With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.933-76-6,4,5-Dichloro-2-methylpyridazin-3(2H)-one,as a common compound, the synthetic route is as follows.,933-76-6
b) Trifluoro-methanesulphonic acid 2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl ester (4b)[0242][0243]3.13 g (27.93 mmoles) of potassium tertbutylate is placed in 25 ml of tetrahydrofuran. At 0 C., a solution of 1.16 ml (27.93 mmoles) of methanol in 10 ml of tetrahydrofuran is added. The mixture is stirred at 0 C. for 10 min. This solution is added drop by drop to mixture cooled to 0 C. of 5 g (27.93 mmoles) of 4,5-dichloro-2-methyl-2H-pyridazin-3-one solubilised in 40 ml of tetrahydrofuran, the temperature of the medium remains below 3 C. during the addition. The mixture is stirred for 1 hour at 0 C., and for 3 hours at ambient temperature. The medium is taken up with dichloromethane and washed with water. After drying on Na2SO4, the organic phase is concentrated to dryness. The residue obtained is purified by flash chromatography (CH2Cl2-AcOEt: 95-5). 4.45 g of white solid is obtained (yield: 91%). TLC silica gel 60 F 254 Merck, CH2Cl2-AcOEt: 90-10, Rf=0.55. 3.37 g (19.3 mmoles) of this solid is placed in 150 ml of tetrahydrofuran in the presence of 2.7 ml (19.3 mmoles) of triethylamine and 0.67 g of 10% palladium on carbon. The medium is placed under hydrogen pressure (7 bar) and left under stirring for 48 hours. After filtering the reaction medium on celite, the filtrate is concentrated. The residue obtained is purified by flash chromatography (CH2Cl2-AcOEt gradient: 90-10 to 10-90). 2.35 g of white solid is obtained (yield: 86%). TLC silica gel 60 F 254 Merck, CH2Cl2-AcOEt: 50-50, Rf=0.17. 2.35 g (16.7 mmoles) of this solid is placed in 250 ml of water in the presence of 9.6 g (16.7 mmoles) of potassium hydroxide. The mixture is heated to 100 C. for 24 hours. The medium cooled to 0 C. is brought to pH 1-2 by adding an aqueous concentrated hydrochloric acid solution. After concentration to dryness, the residue is taken up with a dichloromethane/methanol mixture, the minerals are removed by filtration and the filtrate is concentrated to dryness. The residue obtained is purified by flash chromatography (CH2Cl2-MeOH: 95-5). 1.94 g of pink solid is obtained (yield: 92%). TLC silica gel 60 F 254 Merck, CH2Cl2-MeOH: 80-20, Rf=0.49. 1 g (7.92 mmoles) of this solid is placed in nitrogen in 15 ml of dichloromethane. At -9 C., 1.45 ml (10.3 mmoles) of triethylamine is added, followed by 1.8 ml (10.7 mmoles) of trifluoromethanesulphonic anhydride. After stirring for 20 min to -7 C., 5 ml of an aqueous 1N hydrochloric acid solution is added. The organic phase is washed with water, and with an aqueous 1% sodium bicarbonate solution, followed by a saturated NaCl solution. After drying on Na2SO4, the organic phases are concentrated to dryness. 1.9 g of intermediate 4b is obtained in pink solid form (yield: 93%).[0244]TLC silica gel 60 F 254 Merck, CH2Cl2-MeOH: 95-5, Rf=0.78.
933-76-6 4,5-Dichloro-2-methylpyridazin-3(2H)-one 120462, apyridazine compound, is more and more widely used in various fields.
Reference£º
Patent; PIERRE FABRE MEDICAMENT; Leroy, Isabelle; Dupont-Passelaigue, Elisabeth; Mialhe, Samuel; Junquero, Didier; Valeille, Karine; US2013/40928; (2013); A1;,
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