Cesium fluoride → 1-(2-{4-[2-(3,5-Difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-azepane

HRID 1513872Notes

Reaction equation

HRID 1513872 reaction equation
[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:37]=[CH:36][C:14]([O:15][C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:17]=3OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].[Cs+].[F:40][C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH2:42]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:40][C:41]1[CH:46]=[C:45]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[C:16]=2[O:15][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][N:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:37][CH:36]=2)[CH:44]=[C:43]([F:47])[CH:42]=1

Participants

7

Reactant 4

HCID 25953Cesium fluorideHCID 75806TricyclohexylphosphineHCID 57552539Trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-naphthalen-2-yl esterHCID 866265291,3-Difluoro-benzene boronic acid

Product 1

HCID 114207081-(2-{4-[2-(3,5-Difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-azepaneYield 99.3%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6342AcetonitrileSolvent2×

Procedure

Dissolve trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-naphthalen-2-yl ester (435 mg, 0.80 mmol), cesium fluoride (864 mg, 5.7 mmol) and 1,3-difluoro-benzene boronic acid (383 mg, 2.4 mmol) in dry acetonitrile (5 mL) and stir for 10 minutes. In a separate flask suspend palladium acetate (18 mg, 0.08 mmol), and tricyclohexyl phosphine (33 mg, 0.12 mmol) in dry acetonitrile (15 mL) and sonicate under nitrogen for 10 minutes. Combine contents of both flasks and heat reaction at 60° C. for 15 minutes. Cool reaction and filter through celite and concentrate in vacuo. Purify crude product by silica gel chromatography using a 1-3% gradient of methanol in dichloromethane to yield 400 mg (98%) of the title compound: mass spectrum (ion spray) m/z=504.2 (M+H).

Workup

  1. customIn a separate flask suspend
  2. temperatureCombine contents of both flasks and heat
  3. customreaction at 60° C. for 15 minutes
  4. temperatureCool
  5. customreaction
  6. filtrationfilter through celite
  7. concentrationconcentrate in vacuo
  8. customPurify crude product by silica gel chromatography

Sources & evidence

ORD record
ord-c376f1a279cc483f84d210281bddb76b
Source dataset
uspto-grants-2012_07
Patent number
US08217032B2

Reaction notes

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