Trifluoroacetic acid → 2-(6-fluoro-3-methanesulfonyl-imidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide

HRID 245878Notes

Reaction equation

HRID 245878 reaction equation
[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:44])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:23]=[C:24]([S:32]([CH3:35])(=[O:34])=[O:33])[N:25]5[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=45)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:44])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:23]=[C:24]([S:32]([CH3:35])(=[O:34])=[O:33])[N:25]5[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=45)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 712888502-(6-fluoro-3-methanesulfonyl-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide

Product 1

HCID 712885662-(6-fluoro-3-methanesulfonyl-imidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amideYield 31.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

In a round-bottomed flask, 2-(6-fluoro-3-methanesulfonyl-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (0.024 g, 37.5 μmol, Eq: 1.00) was dissolved in dichloromethane (0.3 ml) and trifluoroacetic acid (0.12 ml, 1.6 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was redissolved in dichloromethane/methanol/ammonium hydroxide (60:10:1) (3.5 ml). The solution was stirred at room temperature overnight then concentrated. The residue was absorbed on silica gel and chromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-7% MeOH) to afford 6 mg (30%) of 2-(6-fluoro-3-methanesulfonyl-imidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a yellow solid. MS: (M+H)+=511; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.92 (br. s., 1H), 9.17 (s, 1H), 9.01-9.10 (m, 1H), 8.95 (d, J=3.0 Hz, 1H), 8.47-8.53 (m, 1H), 8.42 (d, J=7.6 Hz, 1H), 7.43-7.53 (m, 1H), 4.51-4.80 (m, 3H), 4.27 (q, J=9.6 Hz, 1H), 4.11-4.21 (m, 1H), 3.81-3.94 (m, 1H), 3.57 (s, 3H), 1.40 (t, J=6.4 Hz, 3H).

Workup

  1. concentrationthen concentrated
  2. dissolutionThe residue was redissolved in dichloromethane/methanol/ammonium hydroxide (60:10:1) (3.5 ml)
  3. stirringThe solution was stirred at room temperature overnight
  4. concentrationthen concentrated
  5. customThe residue was absorbed on silica gel
  6. customchromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-7% MeOH)

Sources & evidence

ORD record
ord-5193a179dd70451a9c5f80be6f7d364b
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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