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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 800C for 16 h. The product crystallized after the reaction mixture was cooled down to ambient temperature. The crystals were collected and washed with methanol and the mother liquor was concentrated and crystallized again. The total amount of product isolated was 4.954 g (100percent yield).
92%
for 2 h; Reflux
e) Synthesis of methyl 6-oxo-1,6-dihydropyridazine-3-carboxylate 10.00 g of 6-oxo-1,6-dihydropyridazine-3-carboxylic acid, monohydrate, are suspended in 160 ml of methanol in a 500 ml flask provided with magnetic stirrer and drying tube, 5.84 ml of thionyl chloride are carefully added with stirring, and the mixture is boiled under reflux on a steam bath for 2 h, giving a clear solution. The solution is then cooled, the crystals formed are filtered off with suction and dried (K1). The mother liquor was stripped off to dryness, the residue was stirred with a little methanol, filtered off with suction and dried (K2). K1 and K2 are combined. Yield: 10.72 g=56.25 mmol=92percent; TLC: CH2Cl2: MeOH=95:5; Rf approx. 0.3 m.p. 191-193° HPLC: RT=1.36 min.
81%
Reflux
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: 1H NMR (DMSO-d6) δ 13.60 (br. s., 1H), 7.82 (d, J=10.1 Hz, 1H), 6.96 (d, J=9.9 Hz, 1H), 3.84 (s, 3H).
66%
at 70℃; for 16 h; Inert atmosphere
Method 24 Methyl 6-oxo-1,6-dihydropyridazine-3-carboxylate To a solution of 6-oxo-1,6-dihydropyridazine-3-carboxylic acid (1.80 g, 12.85 mmol) in methanol (24 mL) was added thionyl chloride (6 mL, 82.71 mmol) at room temperature. The resulting solution was then stirred for 16 h at 70° C. When the reaction was done, it was quenched by the addition of water (30 mL). The resulting mixture was extracted with ethyl acetate (60 mL*3). The organic phases were combined, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0percent to 80percent gradient) to yield methyl 6-oxo-1,6-dihydropyridazine-3-carboxylate as a light yellow solid (1.31 g, 66percent). MS: m/z=155.0 [M+H]+.
With pyridine; manganese(IV) oxide In toluene at 65℃;
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): 1H NMR (CDCl3, 300 MHz) δ 7.92 (d, IH, J = 9.9 Hz), 7.02 (d, IH, J = 9.8 Hz), 3.99 (s, 3H); HRMS-ESI-TOF m/z 155.0450 ([M+H+, C6H6N2O3 requires 155.0451).
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4392 - 4403
[2] Patent: WO2010/5572, 2010, A2, . Location in patent: Page/Page column 85
With trichlorophosphate; for 2.5h;Heating / reflux;
B. A mixture of 6-hydroxypyridazine-3-carboxylic acid methyl ester obtained above and phosphorous oxychloride were carefully heated to reflux and maintained there for 2.5 h. The reaction mixture was then cooled and evaporated in vacuo to remove excess phosphorylchloride, and the residue was then poured into ice water. The precipitate was collected by filtration, washed with saturated NaHCO3 and water, and dried under vacuum to yield the product as a yellow solid (4.359 g, 79% yield).
68%
With trichlorophosphate; at 110℃; for 5h;
A sample of S48 (333 mg, 2.16 mmol) was dissolved in POCl3 (3.2 mL) and warmed at 110 0C for 5 h. Upon disappearance of starting material, the solution was cooled to room temperature and diluted with EtOAc. The organic layer was poured onto ice and extracted. The organic layer was subsequently washed with saturated aqueous NaCl. The aqueous layer was back extracted with EtOAc and the combined organic phase was dried over Na2SO4 and filtered. The solution was evaporated and the residue was purified by flash chromatography (50% EtOAc-hexanes) to afford the title compound as a yellowish solid (254 mg, 68%): 1H NMR (CDCl3, 400 MHz) delta 8.17 (d, IH, J = 8.8 Hz), 7.68 (d, IH, J = 8.8 Hz), 4.08 (s, 3H); 13C NMR (CDCl3, 100 MHz) 6 159.5, 150.8, 129.8, 128.9, 53.7.
B. A mixture of 6-hydroxypyridazine-3-carboxylic acid methyl ester obtained above and phosphorous oxychloride were carefully heated to reflux temperature and maintained there for 2.5 h. The reaction mixture was then cooled and evaporated in vacuo to remove excess phosphorylchloride, and the residue was then poured into ice water. The precipitate was collected by filtration, washed with saturated NaHCO3 and water, and dried under vacuum to yield the product as a yellow solid (4.359 g, 79percent yield).
50%
With trichlorophosphate; In toluene; at 120℃;
POCl3 (5.60g, 0.036mol) was added to a solution of Example 65A (2.8g, 0.018mol) in toluene at room temperatureand the mixture was heated to 120°C and stirred for 2 hours. The solvent was evaporated to dryness, water (20mL)was added and the mixture was extracted with ethyl acetate (15mL 3 3). The combined organic layer was washed withbrine, dried over sodium sulfate, filtered and the filtrate was evaporated. The residue was purified by column chromatographyto give the title compound (1.5g, yield 50percent). 1H NMR (CHLOROFORM-d, Bruker Avance 400 MHz) ppm 8.17(d, J=8.8 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 4.09 (s, 3H).
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