2-BENZYL-4,5-DICHLORO-2,3-DIHYDROPYRIDAZIN-3-ONE

To a round bottom flask was added 4, 5-dichloropyridazin-3(2H)-one (50 gm, 303.03 mmol), DMF (150 ml), KTo a solution of dichloropyridazinone (50.0 g, 303.0 mmol) in DMF (200 mL) was added KPreparation 3-1); 2-Benzyl-4, 5-dichloro-2H-pyridazin-3-one To a mixture of 4, 5-dichloro-2H-pyridazin-3-one (3.3 g, 20.0 mmol) and Cs186A. A mixture of commercially available 4, 5-dichloropyridazin3(2H)-one (18 mmol), benzyl bromide (19 mmol), potassium carbonate (45 mmol), tetrabutylammonium bromide (1 mmol) and acetonitrile (45 mL) is stirred and heated under reflux for 1 h. After cooling, the solvent is evaporated under reduced pressure. The residue is purified by filtration on a small silica gel column eluting with 10percent EtOAc/Hexane to give compound 186a as a white powder (81percent). [M+H](1) The compound 1 (10 g), benzyl bromide (10.9 g), potassium carbonate (21 g), and tetrabutylammonium bromide (1.0 g) were suspended in acetonitrile (150 mL), and the reaction mixture was stirred for 2 hours under argon atmosphere with heating to reflux. The reaction mixture was cooled to room temperature, and an insoluble substance was filtered off, washed with ethyl acetate, and then the filtrate was concentrated under reduced pressure. The resultant residue was dissolved in chloroform, and the solution was filtered with a silica gel pad (eluent: chloroform). The eluate was concentrated under reduced pressure, and the resultant crystalline residue was suspended and washed in a mixed solvent of ethyl acetate-hexane, taken by filtration, and dried to give the compound 2 (12.2 g) as a pale yellow solid. MS (APCI): 255/257 [M+H][00212] Step 2: 2-Benzyl-5-iodopyridazin-3(2H)-one was prepared according to the method described in Coelho, supra. A solution of Step 2, 2-Benzyl-5-iodopyridazin-3(2H)-one; 2-Bnzyl-4, 5-dichloropyridazin-3(2H)-one (32.3 g, 127 mmol) was dissolved in hydriodic acid (223 niL) and the mixture was refluxed at 1 15 C overnight. The mixture was poured into dichloromethane and 30% sodium thiosulphate (250 mL), and extracted with dichloromethane (3 x 250 mL). The combined organics were washed with 30% sodium thiosulphate several times (total 1 L), dried (sodium sulfate), and concentrated. Dichloromethane was added to the residue and the precipitate was collected by filtration to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) delta 8.17 (s, 1H); 7.61 (s, 1H); 7.23-7.33 (m, 5H); 5.17 (s, 2H). LRMS (APCl) calc'd for (CnHi0IN2O) [M+Hf, 313.0; found 313.0.(2) A mixture of the compound 2 (6.0 g), and 57% hydroiodic acid (35 mL) was stirred for 16 hours with heating to reflux. The reaction mixture was cooled to room temperature, poured into an aqueous solution of sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 85:15'chloroform:methanol = 90:10) to give the compound 3 (5.3 g) as a pale yellow solid. MS (APCI): 313 [M+H]+To a round bottom flask was added To a stirred solution of 4, 5-dichloropyridazin-3(2H)-one (2.0 g, 12.12 mmol), benzyl bromide (1.586 ml, 13.34 mmol), and potassium carbonate (2.178 g, 15.76 mmol) were dissolved in DMF (6 mL). The mixture was heated to 50C in an oil bath and stirred o/n. The reaction was diluted with H2O (50 mL) and extracted with EtOAc (50 mL). The aqueous layer was extracted again with EtOAc (50 mL). The combined organic portions were washed once with H2O (100 mL). The resulting organic layer was dried and concentrated to yield a precipitate that was triturated with Et2O/Hexanes (3:1), filtered, and dried. The resulting solid was dissolved in dry dioxane (10 mL) and the solution cooled on an ice bath. Sodium methoxide (25% in MeOH) (3.31 ml, 12.12 mmol) was added slowly. The reaction was removed from the ice bath and stirred at r.t. for 1 h during which time the solution turned yellow and cloudy. After this time the reaction was diluted with water (20 mL). The reaction was partitioned (50 mL each of water and EtOAc/Dioxane) and the aqueous layer extracted again with EtOAc (50 mL). The combined organic portions were dried, concentrated, and the product purified by chromatography (0, 10, 20% EtOAc/Hexanes) to provide 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one (2.49 g, 9.73 mmol, 88 % yield), as a colorless oil. LCMS m/z = 251 [M+H]+To a round bottom flask was added 4, 5-dichloropyridazin-3(2H)-one (50 gm, 303.03 mmol), DMF (150 ml), K2CO3 (46 gm, 333.33) and benzyl bromide(51.83 gm, 303.03 mmol). The reaction was stirred at rt for 16 hrs. After this time, the reaction mixture was slowly poured