Cesium carbonate → 1-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarbonitrile

HRID 410669

反応式

HRID 410669 の反応式
[CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[S:33][C:32]([C:34]2([C:40]#[N:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[N:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CCOC(C)=O.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]>[CH3:1][C:2]1[CH:7]=[C:6]([C:29]2[S:33][C:32]([C:34]3([C:40]#[N:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[N:31][CH:30]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)[CH:3]=1

参加物

7

反応物 4

HCID 10796Cesium carbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 58456089N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine2 回HCID 674297131-(5-Bromothiazol-2-yl)cyclohexanecarbonitrile

生成物 1

HCID 584561351-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarbonitrile収率 82.6%

試薬・触媒・溶媒 2

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 8857Ethyl Acetate溶媒

反応条件

温度
100 °C

実験手順

N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 3, 134 mg, 0.35 mmol), the compound from Step 2 (96 mg, 0.35 mmol), cesium carbonate (346 mg, 1.06 mmol), X-Phos (16.9 mg, 0.035 mmol) and Pd2(dba)3 (16.2 mg, 0.018 mmol) were placed in a flask and evacuated/purged with N2 for three times. Dioxane (1.5 mL) and water (0.15 mL) were degassed by undersurface N2 bubbling and added to the reaction vessel. The resulting reaction mixture was stirred at 100° C. for 5 hrs and then diluted with EtOAc (5 mL), washed with brine (5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (gradient elution 7% to 60% EtOAc in Hexanes) to give the title compound (128 mg, 0.289 mmol, 82% yield) as an off white foam. MS ESI: [M+H]+ m/z 444.1. 1H NMR (500 MHz, CD3-OD) δ 8.72 (d, J=5.0, 1H), 8.06 (bs, 1H), 8.00 (s, 1H), 7.48 (bs, 1H), 7.16 (bs, 1H), 7.14 (d, J=4.9, 1H), 2.41-2.37 (m, 5H), 2.06-2.00 (m, 2H), 1.94-1.89 (m, 2H), 1.85-1.73 (m, 3H), 1.40 (m, 1H). rhSYK activity=++.

後処理

  1. customevacuated/purged with N2 for three times
  2. customDioxane (1.5 mL) and water (0.15 mL) were degassed by undersurface N2 bubbling
  3. additionadded to the reaction vessel
  4. customThe resulting reaction mixture
  5. washwashed with brine (5 mL)
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by column chromatography on silica (gradient elution 7% to 60% EtOAc in Hexanes)

出典と根拠

ORDレコード
ord-c5883e7a6a5f493e9afa6541b86f69b7
出典データセット
uspto-grants-2014_06
特許番号
US08759366B2

関連ノート

読み込み中…