METHYL 6-OXO-1,6-DIHYDROPYRIDAZINE-3-CARBOXYLATE

A. To a methanol solution of 6-oxo-1 , 6-dihydropyridazine-3-carboxylic acid monohydrate (5.00 g, 31.6 mmol) was added thionyl chloride (0.36 mL, 0.59 g, 4.94 mmol). The reaction mixture was heated to reflux at 80e)The procedure described in WO2006/34440 was followed. 6-oxo-1, 6-dihydropyridazine-3-carboxylic acid monohydrate (8.91 g, 56.4 mmol) was taken up in 90 mL methanol. Thionyl chloride (0.66 mL, 1.1 g, 9.0 mmol) was added, and the mixture was refluxed overnight, until LC-MS analysis indicated that most or all of the acid had been esterified. The reaction mixture was cooled to room temperature, then chilled in the fridge, and the white crystalline precipitate was collected and dried under vacuum. 7.07 g, 81percent yield: Method 24 Manganese dioxide (3.12 g, 35.9 mmol) was suspended as a slurry in toluene (10 mL) and pyridine (720 μL). A sample of S47 (280 mg, 1.8 mmol) was added portionwise to the stirring solution and the resulting mixture was warmed at 65 °C until the disappearance of all starting material (6 h). The warm solution was filtered through a pad of Celite that was washed with several hundred milliliters of hot EtOAc and THF. The organic wash was evaporated to afford a yellowish solid which was used without further purification (160 mg, 58percent): A. To a methanol solution of 6-oxo-1 , 6-dihydropyridazine-3-carboxylic acid monohydrate (5.00 g, 31.6 mmol) was added thionyl chloride (0.36 mL, 0.59 g, 4.94 mmol). The reaction mixture was heated to reflux at 80e)The procedure described in WO2006/34440 was followed. 6-oxo-1, 6-dihydropyridazine-3-carboxylic acid monohydrate (8.91 g, 56.4 mmol) was taken up in 90 mL methanol. Thionyl chloride (0.66 mL, 1.1 g, 9.0 mmol) was added, and the mixture was refluxed overnight, until LC-MS analysis indicated that most or all of the acid had been esterified. The reaction mixture was cooled to room temperature, then chilled in the fridge, and the white crystalline precipitate was collected and dried under vacuum. 7.07 g, 81percent yield: Method 24 Manganese dioxide (3.12 g, 35.9 mmol) was suspended as a slurry in toluene (10 mL) and pyridine (720 μL). A sample of S47 (280 mg, 1.8 mmol) was added portionwise to the stirring solution and the resulting mixture was warmed at 65 °C until the disappearance of all starting material (6 h). The warm solution was filtered through a pad of Celite that was washed with several hundred milliliters of hot EtOAc and THF. The organic wash was evaporated to afford a yellowish solid which was used without further purification (160 mg, 58percent): To a solution of methyl 6-oxo-1 , 6-dihydropyridazine-3-carboxylate (2.5 g, 16.2 mmol) in A/, A/-dimethylformamide (60.0 ml_) was added 1 -bromo-2-fluoroethane (4.12 g, 32.4 mmol) and potassium carbonate (4.48 g, 32.4 mmol). The reaction mixture was stirred at 100 C for 16 h, cooled to room temperature, diluted with water (300 ml_) and extracted with ethyl acetate (80 ml_ c 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 2/1 ) to afford methyl 1 -(2-fluoroethyl)-6-oxo-1 , 6-dihydropyridazine-3-carboxylate (2.2 g, 1 1 .0 mmol, 67.8%) as a white solid. LCMS (ESI) m/z: 201 .1 [M+H]+.To a solution of methyl 6-oxo-1 , 6-dihydropyridazine-3-carboxylate (2.0 g, 13.0 mmol) in A/, A/-dimethylformamide (60 ml_) at room temperature was added 3-iodooxetane (4.77 g, 26.0 mmol) and potassium carbonate (3.58 g, 26.0 mmol). The reaction mixture was stirred at 100 C for 16 h, cooled to room temperature, diluted with water (300 ml_) and extracted with ethyl acetate (80 ml_ c 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 3:1 ) to afford methyl 1 -(oxetan-3-yl)-6-oxo-1 , 6-dihydropyridazine-3-carboxylate (1 .5 g, 7.14 mmol, 55%) as a white solid. LCMS (ESI) m/z: 21 1 .1 [M+H]+.To a solution of methyl 6-oxo-1 , 6-dihydropyridazine-3-carboxylate (1 .1 g, 7.14 mmol) in A/, A/-dimethylformamide (20 ml_) at room temperature was added potassium carbonate (1 .97 g, 14.3 mmol) and iodoethane (2.23 g, 14.3 mmol). The reaction mixture was stirred at 70 C for 16 h, cooled to room temperature, diluted with water (300 ml_) and extracted with ethyl acetate (80 ml_ c 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford methyl 1 -ethyl-6-oxo-1 , 6-dihydropyridazine-3-carboxylate (1 .0 g, 5.49 mmol, 76.9%) as a white solid. LCMS (ESI) m/z: 183.1 [M+H]+.To a solution of methyl 6-oxo-1 , 6-dihydropyridazine-3-carboxylate (1 .0 g, 6.49 mmol), potassium carbonate (2.68 g, 19.5 mmol) in A/, A/-dimethylformamide (15.0 ml_) was added 1 -iodopropane (1 .65 g, 9.74 mmol). The reaction mixture was heated to 60 C and stirred for 3 h. The reaction solution was dissolved in ethyl acetate (50 ml_) and washed with water (50 ml_), dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (silica gel, petroleumether/ethyl acetate = 1 /1 ) to afford methyl 6-oxo-1 -propyl-1 , 6-dihydropyridazine-3-carboxylate (0.700 g, 3.57 mmol, 55%) as a white solid. LCMS (ESI) m/z: 197.2 [M+H]+.

Molecular Weight:154.12
XLogP3:-0.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:154.03784206
Monoisotopic Mass:154.03784206
Topological Polar Surface Area:67.8
Heavy Atom Count:11
Complexity:255
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes