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

HRID 246105Notes

Reaction equation

HRID 246105 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([N:23]5[CH2:25][CH:24]5[CH3:26])=[O:22])=[CH:19][N:18]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C(#N)C.Cl.[C:39]([CH:41]1[CH2:45][CH2:44][NH:43][CH2:42]1)#[N:40].C(N(CC)C(C)C)(C)C>C1COCC1.C(OCC)(=O)C.O>[C:39]([CH:41]1[CH2:45][CH2:44][N:43]([CH2:25][CH:24]([NH:23][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:19]=2)=[O:22])[CH3:26])[CH2:42]1)#[N:40]

Participants

8

Reactant 4

HCID 6342AcetonitrileHCID 81531Diisopropylethylamine2×HCID 42614784Pyrrolidine-3-carbonitrile hydrochloride2×HCID 86677949[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(2-methyl-aziridin-1-yl)-methanone

Product 1

HCID 712861852-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [2-(3-cyano-pyrrolidin-1-yl)-1-methyl-ethyl]-amideYield 25.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
120 °C

Procedure

[2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(2-methyl-aziridin-1-yl)-methanone (70 mg, 0.14 mmol) was dissolved in 1:1 THF: acetonitrile (1.5 ml). 3-Cyanopyrrolidine hydrochloride (28 mg, 0.21 mmol) and N,N-diisopropylethylamine (37 ul, 0.21 mmol) were added and the reaction was heated in a microwave reactor at 120° C. for 2 h. An additional 0.5 eq of 3-cyanopyrrolidine hydrochloride and N,N-diisopropylethylamine were added and the heating was repeated twice more. Water and ethyl acetate were then added to the cooled solution. The aqueous layer was extracted twice more with ethyl acetate and the combined organics were washed with sodium chloride solution and dried over sodium sulfate. After evaporation of solvent the crude residue was purified by silica gel chromatography (ethyl acetate/dichloromethane) to give 21 mg (25%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [2-(3-cyano-pyrrolidin-1-yl)-1-methyl-ethyl]-amide. (M+H)+=593.

Workup

  1. extractionThe aqueous layer was extracted twice more with ethyl acetate
  2. washthe combined organics were washed with sodium chloride solution
  3. dry with materialdried over sodium sulfate
  4. customAfter evaporation of solvent the crude residue
  5. customwas purified by silica gel chromatography (ethyl acetate/dichloromethane)

Sources & evidence

ORD record
ord-7117f49759744f4c81c50cf69b51be38
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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