Diisopropylethylamine → 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-quinoline

温度

100 °C

A solution of 4-chloro-6-bromoquinoline (1.6 g, 6.63 mmol), diisopropylethylamine (1.93 mL, 11.05 mmol) in DMF (20 mL) under nitrogen was degassed by bubbling in nitrogen for 30 min. Tris(dibenzylideneacetone)dipalladium (506 mg, 0.552 mmol), Xantphos (640 mg, 1.105 mmol), and 6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (1.0 g, 5.525 mmol) were added. The reaction mixture was stirred at 100° C. for 18 h. The reaction mixture was cooled to room temperature, and partitioned between 1 N aqueous NaOH and 10% methanol/di-chloromethane. The aqueous layer was extracted with 10% methanol/dichloromethane (3×) and the combined organic layers were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-6% methanol/dichloromethane afforded 468 mg of a (1:1) mixture of 4-chloro-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline and 6-bromo-4-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline as a beige solid. The (1:1) mixture (70 mg) was dissolved in DMF (0.5 mL), and 4-methyl-4H-[1,2,4]triazole-3-thiol (12 mg, 0.1 mmol) was added. The reaction mixture was stirred at 60° C. for 21 h then at 80° C. for 25 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between 1 N aqueous NaOH and 10% methanol/dichloromethane. The aqueous layer was extracted with 10% methanol/dichloromethane (2×) and the combined organic layers were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-10% methanol/dichloromethane afforded 16 mg of 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-quinoline as a cream color solid (78% yield).

1. customby bubbling in nitrogen for 30 min
2. temperatureThe reaction mixture was cooled to room temperature
3. custompartitioned between 1 N aqueous NaOH and 10% methanol/di-chloromethane
4. extractionThe aqueous layer was extracted with 10% methanol/dichloromethane (3×)
5. customPurification by flash chromatography on silica gel using a gradient of 0-6% methanol/dichloromethane
6. customafforded
7. stirringThe reaction mixture was stirred at 60° C. for 21 h
8. waitat 80° C. for 25 h
9. temperatureThe reaction mixture was cooled to room temperature
10. concentrationconcentrated in vacuo
11. customThe residue was partitioned between 1 N aqueous NaOH and 10% methanol/dichloromethane
12. extractionThe aqueous layer was extracted with 10% methanol/dichloromethane (2×)
13. customPurification by flash chromatography on silica gel using a gradient of 0-10% methanol/dichloromethane

ORDレコード

ord-7e9db9b9f5b84d13bb7337877252b527

出典データセット

uspto-grants-2013_08

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08507489B2