Dichloromethane → N-((R)-1-{5-[5-Chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethyl)-acetamide

HRID 1404537Notes

Reaction equation

HRID 1404537 reaction equation
Br[C:2]1[CH:3]=[C:4]([F:14])[C:5]([C@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[N:6][CH:7]=1.C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].Br[C:48]1[CH:53]=[C:52]([Cl:54])[CH:51]=[C:50]([F:55])[C:49]=1[C:56]1[N:60]=[C:59]([CH3:61])[O:58][N:57]=1>CS(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:54][C:52]1[CH:51]=[C:50]([F:55])[C:49]([C:56]2[N:60]=[C:59]([CH3:61])[O:58][N:57]=2)=[C:48]([C:2]2[CH:3]=[C:4]([F:14])[C:5]([C@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[N:6][CH:7]=2)[CH:53]=1

Participants

10

Reactant 6

HCID 6344Dichloromethane2×HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 684506413-(2-Bromo-4-chloro-6-fluorophenyl)-5-methyl-1,2,4-oxadiazole2×HCID 68521974N-[(R)-1-(5-bromo-3-fluoro-pyridin-2-yl)-ethyl]-acetamide2×

Product 1

HCID 67979270N-((R)-1-{5-[5-Chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethyl)-acetamide

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst2×HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent2×

Conditions

Temperature
90 °C

Procedure

A stream of argon was bubbled through a mixture of N—[(R)-1-(5-bromo-3-fluoro-pyridin-2-yl)-ethyl]-acetamide (200 mg, 0.766 mmol, intermediate 12) potassium acetate (226 mg, 2.3 mmol) and bis(pinacolato)diboron (253 mg, 0.996 mmol) in DMSO (1.5 ml) in a sealed tube for 10 min. Then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride 1:1 complex with DCM (31.3 mg, 0.0383 mmol) was added and again a stream of argon was bubbled through the reaction mixture for 10 min. The tube was then sealed and heated to 90° C. for 1.5 h. After cooling to room temperature, potassium carbonate (212 mg, 1.53 mmol), water (198 μl), 3-(2-bromo-4-chloro-6-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole (246 mg, 0.843 mmol, intermediate 10) and additional [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride 1:1 complex with DCM (31.3 mg, 0.0383 mmol) were added and the reaction mixture was heated to 80° C. for 3 h. The mixture was cooled to room temperature, diluted with water and extracted three times with EtOAc. The combined organic layers were washed two times with water and brine, dried with Na2SO4 and evaporated. The remaining brown gum was purified by chromatography (silica gel; heptane/EtOAc 35:65-10:90) and the title compound was obtained as off white foam (200 mg, 66%). MS: 393.1 [M+H]+.

Workup

  1. customagain a stream of argon was bubbled through the reaction mixture for 10 min
  2. customThe tube was then sealed
  3. temperatureAfter cooling to room temperature
  4. temperaturethe reaction mixture was heated to 80° C. for 3 h
  5. temperatureThe mixture was cooled to room temperature
  6. extractionextracted three times with EtOAc
  7. washThe combined organic layers were washed two times with water and brine
  8. dry with materialdried with Na2SO4
  9. customevaporated
  10. customThe remaining brown gum was purified by chromatography (silica gel; heptane/EtOAc 35:65-10:90)

Sources & evidence

ORD record
ord-222a1afc313443a0b2802e7839a24ebd
Source dataset
uspto-grants-2014_12
Patent number
US08912221B2

Reaction notes

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