Diisopropylethylamine → 2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (S)-N-(tetrahydro-pyran-3-yl)-amide

HRID 246133Notes

Reaction equation

HRID 246133 reaction equation
FC(F)(F)C(O)=O.[O:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH2:14])[CH2:9]1.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:26]3[N:27]=[C:28]4[C:34]([C:35](O)=[O:36])=[CH:33][N:32]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:29]4=[N:30][CH:31]=3)=[N:21][N:22]2[CH3:25])=[CH:18][CH:17]=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>[O:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:35]([C:34]2[C:28]3[C:29](=[N:30][CH:31]=[C:26]([C:20]4[C:19]5[C:23](=[CH:24][C:16]([Cl:15])=[CH:17][CH:18]=5)[N:22]([CH3:25])[N:21]=4)[N:27]=3)[N:32]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:33]=2)=[O:36])[CH2:9]1

Participants

8

Reactant 4

HCID 81531Diisopropylethylamine2×HCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate2×HCID 712796712-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acidHCID 71280724(S)-(Tetrahydro-pyran-3-yl)amine trifluoroacetate

Product 1

HCID 712860382-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (S)-N-(tetrahydro-pyran-3-yl)-amideYield 58%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

(S)-(Tetrahydro-pyran-3-yl)amine trifluoroacetate (crude from Step 4) was dissolved in acetonitrile (1.8 ml) to which was then added 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 0.175 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (84 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.15 ml, 0.87 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 (ethyl acetate/hexanes) to afford 55 mg (58%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (S)—N-(tetrahydro-pyran-3-yl)-amide. (M+Na)+=563.

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 (ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-68eb81cff066444d86d0465b0438b059
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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