Cesium fluoride → 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

HRID 246386Notes

Reaction equation

HRID 246386 reaction equation
[F:1][CH:2]([F:42])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([NH:25][C:26]3([CH2:32][OH:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:24])=[CH:21][N:20](COCC[Si](C)(C)C)[C:17]2=[N:18][CH:19]=1.[F-].[Cs+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.ClCCl>[F:42][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([NH:25][C:26]3([CH2:32][OH:33])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[O:24])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1

Participants

6

Reactant 3

HCID 25953Cesium fluorideHCID 2855718-Crown-6HCID 712804842-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

Product 1

HCID 712795142-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamideYield 51.1%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (40 mg, 66.4 μmol) in acetonitrile (6 mL) was added CsF (50.4 mg, 332 μmol, Eq: 5.00) and 18-crown-6 (17.5 mg, 66.4 μmol), the reaction mixture was heated to reflux for 72 h, then diluted with dichloromethane (20 mL), filtered over celite and concentrated. The residue was dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane/MeOH and cyclohexane added to allow solid formation, which was separated by filtration and dried to give 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (16 mg, 33.9 μmol, 51.0%) as an off-white solid. MS (M+H)+=473 (>90% purity); 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.40 (s, 1H), 8.04 (d, J=1.9 Hz, 1H), 7.78-7.88 (m, 2H), 7.37-7.43 (m, 1H), 7.21 (t, J=74.4 Hz, 1H), 4.92 (t, J=5.7 Hz, 1H), 4.19 (s, 3H), 3.73 (d, J=5.7 Hz, 2H), 3.50-3.69 (m, 4H), 2.21 (d, J=13.6 Hz, 2H), 1.70-1.89 (m, 2H). Unreacted starting material (11 mg, 27%) was also recovered.

Workup

  1. temperaturethe reaction mixture was heated
  2. temperatureto reflux for 72 h
  3. filtrationfiltered over celite and
  4. concentrationconcentrated
  5. dissolutionThe residue was dissolved in dichloromethane
  6. custompurified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco)
  7. washeluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane
  8. dissolutionThe pure product dissolved in dichloromethane/MeOH
  9. additioncyclohexane added
  10. customwas separated by filtration
  11. customdried

Sources & evidence

ORD record
ord-e2ee077459554dd7b596249b9e386740
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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