Potassium Phosphate, Tribasic → 2-(5,6-dichloro-indazol-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide

HRID 245967

Reaktionsgleichung

Reaktionsgleichung von HRID 245967
[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[Cl:19])[NH:15][N:14]=[CH:13]2.[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:54])[C@H:29]([NH:33][C:34]([C:36]2[C:44]3[C:39](=[N:40][CH:41]=[C:42](I)[N:43]=3)[N:38]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:37]=2)=[O:35])[CH:30]2[CH2:32][CH2:31]2)[CH2:24][CH2:23]1)#[N:21].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.C1(C)C=CC=CC=1>[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:54])[C@H:29]([NH:33][C:34]([C:36]2[C:44]3[C:39](=[N:40][CH:41]=[C:42]([N:15]4[C:16]5[C:12](=[CH:11][C:10]([Cl:9])=[C:18]([Cl:19])[CH:17]=5)[CH:13]=[N:14]4)[N:43]=3)[N:38]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:52])([CH3:51])[CH3:53])[CH:37]=2)=[O:35])[CH:30]2[CH2:31][CH2:32]2)[CH2:24][CH2:23]1)#[N:21]

Komponenten

7

Edukt 4

HCID 62657Potassium Phosphate, TribasicHCID 4123035,6-dichloro-1H-indazoleHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 866779272-iodo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide

Produkt 1

HCID 712889262-(5,6-dichloro-indazol-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amideAusbeute 98 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)KatalysatorHCID 1140TolueneLösungsmittel

Reaktionsbedingungen

Temperatur
110 °C

Versuchsvorschrift

In a 5 mL microwave vial were placed copper(I) iodide (6 mg, 0.033 mmol), K3PO4 (146 mg, 0.69 mmol), 5,6-dichloro-1H-indazole (74 mg, 0.39 mmol), 2-iodo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (200 mg, 0.33 mmol), toluene (1.2 mL), and trans-N,N′-dimethylcyclohexane-1,2-diamine (9 mg, 0.066 mmol). The vial was purged with a stream of nitrogen then sealed and heated in an oil bath at 110° C. for 48 h. The reaction mixture was cooled to room temperature and diluted with EtOAc then filtered over a Buchner funnel, rinsing with EtOAc. The filtrate was concentrated and the resultant residue was purified by silica gel chromatography with 0% to 2% MeOH/CH2Cl2 (0.5% NH4OH) to afford 215 mg (98%) of 2-(5,6-dichloro-indazol-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a light yellow foam.

Aufarbeitung

  1. customThe vial was purged with a stream of nitrogen
  2. customthen sealed
  3. temperatureThe reaction mixture was cooled to room temperature
  4. additiondiluted with EtOAc
  5. filtrationthen filtered over a Buchner funnel
  6. washrinsing with EtOAc
  7. concentrationThe filtrate was concentrated
  8. customthe resultant residue was purified by silica gel chromatography with 0% to 2% MeOH/CH2Cl2 (0.5% NH4OH)

Quellen und Nachweise

ORD-Eintrag
ord-86781c389225448b96a9b01c2d09dbd3
Quelldatensatz
uspto-grants-2014_02
Patentnummer
US08658646B2

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