Cesium carbonate → 5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-3-((E)-2-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)vinyl)-1H-indazole

HRID 41515Notes

Reaction equation

HRID 41515 reaction equation
[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[C:9](/[CH:17]=[CH:18]/[C:19]2[CH:20]=[N:21][N:22]([CH2:24][CH2:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[CH:23]=2)=[N:8]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[C@H:44]([C:46]1[C:51]([Cl:52])=[CH:50][N:49]=[CH:48][C:47]=1[Cl:53])[CH3:45])(=O)=O>C(#N)C>[Cl:53][C:47]1[CH:48]=[N:49][CH:50]=[C:51]([Cl:52])[C:46]=1[C@H:44]([O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[N:8]=[C:9]2/[CH:17]=[CH:18]/[C:19]1[CH:20]=[N:21][N:22]([CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH:23]=1)[CH3:45]

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 66831604(E)-1-(Tetrahydro-2H-pyran-2-yl)-3-(2-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)vinyl)-1H-indazol-5-olHCID 86647459(S)-1-(3,5-Dichloropyridin-4-yl)ethyl methanesulfonate

Product 1

HCID 666468355-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-3-((E)-2-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)vinyl)-1H-indazole

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

In a 3-neck 250 mL round bottom flask equipped with an internal temperature probe, reflux condenser, nitrogen blanket and magnetic stir bar, slurry (E)-1-(tetrahydro-2H-pyran-2-yl)-3-(2-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)vinyl)-1H-indazol-5-ol (10.0 g, 22.83 mmol) and cesium carbonate (7.88 g, 23.94 mmol) in ACN (92 mL) and warm to 60° C. To the suspension, add (S)-1-(3,5-dichloropyridin-4-yl)ethyl methanesulfonate (7.03 g, 26.02 mmol) and stir overnight. Cool the reaction mixture to RT, filter and wash solids with ACN. Concentrate the filtrate and purify the residue by silica gel chromatography (2-4% (2 M ammonia in methanol)/DCM). Combine product fractions and concentrate in vacuo to a white foam. Yield: 12.5 g (86%). MS (ES) m/z 612 [M+1]+.

Workup

  1. customIn a 3-neck 250 mL round bottom flask equipped with an internal temperature probe
  2. temperaturereflux condenser
  3. filtrationfilter
  4. washwash solids with ACN
  5. concentrationConcentrate the filtrate
  6. custompurify the residue by silica gel chromatography (2-4% (2 M ammonia in methanol)/DCM)
  7. concentrationCombine product fractions and concentrate in vacuo to a white foam

Sources & evidence

ORD record
ord-b82d4bc42ae14b6a84ab704cf5f6d9cf
Source dataset
uspto-grants-2013_09
Patent number
US08530665B2

Reaction notes

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