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Ethylenediamine → 2-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide

HRID 246166
Notes
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Reaction equation

HRID 246166 reaction equation
[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:28])=[CH:24][C:25]=4[F:27])[N:20]([CH3:29])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:28])=[CH:24][C:25]=4[F:27])[N:20]([CH3:29])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 3301EthylenediamineHCID 6422Trifluoroacetic acidHCID 712883412-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide

Product 1

HCID 712857622-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amideYield 55.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

In a 25 mL round-bottom flask, 2-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (40 mg, 0.073 mmol) and TFA (0.60 ml, 7.8 mmol) were combined with dichloromethane (2 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (2 mL) and ethylenediamine (0.40 ml, 5.9 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (dichloromethane/heptane) to afford 17 mg (55%) of 2-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as an off-white solid. MS: [M+H]+=417; 1H NMR (300 MHz, DMSO-d6) δ: 12.68 (br. s., 1H), 9.00 (s, 1H), 8.44 (s, 1H), 8.32 (d, J=8.7 Hz, 1H), 7.89 (d, J=1.5 Hz, 1H), 7.27 (dd, J=10.6, 1.5 Hz, 1H), 4.31 (dt, J=13.5, 7.0 Hz, 1H), 4.19 (s, 3H), 3.45 (dd, J=9.3, 5.8 Hz, 3H), 3.36 (dd, J=9.8, 5.3 Hz, 1H), 3.20 (s, 3H), 1.22 (d, J=6.8 Hz, 3H).

Workup

  1. customto give an orange solution
  2. concentrationthen concentrated under reduced pressure
  3. dissolutionThe resultant crude solid was dissolved in dichloromethane (2 mL)
  4. stirringThe reaction mixture was stirred at room temperature for 18 h
  5. concentrationthen concentrated
  6. customthe residue was precipitated with water
  7. stirringThe suspension was stirred for 1 h
  8. filtrationthe crude solid collected by filtration
  9. customThe crude solid was purified by trituration (dichloromethane/heptane)

Sources & evidence

ORD record
ord-27db5d4336b5409ca1ea494e7fec7efb
Source dataset
uspto-grants-2014_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08658646B2

Reaction notes

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