5,6-dichloro-1-methyl-3-tributylstannanyl-1H-indazole → 2-(5,6-dichloro-1-methyl-1H-indazol-3-yl)-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

HRID 245964Notes

Reaction equation

HRID 245964 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([CH3:12])[N:6]=[C:5]2[Sn](CCCC)(CCCC)CCCC.[C:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:34](=[O:60])[C@H:35]([NH:39][C:40]([C:42]2[C:50]3[C:45](=[N:46][CH:47]=[C:48](Br)[N:49]=3)[N:44]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:59])([CH3:58])[CH3:57])[CH:43]=2)=[O:41])[CH:36]2[CH2:38][CH2:37]2)[CH2:30][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[CH2:33][CH2:32][N:31]([C:34](=[O:60])[C@H:35]([NH:39][C:40]([C:42]2[C:50]3[C:45](=[N:46][CH:47]=[C:48]([C:5]4[C:4]5[C:8](=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=5)[N:7]([CH3:12])[N:6]=4)[N:49]=3)[N:44]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:58])([CH3:57])[CH3:59])[CH:43]=2)=[O:41])[CH:36]2[CH2:37][CH2:38]2)[CH2:30][CH2:29]1)#[N:27]

Participants

6

Reactant 2

HCID 712794905,6-dichloro-1-methyl-3-tributylstannanyl-1H-indazoleHCID 866578732-bromo-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

Product 1

HCID 712861802-(5,6-dichloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amideYield 86.7%

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 5,6-dichloro-1-methyl-3-tributylstannyl-1H-indazole (crude from Step 5, 218 mg, 0.44 mmol) and 2-bromo-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 (125 mg, 0.22 mmol) in DMF (2 mL) were added Pd(PPh3)4 (12.9 mg, 0.011 mmol) and copper(I) iodide (8 mg, 0.044 mmol). The yellow reaction mixture was heated at 90° C. for 1.5 h then cooled to room temperature, 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 residue was purified by silica gel chromatography with 50% to 100% EtOAc/hexanes to isolate 130 mg (86%) of 2-(5,6-dichloro-1-methyl-1H-indazol-3-yl)-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 as a pale yellow foamy solid.

Workup

  1. temperaturethen cooled to room temperature
  2. customquenched 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 residue was purified by silica gel chromatography with 50% to 100% EtOAc/hexanes

Sources & evidence

ORD record
ord-565eb45dfaa8465e9e517c5a761cdb3f
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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