooled and purified by column column chromatography on silica gel, eluting with 0-60% EtOAc/hexanes. Re-precipitation of the major product from EtOAc/hexanes gave 12 (785mg, 67%) as an off-white crystalline solid: mp 133-134C; 1H NMR (CDCl3): delta 7.70 (s, 1H), 7.57 (m, 2H), 7.44 (m, 2H), 7.35 (m, 1H), 5.23 (m, 1H), 4.14 (m, 1H), 3.93 (m, 1H), 3.83 (m, 1H), 3.57 (ddd, J=9.8, 6.2, 3.5Hz, 1H), 3.37 (m, 1H), 2.08 (m, 1H), 1.98 (m, 2H), 1.67 (m, 1H); HRESIMS calcd for C15H1681BrN3NaO2 m/z [M+Na]+ 374.0298, found 374.0299, calcd for C15H1679BrN3NaO2 m/z [M+Na]+ 372.0318, found 372.0319; TLC Rf=0.18 (50% EtOAc/hexanes); HPLC purity: 99.7%.Similar reaction of 30 (1.005g, 3.05mmol, 1.00 equiv), glycinamide hydrochloride (0.70g, 6.31 mol, 2.07 equiv), and pyridine (0.51mL, 6.31mmol, 2.07 equiv) was heated under reflux in a mixture of EtOH (41mL) and DMF (5mL). After 48h starting material remained, so more glycinamide hydrochloride (2.98 equiv) and NEt3 (2.60mL, 18.65mmol, 6.12 equiv) were added and the mixture was heated under reflux for a further 16h. The cooled mixture was filtered through a pad of Celite and the filtrate was diluted with brine, extracted with CH2Cl2 (×3) and the combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue was re-precipitated from MeOH: EtOAc to give 11 (77 mg, 8%) as an amorphous off-white solid: mp 216-219C; 1H NMR (CDCl3): delta 7.75 (s, 1H), 7.56 (br s, 1H), 7.47 (m, 4H), 7.39 (m, 1H), 7.24 (br s, 1H), 6.71 (m, 1H), 4.05 (d, J=6.20Hz, 2H); HRESIMS calcd for C12H1181BrN4NaO2 m/z [M+Na]+ 346.9938, found 346.9947, calcd for C12H1179BrN4NaO2 m/z [M+Na]+ 344.9958, found 344.9963; TLC Rf=0.22 (10% MeOH:EtOAc); HPLC purity: 98.7%.

Molecular Weight:329.97
XLogP3:2.8
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:329.88264
Monoisotopic Mass:327.88469
Topological Polar Surface Area:32.7
Heavy Atom Count:15
Complexity:332
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes