2,2-Difluoro-2-(fluorosulfonyl)acetic acid → 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-difluoromethoxy-1-methyl-ethyl)-amide

HRID 246194Notes

Reaction equation

HRID 246194 reaction equation
[OH:1][CH2:2][C@@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:9]=1)=[O:7])[CH3:4].[F:36][C:37]([F:45])(S(F)(=O)=O)C(O)=O>[Cu]I.C(#N)C>[F:36][CH:37]([F:45])[O:1][CH2:2][C@@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[CH:9]=1)=[O:7])[CH3:4]

Participants

5

Reactant 2

HCID 27375162,2-Difluoro-2-(fluorosulfonyl)acetic acidHCID 712857132-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide

Product 1

HCID 712860132-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-difluoromethoxy-1-methyl-ethyl)-amideYield 19.5%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6342AcetonitrileSolvent

Conditions

Temperature
50 °C

Procedure

In a 25 mL pressure tube, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide (60 mg, 0.12 mmol) and copper(I) iodide (14 mg, 0.070 mmol) were combined with acetonitrile (3 mL) to give a light yellow suspension. The mixture was degassed and placed under argon. The reaction mixture was heated to 50° C. in a sand bath. 2,2-Difluoro-2-(fluorosulfonyl)acetic acid (12 μL, 0.112 mmol) was added dropwise slowly to give a light yellow solution. The reaction was stirred for an additional 5 min. The reaction was quenched with water and extracted with ethyl acetate. The combined organics were successively washed with water, saturated sodium bicarbonate, and brine then dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography over silica gel (gradient: 0% to 50% EtOAc in hexanes) to afford 12 mg (18%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-difluoromethoxy-1-methyl-ethyl)-amide as a white solid. MS: [M+H]+=549.

Workup

  1. customto give a light yellow suspension
  2. customThe mixture was degassed
  3. customto give a light yellow solution
  4. customThe reaction was quenched with water
  5. extractionextracted with ethyl acetate
  6. washThe combined organics were successively washed with water, saturated sodium bicarbonate, and brine
  7. dry with materialthen dried over Na2SO4
  8. concentrationconcentrated
  9. customThe crude material was purified by flash chromatography over silica gel (gradient: 0% to 50% EtOAc in hexanes)

Sources & evidence

ORD record
ord-cc8357b3eb5c4f4799a136fd3229fca0
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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