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 → 5-(2-trimethylsilanyl-ethoxymethyl)-2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyanoazetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide

HRID 245977Notes

Reaction equation

HRID 245977 reaction equation
[CH3:1][N:2]1[C:10]2[CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6][C:5]=2[C:4]([Sn](CCCC)(CCCC)CCCC)=[N:3]1.[C:26]([CH:28]1[CH2:31][N:30]([C:32](=[O:56])[C@H:33]([NH:35][C:36]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[C:44](Br)[N:45]=3)[N:40]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:39]=2)=[O:37])[CH3:34])[CH2:29]1)#[N:27]>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:26]([CH:28]1[CH2:29][N:30]([C:32](=[O:56])[C@H:33]([NH:35][C:36]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[C:44]([C:4]4[C:5]5[CH2:6][CH2:7][C:8]([CH3:11])([CH3:12])[CH2:9][C:10]=5[N:2]([CH3:1])[N:3]=4)[N:45]=3)[N:40]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:39]=2)=[O:37])[CH3:34])[CH2:31]1)#[N:27]

Participants

6

Reactant 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 712794751,6,6-trimethyl-3-tributylstannanyl-4,5,6,7-tetrahydro-1H-indazole

Product 1

HCID 712888955-(2-trimethylsilanyl-ethoxymethyl)-2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyanoazetidin-1-yl)-1-methyl-2-oxo-ethyl]-amideYield 38.3%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 1,6,6-trimethyl-3-tributylstannyl-4,5,6,7-tetrahydro-1H-indazole (110 mg, 0.24 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 (95 mg, 0.19 mmol) in DMF (2 mL) were added Pd(PPh3)4 (11 mg, 0.01 mmol) and copper(I) iodide (7 mg, 0.037 mmol). The reaction mixture was heated at 90° C. for 2 h then cooled to room temperature and stirred overnight. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The crude brown oil was purified by silica gel chromatography with 0% to 3% MeOH/CH2Cl2 to afford 43 mg (38%) of 5-(2-trimethylsilanyl-ethoxymethyl)-2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a pale orange foam.

Workup

  1. temperaturethen cooled to room temperature
  2. customThe reaction was quenched with water
  3. extractionextracted with EtOAc (2×)
  4. washThe combined organics were washed with water (3×) and brine
  5. dry with materialthen dried over MgSO4
  6. concentrationconcentrated
  7. customThe crude brown oil was purified by silica gel chromatography with 0% to 3% MeOH/CH2Cl2

Sources & evidence

ORD record
ord-83c8690d9f7f4785af15f40151e865f4
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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