2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]amide → 2-(6-tert-butyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide

HRID 246028Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 246028
[C:1]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([Sn](CCCC)(CCCC)CCCC)=[N:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([CH:30]1[CH2:33][N:32]([C:34](=[O:58])[C@H:35]([NH:37][C:38]([C:40]2[C:48]3[C:43](=[N:44][CH:45]=[C:46](Br)[N:47]=3)[N:42]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH:41]=2)=[O:39])[CH3:36])[CH2:31]1)#[N:29]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:28]([CH:30]1[CH2:31][N:32]([C:34](=[O:58])[C@H:35]([NH:37][C:38]([C:40]2[C:48]3[C:43](=[N:44][CH:45]=[C:46]([C:9]4[C:8]5[C:12](=[CH:13][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=5)[N:11]([CH3:14])[N:10]=4)[N:47]=3)[N:42]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH:41]=2)=[O:39])[CH3:36])[CH2:33]1)#[N:29]

Komponenten

6

Edukt 2

HCID 584386122-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]amideHCID 712801066-tert-butyl-1-methyl-3-tributylstannanyl-1H-indazole

Produkt 1

HCID 712889062-(6-tert-butyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amideAusbeute 85 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)KatalysatorHCID 178418397HCID 178418397, VerbindungKatalysatorHCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

To a solution of 6-tert-butyl-1-methyl-3-tributylstannyl-1H-indazole (crude from Step 5, 217 mg, 0.45 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (125 mg, 0.25 mmol) in DMF (1.5 mL) were added Pd(PPh3)4 (14 mg, 0.012 mmol) and copper(I) iodide (9 mg, 0.05 mmol). The yellow reaction mixture was purged with argon then heated at 80° C. for 1.5 h then cooled to room temperature, quenched with sat NH4Cl and extracted with EtOAc (2×). The combined organics were washed with sat LiCl and brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 50% to 100% EtOAc/heptane to isolate 129 mg (85%) of 2-(6-tert-butyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white solid.

Aufarbeitung

  1. customThe yellow reaction mixture was purged with argon
  2. temperaturethen cooled to room temperature
  3. customquenched with sat NH4Cl
  4. extractionextracted with EtOAc (2×)
  5. washThe combined organics were washed with sat LiCl and brine
  6. dry with materialthen dried over MgSO4
  7. concentrationconcentrated
  8. customThe crude residue was purified by silica gel chromatography with 50% to 100% EtOAc/heptane

Quellen und Nachweise

ORD-Eintrag
ord-18c7db87151e41bd900ecdc9360d8162
Quelldatensatz
uspto-grants-2014_02
Patentnummer
US08658646B2

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