Diisopropylethylamine → 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methyl-2-pyrazol-1-yl-ethyl)-amide

HRID 246122Notes

Reaction equation

HRID 246122 reaction equation
FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([NH2:16])[CH2:10][N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:28]3[N:29]=[C:30]4[C:36]([C:37](O)=[O:38])=[CH:35][N:34]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:31]4=[N:32][CH:33]=3)=[N:23][N:24]2[CH3:27])=[CH:20][CH:19]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(#N)C.C(OCC)(=O)C.O>[CH3:8][C@@H:9]([NH:16][C:37]([C:36]1[C:30]2[C:31](=[N:32][CH:33]=[C:28]([C:22]3[C:21]4[C:25](=[CH:26][C:18]([F:17])=[CH:19][CH:20]=4)[N:24]([CH3:27])[N:23]=3)[N:29]=2)[N:34]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:35]=1)=[O:38])[CH2:10][N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 712796202-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acidHCID 71279935(R)-1-methyl-2-pyrazol-1-yl-ethylamine trifluoroacetate

Product 1

HCID 712861932-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methyl-2-pyrazol-1-yl-ethyl)-amideYield 81%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

(R)-1-Methyl-2-pyrazol-1-yl-ethylamine trifluoroacetate (crude from Step 4) was dissolved in acetonitrile (1.8 ml) to which was then added 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 0.18 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (87 mg, 0.27 mmol) and N,N-diisopropylethylamine (0.16 ml, 0.91 mmol). The reaction was stirred at room temperature for 18 h and then water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to afford 89 mg (81%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methyl-2-pyrazol-1-yl-ethyl)-amide.

Workup

  1. customThe layers were separated
  2. extractionthe aqueous layer was extracted three times with ethyl acetate
  3. washThe combined organic layers were washed with sodium chloride solution
  4. dry with materialdried over sodium sulfate
  5. customAfter evaporation
  6. customthe residue was purified by silica gel chromatography (methanol/dichloromethane)

Sources & evidence

ORD record
ord-2761b53bce4645a1b4a027d42b1c84c6
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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