Cesium carbonate → 6-(3,3-Difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile

HRID 75308

Reaction equation

HRID 75308 reaction equation
Br[C:2]1[CH:3]=[C:4]2[N:12]([CH3:13])[CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[C:8]#[N:9].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[F:63][C:64]1([F:68])[CH2:67][NH:66][CH2:65]1>O1CCOCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:63][C:64]1([F:68])[CH2:67][N:66]([C:2]2[CH:3]=[C:4]3[N:12]([CH3:13])[CH:11]=[CH:10][C:5]3=[N:6][C:7]=2[C:8]#[N:9])[CH2:65]1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 27582473,3-Difluoroazetidine hydrochlorideHCID 867079636-Bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile

Product 1

HCID 867080076-(3,3-Difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrileYield 29%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalyst2×HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

To a 5 mL vial were added 6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (500 mg, 2.12 mmol), Xantphos (123 mg, 0.212 mmol), palladium (II) acetate (47.6 mg, 0.212 mmol), cesium carbonate (1380 mg, 4.24 mmol) and 3,3-difluoroazetidine hydrochloride (549 mg, 4.24 mmol) in dioxane (5.0 mL). The resulting yellow suspension was heated to 110° C. for 22 hours. LC/MS showed about 50% conversion. More palladium (II) acetate (50 mg) was added and heating was continued at 110° C. for 2 days. The solution was diluted with EtOAc (up to 100 mL) and then washed with saturated aqueous ammonium chloride (100 mL) and filtered to remove solids. The layers were separated, and the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified on a silica gel column (80 g) eluting with a 0-60% ethyl acetate in hexanes to give the title compound as a yellow solid (152 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.79 (s, 3 H), 4.55 (t, J=12.4 Hz, 4 H), 6.55 (dd, J=3.3, 0.8 Hz, 1 H), 7.38 (d, J=0.8 Hz, 1 H), 7.69 (d, J=3.5 Hz, 1 H); ESI-MS m/z [M+H]+ calc'd for C12H10F2N4, 249; found 249.

Workup

  1. temperatureheating
  2. washthen washed with saturated aqueous ammonium chloride (100 mL)
  3. filtrationfiltered
  4. customto remove solids
  5. customThe layers were separated
  6. washthe organic layer was washed with brine
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified on a silica gel column (80 g)
  10. washeluting with a 0-60% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-695edaec2d95408ca47afd35effbe94b
Source dataset
uspto-grants-2014_09
Patent number
US08835420B2

Linked notes

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