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

HRID 246232Notes

Reaction equation

HRID 246232 reaction equation
[NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=5)[N:20]([CH3:28])[N:19]=4)[N:16]=3)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:10]=2)=[O:8])[CH2:2]1.[CH2:37]([N:39](CC)CC)[CH3:38]>ClCCl.BrCC#N>[C:37]([CH2:38][N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=5)[N:20]([CH3:28])[N:19]=4)[N:16]=3)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:10]=2)=[O:8])[CH2:2]1)#[N:39]

Participants

5

Reactant 2

HCID 8471TriethylamineHCID 712883352-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (R)-pyrrolidin-3-ylamide

Product 1

HCID 866779632-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-cyanomethyl-pyrrolidin-3-yl)-amideYield 45%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 11534BromoacetonitrileSolvent

Procedure

2-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (R)-pyrrolidin-3-ylamide from Step 1 was dissolved in dichloromethane with the addition of triethylamine and bromo-acetonitrile. The reaction was concentrated and dried from mixtures of dichloromethane and hexanes. The crude was dissolved in a mixture dichloromethane, tetrahydrofuran, and methanol, supported on silica gel and purified by flash chromatography (4 g silicycle) with 0% to 10% MeOH in dichloromethane (0.5% Et3N). The appropriate fractions were combined and concentrated. The solid obtained was triturated with Et2O and hexanes. The solid was discarded and the mother liquor was concentrated to afford 220 mg (45%) 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-cyanomethyl-pyrrolidin-3-yl)-amide as a white solid, 220 mg (45% yield). LC-MS (M+H)+=549.

Workup

  1. concentrationThe reaction was concentrated
  2. dry with materialdried from mixtures of dichloromethane and hexanes
  3. dissolutionThe crude was dissolved in a mixture dichloromethane, tetrahydrofuran, and methanol
  4. custompurified by flash chromatography (4 g silicycle) with 0% to 10% MeOH in dichloromethane (0.5% Et3N)
  5. concentrationconcentrated
  6. customThe solid obtained
  7. customwas triturated with Et2O and hexanes
  8. concentrationthe mother liquor was concentrated

Sources & evidence

ORD record
ord-63e0407c83e942298d0fa81b70ceefa0
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

Loading…