5-Bromo-3-methylisothiazole → 6-(1-(6-(3-Methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline

온도

-45 °C

To a solution of 5-bromo-3-methylisothiazole (1.00 g, 5.6 mmol) in 10 mL of THF at −45° C. (CH3CN/dry ice) was added isopropylmagnesium chloride LiCl complex (7.9 ml, 7.9 mmol) (LiCl complex, 1M in THF). The mixture was stirred at −45° C. for 20 minutes and was added zinc chloride, 0.5m in thf (17 ml, 8.4 mmol) slowly via a syringe. The mixture was then warmed up to rt and continued to stir for additional 30 minutes. 6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (0.5787 g, 1.9 mmol), tris(dibenzylideneacetone)dipalladium (o) (0.51 g, 0.56 mmol) and Q-Phos (0.65 g) in 15 mL of N,N-dimethyl acetamide was added to the reaction mixture. The reaction was warmed up to 50° C. for 6 h and was quenched with 50 mL of satd. NH4Cl aq. solution. The mixture was extracted with 150 mL of EtOAc and the organic phase was washed with 60 mL of brine. The aqueous phases were extracted with 100 mL EtOAc again. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH in EtOAc) to give red solid as desired product 6-(1-(6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline. MS (ESI, pos. ion) m/z: 373.2 (M+1).

1. temperatureThe mixture was then warmed up to rt
2. stirringto stir for additional 30 minutes
3. temperatureThe reaction was warmed up to 50° C. for 6 h
4. customwas quenched with 50 mL of satd
5. extractionThe mixture was extracted with 150 mL of EtOAc
6. washthe organic phase was washed with 60 mL of brine
7. extractionThe aqueous phases were extracted with 100 mL EtOAc again
8. dry with materialThe combined organic phases were dried over Na2SO4
9. concentrationconcentrated in vacuo
10. customThe residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH in EtOAc)

ORD 기록

ord-d0d8005de9ab4b179aabb396a7613700

출처 데이터셋

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08524900B2