Potassium Phosphate, Tribasic → (3R,4R)-tert-butyl 4-((3-carbamoyl-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-3-ethylpiperidine-1-carboxylate

HRID 877758ノート

反応式

HRID 877758 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]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@H:12]3[CH2:24][CH3:25])=[C:8]([C:26](=[O:28])[NH2:27])[CH:7]=[N:6][N:5]2[CH:29]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.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:26]([C:8]1[CH:7]=[N:6][N:5]2[CH:29]=[C:2]([C:34]3[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][C@@H:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][C@H:12]1[CH2:24][CH3:25])(=[O:28])[NH2:27]

参加物

6

反応物 3

HCID 62657Potassium Phosphate, TribasicHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 68291228(3R,4R)-tert-butyl 4-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-3-ethylpiperidine-1-carboxylate

生成物 1

HCID 68291150(3R,4R)-tert-butyl 4-((3-carbamoyl-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-3-ethylpiperidine-1-carboxylate収率 83%

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 (3R,4R)-tert-butyl 4-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-3-ethylpiperidine-1-carboxylate from Step 1 of Example 125 (349 mg, 0.748 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (467 mg, 2.245 mmol) and PdCl2(dppf)-CH2Cl2 Adduct (61.1 mg, 0.075 mmol) were added dioxane (5.0 ml) and a 2M solution of potassium phosphate (1.1 ml, 2.245 mmol). The suspension was purged with nitrogen for 5 minutes. The vial was sealed and heated at 100° C. for 1 hr. The reaction mixture was diluted with methanol (10 ml), filtered, and concentrated. The residue was partitioned between ethyl acetate (50 ml) and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified via medium pressure chromatography (silica gel column, EtOAc/hexanes eluent, 0-100% gradient elution) to yield (3R,4R)-tert-butyl 4-((3-carbamoyl-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-3-ethylpiperidine-1-carboxylate (288 mg, 0.618 mmol, 83% yield) as a white solid. LCMS (Method K) m/z 468.4 ([M+H]+).

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
  6. customThe residue was partitioned between ethyl acetate (50 ml) and water
  7. washThe organic layer was washed with brine
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe crude product was purified via medium pressure chromatography (silica gel column, EtOAc/hexanes eluent, 0-100% gradient elution)

出典と根拠

ORDレコード
ord-8d55e352360a4cb29eae3b0930fea127
出典データセット
uspto-grants-2015_03
特許番号
US08987268B2

反応ノート

読み込み中…