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

HRID 40388

反応式

HRID 40388 の反応式
Br[C:2]1[S:6][N:5]=[C:4]([CH3:7])[CH:3]=1.CC#N.C(=O)=O.Cl[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([CH:24]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[CH:31][CH:30]=[CH:29]4)[CH3:25])=[N:22][N:23]=2)[N:20]=1>C1COCC1.CN(C)C(=O)C.[Cl-].[Zn+2].[Cl-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[CH3:7][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([CH:24]([C:26]4[CH:27]=[C:28]5[C:33](=[CH:34][CH:35]=4)[N:32]=[CH:31][CH:30]=[CH:29]5)[CH3:25])=[N:22][N:23]=3)[N:20]=2)[S:6][N:5]=1

参加物

9

反応物 3

HCID 6009595-Bromo-3-methylisothiazoleHCID 249687116-(1-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinolineHCID 86587134Acetonitrile dry ice

生成物 1

HCID 441805966-(1-(6-(3-Methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline

試薬・触媒・溶媒 5

HCID 3007855Zincchloride触媒HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 129828017Ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane;iron(2+);(2,3,4,5-tetraphenylcyclopenta-1,4-dien-1-yl)benzene触媒HCID 8028Tetrahydrofuran溶媒2 回HCID 31374Dimethylacetamide溶媒

反応条件

温度
-45 °C

実験手順

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, 1 M in THF). The mixture was stirred at −45° C. for 20 minutes and to this was added zinc chloride, 0.5 M 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 (0) (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 hours 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 further extracted with 100 mL EtOAc. The combined organics 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 afford a red solid. MS (ESI pos. ion) m/z: 373 (MH+). Calc'd exact mass for C20H16N6S: 372.

後処理

  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 hours
  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 further extracted with 100 mL EtOAc
  8. dry with materialThe combined organics 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)
  11. customto give
  12. customafford a red solid

出典と根拠

ORDレコード
ord-bf75e055e03147b1b45b8862ae4bb91c
出典データセット
uspto-grants-2013_09
特許番号
US08524900B2

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