into water (500 ml) and a solid precipitate formed. The slurry was stirred at rt for 1 hr. After this time, the reaction mixture was filtered and the solid was collected. The solid was dried under vacuum to give product To a solution of dichloropyridazinone (50.0 g, 303.0 mmol) in DMF (200 mL) was added K2CO3 (50.3 g, 364.0 mmol) at RT under vigorous stirring. Benzylbromide (40.0 mL, 336.0 mmol) was added in rapid drops via a syringe. The resulting suspension was stirred at 50 C. for 1 h until all the pyridazinone was consumed as judged by HPLC. The reaction mixture was then poured into water (400 mL). The resultant suspension was stirred for 15 min at RT, and then filtered. The collected solid was rinsed thoroughly with water until no color was apparent in the filtrate. The solid was dried in a vacuum oven at 50 C. overnight to give the title compound, Preparation 3-1); 2-Benzyl-4, 5-dichloro-2H-pyridazin-3-one To a mixture of 4, 5-dichloro-2H-pyridazin-3-one (3.3 g, 20.0 mmol) and Cs2CO3(9.77 mg, 1.5 eq) were added DMF (15 mL) and benzyl bromide (3.10 mL, 1.3 eq), which 186A. A mixture of commercially available 4, 5-dichloropyridazin3(2H)-one (18 mmol), benzyl bromide (19 mmol), potassium carbonate (45 mmol), tetrabutylammonium bromide (1 mmol) and acetonitrile (45 mL) is stirred and heated under reflux for 1 h. After cooling, the solvent is evaporated under reduced pressure. The residue is purified by filtration on a small silica gel column eluting with 10% EtOAc/Hexane to give compound 186a as a white powder (81%). [M+H]+=256.3.INTERMEDIATE 1; 3-Bromo-7-(4-fluorophenyl)imidazo[ 1 , 2-6]pyridazine; Step 1. 2-Benzyl-4, 5-dichloropyridazin-3(2H)-one; A stirred mixture of 4, 5-dichloropyridazin-3(2/i)-one (26, 7 g, 160 ratnol), benzyl bromide (19.3 mL, 160 mmol)? tetrabutylammonium bromide (2.61 g, 8.10 mmol), and potassium carbonate (56.O g, 405 mmol) in acetonitrile (405 mL) was heated to reflux for 2 h. The mixture was cooled to room temperature, filtered through a fritted glass, concentrated, and purified by flash chromatography to afford the title compound as a white solid. 1H NMR (500 MHz, CD3SOCD3) delta 8.23 (S5 1H); 7.27-7.35 (m, 5H); 5.27 (s, 2H). LRMS (APCI) calc'd for (CI iH9Cl2N2O) [M+Hf, 255.0; found 255.0.4, 5-dichloropyridazin-3(2H)-one (2.0 g, 12.12 mmol), benzyl bromide (1.586 ml, 13.34 mmol), and potassium carbonate (2.178 g, 15.76 mmol) were dissolved in DMF (6 mL). The mixture was heated to 50C in an oil bath and stirred o/n. The reaction was diluted with H2O (50 mL) and extracted with EtOAc (50 mL). The aqueous layer was extracted again with EtOAc (50 mL). The combined organic portions were washed once with H2O (100 mL). The resulting organic layer was dried and concentrated to yield a precipitate that was triturated with Et2O/Hexanes (3:1), filtered, and dried.(1) The compound 1 (10 g), benzyl bromide (10.9 g), potassium carbonate (21 g), and tetrabutylammonium bromide (1.0 g) were suspended in acetonitrile (150 mL), and the reaction mixture was stirred for 2 hours under argon atmosphere with heating to reflux. The reaction mixture was cooled to room temperature, and an insoluble substance was filtered off, washed with ethyl acetate, and then the filtrate was concentrated under reduced pressure. The resultant residue was dissolved in chloroform, and the solution was filtered with a silica gel pad (eluent: chloroform). The eluate was concentrated under reduced pressure, and the resultant crystalline residue was suspended and washed in a mixed solvent of ethyl acetate-hexane, taken by filtration, and dried to give the compound 2 (12.2 g) as a pale yellow solid. MS (APCI): 255/257 [M+H]+To a solution of 2-benzyl-4, 5-dichloro-2H-pyridazine-3-one (22.31 g, 87.47 mmol), prepared as described in Example 244A, in dry MeOH (175 mL) at 0 C., was added dropwise a solution of sodium methoxide in methanol (25% weight in MeOH, 25 mL). The mixture was slowly warmed up to room temperature and stirred for 18 h. The reaction mixture was diluted with methylene chloride (200 mL) and filtered. The filtrate was concentrated to afford the title compound, 2-benzyl-4-chloro-5-methoxypyridazin-3(2H)-one (22.2 g) which was >95% pure as judged by HPLC and was used in the next reaction, Example 354B, without further purification.REFERENCE EXAMPLE 6

Molecular Weight:255.10
XLogP3:2.6
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:254.0013683
Monoisotopic Mass:254.0013683
Topological Polar Surface Area:32.7
Heavy Atom Count:16
Complexity:346
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes