Ethylenediamine → 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-fluoro-1,2-dimethyl-propyl)-amide

HRID 245883Notes

Reaction equation

HRID 245883 reaction equation
[F:1][C:2]([CH3:37])([CH3:36])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])[CH3:4].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[F:1][C:2]([CH3:36])([CH3:37])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])[CH3:4]

Participants

5

Reactant 3

HCID 3301EthylenediamineHCID 6422Trifluoroacetic acidHCID 712861772-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-fluoro-1,2-dimethyl-propyl)amide

Product 1

HCID 712859602-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-fluoro-1,2-dimethyl-propyl)-amideYield 48.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-fluoro-1,2-dimethyl-propyl)amide (93 mg, 0.176 mmol) was dissolved in dichloromethane (0.9 ml) and trifluoroacetic acid (0.54 ml, 7.0 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.9 ml) and ethylenediamine (0.7 ml, 10.5 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-6% MeOH) then triturated with ethyl acetate to afford 34 mg (46%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-fluoro-1,2-dimethyl-propyl)-amide as a light yellow powder. MS: (M+H)+=399; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.90 (br. s., 1H), 9.12 (s, 1H), 8.45-8.54 (m, 2H), 8.25 (d, J=9.8 Hz, 1H), 7.68 (dd, J=9.8, 2.3 Hz, 1H), 7.09 (td, J=9.1, 2.3 Hz, 1H), 4.30-4.48 (m, 1H), 4.15 (s, 3H), 1.29-1.52 (m, 9H).

Workup

  1. concentrationthen concentrated
  2. dissolutionThe residue was dissolved in dichloromethane (0.9 ml)
  3. stirringThe yellow solution was stirred at room temperature for 1 h
  4. customthen quenched with water
  5. extractionextracted with dichloromethane (2×)
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was absorbed on silica gel
  10. customchromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-6% MeOH)
  11. customthen triturated with ethyl acetate

Sources & evidence

ORD record
ord-533b148c66954f4aa51558d167c6cd1c
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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