Ammonia → 4-(1-methylpiperidin-4-yloxy)-2-(5-methylthiophen-2-yl)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene

HRID 1773885ノート

反応式

HRID 1773885 の反応式
I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1.C[C:25]1[CH:26]=[C:27](B2OC(C)(C)C(C)(C)O2)[S:28][CH:29]=1.[F-].[Cs+].N.O1CCOC[CH2:43]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([O:12][CH:9]2[C:8]3[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=3[CH2:6][CH2:5][N:4]3[C:10]2=[N:11][C:2]([C:29]2[S:28][C:27]([CH3:43])=[CH:26][CH:25]=2)=[CH:3]3)[CH2:14][CH2:15]1

参加物

8

反応物 5

HCID 222AmmoniaHCID 25953Cesium fluoride2 回HCID 312751,4-DioxaneHCID 104435924,4,5,5-Tetramethyl-2-(4-methylthiophen-2-yl)-1,3,2-dioxaborolaneHCID 726957782-iodo-4-(1-methyl piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene

生成物 1

HCID 726944724-(1-methylpiperidin-4-yloxy)-2-(5-methylthiophen-2-yl)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene

試薬・触媒・溶媒 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒2 回HCID 962Water溶媒

反応条件

温度
100 °C

実験手順

To a solution of 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 2A) (50 mg, 0.12 mmoles) in 1,4-dioxane (2.5 mL) in a screw-capped vial under argon are added 4-methylthiophene-2-boronic acid pinacol ester (40 mg, 0.18 mmole), PdCl2(dppf)2 (6.7 mg, 12 μmole), CsF (36 mg, 0.24 mmoles). The reaction mixture is heated at 100° C. overnight. As the reaction is not completed, CsF (18 mg, 0.12 mmole) and PdCl2(dppf)2 (6.7 mg, 12 μmole) are added and the reaction mixture is heated at 100° C. overnight. Water is added, pH is made alkaline by adding concentrated ammonia solution and the aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (98:2:0.2) to (96.5:3.5:0.35) followed by a purification on a preparative TLC over silica gel eluting with (9:1:0.1) to give 4-(1-methylpiperidin-4-yloxy)-2-(5-methylthiophen-2-yl)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.

後処理

  1. temperaturethe reaction mixture is heated at 100° C. overnight
  2. extractionthe aqueous phase is extracted three times with CH2Cl2
  3. dry with materialThe organic phase is dried over magnesium sulphate
  4. filtrationfiltered
  5. customthe solvent is removed under reduced pressure
  6. customThe residue is purified by silica gel chromatography
  7. customfollowed by a purification on a preparative TLC over silica gel eluting with (9:1:0.1)

出典と根拠

ORDレコード
ord-b5154dcbfaa347c3887d36f464288975
出典データセット
uspto-grants-2016_02
特許番号
US09255101B2

反応ノート

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