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

HRID 246128Notes

Reaction equation

HRID 246128 reaction equation
FC(F)(F)C(O)=O.[NH2:8][CH2:9][C@@H:10]([CH3:13])[C:11]#[N:12].[F:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:25]3[N:26]=[C:27]4[C:33]([C:34](O)=[O:35])=[CH:32][N:31]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:28]4=[N:29][CH:30]=3)=[N:20][N:21]2[CH3:24])=[CH:17][CH:16]=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>[C:11]([C@H:10]([CH3:13])[CH2:9][NH:8][C:34]([C:33]1[C:27]2[C:28](=[N:29][CH:30]=[C:25]([C:19]3[C:18]4[C:22](=[CH:23][C:15]([F:14])=[CH:16][CH:17]=4)[N:21]([CH3:24])[N:20]=3)[N:26]=2)[N:31]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:32]=1)=[O:35])#[N:12]

Participants

8

Reactant 4

HCID 81531Diisopropylethylamine2×HCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate2×HCID 712796202-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acidHCID 86677952(R)-3-amino-2-methyl-propionitrile trifluoroacetate

Product 1

HCID 712858582-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-cyano-2-methyl-ethyl)-amideYield 36%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

(R)-3-Amino-2-methyl-propionitrile trifluoroacetate (crude from Step 3) was dissolved in acetonitrile (2.8 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 (70 mg, 0.22 mmol) and N,N-diisopropylethylamine (0.11 ml, 0.63 mmol). The reaction was stirred at room temperature for 18 h. Additional O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (50 mg, 0.16 mmol) and N,N-diisopropylethylamine (0.11 ml, 0.63 mmol) were added and stirring was continued for 24 h. Water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted twice 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 33 mg (36%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-cyano-2-methyl-ethyl)-amide. (M+Na)+=530.

Workup

  1. stirringstirring
  2. waitwas continued for 24 h
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted twice with ethyl acetate
  5. washThe combined organic layers were washed with sodium chloride solution
  6. dry with materialdried over sodium sulfate
  7. customAfter evaporation
  8. customthe residue was purified by silica gel chromatography (methanol/dichloromethane)

Sources & evidence

ORD record
ord-526a2114f66847ee97e953a6145bde36
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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