Thionyl Chloride → 6-chloropyridazine-3-carboxylic Acid

Participants

Reaction Steps

Potassium dichromate (3.3 g, 11.2 mmol) was added in portions to a solution of 3-Chloro-6-methyl-pyridazine (1.2 g, 9.3 mmol) in H2SO4 (10 ml). After addition the mixture is stirred at 50° C. on. The reaction was pored on ice and the mixture was extracted three times with diethyl ether. The combined organic phases were dried and concentrated to give the title compound (840 mg, 57%). LC-MS (M++1): 159 and 161 (3:1). Step 2: 6-Chloro-pyridazine-3-carboxylic acid methyl ester: A solution of 6-chloro-pyridazine-3-carboxylic acid (700 mg, 4.53 mmol) in thionyl chloride (15 ml) was refluxed for 3 h. The reaction was cooled to ambient temperature and evaporated to dryness. Sodium methoxide (244 mg, 4.53 mmol) in MeOH (20 ml) was added to the residue and the solution was stirred on at room temperature (rt). H2O was added and the mixture was extracted three times with DCM. The combined organic phases were dried and concentrated. Flashchromatography (SiO2, Heptane/EtOAc 1:1) afforded 560 mg (72%) of the title compound. 1H NMR (CDCl3), δ (ppm): 4.09 (s, 3 H), 7.69 (d, 1 H), 8.18 (d, 1 H).LC-MS (M++1): 173 and 175 (3:1). Step 3: 6-Methoxy-pyridazine-3-carboxylic acid methyl ester: A solution of 6-chloro-pyridazine-3-carboxylic acid methyl ester in NaOMe in MeOH (1M, 10 ml) was refluxed on. H2O was added and the mixture was extracted three times with DCM to give organic phase I. The combined organic phases I were dried and concentrated to give the title compound (40 mg, 10%). The water phase was acidified with concentrated hydrochloric acid and extracted three times with DCM to give organic phase II. The combined organic phases II were dried and concentrated to give 6-methoxy-pyridazine-3-carboxylic acid (LC-MS (M++1): 155) (230 mg, 65%). A solution of 6-methoxy-pyridazine-3-carboxylic acid in thionyl chloride (6 ml) was refluxed for 3 h. The reaction was cooled to ambient temperature and evaporated to dryness. MeOH (10 ml) was added to the residue and the solution was stirred on at rt. Saturated NaHCO3 (aq) was added and the mixture was extracted three times with DCM. The combined organic phases were dried and concentrated to give the title compound (253 mg, 100%).LC-MS (M++1): 169. Step 4: 4-Ethyl-5-(6-methoxy-pyridazin-3-yl)-2,4-dihydro-[1,2,4]triazole-3-thione: NaOMe (86 mg, 1.6 mmol) was added to a solution of 6-methoxy-pyridazine-3-carboxylic acid methyl ester (210 mg, 1.25 mmol) and 4-ethyl-3-thiosemicarbazide (190 mg, 1.6 mmol) in MeOH (6 ml) and the mixture was heated to 70° C. at 72 h. The reaction was cooled to ambient temperature and evaporated to dryness. H2O (10 ml) was added to the residue and the mixture was acidified with concentrated hydrochloric acid and the title compound 35 mg (12%) was collected by filtration. LC-MS (M++1): 238.

Provenance & Evidence