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

HRID 75308

反応式

HRID 75308 の反応式
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

参加物

8

反応物 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

生成物 1

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

試薬・触媒・溶媒 3

HCID 167845palladium(II) acetate触媒2 回HCID 8857Ethyl Acetate溶媒HCID 312751,4-Dioxane溶媒

反応条件

温度
110 °C

実験手順

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.

後処理

  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

出典と根拠

ORDレコード
ord-695edaec2d95408ca47afd35effbe94b
出典データセット
uspto-grants-2014_09
特許番号
US08835420B2

関連ノート

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