1-iodoisoquinoline → 2-isoquinolin-1-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 246006Notes

Reaction equation

HRID 246006 reaction equation
C[Sn](C)C.C[Sn](C)C.[C:9]([CH:11]1[CH2:14][N:13]([C:15](=[O:39])[C@H:16]([NH:18][C:19]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[C:27](Br)[N:28]=3)[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:22]=2)=[O:20])[CH3:17])[CH2:12]1)#[N:10].I[C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][N:42]=1.IN1C2C(=CC=CC=2)C=CC1>C1(C)C=CC=CC=1.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.CN(C=O)C>[C:9]([CH:11]1[CH2:14][N:13]([C:15](=[O:39])[C@H:16]([NH:18][C:19]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[C:27]([C:41]4[C:50]5[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=5)[CH:44]=[CH:43][N:42]=4)[N:28]=3)[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:22]=2)=[O:20])[CH3:17])[CH2:12]1)#[N:10]

Participants

9

Reactant 4

HCID 6409641-iodoisoquinoline2×HCID 6327618HexamethylditinHCID 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 86677933HCID 86677933, compound

Product 1

HCID 712889362-isoquinolin-1-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]-amideYield 48%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalyst3×HCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
95 °C

Procedure

To a solution of hexamethylditin (90 mg, 0.28 mmol) and 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (100 mg, 0.20 mmol) in toluene (2 mL) was added Pd(Ph3P)4 (23 mg, 0.02 mmol). A stream of nitrogen gas was gently bubbled through the reaction mixture for 15 min then it was heated to 95° C. After 1.5 h 1-iodoisoquinoline (50 mg, 0.20 mmol) and Pd(Ph3P)4 (23 mg, 0.02 mmol) were added as solids in one portion. Heating was continued at 95° C. for 1.5 h and additional 1-iodoisoquinoline (25 mg, 0.10 mmol), DMF (0.5 mL) and copper (I) iodide (5 mg) were added. The reaction mixture was heated at 95° C. overnight. Additional 1-iodoquinoline (25 mg, 0.10 mmol) and Pd(Ph3P)4 (23 mg, 0.02 mmol) were added and heating was continued for 8 h. The reaction was cooled to room temperature, quenched with water, and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine, then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 30% to 80% EtOAc/hexanes to afford 52 mg (48%) of 2-isoquinolin-1-yl-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a yellow foam.

Workup

  1. customA stream of nitrogen gas was gently bubbled through the reaction mixture for 15 min
  2. temperatureHeating
  3. temperatureThe reaction mixture was heated at 95° C. overnight
  4. temperatureheating
  5. waitwas continued for 8 h
  6. temperatureThe reaction was cooled to room temperature
  7. customquenched with water
  8. extractionextracted with EtOAc (3×)
  9. washThe combined organics were washed with water (3×) and brine
  10. dry with materialdried over MgSO4
  11. concentrationconcentrated
  12. customThe residue was purified by silica gel chromatography with 30% to 80% EtOAc/hexanes

Sources & evidence

ORD record
ord-45f9138fc2454368867cc9cb4ccce1ed
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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