Allyl bromide → 2-(1-allyl-6-chloro-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 246041Notes

Reaction equation

HRID 246041 reaction equation
[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[NH:24][N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[H-].[Na+].[CH2:43](Br)[CH:44]=[CH2:45]>CN(C=O)C>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:45][CH:44]=[CH2:43])[N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]

Participants

5

Reactant 3

HCID 7841Allyl bromideHCID 24758Sodium hydrideHCID 712888432-(6-chloro-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

Product 1

HCID 866779372-(1-allyl-6-chloro-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]-amideYield 92.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

In a round-bottomed flask, 2-(6-chloro-1H-indazol-3-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 (see Example 23, 396 mg, 0.68 mmol) was dissolved in DMF (4.5 ml). The reaction mixture was cooled to 0° C. and sodium hydride (60% dispersion in mineral oil, 33 mg, 0.83 mmol) was added. The reaction mixture was stirred at 0° C. for 20 min then allyl bromide (65 μl, 0.75 mmol) was added. The reaction mixture was stirred at 0° C. for 20 min and then at room temperature for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate (2×). The combined organic layers were washed with water, sat LiCl, and brine then dried over MgSO4 and concentrated. The residue was chromatographed over silica gel with 50% to 100% EtOAc/heptane to afford 388 mg (92%) of 2-(1-allyl-6-chloro-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 light yellow foam.

Workup

  1. stirringThe reaction mixture was stirred at 0° C. for 20 min
  2. waitat room temperature for 1 h
  3. customThe reaction mixture was quenched with water
  4. extractionextracted with ethyl acetate (2×)
  5. washThe combined organic layers were washed with water
  6. dry with materialthen dried over MgSO4
  7. concentrationconcentrated
  8. customThe residue was chromatographed over silica gel with 50% to 100% EtOAc/heptane

Sources & evidence

ORD record
ord-509aa9adfecb4875807f29d40f033fe4
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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