Potassium Phosphate, Tribasic → 6-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-4-(((3R,4R)-3-ethyl-1-(methylsulfonyl)piperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 877757

反応式

HRID 877757 の反応式
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:16][CH2:15][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]3[CH2:21][CH3:22])=[C:8]([C:23]([NH2:25])=[O:24])[CH:7]=[N:6][N:5]2[CH:26]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH2:40][CH2:41][C:42]#[N:43])[CH:39]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].C(Cl)Cl.O1CCOCC1>[C:42]([CH2:41][CH2:40][N:38]1[CH:39]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9]([NH:10][C@@H:11]4[CH2:16][CH2:15][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]4[CH2:21][CH3:22])=[C:8]([C:23]([NH2:25])=[O:24])[CH:7]=[N:6][N:5]3[CH:26]=2)[CH:36]=[N:37]1)#[N:43]

参加物

6

反応物 3

HCID 62657Potassium Phosphate, TribasicHCID 569657334-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-propanenitrileHCID 682911046-bromo-4-(((3R,4R)-3-ethyl-1-(methylsulfonyl)piperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide

生成物 1

HCID 682907846-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-4-(((3R,4R)-3-ethyl-1-(methylsulfonyl)piperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide収率 56.9%

試薬・触媒・溶媒 2

HCID 178418807HCID 178418807、化合物触媒HCID 312751,4-Dioxane溶媒

反応条件

温度
100 °C

実験手順

To a vial charged with 6-bromo-4-(((3R,4R)-3-ethyl-1-(methylsulfonyl)piperidin-4-yl)amino) pyrrolo[1,2-b]pyridazine-3-carboxamide (15 mg, 0.034 mmol), 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (16.68 mg, 0.068 mmol) and PdCl2(dppf)-CH2Cl2 Adduct (3.61 mg, 4.42 μmol) were added 1,4-dioxane (225 μl) and a 2M solution of potassium phosphate (50.6 μl, 0.101 mmol). The suspension was purged with nitrogen for 5 minutes. The vial was sealed and heated at 100° C. for 2 hrs. The reaction mixture was diluted with methanol (10 ml), filtered, and concentrated under reduced pressure. The crude product was purified via preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm). The collected fractions were combined and dried via centrifugal evaporation, yielding 6-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-4-(((3R,4R)-3-ethyl-1-(methylsulfonyl)piperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (9.3 mg, 0.019 mmol, 56.9% yield) as a white solid. 1H NMR (500 MHz, 1:1 Chloroform-d/Methanol-d4) δ 8.12 (s, 1H), 7.93 (s, 1H), 7.82 (s, 1H), 7.75 (d, J=1.5 Hz, 1H), 6.91 (d, J=1.0 Hz, 1H), 4.48 (t, J=6.4 Hz, 2H), 4.11 (td, J=8.4, 4.0 Hz, 1H), 3.79-3.61 (m, 2H), 3.25-3.17 (m, 1H), 3.05 (t, J=6.4 Hz, 2H), 2.97-2.85 (m, 4H), 2.43-2.34 (m, 1H), 1.88-1.76 (m, 3H), 1.51-1.40 (m, 1H), 1.04-0.97 (m, 3H). LCMS (Method K) m/z 485.0 ([M+H]+). HPLC (Method F) Rt: 1.14 min.

後処理

  1. customThe suspension was purged with nitrogen for 5 minutes
  2. customThe vial was sealed
  3. additionThe reaction mixture was diluted with methanol (10 ml)
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe crude product was purified via preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm)
  7. customdried via centrifugal evaporation

出典と根拠

ORDレコード
ord-83d8bd8775094ff99710a897992b227b
出典データセット
uspto-grants-2015_03
特許番号
US08987268B2

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